JPH08311032A - Alpha,beta-unsaturated ketone derivative - Google Patents

Abstract

PURPOSE: To obtain the subject compound exhibiting an excellent interleukin production-inhibiting action and useful for medicines for preventing and treating syndromes mediated with the interleukin 1. CONSTITUTION: A compound of formula I the ring A is a group of formula II [the ring B is a (substituted) aromatic ring; R<2> is H, a halogen, (halogenated) lower alkyl, (heterogeneous atom-containing) cycloalkyl, a (substituted) (hetero) aryl(alkyl), etc.; R<3> is H, a (halogenated) lower alkyl, a (heterogeneous atom- containing) cycloalkyl, an alkoxyalkyl, etc.,], a group of formula III, etc.; R<1> is a group of formula IV [R<4> , R<5> are H, a (halogenated) lower alkyl, a (heterogeneous atom-containing) cycloalkyl, etc.; R<6> is H, a (halogenated) lower alkyl, a (heterogeneous atom-containing) cycloalkyl, etc.,], etc.,}, its salt. For example, 1,4-dihydroxy-7-ethyl-2-(4-hydroxy-4-methyl-3-oxo-1-pentenyl)-4-oxo-3, 5,8- trimethoxyquionline.

Description

Detailed Description of the Invention

[0001]

The present invention relates to an α, β-unsaturated ketone derivative having a novel structure, a drug containing the α, β-unsaturated ketone derivative and an α, β-unsaturated ketone derivative. To an intermediate useful in.

[0002]

BACKGROUND OF THE INVENTION and Prior Art Interleukin 1 (hereinafter referred to as IL-1) is a physiologically active protein produced by macrophages, monocytes, neutrophils, etc., and is involved in the maintenance of homeostasis in the living body. On the other hand, when its production is increased, abnormal immune response, inflammatory reaction, etc. are induced, which adversely affects the living body. IL-1 includes various inflammatory cytokines, lymphokines, collagenase and prostaglandin E.
_It induces the production of ₂ etc. and is considered to be a central factor of inflammation and the immune system. In clinical practice, the relationship with autoimmune diseases such as rheumatoid arthritis and inflammatory diseases is becoming clear.

According to a recent report, IL-1 was detected in synovial fluid of patients with rheumatoid arthritis, and IL-1 level in plasma of rheumatoid arthritis was comparable to that in plasma of healthy subjects. The IL-1 level increases and decreases significantly depending on the exacerbation of symptoms and remission, and the L-1 production from synovial tissue depends on the degree of inflammation of synovial tissue and the degree of bone destruction of joints. It is known to be correlated. Therefore, the present inventors mainly suppress the production of IL-1,
We tried to treat and prevent autoimmune diseases such as rheumatoid arthritis and diseases such as inflammatory diseases.

[0004]

[Problems to be Solved by the Invention] Rheumatoid arthritis is a chronic inflammatory disease of unknown cause, and non-steroidal anti-inflammatory drugs and steroid drugs are used as drug treatments. Non-steroidal anti-inflammatory agents typified by indomethacin have an analgesic action, but do not show any improvement in the progression of disease state, and do not suppress the production of IL-1. On the other hand, a steroid drug suppresses the production of inflammatory cytokines typified by IL-1 as one of its pharmacological actions and exhibits a strong anti-inflammatory effect, but its utility is not sufficient in terms of side effects. Therefore, it has been desired to develop a drug that exerts an IL-1 production inhibitory action and prevents and treats IL-1-mediated symptoms. The present inventors have found that IL-
As a result of earnestly investigating the compound having the production suppressing action of No. 1, the inventors have found that the α, β-unsaturated ketone derivative shown below has an excellent action and completed the present invention. JP-A-2-256665 discloses a group of compounds having an antagonistic action on leukotriene D ₄ as a quinoline derivative, but there is no example reported as an IL-1 production inhibitor, and the invention of the present application Such compounds have a structure different from the compounds disclosed in the above publications. Further, in WO93 / 07124,
Although a nitrogen-containing heterocyclic compound having a phosphodiesterase inhibitory action is disclosed, there is no description that the nitrogen-containing heterocyclic compound disclosed in the publication has an IL-1 production inhibitory action or a suggestion for this, and there is no disclosure. The disclosed compound group has a different structure from the compound group of the present application.

[0005]

The present invention is an α, β-unsaturated ketone derivative represented by the following general formula (I) or a pharmaceutically acceptable salt thereof.

[Chemical 7] {In the formula, the ring portion A is a formula

Embedded image [In formula, ring B represents the aromatic ring which may have a substituent.
R ² represents a hydrogen atom, a halogen atom, a lower alkyl group optionally substituted with a halogen atom, a cycloalkyl group optionally containing a hetero atom, an aryl group optionally having a substituent, or a substituent. A heteroaryl group which may have, an arylalkyl group which may have a substituent,
A heteroarylalkyl group which may have a substituent,
Formula -X-R < ¹⁴ > (In formula, X is group represented by formula -O- or formula> S = (O) _n (In formula, n means the integer of 0 or 1-2). R ¹⁴ represents a hydrogen atom, a lower alkyl group which may be substituted with a halogen atom, an alkoxyalkyl group, an aryl group which may have a substituent, or a substituent which may have a substituent. A heteroaryl group, an arylalkyl group which may have a substituent or a heteroarylalkyl group which may have a substituent)), an alkoxyalkyl group,
It means an alkoxyalkoxyalkyl group or an aminoalkyl group which may be mono- or di-substituted. R
³ is a hydrogen atom, a lower alkyl group optionally substituted by a halogen atom, a cycloalkyl group optionally containing a hetero atom, an alkoxyalkyl group, an aryl group optionally having a substituent, a substituent Heteroaryl group which may have, arylalkyl group which may have a substituent, aryloxyalkyl group which may have a substituent, heteroarylalkyl group which may have a substituent , A heteroaryloxyalkyl group which may have a substituent, a carboxyalkyl group which may be protected, or an acyl group. Further, R ² and R ³ may together form a ring with the carbon atom to which R ² and the group represented by the formula R ³ O— are bonded, and the oxygen atom to which R ³ is bonded. Good. This ring may contain a nitrogen atom, an oxygen atom or a sulfur atom in addition to the oxygen atom to which R ³ is bonded, or may have a substituent. ] It means the group selected from the group shown by. R ¹
Is the expression

[Chemical 9] (Wherein R ⁴ and R ⁵ are the same or different hydrogen atoms,
A lower alkyl group which may be substituted with a halogen atom,
A cycloalkyl group which may contain a hetero atom, a lower alkoxy group which may be substituted with a halogen atom, an alkoxyalkyl group, an alkoxyalkoxyalkyl group, an aryl group which may have a substituent, a substituent group Means a heteroaryl group which may have a substituent, an arylalkyl group which may have a substituent or a heteroarylalkyl group which may have a substituent. Also, R ⁴ ,
R ⁵ together with the carbon atom to which they are attached,
In addition, a ring which may contain a nitrogen atom, an oxygen atom or a sulfur atom may be formed. Further, this ring may have a substituent. R ⁶ is a hydrogen atom, a lower alkyl group optionally substituted with a halogen atom, a cycloalkyl group optionally containing a hetero atom, an aryl group optionally having a substituent, or a substituent Optionally a heteroaryl group, an arylalkyl group which may have a substituent,
A heteroarylalkyl group which may have a substituent,
Formula -OR ¹¹ (In the formula, R ¹¹ is a hydrogen atom, a lower alkyl group optionally substituted with a halogen atom, a cycloalkyl group optionally containing a hetero atom, a hydroxyalkyl group, a cyanoalkyl group, an alkoxyalkyl group. A carbamoylalkyl group which may be mono- or di-substituted,
Aryl group optionally having substituent (s), heteroaryl group optionally having substituent (s), arylalkyl group optionally having substituent (s) or heteroarylalkyl optionally having substituent (s) Means a group. Or a group represented by the formula: —NR ¹² R ¹³ (wherein R ¹² and R ¹³ may be the same or different from each other, a hydrogen atom, a lower alkyl group optionally substituted with a halogen atom, or a hetero atom). A cycloalkyl group, an alkylsulfonyl group in which alkyl may be substituted with a halogen atom, an aryl group which may have a substituent, a heteroaryl group which may have a substituent, or a substituent Optionally arylalkyl group, a heteroarylalkyl group optionally having a substituent, an arylsulfonyl group optionally having a substituent,
It means a heteroarylsulfonyl group which may have a substituent, an acyl group or a carbamoyl group which may be mono- or di-substituted. Further, R ¹² and R ¹³ may form a ring which may further contain a nitrogen atom, an oxygen atom or a sulfur atom together with the nitrogen atom to which they are bonded. Further, this ring may have a substituent. ) Means a group represented by. ｝

In the aromatic ring which may have a substituent in the definition of B in the general formula (I), the aromatic ring means an oxygen atom,
It means a 5- or 6-membered ring which may contain a sulfur atom or a nitrogen atom. The following can be mentioned as examples.

[0007]

[Chemical 10]

In this case, e) is most preferred.

The above R ⁷ , R ⁸ , R ⁹ and R ¹⁰ are the same or different from each other, a hydrogen atom, a hydroxyl group, a halogen atom,
Lower alkyl group optionally substituted with halogen atom, lower alkoxy group optionally substituted with halogen atom, cycloalkyl group optionally containing hetero atom, cycloalkyl alkyl group optionally containing hetero atom, alkoxy Alkoxy group, cyano group, mercapto group, alkylthio group in which alkyl may be substituted with a halogen atom, alkylsulfinyl group in which alkyl may be substituted with a halogen atom, alkyl in which alkyl may be substituted with a halogen atom Sulfonyl group, arylthio group which may have a substituent, arylsulfinyl group which may have a substituent, arylsulfonyl group which may have a substituent, which may have a substituent Heteroarylthio group, optionally substituted heteroarylsulfinyl , A heteroarylsulfonyl group which may have a substituent, an aryl group which may have a substituent, a heteroaryl group which may have a substituent, an aryloxy group which may have a substituent A heteroaryloxy group which may have a substituent, an arylalkyl group which may have a substituent, a heteroarylalkyl group which may have a substituent, and a substituent which may have a substituent. Arylalkyloxy group, optionally substituted heteroarylalkyloxy group, nitro group, nitroso group, piperidinyl group, alkoxyalkyl group, alkoxyalkoxyalkyl group, hydroxyalkyl group, acyl group, mono- or di-substituted Optionally protected aminoalkyl group, optionally protected carboxyl group, optionally protected carboxyalkyl group, , And the like protection which may be carboxy alkenyl group. Further, in the present invention, any two of R ⁷ R ⁸ R ⁹ and R ¹⁰ which are bonded to adjacent carbon atoms form a ring together with the carbon atom to which they are bonded. Included in the invention.

In the definition of general formula (I), R ² , R ²
The halogen atom in the definitions of ⁷ , R ⁸ , R ⁹ and R ¹⁰ means a fluorine atom, a chlorine atom, a bromine atom, an iodine atom and the like.

R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R
^{In the} lower alkyl group optionally substituted by a halogen atom in ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ and R ¹⁴ , the lower alkyl group means a straight chain or branched chain having 1 to 8 carbon atoms. -Like alkyl groups such as methyl group, ethyl group, n-
Propyl group, i-propyl group, n-butyl group, i-butyl group, s-butyl group, t-butyl group, n-pentyl group,
i-pentyl group, neopentyl group, 1-methylbutyl group, 2-methylbutyl group, 1,1-dimethylpropyl group, 1,2-dimethylpropyl group, n-hexyl group, n
-Hexyl group, 1-methylpentyl group, 2-methylpentyl group, 3-methylpentyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 2,2-dimethylbutyl group, 1,3- Dimethylbutyl group, 2,3-dimethylbutyl group, 3,3-dimethylbutyl group, 1-ethylbutyl group, 2-ethylbutyl group, 1,1,2-trimethylpropyl group, 1,2,2-trimethylpropyl group, It means a 1-ethyl-1-methylpropyl group, a 1-ethyl-2-methylpropyl group, a heptyl group, an octyl group and the like.
Further, in this case, "may be substituted with a halogen atom" means that one carbon atom of the above lower alkyl group has one halogen atom such as a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, or Means having two or more bonds, for example, a trifluoromethyl group, 1, 1
-Dichloroethyl group, 2,2-dichloroethyl group, 1,
A 2-dichloroethyl group etc. can be mentioned.

R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R
^The cycloalkyl group which may contain a hetero atom in ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² and R ¹³ has 3 carbon atoms.
To 8 cyclic alkyl groups, for example, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group, cyclooctyl group and the like. Among these, those having 3 to 6 carbon atoms can be preferably mentioned.

The cycloalkylalkyl group which may contain a hetero atom in R ⁷ , R ⁸ , R ⁹ and R ¹⁰ is a cycloalkyl group which is bonded to any carbon atom of the above lower alkyl group. means. For example, it means a cyclopropylmethyl group, a cyclobutylmethyl group, a cyclopentylethyl group, a cyclohexylpropyl group, a cycloheptylmethyl group, a cyclooctylethyl group and the like.

In the lower alkoxy group which may be substituted with a halogen atom in R ⁴ , R ⁵ , R ⁷ , R ⁸ , R ⁹ and R ¹⁰ , the lower alkoxy group is a straight chain or a branched chain having 1 to 8 carbon atoms. Branched alkoxy groups such as methoxy group, ethoxy group, n-propoxy group, i-propoxy group, n-butoxy group, s-butoxy group, i-butoxy group, t-butoxy group, n-pentyloxy group, i -Pentyloxy group, neopentyloxy group, 1-methylbutoxy group, 2-methylbutoxy group, 1,1-dimethylpropoxy group, 1,2-dimethylpropoxy group, n-hexyloxy group, n-hexyloxy group, 1-methylpentyloxy group, 2-methylpentyloxy group, 3-methylpentyloxy group, 1,1-dimethylbutoxy group, 1,
2-dimethylbutoxy group, 2,2-dimethylbutoxy group, 1,3-dimethylbutoxy group, 2,3-dimethylbutoxy group, 3,3-dimethylbutoxy group, 1-ethylbutoxy group, 2-ethylbutoxy group, Means 1,1,2-trimethylpropoxy group, 1,2,2-trimethylpropoxy group, 1-ethyl-1-methylpropoxy group, 1-ethyl-2-methylpropoxy group, heptyloxy group, octyloxy group, etc. To do. In addition, “which may be substituted with a halogen atom” means that one or more halogen atoms such as a fluorine atom, a chlorine atom, a bromine atom or an iodine atom are present on any carbon atom of the above lower alkoxy group. Means that are bonded, for example, trifluoromethoxy group, 1,1-dichloroethoxy group, 2,2
Examples thereof include a -dichloroethoxy group and a 1,2-dichloroethoxy group.

The cyanoalkyl group in the definition of R ¹¹ means a cyano group bonded to any carbon atom of the above lower alkyl group. R ⁷ , R ⁸ , R ⁹ ,
The hydroxyalkyl group in the definition of R ¹⁰ and R ¹¹ means a hydroxy group bonded to any carbon atom of the above lower alkyl group. R ² , R ³ , R ⁴ , R
^The alkoxyalkyl group in the definition of ⁵ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , and R ¹⁴ is a lower alkoxy group defined above to any carbon atom of the above lower alkyl group. Means what you are doing. R ⁷ , R ⁸ , R ⁹ and R
^The alkoxyalkoxy group in the definition of ¹⁰ means the above lower alkoxy group bonded to any carbon atom of the above lower alkoxy group. R ² , R ⁴ , R
^The alkoxyalkoxyalkyl group as seen in the definitions of ⁵ , R ⁷ , R ⁸ , R ⁹ and R ¹⁰ means a group in which the above lower alkoxy group is bonded to any carbon atom of the alkoxy in the above alkoxyalkyl group.

The acyl group found in the definitions of R ³ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹² and R ¹³ is, for example, acetyl, propionyl, valeryl, isovaleryl, pivaloyl, lauroyl, stearoyl. Groups derived from aliphatic saturated monocarboxylic acids, acroyl, propioloyl, methacryloyl, crotonoyl, isocrotonoyl, oleoyl, groups derived from aliphatic unsaturated carboxylic acids, benzoyl, naphthoyl, toluoyl, hydroatropoyl , A group derived from a carbocyclic carboxylic acid such as cinnamoyl, a group derived from a heterocyclic carboxylic acid such as furoyl, thenoyl, nicotinoyl, isonicotinoyl, glycoloyl, lactoyl, glyceroyl, tropoyl, benzyloyl, salicyroyl, anisoyl, vanilloyl , Examples thereof include veratroyl, piperonyloyl, galloyl and the like, and groups derived from a hydroxycarboxylic acid or an alkoxycarboxylic acid, preferably an acetyl group, a propionyl group, a pivaloyl group, a benzoyl group, a toluoyl group, a glycoloyl group, a salicyloyl group. , Nicotinoyl group and the like.

In the optionally protected carboxyalkyl group as defined in R ³ , R ⁷ , R ⁸ , R ⁹ and R ¹⁰ , carboxyalkyl means a carboxyl group at any carbon atom of the above lower alkyl group. Means what is bound together. In addition, the protection of the carboxyl group in this case means that a lower alkyl group, an arylalkyl group or the like is ester-bonded or an amide is formed. In short, anything that can be displaced by some means in vivo to become a carboxyl group is included in the protection of the carboxyl group. The optionally protected carboxyalkenyl group in the definition of R ⁷ , R ⁸ , R ⁹ and R ¹⁰ means a carboxyl group bonded to any carbon atom of the alkenyl group. The alkenyl in this case means an alkenyl group having 2 to 8 carbon atoms and one or more double bonds.

R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R
^{In the} aryl group which may have a substituent in ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , and R ¹⁴ , the aryl group is
It means a phenyl group, a 1-naphthyl group, a 2-naphthyl group, an anthracenyl group, or the like, and a phenyl group is preferable.

R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸
, R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , and R ¹⁴ in the heteroaryl group which may have a substituent, the heteroaryl group is preferably a nitrogen atom, an oxygen atom or a sulfur atom. It means a 5- to 6-membered ring or condensed ring containing 4 to 4, and examples thereof include a pyridyl group, a thienyl group, a furyl group, a benzimidazolyl group, a benzothiazolyl group and a quinolylisoquinolyl group, and preferably pyridyl group. A group can be mentioned.

R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸
, R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , R ¹⁴ in the arylalkyl group which may have a substituent, aryl has the same meaning as the above aryl group, and alkyl is the above lower group. It has the same meaning as the alkyl group.

R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R
^{In the} heteroarylalkyl group which may have a substituent in ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ and R ¹⁴ ,
Heteroaryl has the same meaning as the above heteroaryl group, and alkyl has the same meaning as the above lower alkyl group. In the aryloxy group which may have a substituent as shown in the definitions of R ⁷ , R ⁸ , R ⁹ and R ¹⁰ , the aryl of aryloxy has the same meaning as the above aryl group. In the heteroaryloxy group which may have a substituent as shown in the definitions of R ⁷ , R ⁸ , R ⁹ and R ¹⁰ , the heteroaryl of the heteroaryloxy has the same meaning as the above heteroaryl.
In the arylalkyloxy group which may have a substituent and is found in the definitions of R ⁷ , R ⁸ , R ⁹ and R ¹⁰ , arylalkyl has the same meaning as described above. R ⁷ ,
In the heteroarylalkyloxy group which may have a substituent and is found in the definitions of R ⁸ , R ⁹ and R ¹⁰ , the term heteroarylalkyl has the same meaning as described above.

In the aryloxyalkyl group which may have a substituent and is found in the definition of R ³ , aryl has the same meaning as the above aryl. The alkyl in this case has the same meaning as the above lower alkyl. That is, aryloxyalkyl means an aryloxy bonded to any carbon atom of the above lower alkyl. In the heteroaryloxyalkyl group which may have a substituent, which is found in the definition of R ³ ,
Heteroaryl has the same meaning as the above heteroaryl. The alkyl in this case has the same meaning as the above lower alkyl. That is, a heteroaryloxyalkyl means a heteroaryloxy bonded to any carbon atom of the above lower alkyl.

"R ⁴ and R ⁵ may be combined with the carbon atom to which they are bonded to form a ring which may further contain a nitrogen atom, an oxygen atom or a sulfur atom. The ring may have a substituent. "Means that R ⁴ and R ⁵ together with the carbon atom to which they are bound have one or more nitrogen atoms, oxygen atoms or sulfur atoms. It means a 5- or 6-membered ring, which may or may not be included, and preferred examples thereof include a cyclohexane ring, a piperidine ring, a pyrrolidine ring and a saturated pyran ring.

“R ¹² and R ¹³ may combine with the nitrogen atom to which they are bonded to form a ring which may further contain a nitrogen atom, an oxygen atom or a sulfur atom. The ring may have a substituent. "Means that R ¹² and R ¹³ together form a nitrogen atom to which they are bonded, and also a nitrogen atom, an oxygen atom or a sulfur atom. Or, it means forming a 5- or 6-membered ring containing two or more, and specific examples thereof include a morpholine ring, a thiomorpholine ring, a piperazine ring, and a pyrrolidine ring.

In addition, "R ² and R ³ together form R
^A ring may be formed with the carbon atom to which ² and the group represented by the formula R ³ O— are bonded, and the oxygen atom to which R ³ is bonded. This ring may contain a nitrogen atom, an oxygen atom or a sulfur atom in addition to the oxygen atom to which R ³ is bonded, or may have a substituent. Is R ²
And R ³ together, the carbon atom to which R ² is bound,
This means that a ring including the oxygen atom to which R ³ is bonded and the carbon atom to which this oxygen atom is bonded as a constituent atom may be formed. Further formed ring is R
^In addition to the oxygen atom to which ³ is bonded, one or more oxygen atom, sulfur atom, or nitrogen atom may or may not be contained. The following can be mentioned as specific examples.

[0026]

[Chemical 11]

In the alkylsulfonyl group in which alkyl in the definition of R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹² and R ¹³ may be substituted with a halogen atom, alkyl is the same as the above lower alkyl group. Has the meaning of. Further, "the alkyl may be substituted with a halogen atom" means that the halogen atom as defined above may be bonded to any carbon atom of the alkyl. For example, a trifluoromethyl sulfonyl group, a dibromoethyl sulfonyl group, etc. can be mentioned. In the alkylsulfinyl group in which alkyl in the definitions of R ⁷ , R ⁸ , R ⁹ and R ¹⁰ may be substituted with a halogen atom, alkyl has the same meaning as the above lower alkyl group. Further, "the alkyl may be substituted with a halogen atom" means that the halogen atom as defined above may be bonded to any carbon atom of the alkyl. Examples thereof include a trifluoromethylsulfinyl group and a dibromoethylsulfinyl group. R
^{In the} alkylthio group shown in the definitions of ⁷ , R ⁸ , R ⁹ and R ¹⁰ , alkyl has the same meaning as the above lower alkyl group. Further, "the alkyl may be substituted with a halogen atom" means that the halogen atom defined above may be bonded to any carbon atom of the alkyl. Examples thereof include a trifluoromethylthio group and a dibromoethylthio group. R ⁷ ,
In the arylsulfonyl group which may have a substituent as shown in R ⁸ , R ⁹ , R ¹⁰ , R ¹² and R ¹³ , aryl has the same meaning as the above aryl group, and preferably phenyl is mentioned. You can R ⁷ , R ⁸ , R ⁹ ,
In the heteroarylsulfonyl group which may have a substituent and is found in R ¹⁰ , R ¹² and R ¹³ , heteroaryl has the same meaning as the above-mentioned heteroaryl group. R
^{In the} arylsulfinyl group which may have a substituent, which is shown in the definitions of ⁷ , R ⁸ , R ⁹ and R ¹⁰ , aryl has the same meaning as the above aryl group. R ⁷ , R
^{In the} heteroarylsulfinyl group optionally having a substituent, which is found in the definitions of ⁸ , R ⁹ and R ¹⁰ , the term heteroaryl has the same meaning as the above heteroaryl. Further, in the arylthio group which may have a substituent and the heteroarylthio group which may have a substituent, which are found in the definitions of R ⁷ , R ⁸ , R ⁹ and R ¹⁰ , aryl and heteroaryl are , Has the same meaning as defined for the aryl group and heteroaryl group above.

In the optionally substituted mono- or di-substituted aminoalkyl group as defined in R ⁷ , R ⁸ , R ⁹ , R ¹⁰ and R ¹⁴ , aminoalkyl means any carbon atom of the above lower alkyl. Means that an amino group is bonded to. Further, "which may be mono- or di-substituted" means that one or two substituents may be bonded to the amino group of the aminoalkyl or may not be bonded. The carbamoyl group which may be mono- or di-substituted as shown in the definition of R ¹² and R ¹³ means that 1 or 2 substituents are bonded or not bonded to the nitrogen atom constituting carbamoyl. Means that you may. In the mono- or di-substituted carbamoylalkyl group shown in the definition of R ¹¹ , carbamoylalkyl means carbamoyl bonded to any carbon atom of the above lower alkyl.

Further, in the above definition, "aryl group optionally having substituent (s)", "heteroaryl group optionally having substituent (s)", "aryloxy optionally having substituent (s)" Group "," heteroaryloxy group optionally having substituents "," arylalkyl group optionally having substituents "," heteroarylalkyl group optionally having substituents ", "Aryloxyalkyl group optionally having substituent (s)", "heteroaryloxyalkyl group optionally having substituent (s)", "arylalkyloxy group optionally having substituent (s)", " A heteroarylalkyloxy group which may have a substituent ",
The "substituent" in the "mono- or di-substituted carbamoyl group", "mono- or di-substituted carbamoyl alkyl group", "mono- or di-substituted aminoalkyl group" means A hydroxyl group, a halogen atom, a lower alkyl group optionally substituted with a halogen atom, a lower alkoxy group optionally substituted with a halogen atom, an alkylthio group optionally substituted with a halogen atom, and a halogen atom substituted Optionally substituted alkylsulfonyl group, optionally substituted arylthio group, optionally substituted arylsulfonyl group, optionally substituted heteroarylthio group, optionally substituted Optionally substituted heteroarylsulfonyl group, acyl group, nitro group, optionally mono- or di-substituted amide group Group means a mono- or di-optionally substituted carbamoyl group, an optionally protected carboxyl group, optionally protected carboxyalkyl group, and protected optionally carboxy alkenyl group. In this case, the protecting group means an alkyl group, an arylalkyl group or the like. In particular, "mono- or di-substituted carbamoyl group", "mono- or di-substituted carbamoyl alkyl group" and "mono- or di-substituted aminoalkyl group" are di-substituted. When these are present, those which form a ring together with the nitrogen atom to which these substituents are bound are also included in the present invention. This ring may have a substituent or may have an oxygen atom, a sulfur atom or a nitrogen atom in addition to the substituent.

The pharmacologically acceptable salt in the present invention is a conventional non-toxic salt, specifically, an alkali metal salt such as sodium salt and potassium salt, and an alkali salt such as calcium salt and magnesium salt. Organic base salts such as earth metal salts, ammonium salts, trimethylamine salts, N, N′-dibenzylethylenediamine salts, inorganic salts such as hydrochlorides, hydrobromides, sulfates, phosphates, formates, Acetate, trifluoroacetate, maleate, tartrate,
Examples thereof include organic acid salts such as methanesulfonate, benzenesulfonate and toluenesulfonate, salts with amino acids such as arginine salt and ornithine salt.
Specific examples of the above-mentioned ring portion A in the compound group of the present invention include the following structures.

[0031]

[Chemical 12] Among them, preferable ones are (j), (m),
(P) and (t), particularly preferably (j) and (m)
Is.

Further, in the general formula (I), the ring portion A is represented by the formula (a) and the formula (b), and R ³
When is a hydrogen atom, they are in a tautomeric relationship with each other as shown below. It goes without saying that the present invention also includes those that coexist as an equilibrium mixture of the compounds represented by the general formula (Ia) and the general formula (Ib).

[0033]

[Chemical 13]

In order to obtain the α, β-unsaturated ketone derivative represented by the above general formula (I) or a pharmaceutically acceptable salt thereof, the compound represented by the general formula (II) is used as a useful intermediate. Can be used.

[0035]

Embedded image

The intermediate will be described in more detail below.

[0037]

[Chemical 15]

(Definition of rings B, R ² and R ^{3 in} the formula is the same as the definition in formula (I).) The compounds of the present invention can be easily produced by a commonly used method. An example of the method for producing the compounds of the present invention will be given below.

Production Method A Among the compounds represented by the general formula (I), the general formula (6) represented by the following structural formula

[0040]

Embedded image

The compound represented by can be produced by the following method.

[0042]

[Chemical 17]

(In the series of formulas, R ¹ , R ² , R ³ , R ⁷ ,
R ⁸ , R ⁹ and R ¹⁰ have the meanings given above. R ^a , R ^b
Means a lower alkyl group, and Z means a halogen atom. ) That is, the aldehyde compound represented by the general formula (1) is reacted with the phospholane, the phosphoric acid ester or the phosphonium salt represented by the general formula (2), (3) or (4) by the Wittig reaction by a conventional method, or In this method, the target compound (6) is obtained by subjecting the methyl ketone compound represented by the general formula (5) to an aldol reaction by a conventional method.

In the reaction between the aldehyde compound (1) and the phosphorane (2), dichloromethane is used as a reaction solvent.
Examples thereof include benzene, tetrahydrofuran, dimethoxyethane and the like. The reaction temperature is appropriately selected from 0 ° C to the boiling point of the solvent. The reaction of the aldehyde compound (1) with the phosphoric acid ester (3) or the phosphonium salt (4) gives preferable results when carried out in the presence of a base. Examples of the base include sodium hydride, potassium hydride, sodium amide, sodium methoxide, sodium ethoxide, potassium t-butoxide, methyllithium, n-butyllithium and the like.

Preferred examples of the solvent include hydrocarbon organic solvents such as benzene, ether organic solvents such as tetrahydrofuran and dimethoxyethane, dimethylformamide and dimethylsulfoxide. The reaction temperature is about -78 ° C to the boiling point of the solvent, preferably about -20 ° C to room temperature. In addition, in the aldol reaction of the aldehyde compound (1) and the methyl ketone compound (5), lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium methoxide, potassium t-butoxide and the like can be mentioned as the base. As a reaction solvent, alcohols such as methanol and ethanol,
Tetrahydrofuran, water, a mixed solvent thereof and the like can be mentioned. The reaction temperature is about -20 ° C to the boiling point of the solvent, but preferably about room temperature to 60 ° C.

Production Method B The target substance in which R ³ is a hydrogen atom in the general formula (6),
That is, the compound (7) in which the 4-position of the quinoline ring is a hydroxyl group is
It can also be manufactured by the following method.

[0047]

Embedded image

(Wherein R ¹ , R ² , R ⁷ , R ⁸ ,
R ⁹ and R ¹⁰ have the above-mentioned meanings, and R ¹⁵ means a hydroxyl-protecting group. That is, it is a method in which a compound in which the hydroxyl group represented by the general formula (9) is protected by a suitable protecting group is used as a starting material, and this is deprotected by a conventional method to obtain the target material (7). Examples of the protective group include a methoxymethyl group, an ethoxymethyl group, a methoxyethoxymethyl group, a benzyloxymethyl group, a furan-2-yl group, a pyran-2-yl group, and a t-butyldimethylsilyl group. However, the most preferred group is a methoxymethyl group. Examples of the solvent for this reaction include water or a solvent miscible with water, for example, an ether organic solvent such as tetrahydrofuran and dioxane, an alcohol organic solvent such as methanol and ethanol, acetone and acetonitrile. Also, a solvent immiscible with water, for example, esters such as ethyl acetate, aromatic hydrocarbons such as benzene and toluene can be used.

Acids as deprotecting agents include hydrochloric acid, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, D-
10-camphor sulfonic acid, acetic acid, trifluoroacetic acid and the like can be mentioned. When the protective group is a t-butyldimethylsilyl group, tetrabutylammonium fluoride can be used as a deprotecting agent. The reaction temperature is about −
The boiling point is from 40 ° C. to the boiling point of the solvent, preferably about room temperature to the boiling point of the solvent.

Production Method C In the general formula (6), R ³ is a hydrogen atom, an acyl group, a heteroaryl group which may have a substituent or an objective group other than an aryl group which may have a substituent. It can also be manufactured by the following method.

[0051]

[Chemical 19]

(In the series of formulas, R ¹ , R ² , R ⁷ , R
⁸ , R ⁹ and R ¹⁰ have the above-mentioned meanings, and R ¹⁶ is the above-mentioned R ³
To a group excluding a hydrogen atom, an acyl, a heteroaryl which may have a substituent and an aryl which may have a substituent, and Hal means a halogen atom. )

That is, the general formula (6) in which R ³ is a hydrogen atom
The target compound represented by the formula (10) is obtained by reacting R ¹⁶ -Hal with a compound represented by the formula (1) as an alkali metal carbonate such as sodium carbonate or potassium carbonate, or an alkali metal hydride such as sodium hydride as a base. This is a method of obtaining (10). Examples of the reaction solvent include ketones such as acetone and methyl ethyl ketone, N, N-dimethylformamide, and dimethyl sulfoxide. The reaction temperature is about -40 ° C to the boiling point of the solvent, preferably room temperature to the boiling point of the solvent.

Production Method D A target substance in which R ³ is an acyl group in the general formula (6),
That is, the compound (11) in which the 4-position of the quinoline ring is an acyloxy group can also be produced by the following method.

[0055]

Embedded image

(In a series of formulas, R ¹ , R ² , R ⁷ , R
⁸ , R ⁹ and R ¹⁰ have the above-mentioned meanings, and R ¹⁷ means an acyl group. That is, a compound represented by the general formula (7) in which R ³ is a hydrogen atom is prepared by an ordinary method, for example, with an acylating agent such as a desired carboxylic acid or a reactive acid derivative such as an acid halide or an acid anhydride. About 0 of deoxidizing agents such as pyridine and triethylamine
This is a method of obtaining a target substance represented by the formula (11) by reacting at a temperature of from ℃ to the boiling point of the solvent. Preferred examples of the reaction solvent include dichloromethane, chloroform, tetrahydrofuran and the like.

Production Method E Compound (14) or (15) in which R ³ is a hydrogen atom and R ² is an alkylsulfinyl group in the compound represented by the general formula (6) is produced, for example, by the following method. You can also do it.

[0058]

[Chemical 21]

(In the series of formulas, R ¹ , R ⁷ , R ⁸ ,
R ⁹ and R ¹⁰ have the above-mentioned meanings, and R ¹⁸ means an alkyl group. )

That is, when the quinoline derivative represented by the general formula (12) in which the 3-position is an alkylthio group is oxidized with an oxidizing agent such as hydrogen peroxide or m-chloroperbenzoic acid, the general formula (13) is obtained. ) Is a method of obtaining a 3-alkylsulfinylquinoline derivative. The reaction solvent is appropriately selected from water, dichloromethane, chloroform and the like. The reaction temperature is −20 ° C. to the boiling point of the solvent,
It is preferably about 0 ° C. to room temperature. The 3-alkylsulfinylquinoline derivative (13) thus obtained was
By treating the compound (9) in the production method B in the same manner as the compound (9), the target compound represented by the general formula (14) or the general formula (15) can be obtained.

Production Method F In the general formula (6), compound (17) or compound (18) in which R ³ is a hydrogen atom and R ² is an alkylsulfonyl group can be produced, for example, by the following method. You can also

[0062]

[Chemical formula 22]

(In the series of formulas, R ¹ , R ⁷ , R ⁸ and R
⁹ , R ¹⁰ , R ¹⁵ and R ¹⁸ have the meanings given above. ) That is, a quinoline derivative represented by the general formula (16) in which the 3-position is an alkylthio group is treated with, for example, excess hydrogen peroxide, m
-When oxidized with an oxidizing agent such as chloroperbenzoic acid,
It is a method for obtaining a 3-alkylsulfonylquinoline derivative represented by the general formula (17).

As the reaction solvent, water, dichloromethane,
It is appropriately selected from chloroform and the like. The reaction temperature is about −20 ° C. to the boiling point of the solvent, preferably about 0 ° C. to room temperature. The obtained 3-alkylsulfonylquinoline derivative (16) is treated in the same manner as the compound (9) of the production method B to obtain the object represented by the general formula (17) and the general formula (18). The compound can be obtained. Manufacturing method G (in the series of formulas, R ¹ , R ² , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ ,
^Ra , ^Rb , Z and X have the meanings given above. )

[0065]

[Chemical formula 23]

That is, a phospholane, a phosphoric acid ester or a phosphonium salt represented by the general formula (), () or () is usually added to the aldehyde compound represented by the general formula () in the same manner as in the production method A. The target compound () can be obtained by subjecting the compound to the Wittig reaction or by subjecting the methyl ketone compound represented by the general formula () to an aldol reaction according to a conventional method. The compound represented by the above-mentioned general formula (1), which is a starting material in the production of the compound represented by the general formula (6), is used in the production of the quinoline derivative of the present invention which has an excellent action as a medicine. This intermediate (1), which is useful as an important intermediate, can be easily obtained by a commonly used method. Next, an example of the manufacturing method is shown. As described above, when the 4-position is a hydroxyl group in the series of formulas, it has a tautomeric relationship with the 4-quinolone derivative.

Production Method 1 of Starting Material In the above Production Method A, R ³ has a hydrogen atom, an acyl group or a substituent among the compounds represented by the general formula (1) used as the starting material. When the heteroaryl group and the aryl group which may have a substituent are not the same, they are produced, for example, by the following method.

[0068]

[Chemical formula 24]

(In the series of formulas, R ² , R ⁷ , R ⁸ ,
R ⁹ , R ¹⁰ and Hal have the above-mentioned meanings, R ¹⁹ means a lower alkyl group, R ²⁰ represents a hydrogen atom, an acyl group or a heteroaryl group which may have a substituent, from R ³ mentioned above. And a group excluding an aryl group which may have a substituent. )

The first step is 4-hydroxyquinoline-2.
A carboxylic acid ester derivative (19) or (20),
For example, an alkali metal carbonate such as sodium carbonate or potassium carbonate or an alkali metal salt such as sodium hydride is used as a base to react with a halogen compound R ¹⁸ -Hal to produce a 4-alkoxyquinoline-2-carboxylic acid ester derivative (2
This is the step of obtaining 1). In this case, examples of the halogen atom include chlorine atom, bromine atom, iodine atom and the like. Examples of the solvent include ketones such as acetone and methyl ethyl ketone, N, N-dimethylformamide, and dimethyl sulfoxide. Reaction temperature is about -4
The temperature is from 0 ° C. to the boiling point of the solvent, but preferably from room temperature to the boiling point of the solvent. In the next step, the 4-alkoxyquinoline-2-carboxylic acid ester derivative (21) obtained in the previous step is reduced by a conventional method using, for example, diisobutylaluminum hydride to give a 2-hydroxymethylquinoline derivative (22). Obtainable. Examples of the solvent include dichloromethane, diethyl ether, tetrahydrofuran, toluene and the like. The reaction temperature is about -78 ° C to 30 ° C, preferably about -78 ° C to 0 ° C.

In the subsequent step, the 2-hydroxymethylquinoline derivative (22) obtained in the previous step is oxidized to give the desired quinoline-2 represented by the general formula (23).
A carboxaldehyde derivative can be obtained. Examples of the oxidizing agent include manganese dioxide, dimethyl sulfoxide and the like. Examples of the reaction solvent include alcohols such as methanol and ethanol, acetone, etheracetonitrile, benzene, dichloromethane, chloroform, ethyl acetate and the like. The reaction temperature is appropriately selected from about 0 ° C to the boiling point of the solvent.
In addition, when reducing the compound (21), a mixture of the compound (22) and the compound (23) or only the compound (23) may be obtained in some cases.

Production Method 2 of Starting Material In the above production method A, the compound represented by the general formula (1) used as a starting material is produced by the following method when R ³ is a hydrogen atom. can do.

[0073]

[Chemical 25]

(In the series of formulas, R ² , R ⁷ , R ⁸ , R ⁹ ,
R ¹⁰ and R ¹⁹ have the above-mentioned meanings. ) That is, the 4-hydroxyquinoline-2-carboxylic acid ester derivative (24) or (25) is treated in the same manner as the compound (24) is obtained from the compound (19) or (20) in the production method 1 of the starting material. Is a method of obtaining an aldehyde derivative represented by the general formula (28) or (29). When reducing the compounds (24) and (25), a mixture of the compounds (26) or (27) and the compounds (28) or (29) or only the compounds (28) or (29) may be obtained in some cases.

Production Method 3 of Starting Material In the above Production Method A, the compound represented by the general formula (1) used as a starting material is produced by, for example, the following method when R ³ is an acyl group. You can also do it.

[0076]

[Chemical formula 26]

(In the series of formulas, R ² , R ⁷ , R ⁸ , R ⁹ ,
R ¹⁰ has the above-mentioned meaning, and R ²¹ means an alkyl group, an aryl group which may have a substituent or a heteroaryl group which may have a substituent. ) The first step is to prepare the 4-hydroxy-2-methylquinoline derivative (30) or (31) by an ordinary method in the presence of a deoxidizing agent such as pyridine or triethylamine to obtain an acid anhydride,
By reacting with a reactive acid derivative such as a desired carboxylic acid or acid halide at a temperature from 0 ° C. to the boiling point of the solvent, 4-
It is a step of obtaining an acyloxy-2-methylquinoline derivative (32). No solvent as solvent, dichloromethane,
Examples thereof include chloroform and N, N-dimethylformamide tetrahydrofuran. 4-acyloxy-2-methylquinoline derivative (3
2-) represented by the target general formula (33) is obtained by oxidizing 2) by a conventional method, for example, using selenium dioxide.
An acyloxyquinoline-2-carboxaldehyde derivative can be obtained. At this time, examples of the solvent include dioxane, toluene, xylene and the like. The reaction temperature is about 80 ° C. to the boiling point of the solvent.

Production Method 4 of Starting Material In the production method A described above, the compound represented by the general formula (1) used as a starting material has R ³ having a hydrogen atom, an acyl group or a substituent. When it is other than a good heteroaryl group and an aryl group which may have a substituent, it can be produced, for example, by the following method.

[0079]

[Chemical 27]

(In the series of formulas, R ² , R ⁷ , R ⁸ , R ⁹ ,
R ¹⁰ and R ²⁰ have the above-mentioned meanings, and Hal means a halogen atom. ) That is, a 4-hydroxyquinoline-2-carboxaldehyde derivative (28) or (29) is reacted with a halogen compound R ²⁰ -Hal in the same manner as in the production of the compound (21) in the production method 1 of starting materials, This is a method for obtaining the desired 4-alkoxyquinoline-2-carboxaldehyde derivative (23).

Production Method 5 of Starting Material In the production method 4 of starting material, the 4-hydroxyquinoline-2-carboxaldehyde derivative (28) or (29) used as a starting material can also be produced by the following method. it can.

[0082]

[Chemical 28]

(In the series of formulas, R ² , R ⁷ , R ⁸ and R
⁹ , R ¹⁰ and R ¹⁵ have the above-mentioned meanings. That is, a compound represented by the general formula (34) in which the 4-position is protected by a suitable protecting group R ¹⁵ is treated in the same manner as in the production of the compound (7) or (8) in the production method B. This is a method for obtaining the desired aldehyde derivative (28) or (29) by deprotection.

Production Method 6 of Starting Material In the production method 1 of starting material, the 4-hydroxyquinoline-2-carboxylic acid ester derivative (19) or (20) used as a starting material can be produced, for example, by the following method.

[0085]

[Chemical 29]

(In the series of formulas, R ² , R ⁷ , R ⁸ ,
R ⁹ , R ¹⁰ and R ¹⁹ have the above-mentioned meanings. ) The first step is a step of obtaining a condensate (36) by dehydration-condensing the aniline derivative represented by the general formula (34) and the oxaloacetic acid diester derivative represented by the general formula (35). Examples of the solvent include solvent-free hydrocarbons such as cyclohexane, benzene and toluene, and alcohols such as ethanol and propanol. Examples of the acid include hydrochloric acid, sulfuric acid, acetic acid, p-toluenesulfonic acid and the like. The reaction temperature is about room temperature to the boiling point of the solvent, preferably about 80 ° C. to the boiling point of the solvent. In the next step, the condensate (36) obtained in the previous step is subjected to intramolecular cyclization by heating without heating or at a high boiling point solvent such as diphenyl ether at a high temperature, preferably 200 ° C. to the boiling point of the solvent. 4-hydroxyquinoline-2-carboxylic acid ester derivative (1
This is the step of obtaining 9) or (20).

Method 7 for producing starting material In the method 3 for producing starting material, the 4-hydroxy-2-methylquinoline derivative (3
1) or (32) can be produced, for example, by the following method.

[0088]

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(In the series of formulas, R ² , R ⁷ , R ⁸ ,
R ⁹ and R ¹⁰ have the above-mentioned meanings, and R ²² means a lower alkyl group. ) That is, the aniline derivative represented by the general formula (34) and the acetoacetic acid ester derivative represented by the general formula (37) are dehydrated and condensed in the same manner as in the production method 6 of the starting material, and then intramolecular cyclized In this way, the intended 4-hydroxy-2-methylquinoline derivative (30) or (31) is obtained.

Method 8 for producing starting material In the method 1 for producing starting material, when R ² is a halogen atom in the compounds (19) or (20) used as a starting material, for example, the following method is used. It can also be manufactured in.

[0091]

[Chemical 31]

(In the series of formulas, R ⁷ , R ⁸ , R ⁹ ,
R ¹⁰ and R ¹⁹ have the above meanings, and Hal means a halogen atom. ) That is, 4-hydroxyquinoline in which the 3-position is a hydrogen atom
2-Carboxylic acid ester derivative (39) or (40)
Is reacted with a halogenating agent such as chlorine atom, sulfuryl chloride, bromine atom, iodine monochloride, etc.
A hydroxy-3-halogenoquinoline 2-carboxylic acid ester derivative (41) or (42) can be obtained.
Examples of the solvent include acetic acid. The reaction temperature is appropriately selected from about room temperature to the boiling point of the solvent.

Method 9 for producing starting material In the method 1 for producing starting material, when R ⁸ is a halogen atom in the compound (19) or (20) used as a starting material, for example, the following method is used. It can also be manufactured.

[0094]

Embedded image

(In the series of formulas, R ² , R ⁷ , R ⁹ , R
¹⁰ and R ¹⁹ have the above-mentioned meanings, and Hal means halogen. ) That is, 4-hydroxyquinoline in which the 6-position is a hydrogen atom
2-Carboxylic acid ester derivative (43) or (44)
Is treated in the same manner as in the production method 8 of starting materials to obtain the desired 6-halogeno-4-hydroxyquinoline-2-carboxylic acid ester derivative (45) or (46).

Manufacturing Method 10 of Starting Material In the manufacturing method 1 of starting material, in the compound (19) or (20) used as the starting material, R ⁷ and R ¹⁰ are lower alkoxy groups or alkoxyalkoxy groups, and R ⁸ is The following is a description of a specific example of the method for producing a hydrogen atom and R ⁹ being an aminoalkyl group.

[0097]

[Chemical 33]

(In the series of formulas, R ² and R ¹⁹ have the above-mentioned meanings, R ²³ and R ²⁴ are the same or different and each is a lower alkyl group or an alkoxyalkyl group, and R ²⁵ and R ²⁶ are the same. Identical or different from each other, a hydrogen atom, a lower alkyl group, a cycloalkyl group, an aryl group which may have a substituent, a heteroaryl group which may have a substituent, and a substituent which may have a substituent. An arylalkyl group, a heteroarylalkyl group which may have a substituent, and a ring containing an oxygen atom, a sulfur atom or a nitrogen atom in addition to the nitrogen atom to which R ²⁵ and R ²⁶ are bonded are meant. The first step is to prepare the quinoline-2-carboxylic acid ester derivative represented by the general formula (47) or (48) using chloromethyl methyl ether to prepare the compound (21) of the production method 1 of the starting material. When treated in the same manner as in the production, 4-methoxymethoxyquinoline-2-carboxylic acid ester derivative (49)
Can be obtained. In the next step, the ester derivative (49) obtained in the previous step was removed by a conventional method, for example, tetra-n-butylammonium fluoride to remove the silyl group to give a 7-hydroxyalkylquinoline-2-carboxylic acid ester. This is a step of obtaining the derivative (50). Tetrahydrofuran may be used as the solvent. The reaction temperature is about −20 ° C. to the boiling point of the solvent, preferably about 0 ° C. to room temperature. Subsequently, the obtained 7-hydroxyalkylquinoline-2-carboxylic acid ester derivative (50) is reacted with methanesulfonyl chloride by a conventional method in the presence of a deoxidizing agent such as triethylamine, and then reacted with an amine. And a target 7-aminoalkylquinoline-2-carboxylic acid ester derivative (51)
Or (52) can be obtained. At this time, examples of the solvent include tetrahydrofuran and N, N-dimethylformamide. The reaction temperature is appropriately selected from about 0 ° C to the boiling point of the solvent.

Production Method 11 of Starting Material In the compound (21) of Production Method 1 of starting material, R
^In the case where any of ⁷ , R ⁸ , R ⁹ and R ¹⁰ is a hydroxyalkyl group, an alkoxyalkyl group or an alkoxyalkoxyalkyl group and the other is a hydrogen atom,
An example of the specific manufacturing method is as follows.

[0100]

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(In the series of formulas, R ² , R ¹⁹ and R ²⁰ have the above-mentioned meanings, R ²⁷ and R ²⁸ are the same or independently hydrogen and lower alkyl, and R ²⁹ is an alkyl group or alkoxy. Means alkyl, Hal means halogen, and n means 0 or an integer of 1 to 4.) The first step is quinoline-2 represented by the general formula (53).
-Method for producing starting material from carboxylic acid ester derivative 10
This is a step of obtaining a hydroxyalkylquinoline derivative (54) by removing the silyl group by treating in the same manner as in the compound (50). In the next step, the obtained hydroxyquinoline derivative (54) is reacted with a halogen compound using an alkali metal salt such as sodium hydride or potassium hydride as a base to give an alkoxyalkylquinoline derivative (55).
Is a step of obtaining. Examples of the solvent include N, N-dimethylformamide and the like. The reaction temperature is appropriately selected from about 0 ° C to the boiling point of the solvent.

Method 12 for producing starting material In the method 1 for producing starting material, any one of R ⁷ , R ⁸ , R ⁹ and R ^{10 in} the compound represented by the general formula (22) is an alkoxycarbonylvinyl group. The following is a description of an example of a specific manufacturing method in the case where the others are hydrogen atoms.

[0103]

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(In the series of formulas, R ² and R ²⁰ have the above-mentioned meanings, X represents halogen, and R ³⁰ represents a lower alkyl group.) The first step is the general formula (56). Is a step of obtaining a silyl ether derivative (57) by a conventional method from the 2-hydroxymethylquinoline derivative represented by. For example, by using imidazole as a base and reacting it with t-butylchlorodimethylsilane, a silyl ether derivative (57) can be obtained. The obtained silyl ether derivative (57) obtained in the previous step was subjected to a conventional method, for example, an acrylic ester, n.
The compound (58) in which halogen is substituted with alkoxycarbonylvinyl can be obtained by heating and stirring under a nitrogen atmosphere with -butylamine, palladium acetate and tri-0-tolylphosphine. Subsequently, the silyl ether compound (58) obtained in the previous step is treated in the same manner as the compound (50) of the manufacturing method 10 of the starting material to obtain the desired 2-hydroxymethylquinoline derivative (66). it can.

Manufacturing Method 13 of Starting Material In the manufacturing method 1 of starting material, any of R ⁷ , R ⁸ , R ⁹ and R ^{10 in} the compound represented by the general formula (22) is an alkoxycarbonylethyl group. The following is an example of a specific production method for the case where the others are hydrogen atoms.

[0106]

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(In the series of formulas, R ² , R ²⁰ and R ³⁰
Has the meaning given above. ) In the first step, the alkoxycarbonylvinylquinoline derivative represented by the general formula (58) is catalytically hydrogenated by a conventional method, for example, using palladium carbon, to obtain an alkoxycarbonylethylquinoline derivative (60). Examples of the reaction solvent include alcohols such as methanol and ethanol, ethyl acetate, tetrahydrofuran and the like. The reaction temperature is from 0 ° C to room temperature. The desired 2-hydroxyquinoline derivative (61) can be obtained by treating the alkoxycarbonylethylquinoline derivative (60) obtained in the previous step in the same manner as the compound (50) of the manufacturing method 10 of the starting material.

Production Method 14 of Starting Material In the case where R ¹⁸ in the compound (21) of Production Method 1 of starting material is an aryl group which may be substituted,
An example of the specific manufacturing method is as follows.

[0109]

Embedded image

(In the series of formulas, R ² , R ⁷ , R ⁸ ,
R ⁹ , R ¹⁰ and R ¹⁹ have the above-mentioned meanings, and R ³¹ means an optionally substituted aryl group. ) The first step is to heat and reflux the 4-hydroxyquinoline-2-carboxylic acid ester derivative represented by the general formula (24) or (25) by a conventional method, for example, in excess phosphorus oxychloride without a solvent. Allows 4-chloroquinoline-2
-A step of obtaining a carboxylic acid ester derivative (62). In the subsequent step, the 4-chloroquinoline-2-carboxylic acid ester derivative (62) obtained in the previous step and a phenol compound which may be substituted are solvent-free at 150 ° C to
By heating at 200 ° C, the desired quinoline-
In this step, a 2-carboxylic acid ethyl ester derivative (63) is obtained.

Method 15 for producing starting material In the method 3 for producing starting material, the 4-hydroxy-2-methylquinoline derivative (3
When R ² is alkoxymethyl or alkoxyalkoxymethyl in 0) or (31), it can also be produced, for example, by the following method.

[0112]

[Chemical 38]

(In the series of formulas, R ⁷ , R ⁸ , R ⁹ ,
R ¹⁰ has the meaning given above, R ³² means alkyl or acoxyalkyl and Hal means halogen. ) The first step is a step of reacting a 3-hydroxymethylquinoline derivative (64) with a halogen compound using an alkali metal salt such as sodium hydride or potassium hydride as a base to obtain a 3-alkoxymethylquinoline derivative (65). Is. Examples of the solvent include N, N-dimethylformamide and the like. The reaction temperature is appropriately selected from approximately 0 ° C to the boiling point of the solvent. In the subsequent step, when the 3-alkoxymethylquinoline derivative (65) obtained in the previous step is demethoxymethylated under acidic conditions, the desired 4-hydroxy-3-alkoxymethylquinoline derivative (66) or (67) is obtained. Is a step of obtaining. As the solvent, water or a solvent miscible with water, for example, tetrahydrofuran, methanol, ethanol, acetone,
Acetonitrile etc. are mentioned. A solvent immiscible with water, such as ethyl acetate, can also be used.
Examples of the acid include hydrochloric acid, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, D-10-camphorsulfonic acid, acetic acid, trifluoroacetic acid and the like. The reaction temperature is about -40 ° C to the boiling point of the solvent, preferably room temperature to the boiling point of the solvent.

Method 16 for producing starting material 4-hydroxy-2-methylquinoline derivative (30) used as a starting material in method 3 for producing starting material
Alternatively, in (31), when R ² is acylaminomethyl or sulfonylaminomethyl, it can also be produced, for example, by the following method.

[0115]

[Chemical Formula 39]

(In the series of formulas, R ⁷ , R ⁸ , R ⁹ ,
R ¹⁰ has the above meaning, R ³³ means hydrogen, alkyl, optionally substituted aryl, optionally substituted arylalkyl, heteroaryl, heteroarylalkyl, and R ³⁴ and R ³⁵ are It means alkyl, optionally substituted aryl, or heteroaryl. ) In the first step, the hydroxyl group of the 3-hydroxymethylquinoline derivative (64) is converted into chlorine by reacting lithium chloride and methanesulfonyl chloride in the presence of a base such as collidine by a conventional method, and then reacted with an amine. And the step of obtaining a 3-aminomethylquinoline derivative (68). At this time, N, N-dimethylformamide may be used as the solvent. The reaction temperature is from -40 ° C to the boiling point of the solvent, preferably 0 ° C to 50 ° C. In the subsequent step, the 3-aminomethylquinoline derivative (68) obtained in the previous step and a reactive acid derivative such as an acid anhydride or an acid halide or a sulfonic acid halide is treated with a deoxidizing agent such as triethylamine or N-methylmorpholine. 3-acylaminomethylquinoline derivative (69) or 3-sulfonylaminomethylquinoline derivative (70) when reacted in the presence
Can be obtained. Examples of the solvent include solvent-free, dichloromethane, tetrahydrofuran, N, N-dimethylformamide and the like. Reaction temperature is -40 ℃
To the boiling point of the solvent, but preferably 0 ° C to 50 ° C. In the next step, the 3-acylaminomethylquinoline derivative (69) or 3-sulfonylaminomethylquinoline derivative (70) obtained in the previous step was treated with the compound (66) or (67) in the production method 15 of starting materials. When treated in the same manner as in the production, the desired 4-hydroxy-3-acylaminomethylquinoline derivative (71) or (73) or 4
In this step, it is possible to obtain the -hydroxy-3-sulfonylaminomethylquinoline derivative (72) or (74).

Method 17 for producing starting material 3-hydroxymethylquinoline derivative (64) used as a starting material in the method 15 for producing starting material
Can be produced, for example, by the following method.

[0118]

[Chemical 40]

(In the series of formulas, R ⁷ , R ⁸ , R ⁹ ,
R ¹⁰ has the above-mentioned meaning, and R ³⁶ means a lower alkyl group. ) The first step is a step of obtaining a condensate (76) by dehydration-condensing the aniline derivative represented by the general formula (34) and the malonic acid diester derivative represented by the general formula (75). In this case, examples of the solvent include no solvent or cyclohexane, benzene, toluene and the like. Examples of the acid include hydrochloric acid, sulfuric acid, p-toluenesulfonic acid and the like. The reaction temperature is appropriately selected from room temperature to the boiling point of the solvent. The condensate (76) obtained in the previous step is treated in the same manner as in the production method (30) or (31) in the production method 7 of a starting material to obtain a quinoline-3-carboxylic acid ester derivative (83) or (78). be able to. In the next step, the obtained quinoline-3-carboxylic acid ester derivative (77) or (78) was treated with chloromethyl methyl ether in the same manner as in the case of the compound (21) of the production method 1, to give 4-methoxymethoxy. A quinoline-3-carboxylic acid ester derivative (79) can be obtained. Finally, the ester derivative (79) obtained in the previous step is reacted with a reducing agent such as lithium aluminum hydride by a conventional method using, for example, tetrahydrofuran or diethyl ether as a solvent,
Target 3-hydroxymethylquinoline derivative (6
4) can be obtained.

Production Method 18 for Starting Material In the production method 6 for starting material, in the compound (34) used as a starting material, lower alkoxy or alkoxyalkoxy is at the 2,5 position, and R ⁹ is a lower alkyl group or alkoxy. The following is a specific description of an example of the production method for the case of an alkyl group.

[0121]

Embedded image

(In the series of formulas, R ³⁷ and R ³⁹ represent the same or different lower alkyl and alkoxyalkyl, R ³⁸ represents a hydrogen atom, a lower alkyl group and an alkoxyalkyl group, and X represents a halogen atom. The first step is a step of reacting the compound represented by the general formula (80) with a nitrating reagent such as nitric acid to obtain a nitrobenzene derivative (81). As the solvent,
Water, tetrahydrofuran, hexane, dichloromethane,
Examples thereof include nitric acid and a mixed solvent thereof.
The reaction temperature is about -50 ° C to 50 ° C, preferably about -20 ° C to room temperature. In the next step, the carbonyl group of the nitrobenzene derivative (81) obtained in the previous step is reacted with ethyl chloroformate in the presence of a base such as triethylamine according to a conventional method, and then reduced with sodium borohydride. As a result, a nitrobenzene derivative (82) in which carbonyl is reduced can be obtained. Tetrahydrofuran can be used as a solvent when reacting with chloroformic acid ethyl ester, and water, methanol, ethanol, tetrahydrofuran and a mixed solvent thereof can be used when reducing with sodium borohydride. The reaction temperature is approximately −20 ° C. to room temperature. In the next step, the nitrobenzene derivative (82) obtained in the previous step is subjected to a conventional method using an alkali metal salt such as potassium carbonate, sodium hydride or potassium hydride as a base to form a halogen compound R ^39.
This is a step of reacting with —Hal to obtain a dialkoxynitrobenzene derivative (83). In this case, examples of the halogen include chlorine atom, bromine atom, iodine atom and the like. A good example of the solvent is N, N-dimethylformamide. The reaction temperature is about 0 ° C. to the boiling point of the solvent, but preferably about room temperature to the boiling point of the solvent. In the subsequent step, the nitro group of the obtained dialkoxynitrobenzene derivative (83) was prepared by a conventional method.
For example, the target aniline derivative (84) can be obtained by catalytic hydrogenation using a catalyst such as palladium carbon or reduction using stannic chloride or the like. Examples of the reaction solvent include alcohols such as methanol and ethanol, ethyl acetate, tetrahydrofuran and the like. The reaction temperature is 0 ° C to room temperature.

Production Method 19 for Starting Material In the production method 6 for starting material, in the compound (34) used as a starting material, R ⁹ and R ¹⁰ are lower alkyl groups, R ⁸ is a hydrogen atom, and R ⁷ is Regarding the case of a lower alkoxy group or an alkoxyalkoxy group, an example of the production method will be specifically described as follows.

[0124]

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(In the series of formulas, R ⁴⁰ and R ⁴¹ are the same or independent to each other, a lower alkyl group, R ⁴² is a lower alkyl or alkoxyalkyl, and X is a halogen.) The nitrophenol derivative represented by the formula (85) is converted into the compounds (83) and (8) of the production method 18 of the starting material.
This is a method of obtaining the desired aniline derivative (87) when treated in the same manner as in the production of 4).

Method 20 for producing starting material In the method 6 for producing starting material, in the compound (34) used as a starting material, R ⁹ and R ¹⁰ are lower alkyl groups, R ⁸ is a hydrogen atom, and R ⁷ is With respect to the case of a fluorine atom, a specific example of the production method will be described below.

[0127]

[Chemical 43]

(In the series of formulas, R ⁴³ and R ⁴⁴ are the same or independently represent a lower alkyl group.) The first step is to prepare the nitroaniline derivative represented by the general formula (88) by a conventional method. For example, it is a step of treating with sodium nitrite in concentrated hydrochloric acid to form a diazonium salt, and then treating this with difluoroborofluoric acid to obtain a diazonium borofluoride salt (89). When the obtained diazonium borofluoride salt (89) is thermally decomposed, a fluoronitrobenzene derivative (90) can be obtained. Examples of the solvent may include no solvent or a high boiling point solvent such as xylene. Next, the fluoronitrobenzene derivative (90) obtained in the previous step was treated with the compound (8
When treated in the same manner as 4), the desired fluoroaniline derivative (91) can be obtained.

Production Method 21 of Starting Material In the production method 6 of starting material, in the compound (34) used as a starting material, when R ⁹ is an amide, R ⁷ and R ¹⁰ are a lower alkoxy group or an alkoxyalkoxy group. A specific method for producing the same is described below by taking the case where R ⁸ is a hydrogen atom as an example.

[0130]

[Chemical 44]

(In the series of formulas, R ⁴⁵ and R ⁴⁶ are the same or independently lower alkyl and alkoxyalkyl, X is halogen, and R ⁴⁷ and R ⁴⁸ are the same or independently hydrogen. Lower alkyl, optionally substituted aryl, heteroaryl and R ⁴⁷ , together with the nitrogen atom to which R ⁴⁷ and R ⁴⁸ are bonded, means a ring containing an oxygen atom, a sulfur atom or a nitrogen atom. In the step, the benzaldehyde derivative represented by the general formula (92) is converted to the compound (81) in the production method 18 of starting materials
And a step of sequentially treating the compound (83) with the same method as that of the compound (83) to obtain a dialkoxynitrobenzaldehyde derivative (94). Next, the obtained dialkoxynitrobenzaldehyde derivative (94) is oxidized by a conventional method using, for example, sodium hypochlorite, chromic acid, permanganate or the like to obtain a nitrobenzoic acid derivative (95). be able to. Water, dimethyl sulfoxide or the like is used as a reaction solvent, and the temperature is 0 ° C to 50 ° C. Then, the other benzoic acid derivative (95) obtained in the previous step is reacted with an amine by an ordinary method, for example, after introducing it into an acid halide using thionyl chloride, or reacted with an amine by a mixed acid anhydride method. Or reacting with an amine using a condensing agent such as N, N′-dicyclohexylcarbodiimide or N-ethyl-N′-3-dimethylaminopropylcarbodiimide, a nitrobenzoic acid amide derivative (9
6) can be obtained. At this time, as a reaction solvent,
Dichloromethane, tetrahydrofuran, diethyl ether, N, N-dimethylformamide and the like can be mentioned.
The reaction temperature is from -20 ° C to the boiling point of the solvent, preferably 0 ° C to room temperature. In the next step, the nitro group of the nitrobenzoic acid amide derivative (96) obtained in the previous step was treated in the same manner as in the compound (84) of the production method 18 of the starting material to obtain the desired aniline derivative (97). Is a step of obtaining.

Production Method 22 for Starting Material In the production method 6 for starting material, in the compound (34) used as a starting material, when R ⁹ is an amidoalkyl group, R ⁷ and R ¹⁰ are lower alkoxy groups or An example of a specific production method for an alkoxyalkoxy group in which R ⁸ is a hydrogen atom is as follows.

[0133]

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(In the series of formulas, R ⁴⁵ , R ⁴⁶ , R ⁴⁷ and R ⁴⁸ have the above-mentioned meanings.) That is, nitrobenzaldehyde represented by the general formula (94) and a phosphoric acid ester derivative (98) In the presence of a base such as sodium hydride, potassium hydride, sodium methoxide or potassium t-butoxide to give the amide compound (99). Examples of the reaction solvent include tetrahydrofuran, N, N-diethylformamide and dimethoxyethane, and the reaction temperature is-.
20 ° C. to room temperature. The next step is a step of treating the amide derivative (99) obtained in the previous step in the same manner as the compound (60) in the production method 13 of the starting material to obtain the desired aniline derivative (100).

Method 23 for producing a starting material An aniline derivative (107) which is a starting material when the compound (47) or (48) used in the method 10 for producing a starting material is produced according to the method 6 for producing a starting material.
Can be produced, for example, by the following method.

[0136]

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(In the series of formulas, R ⁴⁵ and R ⁴⁶ have the above-mentioned meanings, R ⁴⁹ represents a lower alkyl group, and X represents halogen.) The first step is the general formula (101). The nitrobenzaldehyde derivative represented by phosphorane (102),
When the Wittig reaction is performed with the phosphoric acid ester (103) and the phosphonium salt (104), the unsaturated ester derivative (10
This is the step of obtaining 5). Dichloromethane as solvent,
Examples thereof include chloroform, N, N-dimethylformamide, dimethoxyethane, tetrahydrofuran, ethanol and the like. The reaction temperature is about -40 ° C to the boiling point of the solvent, preferably about 0 ° C to 50 ° C. The next step is to reduce the unsaturated ester derivative (105) obtained in the previous step by a conventional method using a reducing agent such as diisobutylaluminum hydride,
In this step, the alcohol derivative (106) is obtained. Examples of the solvent include dichloromethane, diethyl ether, tetrahydrofuran and the like. The reaction temperature is appropriately selected from -78 ° C to the boiling point of the solvent. In the subsequent step, the alcohol derivative (106) obtained in the previous step is treated by a conventional method with, for example, imidazole or triethylamine as a base to prepare t
It is a step of obtaining a silyl ether derivative (107) by reacting with -butylchlorodimethylsilane or the like. next,
The target aniline derivative (108) can be obtained by catalytically reducing the alcohol derivative (107) obtained in the previous step using palladium carbon by a conventional method.

Method 24 for producing starting material In the method 6 for producing starting material, R ⁷ and R ¹⁰ are the same as those in the compound (34) used as a starting material when R ⁹ is an alkoxyalkyl group or an alkoxyalkoxyalkyl group. The following is a description of a specific production method for an alkoxy group or an alkoxyalkoxy group, where R ⁸ is a hydrogen atom as an example.

[0139]

[Chemical 47]

(In the formula, R ⁴⁵ , R ⁴⁶ and R ⁴⁹ are the same or independently represent lower alkyl or alkoxyalkyl;
Means halogen. ) The first step is to react the nitrobenzaldehyde derivative represented by the general formula (94) with a reducing agent such as sodium borohydride, lithium aluminum hydride or diisobutylaluminum hydride by a conventional method to form nitrobenzyl alcohol. This is a step of obtaining the derivative (109). Examples of the reaction solvent include methanol, ethanol, diethyl ether, tetrahydrofuran, dichloromethane and the like. The reaction temperature is appropriately selected from -78 ° C to the boiling point of the solvent. Next, the nitrobenzyl alcohol derivative (109) obtained in the previous step is reacted with an alkyl halide or an alkoxyalkyl halide in the same manner as in the production of the compound (65) in the production method 15 of a starting material to give a nitrobenzene derivative ( 110) can be obtained. Next, the nitrobenzene derivative (1
When 10) is treated in the same manner as in the production of compound (84) in the production method 18 of starting material, the desired aniline derivative (1
11) can be obtained. Production Method 25 of Starting Material In the production method G, the compound represented by the general formula (113) used as a starting material is produced, for example, by the following method.

[0141]

Embedded image

(In the series of equations, R ² , R ⁷ , R ⁸ ,
R ⁹ , R ¹⁰ and X have the meanings given above. ) That is, the 2-methyl group of the compound represented by the general formula (112) is oxidized to formyl group by using selenium dioxide in the same manner as in the manufacturing method 3 of starting materials, or by J. Chem. Res.
(S), 5, 159 (1980), Indian J. Chem., 25B , 384-389
The target compound (113) can be obtained by converting to a formyl group by the method described in (1986). Starting Material Manufacturing Method 26 In the starting material manufacturing method 25, the 2-position methyl compound used as the starting material can be manufactured, for example, by the following method.

[0143]

[Chemical 49]

(In the series of equations, R ² , R ⁷ , R ⁸ ,
R ⁹ , R ¹⁰ and X have the meanings given above. That is, the compound represented by the general formula (114) is heated by a conventional method, for example, in the presence of triethylamine or sodium acetate in acetic anhydride to obtain the target compound 2
The position methyl compound (115) can be easily obtained. Method 27 for producing starting material In the method 26 for producing starting material, R ² , R ⁹ and R of the ketone compounds (114) used as starting materials are used.
^{When 10} is a lower alkyl group, R ⁸ is a hydrogen atom, R ⁷ is a lower alkoxy group or an alkoxyalkoxy group, and X is an oxygen atom, a specific example of the production method will be described below.

[0145]

Embedded image

(In the series of formulas, R ⁵⁰ and R ⁵³ represent a lower alkyl group, R ⁵¹ represents a hydrogen atom or a lower alkyl group, R ⁵² represents a lower alkyl group or an alkoxyalkyl group, and Hal Means a halogen atom.) That is, a halogen compound R-Hal is prepared by using a compound represented by the general formula (116) as a base and using potassium carbonate as a base.
The compound (117) in which the hydroxyl group at the 4-position is alkylated can be obtained by reacting with. In this case, examples of the halogen atom include chlorine atom, bromine atom, iodine atom and the like. Examples of the solvent include acetone and N, N-dimethylformamide. The reaction temperature is from 0 ° C to the boiling point of the solvent, preferably room temperature. The 2,3-dialkylphenol derivative (118) can be obtained by reducing the carbonyl group of the obtained monoalkoxybenzene derivative (117) by a conventional method, for example, using zinc-amalgam or hydrazine. The resulting 2,3-dialkylphenol derivative (118) is treated with chloromethyl methyl ether in the presence of a base such as sodium hydride or N, N-diisopropylethylamine to obtain a methoxymethoxybenzene derivative (119). be able to. The resulting methoxymethoxybenzene derivative (119) and a strong base such as n-
The benzaldehyde derivative (120) can be obtained by reacting with butyllithium and then reacting with N, N-dimethylformamide. At this time, ethers such as ether and tetrahydrofuran are used as the solvent, and the reaction can be carried out at -78 ° C to 30 ° C, preferably -30 ° C to room temperature. After reacting the obtained benzaldehyde derivative (120) with an organometallic compound,
The ketone derivative (121) can be obtained by oxidizing the obtained alcohol compound according to a conventional method. Examples of the organometallic compound include alkyl lithium and Grignard reagent. Ether as solvent,
Tetrahydrofuran etc. are mentioned. Reaction temperature is -78
C. to 50.degree. C., preferably -78.degree. C. to room temperature. Examples of the oxidizing agent for oxidizing the obtained alcohol derivative include manganese dioxide, permanganate, chromate, dimethyl sulfoxide, and the like. As a reaction solvent, alcohols such as methanol and ethanol,
Acetone, dichloromethane, chloroform, ethyl acetate, pyridine, N, N-dimethylformamide and the like can be mentioned. The reaction temperature is appropriately selected from under ice cooling to the boiling point of the solvent. The desired ketone compound (122) can be obtained by deprotecting the methoxymethyl group of the obtained ketone derivative (121) by a conventional method. Examples of the reaction solvent include water or a solvent miscible with water, for example, ethers such as tetrahydrofuran and dioxane, alcohols such as methanol and ethanol, acetone and the like. Examples of the acid as the deprotecting agent include hydrochloric acid, sulfuric acid, methanesulfonic acid, P-toluenesulfonic acid, D-
10-camphorsulfonic acid, acetic acid, trifluoroacetic acid and the like can be mentioned. The reaction temperature is -40 ° C to the boiling point of the solvent, preferably room temperature to the boiling point of the solvent.

Next, in order to describe the effect of the present invention in detail,
Examples of pharmacological experiments for representative compounds of the compounds of the present invention are shown below. Pharmacological Experimental Example Interleukin-1 (IL-from human peripheral blood monocytes)
1) Inhibitory effect on production Venous blood was collected from a healthy adult male in the presence of citric acid, and mononuclear cells were obtained from this blood by the Ficoll / Paque specific gravity centrifugation method. The cells were treated with HBSS (Mg ²⁺ , Ca ²⁺ f
After being washed 3 times with ree), the cells were suspended in RPMI-1640 culture solution containing 10% inactivated autologous serum at 4 × 10 ⁶ cells / ml. The suspension is put by 0.5ml in 48 well plate for _{cultivation, 37 ℃, 5% CO 2} /9
The cells were cultured at 5% air for 2 hours. The adherent cells after washing the culture plate twice with HBSS and removing the non-adherent cells were used in the experiment as monocytes. The test compound was dissolved in dimethyl sulfoxide, and the final concentration of dimethyl sulfoxide was 0.
It was added to RPMI-1640 culture solution (0.5 ml) containing 10% or 1% inactivated autologous serum to be 1%, and then added to a monocyte culture plate. Then, lipopolysaccharide was added so that the final concentration was 10 ng / ml, and the mixture was incubated at 37 ° C., 5% CO ₂ /95% air for 18 hours. After completion of the culture, the culture supernatant was passed through a Millipore filter and used as a measurement sample for extracellular IL-1. In addition, a culture solution (0.5 ml) was newly added to the adherent cells, the cells were disrupted by ultrasonic waves and then passed through a Millipore filter to obtain an intracellular IL-1 measurement sample. Intracellular and extracellular IL
The amount of -1α and IL-1β was quantified by a commercially available enzyme-linked immunosorbent assay (ELISA) kit (Cayman), and the potency of the test compound was 50% IL-1 production inhibitory concentration (IC).
₅₀ , μM). The results are shown in Tables 1 and 2. The compound numbers in the table correspond to the example numbers described below.

[0148]

[Table 1]

[0149]

[Table 2]

[0150]

[0151]

EXAMPLES Next, examples will be given to facilitate understanding of the present invention. Prior to the examples, intermediates for producing the compounds of the present invention were listed as synthetic examples. Synthesis Example 1 4-Acetyl-1-methylsulfonyl-4-phenylpi
Perazine

[0152]

[Chemical 48]

To a solution of 2.5 g (10.4 mmol) of 4-acetyl-4-phenylpiperazine hydrochloride in dichloromethane (50 ml), 4.3 ml (31 mmol) of triethylamine and 1.2 ml (15.5 mmol) of methanesulfonyl chloride were added under ice cooling. . At room temperature
After stirring for 12 hours, water was added to the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water, diluted hydrochloric acid and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and diisopropyl ether was added to the resulting residue for crystallization to obtain the title compound as pale brown crystals.

¹ H-NMR (400 MHz, CDCl ₃ ) δ; 1.93 (s, 3H), 2.1
0-2.20 (m, 2H), 2.50-2.57 (m, 2H), 2.75 (s, 3H), 2.96-3.04
(m, 2H), 3.56-3.63 (m, 2H), 7.25-7.34 (m, 3H), 7.36-7.42
(m, 2H)

Synthesis Example 2 3-Acetylamino-3-methyl-2-butanone

[0156]

[Chemical 49]

(A) 3-Acetylamino-3-methyl-1
-Synthesis of butyne 1,1-Dimethylpropargylamine 8.3g (0.1mol)
In dichloromethane (100 ml) under ice-cooling, triethylamine 15.3 ml (0.11 mol) and acetyl chloride 7.8 ml (0.11 mol)
mol) was added. After stirring at room temperature for 2 hours, water was added to the reaction solution. The organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the precipitated crystals were collected by filtration to give the title compound (10.6 g, yield 85%) as colorless crystals. ¹ H-NMR (400MHz, CDCl ₃ ) δ; 1.62 (s, 6H), 1.94 (s,
3H), 2.32 (s, 1H), 5.62 (br.s, 1H)

(B) 3-Acetylamino-3-methyl-2
-Synthesis of butanone

[0159]

[Chemical 50]

3.3 g (26.4 mmol) of 3-acetylamino-3-methyl-1-butyne was added to the method of Stacey et al. (Org, S
ynth, 〓 , 13 (1963)) and treated with silver oxide and sulfuric acid to obtain 1.4 g of the title compound (yield 37%) as colorless crystals.

¹ H-NMR (400 MHz, CDCl ₃ ) δ; 1.49 (s, 6H), 1.9
8 (s, 3H), 2.19 (s, 3H), 6.36 (br.s, 1H)

Synthesis Example 3-6 After reacting 1,1-dimethylpropargylamine with an appropriate acid chloride, reactive acid derivative or sulfonyl chloride compound, silver oxide was prepared in the same manner as in Reference Example 2 (b). And treated with sulfuric acid to obtain the compounds shown in the table.

[0163]

[Table 1]

Synthesis Example 7 N- (1,1-dimethyl-2-oxopropyl) -3-
Amino pyridine

[0165]

[Chemical 51]

(A) Synthesis of 3-methyl-3- (3-pyridylamino) -1-butyne

[0167]

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3-Chloro-3-methyl-1-butyne 2.5
g (24 mmol) and 2.8 g (29 mmol) of 3-aminopyridine were used according to the method of Hennion et al. (J. Am. Chem. Soc., 82 ,
4908-4912 (1960)) to give the title compound 1.
42 g (yield 37%) was obtained as pale yellow crystals.

¹ H-NMR (400 MHz, CDCl ₃ ) δ; 1.62 (s, 6H), 2.4
1 (s, 1H), 3.73 (br.s, 1H), 7.12 (m, 1H), 7.34 (m, 1H), 8.05
(m, 1H), 8.23 (d, J = 2.4Hz, 1H)

(B) Synthesis of N- (1,1-dimethyl-2-oxopropyl) -3-aminopyridine

[0171]

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3-Methyl-3- (3-pyridylamino)
When 1.41 g (9 mmol) of -1-butyne was treated with silver oxide and sulfuric acid in the same manner as in (b) of Reference Example 2, the title compound was 1.
34 g (yield 85%) was obtained as red crystals.

¹ H-NMR (400 MHz, CDCl ₃ ) δ; 1.47 (s, 6H), 2.2
3 (s, 3H), 4.21 (br.s, 1H), 6.68 (m, 1H), 7.05 (m, 1H), 7.97
(m, 1H)

Synthesis Example 8 4-Acetyltetrahydropyran-4-ol

[0175]

[Chemical 54]

(A) 4-ethynyltetrahydropyran-4
-All synthesis

[0177]

[Chemical 55]

To a solution of 13.8 g (150 mmol) of lithium acetylide-ethylenediamine complex in tetrahydrofuran (50 ml) was added tetrahydro-4H-pyran- at room temperature.
5.0 g (50 mmol) of 4-one was added and stirred at the same temperature for 1 hour. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was purified by silica gel column chromatography to give 1.05 g of the title compound (yield: 17
%) Was obtained as a colorless oil.

¹ H-NMR (400 MHz, CDCl ₃ ) δ; 1.78-1.86 (m, 2
H), 1.92-1.98 (m, 2H), 2.35 (s, 1H), 2.56 (s, 1H), 3.63-3.71
(m, 2H), 3.88-3.94 (m, 2H)

(B) 4-acetyltetrahydropyran-4
-All

[0181]

[Chemical 56]

By treating 1.05 g (8.3 mmol) of 4-ethynyltetrahydropyran-4-ol in the same manner as in (b) of Reference Example 2, 493 mg (yield 41%) of the title compound was obtained as a colorless oil.

[0183]

[Chemical 57]

¹ H-NMR (400 MHz, CDCl ₃ ) δ; 1.34-1.40 (m, 2
H), 2.08-2.16 (m, 2H), 2.29 (s, 3H), 3.80-3.95 (m, 4H) Synthesis Example 9 4-Acetyl-4-hydroxy-1-methylpiperidine

[0185]

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When 1-methyl-4-piperidone was treated in the same manner as in Reference Example 2, the title compound was obtained as a colorless oil.

¹ H-NMR (400 MHz, CDCl ₃ ) δ; 1.44-1.51 (m, 2
H), 2.05-2.15 (m, 2H), 2.28 (s, 3H), 2.31-2.41 (m, 2H), 2.34
(s, 3H), 2.76-2.82 (s, 2H), 3.80 (br.s, 1H)

Synthesis Example 10 3- (2-Methoxyethoxy) -3-methyl-2-butane
Non

[0189]

Embedded image

(A) 3- (2-methoxyethoxy) -3-
Synthesis of methyl-1-butyne

[0191]

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2-Methyl-3-butyn-2-ol 5.0
g (59.5 mmol) of N, N-dimethylformamide (120 m
l) To the solution under ice cooling, 2.6 g of 60% sodium hydride (65 mm
ol) and 2-bromoethyl ethyl ether 6.7 ml (71 mmo
l) was added. After stirring at the same temperature for 2 hours, water is added to the reaction solution and the mixture is extracted with ethyl acetate. The organic layer was washed and then dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was subjected to silica gel column chromatography (20%
3.2 g of the title compound after purification with ethyl acetate / hexane)
(Yield 38%) was obtained as a light brown oil.

¹ H-NMR (400 MHz, CDCl ₃ ) δ; 1.49 (s, 6H), 2.4
1 (s, 1H), 3.39 (s, 3H), 3.56 (m, 2H), 3.72 (m, 2H)

(B) 3- (2-methoxyethoxy) -3-
Synthesis of methyl-2-butanone

[0195]

[Chemical formula 61]

3- (2-Methoxyethoxy) -3-methyl-1-butyne was treated in the same manner as in Reference Example 2 (b) to give the title compound as a pale brown oil.

¹ H-NMR (400 MHz, CDCl ₃ ) δ; 1.32 (s, 6H), 2.2
4 (s, 3H), 3.40 (s, 3H), 3.45 (m, 2H), 3.55 (m, 2H)

Synthesis Example 11 3- (2-hydroxyethoxy) -3-methyl-2-bu
Tanon

[0199]

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2-methyl-3-butyn-2-ol,
When tetrahydro-2- (2-iodoethoxy) -2H-pyran was used in place of 2-bromoethylethyl ether and treated in the same manner as in Reference Example 10, the title compound was obtained as a colorless oil.

¹ H-NMR (400 MHz, CDCl ₃ ) δ; 1.35 (s, 6H), 2.2
3 (s, 3H), 3.45 (s, 2H), 3.76 (m, 2H)

Synthesis Example 12 3- (2-Cyanoethoxy) -3-methyl-2-butano
The

[0203]

[Chemical formula 63]

(A) Synthesis of 3- (2-cyanoethoxy) -3-methyl-1-butyne

[0205]

[Chemical 64]

2-Methyl-3-butyn-2-ol 5.0
A mixture of g (59.5 mmol), acrylonitrile 4.3 ml (65 mmol) and Triton B 0.1 ml was stirred at room temperature for 30 minutes.
By directly purifying the reaction mixture by silica gel column chromatography (15% ethyl acetate / hexane),
7.7 g (yield 92%) of the title compound was obtained as a colorless oil.

¹ H-NMR (400 MHz, CDCl ₃ ) δ; 1.49 (s, 6H), 2.4
7 (s, 1H), 2.61 (t, J = 6.4Hz, 2H), 3.79 (t, J = 6.4Hz, 2H)

Synthesis Example 13 3- (2-carbamoylethoxy) -3-methyl-2-
Butanone

[0209]

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1.0 g (6.4 mmol) of 3- (2-cyanoethoxy) -3-methyl-2-butanone in 40 ml of concentrated hydrochloric acid at 40.degree.
It was stirred for 24 hours. The solution was neutralized with 1N sodium hydroxide, extracted with ethyl acetate, and dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (ethyl acetate) to obtain 0.47 g (yield 42%) of the title compound as a colorless oil.

¹ H-NMR (400 MHz, CDCl ₃ ) δ; 1.35 (s, 6H), 2.1
9 (s, 3H), 2.50 (m, 2H), 3.59 (m, 2H)

(B) Synthesis of 3- (2-cyanoethoxy) -3-methyl-2-butanone

[0213]

[Chemical formula 66]

3- (2-Cyanoethoxy) -3-methyl-1-butyne was treated in the same manner as in Reference Example 2 (b) to give the title compound as a colorless oil.

¹ H-NMR (400 MHz, CDCl ₃ ) δ; 1.34 (s, 6H), 2.2
5 (s, 3H), 2.64 (t, J = 6.4Hz, 2H), 3.57 (t, J = 6.4Hz, 2H)

Synthesis Example 14 3- (4-hydroxyphenyl) -3-methyl-2-bu
Tanon

[0219]

Embedded image

(A) Synthesis of 2- (4-methoxymethoxyphenyl) propionic acid methyl ester

[0219]

[Chemical 68]

A solution of 23.7 g (113 mmol) of 4-methoxymethoxyphenylacetic acid methyl ester in N, N-dimethylformamide (200 ml) was added at room temperature to 55% sodium hydride.
g (124 mmol) and methyl iodide 8.5 ml (135 mmol) were added. After stirring at the same temperature for 1 hour, water was added to the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline and then dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (5% ethyl acetate / hexane) to give 17.3 g (yield 68%) of the title compound as a colorless oil.

(B) Synthesis of 2- (4-methoxymethoxyphenyl) -2-methylpropionic acid methyl ester

[0222]

[Chemical 69]

N-Butyllithium (2.5 M hexane solution; 34 ml, 85 mmol) was added to a solution of 8.6 g (85 mmol) of diisopropylamine in tetrahydrofuran (150 ml) under ice cooling. After stirring at the same temperature for 15 minutes, this solution was cooled to −70 ° C., and a tetrahydrofuran solution of 17.3 g (77 mmol) of 2- (4-methoxymethoxyphenyl) propionic acid methyl ester was slowly added. After stirring at the same temperature for 1 hour, 32 ml (178 mmol) of hexamethylphosphoric triamide and 9.5 ml (154 mmol) of methyl iodide were added, and the mixture was further stirred for 1 hour. A saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was subjected to silica gel column chromatography (5% ethyl acetate /
17.0 g of the title compound by purification with hexane)
(Yield 92%) was obtained as a colorless oil.

¹ H-NMR (400 MHz, CDCl ₃ ) δ; 1.56 (s, 6H), 3.4
8 (s, 3H), 3.65 (s, 3H), 5.16 (s, 2H), 6.99 (d, J = 8.4Hz, 1H),
7.26 (d, J = 8.4Hz, 1H)

(C) 1- (4-methoxymethoxyphenyl) -1-methylethyl methylsulfinylmethyl
Ketone synthesis

[0226]

Embedded image

2- (4-methoxymethoxyphenyl)-
2-Methylpropionic acid methyl ester 5.0g (21mmo
l) by Corley et al. (J. Am. Chem. Soc., 87 , 1345
-1353 (1965)), the title compound 5.6g
(Yield 93%) was obtained as pale yellow crystals.

¹ H-NMR (400 MHz, CDCl ₃ ) δ; 1.50 (s, 3H), 1.5
2 (s, 3H), 2.61 (s, 3H), 3.49 (s, 3H), 3.53 (d, J = 15.2Hz, 1H),
3.84 (d, J = 15.2Hz, 1H), 5.18 (s, 2H), 7.05 (d, J = 8.0Hz, 2H),
7.17 (d, J = 8.0Hz, 2H)

(D) Synthesis of 3- (4-methoxymethoxyphenyl) -3-methyl-2-butanone

[0230]

Embedded image

1- (4-methoxymethoxyphenyl)-
1-methylethyl methylsulfinyl methyl ketone
5.6 g (20 mmol) was added to the method of Corley et al. (J. Am. Chem. S.
oc., 87 , 1345-1353 (1965)) and treated with aluminum amalgam to give 3.74 g of the title compound (yield 86
%) Was obtained as a pale yellow oil.

¹ H-NMR (400 MHz, CDCl ₃ ) δ; 1.46 (s, 6H), 1.9
1 (s, 3H), 3.80 (s, 3H), 6.88 (d, J = 8.0Hz, 2H), 7.18 (d, J = 8.0
(Hz, 2H)

(E) 3- (4-hydroxyphenyl) -3
-Synthesis of methyl-2-butanone

[0234]

Embedded image

3- (4-methoxymethoxyphenyl)-
To a solution of 3.74 g (17 mmol) of 3-methyl-2-butanone in acetone (50 ml) was added 5 ml of 6N hydrochloric acid, and the mixture was stirred at 50 ° C for 30 minutes. Water was added to the reaction solution, and the mixture was extracted with ethyl sulfate. The organic layer was washed with water and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (3.0 g, yield 100%) as a yellow oil.

¹ H-NMR (400 MHz, CDCl ₃ ) δ; 1.45 (s, 6H), 1.9
2 (s, 3H), 4.99 (s, 1H), 6.82 (d, J = 8.4Hz, 2H), 7.13 (d, J = 8.4
(Hz, 2H)

Synthesis Example 15 3- (4-Methoxyphenyl) -3-methyl-2-buta
Non

[0238]

Embedded image

3- (4-Hydroxyphenyl) -3-methyl-2-butanone To a solution of 1.5 g (8.4 mmol) of N, N-dimethylformamide (30 ml) under ice-cooling, 0.4 g of 60% sodium hydride ( 9.3 mmol) and methyl iodide 0.62 ml (10 mm
ol) was added. After stirring at the same temperature for 30 minutes, water was added to the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was subjected to silica gel column chromatography (5
% Ethyl acetate / hexane) to give 1.33 g (yield 82%) of the title compound as a pale yellow oil.

¹ H-NMR (400 MHz, CDCl ₃ ) δ; 1.46 (s, 6H), 1.9
1 (s, 3H), 3.80 (s, 3H), 6.88 (d, J = 8.0Hz, 2H), 7.18 (d, J = 8.0
(Hz, 2H)

Synthesis Example 16 4- (1,1-dimethyl-2-oxopropyl) pheno
Xylacetic acid ethyl ester

[0242]

[Chemical 74]

1.4 g (7.9 mmol) of 3- (4-hydroxyphenyl) -3-methyl-2-butanone was treated in the same manner as in Reference Example 15 using 0.95 ml (87 mmol) of ethyl bromoacetate instead of methyl iodide. Then, 1.52 g of the title compound (yield 73
%) Was obtained as a pale yellow oil.

¹ H-NMR (400 MHz, CDCl ₃ ) δ; 1.30 (t, J = 7.2 H
z, 3H), 1.45 (s, 6H), 1.91 (s, 3H), 4.28 (q, J = 7.2Hz, 3H), 4.6
2 (s, 2H), 6.89 (d, J = 8.4Hz, 2H), 7.18 (d, J = 8.4Hz, 2H)

Synthesis Example 17 3-Methyl-3- (3-pyridyl) -2-butanone

[0246]

[Chemical 75]

(A) Synthesis of 2-methyl-2- (3-pyridyl) propionic acid ethyl ester

[0248]

[Chemical 76]

3-Pyridyl acetic acid ethyl ester 4.94 g
(30 mmol) by the method of Denny et al. (J. Med. Chem., 37, 371
-380 (1994)), the title compound 1.35g
(23% yield) was obtained as a yellow oil.

¹ H-NMR (400 MHz, CDCl ₃ ) δ; 1.19 (t, J = 7.0H
z, 3H), 1.62 (s, 6H), 4.14 (q, J = 7.0Hz, 2H), 7.26 (m, 1H), 7.6
6 (m, 1H), 8.53 (m, 1H), 8.62 (br.s, 1H)

(B) 3-Methyl-3- (3-pyridyl)-
Synthesis of 2-butanone

[0252]

Embedded image

2-Methyl-2- (3-pyridyl) propionic acid ethyl ester (1.35 g, 7 mmol) was prepared in the same manner as in Reference Example 14.
Treated in the same manner as (c) and (d), 0.54 g of the title compound (yield
47%) as a yellow oil.

¹ H-NMR (400 MHz, CDCl ₃ ) δ; 1.53 (s, 6H), 1.9
7 (s, 3H), 7.29 (m, 1H), 7.58 (m, 1H), 8.54 (dd, J = 1.6Hz, 4.4H
z, 1H), 8.58 (d, J = 2.8Hz, 1H)

Synthesis Example 18 3-Hydroxy-3- (4-methoxyphenyl) -2-
Butanone

[0256]

Embedded image

To a solution of 6.0 g (32 mmol) of 4-bromoanisole in tetrahydrofuran (60 ml) was added n-butyllithium (1.6M hexane solution; 17 ml, 27 mmol) at -70 ° C. After stirring at the same temperature for 1 hour, 3.0 ml (22 mmol) of 3,3-dimethoxy-2-butanone was added, and the mixture was further stirred for 30 minutes. After warming to room temperature, 6N hydrochloric acid was added to acidify, and the mixture was stirred at the same temperature for 30 minutes. Water was added to the reaction solution and extracted with ethyl acetate. The organic layer was washed with water and saturated saline and then dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (10% ethyl acetate / hexane),
3.7 g (84% yield) of the title compound was obtained as a yellow oil.

¹ H-NMR (400 MHz, CDCl ₃ ) δ; 1.76 (s, 3H), 2.0
7 (s, 3H), 3.81 (s, 3H), 4.52 (s, 3H), 6.90 (d, J = 8.8Hz, 2H),
7.35 (d, J = 8.8Hz, 2H)

Synthesis Example 19 3-Hydroxy-3- (3-pyridyl) -2-butanone

[0260]

Embedded image

By treating in the same manner as in Reference Example 18 using 3-bromopyridine in place of 4-bromoanisole, the title compound was obtained as a yellow oil.

¹ H-NMR (400 MHz, CDCl ₃ ) δ; 1.82 (s, 3H), 2.1
4 (s, 3H), 4.65 (s, 1H), 7.33 (m, 1H), 7.78 (m, 1H), 8.58 (dd, J
= 1.6Hz, 4.8Hz, 1H), 8.76 (d, J = 1.6Hz, 1H)

Synthesis Example 20 3-Hydroxy-3- (2-pyridyl) -2-butanone

[0264]

Embedded image

By treating in the same manner as in Reference Example 18 using 2-bromopyridine instead of 4-bromoanisole, the title compound was obtained as a yellow oil.

¹ H-NMR (400 MHz, CDCl ₃ ) δ; 1.71 (s, 3H), 2.2
1 (s, 3H), 5.88 (s, 1H), 7.26 (m, 1H), 7.51 (m, 1H), 7.73 (m, 1
H), 8.56 (m, 1H)

Synthesis Example 21 3-Benzyl-3-hydroxy-2-butanone

[0268]

[Chemical 81]

5.0 g of 3,3-dimethoxy-2-butanone
To a solution of (38 mmol) in tetrahydrofuran (50 ml) was added benzylmagnesium chloride (2M tetrahydrofuran solution; 29 ml, 57 mmol) under ice cooling. After stirring at the same temperature for 1 hour, 6N hydrochloric acid was added to acidify, and the mixture was stirred at room temperature for 30 minutes. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography (10% ethyl acetate / hexane) to give the title compound (5.9 g, yield 88%) as a pale-yellow oil.

¹ H-NMR (400 MHz, CDCl ₃ ) δ; 1.42 (s, 3H), 2.2
4 (s, 3H), 3.00 (m, 2H), 3.58 (s, 1H), 7.20-7.36 (m, 5H)

Synthesis Example 22 (E) -4- (1-hydroxy-1-methyl-2-oxo)
Propyl) cinnamic acid ethyl ester

[0272]

[Chemical formula 82]

(A) 4- (1-hydroxy-1-methyl-)
Synthesis of 2-oxopropyl) benzaldehyde

[0274]

[Chemical 83]

By treating in the same manner as in Reference Example 18 using 4-bromobenzaldehyde dimethyl acetal instead of 4-bromoanisole, the title compound was obtained as a yellow oil.

¹ H-NMR (400 MHz, CDCl ₃ ) δ; 1.82 (s, 3H), 2.1
1 (s, 3H), 4.56 (s, 1H), 7.65 (d, J = 8.4Hz, 2H), 7.90 (d, J = 8.4
Hz, 1H), 10.03 (s, 1H)

(B) Synthesis of (E) -4- (1-hydroxy-1-methyl-2-oxopropyl) cinnamic acid ethyl ester

[0278]

[Chemical 84]

4- (1-hydroxy-1-methyl-2-)
1.09 g (3.1 mmol) of carboethoxymethylene triphenylphosphorane was added to a dichloromethane (10 ml) solution of 0.5 g (2.6 mmol) of oxopropyl) benzaldehyde, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was directly purified by silica gel column chromatography (20% ethyl acetate / hexane) to give the title compound (0.65 g, yield 96%) as a colorless oil.

¹ H-NMR (400 MHz, CDCl ₃ ) δ; 1.34 (t, J = 7.2 H
z, 3H), 1.79 (s, 3H), 2.11 (s, 3H), 4.27 (q, J = 7.2Hz, 2H), 4.5
5 (s, 1H), 6.45 (d, J = 16.0Hz, 1H), 7.47 (d, J = 8.4Hz, 2H), 7.5
4 (d, J = 8.4Hz, 2H), 7.67 (d, J = 16.0Hz, 1H)

Synthesis Example 23 3- (4-Diethylcarbamoylphenyl) -3-hydr
Roxy-2-butanone

[0282]

Embedded image

(A) 4- (1-hydroxy-1-methyl-)
Synthesis of 2-oxopropyl) benzoic acid

[0284]

[Chemical 86]

4- (1-hydroxy-1-methyl-2-)
Oxopropyl) benzaldehyde was treated in the same manner as in Example 4, (a) to give the crude title compound. This was used in the next reaction without further purification.

(B) Synthesis of 3- (4-diethylcarbamoylphenyl) -3-hydroxy-2-butanone

[0287]

[Chemical 87]

Crude 4- (1-hydroxy-1-methyl-2)
-Oxopropyl) benzoic acid triethylamine in a solution of 1.97 g (9.5 mmol) in tetrahydrofuran (30 ml) under ice cooling.
1.3 ml (9.5 mmol) and ethyl chlorocarbonate 0.9 ml (9.5 mmol)
Was added. After stirring at the same temperature for 30 minutes, the insoluble material was filtered off, 1.0 ml (9.5 mmol) of diethylamine was added thereto, and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction solution and extracted with ethyl sulfate. The organic layer was washed with water and saturated saline and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography (50% ethyl acetate / hexane) to give 0.3 g of the title compound as pale yellow crystals.

¹ H-NMR (400 MHz, CDCl ₃ ) δ; 1.05-1.30 (m, 6
H), 1.80 (s, 3H), 2.08 (s, 3H), 3.20-3.26 (m, 2H), 3.52-3.58
(m, 2H), 4.62 (s, 1H), 7.40 (m, 2H), 7.48 (m, 2H)

Synthesis Example 24 3- (4-chlorophenoxy) -3-methyl-2-butane
Non

[0291]

Embedded image

2- (4-chlorophenoxy) -2-methylpropionic acid was prepared by the method of Ward et al. (J. Heterocyclic ch
em., 27, 1709-1712 (1990)) to give the title compound as a brown oil.

¹ H-NMR (400 MHz, CDCl ₃ ) δ; 1.46 (s, 6H), 2.2
5 (s, 3H), 6.70 (m, 2H), 7.19 (m, 2H)

Synthesis Example 25 3-Methyl-3-morpholino-2-butanone

[0295]

[Chemical 89]

(A) 2,3-epoxy-3-methyl-2-
Synthesis of phenylsulfinylbutanone

[0297]

[Chemical 90]

5.5 g (29.2 mmol) of 1-chloroethyl phenyl sulfoxide and 4.3 ml (58.4 mmol) of acetone
Yamakawa et al. (Bull. Chem. Soc. Jpn., 58, 1983-19
90 (1985)) to give 5.7 g (yield 93%) of the title compound as a pale yellow oil. ¹ H-NMR (400MHz, CDCl ₃ ) δ; 1.31 (s, 3H), 1.43 (s, 3H), 1.82
(s, 3H), 7.48-7.56 (m, 3H), 7.62-7.68 (m, 2H) Synthesis Example 26-28 2,3-epoxy-3-methyl-2-phenylsulfinylbutanone and a suitable amine compound, (B) of Reference Example 25
The same treatment as described above was performed to obtain the compounds shown in the table.

(B) 3-Methyl-3-morpholino-2-
Synthesis of butanone 0.6 g (2.9 mmol) of 2,3-epoxy-3-methyl-2-phenylsulfinylbutanone and 0.5 g of morpholine
(5.8 mmol) by the method of Yamakawa et al. (Bull. Chem. Soc. Jpn., 5
9, 457-463 (1986)) to give the title compound
0.3 g (yield 61%) was obtained as a pale yellow oil.

¹ H-NMR (400 MHz, CDCl ₃ ) δ; 1.12 (s, 6H), 2.2
3 (s, 3H), 2.42-2.46 (m, 2H), 3.70-3.74 (m, 2H) Example 1 1,4-dihydro-7-ethyl-2- (4-hydroxy-
4-Methyl-3-oxo-1-pentenyl) -4-oxo-3,5,8-trimethoxyquinoline

[0301]

Embedded image

(A) 2'-hydroxy-5'-methoxy-3'-
Synthesis of nitroacetophenone

[0303]

Embedded image

Concentrated nitric acid (70%; 22.8 ml, 0.36 mol) was slowly added dropwise to a solution of 2'-hydroxy-5'-methoxyacetophenone (50 g, 0.3 mol) in dichloromethane (500 ml) under ice cooling. After stirring at the same temperature for 2 hours, water was added and the mixture was extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained crystals were washed with diisopropyl ether to give the title compound (48.5
g, 76%) was obtained as tan crystals.

Melting point: 111-113 ° C. ¹ H-NMR (400 MHz, CDCl ₃ ) δ; 2.71 (s, 3H), 3.86 (s, 3H), 7.64
(d, J = 3.3Hz, 1H), 7.76 (d, J = 3.3Hz, 1H), 12.28 (s, 1H)

(B) Synthesis of 2-ethyl-4-methoxy-6-nitrophenol

[0307]

Embedded image

Ethyl chloroformate was added to a solution of 2'-hydroxy-5'-methoxy-3'-nitroacetophenone (106.2g, 0.5mol) and triethylamine (55.7g, 0.76mol) in tetrahydrofuran (1.5l) under ice cooling. Ester (52.6ml, 0.
55 mol) was added dropwise. After stirring at the same temperature for 15 minutes, the insoluble material was filtered off and washed with a small amount of tetrahydrofuran. The filtrate was added dropwise to a solution of sodium borohydride (75.7g, 2.0mol) in water (1.2l) under ice cooling over 1.5 hours. After stirring for 1 hour while warming to room temperature, the reaction solution was cooled again with ice water, and 6N-hydrochloric acid (300 ml) was added. It was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The crystals obtained by evaporating the solvent under reduced pressure were washed with a mixed solvent of diisopropyl ether and hexane to give the title compound (63.3 g, 64%) as orange crystals. Further, the filtrate was purified by silica gel column chromatography (5% ethyl acetate / hexane),
The title compound (26.7g, 27%) was obtained as yellow-orange crystals.

Melting point: 62-63 ° C. ¹ H-NMR (400 MHz, CDCl ₃ ) δ; 1.24 (t, J = 7.5 Hz, 3 H), 2.73 (q,
J = 7.5Hz, 2H), 3.81 (s, 3H), 7.11 (d, J = 3.1Hz, 1H), 7.35 (d, J
= 3.1Hz, 1H), 10.77 (s, 1H)

(C) Synthesis of 2,5-dimethoxy-3-ethylnitrobenzene

[0311]

Embedded image

To a solution of 2-ethyl-4-methoxy-6-nitrophenol (10 g, 50.7 mmol) in N, N-dimethylformamide (100 ml) was added 60% sodium hydride (2.43 g, 60.8 mmol) under ice cooling. Was added. After stirring at the same temperature for 5 minutes, methyl iodide (6.3 ml, 101 mmol) was added and the mixture was stirred at 50 ° C for 1
Heated for 5 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography (5% ethyl acetate / hexane).
The title compound (10.7 g, 100%) was obtained as a yellow oil by purification with.

¹ H-NMR (400 MHz, CDCl ₃ ) δ; 1.24 (t, J = 7.5H
z, 3H), 2.71 (q, J = 7.5Hz, 2H), 3.81 (s, 3H), 3.85 (s, 3H), 7.0
0 (d, J = 3.3Hz, 1H), 7.16 (d, J = 3.3Hz, 1H)

(D) Synthesis of 2,5-dimethoxy-3-ethylaniline

[0315]

Embedded image

To a solution of 2,5-dimethoxy-3-ethylnitrobenzene (5.5 g, 26 mmol) in ethyl acetate (100 ml),
10% Palladium carbon (50% water-containing product; 0.5 g) was added, and the mixture was stirred under a hydrogen atmosphere at room temperature and atmospheric pressure for 12 hours. The reaction solution was filtered through Celite, and the filtrate was concentrated under reduced pressure to give the title compound (5.
2 g) was obtained as a colorless oil. This oil was used in the next reaction without further purification.

(E) Synthesis of 1,4-dihydro-7-ethyl-4-oxo-3,5,8-trimethoxy-2-quinolinecarboxylic acid ethyl ester

[0318]

[Chemical 96]

2,5-Dimethoxy-3-ethylaniline (5.2 g) and oxalomethoxy acetic acid diethyl ester (7.
A solution of 5 g, 34.4 mmol) in cyclohexane (60 ml) was heated to reflux for 5 hours using a Dean Stark apparatus. The reaction solution was directly purified by silica gel column chromatography (15% ethyl acetate / hexane to 20% ethyl acetate / hexane) to give (E)-and (Z) -2- (2,5-dimethoxy-3-ethyl). Mixture of two types of diethyl ester of -1-phenyl) amino-3-methoxybutenedioic acid (8.6 g, 79%
) Was obtained as a brown oil. This butenedioic acid derivative mixture (8.6 g, 22.5 mmol) of diphenyl ether (18 m
l) The solution was heated at 250 ° C for 3 hours. After cooling to room temperature, the reaction solution was directly purified by silica gel column chromatography (25% ethyl acetate / hexane-ethyl acetate) to give the title compound (3.5 g, 46%) as brown crystals.

Melting point: 125-126 ° C. ¹ H-NMR (400 MHz, CDCl ₃ ) δ; 1.29 (t, J = 7.5 Hz, 3 H), 1.46 (t,
J = 7.1Hz, 3H), 2.76 (q, J = 7.5Hz, 2H), 3.85 (s, 3H), 3.95 (s, 3
H), 3.98 (s, 3H), 4.50 (q, J = 7,1Hz, 2H), 6.42 (s, 1H), 8.91 (b
rs, 1H)

(F) 7-Ethyl-4-methoxymethoxy-
Synthesis of 3,5,8-trimethoxy-2-quinolinecarboxylic acid ethyl ester

[0322]

Embedded image

1,4-Dihydro-7-ethyl-4-oxo-3,5,8-trimethoxy-2-quinolinecarboxylic acid ethyl ester (3.5 g, 10.4 mmol) and potassium carbonate (3.6 g,
26 mmol) of N, N-dimethylformamide (30 ml) was added to chloromethyl methyl ether (1.6 ml, 21 m) under ice cooling.
mol) was added and the mixture was stirred at the same temperature for 1 hour. Aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate.
The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (25% ethyl acetate / hexane) to give the title compound. (3.8g, 96%
) Was obtained as a yellow oil.

¹ H-NMR (400 MHz, CDCl ₃ ) δ; 1.28 (t, J = 7.5H
z, 3H), 1.44 (t, J = 7.1Hz, 3H), 2.83 (q, J = 7.5Hz, 2H), 3.66
(s, 3H), 3.97 (s, 3H), 4.00 (s, 3H), 4.05 (s, 3H), 4.48 (q, J =
7.1Hz, 2H), 5.27 (s, 2H), 6.74 (s, 1H)

(G) 7-Ethyl-4-methoxymethoxy-
Synthesis of 3,5,8-trimethoxy-2-quinolinecarboxaldehyde

[0326]

Embedded image

7-ethyl-4-methoxymethoxy-3,5,
To a solution of 8-trimethoxy-2-quinolinecarboxylic acid ethyl ester (3.8 g, 10 mmol) in dichloromethane (50 ml) was added diisobutylaluminum hydride (0.93M hexane solution; 21.5 ml, 20 mmol) at -78 ° C under a nitrogen atmosphere. The mixture was stirred at the same temperature for 10 minutes. 50% Hydrous methanol (4 ml) was slowly added dropwise to the reaction solution, dichloromethane and celite were added, and the temperature was raised to room temperature. The resulting suspension was filtered, and the filtrate was concentrated under reduced pressure to give a yellow oil. Manganese dioxide (5.0 g) was added to a solution of this oily substance in dichloromethane (50 ml), and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (20% ethyl acetate / hexane) to give the title compound (2.43
g, 72%) was obtained as yellow crystals.

Melting point: 84 to 86 ° C. ¹ H-NMR (400 MHz, CDCl ₃ ) δ; 1.30 (t, J = 7.5 Hz, 3 H), 2.85 (q,
J = 7.5Hz, 2H), 3.67 (s, 3H), 3.98 (s, 3H), 3.99 (s, 3H), 4.08
(s, 3H), 5.29 (s, 2H), 6.81 (s, 1H), 10.29 (s, 1H)

(H) 1,4-Dihydro-7-ethyl-2-
Synthesis of (4-hydroxy-4-methyl-3-oxo-1-pentenyl) -4-oxo-3,5,8-trimethoxyquinoline

[0330]

Embedded image

7-Ethyl-4-methoxymethoxy-3,5,
8-Trimethoxy-2-quinolinecarboxaldehyde (1.68g, 5mmol) and -3-hydroxy-3-methyl-2
Lithium hydroxide monohydrate (0.21 g, 5 mmol) was added to a solution of butanone (1.0 g, 9.8 mmol) in methanol (25 ml), and the mixture was heated at 50-60 ° C for 1 hour. The reaction solution was cooled to room temperature, ethyl acetate and water were added, and the organic layer was washed with saturated brine. 1N Hydrochloric acid (6 ml) is added to the ethyl acetate solution, and the mixture is stirred at room temperature for 10 minutes. A 1N sodium hydroxide aqueous solution (6 ml) was added to the reaction solution, and further a small amount of a saturated sodium hydrogen carbonate aqueous solution was added. Wash the organic layer with saturated saline,
The solvent was distilled off under reduced pressure. The obtained residue is subjected to silica gel column chromatography (50% ethyl acetate / hexane to 75%
% Ethyl acetate / hexane) to give a yellow oil. Crystallization of this from diisopropyl ether gave the title compound (1.34 g, 71%) as yellow crystals.

Melting point: 120 to 122 ° C. ¹ H-NMR (400 MHz, CD ₃ OD) δ; 1.29 (t, J = 7.5 Hz, 3 H), 1.52 (s,
6H), 2.45 (s, 3H), 2.82 (q, J = 7.5Hz, 2H), 4.07 (s, 3H), 4.12
(s, 3H), 6.63 (s, 1H), 7.87 (d, J = 15.1Hz, 1H), 8.24 (d, J = 15.
(1Hz, 1H)

Example 2 1,4-Dihydro-7,8-dimethyl-2- (4-hydroxy-4-methyl-3-oxo-1-pentenyl) -5-
Methoxy-3- (2-methoxyethoxy) -4-oxoquinoline

[0334]

[Chemical 100]

(A) Synthesis of 3,4-dimethyl-5-nitroanisole

[0336]

[Chemical 101]

3,4-Dimethyl-5-nitrophenol (23 g, 138 mmol) in N, N-dimethylformamide (500 m
l) Potassium carbonate (24 g, 184 mmol) and methyl iodide (25 g, 176 mmol) were added to the solution at room temperature. After stirring at the same temperature for 2 hours, water (500 ml) was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was subjected to silica gel column chromatography (5% ethyl acetate /
The title compound (23.8 g,
96%) was obtained as yellow crystals.

Melting point; 48-50 ° C. ¹ H-NMR (400 MHz, CDCl ₃ ) δ; 2.29 (s, 3H), 2.33 (s, 3H), 3.81
(s, 3H), 6.94 (d, J = 2.8Hz, 1H), 7.13 (d, J = 2.8Hz, 1H)

(B) 7,8-Dimethyl-5-methoxy-3-
(2-methoxyethoxy) -4-methoxymethoxy-2
-Synthesis of quinolinecarboxaldehyde

[0340]

Embedded image

3,4-Dimethyl-5-nitroanilyl was mixed with oxalomethoxyacetic acid diethyl ester (e in Example 1).
Was treated in the same manner as (d)-(g) in Example 1 except that oxalomethoxyethoxyacetic acid diethyl ester was used instead of) to give the title compound as yellow crystals.

Melting point: 66 to 67 ° C. ¹ H-NMR (400 MHz, CDCl ₃ ) δ; 2.49 (s, 3H), 2.70 (s, 3H), 3.41
(s, 3H), 3.65 (s, 3H), 3.78 (m, 2H), 3.98 (s, 3H), 4.28 (m, 2
H), 5.32 (s, 2H), 6.82 (s, 1H), 10.36 (s, 1H)

(C) 7,8-Dimethyl-2- (4-hydroxy-4-methyl-3-oxo-1-pentenyl) -5-
Synthesis of methoxy-3- (2-methoxyethoxy) -4-methoxymethoxyquinoline

[0344]

Embedded image

7,8-Dimethyl-5-methoxy-3- (2
-Methoxyethoxy) -4-methoxymethoxy-2-quinolinecarboxaldehyde (200 mg, 0.57 mmol) and 3
-Hydroxy-3-methyl-2-butanone (70mg, 0.69
mmol) of methanol (5 ml) -tetrahydrofuran (5 m
l) solution, lithium hydroxide monohydrate (48mg, 1.14mmo
l) was added and heated at 50-60 ° C. for 30 minutes. The reaction solution was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (20% ethyl acetate / hexane) to give the title compound (190 mg, 7
7%) was obtained as yellow crystals.

Melting point: 93 to 95 ° C. ¹ H-NMR (400 MHz, CDCl ₃ ) δ; 1.53 (s, 6H), 2.47 (s, 3H), 2.67
(s, 3H), 3.45 (s, 3H), 3.63 (s, 3H), 3.72 (m, 2H), 3.96 (s, 3
H), 4.12 (s, 1H), 4.28 (m, 2H), 5.26 (s, 2H), 6.72 (s, 1H), 7.8
6 (d, J = 15.4Hz, 1H), 8.39 (d, J = 15.4Hz, 1H)

(D) 1,4-dihydro-7,8-dimethyl-2
Synthesis of-(4-hydroxy-4-methyl-3-oxo-1-pentenyl) -5-methoxy-3- (2-methoxyethoxy) -4-oxoquinoline

[0348]

[Chemical 104]

7,8-Dimethyl-2- (4-hydroxy-
4-Methyl-3-oxo-1-pentenyl) -5-methoxy-3- (2-methoxyethoxy) -4-methoxymethoxyquinoline (480 mg, 1.1 mmol) in ethyl acetate (15 m
l) 1N hydrochloric acid (1 ml) was added to the solution, and the mixture was stirred at room temperature for 30 minutes. A 1N aqueous sodium hydroxide solution (1 ml) and water were added, and the mixture was extracted with ethyl acetate. The organic layer is washed with water and dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The obtained residue was washed with a mixed solvent of diisopropyl ether and hexane to give the title compound (380 mg, 88%) as yellow crystals.

Melting point; 97 to 98 ° C. ¹ H-NMR (400 MHz, CDCl ₃ ) δ; 1.53 (s, 6H), 2.45 (s, 3H), 2.64
(s, 3H), 3.48 (s, 3H), 3.76 (m, 2H), 4.05 (s, 3H), 4.14 (s, 1
H), 4.27 (m, 2H), 7.85 (d, J = 15.4Hz, 1H), 8.38 (d, J = 15.4Hz,
1H), 9.83 (s, 1H)

Example 3 1,4-Dihydro-5-fluoro-2- (4-hydroxy-4-methyl-3-oxo-1-pentenyl) -4-oxo-3,7,8-trimethylquinoline

[0352]

Embedded image

(A) Synthesis of 2,3-dimethyl-5-fluoronitrobenzene

[0354]

[Chemical formula 106]

3,4-Dimethyl-5-nitroaniline (16
7 g, 1.0 mol) was added to concentrated hydrochloric acid (1 l), and the mixture was stirred at 70 to 80 ° C for 30 minutes. This solution was ice-cooled, and sodium nitrite (76 g,
1.1 mol) aqueous solution was added below 7 ° C. After stirring at the same temperature for 30 minutes, a cooled 42% borofluoric acid aqueous solution (23
0 g, 1.1 mol) was added at 10 ° C. or lower, and the mixture was further stirred for 20 minutes.
The insoluble material was filtered off, washed with water, methanol and ether in that order, and then air-dried. This insoluble material was suspended in xylene (1 l) and heated under reflux for 20 minutes while passing nitrogen through. After cooling the reaction mixture, dichloromethane was added and the mixture was washed with saturated brine.
The organic layer was dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (10% ethyl acetate / hexane) to give the title compound (62 g, 37%) as a pale-yellow oil.

¹ H-NMR (400 MHz, CDCl ₃ ) δ; 2.34 (s, 3H), 2.3
7 (s, 3H), 7.12 (dd, J = 3.6Hz, 8.0Hz, 1H), 7.34 (dd, J = 3.6Hz,
(8.0Hz, 1H)

(B) 1,4-dihydro-5-fluoro-2-
Synthesis of (4-hydroxy-4-methyl-3-oxo-1-pentenyl) -4-oxo-3,7,8-trimethylquinoline

[0358]

[Chemical formula 107]

2,3-Dimethyl-5-fluoronitrobenzene was replaced with oxalopropionic acid diethyl ester in place of oxalomethoxyacetic acid diethyl ester ((e) in Example 1) to give (d)-(h in Example 1). The title compound was obtained as yellow crystals when treated in the same manner as in (1).

Melting point;> 250 ° C. ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ; 1.29 (s, 6H), 2.06 (s, 3H), 2.
34 (s, 3H), 2.36 (s, 3H), 5.56 (s, 1H), 6.86 (d, J = 13.2Hz, 1
H), 7.49 (d, J = 16.0Hz, 1H), 7.68 (d, J = 16.0Hz, 1H), 9.79 (b
rs, 1H)

Example 4 1,4-Dihydro-5,8-dimethoxy-2- (4-hydroxy-4-methyl-3-oxo-1-pentenyl) -3
-Methyl-7-methylcarbamoyl-4-oxoquinoline

[0362]

[Chemical 108]

(A) Synthesis of 2,5-dimethoxy-3-nitrobenzoic acid

[0364]

[Chemical 109]

2,5-Dimethoxy-3-nitrobenzaldehyde (2.0 g, 9.5 mmol) in t-butyl alcohol (20
2-methyl-2-butene (5 ml, 47 m
mol), sodium dihydrogen phosphate dihydrate (4.4g, 28mmo
l) aqueous solution (30 ml) and sodium chlorite (2.6 g, 2
8 mmol) aqueous solution (20 ml) was added. After stirring at the same temperature for 4 hours, ethyl acetate was added to the reaction solution and washed with a dilute aqueous sodium hydroxide solution. The aqueous layer was acidified with dilute hydrochloric acid and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (1.83 g, 8
5%) was obtained as pale yellow crystals.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ; 3.80 (s, 3H),
3.81 (s, 3H), 7.49 (d, J = 3.6Hz, 1H), 7.64 (d, J = 3.6Hz, 1H)

(B) Synthesis of 2,5-dimethoxy-3-methylcarbamoylnitrobenzene

[0368]

[Chemical 110]

A solution of 2,5-dimethoxy-3-nitrobenzoic acid (1.83 g, 8 mmol) in dichloromethane (20 ml) was added at room temperature to N-ethyl-N'-3-dimethylaminopropylcarbodiimide hydrochloride (1.84 g, 9.6 g). mmol), 1-hydroxybenzotriazole (1.42 g, 10.5 mmol) and methylamine (40% methanol solution; 0.9 ml) were added. At the same temperature
After stirring for 3 days, the reaction solution was washed with water. The organic layer was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure, and the resulting residue was subjected to silica gel column chromatography (1%
(Methanol / dichloromethane)
The title compound (0.6 g, 31%) was obtained as colorless crystals.

¹ H-NMR (400 MHz, CDCl ₃ ) δ; 3.05 (d, J = 8.0 H
z, 3H), 3.87 (s, 3H), 3.90 (s, 3H), 7.25 (d, J = 3.6Hz, 1H), 7.5
0 (br.s, 1H), 7.80 (d, J = 3.6Hz, 1H)

(C) 1,4-dihydro-5,8-dimethoxy-
2- (4-hydroxy-4-methyl-3-oxo-1-
Pentenyl) -3-methyl-7-methylcarbamoyl-
Synthesis of 4-oxoquinoline

[0372]

[Chemical 111]

2,5-dimethoxy-3-methylcarbamoylnitrobenzene was replaced with oxalopropionic acid diethyl ester in place of oxalomethoxyacetic acid diethyl ester ((e) in Example 1) (d) -in Example 1. (h)
The title compound was obtained as yellow crystals when treated in the same manner as.

Melting point: 93 to 94 ° C. ¹ H-NMR (400 MHz, CDCl ₃ ) δ; 1.52 (s, 6 H), 3.80 (d, J = 4.8 Hz,
3H), 4.03 (s, 3H), 4.14 (s, 3H), 4.22 (s, 3H), 7.56 (s, 1H), 7.
84 (d, J = 16.0Hz, 1H), 8.29 (d, J = 16.0Hz, 1H), 8.34 (br.s, 1
H), 9.88 (s, 1H)

Example 5 1,4-Dihydro-2- (4-hydroxy-4-methyl-
3-oxo-1-pentenyl) -7- (2-methoxyethoxy) methyl-3-methyl-4-oxoquinoline

[0376]

[Chemical 112]

(A) Synthesis of 2,5-dimethoxy-3- (2-methoxyethoxy) methylnitrobenzene

[0378]

[Chemical 113]

A solution of 2,5-dimethoxy-3-nitrobenzaldehyde (6.0 g, 28.4 ml) in methanol (60 ml) was added,
Sodium borohydride under ice cooling (750mg, 19.8mmol)
Was added. After stirring at the same temperature for 5 minutes, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure
It was dissolved in N, N-dimethylformamide (50 ml), and 60% sodium hydride (1.36 g, 34 mmol) was added under ice cooling.
After stirring at the same temperature for 5 minutes, 2-bromoethyl methyl ether (3.3 ml, 34 mmol) was added, and the mixture was further stirred at room temperature for 1 hour. Water was added to the reaction solution and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (20% ethyl acetate / hexane) to give the title compound (4.0 g, 52%) was obtained as a yellow oil.

¹ H-NMR (400 MHz, CDCl ₃ ) δ; 3.41 (s, 3H), 3.6
1 (m, 2H), 3.70 (m, 2H), 3.84 (s, 3H), 3.87 (s, 3H), 4.65 (s, 2
H), 7.28 (d, J = 3.3Hz, 1H), 7.30 (d, J = 3.3Hz, 1H)

(B) 1,4-Dihydro-2- (4-hydroxy-4-methyl-3-oxo-1-pentenyl) -7-
(2-Methoxyethoxy) methyl-3-methyl-4-oxoquinoline

[0382]

[Chemical 114]

When 2,5-dimethoxy-3-methoxyethoxymethylnitrobenzene was treated in the same manner as in Example 3, (b), the title compound was obtained as yellow crystals.

Melting point: 109-110 ° C. ¹ H-NMR (400 MHz, CDCl ₃ ) δ; 1.52 (s, 6H), 2.45 (s, 3H), 3.41
(s, 3H), 3.61 (m, 2H), 3.70 (m, 2H), 4.05 (s, 1H), 4.08 (s, 3
H), 4.13 (s, 3H), 4.81 (s, 2H), 6.95 (s, 1H), 7.86 (d, J = 15.2H
z, 1H), 8.23 (d, J = 15.2Hz, 1H), 10.06 (s, 1H)

Example 6-119 The appropriately substituted aniline derivative and oxaloacetic acid diethyl ester derivative were sequentially treated in the same manner as in (e)-(h) of Example 1 to give the compounds shown in Table 1. When isomers are observed in the nuclear magnetic resonance spectrum data, the ratio and the isomer data are also described.

Example 120 1,4-Dihydro-2- (4-hydroxy-4-methyl-
3-oxo-1-pentenyl) -8-methoxymethyl-
3-methyl-4-oxoquinoline

[0387]

[Chemical 115]

(A) Synthesis of 8- (1,1-dimethylethyl) dimethylsilyloxymethyl-4-methoxymethoxy-3-methyl-2-quinolinecarboxylic acid ethyl ester

[0389]

[Chemical formula 116]

When 2-[(1,1-dimethylethyl) dimethylsilyloxymethyl] aniline was treated with oxalopropionic acid diethyl ester in the same manner as in (e) and (f) of Example 1, the title compound was colorless. Obtained as an oil. ¹ H-NMR (400MHz, CDCl ₃ ) δ; 0.16 (s, 6H), 1.00 (s, 9H), 1.46
(t, J = 7.1Hz, 3H), 2.52 (s, 3H), 3.67 (s, 3H), 4.50 (q, J = 7.1H
z, 3H), 5.22 (s, 2H), 5.42 (s, 2H), 7.59 (m, 1H), 7.87 (m, 1H),
7.94 (m, 1H) (b) 8-hydroxymethyl-4-methoxymethoxy-3
-Methyl-2-quinolinecarboxylic acid ethyl ester synthesis

[0391]

[Chemical 117]

8- (1,1-Dimethylethyl) dimethylsilyloxymethyl-4-methoxymethoxy-3-methyl-2-quinolinecarboxylic acid ethyl ester (15 g, 35.7 m
To a tetrahydrofuran (180 ml) solution of (mol) was added tetra-n-butylammonium fluoride (1.0 M tetrahydrofuran solution; 39 ml, 39 mmol) at room temperature, and the mixture was stirred at the same temperature for 15 minutes. It was diluted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The crystals obtained by evaporating the solvent under reduced pressure were washed with diisopropyl ether to give the title compound (10.3 g, 94%) as colorless crystals. Melting point: 84-86 ° C ¹ H-NMR (400MHz, CDCl ₃ ) δ; 1.46 (t, J = 7.1Hz, 3H), 2.59 (s,
3H), 3.67 (s, 3H), 4.48 (q, J = 7.1Hz, 2H), 5.16 (s, 2H), 5.24
(s, 2H), 7.56 @ 7.51 (m, 2H), 8.01 (m, 1H) (c) 4-methoxymethoxy-8-methoxymethyl-3-
Synthesis of methyl-2-quinolinecarboxylic acid ethyl ester

[0393]

[Chemical 118]

A solution of 8-hydroxymethyl-4-methoxymethoxy-3-methyl-2-quinolinecarboxylic acid ethyl ester (1.0 g, 3.28 mmol) in N, N-dimethylformamide (10 ml) was added with 60% under ice cooling. Sodium hydride (0.16
g, 4 mmol) was added. After stirring at the same temperature for 5 minutes, methyl iodide (0.24 ml, 3.86 mmol) was added and the mixture was further stirred for 1 hour while warming to room temperature. After the reaction, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and the residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (10% ethyl acetate / hexane).
The title compound (0.44g, 42%) was obtained as a colorless oil. ¹ H-NMR (400MHz, CDCl ₃ ) δ; 1.46 (t, J = 7.1Hz, 3H), 2.53 (s,
3H), 3.57 (s, 3H), 3,67 (s, 3H), 4.48 (q, J = 7.1Hz, 2H), 5.18
(s, 2H), 5.22 (s, 2H), 7.59 (m, 1H), 7.80 (m, 1H), 7.99 (m, 1H) (d) 1,4-dihydro-2- (4-hydroxy-4 -Methyl-3-oxo-1-pentenyl) -8-methoxymethyl-3-methyl-4-oxoquinoline synthesis

[0395]

[Chemical formula 119]

Treatment of 4-methoxymethoxy-8-methoxymethyl-3-methyl-2-quinolinecarboxylic acid ethyl ester with (g) and (h) of Example 1 gave the title compound as yellow crystals. It was Melting point: 168-169 ° C ¹ H-NMR (400MHz, CDCl ₃ ) δ; 1.51 (s, 6H), 2.27 (s, 3H), 3.49
(s, 3H), 3.96 (s, 1H), 4.81 (s, 2H), 7.07 (d, J = 15.9Hz, 1H),
7.24 (m, 1H), 7.38 (m, 1H), 7.96 (d, J = 15.9Hz, 1H), 8.29 (m, 1
H), 10.00 (br.s, 1H)

Example 121 1,4-Dihydro-3,8-dimethyl-2- (4-hydroxy-4-methyl-3-oxo-1-pentenyl) -7-
Methoxymethyl-4-oxoquinoline

[0398]

[Chemical 120]

When 3- (1,1-dimethylethyl) dimethylsilyloxymethyl-2-methylaniline was treated in the same manner as in Example 120, the title compound was obtained as yellow crystals. Melting point: 179 to 180 ° C. ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ; 1.33 (s, 6H), 2.13 (s, 3H), 2.
47 (s, 3H), 3.17 (s, 3H), 4.54 (s, 2H), 7.29 (d, J = 8.3Hz, 1H),
7.40 (d, J = 16.3Hz, 1H), 7.80 (d, J = 16.3Hz, 1H), 7.94 (d, J =
8.3Hz, 1H), 10.00 (br.s, 1H)

Example 122 1,4-Dihydro-2- (4-hydroxy-4-methyl-
3-oxo-1-pentenyl) -7- (1-methoxyethyl) -3-methyl-4-oxoquinoline

[0401]

[Chemical 121]

When 2,5-dimethoxy-3- [1- (1,1-dimethylethyl) dimethylsilyloxyethyl] aniline was treated in the same manner as in Example 120, the title compound was obtained as yellow crystals.

Melting point: 155 to 156 ° C. ¹ H-NMR (400 MHz, CDCl ₃ ) δ; 1.47 (d, J = 6.4 Hz, 3 H), 1.52 (s,
6H), 2.45 (s, 3H), 3.27 (s, 3H), 4.06 (s, 1H), 4.09 (s, 3H), 4.
14 (s, 3H), 5.00 (q, J = 6.4Hz, 1H), 6.85 (s, 1H), 7.87 (d, J = 1
4.9Hz, 1H), 8.23 (d, J = 14.9Hz, 1H), 10.07 (s, 1H)

Example 123 1,4-Dihydro-2- (4-hydroxy-4-methyl-
3-oxo-1-pentenyl) -8-hydroxymethyl-3-methyl-4-oxoquinoline

[0405]

[Chemical formula 122]

(A) Synthesis of 8- (1,1-dimethylethyl) dimethylsilyloxymethyl-4-methoxymethoxy-3-methyl-2-quinolinecarboxaldehyde

[0407]

[Chemical 123]

When 2-[(1,1-dimethylethyl) dimethylsilyloxymethyl] aniline was treated with oxalopropionic acid diethyl ester in the same manner as in (e)-(g) of Example 1, the title compound was obtained. Obtained as colorless crystals. Melting point: 67 to 68 ° C. ¹ H-NMR (400 MHz, CDCl ₃ ) δ; 0.19 (s, 6H), 1.01 (s, 9H), 2.72
(s, 3H), 3.68 (s, 3H), 5.49 (s, 2H), 7.68 (m, 1H), 7.92 (m, 1
H), 7.99 (m, 1H), 10.27 (s, 1H)

(B) 1,4-dihydro-2- (4-hydroxy-4-methyl-3-oxo-1-pentenyl) -8-
Synthesis of hydroxymethyl-3-methyl-4-oxoquinoline

[0410]

[Chemical formula 124]

8- (1,1-Dimethylethyl) dimethylsilyloxymethyl-4-methoxymethoxy-3-methyl-2-quinolinecarboxaldehyde was prepared from (h) of Example 1.
And subsequent treatments as in Example 120b) gave the title compound as yellow crystals.

Melting point: 192-193 ° C. (decomposition) ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ; 1.29 (S, 6H), 2.15 (s, 3H), 4.
96 (s, 2H), 5.61 (br.s, 1H), 7.24 (m, 1H), 7.51 (d, J = 16.1Hz,
1H), 7.56 (m, 1H), 7.76 (d, J = 16.1Hz, 1H), 8.01 (m, 1H), 10.6
0 (br.s, 1H)

Example 124 1,4-Dihydro-3,8-dimethyl-2- (4-hydroxy-4-methyl-3-oxo-1-pentenyl) -7-
Hydroxymethyl-4-oxoquinoline

[0414]

Embedded image

When 3- (1,1-dimethylethyl) dimethylsilyloxymethyl-2-methylaniline was treated in the same manner as in Example 123, the title compound was obtained as yellow crystals.

Melting point: 109-110 ° C. (decomposition) ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ; 1.30 (s, 6H), 2.13 (s, 3H), 2.
44 (s, 3H), 4.62 (s, 2H), 7.37 (d, J = 8.3Hz, 1H), 7.53 (d, J = 1
6.1Hz, 1H), 7.73 (d, J = 16.1Hz, 1H), 7.94 (d, J = 8.3Hz, 1H),
9.99 (br.s, 1H)

Example 125 1,4-Dihydro-5,8-dimethoxy-7- (1-hydroxyethyl) -2- (4-hydroxy-4-methyl-3)
-Oxo-1-pentenyl) -3-methyl-4-oxoquinoline

[0418]

[Chemical formula 126]

When 2,5-dimethoxy-3- [1- (1,1-dimethylethyl) dimethylsilyloxyethyl] aniline was treated in the same manner as in Example 123, the title compound was obtained as yellow crystals.

Melting point: 150 to 151 ° C. ¹ H-NMR (400 MHz, CDCl ₃ ) δ; 1.52 (s, 6 H), 1.53 (d, J = 4.0 Hz,
3H), 2.44 (s, 3H), 2.66 (m, 1H), 4.04 (s, 3H), 4.07 (s, 1H), 4.
14 (s, 3H), 5.43 (m, 1H), 6.84 (s, 1H), 7.87 (d, J = 14.9Hz, 1
H), 8.21 (d, J = 14.9Hz, 1H), 10.01 (s, 1H)

Example 126 1,4-Dihydro-5,8-dimethoxy-2- (4-hydroxy-4-methyl-3-oxo-1-pentenyl) -3
-Methyl-7- (3-morpholino-1-propyl) -4
-Oxoquinoline hydrochloride

[0422]

Embedded image

(A) Synthesis of 3- (2,5-dimethoxy-3-nitrophenyl) -2-propenoic acid ethyl ester

[0424]

[Chemical 128]

2,5-Dimethoxy-3-nitrobenzaldehyde (18.7 g, 88.6 mmol) in cyclochloromethane (150 ml)
) Carboethoxymethylenetriphenylphosphorane (33.9 g, 97.3 mmol) was added to the solution), and the mixture was stirred at room temperature for 12 hours. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel chromatography (20% ethyl acetate / hexane) to give a mixture of the E form and Z form of the title compound (23.6 g, 95%) as yellow crystals. Was obtained.

¹ H-NMR (400 MHz, CDCl ₃ ) (E isomer) δ; 1.36 (t, J = 7.2 Hz, 3H), 3.86 (s, 3H), 3.89 (s, 3)
H), 4.29 (q, J = 7.2Hz, 2H), 6.51 (d, J = 16.4Hz, 1H), 7.29 (d, J
= 3.2Hz, 1H), 7.36 (d, J = 3.2Hz, 1H), 7.89 (d, J = 16.4Hz, 1H) (Z body) δ; 1.22 (t, J = 7.2Hz, 3H), 3.83 ( s, 3H), 3.84 (s, 3
H), 4.16 (q, J = 7.2Hz, 2H), 6.15 (d, J = 12.4Hz, 1H), 7.09 (d, J
= 12.4Hz, 1H), 7.32 (d, J = 3.2Hz, 1H), 7.34 (d, J = 3.2Hz, 1H) Dunlak 1 (b) 1,4-dimethoxy-2- [3- (1,1 -Dimethylethyl) dimethylsilyloxy-1-propenyl) -6-
Synthesis of nitrobenzene

[0427]

[Chemical formula 129]

3- (2,5-Dimethoxy-3-nitrophenyl) -2-propenoic acid ethyl ester (7.0 g, 24.9 mm
ol) in tetrahydrofuran (120 ml) was added diisobutylaluminum hydride (1.5 M toluene solution; 37.1 ml, 55.7 mmol) under an ice-cold nitrogen atmosphere. After stirring at the same temperature for 5 minutes, 50% hydrous methanol (6 ml) was added to the reaction solution. After further diluting with ethyl acetate, Celite was added and the mixture was stirred at room temperature for 2 hours. The suspension was filtered and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to give yellow crystals (5.9 g). A solution of the obtained crystals (2.9 g), imidazole (1.0 g, 14.7 mmol) and t-butyldimethylchlorosilane (2.0 g, 13.3 mmol) in N, N-dimethylformamide (50 ml) was stirred at room temperature for 3 hours. . Water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (10% ethyl acetate / hexane) to give the title compound E
A mixture of isomer and Z isomer (4.2 g, 97%) was obtained as a yellow oil.

¹ H-NMR (400 MHz, CDCl ₃ ) (E form) δ; 0.12 (s, 6H), 0.95 (s, 9H), 3.83 (s, 3H), 3.84
(s, 3H), 4.39 (m, 2H), 6.36 (m, 1H), 6.87 (m, 1H), 7.19 (m, 1
H), 7.21 (m, 2H) (Z body) δ; 0.05 (s, 6H), 0.88 (s, 9H), 3.81 (s, 3H), 3.83
(s, 3H), 4.11 (m, 2H), 6.01 (m, 1H), 6.58 (m, 1H), 6.97 (m, 1
H), 7.21 (m, 1H)

(C) 5,8-dimethoxy-7- [3- (1,1
-Dimethylethyl) dimethylsilyloxy-1-propyl] -4-methoxymethoxy-3-methylquinoline-2
-Synthesis of carboxylic acid ethyl ester

[0431]

Embedded image

Using 1,4-dimethoxy-2- [3- (1,1-dimethylethyl) dimethylsilyloxy-1-propenyl] -6-nitrobenzene with oxalopropionic acid diethyl ester as in Example 1, Treatment as in d)-(f) gave the title compound as a yellow oil.

¹ H-NMR (400 MHz, CDCl ₃ ) δ; 0.07 (s, 6H), 0.9
2 (s, 9H), 1.44 (t, J = 7.1Hz, 3H), 1.88 (m, 2H), 2.54 (s, 3H),
2.85 (m, 2H), 3.64 (s, 3H), 3.69 (m, 2H), 3.94 (s, 3H), 4.05
(s, 3H), 4.47 (q, J = 7.1Hz, 2H), 5.13 (s, 2H), 6.75 (s, 1H) (d) 5,8-dimethoxy-7- (3-hydroxy-1-propyl ) -4-Methoxymethoxy-3-methyl-2-quinolinecarboxylic acid ethyl ester synthesis

[0434]

[Chemical 131]

5,8-Dimethoxy-7- [3- (1,1-dimethylethyl) dimethylsilyloxy-1-propyl]
When 4-methoxymethoxy-3-methylquinoline-2-carboxylic acid ethyl ester was treated in the same manner as in Example 120 (b), the title compound was obtained as pale yellow crystals.

Melting point: 80-83 ° C. ¹ H-NMR (400 MHz, CDCl ₃ ) δ; 1.44 (t, J = 7.1 Hz, 3 H), 1.91 (m,
2H), 2.20 (m, 1H), 2.55 (s, 3H), 2.91 (t, J = 7.3Hz, 2H), 3.58
(m, 2H), 3.64 (s, 3H), 3.94 (s, 3H), 4.09 (s, 3H), 4.47 (q, J =
7.1Hz, 2H), 5.13 (s, 2H), 6.71 (s, 1H)

(E) 4-benzyloxymethoxy-5,8-
Dimethoxy-3-methyl-7- (3-morpholino-1-
Propyl) -2-quinolinecarboxylic acid ethyl ester

[0438]

[Chemical 132]

5,8-Dimethoxy-7- (3-hydroxy-1-propyl) -4-methoxymethoxy-3-methyl-2-quinolinecarboxylic acid ethyl ester (2.0 g, 5.06
mmol) and triethylamine (0.91 ml, 6.53 mmol) in dichloromethane (25 ml), methanesulfonyl chloride (0.46 ml, 5.94 mmol) was added dropwise under ice cooling. After stirring for 1 hour at the same temperature, ethyl acetate was added and the mixture was washed with water. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was dissolved in tetrahydrofuran (25 ml), morpholine (1.3 ml, 14.9 mmol) and a catalytic amount of tetraethylammonium iodide were added, and the mixture was heated under reflux for 5.5 hours. After removing the insoluble matter by filtration, the filtrate was concentrated under reduced pressure. The obtained residue is N, N
-Dissolved in dimethylformamide (10 ml), potassium carbonate (1.7 g, 12.3 mmol) and benzyl chloromethyl methyl ether (1.6 g, 10.2 mmol) were added under ice cooling. After stirring from ice cooling to water cooling for 3 days, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate to 0.5% ammonia / ethyl acetate) to give the title compound (0.9 g, 33%) as a yellow oil.

¹ H-NMR (400 MHz, CDCl ₃ ) δ; 1.44 (t, J = 7.1H
z, 2H), 1.87 (m, 2H), 2.41-2.48 (m, 6H), 2.83 (m, 2H), 3.73
(m, 4H), 3.92 (s, 3H), 4.07 (s, 3H), 4.47 (q, J = 7.1Hz, 2H), 4.
90 (s, 2H), 5.27 (s, 2H), 6.74 (s, 1H), 7.31-7.36 (m, 5H)

(F) 1,4-dihydro-5,8-dimethoxy-
2- (4-hydroxy-4-methyl-3-oxo-1-
Pentenyl) -3-methyl-7- (3-morpholino-1
-Propyl) -4-oxoquinoline hydrochloride synthesis

[0442]

Embedded image

4-Benzyloxymethoxy-5,8-dimethoxy-3-methyl-7- (3-morpholino-1-propyl) -2-quinolinecarboxylic acid ethyl ester was added to Example 1 (g) and (h). When treated in the same manner as in 1,4-dihydro-5,8-dimethoxy-2- (4-hydroxy-4-methyl-3-oxo-1-pentenyl) -3-methyl-7
There was obtained-(3-morpholino-1-propyl) -4-oxoquinoline. This was treated with ethanol containing hydrochloric acid to give the title compound as yellow crystals.

Melting point: 126 to 127 ° C. (decomposition) ¹ H-NMR (400 MHz, D ₂ Od ₆ ) δ; 1.30 (s, 6H), 2.01 (m, 2H), 2.
03 (s, 3H), 2.76 (m, 2H), 2.99-3.10 (m, 4H), 3.35 (m, 2H), 3.6
2 (m, 2H), 3.72 (s, 3H), 3.84 (s, 3H), 3.93 (m, 2H), 6.73 (s, 1
H), 7.27 (d, J = 16.0Hz, 1H), 7.66 (d, J = 16.0Hz, 1H)

Example 127 1,4-Dihydro-5,8-dimethoxy-2- (4-hydroxy-4-methyl-3-oxo-1-pentenyl) -7
-(3-Methoxy-1-propyl) -3-methyl-4-
Oxoquinoline

[0446]

Embedded image

5,8-Dimethoxy-7- (3-hydroxy-1-propyl) -4-methoxymethoxy-3-methyl-2-quinolinecarboxylic acid ethyl ester (Example 126)
When d) was treated in the same manner as (c) and (d) of Example 120, the title compound was obtained as yellow crystals.

Melting point: 142 to 143 ° C. ¹ H-NMR (400 MHz, CD ₃ OD) δ; 1.41 (s, 6H), 1.95 (m, 2H), 2.20
(s, 3H), 2,85 (m, 2H), 3.36 (s, 3H), 3.46 (m, 2H), 3.86 (s, 3
H), 3.88 (s, 3H), 6.63 (s, 1H), 7.51 ((d, J = 16.1Hz, 1H), 7.84
(d, J = 16.1Hz, 1H)

Example 128 1,4-Dihydro-5,8-dimethoxy-2- (4-hydroxy-4-methyl-3-oxo-1-pentenyl) -7
-(3-Hydroxy-1-propyl) -3-methyl-4
-Oxoquinoline

[0450]

[Chemical 135]

5,8-Dimethoxy-7- [3- (1,1-dimethylethyl) dimethylsilyloxy-1-propyl]
-4-Methoxymethoxy-3-methylquinoline-2-carboxylic acid ethyl ester (c of Example 126) was prepared in Example 1.
When treated in the same manner as in g) of Example 1 and b) of Example, the title compound was obtained as yellow crystals.

Melting point: 143 to 144 ° C. ¹ H-NMR (400 MHz, CD ₃ OD) δ; 1.42 (s, 6H), 1.91 (m, 2H), 2.20
(s, 3H), 2,85 (m, 2H), 3.64 (m, 2H), 3.87 (s, 3H), 3.88 (s, 3
H), 6.64 (s, 1H), 7.52 (d, J = 16.1Hz, 1H), 7.84 (d, J = 16.1Hz,
1H)

Example 129 1,4-dihydro-2- (4-hydroxy-4-methyl-
3-oxo-1-pentenyl) -8- (4-methylphenyl) sulfonylaminomethyl-4-oxoquinoline

[0454]

[Chemical 136]

(A) 2- (Acetyloxy) methyl-8-
(1,1-Dimethylethyl) dimethylsilyloxymethyl-4-methoxymethoxyquinoline

[0456]

[Chemical 137]

8- (1,1-Dimethylethyl) dimethylsilyloxymethyl-4-methoxymethoxy-3-methyl-2-quinolinecarboxylic acid ethyl ester (Example 120)
A) was treated with diisobutylaluminum hydride in the same manner as in (g) of Example 1 to obtain 8- (1,1-dimethyl) dimethylsilyloxymethyl-2-hydroxymethyl-4-methoxymethoxy- 3-methylquinoline (13.8
g, 36.6mmol), acetic anhydride (6.3ml, 66.8mmol) and pyridine (8.9ml, 110mmol) in tetrahydrofuran (190m
l) A catalytic amount of 4-dimethylaminopyridine was added to the solution and stirred at room temperature for 3 days. The reaction solution was concentrated under reduced pressure,
Purification by silica gel column chromatography (10% ethyl acetate / hexane) gave the title compound (14.7
g, 96%) was obtained as a colorless oil. ¹ H-NMR (400MHz, CDCl ₃ ) δ; 0.17 (s, 6H), 1.01 (s, 9H), 2.22
(s, 3H), 2.41 (s, 3H), 3.68 (s, 3H), 5.21 (s, 2H), 5.39 (s, 2
H), 5.41 (s, 2H), 7.54 (m, 1H), 7.84 (m, 1H), 7.90 (m, 1H)

(B) 2- (Acetyloxy) methyl-8-
Synthesis of hydroxymethyl-4-methoxymethoxy-3-methylquinoline

[0459]

[Chemical 138]

2-acetyloxymethyl-8- (1,1-
When dimethylethyl) dimethylsilyloxymethyl-4-methoxymethoxyquinoline was treated in the same manner as in Example 120 (b), the title compound was obtained as colorless crystals.

Melting point: 72-74 ° C. ¹ H-NMR (400 MHz, CDCl ₃ ) δ; 2.25 (s, 3H), 2.43 (s, 3H), 3.68
(s, 3H), 5.13 (d, J = 6.6Hz, 2H), 5.22 (s, 2H), 5.26 (t, J = 6.6H
z, 1H), 5.40 (s, 2H), 7.45 @ 7.52 (m, 2H), 7.96 (m, 1H)

(C) (2-acetyloxymethyl-4-methoxymethoxy-3-methyl-8-quinolylmethyl)
[(4-Methylphenyl) sulfonyl] carbamic acid t
-Synthesis of butyl ester

[0463]

[Chemical 139]

2-Acetyloxymethyl-8-hydroxymethyl-4-methoxymethoxyquinoline (0.5 g, 1.64
mmol), triphenylphosphine (1.3 g, 5 mmol) and [(4-methylphenyl) sulfonyl] carbamic acid t
-Butyl ester (667 mg, 2.46 mmol) in tetrahydrofuran (25 ml) was added diethyl azodicarboxylate (0.65 ml, 4.1 mmol) at room temperature under nitrogen atmosphere,
Stir for minutes. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (25% ethyl acetate / hexane) to give [(4-methylphenyl) sulfonyl] carbamic acid t-butyl ester containing the title compound (0.95 g). Was obtained as a colorless oil. Used in the next step without further purification.

¹ H-NMR (400 MHz, CDCl ₃ ) δ; 1.29 (s, 9H), 2.1
9 (s, 3H), 2.44 (s, 3H), 2.45 (s, 3H), 3.69 (s, 3H), 5.21 (s, 2
H), 5.40 (s, 2H), 5.77 (s, 2H), 7.31 (m, 2H), 7.52 (m, 1H), 7.6
1 (m, 1H), 7.84 (m, 2H), 7.94 (m, 1H)

(D) Synthesis of (2-formyl-4-methoxymethoxy-3-methyl-8-quinolylmethyl) [(4-methylphenyl) sulfonyl] carbamic acid t-butyl ester

[0467]

[Chemical 140]

(2-Acetyloxymethyl-4-methoxymethoxy-3-methyl-8-quinolylmethyl) [(4
-Methylphenyl) sulfonyl] carbamic acid t-butyl ester crude product (1.9g) was dissolved in a mixed solvent of water (20ml), methanol (20ml) and tetrahydrofuran (20ml), and lithium hydroxide monohydrate was added. Thing (210mg, 5mm
ol) was added and the mixture was stirred at room temperature for 20 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was dissolved in dichloromethane (100 ml), manganese dioxide (10 g) was added, and the mixture was stirred at room temperature for 12 hours. The reaction mixture was filtered through Celite, the filtrate was concentrated under reduced pressure, and then purified by silica gel column chromatography (25% ethyl acetate / hexane) to give the title compound (0.9 g, 54%) as a colorless oil. It was

¹ H-NMR (400 MHz, CDCl ₃ ) δ; 1.31 (s, 9H), 2.4
6 (s, 3H), 2.73 (s, 3H), 3.69 (s, 3H), 5.23 (s, 2H), 5.85 (s, 2
H), 7.31 (m, 2H), 7.67 (m, 1H), 7.75 (m, 1H), 7.83 (m, 2H), 8.0
4 (m, 1H), 10.29 (s, 1H)

(E) 1,4-Dihydro-2- (4-hydroxy-4-methyl-3-oxo-1-pentenyl) -8-
(4-Methylphenyl) sulfonylaminomethyl-4-
Synthesis of oxoquinoline

[0471]

[Chemical 141]

(2-formyl-4-methoxymethoxy-
3-methyl-8-quinolylmethyl) [(4-methylphenyl) sulphonyl] carbamic acid t-butyl ester (0.9g, 1.75mmol) and 3-hydroxy-3-methyl-2
-Butanone (0.27g, 2.64mmol) in methanol (10ml)
Lithium hydroxide monohydrate (74 mg, 1.76 mmol) was added to the solution, and the mixture was heated with stirring at 50 ° C. for 3 hours. Water was added to the reaction solution and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (25%
Purification with ethyl acetate / hexane) gave a colorless crystalline residue (0.6g). Dissolve this in dichloromethane (20 ml), add trifluoroacetic acid, and at room temperature.
It was stirred for 4 days. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. After washing with saturated saline,
It was dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was washed with ethyl acetate to give the title compound (0.14 g, 20%) as yellow crystals.

Melting point: 241-242 ° C. (decomposition) ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ; 1.34 (s, 6H), 2.14 (s, 3H), 2.
36 (s, 3H), 4.40 (m, 2H), 5.45 (s, 1H), 7.21 (m, 1H), 7.35 (m, 2
H), 7.52 (m, 1H), 7.63 (d, J = 16.1Hz, 1H), 7.69 (m, 2H), 7.72
(d, J = 16.1Hz, 1H), 8.02 (m, 1H), 8.28 (m, 1H)

Example 130 1,4-Dihydro-7,8-dimethyl-2- (4-hydroxy-4-methyl-3-oxo-1-pentenyl) -4-
Oxo-3- (methylsulfinyl) quinoline

[0475]

[Chemical 142]

(A) Synthesis of 7,8-dimethyl-4-methoxymethoxy-3-methylthio-2-quinolinecarboxaldehyde

[0477]

[Chemical 143]

When 2,3-dimethylaniline and oxalomethylthioacetic acid diethyl ester were treated in the same manner as in (e)-(g) of Example 1, the title compound was obtained as yellow crystals. ¹ H-NMR (400MHz, CDCl ₃ ) δ; 2.46 (s, 3H), 2.53 (s, 3H), 2.80
(s, 3H), 3.66 (s, 3H), 5.47 (s, 2H), 7.51 (d, J = 8.4Hz, 1H), 7.
99 (d, J = 8.4Hz, 1H), 10.50 (s, 1H)

(B) Synthesis of 7,8-dimethyl-2- (4-hydroxy-4-methyl-3-oxo-1-pentenyl) 4-methoxymethoxy-3- (methylthio) quinoline

[0480]

[Chemical 144]

7,8-Dimethyl-4-methoxymethoxy-
3-Methylthio-2-quinolinecarboxaldehyde (5.0 g, 16.8 mmol) and 3-hydroxy-3-methyl-2
-Butanone (2.05g, 20.1mmol) was dissolved in a mixed solvent of tetrahydrofuran (30ml) -methanol (10ml), lithium hydroxide monohydrate (2.1g, 50.4mmol) was added thereto,
Heated at 50 ° C. for 30 minutes. After cooling the reaction solution to room temperature,
Water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (15% ethyl acetate / hexane) to give the title compound (3.8 g, 59%) as yellow crystals.

¹ H-NMR (400 MHz, CDCl ₃ ) δ; 1.55 (s, 6H), 2.3
8 (s, 3H), 2.51 (s, 3H), 2.78 (s, 3H), 3.67 (s, 3H), 4.09 (s, 1
H), 5.45 (s, 2H), 7.40 (d, J = 8.4Hz, 1H), 7.87 (d, J = 15.0Hz, 1
H), 7.93 (d, J = 8.4Hz, 1H), 8.80 (d, J = 15.0Hz, 1H) (c) 7,8-Dimethyl-2- (4-hydroxy-4-methyl-3-oxo- Synthesis of 1-pentenyl) -4-methoxymethoxy-3- (methylsulfinyl) quinoline

[0483]

[Chemical 145]

7,8-Dimethyl-2- (4-hydroxy-
4-Methyl-3-oxo-1-pentenyl) -4-methoxymethoxy-3- (methylthio) quinoline (0.9 g, 2.
To a solution of 4 mmol) in dichloromethane was added metachloroperbenzoic acid (purity 55%; 0.74 g, 2.4 mmol) under ice cooling. After stirring at the same temperature for 1 hour, an aqueous sodium thiosulfate solution and an aqueous sodium hydrogen carbonate solution were added, and the mixture was further stirred for 20 minutes. It was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound (0.94 g, 100%) as a yellow oil.

¹ H-NMR (400 MHz, CDCl ₃ ) δ; 1.55 (s, 3H), 1.5
6 (s, 3H), 2.54 (s, 3H), 2.79 (s, 3H), 3.09 (s, 3H), 3.73 (s, 3
H), 5.32 (m, 2H), 7.68 (d, J = 8.8Hz, 1H), 7.88 (d, J = 8.8Hz, 1
H), 7.91 (d, J = 15.0Hz, 1H), 8.99 (d, J = 15.0Hz, 1H)

(D) 1,4-dihydro-7,8-dimethyl-2
-(4-Hydroxy-4-methyl-3-oxo-1-pentenyl) -4-oxo-3- (methylsulfinyl)
Quinoline synthesis

[0487]

[Chemical 146]

7,8-Dimethyl-2- (4-hydroxy-
4-Methyl-3-oxo-1-pentenyl) -4-methoxymethoxy-3- (methylsulfinyl) quinoline (500 mg, 12.6 mmol) was dissolved in a mixed solvent of tetrahydrofuran (30 ml) and water (3 ml). Methanesulfonic acid (30 mg) was added, and the mixture was stirred at room temperature for 20 minutes. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the precipitated crystals were collected by filtration to give the title compound (270 m
g, 64%) was obtained as yellow crystals.

Melting point: 189-190 ° C. (decomposition) ¹ H-NMR (400 MHz, CD ₃ OD) δ; 1.42 (s, 6H), 2.48 (s, 3H), 2,54
(s, 3H), 3.21 (s, 3H), 7.32 (d, J = 8.0Hz, 1H), 7.56 (d, J = 16.0
Hz, 1H), 8.00 (d, J = 8.0Hz, 1H), 8.25 (d, J = 16.0Hz, 1H)

Example 131 1,4-Dihydro-7,8-dimethyl-2- (4-hydroxy-4-methyl-3-oxo-1-pentenyl) -4-
Oxo-3- (methylsulfonyl) quinoline

[0491]

[Chemical 147]

(A) 7,8-Dimethyl-2- (4-hydroxy-4-methyl-3-oxo-1-pentenyl) -4-
Synthesis of methoxymethoxy-3- (methylsulfonyl) quinoline

[0493]

Embedded image

7,8-Dimethyl-2- (4-hydroxy-
4-Methyl-3-oxo-1-pentenyl) -4-methoxymethoxy-3- (methylthio) quinoline (1.0 g, 2.
To a solution of 6 mmol) in dichloromethane (30 ml) was added metachloroperbenzoic acid (purity 50%; 2.0 g, 5.8 mmol) under ice cooling. After stirring at the same temperature for 4 hours, an aqueous sodium thiosulfate solution and an aqueous sodium hydrogen carbonate solution were added, and the mixture was further stirred for 30 minutes. After extraction with ethyl acetate and washing with saturated saline,
It was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography (70% ethyl acetate / hexane) to give
The title compound (0.3g, 28%) was obtained as yellow crystals.

¹ H-NMR (400 MHz, CDCl ₃ ) δ; 1.54 (s, 6H), 2.5
5 (s, 3H), 2,79 (s, 3H), 3.38 (s, 3H), 3.78 (s, 3H), 5.35 (s, 2
H), 7.50 (d, J = 8.8Hz, 1H), 7.73 (d, J = 15.0Hz, 1H), 8.09 (d, J
= 8.8Hz, 1H), 8.99 (d, J = 15.0Hz, 1H)

(B) 1,4-dihydro-7,8-dimethyl-2
-(4-Hydroxy-4-methyl-3-oxo-1-pentenyl) -4-oxo-3- (methylsulfonyl)
Quinoline synthesis

[0497]

[Chemical 149]

7,8-Dimethyl-2- (4-hydroxy-
4-Methyl-3-oxo-1-pentenyl) -4-methoxymethoxy-3- (methylsulfonyl) quinoline (0.3 g, 0.72 mmol) in tetrahydrofuran (20 ml) was added 1N hydrochloric acid (0.3 ml) at room temperature. Stir for 10 minutes. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the precipitated crystals were collected by filtration to give the title compound (205 mg, 77%) as yellow crystals.

Melting point: 230-231 ° C. (decomposition) ¹ H-NMR (400 MHz, CD ₃ OD) δ: 1.42 (s, 6H), 2.49 (s, 3H), 2.54
(s, 3H), 3.37 (s, 3H), 7.37 (d, J = 8.0Hz, 1H), 7.45 (d, J = 16.0
Hz, 1H), 8.04 (d, J = 8.0Hz, 1H), 8.31 (d, J = 16.0Hz, 1H)

Example 132 3-Chloro-1,4-dihydro-8-ethyl-2- (4-
Hydroxy-4-methyl-3-oxo-1-pentenyl) -4-oxoquinoline

[0501]

[Chemical 150]

(A) Synthesis of 3-chloro-1,4-dihydro-8-ethyl-4-oxo-2-quinolinecarboxylic acid ethyl ester

[0503]

Embedded image

1,4-Dihydro-8-ethyl-4-oxo-2-quinolinecarboxylic acid ethyl ester (2.45 g, 10 m
mol) in acetic acid (20 ml) and sulfuryl chloride (0.8 ml,
10 mmol) and a catalytic amount of iodine (25 mg) were added, and the mixture was heated at 80 ° C
Stir for minutes. After heating under reflux for a further 20 minutes, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and the residue obtained by distilling off the solvent under reduced pressure was applied to silica gel column chromatography (15% ethyl acetate /
The title compound (1.06 g,
38%) was obtained as colorless crystals.

Melting point: 143-144 ° C. ¹ H-NMR (400 MHz, CDCl ₃ ) δ; 1.42 (t, J = 7.5 Hz, 3 H), 1.52 (t,
J = 7.1Hz, 3H), 2.92 (q, J = 7.5Hz, 2H), 4.59 (q, J = 7.1Hz, 2H),
7.35 (t, J = 8.0Hz, 1H), 7.55 (d, J = 8.0Hz, 1H), 8.27 (d, J = 8.0
Hz, 1H), 9.31 (br.s, 1H)

(B) Synthesis of 3-chloro-1,4-dihydro-8-ethyl-2- (4-hydroxy-4-methyl-3-oxo-1-pentenyl) -4-oxoquinoline

[0507]

[Chemical 152]

Treatment of 3-chloro-1,4-dihydro-8-ethyl-4-oxo-2-quinolinecarboxylic acid ethyl ester with the same procedure as in Example 1, f) -h) gave the title compound as yellow crystals. Was obtained.

Melting point: 169-170 ° C. ¹ H-NMR (400 MHz, CDCl ₃ ) δ; 1.43 (t, J = 7.6 Hz, 3 H), 1.52 (s,
6H), 2.84 (q, J = 7.6Hz, 2H), 3.57 (br.s, 1H), 7.33 (m, 1H), 7.
34 (d, J = 16.4Hz, 1H), 7.51 (d, J = 7.2Hz, 1H), 8.01 (d, J = 16.4
Hz, 1H), 8.19 (br.s, 1H), 8.23 (d, J = 8.0Hz, 1H)

Example 13 3-Chloro-1,4-dihydro-7,8-dimethyl-2-
(4-Hydroxy-4-methyl-3-oxo-1-pentenyl) -4-oxoquinoline

[0511]

[Chemical 153]

1,4-Dihydro-7,8-dimethyl-4-oxo-2-quinolinecarboxylic acid ethyl ester is used as an example.
Treatment as in 132 gave the title compound as yellow crystals.

Melting point: 207-208 ° C. ¹ H-NMR (400 MHz, CD ₃ OD) δ; 1.43 (s, 6H), 2,49 (s, 3H), 2.56
(s, 3H), 7.31 (d, J = 8.4Hz, 1H), 7.79 (d, J = 16.0Hz, 1H), 7.96
(d, J = 16.0Hz, 1H), 8.04 (d, J = 8.4Hz, 1H)

Example 134 6-Chloro-1,4-dihydro-3,7-dimethyl-2-
(4-Hydroxy-4-methyl-3-oxo-1-pentenyl) -8-methoxy-4-oxoquinoline

[0515]

Embedded image

(A) 3-chloro-1,4-dihydro-3,7-
Synthesis of dimethyl-8-methoxy-4-oxo-2-quinolinecarboxylic acid ethyl ester

[0517]

[Chemical 155]

2-Methoxy-3-methylaniline and oxalopropionic acid diethyl ester were prepared according to (e) of Example 1.
1,4-dihydro-3,7-dimethyl-8-methoxy-4-oxo-2-quinolinecarboxylic acid ethyl ester obtained by treating in the same manner as in Example 132 (a), The compound was obtained as yellow crystals.

Melting point: 148-149 ° C. ¹ H-NMR (400 MHz, CDCl ₃ ) δ; 1.49 (t, J = 7.1 Hz, 3 H), 2.45 (s,
3H), 2.47 (s, 3H), 3.91 (s, 3H), 4.53 (q, J = 7.1Hz, 3H), 8.10
(s, 1H), 9.28 (br.s, 1H)

(B) 6-chloro-1,4-dihydro-3,7-
Synthesis of dimethyl-2- (4-hydroxy-4-methyl-3-oxo-1-pentenyl) -8-methoxy-4-oxoquinoline

[0521]

[Chemical 156]

3-Chloro-1,4-dihydro-3,7-dimethyl-8-methoxy-4-oxo-2-quinolinecarboxylic acid ethyl ester was treated as in Example 1, (f)-(h). Then, the title compound was obtained as yellow crystals.

Melting point: 200-201 ° C. ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ; 1.29 (s, 6H), 2.12 (s, 3H), 2.
38 (s, 3H), 3.83 (s, 3H), 5.53 (s, 1H), 7.51 (d, J = 16.0Hz, 1
H), 7.69 (d, J = 16.0Hz, 1H), 7.82 (s, 1H), 10.86 (br.s, 1H)

Example 135 6-Chloro-1,4-dihydro-3,8-dimethyl-2-
(4-Hydroxy-4-methyl-3-oxo-1-pentenyl) -7-methoxy-4-oxoquinoline

[0525]

[Chemical 157]

3-Methoxy-2-methylaniline and oxalopropionic acid diethyl ester were added to (e) of Example 1
When 1,4-dihydro-3,8-dimethyl-7-methoxy-4-oxo-2-quinolinecarboxylic acid ethyl ester obtained by treating in the same manner as in Example 134 was treated in the same manner as in Example 134,
The title compound was obtained as yellow crystals.

Melting point: 205-206 ° C. ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ; 1.30 (s, 6H), 2.11 (s, 3H), 2.
48 (s, 3H), 3.80 (s, 3H), 5.56 (s, 1H), 7.51 (d, J = 16.1Hz, 1
H), 7.70 (d, J = 16.1Hz, 1H), 7.96 (s, 1H), 10.21 (br.s, 1H)

Example 136 6-Chloro-1,4-dihydro-2- (4-hydroxy-
4-Methyl-3-oxo-1-pentenyl) -5-methoxy-4-oxo-3,7,8-trimethylquinoline

[0529]

[Chemical 158]

2,3-Dimethyl-5-methoxyaniline and oxalopropionic acid diethyl ester were prepared according to the procedure of Example 1.
1,4-dihydro-5-methoxy-4-oxo-3,7,8-trimethylquinoline-2 obtained by treating in the same manner as in (e)
Treatment of the carboxylic acid ethyl ester as in Example 134 gave the title compound as yellow crystals.

Melting point: 153-154 ° C. ¹ H-NMR (400 MHz, CDCl ₃ ) δ; 1.53 (s, 6H), 2.46 (s, 3H), 2.54
(s, 3H), 2.77 (s, 3H), 4.06 (s, 3H), 7.84 (d, J = 15.0Hz, 1H),
8.22 (d, J = 15.0Hz, 1H), 10.16 (s, 1H)

Example 137 6-chloro-1,4-dihydro-2- (4-hydroxy-
4-Methyl-3-oxo-1-pentenyl) -8-methoxy-3,5,7-trimethylquinoline

[0533]

[Chemical 159]

3,5-Dimethyl-2-methoxyaniline and oxalopropionic acid diethyl ester were prepared according to the procedure described in Example 1.
When 1,4-dihydro-8-methoxy-4-oxo-3,5,7-trimethylquinolinecarboxylic acid ethyl ester obtained by treating in the same manner as in (e) was treated in the same manner as in Example 134, the title compound was obtained. Obtained as yellow crystals.

Melting point: 180-181 ° C. ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ; 1.29 (s, 6H), 2.08 (s, 3H), 2.
39 (s, 3H), 2.90 (s, 3H), 3.78 (s, 3H), 5.53 (s, 1H), 7.49 (d, J
= 16.0Hz, 1H), 7.69 (d, J = 16.0Hz, 1H), 10.41 (s, 1H)

Example 138 6-chloro-1,4-dihydro-2- (4-hydroxy-
4-Methyl-3-oxo-1-pentenyl) -4-oxo-3,7,8-trimethylquinoline

[0537]

[Chemical 160]

1,4-Dihydro-4-oxo-3,7,8-obtained by treating 2,3-dimethylaniline and oxalopropionic acid diethyl ester in the same manner as in (e) of Example 1.
Example of trimethylquinolinecarboxylic acid ethyl ester
Treatment as in 134 gave the title compound as yellow crystals.

Melting point: 181-282 ° C. ¹ H-NMR (400 MHz, CDCl ₃ ) δ; 1.53 (s, 6H), 2.14 (s, 3H), 2.31
(s, 3H), 2.43 (s, 3H), 7.23 (d, J = 16.0Hz, 1H), 7.82 (d, J = 16.
0Hz, 1H), 8.11 (s, 1H)

Example 139 1,4-Dihydro-5,8-dimethoxy-2- (4-hydroxy-4-methyl-3-oxo-1-pentenyl) -3
-Methyl-4-oxo-7- (3-oxo-3-piperidino-1-propyl) quinoline

[0541]

[Chemical 161]

(A) Synthesis of 2,5-dimethoxy-3-nitrocinnamic acid piperidine amide

[0543]

[Chemical 162]

Sodium hydride (60%; 1.04g, 26.1mmo
l) N, N-dimethylformamide suspension (50 ml),
N- (Diethoxyphosphoryl) acetylpiperidine (6.9 g, 26.1 mmol) was added under ice cooling. After stirring at room temperature for 20 minutes, the mixture was ice-cooled again, and 2,5-dimethoxy-3-nitrobenzaldehyde (5.0 g, 23.7 mmol) was added. After stirring at room temperature for 30 minutes, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and the residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (50% ethyl acetate / hexane) to give the title compound (6.1 g, 80 %) Was obtained as yellow crystals.

Melting point: 129-130 ° C. ¹ H-NMR (400 MHz, CDCl ₃ ) δ; 1.58@1.74 (m, 6H), 3.58 (m, 2
H), 3.68 (m, 2H), 3.86 (s, 3H), 3.88 (s, 3H), 7.03 (d, J = 15.6H
z, 1H), 7.26 (d, J = 3.1Hz, 1H), 7.30 (d, J = 3.1Hz, 1H), 7.76 (J
(= 15.6Hz, 1H)

(B) Synthesis of 3- (3-amino-2,5-dimethoxy-1-phenyl) propionic acid piperidine amide

[0547]

[Chemical formula 163]

2,5-Dimethoxy-3-nitrocinnamic acid piperidineamide (6.1 g, 18.9 mmol) in ethyl acetate (70 m
l) -Methanol (70 ml) solution was added with 10% palladium carbon (50% water-containing product; 0.6 g), and the mixture was stirred under a hydrogen atmosphere at room temperature and atmospheric pressure for 12 hours. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to give the title compound (5.52 g, 100%) as a yellow oil.

¹ H-NMR (400 MHz, CDCl ₃ ) δ; 1.52 (m, 4H), 1.6
3 (m, 2H), 2.60 (m, 2H), 2.90 (m, 2H), 3.38 (m, 2H), 3.57 (m, 2
H), 3.72 (s, 6H), 3.80 (br.s, 2H), 6.14 (d, J = 2.9Hz, 1H), 6.1
9 (d, J = 2.9Hz, 1H)

(C) 1,4-dihydro-5,8-dimethoxy-
2,3-Dimethyl-4-oxo-7- (3-oxo-3-
Synthesis of piperidino-1-propyl) quinoline

[0551]

[Chemical 164]

1- (3-amino-2,5-dimethoxy-1
-Phenyl) propionic acid piperidine amide (5.5g, 1
8.8 mmol) of 2-methylacetoacetic acid ethyl ester (3.4
g, 23.8 mmol) and a catalytic amount of p-toluenesulfonic acid were treated in the same manner as in (e) of Example 1 to obtain the title compound (2.6 g 37%) as colorless crystals.

Melting point: 202-204 ° C. ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ; 1.50 (m, 4H), 1.55 (m, 2H), 1.
85 (s, 3H), 2.36 (s, 3H), 2.62 (m, 2H), 2.87 (m, 2H), 3.40 (m, 4
H), 3.70 (s, 3H), 3.72 (s, 3H), 6.53 (s, 1H), 10.24 (s, 1H)

(D) Synthesis of 4-acetyloxy-5,8-dimethoxy-2,3-dimethyl-7- (3-oxo-3-piperidino-1-propyl) quinoline

[0555]

[Chemical 165]

1,4-dihydro-5,8-dimethoxy-2,3
A solution of -dimethyl-4-oxo-7- (3-oxo-3-piperidino-1-propyl) quinoline (2.6 g, 7.0 mmol) in dichloromethane (30 ml) was added with triethylamine (1.93 ml, 14 mmol) under ice cooling. Acetic anhydride (1.3 ml, 14 mmol)
Was added. After stirring at room temperature for 12 hours, water was added and the mixture was extracted with dichloromethane. The organic layer was washed with water and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (50% ethyl acetate / hexane) to give the title compound (2.4
g, 84%) was obtained as colorless crystals.

Melting point; 122-123 ° C. ¹ H-NMR (400 MHz, CDCl ₃ ) δ; 1.42@1.64 (m, 6H), 2.24 (s, 3
H), 2.41 (s, 3H), 2.66 (m, 2H), 2.71 (s, 3H), 3.06 (m, 2H), 3.4
0 (m, 2H), 3.57 (m, 2H), 3.88 (s, 3H), 4.03 (s, 3H), 6.68 (s, 1
H)

(E) 4-Acetyloxy-5,8-dimethoxy-3-methyl-7- (3-oxo-3-piperidino-
Synthesis of 1-propyl) -2-quinolinecarboxaldehyde

[0559]

[Chemical 166]

4-acetyloxy-5,8-dimethoxy-
2,3-Dimethyl-7- (3-oxo-3-piperidino-
Selenium dioxide (910 mg, 8.2 mmol) was added to a solution of 1-propyl) quinoline (2.4 g, 5.8 mmol) in xylene (40 ml), and the mixture was heated under reflux for 3 hours. After cooling to room temperature, insoluble matter was removed by filtration through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (50% ethyl acetate / hexane) to give the title compound (1.25
g, 50%) was obtained as yellow crystals.

Melting point: 135-136 ° C. ¹ H-NMR (400 MHz, CDCl ₃ ) δ; 1.44@1.64 (m, 6H), 2.43 (s, 3
H), 2.58 (s, 3H), 2.68 (m, 2H), 3.12 (m, 2H), 3.39 (m, 2H), 3.5
6 (m, 2H), 3.92 (s, 3H), 4.12 (s, 3H), 6.90 (s, 1H), 10.30 (s, 1
H)

(F) 1,4-dihydro-5,8-dimethoxy-
2- (4-hydroxy-4-methyl-3-oxo-1-
Synthesis of pentenyl) -3-methyl-4-oxo-7- (3-oxo-3-piperidino-1-propyl) quinoline

[0563]

[Chemical 167]

4-acetyloxy-5,8-dimethoxy-
3-Methyl-7- (3-oxo-3-piperidino-1-
Propyl) -2-quinolinecarboxaldehyde (480m
g, 1.12 mmol) and 3-hydroxy-3-methyl-2-butanone (137 mg, 1.34 mmol) in tetrahydrofuran (15
ml) and methanol (15 ml) mixed solvent, lithium hydroxide monohydrate (141 mg, 3.36 mmol) was added to this,
Heated at 50 ° C. for 1 hour. After cooling the reaction solution to room temperature,
1N Hydrochloric acid (3.3 ml) and water were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and the residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (ethyl acetate) to give the title compound (250 mg, 47%) as yellow crystals. Was obtained as.

Melting point: 131-132 ° C. ¹ H-NMR (400 MHz, CDCl ₃ ) δ; 1.48@1.65 (m, 6H), 1.52 (s, 6
H), 2.44 (s, 3H), 2.64 (m, 2H), 3.08 (m, 2H), 3.41 (m, 2H), 3.5
7 (m, 2H), 4.05 (s, 1H), 4.06 (s, 3H), 4.13 (s, 1H), 6.71 (s, 1
H), 7.85 (d, J = 14.8Hz, 1H), 8.23 (d, J = 14.8Hz, 1H), 10.02
(s, 1H)

Example 140 1,4-Dihydro-7,8-dimethyl-2- (4-hydroxy-4-methyl-3-oxo-1-pentenyl) -3-
Methoxymethyl-4-oxoquinoline

[0567]

[Chemical 168]

(A) Synthesis of 4-methoxymethoxy-2,7,8-trimethyl-3-quinolinecarboxylic acid ethyl ester

[0569]

[Chemical 169]

2,3-Dimethylaniline (20 g, 165 mmol)
And acetylmalonic acid diethyl ester (33.3g, 165mmo
The mixture of l) was stirred at room temperature for 12 days. The reaction mixture is purified by silica gel column chromatography (2% ethyl acetate / hexane), then heat-treated in diphenyl ether as in (e) of Example 1, and then treated as in (f) of Example 1. Thus, the title compound (31 g, 62%) was obtained as a colorless oil.

¹ H-NMR (400 MHz, CDCl ₃ ) δ; 1.43 (t, J = 7.0H
z, 3H), 2.49 (s, 3H), 2.73 (s, 6H), 3.59 (s, 3H), 4.46 (q, J = 7.
0Hz, 2H), 5.24 (s, 2H), 7.33 (d, J = 8.4Hz, 1H), 7.89 (d, J = 8.4
(Hz, 1H)

(B) Synthesis of 3-hydroxymethyl-4-methoxymethoxy-2,7,8-trimethylquinoline

[0573]

[Chemical 170]

4-Methoxymethoxy-2,7,8-trimethyl-3-quinolinecarboxylic acid ethyl ester (1.0 g, 3.
3 mmol) in anhydrous tetrahydrofuran (20 ml) under ice-cooling lithium aluminum hydride (310 mg, 8.2 mmol)
Was added. After stirring at the same temperature for 50 minutes, the reaction solution was poured into ice water. The insoluble material is filtered off, and the mixture is extracted with ethyl acetate.
The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (0.8 g, 93
%) Was obtained as colorless crystals. ¹ H-NMR (400MHz, CDCl ₃ )
δ; 2.49 (s, 3H), 2.75 (s, 3H), 2.87 (s, 3H), 3.70 (s, 3H), 4.
81 (d, J = 6.8Hz, 1H), 5.17 (s, 2H), 7.31 (d, J = 8.4Hz, 1H), 7.6
6 (d, J = 8.4Hz, 1H)

(C) Synthesis of 4-methoxymethoxy-3-methoxymethyl-2,7,8-trimethylquinoline

[0576]

[Chemical 171]

3-Hydroxymethyl-4-methoxymethoxy-2,7,8-trimethylquinoline (0.8 g, 3.1 mmol)
Sodium hydride (60%; 0.14 g, 3.4 mmol) was added to a solution of N, N-dimethylformamide (20 ml) in ice under ice cooling. After stirring at room temperature for 20 minutes, the mixture was ice-cooled again, and methyl iodide (0.19 ml, 3.1 mmol) was added. After stirring at room temperature for 3 hours, water is added to the reaction solution and the mixture is extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (0.8 g, 94%
) Was obtained as yellow crystals.

¹ H-NMR (400 MHz, CDCl ₃ ) δ; 2.48 (s, 3H), 2.7
3 (s, 3H), 2.80 (s, 3H), 3.44 (s, 3H), 3.65 (s, 3H), 4.65 (s, 2
H), 5.23 (s, 2H), 7.30 (d, J = 8.4Hz, 1H), 7.81 (d, J = 8.4Hz, 1
H)

(D) Synthesis of 1,4-dihydro-3-methoxymethyl-4-oxo-2,7,8-trimethylquinoline

[0580]

[Chemical 172]

To a solution of 4-methoxymethoxy-3-methoxymethyl-2,7,8-trimethylquinoline (0.6 g, 2.18 mg) in ethanol (10 ml) was added 1N hydrochloric acid (1 ml), and the mixture was stirred at room temperature for 30 minutes. did. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to give the title compound (0.5 g, 100%).
Was obtained as colorless crystals.

¹ H-NMR (400 MHz, CDCl ₃ ) δ; 2.38 (s, 3H), 2.4
4 (s, 3H), 2.55 (s, 3H), 3.39 (s, 3H), 4.58 (s, 2H), 7.14 (d, J =
8.0Hz, 1H), 8.14 (d, J = 8.0Hz, 1H)

(E) Synthesis of 4-benzoyloxy-3-methoxymethyl-2,7,8-trimethylquinoline

[0584]

[Chemical 173]

1,4-dihydro-3-methoxymethyl-4
-Oxo-2,7,8-trimethylquinoline (0.2g, 0.87mm
was treated with benzoyl chloride in the same manner as in Example 139 (d) to give the title compound (0.3 g, 100%) as colorless crystals. ¹ H-NMR (400MHz, CDCl ₃ ) δ; 2.48 (s, 3H), 2.77 (s, 3H), 2.86
(s, 3H), 3.31 (s, 3H), 4.59 (s, 2H), 7.47-7.76 (m, 5H), 8.14-
8.19 (m, 1H), 8.30-8.35 (m, 1H)

(F) 1,4-Dihydro-7,8-dimethyl-2
Synthesis of-(4-hydroxy-4-methyl-3-oxo-1-pentenyl) -3-methoxymethyl-4-oxoquinoline

[0587]

[Chemical 174]

4-Benzoyloxy-3-methoxymethyl-2,7,8-trimethylquinoline was used as in Example 139 (e).
When treated in the same manner as in (f), the title compound was obtained as yellow crystals.

Melting point: 147-148 ° C. ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ; 1.30 (s, 6H), 2.38 (s, 3H), 2.
44 (s, 3H), 3.27 (s, 3H), 4.38 (s, 2H), 5.55 (S, 1H), 7.17 (d, J
= 8.0Hz, 1H), 7.67 (d, J = 16.0Hz, 1H), 7.74 (d, J = 16.0Hz, 1
H), 7.87 (d, J = 8.0Hz, 1H), 10.21 (br.s, 1H)

Example 141 1,4-Dihydro-7,8-dimethyl-2- (4-hydroxy-4-methyl-3-oxo-1-pentenyl) -3-
Methoxyethoxymethyl-4-oxoquinoline

[0591]

[Chemical 175]

The treatment of Example 140 (c) was performed using 2-bromoethyl methyl ether instead of methyl iodide, and then the same treatment as in Example 140 (d)-(f) was carried out. Obtained as yellow crystals.

Melting point: 140-141 ° C. ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ; 1.30 (s, 6H), 2.38 (s, 3H), 2.
44 (s, 3H), 3.21 (s, 3H), 3.46 (m, 2H), 3.56 (m, 2H), 4.46 (s, 2
H), 5.49 (s, 1H), 7.17 (d, J = 8.0Hz, 1H), 7.69 (d, J = 16.0Hz, 1
H), 7.76 (d, J = 16.0Hz, 1H), 7.87 (d, J = 8.0Hz, 1H), 10.21 (s,
1H)

Example 142 1,4-Dihydro-7,8-dimethyl-2- (4-hydroxy-4-methyl-3-oxo-1-pentenyl) -3-
(N-methyl-t-butylcarbonylaminomethyl)-
4-oxoquinoline

[0595]

[Chemical 176]

(A) 4-Methoxymethoxy-3- (N-methyl-t-butylcarbonylaminomethyl) -2,7,8-
Synthesis of trimethylquinoline

[0597]

[Chemical 177]

3-hydroxymethyl-4-methoxymethoxy-2,7,8-trimethylquinoline (1.56 g, 6 mmol),
2,4,6-Colidine (1.6 ml, 12 mmol) and lithium chloride (0.28 g, 6.6 mmol) in N, N-dimethylformamide (50
methanesulfonyl chloride (0.51 ml,
6.6 mmol) was added and the mixture was stirred at the same temperature for 40 minutes. Methylamine (40% methanol solution; 30 ml) was added to the reaction solution, and the mixture was stirred at room temperature for 30 minutes. The reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give crude 4-methoxymethoxy-3- (N-methylaminomethyl) -2,7,8-trimethylquinoline. Obtained as a brown oil. This oil, triethylamine (2.5 ml,
Pivaloyl chloride (1.1 g, 9 mmol) was added to dichloromethane (30 ml) of 18 mmol) and a catalytic amount of 4-dimethylaminopyridine (5 mg), and the mixture was stirred at room temperature for 12 hours. The reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (30% ethyl acetate / hexane) to give the title compound ( 0.7g, 33%) was obtained as colorless crystals. ¹ H-NMR (400MHz, CDCl ₃ ) δ; 1.33 (s, 9H), 2.49 (s, 3H), 2.63
(s, 3H), 2.74 (s, 3H), 2.85 (s, 3H), 3.65 (s, 3H), 5.01 (s, 2
H), 5.19 (s, 2H), 7.33 (d, J = 8.4Hz, 1H), 7.74 (d, J = 8.4Hz, 1
H) (b) 1,4-dihydro-7,8-dimethyl-2- (4-hydroxy-4-methyl-3-oxo-1-pentenyl)-
Synthesis of 3- (N-methyl-t-butylcarbonylaminomethyl) -4-oxoquinoline

[0599]

[Chemical 178]

When 4-methoxymethoxy-3- (N-methyl-t-butylcarbonylaminomethyl) -2,7,8-trimethylquinoline was treated in the same manner as in Example 140 (d)-(f), the title compound was obtained. The compound was obtained as pale yellow crystals.

Melting point: 160-161 ° C. ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ; 1.14 (s, 9H), 1.28 (s, 6H), 2.
39 (s, 3H), 2.46 (s, 3H), 2.88 (s, 3H), 4.60 (s, 2H), 5.48 (br.
s, 1H), 7.19 (d, J = 8.0Hz, 1H), 7.51 (d, J = 16.0Hz, 1H), 7.67
(d, J = 16.0Hz, 1H), 7.89 (d, J = 8.0Hz, 1H), 9.97 (s, 1H)

Example 143 1,4-Dihydro-7,8-dimethyl-2- (4-hydroxy-4-methyl-3-oxo-1-pentenyl) -3-
(N-Methylbenzoylaminomethyl) -4-oxoquinoline

[0603]

[Chemical 179]

Treatment of Example 142 with benzoyl chloride instead of pivaloyl chloride (step a) gives:
The title compound was obtained as yellow crystals.

Melting point: 172-173 ° C. ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ; 1.30 (s, 6H), 2.41 (s, 3H), 2.
50 (s, 3H), 2.71 (br.s, 1H), 4.77 (br.s, 2H), 5.56 (br.s, 1
H), 7.22 (d, J = 8.4Hz, 1H), 7.25-7.65 (m, 6H), 7.85-7.95 (m,
2H), 10.11 (s, 1H)

Example 144 1,4-Dihydro-7,8-dimethyl-2- (4-hydroxy-4-methyl-3-oxo-1-pentenyl) -3-
(N-methylbenzenesulfonylaminomethyl) -4-
Oxoquinoline

[0607]

[Chemical 180]

Treatment of Example 142 with benzenesulfonyl chloride instead of pivaloyl chloride (step a) gave the title compound as yellow crystals. Melting point: 169-170 ° C ¹ H-NMR (400MHz, CDCl ₃ ) δ; 1.55 (s, 6H), 2.42 (s, 3H), 2.47
(s, 3H), 2.61 (s, 3H), 3.69 (s, 1H), 4.36 (s, 2H), 7.20 (d, J =
8.4Hz, 1H), 7.31 (d, J = 16.0Hz, 1H), 7.54-7.67 (m, 3H), 7.84
-7.88 (m, 2H), 8.05 (d, J = 8.4Hz, 1H), 8.09 (br.s, 1H), 8.27
(d, J = 16.0Hz, 1H)

Example 145-220 A quinoline-2-carboxaldehyde derivative obtained by treating an appropriately substituted aniline derivative and an oxaloacetic acid diethyl ester derivative in the same manner as in (e)-(g) of Example 1 was used. When the methyl ketone compound was treated in the same manner as in (h) of Example 1, the compounds shown in Table 2 were obtained. When isomers are observed in nuclear magnetic resonance spectrum data, the ratios and isomer data are also described.

Example 221 1,4-dihydro-7-ethyl-4-oxo-2- (3-
Oxo-1-butenyl) -3,5,8-trimethoxyquinoline

[0611]

[Chemical 181]

(A) 7-Ethyl-4-methoxymethoxy-
Synthesis of 2- (3-oxo-1-butenyl) -3,5,8-trimethoxyquinoline

[0613]

[Chemical 182]

7-Ethyl-4 obtained in (g) of Example 1
1-Triphenylphosphoranylidene-2-propanone (1.36 g, 4.3 mmol) was added to a solution of -methoxymethoxy-3,5,8-trimethoxy-2-quinolinecarboxaldehyde (600 mg, 1.8 mmol) in dichloromethane (20 ml). In addition,
The mixture was heated under reflux for 1 hour. After evaporating the solvent under reduced pressure, the title compound (670 mg, 100%) was purified by silica gel column chromatography (15% ethyl acetate / hexane).
Was obtained as yellow crystals.

Melting point: 72-73 ° C. ¹ H-NMR (400 MHz, CDCl ₃ ) δ; 1.28 (t, J = 7.6 Hz, 3 H), 2.46
(s, 3H), 2.82 (q, J = 7.6Hz, 2H), 3.66 (s, 3H), 3.96 (s, 3H), 3.
97 (s, 3H), 4.07 (s, 3H), 5.25 (s, 2H), 6.69 (s, 1H), 7.52 (d, J
= 16.0Hz, 1H), 7.96 (d, J = 16.0Hz, 1H)

(B) Synthesis of 1,4-dihydro-7-ethyl-4-oxo-2- (3-oxo-1-butenyl) -3,5,8-trimethoxyquinoline

[0617]

[Chemical 183]

7-Ethyl-4-methoxymethoxy-2-
1N Hydrochloric acid (0.5 ml) was added to a solution of (3-oxo-1-butenyl) -3,5,8-trimethoxyquinoline (670 mg, 1.8 mmol) in ethyl acetate (30 ml), and the mixture was stirred at room temperature for 15 minutes. 1N
Aqueous sodium hydroxide solution (0.5 ml) and water were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was crystallized from diisopropyl ether to give the title compound (450 mg, 76%) as yellow crystals.

Melting point: 113 to 114 ° C. ¹ H-NMR (400 MHz, CD ₃ OD) δ; 1.31 (t, J = 7.6 Hz, 3 H), 2.45
(s, 3H), 2.81 (q, J = 7.6Hz, 2H), 3.85 (s, 3H), 3.90 (s, 6H), 6.
64 (s, 1H), 7.19 (d, J = 16.4Hz, 1H), 7.78 (d, J = 16.4Hz, 1H)

Examples 222-236 A quinoline-2-carboxaldehyde derivative obtained by treating an appropriately substituted aniline derivative and an oxaloacetic acid diethyl ester derivative in the same manner as in (e)-(g) of Example 1 was carried out. By treating in the same manner as in Example 221, the compounds shown in Table 3 were obtained.

Example 237 4-Acetyloxy-7-ethyl-2- (4-hydroxy-4-methyl-3-oxo-1-pentenyl) -3,5,
8-trimethoxyquinoline

[0622]

Embedded image

1,4-dihydro-7-obtained in Example 1
Ethyl-2- (4-hydroxy-4-methyl-3-oxo-1-pentenyl) -4-oxo-3,5,8-trimethoxyquinoline (6.0 g, 16 mmol) in dichloromethane (80 m
l) solution, under ice cooling, triethylamine (1.94g, 19.2mm
ol) and acetic anhydride (1.66 ml, 17.6 mmol) were added. After stirring at the same temperature for 10 minutes, the mixture was stirred at room temperature for 7 days. The solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography (15% ethyl acetate / hexane), and then crystallized from a mixed solvent of hexane and diisopropyl ether (1: 1) to give the title compound (5.68 g, 85%). ) Was obtained as yellow crystals.

Melting point: 103 to 104 ° C. ¹ H-NMR (400 MHz, CDCl ₃ ) δ; 1.28 (t, J = 7.6 Hz, 3 H), 1.52
(s, 6H), 2.45 (s, 3H), 2.82 (q, J = 7.6Hz, 2H), 3.92 (s, 3H), 3.
94 (s, 3H), 4.03 (s, 1H), 4.10 (s, 1H), 6.70 (s, 1H), 7.90 (d, J
= 15.2Hz, 1H), 8.24 (d, J = 15.2Hz, 1H)

Examples 238-242 By treating the compounds of Examples 23, 59, 3, 2 and 166 in the same manner as in Example 237, the compounds shown in Table 4 were obtained.

Example 243 4-benzyloxy-2- (4-hydroxy-4-methyl-3-oxo-1-pentenyl) -3-methylquinoline

[0627]

[Chemical 185]

(A) Synthesis of 1,4-dihydro-3-methyl-oxo-2-quinolinecarboxaldehyde

[0629]

[Chemical 186]

4-Methoxymethoxy-3-methyl-2-obtained by treating aniline and oxalopropionic acid diethyl ester in the same manner as in (e)-(g) of Example 1.
1N Hydrochloric acid (10 ml) was added to a solution of quinolinecarboxaldehyde (10.7 g, 46 mmol) in ethyl acetate (150 ml), and the mixture was stirred at room temperature for 1 hour. The precipitated crystals were collected by filtration, washed with water and dried to give the title compound (7.7 g, 89%) as pale yellow crystals.

Melting point: 183-185 ° C. (decomposition) ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ; 2.38 (s, 3H), 7.29 (m, 1H),
7.65 (m, 1H), 7.88 (d, J = 8.0Hz, 1H), 8.07 (d, J = 8.0Hz, 1H), 1
0.36 (s, 1H), 11.52 (br.s, 1H) (b) Synthesis of 4-benzyloxy-3-methyl-2-quinolinecarboxaldehyde

[0632]

[Chemical 187]

1,4-Dihydro-3-methyl-4-oxo-2-quinolinecarboxaldehyde (1.0 g, 5.3 mmol
) In N, N-dimethylformamide (20 ml) solution with potassium carbonate (1.1 g, 8.0 mmol) and benzyl bromide (0.95 ml,
8.0 mmol) was added, and the mixture was stirred at room temperature for 12 hours. Water was added to the reaction solution and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue obtained was purified by silica gel column chromatography (5% ethyl acetate / hexane) to give the title compound (900 mg, 61%). Obtained as colorless crystals.

Melting point: 110-111 ° C. ¹ H-NMR (400 MHz, CDCl ₃ ) δ; 2.71 (s, 3H), 5.09 (s, 2H), 7.
38@7.47 (m, 3H), 7.48 @ 7.54 (m, 2H), 7.64 (m, 1H), 7.76 (m, 1
H), 8.10 (m, 1H), 8.22 (d, J = 8.8Hz, 1H), 10.32 (s, 1H)

(C) 4-Benzyloxy-2- (4-hydroxy-4-methyl-3-oxo-1-pentenyl) -3
-Methylquinoline synthesis

[0636]

[Chemical 188]

4-benzyloxy-3-methyl-2-quinolinecarboxaldehyde (300 mg, 1.08 mmol) and 3
-Hydroxy-3-methyl-2-butanone (133 mg, 1.3
mmol) to methanol (20 ml) and tetrahydrofuran (10
ml) and lithium hydroxide monohydrate (136 mg,
3.24 mmol) was added and the mixture was stirred at room temperature for 12 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and the residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (20% ethyl acetate / hexane) to give the title compound (110 mg, 28%). Obtained as pale yellow crystals.

Melting point: 92-93 ° C. ¹ H-NMR (400 MHz, CDCl ₃ ) δ; 1.55 (s, 6H), 2.51 (s, 3H), 4.
03 (s, 1H), 5.08 (s, 2H), 7.38 @ 7.56 (m, 6H), 7.69 (m, 1H), 7.8
4 (d, J = 14.8Hz, 1H), 8.04 (d, J = 8.4Hz, 1H), 8.10 (d, J = 8.4H
z, 1H), 8.22 (d, J = 14.8Hz, 1H)

Example 24 4-benzyloxy-6-chloro-2- (4-hydroxy-4-methyl-3-oxo-1-pentenyl) -3-
Methyl quinoline

[0640]

[Chemical 189]

(A) 4-Benzyloxy-6-chloro-3
-Methyl-2-quinolinecarboxaldehyde synthesis

[0642]

Embedded image

4-Chloroaniline and oxalopropionic acid diethyl ester were treated with (e)-(g) of Example 1 and Example 24.
Subsequent treatment in the same manner as in (a) and (b) of 3 gave the title compound as colorless crystals. Melting point: 123-124 ° C. ¹ H-NMR (400 MHz, CDCl ₃ ) δ; 2.70 (s, 3H), 5.08 (s, 2H), 7.
38@7.50 (m, 5H), 7.67 (dd, J = 2.4Hz, 9.0Hz, 1H), 8.02 (d, J =
2.4Hz, 1H), 8.13 (d, J = 9.0Hz, 1H), 10.28 (s, 1H) (b) 4-benzyloxy-6-chloro-2- (4-hydroxy-4-methyl-3-oxo -1-pentenyl) -3
-Methylquinoline synthesis

[0644]

[Chemical 191]

4-Benzyloxy-6-chloro-3-methyl-2-quinolinecarboxaldehyde was prepared in Example 243.
When treated in the same manner as in (c) of, the title compound was obtained as pale yellow crystals. Melting point: 106-107 ° C. Example 245-249 4-Benzyloxy-6-chloro-3-methyl-2-quinolinecarboxaldehyde and a suitable methylketone derivative were treated in the same manner as in Example (c) to give Table 5 The compound described is obtained. Example 250 2- (4,4-Dimethoxy-3-oxo-1-pentenyl) -8-ethyl-3-methyl-4- (3-phenyl-
1-propoxy) quinoline

[0646]

[Chemical 192]

1,4-Dihydro-8-ethyl-3-methyl-2-quinolinecarboxaldehyde was converted into 3-phenyl-
Treatment with 1-bromopropane and 3,3-dimethoxy-2-butanone in the same manner as in Example 243 (b) and (c) gave the title compound as yellow crystals. Melting point: 91-92 ° C ¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.42 (t, J = 7.5Hz, 3H), 1.53
(s, 3H), 2.21 @ 2.31 (m, 2H), 2.53 (s, 3H), 2.94 (t, J = 7.8Hz, 2
H), 3.33 (q, J = 7.5Hz, 2H), 3.35 (s, 6H), 4.02 (t, J = 6.5Hz, 2
H), 7.20 @ 7.29 (m, 3H), 7.30 @ 7.35 (m, 2H), 7.43 (dd, J = 7.0H
z, 8.2Hz, 1H), 7.48 @ 7.52 (m, 1H), 7.85 (dd, J = 1.4Hz, 8.2Hz,
1H), 8.00 (d, J = 15.2Hz, 1H), 8.19 (d, J = 15.2Hz, 1H)

Example 25 16-Chloro-4-methoxy-3-methyl-2- (3-oxo-1-butenyl) quinoline

[0649]

[Chemical formula 193]

6-Chloro-1,4-dihydro-3-methyl-4-oxo-2- (3-oxo-1-butenyl) quinoline (Example 222) was used in Example 243 using methyl iodide.
When treated in the same manner as in (b) of, the title compound was obtained as colorless crystals.

Melting point: 147-148 ° C. ¹ H-NMR (400 MHz, CDCl ₃ ) δ; 2.46 (s, 3H), 2.53 (s, 3H), 3.
97 (s, 3H), 7.47 (d, J = 15.4Hz, 1H), 7.60 (dd, J = 2.4Hz, 9.1H
z, 1H), 7.90 (d, J = 15.4Hz, 1H), 7.98 (d, J = 9.1Hz, 1H), 8.00
(d, J = 2.4Hz, 1H)

Example 25 4-benzyloxy-6-chloro-3-methyl-2-
(3-oxo-1-butenyl) quinoline

[0653]

[Chemical 194]

6-Chloro-1,4 obtained in Example 222
Treatment of -dihydro-3-methyl-4-oxo-2-(3-oxo-1-butenyl) quinoline in the same manner as in Example 243 (b) gave the title compound as colorless crystals.

Melting point: 126 to 127 ° C. ¹ H-NMR (400 MHz, CDCl ₃ ) δ; 2.46 (s, 3H), 2.47 (s, 3H), 5.
07 (s, 2H), 7.39 @ 7.47 (m, 6H), 7.60 (dd, J = 2.4Hz, 9.0Hz, 1
H), 7.88 (d, J = 15.4Hz, 1H), 7.96 (d, J = 2.4Hz, 1H), 8.00 (d, J
= 9.0Hz, 1H)

Example 253 4-benzyloxy-8-ethyl-2- (4-hydroxy-4-methyl-3-oxo-1-pentenyl) -3-
Methyl quinoline

[0657]

[Chemical 195]

1,4-dihydro-8 obtained in Example 20
-Ethyl-2- (4-hydroxy-4-methyl-3-oxo-1-pentenyl) -3-methyl-4-oxoquinoline was treated as in Example 243 (b) to give the title compound as colorless crystals. Was obtained as.

Melting point: 87-88 ° C. ¹ H-NMR (400 MHz, CDCl ₃ ) δ; 1.43 (t, J = 7.6 Hz, 3 H), 1.55
(s, 6H), 2.51 (s, 3H), 3.33 (q, J = 7.6Hz, 2H), 4.07 (s, 1H), 5.
05 (s, 2H), 7.38 @ 7.55 (m, 7H), 7.91 (d, J = 14.8Hz, 1H), 7.92
(dd, J = 1.6Hz, 8.0Hz, 1H), 8.23 (d, J = 14.8Hz, 1H)

Example 254 6-chloro-2- (4-hydroxy-4-methyl-3-)
Oxo-1-pentenyl) -3-methyl-4- (4-methylphenoxy) quinoline

[0661]

[Chemical 196]

(A) 6-chloro-3-methyl-4- (4-
Synthesis of methylphenoxy) -2-quinolinecarboxylic acid ethyl ester

[0663]

[Chemical 197]

4,5-Dichloro-3-methyl-2-quinolinecarboxylic acid ethyl ester (600 mg, 2.1 mmol) and 4-
Methylphenol (1.14g, 10.5mmol) was heated with stirring at 180 ° C for 2 hours. After cooling, the reaction mixture was purified by silica gel column chromatography (10% ethyl acetate / hexane) to give a mixture of the title compound and 4-methylphenol (520 mg). This was used in the next reaction without further purification. (b) Synthesis of 6-chloro-3-methyl-4- (4-methylphenoxy) -2-quinolinecarboxaldehyde

[0665]

[Chemical 198]

Crude 6-chloro-3-methyl-4- (4-methylphenoxy) -2-quinolinecarboxylic acid ethyl ester (520 mg) was treated in the same manner as in Example 1 (g) to give
The title compound (270 mg) was obtained as colorless crystals. Melting point; 129-130 ° C ¹ H-NMR (400MHz, CDCl ₃ ) δ; 2.31 (s, 3H), 2.55 (s, 3H), 6.
67 (d, J = 8.4Hz, 2H), 7.09 ((d, J = 8.4Hz, 2H), 7.70 (dd, J = 2.0
Hz, 8.8Hz, 1H), 7.92 (d, J = 2.0Hz, 1H), 8.18 (d, J = 8.8Hz, 1
H), 10.32 (s, 1H)

(C) 6-Chloro-2- (4-hydroxy-)
Synthesis of 4-methyl-3-oxo-1-pentenyl) -3-methyl-4- (4-methylphenoxy) quinoline

[0668]

[Chemical formula 199]

6-Chloro-3-methyl-4- (4-methylphenoxy) -2-quinolinecarboxaldehyde (270 mg, 0.87 mmol) was treated in the same manner as in Example 243 (c) to give the title compound (88 mg, 26%) was obtained as colorless crystals.

Melting point: 164-165 ° C. (decomposition) ¹ H-NMR (400 MHz, CDCl ₃ ) δ; 1.56 (s, 6H), 2.31 (s, 3H), 2.
40 (s, 3H), 3.97 (s, 1H), 6.67 (d, J = 8.8Hz, 2H), 7.08 (d, J = 8.
8Hz, 2H), 7.60 (dd, J = 1.6Hz, 8.4Hz, 1H), 7.84 (d, J = 1.6Hz, 1
H), 7.87 (d, J = 15.2Hz, 1H), 8.06 (d, J = 8.4Hz, 1H), 8.20 (d, J
(= 15.2Hz, 1H)

Example 255 4- (1-Carboxyethylphenoxy) -6-chloro-2- (4-hydroxy-4-methyl-3-oxo-1)
-Pentenyl) -3-methylquinoline

[0672]

[Chemical 200]

Example 254 was prepared using 4,5-dichloro-3-methyl-2-quinolinecarboxaldehyde and 2- (4-hydroxyphenyl) propionic acid methyl ester.
By treating in the same manner as (a) and (c), the title compound was obtained as pale yellow crystals.

Melting point: 169-171 ° C. (decomposition) ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ; 1.29 (s, 6H), 1.31 (d, J = 7.
5Hz, 3H), 2.34 (s, 3H), 3.62 (q, J = 7.5Hz, 1H), 5.63 (br.s, 1
H), 6.83 (d, J = 8.0Hz, 2H), 7.23 (d, J = 8.0Hz, 2H), 7.73 (d, J =
1.6Hz, 1H), 7.77 (dd, J = 1.6Hz, 9.0Hz, 1H), 7.92 (d, J = 15.2H
z, 1H), 8.10 (d, J = 15.2Hz, 1H), 8.14 (d, J = 9.0Hz, 1H), 12.22
(br.s, 1H)

Example 256 4- (4-Carboxybenzyloxy) -2- (4-hydroxy-4-methyl-3-oxo-1-propenyl)
-3-Methylquinoline

[0676]

[Chemical 201]

(A) Synthesis of 4- (4-methoxycarbonylbenzyloxy) -3-methyl-2-quinolinecarboxaldehyde

[0678]

Embedded image

1,4-Dihydro-3-methyl-4-oxo-2-quinolinecarboxaldehyde (a in Example 24)
This was treated with 4-methoxycarbonylbenzyl bromide in the same manner as in Example 243 (b) to give the title compound as colorless crystals.

Melting point: 115 to 116 ° C. ¹ H-NMR (400 MHz, CDCl ₃ ) δ; 2.71 (s, 3H), 3.96 (s, 3H), 5.
14 (s, 2H), 7.60 (d, J = 8.4Hz, 2H), 7.65 (m, 1H), 7.77 (m, 1H),
8.06 (m, 1H), 8.12 (d, J = 8.4Hz, 2H), 8.22 (m, 1H)

(B) Synthesis of 4- (4-carboxybenzyloxy) -2- (4-hydroxy-4-methyl-3-oxo-1-propenyl) -3-methylquinoline

[0682]

[Chemical 203]

When 4- (4-methoxycarbonylbenzyloxy) -3-methyl-2-quinolinecarboxaldehyde was treated in the same manner as in Example 243 (c), the title compound was obtained as pale yellow crystals.

Melting point: 154-155 ° C. (decomposition) ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ; 1.29 (s, 6H), 2.48 (s, 3H),
5.18 (s, 2H), 5.62 (s, 2H), 7.59 (m, 1H), 7.68 (d, J = 8.4Hz, 2
H), 7.74 (m, 1H), 7.93 (d, J = 15.2Hz, 1H), 7.97 @ 8.07 (m, 4H),
8.07 (d, J = 15.2Hz, 1H), 13.03 (br.s, 1H)

Example 257-261 1,4-dihydro-3-methyl-4-oxo-2-quinolinecarboxaldehyde, 1,4-dihydro-8-methoxy-3-methyl-4-oxo-2-quinolinecarboxy Aldehydes or 6-chloro-1,4-dihydro-3-methyl-4-oxo-2-quinolinecarboxaldehyde were used with the appropriate halogen compounds having a carboxylic ester to give (b), (c) of Example 243. When treated in the same manner as in, the compounds shown in Table 6 were obtained.

Example 26 4- (5-Carboxy-1-pentyloxy) -7-ethyl-2- (4-hydroxy-4-methyl-3-oxo-1-pentenyl) -3,5,8-tri Methoxyquinoline

[0687]

[Chemical 204]

7-Ethyl-4-methoxymethoxy-3,5,
After treating 8-trimethoxy-2-quinolinecarboxaldehyde (g in Example 1) in the same manner as in Example 243 (a), 6-bromohexanoic acid ethyl ester was used in Example 243 (b), ( Treatment as in c) gave the title compound as a yellow-brown oil.

¹ H-NMR (400 MHz, CDCl ₃ ) δ; 1.29 (t, J = 7.6
Hz, 3H), 1.53 (s, 6H), 1.60 @ 1.67 (m, 2H), 1.73 @ 1.83 (m, 2H),
1.87@1.96 (m, 2H), 2.43 (t, J = 7.4Hz, 2H), 2.83 (q, J = 7.6Hz,
2H), 3.96 (s, 3H), 3.97 (s, 3H), 4.10 (s, 3H), 4.12 (t, J = 6.9H
z, 2H), 6.88 (s, 1H), 7.90 (d, J = 15.4Hz, 1H), 8.28 (d, J = 15.4
(Hz, 1H)

Example 263 4- (5-Carboxy-1-pentyloxy) -6-chloro-3-methyl-2- (3-oxo-1-butenyl)
Quinoline

[0692]

[Chemical 205]

(A) Synthesis of 4- (5-carboxy-1-pentyloxy) -6-chloro-3-methyl-2- (3-oxo-1-butenyl) quinoline methoxymethyl ester

[0693]

[Chemical 206]

6-Chloro-1,4 obtained in Example 222
Treatment of -dihydro-3-methyl-4-oxo-2-(3-oxo-1-butenyl) quinoline with 6-bromohexanoic acid methoxymethyl ester in the same manner as in Example 243 (b) gave the title compound. Obtained as pale yellow crystals.

¹ H-NMR (400MHz, CDCl ₃ ) δ; 1.61@1.71 (m,
2H), 1.76 @ 1.86 (m, 2H), 1.93 @ 2.02 (m, 2H), 2.45 (s, 3H), 2.4
6 (t, J = 7.2Hz, 2H), 2.52 (s, 3H), 3.48 (s, 3H), 4.00 (m, 2H),
5.24 (s, 2H), 7.47 (d, J = 15.6Hz, 1H), 7.60 (dd, J = 2.4Hz, 8.8
Hz, 1H), 7.89 (d, J = 15.6Hz, 1H), 7.95 (d, J = 2.4Hz, 1H), 7.98
(d, J = 8.8Hz, 1H)

(B) Synthesis of 4- (5-carboxy-1-pentyloxy) -6-chloro-3-methyl-2- (3-oxo-1-butenyl) quinoline

[0697]

Embedded image

4- (5-Carboxy-1-pentyloxy) -6-chloro-3-methyl-2- (3-oxo-1)
-Butenyl) quinoline (650 mg, 1.55 mmol) was added to acetic acid (12
ml) -water (8 ml) dissolved in a mixed solvent, which is stored at 60 ° C for 30
Heated for minutes. After cooling the reaction solution to room temperature, water was added,
It was extracted with ethyl acetate. After washing the organic layer with saturated saline,
It was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (20% ethyl acetate / hexane-3% methanol / dichloromethane) and recrystallized from ethanol to give the title compound (156 mg, 27%) as yellow crystals.

Melting point: 128-129 ° C. ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ; 1.48@1.64 (m, 4H), 1.80 @
1.91 (m, 2H), 2.26 (t, J = 7.0Hz, 2H), 2.43 (s, 3H), 2.48 (s, 3
H), 3.99 (t, J = 6.2Hz, 2H), 7.23 (d, J = 15.6Hz, 1H), 7.71 (d, J
= 9.0Hz, 1H), 7.86 (d, J = 15.6Hz, 1H), 7.95 (s, 1H), 7.99 (d, J
= 9.0Hz, 1H), 12.02 (br.s, 1H)

Example 264 4- [3- (4-Carbomethoxyphenyl) -1-propoxy] -6-chloro-2- (4-hydroxy-4-methyl-3-oxo-1-pentenyl) -3- Methyl quinoline

[0701]

[Chemical 208]

6-chloro-1,4-obtained in Example 22
Dihydro-2- (4-hydroxy-4-methyl-3-oxo-1-pentenyl) -3-methylquinoline was converted to 3-
Treatment with (4-carbomethoxyphenyl) -1-bromopropane in the same manner as in Example 243 (b) gave the title compound as pale yellow crystals.

Melting point: 95-96 ° C. ¹ H-NMR (400 MHz, CDCl ₃ ) δ; 1.54 (s, 6H), 2.25 @ 2.34 (m, 2
H), 2.52 (s, 3H), 3.02 (t, J = 7.8Hz, 2H), 3.92 (s, 3H), 3.96
(s, 1H), 4.02 (t, J = 6.3Hz, 2H), 7.36 (d, J = 8.1Hz, 2H), 7.61
(dd, J = 2.4Hz, 9.0Hz, 1H), 7.81 (d, J = 14.8Hz, 1H), 7.95 (d, J
= 2.4Hz, 1H), 8.00 @ 8.04 (m, 1H), 8.02 (d, J = 8.1Hz, 2H), 8.18
(d, J = 15.0Hz, 1H)

Example 265 4- [3- (4-Carboxyphenyl) -1-propoxy] -6-chloro-2- (4-hydroxy-4-methyl-3-oxo-1-pentenyl) -3-methyl Quinoline

[0705]

[Chemical 209]

4- [3- (4-) obtained in Example 264
Carbomethoxyphenyl) -1-propoxy] -6-chloro-2- (4-hydroxy-4-methyl-3-oxo-1-pentenyl) -3-methylquinoline (726 mg, 1.51
mmol) is dissolved in a mixed solvent of water (5 ml) -methanol (6 ml) -tetrahydrofuran (6 ml), lithium hydroxide / hydrate (190 mg, 4.53 mmol) is added thereto, and the mixture is heated at 60 ° C for 30
Heated for minutes. After cooling the reaction solution to room temperature, water and 1N
Hydrochloric acid (4.5 ml) was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (5% methanol / dichloromethane) to give the title compound (200 mg, 28%) as pale yellow crystals.

Melting point: 156-158 ° C. (decomposition) ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ; 1.27 (s, 6H), 2.15@2.26
(m, 2H), 2.48 (s, 3H), 2.93 (t, J = 7.7Hz, 2H), 4.03 (t, J = 6.2H
z, 2H), 5.60 (s, 1H), 7.42 (d, J = 7.9Hz, 2H), 7.71 (dd, J = 2.3H
z, 9.0Hz, 1H), 7.81 @ 7.97 (m, 4H), 8.03 (d, J = 9.0Hz, 1H), 8.0
4 (d, J = 14.8Hz, 1H)

Example 266 (E) -3- [2- (4-Hydroxy-4-methyl-3-methyl-
Oxo-1-pentenyl) -3-methyl-4- (3-phenyl-1-propyloxy) -8-quinolyl] -2-
Propenoic acid

[0709]

[Chemical 210]

(A) 8-Bromo-3-methyl-4- (3-
Synthesis of phenyl-1-propyloxy) -2-quinolinecarboxylic acid ethyl ester

[0711]

[Chemical 211]

2-Bromoaniline and oxalopropionic acid diethyl ester were treated in the same manner as in Example 1 (e), and then treated with 1-bromo-3-phenylpropane in the same manner as in Example 1 (f). Then, the title compound was obtained as colorless crystals. ¹ H-NMR (400MHz, CDCl ₃ ) δ; 1.48 (t, J = 7.1Hz, 3H), 2.26
(m, 2H), 2.52 (s, 3H), 2.93 (m, 2H), 4.07 (m, 2H), 4.52 (q, J =
7.1Hz, 2H), 7.21 @ 7.28 (m, 3H), 7.31 @ 7.35 (m, 2H), 7.40 (m, 1
H), 8.01 @ 8.03 (m, 2H)

(B) 8-Bromo- (1,1-dimethylethyldimethylsilyloxymethyl) -3-methyl-4- (3
Synthesis of -phenyl-1-propyloxy) quinoline

[0714]

[Chemical 212]

8-Bromo-3-methyl-4- (3-phenyl-1-propyloxy) -2-quinolinecarboxylic acid ethyl ester was treated in the same manner as in Example 126 (b) to give the title compound as a colorless oil. It was obtained as a thing.

¹ H-NMR (400 MHz, CDCl ₃ ) δ; 0.10 (s, 6H),
0.89 (s, 9H), 2.25 (m, 2H), 2.49 (s, 3H), 2.93 (m, 2H), 4.03
(m, 2H), 5.02 (s, 2H), 7.20 @ 7.35 (m, 6H), 7.95 (dd, J = 1.3Hz,
7.5Hz, 1H), 7.98 (dd, J = 1.3Hz, 8.2Hz, 1H)

(C) (E) -3- [2- (1,1-Dimethylethyldimethylsilyloxymethyl) -3-methyl-4-
Synthesis of (3-phenyl-1-propyloxy) -8-quinolyl] -2-propenoic acid ethyl ester

[0718]

[Chemical 213]

8-Bromo- (1,1-dimethylethyldimethylsilyloxymethyl) -3-methyl-4- (3-phenyl-1-propyloxy) quinoline (11.6 g, 23 mmo
l), acrylic acid ethyl ester (3 ml, 27.7 mmol) and n-butylamine (6.6 ml, 27.7 mmol) to a mixture of palladium acetate (103 mg, 0.46 mmol) and tri-0-tolylphosphine (280 mg, 0.92 mmol). In addition, the mixture was heated and stirred at 100 ° C. for 7 hours under a nitrogen atmosphere. It was diluted with ethyl acetate and washed with water and saturated brine. The crystals obtained by drying over anhydrous magnesium sulfate and evaporating the solvent under reduced pressure were washed with 5% ethyl acetate / hexane to give the title compound (1
1.8 g, 98%) was obtained as colorless crystals.

Melting point: 97-98 ° C. ¹ H-NMR (400 MHz, CDCl ₃ ) δ; 0.10 (s, 6H), 0.90 (s, 9H), 1.
37 (t, J = 7.1Hz, 3H), 2.26 (m, 2H), 2.48 (s, 3H), 2.94 (m, 2H),
4.04 (m, 2H), 4.31 (q, J = 7.1Hz, 2H), 5.01 (s, 2H), 6.83 (d, J =
16.3Hz, 1H), 7.21 @ 7.35 (m, 5H), 749 (m, 1H), 7.91 (m, 1H), 8.
06 (m, 1H), 8.94 (d, J = 16.3Hz, 1H)

(D) (E) -3- [2-Formyl-3-methyl-4- (3-phenyl-1-propyloxy) -8-
Synthesis of quinolyl] -2-propenoic acid ethyl ester

[0722]

[Chemical 214]

(E) -3- [2- (1,1-Dimethylethyldimethylsilyloxymethyl) -3-methyl-4- (3
-Phenyl-1-propyloxy) -8-quinolyl]-
The 2-propenoic acid ethyl ester was treated in the same manner as in Example 120 (b) and then treated with manganese dioxide in the same manner as in Example 1 (g) to obtain the title compound as colorless crystals.

Melting point; 117 to 118 ° C. ¹ H-NMR (400 MHz, CDCl ₃ ) δ; 1.38 (t, J = 7.1 Hz, 3 H), 2.38
(m, 2H), 2.70 (s, 3H), 2.94 (m, 2H), 4.06 (m, 2H), 4.33 (q, J =
7.1Hz, 2H), 6.88 (d, J = 16.3Hz, 1H), 7.21 @ 7.35 (m, 5H), 7.65
(m, 1H), 8.01 (m, 1H), 8.12 (m, 1H), 8.95 (d, J = 16.3Hz, 1H), 1
0.35 (s, 1H)

(E) (E) -3- [2- (4-hydroxy-
4-Methyl-3-oxo-1-pentenyl) -3-methyl-4- (3-phenyl-1-propyloxy) -8-
Synthesis of quinolyl] -2-propenoic acid

[0726]

Embedded image

(E) -3- [2-Formyl-3-methyl-
4- (3-Phenyl-1-propyloxy) -8-quinolyl] -2-propenoic acid ethyl ester was prepared according to the procedure of Example 243.
When treated in the same manner as in (c), the title compound was obtained as pale yellow crystals.

Melting point: 179 to 180 ° C. ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ; 1.30 (s, 6H), 2.18 (m, 2H),
2.48 (s, 3H), 2.85 (m, 2H), 4.04 (m, 2H), 5.58 (s, 1H), 6.89
(d, J = 16.1Hz, 1H), 7.16 @ 7.32 (m, 5H), 7.62 (m, 1H), 7.95 (d,
J = 15.4Hz, 1H), 8.01 (d, J = 15.4Hz, 1H), 8.08 (m, 1H), 8.20
(m, 1H), 8.78 (d, J = 16.1Hz, 1H), 12.43 (br.s, 1H)

Example 267 8- (3-Carboxy-1-propyl) -2- (4-hydroxy-4-methyl-3-oxo-1-pentenyl)
-3-Methyl-4- (3-phenyl-1-propyloxy) quinoline

[0730]

[Chemical 216]

(E) -3- [2- (1,1-Dimethylethyldimethylsilyloxymethyl) -3-methyl-4- (3
-Phenyl-1-propyloxy) -8-quinolyl]-
2-Propenoic acid ethyl ester (c of Example 267) was hydrogenated by the same treatment as in Example 1, (d), and then the
The title compound was obtained as light brown crystals by treating in the same manner as in (d) and (e) of 267.

Melting point: 161-162 ° C. ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ; 1.29 (s, 6H), 2.16 (m, 2H),
2.48 (s, 3H), 2.73 (m, 2H), 2.85 (m, 2H), 3.43 (m, 2H), 4.01
(m, 2H), 5.49 (br.s, 1H), 7.16 @ 7.32 (m, 5H), 7.48 (m, 1H), 7.
57 (m, 1H), 7.87 (m, 1H), 7.94 (d, J = 15.3Hz, 1H), 8.02 (d, J = 1
5.3Hz, 1H), 12.09 (br.s, 1H)

Example 268 4-benzyloxy-2- (4-hydroxy-4-methyl-3-oxo-1-pentenyl) -3-methyl-6-
Quinolinecarboxylic acid

[0734]

Embedded image

(A) Synthesis of 1,4-dihydro-3-methyl-4-oxo-2,6-quinolinedicarboxylic acid diethyl ester

[0736]

[Chemical 218]

4-Aminobenzoic acid ethyl ester (50.7
g, 307 mmol) was treated with oxalopropionic acid diethyl ester (68.3 g, 338 mmol) in the same manner as in (e) of Example 1 to obtain the title compound (59.6 g, 64%) as pale yellow crystals.

Melting point:> 250 ° C. ¹ H-NMR (400 MHz, CDCl ₃ ) δ; 1.42 (t, J = 7.2 Hz, 3 H), 1.49
(t, J = 7.2Hz, 3H), 2.49 (s, 3H), 4.41 (q, J = 7.2Hz, 2H), 4.52
(q, J = 7.2Hz, 2H), 7.40 (d, J = 8.8Hz, 1H), 8.25 (dd, J = 2.0Hz,
8.8Hz, 1H), 9.03 (d, J = 2.0Hz, 1H), 9.20 (br.s, 1H)

(B) 4-benzyloxy-3-methyl-2,
Synthesis of 6-quinolinedicarboxylic acid diethyl ester

[0740]

[Chemical 219]

1,4-Dihydro-3-methyl-4-oxo-2,6-quinolinedicarboxylic acid diethyl ester (15.0
g, 49.5mmol) of N, N-dimethylformamide (150ml
) To the solution, under ice cooling, potassium carbonate (10.2 g, 74 mmol)
And benzyl bromide (8.8 ml, 74 mmol) were added. At the same temperature
After stirring for 30 minutes, the mixture was further stirred at room temperature for 12 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. After washing the organic layer with water,
The residue obtained by drying over anhydrous magnesium sulfate and evaporating the solvent under reduced pressure was subjected to silica gel column chromatography (15
% Ethyl acetate / hexane) to give the title compound (16.2 g, 83%) as colorless crystals.

Melting point: 95-96 ° C. ¹ H-NMR (400 MHz, CDCl ₃ ) δ; 1.44 (t, J = 7.2 Hz, 3 H), 1.48
(t, J = 7.2Hz, 3H), 2.53 (s, 3H), 4.44 (q, J = 7.2Hz, 2H), 4.54
(q, J = 7.2Hz, 2H), 5.14 (s, 2H), 7.38 @ 7.47 (m, 3H), 7.49 @ 7.5
5 (m, 2H), 8.19 (d, J = 8.8Hz, 1H), 8.28 (dd, J = 1.8Hz, 8.8Hz, 1
H), 8.81 (d, J = 1.8Hz, 1H)

(C) Synthesis of 4-benzyloxy-6-ethoxycarbonyl-3-methyl-2-quinolinecarboxaldehyde

[0744]

[Chemical 220]

4-benzyloxy-3-methyl-2,6-
Quinoline dicarboxylic acid diethyl ester (16.2g, 41mmo
l) was treated in the same manner as in (g) of Example 1 to give the title compound (1.0 g, 7%) as colorless crystals. Melting point; 134-135 ° C ¹ H-NMR (400MHz, CDCl ₃ ) δ; 1.45 (t, J = 7.2Hz, 3H), 2.71
(s, 3H), 4.45 (q, J = 7.2Hz, 2H), 5.13 (s, 2H), 7.38 @ 7.47 (m, 3
H), 7.49 @ 7.54 (m, 2H), 8.24 (d, J = 8.8Hz, 1H), 8.33 (dd, J = 2.
0Hz, 8.8Hz, 1H), 8.83 (d, J = 2.0Hz, 1H), 10.32 (s, 1H)

At the same time, 4-benzyloxy-6-hydroxymethyl-3-methyl-2-quinolinecarboxaldehyde (2.8 g, 22%) was also obtained as colorless crystals. Melting point; 126-128 ° C ¹ H-NMR (400MHz, CDCl ₃ ) δ; 1.90 (t, J = 6.0Hz, 1H), 2.68
(s, 3H), 4.88 (d, J = 6.0Hz, 2H), 5.09 (s, 2H), 7.38 @ 7.52 (m, 5
H), 7.74 (dd, J = 2.0Hz, 8.8Hz, 1H), 8.01 (s, 1H), 8.19 (d, J =
8.8Hz, 1H), 10.31 (s, 1H)

(D) 4-Benzyloxy-2- (4-hydroxy-4-methyl-3-oxo-1-pentenyl) -3
-Methyl-6-quinolinecarboxylic acid synthesis

[0748]

[Chemical 221]

Treatment of 4-benzyloxy-6-ethoxycarbonyl-3-methyl-2-quinolinecarboxaldehyde (850 mg, 2.4 mmol) in the same manner as in Example 243 (c) gave the title compound (430 mg, 44%). Was obtained as pale yellow crystals. Melting point: 186-187 ° C ¹ H-NMR (400MHz, DMSO-d ₆ ) δ; 1.29 (s, 6H), 2.49 (s, 3H),
5.14 (s, 2H), 5.64 (s, 1H), 7.36 @ 7.46 (m, 3H), 7.49 @ 7.54 (m,
2H), 7.92 (d, J = 15.2Hz, 1H), 8.09 (d, J = 8.8Hz, 1H), 8.10 (d,
J = 15.2Hz, 1H), 8.15 (dd, J = 1.6Hz, 8.8Hz, 1H), 8.61 (d, J = 1.
6Hz, 1H), 13.25 (br.s, 1H)

Example 269 (E) -3- [4-benzyloxy-2- (4-hydroxy-4-methyl-3-oxo-1-pentenyl) -3-
Methyl-6-quinolyl] -2-methylpropenoic acid

[0751]

Embedded image

(A) 4-Benzyloxy-2- (4-hydroxy-4-methyl-3-oxo-1-pentenyl) -6
-Synthesis of hydroxymethylquinoline

[0753]

[Chemical formula 223]

4-Benzyloxy-6-hydroxymethyl-3-methyl-2-quinolinecarboxaldehyde (1.24 g, 4 mmol) was treated in the same manner as in Example 243 (c) to give the title compound (760 mg, 48%). Was obtained as yellow crystals.

Melting point: 120 to 121 ° C. ¹ H-NMR (400 MHz, CDCl ₃ ) δ; 1.55 (s, 6H), 1.88 (m, 1H), 2.
51 (s, 3H), 4.03 (s, 1H), 4.86 (d, J = 5.6Hz, 2H), 5.08 (s, 2H),
7.38@7.50 (m, 5H), 7.67 (dd, J = 2.0Hz, 8.8Hz, 1H), 7.83 (d, J
= 14.8Hz, 1H), 7.94 (br.s, 1H), 8.08 (d, J = 8.8Hz, 1H), 8.21
(d, J = 14.8Hz, 1H)

(B) 4-Benzyloxy-2- (4-hydroxy-4-methyl-3-oxo-1-pentenyl) -3
-Methyl-6-quinolinecarboxaldehyde synthesis

[0757]

[Chemical formula 224]

4-Benzyloxy-2- (4-hydroxy-4-methyl-3-oxo-1-pentenyl) -6-
Manganese dioxide (3.5 g) was added to a solution of hydroxymethylquinoline (760 mg, 1.94 mmol) in dichloromethane (10 ml), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was filtered through Celite, the filtrate was concentrated under reduced pressure, and then purified by silica gel column chromatography (20% ethyl acetate / hexane) to give the title compound (370 mg, 49%) as yellow crystals. .

Melting point: 142-144 ° C. ¹ H-NMR (400 MHz, CDCl ₃ ) δ; 1.56 (s, 6H), 2.56 (s, 3H), 3.
94 (s, 1H), 5.15 (s, 2H), 7.40 @ 7.50 (m, 5H), 7.90 (d, J = 14.8H
z, 1H), 8.12 @ 8.19 (m, 2H), 8.21 (d, J = 14.8Hz, 1H), 8.41 (s, 1
H), 10.08 (s, 1H)

(C) (E) -3- [4-benzyloxy-2]
Synthesis of-(4-hydroxy-4-methyl-3-oxo-1-pentenyl) -3-methyl-6-quinolyl] -2-methylpropenoic acid

[0761]

Embedded image

4-benzyloxy-2- (4-hydroxy-4-methyl-3-oxo-1-pentenyl) -3-
Methyl-6-quinolinecarboxaldehyde (500 mg,
1.28 mmol) in dichloromethane (10 ml) was added to carboethoxyethylidene triphenylphosphorane (560 mg,
1.55 mmol) was added and the mixture was stirred at room temperature for 3 hours. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (20% ethyl acetate / hexane) to give the ethyl ester form of the title compound (590 mg).
Dissolve this in tetrahydrofuran (50 ml) and water (25 ml), and under ice cooling, lithium hydroxide / hydrate (156 mg, 3.7 mmo
l) was added. After stirring at room temperature for 24 hours, mix with water under ice cooling.
N hydrochloric acid (3.7 ml) was added, and the mixture was extracted with ethyl acetate. The organic layer is washed with water, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The residue obtained is purified by silica gel column chromatography (3% methanol / dichloromethane) to give the title compound (420 mg, 74%). Was obtained as yellow crystals.

Melting point: 167-168 ° C. (decomposition) ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ; 1.29 (s, 6H), 2.03 (d, J = 1.
2Hz, 3H), 2.48 (s, 3H), 5.14 (s, 2H), 5.62 (s, 1H), 7.36 @ 7.46
(m, 3H), 7.50 @ 7.55 (m, 2H), 7.73 (s, 1H), 7.80 (dd, J = 2.0Hz,
8.8Hz, 1H), 7.92 (d, J = 15.2Hz, 1H), 8.02 @ 8.12 (m, 3H), 12.6
5 (br.s, 1H) Example 270 2- (4-hydroxy-4-methyl-3-oxo-1-)
Pentenyl) -5-methoxy-4-oxo-3,7,8
-Trimethyl-4H-1-benzopyran

[0764]

[Chemical formula 226]

(A) Synthesis of 2,4-dihydroxy-6-methylbenzaldehyde

[0766]

[Chemical 227]

45 g of 3,5-dihydroxytoluene (363 m
mol) and triethyl orthoformate 430ml (2.9mol) in benzene (400ml) solution under ice cooling, aluminum chloride 71g
(544 mmol) was added slowly. After stirring at room temperature for 30 minutes, carefully add dilute hydrochloric acid (100 ml) carefully, and
Stir for 20 minutes. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the precipitated crystals were collected by filtration and washed with dichloromethane to give the title compound 28
g (51% yield) are obtained as pale yellow crystals. The filtrate was subjected to silica gel column chromatography (10% ethyl acetate /
Hexane) to give the title compound 6.7
g (12% yield) was obtained.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ; 2.45 (s, 3H),
6.12 (s, 1H), 6.20 (s, 1H), 10.05 (s, 1H), 10.69 (s, 1H), 12.0
5 (s, 1H)

(B) 2-hydroxy-4-methoxy-6-
Synthesis of methylbenzaldehyde

[0770]

[Chemical 228]

To a solution of 2,4-dihydroxy-6-methylbenzaldehyde (34.7 g, 228 mmol) in N, N-dimethylformamide (200 ml) was added 41 g of potassium carbonate (30 ml) under ice cooling.
0 mmol) and 15.6 ml of methyl iodide (251 mmol) were added. After stirring at room temperature for 12 hours, the reaction solution was poured into water, acidified with diluted hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with water and saturated saline and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography (5% ethyl acetate / hexane) to give 19.2 g (yield 51%) of the title compound as colorless crystals.

¹ H-NMR (400 MHz, CDCl ₃ ) δ; 2.54 (s, 3H), 3.8
2 (s, 3H), 6.25 (s, 2H), 10.10 (s, 1H), 12.48 (s, 1H)

(C) Synthesis of 2,3-dimethyl-5-methoxyphenol

[0774]

[Chemical formula 229]

47 g (0.72 mol) of zinc and 3.7 g of mercuric chloride
(13.8 mmol) is stirred in water (56 ml) -concentrated hydrochloric acid (2.3 ml) for 5 minutes. After removing the aqueous layer, add 110 ml of water and concentrated hydrochloric acid.
142 ml was added, and 2-hydroxy-4-methoxy-
A solution of 19.1 g (115 mmol) of 6-methylbenzaldehyde in ethanol (100 ml) was added. After refluxing for 40 minutes, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline and then dried over anhydrous magnesium sulfate. When the solvent was distilled off under reduced pressure, 17.2 g (yield 98%) of the title compound was obtained as pale yellow crystals.

¹ H-NMR (400 MHz, CDCl ₃ ) δ; 2.09 (s, 3H), 2.2
5 (s, 3H), 3.75 (s, 3H), 4.45 (br.s, 1H), 6.25 (d, J = 2.4Hz, 1
H), 6.35 (d, J = 2.4Hz, 1H)

(D) 3,4-Dimethyl-5-methoxymethoxyanisole

[0778]

[Chemical 230]

2,3-Dimethyl-5-methoxyphenol 18 g (118 mmol) of N, N-dimethylformamide (30
0 ml) solution, under ice cooling, 60% sodium hydride 5.2 g (13
0 mmol) and 8.8 ml of methyl iodide (142 mmol) were added. After stirring at room temperature for 1 hour, the reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with water and saturated saline and then dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was subjected to silica gel column chromatography (5%
20.8 g of the title compound after purification with ethyl acetate / hexane)
(Yield 90%) was obtained as a pale yellow oil.

¹ H-NMR (400 MHz, CDCl ₃ ) δ; 2.10 (s, 3H), 2.2
5 (s, 3H), 3.49 (s, 3H), 3.77 (s, 3H), 5.17 (s, 2H), 6.42 (br.
s, 1H), 6.55 (br.s, 1H)

(E) 3,4-Dimethyl-6-methoxy-2
-Methoxymethoxybenzaldehyde synthesis

[0782]

[Chemical formula 231]

To a solution of 2,4-dimethyl-5-methoxymethoxyanisole (20.8 g, 106 mmol) in anhydrous ether (200 ml) was added n-butyllithium (2.5M) under ice-cooled nitrogen atmosphere.
Hexane solution; 63.6 ml, 159 mmol) was added slowly. After stirring at room temperature for 2 hours, the reaction solution was cooled to -50 ° C, and N,
23 ml (318 mmol) N-dimethylformamide were added. After the temperature was raised to room temperature, the reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate. When the solvent is distilled off under reduced pressure, the crude title compound is 25.4 g.
Was obtained as a yellow oil. This was used in the next reaction without further purification.

¹ H-NMR (400 MHz, CDCl ₃ ) δ; 2.17 (s, 3H), 2.3
2 (s, 3H), 3.59 (s, 3H), 3.88 (s, 3H), 5.04 (s, 2H), 6.60 (s, 1
H), 10.41 (s, 1H)

(F) Synthesis of 3 ', 4'-dimethyl-6'-methoxy-2'-methoxymethoxypropiophenone

[0786]

[Chemical 232]

To a solution of 3,4-dimethyl-6-methoxy-2-methoxymethoxybenzaldehyde (25.4 g, 113 mmol) in tetrahydrofuran (200 ml) was added a nitrogen atmosphere at -50 ° C.
With magnesium chloride (2M tetrahydrofuran solution; 73
(ml, 147 mmol) was added slowly. After stirring at the same temperature for 2 hours, the temperature was raised to room temperature. The reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with water and saturated saline and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue obtained was N, N-dimethylformamide (200 ml).
To the solution was added 51 g (136 mmol) of pyridinium dichromate,
It was stirred at room temperature for 1 hour. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline and then dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was subjected to silica gel column chromatography (10%
Purify with ethyl acetate / hexane) to give the title compound 20.7
g (73% yield) was obtained as a yellow oil.

¹ H-NMR (400 MHz, CDCl ₃ ) δ; 1.14 (t, J = 7.2 H
z, 3H), 2.13 (s, 3H), 2.28 (s, 3H), 2.80 (q, J = 7.2Hz, 3H), 3.5
0 (s, 3H), 3.77 (s, 3H), 4.89 (s, 2H), 6.55 (s, 1H)

(G) Synthesis of 3 ', 4'-dimethyl-2'-hydroxy-6'-methoxypropiophenone

[0790]

[Chemical formula 233]

3 ', 4'-Dimethyl-6'-methoxy-
2'-Methoxymethoxypropiophenone 20.7g (82mm
ol) in acetone (200 ml) was added with 5 ml of concentrated hydrochloric acid and stirred at room temperature for 30 minutes. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 16.6 g (yield 97%) of the title compound as light brown crystals.

¹ H-NMR (400 MHz, CDCl ₃ ) δ; 1.16 (t, J = 7.2 H
z, 3H), 2.09 (s, 3H), 2.28 (s, 3H), 3.07 (q, J = 7.2Hz, 3H), 3.8
6 (s, 3H), 6.21 (s, 1H), 13.81 (s, 1H)

(H) 5-methoxy-4-oxo-2,3,
Synthesis of 7,8-tetramethyl-4H-1-benzopyran

[0794]

[Chemical formula 234]

16.6 g (80 mmol) of 3 ', 4'-dimethyl-2'-hydroxy-6'-methoxypropiophenone,
Sodium acetate 5.9g (72mmol) and acetic anhydride 15ml (14
The mixture (4 mmol) was heated with stirring at 180 ° C. for 5 hours. After cooling to room temperature, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography (30% ethyl acetate / hexane) to give 13.8 g (yield 74%) of the title compound as light brown crystals.

¹ H-NMR (400 MHz, CDCl ₃ ) δ; 1.99 (s, 3H), 2.2
5 (s, 3H), 2.37 (s, 6H), 3.93 (s, 3H), 6.58 (s, 1H)

(I) 5-methoxy-4-oxo-3,7,
Synthesis of 8-trimethyl-4H-1-benzopyran-2-carboxaldehyde

[0798]

[Chemical formula 235]

5-methoxy-4-oxo-2,3,7,
8-Tetramethyl-4H-1-benzopyran 13.8 g (5
9.5 mmol) was treated with selenium dioxide using dioxane (92 ml) -water (5 ml) as a solvent in the same manner as in Example (). 9.0 g (yield 62%) of the title compound was obtained as tan crystals.

¹ H-NMR (400 MHz, CDCl ₃ ) δ; 2.34 (s, 3H), 2.3
9 (s, 3H), 2.41 (s, 3H), 3.96 (s, 3H), 6.65 (s, 1H), 10.20 (s, 1
H)

(J) 2- (4-hydroxy-4-methyl-
Synthesis of 3-oxo-1-pentenyl) -5-methoxy-4-oxo-3,7,8-trimethyl-4H-1-benzopyran

[0802]

[Chemical 236]

5-Methoxy-4-oxo-3,7,8-
Trimethyl-4H-1-benzopyran-2-carboxaldehyde was treated in the same manner as in the example to give the title compound as yellow crystals.

Melting point;> 220 ° C. ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ; 1.29 (s, 6H), 2.06 (s, 3H), 2.
31 (s, 3H), 2.38 (s, 3H), 3.81 (s, 3H), 5.70 (br.s, 1H), 6.83
(s, 1H), 7.57 (d, J = 15.6Hz, 1H), 7.74 (d, J = 15.6Hz, 1H)

Examples 271-279 4-oxo-4H-1-benzopyran-2-obtained by treating the appropriate 2'-hydroxypropiophenone derivative in the same manner as in Example 270 (h) and (i). The carboxaldehyde derivative and 3-hydroxy-3-methyl-2-butanone or the methyl ketone derivative described in the Synthesis Example were used in Example 270.
The same treatment as in (j) above was performed to obtain the compounds shown in the table.

[0806]

[Table 3]

[Table 4]

[Table 5]

[Table 6]

[Table 7]

[Table 8]

[Table 9]

[Table 10]

[Table 11]

[Table 12]

[Table 13]

[Table 14]

[Table 15]

[Table 16]

[Table 17]

[Table 18]

[Table 19]

[Table 20]

[Table 21]

[Table 22]

[Table 23]

[Table 24]

[Table 25]

[Table 26]

[Table 27]

[Table 28]

[Table 29]

[Table 30]

[Table 31]

[Table 32]

[Table 33]

[Table 34]

[Table 35]

[Table 36]

[Table 37]

[Table 38]

[Table 39]

[Table 40]

[Table 41]

[Table 42]

[Table 43]

[Table 44]

[Table 45]

[Table 46]

[Table 47]

[Table 48]

[Table 49]

[Table 50]

[Table 51]

[Table 52]

[Table 53]

[Chemical 237]

[Chemical 238]

[Chemical 239]

[Chemical 240]

[Table 54]

[Table 55]

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical display location A61K 31/495 AED A61K 31/495 AED 31/505 ABE 31/505 ABE C07D 215/36 C07D 215 / 36 215/48 215/48 311/58 311/58 335/06 335/06 471/04 113 471/04 113 114 114A 118 118A 491/052 9271-4C 491/052 495/04 111 495/04 111 (72 ) Inventor Hirofumi Akamatsu 2-23-5 Amakubo, Tsukuba City, Ibaraki Prefecture No. 201 (72) Inventor Kenichi Chiba 5-20 401 Omachi, Tsuchiura City, Ibaraki Prefecture (72) Inventor Hiroshi Obishi Tsukuba, Ibaraki Prefecture 2-23-5 Amakubo, Ichiku City, No. 307, Maison Gakuen (72) Hideki Sakurai Inventor Hideki Abe, Shinjuku Abe, Utsuku City, Ibaraki Prefecture Woman, Hideki Sakurai, 4-8-3, Ninomiya, Tsukuba, Ibaraki Prefecture Conversion 1083-44 (72) inventor Kobayashi Tsuchiura, Ibaraki Prefecture Seiichi Nakatakatsu 2-10-26 (72) inventor mountains KanaeTsukasa Tsukuba, Ibaraki Prefecture Shimohirooka 725-25

Claims (3)

[Claims] 1. A compound represented by the general formula (I): {In the formula, the ring portion A is represented by the formula: [In formula, ring B represents the aromatic ring which may have a substituent.
R ² represents a hydrogen atom, a halogen atom, a lower alkyl group optionally substituted with a halogen atom, a cycloalkyl group optionally containing a hetero atom, an aryl group optionally having a substituent, or a substituent. A heteroaryl group which may have, an arylalkyl group which may have a substituent,
A heteroarylalkyl group which may have a substituent,
Formula -X-R < ¹⁴ > (In formula, X is group represented by formula -O- or formula> S = (O) _n (In formula, n means the integer of 0 or 1-2). R ¹⁴ represents a hydrogen atom, a lower alkyl group which may be substituted with a halogen atom, an alkoxyalkyl group, an aryl group which may have a substituent, or a substituent which may have a substituent. A heteroaryl group, an arylalkyl group which may have a substituent or a heteroarylalkyl group which may have a substituent)), an alkoxyalkyl group,
It means an alkoxyalkoxyalkyl group or an aminoalkyl group which may be mono- or di-substituted. R
³ is a hydrogen atom, a lower alkyl group optionally substituted by a halogen atom, a cycloalkyl group optionally containing a hetero atom, an alkoxyalkyl group, an aryl group optionally having a substituent, a substituent Heteroaryl group which may have, arylalkyl group which may have a substituent, aryloxyalkyl group which may have a substituent, heteroarylalkyl group which may have a substituent , A heteroaryloxyalkyl group which may have a substituent, a carboxyalkyl group which may be protected, or an acyl group. Further, R ² and R ³ may together form a ring with the carbon atom to which R ² and the group represented by the formula R ³ O— are bonded, and the oxygen atom to which R ³ is bonded. Good. This ring may contain a nitrogen atom, an oxygen atom or a sulfur atom in addition to the oxygen atom to which R ³ is bonded, or may have a substituent. ] It means the group selected from the group shown by. R ¹
Is the formula (Wherein R ⁴ and R ⁵ are the same or different hydrogen atoms,
A lower alkyl group which may be substituted with a halogen atom,
A cycloalkyl group which may contain a hetero atom, a lower alkoxy group which may be substituted with a halogen atom, an alkoxyalkyl group, an alkoxyalkoxyalkyl group, an aryl group which may have a substituent, a substituent group Means a heteroaryl group which may have a substituent, an arylalkyl group which may have a substituent or a heteroarylalkyl group which may have a substituent. Also, R ⁴ ,
R ⁵ together with the carbon atom to which they are attached,
In addition, a ring which may contain a nitrogen atom, an oxygen atom or a sulfur atom may be formed. Further, this ring may have a substituent. R ⁶ is a hydrogen atom, a lower alkyl group optionally substituted with a halogen atom, a cycloalkyl group optionally containing a hetero atom, an aryl group optionally having a substituent, or a substituent Optionally a heteroaryl group, an arylalkyl group which may have a substituent,
A heteroarylalkyl group which may have a substituent,
Formula -OR ¹¹ (In the formula, R ¹¹ is a hydrogen atom, a lower alkyl group optionally substituted with a halogen atom, a cycloalkyl group optionally containing a hetero atom, a hydroxyalkyl group, a cyanoalkyl group, an alkoxyalkyl group. A carbamoylalkyl group which may be mono- or di-substituted,
Aryl group optionally having substituent (s), heteroaryl group optionally having substituent (s), arylalkyl group optionally having substituent (s) or heteroarylalkyl optionally having substituent (s) Means a group. Or a group represented by the formula: —NR ¹² R ¹³ (wherein R ¹² and R ¹³ may be the same or different from each other, a hydrogen atom, a lower alkyl group optionally substituted with a halogen atom, or a hetero atom). A cycloalkyl group, an alkylsulfonyl group in which alkyl may be substituted with a halogen atom, an aryl group which may have a substituent, a heteroaryl group which may have a substituent, or a substituent Optionally arylalkyl group, a heteroarylalkyl group optionally having a substituent, an arylsulfonyl group optionally having a substituent,
It means a heteroarylsulfonyl group which may have a substituent, an acyl group or a carbamoyl group which may be mono- or di-substituted. Further, R ¹² and R ¹³ may form a ring which may further contain a nitrogen atom, an oxygen atom or a sulfur atom together with the nitrogen atom to which they are bonded. Further, this ring may have a substituent. ) Means a group represented by. }, Α, β
-Unsaturated ketone derivatives or their pharmacologically acceptable salts. 2. General formula (II): {Wherein the ring portion A is of the formula: [In formula, ring B represents the aromatic ring which may have a substituent.
R ² represents a hydrogen atom, a halogen atom, a lower alkyl group optionally substituted with a halogen atom, a cycloalkyl group optionally containing a hetero atom, an aryl group optionally having a substituent, or a substituent. A heteroaryl group which may have, an arylalkyl group which may have a substituent,
A heteroarylalkyl group which may have a substituent,
Formula -X-R < ¹⁴ > (In formula, X is group represented by formula -O- or formula> S = (O) _n (In formula, n means the integer of 0 or 1-2). R ¹⁴ represents a hydrogen atom, a lower alkyl group which may be substituted with a halogen atom, an alkoxyalkyl group, an aryl group which may have a substituent, or a substituent which may have a substituent. A heteroaryl group, an arylalkyl group which may have a substituent or a heteroarylalkyl group which may have a substituent)), an alkoxyalkyl group,
It means an alkoxyalkoxyalkyl group or an aminoalkyl group which may be mono- or di-substituted. R
³ is a hydrogen atom, a lower alkyl group optionally substituted by a halogen atom, a cycloalkyl group optionally containing a hetero atom, an alkoxyalkyl group, an aryl group optionally having a substituent, a substituent Heteroaryl group which may have, arylalkyl group which may have a substituent, aryloxyalkyl group which may have a substituent, heteroarylalkyl group which may have a substituent , A heteroaryloxyalkyl group which may have a substituent, a carboxyalkyl group which may be protected, or an acyl group. Further, R ² and R ³ may together form a ring with the carbon atom to which R ² and the group represented by the formula R ³ O— are bonded, and the oxygen atom to which R ³ is bonded. Good. This ring may contain a nitrogen atom, an oxygen atom or a sulfur atom in addition to the oxygen atom to which R ³ is bonded, or may have a substituent. ] It means the group selected from the group shown by. } The compound represented by these, or those pharmacologically acceptable salt. 3. Ring B is embedded image (Wherein R ⁷ , R ⁸ , R ⁹ and R ¹⁰ are the same or different from each other, a hydrogen atom, a hydroxyl group, a halogen atom, a lower alkyl group optionally substituted with a halogen atom, a lower alkyl group optionally substituted with a halogen atom) Alkoxy group, cycloalkyl group which may contain a hetero atom, cycloalkylalkyl group which may contain a hetero atom, alkoxyalkoxy group, cyano group, mercapto group, alkylthio which alkyl may be substituted by a halogen atom. Group, an alkylsulfinyl group in which alkyl may be substituted with a halogen atom, an alkylsulfonyl group in which alkyl may be substituted with a halogen atom, an arylthio group which may have a substituent, a substituent Optionally arylsulfinyl group, optionally substituted arylsulfonyl group, substituted A heteroarylthio group which may have a heteroarylsulfinyl group which may have a substituent, a heteroarylsulfonyl group which may have a substituent, an aryl group which may have a substituent , A heteroaryl group which may have a substituent, an aryloxy group which may have a substituent, a heteroaryloxy group which may have a substituent, an arylalkyl which may have a substituent Group, heteroarylalkyl group which may have a substituent, arylalkyloxy group which may have a substituent, heteroarylalkyloxy group which may have a substituent, nitro group, nitroso group , Piperidinyl group, alkoxyalkyl group, alkoxyalkoxyalkyl group, hydroxyalkyl group, acyl group, mono- or di-substituted amino Examples thereof include an alkyl group, an optionally protected carboxyl group, an optionally protected carboxyalkyl group, an optionally protected carboxyalkenyl group, etc. Further,
Any two of R ⁷ R ⁸ R ⁹ and R ¹⁰ which are bonded to adjacent carbon atoms may form a ring together with the carbon atom to which they are bonded. 3.) The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof selected from the above.