JP2010043004A - New bicyclic heterocyclic compound - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a medicine having an SNS-inhibiting action that exhibits a therapeutic or a prophylactic action on a disease associated with SNS such as neuropathic pain, nociceptive pain, micturition disorder and multiple sclerosis. <P>SOLUTION: There are disclosed a compound or the like represented by formula (1) [in the formula, R<SP>1</SP>represents a halogen atom or the like, R<SP>2</SP>represents a hydrogen atom or the like, or R<SP>1</SP>and R<SP>2</SP>may together form a 5 to 7 membered ring; m represents a natural number of 0 to 5; R<SP>7</SP>represents a hydrogen atom or the like; R<SP>3</SP>and R<SP>4</SP>independently represent a substituted or an unsubstituted alkyl group or the like; R<SP>8</SP>and R<SP>9</SP>independently represent a hydrogen atom or the like; n represents an integer of 1 to 6; and A represents a fluorine atom or the like], and a pharmacologically acceptable salt thereof. <P>COPYRIGHT: (C)2010,JPO&INPIT

Description

The present invention relates to a therapeutic agent for all pathological conditions involving SNS (sensory neuron specific sodium channel) containing a novel compound having a 2-quinolone skeleton as a bicyclic heterocycle or a pharmaceutically acceptable salt thereof as an active ingredient. Or it relates to preventive drugs. Specifically, the present invention relates to a therapeutic or prophylactic agent for diseases such as neuropathic pain, nociceptive pain, dysuria, or multiple sclerosis.

In 1953, Hodgkins and Huxley showed that the body of neural activity was the Na channel, after which Na channel inhibitors continued to be developed as antiarrhythmic or local anesthetics. In 1961, it was discovered that lidocaine, one of the Na channel inhibitors, has an analgesic effect, and its clinical application as an analgesic was started. However, since Na channels are also present in non-neural tissues such as muscle and heart, side effects caused by systemic administration remained a problem.
On the other hand, with the progress of molecular biology, Na channel subtypes have been revealed one after another, and it is known that there are currently 10 types of α subunits that form Na channel pores. sensory neuron specific sodium channel, or SNS, is one of such Na channel α subunits and is localized in small diameter cells (C fibers) of dorsal root ganglia involved in nerve perception Tetrodotoxin (TTX) resistant Na channel, also called SCN10A, PN3, or NaV1.8 (Non-patent Documents 1 and 2). SNS knockout mice are numb in response to mechanical stimuli, and administration of antisense to SNS attenuates hypersensitivity and abnormalities in neuropathic or inflammatory pain models It has been reported.
Therefore, it is considered that SNS inhibitors can be drugs that have an analgesic effect on diseases such as neuropathic pain and nociceptive pain accompanied by pain, numbness, burning sensation, dull pain, etc. involving C fiber. It was. Furthermore, since SNS is not expressed in non-neural tissues and central nerves, it was considered that drugs that selectively inhibit SNS could be drugs without side effects derived from non-neural tissues or central nerves.

In dysuria, frequent urination, which is the main symptom, is caused by C fiber overactivity, that is, overactive bladder and bladder pain are associated with dysfunction of the afferent sensory nerve tract from the lower urinary tract It is becoming clear that suppression of C-fiber sensory nerves from the bladder is effective (Non-patent Document 3). Therefore, a drug that inhibits SNS, which is the main body of C fiber nerve activity, is expected to be a therapeutic or preventive drug for dysuria having a novel action point.
On the other hand, it was recently reported that SNS, which is found only in C fibers, is ectopically expressed in cerebellar Purkinje cells of patients with multiple sclerosis and is involved in the development of abnormal cerebellar firing patterns ( Non-patent document 4). Therefore, an SNS inhibitor is expected to be the first therapeutic or preventive agent for the induction of symptoms such as ataxia due to abnormal firing of the cerebellar nerve accompanying SNS expression in multiple sclerosis.

The current state of treatment in the clinical field for the above diseases is shown below.
(1) Neuropathic pain
Neuropathic pain refers to pain in which there is no trauma, or there is no inflammatory involvement of the tissue due to complete cure, and spontaneous pain or chronic pain has occurred due to nerve damage or nerve stimulation. Examples include post-lumbar neuralgia, diabetic neuropathy, postherpetic neuralgia, reflex sympathetic nerve, phantom limb pain, spinal injury, end-stage cancer, prolonged postoperative pain. NSAIDS (non-steroidal anti-inflammatory drugs) such as aspirin are completely ineffective against neuropathic pain, and opioids such as morphine have problems with drug resistance and psychiatric symptoms.
At present, mexiletine, which is indicated for diabetic neuropathy, is the only drug marketed for the treatment of neuropathic pain. Although mexiletine has an analgesic effect, it has been reported that side effects are concerned due to lack of selectivity for Na channel, and it cannot be taken at high doses. In addition, some drugs have been supplementarily indicated in the clinic. For example, antidepressants (sulpiride, trazodone, fluvoxatin, milnacipran), adrenergic drugs (clonidine, dexamedetomidine), NMDA receptor antagonists (ketamine hydrochloride, dextromethorphan), anxiolytics (diazepam, lorazepam, etizolam, Hydroxyzine hydrochloride), anticonvulsants (carbamazepine, phenytoin, sodium valproate, zonisamide), calcium antagonists (nifedipine, verapamil hydrochloride, romeridine hydrochloride), etc., all of which are used as supplements. From the above, there is no definitive therapeutic agent that has no side effects derived from non-neural tissues and central nerves and that exhibits analgesic effects specifically for pain.

(2) nociceptive pain
Nociceptive pain refers to pain caused by activation of nociceptors (Aδ, C fibers) due to mechanical, thermal or chemical noxious stimuli due to tissue injury or the like. Nociceptors are sensitized by endogenous chemical stimuli (pain substances) such as serotonin, substance P, bradykinin, prostaglandins, or histamine. Examples of nociceptive pain include low back pain, abdominal pain, rheumatoid arthritis, and pain caused by osteoarthritis. In clinical practice, NSAIDS (acetylsalicylic acid, acetaminophen, diclofenac sodium, indomethacin, mofezolac, flurbiprofen, loxoprofen sodium, ampiroxicam), and steroid drugs (prednisolone, methylprednisolone, dexamethasone, betamethasone), PGE1 (prostaglandin) Gin E1) (alprostadil, lipoylated alprostadil, limaprostal prostadil), PGI2 (beraprost sodium) are used.

(3) Urinary disturbance
Urination disorder is a disease mainly having frequent urination, urinary leakage, residual urine sensation, and micturition pain. Currently, pharmacotherapy for overactive bladder is centered on muscarinic receptor inhibitors that suppress the bladder parasympathetic nerve pathway, but the limitations are also clear. Capsaicin and resiniferatoxin, which are vanilloid receptor stimulants, have been reported to specifically act on C fibers and suppress their functions, but we found drugs that act on SNS localized in C fibers. It has not been.

(4) Multiple sclerosis
Multiple sclerosis is a type of demyelinating disease in which demyelinating foci are scattered in the white matter of the central nervous system, and the foci vary from old to new. Lesions frequently occur in white matter around the lateral ventricle, optic nerve, brain stem, and spinal cord. Histologically, the myelin sheath is destroyed and axons and nerve cells are not affected. Clinical symptoms include optic neuritis, diplopia, nystagmus such as nystagmus, spastic paralysis, painful tonic seizures, Lermit's syndrome, ataxia, speech disorder, bladder rectal disorder, etc. . The cause is unknown, but the theory of autoimmune disease and infection is advocated. Currently, there are no effective prophylactic and therapeutic agents for multiple sclerosis.

In addition, pyrazole derivatives, such as pyrazole amide compounds and pyrazole sulfonamide compounds, piperidine derivatives, and pyrazolopyrimidine derivatives have been disclosed as drugs exhibiting an SNS inhibitory action (Patent Documents 1, 2, and 3).
In addition, as a drug having a 2-quinolone skeleton, a therapeutic agent for a neuropsychiatric disorder that acts as a dopamine D4 ligand, an anti-inflammatory agent that inhibits production of interleukin-1, and an immunosuppressive agent that acts on a cannabinoid receptor have been used so far. (Patent Documents 4, 5, and 6)

International Publication No. 03/037274 Pamphlet International Publication No. 03/037890 Pamphlet International Publication No. 03/037900 Pamphlet International Publication No. 94/020471 Pamphlet International Publication No. 91/007401 Pamphlet WO00 / 040562 pamphlet Nature 379: 257, 1996 Pain 78: 107,1998 Urology 57: 116,2001 Brain Research 959: 235,2003

An object of the present invention is to provide a therapeutic or prophylactic agent for diseases associated with SNS in general, specifically neuropathic pain, nociceptive pain, dysuria, or multiple sclerosis. .

The present inventors have found that a compound having a 2-quinolone skeleton or a pharmaceutically acceptable salt thereof inhibits a TTX-resistant Na channel in human SNS gene-expressing cells, that is, has an SNS inhibitory activity. .

That is, the present invention
[1] Formula (1):

［式中、Ｒ¹は、ハロゲン原子、シアノ基、ニトロ基、カルボキシル基、炭素数１〜４のアルキル基、炭素数１〜４のハロアルキル基、炭素数１〜４のアルコキシ基、炭素数１〜４のハロアルコキシ基、炭素数１〜４のアルキルチオ基、炭素数２〜４のアルコキシカルボニル基、炭素数２〜４のアルキルカルボニル基、１個もしくは同一もしくは異なる２個のアルキル基で置換されていてもよいアミノ基、又は式：−Ｌ¹−Ｒ¹⁰〔式中、Ｌ¹は、単結合、−Ｏ−、−ＯＣＨ₂−、又は式：−Ｎ（Ｒ¹¹）−（式中、Ｒ¹¹は、水素原子、又は炭素数１〜４のアルキル基を表す。）を表し、Ｒ¹⁰は、置換もしくは無置換の飽和もしくは不飽和の脂肪族複素環基、置換もしくは無置換のフェニル基、又は置換もしくは無置換の芳香族複素環基を表す。〕で表される基を表し、
Ｒ²は、水素原子、ハロゲン原子、シアノ基、ニトロ基、カルボキシル基、炭素数１〜４のアルキル基、炭素数１〜４のハロアルキル基、炭素数１〜４のアルコキシ基、炭素数１〜４のハロアルコキシ基、炭素数１〜４のアルキルチオ基、炭素数２〜４のアルコキシカルボニル基、炭素数２〜４のアルキルカルボニル基、１個もしくは同一もしくは異なる２個のアルキル基で置換されていてもよいアミノ基、又は式：−Ｌ²−Ｒ¹²〔式中、Ｌ²は、単結合、−Ｏ−、−ＯＣＨ₂−、又は式：−Ｎ（Ｒ¹³）−（式中、Ｒ¹³は、水素原子、又は炭素数１〜４のアルキル基を表す。）を表し、Ｒ¹²は、置換もしくは無置換の飽和もしくは不飽和の脂肪族複素環基、置換もしくは無置換のフェニル基、又は置換もしくは無置換の芳香族複素環基を表す。〕で表される基を表すか、
又はＲ¹とＲ²が結合して、５〜７員環を形成してもよい。
ｍは、０〜５の整数を表す。
Ｒ⁷は、水素原子、又は炭素数１〜６のアルキル基を表す。
Ｒ³及びＲ⁴は独立して、水素原子、置換もしくは無置換のアルキル基、ハロアルキル基、置換もしくは無置換のアルケニル基、置換もしくは無置換のアルキニル基、置換もしくは無置換のシクロアルキル基、置換もしくは無置換のシクロアルケニル基、置換もしくは無置換の飽和もしくは不飽和の脂肪族複素環基、置換もしくは無置換のアリール基、又は置換もしくは無置換の芳香族複素環基を表すか、又はＲ³とＲ⁴は結合して、それらが結合する窒素原子と共に、置換もしくは無置換の、５〜１０員の飽和もしくは不飽和の含窒素脂肪族複素環を形成してもよく、当該含窒素脂肪族複素環は、０〜２個の酸素原子、０〜２個の硫黄原子、及び１〜３個の窒素原子を含む。
Ｒ⁸及びＲ⁹は独立して、水素原子、フッ素原子、又は炭素数１〜６のアルキル基を表すか、Ｒ⁸とＲ⁹が結合して、それらが結合する炭素原子と共に、３〜７員のシクロアルカンを形成してもよい。
ｎは、１〜６の整数を表し、複数のＲ⁸及び複数のＲ⁹は独立して、同一又は異なってよい。
Ａは、以下の（ａ）〜（ｃ）：
（ａ）フッ素原子；
（ｂ）式：−ＯＲ¹⁴で表される基
〔式中、Ｒ¹⁴は、水素原子、置換もしくは無置換のアルキル基、ハロアルキル基、置換もしくは無置換のシクロアルキル基、置換もしくは無置換の飽和もしくは不飽和の脂肪族複素環基、置換もしくは無置換のアリール基、又は置換もしくは無置換の芳香族複素環基を表すか、Ｒ¹⁴と１つのＲ⁸が結合して、４〜７員の飽和もしくは不飽和の含酸素脂肪族複素環を形成してもよい。〕；
（ｃ）式：−Ｎ（Ｒ⁵）−Ｌ³−Ｒ⁶で表される基
〔式中、Ｌ³は、−Ｃ（＝Ｏ）−、−Ｓ（＝Ｏ）₂−、又は−Ｃ（＝Ｏ）Ｏ−を表す。
Ｒ⁵は、水素原子、置換もしくは無置換のアルキル基、又はハロアルキル基を表し、
Ｒ⁶は、置換もしくは無置換のアルキル基、ハロアルキル基、置換もしくは無置換のシクロアルキル基、置換もしくは無置換の飽和もしくは不飽和の脂肪族複素環基、置換もしくは無置換のアリール基、置換もしくは無置換の芳香族複素環基、又は置換もしくは無置換のアミノ基を表すか、又は、Ｒ⁵とＲ⁶が結合してそれらが結合する−Ｎ−Ｌ³−と共に置換もしくは無置換の５〜８員の飽和もしくは不飽和の含窒素脂肪族複素環を形成するか、Ｒ⁵と１つのＲ⁸が結合して５〜１０員の飽和もしくは不飽和の含窒素脂肪族複素環を形成するか、もしくはＲ⁶と１つのＲ⁸が結合して５〜８員の飽和もしくは不飽和の含窒素脂肪族複素環を形成してもよい。
ただし、Ｒ⁶が置換もしくは無置換のアミノ基を表すときは、Ｌ³は−Ｃ（＝Ｏ）−又は−Ｓ（＝Ｏ）₂−である。〕
から選択される基を表す。]
で表される化合物、又はその薬学的に許容される塩；
〔２〕 Ｒ¹が、ハロゲン原子、炭素数１〜４のアルキル基、炭素数１〜４のハロアルキル基、炭素数１〜４のアルコキシ基、炭素数１〜４のハロアルコキシ基、１個もしくは同一もしくは異なる２個のアルキル基で置換されていてもよいアミノ基、又は式：−Ｌ¹−Ｒ¹⁰〔式中、Ｌ¹、Ｒ¹⁰は、〔１〕と同義である。〕で表される基を表し、Ｒ²は、水素原子、ハロゲン原子、炭素数１〜４のアルキル基、炭素数１〜４のハロアルキル基、炭素数１〜４のアルコキシ基、炭素数１〜４のハロアルコキシ基、１個もしくは同一もしくは異なる２個のアルキル基で置換されていてもよいアミノ基、又は式：−Ｌ²−Ｒ¹²〔式中、Ｌ²、Ｒ¹²は、〔１〕と同義である。〕で表される基を表す、〔１〕に記載の化合物、又はその薬学的に許容される塩；
〔３〕 Ｒ¹が、ハロゲン原子、炭素数１〜４のアルコキシ基、炭素数１〜４のハロアルコキシ基、又は式：−Ｌ¹−Ｒ¹⁰〔式中、Ｌ¹、Ｒ¹⁰は、〔１〕と同義である。〕で表される基を表し、Ｒ²は、水素原子、ハロゲン原子、炭素数１〜４のアルコキシ基、炭素数１〜４のハロアルコキシ基、又は式：−Ｌ²−Ｒ¹²〔式中、Ｌ²、Ｒ¹²は、〔１〕と同義である。〕で表される基を表す、〔１〕又は〔２〕に記載の化合物、又はその薬学的に許容される塩；
〔４〕 ｍが０〜２の整数を表し、Ｒ⁷が水素原子を表す、〔１〕〜〔３〕のいずれかに記載の化合物、又はその薬学的に許容される塩；
〔５〕 ｎが２〜３の整数を表し、複数のＲ⁸及び複数のＲ⁹が独立して水素原子、フッ素原子又は炭素数１〜６のアルキル基を表す、〔１〕〜〔４〕のいずれかに記載の化合物、又はその薬学的に許容される塩；
〔６〕 Ａがフッ素原子を表す、〔１〕〜〔５〕のいずれかに記載の化合物、又はその薬学的に許容される塩；
〔７〕 Ａが式：−ＯＲ¹⁴〔式中、Ｒ¹⁴は〔１〕と同義である。〕で表される基である、〔１〕〜〔５〕のいずれかに記載の化合物、又はその薬学的に許容される塩；
〔８〕 Ａが式：−Ｎ（Ｒ⁵）−Ｌ³−Ｒ⁶〔式中、Ｒ⁵、Ｌ³、Ｒ⁶は〔１〕と同義である。〕で表される基である、〔１〕〜〔５〕のいずれかに記載の化合物、又はその薬学的に許容される塩；
〔９〕 式（２）：

[Wherein, R ¹ represents a halogen atom, a cyano group, a nitro group, a carboxyl group, an alkyl group having 1 to 4 carbon atoms, a haloalkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, or 1 carbon atom. Substituted with 1 to 4 haloalkoxy groups, 1 to 4 alkylthio groups, 2 to 4 alkoxycarbonyl groups, 2 to 4 alkylcarbonyl groups, one or the same or different alkyl groups. An amino group optionally represented by the formula: -L ¹ -R ¹⁰ [wherein L ¹ is a single bond, -O-, -OCH _2- , or a formula: -N (R ¹¹ )-(wherein R ¹¹ represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms.), And R ¹⁰ represents a substituted or unsubstituted saturated or unsaturated aliphatic heterocyclic group, a substituted or unsubstituted phenyl group. Or a substituted or unsubstituted aromatic heterocyclic group. Represents a group represented by
R ² is a hydrogen atom, a halogen atom, a cyano group, a nitro group, a carboxyl group, an alkyl group having 1 to 4 carbon atoms, a haloalkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, or 1 to carbon atoms. 4 haloalkoxy groups, an alkylthio group having 1 to 4 carbon atoms, an alkoxycarbonyl group having 2 to 4 carbon atoms, an alkylcarbonyl group having 2 to 4 carbon atoms, and one or two identical or different alkyl groups. An amino group which may be represented by the formula: -L ² -R ¹² [wherein L ² is a single bond, —O—, —OCH ₂ —, or a formula: —N (R ¹³ ) — (where R ¹³ represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms.), R ¹² represents a substituted or unsubstituted saturated or unsaturated aliphatic heterocyclic group, a substituted or unsubstituted phenyl group, Or a substituted or unsubstituted aromatic heterocyclic group Or a group represented by
Or R < ¹ > and R < ² > may combine to form a 5- to 7-membered ring.
m represents an integer of 0 to 5.
R ⁷ represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms.
R ³ and R ⁴ are independently hydrogen atom, substituted or unsubstituted alkyl group, haloalkyl group, substituted or unsubstituted alkenyl group, substituted or unsubstituted alkynyl group, substituted or unsubstituted cycloalkyl group, substituted Or an unsubstituted cycloalkenyl group, a substituted or unsubstituted saturated or unsaturated aliphatic heterocyclic group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted aromatic heterocyclic group, or R ³ And R ⁴ together with the nitrogen atom to which they are bonded may form a substituted or unsubstituted 5- to 10-membered saturated or unsaturated nitrogen-containing aliphatic heterocycle, and the nitrogen-containing aliphatic The heterocycle contains 0 to 2 oxygen atoms, 0 to 2 sulfur atoms, and 1 to 3 nitrogen atoms.
R ⁸ and R ⁹ independently represent a hydrogen atom, a fluorine atom, or an alkyl group having 1 to 6 carbon atoms, or R ⁸ and R ⁹ are bonded together with the carbon atom to which they are bonded to 3 to 7 A membered cycloalkane may be formed.
n represents an integer of 1 to 6, and the plurality of R ⁸ and the plurality of R ⁹ may be independently the same or different.
A is the following (a) to (c):
(A) a fluorine atom;
(B) Formula: a group represented by —OR ¹⁴ wherein R ¹⁴ is a hydrogen atom, a substituted or unsubstituted alkyl group, a haloalkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted saturation Or an unsaturated aliphatic heterocyclic group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted aromatic heterocyclic group, or R ¹⁴ and one R ⁸ are bonded to form a 4- to 7-membered A saturated or unsaturated oxygen-containing aliphatic heterocyclic ring may be formed. ];
(C) Formula: —N (R ⁵ ) —L ³ —R ⁶ [wherein L ³ is —C (═O) —, —S (═O) ₂ —, or —C (= O) represents O-.
R ⁵ represents a hydrogen atom, a substituted or unsubstituted alkyl group, or a haloalkyl group,
R ⁶ represents a substituted or unsubstituted alkyl group, a haloalkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted saturated or unsaturated aliphatic heterocyclic group, a substituted or unsubstituted aryl group, substituted or unsubstituted It represents an unsubstituted aromatic heterocyclic group, or a substituted or unsubstituted amino group, or a substituted or unsubstituted ⁵ -N-L ³ — with which R ⁵ and R ⁶ are bonded to each other. Whether to form an 8-membered saturated or unsaturated nitrogen-containing aliphatic heterocyclic ring, or R ⁵ and one R ⁸ combine to form a 5- to 10-membered saturated or unsaturated nitrogen-containing aliphatic heterocyclic ring Alternatively, R ⁶ and one R ⁸ may combine to form a 5- to 8-membered saturated or unsaturated nitrogen-containing aliphatic heterocycle.
Provided that when R ⁶ is to represent a substituted or unsubstituted amino group, L ³ is -C (= O) - or -S (= O) ₂ - a. ]
Represents a group selected from: ]
Or a pharmaceutically acceptable salt thereof;
[2] R ¹ is a halogen atom, an alkyl group having 1 to 4 carbon atoms, a haloalkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, a haloalkoxy group having 1 to 4 carbon atoms, one or An amino group which may be substituted with two identical or different alkyl groups, or a formula: -L ¹ -R ¹⁰ [wherein L ¹ and R ¹⁰ are as defined in [1]. R ² is a hydrogen atom, a halogen atom, an alkyl group having 1 to 4 carbon atoms, a haloalkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, or 1 to carbon atoms. 4 haloalkoxy groups, an amino group optionally substituted by one or two identical or different alkyl groups, or a formula: -L ² -R ^{12 wherein} L ² and R ¹² are [1] It is synonymous with. Or a pharmaceutically acceptable salt thereof; or a pharmaceutically acceptable salt thereof;
[3] R ¹ is a halogen atom, an alkoxy group having 1 to 4 carbon atoms, a haloalkoxy group having 1 to 4 carbon atoms, or a formula: -L ¹ -R ¹⁰ [wherein L ¹ and R ¹⁰ are [ 1]. R ² is a hydrogen atom, a halogen atom, an alkoxy group having 1 to 4 carbon atoms, a haloalkoxy group having 1 to 4 carbon atoms, or a formula: -L ² -R ¹² [wherein , L ² and R ¹² are synonymous with [1]. A compound represented by [1] or [2], or a pharmaceutically acceptable salt thereof;
[4] The compound according to any one of [1] to [3], or a pharmaceutically acceptable salt thereof, wherein m represents an integer of 0 to 2 and R ⁷ represents a hydrogen atom;
[5] n represents an integer of 2 to 3, and a plurality of R ⁸ and a plurality of R ⁹ independently represent a hydrogen atom, a fluorine atom, or an alkyl group having 1 to 6 carbon atoms, [1] to [4] Or a pharmaceutically acceptable salt thereof;
[6] The compound according to any one of [1] to [5], wherein A represents a fluorine atom, or a pharmaceutically acceptable salt thereof;
[7] A is a formula: —OR ^{14 wherein} R ¹⁴ is as defined in [1]. A compound represented by any one of [1] to [5], or a pharmaceutically acceptable salt thereof;
[8] A is a formula: —N (R ⁵ ) -L ³ —R ⁶ [wherein R ⁵ , L ³ , R ⁶ are as defined in [1]. A compound represented by any one of [1] to [5], or a pharmaceutically acceptable salt thereof;
[9] Formula (2):

〔式中、Ｒ¹、Ｒ²、Ｒ⁷、Ｒ⁸、Ｒ⁹、Ａ、ｍ、及びｎは、〔１〕と同義であり、
ｐは、１〜４の整数を表し、
Ｒ^4aは、水素原子、又はアルキル基を表し、
Ｒ¹⁴は、置換もしくは無置換のアリール基、置換もしくは無置換の芳香族複素環基、置換もしくは無置換のアミノ基、又は置換もしくは無置換のカルバモイル基を表す。〕
で表される、〔１〕〜〔８〕のいずれかに記載の化合物、又はその薬学的に許容される塩；
〔１０〕 〔１〕〜〔９〕のいずれかに記載の化合物又はその薬学的に許容される塩を有効成分とする医薬；
〔１１〕 〔１〕〜〔９〕のいずれかに記載の化合物又はその薬学的に許容される塩を有効成分として含有するＳＮＳ阻害剤；
〔１２〕 〔１〕〜〔９〕のいずれかに記載の化合物又はその薬学的に許容される塩を有効成分として含有する神経因性疼痛、侵害受容性疼痛、排尿障害、又は多発性硬化症の治療薬又は予防薬；
に関する。

[Wherein, R ¹ , R ² , R ⁷ , R ⁸ , R ⁹ , A, m, and n are as defined in [1],
p represents an integer of 1 to 4,
R ^4a represents a hydrogen atom or an alkyl group,
R ¹⁴ represents a substituted or unsubstituted aryl group, a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted amino group, or a substituted or unsubstituted carbamoyl group. ]
Or a pharmaceutically acceptable salt thereof according to any one of [1] to [8],
[10] A pharmaceutical comprising the compound according to any one of [1] to [9] or a pharmaceutically acceptable salt thereof as an active ingredient;
[11] An SNS inhibitor comprising the compound according to any one of [1] to [9] or a pharmaceutically acceptable salt thereof as an active ingredient;
[12] Neuropathic pain, nociceptive pain, dysuria, or multiple sclerosis comprising the compound according to any one of [1] to [9] or a pharmaceutically acceptable salt thereof as an active ingredient Therapeutic or prophylactic agent for
About.

According to the present invention, an SNS inhibitor comprising a compound having a 2-quinolone skeleton or a pharmaceutically acceptable salt thereof is provided. The SNS inhibitor of the present invention is useful as a therapeutic or prophylactic agent for all pathologies involving SNS, specifically patients with neuropathic pain, nociceptive pain, dysuria, multiple sclerosis, etc. Is applicable.

  In the present specification, examples of the “halogen atom” include a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.

  "Alkyl group" represents a linear or branched alkyl group having 1 to 6 carbon atoms, specifically a methyl group, an ethyl group, a propyl group (1-propyl group), an isopropyl group (2-propyl group), Butyl group (1-butyl group), sec-butyl group (2-butyl group), isobutyl group (2-methyl-1-propyl group), t-butyl group (2-methyl-2-propyl group), pentyl group (1-pentyl group) or hexyl group (1-hexyl group) can be mentioned. Among them, preferred is an alkyl group having 1 to 4 carbon atoms.

  Examples of the “haloalkyl group” include a linear or branched alkyl group having 1 to 6 carbon atoms substituted with 1 to 5 identical or different halogen atoms, specifically, a trifluoromethyl group, 2, A 2-difluoroethyl group, a 2,2,2-trifluoroethyl group, a 2-chloroethyl group, a pentafluoroethyl group, a 3,3,3-trifluoropropyl group and the like can be exemplified. Preferably a C1-C4 haloalkyl group is mentioned.

  “Alkenyl group” means a straight chain or branched alkenyl group having 2 to 6 carbon atoms, specifically vinyl group, 1-propenyl group, 2-propenyl group, 1-methylvinyl group, 1-butenyl group, 1-ethylvinyl group, 1-methyl-2-propenyl group, 2-butenyl group, 3-butenyl group, 2-methyl-1-propenyl group, 2-methyl-2-propenyl group, 1-pentenyl group, 1-hexenyl Groups and the like. Among them, preferred is an alkenyl group having 2 to 4 carbon atoms.

  The “alkynyl group” is a straight chain or branched alkynyl group having 2 to 6 carbon atoms, and specifically includes an ethynyl group, a 1-propynyl group, a 2-propynyl group, a 1-butynyl group, a 1-methyl-2 group. -Propynyl group, 3-butynyl group, 1-pentynyl group, 1-hexynyl group and the like can be mentioned. Among them, preferred is an alkynyl group having 2 to 4 carbon atoms.

  “Alkoxy group” represents a straight or branched alkoxy group having 1 to 6 carbon atoms, specifically, a methoxy group, an ethoxy group, a propoxy group, a 1-methylethoxy group, a butoxy group, a 1-methylpropoxy group, A 2-methylpropoxy group, a 1,1-dimethylethoxy group, a pentyloxy group or a hexyloxy group can be exemplified. Among them, preferred is an alkoxy group having 1 to 4 carbon atoms.

  Examples of the “haloalkoxy group” include a linear or branched alkoxy group having 1 to 6 carbon atoms substituted with 1 to 5 identical or different halogen atoms, specifically a trifluoromethoxy group, 2 , 2-difluoroethoxy group, 2,2,2-trifluoroethoxy group, 2-chloroethoxy group, pentafluoroethoxy group, 3,3,3-trifluoropropoxy group, and the like. Preferably a C1-C4 haloalkoxy group is mentioned.

  “Alkylthio group” refers to a linear or branched alkylthio group having 1 to 6 carbon atoms, specifically, methylthio group, ethylthio group, propylthio group, 1-methylethylthio group, butylthio group, 1-methylpropylthio group. Group, 2-methylpropylthio group, 1,1-dimethylethylthio group, pentylthio group or hexylthio group. Among them, preferred is an alkylthio group having 1 to 4 carbon atoms.

  Examples of the alkyl in the “alkylcarbonyl group” include the same alkyl groups as those described above. Preferred examples of the alkylcarbonyl group include an acetyl group, a propionyl group, and a butyryl group.

  The “alkylcarbonyloxy group” represents a group in which an oxygen atom is bonded to the “alkylcarbonyl group”.

  Examples of the alkyl in the “alkylsulfonyl group” include the same as the above “alkyl group”. Preferred examples of the alkylsulfonyl group include a methylsulfonyl group, an ethylsulfonyl group, and a propylsulfonyl group.

  Examples of the alkoxy in the “alkoxycarbonyl group” include the same as the “alkoxy group”. Preferred examples of the alkoxycarbonyl group include a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, and a butoxycarbonyl group.

  Examples of the alkyl group in the “amino group optionally substituted with one or the same or different two alkyl groups” include the same as the above “alkyl group”, preferably a methylamino group, an ethylamino group, A propylamino group, a dimethylamino group, a diethylamino group, a methylethylamino group, etc. can be mentioned.

  “Cycloalkyl group” refers to a 3- to 8-membered cycloalkyl group, and specific examples include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, and a cyclooctyl group. Of these, a 4- to 6-membered cycloalkyl group is preferable.

  “Cycloalkenyl group” refers to a 4- to 8-membered cycloalkenyl group, and specific examples include a cyclobutenyl group, a cyclopentenyl group, a cyclohexenyl group, a cycloheptenyl group, and a cyclooctenyl group, and the bonding position is not particularly limited. Among them, preferred is a 5- or 6-membered cycloalkenyl group.

  A “saturated aliphatic heterocyclic group” is a 4 to 8 member containing 1 to 3 heteroatoms selected from 0 to 3 nitrogen atoms, 0 to 2 oxygen atoms and 0 to 2 sulfur atoms. As long as it is chemically stable, the bonding position is not particularly limited. Specifically, azetidinyl group, pyrrolidinyl group, piperidyl group, piperidino group, piperazinyl group, azepanyl group, azocanyl group, tetrahydrofuryl group, tetrahydrothienyl group, tetrahydropyranyl group, morpholinyl group, morpholino group, thiomorpholinyl group, 1, 4-dioxanyl group etc. can be mentioned.

  The “unsaturated aliphatic heterocyclic group” includes 1 to 3 heteroatoms selected from 0 to 3 nitrogen atoms, 0 to 2 oxygen atoms and 0 to 2 sulfur atoms. A 5- to 10-membered monocyclic or bicyclic unsaturated aliphatic heterocyclic group containing 3 double bonds is shown, and the bonding position is not particularly limited as long as it is chemically stable. Specifically, a 2-pyrrolinyl group, a 2-imidazolinyl group, a tetrahydroisoquinoline group, and the like can be given.

  “Aryl group” refers to a 6 to 10-membered aryl group, and specific examples include a phenyl group, a 1-naphthyl group, and a 2-naphthyl group.

  The aryl group in the “aryloxy group”, “arylcarbonyl group”, or “arylsulfonyl group” has the same meaning as described above.

  The “aromatic heterocyclic group” is a 5- to 10-membered member containing 1 to 4 heteroatoms selected from 0 to 4 nitrogen atoms, 0 to 2 oxygen atoms and 0 to 2 sulfur atoms. It represents a monocyclic or bicyclic aromatic heterocyclic group, and the bonding position is not particularly limited as long as it is chemically stable. Specifically, furyl group, thienyl group, pyrrolyl group, oxazolyl group, isoxazolyl group, thiazolyl group, isothiazolyl group, imidazolyl group, pyrazolyl group, furazanyl group, oxadiazolyl group, triazolyl group, pyridyl group, pyrimidinyl group, pyrazinyl group, An indolyl group, a quinolyl group, an isoquinolyl group, a quinazolinyl group, an imidazo [2,1-b] [1,3] thiazolyl group, and the like can be given.

The “aromatic heterocyclic group” in the “aromatic heterocyclic oxy group”, “aromatic heterocyclic carbonyl group”, or “aromatic heterocyclic sulfonyl group” has the same meaning as described above.

Formula in R ¹ : -L ¹ -R ¹⁰ [wherein L ¹ is a single bond, —O—, —OCH ₂ —, or —N (R ¹¹ ) — (wherein R ¹¹ is a hydrogen atom, R ¹⁰ represents a substituted or unsubstituted saturated or unsaturated aliphatic heterocyclic group, a substituted or unsubstituted phenyl group, or a substituted or unsubstituted group. Represents an aromatic heterocyclic group. In the group represented by formula (I), when L ¹ is —OCH ₂ —, it represents that a 2-quinolone skeleton is bonded to the left side of —OCH ₂ — and R ¹⁰ is bonded to the right side. Examples of the saturated or unsaturated aliphatic heterocyclic group for R ¹⁰ include the same as the saturated aliphatic heterocyclic group or unsaturated aliphatic heterocyclic group. Examples of the aromatic heterocyclic group for R ¹⁰ include the same aromatic heterocyclic groups as described above, and preferred examples include a pyridyl group, a furyl group, a thienyl group, a pyrimidinyl group, and a pyrazinyl group. In R ¹⁰ , when a saturated or unsaturated aliphatic heterocyclic group, phenyl group, or aromatic heterocyclic group is substituted, the substituent may be a halogen atom, an alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group. Group, hydroxyl group, alkylthio group, and dimethylamino group. The group represented by the formula: -L ¹ -R ¹⁰ is preferably a substituted or unsubstituted phenyl group, a substituted or unsubstituted pyridyl group, a substituted or unsubstituted phenyloxy group, or a substituted or unsubstituted benzyloxy Among them, a substituted or unsubstituted pyridyl group or a substituted or unsubstituted phenyloxy group is particularly preferable.

Wherein in R ^2: -L ² -R ¹² wherein, L ² represents a single _{bond, -O -, - OCH 2 -} , or -N (R ¹³⁾ - (wherein, R ¹³ is a hydrogen atom, Or an alkyl group having 1 to 4 carbon atoms), and R ¹² represents a substituted or unsubstituted saturated or unsaturated aliphatic heterocyclic group, a substituted or unsubstituted phenyl group, or a substituted or unsubstituted group. Represents an aromatic heterocyclic group. In the group represented by formula (I), when L ² is —OCH ₂ —, it represents that a 2-quinolone skeleton is bonded to the left side of —OCH ₂ — and R ¹² is bonded to the right side. Examples of the saturated or unsaturated aliphatic heterocyclic group for R ¹² include the same as the saturated aliphatic heterocyclic group or the unsaturated aliphatic heterocyclic group. As the aromatic heterocyclic group for R ¹² , the same aromatic heterocyclic groups as those described above can be mentioned, and preferred examples include pyridyl group, furyl group, thienyl group, pyrimidinyl group, pyrazinyl group and the like. In R ¹² , when a saturated or unsaturated aliphatic heterocyclic group, phenyl group, or aromatic heterocyclic group is substituted, the substituent may be a halogen atom, an alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group. Group, hydroxyl group, alkylthio group, and dimethylamino group. The group represented by the formula: -L ² -R ¹² is preferably a substituted or unsubstituted phenyl group, a substituted or unsubstituted pyridyl group, a substituted or unsubstituted phenyloxy group, or a substituted or unsubstituted benzyloxy Among them, a substituted or unsubstituted pyridyl group or a substituted or unsubstituted phenyloxy group is particularly preferable.

R ¹ and 5 to 7-membered ring R ² is formed by bonding, respectively attached to a carbon atom adjacent the R ¹ and R ^2, and further R ¹ and R ² together trimethylene Represents a 5- to 7-membered ring formed by representing a group, a tetramethylene group, a pentamethylene group, a methylenedioxy group, an ethylenedioxy group, or a trimethylenedioxy group. Preferably, R ¹ bonded to the 6th carbon atom of the 2-quinolone skeleton and R ² bonded to the 7th carbon atom are combined to form a trimethylene group, a tetramethylene group, a pentamethylene group, a methylenedioxy group, As a 2-quinolone skeleton in which a 5- to 7-membered ring formed by representing an ethylenedioxy group or a trimethylenedioxy group is formed, specifically, a formula The thing shown to (C1)-(C6) etc. are mentioned.

またＲ¹とＲ²が結合して形成される５〜７員環として、さらに好ましくは、２−キノロン骨格の６位炭素原子に結合したＲ¹と７位炭素原子に結合したＲ²とが一緒になって、トリメチレン基、又はメチレンジオキシ基を表すことにより形成される５員環、すなわち前記の式（Ｃ１）と式（Ｃ４）が挙げられる。

The 5- to 7-membered ring formed by combining R ¹ and R ² is more preferably R ¹ bonded to the 6-position carbon atom of the 2-quinolone skeleton and R ² bonded to the 7-position carbon atom. The five-membered ring formed by representing a trimethylene group or a methylenedioxy group together, that is, the above formulas (C1) and (C4) may be mentioned.

The 5- to 10-membered saturated or unsaturated nitrogen-containing aliphatic heterocycle formed by combining R ³ and R ⁴ together with the nitrogen atom to which they are bonded includes 0 to 2 oxygen atoms, 0 to 2 And a nitrogen-containing aliphatic heterocyclic ring having 5 to 10 membered 0 to 3 double bonds containing 1 to 3 nitrogen atoms, specifically, pyrrolidine, piperidine, azepan, azocane Imidazolidine, piperazine, oxazolidine, morpholine, thiomorpholine, tetrahydroisoquinoline and the like.

Cyclopropane, cyclobutane, cyclopentane, cyclohexane, and cycloheptane are mentioned as a 3-7 membered cycloalkane formed by combining R ⁸ and R ⁹ together with the carbon atom to which they are bonded.

Specific examples of the 4- to 7-membered saturated or unsaturated oxygen-containing aliphatic heterocyclic ring formed by combining R ¹⁴ and R ⁸ include oxetane, tetrahydrofuran, tetrahydropyran, oxepane, dihydrofuran, and dihydropyran. Etc. Preferably, tetrahydrofuran and tetrahydropyran are used.

A 5- to 8-membered saturated or unsaturated nitrogen-containing aliphatic heterocycle formed together with —N—L ³ — to which R ⁵ and R ⁶ are bonded and R ⁶ and R ⁸ are bonded Specific examples of the 5- to 8-membered saturated or unsaturated nitrogen-containing aliphatic heterocycle formed include those shown in the formulas (C7) to (C22).

A 5- to 10-membered saturated or unsaturated nitrogen-containing aliphatic heterocyclic ring formed by combining R ⁵ and R ⁸ has 0 to 2 oxygen atoms, 0 to 2 sulfur atoms, and 1 to 3 Specific examples include pyrrolidine, piperidine, azepane, azocan, imidazolidine, piperazine, oxazolidine, morpholine, thiomorpholine, tetrahydroisoquinoline and the like. Pyrrolidine, piperidine, and morpholine are preferable.

R ¹ is preferably a halogen atom, an alkyl group having 1 to 4 carbon atoms, a haloalkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, a haloalkoxy group having 1 to 4 carbon atoms, one or the same or different two alkyl amino group which may be substituted with a group, or the formula: -L ¹ -R ¹⁰ wherein, L ^1, R ¹⁰ has the same meaning as defined above. And more preferably a halogen atom, an alkoxy group having 1 to 4 carbon atoms, a haloalkoxy group having 1 to 4 carbon atoms, or a formula: -L ¹ -R ¹⁰ [wherein L ¹ and R ¹⁰ are as defined above. The group represented by this is mentioned. Specifically, R ¹ is preferably a fluorine atom, chlorine atom, methyl group, ethyl group, propyl group, trifluoromethyl group, methoxy group, trifluoromethoxy group, dimethylamino group, pyrrolidino group, morpholino group, substituted Or an unsubstituted phenyl group, a substituted or unsubstituted pyridyl group, a substituted or unsubstituted phenyloxy group, or a substituted or unsubstituted benzyloxy group, among which a trifluoromethoxy group, a substituted or unsubstituted pyridyl group Or a substituted or unsubstituted phenyloxy group is particularly preferred.
R ² is preferably a hydrogen atom, a halogen atom, an alkyl group having 1 to 4 carbon atoms, a haloalkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, a haloalkoxy group having 1 to 4 carbon atoms, Or an amino group which may be substituted with two or the same or different alkyl groups, or a formula: -L ² -R ¹² wherein L ² and R ¹² are as defined above. And more preferably a hydrogen atom, a halogen atom, an alkoxy group having 1 to 4 carbon atoms, a haloalkoxy group having 1 to 4 carbon atoms, or a formula: -L ² -R ¹² [formula In the formula, L ² and R ¹² are as defined above. The group represented by this is mentioned. Specifically, R ² is preferably a hydrogen atom, fluorine atom, chlorine atom, methyl group, ethyl group, propyl group, trifluoromethyl group, methoxy group, trifluoromethoxy group, dimethylamino group, pyrrolidino group, morpholino. Group, substituted or unsubstituted phenyl group, substituted or unsubstituted pyridyl group, substituted or unsubstituted phenyloxy group, or substituted or unsubstituted benzyloxy group, among which hydrogen atom, trifluoromethoxy group, substituted Or an unsubstituted pyridyl group or a substituted or unsubstituted phenyloxy group is particularly preferred.

R ⁷ is preferably a hydrogen atom, a methyl group, or an ethyl group, more preferably a hydrogen atom or a methyl group, and particularly preferably a hydrogen atom.
Preferably, m is an integer of 0 to 2.
R ⁸ and R ⁹ are preferably a hydrogen atom, a fluorine atom, or an alkyl group having 1 to 6 carbon atoms. Specifically, R ⁸ and R ⁹ are preferably a hydrogen atom, a fluorine atom, a methyl group, or an ethyl group, more preferably a hydrogen atom, a fluorine atom, or a methyl group, and particularly preferably a hydrogen atom.
n is preferably an integer of 2 to 3. The plurality of R ⁸ and the plurality of R ⁹ may be independently the same or different.
R ⁵ is preferably a hydrogen atom, a methyl group, or an ethyl group, more preferably a hydrogen atom or a methyl group, and particularly preferably a hydrogen atom.

R ³ and R ⁴ are preferably each independently a hydrogen atom or a substituted or unsubstituted alkyl group, or a substituted or unsubstituted group formed by combining R ³ and R ⁴ together with the nitrogen atom to which they are bonded. 5 to 10-membered saturated or unsaturated nitrogen-containing aliphatic heterocycle.
R ⁴ is more preferably a hydrogen atom or a substituted or unsubstituted alkyl group, more preferably a hydrogen atom or an unsubstituted alkyl group, and particularly preferably a hydrogen atom.
R ^4a is preferably a hydrogen atom.
R ³ is more preferably a substituted alkyl group. When the alkyl group in R ³ is substituted, the substituent is preferably a substituted or unsubstituted aryl group, a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted amino group, or a substituted or unsubstituted group. A substituted carbamoyl group may be mentioned. Specific examples of the aryl group and the aromatic heterocyclic group include a phenyl group, a furyl group, a thiazolyl group, an imidazolyl group, a pyrazolyl group, a furanyl group, and an indolyl group.

When the “alkyl group”, “alkenyl group”, or “alkynyl group” is substituted, the substituent is selected from the following groups (i) to (v), and the same or different substituents are substituted multiple times: You may have:
(I) halogen atom, hydroxyl group, carboxyl group, cyano group;
(Ii) a substituted or unsubstituted amino group, a substituted or unsubstituted carbamoyl group, a substituted or unsubstituted sulfamoyl group;
(Iii) an alkoxy group, a haloalkoxy group, an alkylcarbonyl group, an alkylcarbonyloxy group, an alkoxycarbonyl group, an alkylthio group, an alkylsulfonyl group [these groups are a halogen atom, a hydroxyl group, a carboxyl group, one or the same or different 2 Selected from an amino group optionally substituted with an alkyl group, an alkoxy group, a haloalkoxy group, an alkoxycarbonyl group, an optionally substituted aryl group, and an optionally substituted aromatic heterocyclic group One or more substituents may be substituted with a substituent. Examples of the substituent of the aryl group and the aromatic heterocyclic group include a halogen atom, a hydroxyl group, a carboxyl group, an alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, an alkoxycarbonyl group, a nitro group, a cyano group, and a carbamoyl group. Can be mentioned. ];
(Iv) a cycloalkyl group, a cycloalkenyl group, a saturated or unsaturated aliphatic heterocyclic group [these groups are a halogen atom, a hydroxyl group, a carboxyl group, an oxo group, a thioxo group, one or two identical or different Amino group optionally substituted with an alkyl group, alkoxy group, haloalkoxy group, alkoxycarbonyl group, optionally substituted alkyl group, optionally substituted aryl group, and optionally substituted aromatic group One or more substituents may be substituted with a substituent selected from a group hetero-converting group. Examples of the substituent of the alkyl group include a halogen atom, a hydroxyl group, a carboxyl group, an alkoxy group, and a haloalkoxy group. Examples of the substituent of the aryl group and the aromatic heterocyclic group include a halogen atom, a hydroxyl group, and a carboxyl group. An alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, an alkoxycarbonyl group, a nitro group, a cyano group, and a carbamoyl group. ];
(V) an aryl group, an aromatic heterocyclic group, an aryloxy group, an aromatic heterocyclic oxy group, an arylcarbonyl group, an aromatic heterocyclic carbonyl group, an arylsulfonyl group, an aromatic heterocyclic sulfonyl group [these groups are Halogen atom, hydroxyl group, carboxyl group, substituted or unsubstituted amino group, substituted or unsubstituted carbamoyl group, substituted or unsubstituted sulfamoyl group, alkoxy group, haloalkoxy group, alkoxycarbonyl group, optionally substituted alkyl One or more substituents may be substituted with a substituent selected from a group, an optionally substituted aryl group, and an optionally substituted aromatic heterocyclic group. Examples of the substituent of the alkyl group include a halogen atom, a hydroxyl group, a carboxyl group, an alkoxy group, and a haloalkoxy group. Examples of the substituent of the aryl group and the aromatic heterocyclic group include a halogen atom, a hydroxyl group, and a carboxyl group. An alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, an alkoxycarbonyl group, a nitro group, a cyano group, and a carbamoyl group. ].

When the “cycloalkyl group”, “cycloalkenyl group”, or “saturated or unsaturated aliphatic heterocyclic group” is substituted, the substituent is selected from the following groups (vi) to (x) A plurality of the same or different substituents may be substituted:
(Vi) halogen atom, hydroxyl group, carboxyl group, cyano group, oxo group, thioxo group;
(Vii) a substituted or unsubstituted amino group, a substituted or unsubstituted carbamoyl group, a substituted or unsubstituted sulfamoyl group;
(Viii) alkyl group, haloalkyl group, alkoxy group, haloalkoxy group, alkylcarbonyl group, alkylcarbonyloxy group, alkoxycarbonyl group, alkylthio group, alkylsulfonyl group [these groups are a halogen atom, a hydroxyl group, a carboxyl group, 1 An amino group, an alkoxy group, a haloalkoxy group, an alkoxycarbonyl group, an optionally substituted aryl group, and an optionally substituted aromatic complex, each of which may be substituted with two or the same or different alkyl groups. One or more substituents may be substituted with a substituent selected from substituents. Examples of the substituent of the aryl group and the aromatic heterocyclic group include a halogen atom, a hydroxyl group, a carboxyl group, an alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, an alkoxycarbonyl group, a nitro group, a cyano group, and a carbamoyl group. Can be mentioned. ];
(Ix) a cycloalkyl group, a cycloalkenyl group, a saturated or unsaturated aliphatic heterocyclic group [these groups are a halogen atom, a hydroxyl group, a carboxyl group, an oxo group, a thioxo group, one or two identical or different Amino group optionally substituted with an alkyl group, alkoxy group, haloalkoxy group, alkoxycarbonyl group, optionally substituted alkyl group, optionally substituted aryl group, and optionally substituted aromatic group One or more substituents may be substituted with a substituent selected from a group hetero-converting group. Examples of the substituent of the alkyl group include a halogen atom, a hydroxyl group, a carboxyl group, an alkoxy group, and a haloalkoxy group. Examples of the substituent of the aryl group and the aromatic heterocyclic group include a halogen atom, a hydroxyl group, and a carboxyl group. An alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, an alkoxycarbonyl group, a nitro group, a cyano group, and a carbamoyl group. ];
(X) aryl group, aromatic heterocyclic group, aryloxy group, aromatic heterocyclic oxy group, arylcarbonyl group, aromatic heterocyclic carbonyl group, arylsulfonyl group, aromatic heterocyclic sulfonyl group [these groups are Halogen atom, hydroxyl group, carboxyl group, substituted or unsubstituted amino group, substituted or unsubstituted carbamoyl group, substituted or unsubstituted sulfamoyl group, alkoxy group, haloalkoxy group, alkoxycarbonyl group, optionally substituted alkyl One or more substituents may be substituted with a substituent selected from a group, an optionally substituted aryl group, and an optionally substituted aromatic heterocyclic group. Examples of the substituent of the alkyl group include a halogen atom, a hydroxyl group, a carboxyl group, an alkoxy group, and a haloalkoxy group. Examples of the substituent of the aryl group and the aromatic heterocyclic group include a halogen atom, a hydroxyl group, and a carboxyl group. An alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, an alkoxycarbonyl group, a nitro group, a cyano group, and a carbamoyl group. ].
Further, substituents when R ³ and the nitrogen-containing aliphatic heterocyclic saturated or unsaturated 5 to 10 membered R ⁴ form together with the bond to the nitrogen atom to which they are attached is substituted, and the R ⁵ In the case where the 5- to 8-membered saturated or unsaturated nitrogen-containing aliphatic heterocyclic ring formed together with —N—L ³ — to which R ⁶ is bonded and bonded thereto is substituted, It is selected from the group (vi) to (x), and 1 to 5 identical or different substituents may be substituted.

“Phenyl group”, “aryl group”, “aromatic heterocyclic group”, “aryloxy group”, “aromatic heterocyclic oxy group”, “arylcarbonyl group”, “aromatic heterocyclic carbonyl group”, “aryl” The substituent when “aryl” or “aromatic heterocycle” of “sulfonyl group” or “aromatic heterocyclic sulfonyl group” is substituted is selected from the following groups (xi) to (xv) , 1 to 5 of the same or different substituents may be substituted:
(Xi) halogen atom, hydroxyl group, carboxyl group, cyano group, nitro group, methylenedioxy group, ethylenedioxy group;
(Xii) a substituted or unsubstituted amino group, a substituted or unsubstituted carbamoyl group, a substituted or unsubstituted sulfamoyl group;
(Xiii) alkyl group, haloalkyl group, alkenyl group, alkynyl group, alkoxy group, haloalkoxy group, alkylcarbonyl group, alkylcarbonyloxy group, alkoxycarbonyl group, alkylthio group, alkylsulfonyl group [these groups are halogen atoms, A hydroxyl group, a carboxyl group, an amino group optionally substituted with one or two identical or different alkyl groups, an alkoxy group, a haloalkoxy group, an alkoxycarbonyl group, an optionally substituted aryl group, and a substituted group; One or more substituents may be substituted with a substituent selected from the optionally substituted aromatic heterocyclic groups. Examples of the substituent of the aryl group and the aromatic heterocyclic group include a halogen atom, a hydroxyl group, a carboxyl group, an alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, an alkoxycarbonyl group, a nitro group, a cyano group, and a carbamoyl group. Can be mentioned. ];
(Xiv) a cycloalkyl group, a cycloalkenyl group, a saturated or unsaturated aliphatic heterocyclic group [these groups are a halogen atom, a hydroxyl group, a carboxyl group, an oxo group, a thioxo group, one or two identical or different Amino group optionally substituted with an alkyl group, alkoxy group, haloalkoxy group, alkoxycarbonyl group, optionally substituted alkyl group, optionally substituted aryl group, and optionally substituted aromatic group One or a plurality of substituents may be substituted with a substituent selected from a group heterocyclic substituent. Examples of the substituent of the alkyl group include a halogen atom, a hydroxyl group, a carboxyl group, an alkoxy group, and a haloalkoxy group. Examples of the substituent of the aryl group and the aromatic heterocyclic group include a halogen atom, a hydroxyl group, and a carboxyl group. An alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, an alkoxycarbonyl group, a nitro group, a cyano group, and a carbamoyl group. ];
(Xv) aryl group, aromatic heterocyclic group, aryloxy group, aromatic heterocyclic oxy group, arylcarbonyl group, aromatic heterocyclic carbonyl group, arylsulfonyl group, aromatic heterocyclic sulfonyl group [these groups are Halogen atom, hydroxyl group, carboxyl group, substituted or unsubstituted amino group, substituted or unsubstituted carbamoyl group, substituted or unsubstituted sulfamoyl group, alkoxy group, haloalkoxy group, alkoxycarbonyl group, optionally substituted alkyl One or more substituents may be substituted with a substituent selected from a group, an optionally substituted aryl group, and an optionally substituted aromatic heterocyclic group. Examples of the substituent of the alkyl group include a halogen atom, a hydroxyl group, a carboxyl group, an alkoxy group, and a haloalkoxy group. Examples of the substituent of the aryl group and the aromatic heterocyclic group include a halogen atom, a hydroxyl group, and a carboxyl group. An alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, an alkoxycarbonyl group, a nitro group, a cyano group, and a carbamoyl group. ].

When the “amino group”, “carbamoyl group”, or “sulfamoyl group” is substituted, the substituent is selected from the following groups (xvi) to (xviii), and the same or different substituents are substituted multiple times: You may have:
(Xvi) an alkyl group, a haloalkyl group, an alkenyl group, an alkynyl group, an alkylcarbonyl group, an alkylsulfonyl group, an alkoxycarbonyl group [these groups are a halogen atom, a hydroxyl group, a carboxyl group, one or two identical or different alkyls A substituent selected from an amino group, an alkoxy group, a haloalkoxy group, an alkoxycarbonyl group, an optionally substituted aryl group, and an optionally substituted aromatic heterocyclic group. One or more may be substituted. Examples of the substituent of the aryl group and the aromatic heterocyclic group include a halogen atom, a hydroxyl group, a carboxyl group, an alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, an alkoxycarbonyl group, a nitro group, a cyano group, and a carbamoyl group. Can be mentioned. ];
(Xvii) a cycloalkyl group, a cycloalkenyl group, a saturated or unsaturated aliphatic heterocyclic group [these groups are a halogen atom, a hydroxyl group, a carboxyl group, an oxo group, a thioxo group, one, or the same or different two Amino group optionally substituted with an alkyl group, alkoxy group, haloalkoxy group, alkoxycarbonyl group, optionally substituted alkyl group, optionally substituted aryl group, and optionally substituted aromatic group One or a plurality of substituents may be substituted with a substituent selected from a group heterocyclic substituent. Examples of the substituent of the alkyl group include a halogen atom, a hydroxyl group, a carboxyl group, an alkoxy group, and a haloalkoxy group. Examples of the substituent of the aryl group and the aromatic heterocyclic group include a halogen atom, a hydroxyl group, and a carboxyl group. An alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, an alkoxycarbonyl group, a nitro group, a cyano group, and a carbamoyl group. ];
(Xviii) aryl group, aromatic heterocyclic group, arylcarbonyl group, aromatic heterocyclic carbonyl group, arylsulfonyl group, aromatic heterocyclic sulfonyl group [these groups are a halogen atom, a hydroxyl group, a carboxyl group, one or An amino group optionally substituted with two identical or different alkyl groups, a carbamoyl group optionally substituted with one or two identical or different alkyl groups, one or two identical or different alkyl groups Sulfamoyl group optionally substituted with, alkoxy group, haloalkoxy group, alkoxycarbonyl group, optionally substituted alkyl group, optionally substituted aryl group, and optionally substituted aromatic complex One or more substituents may be substituted with a substituent selected from the group. Examples of the substituent of the alkyl group include a halogen atom, a hydroxyl group, a carboxyl group, an alkoxy group, and a haloalkoxy group. Examples of the substituent of the aryl group and the aromatic heterocyclic group include a halogen atom, a hydroxyl group, and a carboxyl group. An alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, an alkoxycarbonyl group, a nitro group, a cyano group, and a carbamoyl group. ].
Furthermore, two substituents on the “amino group”, “carbamoyl group”, or “sulfamoyl group” may be bonded to form a 5- to 10-membered nitrogen-containing aliphatic heterocycle with the adjacent nitrogen atom. .
[Examples of the nitrogen-containing aliphatic heterocyclic ring include pyrrolidine, piperidine, azepane, azocane, piperazine, morpholine, thiomorpholine, and tetrahydroisoquinoline. In addition, the nitrogen-containing aliphatic heterocyclic ring may be substituted with one or more groups selected from a halogen, a hydroxyl group, a carboxyl group, an alkyl group, a haloalkyl group, an alkoxy group, and a haloalkoxy group. ]

This invention compound represented by General formula (1) can be manufactured, for example with the method shown below.
In the general formula (1), the compound of the present invention represented by the formula (1A) in which R ⁷ is a hydrogen atom can be produced by, for example, the following method.
Reaction Formula-1

（式中、Ｒ¹、Ｒ²、Ｒ³、Ｒ⁴、Ｒ⁸、Ｒ⁹、ｍ、ｎ及びＡは前記と同義である。）
式（１Ａ）で表される化合物は、化合物（１−１）と所望のアミン化合物との還元的アミノ化反応をすることで製造することができる。また、化合物（１−１）と所望の１級アミン化合物との還元的アミノ化により化合物（１−２）を得た後に、所望のアルデヒドと還元的アミノ化することによっても製造することができる。溶媒としては、テトラヒドロフランや１,４−ジオキサンなどのエーテル系溶媒、ジクロロメタン、クロロホルム、１,２−ジクロロエタンなどのハロゲン系溶媒、酢酸エチル、Ｎ，Ｎ’−ジメチルホルムアミド、アセトニトリルなどを用いることができる。還元剤としては、水素化ホウ素ナトリウム、トリアセトキシ水素化ホウ素ナトリウム、水素化シアノホウ素ナトリウムなどを用いることができる。反応温度は−２０℃から反応溶媒の還流温度までで、０℃から室温付近が特に好ましい。

(Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁸ , R ⁹ , m, n and A are as defined above.)
The compound represented by the formula (1A) can be produced by performing a reductive amination reaction between the compound (1-1) and a desired amine compound. It can also be produced by reductive amination with a desired aldehyde after obtaining compound (1-2) by reductive amination of compound (1-1) with the desired primary amine compound. . As the solvent, ether solvents such as tetrahydrofuran and 1,4-dioxane, halogen solvents such as dichloromethane, chloroform and 1,2-dichloroethane, ethyl acetate, N, N′-dimethylformamide, acetonitrile and the like can be used. . As the reducing agent, sodium borohydride, sodium triacetoxyborohydride, sodium cyanoborohydride and the like can be used. The reaction temperature is from −20 ° C. to the reflux temperature of the reaction solvent, and particularly preferably from 0 ° C. to around room temperature.

Further, the compound of the formula (1A) can also be produced from the compound (1-2) by the method shown in the following reaction formula-2.
Reaction formula-2

（式中、Ｒ¹、Ｒ²、Ｒ³、Ｒ⁴、Ｒ⁸、Ｒ⁹、ｍ、ｎ及びＡは前記と同義であり、Ｘはハロゲン原子、メシル基、トシル基などの脱離能を持つ置換基を表す。）
化合物（１−２）と式：Ｒ³−Ｘで表される化合物を塩基存在下、テトラヒドロフランや１,４−ジオキサンなどのエーテル系溶媒、ジクロロメタン、クロロホルム、１,２−ジクロロエタンなどのハロゲン系溶媒、酢酸エチル、Ｎ，Ｎ’−ジメチルホルムアミド、アセトニトリルなどの溶媒中、０℃から反応溶媒の還流温度で反応させることにより製造できる。塩基として、炭酸カリウム、炭酸セシウム、水酸化ナトリウム、水素化ナトリウム、水素化カリウム、カリウム ｔ−ブトキシドなどを用いることができるが、特に限定はされない。

(In the formula, R ¹ , R ² , R ³ , R ⁴ , R ⁸ , R ⁹ , m, n and A are as defined above, and X represents the ability to remove halogen atoms, mesyl groups, tosyl groups, etc. Represents a substituted group.)
Compound (1-2) and a compound represented by the formula: R ³ —X in the presence of a base, ether solvents such as tetrahydrofuran and 1,4-dioxane, halogen solvents such as dichloromethane, chloroform and 1,2-dichloroethane , Ethyl acetate, N, N′-dimethylformamide, acetonitrile and the like, by reacting at 0 ° C. to the reflux temperature of the reaction solvent. As the base, potassium carbonate, cesium carbonate, sodium hydroxide, sodium hydride, potassium hydride, potassium t-butoxide and the like can be used, but there is no particular limitation.

Furthermore, the compound represented by Formula (1A) can also be produced by the method represented by Reaction Formula-3.
Reaction formula-3

（式中、Ｒ¹、Ｒ²、Ｒ³、Ｒ⁴、Ｒ⁸、Ｒ⁹、ｍ、ｎ、Ａ及びＸは前記と同義である。）
化合物(１−３)と所望のアミン化合物を、塩基存在下、テトラヒドロフラン、１,４−ジオキサンなどのエーテル系溶媒、ジクロロメタン、クロロホルム、１,２−ジクロロエタンなどのハロゲン系溶媒、酢酸エチル、Ｎ，Ｎ’−ジメチルホルムアミド、アセトニトリルなどの溶媒中、０℃から反応溶媒の還流温度で反応させることにより製造できる。塩基として、炭酸カリウム、炭酸セシウム、水酸化ナトリウム、水素化ナトリウム、水素化カリウム、カリウム ｔ−ブトキシドなどを用いることができるが、特に限定はされない。

(Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁸ , R ⁹ , m, n, A and X are as defined above.)
Compound (1-3) and the desired amine compound are added in the presence of a base with an ether solvent such as tetrahydrofuran, 1,4-dioxane, a halogen solvent such as dichloromethane, chloroform, 1,2-dichloroethane, ethyl acetate, N, It can be produced by reacting at 0 ° C. to the reflux temperature of the reaction solvent in a solvent such as N′-dimethylformamide or acetonitrile. As the base, potassium carbonate, cesium carbonate, sodium hydroxide, sodium hydride, potassium hydride, potassium t-butoxide and the like can be used, but there is no particular limitation.

In the general formula (1), the compound of the present invention represented by the formula (1B) in which R ⁷ is an alkyl group having 1 to 6 carbon atoms can be obtained from the formula (1-4) to the reaction formula-1 as shown below, for example. It can be manufactured by the same method.
Reaction formula-4

（式中、Ｒ¹、Ｒ²、Ｒ³、Ｒ⁴、Ｒ⁸、Ｒ⁹、ｍ、ｎ及びＡは前記と同義であり、Ｒ²⁰は炭素数１〜６のアルキル基を示す。）

(Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁸ , R ⁹ , m, n and A are as defined above, and R ²⁰ represents an alkyl group having 1 to 6 carbon atoms.)

Compound (1-5) in which m is 0 in the above-mentioned compound (1-1) can be produced, for example, by the method shown in the following Reaction Scheme-5.
Reaction formula-5

（式中、Ｒ¹、Ｒ²、Ｒ⁸、Ｒ⁹、n、Ａ及びＸは前記と同義であり、Protは保護基を表す。）
化合物（１−６）と市販または公知の方法によって得られる化合物（１−７）を、塩基存在下、テトラヒドロフラン、ジメトキシエタン、１,４−ジオキサンなどのエーテル系溶媒、ジクロロメタン、クロロホルム、１,２−ジクロロエタンなどのハロゲン系溶媒、酢酸エチル、Ｎ，Ｎ’−ジメチルホルムアミド、アセトニトリルなどの溶媒中、０℃から反応溶媒の還流温度で反応させることにより製造できる。塩基として、炭酸カリウム、炭酸セシウム、水酸化ナトリウム、水素化ナトリウム、水素化カリウム、カリウム ｔ−ブトキシドなどを用いることができ、より好ましくは炭酸セシウムが用いられる。この方法では、Ｎ−アルキル化体とＯ−アルキル化体の混合物を与える。より選択的にＮ−アルキル化体を得るには、化合物（１−６）のアルデヒドを保護し化合物（１−８）とした後、例えば文献（P.Curran et al, Tetrahedron Lett. 1995, 36, 8917）に従い、塩基として水素化ナトリウム、添加剤として臭化リチウムを用いると好結果を与える。Protの種類については当業者に良く知られたものを用いればよく、例えば「プロテクティブ グループス イン オーガニック シンセシス（T. W. グリーンら著、John Wiley & Sons, Inc.発行 1991）」等を参考にすればよい。中でも、保護基Protとしてジメチルアセタールを用いることが好ましく、これはアセトン−水溶媒中、ｐ−トルエンスルホン酸を用いて脱保護することができる。

(Wherein R ¹ , R ² , R ⁸ , R ⁹ , n, A and X are as defined above, and Prot represents a protecting group.)
Compound (1-6) and compound (1-7) obtained commercially or by a known method are converted into ether solvents such as tetrahydrofuran, dimethoxyethane, 1,4-dioxane, dichloromethane, chloroform, 1,2 in the presence of a base. -It can be produced by reacting at 0 ° C to the reflux temperature of the reaction solvent in a halogen-based solvent such as dichloroethane, a solvent such as ethyl acetate, N, N'-dimethylformamide, and acetonitrile. As the base, potassium carbonate, cesium carbonate, sodium hydroxide, sodium hydride, potassium hydride, potassium t-butoxide and the like can be used, and cesium carbonate is more preferably used. This method provides a mixture of N-alkylated and O-alkylated forms. In order to obtain an N-alkylated compound more selectively, after the aldehyde of compound (1-6) is protected to give compound (1-8), for example, literature (P. Curran et al, Tetrahedron Lett. 1995, 36). 8917) with sodium hydride as base and lithium bromide as additive gives good results. For Prot types, those well known to those skilled in the art may be used. For example, “Protective Groups in Organic Synthesis (TW Green et al., Published by John Wiley & Sons, Inc. 1991)” may be referred to. . Among them, dimethyl acetal is preferably used as the protective group Prot, and this can be deprotected using p-toluenesulfonic acid in an acetone-water solvent.

The aforementioned compound (1-1) and compound (2-3) can also be produced, for example, by the method shown in the following reaction formula-6.
Reaction formula-6

（式中、Ｒ¹、Ｒ²、Ｒ⁸、Ｒ⁹、ｍ、ｎ、Ａ及びＸは前記と同義である。）
化合物（２−１）から反応式−５と同様の方法により化合物（２−２）を得た後、二重結合の酸化反応により化合物（１−１）、又は化合物（２−３）を得ることができる。化合物（１−１）を得る酸化反応としては、オゾン分解が挙げられる。また、四酸化オスミウムでジオール化後、過ヨウ素酸ナトリウムや四酢酸鉛などにより酸化開裂してもよい。化合物（２−３）を得る酸化反応としては、ヒドロホウ素化と続く酸化反応が挙げられる。ヒドロホウ素化の試薬としては、例えば、ボラン、ｔ−ヘキシルボラン、９−ＢＢＮなどが挙げられ、続く酸化反応としては、例えばスワン酸化、ＳＯ₃−ピリジン酸化、ＰＣＣ酸化などが挙げられる。

(Wherein R ¹ , R ² , R ⁸ , R ⁹ , m, n, A and X are as defined above.)
After obtaining compound (2-2) from compound (2-1) by the same method as in Reaction Scheme-5, compound (1-1) or compound (2-3) is obtained by oxidation reaction of double bond. be able to. Oxidation is mentioned as an oxidation reaction which obtains a compound (1-1). Alternatively, after diolification with osmium tetroxide, oxidative cleavage may be performed with sodium periodate, lead tetraacetate, or the like. Examples of the oxidation reaction for obtaining the compound (2-3) include hydroboration and subsequent oxidation reaction. Examples of the hydroboration reagent include borane, t-hexylborane, and 9-BBN. Examples of the subsequent oxidation reaction include swan oxidation, SO ₃ -pyridine oxidation, and PCC oxidation.

The aforementioned compound (1-3) can be produced, for example, by the method shown in the following Reaction Scheme-7.
Reaction formula-7

（式中、Ｒ¹、Ｒ²、Ｒ⁸、Ｒ⁹、ｍ、ｎ、Ａ及びＸは前記と同義である。）
化合物（１−３）は、化合物（１−１）を還元反応によりアルコールに変換後、水酸基を脱離基Ｘに変換することで製造することができる。還元工程は、溶媒として、テトラヒドロフラン、ジエチルエーテルなどのエーテル系溶媒、ジクロロメタン、１,２−ジクロロエタンなどのハロゲン系溶媒、メタノール、エタノールなどのアルコール系溶媒を用い、還元剤としては、水素化ホウ素ナトリウム、水素化リチウムアルミニウム、水素化ジイソブチルアルミニウムなどを用い、−７８℃〜０℃で行う。脱離基への変換工程は、脱離基Ｘがメシル基、又はトシル基である場合には、トリエチルアミン、ピリジンなどの塩基存在下、対応する塩化物（メシルクロライド、トシルクロライド）を反応させることでメシル体、又はトシル体を得ることができる。脱離基Ｘがハロゲン原子である場合には、コンプリヘンシブ・オーガニック・トランスフォーメーション〔R.C.ラロック著、VCH パブリッシャーズＩｎｃ．（1989）〕、第４版実験化学講座（丸善）、新実験化学講座（丸善）等に記載された方法に準じればよいが、例えば、ジクロロメタン中トリフェニルホスフィンと四臭化炭素を加えることで臭化物を得ることができる。

(Wherein R ¹ , R ² , R ⁸ , R ⁹ , m, n, A and X are as defined above.)
Compound (1-3) can be produced by converting compound (1-1) to an alcohol by a reduction reaction and then converting the hydroxyl group to leaving group X. The reduction step uses an ether solvent such as tetrahydrofuran or diethyl ether as a solvent, a halogen solvent such as dichloromethane or 1,2-dichloroethane, or an alcohol solvent such as methanol or ethanol, and sodium borohydride as a reducing agent. , Lithium aluminum hydride, diisobutylaluminum hydride and the like are used at −78 ° C. to 0 ° C. In the step of converting to a leaving group, when the leaving group X is a mesyl group or a tosyl group, the corresponding chloride (mesyl chloride, tosyl chloride) is reacted in the presence of a base such as triethylamine or pyridine. A mesyl body or a tosyl body can be obtained. In the case where the leaving group X is a halogen atom, a comprehensive organic transformation [RC Laroc, VCH Publishers Inc. (1989)], 4th edition Experimental Chemistry Course (Maruzen), New Experimental Chemistry Course (Maruzen), etc. may be used. For example, adding triphenylphosphine and carbon tetrabromide in dichloromethane. The bromide can be obtained.

In compound (1-2), compound (2-4) in which R ³ represents a hydrogen atom can be produced, for example, by the method shown in the following reaction formula-8.
Reaction formula-8

（式中、Ｒ¹、Ｒ²、Ｒ⁸、Ｒ⁹、ｍ、ｎ、Ａ及びＸは前記と同義である。）
化合物（２−４）は、化合物（１−３）とシアン化ナトリウムまたはシアン化カリウムを反応させることによりニトリル化を行い、続いて還元反応を行うことにより製造できる。ニトリル化においては、溶媒としてはＮ，Ｎ’−ジメチルホルムアミドなどが挙げられ、反応温度としては室温から溶媒の還流温度が挙げられる。ニトリル基の還元反応は、水素化ジイソブチルアルミニウムや水素化リチウムアルミニウムなどの金属水素化物により、または、Ｐｄ−Ｃなどを用いる接触水素添加により行うことができる。具体的には、化合物（１−３）をＮ，Ｎ’−ジメチルホルムアミド中、室温でシアン化ナトリウムと反応させニトリル体を得た後、ジクロロメタン中、過剰量の水素化ジイソブチルアルミニウムを0℃で加えることで、化合物（２−４）を得ることができる。

(Wherein R ¹ , R ² , R ⁸ , R ⁹ , m, n, A and X are as defined above.)
Compound (2-4) can be produced by reacting compound (1-3) with sodium cyanide or potassium cyanide, followed by nitrification, followed by a reduction reaction. In nitrification, examples of the solvent include N, N′-dimethylformamide, and examples of the reaction temperature include room temperature to the reflux temperature of the solvent. The reduction reaction of the nitrile group can be performed by metal hydride such as diisobutylaluminum hydride or lithium aluminum hydride, or by catalytic hydrogenation using Pd—C or the like. Specifically, the compound (1-3) was reacted with sodium cyanide in N, N′-dimethylformamide at room temperature to obtain a nitrile body, and then an excess amount of diisobutylaluminum hydride in dichloromethane at 0 ° C. By adding, compound (2-4) can be obtained.

The aforementioned compound (1-4) can be produced, for example, by the method shown in the following Reaction Scheme-9.
Reaction formula-9

（式中、Ｒ¹、Ｒ²、Ｒ⁸、Ｒ⁹、Ｒ²⁰、ｍ、ｎ及びＡは前記と同義である。）
化合物（１−４）は、化合物（１−１）を市販または公知であるＲ²⁰−ＭｇＢｒ（炭素数１〜６のアルキルマグネシウムブロミド）やＲ²⁰−Ｌｉ（炭素数１〜６のアルキルリチウム）と反応後、2級水酸基を一般的な方法で酸化することで製造することができる。具体的には、ｍが０である化合物（１−１）に対し、メチルマグネシウムブロミドをテトラヒドロフラン中0℃で反応させ、得られるアルコールを二酸化マンガンで酸化することにより得ることができる。

(In the formula, R ¹ , R ² , R ⁸ , R ⁹ , R ²⁰ , m, n, and A are as defined above.)
Compound (1-4) are commercially available or known compound (1-1) R ²⁰ -MgBr (alkyl magnesium bromide of 1 to 6 carbon atoms) and R ²⁰ -Li (alkyllithium having 1 to 6 carbon atoms) After the reaction, the secondary hydroxyl group can be oxidized by a general method. Specifically, the compound (1-1) in which m is 0 can be obtained by reacting methylmagnesium bromide in tetrahydrofuran at 0 ° C. and oxidizing the resulting alcohol with manganese dioxide.

The above-mentioned compound (1-6) and compound (2-1) can be produced, for example, by the method shown in the following reaction formula-10.
Reaction formula-10

（式中、Ｒ¹、Ｒ²及びmは前記と同義である。）
化合物（１−６）は化合物（２−５）を加水分解することにより製造することができ、化合物（２−１）は化合物（２−６）を加水分解することにより製造することができる。これらの加水分解は酸性あるいは塩基性条件下加熱することで行えるが、酸性条件下で行うことがより好ましい。酸としては、酢酸、塩酸、硫酸、トリフルオロ酢酸等が用いられ、溶媒としては、テトラヒドロフラン、１,４−ジオキサンなどのエーテル系溶媒、メタノール、エタノールなどのアルコール系溶媒、酢酸、Ｎ，Ｎ’−ジメチルホルムアミド、アセトニトリル、水、又はこれらの混合溶媒が用いられる。反応温度は、室温から溶媒の還流温度である。

(Wherein R ¹ , R ² and m are as defined above.)
Compound (1-6) can be produced by hydrolyzing compound (2-5), and compound (2-1) can be produced by hydrolyzing compound (2-6). These hydrolysiss can be performed by heating under acidic or basic conditions, but it is more preferable to perform them under acidic conditions. As the acid, acetic acid, hydrochloric acid, sulfuric acid, trifluoroacetic acid and the like are used. As the solvent, ether solvents such as tetrahydrofuran and 1,4-dioxane, alcohol solvents such as methanol and ethanol, acetic acid, N, N ′ -Dimethylformamide, acetonitrile, water, or a mixed solvent thereof is used. The reaction temperature is from room temperature to the reflux temperature of the solvent.

The compound (2-5) and compound (2-6) described above are prepared according to the method described in the literature (O. Meth-Cohn et al, J. Chem. Soc. Perkin I, 1981, 1520.). It can be manufactured by the method shown in Formula-11.
Reaction formula-11

（式中、Ｒ¹、Ｒ²及びmは前記と同義である。）
具体的には、化合物（２−７）、又は化合物（２−８）を、3〜10当量のオキシ塩化リン、1〜4当量のＮ，Ｎ’−ジメチルホルムアミドと混ぜ、加熱することにより化合物（２−５）、又は化合物（２−６）を製造できる。化合物（２−５）を製造するには、7当量のオキシ塩化リン、2.5当量のＮ，Ｎ’−ジメチルホルムアミドを用いるのが好ましく、化合物（２−６）を製造するには、7当量のオキシ塩化リン、1.5当量のＮ，Ｎ’−ジメチルホルムアミドを用いるのが好ましい。

(Wherein R ¹ , R ² and m are as defined above.)
Specifically, compound (2-7) or compound (2-8) is mixed with 3 to 10 equivalents of phosphorus oxychloride and 1 to 4 equivalents of N, N′-dimethylformamide and heated to heat the compound. (2-5) or compound (2-6) can be produced. In order to produce the compound (2-5), it is preferable to use 7 equivalents of phosphorus oxychloride and 2.5 equivalents of N, N′-dimethylformamide, and in order to produce the compound (2-6), 7 equivalents of Preference is given to using phosphorus oxychloride, 1.5 equivalents of N, N′-dimethylformamide.

The aforementioned compound (2-7) can be produced by the method shown in the following reaction formula-13.
Reaction formula-12

（式中、Ｒ¹及びＲ²は前記と同義である。）
化合物（２−７）は、市販あるいは公知化合物である置換アニリンを、塩基存在下、無水酢酸又はアセチルクロリドを用いて、テトラヒドロフラン、１，４−ジオキサンなどのエーテル系溶媒、ジクロロメタン、クロロホルムなどのハロゲン系溶媒、酢酸エチル、Ｎ，Ｎ’−ジメチルホルムアミド、アセトニトリルなどの溶媒中、０℃から室温で、アセチル化することにより製造することができる。塩基として、ピリジン、トリエチルアミン、ジメチルアミノピリジンなどを用いることができるが、特に限定はされない。

(In the formula, R ¹ and R ² are as defined above.)
Compound (2-7) is a commercially available or known compound, such as substituted aniline, in the presence of a base, using acetic anhydride or acetyl chloride, ether solvents such as tetrahydrofuran and 1,4-dioxane, halogens such as dichloromethane and chloroform. It can be produced by acetylation in a solvent such as a system solvent, ethyl acetate, N, N′-dimethylformamide, and acetonitrile at 0 ° C. to room temperature. As the base, pyridine, triethylamine, dimethylaminopyridine and the like can be used, but are not particularly limited.

The above-mentioned compound (2-8) can be produced by the method shown in the following reaction formula-13.
Reaction formula-13

（式中、Ｒ¹、Ｒ²及びｍは前記と同義である。）
化合物（２−８）は、市販あるいは公知化合物である置換アニリンを、塩基存在下、市販あるいは公知であるカルボン酸から塩化オキザリルなどを用いて変換できる酸塩化物と、テトラヒドロフラン、ジエチルエーテル、１，４−ジオキサンなどのエーテル系溶媒、ジクロロメタン、クロロホルムなどのハロゲン系溶媒、酢酸エチル、Ｎ，Ｎ’−ジメチルホルムアミド、アセトニトリルなどの溶媒中、０℃から室温で反応させることにより製造することができる。塩基として、ピリジン、トリエチルアミン、ジメチルアミノピリジンなどを用いることができるが、特に限定はされない。

(Wherein R ¹ , R ² and m are as defined above.)
Compound (2-8) is a commercially available or known compound, substituted aniline, in the presence of a base, an acid chloride that can be converted from a commercially available or known carboxylic acid using oxalyl chloride, tetrahydrofuran, diethyl ether, 1, It can be prepared by reacting at 0 ° C. to room temperature in an ether solvent such as 4-dioxane, a halogen solvent such as dichloromethane and chloroform, a solvent such as ethyl acetate, N, N′-dimethylformamide, and acetonitrile. As the base, pyridine, triethylamine, dimethylaminopyridine and the like can be used, but are not particularly limited.

In the general formula (1), n represents an integer of 2 or 3, m represents 0, R ⁷ , a plurality of R ^{8 s} , and a plurality of R ⁹ all represent a hydrogen atom, and A represents a formula: —N ( R ⁵⁾ -L compound of the invention which is ³ -R ^6, i.e. the compound of the present invention represented by the general formula (1C) can also be prepared by the method, for example by the following reaction formula -14.
Reaction formula-14

（式中、Ｒ¹、Ｒ²、Ｒ³、Ｒ⁴、Ｒ⁵、Ｒ⁶及びＬ³は前記と同義であり、ｑは１又は２の整数を表す。）
式（１Ｃ）で表される化合物は、化合物（３−１）と酸ハライド、酸無水物、スルホニルハライド、イソシアナート、クロロホルメートなどとの縮合反応により製造することができる。例えば、化合物（３−１）を無水酢酸とピリジン中、室温で反応させることでアセチル体を、ジクロロメタン中、トリエチルアミン存在下メタンスルホニルクロリドを0℃から室温で反応させることでメタンスルホニル体を得ることができる。

(In the formula, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and L ³ are as defined above, and q represents an integer of 1 or 2.)
The compound represented by the formula (1C) can be produced by a condensation reaction between the compound (3-1) and an acid halide, an acid anhydride, a sulfonyl halide, an isocyanate, a chloroformate, or the like. For example, the compound (3-1) is reacted at room temperature in acetic anhydride and pyridine, and the methanesulfonyl compound is obtained by reacting methanesulfonyl chloride in dichloromethane in the presence of triethylamine at room temperature from 0 ° C. Can do.

The compound represented by the above formula (3-1) can be produced, for example, from the compound represented by the formula (3-3) by the method represented by the following reaction formula-15.
Reaction formula-15

（式中、Ｒ¹、Ｒ²、Ｒ³、Ｒ⁴、Ｒ⁵、ｑ及びＸは前記と同義である。）
化合物(３−３)から、前記反応式−７に示した脱離基への変換工程と同様の製造方法で化合物（３−２）を製造できる。化合物（３−１）への変換は、反応式−３と同様の方法により行える。Ｒ⁵が水素原子の場合は、例えば、フタルイミドカリウムを反応させ、酸や塩基、ヒドラジンなどで加水分解することで得ることができる。

(Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , q and X are as defined above.)
Compound (3-2) can be produced from compound (3-3) by the same production method as in the conversion step to the leaving group shown in the above Reaction Scheme-7. Conversion to compound (3-1) can be carried out by the same method as in Reaction Scheme-3. When R ⁵ is a hydrogen atom, it can be obtained, for example, by reacting potassium phthalimide and hydrolyzing with acid, base, hydrazine or the like.

The compound represented by the above formula (3-3) can be produced, for example, from the compound represented by the formula (1-6) by the method represented by the following reaction formula-16.
Reaction formula-16

（式中、Ｒ¹、Ｒ²、Ｒ³、Ｒ⁴、Ｘ及びｑは前記と同義であり、Protは保護基を表す。）
化合物(３−３)は、化合物（１−６）から前記反応式−１と同様の方法で得られる化合物（３−４）を化合物（３−６）と前記反応式−５と同様の方法により反応させた後、脱保護することで化合物（３−３）を製造できる。Protの種類、脱保護については当業者に良く知られたものを用いればよく、例えば「プロテクティブ グループス イン オーガニック シンセシス（T. W. グリーンら著、John Wiley & Sons, Inc.発行 1991）」等を参考にすればよい。保護基としてt−ブチルジメチルシリル基を用いるのが好ましく、これはフッ化テトラブチルアンモニウムで脱保護することができる。又は、化合物（１−６）を先に化合物（３−６）と反応させ化合物（３−５）を得た後、還元的アミノ化、脱保護をすることで化合物（３−３）を得ることもできる。

(Wherein R ¹ , R ² , R ³ , R ⁴ , X and q are as defined above, and Prot represents a protecting group.)
Compound (3-3) is compound (3-4) obtained from compound (1-6) by the same method as in the above Reaction Scheme-1 and the same method as in Compound (3-6) and above Reaction Scheme-5. Then, the compound (3-3) can be produced by deprotection. For Prot types and deprotection, those well known to those skilled in the art may be used. do it. A t-butyldimethylsilyl group is preferably used as a protecting group, which can be deprotected with tetrabutylammonium fluoride. Alternatively, compound (1-6) is first reacted with compound (3-6) to give compound (3-5), and then reductive amination and deprotection give compound (3-3). You can also

In the general formula (1), when m represents 0 and R ¹ is a substituted or unsubstituted phenyl group, or a substituted or unsubstituted aromatic heterocyclic group, that is, a book represented by the general formula (1D) The inventive compound can be produced, for example, by the method shown in the following Reaction Scheme-17.
Reaction Formula-17

（式中、Ｒ²、Ｒ³、Ｒ⁴、Ｒ⁸、Ｒ⁹、ｎ及びＡは前記と同義であり、Ｙは置換もしくは無置換のフェニル基、又は置換もしくは無置換の芳香族複素環基を表す。）
化合物(１Ｄ)は、化合物（４−２）から反応式−１と同様の方法で得ることができる。化合物（４−２）は、化合物（４−１）と所望のボラン酸化合物とパラジウム触媒、リガンド、塩基を用い、ジメトキシエタン、１，４−ジオキサン、トルエン、エタノールなどの溶媒中、室温から溶媒の還流温度で反応させることで製造できる。パラジウム触媒としては、酢酸パラジウム、テトラキストリフェニルフォスフィンパラジウム、トリスベンジリデンアセトンジパラジウムなどが挙げられるが、特に限定はされない。リガンドとしては、トリフェニルフォスフィン、トリ-o-トリルフォスフィン、トリ−ｔ−ブチルフォスフィンなどが挙げられるが、特に限定はされない。塩基として炭酸ナトリウム、炭酸カリウム、炭酸セシウムなどが挙げられるが特に限定はされない。溶媒として、ジメトキシエタン、１，４−ジオキサン、トルエン、エタノールなどが挙げられるが特に限定はされない。

Wherein R ² , R ³ , R ⁴ , R ⁸ , R ⁹ , n and A are as defined above, Y is a substituted or unsubstituted phenyl group, or a substituted or unsubstituted aromatic heterocyclic group. Represents.)
Compound (1D) can be obtained from compound (4-2) in the same manner as in Reaction Scheme-1. Compound (4-2) is a solvent from room temperature in a solvent such as dimethoxyethane, 1,4-dioxane, toluene, ethanol, etc., using compound (4-1), the desired boranoic acid compound, a palladium catalyst, a ligand, and a base. It can manufacture by making it react at the reflux temperature of. Examples of the palladium catalyst include palladium acetate, tetrakistriphenylphosphine palladium, and trisbenzylideneacetone dipalladium, but are not particularly limited. Examples of the ligand include triphenylphosphine, tri-o-tolylphosphine, tri-t-butylphosphine, and the like, but are not particularly limited. Examples of the base include sodium carbonate, potassium carbonate and cesium carbonate, but are not particularly limited. Examples of the solvent include dimethoxyethane, 1,4-dioxane, toluene, ethanol and the like, but are not particularly limited.

For each of the above reactions, Examples in the present specification and Comprehensive Organic Transformation [RC Rallock, VCH Publishers Inc. (1989)], 4th edition Experimental Chemistry Course (Maruzen), New Experimental Chemistry Course (Maruzen), and the like.
Moreover, the raw material compound used in the above-described production method can be appropriately prepared using a commercially available product or a method known to those skilled in the art.
Moreover, when manufacturing the compound of this invention or those pharmacologically acceptable salts, functional groups, such as a hydroxyl group, a carboxyl group, or an amino group, can be protected and deprotected as needed at an arbitrary step. For the types of protecting groups and the methods for protecting and deprotecting, those well known to those skilled in the art may be used. ) ”Etc. may be referred to.

The compound represented by the general formula (1) can be made into an acid addition salt or an alkali addition salt with a pharmaceutically acceptable inorganic acid or organic acid, if necessary. Examples of such acid addition salts include inorganic acid salts such as hydrochloride, hydrobromide, sulfate, and phosphate, and formate, acetate, fumarate, maleate, oxalate, Salts with organic carboxylic acids such as citrate, malate, tartrate, aspartate, glutamate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, hydroxybenzenesulfonate, dihydroxy Examples of salts with sulfonic acids such as benzenesulfonate and pharmacologically acceptable alkali addition salts include ammonium salts, lithium salts, sodium salts, potassium salts, calcium salts, and magnesium salts.
The present invention also includes solvates such as a hydrate of the compound represented by the general formula (1) or a pharmaceutically acceptable salt thereof, and an ethanol solvate. Furthermore, the present invention also includes all tautomers, stereoisomers such as optical isomers, and all crystal forms of the compound represented by the general formula (1). These can be appropriately purified using methods such as silica gel column chromatography, HPLC, ion exchange chromatography, and recrystallization well known to those skilled in the art.
In order to obtain the optical isomer purely, an optical resolution method known to those skilled in the art may be used. Specifically, when the compound of the present invention or an intermediate thereof has a basic functional group, an optically active acid (for example, monocarboxylic acid such as mandelic acid, N-benzyloxyalanine, lactic acid, etc.) in an inert solvent. Acid, tartaric acid, o-diisopropylidene tartaric acid, dicarboxylic acids such as malic acid, and sulfonic acids such as camphor sulfonic acid and bromocamphor sulfonic acid). When the compound of the present invention or an intermediate thereof has an acidic substituent, a salt is formed with an optically active amine (for example, organic amines such as α-phenethylamine, quinine, quinidine, cinchonidine, cinchonine, strychnine). You can also. The temperature at which the salt is formed includes a range from room temperature to the boiling point of the solvent.

  The compound having a 2-quinolone skeleton of the present invention or a pharmaceutically acceptable salt thereof has an SNS inhibitory activity and can be used as a therapeutic or prophylactic agent for neuropathic pain and nociceptive pain. Examples of neuropathic pain include lumbar postoperative neuralgia, diabetic neuropathy, postherpetic neuralgia, reflex sympathetic nerve, phantom limb pain, spinal injury, end-stage cancer, and prolonged postoperative pain. It is done. Examples of nociceptive pain include low back pain, abdominal pain, rheumatoid arthritis, pain due to osteoarthritis, and the like. The compounds of the present invention or their pharmaceutically acceptable salts can also be used as a therapeutic or prophylactic agent for dysuria. Examples of dysuria include frequent urination and bladder pain due to enlarged prostate. Furthermore, it can also be used as a therapeutic or prophylactic agent that suppresses abnormal nerve firing of the cerebellum in multiple sclerosis. As a drug having no side effect derived from non-neural tissue or central nervous system, a compound having SNS selective inhibitory activity is more preferable.

The therapeutic agent or preventive agent for neuropathic pain, nociceptive pain, dysuria, or multiple sclerosis of the present invention is a pharmaceutically acceptable normal carrier, binder, stabilizer, excipient, Various compounding ingredients for preparations such as a diluent, a pH buffer, a disintegrant, a solubilizer, a solubilizer, and an isotonic agent can be added. Moreover, these therapeutic agents or preventive agents can be administered orally or parenterally. That is, orally, it can be administered orally in a commonly used dosage form such as tablets, pills, powders, granules, capsules, syrups, emulsions and suspensions. For parenteral use, for example, it can be prepared in the form of intravenous injection (instillation), intramuscular injection, subcutaneous injection, coating agent, eye drop, eye ointment and the like.
Solid preparations such as tablets contain active ingredients as usual pharmacologically acceptable carriers or excipients such as lactose, sucrose and corn starch, binders such as hydroxypropylcellulose, polyvinylpyrrolidone, hydroxypropylmethylcellulose, It is prepared by mixing with a disintegrant such as sodium carboxymethylcellulose or sodium starch glycolate, a lubricant such as stearic acid or magnesium stearate, or a preservative.
For parenteral administration, the active ingredient is dissolved or suspended in a physiologically acceptable carrier such as water, physiological saline, oil, glucose aqueous solution, etc., and this is used as an emulsifier, stabilizer, osmotic pressure adjusting salt. Or you may contain a buffering agent as needed.

The dose and the number of administrations vary depending on the administration method and the age, weight, medical condition, etc. of the patient, but a method of locally administering to the bed part is preferred. Moreover, it is preferable to administer once or twice or more per day. When administered twice or more, it is desirable to administer repeatedly every day or at appropriate intervals.
Dosage can be several tens of μg to 2 g, preferably 1 to several hundred mg, more preferably several tens of mg or less as the amount of active ingredient per adult patient, and can be used once or several times a day. It can be administered separately. Parenteral administration includes a dose of 0.1 to 100 mg / day, more preferably 0.3 to 50 mg / day per adult patient, and can be administered once or divided into several times a day. Sustained release preparations can also be used to reduce the number of administrations.
Moreover, the therapeutic agent or prophylactic agent for neuropathic pain, nociceptive pain, dysuria, or multiple sclerosis of the present invention can be used as an animal drug.

EXAMPLES Hereinafter, although an Example and a test example demonstrate this invention further in detail, the technical scope of this invention is not limited to these Examples.

(Reference Example 1)

氷冷下、3-フェノキシアニリン（34.7g, 188mmol）の酢酸エチル(300ml)溶液にピリジン(16.6ml, 206mmol)次いで無水酢酸(19.5ml, 206mmol)をゆっくりと滴下した。同温下で30分間撹拌後、室温で1時間半撹拌した。反応液に水を加え、酢酸エチルで抽出した。有機層を飽和食塩水にて洗浄後、硫酸ナトリウムで乾燥し、減圧濃縮した。残渣をヘキサン−酢酸エチルから結晶化させ、ろ取、減圧乾燥し、目的物(34.2g, 80%)を得た。
¹H-NMR (CDCl₃) δ 2.14(s, 3H), 6.74(m, 1H), 7.00-7.38(m, 9H)

（参考例２）

Pyridine (16.6 ml, 206 mmol) and then acetic anhydride (19.5 ml, 206 mmol) were slowly added dropwise to a solution of 3-phenoxyaniline (34.7 g, 188 mmol) in ethyl acetate (300 ml) under ice cooling. The mixture was stirred at the same temperature for 30 minutes and then stirred at room temperature for 1.5 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was crystallized from hexane-ethyl acetate, collected by filtration and dried under reduced pressure to obtain the desired product (34.2 g, 80%).
¹ H-NMR (CDCl ₃ ) δ 2.14 (s, 3H), 6.74 (m, 1H), 7.00-7.38 (m, 9H)

(Reference Example 2)

オキシ塩化リン（97ml, 1.05mol）を氷冷し、Ｎ，Ｎ’−ジメチルホルムアミド（31ml, 0.37mol）をゆっくり滴下し、15分撹拌した。参考例１で得た化合物(34g, 0.15mol)を少量ずつ加えた後、反応液を80℃で4時間撹拌した。冷却後、反応液を氷中にゆっくり流し込み、室温で2時間撹拌した。生じた沈殿をろ取、減圧乾燥し、粗生成物を得た。得られた粗生成物をアセトニトリル−水（１：１，500ml）に懸濁し室温で1時間撹拌後、ろ取、減圧乾燥し、目的物（41g，97％）を得た。
¹H-NMR (CDCl₃) δ 7.14-7.19(m, 2H), 7.27-7.32(m, 2H), 7.43-7.48(m, 3H), 7.95(d, J=9.0Hz, 1H), 8.70(s, 1H), 10.50(s, 1H)

（参考例３）

Phosphorus oxychloride (97 ml, 1.05 mol) was ice-cooled, and N, N′-dimethylformamide (31 ml, 0.37 mol) was slowly added dropwise and stirred for 15 minutes. The compound obtained in Reference Example 1 (34 g, 0.15 mol) was added in small portions, and the reaction solution was stirred at 80 ° C. for 4 hours. After cooling, the reaction solution was slowly poured into ice and stirred at room temperature for 2 hours. The resulting precipitate was collected by filtration and dried under reduced pressure to obtain a crude product. The obtained crude product was suspended in acetonitrile-water (1: 1,500 ml), stirred at room temperature for 1 hour, filtered and dried under reduced pressure to obtain the desired product (41 g, 97%).
¹ H-NMR (CDCl ₃ ) δ 7.14-7.19 (m, 2H), 7.27-7.32 (m, 2H), 7.43-7.48 (m, 3H), 7.95 (d, J = 9.0Hz, 1H), 8.70 ( s, 1H), 10.50 (s, 1H)

(Reference Example 3)

参考例２で得た化合物(30g, 0.11mol)、酢酸（300ml）及び水(30ml)を混ぜ、90℃で5時間撹拌した。反応液を冷却し、水を加えた後、室温で一晩撹拌した。生じた結晶をろ取、減圧乾燥し、目的物（21g, 75%）を得た。
¹H-NMR (DMSO) δ 6.79(d, J=2.4Hz, 1H), 6.95(dd, J=8.8, 2.4Hz, 1H), 7.18-7.33(m, 3H), 7.48-7.54(m, 2H), 7.94(d, J=8.8Hz, 1H), 8.48(s, 1H), 10.18(s, 1H), 11.96(br, 1H)

（参考例４）

The compound obtained in Reference Example 2 (30 g, 0.11 mol), acetic acid (300 ml) and water (30 ml) were mixed and stirred at 90 ° C. for 5 hours. The reaction mixture was cooled, water was added, and the mixture was stirred overnight at room temperature. The resulting crystals were collected by filtration and dried under reduced pressure to obtain the desired product (21 g, 75%).
¹ H-NMR (DMSO) δ 6.79 (d, J = 2.4Hz, 1H), 6.95 (dd, J = 8.8, 2.4Hz, 1H), 7.18-7.33 (m, 3H), 7.48-7.54 (m, 2H ), 7.94 (d, J = 8.8Hz, 1H), 8.48 (s, 1H), 10.18 (s, 1H), 11.96 (br, 1H)

(Reference Example 4)

参考例３で得た化合物（0.50g, 1.9mmol）をＮ，Ｎ’−ジメチルホルムアミド(15ml)に溶かし、室温で炭酸セシウム(0.92g, 2.8mmol)及び2-ブロモエチルエチルエーテル(0.32ml, 2.8mmol)を加えた。反応液を80℃で1.5時間撹拌後、水及び酢酸エチルを加え分液、抽出した。有機層を水洗、乾燥、濃縮し、残渣をシリカゲルカラム（酢酸エチル：ヘキサン=1:5〜1:1）で精製し、目的物(0.39g, 61%)とO−アルキル体(0.17g, 27%)を得た。
¹H-NMR (CDCl₃) δ 1.10(t, J=7.1Hz, 3H), 3.43(q, J=7.1Hz, 2H), 3.71-3.74(m, 2H), 4.37-4.40(m, 2H), 6.89(dd, J=8.8, 2.2Hz, 1H), 7.11-7.16(m, 3H), 7.24-7.28(m, 1H), 7.42-7.46(m, 2H), 7.64(d, J=8.8Hz, 1H), 8.33(s, 1H), 10.42(s, 1H)

参考例４で得た化合物は、以下の参考例５及び６に示した方法により選択的に合成することができる。

（参考例５）

The compound obtained in Reference Example 3 (0.50 g, 1.9 mmol) was dissolved in N, N′-dimethylformamide (15 ml), and cesium carbonate (0.92 g, 2.8 mmol) and 2-bromoethyl ethyl ether (0.32 ml, 2.8 mmol) was added. The reaction solution was stirred at 80 ° C. for 1.5 hours, and then water and ethyl acetate were added to separate and extract. The organic layer was washed with water, dried and concentrated, and the residue was purified with a silica gel column (ethyl acetate: hexane = 1: 5 to 1: 1) to obtain the desired product (0.39 g, 61%) and the O-alkyl compound (0.17 g, 27%).
¹ H-NMR (CDCl ₃ ) δ 1.10 (t, J = 7.1Hz, 3H), 3.43 (q, J = 7.1Hz, 2H), 3.71-3.74 (m, 2H), 4.37-4.40 (m, 2H) , 6.89 (dd, J = 8.8, 2.2Hz, 1H), 7.11-7.16 (m, 3H), 7.24-7.28 (m, 1H), 7.42-7.46 (m, 2H), 7.64 (d, J = 8.8Hz , 1H), 8.33 (s, 1H), 10.42 (s, 1H)

The compound obtained in Reference Example 4 can be selectively synthesized by the methods shown in Reference Examples 5 and 6 below.

(Reference Example 5)

参考例３で得た化合物（21g, 79mmol）、オルトギ酸メチル(150ml)及びp-トルエンスルホン酸1水和物（4.5g）の混合物を2時間加熱還流した。室温に冷却後、ヘキサン（40ml）を加え一晩撹拌した。生じた沈殿をろ取、減圧乾燥し、目的物（16.6g, 67%）を得た。
¹H-NMR (CDCl₃) δ 3.45(s, 6H), 5.54(s, 1H), 6.83-6.90(m, 2H), 7.07-7.24(m, 3H), 7.37-7.44(m, 2H), 7.54(d, J=8.4Hz, 1H), 7.96(s, 1H)

（参考例６）

A mixture of the compound obtained in Reference Example 3 (21 g, 79 mmol), methyl orthoformate (150 ml) and p-toluenesulfonic acid monohydrate (4.5 g) was heated to reflux for 2 hours. After cooling to room temperature, hexane (40 ml) was added and stirred overnight. The resulting precipitate was collected by filtration and dried under reduced pressure to obtain the desired product (16.6 g, 67%).
¹ H-NMR (CDCl ₃ ) δ 3.45 (s, 6H), 5.54 (s, 1H), 6.83-6.90 (m, 2H), 7.07-7.24 (m, 3H), 7.37-7.44 (m, 2H), 7.54 (d, J = 8.4Hz, 1H), 7.96 (s, 1H)

(Reference Example 6)

参考例５で得た化合物(9.6g, 32mmol)をＮ，Ｎ’−ジメチルホルムアミド(200ml)に溶かし、氷冷下、水素化ナトリウム(1.93g, 60% in oil, 48mmol)を加えた。15分後、臭化リチウム（8.4g, 96mmol）を加え30分撹拌した。2-ブロモエチルエチルエーテル（5.4ml, 48mmol）を添加し20分撹拌後、反応液を80℃で2時間撹拌した。水を加え反応停止後、酢酸エチルで抽出した。有機層を水洗、乾燥、濃縮し、残渣をアセトン（150ml）及び水（15ml）に溶かした。室温でp-トルエンスルホン酸1水和物（0.64g, 3.4mmol）を加え15分撹拌した。アセトンを濃縮後、飽和炭酸水素ナトリウム水溶液中に流し込み、酢酸エチルで抽出した。有機層を水洗、乾燥、濃縮し、残渣を酢酸エチル−ヘキサン＝1：2で結晶化させ、ろ取、減圧乾燥し、目的物（6.3g, 61%）を得た。ろ液を濃縮し、残渣をシリカゲルカラム（酢酸エチル：ヘキサン=1:3〜1:1）で精製し、目的物(2.0 g, 19%)とO−アルキル体(1.0g, 10%)を得た。

The compound (9.6 g, 32 mmol) obtained in Reference Example 5 was dissolved in N, N′-dimethylformamide (200 ml), and sodium hydride (1.93 g, 60% in oil, 48 mmol) was added under ice cooling. After 15 minutes, lithium bromide (8.4 g, 96 mmol) was added and stirred for 30 minutes. 2-Bromoethyl ethyl ether (5.4 ml, 48 mmol) was added and stirred for 20 minutes, and then the reaction solution was stirred at 80 ° C. for 2 hours. Water was added to stop the reaction, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried and concentrated, and the residue was dissolved in acetone (150 ml) and water (15 ml). At room temperature, p-toluenesulfonic acid monohydrate (0.64 g, 3.4 mmol) was added and stirred for 15 minutes. Acetone was concentrated, poured into a saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The organic layer was washed with water, dried and concentrated, and the residue was crystallized with ethyl acetate-hexane = 1: 2, filtered and dried under reduced pressure to obtain the desired product (6.3 g, 61%). The filtrate was concentrated, and the residue was purified with a silica gel column (ethyl acetate: hexane = 1: 3 to 1: 1) to obtain the desired product (2.0 g, 19%) and O-alkyl (1.0 g, 10%). Obtained.

(S) -2-{[1- (2-Ethoxy-ethyl) -2-oxo-7-phenoxy-1,2-dihydro-quinolin-3-ylmethyl] -amino} -propionamide

参考例４で得た化合物（1.0g, 3.0mmol）をジクロロメタンに溶かし、室温で（L）-アラニンアミド塩酸塩（0.74g, 5.9mmol）、トリアセトキシ水素化ホウ素ナトリウム(1.26g, 5.9mmol)を加え2時間撹拌した。反応液を飽和炭酸水素ナトリウム水溶液中に流し込み、酢酸エチルで抽出した。有機層を水洗、乾燥、濃縮し、残渣をシリカゲルカラム（クロロホルム：メタノール=50:1〜20:1）で精製し、目的物(0.9 g, 74%)を得た。
¹H-NMR (CDCl₃) δ 1.11(t, J=7.0Hz, 3H), 1.34(d, J=7.0Hz, 3H), 3.26(q, J=7.0Hz, 1H), 3.44(q, J=7.0Hz, 2H), 3.62(d, J=13.2Hz, 1H), 3.68-3.72(m, 2H), 3.84(d, J=13.2Hz, 1H), 4.31-4.47(m, 2H), 5.69(br.s, 1H), 6.87(dd, J=8.6, 2.0Hz, 1H), 7.06-7.09(m, 2H), 7.17-7.22(m, 2H), 7.37-7.42(m, 2H), 7.48(d, J=8.6Hz, 1H), 7.60(s, 1H), 7.81(br.s, 1H)

The compound (1.0 g, 3.0 mmol) obtained in Reference Example 4 was dissolved in dichloromethane, and (L) -alaninamide hydrochloride (0.74 g, 5.9 mmol) and sodium triacetoxyborohydride (1.26 g, 5.9 mmol) were dissolved at room temperature. Was added and stirred for 2 hours. The reaction solution was poured into a saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was washed with water, dried and concentrated, and the residue was purified with a silica gel column (chloroform: methanol = 50: 1 to 20: 1) to obtain the desired product (0.9 g, 74%).
¹ H-NMR (CDCl ₃ ) δ 1.11 (t, J = 7.0Hz, 3H), 1.34 (d, J = 7.0Hz, 3H), 3.26 (q, J = 7.0Hz, 1H), 3.44 (q, J = 7.0Hz, 2H), 3.62 (d, J = 13.2Hz, 1H), 3.68-3.72 (m, 2H), 3.84 (d, J = 13.2Hz, 1H), 4.31-4.47 (m, 2H), 5.69 (br.s, 1H), 6.87 (dd, J = 8.6, 2.0Hz, 1H), 7.06-7.09 (m, 2H), 7.17-7.22 (m, 2H), 7.37-7.42 (m, 2H), 7.48 (d, J = 8.6Hz, 1H), 7.60 (s, 1H), 7.81 (br.s, 1H)

In the same manner as in Reference Examples 1 to 6 and Example 1, the compounds of Examples 2 to 33 shown in Tables 1 to 9 below were obtained.

(Reference Example 7)

氷冷下、3-エトキシ-1-プロパノール（1.02g, 9.79mmol）のジクロロメタン(100ml)溶液に、トリエチルアミン(2.05ml, 14.7mmol)及びｐ-トルエンスルホニルクロリド(2.05g, 10.8mmol)を加え1時間撹拌した。反応液を飽和炭酸水素ナトリウム水溶液中に流し込み、クロロホルムで抽出した。有機層を飽和食塩水にて洗浄後、硫酸ナトリウムで乾燥し、減圧濃縮した。残渣に酢酸エチルと飽和炭酸水素ナトリウムを加え撹拌した。有機層を酢酸エチルで抽出、飽和食塩水にて洗浄後、硫酸ナトリウムで乾燥し、減圧濃縮した。残渣をシリカゲルカラム（ヘキサンのみ〜ヘキサン：酢酸エチル=１：１）で精製し、目的物(0.40g, 16%)を得た。
¹H-NMR (CDCl₃) δ 1.11(t, J=7.1Hz, 3H), 1.90(tt, J=6.2, 6.2Hz, 2H), 2.45(s, 3H), 3.36(q, J=7.1Hz, 2H), 3.42(t, J=6.2Hz, 2H), 4.14(t, J=6.2Hz, 2H), 7.34-7.36(m, 2H), 7.78-7.81(m, 2H)

（参考例８）

Under ice-cooling, triethylamine (2.05 ml, 14.7 mmol) and p-toluenesulfonyl chloride (2.05 g, 10.8 mmol) were added to a solution of 3-ethoxy-1-propanol (1.02 g, 9.79 mmol) in dichloromethane (100 ml). Stir for hours. The reaction solution was poured into a saturated aqueous sodium hydrogen carbonate solution and extracted with chloroform. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. Ethyl acetate and saturated sodium bicarbonate were added to the residue and stirred. The organic layer was extracted with ethyl acetate, washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by a silica gel column (hexane only to hexane: ethyl acetate = 1: 1) to obtain the desired product (0.40 g, 16%).
¹ H-NMR (CDCl ₃ ) δ 1.11 (t, J = 7.1Hz, 3H), 1.90 (tt, J = 6.2, 6.2Hz, 2H), 2.45 (s, 3H), 3.36 (q, J = 7.1Hz , 2H), 3.42 (t, J = 6.2Hz, 2H), 4.14 (t, J = 6.2Hz, 2H), 7.34-7.36 (m, 2H), 7.78-7.81 (m, 2H)

(Reference Example 8)

参考例５で得た化合物(0.22g, 0.72mmol)をＮ，Ｎ’−ジメチルホルムアミド(7.2ml)に溶かし、氷冷下水素化ナトリウム(86mg, 60% in oil, 2.2mmol)を加えた。15分後、臭化リチウム（0.31g, 3.6mmol）を加え30分撹拌した。参考例７で得た化合物（0.28g, 1.1mmol）を添加し20分撹拌後、反応液を80℃で2時間撹拌した。水を加え反応停止後、酢酸エチルで抽出した。有機層を飽和食塩水にて洗浄後、硫酸ナトリウムで乾燥し、減圧濃縮した。残渣をシリカゲルカラム（ヘキサンのみ〜ヘキサン：酢酸エチル=７：３）で精製し、N−アルキル体とO−アルキル体の粗生成物を得た。N−アルキル体をアセトン（6.4ml）及び水（0.6ml）に溶かし、室温でp-トルエンスルホン酸1水和物（0.15g, 0.64mmol）を加え終夜撹拌した。アセトンを濃縮後、残渣を飽和炭酸水素ナトリウム水溶液中に流し込み、酢酸エチルで抽出した。有機層を飽和食塩水にて洗浄後、硫酸ナトリウムで乾燥し、減圧濃縮した。残渣をシリカゲルカラム（酢酸エチル：ヘキサン=４:１〜１:１）で精製し、目的物(0.18g, 69%)を得た。
¹H-NMR (CDCl₃) δ 1.17(t, J=7.1Hz, 3H), 1.96-2.03(m, 2H), 3.44(q, J=7.1Hz, 2H), 3.47-3.50(m, 2H), 4.31-4.34(m, 2H), 6.85(dd, J=8.5, 2.2Hz, 1H), 7.10-7.13(m, 2H), 7.14(d, J=2.2Hz, 1H), 7.23-7.27(m, 1H), 7.41-7.46(m, 2H), 7.65(d, J=8.5Hz, 1H), 8.32(s, 1H), 10.44(s, 1H)

実施例３４

The compound (0.22 g, 0.72 mmol) obtained in Reference Example 5 was dissolved in N, N′-dimethylformamide (7.2 ml), and sodium hydride (86 mg, 60% in oil, 2.2 mmol) was added under ice cooling. After 15 minutes, lithium bromide (0.31 g, 3.6 mmol) was added and stirred for 30 minutes. The compound obtained in Reference Example 7 (0.28 g, 1.1 mmol) was added and stirred for 20 minutes, and then the reaction solution was stirred at 80 ° C. for 2 hours. Water was added to stop the reaction, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by a silica gel column (hexane only to hexane: ethyl acetate = 7: 3) to obtain a crude product of N-alkyl and O-alkyl. The N-alkyl compound was dissolved in acetone (6.4 ml) and water (0.6 ml), p-toluenesulfonic acid monohydrate (0.15 g, 0.64 mmol) was added at room temperature, and the mixture was stirred overnight. After concentrating acetone, the residue was poured into a saturated aqueous solution of sodium bicarbonate and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column (ethyl acetate: hexane = 4: 1 to 1: 1) to obtain the desired product (0.18 g, 69%).
¹ H-NMR (CDCl ₃ ) δ 1.17 (t, J = 7.1Hz, 3H), 1.96-2.03 (m, 2H), 3.44 (q, J = 7.1Hz, 2H), 3.47-3.50 (m, 2H) , 4.31-4.34 (m, 2H), 6.85 (dd, J = 8.5, 2.2Hz, 1H), 7.10-7.13 (m, 2H), 7.14 (d, J = 2.2Hz, 1H), 7.23-7.27 (m , 1H), 7.41-7.46 (m, 2H), 7.65 (d, J = 8.5Hz, 1H), 8.32 (s, 1H), 10.44 (s, 1H)

Example 34

(S) -2-{[1- (3-Ethoxy-propyl) -2-oxo-7-phenoxy-1,2-dihydro-quinolin-3-ylmethyl] -amino} -propionamide

参考例８で得た化合物を原料に用いて、実施例１と同様の方法により目的物を得た。
¹H-NMR (CDCl₃) δ 1.16(t, J=7.1Hz, 3H), 1.34(d, J=7.1Hz, 3H), 1.94(br.s, 1H), 1.97-2.02(m, 2H), 3.26(q, J=7.1Hz, 1H), 3.43(q, J=7.1Hz, 2H), 3.47(t, J=5.9Hz, 2H), 3.62(d, J=13.4Hz, 1H), 3.85(d, J=13.4Hz, 1H), 4.25-4.38(m, 2H), 5.60(br.s, 1H), 6.84(dd, J=2.2, 8.6Hz, 1H), 7.06-7.08(m, 2H), 7.16-7.20(m, 2H), 7.37-7.42(m, 2H), 7.48(d, J=8.6Hz, 1H), 7.59(s, 1H), 7.83(br.s, 1H)

実施例３５

The target product was obtained in the same manner as in Example 1 using the compound obtained in Reference Example 8 as a raw material.
¹ H-NMR (CDCl ₃ ) δ 1.16 (t, J = 7.1Hz, 3H), 1.34 (d, J = 7.1Hz, 3H), 1.94 (br.s, 1H), 1.97-2.02 (m, 2H) , 3.26 (q, J = 7.1Hz, 1H), 3.43 (q, J = 7.1Hz, 2H), 3.47 (t, J = 5.9Hz, 2H), 3.62 (d, J = 13.4Hz, 1H), 3.85 (d, J = 13.4Hz, 1H), 4.25-4.38 (m, 2H), 5.60 (br.s, 1H), 6.84 (dd, J = 2.2, 8.6Hz, 1H), 7.06-7.08 (m, 2H ), 7.16-7.20 (m, 2H), 7.37-7.42 (m, 2H), 7.48 (d, J = 8.6Hz, 1H), 7.59 (s, 1H), 7.83 (br.s, 1H)

Example 35

1- (3-Ethoxy-propyl) -3-[(4-fluoro-benzylamino) -methyl] -7-phenoxy-1H-quinolin-2-one

参考例８で得た化合物を原料に用いて、実施例１と同様の方法により目的物を得た。
¹H-NMR (CDCl₃) δ 1.16(t, J=7.1Hz, 3H), 1.94-2.01(m, 2H), 2.08(br.s, 1H), 3.42(q, J=7.1Hz, 2H), 3.46(t, J=5.9Hz, 2H), 3.77(s, 2H), 3.81(s, 2H), 4.29-4.32(m, 2H), 6.83(dd, J=2.2, 8.6Hz, 1H), 6.98-7.03(m, 2H), 7.05-7.08(m, 2H), 7.15-7.19(m, 2H), 7.31-7.35(m, 2H), 7.36-7.41(m, 2H), 7.48(d, J=8.6Hz, 1H), 7.63(s, 1H)

（参考例９）

The target product was obtained in the same manner as in Example 1 using the compound obtained in Reference Example 8 as a raw material.
¹ H-NMR (CDCl ₃ ) δ 1.16 (t, J = 7.1Hz, 3H), 1.94-2.01 (m, 2H), 2.08 (br.s, 1H), 3.42 (q, J = 7.1Hz, 2H) , 3.46 (t, J = 5.9Hz, 2H), 3.77 (s, 2H), 3.81 (s, 2H), 4.29-4.32 (m, 2H), 6.83 (dd, J = 2.2, 8.6Hz, 1H), 6.98-7.03 (m, 2H), 7.05-7.08 (m, 2H), 7.15-7.19 (m, 2H), 7.31-7.35 (m, 2H), 7.36-7.41 (m, 2H), 7.48 (d, J = 8.6Hz, 1H), 7.63 (s, 1H)

(Reference Example 9)

参考例１〜６と同様の方法で得られる上記原料化合物(107mg, 0.327mmol)を1, 4-ジオキサン(2.9ml)及び水(0.4ml)に溶かし、テトラキス（トリフェニルホスフィン）パラジウム（０）(18.9mg, 16.4μmol)、３−ピリジンボロン酸(60.3mg, 0.491mmol)及び炭酸カリウム(136mg, 0.981mmol)を加えた。反応液を110℃で2時間撹拌後、水を加えクロロホルムで抽出した。有機層を飽和食塩水にて洗浄後、硫酸ナトリウムで乾燥し、減圧濃縮した。残渣をクロロホルム：ヘキサン＝1：５で結晶化させ、ろ取、減圧乾燥し、目的物(64mg, 61%)を得た。
¹H-NMR (CDCl₃) δ 1.14(t, J=7.1Hz, 3H), 3.50(q, J=7.1Hz, 2H), 3.86-3.89(m, 2H), 4.59-4.62(m, 2H), 7.44-7.47(m, 1H), 7.50(dd, J=8.3, 1.7Hz, 1H), 7.82(d, J=8.3Hz, 1H), 7.92(m, 1H), 7.96-7.99(m, 1H), 8.43(s, 1H), 8.69-8.71(m, 1H), 8.95(m, 1H), 10.50(s, 1H)

実施例３６

The above starting material compound (107 mg, 0.327 mmol) obtained in the same manner as in Reference Examples 1 to 6 was dissolved in 1,4-dioxane (2.9 ml) and water (0.4 ml), and tetrakis (triphenylphosphine) palladium (0) (18.9 mg, 16.4 μmol), 3-pyridineboronic acid (60.3 mg, 0.491 mmol) and potassium carbonate (136 mg, 0.981 mmol) were added. The reaction mixture was stirred at 110 ° C. for 2 hr, water was added, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was crystallized with chloroform: hexane = 1: 5, filtered and dried under reduced pressure to obtain the desired product (64 mg, 61%).
¹ H-NMR (CDCl ₃ ) δ 1.14 (t, J = 7.1Hz, 3H), 3.50 (q, J = 7.1Hz, 2H), 3.86-3.89 (m, 2H), 4.59-4.62 (m, 2H) , 7.44-7.47 (m, 1H), 7.50 (dd, J = 8.3, 1.7Hz, 1H), 7.82 (d, J = 8.3Hz, 1H), 7.92 (m, 1H), 7.96-7.99 (m, 1H ), 8.43 (s, 1H), 8.69-8.71 (m, 1H), 8.95 (m, 1H), 10.50 (s, 1H)

Example 36

(S) -2-{[1- (2-Ethoxy-ethyl) -2-oxo-7-pyridin-3-yl-1,2-dihydro-quinolin-3-ylmethyl] -amino} -propionamide

参考例９で得た化合物を原料に用いて、実施例１と同様の方法で目的物を得た。
¹H-NMR (CDCl₃) δ 1.15(t, J=7.1Hz, 3H), 1.36(d, J=7.1Hz, 3H), 3.28(q, J=7.1Hz, 1H), 3.51(q, J=7.1Hz, 2H), 3.68(d, J=13.7Hz, 1H), 3.83(t, J=5.9Hz, 2H), 3.89(d, J=13.7Hz, 1H), 4.56-4.61(m, 2H), 5.50(br.s, 1H), 7.42-7.45(m, 1H), 7.46(dd, J=8.0, 1.4Hz, 1H), 7.65(d, J=8.0Hz, 1H), 7.70(s, 1H), 7.77(br.s, 1H), 7.85(s, 1H), 7.95-7.98(m, 1H), 8.66(dd, J=4.6, 1.5Hz, 1H), 8.92-8.93(m, 1H)

参考例１〜６、９、及び実施例１と同様の方法により、以下の表１０〜表１３に示す実施例３７〜４８の化合物を得た。

The target product was obtained in the same manner as in Example 1 using the compound obtained in Reference Example 9 as a raw material.
¹ H-NMR (CDCl ₃ ) δ 1.15 (t, J = 7.1Hz, 3H), 1.36 (d, J = 7.1Hz, 3H), 3.28 (q, J = 7.1Hz, 1H), 3.51 (q, J = 7.1Hz, 2H), 3.68 (d, J = 13.7Hz, 1H), 3.83 (t, J = 5.9Hz, 2H), 3.89 (d, J = 13.7Hz, 1H), 4.56-4.61 (m, 2H ), 5.50 (br.s, 1H), 7.42-7.45 (m, 1H), 7.46 (dd, J = 8.0, 1.4Hz, 1H), 7.65 (d, J = 8.0Hz, 1H), 7.70 (s, 1H), 7.77 (br.s, 1H), 7.85 (s, 1H), 7.95-7.98 (m, 1H), 8.66 (dd, J = 4.6, 1.5Hz, 1H), 8.92-8.93 (m, 1H)

The compounds of Examples 37 to 48 shown in Tables 10 to 13 below were obtained in the same manner as in Reference Examples 1 to 6, 9 and Example 1.

(Reference Example 10)

参考例1〜3と同様の方法で得た上記原料化合物(0.33g, 1.5mmol)のＮ，Ｎ’−ジメチルホルムアミド(15ml)溶液に２−フルオロベンジルアミン(0.23g, 1.8mmol)、酢酸（触媒量）、トリアセトキシ水素化ホウ素ナトリウム(0.39g, 1.8mmol)を加えた。１時間撹拌後、ジ-tert-ブチルジカルボナート(0.40g, 1.8mmol)を加え終夜撹拌した。反応液に水を加え、結晶を桐山ロートでろ取し、減圧乾燥することで目的物(0.58g, 89%)を得た。
¹H-NMR (CDCl₃) δ 1.48(s, 9H), 2.08-2.18(m, 2H), 2.94-3.01(m, 4H), 4.36-4.44(m, 2H), 4.59(s, 2H), 6.98-7.04(m, 2H), 7.17(br.s, 1H), 7.26-7.37(m, 4H)

（参考例１１）

To a solution of the above raw material compound (0.33 g, 1.5 mmol) obtained in the same manner as in Reference Examples 1 to 3 in N, N′-dimethylformamide (15 ml), 2-fluorobenzylamine (0.23 g, 1.8 mmol), acetic acid ( Catalyst amount), sodium triacetoxyborohydride (0.39 g, 1.8 mmol) was added. After stirring for 1 hour, di-tert-butyl dicarbonate (0.40 g, 1.8 mmol) was added and stirred overnight. Water was added to the reaction mixture, and the crystals were collected by filtration with a Kiriyama funnel and dried under reduced pressure to obtain the desired product (0.58 g, 89%).
¹ H-NMR (CDCl ₃ ) δ 1.48 (s, 9H), 2.08-2.18 (m, 2H), 2.94-3.01 (m, 4H), 4.36-4.44 (m, 2H), 4.59 (s, 2H), 6.98-7.04 (m, 2H), 7.17 (br.s, 1H), 7.26-7.37 (m, 4H)

(Reference Example 11)

参考例１０で得た化合物(0.97g, 2.3mmol)のＮ，Ｎ’−ジメチルホルムアミド(23ml)溶液に水素化ナトリウム(0.11g, 60% in oil, 2.8mmol)、（２−ブロモエトキシ）−tert−ブチルジメチルシラン(0.66g, 2.8mmol)を加え、80℃まで加熱した。1時間後、反応液を室温まで放冷し、水を加えた後に酢酸エチルで抽出した。水及び飽和食塩水で洗浄後、硫酸ナトリウムで乾燥し、減圧濃縮した。得られた残渣にテトラヒドロフラン(26ml)及びフッ化テトラブチルアンモニウム(3.0ml, 1Mテトラヒドロフラン溶液, 3.0mmol)を加えた。2時間半撹拌した後に水を加え、酢酸エチルで抽出した。飽和食塩水で洗浄後、硫酸ナトリウムで乾燥し、減圧濃縮した。得られた残渣をシリカゲルカラム(ヘキサン：酢酸エチル=７:３〜１:１, クロロホルム：メタノール=９:１)で精製し、目的物(0.71g, 66%)とO-アルキル体(0.15g, 14%)を得た。
¹H-NMR (CDCl₃) δ 1.46(s, 9H), 2.11-2.19(m, 2H), 2.98-3.05(m, 4H), 3.53(br.s, 1H), 4.01(br.s, 2H), 4.32-4.40(m, 2H), 4.53(s, 4H), 6.95-7.01(m, 2H), 7.27-7.46(m, 5H)

（参考例１２）

To a solution of the compound obtained in Reference Example 10 (0.97 g, 2.3 mmol) in N, N′-dimethylformamide (23 ml), sodium hydride (0.11 g, 60% in oil, 2.8 mmol), (2-bromoethoxy)- tert-Butyldimethylsilane (0.66 g, 2.8 mmol) was added and heated to 80 ° C. After 1 hour, the reaction mixture was allowed to cool to room temperature, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. Tetrahydrofuran (26 ml) and tetrabutylammonium fluoride (3.0 ml, 1M tetrahydrofuran solution, 3.0 mmol) were added to the resulting residue. After stirring for 2.5 hours, water was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified with a silica gel column (hexane: ethyl acetate = 7: 3 to 1: 1, chloroform: methanol = 9: 1) to obtain the desired product (0.71 g, 66%) and an O-alkyl compound (0.15 g). , 14%).
¹ H-NMR (CDCl ₃ ) δ 1.46 (s, 9H), 2.11-2.19 (m, 2H), 2.98-3.05 (m, 4H), 3.53 (br.s, 1H), 4.01 (br.s, 2H ), 4.32-4.40 (m, 2H), 4.53 (s, 4H), 6.95-7.01 (m, 2H), 7.27-7.46 (m, 5H)

(Reference Example 12)

参考例１１で得た化合物(0.11g, 0.24mmol)のジクロロメタン(2.4ml)溶液にトリエチルアミン(72mg, 0.72mmol)を加え-10℃に冷却した。メタンスルホニルクロリド(54mg, 0.48mmol)を加え、３０分間撹拌した。フタルイミドカリウム(0.18g, 0.96mmol)のテトラヒドロフラン(2.4ml)溶液を加え、室温に昇温した。終夜撹拌し、水を加え、クロロホルムで抽出した。飽和炭酸カリウム水溶液及び飽和食塩水で洗浄後、硫酸ナトリウムで乾燥し減圧濃縮した。得られた残渣をシリカゲルカラムによって精製することで目的物 (22mg, 16%)を得た。
¹H-NMR (CDCl₃) δ 1.46(s, 9H), 2.04-2.08(m, 2H), 2.88-2.96(m, 4H), 4.10(t, J=6.0Hz, 2H), 4.22(br.s, 1H), 4.32(m, 1H), 4.39-4.42(m, 2H), 4.62(t, J=6.0Hz, 2H), 6.94-7.00(m, 2H), 7.21-7.41(m, 5H), 7.62-7.68(m, 2H), 7.76-7.79(m, 2H)

（参考例１３）

Triethylamine (72 mg, 0.72 mmol) was added to a solution of the compound obtained in Reference Example 11 (0.11 g, 0.24 mmol) in dichloromethane (2.4 ml) and cooled to −10 ° C. Methanesulfonyl chloride (54 mg, 0.48 mmol) was added and stirred for 30 minutes. A solution of potassium phthalimide (0.18 g, 0.96 mmol) in tetrahydrofuran (2.4 ml) was added, and the temperature was raised to room temperature. The mixture was stirred overnight, water was added, and the mixture was extracted with chloroform. The extract was washed with a saturated aqueous potassium carbonate solution and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by a silica gel column to give the object product (22 mg, 16%).
¹ H-NMR (CDCl ₃ ) δ 1.46 (s, 9H), 2.04-2.08 (m, 2H), 2.88-2.96 (m, 4H), 4.10 (t, J = 6.0Hz, 2H), 4.22 (br. s, 1H), 4.32 (m, 1H), 4.39-4.42 (m, 2H), 4.62 (t, J = 6.0Hz, 2H), 6.94-7.00 (m, 2H), 7.21-7.41 (m, 5H) , 7.62-7.68 (m, 2H), 7.76-7.79 (m, 2H)

(Reference Example 13)

参考例１２で得た化合物(0.26g, 0.43mmol)のメタノール溶液(4.3ml)にヒドラジン・一水和物(21mg, 0.65mmol)を加え、60℃まで加熱した。２時間撹拌した後に減圧濃縮し、水を加えクロロホルムで抽出した。飽和食塩水で洗浄後、硫酸ナトリウムで乾燥し、減圧濃縮することで目的物(0.17g, 82%)を得た。
¹H-NMR (CDCl₃) δ 1.46(s, 9H), 2.12-2.16(m, 2H), 2.83-3.08(m, 6H), 4.33-4.40(m, 4H), 4.46(s, 2H), 6.96(m, 2H), 7.28-7.44(m, 5H)

実施例４９

Hydrazine monohydrate (21 mg, 0.65 mmol) was added to a methanol solution (4.3 ml) of the compound (0.26 g, 0.43 mmol) obtained in Reference Example 12 and heated to 60 ° C. After stirring for 2 hours, the mixture was concentrated under reduced pressure, water was added, and the mixture was extracted with chloroform. The extract was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure to obtain the desired product (0.17 g, 82%).
¹ H-NMR (CDCl ₃ ) δ 1.46 (s, 9H), 2.12-2.16 (m, 2H), 2.83-3.08 (m, 6H), 4.33-4.40 (m, 4H), 4.46 (s, 2H), 6.96 (m, 2H), 7.28-7.44 (m, 5H)

Example 49

N- (2- {3-[(4-Fluoro-benzylamino) -methyl] -2-oxo-2,6,7,8-tetrahydro-cyclopenta [g] quinolin-1-yl} -ethyl) -acetamide

参考例１３で得た化合物（39mg, 84μmol）の酢酸エチル(3.0ml)溶液に、氷冷下、ピリジン(7.5mg, 93μmol)及び無水酢酸(9.5mg, 93μmmol)を加え20分間撹拌した。反応液を1N水酸化ナトリウム水溶液中に流し込み、クロロホルムで抽出した。有機層を飽和食塩水にて洗浄後、硫酸ナトリウムで乾燥し、減圧濃縮した。残渣にトリフルオロ酢酸(1.0ml)とメタノール(3ml)を加えた。3時間撹拌後、水とクロロホルムを加え分液、抽出した。水層に1N水酸化ナトリウム水溶液を加えアルカリ性とし、クロロホルムで抽出した。有機層を併せ、飽和食塩水にて洗浄後、硫酸ナトリウムで乾燥し、減圧濃縮することで目的物(9.8mg, 29%)を得た。
¹H-NMR (CDCl₃) δ 1.94(s, 3H), 2.14(tt, J=7.3, 7.3Hz, 2H), 2.97(t, J=7.3Hz, 2H), 3.06(t, J=7.3Hz, 2H), 3.61-3.67(m, 2H), 3.78(s, 2H), 3.81(s, 2H), 4.48-4.52(m, 2H), 6.57(br.s, 1H), 6.98-7.04(m, 2H), 7.31-7.35(m, 2H), 7.38-7.44(m, 2H), 7.66(s, 1H)

参考例１〜３、１０〜１３、及び実施例４９と同様の方法により、以下の表１４〜１５に示す実施例５０〜５４の化合物を得た。

Pyridine (7.5 mg, 93 μmol) and acetic anhydride (9.5 mg, 93 μmmol) were added to a solution of the compound obtained in Reference Example 13 (39 mg, 84 μmol) in ethyl acetate (3.0 ml) under ice cooling, and the mixture was stirred for 20 minutes. The reaction solution was poured into 1N aqueous sodium hydroxide solution and extracted with chloroform. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. To the residue were added trifluoroacetic acid (1.0 ml) and methanol (3 ml). After stirring for 3 hours, water and chloroform were added to separate and extract. The aqueous layer was made alkaline with 1N aqueous sodium hydroxide solution and extracted with chloroform. The organic layers were combined, washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure to obtain the desired product (9.8 mg, 29%).
¹ H-NMR (CDCl ₃ ) δ 1.94 (s, 3H), 2.14 (tt, J = 7.3, 7.3Hz, 2H), 2.97 (t, J = 7.3Hz, 2H), 3.06 (t, J = 7.3Hz , 2H), 3.61-3.67 (m, 2H), 3.78 (s, 2H), 3.81 (s, 2H), 4.48-4.52 (m, 2H), 6.57 (br.s, 1H), 6.98-7.04 (m , 2H), 7.31-7.35 (m, 2H), 7.38-7.44 (m, 2H), 7.66 (s, 1H)

In the same manner as in Reference Examples 1 to 3, 10 to 13, and Example 49, the compounds of Examples 50 to 54 shown in Tables 14 to 15 below were obtained.

（参考例１４）

(Reference Example 14)

参考例２で得た化合物（2.0ｇ、7.1mmol）、メタノール（30ｍｌ）及びカリウムｔ−ブトキシド（1.2ｇ、10.6mmol）を混ぜ、加熱還流した。1時間後、反応液に水を加え、メタノールを半分濃縮した。クロロホルムで抽出後、有機層を乾燥、濃縮し、目的物（2.0ｇ、100％）を得た。
¹H-NMR (CDCl₃) δ 4.12(s, 3H), 7.13-7.27(m, 5H), 7.41-7.48(m, 2H), 7.81(d, J=8.4Hz, 1H), 8.54(s, 1H), 10.42(s, 1H)

（参考例１５）

The compound obtained in Reference Example 2 (2.0 g, 7.1 mmol), methanol (30 ml) and potassium t-butoxide (1.2 g, 10.6 mmol) were mixed and heated to reflux. After 1 hour, water was added to the reaction solution, and methanol was half concentrated. After extraction with chloroform, the organic layer was dried and concentrated to obtain the desired product (2.0 g, 100%).
¹ H-NMR (CDCl ₃ ) δ 4.12 (s, 3H), 7.13-7.27 (m, 5H), 7.41-7.48 (m, 2H), 7.81 (d, J = 8.4Hz, 1H), 8.54 (s, 1H), 10.42 (s, 1H)

(Reference Example 15)

参考例１４で得た化合物（2.0g, 7.1mmol）をテトラヒドロフラン(50ml)に溶かし、氷冷下、臭化メチルマグネシウム（0.96Mテトラヒドロフラン溶液, 10ml, 9.6mmol）を加えた。1時間後、飽和塩化アンモニウム水溶液を加え反応を停止後、酢酸エチルで抽出した。有機層を水洗、乾燥、濃縮し、残渣をシリカゲルカラム（酢酸エチル：ヘキサン＝１：３〜１：２）で精製しアルコール体（1.65ｇ、78％）を得た。得られたアルコール体をトルエン(30ml)に溶解後、二酸化マンガン（5.0ｇ, 56mmol）を加え80℃で撹拌した。2時間後、反応液をセライトろ過し、ろ液を濃縮することで、目的物（1.3g, 79%）を得た。
¹H-NMR (CDCl₃) δ 2.69(s, 3H), 4.10(s, 3H), 7.12-7.27(m, 5H), 7.39-7.47(m, 2H), 7.78(m,1H), 8.50(s, 1H)

（参考例１６）

The compound (2.0 g, 7.1 mmol) obtained in Reference Example 14 was dissolved in tetrahydrofuran (50 ml), and methylmagnesium bromide (0.96 M tetrahydrofuran solution, 10 ml, 9.6 mmol) was added under ice cooling. After 1 hour, saturated aqueous ammonium chloride solution was added to stop the reaction, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried and concentrated, and the residue was purified with a silica gel column (ethyl acetate: hexane = 1: 3 to 1: 2) to obtain an alcohol form (1.65 g, 78%). The obtained alcohol was dissolved in toluene (30 ml), manganese dioxide (5.0 g, 56 mmol) was added, and the mixture was stirred at 80 ° C. After 2 hours, the reaction solution was filtered through Celite, and the filtrate was concentrated to obtain the desired product (1.3 g, 79%).
¹ H-NMR (CDCl ₃ ) δ 2.69 (s, 3H), 4.10 (s, 3H), 7.12-7.27 (m, 5H), 7.39-7.47 (m, 2H), 7.78 (m, 1H), 8.50 ( s, 1H)

(Reference Example 16)

参考例１５で得た化合物（1.1g, 3.8mmol）、5N塩酸（20ml）を混ぜ、80℃で撹拌した。4時間後、反応液を氷中に流し込み、2時間撹拌した。生じた沈殿をろ取、減圧乾燥し、目的物（0.97g, 93%）を得た。
¹H-NMR（DMSO）δ 2.59(s, 3H), 6.80(d, J=2.4Hz, 1H), 6.92(dd, J=8.8, 2.4Hz, 1H), 7.15-7.32(m, 3H), 7.45-7.55(m, 2H), 7.90(d, J=8.8Hz, 1H), 8.46(s, 1H), 11.90(br, 1H)

（参考例１７）

The compound obtained in Reference Example 15 (1.1 g, 3.8 mmol) and 5N hydrochloric acid (20 ml) were mixed and stirred at 80 ° C. After 4 hours, the reaction solution was poured into ice and stirred for 2 hours. The resulting precipitate was collected by filtration and dried under reduced pressure to obtain the desired product (0.97 g, 93%).
¹ H-NMR (DMSO) δ 2.59 (s, 3H), 6.80 (d, J = 2.4Hz, 1H), 6.92 (dd, J = 8.8, 2.4Hz, 1H), 7.15-7.32 (m, 3H), 7.45-7.55 (m, 2H), 7.90 (d, J = 8.8Hz, 1H), 8.46 (s, 1H), 11.90 (br, 1H)

(Reference Example 17)

参考例４と同様の方法で目的物を得た。
¹H-NMR (CDCl₃) δ 1.11(t, J=7.0Hz, 3H), 2.75(s, 3H), 3.44(quart, J=7.0Hz, 2H), 3.72(t, J=6.0Hz, 2H), 4.38(t, J=6.0Hz, 2H), 6.88(dd, J=8.6, 2.2Hz, 1H), 7.08-7.15(m, 3H), 7.24(m, 1H), 7.39-7.46(m, 2H), 7.62(d, J=8.8Hz, 1H), 8.41(s, 1H)

実施例５５

The target product was obtained in the same manner as in Reference Example 4.
¹ H-NMR (CDCl ₃ ) δ 1.11 (t, J = 7.0Hz, 3H), 2.75 (s, 3H), 3.44 (quart, J = 7.0Hz, 2H), 3.72 (t, J = 6.0Hz, 2H ), 4.38 (t, J = 6.0Hz, 2H), 6.88 (dd, J = 8.6, 2.2Hz, 1H), 7.08-7.15 (m, 3H), 7.24 (m, 1H), 7.39-7.46 (m, 2H), 7.62 (d, J = 8.8Hz, 1H), 8.41 (s, 1H)

Example 55

1- (2-Ethoxy-ethyl) -3- [1- (4-fluoro-benzylamino) -ethyl] -7-phenoxy-1H-quinolin-2-one

参考例１７で得た化合物を原料に用いて、実施例１と同様の方法で目的物を得た。
¹H-NMR (CDCl₃) δ 1.11(t, J=7.1Hz, 3H), 1.43(d, J=6.6Hz, 3H), 3.46(quart, J=7.1Hz, 2H), 3.62-3.76(m, 4H), 4.05(quart, J=6.6Hz, 1H), 4.40(t, J=6.2Hz, 2H), 6.87(dd, J=8.5, 2.0Hz, 1H), 6.95-7.43(m, 10H), 7.50(d, J=8.5Hz, 1H), 7.70(s, 1H)

実施例５６

The target product was obtained in the same manner as in Example 1 using the compound obtained in Reference Example 17 as a raw material.
¹ H-NMR (CDCl ₃ ) δ 1.11 (t, J = 7.1Hz, 3H), 1.43 (d, J = 6.6Hz, 3H), 3.46 (quart, J = 7.1Hz, 2H), 3.62-3.76 (m , 4H), 4.05 (quart, J = 6.6Hz, 1H), 4.40 (t, J = 6.2Hz, 2H), 6.87 (dd, J = 8.5, 2.0Hz, 1H), 6.95-7.43 (m, 10H) , 7.50 (d, J = 8.5Hz, 1H), 7.70 (s, 1H)

Example 56

1- (2-Ethoxy-ethyl) -3- {1-[(furan-2-ylmethyl) -amino] -ethyl} -7-phenoxy-1H-quinolin-2-one

参考例１７で得た化合物を原料に用いて、実施例１と同様の方法で目的物を得た。
¹H-NMR (CDCl₃) δ 1.11(t, J=7.1Hz, 3H), 1.41(d, J=6.6Hz, 3H), 3.46(quart, J=7.1Hz, 2H), 3.67-3.86(m, 4H), 4.07(quart, J=6.6Hz, 1H), 4.39(t, J=6.3Hz, 2H), 6.15(d, J=3.2Hz, 1H), 6.28(m, 1H), 6.86(dd, J=8.5, 1.7Hz, 1H), 7.05-7.20(m, 4H), 7.33-7.41(m, 3H), 7.51(d, J=8.5Hz, 1H), 7.73(s, 1H)

実施例５７

The target product was obtained in the same manner as in Example 1 using the compound obtained in Reference Example 17 as a raw material.
¹ H-NMR (CDCl ₃ ) δ 1.11 (t, J = 7.1Hz, 3H), 1.41 (d, J = 6.6Hz, 3H), 3.46 (quart, J = 7.1Hz, 2H), 3.67-3.86 (m , 4H), 4.07 (quart, J = 6.6Hz, 1H), 4.39 (t, J = 6.3Hz, 2H), 6.15 (d, J = 3.2Hz, 1H), 6.28 (m, 1H), 6.86 (dd , J = 8.5, 1.7Hz, 1H), 7.05-7.20 (m, 4H), 7.33-7.41 (m, 3H), 7.51 (d, J = 8.5Hz, 1H), 7.73 (s, 1H)

Example 57

1- (2-Ethoxy-ethyl) -7-phenoxy-3- {1-[(thiophen-2-ylmethyl) -amino] -ethyl} -1H-quinolin-2-one

参考例１７で得た化合物を原料に用いて、実施例１と同様の方法で目的物を得た。
¹H-NMR (CDCl₃) δ 1.11(t, J=7.0Hz, 3H), 1.43(d, J=6.6Hz, 3H), 3.46(quart, J=7.0Hz, 2H), 3.71(t, J=6.2Hz, 2H), 3.91(s, 2H), 4.10(quart, J=6.6Hz, 1H), 4.39(t, J=6.2Hz, 2H), 6.85-7.20(m, 8H), 7.35-7.40(m, 2H), 7.51(d, J=8.6Hz, 1H), 7.74(s, 1H)

（参考例１８）

The target product was obtained in the same manner as in Example 1 using the compound obtained in Reference Example 17 as a raw material.
¹ H-NMR (CDCl ₃ ) δ 1.11 (t, J = 7.0Hz, 3H), 1.43 (d, J = 6.6Hz, 3H), 3.46 (quart, J = 7.0Hz, 2H), 3.71 (t, J = 6.2Hz, 2H), 3.91 (s, 2H), 4.10 (quart, J = 6.6Hz, 1H), 4.39 (t, J = 6.2Hz, 2H), 6.85-7.20 (m, 8H), 7.35-7.40 (m, 2H), 7.51 (d, J = 8.6Hz, 1H), 7.74 (s, 1H)

(Reference Example 18)

参考例４で得た化合物（0.50g, 1.48mmol）をメタノール（10ml）に懸濁し、氷冷下、水素化ホウ素ナトリウム（68mg, 1.78mmol）を加えた。1時間後、1N塩酸を加え反応を停止後、酢酸エチルで抽出した。有機層を水洗、乾燥、濃縮し、残渣をジクロロメタン（10ml）に溶かした。氷冷下、トリエチルアミン（0.44ml, 2.96mmol）及びメタンスルホニルクロリド（0.23ml, 2.96mmol）を加え、室温で一晩撹拌した。反応液に水を加え、酢酸エチルで抽出した。有機層を水洗、乾燥、濃縮し、残渣をシリカゲルカラム（酢酸エチル：ヘキサン＝1：4〜1：2）で精製し、目的物（0.48g, 91%）を得た。
¹H-NMR (CDCl₃) δ 1.10(t, J=7.0Hz, 3H), 3.44(quart, J=7.0Hz, 2H), 4.39(t, J=6.2Hz, 2H), 4.39(t, J=6.2Hz, 2H), 4.65(s, 2H), 6.88(dd, J=8.5, 2.1Hz, 1H), 7.05-7.23(m, 4H), 7.36-7.43(m, 2H), 7.52(d, J=8.5Hz, 1H), 7.84(s, 1H)

（参考例１９）

The compound obtained in Reference Example 4 (0.50 g, 1.48 mmol) was suspended in methanol (10 ml), and sodium borohydride (68 mg, 1.78 mmol) was added under ice cooling. After 1 hour, 1N hydrochloric acid was added to stop the reaction, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried and concentrated, and the residue was dissolved in dichloromethane (10 ml). Under ice-cooling, triethylamine (0.44 ml, 2.96 mmol) and methanesulfonyl chloride (0.23 ml, 2.96 mmol) were added, and the mixture was stirred overnight at room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried and concentrated, and the residue was purified with a silica gel column (ethyl acetate: hexane = 1: 4 to 1: 2) to obtain the desired product (0.48 g, 91%).
¹ H-NMR (CDCl ₃ ) δ 1.10 (t, J = 7.0Hz, 3H), 3.44 (quart, J = 7.0Hz, 2H), 4.39 (t, J = 6.2Hz, 2H), 4.39 (t, J = 6.2Hz, 2H), 4.65 (s, 2H), 6.88 (dd, J = 8.5, 2.1Hz, 1H), 7.05-7.23 (m, 4H), 7.36-7.43 (m, 2H), 7.52 (d, J = 8.5Hz, 1H), 7.84 (s, 1H)

(Reference Example 19)

参考例１８で得られた化合物（0.48g, 1.34mmol）をＮ，Ｎ’−ジメチルホルムアミド(10ml)に溶かし、室温でシアン化ナトリウム（97mg, 1.98mmol）を加えた。4時間後、反応液に水を加え、酢酸エチルで抽出した。有機層を水洗、乾燥、濃縮し、残渣をシリカゲルカラム（酢酸エチル：ヘキサン＝1：2〜2：1）で精製し、目的物（0.34g, 73%）を得た。
¹H-NMR (CDCl₃) δ 1.10(t, J=7.0Hz, 3H), 3.44(quart, J=7.0Hz, 2H), 3.70(t, J=6.1Hz, 2H), 3.74(d, J=1.2Hz, 2H), 4.39(t, J=6.1Hz, 2H), 6.91(dd, J=8.5, 2.2Hz, 1H), 7.07-7.23(m, 4H), 7.37-7.43(m, 2H), 7.55(d, J=8.5Hz, 1H), 7.89(s, 1H)

実施例５８

The compound obtained in Reference Example 18 (0.48 g, 1.34 mmol) was dissolved in N, N′-dimethylformamide (10 ml), and sodium cyanide (97 mg, 1.98 mmol) was added at room temperature. After 4 hours, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried and concentrated, and the residue was purified with a silica gel column (ethyl acetate: hexane = 1: 2 to 2: 1) to obtain the desired product (0.34 g, 73%).
¹ H-NMR (CDCl ₃ ) δ 1.10 (t, J = 7.0Hz, 3H), 3.44 (quart, J = 7.0Hz, 2H), 3.70 (t, J = 6.1Hz, 2H), 3.74 (d, J = 1.2Hz, 2H), 4.39 (t, J = 6.1Hz, 2H), 6.91 (dd, J = 8.5, 2.2Hz, 1H), 7.07-7.23 (m, 4H), 7.37-7.43 (m, 2H) , 7.55 (d, J = 8.5Hz, 1H), 7.89 (s, 1H)

Example 58

3- (2-Amino-ethyl) -1- (2-ethoxy-ethyl) -7-phenoxy-1H-quinolin-2-one

参考例１９で得た化合物（0.34g, 0.98mmol）をジクロロメタン（10ml）に溶かし、-78℃で水素化ジイソブチルアルミニウム（1.01Mトルエン溶液, 1.0ml, 1.07mmol）を滴下した。30分後、水素化ジイソブチルアルミニウムを1.5ml追加した。20分後、0℃で20分撹拌した。メタノールで反応を停止後、反応液を酒石酸ナトリウムカリウム水溶液中に流し込み、室温で2時間撹拌した。有機層を分離後、水、1N塩酸を加え、分液した。水層をアルカリ性にし、クロロホルムで抽出した。有機層を乾燥、濃縮し、目的物（0.12g, 35%）を得た。
¹H-NMR (CDCl₃) δ 1.11(t, J=7.0Hz, 3H), 2.77(t, J=6.7Hz, 2H), 3.01(t, J=6.7Hz, 2H), 3.45(quart, J=7.0Hz, 2H), 3.70(t, J=6.2Hz, 2H), 4.39(t, J=6.2Hz, 2H), 6.85(dd, J=8.5, 2.2Hz, 1H), 7.04-7.08(m, 2H), 7.14-7.20(m, 2H), 7.35-7.41(m, 2H), 7.45(d, J=8.5Hz, 1H), 7.54(s, 1H)

実施例５９

The compound (0.34 g, 0.98 mmol) obtained in Reference Example 19 was dissolved in dichloromethane (10 ml), and diisobutylaluminum hydride (1.01 M toluene solution, 1.0 ml, 1.07 mmol) was added dropwise at −78 ° C. After 30 minutes, 1.5 ml of diisobutylaluminum hydride was added. After 20 minutes, the mixture was stirred at 0 ° C. for 20 minutes. After stopping the reaction with methanol, the reaction solution was poured into an aqueous sodium potassium tartrate solution and stirred at room temperature for 2 hours. After separating the organic layer, water and 1N hydrochloric acid were added to separate the layers. The aqueous layer was made alkaline and extracted with chloroform. The organic layer was dried and concentrated to obtain the desired product (0.12 g, 35%).
¹ H-NMR (CDCl ₃ ) δ 1.11 (t, J = 7.0Hz, 3H), 2.77 (t, J = 6.7Hz, 2H), 3.01 (t, J = 6.7Hz, 2H), 3.45 (quart, J = 7.0Hz, 2H), 3.70 (t, J = 6.2Hz, 2H), 4.39 (t, J = 6.2Hz, 2H), 6.85 (dd, J = 8.5, 2.2Hz, 1H), 7.04-7.08 (m , 2H), 7.14-7.20 (m, 2H), 7.35-7.41 (m, 2H), 7.45 (d, J = 8.5Hz, 1H), 7.54 (s, 1H)

Example 59

1- (2-Ethoxy-ethyl) -3- {2-[(furan-2-ylmethyl) -amino] -ethyl} -7-phenoxy-1H-quinolin-2-one

実施例５８で得た化合物（20mg, 0.057mmol）をジクロロメタン（1ml）に溶かし、フルフラール（0.01ml, 0.11mmol）及びトリアセトキシ水素化ホウ素ナトリウム（24mg, 0.11mmol）を加え、室温で1時間撹拌した。反応液を飽和炭酸水素ナトリウム水溶液に流し込み、酢酸エチルで抽出した。有機層を水洗、乾燥、濃縮し、残渣をシリカゲルカラム（酢酸エチル：ヘキサン＝1：2〜クロロホルム：メタノール＝50：1）で精製し、目的物（5.0mg, 20%）を得た。
¹H-NMR (CDCl₃) δ 1.11(t, J=7.0Hz, 3H), 2.82(t, J=6.8Hz, 2H), 2.94(t, J=6.8Hz, 2H), 3.45(quart, J=7.0Hz, 2H), 3.69(t, J=6.2Hz, 2H), 3.83(s, 2H), 4.38(t, J=6.2Hz, 2H), 6.18(d, J=3.2Hz, 1H), 6.30(m, 1H), 6.84(dd, J=8.5, 2.2Hz, 1H), 7.02-7.20(m, 4H), 7.34-7.40(m, 3H), 7.43(d, J=8.5Hz, 1H), 7.52(s, 1H)

実施例６０

The compound obtained in Example 58 (20 mg, 0.057 mmol) was dissolved in dichloromethane (1 ml), furfural (0.01 ml, 0.11 mmol) and sodium triacetoxyborohydride (24 mg, 0.11 mmol) were added, and the mixture was stirred at room temperature for 1 hour. did. The reaction solution was poured into a saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was washed with water, dried and concentrated, and the residue was purified with a silica gel column (ethyl acetate: hexane = 1: 2 to chloroform: methanol = 50: 1) to obtain the desired product (5.0 mg, 20%).
¹ H-NMR (CDCl ₃ ) δ 1.11 (t, J = 7.0Hz, 3H), 2.82 (t, J = 6.8Hz, 2H), 2.94 (t, J = 6.8Hz, 2H), 3.45 (quart, J = 7.0Hz, 2H), 3.69 (t, J = 6.2Hz, 2H), 3.83 (s, 2H), 4.38 (t, J = 6.2Hz, 2H), 6.18 (d, J = 3.2Hz, 1H), 6.30 (m, 1H), 6.84 (dd, J = 8.5, 2.2Hz, 1H), 7.02-7.20 (m, 4H), 7.34-7.40 (m, 3H), 7.43 (d, J = 8.5Hz, 1H) , 7.52 (s, 1H)

Example 60

1- (2-Ethoxy-ethyl) -3- [2- (4-fluoro-benzylamino) -ethyl] -7-phenoxy-1H-quinolin-2-one

実施例５９と同様の方法により、目的物を得た。
¹H-NMR (CDCl₃) δ 1.10(t, J=7.0Hz, 3H), 2.83(t, J=6.6Hz, 2H), 2.94(t, J=6.6Hz, 2H), 3.45(quart, J=7.0Hz, 2H), 3.69(t, J=6.3Hz, 2H), 3.80(s, 2H), 4.38(t, J=6.3Hz, 2H), 6.85(dd, J=8.5, 2.2Hz, 1H), 6.96-7.20(m, 6H), 7.26-7.40(m, 4H), 7.43(d, J=8.5Hz, 1H), 7.52(s, 1H)
実施例６１

The target product was obtained in the same manner as in Example 59.
¹ H-NMR (CDCl ₃ ) δ 1.10 (t, J = 7.0Hz, 3H), 2.83 (t, J = 6.6Hz, 2H), 2.94 (t, J = 6.6Hz, 2H), 3.45 (quart, J = 7.0Hz, 2H), 3.69 (t, J = 6.3Hz, 2H), 3.80 (s, 2H), 4.38 (t, J = 6.3Hz, 2H), 6.85 (dd, J = 8.5, 2.2Hz, 1H ), 6.96-7.20 (m, 6H), 7.26-7.40 (m, 4H), 7.43 (d, J = 8.5Hz, 1H), 7.52 (s, 1H)
Example 61

1- (2-Ethoxy-ethyl) -3- [2- (1-furan-2-yl-ethylamino) -ethyl] -7-phenoxy-1H-quinolin-2-one

実施例５９と同様の方法により、目的物を得た。
¹H-NMR (CDCl₃) δ 1.10(t, J=7.0Hz, 3H), 1.41(d, J=6.8Hz, 3H), 2.74-2.90(m, 4H), 3.45(quart, J=7.0Hz, 2H), 3.69(t, J=6.2Hz, 2H), 3.92(quart, J=6.8Hz, 1H), 4.37(t, J=6.2Hz, 2H), 6.13(m, 1H), 6.29(m, 1H), 6.84(dd, J=8.5, 2.2Hz, 1H), 7.03-7.20(m, 4H), 7.31-7.44(m, 4H), 7.49(s, 1H)

実施例６２

The target product was obtained in the same manner as in Example 59.
¹ H-NMR (CDCl ₃ ) δ 1.10 (t, J = 7.0Hz, 3H), 1.41 (d, J = 6.8Hz, 3H), 2.74-2.90 (m, 4H), 3.45 (quart, J = 7.0Hz , 2H), 3.69 (t, J = 6.2Hz, 2H), 3.92 (quart, J = 6.8Hz, 1H), 4.37 (t, J = 6.2Hz, 2H), 6.13 (m, 1H), 6.29 (m , 1H), 6.84 (dd, J = 8.5, 2.2Hz, 1H), 7.03-7.20 (m, 4H), 7.31-7.44 (m, 4H), 7.49 (s, 1H)

Example 62

1- (2-Ethoxy-ethyl) -3- {2- [1- (4-fluoro-phenyl) -ethylamino] -ethyl} -7-phenoxy-1H-quinolin-2-one

実施例５９と同様の方法により、目的物を得た。
¹H-NMR (CDCl₃) δ 1.10(t, J=7.0Hz, 3H), 1.32(d, J=6.6Hz, 3H), 2.60-2.88(m, 4H), 3.45(quart, J=7.0Hz, 2H), 3.68(t, J=6.2Hz, 2H), 3.81(quart, J=6.6Hz, 1H), 4.36(t, J=6.2Hz, 2H), 6.84(dd, J=8.5, 2.0Hz, 1H), 6.94-7.43(m, 11H), 7.46(s, 1H)

実施例６３

The target product was obtained in the same manner as in Example 59.
¹ H-NMR (CDCl ₃ ) δ 1.10 (t, J = 7.0Hz, 3H), 1.32 (d, J = 6.6Hz, 3H), 2.60-2.88 (m, 4H), 3.45 (quart, J = 7.0Hz , 2H), 3.68 (t, J = 6.2Hz, 2H), 3.81 (quart, J = 6.6Hz, 1H), 4.36 (t, J = 6.2Hz, 2H), 6.84 (dd, J = 8.5, 2.0Hz , 1H), 6.94-7.43 (m, 11H), 7.46 (s, 1H)

Example 63

2- {2- [1- (2-Ethoxy-ethyl) -2-oxo-7-phenoxy-1,2-dihydro-quinolin-3-yl] -ethylamino} -acetamide

実施例５８で得た化合物（20mg, 0.057mmol）をアセトニトリル（1ml）に溶かし、2-クロロアセトアミド（15mg, 0.16mmol）、炭酸カリウム（15mg, 0.11mmol）を加え、70℃で5時間撹拌した。反応液に水を加え、酢酸エチルで抽出した。有機層を水洗、乾燥、濃縮し、残渣をシリカゲルカラム（クロロホルム：メタノール＝50：1〜20：1）で精製し、目的物（6mg, 26%）を得た。
¹H-NMR (CDCl₃) δ 1.10(t, J=7.0Hz, 3H), 2.81(t, J=6.6Hz, 2H), 2.95(t, J=6.6Hz, 2H), 3.31(s, 2H), 3.45(quart, J=7.0Hz, 2H), 3.70(t, J=6.2Hz, 2H), 4.38(t, J=6.2Hz, 2H), 6.86(dd, J=8.5, 2.2Hz, 1H), 7.04-7.22(m, 5H), 7.35-7.42(m, 2H), 7.45(d, J=8.5Hz, 1H), 7.53(s, 1H)

（参考例２０）

The compound (20 mg, 0.057 mmol) obtained in Example 58 was dissolved in acetonitrile (1 ml), 2-chloroacetamide (15 mg, 0.16 mmol) and potassium carbonate (15 mg, 0.11 mmol) were added, and the mixture was stirred at 70 ° C. for 5 hours. . Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried and concentrated, and the residue was purified with a silica gel column (chloroform: methanol = 50: 1 to 20: 1) to obtain the desired product (6 mg, 26%).
¹ H-NMR (CDCl ₃ ) δ 1.10 (t, J = 7.0Hz, 3H), 2.81 (t, J = 6.6Hz, 2H), 2.95 (t, J = 6.6Hz, 2H), 3.31 (s, 2H ), 3.45 (quart, J = 7.0Hz, 2H), 3.70 (t, J = 6.2Hz, 2H), 4.38 (t, J = 6.2Hz, 2H), 6.86 (dd, J = 8.5, 2.2Hz, 1H ), 7.04-7.22 (m, 5H), 7.35-7.42 (m, 2H), 7.45 (d, J = 8.5Hz, 1H), 7.53 (s, 1H)

(Reference Example 20)

窒素雰囲気下、氷冷下にて4-ペンテン酸（4.0g, 40mmol）に、Ｎ，Ｎ’−ジメチルホルムアミド(1滴)、二塩化オキサリル (4.19ml, 48mmol)を加え、室温で3時間撹拌した。得られた反応液をそのまま次の反応に使用した。
窒素雰囲気下、氷冷下にて3-フェノキシアニリン（5.9g, 32mmol）の無水エーテル溶液（18ml）にトリエチルアミン(5.02 ml, 36mml)を加えた。上記で合成した塩化アシル（4.27g, 36mmol）の無水エーテル溶液を反応液にゆっくり加え、室温で16時間撹拌した。反応液を1%塩酸、飽和炭酸水素ナトリウム水溶液、飽和食塩水で洗浄後、硫酸ナトリウムにて乾燥し、減圧濃縮した。残渣をシリカゲルカラム(ヘキサンのみ〜ヘキサン：酢酸エチル＝２：１)にて精製し、目的物(8.04g, 94%)を得た。
¹H-NMR (CDCl₃) δ 2.36-2.50 (m, 4H), 4.99-5.13 (m, 2H), 5.83 (m, 1H), 6.73 (dt, J=2.0, 6.8Hz, 1H), 6.97-7.03 (m, 2H), 7.09 (m, 1H), 7.18-7.36 (m, 5H), 7.55 (br s, 1H)

（参考例２１）

N, N'-dimethylformamide (1 drop) and oxalyl dichloride (4.19 ml, 48 mmol) were added to 4-pentenoic acid (4.0 g, 40 mmol) under a nitrogen atmosphere and ice cooling, and the mixture was stirred at room temperature for 3 hours. did. The obtained reaction solution was directly used for the next reaction.
Triethylamine (5.02 ml, 36 mml) was added to an anhydrous ether solution (18 ml) of 3-phenoxyaniline (5.9 g, 32 mmol) under a nitrogen atmosphere under ice cooling. An acyl ether solution of acyl chloride (4.27 g, 36 mmol) synthesized above was slowly added to the reaction solution, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was washed with 1% hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified with a silica gel column (hexane only to hexane: ethyl acetate = 2: 1) to obtain the desired product (8.04 g, 94%).
¹ H-NMR (CDCl ₃ ) δ 2.36-2.50 (m, 4H), 4.99-5.13 (m, 2H), 5.83 (m, 1H), 6.73 (dt, J = 2.0, 6.8Hz, 1H), 6.97- 7.03 (m, 2H), 7.09 (m, 1H), 7.18-7.36 (m, 5H), 7.55 (br s, 1H)

(Reference Example 21)

オキシ塩化リン（27.81g, 182mmol）を氷冷し、Ｎ，Ｎ’−ジメチルホルムアミド（3.33ml, 43mmol）をゆっくり滴下した。15分後、参考例２０で得た化合物(8.04g, 30mmol)を少量ずつ加えた。原料を加えた後、反応液を80℃に昇温し、3時間撹拌した。反応液を冷却後、氷中にゆっくり流し込み、室温で2時間撹拌した。反応液をクロロホルムで3回抽出した。硫酸ナトリウムで乾燥後、減圧乾燥し、得られた残渣をシリカゲルカラム(ヘキサンのみ〜ヘキサン：酢酸エチル＝２：１)にて精製し、目的物(7.10g, 80%)を得た。
¹H-NMR (CDCl₃) δ 3.60 (br d, J=6.0Hz, 2H), 5.11-5.24 (m, 2H), 6.03 (m, 1H), 7.07-7.15 (m, 2H), 7.20 (m, 1H), 7.31-7.43 (m, 4H), 7.73 (dd, J=1.2, 8.6Hz, 1H), 7.91 (s, 1H)

（参考例２２）

Phosphorus oxychloride (27.81 g, 182 mmol) was ice-cooled, and N, N′-dimethylformamide (3.33 ml, 43 mmol) was slowly added dropwise. After 15 minutes, the compound obtained in Reference Example 20 (8.04 g, 30 mmol) was added in small portions. After adding the raw materials, the reaction solution was heated to 80 ° C. and stirred for 3 hours. The reaction mixture was cooled, poured slowly into ice, and stirred at room temperature for 2 hours. The reaction solution was extracted with chloroform three times. After drying over sodium sulfate and drying under reduced pressure, the resulting residue was purified with a silica gel column (hexane only to hexane: ethyl acetate = 2: 1) to obtain the desired product (7.10 g, 80%).
¹ H-NMR (CDCl ₃ ) δ 3.60 (br d, J = 6.0Hz, 2H), 5.11-5.24 (m, 2H), 6.03 (m, 1H), 7.07-7.15 (m, 2H), 7.20 (m , 1H), 7.31-7.43 (m, 4H), 7.73 (dd, J = 1.2, 8.6Hz, 1H), 7.91 (s, 1H)

(Reference Example 22)

参考例２１で得た化合物(7.10g, 24mmol)と酢酸（80ml）の混合物を3時間加熱還流した。冷却後、酢酸を減圧留去し、得られた結晶をろ取、エーテルで洗浄し、目的物（5.56g, 83%）を得た。
¹H-NMR (CDCl₃) δ 3.34 (dd, J=1.2, 6.6 Hz, 2H), 5.12-5.22 (m, 2H), 6.00 (m, 1H), 6.86 (dd, J=2.2, 8.6 Hz, 1H), 6.91 (d, J=2.2Hz, 1H), 7.05-7.11 (m, 2H), 7.18 (m, 1H), 7.34-7.44 (m, 2H), 7.45 (d, J=8.6Hz, 1H), 7.57 (s, 1H), 11.77 (br s, 1H)

（参考例２３）

A mixture of the compound obtained in Reference Example 21 (7.10 g, 24 mmol) and acetic acid (80 ml) was heated to reflux for 3 hours. After cooling, acetic acid was distilled off under reduced pressure, and the resulting crystals were collected by filtration and washed with ether to obtain the desired product (5.56 g, 83%).
¹ H-NMR (CDCl ₃ ) δ 3.34 (dd, J = 1.2, 6.6 Hz, 2H), 5.12-5.22 (m, 2H), 6.00 (m, 1H), 6.86 (dd, J = 2.2, 8.6 Hz, 1H), 6.91 (d, J = 2.2Hz, 1H), 7.05-7.11 (m, 2H), 7.18 (m, 1H), 7.34-7.44 (m, 2H), 7.45 (d, J = 8.6Hz, 1H ), 7.57 (s, 1H), 11.77 (br s, 1H)

(Reference Example 23)

窒素雰囲気下、参考例２２で得た化合物(2.50g, 9mmol)をＮ，Ｎ’−ジメチルホルムアミド(45ml)に懸濁し、氷冷下、水素化ナトリウム(396mg, 60% in oil, 9.9mmol)を加えた。10分後、臭化リチウム（1.55g, 18mmol）を加え15分撹拌した。2-ブロモエチルエチルエーテル（2.75g, 18mmol）を添加し20分撹拌後、反応液を70℃で3時間撹拌した。水を加え反応停止後、酢酸エチルで抽出した。有機層を水洗、乾燥、濃縮し、残渣をシリカゲルカラム（ヘキサン：酢酸エチル=10:1〜2:1）で精製し、目的物(2.42g, 77%)とO−アルキル体(0.33g, 11%)を得た。
¹H-NMR (CDCl₃) δ 1.10 (t, J=6.8Hz, 3H), 3.38 (dd, J=1.3, 6.8Hz, 2H), 3.45 (quart, J=6.8Hz, 2H), 3.70 (t, J =6.3Hz, 2H), 4.39 (t, J=6.3Hz, 2H), 5.15-5.24 (m, 2H), 6.02 (m, 1H), 6.85 (dd, J=2.2, 8.5Hz, 1H), 7.03-7.09 (m, 2H), 7.13-7.20 (m, 2H), 7.33-7.42 (m, 2H), 7.45 (d, J=8.5Hz, 1H), 7.49 (s, 1H)

（参考例２４）

Under a nitrogen atmosphere, the compound (2.50 g, 9 mmol) obtained in Reference Example 22 was suspended in N, N′-dimethylformamide (45 ml), and sodium hydride (396 mg, 60% in oil, 9.9 mmol) was cooled with ice. Was added. After 10 minutes, lithium bromide (1.55 g, 18 mmol) was added and stirred for 15 minutes. 2-Bromoethyl ethyl ether (2.75 g, 18 mmol) was added and stirred for 20 minutes, and then the reaction solution was stirred at 70 ° C. for 3 hours. Water was added to stop the reaction, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried and concentrated, and the residue was purified with a silica gel column (hexane: ethyl acetate = 10: 1 to 2: 1). 11%).
¹ H-NMR (CDCl ₃ ) δ 1.10 (t, J = 6.8Hz, 3H), 3.38 (dd, J = 1.3, 6.8Hz, 2H), 3.45 (quart, J = 6.8Hz, 2H), 3.70 (t , J = 6.3Hz, 2H), 4.39 (t, J = 6.3Hz, 2H), 5.15-5.24 (m, 2H), 6.02 (m, 1H), 6.85 (dd, J = 2.2, 8.5Hz, 1H) , 7.03-7.09 (m, 2H), 7.13-7.20 (m, 2H), 7.33-7.42 (m, 2H), 7.45 (d, J = 8.5Hz, 1H), 7.49 (s, 1H)

(Reference Example 24)

窒素雰囲気下、参考例２３で得た化合物（1.05g, 3mmol）のテトラヒドロフラン溶液に、ボラン (1.0Mテトラヒドロフラン溶液3.50ml, 3.5mmol)をゆっくり加え、室温で3時間撹拌した。3N水酸化ナトリウム溶液(1.5 ml, 4.5mmol)をゆっくり加え、60℃で2時間撹拌した。反応溶液を0℃に冷却し、30％過酸化水素水溶液を内温が30〜50℃になるように加え、50℃で2時間撹拌した。反応液に20％亜硫酸水素ナトリウムを加え、エーテルにて抽出した。有機層を飽和食塩水で洗浄後、硫酸ナトリウムにて乾燥し、減圧濃縮した。残渣をシリカゲルカラム(ヘキサン：酢酸エチル＝１:１〜酢酸エチルのみ)にて精製し、目的物(0.43g, 39%)を得た。
¹H-NMR (CDCl₃) δ 1.10 (t, J=7.0Hz, 3H), 1.81-1.93 (m, 2H), 2.77 (t, J=7.0Hz, 2H), 3.44 (quart, J=7.0Hz, 2H), 3.47 (m, 1H), 3.56-3.64 (m, 2H), 3.70 (t, J=6.0Hz, 2H), 4.41 (t, J=6.0Hz, 2H), 6.78 (dd, J=2.2, 8.6Hz, 1H), 7.03-7.10 (m, 2H), 7.14-7.22 (m, 2H), 7.35-7.42 (m, 2H), 7.46 (d, J=8.6Hz, 1H), 7.57 (1H, s)

（参考例２５）

Under a nitrogen atmosphere, borane (1.0 M tetrahydrofuran solution 3.50 ml, 3.5 mmol) was slowly added to a tetrahydrofuran solution of the compound obtained in Reference Example 23 (1.05 g, 3 mmol), and the mixture was stirred at room temperature for 3 hours. 3N sodium hydroxide solution (1.5 ml, 4.5 mmol) was slowly added and stirred at 60 ° C. for 2 hours. The reaction solution was cooled to 0 ° C., a 30% aqueous hydrogen peroxide solution was added so that the internal temperature was 30 to 50 ° C., and the mixture was stirred at 50 ° C. for 2 hours. 20% sodium bisulfite was added to the reaction mixture, and the mixture was extracted with ether. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column (hexane: ethyl acetate = 1: 1 to ethyl acetate only) to obtain the desired product (0.43 g, 39%).
¹ H-NMR (CDCl ₃ ) δ 1.10 (t, J = 7.0Hz, 3H), 1.81-1.93 (m, 2H), 2.77 (t, J = 7.0Hz, 2H), 3.44 (quart, J = 7.0Hz , 2H), 3.47 (m, 1H), 3.56-3.64 (m, 2H), 3.70 (t, J = 6.0Hz, 2H), 4.41 (t, J = 6.0Hz, 2H), 6.78 (dd, J = 2.2, 8.6Hz, 1H), 7.03-7.10 (m, 2H), 7.14-7.22 (m, 2H), 7.35-7.42 (m, 2H), 7.46 (d, J = 8.6Hz, 1H), 7.57 (1H , s)

(Reference Example 25)

窒素雰囲気下、−70℃にて二塩化オキサリル（123μl, 1.41mmol）の無水ジクロロメタン溶液(5ml)に、ジメチルスルホキシド (216μl, 3.04mmol)を内温が−60℃以下になるような速度で加え、−70℃で30分撹拌した。参考例２４で得た化合物(430mg, 1.17 mmol)の無水ジクロロメタン溶液(1.5 ml)を内温が−60℃以下になるような速度で加え、−70℃で１時間撹拌した。トリエチルアミン(815μl, 5.85mmol) を内温が−60℃以下になるような速度で加え、室温で20分間撹拌した。反応液に水を加え10分撹拌後、分液した。水層をジクロロメタンで抽出し、有機層を併せ硫酸ナトリウムにて乾燥し、減圧濃縮した。残渣をシリカゲルカラム(ヘキサン：酢酸エチル＝１０:１〜２：１)にて精製し、目的物(0.36g, 84%)を得た。
¹H-NMR (CDCl₃) δ 1.11 (t, J=7.0Hz, 3H), 2.81-2.88 (m, 2H), 2.91-2.98 (m, 2H), 3.45 (quart, J=7.0Hz, 2H), 3.69 (t, J=6.1Hz, 2H), 4.38 (t, J=6.1Hz, 2H), 6.85 (dd, J=2.2, 8.6Hz, 1H), 7.03-7.09 (m, 2H), 7.14-7.21 (m, 2H), 7.34-7.42 (m, 2H), 7.45 (d, J=8.6Hz, 1H), 7.56 (s, 1H), 9.84 (t, J=1.3Hz, 1H)

実施例６４

Add dimethylsulfoxide (216 μl, 3.04 mmol) to oxalyl dichloride (123 μl, 1.41 mmol) in anhydrous dichloromethane (5 ml) at −70 ° C. under a nitrogen atmosphere at such a rate that the internal temperature becomes −60 ° C. or lower. The mixture was stirred at −70 ° C. for 30 minutes. An anhydrous dichloromethane solution (1.5 ml) of the compound (430 mg, 1.17 mmol) obtained in Reference Example 24 was added at such a rate that the internal temperature became −60 ° C. or lower, and the mixture was stirred at −70 ° C. for 1 hour. Triethylamine (815 μl, 5.85 mmol) was added at such a rate that the internal temperature was −60 ° C. or lower, and the mixture was stirred at room temperature for 20 minutes. Water was added to the reaction solution and the mixture was stirred for 10 minutes and then separated. The aqueous layer was extracted with dichloromethane, and the organic layers were combined, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by a silica gel column (hexane: ethyl acetate = 10: 1 to 2: 1) to obtain the desired product (0.36 g, 84%).
¹ H-NMR (CDCl ₃ ) δ 1.11 (t, J = 7.0Hz, 3H), 2.81-2.88 (m, 2H), 2.91-2.98 (m, 2H), 3.45 (quart, J = 7.0Hz, 2H) , 3.69 (t, J = 6.1Hz, 2H), 4.38 (t, J = 6.1Hz, 2H), 6.85 (dd, J = 2.2, 8.6Hz, 1H), 7.03-7.09 (m, 2H), 7.14- 7.21 (m, 2H), 7.34-7.42 (m, 2H), 7.45 (d, J = 8.6Hz, 1H), 7.56 (s, 1H), 9.84 (t, J = 1.3Hz, 1H)

Example 64

 (S) -2- {3- [1- (2-Ethoxy-ethyl) -2-oxo-7-phenoxy-1,2-dihydro-quinolin-3-yl] -propylamino} -propionamide

参考例２５で得られた化合物を原料に用いて、実施例１と同様の方法により、目的物を得た。
¹H-NMR (CDCl₃) δ 1.11 (t, J=6.8Hz, 3H), 1.35 (d, J=6.8Hz, 3H), 1.85 (quintet, J=7.1Hz, 2H), 2.39 (br s, 1H), 2.61-2.79 (m, 4H), 3.23 (quart, J=6.8Hz, 1H), 3.45 (quart, J=6.8Hz, 2H), 3.69 (t, J=6.2Hz, 2H), 4.39 (t, J=6.2Hz, 2H), 5.78 (br s, 1H), 6.86 (dd, J=1.9, 8.6Hz, 1H), 7.06 (d, J=7.9Hz, 2H), 7.14-7.21 (m, 2H), 7.31 (br s, 1H), 7.38 (t, J=7.9Hz, 2H), 7.45 (d, J=8.6Hz, 1H), 7.51 (s, 1H)

実施例６５

The target product was obtained in the same manner as in Example 1 using the compound obtained in Reference Example 25 as a raw material.
¹ H-NMR (CDCl ₃ ) δ 1.11 (t, J = 6.8Hz, 3H), 1.35 (d, J = 6.8Hz, 3H), 1.85 (quintet, J = 7.1Hz, 2H), 2.39 (br s, 1H), 2.61-2.79 (m, 4H), 3.23 (quart, J = 6.8Hz, 1H), 3.45 (quart, J = 6.8Hz, 2H), 3.69 (t, J = 6.2Hz, 2H), 4.39 ( t, J = 6.2Hz, 2H), 5.78 (br s, 1H), 6.86 (dd, J = 1.9, 8.6Hz, 1H), 7.06 (d, J = 7.9Hz, 2H), 7.14-7.21 (m, 2H), 7.31 (br s, 1H), 7.38 (t, J = 7.9Hz, 2H), 7.45 (d, J = 8.6Hz, 1H), 7.51 (s, 1H)

Example 65

1- (2-Ethoxy-ethyl) -3- [3- (4-fluoro-benzylamino) -propyl] -7-phenoxy-1H-quinolin-2-one

参考例２５で得られた化合物を原料に用いて、実施例１と同様の方法により、目的物を得た。
¹H-NMR (CDCl₃) δ 1.10 (t, J=6.8Hz, 3H), 2.00 (quintet, J=6.9Hz, 2H), 2.69 (t, J=6.9Hz, 2H), 2.78 (t, J=6.9Hz, 2H), 3.44 (quart, J=6.8Hz, 2H), 3.67 (d, J=6.0Hz, 2H), 3.89 (s, 2H), 4.37 (t, J=6.0Hz, 2H), 4.52 (br s, 1H), 6.86 (dd, J=1.5, 8.6Hz, 1H), 6.96-7.10 (m, 4H), 7.15-7.22 (m, 2H), 7.32-7.49 (m, 5H), 7.54 (s, 1H)

（参考例２６）

The target product was obtained in the same manner as in Example 1 using the compound obtained in Reference Example 25 as a raw material.
¹ H-NMR (CDCl ₃ ) δ 1.10 (t, J = 6.8Hz, 3H), 2.00 (quintet, J = 6.9Hz, 2H), 2.69 (t, J = 6.9Hz, 2H), 2.78 (t, J = 6.9Hz, 2H), 3.44 (quart, J = 6.8Hz, 2H), 3.67 (d, J = 6.0Hz, 2H), 3.89 (s, 2H), 4.37 (t, J = 6.0Hz, 2H), 4.52 (br s, 1H), 6.86 (dd, J = 1.5, 8.6Hz, 1H), 6.96-7.10 (m, 4H), 7.15-7.22 (m, 2H), 7.32-7.49 (m, 5H), 7.54 (s, 1H)

(Reference Example 26)

参考例２３で得た化合物（349mg, 1mmol）のメタノール溶液に、−70℃でオゾンを導入しながら30分間撹拌した。反応液にジメチルスルフィド(2.0ml, 27mmol)を加え、室温で２時間撹拌した。反応液に水を加え、酢酸エチルにて抽出した。水層を酢酸エチルで抽出し、有機層を併せた。有機層を20％亜硫酸水素ナトリウムで洗浄後、硫酸ナトリウムにて乾燥し、減圧濃縮した。残渣をシリカゲルカラム(クロロホルムのみ〜クロロホルム：メタノール＝９：１)にて精製しアルデヒド体を得た。

実施例６６

The methanol solution of the compound obtained in Reference Example 23 (349 mg, 1 mmol) was stirred for 30 minutes while introducing ozone at −70 ° C. Dimethyl sulfide (2.0 ml, 27 mmol) was added to the reaction solution, and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The aqueous layer was extracted with ethyl acetate and the organic layers were combined. The organic layer was washed with 20% sodium bisulfite, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified with a silica gel column (chloroform only to chloroform: methanol = 9: 1) to obtain an aldehyde form.

Example 66

 (S) -2- {2- [1- (2-Ethoxy-ethyl) -2-oxo-7-phenoxy-1,2-dihydro-quinolin-3-yl] -ethylamino} -propionamide

参考例２６で得た化合物（176mg, 0. 5mmol）をジクロロメタン(2ml)に溶かし、室温で（L）-アラニンアミド塩酸塩（62mg, 0.5mmol）を加え、10分間撹拌した。トリアセトキシ水素化ホウ素ナトリウム(159mg, 0.75mmol)を加え７０時間撹拌後、反応液に飽和炭酸水素ナトリウム水溶液を加え、ジクロロメタンで抽出した。有機層を水洗、乾燥、濃縮し、残渣をシリカゲル分取TLC（クロロホルム：メタノール=6:1）で精製し、目的物(24mg, 11%)を得た。
¹H-NMR (CDCl₃) δ 1.10 (t, J=7.1Hz, 3H), 1.33 (d, J=7.0Hz, 3H), 2.65 (br s, 1H), 2.81 (t, J=6.8Hz, 2H), 2.87-3.02 (m, 2H), 3.28 (quart, J=7.0Hz, 1H), 3.44 (quart, J=7.1Hz, 2H), 3.69 (t, J=6.1Hz, 2H), 4.38 (t, J=6.1Hz, 2H), 5.75 (br s, 1H), 6.86 (dd, J=2.0, 8.6Hz, 1H), 7.07 (d, J=7.9Hz, 2H), 7.13-7.24 (m, 3H), 7.38 (t, J=7.9Hz, 2H), 7.45 (d, J=8.6Hz, 1H), 7.53 (s, 1H)

The compound obtained in Reference Example 26 (176 mg, 0.5 mmol) was dissolved in dichloromethane (2 ml), (L) -alaninamide hydrochloride (62 mg, 0.5 mmol) was added at room temperature, and the mixture was stirred for 10 minutes. Sodium triacetoxyborohydride (159 mg, 0.75 mmol) was added and stirred for 70 hours, and then saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with water, dried and concentrated, and the residue was purified by silica gel preparative TLC (chloroform: methanol = 6: 1) to obtain the desired product (24 mg, 11%).
¹ H-NMR (CDCl ₃ ) δ 1.10 (t, J = 7.1Hz, 3H), 1.33 (d, J = 7.0Hz, 3H), 2.65 (br s, 1H), 2.81 (t, J = 6.8Hz, 2H), 2.87-3.02 (m, 2H), 3.28 (quart, J = 7.0Hz, 1H), 3.44 (quart, J = 7.1Hz, 2H), 3.69 (t, J = 6.1Hz, 2H), 4.38 ( t, J = 6.1Hz, 2H), 5.75 (br s, 1H), 6.86 (dd, J = 2.0, 8.6Hz, 1H), 7.07 (d, J = 7.9Hz, 2H), 7.13-7.24 (m, 3H), 7.38 (t, J = 7.9Hz, 2H), 7.45 (d, J = 8.6Hz, 1H), 7.53 (s, 1H)

(Test Example 1)
Inhibition experiment of human SNS gene-expressing cells against TTX-resistant Na channel Human SNS gene-expressing cells are obtained by incorporating the human SNS gene into a Chinese hamster ovary cell (CHO-K1) and stably expressing it, originally CHO-K1 cells Has no TTX-resistant Na channel component, the TTX-resistant Na channel component in human SNS gene-expressing cells is SNS. Therefore, it was considered that the compound of the present invention is an SNS inhibitor.
1) Construction of human SNS-expressing cells and confirmation of SNS function expression The full length of the human SNSα subunit gene is incorporated into an expression plasmid (pcDNA3.1Zeo (+)) containing the Zeocin resistance gene, and the full length of the Annexin II light chain gene is Neomycin. It was introduced into a resistance gene-containing expression plasmid (pcDNA3.1 (+)). These two genes were simultaneously introduced into CHO-K1 cells using lipofectamine 2000, cultured in F-12 medium containing Neomycin and Zeocin, and both drug-resistant cells, that is, cells into which both genes had been incorporated were selected. . Both of these drug-resistant strains were subjected to limiting dilution twice and the SNS gene-incorporated cells were cloned. The introduction of SNS was confirmed by RT-PCR, and a TTX resistance component responding to Na channel stimulation was detected using a membrane potential sensing fluorescent indicator to confirm the functional expression of SNS.
2) Pharmacological effect of human SNS gene-expressing cells on TTX-resistant Na channel Using the human SNS-expressing cells obtained in 1 above, the SNS inhibitory action of the compound of the present invention was evaluated. That is, a test compound is added to human SNS-expressing cells in advance, and approximately 30 minutes later, veratridine (50 μM), a Na channel stimulator, is added in the presence of TTX (1 μM), and TTX-resistant Na channels are added. The membrane potential was increased, and the inhibitory effect on the membrane potential increase of the test compound was evaluated.
3) Pharmacological evaluation method The SNS inhibition rate of the test compound was determined by the following formula.
SNS inhibition rate (%) = 100 × [(peak value of veratridine stimulation only without evaluation compound) − (peak value of veratridine stimulation with evaluation compound)] / [(peak value of veratridine stimulation only without evaluation compound)] -(Reference value without stimulation)]
4) Test results As a result of evaluating the inhibitory action (SNS inhibition rate) on the TTX-resistant Na channel of human SNS-expressing cells for the compounds obtained in the Examples, the compounds of the present invention were obtained as shown in Tables 16 to 18 below. It was observed to show SNS inhibitory action.

  The novel 2-quinolone derivative according to the present invention is an excellent therapeutic agent for pathological conditions involving SNS, specifically, diseases such as neuropathic pain, nociceptive pain, dysuria, or multiple sclerosis. Or it can be used as a preventive agent.

Claims (12)

Formula (1):

[Wherein, R ¹ represents a halogen atom, a cyano group, a nitro group, a carboxyl group, an alkyl group having 1 to 4 carbon atoms, a haloalkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, or 1 carbon atom. Substituted with 1 to 4 haloalkoxy groups, 1 to 4 alkylthio groups, 2 to 4 alkoxycarbonyl groups, 2 to 4 alkylcarbonyl groups, one or the same or different alkyl groups. An amino group optionally represented by the formula: -L ¹ -R ¹⁰ [wherein L ¹ is a single bond, -O-, -OCH _2- , or a formula: -N (R ¹¹ )-(wherein R ¹¹ represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms.), And R ¹⁰ represents a substituted or unsubstituted saturated or unsaturated aliphatic heterocyclic group, a substituted or unsubstituted phenyl group. Or a substituted or unsubstituted aromatic heterocyclic group. Represents a group represented by
R ² is a hydrogen atom, a halogen atom, a cyano group, a nitro group, a carboxyl group, an alkyl group having 1 to 4 carbon atoms, a haloalkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, or 1 to carbon atoms. 4 haloalkoxy groups, an alkylthio group having 1 to 4 carbon atoms, an alkoxycarbonyl group having 2 to 4 carbon atoms, an alkylcarbonyl group having 2 to 4 carbon atoms, and one or two identical or different alkyl groups. An amino group which may be represented by the formula: -L ² -R ¹² [wherein L ² is a single bond, —O—, —OCH ₂ —, or a formula: —N (R ¹³ ) — (where R ¹³ represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms.), R ¹² represents a substituted or unsubstituted saturated or unsaturated aliphatic heterocyclic group, a substituted or unsubstituted phenyl group, Or a substituted or unsubstituted aromatic heterocyclic group Or a group represented by
Or R < ¹ > and R < ² > may combine to form a 5- to 7-membered ring.
m represents an integer of 0 to 5.
R ⁷ represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms.
R ³ and R ⁴ are independently hydrogen atom, substituted or unsubstituted alkyl group, haloalkyl group, substituted or unsubstituted alkenyl group, substituted or unsubstituted alkynyl group, substituted or unsubstituted cycloalkyl group, substituted Or an unsubstituted cycloalkenyl group, a substituted or unsubstituted saturated or unsaturated aliphatic heterocyclic group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted aromatic heterocyclic group, or R ³ And R ⁴ together with the nitrogen atom to which they are bonded may form a substituted or unsubstituted 5- to 10-membered saturated or unsaturated nitrogen-containing aliphatic heterocycle, and the nitrogen-containing aliphatic The heterocycle contains 0 to 2 oxygen atoms, 0 to 2 sulfur atoms, and 1 to 3 nitrogen atoms.
R ⁸ and R ⁹ independently represent a hydrogen atom, a fluorine atom, or an alkyl group having 1 to 6 carbon atoms, or R ⁸ and R ⁹ are bonded together with the carbon atom to which they are bonded to 3 to 7 A membered cycloalkane may be formed.
n represents an integer of 1 to 6, and the plurality of R ⁸ and the plurality of R ⁹ may be independently the same or different.
A is the following (a) to (c):
(A) a fluorine atom;
(B) Formula: a group represented by —OR ¹⁴ wherein R ¹⁴ is a hydrogen atom, a substituted or unsubstituted alkyl group, a haloalkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted saturation Or an unsaturated aliphatic heterocyclic group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted aromatic heterocyclic group, or R ¹⁴ and one R ⁸ are bonded to form a 4- to 7-membered A saturated or unsaturated oxygen-containing aliphatic heterocyclic ring may be formed. ];
(C) Formula: —N (R ⁵ ) —L ³ —R ⁶ [wherein L ³ is —C (═O) —, —S (═O) ₂ —, or —C (= O) represents O-.
R ⁵ represents a hydrogen atom, a substituted or unsubstituted alkyl group, or a haloalkyl group,
R ⁶ represents a substituted or unsubstituted alkyl group, a haloalkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted saturated or unsaturated aliphatic heterocyclic group, a substituted or unsubstituted aryl group, substituted or unsubstituted It represents an unsubstituted aromatic heterocyclic group, or a substituted or unsubstituted amino group, or a substituted or unsubstituted ⁵ -N-L ³ — with which R ⁵ and R ⁶ are bonded to each other. Whether to form an 8-membered saturated or unsaturated nitrogen-containing aliphatic heterocyclic ring, or R ⁵ and one R ⁸ combine to form a 5- to 10-membered saturated or unsaturated nitrogen-containing aliphatic heterocyclic ring Alternatively, R ⁶ and one R ⁸ may combine to form a 5- to 8-membered saturated or unsaturated nitrogen-containing aliphatic heterocycle.
Provided that when R ⁶ is to represent a substituted or unsubstituted amino group, L ³ is -C (= O) - or -S (= O) ₂ - a. ]
Represents a group selected from: ]
Or a pharmaceutically acceptable salt thereof. R ¹ is a halogen atom, an alkyl group having 1 to 4 carbon atoms, a haloalkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, a haloalkoxy group having 1 to 4 carbon atoms, one, or the same or different An amino group which may be substituted with two alkyl groups, or the formula: -L ¹ -R ¹⁰ [wherein L ¹ and R ¹⁰ are as defined in claim 1; R ² is a hydrogen atom, a halogen atom, an alkyl group having 1 to 4 carbon atoms, a haloalkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, or 1 to carbon atoms. 4 haloalkoxy groups, an amino group optionally substituted by one or two identical or different alkyl groups, or a formula: -L ² -R ^{12 wherein} L ² and R ¹² are It is synonymous with. The compound of Claim 1 showing the group represented by this, or its pharmacologically acceptable salt. R ¹ is a halogen atom, an alkoxy group having 1 to 4 carbon atoms, a haloalkoxy group having 1 to 4 carbon atoms, or a formula: -L ¹ -R ^{10 wherein} L ¹ and R ¹⁰ are It is synonymous. R ² is a hydrogen atom, a halogen atom, an alkoxy group having 1 to 4 carbon atoms, a haloalkoxy group having 1 to 4 carbon atoms, or a formula: -L ² -R ¹² [wherein , L ² and R ¹² are as defined in claim 1. The compound of Claim 1 or 2 showing the group represented by this, or its pharmacologically acceptable salt. m represents an integer of 0 to 2, R ⁷ represents a hydrogen atom, the compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof. n represents an integer of 2-3, a plurality of R ⁸ and a plurality of R ⁹ is independently a hydrogen atom, a fluorine atom or an alkyl group having 1 to 6 carbon atoms, any one of the preceding claims Or a pharmaceutically acceptable salt thereof.   The compound as described in any one of Claims 1-5 whose A represents a fluorine atom, or its pharmaceutically acceptable salt. A is a formula: —OR ^{14 wherein} R ¹⁴ has the same meaning as in claim 1. ] The compound or its pharmaceutically acceptable salt as described in any one of Claims 1-5 which is group represented by these. A represents the formula: —N (R ⁵ ) —L ³ —R ^{6 wherein} R ⁵ , L ³ and R ⁶ are as defined in claim 1. ] The compound or its pharmaceutically acceptable salt as described in any one of Claims 1-5 which is group represented by these. Formula (2):

[Wherein R ¹ , R ² , R ⁷ , R ⁸ , R ⁹ , A, m, and n are as defined in claim 1;
p represents an integer of 1 to 4,
R ^4a represents a hydrogen atom or an alkyl group,
R ¹⁴ represents a substituted or unsubstituted aryl group, a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted amino group, or a substituted or unsubstituted carbamoyl group. ]
The compound as described in any one of Claims 1-8 represented by these, or its pharmaceutically acceptable salt.   The pharmaceutical which contains the compound or its pharmaceutically acceptable salt as described in any one of Claims 1-9 as an active ingredient.   The SNS inhibitor which contains the compound as described in any one of Claims 1-9, or its pharmacologically acceptable salt as an active ingredient.   A therapeutic agent for neuropathic pain, nociceptive pain, dysuria, or multiple sclerosis comprising the compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof as an active ingredient. Or prophylactic drugs.