JP2016147807A - Hydroxamic acid derivative and salt thereof - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a hydroxamic acid derivative useful as a histone deacetylation enzyme inhibitor or a salt thereof, further a pharmaceutical composition containing the hydroxamic acid derivative or the salt thereof, the histone deacetylation enzyme inhibitor and an antitumor agent.SOLUTION: There is provided a hydroxamic acid derivative represented by a general formula (A) or a salt thereof.SELECTED DRAWING: None

Description

  The present invention relates to hydroxamic acid derivatives or salts thereof useful as histone deacetylase inhibitors.

  Conventionally, the expression of genetic traits has been realized as a result of realizing the genetic information recorded in DNA as a phenotype through the pathway proposed by Central Dogma of DNA replication, RNA transcription, translation into protein, and expression of traits. . In the central dogma, changes in gene expression are changes in the primary sequence of DNA, and it has been demonstrated that most changes in gene expression result from changes in the DNA sequence.

  On the other hand, a mechanism has also been found in which gene expression changes due to an acquired action on DNA without accompanying changes in the DNA sequence. For example, changes based on mechanisms such as changes in gene expression due to chemical modification of histones (histone methylation, acetylation, phosphorylation, etc.) are independent of DNA sequence changes.

  For example, it is known that histone acetylation is controlled by the balance between histone acetylase and histone deacetylase. In recent years, histone acetylases and histone deacetylases have been identified and their importance in transcriptional regulation has become clear. As histone deacetylases (hereinafter sometimes referred to as “HDACs”), 11 types of HDACs 1 to 11 have been identified so far (see, for example, Non-Patent Document 1), and these HDACs express genes. It is thought that it is suppressing. Thus, attempts have been made to activate the expression of specific genes by inhibiting HDAC.

  HDAC inhibitors inhibit HDAC functioning in the transcription mechanism and induce histone hyperacetylation, thereby exhibiting cell cycle arrest, normalization of transformed cells, induction of differentiation, apoptosis-inducing action, etc. It is expected to be used as an antitumor agent. For example, Patent Document 1 discloses that administration of a pharmaceutical composition containing suberoylanilide hydroxamic acid (SAHA) as an HDAC inhibitor selectively induces terminal differentiation, cell growth arrest, and apoptosis of neoplastic cells. Methods for inhibiting deacetylase have been proposed.

  Under such circumstances, development of compounds useful as histone deacetylase inhibitors is desired.

JP 2010-1302 A

Cancer Letters 277 (2009) 8-21

  The main object of the present invention is to provide a hydroxamic acid derivative or a salt thereof useful as a histone deacetylase inhibitor. Another object of the present invention is to provide a pharmaceutical composition comprising a hydroxamic acid derivative or a salt thereof as an active ingredient, a histone deacetylase inhibitor, and an antitumor agent.

  As a result of intensive studies to solve the above problems, the present inventors have found that the hydroxamic acid derivative represented by the general formula (A) or a salt thereof is useful as a histone deacetylase inhibitor. It was. The present invention has been completed by further studies based on such knowledge.

That is, this invention provides invention of the following aspect.
Item 1. A hydroxamic acid derivative represented by the following general formula (A) or a salt thereof.
[In the general formula (A), the group A is an oxygen atom, a nitrogen atom, or —NR ⁶ —.
When the group A is an oxygen atom or —NR ⁶ —, the bond between the first-position group A and the second-position carbon atom of the heterocyclic ring is a single bond, and when the group A is a nitrogen atom, The bond between the carbon atom at the 1st position and the carbon atom at the 2nd position of the ring is a double bond. The group R ⁶ is a lower alkyl group which may have a substituent, or a hydrogen atom.
The group B is an oxygen atom or an optionally substituted lower alkoxy group. When the group B is an oxygen atom, the bond between the group B and the carbon atom at the 2-position of the heterocyclic ring is double. When it is a bond and the group B is an optionally substituted lower alkoxy group, the bond between the group B and the carbon atom at the 2-position of the heterocyclic ring is a single bond.
The group R ¹ and the group R ³ are each independently a hydrogen atom or an optionally substituted lower alkyl group, or either the group R ¹ or the group R ³ is substituted with the group X. Yes.
The group R ² and the group R ⁴ are each independently a hydrogen atom or a lower alkyl group which may have a substituent, or bonded to each other to form a 3-position carbon atom and a 4-position carbon. It forms a double bond with the atom.
The group R _n ⁵ is n = 0 to 3 substituents substituted with hydrogen atoms on the benzene ring to which the heterocycle is condensed, and each independently has a halogen atom or a substituent. A good lower alkyl group.
The group X is substituted with a hydrogen atom on the benzene ring, a hydrogen atom on the heterocyclic ring, or one of the group R ¹ and the group R ³ , and the group X is a single bond, an oxygen atom, —CONH -, - NHCO -, - SO 2 NH-, or -NHSO ₂ - a.
The group Y is a single bond, a saturated or unsaturated alkylene group having 1 to 10 carbon atoms, or a group —Y ¹ —Y ² —Y ³ —. The group Y ¹ is a saturated or unsaturated alkylene group having 1 to 6 carbon atoms, or a single bond. The group Y ² is an optionally substituted phenylene group or an optionally substituted cyclohexylene group. The group Y ³ is a saturated or unsaturated alkylene group having 1 to 6 carbon atoms. ]
Item 2. In the general formula (A), the group R ¹ and the group R ³ are each independently a hydrogen atom or a lower alkyl group which may have a substituent, and the group X is a hydrogen atom on the benzene ring. substituted and the group X is a single bond, an oxygen atom, -CONH -, - NHCO -, - SO 2 NH-, or -NHSO ₂ - and is, hydroxamic acid derivative or salt thereof according to claim 1.
Item 3. A hydroxamic acid derivative represented by the following general formula (A1) or a salt thereof,
In the general formula (A1), the group R ⁶ is a methyl group or a hydrogen atom,
The group R ¹ is a hydrogen atom or a methyl group, the group R ³ is a hydrogen atom, the group R ² is a hydrogen atom or a methyl group, or is bonded to the group R ⁴ to form a 3 A carbon atom at the position and a carbon atom at the 4th position, and the group R ⁴ is a hydrogen atom or bonded to the group R ² to form a carbon atom at the 3rd position of the heterocyclic ring. Forming a double bond with the 4-position carbon atom,
The group R ⁵ is a hydrogen atom or a fluorine atom;
Group X is substituted with a hydrogen atom on the benzene ring, the group X represents an oxygen atom, -CONH -, - NHCO -, - SO 2 NH-, or -NHSO ₂ - and is,
The group Y is a saturated or unsaturated alkylene group having 3 to 7 carbon atoms, or a group —Y ¹ —Y ² —Y ³ —, and the group Y ¹ is a saturated or unsaturated alkylene group having 2 carbon atoms ( a -CH = CH-, group Y ² is a phenylene group or a cyclohexylene group, group Y ³ is a methylene group, a hydroxamic acid derivative or salt thereof according to claim 2.
Item 4. A hydroxamic acid derivative represented by the following general formula (A2) or a salt thereof,
In the general formula (A2), the group R ¹ is a hydrogen atom or a methyl group, the group R ³ is a hydrogen atom, and the group R ² is a hydrogen atom or a methyl group, or is bonded to the group R ^4. A double bond is formed between the carbon atom at the 3rd position and the carbon atom at the 4th position of the heterocyclic ring, and the group R ⁴ is a hydrogen atom or bonded to the group R ² to form the heterocyclic ring. Forming a double bond between the 3-position carbon atom and 4-position carbon atom of
The group R ⁷ is a methyl group or an ethyl group,
The group X is substituted with a hydrogen atom on the benzene ring, the group X is an oxygen atom, -CONH-, or -NHCO-;
Item 3. The hydroxamic acid derivative or a salt thereof according to Item 2, wherein the group Y is a saturated or unsaturated alkylene group having 3 to 7 carbon atoms.
Item 5. A hydroxamic acid derivative represented by the following general formula (A3) or a salt thereof,
In the general formula (A3), the group X is substituted with a hydrogen atom on the benzene ring, the group X is an oxygen atom, -CONH-, or -NHCO-,
Item 3. The hydroxamic acid derivative or a salt thereof according to Item 2, wherein the group Y is a saturated or unsaturated alkylene group having 3 to 7 carbon atoms.
Item 6. Item 6. A pharmaceutical composition comprising the hydroxamic acid derivative or a salt thereof according to any one of Items 1 to 5 as an active ingredient.
Item 7. The histone deacetylase inhibitor which uses the hydroxamic acid derivative or its salt in any one of claim | item 1 -5 as an active ingredient.
Item 8. Item 6. An antitumor agent comprising the hydroxamic acid derivative or a salt thereof according to any one of Items 1 to 5 as an active ingredient.
Item 9. A method for producing a hydroxamic acid derivative represented by the following general formula (Aa) or a salt thereof,
[In General Formula (Aa), group A, group B, groups R ^{1 to} R ⁴ , group R _n ⁵ , and group Y are the same as in general formula (A). ]
Step 1 of synthesizing the following compound D3 by a coupling reaction of the following compound D1 and the following compound D2 represented by the following scheme 1:
[In Scheme 1, M is an alkyl group or a benzyl group, X ¹ is a halogen atom, the group A, the group B, the groups R ^{1 to} R ⁴ , the group R _n ⁵ , and the group Y are represented by the general formula Same as (A). ]
Step 2 of converting the ester group of the compound D3 represented by the following Scheme 2 to a hydroxamic acid group by reacting with NH ₂ OH;
[In the scheme 2, the group M is the same as that in the scheme 1, and the group A, the group B, the groups R ^{1 to} R ⁴ , the group R _n ⁵ , and the group Y are the same as those in the general formula (A). ]
A process for producing a hydroxamic acid derivative represented by the general formula (Aa) or a salt thereof.
Item 10. A method for producing a hydroxamic acid derivative represented by the following general formula (Ab) or a salt thereof,
[In the general formula (Ab), the group A, the group B, the groups R ^{1 to} R ⁴ , the group R _n ⁵ , and the group Y are the same as those in the general formula (A). ]
Step 1 for synthesizing Compound D6 by a coupling reaction of Compound D4 and Compound D5 shown below in Scheme 3;
[In scheme 3, M is an alkyl group or a benzyl group, and group A, group B, groups R ^{1 to} R ⁴ , group R _n ⁵ , and group Y are the same as those in formula (A). ]
Step 2 of converting the ester group of compound D6 represented by the following Scheme 4 to a hydroxamic acid group by reacting with NH ₂ OH;
[In the scheme 4, the group M is the same as that in the scheme 3, and the group A, the group B, the groups R ^{1 to} R ⁴ , the group R _n ⁵ , and the group Y are the same as those in the general formula (A). ]
A process for producing a hydroxamic acid derivative represented by the general formula (Ab) or a salt thereof.
Item 11. A method for producing a hydroxamic acid derivative represented by the following general formula (Ac) or a salt thereof,
[In General Formula (Ac), group A, group B, groups R ^{1 to} R ⁴ , group R _n ⁵ , and group Y are the same as in general formula (A). ]
Step 1 for synthesizing Compound D9 represented by the following Scheme 5 by a coupling reaction between Compound D7 and Compound D8,
[In scheme 5, M is an alkyl group or a benzyl group, and the group A, the group B, the groups R ^{1 to} R ⁴ , the group R _n ⁵ , and the group Y are the same as those in the general formula (A). ]
Step 2 of converting the ester group of the following compound D9 represented by the following Scheme 6 into a hydroxamic acid group by reacting with NH ₂ OH;
[In scheme 6, group M is the same as scheme 5, and group A, group B, groups R ^{1 to} R ⁴ , group R _n ⁵ , and group Y are the same as in general formula (A). ]
A process for producing a hydroxamic acid derivative represented by the general formula (Ac) or a salt thereof, comprising:
Item 12. A method for producing a hydroxamic acid derivative represented by the following general formula (Ad) or a salt thereof,
[In General Formula (Ad), group A, group B, groups R ^{1 to} R ⁴ , group R _n ⁵ , and group Y are the same as in general formula (A). ]
Step 1 of synthesizing Compound D12 represented by the following Scheme 7 by a coupling reaction of Compound D10 and Compound D11 below;
[In Scheme 7, the group M is an alkyl group or a benzyl group, and the group A, the group B, the groups R ^{1 to} R ⁴ , the group R _n ⁵ , and the group Y are the same as those in the general formula (A). ]
Step 2 of converting the ester group of the following compound D12 represented by the following Scheme 8 into a hydroxamic acid group by reacting with NH ₂ OH;
[In scheme 8, the group M is the same as in scheme 7, and the group A, the group B, the groups R ^{1 to} R ⁴ , the group R _n ⁵ , and the group Y are the same as those in the general formula (A). ]
A process for producing a hydroxamic acid derivative represented by the general formula (Ad) or a salt thereof, comprising:
Item 13. A method for producing a hydroxamic acid derivative represented by the following general formula (Ae) or a salt thereof,
[In the general formula (Ae), the group A, the group B, the groups R ^{1 to} R ⁴ , the group R _n ⁵ , and the group Y are the same as those in the general formula (A). ]
Step 1 of synthesizing Compound D15 represented by the following Scheme 9 by a coupling reaction of Compound D13 and Compound D14 below;
[In the scheme 9, the group M is an alkyl group or a benzyl group, and the group A, the group B, the groups R ^{1 to} R ⁴ , the group R _n ⁵ , and the group Y are the same as those in the general formula (A). ]
Represented by the following Scheme 10, is reacted with NH ₂ OH to an ester group of the following compounds D15, and step 2 of converting a hydroxamic acid group,
[In scheme 10, group M is the same as in scheme 9, and group A, group B, groups R ^{1 to} R ⁴ , group R _n ⁵ , and group Y are the same as in general formula (A). ]
The manufacturing method of the hydroxamic acid derivative represented by general formula (Ae) or its salt containing these.

  According to the present invention, a hydroxamic acid derivative or a salt thereof useful as a histone deacetylase inhibitor can be provided. Moreover, according to this invention, the pharmaceutical composition which uses the said hydroxamic acid derivative or its salt as an active ingredient, a histone deacetylase inhibitor, and an antitumor agent can be provided.

1. Hydroxamic acid derivative or salt thereof represented by general formula (A) The hydroxamic acid derivative or salt thereof of the present invention is represented by the following general formula (A).

In the general formula (A), the group A is an oxygen atom, a nitrogen atom, or —NR ⁶ —. When the group A is an oxygen atom or —NR ⁶ —, the bond between the 1-position group A and the 2-position carbon atom of the heterocyclic ring is a single bond. At this time, the group R ⁶ is a lower alkyl group which may have a substituent, or a hydrogen atom. As a lower alkyl group, C1-C3 alkyl groups, such as a methyl group, an ethyl group, a propyl group, are mentioned, for example. Examples of the substituent that the lower alkyl group may have include a halogen atom, preferably a fluorine atom. The group R ⁶ is preferably a methyl group or a hydrogen atom. When group A is a nitrogen atom, the bond between the 1st carbon atom and the 2nd carbon atom of the heterocyclic ring is a double bond.

  In the general formula (A), the group B is an oxygen atom or a lower alkoxy group which may have a substituent. As a lower alkoxy group, C1-C3 alkoxy groups, such as a methoxy group, an ethoxy group, a propoxy group, are mentioned, for example. Examples of the substituent that the lower alkoxy group may have include, for example, a halogen atom, preferably a fluorine atom. The group B is preferably an oxygen atom or a methoxy group. When group B is an oxygen atom, the bond between group B and the carbon atom at the 2-position of the heterocyclic ring is a double bond. When the group B is a lower alkoxy group which may have a substituent, the bond between the group B and the carbon atom at the 2-position of the heterocyclic ring is a single bond.

In the general formula (A), the group R ¹ and the group R ³ are each independently a hydrogen atom or a lower alkyl group which may have a substituent, or one of the group R ¹ and the group R ^3. Substitutes the group X. The group R ¹ and the group R ³ are preferably each independently a hydrogen atom or a lower alkyl group which may have a substituent. In the group R ¹ and the group R ³ , examples of the lower alkyl group include alkyl groups having 1 to 3 carbon atoms such as a methyl group, an ethyl group, and a propyl group. Examples of the substituent that the lower alkyl group may have include a halogen atom, preferably a fluorine atom. The group R ¹ is preferably a hydrogen atom or a methyl group. The group R ³ is preferably a hydrogen atom. The group R ² and the group R ⁴ are each independently a hydrogen atom or a lower alkyl group which may have a substituent, or bonded to each other to form a 3-position carbon atom and a 4-position carbon. It forms a double bond with the atom. In the group R ² and the group R ⁴ , examples of the lower alkyl group include alkyl groups having 1 to 3 carbon atoms such as a methyl group, an ethyl group, and a propyl group. Examples of the substituent that the lower alkyl group may have include a halogen atom, preferably a fluorine atom. The group R ² is preferably a hydrogen atom or a methyl group, or is bonded to the group R ⁴ to form a double bond between the 3-position carbon atom and the 4-position carbon atom of the heterocyclic ring. . The group R ⁴ is preferably a hydrogen atom or bonded to the group R ² to form a double bond between the 3-position carbon atom and the 4-position carbon atom of the heterocyclic ring.

In the general formula (A), the group R _n ⁵ is n = 0 to 3 substituents substituted with hydrogen atoms on the benzene ring to which the heterocycle is condensed. Each of the n groups R _n ⁵ is independently a halogen atom or a lower alkyl group which may have a substituent. As a lower alkyl group, C1-C3 alkyl groups, such as a methyl group, an ethyl group, a propyl group, are mentioned, for example. Examples of the substituent that the lower alkyl group may have include a halogen atom, preferably a fluorine atom. The number (n) of the radicals R _n ⁵ is preferably 0 or 1. The halogen atom of the group R _n ⁵ is preferably a fluorine atom.

In the general formula (A), the group X is substituted with a hydrogen atom on the benzene ring, a hydrogen atom on the heterocyclic ring, or one of the groups R ¹ and R ³ , preferably the benzene ring It replaces the hydrogen atom on the top and the hydrogen atom on the heterocycle. The group X is a single bond, an oxygen atom, —CONH—, —NHCO—, —SO ₂ NH—, or —NHSO ₂ —, preferably an oxygen atom, —CONH—, —NHCO—, —SO _2. NH-, or -NHSO ₂ -; and particularly from the viewpoint of having a high histone deacetylase inhibitory activity, more preferably -CONH- or -NHCO-.

In the general formula (A), the group Y is a single bond, a saturated or unsaturated alkylene group having 1 to 10 carbon atoms, or a group —Y ¹ —Y ² —Y ³ —, preferably saturated or unsaturated. is more preferably an alkylene group or a group -Y ¹ -Y ² -Y 3 to 7 carbon atoms, saturated ³ - - number 3-7 alkylene group or a group -Y ¹ -Y ² -Y ³ carbon is . The group Y ¹ is bonded to the carbonyl carbon of the hydroxamic acid group. The group Y ¹ is a saturated or unsaturated alkylene group having 1 to 6 carbon atoms, or a single bond, preferably a saturated or unsaturated alkylene group having 2 to 4 carbon atoms, more preferably an unsaturated carbon. It is an alkylene group of formula 2 (—CH═CH—). The group Y ² is a phenylene group which may have a substituent or a cyclohexylene group which may have a substituent. Examples of the substituent that the phenylene group or cyclohexylene group may have include a halogen atom, preferably a fluorine atom. The group Y ² is preferably a phenylene group or a cyclohexylene group. The group Y ³ is bonded to the group X and is a saturated or unsaturated alkylene group having 1 to 6 carbon atoms, preferably a saturated or unsaturated alkylene group having 1 to 3 carbon atoms, more preferably A methylene group. When the group Y ² is a phenylene group, the group Y ¹ and the group Y ³ may be bonded to the group Y ^{2 in} any positional relationship of ortho, meta, and para on the benzene ring. Further, when the group Y ² is a cyclohexylene group, the group Y ¹ and the group Y ³ are any of the 1-position, 1-position, 1-position and 2-position, 1-position and 3-position, 1-position and 4-position of the cyclohexane ring. it may be bonded in a positional relationship between the group Y ^2, or may be bonded to the group Y ² in any stereostructure of cis and trans.

In the present invention, among hydroxamic acid derivatives represented by the general formula (A) or salts thereof, preferred are hydroxamic acid derivatives represented by the following general formula (A1) or salts thereof.

In the general formula (A1), the group R ⁶ is a methyl group or a hydrogen atom. The group R ¹ is a hydrogen atom or a methyl group. The group R ³ is a hydrogen atom. The group R ² is a hydrogen atom or a methyl group, or is bonded to the group R ⁴ to form a double bond between the 3-position carbon atom and the 4-position carbon atom of the heterocyclic ring. The group R ⁴ is a hydrogen atom or is bonded to the group R ² to form a double bond between the 3-position carbon atom and the 4-position carbon atom of the heterocyclic ring. The group R ⁵ is a hydrogen atom or a fluorine atom.

In the general formula (A1), the group X is substituted with a hydrogen atom on the benzene ring, and the group X is an oxygen atom, —CONH—, —NHCO—, —SO ₂ NH—, or —NHSO. ₂ −. The group Y is a saturated or unsaturated alkylene group having 3 to 7 carbon atoms, or a group —Y ¹ —Y ² —Y ³ —, preferably a saturated alkylene group having 3 to 7 carbon atoms, or the group —Y. ¹ -Y ² -Y ^3- . The group Y ¹ is a saturated or unsaturated alkylene group having 2 carbon atoms. The group Y ² is a phenylene group or a cyclohexylene group. The group Y ³ is a methylene group. When the group Y ² is a phenylene group, the group Y ¹ and the group Y ³ may be bonded to the group Y ^{2 in} any positional relationship of ortho, meta, and para on the benzene ring. Further, when the group Y ² is a cyclohexylene group, the group Y ¹ and the group Y ³ are any of the 1-position, 1-position, 1-position and 2-position, 1-position and 3-position, 1-position and 4-position of the cyclohexane ring. it may be bonded in a positional relationship between the group Y ^2, or may be bonded to the group Y ² in any stereostructure of cis and trans.

Among the hydroxamic acid derivatives represented by the general formula (A1) or salts thereof, more preferred are hydroxamic acid derivatives represented by the following general formulas (A11) to (A13) or salts thereof.

In the general formulas (A11) to (A13), the group R ⁵ , the group R ⁶ , the group X, and the group Y are the same as those in the general formula (A1).

In the present invention, among hydroxamic acid derivatives represented by the general formula (A) or salts thereof, hydroxamic acid derivatives represented by the following general formula (A2) or salts thereof are also represented by the general formula (A1). A preferred example is a hydroxamic acid derivative or a salt thereof.

In the general formula (A2), the group R ¹ is a hydrogen atom or a methyl group. The group R ³ is a hydrogen atom. The group R ² is a hydrogen atom or a methyl group, or is bonded to the group R ⁴ to form a double bond between the 3-position carbon atom and the 4-position carbon atom of the heterocyclic ring. The group R ⁴ is a hydrogen atom or is bonded to the group R ² to form a double bond between the third and fourth carbon atoms of the heterocyclic ring. The group R ⁷ is a methyl group or an ethyl group.

  In general formula (A2), group X is substituted with a hydrogen atom on the benzene ring. The group X is an oxygen atom, —CONH—, or —NHCO—. The group Y is a saturated or unsaturated alkylene group having 3 to 7 carbon atoms, preferably a saturated alkylene group having 3 to 7 carbon atoms.

Among the hydroxamic acid derivatives represented by the general formula (A2) or salts thereof, more preferred are hydroxamic acid derivatives represented by the following general formulas (A21) and (A22) or salts thereof.

In the general formulas (A21) and (A22), the group R ⁷ , the group X, and the group Y are the same as those in the general formula (A2).

Furthermore, in the present invention, among the hydroxamic acid derivatives represented by the general formula (A) or salts thereof, the hydroxamic acid derivatives represented by the following general formula (A3) or salts thereof are also represented by the above general formulas (A1) and ( A preferred example is a hydroxamic acid derivative represented by A2) or a salt thereof.

  In the general formula (A3), the group X is substituted with a hydrogen atom on the benzene ring. The group X is an oxygen atom, —CONH—, or —NHCO—. The group Y is a saturated or unsaturated alkylene group having 3 to 7 carbon atoms, preferably a saturated alkylene group having 3 to 7 carbon atoms.

  The hydroxamic acid derivative of the present invention or a salt thereof is not particularly limited as long as it is a pharmacologically acceptable salt. For example, a salt with an inorganic base such as sodium, potassium, lithium or calcium; a third such as triethylamine And organic amine salts such as quaternary amines such as quaternary amines and tetramethylammonium.

  The hydroxamic acid derivative of the present invention or a salt thereof has inhibitory activity against histone deacetylase and can be used as a histone deacetylase inhibitor. In addition, histone deacetylase is used to develop tumors (such as cancers such as T cell lymphoma), memory disorders (such as Alzheimer), inflammation, HIV latent infection, neurodegenerative diseases, depression, autoimmune diseases, Huntington's disease, etc. And the compounds of the present invention can be used as preventive or therapeutic agents for these diseases. Among histone deacetylases, HDAC1, HDAC2, and HDAC8 are known to be involved in the development of cancer. In particular, in the hydroxamic acid derivative represented by the general formula (A) of the present invention or a salt thereof, when the group X has a structure represented by -CONH- and -NHCO-, high activity in HDAC1, HDAC2, and HDAC8 Therefore, it is useful as a therapeutic agent for cancer. What is necessary is just to provide the hydroxamic acid derivative or its salt of this invention as a pharmaceutical composition, when using it for the said use.

  The hydroxamic acid derivative of the present invention or a salt thereof is converted in vivo into a hydroxamic acid derivative represented by the general formula (A) or a salt thereof (that is, a so-called prodrug) in the present invention. May be provided as

  The hydroxamic acid derivatives or salts thereof (including prodrugs) of the present invention can be left in the atmosphere or recrystallized to absorb moisture and other solvents, and adsorbed water and solvents can be attached. May be hydrated or solvated. When such a hydrate or solvate is formed, a hydrate or solvate of the hydroxamic acid derivative or salt thereof of the present invention is also included in the hydroxamic acid derivative or salt thereof of the present invention.

  When the hydroxamic acid derivative of the present invention or a salt thereof is used for the above application, the hydroxamic acid derivative represented by the general formula (A) or a salt thereof may be used alone or in combination of two or more. May be used. Further, the pharmaceutical composition containing the hydroxamic acid derivative of the present invention or a salt thereof is formulated with a pharmaceutically acceptable additive such as an excipient, a diluent, a solubilizing agent, etc. It is prepared into dosage forms such as a capsule, capsule, injection, suppository and ointment. The administration form of the pharmaceutical composition is not particularly limited, and may be oral administration or parenteral administration such as systemic administration and local administration. The content of the hydroxamic acid derivative of the present invention or a salt thereof in the pharmaceutical composition varies depending on the dosage form and the like, and is, for example, about 0.1 to 100% by mass. The dosage of the pharmaceutical composition varies depending on the administration route, the age of the patient, the actual symptoms to be prevented or treated, the dosage form, etc. For example, when administered orally to an adult, the hydroxamic acid derivative of the present invention or a salt thereof In terms of amount, it can be about 0.01 mg to 2000 mg per day, preferably about 0.1 mg to 1000 mg per day, and can be divided into 1 to several times per day.

2. Process for producing hydroxamic acid derivative represented by general formula (A) or a salt thereof The hydroxamic acid derivative represented by general formula (A) of the present invention or a salt thereof can be produced by a known method, for example, J. et al. Med. Chem. 2010, 53, 2952-2963, J. MoI. Med. Chem. 2006, 49, 4809-4812, Experimental Chemistry Course 5th edition, 14, J. MoI. Med. Chem. 2010, 53, 1937-1950, J. MoI. Med. Chem. 2010, 53, 3038-3047, J. MoI. Med. Chem. 2009, 52, 2776-2785, J. MoI. Org. Chem. 2009, 74, 3540-3543, J. MoI. Med. Chem. It can be produced by the literatures such as 2007, 50, 4405-4418 and the methods exemplified in the examples.

(1) In the general formula (A), when the group X is an oxygen atom, for example, the compound represented by the general formula (A) of the present invention has, for example, the following scheme when the group X is an oxygen atom: Step 1 of synthesizing compound D3 by a coupling reaction between compound D1 and compound D2 as shown in FIG.
[In Scheme 1, M is an alkyl group such as a methyl group, an ethyl group, or a propyl group, or a benzyl group; X ¹ is a halogen atom such as Cl, Br, or I; _n ⁵ , groups R ^{1 to} R ⁴ , and group Y are the same as those in formula (A). ]
As shown in the following scheme 2, the ester group of compound D3 is reacted with NH ₂ OH to convert it into a hydroxamic acid group,
[In the scheme 2, the group M is the same as that in the scheme 1, and the group A, the group B, the groups R ^{1 to} R ⁴ , the group R _n ⁵ , and the group Y are the same as those in the general formula (A). ]
It can manufacture by the method containing.

In Scheme 1, coupling reaction of the compound D2 with the compound D1 is, if the reaction of hydroxyl groups of halogen X ¹ and compound D2 compound D1, is not particularly limited, for example, by using a base such as NaH It can be carried out. In the coupling reaction, a solvent may be used, and the solvent is not particularly limited, and for example, DMF can be used. What is necessary is just to set reaction time, reaction temperature, etc. suitably, for example, it can be made to react for about 0.5 to 24 hours at the temperature of about -78 degreeC-150 degreeC.

In Scheme 2, the method of obtaining the hydroxamic acid derivative represented by the general formula (Aa) or a salt thereof by reacting the ester group of compound D3 with NH ₂ OH to convert it into a hydroxamic acid group is not particularly limited. For example, it can be carried out in the presence of a base such as NaOCH ₃ . What is necessary is just to set reaction time, reaction temperature, etc. suitably, for example, it can be made to react for about 0.5 to 24 hours at the temperature of about -10-100 degreeC.

(2) In the general formula (A), when the group X is —NHCO—, for example, when the group X is —NHCO—, the compound represented by the general formula (A) of the present invention is, for example, Step 1 for synthesizing Compound D6 by a coupling reaction of Compound D4 and Compound D5 as shown in Scheme 3 below,
[In scheme 3, M is an alkyl group such as a methyl group, an ethyl group, a propyl group, or a benzyl group, and the group A, the group B, the groups R ^{1 to} R ⁴ , the group R _n ⁵ , and the group Y are It is the same as formula (A). ]
As shown in the following scheme 4, the ester group of compound D6 is reacted with NH ₂ OH to convert it into a hydroxamic acid group,
[In the scheme 4, the group M is the same as that in the scheme 3, and the group A, the group B, the groups R ^{1 to} R ⁴ , the group R _n ⁵ , and the group Y are the same as those in the general formula (A). ]
It can manufacture by the method containing.

In scheme 3, the coupling reaction between compound D4 and compound D5 is not particularly limited as long as the group NH ₂ of compound D4 and the group COOH of compound D5 can be reacted. For example, diphenyl phosphate azide (DPPA) , 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDCI) and the like, and amine such as triethylamine can be used. In the coupling reaction, a solvent may be used, and the solvent is not particularly limited, and for example, DMF can be used. What is necessary is just to set reaction time, reaction temperature, etc. suitably, for example, it can be made to react for about 0.5 to 24 hours at the temperature of about -78 degreeC-150 degreeC.

In Scheme 4, the method of obtaining the hydroxamic acid derivative represented by the general formula (Ab) or a salt thereof by reacting the ester group of compound D6 with NH ₂ OH to convert it into a hydroxamic acid group is not particularly limited. For example, it can be carried out in the presence of a base such as NaOCH ₃ . What is necessary is just to set reaction time, reaction temperature, etc. suitably, for example, it can be made to react for about 0.5 to 24 hours at the temperature of about -10-100 degreeC.

(3) In the general formula (A), when the group X is —CONH—, for example, the compound represented by the general formula (A) of the present invention is, for example, when the group X is —CONH—, Step 1 of synthesizing compound D9 by a coupling reaction between compound D7 and compound D8 as shown in Scheme 5 below,
[In Scheme 5, the group M is an alkyl group such as a methyl group, an ethyl group, a propyl group, or a benzyl group, and the group A, the group B, the groups R ^{1 to} R ⁴ , the group R _n ⁵ , and the group Y are It is the same as general formula (A). ]
As shown in the following scheme 6, the ester group of compound D9 is reacted with NH ₂ OH to convert it into a hydroxamic acid group,
[In scheme 6, group M is the same as scheme 5, and group A, group B, groups R ^{1 to} R ⁴ , group R _n ⁵ , and group Y are the same as in general formula (A). ]
It can manufacture by the method containing.

In scheme 5, the coupling reaction between compound D7 and compound D8 is not particularly limited as long as the group COOH of compound D7 and the group NH ₂ of compound D8 can be reacted. For example, in the presence of an amine such as triethylamine. Can be done. In the coupling reaction, a solvent may be used, and the solvent is not particularly limited, and for example, DMF can be used. What is necessary is just to set reaction time, reaction temperature, etc. suitably, for example, it can be made to react for about 0.5 to 24 hours at the temperature of about -78 degreeC-150 degreeC.

In Scheme 6, the method of obtaining the hydroxamic acid derivative represented by the general formula (Ac) or a salt thereof by reacting the ester group of compound D9 with NH ₂ OH to convert it into a hydroxamic acid group is not particularly limited. For example, it can be carried out in the presence of a base such as NaOCH ₃ . What is necessary is just to set reaction time, reaction temperature, etc. suitably, for example, it can be made to react for about 0.5 to 24 hours at the temperature of about -10-100 degreeC.

(4) In formula (A), the group X is -NHSO ₂ - For example, when a compound represented by the general formula (A) of the present invention, group X is -NHSO ₂ - if it is, the For example, as shown in Scheme 7 below, Step 1 for synthesizing Compound 12 by a coupling reaction between Compound D10 and Compound D11;
[In Scheme 7, the group M is an alkyl group such as a methyl group, an ethyl group, a propyl group, or a benzyl group, and the group A, the group B, the groups R ^{1 to} R ⁴ , the group R _n ⁵ , and the group Y are It is the same as general formula (A). ]
As shown in the following scheme 8, the ester group of compound D12 is reacted with NH ₂ OH to convert it into a hydroxamic acid group,
[In scheme 8, the group M is the same as in scheme 7, and the group A, the group B, the groups R ^{1 to} R ⁴ , the group R _n ⁵ , and the group Y are the same as those in the general formula (A). ]
It can manufacture by the method containing.

In Scheme 7, the coupling reaction between the compound D10 and the compound D11 is not particularly limited as long as the group NH ₂ of the compound D10 and the group SO ₂ Cl of the compound D11 can be reacted. For example, an amine such as triethylamine Can be done in the presence. In the coupling reaction, a solvent may be used, and the solvent is not particularly limited, and for example, dichloromethane can be used. What is necessary is just to set reaction time, reaction temperature, etc. suitably, for example, it can be made to react for about 0.5 to 24 hours at the temperature of about -78 degreeC-80 degreeC.

In Scheme 8, the method of obtaining the hydroxamic acid derivative represented by the general formula (Ad) or a salt thereof by reacting the ester group of compound D12 with NH ₂ OH to convert it into a hydroxamic acid group is not particularly limited. For example, it can be carried out in the presence of a base such as NaOCH ₃ . What is necessary is just to set reaction time, reaction temperature, etc. suitably, for example, it can be made to react for about 0.5 to 24 hours at the temperature of about -10 degreeC-100 degreeC.

(5) In the general formula (A), when the group X is —SO ₂ NH— For example, the compound represented by the general formula (A) of the present invention may be used when the group X is —SO ₂ NH—. For example, as shown in Scheme 9 below, Step 1 for synthesizing Compound 15 by a coupling reaction of Compound D13 and Compound D14;
[In scheme 9, the group M is an alkyl group such as a methyl group, an ethyl group, a propyl group or a benzyl group, and the group A, the group B, the groups R ^{1 to} R ⁴ , the group R _n ⁵ , and the group Y are It is the same as general formula (A). ]
As shown in Scheme 10 below, the ester group of compound D15 is reacted with NH ₂ OH to convert it into a hydroxamic acid group,
[In scheme 10, group M is the same as in scheme 9, and group A, group B, groups R ^{1 to} R ⁴ , group R _n ⁵ , and group Y are the same as in general formula (A). ]
It can manufacture by the method containing.

In Scheme 9, the coupling reaction between the compound D13 and the compound D14 is not particularly limited as long as the group SO ₃ H of the compound D13 and the group NH ₂ of the compound D14 can be reacted. For example, an amine such as triethylamine It can be carried out using a condensing agent such as trichlorotriazine. In addition, a solvent may be used for the coupling reaction, and the solvent is not particularly limited, and for example, acetone or the like can be used. What is necessary is just to set reaction time, reaction temperature, etc. suitably, for example, it can be made to react for about 0.25 to 24 hours at the temperature of about -0 degreeC-100 degreeC.

In Scheme 10, the method of obtaining the hydroxamic acid derivative represented by the general formula (Ae) or a salt thereof by reacting the ester group of compound D15 with NH ₂ OH to convert it into a hydroxamic acid group is not particularly limited. For example, it can be carried out in the presence of a base such as NaOCH ₃ . What is necessary is just to set reaction time, reaction temperature, etc. suitably, for example, it can be made to react for about 0.5 to 24 hours at the temperature of about -10 degreeC-100 degreeC.

  Hereinafter, the present invention will be described in detail with reference to examples. However, the present invention is not limited to the examples.

1. Production of various hydroxamic acid derivatives
Example 1 (Synthesis of 6- (3,4-dihydrocarbostyril-6-yloxy) hexanoic acid hydroxyamide)
First, 6- (3,4-dihydrocarbostyril-6-yloxy) hexanoic acid ethyl ester was synthesized according to the following scheme.
In a 100 ml eggplant flask, 0.59 g (14.709 mmol, 1.2 eq.) Of NaH (60% in mineral oil) was taken, and 5 ml of DMF was added to form a white suspension. Attach a calcium chloride tube and a dropping funnel, stir in an ice bath and stir, dissolve 2.00 g (12.257 mmol) of 6-hydroxy-3,4-dihydrocarbostyril in 9 ml of DMF and 1 ml of washed DMF for 14 minutes. And dripped. The mixture was stirred for 20 minutes on an ice bath, and 6 ml of 6-bromohexanoic acid ethyl ester (13.483 mmol, 1.1 eq.) And 1 ml of washed DMF were added dropwise over 7 minutes. Allow the ice to melt and stir overnight. The mixture was stirred for 3 hours on an oil bath at 110 ° C. and allowed to cool. 100 ml of water was added, extraction was performed with AcOEt 100 ml × 3, washed sequentially with water 100 ml × 1, brine 100 ml × 1, and dried over anhydrous Na ₂ SO ₄ . Filtration through a Kiriyama funnel and evaporation gave 4.13 g of pale orange crude crystals. Purification was performed with an open silica gel column (n-hexane: AcOEt = 1: 2) to obtain 2.56 g (8.376 mmol, y.68%) of white crude crystals.

Next, 6- (3,4-dihydrocarbostyril-6-yloxy) hexanoic acid hydroxyamide (Compound 1) described in Table 1 was synthesized according to the following scheme.
To a 20 ml eggplant flask, 200 mg (0.655 mmol) of 6- (3,4-dihydrocarbostyril-6-yloxy) hexanoic acid ethyl ester was taken and dissolved by adding 1.2 ml (6.549 mmol, 10 eq.) Of MeOH. On an ice bath, under stirring, it has been deposited, the _{NH 2 OH in water 50% 0.40} ml was added dropwise via syringe and the stopcock. The solution was stirred for 4 minutes on an ice bath, and NaOMe in MeOH 25% 0.75 ml (3.275 mmol, 5 eq.) Was added dropwise with a syringe. The white suspension gradually dissolved. The mixture was stirred on the ice bath for 1 hour and 15 minutes, and sat.NH ₄ Cl (10 ml) was added. The precipitate was collected by filtration with a Kiriyama funnel, washed successively with water and n-hexane and air-dried. It moved to the eggplant flask and dried with the vacuum pump, and 173 mg (0.591 mmol, y, 90%) of white crude crystals were obtained. colorless powder (AcOEt) .mp.178-179 ° C. ¹ H-NMR (300 MHz / DMSO / TMS) δ1.31-1.41 (2H, m, CH ₂ ), 1.49-1.59 (2H, m, CH ₂ ) , 1.62-1.71 (2H, m, CH ₂ ), 1.96 (2H, t, J = 7.2 Hz, CH ₂ ), 2.39 (2H, t, J = 7.5 Hz, CH ₂ ), 2.82 (2H, t, J = 7.7 Hz, CH ₂ ), 3.87 (2H, t, J = 6.5 Hz, CH ₂ ), 6.69 (1H, dd, J = 8.6 Hz, 2.6 Hz, ArH), 6.75 (1H, d, J = 8.1 Hz , ArH), 6.76 (1H, s, ArH), 8.66 (1H, s, NH), 9.88 (1H, bs, NOH). LRMS (EI) m / z 292 (M ⁺ ). LRMS (ESI +) m / z 293 ([M + H] ⁺ ). LRMS (ESI-) m / z 291 ([MH]-).

Examples 2-11
The hydroxamic acid derivatives (compounds 2 to 11) shown in Table 1 were synthesized in the same manner as in Example 1 except that the raw materials were changed.

Example 12 (Synthesis of 7-[(3,4-dihydrocarbostyril-6-carbony) amino] heptanoic acid hydroxyamide)
First, 7-aminoheptanoic acid benzyl ester was synthesized according to the following scheme.
Add DPPA 1.25 g (4.540 mmol, 1.2 eq.), Suberic acid monobenzyl ester 1.00 g (3.793 mmol), Et ₃ N 0.77 g (7.567 mmol, 2.0 eq.), And t-BuOH 10 ml to a 50 ml eggplant flask. The reaction was stopped for 2 hours on an oil bath at 100 ° C. and allowed to cool. Evaporation gave a pale yellow oil as a residue. AcOEt (8.3 ml) and conc. HCl (0.5 ml) were added, and the mixture was stirred for 1 hour and 30 minutes on an oil bath at 100 ° C. It added sat.NaHCO ₃ 30 ml, further, was pH 8 by adding NaHCO _3. Water (20 ml) was added and the mixture was extracted with AcOEt (30 ml × 3), washed successively with water (30 ml × 1, brine 30 ml × 1) and dried over anhydrous Na ₂ SO ₄ . Filtration through a Kiriyama funnel and evaporation gave 1.01 g of yellow oil. Purification with an open silica gel column (n-hexane: AcOEt = 2: 1) gave a clear oil 0.47 g (1.979 mmol, y.52%).

Next, 7-[(3,4-dihydrocarbostyril-6-carbony) amino] heptanoic acid benzyl ester was synthesized according to the following scheme.
In a 20 ml eggplant flask, 7-aminoheptanoic acid benzyl ester 304 mg (1.291 mmol, 1.0 eq.), 3,4-dihydrocarbostyril-6-carboxylic acid 247 mg (1.291 mmol), HOBt 175 mg (1.291 mmol, 1.0 eq. ), Et ₃ N 131 mg (1.291 mmol, 1.0 eq.), Add DMF 6 ml, add EDCI · HCl 248 mg (1.291 mmol, 1.0 eq.), Turn off the stopper, and stir at room temperature overnight. did. Sat. NaHCO ₃ 50 ml was added, extracted with AcOEt 50 ml × 3, washed successively with water 50 ml × 1, 1N HCl 50 ml × 1, brine 50 ml × 1, and dried over anhydrous Na ₂ SO ₄ . Filtration through a Kiriyama funnel and evaporation gave 586 mg of beige oil. Purification by an open silica gel column (n-hexane: AcOEt = 1: 4) gave 95 mg (0.232 mmol, y.18%) of white crude crystals.

Next, in the same manner as in Example 1, 7-[(3,4-dihydrocarbostyril-6-carbony) amino] heptanoic acid hydroxyamide (Compound 12) shown in Table 2 was synthesized according to the following scheme.
colorless powder (AcOEt) .mp.189-190 ℃. ¹ H-NMR (300 MHz / DMSO / TMS) δ1.27-1.28 (4H, m, CH ₂ × 2), 1.46-1.51 (4H, m, CH ₂ × 2), 1.94 (2H, t, J = 7.4 Hz, CH ₂ ), 2.47 (2H, m, CH ₂ ), 2.91 (2H, t, J = 7.4 Hz, CH ₂ ), 3.18-3.24 (2H , m, CH ₂ ), 6.86 (1H, d, J = 8.1 Hz, ArH), 7.63 (1H, d, J = 8.4 Hz, ArH), 7.67 (1H, s, ArH), 8.25 (1H, t, J = 5.4 Hz, NH), 8.64 (1H, s, NH), 10.26 (1H, s, NH), 10.32 (1H, s, NOH). LRMS (ESI +) m / z 334 ([M + H] ⁺ LRMS (ESI-) m / z 332 [MH] ^- ).

Examples 13-22
Hydroxamic acid derivatives (compounds 13 to 22) listed in Table 2 were synthesized in the same manner as in Example 12 except that the raw materials were changed.

Example 23 (Synthesis of 7- (3,4-dihydrocarbostyril-6-ylcarbamoyl) heptanoic acid hydroxyamide)
First, suberic acid monobenzyl ester was synthesized according to the following scheme.
In 20 ml eggplant-shaped flask, BnOH 62 mg (0.574 mmol, 1.0 eq.) Takes dissolved by adding _{CH 2 Cl 2 2 ml, suberic} acid 100 mg (0.574 mmol), DMAP 130 mg (1.148 mmol, 2.0 eq. ) And DCC 130 mg (0.631 mmol, 1.1 eq.) Were added to form a white suspension, which was stoppered and stirred overnight at room temperature. Evaporate and add 20 ml of 2N HCl. The mixture was extracted with AcOEt 30 ml × 3, washed successively with water 30 ml × 1, brine 30 ml × 1, and dried over anhydrous Na ₂ SO ₄ . Filtration through a Kiriyama funnel and evaporation gave 220 mg of white crude crystals. 5 ml of a mixed solution of n-hexane: AcOEt = 4: 1 was added for solid-liquid extraction, insoluble matter was filtered through a Kiriyama funnel, and washed with n-hexane. Evaporation gave 128 mg (0.484 mmol, y.84%) of a clear oil.

Next, 7- (3,4-dihydrocarbostyril-6-ylcarbamoyl) heptanoic acid benzyl ester was synthesized according to the following scheme.
In a 20 ml eggplant flask, suberic acid monobenzyl ester 128 mg (0.484 mmol, 1.0 eq.), 6-amino-3,4-dihydrocarbostyril 78 mg (0.484 mmol), HOBt 65 mg (0.484 mmol, 1.0 eq.), Et ₃ N 49 mg (0.484 mmol, 1.0 eq.), DMF 2 ml, EDCI · HCl 93 mg (0.484 mmol, 1.0 eq.) Were taken, stoppered and stirred at room temperature overnight. 30 ml of sat. NaHCO ₃ was added and extracted with 30 ml × 3 of AcOEt, washed successively with 30 ml × 1 of 2NHCl and 30 ml × 1 of brine, and dried over anhydrous Na ₂ SO ₄ . Filtration through a Kiriyama funnel and evaporation gave 209 mg of orange crude crystals. Purification by an open silica gel column (AcOEt only) gave 101 mg (0.247 mmol, y.51%) of pale orange crude crystals.

Next, in the same manner as in Example 1, 7- (3,4-dihydrocarbostyril-6-ylcarbamoyl) heptanoic acid hydroxyamide (Compound 23) shown in Table 3 was synthesized according to the following scheme.
colorless powder (AcOEt) .mp.196-197 ° C. ¹ H-NMR (300 MHz / DMSO / TMS) at δ1.26-1.28 (4H, m, CH ₂ × 2), 1.46-1.56 (4H, m, CH ₂ × 2), 1.94 (2H, t, J = 7.4 Hz, CH ₂ ), 2.25 (2H, t, J = 7.2 Hz, CH ₂ ), 2.41 (2H, t, J = 7.5 Hz, CH ₂ ) , 2.82 (2H, t, J = 8.6 Hz, 2.3 Hz, ArH), 6.76 (1H, d, J = 8.4 Hz, ArH), 7.29 (1H, dd, J = 8.6 Hz, 2.3 Hz, ArH), 7.43 (1H, d, J = 1.5 Hz, ArH), 8.65 (1H, s, ArH), 9.73 (1H, s, NH), 9.98 (1H, s, NH), 10.33 (1H, s, NOH). LRMS (ESI +) m / z 334 ([M + H] ⁺ ). LRMS (ESI-) m / z 332 ([MH]-).

Examples 24-32
Hydroxamic acid derivatives (compounds 24-32) listed in Table 3 were synthesized in the same manner as in Example 23 except that the raw materials were changed.

Example 33 (Synthesis of 4,4-dimethyl-3,4-dihydrocarbostyril-6-carboxylic acid 3- (2-hydroxycarbamoylvinyl) benzylamide)
First, 2- (3-bromobenzyl) isoindole-1,3-dione was synthesized according to the following scheme.
To a 50 ml eggplant flask, 1.00 g (4.001 mmol) of m-bromobenzyl bromide and 0.82 g (4.401 mmol, 1.1 eq.) Of phthalimide potassium salt were added, and 10 ml of DMF was added. A calcium chloride tube was attached, and the mixture was stirred for 8 hours and 30 minutes on an oil bath at 100 ° C. and allowed to cool. 50 ml of water was added and extracted with 50 ml × 3 AcOEt, washed with 50 ml × 1, 50 ml × 1, and dried over anhydrous Na ₂ SO ₄ . Filtration through a Kiriyama funnel and evaporation gave 1.27 g (4.018 mmol, y.100%) of white crude crystals.

Next, 3-bromobenzylamine was synthesized according to the following scheme.
In a 50 ml eggplant flask, take 317 mg (6.326 mmol, 2.0 eq.) Of H ₂ NNH ₂ and H ₂ O (100%), 10 ml of MeOH, 1.00 g of 2- (3-bromobenzyl) isoindole-1,3-dione (3.163 mmol) was added and the mixture was stirred on an oil bath at 90 ° C. for 1 hour and 30 minutes and allowed to cool. After evaporation, MeOH was distilled off and 4 ml of conc. HCl was added. The mixture was stirred for 1 hour and 30 minutes on an oil bath at 120 ° C. and allowed to cool. The insoluble material was filtered through a Kiriyama funnel and washed successively with 2N HCl and water. The filtrate was adjusted to pH 11 by adding 40 ml of 2N NaOH. Extracted with AcOEt 30 ml × 3, washed with water 30 ml × 1, brine 30 ml × 1, and dried over anhydrous Na ₂ SO ₄ . Filtration through a Kiriyama funnel and evaporation gave 557 mg (2.996 mmol, y.95%) of a pale yellow liquid.

Next, (3-bromobenzyl) carbamic acid t-butyl ester was synthesized according to the following scheme.
To a 20 ml eggplant flask, 500 mg (2.687 mmol) of 3-bromobenzylamine was taken, and CH ₂ Cl ₂ 5 ml and Et ₃ N 299 mg (2.956 mmol, 1.1 eq.) Were added and dissolved. Under stirring in an ice bath, Boc ₂ O (645 mg, 2.656 mmol, 1.1 eq.) Dissolved in CH ₂ Cl _{2 (} 4 ml) and washed CH ₂ Cl _{2 (} 2 ml) were added dropwise over 3 minutes. The ice bath was removed and the mixture was stirred overnight at room temperature. 30 ml of water was added, the organic layer was separated, the aqueous layer was extracted with 3 ml of CHCl ₃ 30 ml, and the organic layers were combined. The organic layer was washed successively with water 30 ml × 1, brine 30 ml × 1, and dried over anhydrous Na ₂ SO ₄ . Filtration through a Kiriyama funnel and evaporation gave 862 mg of a pale yellow oil. Purification was performed using an open silica gel column (n-hexane: AcOEt = 4: 1) to obtain 734 mg (2.566 mmol, y.95%) of white crude crystals.

Next, 3- [3- (tert-butoxycarbonylaminomethyl) phenyl] acrylic acid ethyl ester was synthesized according to the following scheme.
In a 20 ml eggplant flask, (3-bromobenzyl) carbamic acid t-butyl ester 100 mg (0.349 mmol), ethyl acrylate 38 mg (0.384 mmol, 1.1 eq.), P (o-tolyl) ₃ 21 mg (0.070 mmol, 0.2 eq.), EtCN 1.5 ml , DMF 0.4 ml, DIEA 0.13 ml (0.748 mmol, take 2.1 eq.), at room temperature under _{stirring, Pd (OAc) 2 8 mg} (0.035 mmol, a 0.1 eq.) was added It was. A nitrogen balloon, a three-way cock and a Jimroth were attached, and the nitrogen was simply replaced. The mixture was stirred at room temperature for 10 minutes as it was, then stirred on an oil bath at 90 ° C. for 7 hours and 30 minutes and allowed to cool. 30 ml of water was added, extraction was performed with AcOEt 30 ml × 3, washed successively with water 30 ml × 1, brine 30 ml × 1, and dried over anhydrous Na ₂ SO ₄ . Filtration through a Kiriyama funnel and evaporation gave 152 mg of a brown oil. Purification by an open silica gel column (n-hexane: AcOEt = 2: 1) gave 103 mg (0.337 mmol, y.96%) of a yellow oil.

Next, 3- (3-aminomethylphenyl) acrylic acid ethyl ester was synthesized according to the following scheme.
In a 20 ml eggplant flask, take 61 mg (0.200 mmol) of 3- [3- (tert-butoxycarbonylaminomethyl) phenyl] acrylic acid ethyl ester, add 1 ml of CH ₂ Cl _{2 and} 1 ml of TFA, and stir at room temperature for 1 hour. did. Evaporate to remove CH ₂ Cl ₂ and TFA, and add sat. NaHCO ₃ 30 ml. Extracted with AcOEt 30 ml × 3, washed with water 30 ml × 1, brine 30 ml × 1, and dried over anhydrous Na ₂ SO ₄ . Filtration through a Kiriyama funnel and evaporation gave 44 mg (quant. Y.) Of yellow oil.

Next, according to the following scheme, 3- [3-[[(4,4-dimethyl-2-oxo-1,2,3,4-tetrahydro-quinoline-6-carbonyl) amino] methyl] phenyl] acrylic acid Ethyl ester was synthesized.
In a 20 ml eggplant flask, 3- (3-aminomethylphenyl) acrylic acid ethyl ester 100 mg (0.487 mmol), 4,4-dimethyl-3,4-dihydrocarbostyril 107 mg (0.487 mmol, 1.0 eq.), HOBt 66 mg ( 0.4870 mmol, 1.0 eq.), DMF 2 ml, Et ₃ N 5 mg (0.487 mmol, 1.0 eq.), Add EDCI-HCl 93 mg (0.487 mmol, 1.0 eq.) And stirred overnight. 30 ml of water was added and extracted with 30 ml × 3 AcOEt, washed with 30 ml × 1, 30 ml × 1 water and dried over anhydrous Na ₂ SO ₄ . Filtration through a Kiriyama funnel and evaporation gave 296 mg of pale yellow crude crystals. Purification with an open silica gel column (n-hexane: AcOEt = 1: 4, then AcOEt only, then AcOEt: MeOH = 10: 1) gave 139 mg (0.342 mmol, y.70%) of white crude crystals. It was.

Next, according to the following scheme, 4,4-dimethyl-3,4-dihydrocarbostyril-6-carboxylic acid 3- (2-hydroxycarbamoylvinyl) benzylamide (Compound 33) described in Table 4 was synthesized.
3- [3-[[(4,4-dimethyl-2-oxo-1,2,3,4-tetrahydro-quinoline-6-carbonyl) amino] methyl] phenyl] acrylic acid ethyl ester 123 mg (0.304 mmol) taken up in 20 ml eggplant flask, a white suspension was added to MeOH 3 ml, stirring the solution at an _{ice-bath, NH 2 OH in water 50%} 0.19 ml (3.036 mmol, 10 eq.) for 1 minute with a syringe It was dripped over. The stopcock was put on, stirred for 10 minutes on an ice bath, the stopcock was removed, and NaOMe in MeOH 25% 0.35 ml (1.518 mmol, 5 eq.) Was added dropwise with a syringe over 4 minutes. The stopcock was put on, and the mixture was stirred for 1 hour and 30 minutes on an ice bath, and 2 ml of MeOH was added. Further, the mixture was stirred for 1 hour and 30 minutes on an ice bath, the ice bath was removed, 4 ml of MeOH was added, and the mixture was stirred overnight at room temperature. Evaporate to remove MeOH and add sat.NH ₄ Cl 20 ml. The insoluble material was collected by filtration with a Kiriyama funnel, washed successively with sat.NH ₄ Cl, water, a mixed solution of n-hexane: AcOEt = 1: 1, n-hexane, and air-dried. It moved to the eggplant flask and dried with the vacuum pump, and 89 mg (0.227 mmol, y.75%) of beige crude crystals were obtained. colorless powder (AcOEt / MeOH) .mp.159-163 ° C. ¹ H-NMR (300 MHz / DMSO / TMS) δ1.26 (6H, s, CH ₃ × 2), 2.39 (2H, s, CH ₂ ) , 4.49 (2H, d, J = 5.1 Hz, CH ₂ ), 6.46 (1H, d, J = 15.9 Hz, CH =), 6.92 (1H, d, J = 9.0 Hz, ArH), 7.33-7.60 (5H , m, ArH and CH =), 7.74 (1H, d, J = 9.0 Hz, ArH), 7.86 (1H, s, ArH), 9.01 (1H, s, NH), 10.39 (1H, s, NH). LRMS (ESI +) m / z 394 ([M + H] ⁺ ). LRMS (ESI-) m / z 392 ([MH] ^- ).

Examples 34-35
Hydroxamic acid derivatives (compounds 34 to 35) listed in Table 4 were synthesized in the same manner as in Example 33 except that the raw materials were changed.

Example 36 (Synthesis of 4,4-dimethyl-3,4-dihydrocarbostyril-6-carboxylic acid [trans-4- (2-hydroxycarbamoylvinyl) -cyclohexyl-methyl] amide)
First, (trans-4-benzyloxymethyloxycyclohexyl) methanol was synthesized according to the following scheme.
To a 20 ml eggplant flask, 42 mg (1.040 mmol, 0.5 eq.) Of NaH (60% in mineral oil) was taken, and 1 ml of DMF was added to form a white suspension, and a calcium chloride tube and a dropping funnel were attached. In an ice bath, with stirring, trans-1,4-cyclohexanedimethanol 300 mg (2.080 mmol) dissolved in DMF 1.5 ml and washed DMF 0.5 ml were added dropwise over 3 minutes. After stirring for 30 minutes on an ice bath, BnBr 178 mg (1.040 mmol, 1.5 eq.) Dissolved in DMF 1.5 ml and washed DMF 0.5 ml were added dropwise over 1 minute. The mixture was stirred for 1 hour and 30 minutes on the ice bath, removed from the ice bath and stirred overnight at room temperature. Further, the mixture was stirred for 2 hours on an oil bath at 60 ° C. and allowed to cool. 30 ml of water was added, extraction was performed with AcOEt 50 ml × 3, washed sequentially with water 30 ml × 1, brine 30 ml × 1, and dried over anhydrous Na ₂ SO ₄ . Filtration through a Kiriyama funnel and evaporation gave 340 mg of a clear oil. Purification with an open silica gel column (n-hexane: AcOEt = 2: 1) gave a clear oil of 177 mg (0.753 mmol, y.36%).

Next, trans-methanesulfonic acid trans-4-benzyloxymethylcyclohexylmethyl ester was synthesized according to the following scheme.
In a 20 ml eggplant flask, take 177 mg (0.753 mmol) of (trans-4-benzyloxymethyloxycyclohexyl) methanol, add CH ₂ Cl ₂ 1.8 ml, Et ₃ N 229 mg (2.260 mmol, 3.0 eq.), Dissolve, and add calcium chloride. A tube and dropping funnel were attached. On ice bath, with stirring, MsCl 104 mg (0.904 mmol, 1.2 eq.) Dissolved in CH ₂ Cl ₂ 1 ml and washed CH ₂ Cl ₂ 1 ml were added dropwise over 1 minute. The ice bath was removed and the mixture was stirred overnight at room temperature. 30 ml of water was added, and the mixture was extracted with 30 ml × 3 of CHCl ₃ , washed successively with 30 ml of water and 30 ml × 1 of brine, and dried over anhydrous Na ₂ SO ₄ . Filtration through a Kiriyama funnel and evaporation gave 250 mg of a yellow oil. Purification using an open silica gel column (φ = 2 cm, SiO ₂ = 20 g, fr. = 10 ml, n-hexane: AcOEt = 4: 1), and 199 mg (0.637 mmol, y.85%) of clear oil Obtained.

Next, 2- (trans-4-benzyloxymethylcyclohexylmethyl) isoindole-1,3-dione was synthesized according to the following scheme.
In a 20 ml eggplant flask, take 182 mg (0.582 mmol) of methanesulfonic acid trans-4-benzyloxymethyl cyclohexylmethyl ester and 108 mg (0.582 mmol, 1.0 eq.) Of phthalimide potassium salt, add 4 ml of DMF, and attach a calcium chloride tube. Stir overnight at room temperature. Further, the mixture was stirred for 1 hour in an oil bath at 80 ° C. and allowed to cool. 30 ml of water was added, extraction was performed with AcOEt 50 ml × 3, washed sequentially with water 30 ml × 1, brine 30 ml × 1, and dried over anhydrous Na ₂ SO ₄ . Filtration through a Kiriyama funnel and evaporation gave 325 mg of white crude crystals. Purification was performed with an open silica gel column (n-hexane: AcOEt = 4: 1) to obtain 184 mg (0.507 mmol, y.87%) of white crude crystals.

Next, (trans-4-azidomethylcyclohexylmethyl) benzene was synthesized according to the following scheme.
In a 20 ml eggplant flask, take 200 mg (0.640 mmol) of methanesulfonic acid trans-4-benzyloxymethyl cyclohexylmethyl ester, add 2 ml of DMF and 42 mg of NaN ₃ (0.640 mmol, 1.0 eq.) Stir overnight. Further, the mixture was stirred for 1 hour and 30 minutes on an oil bath at 80 ° C. and allowed to cool. 30 ml of water was added and the mixture was extracted with 30 ml × 3 AcOEt, washed successively with 30 ml × 1, 30 ml × 1 brine, and dried over anhydrous Na ₂ SO ₄ . Filtration through a Kiriyama funnel and evaporation gave 231 mg of a clear oil. Purification was performed with an open silica gel column (n-hexane: AcOEt = 5: 1) to obtain 184 mg (quant.y.) Of a clear oil.

Next, C- (trans-4-benzyloxymethylcyclohexyl) methylamine was synthesized according to the following scheme.
To a 100 ml glass autoclave, 1.57 g (6065 mmol) of (trans-4-azidomethylcyclohexylmethyl) benzene was taken, and 0.16 g of 10% Pd—C and 15 ml of EtOH were added to form a black suspension. After hydrogen substitution, catalytic hydrogen reduction was performed at room temperature at 0.18 MPa for 7 hours. The solution was leaked, filtered through a Kiriyama funnel, washed with MeOH, and then evaporated to obtain 1.36 g (5.807 mmol, y.96%) of white crude crystals.

Next, 4,4-dimethyl-3,4-dihydrocarbostyril-6-carboxylic acid (trans-4-benzyloxymethylcyclohexyl-methyl) amide was synthesized according to the following scheme.
In a 20 ml eggplant flask, (trans-4-benzyloxymethylcyclohexyl) methylamine 106 mg (0.456 mmol), 4,4-dimethyl-3,4-dihydrocarbostyril-6-carboxylic acid 100 mg (0.456 mmol, 1.0 eq.), HOBt 62 mg (0.456 mmol, 1.0 eq.), DMF 2 ml, Et ₃ N 46 mg (0.456 mmol, 1.0 eq.), EDCI / HCl 87 mg (0.456 mmol, 1.0 eq.) And stirred overnight. 30 ml of sat. NaHCO ₃ was added and extracted with 30 ml × 3 AcOEt, washed successively with 30 ml × 1N HCl and 30 ml × brine, and dried over anhydrous Na ₂ SO ₄ . Filtration through a Kiriyama funnel and evaporation gave 233 mg of an orange oil. Purification by an open silica gel column (n-hexane: AcOEt = 1: 4) gave 94 mg (0.215 mmol, y.47%) of white crude crystals.

Next, 4,4-dimethyl-3,4-dihydrocarbostyril-6-carboxylic acid (trans-4-hydroxymethylcyclohexyl-methyl) amide was synthesized according to the following scheme.
In a 100 ml glass autoclave, take 4,4-dimethyl-3,4-dihydrocarbostyril-6-carboxylic acid (trans-4-benzyloxymethylcyclohexylmethyl) amide 81 mg (0.185 mmol), 10% Pd-C 8 mg, EtOH 3 ml To give a black suspension. After hydrogen substitution, catalytic hydrogen reduction was performed at 0.30 MPa at room temperature for 7 hours. Leaked and filtered through Kiriyama funnel, washed with MeOH and evaporated to give 51 mg (0.149 mmol, y.80%) clear oil.

Next, 4,4-dimethyl-3,4-dihydrocarbostyril-6-carboxylic acid (trans-4-formylcyclohexylmethyl) amide was synthesized according to the following scheme.
In a 20 ml eggplant flask, take 4,4-dimethyl-3,4-dihydrocarbostyril-6-carboxylic acid (trans-4-hydroxymethylcyclohexylmethyl) amide 50 mg (0.145 mmol), add 1 ml of CH ₂ Cl ₂ and dissolve. A calcium chloride tube and a dropping funnel were attached. While stirring at room temperature, 68 mg (0.160 mmol, 1.1 eq.) Of Dess-Martin periodinane suspended in 2 ml of CH ₂ Cl _{2 and} 1 ml of washed CH ₂ Cl ₂ were added dropwise over 3 minutes. . The mixture was stirred overnight at room temperature, and a small amount of Na ₂ S ₂ O ₃ added to 30 ml of sat. NaHCO ₃ was added to the reaction solution. Extracted with CHCl ₃ 30 ml × 3, washed with brine 30 ml × 1, and dried over anhydrous Na ₂ SO ₄ . Filtration through a Kiriyama funnel and evaporation gave 41 mg (0.120 mmol, y.83%) of a clear oil.

Next, 3- [trans-4-[[(4,4-dimethyl-3,4-dihydrocarbostyril-6-carbonyl) amino] methyl] cyclohexyl] acrylic acid ethyl ester was synthesized according to the following scheme.
Take NaH (60% ni mineral oil) 5 mg (0.132 mmol, 1.1 eq.) In three 100 ml necks, attach a stopcock, septum, three-way cock, and Dimroth, and replace with nitrogen using a vacuum pump. 5 ml was added to give a white suspension. In an ice bath, with stirring, triethyl phosphonoacetate 30 mg (0.132 mmol, 1.1 eq.) Dissolved in THF 1 ml and washed THF 1 ml were added dropwise over 2 minutes. Stir for 15 minutes in an ice bath, and dissolve 4,4-dimethyl-3,4-dihydrocarbostyril-6-carboxylic acid (trans-4-formylcyclohexylmethyl) amide 41 mg (0.120 mmol) in 1 ml of THF. Then, 1 ml of washed THF was added dropwise over 4 minutes with stirring on an ice bath. The mixture was stirred for 6 hours on an ice bath and evaporated to remove THF. 30 ml of water was added and extracted with AcOEt 30 ml × 3, washed with brine 30 ml × 1, and dried over anhydrous Na ₂ SO ₄ . Filtration through a Kiriyama funnel and evaporation gave 49 mg of a white oil. Purification was performed with an open silica gel column (n-hexane: AcOEt = 1: 4) to obtain 33 mg (0.080 mmol, y.66%) of a white oil.

Next, in the same manner as in Example 1, according to the following scheme, 4,4-dimethyl-3,4-dihydrocarbostyril-6-carboxylic acid described in Table 5 [trans-4- (2-hydroxycarbamoylvinyl) -cyclohexyl- methyl] amide (Compound 36) was synthesized.
colorless cotton (n-hexane / AcOEt / MeOH) .mp.184-187 ° C. ¹ H-NMR (300 MHz / DMSO / TMS) δ1.01-1.06 (4H, m, CH ₂ × 2), 1.26 (6H , s, CH ₃ × 2), 1.52 (2H, bs, CH × 2), 1.73-1.80 (4H, m, CH ₂ × 2), 2.38 (2H, s, CH ₂ ), 3.11 (2H, t, J = 5.9 Hz, CH ₂ ), 5.70 (1H, d, J = 15.6 Hz, CH =), 6.59 (1H, dd, J = 15.5 Hz, 6.8 Hz, CH =), 6.89 (1H, d, J = 8.4 ArH), 7.67 (1H, d, J = 8.1 Hz, ArH), 7.79 (1H, s, ArH), 8.35 (1H, t, J = 5.6 Hz, NH), 10.34 (1H, s, OH). LRMS (ESI +) m / z 400 ([M + H] ⁺ ). LRMS (ESI-) m / z 398 ([MH] ^- ).

Example 37
Hydroxamic acid derivatives (Compound 37) shown in Table 5 were synthesized in the same manner as in Example 36 except that the raw materials were changed.

Example 38 (Synthesis of 4,4-Dimethyl-3,4-dihydrocarbostyril-6-carboxylic acid [trans-4- (2-hydroxycarbamoylethyl) -cyclohexylmethyl] amide)
First, 3- [trans-4-[[(4,4-dimethyl-3,4-dihydrocarbostyril-6-carbonyl) amino] methyl] cyclohexyl] propionic acid ethyl ester was synthesized according to the following scheme.
3- [trans-4-[[(4,4-dimethyl-3,4-dihydrocarbostyril-6-carbonyl) amino] methyl] cyclohexyl] acrylic acid ethyl ester 107 mg (0.260 mmol), 10% Pd-C 11 mg Was taken up in a 100 ml glass autoclave and 4 mg of MeOH was added to make a black suspension, which was purged with hydrogen and stirred at room temperature at 0.16 MPa for 3 days. Filtration through a Kiriyama funnel, washing with MeOH, and evaporation gave 100 mg of a clear oil. Purification was performed with an open silica gel column (n-hexane: AcOEt = 1: 4) to obtain 78 mg (0.188 mmol, y.72%) of a white oil.

Next, 4,4-Dimethyl-3,4-dihydrocarbostyril-6-carboxylic acid [trans-4- (2-hydroxycarbamoylethyl) cyclohexylmethyl] amide (Compound 38) shown in Table 6 was synthesized according to the following scheme.
Take 3- [trans-4-[[(4,4-dimethyl-3,4-dihydrocarbostyril-6-carbonyl) amino] methyl] cyclohexyl] propionic acid ethyl ester 105 mg (0.254 mmol) in a 20 ml eggplant flask, 2 ml of MeOH was added to dissolve. Under stirring in an ice bath, NH ₂ OH in water 50% 0.16 ml (2.538 mmol, 10 eq.) Was added dropwise with a syringe, the stopper was put on, and the mixture was stirred on an ice bath for 10 minutes. NaOMe in MeOH 25% 0.29 ml (1.269 mmol, 5 eq.) Was added dropwise with a syringe. The stopcock was put on, and the mixture was stirred on an ice bath for 2 hours, and 30 ml of sat.NH ₄ Cl was added. The precipitate was collected by filtration with a Kiriyama funnel, washed successively with water and n-hexane and air-dried. It moved to the eggplant flask and dried with the vacuum pump, and 91 mg of white crude crystals were obtained. On the other hand, the filtrate was extracted with AcOEt 30 ml × 2, washed with brine 30 ml × 1, and dried over anhydrous Na ₂ SO ₄ . Filtration through a Kiriyama funnel and evaporation gave 20 mg of white crude crystals. Both were combined and purified with an open silica gel column (AcOEt: MeOH = 5: 1) to obtain 81 mg (0.202 mmol, y.80%) of white crude crystals. colorless powder (AcOEt / MeOH) .mp.195-197 ° C. ¹ H-NMR (300 MHz / DMSO / TMS) δ0.81-0.88 (4H, m, CH ₂ × 2), 1.26 (6H, s, CH ₃ × 2), 1.37-1.42 (2H, m, CH ₂ ), 1.47 (2H, bs, CH × 2), 1.71-1.73 (4H, m, CH ₂ × 2), 1.95 (2H, t, J = 7.7 Hz, CH ₂ ), 2.38 (2H, s, CH ₂ ), 3.08 (2H, t, J = 6.3 Hz, NCH ₂ ), 6.88 (1H, d, J = 5.7 Hz, ArH), 7.66 (1H, dd, J = 8.4 Hz, 1.8 Hz, ArH), 7.68 (1H, d, J = 1.8 Hz, ArH), 8.32 (1H, t, J = 5.7 Hz, ArH), 8.65 (1H, s, NH), 10.34 (2H, s, OH and NH). LRMS (ESI +) m / z 402 ([M + H] ⁺ ). LRMS (ESI-) m / z 400 ([MH] ^- ).

Example 39
A hydroxamic acid derivative (Compound 39) shown in Table 6 was synthesized in the same manner as in Example 38 except that the raw materials were changed.

Example 40 (Synthesis of 7- (6-aminosulfonylcarbostyril) heptanohydroxamicaci)
First, 7-aminoheptanoic acid methyl ester hydrochloride was synthesized according to the following scheme.
In a 50 ml eggplant flask, 1.4 g (9.4 mmol) of 7-aminoheptanoic acid was taken, and 8.8 ml of MeOH was added to form a suspension in a nitrogen atmosphere. While stirring at room temperature, 1.2 ml (9.3 mmol, 1.0 eq.) Of trimethylchlorosilane was added, and the mixture was stirred as it was at room temperature for 16 hours. The reaction solution was distilled off under reduced pressure to obtain 1.9 g (9.0 mmol, y. 96%) of white crude crystals.

Next, 2-oxo-1,2-dihydroquinoline-6-sulfonyl chloride was synthesized according to the following scheme.
To a 30 ml eggplant flask, take 1.0 g (6.8 mmol) of 2-quinolinol and 3.0 ml (45 mmol, 6.6 eq.) Of chlorosulfonic acid, attach a three-way cock equipped with a nitrogen balloon, and stir for 3 hours on an oil bath at 65 ° C. did. After allowing to cool, the reaction solution was poured into ice water, and the precipitate was filtered with a Kiriyama funnel, washed with water, and air-dried. It moved to the eggplant flask and dried with the vacuum pump, and 1.1 g (4.6 mmol, y. 68%) of white crude crystals were obtained.

Next, 7- (6-aminosulfonylcarbostyril) heptanoicacid methyl ester was synthesized according to the following scheme.
In a 30 ml eggplant flask, take 142 mg (0.73 mmol, 1.3 eq.) Of 7-aminoheptanoic acid methyl ester hydrochloride, add 2.0 ml of CH ₂ Cl ₂ and dissolve, and dissolve in 2-oxo-1,2-dihydroquinoline-6-sulfonyl. a suspension by adding chloride 138 mg of (0.57 mmol), followed by _{Et 3 N 114 mg (3.24 mmol} , 5.7 eq.) and the _{CH 2 Cl 2 CH 2 Cl 2} 0.5 ml inclusive washing as dissolved in 0.5 ml It was dripped with a syringe. White smoke was generated during the dropping process, and the reaction liquid changed to a pink suspension. This suspension was stirred at room temperature for 16 hours, 10 ml of water, 10 ml of AcOEt, and 2 ml of n-hexane were sequentially added to the reaction solution, and the precipitate was collected by filtration with a Kiriyama funnel, washed with water and air-dried. It moved to the eggplant flask and dried with the vacuum pump, and 127 mg (0.35 mmol, y. 61%) of pink coarse crystals were obtained.

Next, 7- (6-aminosulfonylcarbostyril) heptanohydroxamicacid (compound 40) shown in Table 7 was synthesized according to the following scheme.
In a 50 ml eggplant flask, 44 mg (0.12 mmol) of 7- (aminosulfonylcarbostyril) heptanoicacid methyl ester was taken and dissolved by adding 1.5 ml of MeOH. Under stirring in an ice bath, 0.10 mL (1.7 mmol, 14.2 eq.) Of NH ₂ OH (50% in water) was added dropwise with a syringe, and the stopcock was put on. After stirring for 5 minutes on an ice bath, 0.20 ml (0.82 mmol, 6.8 eq.) Of NaOMe (25% in MeOH,) was added dropwise with a syringe, followed by stirring for 2 hours on an ice bath. After adding 15 ml of sat.NH ₄ Cl and stirring for 15 minutes under ice cooling, the white precipitate was collected by filtration with a Kiriyama funnel, washed successively with 10 ml of sat.NH ₄ Cl and 10 ml of water, and dried under reduced pressure at 50 ° C. As a result, 36 mg of white crude crystals were obtained. To this crude crystal, 2.0 ml of MeOH was added to make a suspension, stirred at room temperature for 1 hour, and filtered through a Kiriyama funnel. , Washed sequentially with MeOH, CHCl ₃ and air dried. It moved to the eggplant flask and dried with the vacuum pump, and white crude crystal 9.3 mg (0.025 mmol, y. 21%) was obtained. colorless powder (MeOH). mp. Unknown (carbonized at 242 ° C). ¹ H-NMR (300 MHz / DMSO / TMS) δ1.08-1.24 (4H, m, CH ₂ CH ₂ ), 1.32-1.47 (4H, m, CH ₂ CH ₂ ), 1.89 (2H, t, J = 7.4 Hz, C (O) CH ₂ ), 2.72-2.74 (2H, m, NCH ₂ ), 6.61 (1H, d, J = 9.6 Hz, CH = CH), 7.43 (1H, d, J = 8.7 Hz ArH), 7.52 (1H, br, NH), 7.84 (1H, dd, J = 8.7, 1.8 Hz ArH), 8.07 (1H, d, J = 9.6 Hz, CH = CH), 8.62 (1H, d, J = 1.8 Hz, ArH), 8.96 (1H, br, OH), 10.31 (1H, br, NH).

Examples 41-42
Hydroxamic acid derivatives (compounds 41 to 42) shown in Table 7 were synthesized in the same manner as in Example 40 except that the raw materials were changed.

Example 43 (Synthesis of 7- (6-sulfonylamino-3,4-dihydrocarbostyril) heptanohydroxamicacid)
First, 7- (chlorosulfonyl) heptanoic acid methyl ester was synthesized according to the following scheme.
In a 20 ml eggplant flask, 800 mg (3.6 mmol) of 7-bromoheptanoic acid methyl ester, 580 mg of Na ₂ SO ₃ (4.6 mmol, 1.3 eq.) And 3.6 ml of water were taken and heated to reflux on an oil bath for 17 hours. . The mixture was allowed to cool, filtered through a Kiriyama funnel, washed with Et ₂ O 10 ml × 3, and air-dried. It transferred to the eggplant flask and dried with a vacuum pump to obtain 1.4 g of white crude crystals. The obtained crude crystals were used for the next reaction without purification after confirming that the substrate pass-through rate reached> 99% by ¹ H-NMR.

Next, 7- (6-sulfonylamino-3,4-dihydrocarbostyril) heptanoicacid methyl ester was synthesized according to the following scheme.
Add 10 g (4.6 mmol) of 7- (chlorosulfonyl) heptanoic acid methyl ester to a vial for 10-20 mL MW reaction, add 8.0 ml of acetone to make a suspension, and add 926 mg (5.0 mmol, 1.1 eq.) Of trichlorotriazine. added. Next, Et ₃ N 530 mg (5.2 mmol, 1.1 eq.) Dissolved in acetone 1.0 ml and washed acetone 1.0 ml were added dropwise over 5 minutes with a syringe. The reaction solution became a pale yellow suspension. This suspension was heated at 80 ° C. for 20 minutes using a microwave synthesizer (InitiatorTM Eight, Biotage) and then air-cooled. The contents were filtered through Celite, and the filtrate was filtered with 2N NaOH 3.0 ml, THF 2.5 ml, 6- Amino-3,4-dihydrocarbostyril 800 mg (4.9 mmol, 1.1 eq.) was added, and the mixture was heated at 80 ° C. for 20 minutes using a microwave synthesizer. After air cooling, the contents were filtered through Celite, 15 ml of water and 15 ml of AcOEt were added to the filtrate, and the organic layer was separated. The aqueous layer was extracted with AcOEt 10 ml × 3, and the organic layers were combined. The organic layer was washed with brine 15 ml × 2. Dried over anhydrous Na ₂ SO ₄ . The residue obtained by filtration through a Kiriyama funnel and evaporation was purified by silica gel column chromatography (AcOEt: MeOH = 7: 1) to obtain 223 mg (0.62 mmol, y. 13%) of pale pink crude crystals.

Next, 7- (6-sulfonylamino-3,4-dihydrocarbostyril) heptanohydroxamicacid (compound 43) described in Table 8 was synthesized according to the following scheme.
In 30 ml recovery flask, 7- take (6-sulfonylamino-3,4-dihydrocarbostyril ) heptanoicacid methyl ester 136 mg (0.37 mmol), dissolved by addition of MeOH 3.3 ml, on an ice bath, under stirring, NH ₂ OH ( 503 in water) 0.23 ml (3.5 mmol, 9.5 eq.) Was added dropwise with a syringe, and the stopcock was put on. After stirring for 5 minutes on the ice bath, 0.41 mL (1.8 mmol, 4.9 eq.) Of NaOMe (25% in MeOH) was added dropwise with a syringe, and the stirring was continued for 2 hours on the ice bath. Then, 20 mL of sat.NH ₄ Cl was added, and the mixture was stirred for 15 minutes under ice-cooling. The reaction solution was filtered through a Kiriyama funnel, washed successively with 10 ml of sat.NH ₄ Cl, 10 ml of water, and 10 ml of CHCl _3. The layers were separated and washed with 10 ml AcOEt and 2.0 mL 1N HCl was added. The white precipitate was collected by filtration with a Kiriyama funnel, washed sequentially with 10 ml of water and 2.0 ml of 1N HCl, and dried under reduced pressure while heating to 50 ° C. to obtain 60 mg (0.16 mmol, y. 44%) of white crude crystals. It was. colorless powder (H ₂ O) .mp. 133-135 ° C. ¹ H-NMR (300 MHz / DMSO / TMS) δ1.16-1.36 (4H, m, CH ₂ CH ₂ ), 1.39-1.49 (2H, m , CH ₂ ), 1.58-1.68 (2H, m, CH ₂ ), 1.91 (2H, t, J = 7.4 Hz, CH ₂ ), 2.39-2.44 (2H, m, CH ₂ ), 2.83 (2H, t, J = 7.5 Hz, C (O) CH ₂ ), 2.95-3.00 (2H, m, NCH ₂ ), 6.80 (1H, d, J = 8.4 Hz, ArH), 6.96-7.00 (2H, m, ArH), 7.24 (1H, br, NH), 8.67 (1H, br, NH), 10.04 (1H, br, OH), 10.35 (1H, br, NH).

Reference Example 1 (Synthesis of 7- (3,4-dihydrocarbostyril-6-ylcarbamoyl) heptanoic acid N-hydroxy-N-methylamide)
According to the following scheme, 7- (3,4-dihydrocarbostyril-6-ylcarbamoyl) heptanoic acid N-hydroxy-N-methylamide (Compound 44) shown in Table 9 was synthesized.

Reference Example 2 (Synthesis of 7- (3,4-dihydrocarbostyril-6-ylcarbamoyl) heptanoic acid N-hydroxy-N-methylamide)
According to the following scheme, 7- (3,4-dihydrocarbostyril-6-ylcarbamoyl) heptanoic acid N-hydroxy-N-methylamide (Compound 45) shown in Table 10 was synthesized.

Reference Example 3 (Synthesis of 7- (3,4-dihydrocarbostyril-6-ylcarbamoyl) heptanoic acid N-hydroxy-N-methylamide)
According to the following scheme, 7- (3,4-dihydrocarbostyril-6-ylcarbamoyl) heptanoic acid N-hydroxy-N-methylamide (Compound 46) shown in Table 11 was synthesized.

Reference Example 4 (Synthesis of 7-[(4,4-dimethyl-3,4-dihydrocarbostyril-6-carbonyl) amino] heptanoic acid N-hydroxyl-N-ethylamide)
According to the following scheme, 7-[(4,4-dimethyl-3,4-dihydrocarbostyril-6-carbonyl) amino] heptanoic acid N-hydroxyl-N-ethylamide (Compound 47) shown in Table 12 was synthesized.

Reference Example 5 (Synthesis of 7-[(4,4-dimethyl-3,4-dihydrocarbostyril-6-carbonyl) amino] heptanoic acid N-hydroxyl-N-isopropylamide)
7-[(4,4-dimethyl-3,4-dihydrocarbostyril-6-carbonyl) amino] heptanoic acid N-hydroxyl-N-isopropylamide (Compound 48) described in Table 13 was synthesized according to the following scheme.

Reference Example 6 (Synthesis of suberoylanilide hydroxamic acid (SAHA))
First, 7-phenylcarbamoylheptanoic acid benzyl ester was synthesized according to the following scheme.
In a 50 ml eggplant flask, suberic acid monobenzyl ester 851 mg (3.221 mmol, 1.0 eq.), Aniline 300 mg (3.221 mmol), EDCI ・ HCl 618 mg (3.221 mmol, 1.0 eq.), HOBt 435 mg (3.221 mmol, 1.0 eq.), Et ₃ N 326 mg (3.221 mmol, 1.0 eq.), And DMF 13 ml were taken, stoppered and stirred at room temperature overnight. 30 ml of sat. NaHCO ₃ was added, extracted with AcOEt 30 ml × 3, washed successively with water 30 ml × 1, 2NHCl 30 ml × 1, brine 30 ml × 1, and dried over anhydrous Na ₂ SO ₄ . Filtration through a Kiriyama funnel and evaporation gave 1.058 g of white crude crystals. Purification by an open silica gel column (n-hexane: AcOEt = 2: 1) gave 942 mg (2.775 mmol, y.86%) of white crude crystals.

Next, according to the following scheme, suberoylanilide hydroxamic acid (compound 49) described in Table 14 was synthesized.
In a 20 ml eggplant flask, 300 mg (0.884 mmol) of 7-phenylcarbamoylheptanoic acid benzyl ester was taken and dissolved by adding 2 ml of MeOH. Stirring the solution at an _{ice-bath, NH 2 OH in water 50%} 0.54 ml (8.838 mmol, 10 eq.) Was added dropwise over 1 min via syringe. Since it precipitated in the middle, 1 ml of MeOH was added to stop the cock, and the mixture was stirred on an ice bath for 5 minutes, and NaOMe in MeOH 25% 1.01 ml (4.419 mmol, 5 eq.) Was added dropwise over 1 minute with a syringe. It became a solution. The stopper was put on, and the mixture was stirred for 2 hours on an ice bath, and 20 ml of sat.NH ₄ Cl was added. It became cloudy. The mixture was diluted with 10 ml of water, filtered through a Kiriyama funnel, washed successively with water and n-hexane, and air-dried. It moved to the eggplant flask and dried with the vacuum pump, and white crude crystal 179 mg (0.675 mmol, y.76%) was obtained. colorless powder (n-hexane / AcOEt / MeOH) .mp.158-159 ° C. ¹ H-NMR (300 MHz / DMSO / TMS) δ1.26-1.29 (4H, m, CH ₂ × 2), 1.44-1.51 (2H, m, CH ₂ ), 1.55-1.60 (2H, m, CH ₂ ), 1.94 (2H, t, J = 7.4 Hz, CH ₂ ), 2.29 (2H, t, J = 7.4 Hz, CH ₂ ) , 7.01 (1H, t, J = 7.4 Hz, ArH), 7.27 (2H, t, J = 7.8 Hz, ArH), 7.59 (2H, d, J = 7.5 Hz, ArH), 8.66 (1H, s, NH ), 9.88 (1H, s, NH), 10.35 (1H, s, NOH). LRMS (ESI +) m / z 265 ([M + H] ⁺ ). LRMS (ESI-) m / z 263 ([MH] ^- ).

Test Example 1 (Measurement of histone deacetylase inhibitory activity)
About each of the compounds 1-49 obtained in Examples 1-43 and Reference Examples 1-6, Yoshida M et al. Cancer Chemother Pharmacol. 48 (Suppl1): According to the method described in S20, 2001, histone deacetylase inhibitory activity (%) was measured at the compound concentrations of 0.1 μM and 10 μM, respectively, under the following conditions (n = 2). In this test, since a mixture of HDAC1 to 11 (manufactured by rat river HDACs Merck) is used as the histone deacetylase, compounds that inhibit nonspecifically the histone deacetylase subtype are A histone deacetylase inhibitory activity (%) has a high value, and a compound that specifically inhibits a histone deacetylase subtype has a low histone deacetylase inhibitory activity (%).

Incubation buffer: 25 mM Tris-HCL, 137 mM NaCl, 2.7 mM KCl, 1 mM MgCl ₂ , pH 8.0
Assay:
Compound (1% DMSO ^* ) 1 μl
Histone deacetylase (32 μg / ml ^* ) 50 μl
Boc-Lys (Ac) -AMC (250 μM ^* ) 50 μl
* Final concentration Procedure:
1. Mix compound with histone deacetylase.
2. Immediately read the fluorometer value as background.
3. Pre-incubate for 15 minutes at 37 ° C.
4). To start the reaction, warm Boc-Lys (Ac) -AMC is added.
5. Seal and incubate at 37 ° C. for 30 minutes.
6). Add 10 μl diluted Developer Concentrate to quench the reaction.
7. Place at 37 ° C. for 1 hour.
8). The value of the fluorometer is read (excitation light: 360 nm, emission: 465 nm).

The results obtained are shown in Table 15. From the results of Test Example 1, all of the compounds of Examples exhibit histone deacetylase inhibitory activity, and in particular, the compounds of Examples 12 to 39 in which the group X is —CONH— or —NHCO— have extremely high activity. It was high and had an activity equal to or higher than that of the compound of Reference Example 6 which is a known histone deacetylase inhibitor.

Test Example 2 (Evaluation of histone deacetylase inhibitory activity)
Examples 12, 13, 23, 24, 36 and Reference Examples using HDAC1-11 (see Cancer Letters 277 (2009) 8-21), which have been identified as histone deacetylases, to date alone With respect to the compounds 12, 13, 23, 24, 36 and 49 obtained in 6, the 50% inhibitory concentrations (IC ₅₀ values) of these compounds against the respective HDACs 1 to 11 were measured. The 50% inhibitory concentration (IC50 value) was determined by using HDAC-Glo ^™ I / II Assay and Screening System G6420 manufactured by Promega as a measurement kit. / 50 ml μl was calculated based on histone deacetylase inhibitory activity (n = 3 or more).

The obtained results are shown in Table 16. From the results of Test Example 2, it can be seen that when the group X has a structure represented by -CONH- and -NHCO-, HDAC1, HDAC2, and HDAC8 have high activity.

Claims (13)

A hydroxamic acid derivative represented by the following general formula (A) or a salt thereof.
[In the general formula (A), the group A is an oxygen atom, a nitrogen atom, or —NR ⁶ —.
When the group A is an oxygen atom or —NR ⁶ —, the bond between the first-position group A and the second-position carbon atom of the heterocyclic ring is a single bond, and when the group A is a nitrogen atom, The bond between the carbon atom at the 1st position and the carbon atom at the 2nd position of the ring is a double bond. The group R ⁶ is a lower alkyl group which may have a substituent, or a hydrogen atom.
The group B is an oxygen atom or an optionally substituted lower alkoxy group. When the group B is an oxygen atom, the bond between the group B and the carbon atom at the 2-position of the heterocyclic ring is double. When it is a bond and the group B is an optionally substituted lower alkoxy group, the bond between the group B and the carbon atom at the 2-position of the heterocyclic ring is a single bond.
The group R ¹ and the group R ³ are each independently a hydrogen atom or an optionally substituted lower alkyl group, or either the group R ¹ or the group R ³ is substituted with the group X. Yes.
The group R ² and the group R ⁴ are each independently a hydrogen atom or a lower alkyl group which may have a substituent, or bonded to each other to form a 3-position carbon atom and a 4-position carbon. It forms a double bond with the atom.
The group R _n ⁵ is n = 0 to 3 substituents substituted with hydrogen atoms on the benzene ring to which the heterocycle is condensed, and each independently has a halogen atom or a substituent. A good lower alkyl group.
The group X is substituted with a hydrogen atom on the benzene ring, a hydrogen atom on the heterocyclic ring, or one of the group R ¹ and the group R ³ , and the group X is a single bond, an oxygen atom, —CONH -, - NHCO -, - SO 2 NH-, or -NHSO ₂ - a.
The group Y is a single bond, a saturated or unsaturated alkylene group having 1 to 10 carbon atoms, or a group —Y ¹ —Y ² —Y ³ —. The group Y ¹ is a saturated or unsaturated alkylene group having 1 to 6 carbon atoms, or a single bond. The group Y ² is an optionally substituted phenylene group or an optionally substituted cyclohexylene group. The group Y ³ is a saturated or unsaturated alkylene group having 1 to 6 carbon atoms. ] In the general formula (A), the group R ¹ and the group R ³ are each independently a hydrogen atom or a lower alkyl group which may have a substituent, and the group X is a hydrogen atom on the benzene ring. substituted and the group X is a single bond, an oxygen atom, -CONH -, - NHCO -, - SO 2 NH-, or -NHSO ₂ - and is, hydroxamic acid derivative or salt thereof according to claim 1. A hydroxamic acid derivative represented by the following general formula (A1) or a salt thereof,
In the general formula (A1), the group R ⁶ is a methyl group or a hydrogen atom,
The group R ¹ is a hydrogen atom or a methyl group, the group R ³ is a hydrogen atom, the group R ² is a hydrogen atom or a methyl group, or is bonded to the group R ⁴ to form a 3 A carbon atom at the position and a carbon atom at the 4th position, and the group R ⁴ is a hydrogen atom or bonded to the group R ² to form a carbon atom at the 3rd position of the heterocyclic ring. Forming a double bond with the 4-position carbon atom,
The group R ⁵ is a hydrogen atom or a fluorine atom;
Group X is substituted with a hydrogen atom on the benzene ring, the group X represents an oxygen atom, -CONH -, - NHCO -, - SO 2 NH-, or -NHSO ₂ - and is,
The group Y is a saturated or unsaturated alkylene group having 3 to 7 carbon atoms, or a group —Y ¹ —Y ² —Y ³ —, and the group Y ¹ is a saturated or unsaturated alkylene group having 2 carbon atoms ( a -CH = CH-, group Y ² is a phenylene group or a cyclohexylene group, group Y ³ is a methylene group, a hydroxamic acid derivative or salt thereof according to claim 2. A hydroxamic acid derivative represented by the following general formula (A2) or a salt thereof,
In the general formula (A2), the group R ¹ is a hydrogen atom or a methyl group, the group R ³ is a hydrogen atom, and the group R ² is a hydrogen atom or a methyl group, or is bonded to the group R ^4. A double bond is formed between the carbon atom at the 3rd position and the carbon atom at the 4th position of the heterocyclic ring, and the group R ⁴ is a hydrogen atom or bonded to the group R ² to form the heterocyclic ring. Forming a double bond between the 3-position carbon atom and 4-position carbon atom of
The group R ⁷ is a methyl group or an ethyl group,
The group X is substituted with a hydrogen atom on the benzene ring, the group X is an oxygen atom, -CONH-, or -NHCO-;
The hydroxamic acid derivative or a salt thereof according to claim 2, wherein the group Y is a saturated or unsaturated alkylene group having 3 to 7 carbon atoms. A hydroxamic acid derivative represented by the following general formula (A3) or a salt thereof,
In the general formula (A3), the group X is substituted with a hydrogen atom on the benzene ring, the group X is an oxygen atom, -CONH-, or -NHCO-,
The hydroxamic acid derivative or a salt thereof according to claim 2, wherein the group Y is a saturated or unsaturated alkylene group having 3 to 7 carbon atoms.   The pharmaceutical composition containing the hydroxamic acid derivative or its salt in any one of Claims 1-5.   The histone deacetylase inhibitor which uses the hydroxamic acid derivative in any one of Claims 1-5, or its salt as an active ingredient. The antitumor agent which uses the hydroxamic acid derivative in any one of Claims 1-5, or its salt as an active ingredient. A method for producing a hydroxamic acid derivative represented by the following general formula (Aa) or a salt thereof,
[In General Formula (Aa), group A, group B, groups R ^{1 to} R ⁴ , group R _n ⁵ , and group Y are the same as in general formula (A). ]
Step 1 of synthesizing the following compound D3 by a coupling reaction of the following compound D1 and the following compound D2 represented by the following scheme 1:
[In Scheme 1, M is an alkyl group or a benzyl group, X ¹ is a halogen atom, the group A, the group B, the groups R ^{1 to} R ⁴ , the group R _n ⁵ , and the group Y are represented by the general formula Same as (A). ]
Step 2 of converting the ester group of the compound D3 represented by the following Scheme 2 to a hydroxamic acid group by reacting with NH ₂ OH;
[In the scheme 2, the group M is the same as that in the scheme 1, and the group A, the group B, the groups R ^{1 to} R ⁴ , the group R _n ⁵ , and the group Y are the same as those in the general formula (A). ]
A process for producing a hydroxamic acid derivative represented by the general formula (Aa) or a salt thereof. A method for producing a hydroxamic acid derivative represented by the following general formula (Ab) or a salt thereof,
[In the general formula (Ab), the group A, the group B, the groups R ^{1 to} R ⁴ , the group R _n ⁵ , and the group Y are the same as those in the general formula (A). ]
Step 1 for synthesizing Compound D6 by a coupling reaction of Compound D4 and Compound D5 shown below in Scheme 3;
[In scheme 3, M is an alkyl group or a benzyl group, and group A, group B, groups R ^{1 to} R ⁴ , group R _n ⁵ , and group Y are the same as those in formula (A). ]
Step 2 of converting the ester group of compound D6 represented by the following Scheme 4 to a hydroxamic acid group by reacting with NH ₂ OH;
[In the scheme 4, the group M is the same as that in the scheme 3, and the group A, the group B, the groups R ^{1 to} R ⁴ , the group R _n ⁵ , and the group Y are the same as those in the general formula (A). ]
A process for producing a hydroxamic acid derivative represented by the general formula (Ab) or a salt thereof. A method for producing a hydroxamic acid derivative represented by the following general formula (Ac) or a salt thereof,
[In General Formula (Ac), group A, group B, groups R ^{1 to} R ⁴ , group R _n ⁵ , and group Y are the same as in general formula (A). ]
Step 1 for synthesizing Compound D9 represented by the following Scheme 5 by a coupling reaction between Compound D7 and Compound D8,
[In scheme 5, M is an alkyl group or a benzyl group, and the group A, the group B, the groups R ^{1 to} R ⁴ , the group R _n ⁵ , and the group Y are the same as those in the general formula (A). ]
Step 2 of converting the ester group of the following compound D9 represented by the following Scheme 6 into a hydroxamic acid group by reacting with NH ₂ OH;
[In scheme 6, group M is the same as scheme 5, and group A, group B, groups R ^{1 to} R ⁴ , group R _n ⁵ , and group Y are the same as in general formula (A). ]
A process for producing a hydroxamic acid derivative represented by the general formula (Ac) or a salt thereof, comprising: A method for producing a hydroxamic acid derivative represented by the following general formula (Ad) or a salt thereof,
[In General Formula (Ad), group A, group B, groups R ^{1 to} R ⁴ , group R _n ⁵ , and group Y are the same as in general formula (A). ]
Step 1 of synthesizing Compound D12 represented by the following Scheme 7 by a coupling reaction of Compound D10 and Compound D11 below;
[In Scheme 7, the group M is an alkyl group or a benzyl group, and the group A, the group B, the groups R ^{1 to} R ⁴ , the group R _n ⁵ , and the group Y are the same as those in the general formula (A). ]
Step 2 of converting the ester group of the following compound D12 represented by the following Scheme 8 into a hydroxamic acid group by reacting with NH ₂ OH;
[In scheme 8, the group M is the same as in scheme 7, and the group A, the group B, the groups R ^{1 to} R ⁴ , the group R _n ⁵ , and the group Y are the same as those in the general formula (A). ]
A process for producing a hydroxamic acid derivative represented by the general formula (Ad) or a salt thereof, comprising: A method for producing a hydroxamic acid derivative represented by the following general formula (Ae) or a salt thereof,
[In the general formula (Ae), the group A, the group B, the groups R ^{1 to} R ⁴ , the group R _n ⁵ , and the group Y are the same as those in the general formula (A). ]
Step 1 of synthesizing Compound D15 represented by the following Scheme 9 by a coupling reaction of Compound D13 and Compound D14 below;
[In the scheme 9, the group M is an alkyl group or a benzyl group, and the group A, the group B, the groups R ^{1 to} R ⁴ , the group R _n ⁵ , and the group Y are the same as those in the general formula (A). ]
Represented by the following Scheme 10, is reacted with NH ₂ OH to an ester group of the following compounds D15, and step 2 of converting a hydroxamic acid group,
[In scheme 10, group M is the same as in scheme 9, and group A, group B, groups R ^{1 to} R ⁴ , group R _n ⁵ , and group Y are the same as in general formula (A). ]
The manufacturing method of the hydroxamic acid derivative represented by general formula (Ae) or its salt containing these.