JPH1180156A - 1-(substitutedaryl)alkyl-1h-imidazopyridin-4-amine derivative - Google Patents

1-(substitutedaryl)alkyl-1h-imidazopyridin-4-amine derivative

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Publication number
JPH1180156A
JPH1180156A JP25592697A JP25592697A JPH1180156A JP H1180156 A JPH1180156 A JP H1180156A JP 25592697 A JP25592697 A JP 25592697A JP 25592697 A JP25592697 A JP 25592697A JP H1180156 A JPH1180156 A JP H1180156A
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Prior art keywords
ethyl
imidazo
phenyl
1h
quinolin
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Japanese (ja)
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Makoto Aoyama
Hideo Kato
Jun Sakaguchi
Katsutoshi Tsubouchi
日出男 加藤
順 坂口
勝俊 坪内
真 青山
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Hokuriku Seiyaku Co Ltd
北陸製薬株式会社
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Priority to JP25592697A priority Critical patent/JPH1180156A/en
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Abstract

PROBLEM TO BE SOLVED: To provide the subject new compound inducing the biosynthesis of interferon and useful as an antiviral agent and carcinostatic agent. SOLUTION: The objective compound is expressed by formula I [R<1> is COR<7> , SO2 NR<8> R<9> , NR<10> R<11> , etc., (R<7> is OH, an alkyl or an alkoxy; R<8> and R<9> are each H or an alkyl; R<10> is H, an alkyl, etc.; R<11> is H, an alkyl, an alkanesulfonyl, etc.); (m) is 0-1; (n) is 1-3; X is an alkylene chain or a carbon chain of the formula; CH=CH; Y is S or a carbon chain of the formula CH=CH; the combination of dotted line and solid line is single bond or double bond], e.g. 1-[2-[4-(1-aminoethyl)phenyl]ethyl]-1H-imidazo[4,5-c]quinolin-4-amine. The compound of the formula I can be produced from a compound of formula II through 7 steps. It is extremely useful for the treatment of diseases caused by viruses such as rheumatic arthritis, verruca, hepatitis B and hepatitis C, cancer and other neoplastic diseases.

Description

【発明の詳細な説明】 DETAILED DESCRIPTION OF THE INVENTION

【0001】 [0001]

【発明の属する技術分野】本発明はインターフェロンの生合成を誘導し、抗ウイルス剤又は抗癌剤として有用である新規な1−(置換アリール)アルキル−1H−イミダゾピリジン−4−アミン誘導体、又はその薬理学的に許容しうる塩に関するものである。 The present invention relates to induce the biosynthesis of interferon, the novel 1- (substituted aryl) alkyl -1H- imidazo-4-amine derivatives useful as antiviral or anticancer agent, or a drug it relates salts pharmacologically acceptable.

【0002】 [0002]

【従来の技術】1H−イミダゾピリジン−4−アミン骨格を有する化合物としては、特開昭60−123488 Examples of the compound having the Related Art 1H- imidazopyridine-4-amine skeleton, JP 60-123488
号に抗ウイルス作用を有する化合物として、1−イソブチル−1H−イミダゾ〔4,5−c〕キノリン−4−アミン(一般名:imiquimod ,イミキモド), 1−(2− No. to as compounds having antiviral activity, 1-isobutyl--1H- imidazo [4,5-c] quinolin-4-amine (common name: imiquimod, imiquimod), 1- (2-
フェニルエチル)−1H−イミダゾ〔4,5−c〕キノリン−4−アミン等が開示されているが、本発明に係る様な1位のアリールアルキル基の芳香環上にスルファモイル基,カルバモイル基,アミノ基, アミド基,スルホンアミド基,シアノ基,カルボキシル基,ウレイド基, Phenylethyl)-1H-but-imidazo [4,5-c] quinolin-4-amine is disclosed, an aromatic ring on a sulfamoyl group arylalkyl group such position 1 according to the present invention, a carbamoyl group, amino group, an amido group, a sulfonamido group, a cyano group, a carboxyl group, a ureido group,
チオウレイド基,ヒドロキシイミノメチル基又は水酸基等の官能基を持った置換基を有する1H−イミダゾピリジン−4−アミン誘導体はこれまで全く知られていない。 Thioureido group, 1H-imidazopyridine-4-amine derivative having a substituent having a functional group such as a hydroxyiminomethyl group or a hydroxyl group has not been known at all so far.

【0003】 [0003]

【発明が解決しようとする課題】前述のイミキモドにはインターフェロンの生合成を誘導する作用のあることが、ジャーナル・オブ・インターフェロン・リサ−チ(Journal of Interferon Research),14巻,81頁(1994年)等で知られており、その他に同様の作用を有する化合物として、2−アミノ−5−ブロモ−6− [SUMMARY OF THE INVENTION] It is the aforementioned imiquimod of action of inducing the biosynthesis of interferon, Journal of Interferon Lisa - Chi (Journal of Interferon Research), 14 vol., 81 pp. (1994 known in years) or the like, as a compound other to have the same action, 2-amino-5-bromo-6-
フェニル−4(3H)−ピリミジノン(一般名:bropir Phenyl -4 (3H) - pyrimidinone (common name: Bropir
imine ,ブロピリミン)〔ジャーナル・オブ・メディシナル・ケミストリー(Journal of Medicinal Chemistr imine, bropirimine) [Journal of Medicinal Chemistry (Journal of Medicinal Chemistr
y),23巻,237頁(1980年)〕や、2,7− y), 23 vol., 237 (1980)] and, 2,7
ビス〔2−(ジエチルアミノ)エトキシ〕−9H−フルオレン−9−オン(一般名:tilorone,チロロン)〔ザ・メルク・インデックス(The Merck Index ),12 Bis [2- (diethylamino) ethoxy] -9H- fluoren-9-one (common name: tilorone, tilorone) [The Merck Index (The Merck Index), 12
版,9581〕等が知られているが、未だその活性は十分なものとは言えないのが現状である。 Edition, although 9581] and the like have been known, at present, it can not be said yet what the activity is sufficient.

【0004】本発明の課題は、優れたインターフェロン誘導能を有し、リウマチ性関節炎,いぼ,B型肝炎,C An object of the present invention has excellent interferon-inducing ability, rheumatoid arthritis, warts, B hepatitis, C
型肝炎等のウイルスの関与に起因する疾患及び癌やその他の腫瘍性疾患に有用である新規な化合物を提供することにある。 It is to provide novel compounds useful in diseases and cancer and other neoplastic diseases caused by the involvement of viruses Hepatitis like.

【0005】 [0005]

【課題を解決するための手段】本発明者らは、この様な課題を解決すべく鋭意研究した結果、1位のアリールアルキル基の芳香環上にスルファモイル基,カルバモイル基,アミノ基, アミド基,スルホンアミド基,シアノ基,カルボキシル基,ウレイド基,チオウレイド基,ヒドロキシイミノメチル基又は水酸基等の官能基を持った置換基を有する新規な1−(置換アリール)アルキル− The present inventors Means for Solving the Problems] The intensive research as a result to solve such a problem, the 1-position of the aromatic ring on the sulfamoyl group of the arylalkyl group, a carbamoyl group, an amino group, an amide group , a sulfonamido group, a cyano group, a carboxyl group, a ureido group, a thioureido group, a hydroxyiminomethyl group or novel 1- (substituted aryl) having a substituent group having a functional group such as hydroxyl alkyl -
1H−イミダゾピリジン−4−アミン誘導体、又はその薬理学的に許容しうる塩が優れたインターフェロン誘導能を有することを見出し、本発明を完成させた。 1H- imidazo-4-amine derivative, or found to have interferon inducibility salt superior acceptable its pharmacological, and completed the present invention.

【0006】即ち、本発明は次の一般式(I) [0006] That is, the present invention relates to the following general formula (I)

【化2】 ## STR2 ## (式中、R 1はCOR 7 ,SO 2 NR 89 ,CONR (In the formula, R 1 is COR 7, SO 2 NR 8 R 9, CONR
89 ,NR 1011 ,C(R 12 )=NOHで示される基,水酸基又はシアノ基を、R 2とR 3は同一又は異なって水素原子又は低級アルキル基を表し、R 4は水素原子あるいは1個又は複数個の水酸基,低級アルコキシ基,環状アルキル基もしくはハロゲン原子で置換されても良い炭素数1〜10個の直鎖状又は分枝鎖状アルキル基を表し、R 5は水素原子又は低級アルキル基を、R 6 8 R 9, NR 10 R 11 , C (R 12) = groups represented by NOH, a hydroxyl group or a cyano group, R 2 and R 3 represents a hydrogen atom or a lower alkyl group the same or different, R 4 is hydrogen atoms or one or more hydroxyl, lower alkoxy group, a cyclic alkyl group or substituted by a halogen atom good number 1-10 straight even or branched alkyl group, R 5 is hydrogen the atom or a lower alkyl group, R 6
は水素原子,低級アルキル基,低級アルコキシ基又はハロゲン原子を、R 7は水酸基,低級アルキル基又は低級アルコキシ基を表し、R 8とR 9は同一又は異なって水素原子又は低級アルキル基を、R It is a hydrogen atom, a lower alkyl group, a lower alkoxy group or a halogen atom, R 7 is a hydroxyl group, a lower alkyl group or a lower alkoxy group, a R 8 and R 9 are the same or different and each represents a hydrogen atom or a lower alkyl radical, R 10は水素原子,低級アルキル基,ベンジル基を表し、R 11は水素原子,低級アルキル基,ベンジル基,低級アルカンスルホニル基,低級アルカノイル基,置換もしくは未置換のカルバモイル基,置換もしくは未置換のチオカルバモイル基又は置換もしくは未置換のベンゼンスルホニル基を表し、R 12は水素原子,低級アルキル基を、mは0〜1の整数、nは1〜3の整数を表し、Xは炭素数1〜3個のアルキレン鎖又はCH=CHで示される炭素鎖を表し、Yは硫黄原子又はCH=CHで示される炭素鎖を表し、実線と点線とで示される結合は単結合又は二重結合を表す。 10 is a hydrogen atom, a lower alkyl group, a benzyl group, R 11 is a hydrogen atom, a lower alkyl group, a benzyl group, a lower alkanesulfonyl group, a lower alkanoyl group, a substituted or unsubstituted carbamoyl group, a substituted or unsubstituted thio a carbamoyl group or a substituted or unsubstituted benzenesulfonyl group, R 12 is a hydrogen atom, a lower alkyl group, m is an integer of 0 to 1, n represents an integer of 1 to 3, X is 1 to 3 carbon atoms number of alkylene chains or carbon chain represented by CH = CH, Y represents a carbon chain represented by a sulfur atom or CH = CH, bond represented by the solid line and the dotted line represents a single bond or a double bond. )で示される1−(置換アリール)アルキル−1H−イミダゾピリジン−4−アミン誘導体、又はその薬理学的に許容しうる塩に関するものである。 1- (substituted aryl) alkyl -1H- imidazo-4-amine derivative represented by), or relates to the pharmacologically acceptable salts thereof.

【0007】 [0007]

【発明の実施の形態】前記一般式(I)において、 DETAILED DESCRIPTION OF THE INVENTION In the general formula (I),
2 ,R 3 ,R 5 ,R 6 ,R 7 ,R 8 ,R 9 ,R 10 ,R R 2, R 3, R 5 , R 6, R 7, R 8, R 9, R 10, R
11又はR 12で示される低級アルキル基としては、例えば、メチル基,エチル基,n-プロピル基,イソプロピル基,n-ブチル基,イソブチル基,sec-ブチル基,tert- The lower alkyl group shown by 11, or R 12, for example, a methyl group, an ethyl group, n- propyl group, an isopropyl group, n- butyl group, isobutyl group, sec- butyl group, tert-
ブチル基等が挙げられ、R 4で示される炭素数1〜10 Butyl group and the like, carbon atoms represented by R 4 1 to 10
個の直鎖状あるいは分枝鎖状アルキル基としては、例えば、メチル基,エチル基,n-プロピル基,イソプロピル基,n-ブチル基,イソブチル基,sec-ブチル基,tert- The number of linear or branched alkyl group, e.g., methyl group, ethyl group, n- propyl group, an isopropyl group, n- butyl group, isobutyl group, sec- butyl group, tert-
ブチル基,n-ペンチル基,イソペンチル基,ネオペンチル基,n-ヘキシル基,n-ヘプチル基,n-オクチル基,n- Butyl group, n- pentyl group, isopentyl group, neopentyl group, n- hexyl, n- heptyl, n- octyl, n-
ノニル基,n-デシル基等が挙げられ、当該アルキル基に置換していても良い低級アルコキシ基としては、例えば、メトキシ基,エトキシ基,n-プロポキシ基,イソプロポキシ基,n-ブトキシ基,イソブトキシ基,sec-ブトキシ基,tert- ブトキシ基等が挙げられ、当該アルキル基に置換していても良い環状アルキル基としては、例えば、シクロプロピル基,シクロブチル基,シクロペンチル基,シクロヘキシル基,シクロヘプチル基等が挙げられ、当該アルキル基に置換していても良いハロゲン原子としては、例えば、フッ素原子,塩素原子,臭素原子, Nonyl, n- decyl and the like, and the lower alkoxy group which may be substituted on the alkyl group include a methoxy group, an ethoxy group, n- propoxy group, isopropoxy group, n- butoxy group, isobutoxy, sec- butoxy, tert- butoxy and the like, and good cyclic alkyl group optionally substituted on the alkyl group, for example, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group. Examples of the substituted optionally halogen atom in the alkyl group, for example, a fluorine atom, a chlorine atom, a bromine atom,
ヨウ素原子が挙げられる。 And an iodine atom. 又、R 6又はR 7で示される低級アルコキシ基としては、例えば、メトキシ基,エトキシ基,n-プロポキシ基,イソプロポキシ基,n-ブトキシ基,イソブトキシ基,sec-ブトキシ基,tert- ブトキシ基等が挙げられ、R 6で示されるハロゲン原子としては、例えば、フッ素原子,塩素原子,臭素原子,ヨウ素原子が挙げられる。 As the lower alkoxy group represented by R 6 or R 7, for example, a methoxy group, an ethoxy group, n- propoxy group, isopropoxy group, n- butoxy group, isobutoxy group, sec- butoxy group, tert- butoxy group etc., and the halogen atom represented by R 6, for example, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom. 11で示される低級アルカンスルホニル基としてはメタンスルホニル基,プロパンスルホニル基,ブタンスルホニル基等が挙げられ、R 11で示される低級アルカノイル基としてはアセチル基,プロピオニル基,ブチリル基等が挙げられる。 R 11 in lower alkanesulfonyl The group methanesulfonyl group represented, propanesulfonyl group, butanesulfonyl group and the like, an acetyl group as lower alkanoyl group represented by R 11, a propionyl group, a butyryl group and the like. 又、R 11で示される置換もしくは未置換のカルバモイル基,置換もしくは未置換のチオカルバモイル基又は置換もしくは未置換のベンゼンスルホニル基の置換基としては、例えば、低級アルキル基,低級アルコキシ基又はハロゲン原子等が挙げられる。 As the substituent of the substituted or unsubstituted carbamoyl group, a substituted or unsubstituted thiocarbamoyl group, or a substituted or unsubstituted benzenesulfonyl group represented by R 11, for example, a lower alkyl group, lower alkoxy group or a halogen atom etc. the.

【0008】本発明の前記一般式(I)で示される化合物は、所望に応じて薬理学的に許容しうる塩に変換することも、又は生成した塩から塩基を遊離させることもできる。 [0008] Compounds represented by the above-described general formula (I) of the present invention, pharmaceutically also be converted into acceptable salts, or base may be liberated from the resulting salts if desired.

【0009】本発明の前記一般式(I)で示される化合物の薬理学的に許容しうる塩としては、例えば、酸付加塩が挙げられ、塩酸,臭化水素酸,ヨウ化水素酸,硝酸,硫酸,燐酸等の鉱酸塩、あるいは、酢酸,マレイン酸,フマル酸,クエン酸,シュウ酸,リンゴ酸,メタンスルホン酸,p-トルエンスルホン酸,マンデル酸,10- [0009] Pharmaceutically acceptable salts of the formula (I) compounds represented by the present invention include, for example, include acid addition salts include hydrochloric, hydrobromic, hydroiodic, nitric , sulfuric acid, phosphoric acid and the like mineral or acetic acid, maleic acid, fumaric acid, citric acid, oxalic acid, malic acid, methanesulfonic acid, p- toluenesulfonic acid, mandelic acid, 10
カンファースルホン酸,酒石酸等の有機酸塩が挙げられる。 Camphorsulfonic acid, and organic acids tartaric acid or the like.

【0010】本発明の前記一般式(I)で示される化合物中不斉炭素を有する化合物には、光学異性体が存在し得るが、本発明にはこれら光学活性体及びその混合物も包含される。 [0010] Formula (I) compounds having the asymmetric carbon in the compound represented by the present invention, an optical isomer may exist, it is included also these optically active isomers and their mixtures in the present invention .

【0011】又、本発明の前記一般式(I)で示される化合物又はその薬理学的に許容しうる塩は、製造条件により任意の結晶形として存在することができ、任意の水和物として存在することもできるが、これらの結晶形や水和物及びその混合物も本発明の範囲に包含される。 [0011] Further, the compounds of general formula or acceptable salts thereof pharmacologically represented by (I) of the present invention may exist as any crystal form by the production conditions, as any hydrate It can also be present, even these crystalline forms and hydrates and mixtures thereof are encompassed within the scope of the present invention.

【0012】本発明の1−(置換アリール)アルキル− [0012] The present invention 1- (substituted aryl) alkyl -
1H−イミダゾピリジン−4−アミン誘導体の好ましい態様としては、後述する実施例記載化合物や下記の化合物、又はそれらの薬理学的に許容しうる塩を挙げることができるが、本発明はこれらの例に限定されることはない。 A preferred embodiment of the 1H- imidazo-4-amine derivatives, there may be mentioned compounds of Examples described compounds or below to be described later, or their pharmacologically acceptable salts, the invention of these examples is is it is not limited to. (1) 1−〔2−〔4−(1−アミノエチル)フェニル〕エチル〕−1H−イミダゾ〔4, 5−c〕キノリン−4−アミン (2) 1−〔2−〔4−(1−アミノエチル)フェニル〕エチル〕−2−メチル−1H−イミダゾ〔4, 5− (1) 1- [2- [4- (1-aminoethyl) phenyl] ethyl] -1H- imidazo [4, 5-c] quinolin-4-amine (2) 1- [2- [4- (1 - aminoethyl) phenyl] ethyl] -2-methyl -1H- imidazo [4, 5-
c〕キノリン−4−アミン (3) 1−〔2−〔4−(1−アミノエチル)フェニル〕エチル〕−2−エチル−1H−イミダゾ〔4, 5− c] quinolin-4-amine (3) 1- [2- [4- (1-aminoethyl) phenyl] ethyl] -2-ethyl -1H- imidazo [4, 5-
c〕キノリン−4−アミン (4) 1−〔2−〔4−(1−アミノエチル)フェニル〕エチル〕−2−n-プロピル−1H−イミダゾ〔4, c] quinolin-4-amine (4) 1- [2- [4- (1-aminoethyl) phenyl] ethyl] -2-n-propyl--1H- imidazo [4,
5−c〕キノリン−4−アミン (5) 1−〔2−〔4−(1−アミノエチル)フェニル〕エチル〕−2−n-ブチル−1H−イミダゾ〔4, 5 5-c] quinolin-4-amine (5) 1- [2- [4- (1-aminoethyl) phenyl] ethyl] -2-n-butyl -1H- imidazo [4, 5
−c〕キノリン−4−アミン (6) 1−〔2−〔4−(1−アミノエチル)フェニル〕エチル〕−2−シクロプロピルメチル−1H−イミダゾ〔4, 5−c〕キノリン−4−アミン (7) 1−〔2−〔4−(1−アミノエチル)フェニル〕エチル〕−2−エトキシメチル−1H−イミダゾ〔4, 5−c〕キノリン−4−アミン (8) 1−〔2−〔4−(1−アミノエチル)フェニル〕エチル〕−6, 7, 8, 9−テトラヒドロ−1H− -c] quinolin-4-amine (6) 1- [2- [4- (1-aminoethyl) phenyl] ethyl] -2-cyclopropylmethyl -1H- imidazo [4, 5-c] quinolin-4 amine (7) 1- [2- [4- (1-aminoethyl) phenyl] ethyl] -2-ethoxymethyl--1H- imidazo [4, 5-c] quinolin-4-amine (8) 1- [2 - [4- (1-aminoethyl) phenyl] ethyl] -6, 7, 8, 9-tetrahydro -1H-
イミダゾ〔4, 5−c〕キノリン−4−アミン (9) 1−〔2−〔4−(1−アミノエチル)フェニル〕エチル〕−6, 7, 8, 9−テトラヒドロ−2−メチル−1H−イミダゾ〔4, 5−c〕キノリン−4−アミン (10) 1−〔2−〔4−(1−アミノエチル)フェニル〕エチル〕−2−エチル−6, 7, 8, 9−テトラヒドロ−1H−イミダゾ〔4, 5−c〕キノリン−4−アミン (11) 1−〔2−〔4−(1−アミノエチル)フェニル〕エチル〕−6, 7, 8, 9−テトラヒドロ−2−n- Imidazo [4, 5-c] quinolin-4-amine (9) 1- [2- [4- (1-aminoethyl) phenyl] ethyl] -6, 7, 8, 9-tetrahydro-2-methyl -1H - imidazo [4, 5-c] quinolin-4-amine (10) 1- [2- [4- (1-aminoethyl) phenyl] ethyl] -2-ethyl-6, 7, 8, 9-tetrahydro - 1H- imidazo [4, 5-c] quinolin-4-amine (11) 1- [2- [4- (1-aminoethyl) phenyl] ethyl] -6, 7, 8, 9-tetrahydro -2-n -
プロピル−1H−イミダゾ〔4, 5−c〕キノリン−4 Propyl -1H- imidazo [4, 5-c] quinolin -4
−アミン (12) 1−〔2−〔4−(1−アミノエチル)フェニル〕エチル〕−2−n-ブチル−6, 7, 8, 9−テトラヒドロ−1H−イミダゾ〔4, 5−c〕キノリン−4− - amine (12) 1- [2- [4- (1-aminoethyl) phenyl] ethyl] -2-n-butyl-6, 7, 8, 9-tetrahydro -1H- imidazo [4, 5-c] quinoline-4
アミン (13) 1−〔2−〔4−(1−アミノエチル)フェニル〕エチル〕−2−シクロプロピルメチル−6, 7, Amine (13) 1- [2- [4- (1-aminoethyl) phenyl] ethyl] -2-cyclopropylmethyl-6, 7,
8, 9−テトラヒドロ−1H−イミダゾ〔4, 5−c〕 8, 9-tetrahydro -1H- imidazo [4, 5-c]
キノリン−4−アミン (14) 1−〔2−〔4−(1−アミノエチル)フェニル〕エチル〕−2−エトキシメチル−6, 7, 8, 9− Quinolin-4-amine (14) 1- [2- [4- (1-aminoethyl) phenyl] ethyl] -2-ethoxymethyl-6, 7, 8, 9
テトラヒドロ−1H−イミダゾ〔4, 5−c〕キノリン−4−アミン (15) 1−〔2−〔4−(1−アミノエチル)フェニル〕エチル〕−1,6,7,8−テトラヒドロシクロペンタ〔b〕イミダゾ〔4, 5−d〕ピリジン−4−アミン (16) 1−〔2−〔4−(1−アミノエチル)フェニル〕エチル〕−1,6,7,8−テトラヒドロ−2−メチルシクロペンタ〔b〕イミダゾ〔4, 5−d〕ピリジン−4−アミン (17) 1−〔2−〔4−(1−アミノエチル)フェニル〕エチル〕−2−エチル−1,6,7,8−テトラヒドロシクロペンタ〔b〕イミダゾ〔4, 5−d〕ピリジン−4−アミン (18) 1−〔2−〔4−(1−アミノエチル)フェニル〕エチル〕−1,6,7,8−テトラヒドロ−2−n- Tetrahydro -1H- imidazo [4, 5-c] quinolin-4-amine (15) 1- [2- [4- (1-aminoethyl) phenyl] ethyl] -1,6,7,8- tetrahydrocyclopenta [b] imidazo [4, 5-d] pyridin-4-amine (16) 1- [2- [4- (1-aminoethyl) phenyl] ethyl] -1,6,7,8- tetrahydro-2 cyclopentasiloxane [b] imidazo [4, 5-d] pyridin-4-amine (17) 1- [2- [4- (1-aminoethyl) phenyl] ethyl] -2-ethyl -1,6,7 , 8 tetrahydrocyclopenta [b] imidazo [4, 5-d] pyridin-4-amine (18) 1- [2- [4- (1-aminoethyl) phenyl] ethyl] -1,6,7, 8-tetrahydro -2-n-
プロピルシクロペンタ〔b〕イミダゾ〔4, 5−d〕ピリジン−4−アミン (19) 1−〔2−〔4−(1−アミノエチル)フェニル〕エチル〕−2−n-ブチル−1,6,7,8−テトラヒドロシクロペンタ〔b〕イミダゾ〔4, 5−d〕ピリジン−4−アミン (20) 1−〔2−〔4−(1−アミノエチル)フェニル〕エチル〕−2−シクロプロピルメチル−1,6, Propylcyclopentadienyl [b] imidazo [4, 5-d] pyridin-4-amine (19) 1- [2- [4- (1-aminoethyl) phenyl] ethyl] -2-n-butyl-1,6 7,8-tetrahydrocyclopenta [b] imidazo [4, 5-d] pyridin-4-amine (20) 1- [2- [4- (1-aminoethyl) phenyl] ethyl] -2-cyclopropyl methyl-1,6,
7,8−テトラヒドロシクロペンタ〔b〕イミダゾ〔4, 5−d〕ピリジン−4−アミン 7,8-tetrahydrocyclopenta [b] imidazo [4, 5-d] pyridin-4-amine

【0013】(21) 1−〔2−〔4−(1−アミノエチル)フェニル〕エチル〕−2−エトキシメチル−1, [0013] (21) 1- [2- [4- (1-aminoethyl) phenyl] ethyl] -2-ethoxymethyl-1,
6,7,8−テトラヒドロシクロペンタ〔b〕イミダゾ〔4, 5−d〕ピリジン−4−アミン (22) 1−〔2−〔4−(1−アミノエチル)フェニル〕エチル〕−1,6,7,8,9,10−ヘキサヒドロシクロヘプタ〔b〕イミダゾ〔4, 5−d〕ピリジン−4−アミン (23) 1−〔2−〔4−(1−アミノエチル)フェニル〕エチル〕−1,6,7,8,9,10−ヘキサヒドロ−2−メチルシクロヘプタ〔b〕イミダゾ〔4,5− 6,7,8-tetrahydrocyclopenta [b] imidazo [4, 5-d] pyridin-4-amine (22) 1- [2- [4- (1-aminoethyl) phenyl] ethyl] 1,6 , 7,8,9,10-hexahydrocycloocta hepta [b] imidazo [4, 5-d] pyridin-4-amine (23) 1- [2- [4- (1-aminoethyl) phenyl] ethyl] -1,6,7,8,9,10- hexahydro-2-methyl cycloheptanone [b] imidazo [4,5
d〕ピリジン−4−アミン (24) 1−〔2−〔4−(1−アミノエチル)フェニル〕エチル〕−2−エチル−1,6,7,8,9,10 d] pyridin-4-amine (24) 1- [2- [4- (1-aminoethyl) phenyl] ethyl] -2-ethyl -1,6,7,8,9,10
−ヘキサヒドロシクロヘプタ〔b〕イミダゾ〔4,5− - hexahydrocyclopenta hepta [b] imidazo [4,5
d〕ピリジン−4−アミン (25) 1−〔2−〔4−(1−アミノエチル)フェニル〕エチル〕−1,6,7,8,9,10−ヘキサヒドロ−2−n-プロピルシクロヘプタ〔b〕イミダゾ〔4, d] pyridin-4-amine (25) 1- [2- [4- (1-aminoethyl) phenyl] ethyl] -1,6,7,8,9,10- hexahydro -2-n-propyl-cycloheptanone [b] imidazo [4,
5−d〕ピリジン−4−アミン (26) 1−〔2−〔4−(1−アミノエチル)フェニル〕エチル〕−2−n-ブチル−1,6,7,8,9,1 5-d] pyridin-4-amine (26) 1- [2- [4- (1-aminoethyl) phenyl] ethyl] -2-n-butyl -1,6,7,8,9,1
0−ヘキサヒドロシクロヘプタ〔b〕イミダゾ〔4, 5 0 hexahydrocycloocta hepta [b] imidazo [4, 5
−d〕ピリジン−4−アミン (27) 1−〔2−〔4−(1−アミノエチル)フェニル〕エチル〕−2−シクロプロピルメチル−1,6, -d] pyridin-4-amine (27) 1- [2- [4- (1-aminoethyl) phenyl] ethyl] -2-cyclopropylmethyl-1,6,
7,8,9,10−ヘキサヒドロシクロヘプタ〔b〕イミダゾ〔4, 5−d〕ピリジン−4−アミン (28) 1−〔2−〔4−(1−アミノエチル)フェニル〕エチル〕−2−エトキシメチル−1,6,7,8, 7,8,9,10 hexahydrocycloocta hepta [b] imidazo [4, 5-d] pyridin-4-amine (28) 1- [2- [4- (1-aminoethyl) phenyl] ethyl] - 2-ethoxymethyl -1,6,7,8,
9,10−ヘキサヒドロシクロヘプタ〔b〕イミダゾ〔4, 5−d〕ピリジン−4−アミン (29) N−〔1−〔4−〔2−(4−アミノ−1H−イミダゾ〔4, 5−c〕キノリン−1−イル)エチル〕フェニル〕エチル〕アセトアミド (30) N−〔1−〔4−〔2−(4−アミノ―2−メチル−1H−イミダゾ〔4, 5−c〕キノリン−1−イル)エチル〕フェニル〕エチル〕アセトアミド (31) N−〔1−〔4−〔2−(4−アミノ−2−エチル−1H−イミダゾ〔4, 5−c〕キノリン−1−イル)エチル〕フェニル〕エチル〕アセトアミド (32) N−〔1−〔4−〔2−(4−アミノ−2−n-プロピル−1H−イミダゾ〔4, 5−c〕キノリン−1− 9,10 hexahydrocycloocta hepta [b] imidazo [4, 5-d] pyridin-4-amine (29) N-[1- [4- [2- (4-amino -1H- imidazo [4, 5 -c] quinolin-1-yl) ethyl] phenyl] ethyl] acetamide (30) N-[1- [4- [2- (4-amino-2-methyl -1H- imidazo [4, 5-c] quinoline 1-yl) ethyl] phenyl] ethyl] acetamide (31) N-[1- [4- [2- (4-amino-2-ethyl--1H- imidazo [4, 5-c] quinolin-1-yl ) ethyl] phenyl] ethyl] acetamide (32) N-[1- [4- [2- (4-amino -2-n-propyl--1H- imidazo [4, 5-c] quinolin-1
イル)エチル〕フェニル〕エチル〕アセトアミド (33) N−〔1−〔4−〔2−(4−アミノ−2−n-ブチル−1H−イミダゾ〔4, 5−c〕キノリン−1−イル)エチル〕フェニル〕エチル〕アセトアミド (34) N−〔1−〔4−〔2−(4−アミノ−2−シクロプロピルメチル−1H−イミダゾ〔4, 5−c〕キノリン−1−イル)エチル〕フェニル〕エチル〕アセトアミド (35) N−〔1−〔4−〔2−(4−アミノ−2−エトキシメチル−1H−イミダゾ〔4, 5−c〕キノリン− Yl) ethyl] phenyl] ethyl] acetamide (33) N-[1- [4- [2- (4-amino -2-n-butyl -1H- imidazo [4, 5-c] quinolin-1-yl) ethyl] phenyl] ethyl] acetamide (34) N-[1- [4- [2- (4-amino-2-cyclopropylmethyl -1H- imidazo [4, 5-c] quinolin-1-yl) ethyl] phenyl] ethyl] acetamide (35) N-[1- [4- [2- (4-amino-2-ethoxymethyl--1H- imidazo [4, 5-c] quinolin -
1−イル)エチル〕フェニル〕エチル〕アセトアミド (36) N−〔1−〔4−〔2−(4−アミノ−6, 7, 1-yl) ethyl] phenyl] ethyl] acetamide (36) N-[1- [4- [2- (4-amino-6, 7,
8, 9−テトラヒドロ−1H−イミダゾ〔4, 5−c〕 8, 9-tetrahydro -1H- imidazo [4, 5-c]
キノリン−1−イル)エチル〕フェニル〕エチル〕アセトアミド (37) N−〔1−〔4−〔2−(4−アミノ−6, 7, Quinolin-1-yl) ethyl] phenyl] ethyl] acetamide (37) N-[1- [4- [2- (4-amino-6, 7,
8, 9−テトラヒドロ−2−メチル−1H−イミダゾ〔4, 5−c〕キノリン−1−イル)エチル〕フェニル〕エチル〕アセトアミド (38) N−〔1−〔4−〔2−(4−アミノ−2−エチル−6, 7, 8, 9−テトラヒドロ−1H−イミダゾ〔4, 5−c〕キノリン−1−イル)エチル〕フェニル〕エチル〕アセトアミド (39) N−〔1−〔4−〔2−(4−アミノ−6, 7, 8, 9-tetrahydro-2-methyl -1H- imidazo [4, 5-c] quinolin-1-yl) ethyl] phenyl] ethyl] acetamide (38) N-[1- [4- [2- (4- amino-2-ethyl-6, 7, 8, 9-tetrahydro -1H- imidazo [4, 5-c] quinolin-1-yl) ethyl] phenyl] ethyl] acetamide (39) N-[1- [4- [2- (4-amino-6, 7,
8, 9−テトラヒドロ−2−n-プロピル−1H−イミダゾ〔4, 5−c〕キノリン−1−イル)エチル〕フェニル〕エチル〕アセトアミド (40) N−〔1−〔4−〔2−(4−アミノ−2−n-ブチル−6, 7, 8, 9−テトラヒドロ−1H−イミダゾ〔4, 5−c〕キノリン−1−イル)エチル〕フェニル〕エチル〕アセトアミド 8, 9-tetrahydro -2-n-propyl--1H- imidazo [4, 5-c] quinolin-1-yl) ethyl] phenyl] ethyl] acetamide (40) N-[1- [4- [2- ( 4-amino -2-n-butyl-6, 7, 8, 9-tetrahydro -1H- imidazo [4, 5-c] quinolin-1-yl) ethyl] phenyl] ethyl] acetamide

【0014】(41) N−〔1−〔4−〔2−(4−アミノ−2−シクロプロピルメチル−6,7, 8, 9−テトラヒドロ−1H−イミダゾ〔4, 5−c〕キノリン−1 [0014] (41) N-[1- [4- [2- (4-amino-2-cyclopropylmethyl -6,7, 8, 9-tetrahydro -1H- imidazo [4, 5-c] quinolin - 1
−イル)エチル〕フェニル〕エチル〕アセトアミド (42) N−〔1−〔4−〔2−(4−アミノ−2−エトキシメチル−6, 7, 8, 9−テトラヒドロ−1H−イミダゾ〔4, 5−c〕キノリン−1−イル)エチル〕フェニル〕エチル〕アセトアミド (43) N−〔1−〔4−〔2−(4−アミノ−1,6, - yl) ethyl] phenyl] ethyl] acetamide (42) N-[1- [4- [2- (4-amino-2-ethoxymethyl-6, 7, 8, 9-tetrahydro -1H- imidazo [4, 5-c] quinolin-1-yl) ethyl] phenyl] ethyl] acetamide (43) N-[1- [4- [2- (4-amino-1,6,
7,8−テトラヒドロシクロペンタ〔b〕イミダゾ〔4, 5−d〕ピリジン−1−イル)エチル〕フェニル〕エチル〕アセトアミド (44) N−〔1−〔4−〔2−(4−アミノ−1,6, 7,8-tetrahydrocyclopenta [b] imidazo [4, 5-d] pyridin-1-yl) ethyl] phenyl] ethyl] acetamide (44) N-[1- [4- [2- (4-amino - 1,6,
7,8−テトラヒドロ−2−メチルシクロペンタ〔b〕 7,8-tetrahydro-2-methylcyclopentadienyl [b]
イミダゾ〔4, 5−d〕ピリジン−1−イル)エチル〕 Imidazo [4, 5-d] pyridin-1-yl) ethyl]
フェニル〕エチル〕アセトアミド (45) N−〔1−〔4−〔2−(4−アミノ−2−エチル−1,6,7,8−テトラヒドロシクロペンタ〔b〕 Phenyl] ethyl] acetamide (45) N-[1- [4- [2- (4-amino-2-ethyl -1,6,7,8- tetrahydrocyclopenta [b]
イミダゾ〔4, 5−d〕ピリジン−1−イル)エチル〕 Imidazo [4, 5-d] pyridin-1-yl) ethyl]
フェニル〕エチル〕アセトアミド (46) N−〔1−〔4−〔2−(4−アミノ−1,6, Phenyl] ethyl] acetamide (46) N-[1- [4- [2- (4-Amino-1,6,
7,8−テトラヒドロ−2−n-プロピルシクロペンタ〔b〕イミダゾ〔4, 5−d〕ピリジン−1−イル)エチル〕フェニル〕エチル〕アセトアミド (47) N−〔1−〔4−〔2−(4−アミノ−2−n-ブチル−1,6,7,8−テトラヒドロシクロペンタ〔b〕イミダゾ〔4, 5−d〕ピリジン−1−イル)エチル〕フェニル〕エチル〕アセトアミド (48) N−〔1−〔4−〔2−(4−アミノ−2−シクロプロピルメチル−1,6,7,8−テトラヒドロシクロペンタ〔b〕イミダゾ〔4, 5−d〕ピリジン−1− 7,8-tetrahydro -2-n-propyl-cyclopentadienyl [b] imidazo [4, 5-d] pyridin-1-yl) ethyl] phenyl] ethyl] acetamide (47) N-[1- [4- [2 - (4-amino -2-n-butyl -1,6,7,8- tetrahydrocyclopenta [b] imidazo [4, 5-d] pyridin-1-yl) ethyl] phenyl] ethyl] acetamide (48) N- [1- [4- [2- (4-amino-2-cyclopropylmethyl--1,6,7,8- tetrahydrocyclopenta [b] imidazo [4, 5-d] pyridin-1
イル)エチル〕フェニル〕エチル〕アセトアミド (49) N−〔1−〔4−〔2−(4−アミノ−2−エトキシメチル−1,6,7,8−テトラヒドロシクロペンタ〔b〕イミダゾ〔4, 5−d〕ピリジン−1−イル) Yl) ethyl] phenyl] ethyl] acetamide (49) N-[1- [4- [2- (4-amino-2-ethoxymethyl--1,6,7,8- tetrahydrocyclopenta [b] imidazo [4 , 5-d] pyridin-1-yl)
エチル〕フェニル〕エチル〕アセトアミド (50) N−〔1−〔4−〔2−(4−アミノ−1,6, Ethyl] phenyl] ethyl] acetamide (50) N-[1- [4- [2- (4-Amino-1,6,
7,8,9,10−ヘキサヒドロシクロヘプタ〔b〕イミダゾ〔4, 5−d〕ピリジン−1−イル)エチル〕フェニル〕エチル〕アセトアミド (51) N−〔1−〔4−〔2−(4−アミノ−1,6, 7,8,9,10 hexahydrocycloocta hepta [b] imidazo [4, 5-d] pyridin-1-yl) ethyl] phenyl] ethyl] acetamide (51) N-[1- [4- [2- (4-amino-1,6,
7,8,9,10−ヘキサヒドロ−2−メチルシクロヘプタ〔b〕イミダゾ〔4, 5−d〕ピリジン−1−イル)エチル〕フェニル〕エチル〕アセトアミド(52) 7,8,9,10-hexahydro-2-methyl cycloheptanone [b] imidazo [4, 5-d] pyridin-1-yl) ethyl] phenyl] ethyl] acetamide (52)
N−〔1−〔4−〔2−(4−アミノ−2−エチル− N- [1- [4- [2- (4-amino-2-ethyl -
1,6,7,8,9,10−ヘキサヒドロシクロヘプタ〔b〕イミダゾ〔4, 5−d〕ピリジン−1−イル)エチル〕フェニル〕エチル〕アセトアミド (53) N−〔1−〔4−〔2−(4−アミノ−1,6, 1,6,7,8,9,10- hexahydrocycloocta hepta [b] imidazo [4, 5-d] pyridin-1-yl) ethyl] phenyl] ethyl] acetamide (53) N-[1- [4 - [2- (4-amino-1,6,
7,8,9,10−ヘキサヒドロ−2−n-プロピルシクロヘプタ〔b〕イミダゾ〔4, 5−d〕ピリジン−1− 7,8,9,10-hexahydro -2-n-propyl-cycloheptanone [b] imidazo [4, 5-d] pyridin-1
イル)エチル〕フェニル〕エチル〕アセトアミド (54) N−〔1−〔4−〔2−(4−アミノ−2−n-ブチル−1,6,7,8,9,10−ヘキサヒドロシクロヘプタ〔b〕イミダゾ〔4, 5−d〕ピリジン−1−イル)エチル〕フェニル〕エチル〕アセトアミド (55) N−〔1−〔4−〔2−(4−アミノ−2−シクロプロピルメチル−1,6,7,8,9,10−ヘキサヒドロシクロヘプタ〔b〕イミダゾ〔4, 5−d〕ピリジン−1−イル)エチル〕フェニル〕エチル〕アセトアミド (56) N−〔1−〔4−〔2−(4−アミノ−2−エトキシメチル−1,6,7,8,9,10−ヘキサヒドロシクロヘプタ〔b〕イミダゾ〔4, 5−d〕ピリジン− Yl) ethyl] phenyl] ethyl] acetamide (54) N-[1- [4- [2- (4-amino -2-n-butyl -1,6,7,8,9,10- hexahydrocycloocta hepta [b] imidazo [4, 5-d] pyridin-1-yl) ethyl] phenyl] ethyl] acetamide (55) N-[1- [4- [2- (4-amino-2-cyclopropylmethyl -1 , 6,7,8,9,10- hexahydrocycloocta hepta [b] imidazo [4, 5-d] pyridin-1-yl) ethyl] phenyl] ethyl] acetamide (56) N-[1- [4- [2- (4-amino-2-ethoxymethyl--1,6,7,8,9,10- hexahydrocycloocta hepta [b] imidazo [4, 5-d] pyridine -
1−イル)エチル〕フェニル〕エチル〕アセトアミド (57) 1−〔2−〔4−(アミノメチル)フェニル〕エチル〕−1H−イミダゾ〔4, 5−c〕キノリン−4− 1-yl) ethyl] phenyl] ethyl] acetamide (57) 1- [2- [4- (aminomethyl) phenyl] ethyl] -1H- imidazo [4, 5-c] quinolin-4
アミン (58) 1−〔2−〔4−(アミノメチル)フェニル〕エチル〕−2−メチル−1H−イミダゾ〔4, 5−c〕キノリン−4−アミン (59) 1−〔2−〔4−(アミノメチル)フェニル〕エチル〕−2−エチル−1H−イミダゾ〔4, 5−c〕キノリン−4−アミン (60) 1−〔2−〔4−(アミノメチル)フェニル〕エチル〕−2−n-プロピル−1H−イミダゾ〔4, 5− Amine (58) 1- [2- [4- (aminomethyl) phenyl] ethyl] -2-methyl -1H- imidazo [4, 5-c] quinolin-4-amine (59) 1- [2- [4 - (aminomethyl) phenyl] ethyl] -2-ethyl -1H- imidazo [4, 5-c] quinolin-4-amine (60) 1- [2- [4- (aminomethyl) phenyl] ethyl] -2 -n- propyl -1H- imidazo [4, 5-
c〕キノリン−4−アミン c] quinoline-4-amine

【0015】(61) 1−〔2−〔4−(アミノメチル) [0015] (61) 1- [2- [4- (aminomethyl)
フェニル〕エチル〕−2−n-ブチル−1H−イミダゾ〔4, 5−c〕キノリン−4−アミン (62) 1−〔2−〔4−(アミノメチル)フェニル〕エチル〕−2−シクロプロピルメチル−1H−イミダゾ〔4, 5−c〕キノリン−4−アミン (63) 1−〔2−〔4−(アミノメチル)フェニル〕エチル〕−2−エトキシメチル−1H−イミダゾ〔4, 5 Phenyl] ethyl] -2-n-butyl -1H- imidazo [4, 5-c] quinolin-4-amine (62) 1- [2- [4- (aminomethyl) phenyl] ethyl] -2-cyclopropyl methyl -1H- imidazo [4, 5-c] quinolin-4-amine (63) 1- [2- [4- (aminomethyl) phenyl] ethyl] -2-ethoxymethyl--1H- imidazo [4, 5
−c〕キノリン−4−アミン (64) 1−〔2−〔4−(アミノメチル)フェニル〕エチル〕−6, 7, 8, 9−テトラヒドロ−1H−イミダゾ〔4, 5−c〕キノリン−4−アミン (65) 1−〔2−〔4−(アミノメチル)フェニル〕エチル〕−6, 7, 8, 9−テトラヒドロ−2−メチル− -c] quinolin-4-amine (64) 1- [2- [4- (aminomethyl) phenyl] ethyl] -6, 7, 8, 9-tetrahydro -1H- imidazo [4, 5-c] quinolin - 4- amine (65) 1- [2- [4- (aminomethyl) phenyl] ethyl] -6, 7, 8, 9-tetrahydro-2-methyl -
1H−イミダゾ〔4, 5−c〕キノリン−4−アミン (66) 1−〔2−〔4−(アミノメチル)フェニル〕エチル〕−2−エチル−6, 7, 8, 9−テトラヒドロ− 1H- imidazo [4, 5-c] quinolin-4-amine (66) 1- [2- [4- (aminomethyl) phenyl] ethyl] -2-ethyl-6, 7, 8, 9-tetrahydro -
1H−イミダゾ〔4, 5−c〕キノリン−4−アミン (67) 1−〔2−〔4−(アミノメチル)フェニル〕エチル〕−6, 7, 8, 9−テトラヒドロ−2−n-プロピル−1H−イミダゾ〔4, 5−c〕キノリン−4−アミン (68) 1−〔2−〔4−(アミノメチル)フェニル〕エチル〕−2−n-ブチル−6, 7, 8, 9−テトラヒドロ−1H−イミダゾ〔4, 5−c〕キノリン−4−アミン (69) 1−〔2−〔4−(アミノメチル)フェニル〕エチル〕−2−シクロプロピルメチル−6, 7, 8, 9− 1H- imidazo [4, 5-c] quinolin-4-amine (67) 1- [2- [4- (aminomethyl) phenyl] ethyl] -6, 7, 8, 9-tetrahydro -2-n-propyl -1H- imidazo [4, 5-c] quinolin-4-amine (68) 1- [2- [4- (aminomethyl) phenyl] ethyl] -2-n-butyl-6, 7, 8, 9 tetrahydro -1H- imidazo [4, 5-c] quinolin-4-amine (69) 1- [2- [4- (aminomethyl) phenyl] ethyl] -2-cyclopropylmethyl-6, 7, 8, 9 -
テトラヒドロ−1H−イミダゾ〔4, 5−c〕キノリン−4−アミン (70) 1−〔2−〔4−(アミノメチル)フェニル〕エチル〕−2−エトキシメチル−6, 7, 8, 9−テトラヒドロ−1H−イミダゾ〔4, 5−c〕キノリン−4− Tetrahydro -1H- imidazo [4, 5-c] quinolin-4-amine (70) 1- [2- [4- (aminomethyl) phenyl] ethyl] -2-ethoxymethyl-6, 7, 8, 9 tetrahydro -1H- imidazo [4, 5-c] quinolin-4
アミン (71) 1−〔2−〔4−(アミノメチル)フェニル〕エチル〕−1,6,7,8−テトラヒドロシクロペンタ〔b〕イミダゾ〔4, 5−d〕ピリジン−4−アミン (72) 1−〔2−〔4−(アミノメチル)フェニル〕エチル〕−1,6,7,8−テトラヒドロ−2−メチルシクロペンタ〔b〕イミダゾ〔4, 5−d〕ピリジン−4 Amine (71) 1- [2- [4- (aminomethyl) phenyl] ethyl] -1,6,7,8- tetrahydrocyclopenta [b] imidazo [4, 5-d] pyridin-4-amine (72 ) 1- [2- [4- (aminomethyl) phenyl] ethyl] -1,6,7,8- tetrahydro-2-methylcyclopentadienyl [b] imidazo [4, 5-d] pyridine -4
−アミン (73) 1−〔2−〔4−(アミノメチル)フェニル〕エチル〕−2−エチル−1,6,7,8−テトラヒドロシクロペンタ〔b〕イミダゾ〔4, 5−d〕ピリジン−4 - amine (73) 1- [2- [4- (aminomethyl) phenyl] ethyl] -2-ethyl -1,6,7,8- tetrahydrocyclopenta [b] imidazo [4, 5-d] pyridine - 4
−アミン (74) 1−〔2−〔4−(アミノメチル)フェニル〕エチル〕−1,6,7,8−テトラヒドロ−2−n-プロピルシクロペンタ〔b〕イミダゾ〔4, 5−d〕ピリジン−4−アミン (75) 1−〔2−〔4−(アミノメチル)フェニル〕エチル〕−2−n-ブチル−1,6,7,8−テトラヒドロシクロペンタ〔b〕イミダゾ〔4, 5−d〕ピリジン− - amine (74) 1- [2- [4- (aminomethyl) phenyl] ethyl] -1,6,7,8- tetrahydro -2-n-propyl-cyclopentadienyl [b] imidazo [4, 5-d] pyridin-4-amine (75) 1- [2- [4- (aminomethyl) phenyl] ethyl] -2-n-butyl -1,6,7,8- tetrahydrocyclopenta [b] imidazo [4, 5 -d] pyridine -
4−アミン (76) 1−〔2−〔4−(アミノメチル)フェニル〕エチル〕−2−シクロプロピルメチル−1,6,7,8− 4- amine (76) 1- [2- [4- (aminomethyl) phenyl] ethyl] -2-cyclopropylmethyl -1,6,7,8-
テトラヒドロシクロペンタ〔b〕イミダゾ〔4,5− Tetrahydrocyclopenta [b] imidazo [4,5
d〕ピリジン−4−アミン (77) 1−〔2−〔4−(アミノメチル)フェニル〕エチル〕−2−エトキシメチル−1,6,7,8−テトラヒドロシクロペンタ〔b〕イミダゾ〔4, 5−d〕ピリジン−4−アミン (78) 1−〔2−〔4−(アミノメチル)フェニル〕エチル〕−1,6,7,8,9,10−ヘキサヒドロシクロヘプタ〔b〕イミダゾ〔4, 5−d〕ピリジン−4− d] pyridin-4-amine (77) 1- [2- [4- (aminomethyl) phenyl] ethyl] -2-ethoxymethyl -1,6,7,8- tetrahydrocyclopenta [b] imidazo [4, 5-d] pyridin-4-amine (78) 1- [2- [4- (aminomethyl) phenyl] ethyl] -1,6,7,8,9,10- hexahydrocycloocta hepta [b] imidazo [ 4, 5-d] pyridine-4
アミン (79) 1−〔2−〔4−(アミノメチル)フェニル〕エチル〕−1,6,7,8,9,10−ヘキサヒドロ−2 Amine (79) 1- [2- [4- (aminomethyl) phenyl] ethyl] -1,6,7,8,9,10- hexahydro -2
−メチルシクロヘプタ〔b〕イミダゾ〔4, 5−d〕ピリジン−4−アミン (80) 1−〔2−〔4−(アミノメチル)フェニル〕エチル〕−2−エチル−1,6,7,8,9,10−ヘキサヒドロシクロヘプタ〔b〕イミダゾ〔4, 5−d〕ピリジン−4−アミン - methyl cycloheptanone [b] imidazo [4, 5-d] pyridin-4-amine (80) 1- [2- [4- (aminomethyl) phenyl] ethyl] -2-ethyl -1,6,7, 8,9,10 hexahydrocycloocta hepta [b] imidazo [4, 5-d] pyridin-4-amine

【0016】(81) 1−〔2−〔4−(アミノメチル) [0016] (81) 1- [2- [4- (aminomethyl)
フェニル〕エチル〕−1,6,7,8,9,10−ヘキサヒドロ−2−n-プロピルシクロヘプタ〔b〕イミダゾ〔4,5−d〕ピリジン−4−アミン (82) 1−〔2−〔4−(アミノメチル)フェニル〕エチル〕−2−n-ブチル−1,6,7,8,9,10−ヘキサヒドロシクロヘプタ〔b〕イミダゾ〔4, 5−d〕 Phenyl] ethyl] -1,6,7,8,9,10- hexahydro -2-n-propyl-cycloheptanone [b] imidazo [4,5-d] pyridin-4-amine (82) 1- [2- [4- (aminomethyl) phenyl] ethyl] -2-n-butyl -1,6,7,8,9,10- hexahydrocycloocta hepta [b] imidazo [4, 5-d]
ピリジン−4−アミン (83) 1−〔2−〔4−(アミノメチル)フェニル〕エチル〕−2−シクロプロピルメチル−1,6,7,8, Pyridin-4-amine (83) 1- [2- [4- (aminomethyl) phenyl] ethyl] -2-cyclopropylmethyl -1,6,7,8,
9,10−ヘキサヒドロシクロヘプタ〔b〕イミダゾ〔4, 5−d〕ピリジン−4−アミン (84) 1−〔2−〔4−(アミノメチル)フェニル〕エチル〕−2−エトキシメチル−1,6,7,8,9,1 9,10 hexahydrocycloocta hepta [b] imidazo [4, 5-d] pyridin-4-amine (84) 1- [2- [4- (aminomethyl) phenyl] ethyl] -2-ethoxymethyl -1 , 6,7,8,9,1
0−ヘキサヒドロシクロヘプタ〔b〕イミダゾ〔4, 5 0 hexahydrocycloocta hepta [b] imidazo [4, 5
−d〕ピリジン−4−アミン (85) 1−〔2−(4−アミノフェニル)エチル〕−1 -d] pyridin-4-amine (85) 1- [2- (4-aminophenyl) ethyl] -1
H−イミダゾ〔4, 5−c〕キノリン−4−アミン (86) 1−〔2−(4−アミノフェニル)エチル〕−2 H- imidazo [4, 5-c] quinolin-4-amine (86) 1- [2- (4-aminophenyl) ethyl] -2
−メチル−1H−イミダゾ〔4, 5−c〕キノリン−4 - methyl -1H- imidazo [4, 5-c] quinolin -4
−アミン (87) 1−〔2−(4−アミノフェニル)エチル〕−2 - amine (87) 1- [2- (4-aminophenyl) ethyl] -2
−エチル−1H−イミダゾ〔4, 5−c〕キノリン−4 - ethyl -1H- imidazo [4, 5-c] quinolin -4
−アミン (88) 1−〔2−(4−アミノフェニル)エチル〕−2 - amine (88) 1- [2- (4-aminophenyl) ethyl] -2
−n-プロピル−1H−イミダゾ〔4, 5−c〕キノリン−4−アミン (89) 1−〔2−(4−アミノフェニル)エチル〕−2 -n- propyl -1H- imidazo [4, 5-c] quinolin-4-amine (89) 1- [2- (4-aminophenyl) ethyl] -2
−n-ブチル−1H−イミダゾ〔4, 5−c〕キノリン− -n- butyl -1H- imidazo [4, 5-c] quinolin -
4−アミン (90) 1−〔2−(4−アミノフェニル)エチル〕−2 4- amine (90) 1- [2- (4-aminophenyl) ethyl] -2
−シクロプロピルメチル−1H−イミダゾ〔4, 5− - cyclopropylmethyl -1H- imidazo [4, 5-
c〕キノリン−4−アミン (91) 1−〔2−(4−アミノフェニル)エチル〕−2 c] quinolin-4-amine (91) 1- [2- (4-aminophenyl) ethyl] -2
−エトキシメチル−1H−イミダゾ〔4, 5−c〕キノリン−4−アミン (92) 1−〔2−(4−アミノフェニル)エチル〕− - ethoxymethyl -1H- imidazo [4, 5-c] quinolin-4-amine (92) 1- [2- (4-aminophenyl) ethyl] -
6, 7, 8, 9−テトラヒドロ−1H−イミダゾ〔4, 6, 7, 8, 9-tetrahydro -1H- imidazo [4,
5−c〕キノリン−4−アミン (93) 1−〔2−(4−アミノフェニル)エチル〕− 5-c] quinolin-4-amine (93) 1- [2- (4-aminophenyl) ethyl] -
6, 7, 8, 9−テトラヒドロ−2−メチル−1H−イミダゾ〔4, 5−c〕キノリン−4−アミン (94) 1−〔2−(4−アミノフェニル)エチル〕−2 6, 7, 8, 9-tetrahydro-2-methyl -1H- imidazo [4, 5-c] quinolin-4-amine (94) 1- [2- (4-aminophenyl) ethyl] -2
−エチル−6, 7, 8,9−テトラヒドロ−1H−イミダゾ〔4, 5−c〕キノリン−4−アミン (95) 1−〔2−(4−アミノフェニル)エチル〕− - ethyl -6, 7, 8,9-tetrahydro -1H- imidazo [4, 5-c] quinolin-4-amine (95) 1- [2- (4-aminophenyl) ethyl] -
6, 7, 8, 9−テトラヒドロ−2−n-プロピル−1H 6, 7, 8, 9-tetrahydro -2-n-propyl -1H
−イミダゾ〔4, 5−c〕キノリン−4−アミン (96) 1−〔2−(4−アミノフェニル)エチル〕−2 - imidazo [4, 5-c] quinolin-4-amine (96) 1- [2- (4-aminophenyl) ethyl] -2
−n-ブチル−6, 7, 8, 9−テトラヒドロ−1H−イミダゾ〔4, 5−c〕キノリン−4−アミン (97) 1−〔2−(4−アミノフェニル)エチル〕−2 -n- butyl -6, 7, 8, 9-tetrahydro -1H- imidazo [4, 5-c] quinolin-4-amine (97) 1- [2- (4-aminophenyl) ethyl] -2
−シクロプロピルメチル−6, 7, 8, 9−テトラヒドロ−1H−イミダゾ〔4, 5−c〕キノリン−4−アミン (98) 1−〔2−(4−アミノフェニル)エチル〕−2 - cyclopropylmethyl-6, 7, 8, 9-tetrahydro -1H- imidazo [4, 5-c] quinolin-4-amine (98) 1- [2- (4-aminophenyl) ethyl] -2
−エトキシメチル−6,7, 8, 9−テトラヒドロ−1 - ethoxymethyl -6,7, 8, 9-tetrahydro -1
H−イミダゾ〔4, 5−c〕キノリン−4−アミン (99) 1−〔2−(4−アミノフェニル)エチル〕− H- imidazo [4, 5-c] quinolin-4-amine (99) 1- [2- (4-aminophenyl) ethyl] -
1,6,7,8−テトラヒドロシクロペンタ〔b〕イミダゾ〔4, 5−d〕ピリジン−4−アミン (100) 1−〔2−(4−アミノフェニル)エチル〕− 1,6,7,8-tetrahydrocyclopenta [b] imidazo [4, 5-d] pyridin-4-amine (100) 1- [2- (4-aminophenyl) ethyl] -
1,6,7,8−テトラヒドロ−2−メチルシクロペンタ〔b〕イミダゾ〔4, 5−d〕ピリジン−4−アミン 1,6,7,8-tetrahydro-2-methylcyclopentadienyl [b] imidazo [4, 5-d] pyridin-4-amine

【0017】(101) 1−〔2−(4−アミノフェニル)エチル〕−2−エチル−1,6,7,8−テトラヒドロシクロペンタ〔b〕イミダゾ〔4, 5−d〕ピリジン−4−アミン (102) 1−〔2−(4−アミノフェニル)エチル〕− [0017] (101) 1- [2- (4-aminophenyl) ethyl] -2-ethyl -1,6,7,8- tetrahydrocyclopenta [b] imidazo [4, 5-d] pyridin-4 amine (102) 1- [2- (4-aminophenyl) ethyl] -
1,6,7,8−テトラヒドロ−2−n-プロピルシクロペンタ〔b〕イミダゾ〔4, 5−d〕ピリジン−4−アミン (103) 1−〔2−(4−アミノフェニル)エチル〕− 1,6,7,8-tetrahydro -2-n-propyl-cyclopentadienyl [b] imidazo [4, 5-d] pyridin-4-amine (103) 1- [2- (4-aminophenyl) ethyl] -
2−n-ブチル−1,6,7,8−テトラヒドロシクロペンタ〔b〕イミダゾ〔4, 5−d〕ピリジン−4−アミン (104) 1−〔2−(4−アミノフェニル)エチル〕− 2-n-butyl -1,6,7,8- tetrahydrocyclopenta [b] imidazo [4, 5-d] pyridin-4-amine (104) 1- [2- (4-aminophenyl) ethyl] -
2−シクロプロピルメチル−1,6,7,8−テトラヒドロシクロペンタ〔b〕イミダゾ〔4, 5−d〕ピリジン−4−アミン (105) 1−〔2−(4−アミノフェニル)エチル〕− 2-cyclopropylmethyl -1,6,7,8- tetrahydrocyclopenta [b] imidazo [4, 5-d] pyridin-4-amine (105) 1- [2- (4-aminophenyl) ethyl] -
2−エトキシメチル−1,6,7,8−テトラヒドロシクロペンタ〔b〕イミダゾ〔4, 5−d〕ピリジン−4 2-ethoxymethyl -1,6,7,8- tetrahydrocyclopenta [b] imidazo [4, 5-d] pyridine -4
−アミン (106) 1−〔2−(4−アミノフェニル)エチル〕− - amine (106) 1- [2- (4-aminophenyl) ethyl] -
1,6,7,8,9,10−ヘキサヒドロシクロヘプタ〔b〕イミダゾ〔4, 5−d〕ピリジン−4−アミン (107) 1−〔2−(4−アミノフェニル)エチル〕− 1,6,7,8,9,10- hexahydrocycloocta hepta [b] imidazo [4, 5-d] pyridin-4-amine (107) 1- [2- (4-aminophenyl) ethyl] -
1,6,7,8,9,10−ヘキサヒドロ−2−メチルシクロヘプタ〔b〕イミダゾ〔4, 5−d〕ピリジン− 1,6,7,8,9,10- hexahydro-2-methyl cycloheptanone [b] imidazo [4, 5-d] pyridine -
4−アミン (108) 1−〔2−(4−アミノフェニル)エチル〕− 4- amine (108) 1- [2- (4-aminophenyl) ethyl] -
2−エチル−1,6,7,8,9,10−ヘキサヒドロシクロヘプタ〔b〕イミダゾ〔4, 5−d〕ピリジン− 2-ethyl -1,6,7,8,9,10- hexahydrocycloocta hepta [b] imidazo [4, 5-d] pyridine -
4−アミン (109) 1−〔2−(4−アミノフェニル)エチル〕− 4- amine (109) 1- [2- (4-aminophenyl) ethyl] -
1,6,7,8,9,10−ヘキサヒドロ−2−n-プロピルシクロヘプタ〔b〕イミダゾ〔4, 5−d〕ピリジン−4−アミン (110) 1−〔2−(4−アミノフェニル)エチル〕− 1,6,7,8,9,10- hexahydro -2-n-propyl-cycloheptanone [b] imidazo [4, 5-d] pyridin-4-amine (110) 1- [2- (4-aminophenyl ) ethyl] -
2−n-ブチル−1,6,7,8,9,10−ヘキサヒドロシクロヘプタ〔b〕イミダゾ〔4, 5−d〕ピリジン−4−アミン (111) 1−〔2−(4−アミノフェニル)エチル〕− 2-n-butyl -1,6,7,8,9,10- hexahydrocycloocta hepta [b] imidazo [4, 5-d] pyridin-4-amine (111) 1- [2- (4-amino phenyl) ethyl] -
2−シクロプロピルメチル−1,6,7,8,9,10 2-cyclopropylmethyl -1,6,7,8,9,10
−ヘキサヒドロシクロヘプタ〔b〕イミダゾ〔4, 5− - hexahydrocyclopenta hepta [b] imidazo [4, 5-
d〕ピリジン−4−アミン (112) 1−〔2−(4−アミノフェニル)エチル〕− d] pyridin-4-amine (112) 1- [2- (4-aminophenyl) ethyl] -
2−エトキシメチル−1,6,7,8,9,10−ヘキサヒドロシクロヘプタ〔b〕イミダゾ〔4, 5−d〕ピリジン−4−アミン (113) N−〔4−〔2−(4−アミノ−1H−イミダゾ〔4, 5−c〕キノリン−1−イル)エチル〕フェニル〕アセトアミド (114) N−〔4−〔2−(4−アミノ−2−メチル− 2-ethoxymethyl -1,6,7,8,9,10- hexahydrocycloocta hepta [b] imidazo [4, 5-d] pyridin-4-amine (113) N-[4- [2- (4 - amino -1H- imidazo [4, 5-c] quinolin-1-yl) ethyl] phenyl] acetamide (114) N-[4- [2- (4-amino-2-methyl -
1H−イミダゾ〔4, 5−c〕キノリン−1−イル)エチル〕フェニル〕アセトアミド (115) N−〔4−〔2−(4−アミノ−2−エチル− 1H- imidazo [4, 5-c] quinolin-1-yl) ethyl] phenyl] acetamide (115) N-[4- [2- (4-amino-2-ethyl -
1H−イミダゾ〔4, 5−c〕キノリン−1−イル)エチル〕フェニル〕アセトアミド (116) N−〔4−〔2−(4−アミノ−2−n-プロピル−1H−イミダゾ〔4, 5−c〕キノリン−1−イル)エチル〕フェニル〕アセトアミド (117) N−〔4−〔2−(4−アミノ−2−n-ブチル−1H−イミダゾ〔4,5−c〕キノリン−1−イル) 1H- imidazo [4, 5-c] quinolin-1-yl) ethyl] phenyl] acetamide (116) N-[4- [2- (4-amino -2-n-propyl--1H- imidazo [4, 5 -c] quinolin-1-yl) ethyl] phenyl] acetamide (117) N-[4- [2- (4-amino -2-n-butyl -1H- imidazo [4,5-c] quinolin-1 yl)
エチル〕フェニル〕アセトアミド (118) N−〔4−〔2−(4−アミノ−2−シクロプロピルメチル−1H−イミダゾ〔4, 5−c〕キノリン−1−イル)エチル〕フェニル〕アセトアミド (119) N−〔4−〔2−(4−アミノ−2−エトキシメチル−1H−イミダゾ〔4, 5−c〕キノリン−1− Ethyl] phenyl] acetamide (118) N-[4- [2- (4-amino-2-cyclopropylmethyl -1H- imidazo [4, 5-c] quinolin-1-yl) ethyl] phenyl] acetamide (119 ) N- [4- [2- (4-amino-2-ethoxymethyl--1H- imidazo [4, 5-c] quinolin-1
イル)エチル〕フェニル〕アセトアミド (120) N−〔4−〔2−(4−アミノ−6, 7, 8, Yl) ethyl] phenyl] acetamide (120) N-[4- [2- (4-amino-6, 7, 8,
9−テトラヒドロ−1H−イミダゾ〔4, 5−c〕キノリン−1−イル)エチル〕フェニル〕アセトアミド 9-tetrahydro -1H- imidazo [4, 5-c] quinolin-1-yl) ethyl] phenyl] acetamide

【0018】(121) N−〔4−〔2−(4−アミノ− [0018] (121) N-[4- [2- (4-amino -
6, 7, 8, 9−テトラヒドロ−2−メチル−1H−イミダゾ〔4, 5−c〕キノリン−1−イル)エチル〕フェニル〕アセトアミド (122) N−〔4−〔2−(4−アミノ−2−エチル− 6, 7, 8, 9-tetrahydro-2-methyl -1H- imidazo [4, 5-c] quinolin-1-yl) ethyl] phenyl] acetamide (122) N-[4- [2- (4-amino 2-ethyl -
6, 7, 8, 9−テトラヒドロ−1H−イミダゾ〔4, 6, 7, 8, 9-tetrahydro -1H- imidazo [4,
5−c〕キノリン−1−イル)エチル〕フェニル〕アセトアミド (123) N−〔4−〔2−(4−アミノ−6, 7, 8, 5-c] quinolin-1-yl) ethyl] phenyl] acetamide (123) N-[4- [2- (4-amino-6, 7, 8,
9−テトラヒドロ−2−n-プロピル−1H−イミダゾ〔4, 5−c〕キノリン−1−イル)エチル〕フェニル〕アセトアミド (124) N−〔4−〔2−(4−アミノ−2−n-ブチル−6, 7, 8, 9−テトラヒドロ−1H−イミダゾ〔4, 5−c〕キノリン−1−イル)エチル〕フェニル〕アセトアミド (125) N−〔4−〔2−(4−アミノ−2−シクロプロピルメチル−6, 7,8, 9−テトラヒドロ−1H− 9- tetrahydro -2-n-propyl--1H- imidazo [4, 5-c] quinolin-1-yl) ethyl] phenyl] acetamide (124) N-[4- [2- (4-amino -2-n - butyl-6, 7, 8, 9-tetrahydro -1H- imidazo [4, 5-c] quinolin-1-yl) ethyl] phenyl] acetamide (125) N-[4- [2- (4-amino - 2-cyclopropylmethyl-6, 7, 8, 9-tetrahydro -1H-
イミダゾ〔4, 5−c〕キノリン−1−イル)エチル〕 Imidazo [4, 5-c] quinolin-1-yl) ethyl]
フェニル〕アセトアミド (126) N−〔4−〔2−(4−アミノ−2−エトキシメチル−6, 7, 8, 9−テトラヒドロ−1H−イミダゾ〔4, 5−c〕キノリン−1−イル)エチル〕フェニル〕アセトアミド (127) N−〔4−〔2−(4−アミノ−1,6,7, Phenyl] acetamide (126) N-[4- [2- (4-amino-2-ethoxymethyl-6, 7, 8, 9-tetrahydro -1H- imidazo [4, 5-c] quinolin-1-yl) ethyl] phenyl] acetamide (127) N-[4- [2- (4-amino -1,6,7,
8−テトラヒドロシクロペンタ〔b〕イミダゾ〔4, 5 8 tetrahydrocyclopenta [b] imidazo [4, 5
−d〕ピリジン−1−イル)エチル〕フェニル〕アセトアミド (128) N−〔4−〔2−(4−アミノ−1,6,7, -d] pyridin-1-yl) ethyl] phenyl] acetamide (128) N-[4- [2- (4-amino -1,6,7,
8−テトラヒドロ−2−メチルシクロペンタ〔b〕イミダゾ〔4, 5−d〕ピリジン−1−イル)エチル〕フェニル〕アセトアミド (129) N−〔4−〔2−(4−アミノ−2−エチル− 8-tetrahydro-2-methylcyclopentadienyl [b] imidazo [4, 5-d] pyridin-1-yl) ethyl] phenyl] acetamide (129) N-[4- [2- (4-amino-2-ethyl -
1,6,7,8−テトラヒドロシクロペンタ〔b〕イミダゾ〔4, 5−d〕ピリジン−1−イル)エチル〕フェニル〕アセトアミド (130) N−〔4−〔2−(4−アミノ−1,6,7, 1,6,7,8-tetrahydrocyclopenta [b] imidazo [4, 5-d] pyridin-1-yl) ethyl] phenyl] acetamide (130) N-[4- [2- (4-amino-1 , 6, 7,
8−テトラヒドロ−2−n-プロピルシクロペンタ〔b〕 8-tetrahydro -2-n-propyl-cyclopentadienyl [b]
イミダゾ〔4, 5−d〕ピリジン−1−イル)エチル〕 Imidazo [4, 5-d] pyridin-1-yl) ethyl]
フェニル〕アセトアミド (131) N−〔4−〔2−(4−アミノ−2−n-ブチル−1,6,7,8−テトラヒドロ−2−シクロペンタ〔b〕イミダゾ〔4, 5−d〕ピリジン−1−イル)エチル〕フェニル〕アセトアミド (132) N−〔4−〔2−(4−アミノ−2−シクロプロピルメチル−1,6,7,8−テトラヒドロシクロペンタ〔b〕イミダゾ〔4, 5−d〕ピリジン−1−イル)エチル〕フェニル〕アセトアミド (133) N−〔4−〔2−(4−アミノ−2−エトキシメチル−1,6,7,8−テトラヒドロシクロペンタ〔b〕イミダゾ〔4, 5−d〕ピリジン−1−イル)エチル〕フェニル〕アセトアミド (134) N−〔4−〔2−(4−アミノ−1,6,7, Phenyl] acetamide (131) N-[4- [2- (4-amino -2-n-butyl--1,6,7,8- tetrahydro-2-cyclopenta [b] imidazo [4, 5-d] pyridine 1-yl) ethyl] phenyl] acetamide (132) N-[4- [2- (4-amino-2-cyclopropylmethyl--1,6,7,8- tetrahydrocyclopenta [b] imidazo [4, 5-d] pyridin-1-yl) ethyl] phenyl] acetamide (133) N-[4- [2- (4-amino-2-ethoxymethyl--1,6,7,8- tetrahydrocyclopenta [b] imidazo [4, 5-d] pyridin-1-yl) ethyl] phenyl] acetamide (134) N-[4- [2- (4-amino -1,6,7,
8,9,10−ヘキサヒドロシクロヘプタ〔b〕イミダゾ〔4, 5−d〕ピリジン−1−イル)エチル〕フェニル〕アセトアミド (135) N−〔4−〔2−(4−アミノ−1,6,7, 8,9,10 hexahydrocycloocta hepta [b] imidazo [4, 5-d] pyridin-1-yl) ethyl] phenyl] acetamide (135) N-[4- [2- (4-amino-1, 6, 7,
8,9,10−ヘキサヒドロ−2−メチルシクロヘプタ〔b〕イミダゾ〔4, 5−d〕ピリジン−1−イル)エチル〕フェニル〕アセトアミド (136) N−〔4−〔2−(4−アミノ−2−エチル− 8,9,10-hexahydro-2-methyl cycloheptanone [b] imidazo [4, 5-d] pyridin-1-yl) ethyl] phenyl] acetamide (136) N-[4- [2- (4-amino 2-ethyl -
1,6,7,8,9,10−ヘキサヒドロシクロヘプタ〔b〕イミダゾ〔4, 5−d〕ピリジン−1−イル)エチル〕フェニル〕アセトアミド (137) N−〔4−〔2−(4−アミノ−1,6,7, 1,6,7,8,9,10- hexahydrocycloocta hepta [b] imidazo [4, 5-d] pyridin-1-yl) ethyl] phenyl] acetamide (137) N-[4- [2- ( 4-amino -1,6,7,
8,9,10−ヘキサヒドロ−2−n-プロピルシクロヘプタ〔b〕イミダゾ〔4, 5−d〕ピリジン−1−イル)エチル〕フェニル〕アセトアミド (138) N−〔4−〔2−(4−アミノ−2−n-ブチル−1,6,7,8,9,10−ヘキサヒドロシクロヘプタ〔b〕イミダゾ〔4, 5−d〕ピリジン−1−イル) 8,9,10-hexahydro -2-n-propyl-cycloheptanone [b] imidazo [4, 5-d] pyridin-1-yl) ethyl] phenyl] acetamide (138) N-[4- [2- (4 - amino -2-n-butyl -1,6,7,8,9,10- hexahydrocycloocta hepta [b] imidazo [4, 5-d] pyridin-1-yl)
エチル〕フェニル〕アセトアミド (139) N−〔4−〔2−(4−アミノ−2−シクロプロピルメチル−1,6,7,8,9,10−ヘキサヒドロシクロヘプタ〔b〕イミダゾ〔4, 5−d〕ピリジン−1−イル)エチル〕フェニル〕アセトアミド (140) N−〔4−〔2−(4−アミノ−2−エトキシメチル−1,6,7,8,9,10−ヘキサヒドロシクロヘプタ〔b〕イミダゾ〔4, 5−d〕ピリジン−1− Ethyl] phenyl] acetamide (139) N-[4- [2- (4-amino-2-cyclopropylmethyl--1,6,7,8,9,10- hexahydrocycloocta hepta [b] imidazo [4, 5-d] pyridin-1-yl) ethyl] phenyl] acetamide (140) N-[4- [2- (4-amino-2-ethoxymethyl--1,6,7,8,9,10- hexahydro cyclohepta [b] imidazo [4, 5-d] pyridin-1
イル)エチル〕フェニル〕アセトアミド Yl) ethyl] phenyl] acetamide

【0019】(141) 1−〔2−〔4−(メチルアミノ)フェニル〕エチル〕−1H−イミダゾ〔4, 5− [0019] (141) 1- [2- [4- (methylamino) phenyl] ethyl] -1H- imidazo [4, 5-
c〕キノリン−4−アミン (142) 2−メチル−1−〔2−〔4−(メチルアミノ)フェニル〕エチル〕−1H−イミダゾ〔4, 5− c] quinolin-4-amine (142) 2-methyl-1- [2- [4- (methylamino) phenyl] ethyl] -1H- imidazo [4, 5-
c〕キノリン−4−アミン (143) 2−エチル−1−〔2−〔4−(メチルアミノ)フェニル〕エチル〕−1H−イミダゾ〔4, 5− c] quinolin-4-amine (143) 2-Ethyl-1- [2- [4- (methylamino) phenyl] ethyl] -1H- imidazo [4, 5-
c〕キノリン−4−アミン (144) 〔2−〔4−(メチルアミノ)フェニル〕エチル〕−2−n-プロピル−1H−イミダゾ〔4, 5−c〕 c] quinolin-4-amine (144) [2- [4- (methylamino) phenyl] ethyl] -2-n-propyl--1H- imidazo [4, 5-c]
キノリン−4−アミン (145) 2−n-ブチル−1−〔2−〔4−(メチルアミノ)フェニル〕エチル〕−1H−イミダゾ〔4, 5− Quinolin-4-amine (145) 2-n-butyl-1- [2- [4- (methylamino) phenyl] ethyl] -1H- imidazo [4, 5-
c〕キノリン−4−アミン (146) 2−シクロプロピルメチル−1−〔2−〔4− c] quinolin-4-amine (146) 2-cyclopropylmethyl-1- [2- [4-
(メチルアミノ)フェニル〕エチル〕−1H−イミダゾ〔4, 5−c〕キノリン−4−アミン (147) 2−エトキシメチル−1−〔2−〔4−(メチルアミノ)フェニル〕エチル〕−1H−イミダゾ〔4, (Methylamino) phenyl] ethyl] -1H- imidazo [4, 5-c] quinolin-4-amine (147) 2-ethoxymethyl-1- [2- [4- (methylamino) phenyl] ethyl] -1H - imidazo [4,
5−c〕キノリン−4−アミン (148) 6, 7, 8, 9−テトラヒドロ−1−〔2− 5-c] quinolin-4-amine (148) 6, 7, 8, 9-tetrahydro-1- [2-
〔4−(メチルアミノ)フェニル〕エチル〕−1H−イミダゾ〔4, 5−c〕キノリン−4−アミン (149) 6, 7, 8, 9−テトラヒドロ−2−メチル− [4- (methylamino) phenyl] ethyl] -1H- imidazo [4, 5-c] quinolin-4-amine (149) 6, 7, 8, 9-tetrahydro-2-methyl -
1−〔2−〔4−(メチルアミノ)フェニル〕エチル〕 1- [2- [4- (methylamino) phenyl] ethyl]
−1H−イミダゾ〔4, 5−c〕キノリン−4−アミン (150) 2−エチル−6, 7, 8, 9−テトラヒドロ− -1H- imidazo [4, 5-c] quinolin-4-amine (150) 2-ethyl-6, 7, 8, 9-tetrahydro -
1−〔2−〔4−(メチルアミノ)フェニル〕エチル〕 1- [2- [4- (methylamino) phenyl] ethyl]
−1H−イミダゾ〔4, 5−c〕キノリン−4−アミン (151) 6, 7, 8, 9−テトラヒドロ−1−〔2− -1H- imidazo [4, 5-c] quinolin-4-amine (151) 6, 7, 8, 9-tetrahydro-1- [2-
〔4−(メチルアミノ)フェニル〕エチル〕−2−n-プロピル−1H−イミダゾ〔4, 5−c〕キノリン−4− [4- (methylamino) phenyl] ethyl] -2-n-propyl--1H- imidazo [4, 5-c] quinolin-4
アミン (152) 2−n-ブチル−6, 7, 8, 9−テトラヒドロ−1−〔2−〔4−(メチルアミノ)フェニル〕エチル〕−1H−イミダゾ〔4, 5−c〕キノリン−4−アミン (153) 2−シクロプロピルメチル−6, 7, 8, 9− Amine (152) 2-n-butyl-6, 7, 8, 9-tetrahydro-1- [2- [4- (methylamino) phenyl] ethyl] -1H- imidazo [4, 5-c] quinolin -4 - amine (153) 2-cyclopropylmethyl-6, 7, 8, 9
テトラヒドロ−1−〔2−〔4−(メチルアミノ)フェニル〕エチル〕−1H−イミダゾ〔4, 5−c〕キノリン−4−アミン (154) 2−エトキシメチル−6, 7, 8, 9−テトラヒドロ−1−〔2−〔4−(メチルアミノ)フェニル〕 Tetrahydro-1- [2- [4- (methylamino) phenyl] ethyl] -1H- imidazo [4, 5-c] quinolin-4-amine (154) 2-ethoxymethyl-6, 7, 8, 9 tetrahydro-1- [2- [4- (methylamino) phenyl]
エチル〕−1H−イミダゾ〔4, 5−c〕キノリン−4 Ethyl] -1H- imidazo [4, 5-c] quinolin -4
−アミン (155) 1,6,7,8−テトラヒドロ−1−〔2− - amine (155) 1,6,7,8-tetrahydro-1- [2-
〔4−(メチルアミノ)フェニル〕エチル〕シクロペンタ〔b〕イミダゾ〔4, 5−d〕ピリジン−4−アミン (156) 1,6,7,8−テトラヒドロ−2−メチル− [4- (methylamino) phenyl] ethyl] cyclopenta [b] imidazo [4, 5-d] pyridin-4-amine (156) 1,6,7,8-tetrahydro-2-methyl -
1−〔2−〔4−(メチルアミノ)フェニル〕エチル〕 1- [2- [4- (methylamino) phenyl] ethyl]
シクロペンタ〔b〕イミダゾ〔4, 5−d〕ピリジン− Cyclopenta [b] imidazo [4, 5-d] pyridine -
4−アミン (157) 2−エチル−1,6,7,8−テトラヒドロ− 4- amine (157) 2-ethyl -1,6,7,8- tetrahydro -
1−〔2−〔4−(メチルアミノ)フェニル〕エチル〕 1- [2- [4- (methylamino) phenyl] ethyl]
シクロペンタ〔b〕イミダゾ〔4, 5−d〕ピリジン− Cyclopenta [b] imidazo [4, 5-d] pyridine -
4−アミン (158) 1,6,7,8−テトラヒドロ−1−〔2− 4- amine (158) 1,6,7,8-tetrahydro-1- [2-
〔4−(メチルアミノ)フェニル〕エチル〕−2−n-プロピルシクロペンタ〔b〕イミダゾ〔4, 5−d〕ピリジン−4−アミン (159) 2−n-ブチル−1,6,7,8−テトラヒドロ−1−〔2−〔4−(メチルアミノ)フェニル〕エチル〕シクロペンタ〔b〕イミダゾ〔4, 5−d〕ピリジン−4−アミン (160) 2−シクロプロピルメチル−1,6,7,8− [4- (methylamino) phenyl] ethyl] -2-n-propyl-cyclopentadienyl [b] imidazo [4, 5-d] pyridin-4-amine (159) 2-n-butyl -1,6,7, 8-tetrahydro-1- [2- [4- (methylamino) phenyl] ethyl] cyclopenta [b] imidazo [4, 5-d] pyridin-4-amine (160) 2-cyclopropylmethyl-1,6, 7,8
テトラヒドロ−1−〔2−〔4−(メチルアミノ)フェニル〕エチル〕シクロペンタ〔b〕イミダゾ〔4, 5− Tetrahydro-1- [2- [4- (methylamino) phenyl] ethyl] cyclopenta [b] imidazo [4, 5-
d〕ピリジン−4−アミン d] pyridine-4-amine

【0020】(161) 2−エトキシメチル−1,6, [0020] (161) 2-ethoxymethyl-1,6,
7,8−テトラヒドロ−1−〔2−〔4−(メチルアミノ)フェニル〕エチル〕シクロペンタ〔b〕イミダゾ〔4, 5−d〕ピリジン−4−アミン (162) 1,6,7,8,9,10−ヘキサヒドロ−1 7,8-tetrahydro-1- [2- [4- (methylamino) phenyl] ethyl] cyclopenta [b] imidazo [4, 5-d] pyridin-4-amine (162) 1, 6, 7, 8, 9,10-hexahydro-1
−〔2−〔4−(メチルアミノ)フェニル〕エチル〕シクロヘプタ〔b〕イミダゾ〔4, 5−d〕ピリジン−4 - [2- [4- (methylamino) phenyl] ethyl] cyclohepta [b] imidazo [4, 5-d] pyridine -4
−アミン (163) 1,6,7,8,9,10−ヘキサヒドロ−2 - amine (163) 1,6,7,8,9,10- hexahydro -2
−メチル−1−〔2−〔4−(メチルアミノ)フェニル〕エチル〕シクロヘプタ〔b〕イミダゾ〔4, 5− - methyl-1- [2- [4- (methylamino) phenyl] ethyl] cyclohepta [b] imidazo [4, 5-
d〕ピリジン−4−アミン (164) 2−エチル−1,6,7,8,9,10−ヘキサヒドロ−1−〔2−〔4−(メチルアミノ)フェニル〕エチル〕シクロヘプタ〔b〕イミダゾ〔4, 5− d] pyridin-4-amine (164) 2-ethyl--1,6,7,8,9,10- hexahydro-1- [2- [4- (methylamino) phenyl] ethyl] cyclohepta [b] imidazo [ 4, 5
d〕ピリジン−4−アミン (165) 1,6,7,8,9,10−ヘキサヒドロ−1 d] pyridin-4-amine (165) 1,6,7,8,9,10- hexahydro-1
−〔2−〔4−(メチルアミノ)フェニル〕エチル〕− - [2- [4- (methylamino) phenyl] ethyl] -
2−n-プロピルシクロヘプタ〔b〕イミダゾ〔4, 5− 2-n-propyl-cycloheptanone [b] imidazo [4, 5-
d〕ピリジン−4−アミン (166) 2−n-ブチル−1,6,7,8,9,10−ヘキサヒドロ−1−〔2−〔4−(メチルアミノ)フェニル〕エチル〕シクロヘプタ〔b〕イミダゾ〔4,5− d] pyridin-4-amine (166) 2-n-butyl--1,6,7,8,9,10- hexahydro-1- [2- [4- (methylamino) phenyl] ethyl] cyclohepta [b] imidazo [4,5
d〕ピリジン−4−アミン (167) 2−シクロプロピルメチル−1,6,7,8, d] pyridin-4-amine (167) 2-cyclopropylmethyl -1,6,7,8,
9,10−ヘキサヒドロ−1−〔2−〔4−(メチルアミノ)フェニル〕エチル〕シクロヘプタ〔b〕イミダゾ〔4, 5−d〕ピリジン−4−アミン (168) 2−エトキシメチル−1,6,7,8,9,1 9,10-hexahydro-1- [2- [4- (methylamino) phenyl] ethyl] cyclohepta [b] imidazo [4, 5-d] pyridin-4-amine (168) 2-ethoxymethyl-1,6 , 7,8,9,1
0−ヘキサヒドロ−1−〔2−〔4−(メチルアミノ) 0-hexahydro-1- [2- [4- (methylamino)
フェニル〕エチル〕シクロヘプタ〔b〕イミダゾ〔4, Phenyl] ethyl] cyclohepta [b] imidazo [4,
5−d〕ピリジン−4−アミン 5-d] pyridin-4-amine

【0021】本発明の前記一般式(I)で示される新規な1−(置換アリール)アルキル−1H−イミダゾピリジン−4−アミン誘導体の製造は種々の方法により行うことができる。 The preparation of the novel 1- (substituted aryl) alkyl -1H- imidazopyridine-4-amine derivative represented by the above-described general formula (I) of the present invention can be carried out by various methods. 本発明の製造方法の第一の様式としては、特開平3−206078号に開示された方法に準じた以下の製造方法を挙げることができ、この製造方法により一般式(I)において、R 1がSO 2 NR 89 The first mode of the manufacturing method of the present invention, there may be mentioned the following manufacturing method according to the method disclosed in JP-A-3-206078, in the general formula (I) by this manufacturing method, R 1 There SO 2 NR 8 R 9,
CONR 89 ,NR 1011で示される基又は水酸基、 Or hydroxyl group represented by CONR 8 R 9, NR 10 R 11,
5が水素原子であり、その中でR 10が低級アルキル基またはベンジル基で、R 11が低級アルキル基,ベンジル基,低級アルカンスルホニル基,低級アルカノイル基又は置換もしくは未置換のベンゼンスルホニル基である化合物を合成することができる。 R 5 is a hydrogen atom, with in which R 10 is a lower alkyl group or a benzyl group, R 11 is a lower alkyl group, a benzyl group, a lower alkanesulfonyl group, a lower alkanoyl group or a substituted or unsubstituted benzenesulfonyl group it can be synthesized a compound.

【0022】 [0022]

【化3】 [Formula 3] (式中、R 1 'はSO 2 NR 89 ,CONR 89 ,N (In the formula, R 1 'is SO 2 NR 8 R 9, CONR 8 R 9, N
10 ' R 11 ' で示される基又は水酸基を表し、R 10 ' が水素原子の場合、R 11 ' は低級アルカンスルホニル基, It represents a group or a hydroxy group represented by R 10 'R 11', 'when the hydrogen atom, R 11' R 10 is a lower alkanesulfonyl group,
低級アルカノイル基,低級アルキル基又は置換もしくは未置換のベンゼンスルホニル基を表し、R 10 ' が低級アルキル基又はベンジル基の場合、R 11 ' は低級アルキル基,ベンジル基,低級アルカンスルホニル基,低級アルカノイル基又は置換もしくは未置換のベンゼンスルホニル基を表し、R 2 ,R 3 ,R 4 ,R 6 ,R 8 ,R 9 Lower alkanoyl group, a lower alkyl group or a substituted or unsubstituted benzenesulfonyl group, 'If a lower alkyl group or a benzyl group, R 11' R 10 is a lower alkyl group, a benzyl group, a lower alkanesulfonyl group, a lower alkanoyl It represents a group or a substituted or unsubstituted benzenesulfonyl group, R 2, R 3, R 4, R 6, R 8, R 9,
m,n,X,Y及び点線と実線で示される結合は前述と同意義を表す。 m, n bond, X, represented by Y and the dotted line and the solid line has the same meanings as that described above. )

【0023】本発明の製造方法において出発原料となる一般式(II)及び(III)で示される化合物は、既知の化合物あるいは市販化合物であり、その製造方法はJourna The compounds of the formula as a starting material in the production method of the present invention (II) and (III) are known compounds or commercially available compounds, methods of making Journa
l ofMedicinal Chemistry,18巻,726頁(197 l ofMedicinal Chemistry, 18, pp. 726, pp. (197
5年)等に開示されている。 It is disclosed in 5 years), and the like.

【0024】即ち、工程1においては、一般式(II)で示される化合物を酢酸等の溶媒の存在下あるいは非存在下、発煙硝酸等のニトロ化剤を用い、0℃から溶媒の還流温度の間で反応を行って、一般式(III)の化合物を得ることができる。 [0024] That is, in the step 1, the formula in the presence or absence of a solvent such as acetic acid a compound represented by (II), using a nitrating agent such as fuming nitric acid, the reflux temperature 0 ℃ solvent the reaction was carried out between, to give compounds of general formula (III).

【0025】工程2においては、一般式(III) の化合物を塩素化剤、例えば、オキシ塩化リン,塩化チオニル, [0025] In step 2, the chlorinating agent a compound of formula (III), for example, phosphorus oxychloride, thionyl chloride,
ホスゲン,塩化オキザリル,五塩化リン等を用いて、 Phosgene, oxalyl chloride, using phosphorus pentachloride, etc.,
N,N−ジメチルホルムアミド又は塩化メチレン等の不活性溶媒の存在下あるいは非存在下に、0℃から溶媒の還流温度の間で反応を行って、一般式(IV)の化合物を得ることができる。 N, N- dimethylformamide or in the presence or absence of an inert solvent, such as methylene chloride, The reaction was carried out at between 0 ℃ the reflux temperature of the solvent, to give compounds of general formula (IV) .

【0026】工程3においては、特開平2−6461 [0026] In step 3, Hei 2-6461
号,特開昭62−116575号,特開昭59−484 JP, JP-A-62-116575, JP-A-59-484
47号,特開昭52−85137号及びJournal of Med No. 47, JP-A-52-85137 and Journal of Med
icinalChemistry,20巻,1212頁(1977年) icinalChemistry, 20, pp. 1212 (1977)
等にその製造方法が開示されている次の一般式(IX) The following general formula in which the manufacturing method and the like have been disclosed (IX)

【化4】 [Of 4] (式中、R 1 ',R 2 ,R 3 ,m,n及びYは前述と同意義を表す。)で示されるアミンと一般式(IV)の化合物を、N,N−ジメチルホルムアミド又は塩化メチレン等の不活性溶媒中、トリエチルアミン,炭酸カリウム等の塩基の存在下又は非存在下に、−10℃から溶媒の還流温度の間で反応することにより、一般式(V)の化合物を得ることができる。 (Wherein, R 1 ', R 2, R 3, m, n and Y. Representing the same meaning as described above) amine and the general formula represented by the compound of (IV), N, N-dimethylformamide or chloride inert solvent methylene such as triethylamine, in the presence or absence of a base such as potassium carbonate, by reacting at between -10 ° C. to the reflux temperature of the solvent, to give a compound of general formula (V) can.

【0027】工程4においては、一般式(V)の化合物のニトロ基を適当な還元方法、例えば、白金,ラネーニッケル,パラジウム炭素等の触媒を用いた接触還元法、 [0027] In step 4, an appropriate reduction method of the nitro group of the compound of the general formula (V), for example, catalytic reduction using platinum, Raney nickel, a catalyst of palladium carbon or the like,
塩化ニッケルと水素化ホウ素ナトリウムを用いた還元法、鉄粉と塩酸を用いた還元法等で還元して、一般式(V Reduction method using nickel chloride and sodium borohydride, is reduced with a reducing method using iron powder and hydrochloric acid, the general formula (V
I)の化合物を得ることができる。 To give a compound of I).

【0028】工程5においては、一般式(VI)の化合物を次の一般式(X) R 4 C(OR) 3 (X) (式中、Rは低級アルキル基を、R 4は前述と同意義を表す。)で示されるトリアルキルオルトエステルと共に、塩酸又は硫酸等の酸触媒の存在下あるいは非存在下、N,N−ジメチルホルムアミド又は塩化メチレン等の不活性溶媒の存在下あるいは非存在下に、0℃から2 [0028] In step 5, the compound of the general formula of general formula (VI) (X) R 4 C (OR) 3 (X) ( wherein, R a lower alkyl group, R 4 is the same as above represents the significance. with trialkyl ortho ester represented by), the presence or absence of an acid catalyst such as hydrochloric acid or sulfuric acid, N, N-dimethylformamide or the presence or absence of an inert solvent such as methylene chloride to, 2 from 0 ℃
00℃の間で反応することにより、一般式(VII) (ただし、一般式(VI)のR 1 'がSO 2 NH 2基の場合、反応条件によってはR 1 'はSO 2 N=C(OR)R 4基を表す。)の化合物を得ることができる。 By reaction between 00 ° C., the general formula (VII) (where 'if is SO 2 NH 2 group, depending on the reaction conditions R 1' R 1 of the general formula (VI) SO 2 N = C ( to give the compound of the OR) representing the R 4 group.). ただし、化合物によっては一般式(VI)から一般式(VII) への反応中間体である次の一般式(XI) However, the following general formula by a compound which is a reaction intermediate of the general formulas (VI) to formula (VII) (XI)

【化5】 [Of 5] (式中、R,R 1 ',R 2 ,R 3 ,R 4 ,R 6 ,m,n, (Wherein, R, R 1 ', R 2, R 3, R 4, R 6, m, n,
X及びYは前述と同意義を表す。 X and Y has the same meanings as that described above. )から反応が進行しにくい場合もあり、その場合には得られた中間体(XI)を ) From some cases the reaction is difficult to proceed, the intermediate obtained in that case the (XI)
p-トルエンスルホン酸等の酸触媒の存在下あるいは非存在下、N,N−ジメチルホルムアミド,アセトニトリル又はトルエン等の不活性溶媒の存在下あるいは非存在下に、0℃から200℃の間で反応することにより一般式 Presence or absence of an acid catalyst such as p- toluenesulfonic acid, N, N- dimethylformamide, in the presence or absence of an inert solvent such as acetonitrile or toluene, the reaction between 200 ° C. from 0 ℃ the general formula by
(VII) の化合物を得ることができる。 The compounds of (VII) can be obtained.

【0029】また、その他の方法として、一般式(VI)の化合物を次の一般式(XII) R 4 COZ (XII) (式中、Zは塩素原子又は臭素原子を、R 4は前述と同意義を表す。)で示される化合物と共に、p-トルエンスルホン酸等の酸触媒の存在下あるいは非存在下、N,N Further, as another method, the compound of the general formula (XII) R 4 COZ (XII ) ( wherein in the general formula (VI), Z is a chlorine atom or a bromine atom, R 4 is the same as above with compounds represented by the representative of the meaning.), the presence or absence of an acid catalyst such as p- toluenesulfonic acid, N, N
−ジメチルホルムアミド,アセトニトリル又はトルエン等の不活性溶媒の存在下あるいは非存在下に、0℃から200℃の間で反応することによって一般式(VII)(ただし、一般式(VI)のR 1 'が水酸基の場合、R 1 'はOC - dimethylformamide, in the presence or absence of an inert solvent such as acetonitrile or toluene, formula by reaction between 200 ° C. from 0 ℃ (VII) (provided that, R 1 of the general formula (VI) ' If is a hydroxyl group, R 1 'is OC
OR 4基を表す。 It represents an OR 4 group. )の化合物を得ることができる。 ) Can be obtained of the compound.

【0030】さらに、その他の方法として、一般式(VI) [0030] In addition, as other methods, the general formula (VI)
の化合物を次の一般式(XIII) R 4 COOH (XIII) (式中、R 4は前述と同意義を表す。)で示される化合物と共に、塩酸又は硫酸等の酸触媒の存在下あるいは非存在下、N,N−ジメチルホルムアミド又は塩化メチレン等の不活性溶媒の存在下あるいは非存在下に、0℃から200℃の間で反応することにより次の一般式(XIV) (Wherein, R 4 represents. The same meaning as described above) the general formula of the compounds of the (XIII) R 4 COOH (XIII) with a compound represented by the presence or absence of an acid catalyst such as hydrochloric acid or sulfuric lower, N, N-dimethylformamide or in the presence or absence of an inert solvent such as methylene chloride, the following general formula by reaction between 200 ° C. from 0 ° C. (XIV)

【化6】 [Omitted] (式中、一般式(VI)のR 1 'が水酸基の場合R 1 'はOC (In the formula, R 1 'when the hydroxyl group R 1' is OC of formula (VI)
OR 4基を表し、その他の場合はR 1 ',R 2 ,R 3 ,R Represents OR 4 group, R 1 is otherwise ', R 2, R 3, R
4 ,R 6 ,m,n,X及びYは前述と同意義を表す。 4, R 6, m, n , X and Y has the same meanings as that described above. )
の化合物を得た後、この化合物を塩素化剤と処理することにより一般式(VII)の化合物を得ることができる。 After obtaining the compound, to give compounds of general formula (VII) by treating the compound with a chlorinating agent. この塩素化反応に際し、一般式(XIV)の化合物のR 4が水素原子あるいは低級アルコキシ基,ハロゲン原子もしくは環状アルキル基で置換された直鎖又は分枝鎖状のアルキル基である場合は、一般式(XIV)の化合物をそのまま塩素化剤と反応し、一方、一般式(XIV)の化合物のR 4 Upon chlorination reaction, when R 4 in compounds of general formula (XIV) is a hydrogen atom or a lower alkoxy group, a linear or branched alkyl group substituted with a halogen atom or cyclic alkyl group generally directly reacted with a chlorinating agent compound of formula (XIV), whereas, R 4 of the compounds of general formula (XIV)
が一個又は複数個の水酸基を有した直鎖又は分枝鎖状のアルキル基である場合は、その水酸基をアセチル基等の保護基で保護した後に(この場合、R 4はアセチル基等の保護基で保護された一個又は複数個の水酸基を有する直鎖又は分枝鎖状のアルキル基を表す。)、塩素化剤と反応することにより製造することができる。 If There is a single or a plurality of linear having a hydroxyl group or a branched alkyl group, the (in this case after protecting the hydroxyl group with a protective group such as an acetyl group, R 4 is protected, such as an acetyl group represents a linear or branched alkyl group having one or more hydroxyl groups protected with a group.) can be prepared by reacting with a chlorinating agent.

【0031】この塩素化反応においては、適当な塩素化剤、例えば、オキシ塩化リン,塩化チオニル,ホスゲン,塩化オキザリル,五塩化リン等を、N,N−ジメチルホルムアミド又は塩化メチレン等の不活性溶媒の存在下あるいは非存在下に、0℃から溶媒の還流温度の間で反応させることにより、一般式(VII)(ただし、一般式(XIV)のR 4が一個又は複数個の水酸基を有した直鎖又は分枝鎖状のアルキル基である場合は、R 4はアセチル基等の保護基で保護された一個又は複数個の水酸基を有する直鎖又は分枝鎖状のアルキル基を表す。)の化合物を得ることができる。 [0031] In the chlorination reaction, a suitable chlorinating agent, for example, phosphorus oxychloride, thionyl chloride, phosgene, oxalyl chloride, phosphorus pentachloride or the like, N, N-dimethylformamide or an inert solvent such as methylene chloride presence or absence of, by reacting at between 0 ℃ the reflux temperature of the solvent, the general formula (VII) (provided that, R 4 in the general formula (XIV) had a one or more hydroxyl groups If a linear or branched alkyl group, R 4 represents a linear or branched alkyl group having one or more hydroxyl groups protected with a protecting group such as an acetyl group.) it can be obtained of the compound.

【0032】工程6においては、一般式(VII) の化合物とフェノールを、水酸化ナトリウムや水酸化カリウム等のアルカリと共に、N,N−ジメチルホルムアミド又は塩化メチレン等の不活性溶媒の存在下あるいは非存在下に、0℃から200℃の間で反応することにより、一般式(VIII)の化合物を得ることができる。 [0032] In step 6, a compound with a phenol formula (VII), with an alkali such as sodium hydroxide or potassium hydroxide, N, N-dimethylformamide or in the presence of an inert solvent such as methylene chloride or non in the presence, by reaction between 200 ° C. from 0 ° C., to give compounds of general formula (VIII).

【0033】工程7においては、一般式(VIII)の化合物を酢酸アンモニウムと共に、N,N−ジメチルホルムアミド又は塩化メチレン等の不活性溶媒の存在下あるいは非存在下に、0℃から200℃の間で反応することにより、一般式(I)の化合物を得ることができる。 [0033] In step 7, a compound of general formula (VIII) with ammonium acetate, N, N-dimethylformamide or in the presence or absence of an inert solvent such as methylene chloride, between 200 ° C. from 0 ℃ in by reacting, to give compounds of general formula (I).

【0034】また、製造方法の第二の様式としては以下の製造方法を挙げることができる。 Further, as the second mode of the manufacturing method may include the following production methods.

【化7】 [Omitted] (式中、R 13は低級アルキル基又はベンジル基を表し、 (Wherein, R 13 represents a lower alkyl group or a benzyl group,
1 ',R 2 ,R 3 ,R 4 ,R 6 ,m,n,X及びYは前述と同意義を表す。 R 1 ', R 2, R 3, R 4, R 6, m, n, X and Y has the same meanings as that described above. ) 即ち、工程8においては前述の第一の様式により得られる一般式(V)の化合物とジベンジルアミンあるいはN ) Namely, the compound of the general formula in the process 8 is obtained by the first mode of the above-mentioned (V) and dibenzylamine or N
−低級アルキル−N−ベンジルアミンを、N,N−ジメチルホルムアミド又は塩化メチレン等の不活性溶媒の存在下あるいは非存在下、トリエチルアミンや炭酸カリウム等の塩基の存在下あるいは非存在下に、0℃から20 - lower alkyl -N- benzylamine, N, N-dimethylformamide or the presence or absence of an inert solvent such as methylene chloride, in the presence or absence of a base such as triethylamine or potassium carbonate, 0 ° C. from 20
0℃の間で反応することにより、一般式(XV)の化合物を得ることができる。 By reaction between 0 ° C., to give compounds of general formula (XV).

【0035】工程9においては一般式(XV)の化合物のニトロ基を適当な還元方法、例えば、塩化ニッケルと水素化ホウ素ナトリウムを用いた還元法、鉄粉と塩酸を用いた還元法等により還元して、一般式(XVI)の化合物を得ることができる。 [0035] Suitable reduction method of the nitro group of the compound of the general formula in step 9 (XV), for example, reduced by a reducing method using the reducing method using nickel chloride and sodium borohydride, iron powder and hydrochloric acid , it is possible to obtain a compound of general formula (XVI).

【0036】工程10においては一般式(XVI)の化合物を前述の工程5と同様に、一般式(X)、一般式(XII) [0036] Formula In step 10 the compound of (XVI) in the same manner as the aforementioned Step 5, the general formula (X), the general formula (XII)
あるいは一般式(XIII)の化合物と共に、同様の条件で反応することにより、一般式(XVII)の化合物を得ることができる。 Or together with compounds of the general formula (XIII), by reaction in the same conditions, to give compounds of general formula (XVII).

【0037】工程11においては一般式(XVII)の化合物を適当な脱ベンジル反応、例えば、ギ酸アンモニウム,ギ酸等の水素ドナーの存在下、パラジウム炭素,パールマンズ試薬等の触媒を用いた接触還元により脱ベンジル反応を行い、一般式(I)の化合物を得ることができる。 The general formula in step 11 (XVII) compounds suitable debenzylation, for example, ammonium formate in the presence of hydrogen donor such as formic acid, palladium on carbon, by catalytic reduction using a catalyst such as Pearlman's reagent perform debenzylation reaction, to give compounds of general formula (I).

【0038】また、製造方法の第三の様式としては、R [0038] In addition, as a third mode of production method, R
1がNR 1011で示される基であり、かつR 11が水素原子である一般式(I)の化合物の製造方法を挙げることができる。 1 is a group represented by NR 10 R 11, and can be exemplified a process for the preparation of a compound of the general formula R 11 is a hydrogen atom (I). 即ち、前述の第一の様式で得ることができるR 1がNR 1011で示される基であり、かつR 11が低級アルカノイル基である一般式(I)の化合物を、水あるいはメタノール,エタノール,n-プロパノール,イソプロパノール,n-ブタノール,sec-ブタノール,tert- ブタノール等のアルコール系溶媒あるいは水とアルコールとの混合溶媒中、塩酸や硫酸等の酸あるいは水酸化ナトリウムや水酸化カリウム等のアルカリを用い、室温から溶媒の還流温度の範囲で加水分解することにより製造することができる。 That is a group R 1 which can be obtained in the first mode of the aforementioned represented by NR 10 R 11, and a compound of the general formula R 11 is a lower alkanoyl group (I), water or methanol, ethanol , n- propanol, isopropanol, n- butanol, sec- butanol, tert- alcohol solvent or water and a mixed solvent of alcohol such as butanol, an alkali such as an acid or as sodium hydroxide or potassium hydroxide, such as hydrochloric acid or sulfuric the use can be prepared by hydrolysis in the range of the reflux temperature of the solvent at room temperature.

【0039】また、製造方法の第四の様式は、R 1がN Further, a fourth mode of the manufacturing method, R 1 is N
1011で示される基であり、かつR 10とR 11の少なくとも一方が水素原子で、もう一方が水素原子又は低級アルキル基である一般式(I)の化合物の製造方法に関する。 A group represented by R 10 R 11, and at least one hydrogen atom of R 10 and R 11, the other methods for the preparation of compounds of general formula (I) is a hydrogen atom or a lower alkyl group. 即ち、前述の製造方法の第一又は第二の様式により得ることができる次の一般式(XVIII ) That is, the following formula can be obtained by the first or second mode of the aforementioned method (XVIII)

【化8】 [Of 8] (式中、R 14は低級アルキル基又はベンジル基を、R 15 (Wherein, R 14 is a lower alkyl group or a benzyl group, R 15
は水素原子又はベンジル基を、R 16は水素原子、低級アルキル基又はベンジル基を表し、R 2 ,R 3 ,R 4 ,R The hydrogen atom or a benzyl group, R 16 represents a hydrogen atom, a lower alkyl group or a benzyl group, R 2, R 3, R 4, R
6 ,m,n,X又はYは前述と同意義を表す。 6, m, n, X or Y has the same meanings as that described above. )で示される化合物を、水素,ギ酸やギ酸アンモニウム等の水素ドナーの存在下に、パラジウム炭素やパールマンズ試薬等の触媒を用いた接触還元等により脱ベンジルすることにより一般式(I)の化合物を得ることができる。 The compound represented by), hydrogen in the presence of a hydrogen donor such as ammonium formate or formic acid, a compound of the general formula (I) by debenzylation by catalytic reduction using a catalyst such as palladium-carbon or Pearlman's reagent it is possible to obtain.

【0040】また、製造方法の第五の様式としては以下の製造方法を挙げることもできる。 [0040] In addition, as the fifth mode of the manufacturing method can also be mentioned the following manufacturing method.

【化9】 [Omitted] (式中、R 17は水素原子又は低級アルキル基を、Wは酸素原子又は硫黄原子を表し、R 2 ,R 3 ,R 4 ,R 5 (Wherein the R 17 is a hydrogen atom or a lower alkyl group, W is an oxygen atom or a sulfur atom, R 2, R 3, R 4, R 5,
6 ,m,n,X又はYは前述と同意義を表す。 R 6, m, n, X or Y has the same meanings as that described above. ) 即ち、工程12において前述の製造方法の第三又は第四の様式により得ることができる一般式(XIX) の化合物を、適当な尿素化剤あるいはチオ尿素化剤と共にN,N ) That is, the third or the compound of general formula (XIX) can be obtained by a fourth manner, N with an appropriate urea agents or thiourea agent of the aforementioned manufacturing method in step 12, N
−ジメチルホルムアミド,アセトニトリル又はトルエン等の不活性溶媒の存在下あるいは非存在下に、0℃から200℃の間で反応を行うことにより、一般式(XX)で示される化合物を得ることができる。 - dimethylformamide, in the presence or absence of an inert solvent such as acetonitrile or toluene, by carrying out the reaction between 200 ° C. from 0 ° C., to give a compound represented by the general formula (XX). 適当な尿素化剤としては、例えば、尿素,シアン酸,シアン酸ナトリウム, Suitable urea agents, e.g., urea, cyanate, sodium cyanate,
シアン酸カリウム,ウレタン,アルキルウレタン,アルキルイソシアナート等が挙げられ、又、チオ尿素化剤としては、例えば、チオウレタン,アルキルチオウレタン,アルキルイソチオシアナート等が挙げられる。 Potassium cyanate, urethane, alkyl urethanes, alkyl isocyanates and the like, and also, as the thiourea agents, for example, thiourethane, alkyl thio urethane, and alkyl isothiocyanate and the like.

【0041】また、製造方法の第六の様式としては以下の製造方法を挙げることもできる。 [0041] In addition, as the sixth mode of the manufacturing method can also be mentioned the following manufacturing method.

【化10】 [Of 10] (式中、R 2 ,R 3 ,R 4 ,R 6 ,m,n,X又はYは前述と同意義を表す。) 即ち、工程13においては前述の製造方法の第一又は第二の様式により得ることができる一般式(XXI) の化合物を、適当な脱水剤と共に0℃から200℃の間で反応を行うことにより、一般式(XXII)で示される化合物を得ることができる。 (Wherein, R 2, R 3, R 4, R 6, m, n, X or Y has the same meanings as that described above.) That is, the first or second mode of the aforementioned manufacturing method in step 13 compounds of general formula (XXI) can be obtained by a, by carrying out the reaction between 200 ° C. from 0 ℃ with a suitable dehydrating agent, to give a compound represented by the general formula (XXII). 適当な脱水剤としては、例えば、オキシ塩化リン,塩化チオニル,五酸化二リン,p-トルエンスルホニルクロリド,メタンスルホニルクロリド,N, Suitable dehydrating agents include, for example, phosphorus oxychloride, thionyl chloride, phosphorus pentoxide, p- toluenesulfonyl chloride, methanesulfonyl chloride, N,
N'−ジシクロヘキシルカルボジイミド,無水酢酸,無水トリフルオロ酢酸等が挙げられる。 N'- dicyclohexylcarbodiimide, acetic anhydride, and the like trifluoroacetic anhydride.

【0042】工程14においては一般式(XXII)の化合物を、前述の工程7と同様の方法で反応することより、一般式(XXIII) で示される化合物を得ることができる。 [0042] Formula In step 14 the compound of (XXII), than to the reaction in the same manner as in Step 7 described above, it is possible to obtain a compound represented by the general formula (XXIII).

【0043】また、製造方法の第七の様式としては以下の製造方法を挙げることもできる。 [0043] In addition, as the seventh mode of the manufacturing method can also be mentioned the following manufacturing method.

【化11】 [Of 11] (式中、R 18は低級アルキル基を表し、R 2 ,R 3 ,R (Wherein, R 18 represents a lower alkyl group, R 2, R 3, R
4 ,R 6 ,m,n,X又はYは前述と同意義を表す。 4, R 6, m, n , X or Y has the same meanings as that described above. ) 即ち、工程15においては前述の製造方法の第一の様式により得ることができる一般式(XXIV)の化合物を、前述の工程6と同様の方法で反応を行うことにより、一般式 ) In other words, the general formula can be obtained by the first mode of the aforementioned manufacturing method in step 15 the compound of (XXIV), by carrying out the reaction in the same manner as in Step 6 above, the general formula
(XXV) で示される化合物を得、工程16においては、一般式(XXV)の化合物を前述の工程7と同様の方法で反応を行うことにより、一般式(XXVI)で示される化合物を得ることができる。 To give a compound represented by (XXV), in step 16, the compounds of the general formula (XXV) carrying out the reaction in the same manner as in Step 7 described above, to give a compound represented by the general formula (XXVI) can.

【0044】工程17においては、一般式(XXVI)の化合物をメタノール,エタノール等のアルコールと、適当な酸触媒の存在下、室温から溶媒の還流温度の範囲で反応させることにより、一般式(XXVII) で示される化合物を得ることができる。 [0044] In step 17, methanol compound of the general formula (XXVI), an alcohol such as ethanol in the presence of a suitable acid catalyst, by reacting in the range of the reflux temperature of the solvent at room temperature and has the general formula (XXVII compounds can be obtained as indicated by). 適当な酸触媒としては、例えば、 Suitable acid catalysts, for example,
濃塩酸,濃硫酸,塩化チオニルやアルコール性塩化水素等が挙げられる。 Concentrated hydrochloric acid, concentrated sulfuric acid, thionyl chloride or alcoholic hydrogen chloride.

【0045】また、製造方法の第八の様式としては以下の製造方法を挙げることもできる。 Further, as the eighth mode of the manufacturing method may also include the following production methods.

【化12】 [Of 12] (式中、R 19は低級アルキル基を表し、R 2 ,R 3 ,R (Wherein, R 19 represents a lower alkyl group, R 2, R 3, R
4 ,R 6 ,m,n,X又はYは前述と同意義を表す。 4, R 6, m, n , X or Y has the same meanings as that described above. ) 即ち、工程18においては前述の製造方法の第一の様式により得ることができる一般式(XXVIII)の化合物を、前述の工程7と同様の方法で反応を行うことにより、一般式(XXIX)で示される化合物を得ることができる。 ) In other words, the general formula can be obtained by the first mode of the aforementioned manufacturing method in step 18 the compound of (XXVIII), by carrying out the reaction in the same manner as in Step 7 described above, the general formula (XXIX) in compound can be obtained as shown.

【0046】工程19においては、一般式(XXIX)の化合物と塩酸ヒドキシルアミンを、酢酸ナトリウム,トリエチルアミン,炭酸カリウム等の塩基の存在下あるいは非存在下、N,N−ジメチルホルムアミド,メタノール,エタノール等のアルコール又は塩化メチレン等の不活性溶媒の存在下あるいは非存在下、0℃から200℃ [0046] In step 19, a compound with hydrochloric Hidokishiruamin of general formula (XXIX), sodium acetate, triethylamine, presence or absence of a base such as potassium carbonate, N, N- dimethylformamide, methanol, ethanol alcohol or the presence or absence of an inert solvent such as methylene chloride etc., 200 ° C. from 0 ℃
の範囲で反応を行うことにより、一般式(XXX) で示される化合物を得ることができる。 By carrying out the reaction in the range of, it is possible to obtain a compound represented by the general formula (XXX).

【0047】工程20においては、一般式(XXX)の化合物を適当な触媒を用いた接触還元法等によりオキシム基を還元して、一般式(XXXI)で示される化合物を得ることができる。 [0047] In step 20, a compound of general formula (XXX) by reducing an oxime group by a catalytic reduction method using a suitable catalyst, to give a compound represented by the general formula (XXXI). 適当な触媒としては、例えば、白金,ラネーニッケル,パラジウム炭素等が挙げられ、反応は水あるいはメタノール,エタノール等のアルコール性溶媒又は水とアルコール性溶媒の混液等の溶媒中、アンモニア水やアンモニアガスの存在下あるいは非存在下に、室温から200℃の温度条件下、常圧から100気圧の範囲で行うことができる。 Suitable catalysts, e.g., platinum, Raney nickel, palladium carbon and the like, the reaction is water or methanol, the mixture such alcoholic solvent or water and an alcohol solvent such as ethanol in the solvent, aqueous ammonia or ammonia gas or under the absence present, it may be in the range of 100 atmospheres temperature conditions, atmospheric pressure 200 ° C. from room temperature.

【0048】この様にして製造される前記一般式(I) [0048] The general formula produced in this way (I)
で示される新規な1−(置換アリール)アルキル−1H In novel 1- (substituted aryl) indicated alkyl -1H
−イミダゾピリジン−4−アミン誘導体、又はその薬理学的に許容しうる塩を有効成分とする医薬は、通常、カプセル剤,錠剤,細粒剤,顆粒剤,散剤,シロップ剤等の経口投与製剤、あるいは注射剤,坐剤,点眼剤,眼軟膏,点耳剤,外皮用剤等の非経口投与製剤として投与される。 - imidazopyridine-4-amine derivative, or a pharmaceutically converted into their pharmaceutically acceptable active ingredient salt is typically capsules, tablets, fine granules, granules, powders, oral administration preparations such as syrups or injections, suppositories, eye drops, eye ointments, ear drops, is administered as a parenteral preparation such as dermatological agents. これらの製剤は、薬理学的,製剤学的に許容しうる添加物を加え、常法により製造できる。 These formulations, pharmacologic, additives acceptable in pharmaceutically added, can be manufactured in a conventional manner. すなわち経口剤及び坐剤にあっては、賦形剤(乳糖,D-マンニトール,トウモロコシデンプン,結晶セルロース等),崩壊剤(カルボキシメチルセルロース,カルボキシメチルセルロースカルシウム等),結合剤(ヒドロキシプロピルセルロース,ヒドロキシプロピルメチルセルロース,ポリビニルピロリドン等),滑沢剤(ステアリン酸マグネシウム,タルク等),コーティング剤(ヒドロキシプロピルメチルセルロース,白糖,酸化チタン等),基剤(ポリエチレングリコール,ハードファット等)等の製剤用成分が、注射剤あるいは点眼,点耳剤にあっては水性あるいは用時溶解型剤型を構成しうる溶解剤ないし溶解補助剤(注射用蒸留水,生理食塩水,プロピレングリコール等),pH調節剤(無機又は有機の酸あるいは塩基),等張化 That In the oral and suppository, an excipient (lactose, D- mannitol, corn starch, crystalline cellulose, etc.), disintegrating agents (carboxymethylcellulose, carboxymethylcellulose calcium, etc.), binders (hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, etc.), lubricants (magnesium stearate, talc, etc.), coating agent (hydroxypropylmethylcellulose, white sugar, titanium oxide, etc.), bases (polyethylene glycol, formulation ingredients hard fat) and the like, injections or eye drops, solubilizers in the eardrops can constitute at dissolving agent type use or aqueous or solubilizing agent (distilled water for injection, physiological saline, propylene glycol, etc.), pH adjusting agents (inorganic or organic acids or bases), tonicity 剤(食塩,ブドウ糖,グリセリン等),安定化剤等の製剤成分が、又、眼軟膏剤,外皮用剤にあっては、軟膏剤,クリーム剤,貼付剤として適切な製剤成分(白色ワセリン,マクロゴール,グリセリン,綿布等)が使用される。 Agent (sodium chloride, dextrose, glycerin, etc.), formulation components such as stabilizers, also eye ointment, in the dermatological agents, ointments, creams, suitable formulation components as plaster (white petrolatum, macrogol, glycerin, cotton cloth, etc.) are used.

【0049】本化合物の治療患者への投与量は、患者の症状にもよるが、通常成人の場合一日量として、経口投与で0.1〜1000mg程度、非経口投与で0.01〜 The dosage for treatment patients present compounds depends on the condition of the patient, as a daily dose for normal adults, 0.1 to 1000 mg approximately oral administration, 0.01 for parenteral administration
500mg程度である。 It is about 500mg.

【0050】 [0050]

【実施例】以下、本発明を参考例及び実施例によって説明するが、本発明はこれらの例に限定されるものではない。 EXAMPLES Hereinafter, the present invention will be described reference examples and examples, the present invention is not limited to these examples.

【0051】参考例1 2−〔4−(メチルアミノ)フェニル〕エチルアミン・ [0051] Reference Example 1 2- [4- (methylamino) phenyl] ethylamine
塩酸塩 (1) N−〔4−(シアノメチル)フェニル〕ホルムアミド 無水酢酸71ml及び蟻酸40mlの混液を50℃で30分間攪拌した後、氷冷攪拌下、4−アミノベンジルシアニド20.0gを加え、室温で30分間攪拌した。 After stirring the mixture of hydrochloride (1) N-[4- (cyanomethyl) phenyl] formamide acetic anhydride 71ml and formic acid 40 ml 30 minutes at 50 ° C., with stirring under ice-cooling, a 4-aminobenzyl cyanide 20.0g added and stirred for 30 minutes at room temperature. 反応液に20%水酸化ナトリウム水溶液を加え、液性をpH8に調整した。 20% aqueous sodium hydroxide was added to the reaction solution, to adjust the mixture to pH 8. 析出結晶を濾取後、水洗して19.0gのN After the precipitated crystals were collected by filtration, washed with water to 19.0g of N
−〔4−(シアノメチル)フェニル〕ホルムアミド(融点103.0〜105.0℃)を得た。 - was obtained [4- (cyanomethyl) phenyl] formamide (mp 103.0 to 105.0 ° C.). (2) 2−〔4−(メチルアミノ)フェニル〕エチルアミン・塩酸塩 窒素気流下、水素化リチウムアルミニウム22.8g及び無水テトラヒドロフラン500mlの懸濁液に氷冷攪拌下、濃硫酸29.5g及び無水テトラヒドロフラン10 (2) 2- [4- (methylamino) phenyl] ethylamine hydrochloride Under a nitrogen stream, stirring under ice-cooling to a suspension of lithium aluminum hydride 22.8g and anhydrous tetrahydrofuran 500 ml, concentrated sulfuric acid 29.5g and anhydrous tetrahydrofuran 10
0mlの混液を30分間かけて滴下した。 It was added dropwise over a mixture of 0ml 30 minutes. 混合物を室温まで加温した後、N−〔4−(シアノメチル)フェニル〕 After the mixture was warmed to room temperature, N- [4- (cyanomethyl) phenyl]
ホルムアミド19.3gの無水テトラヒドロフラン40 Anhydrous dimethylformamide 19.3g tetrahydrofuran 40
0mlの溶液を1時間かけて滴下した。 Solution of 0ml was dropped over a period of 1 hour. 室温で1時間攪拌後、氷冷下、水60ml及びテトラヒドロフラン120ml After stirring at room temperature for 1 hour under ice-cooling, water 60ml and tetrahydrofuran 120ml
の混液を滴下した。 Mixture was added dropwise of. 炭酸カリウム9.5gを加えた後、 After addition of potassium carbonate 9.5 g,
室温で14時間攪拌した。 And the mixture was stirred at room temperature for 14 hours. 不溶物を濾去し、テトラヒドロフラン及び塩化メチレンで洗浄した。 The insoluble material was filtered off, washed with tetrahydrofuran and methylene chloride. 濾液は乾燥後、 The filtrate is dried,
エタノール性塩化水素を加え、液性をpH2に調整した。 Ethanolic hydrogen chloride was added, to adjust the mixture to pH 2.
析出結晶を濾取し、テトラヒドロフランで洗浄して、淡褐色結晶18.9gを得た。 And the precipitated crystals were collected by filtration and washed with tetrahydrofuran to give pale brown crystals 18.9 g. エタノールから再結晶して、融点215.0〜220.0℃の淡褐色結晶を得た。 Recrystallization from ethanol to give pale brown crystals of melting point 215.0-220.0 ° C.. 元素分析値 C 9142・2HCl 理論値 C, 48.44; H, 7.23; N, 12.55 実験値 C, 48.39; H, 7.29; N, 12.59 Elemental analysis C 9 H 14 N 2 · 2HCl theory C, 48.44; H, 7.23; N, 12.55 Found C, 48.39; H, 7.29; N, 12.59

【0052】参考例2 2−〔4−(2−アミノエチル)フェニル〕−2−メチル−1,3−ジオキソラン (1) N−〔2−〔4−(2−メチル−1,3−ジオキソラン−2−イル)フェニル〕エチル〕トリフルオロアセトアミド N−〔2−(4−アセチルフェニル)エチル〕トリフルオロアセトアミド10.0gをトルエン100mlに溶解して、エチレングリコール12.0g及びp-トルエンスルホン酸・1水和物0.4gを加え、ディーンスターク装置を用いて15時間還流した。 [0052] Reference Example 2 2- [4- (2-aminoethyl) phenyl] -2-methyl-1,3-dioxolane (1) N-[2- [4- (2-methyl-1,3-dioxolane -2-yl) phenyl] ethyl] trifluoroacetamide N- [2- (4-acetylphenyl) ethyl] trifluoroacetamide 10.0g was dissolved in toluene 100 ml, ethylene glycol 12.0g and p- toluenesulfonic acid monohydrate 0.4g and the mixture was refluxed for 15 hours using a Dean-Stark apparatus. 反応液を冷却した後、 After the reaction mixture was cooled,
水洗して脱水後、溶媒を減圧留去して11.0gのN− After washing with water and dehydration, the solvent was evaporated under reduced pressure to 11.0g of N-
〔2−〔4−(2−メチル−1,3−ジオキソラン−2 [2- [4- (2-methyl-1,3-dioxolane -2
−イル)フェニル〕エチル〕トリフルオロアセトアミド(融点72.0〜74.0℃)を得た。 - yl) phenyl] ethyl] trifluoroacetamide (mp 72.0-74.0 ° C.). (2) 2−〔4−(2−アミノエチル)フェニル〕−2− (2) 2- [4- (2-aminoethyl) phenyl] -2-
メチル−1,3−ジオキソラン N−〔2−〔4−(2−メチル−1,3−ジオキソラン−2−イル)フェニル〕エチル〕トリフルオロアセトアミド11.0gをメタノール30mlに溶解して、10% Methyl-1,3-dioxolane N- [2- [4- (2-methyl-1,3-dioxolan-2-yl) phenyl] ethyl] trifluoroacetamide 11.0g was dissolved in methanol 30 ml, 10%
水酸化ナトリウム水溶液20mlを加え、室温で2時間攪拌した。 Aqueous sodium hydroxide solution 20ml was added and stirred at room temperature for 2 hours. 反応液を減圧濃縮後、塩化メチレンとメタノール(10:1)の混液で抽出し、乾燥後溶媒を減圧留去して、褐色液体7.20gを得た。 The reaction mixture was concentrated under reduced pressure, methylene chloride and methanol: extracted with a mixture of (10 1), after drying the solvent was evaporated under reduced pressure to give a brown liquid 7.20 g. マススペクトル m/z : 207 (M + ) NMRスペクトル δ (CDCl 3 ) ppm : 1.65(3H,s),2. Mass spectrum m / z: 207 (M + ) NMR spectrum δ (CDCl 3) ppm: 1.65 (3H, s), 2.
74(2H,t,J=6.5Hz),2.97-3.00(2H,m),3.79(2H,t,J=2Hz), 74 (2H, t, J = 6.5Hz), 2.97-3.00 (2H, m), 3.79 (2H, t, J = 2Hz),
4.03(2H,t,J=2Hz),7.18(2H,d,J=8Hz),7.41(2H,d,J=8Hz) 4.03 (2H, t, J = 2Hz), 7.18 (2H, d, J = 8Hz), 7.41 (2H, d, J = 8Hz)

【0053】参考例3 N−〔1−〔4−(2−アミノエチル)フェニル〕エチル〕アセトアミド・塩酸塩 (1) N−〔1−〔4−〔2−(tert- ブトキシカルボニルアミノ)エチル〕フェニル〕エチル〕アセトアミド 4−〔2−(tert- ブトキシカルボニルアミノ)エチル〕アセトフェノン10.0gに10%メタノール性アンモニア100ml及びラネーニッケル1mlを加え、水素雰囲気下、60℃80気圧で48時間攪拌した。 [0053] Reference Example 3 N-[1- [4- (2-aminoethyl) phenyl] ethyl] acetamide hydrochloride (1) N-[1- [4- [2- (tert- butoxycarbonylamino) ethyl ] phenyl] ethyl] acetamide 4- [2- (tert- butoxycarbonylamino) ethyl] acetophenone 10.0g of 10% methanolic ammonia 100ml and Raney nickel 1ml addition, under a hydrogen atmosphere and stirred for 48 hours at 60 ° C. 80 atm . 反応液を冷却後、触媒を濾去して減圧濃縮した。 After cooling, the reaction solution was concentrated under reduced pressure The catalyst was filtered off. 得られた緑色液体を塩化メチレン70mlに溶解して、氷冷攪拌下、トリエチルアミン5.8ml及び無水酢酸3.9mlを加え3 The resulting green liquid was dissolved in methylene chloride 70 ml, with stirring under ice-cooling, triethylamine 5.8ml and acetic anhydride 3.9ml added 3
0分間攪拌した。 And the mixture was stirred for 10 minutes. 水を加え、塩化メチレンで抽出した後、乾燥して減圧濃縮した。 Water was added and extracted with methylene chloride, and concentrated under reduced pressure and dried. 残渣をジエチルエーテルで洗浄して、9.30gのN−〔1−〔4−〔2−(tert The residue was washed with diethyl ether, N- of 9.30g [1- [4- [2-(tert
- ブトキシカルボニルアミノ)エチル〕フェニル〕エチル〕アセトアミド(融点138.0〜140.0℃)を得た。 - give the butoxycarbonylamino) ethyl] phenyl] ethyl] acetamide (mp 138.0 to 140.0 ° C.). (2) N−〔1−〔4−(2−アミノエチル)フェニル〕 (2) N-[1- [4- (2-aminoethyl) phenyl]
エチル〕アセトアミド・塩酸塩 N−〔1−〔4−〔2−(tert- ブトキシカルボニルアミノ)エチル〕フェニル〕エチル〕アセトアミド9.0 Ethyl] acetamide hydrochloride N- [1- [4- [2- (tert- butoxycarbonylamino) ethyl] phenyl] ethyl] acetamide 9.0
0gをメタノール18mlに溶解して15%酢酸エチル性塩化水素27mlを加え、室温で1時間攪拌した。 0g was by 15% ethyl acetate hydrogen chloride 27ml was added dissolved in methanol 18 ml, and stirred at room temperature for 1 hour. 反応液を減圧濃縮後、イソプロピルアルコール10mlを加え、 The reaction solution was concentrated under reduced pressure, isopropyl alcohol 10ml was added,
氷冷攪拌して、析出した結晶を濾取して、無色結晶6. And ice-cooling and stirring, and the precipitated crystals were collected by filtration, colorless crystals 6.
0gを得た。 It was obtained 0g. エタノールから再結晶して、融点212. Recrystallization from ethanol, melting point 212.
0〜214.0℃の無色結晶を得た。 0 to 214.0 to give colorless crystals ° C.. 元素分析値 C 12182 O・HCl 理論値 C, 59.37; H, 7.89; N, 11.54 実験値 C, 59.25; H, 7.61; N, 11.48 Elemental analysis C 12 H 18 N 2 O · HCl theory C, 59.37; H, 7.89; N, 11.54 Found C, 59.25; H, 7.61; N, 11.48

【0054】参考例4 2−〔4−(ジベンジルアミノ)フェニル〕エチルアミン・塩酸塩 (1) N−〔2−〔4−(ジベンジルアミノ)フェニル〕 [0054] Reference Example 4 2- [4- (dibenzylamino) phenyl] ethylamine hydrochloride (1) N-[2- [4- (dibenzylamino) phenyl]
エチル〕トリフルオロアセトアミド N−〔2−(4−アミノフェニル)エチル〕トリフルオロアセトアミド1.00gに炭酸カリウム600mg, Ethyl] trifluoroacetamide N- [2- (4-aminophenyl) ethyl] Potassium carbonate trifluoroacetamide 1.00 g 600 mg,
N,N−ジメチルホルムアミド10ml及び臭化ベンジル1.1mlを加え、50℃で1時間攪拌した。 N, N- dimethylformamide 10ml and benzyl bromide 1.1ml was added and stirred for 1 hour at 50 ° C.. 水を加えジエチルエーテルで抽出した後、乾燥して減圧濃縮した。 After extraction with water was added diethyl ether, and concentrated under reduced pressure and dried.
残渣をイソプロピルエーテルで洗浄して、1.10gのN−〔2−〔4−(ジベンジルアミノ)フェニル〕エチル〕トリフルオロアセトアミド(融点142.0〜14 The residue was washed with isopropyl ether, 1.10 g of N- [2- [4- (dibenzylamino) phenyl] ethyl] trifluoroacetamide (melting point 142.0 to 14
4.0℃)を得た。 4.0 ℃) was obtained. (2) 2−〔4−(ジベンジルアミノ)フェニル〕エチルアミン・塩酸塩 N−〔2−〔4−(ジベンジルアミノ)フェニル〕エチル〕トリフルオロアセトアミド1.00gにメタノール3ml及び10%水酸化ナトリウム水溶液2mlを加え、6 (2) 2- [4- (dibenzylamino) phenyl] ethylamine hydrochloride N- [2- [4- (dibenzylamino) phenyl] ethyl] methanol 3ml and 10% hydroxide trifluoroacetamide 1.00g It was added an aqueous solution of sodium 2 ml, 6
0℃で30分間攪拌した。 And the mixture was stirred for 30 minutes at 0 ℃. 反応液を減圧濃縮した後水を加え、塩化メチレンで抽出し乾燥した。 The reaction solution was added water was concentrated under reduced pressure and extracted with methylene chloride and dried. 塩化メチレン層にエタノール性塩化水素を加え、氷冷攪拌後、析出した結晶を濾取して、無色結晶1.00gを得た。 Ethanolic hydrogen chloride in methylene chloride layer was ice-cooling and stirring, and the precipitated crystals were collected by filtration to give colorless crystals 1.00 g. 塩化メチレンとエタノールの混液から再結晶して、融点168. Recrystallization from a mixture of methylene chloride and ethanol, melting point 168.
0〜170.0℃の無色結晶を得た。 0 to 170.0 to give colorless crystals ° C.. 元素分析値 C 22242・2HCl・1/4H 2 O 理論値 C, 67.09; H, 6.78; N, 7.11 実験値 C, 67.01; H, 6.81; N, 7.23 Elemental analysis C 22 H 24 N 2 · 2HCl · 1 / 4H 2 O Theoretical value C, 67.09; H, 6.78; N, 7.11 Found C, 67.01; H, 6.81; N, 7.23

【0055】参考例5 4−(2−アミノエチル)−α−メチルベンジルアルコール・塩酸塩 4−(2−アジドエチル)アセトフェノン10.0gをメタノール50mlに溶解して、水素化ホウ素ナトリウム2.0gを加え、室温で1時間攪拌した。 [0055] In Reference Example 5 4- (2-aminoethyl)-.alpha.-methylbenzyl alcohol hydrochloride 4- (2-azidoethyl) acetophenone 10.0g was dissolved in methanol 50 ml, the sodium borohydride 2.0g It was added and stirred for 1 hour at room temperature. 反応液を減圧濃縮した後水を加え、ジエチルエーテルで抽出し、乾燥後減圧濃縮した。 The reaction solution was added water after concentration under reduced pressure, and extracted with diethyl ether, and dried under reduced pressure and concentrated. 得られた微黄色液体をテトラヒドロフラン150mlに溶解して、トリフェニルホスフィン2 The pale yellow liquid thus obtained was dissolved in tetrahydrofuran 150 ml, triphenylphosphine 2
1.7g及び水2.5mlを加え、室温で10時間攪拌した。 Added 1.7g and water 2.5 ml, and stirred at room temperature for 10 hours. 反応液を減圧濃縮後、エタノール100mlに溶解してエタノール性塩化水素を加え、氷冷攪拌した。 The reaction mixture was concentrated under reduced pressure, the ethanolic hydrogen chloride added and dissolved in ethanol 100 ml, and ice-cooling and stirring. 析出した結晶を濾取して、無色結晶9.00gを得た。 And precipitated crystals were collected by filtration to give colorless crystals 9.00 g. エタノールから再結晶して、融点171.0〜172.0℃の無色結晶を得た。 Recrystallization from ethanol gave colorless crystals of melting point from 171.0 to 172.0 ° C.. 元素分析値 C 1015 NO・HCl 理論値 C, 59.55; H, 8.00; N, 6.94 実験値 C, 59.29; H, 8.27; N, 6.85 Elemental analysis C 10 H 15 NO · HCl theory C, 59.55; H, 8.00; N, 6.94 Found C, 59.29; H, 8.27; N, 6.85

【0056】参考例6 4−(3−アミノプロピル)ベンゼンスルホンアミド・ [0056] Reference Example 6 4- (3-aminopropyl) benzenesulfonamide
塩酸塩 (1) N−(3−フェニルプロピル)アセトアミド 3−フェニルプロピルアミン1.00gのピリジン25 Pyridine hydrochloride (1) N-(3-phenylpropyl) acetamide 3-phenylpropylamine 1.00 g 25
ml溶液に、氷冷下、無水酢酸3.8mlを滴下後、室温で1時間攪拌した。 To ml solution, under ice-cooling, acetic anhydride was dropped therein 3.8 ml, and stirred at room temperature for 1 hour. 溶媒を減圧留去し、残渣に酢酸エチルと10%塩酸を加え、液性をpH3〜4に調整した後分液した。 The solvent was distilled off under reduced pressure and the residue partitioned between ethyl acetate and 10% hydrochloric acid was added, followed by liquid separation after adjusting the liquid to pH 3-4. 有機層は水と飽和食塩水で順次洗浄し脱水した後、溶媒を減圧留去し、6.20gのN−(3−フェニルプロピル)アセトアミドを得た。 The organic layer was successively washed dehydrated with water and saturated brine, the solvent was evaporated under reduced pressure to give N- (3- phenylpropyl) acetamide 6.20 g. (2) 4−〔3−(アセチルアミノ)プロピル〕ベンゼンスルホニルクロリド N−(3−フェニルプロピル)アセトアミド1.00g (2) 4- [3- (acetylamino) propyl] benzenesulfonyl chloride N- (3- phenylpropyl) acetamide 1.00g
の塩化メチレン10ml溶液に、氷冷下クロルスルホン酸3.40gを滴下後、1時間還流した。 Of methylene chloride 10ml solution, was added dropwise under ice-cooling 3.40g chlorosulfonic acid was refluxed for 1 hour. 反応混合物を氷水中に注ぎ、分液後有機層を飽和食塩水で洗浄した。 The reaction mixture was poured into ice water, the separated after the organic layer was washed with saturated brine. 有機層は脱水した後、溶媒を減圧留去し、1.20gの4 The organic layer was dried, the solvent was distilled off under reduced pressure, 4 1.20g
−〔3−(アセチルアミノ)プロピル〕ベンゼンスルホニルクロリドを得た。 - was obtained [3- (acetylamino) propyl] benzenesulfonyl chloride. (3) 4−〔3−(アセチルアミノ)プロピル〕ベンゼンスルホンアミド 4−〔3−(アセチルアミノ)プロピル〕ベンゼンスルホニルクロリド1.20g,テトラヒドロフラン6ml及びアンモニア水3.0gの混合物を、室温で7時間攪拌した。 (3) 4- [3- (acetylamino) propyl] benzenesulfonamide 4- [3- (acetylamino) propyl] benzenesulfonyl chloride 1.20 g, a mixture of tetrahydrofuran 6ml and aqueous ammonia 3.0 g, at room temperature 7 time and the mixture was stirred. 溶媒を減圧留去し、残渣にメタノールを加えた後、不溶物を濾去した。 The solvent was distilled off under reduced pressure, methanol was added to the residue, and the insoluble material was removed by filtration. 濾液を濃縮して、0.50gの4−〔3−(アセチルアミノ)プロピル〕ベンゼンスルホンアミドを得た。 The filtrate was concentrated to give 0.50g of 4- [3- (acetylamino) propyl] benzenesulfonamide. (4) 4−(3−アミノプロピル)ベンゼンスルホンアミド・塩酸塩 4−〔3−(アセチルアミノ)プロピル〕ベンゼンスルホンアミド1.95g及び6規定塩酸20mlの混合物を、110〜120℃で6時間攪拌した。 (4) 4- (3-aminopropyl) benzenesulfonamide hydrochloride 4- [3- (acetylamino) propyl] benzenesulfonamide 1.95g and 6N hydrochloric acid 20 ml, 6 hours at 110 to 120 ° C. and the mixture was stirred. 反応混合物を減圧濃縮し、残渣をエタノールで洗浄して、無色結晶0.95gを得た。 The reaction mixture was concentrated in vacuo and the residue washed with ethanol to give colorless crystals 0.95 g. NMRスペクトル δ (DMSO) ppm: 1.89(2H,quint,J NMR spectrum δ (DMSO) ppm: 1.89 (2H, quint, J
=8Hz),2.74(2H,t,J=8Hz),2.80(2H,t,J=8Hz),7.20(2H,br = 8Hz), 2.74 (2H, t, J = 8Hz), 2.80 (2H, t, J = 8Hz), 7.20 (2H, br
-s),7.40(2H,d,J=8.5Hz),7.76(2H,d,J=8.5Hz),7.93(2H, -s), 7.40 (2H, d, J = 8.5Hz), 7.76 (2H, d, J = 8.5Hz), 7.93 (2H,
br-s) br-s)

【0057】参考例7 N−〔4−(2−アミノエチル)フェニル〕−4−メチルベンゼンスルホンアミド (1) N−〔2−(4−ニトロフェニル)エチル〕トリフルオロアセトアミド2−(4−ニトロフェニル)エチルアミン・塩酸塩5.00g及び塩化メチレン50mlの混合物に、氷冷下、トリエチルアミン3.4ml及びトリフルオロ酢酸無水物10.5mlを加え、室温で30分間攪拌した。 [0057] REFERENCE EXAMPLE 7 N-[4- (2-aminoethyl) phenyl] -4-methylbenzenesulfonamide (1) N-[2- (4-nitrophenyl) ethyl] trifluoroacetamide 2- (4- to a mixture of nitro-phenyl) ethylamine hydrochloride 5.00g and methylene chloride 50 ml, under ice-cooling, triethylamine 3.4ml and trifluoroacetic anhydride 10.5ml was added and stirred for 30 minutes at room temperature. 反応混合物を減圧濃縮し、残渣に水を加えた後、塩化メチレンで抽出した。 The reaction mixture was concentrated under reduced pressure, water was added to the residue and extracted with methylene chloride. 抽出液は飽和食塩水で洗浄後脱水し、溶媒を減圧留去して、8.50gのN− The extract was dehydrated washed with saturated brine, the solvent was distilled off under reduced pressure, the 8.50 g N-
〔2−(4−ニトロフェニル)エチル〕トリフルオロアセトアミドを得た。 Was obtained [2- (4-nitrophenyl) ethyl] trifluoroacetamide. (2) N−〔2−(4−アミノフェニル)エチル〕トリフルオロアセトアミドN−〔2−(4−ニトロフェニル) (2) N- [2- (4-aminophenyl) ethyl] trifluoroacetamide N- [2- (4-nitrophenyl)
エチル〕トリフルオロアセトアミド36.3gをメタノール180mlに溶解し、5%パラジウム−炭素1.8g Ethyl] trifluoroacetamide 36.3g was dissolved in methanol 180 ml, 5% palladium - carbon 1.8g
を加え、常温常圧下17時間接触還元を行った。 It was added thereto to carry out a catalytic reduction at room temperature under atmospheric pressure for 17 hours. 触媒を濾去し、濾液を減圧濃縮し、N−〔2−(4−アミノフェニル)エチル〕トリフルオロアセトアミド33.4g The catalyst was filtered off, the filtrate was concentrated under reduced pressure, N- [2- (4-aminophenyl) ethyl] trifluoroacetamide 33.4g
を得た。 It was obtained. (3) N−〔4−〔2−(トリフルオロアセチルアミノ) (3) N-[4- [2- (trifluoroacetylamino)
エチル〕フェニル〕−4−メチルベンゼンスルホンアミド 氷冷攪拌下、N−〔2−(4−アミノフェニル)エチル〕トリフルオロアセトアミド10.0g,塩化メチレン50ml及びトリエチルアミン7.9mlの混合物中に、 Ethyl] phenyl] -4-methylbenzenesulfonamide stirring under ice-cooling, N- [2- (4-aminophenyl) ethyl] trifluoroacetamide 10.0 g, in a mixture of methylene chloride 50ml and triethylamine 7.9 ml,
p-トルエンスルホニルクロリド10.8gの塩化メチレン10ml溶液を滴下し、そのまま1時間攪拌した。 It was added dropwise a methylene chloride 10ml solution of p- toluenesulfonyl chloride 10.8 g, followed by stirring for 1 hour. 反応混合物に水を加え、析出した結晶を濾取し、10.7g Water was added to the reaction mixture, and the precipitated crystals were collected by filtration, 10.7 g
のN−〔4−〔2−(トリフルオロアセチルアミノ)エチル〕フェニル〕−4−メチルベンゼンスルホンアミドを得た。 Yield of N- and [4- [2- (trifluoroacetylamino) ethyl] phenyl] -4-methylbenzenesulfonamide. (4) N−〔4−(2−アミノエチル)フェニル〕−4− (4) N-[4- (2-aminoethyl) phenyl] -4-
メチルベンゼンスルホンアミド N−〔4−〔2−(トリフルオロアセチルアミノ)エチル〕フェニル〕−4−メチルベンゼンスルホンアミド1 Methylbenzenesulfonamide N- [4- [2- (trifluoroacetylamino) ethyl] phenyl] -4-methylbenzenesulfonamide 1
3.4g,メタノール130ml及び10%水酸化ナトリウム水溶液80mlの混合物を室温で30分間攪拌した。 3.4 g, was a mixture of methanol 130ml and 10% sodium hydroxide solution 80ml was stirred for 30 minutes at room temperature.
反応混合物に10%塩酸を加え、液性をpH7に調整した後、減圧濃縮した。 10% hydrochloric acid was added to the reaction mixture, after adjusting the liquid to pH 7, and concentrated under reduced pressure. 残渣にエタノールを加え不溶物を濾去した後、濾液を減圧濃縮して、淡黄色液体12.0g After filtering off the residue ethanol was added to the insoluble matter, the filtrate was concentrated under reduced pressure, a pale yellow liquid 12.0g
を得た。 It was obtained. NMRスペクトル δ (DMSO) ppm: 2.33(3H,s),2.76 NMR spectrum δ (DMSO) ppm: 2.33 (3H, s), 2.76
(2H,t,J=8.5Hz),2.96(2H,t,J=8.5Hz),7.05(2H,d,J=8.5H (2H, t, J = 8.5Hz), 2.96 (2H, t, J = 8.5Hz), 7.05 (2H, d, J = 8.5H
z),7.10(2H,d,J=8.5Hz),7.34(2H,d,J=8Hz),7.65(2H,d,J z), 7.10 (2H, d, J = 8.5Hz), 7.34 (2H, d, J = 8Hz), 7.65 (2H, d, J
=8Hz),8.40(2H,br-s) = 8Hz), 8.40 (2H, br-s)

【0058】参考例8 4−(2−アミノエチル)−N−メチルベンゼンスルホンアミド・塩酸塩 (1) N−(2−フェニルエチル)アセトアミド 2−フェニルエチルアミン15.0gのピリジン75ml [0058] Reference Example 8 4- (2-aminoethyl) -N- methylbenzenesulfonamide hydrochloride (1) N-(2-phenylethyl) pyridine acetamide 2-phenylethylamine 15.0 g 75 ml
溶液に、氷冷下、無水酢酸12.8mlを滴下し、室温で1時間攪拌した。 Was added under ice-cooling, it was added dropwise acetic anhydride 12.8 ml, and stirred at room temperature for 1 hour. 反応混合物を減圧濃縮し、残渣に10 The reaction mixture was concentrated under reduced pressure, 10 to the residue
%塩酸を加えて液性をpH3〜4に調整した後、酢酸エチルで抽出した。 % After adjusting the mixture to around pH3~4 by adding hydrochloric acid, and extracted with ethyl acetate. 抽出液は、水及び飽和食塩水で順次洗浄した後脱水し、溶媒を減圧留去して、27.7gのN− Extract, dehydrated washed successively with water and brine, the solvent was distilled off under reduced pressure, the 27.7 g N-
(2−フェニルエチル)アセトアミドを得た。 (2-phenylethyl) acetamide. (2) 4−〔2−(アセチルアミノ)エチル〕ベンゼンスルホニルクロリド N−(2−フェニルエチル)アセトアミド98.2g及び塩化メチレン500mlの混液に、氷冷下クロルスルホン酸362gを滴下した。 (2) 4 in a mixture of [2- (acetylamino) ethyl] benzenesulfonyl chloride N-(2-phenylethyl) acetamide 98.2g and methylene chloride 500 ml, was added dropwise under ice-cooling 362g of chlorosulfonic acid. 2時間還流した後、反応液を氷水中に注いだ。 After refluxing for 2 hours, the reaction mixture was poured into ice water. 析出結晶を濾取した後水洗し、88. Precipitated crystals then washed with water was collected by filtration, 88.
3gの4−〔2−(アセチルアミノ)エチル〕ベンゼンスルホニルクロリドを得た。 To give 3g of 4- [2- (acetylamino) ethyl] benzenesulfonyl chloride. (3) 4−〔2−(アセチルアミノ)エチル〕−N−メチルベンゼンスルホンアミド 4−〔2−(アセチルアミノ)エチル〕ベンゼンスルホニルクロリド5.00gのテトラヒドロフラン25ml溶液に、室温下、40%メチルアミン水溶液14.8gを加えた。 (3) 4 in tetrahydrofuran 25ml solution of [2- (acetylamino) ethyl] -N- methylbenzenesulfonamide 4- [2- (acetylamino) ethyl] benzenesulfonyl chloride 5.00 g, room temperature, 40% methyl aqueous amine solution 14.8g was added. 5時間還流した後、減圧濃縮して5.90gの4−〔2−(アセチルアミノ)エチル〕−N−メチルベンゼンスルホンアミドを得た。 After refluxing for 5 hours, the 5.90g concentrated in vacuo 4 to give the [2- (acetylamino) ethyl] -N- methylbenzenesulfonamide. (4) 4−(2−アミノエチル)−N−メチルベンゼンスルホンアミド・塩酸塩 4−〔2−(アセチルアミノ)エチル〕−N−メチルベンゼンスルホンアミド34.0g及び6規定塩酸170 (4) 4- (2-aminoethyl) -N- methylbenzenesulfonamide hydrochloride 4- [2- (acetylamino) ethyl] -N- methylbenzenesulfonamide 34.0g and 6 N hydrochloric acid 170
mlの混合物を、110℃で5時間攪拌した。 A mixture of ml, and stirred for 5 hours at 110 ° C.. 反応混合物を減圧濃縮し、残渣をメタノールで洗浄して、無色結晶10.6gを得た。 The reaction mixture was concentrated under reduced pressure, the residue was washed with methanol to give colorless crystals 10.6 g. NMRスペクトル δ (DMSO) ppm: 2.42(3H,s),3.02 NMR spectrum δ (DMSO) ppm: 2.42 (3H, s), 3.02
(2H,t,J=5Hz),3.07(2H,t,J=5Hz),7.40(1H,br-s),7.57(2 (2H, t, J = 5Hz), 3.07 (2H, t, J = 5Hz), 7.40 (1H, br-s), 7.57 (2
H,d,J=8Hz),7.74(2H,d,J=8Hz),8.08(2H,br-s) H, d, J = 8Hz), 7.74 (2H, d, J = 8Hz), 8.08 (2H, br-s)

【0059】参考例9 4−(2−アミノエチル)−N−プロピルベンゼンスルホンアミド (1) N−プロピル−4−〔2−(トリフルオロアセチルアミノ)エチル〕ベンゼンスルホンアミド 4−〔2−(トリフルオロアセチルアミノ)エチル〕ベンゼンスルホニルクロリド13.4gのテトラヒドロフラン20ml溶液に、氷冷下、プロピルアミン6.9mlを加え、氷冷下3時間攪拌した。 [0059] Reference Example 9 4- (2-aminoethyl) -N- propyl benzenesulfonamide (1) N-propyl-4 [2- (trifluoroacetylamino) ethyl] benzenesulfonamide 4- [2- ( tetrahydrofuran 20ml solution of trifluoroacetic acetylamino) ethyl] benzenesulfonyl chloride 13.4 g, under ice-cooling, propylamine 6.9ml was added and stirred under ice cooling for 3 hours. 反応混合物は減圧濃縮し、残渣に水及び塩化メチレンを加えた。 The reaction mixture was concentrated under reduced pressure, water was added and methylene chloride to the residue. 析出結晶を濾取し、15.3gのN−プロピル−4−〔2−(トリフルオロアセチルアミノ)エチル〕ベンゼンスルホンアミドを得た。 And the precipitated crystals were collected by filtration to give N- propyl-4- [2- (trifluoroacetylamino) ethyl] benzenesulfonamide 15.3 g. (2) 4−(2−アミノエチル)−N−プロピルベンゼンスルホンアミド N−プロピル−4−〔2−(トリフルオロアセチルアミノ)エチル〕ベンゼンスルホンアミド15.3gのメタノール150ml溶液に、室温下10%水酸化ナトリウム水溶液92mlを加え、30分間攪拌した。 (2) 4- to (2-aminoethyl) -N- propyl benzenesulfonamide N- propyl-4- [2- (trifluoroacetylamino) ethyl] methanol 150ml solution of benzenesulfonamide 15.3 g, at room temperature for 10 % aqueous solution of sodium 92ml hydroxide, and the mixture was stirred for 30 minutes. 反応混合物に10%塩酸を加え、液性をpH7〜8に調整した後、減圧濃縮した。 10% hydrochloric acid was added to the reaction mixture, after adjusting the liquid to pH 7-8, and concentrated under reduced pressure. 残渣にエタノールを加え、不溶物を濾去した後、濾液を減圧濃縮して、無色液体12.7gを得た。 Ethanol was added to the residue, after the insoluble material was removed by filtration, the filtrate was concentrated under reduced pressure to give a colorless liquid 12.7 g. NMRスペクトル δ (DMSO) ppm: 0.80(3H,t,J=7H NMR spectrum δ (DMSO) ppm: 0.80 (3H, t, J = 7H
z),1.40(2H,sextet,J=7Hz),2.70(2H,t,J=7Hz),2.97(2H, z), 1.40 (2H, sextet, J = 7Hz), 2.70 (2H, t, J = 7Hz), 2.97 (2H,
t,J=7.5Hz),3.09(2H,t,J=7.5Hz),4.23(1H,br-s),7.46(2 t, J = 7.5Hz), 3.09 (2H, t, J = 7.5Hz), 4.23 (1H, br-s), 7.46 (2
H,d,J=8Hz),7.74(2H,d,J=8Hz),7.80-8.00(2H,br-s) H, d, J = 8Hz), 7.74 (2H, d, J = 8Hz), 7.80-8.00 (2H, br-s)

【0060】参考例10 4−(2−アミノエチル)−N,N−ジメチルベンゼンスルホンアミド・塩酸塩 (1) 4−〔2−(アセチルアミノ)エチル〕−N,N− [0060] Reference Example 10 4- (2-aminoethyl) -N, N-dimethyl benzenesulfonamide hydrochloride (1) 4- [2- (acetylamino) ethyl] -N, N-
ジメチルベンゼンスルホンアミド 4−〔2−(アセチルアミノ)エチル〕ベンゼンスルホニルクロリド5.00gのテトラヒドロフラン25ml溶液に、室温下、50%ジメチルアミン水溶液17.2g Tetrahydrofuran 25ml solution of dimethyl benzenesulfonamide 4- [2- (acetylamino) ethyl] benzenesulfonyl chloride 5.00 g, room temperature, 50% aqueous dimethylamine solution 17.2g
を加え、5時間還流した。 And the mixture was refluxed for 5 hours. 反応混合物を減圧濃縮し、 The reaction mixture was concentrated under reduced pressure,
4.10gの4−〔2−(アセチルアミノ)エチル〕− 4- 4.10g [2- (acetylamino) ethyl] -
N,N−ジメチルベンゼンスルホンアミドを得た。 N, was obtained N- dimethylbenzenesulfonamide. (2) 4−(2−アミノエチル)−N,N−ジメチルベンゼンスルホンアミド・塩酸塩 4−〔2−(アセチルアミノ)エチル〕−N,N−ジメチルベンゼンスルホンアミド4.10g及び6規定塩酸40mlの混合物を100℃で6時間攪拌した。 (2) 4- (2-aminoethyl) -N, N-dimethyl benzenesulfonamide hydrochloride 4- [2- (acetylamino) ethyl] -N, N-dimethyl benzenesulfonamide 4.10g and 6 N hydrochloric acid a mixture of 40ml was stirred for 6 hours at 100 ° C.. 反応混合物を減圧濃縮し、残渣をメタノールで洗浄して、無色結晶1.00gを得た。 The reaction mixture was concentrated under reduced pressure, the residue was washed with methanol to give colorless crystals 1.00 g. NMRスペクトル δ (DMSO) ppm: 2.62(6H,s),3.01 NMR spectrum δ (DMSO) ppm: 2.62 (6H, s), 3.01
(2H,t,J=8.5Hz),3.11(2H,t,J=8.5Hz),7.54(2H,d,J=8H (2H, t, J = 8.5Hz), 3.11 (2H, t, J = 8.5Hz), 7.54 (2H, d, J = 8H
z),7.70(2H,d,J=8Hz),8.00(2H,br-s) z), 7.70 (2H, d, J = 8Hz), 8.00 (2H, br-s)

【0061】参考例11 2−(2−アミノエチル)ベンゼンスルホンアミド (1) 5−ブロモ−2−〔2−(トリフルオロアセチルアミノ)エチル〕ベンゼンスルホニルクロリド N−〔2−(4−ブロモフェニル)エチル〕トリフルオロアセトアミド15.5gの塩化メチレン45ml溶液に、氷冷下、クロルスルホン酸10mlを加え、2日間還流した。 [0061] Reference Example 11 2- (2-aminoethyl) benzenesulfonamide (1) 5-bromo-2- [2- (trifluoroacetylamino) ethyl] benzenesulfonyl chloride N- [2- (4-bromophenyl ) ethyl] in methylene chloride 45ml solution of trifluoroacetamide 15.5 g, under ice-cooling, a chlorosulfonic acid 10ml and the mixture was refluxed for 2 days. 反応混合物を氷水中に注ぎ分液した後、有機層を水及び飽和食塩水で順次洗浄した。 After pouring liquid separation into ice water and the reaction mixture, and the organic layer was successively washed with water and brine. 有機層を脱水した後、溶媒を減圧留去した。 After drying the organic layer, the solvent was distilled off under reduced pressure. 残渣にn-ヘキサンと酢酸エチル(6:1)の混液を加え、不溶物を濾去した。 Residue n- hexane and ethyl acetate (6: 1) mixture was added and the insoluble material was removed by filtration. 濾液を減圧濃縮した後、残渣をカラムクロマトグラフィー〔シリカゲル,n-ヘキサン−酢酸エチル(6:1)〕で精製して、4.90gの5−ブロモ−2−〔2−(トリフルオロアセチルアミノ)エチル〕ベンゼンスルホニルクロリドを得た。 After the filtrate was concentrated under reduced pressure, the residue was purified by column chromatography [silica gel, n- hexane - ethyl acetate (6: 1)] to afford the 4.90 g 5-bromo-2- [2- (trifluoroacetylamino ) ethyl] to give benzenesulfonyl chloride. (2) 5−ブロモ−2−〔2−(トリフルオロアセチルアミノ)エチル〕ベンゼンスルホンアミド 5−ブロモ−2−〔2−(トリフルオロアセチルアミノ)エチル〕ベンゼンスルホニルクロリド25.5gのテトラヒドロフラン38ml溶液に、氷冷下、アンモニア水45mlを加え、室温で1時間攪拌した。 (2) 5-bromo-2- [2- (trifluoroacetylamino) ethyl] benzenesulfonamide 5-Bromo-2- [2- (trifluoroacetylamino) ethyl] tetrahydrofuran 38ml solution of benzenesulfonyl chloride 25.5g to under ice cooling, ammonia water 45ml was added and stirred for 1 hour at room temperature. 反応混合物を減圧濃縮し、残渣を塩化メチレンで洗浄して、22.0 The reaction mixture was concentrated in vacuo and the residue was washed with methylene chloride, 22.0
gの5−ブロモ−2−〔2−(トリフルオロアセチルアミノ)エチル〕ベンゼンスルホンアミドを得た。 It was obtained g of 5-bromo-2- [2- (trifluoroacetylamino) ethyl] benzenesulfonamide. (3) 2−〔2−(トリフルオロアセチルアミノ)エチル〕ベンゼンスルホンアミド 5−ブロモ−2−〔2−(トリフルオロアセチルアミノ)エチル〕ベンゼンスルホンアミド12.0g,メタノール120ml及び10%パラジウム−炭素1.2gの混合物を常温常圧下、4時間接触還元を行った。 (3) 2- [2- (trifluoroacetylamino) ethyl] benzenesulfonamide 5-Bromo-2- [2- (trifluoroacetylamino) ethyl] benzenesulfonamide 12.0 g, methanol 120ml and 10% palladium - the mixture normal temperature and pressure of the carbon 1.2g, was carried out for 4 hours catalytic reduction. 触媒を濾去した後、濾液を減圧濃縮して11.0gの2−〔2 After filtering off the catalyst, the filtrate was concentrated under reduced pressure 11.0g of 2- [2
−(トリフルオロアセチルアミノ)エチル〕ベンゼンスルホンアミドを得た。 - was obtained (trifluoroacetyl amino) ethyl] benzenesulfonamide. (4) 2−(2−アミノエチル)ベンゼンスルホンアミド 2−〔2−(トリフルオロアセチルアミノ)エチル〕ベンゼンスルホンアミド11.0g,メタノール110ml (4) 2- (2-aminoethyl) benzenesulfonamide 2- [2- (trifluoroacetylamino) ethyl] benzenesulfonamide 11.0 g, methanol 110ml
及び10%水酸化ナトリウム水溶液66mlの混合物を、 The and 10% mixture of sodium hydroxide aqueous solution 66 ml,
室温で1時間攪拌した。 And the mixture was stirred for 1 hour at room temperature. 反応混合物に10%塩酸を加え、液性をpH7〜8に調整した後、減圧濃縮した。 10% hydrochloric acid was added to the reaction mixture, after adjusting the liquid to pH 7-8, and concentrated under reduced pressure. 残渣にエタノールを加え、不溶物を濾去した後濾液を減圧留去して、無色結晶8.0gを得た。 Ethanol was added to the residue, the filtrate after filtering off the insoluble matter was distilled off under reduced pressure, to give colorless crystals 8.0 g. NMRスペクトル δ (DMSO) ppm: 3.10(2H,t,J=7H NMR spectrum δ (DMSO) ppm: 3.10 (2H, t, J = 7H
z),3.30(2H,t,J=7Hz),7.43-7.47(2H,m),7.50-7.60(5H, z), 3.30 (2H, t, J = 7Hz), 7.43-7.47 (2H, m), 7.50-7.60 (5H,
m),7.90-7.93(1H,m) m), 7.90-7.93 (1H, m)

【0062】参考例12 3−(2−アミノエチル)ベンゼンスルホンアミド (1) N−〔2−(4−ブロモフェニル)エチル〕トリフルオロアセトアミド 2−(4−ブロモフェニル)エチルアミン10.0gの塩化メチレン100ml溶液に、氷冷下、無水トリフルオロ酢酸21mlを加え、室温下30分間攪拌した。 [0062] chloride of Reference Example 12 3- (2-aminoethyl) benzenesulfonamide (1) N-[2- (4-bromophenyl) ethyl] trifluoroacetamide 2- (4-bromophenyl) ethylamine 10.0g methylene 100ml solution, under ice-cooling, trifluoroacetic anhydride 21ml, and the mixture was stirred at room temperature for 30 minutes. 反応混合物を減圧濃縮し、残渣をイソプロピルエーテルで洗浄して、13.7gのN−〔2−(4−ブロモフェニル) The reaction mixture was concentrated in vacuo and the residue was washed with isopropyl ether, N- of 13.7g [2- (4-bromophenyl)
エチル〕トリフルオロアセトアミドを得た。 Ethyl] to give trifluoroacetamide. (2) 2−ブロモ−5−〔2−(トリフルオロアセチルアミノ)エチル〕ベンゼンスルホニルクロリド N−〔2−(4−ブロモフェニル)エチル〕トリフルオロアセトアミド15.5gの塩化メチレン45ml溶液に、氷冷下、クロルスルホン酸10mlを加え、2日間還流した。 (2) 2-bromo-5- [2- (trifluoroacetylamino) ethyl] benzenesulfonyl chloride N- [2- (4-bromophenyl) ethyl] methylene chloride 45ml solution of trifluoroacetamide 15.5 g, glacial under cooling, the chlorosulfonic acid 10ml and the mixture was refluxed for 2 days. 反応混合物を氷水中に注ぎ分液した後、有機層を水及び飽和食塩水で順次洗浄した。 After pouring liquid separation into ice water and the reaction mixture, and the organic layer was successively washed with water and brine. 有機層を脱水した後、溶媒を減圧留去した。 After drying the organic layer, the solvent was distilled off under reduced pressure. 残渣をn-ヘキサンと酢酸エチル(6:1)の混液で洗浄して、8.20gの2−ブロモ−5−〔2−(トリフルオロアセチルアミノ)エチル〕ベンゼンスルホニルクロリドを得た。 The residue n- hexane and ethyl acetate (6: 1) and washed with a mixture of, to give 2-bromo-5- [2- (trifluoroacetylamino) ethyl] benzenesulfonyl chloride 8.20 g. (3) 2−ブロモ−5−〔2−(トリフルオロアセチルアミノ)エチル〕ベンゼンスルホンアミド 2−ブロモ−5−〔2−(トリフルオロアセチルアミノ)エチル〕ベンゼンスルホニルクロリド8.20gのテトラヒドロフラン12ml溶液に、氷冷下、アンモニア水14.4mlを加え、室温で1時間攪拌した。 (3) 2-bromo-5- [2- (trifluoroacetylamino) ethyl] benzenesulfonamide 2-Bromo-5- [2- (trifluoroacetylamino) ethyl] tetrahydrofuran 12ml solution of benzenesulfonyl chloride 8.20g to under ice cooling, ammonia water 14.4ml added and stirred at room temperature for 1 hour. 反応混合物を減圧濃縮し、残渣をエタノールで洗浄して、5.3 The reaction mixture was concentrated in vacuo and the residue washed with ethanol, 5.3
0gの2−ブロモ−5−〔2−(トリフルオロアセチルアミノ)エチル〕ベンゼンスルホンアミドを得た。 It was obtained 0g of 2-bromo-5- [2- (trifluoroacetylamino) ethyl] benzenesulfonamide. (4) 3−〔2−(トリフルオロアセチルアミノ)エチル〕ベンゼンスルホンアミド 2−ブロモ−5−〔2−(トリフルオロアセチルアミノ)エチル〕ベンゼンスルホンアミド5.30g,メタノール50ml及び10%パラジウム−炭素0.5gの混合物を、常温常圧下11時間接触還元を行った。 (4) 3- [2- (trifluoroacetylamino) ethyl] benzenesulfonamide 2-Bromo-5- [2- (trifluoroacetylamino) ethyl] benzenesulfonamide 5.30 g, 50ml of methanol and 10% palladium - the mixture of carbon 0.5g, was catalytically reduced normal temperature and normal pressure for 11 hours. 触媒を濾去した後、濾液を減圧濃縮して、4.00gの3− After filtering off the catalyst, the filtrate was concentrated under reduced pressure, the 4.00 g 3-
〔2−(トリフルオロアセチルアミノ)エチル〕ベンゼンスルホンアミドを得た。 It was obtained [2- (trifluoroacetylamino) ethyl] benzenesulfonamide. (5) 3−(2−アミノエチル)ベンゼンスルホンアミド 3−〔2−(トリフルオロアセチルアミノ)エチル〕ベンゼンスルホンアミド4.00g,メタノール40ml及び10%水酸化ナトリウム水溶液24mlの混合物を室温で3時間攪拌した。 (5) 3- (2-aminoethyl) benzenesulfonamide 3- [2- (trifluoroacetylamino) ethyl] benzenesulfonamide 4.00 g, 3 a mixture of methanol 40ml and 10% aqueous sodium hydroxide solution 24ml at room temperature time and the mixture was stirred. 反応混合物に10%塩酸を加え、液性をpH7〜8に調整した後、減圧濃縮した。 10% hydrochloric acid was added to the reaction mixture, after adjusting the liquid to pH 7-8, and concentrated under reduced pressure. 残渣にエタノールを加え、不溶物を濾去した後、濾液を減圧濃縮して、無色結晶4.30gを得た。 To the residue ethanol was added, after the insoluble material was removed by filtration, the filtrate was concentrated under reduced pressure, to give colorless crystals 4.30 g. NMRスペクトル δ (DMSO) ppm: 2.98(2H,t,J=8H NMR spectrum δ (DMSO) ppm: 2.98 (2H, t, J = 8H
z),3.08(2H,t,J=8Hz),7.25(2H,br-s),7.48-7.58(2H,m), z), 3.08 (2H, t, J = 8Hz), 7.25 (2H, br-s), 7.48-7.58 (2H, m),
7.70-7.78(2H,m),7.81(2H,br-s) 7.70-7.78 (2H, m), 7.81 (2H, br-s)

【0063】参考例13 4−〔2−〔(2−クロロ−3−ニトロキノリン−4− [0063] Reference Example 13 4- [2 - [(2-chloro-3-nitro-4-
イル)アミノ〕エチル〕ベンズアミド 2,4−ジクロロ−3−ニトロキノリン8.03g及びトリエチルアミン18.5mlのN,N−ジメチルホルムアミド溶液に、氷冷攪拌下、4−(2−アミノエチル) Yl) amino] ethyl] benzamide 2,4-dichloro-3-nitroquinoline 8.03g and triethylamine 18.5ml of N, N- dimethylformamide solution, with stirring under ice-cooling, 4- (2-aminoethyl)
ベンズアミド4.35gを加え、氷冷下5時間攪拌した。 Benzamide 4.35g was added, and the mixture was stirred under ice cooling for 5 hours. 反応液に水及び10%塩酸を加え、液性をpH8に調整した後、酢酸エチルで抽出した。 Water and 10% hydrochloric acid was added to the reaction solution, after adjusting the liquid to pH 8, and extracted with ethyl acetate. 有機層を飽和食塩水で洗浄後脱水し、溶媒を減圧留去した。 The organic layer was washed dried with brine, and the solvent was evaporated under reduced pressure. 残渣をイソプロピルエーテルで洗浄し、褐色結晶5.89gを得た。 The residue was washed with isopropyl ether to give brown crystals 5.89 g. エタノールから再結晶して、融点217.5〜218.5 Recrystallization from ethanol, melting point 217.5 to 218.5
℃の黄褐色プリズム晶を得た。 ℃ give a tan prisms of. 元素分析値 C 1815 ClN 43理論値 C, 58.31; H, 4.08; N, 15.11 実験値 C, 58.32; H, 3.88; N, 15.04 Elemental analysis C 18 H 15 ClN 4 O 3 theory C, 58.31; H, 4.08; N, 15.11 Found C, 58.32; H, 3.88; N, 15.04

【0064】参考例13の方法に従って、表1〜表9に示した参考例14〜46の化合物を得た。 [0064] according to the method of Reference Example 13 to give the compound of Reference Example 14 to 46 shown in Table 1 to Table 9.

【0065】 [0065]

【表1】 [Table 1]

【0066】 [0066]

【表2】 [Table 2]

【0067】 [0067]

【表3】 [Table 3]

【0068】 [0068]

【表4】 [Table 4]

【0069】 [0069]

【表5】 [Table 5]

【0070】 [0070]

【表6】 [Table 6]

【0071】 [0071]

【表7】 [Table 7]

【0072】 [0072]

【表8】 [Table 8]

【0073】 [0073]

【表9】 [Table 9]

【0074】参考例47 N−〔4−〔2−〔(2−クロロ−3−ニトロキノリン−4−イル)アミノ〕エチル〕フェニル〕−N−メチルアセトアミド 2−クロロ−N−〔2−〔4−(メチルアミノ)フェニル〕エチル〕−3−ニトロキノリン−4−アミン2.5 [0074] Reference Example 47 N-- 2-Chloro -N- [4- [2 [(2-chloro-3-nitro-4-yl) amino] ethyl] phenyl] -N- methylacetamide [2- [ 4- (methylamino) phenyl] ethyl] -3-nitro-quinolin-4-amine 2.5
9gにピリジン26ml及び無水酢酸6.9mlを加え、室温で1.5時間攪拌した。 Pyridine 26ml and acetic anhydride 6.9ml was added to 9 g, and stirred at room temperature for 1.5 hours. 溶媒を減圧留去し、残渣をイソプロピルエーテルで洗浄して、黄色結晶2.72gを得た。 The solvent was distilled off under reduced pressure, and the residue was washed with isopropyl ether to give yellow crystals 2.72 g. エタノールから再結晶して、融点176.5〜1 Recrystallization from ethanol, melting point 176.5 to 1
77.0℃の黄色プリズム晶を得た。 77.0 was obtained yellow prisms of ° C.. 元素分析値 C 2019 ClN 43理論値 C, 60.23; H, 4.80; N, 14.05 実験値 C, 60.28; H, 4.70; N, 14.01 Elemental analysis C 20 H 19 ClN 4 O 3 theory C, 60.23; H, 4.80; N, 14.05 Found C, 60.28; H, 4.70; N, 14.01

【0075】参考例47の方法に従って、表10に示した参考例48の化合物を得た。 [0075] according to the method of Reference Example 47 to give the compound of Reference Example 48 shown in Table 10.

【0076】 [0076]

【表10】 [Table 10]

【0077】参考例49 2−クロロ−5,6,7,8−テトラヒドロ−N−〔2 [0077] Reference Example 49 2-Chloro-5,6,7,8-tetrahydro -N- [2
−〔4−(N−メチルベンジルアミノ)フェニル〕エチル〕−3−ニトロキノリン−4−アミン2−クロロ− - [4-(N-methyl-benzylamino) phenyl] ethyl] -3-nitro-quinolin-4-amine 2-chloro -
5,6,7,8−テトラヒドロ−N−〔2−〔4−(メチルアミノ)フェニル〕エチル〕−3−ニトロキノリン−4−アミン36.8g,炭酸カリウム14.1g及びN,N−ジメチルホルムアミド370mlの懸濁液中に、 5,6,7,8-tetrahydro--N- [2- [4- (methylamino) phenyl] ethyl] -3-nitro-quinolin-4-amine 36.8 g, potassium carbonate 14.1g and N, N- dimethyl to a suspension of formamide 370 ml,
室温攪拌下、臭化ベンジル12.4mlを滴下した。 Under stirring at room temperature, it was added dropwise benzyl bromide 12.4 ml. 室温で14時間攪拌後、反応混合物を氷水中に加え、塩化メチレンで抽出した。 After stirring at room temperature for 14 hours, the reaction mixture was added to ice water, and extracted with methylene chloride. 抽出液は水洗後脱水し、減圧濃縮した。 The extract was dried after washing with water, and concentrated under reduced pressure. 残渣をカラムクロマトグラフィー〔シリカゲル,塩化メチレン−n-ヘキサン(1:1)〕で精製し、赤色液体41.9gを得た。 The residue was purified by column chromatography [silica gel, methylene chloride -n- hexane (1: 1)] to give the red liquid 41.9 g. IRスペクトル ν (liq) cm -1 : 3432 , 1580 IR spectrum ν (liq) cm -1: 3432 , 1580
, 1522 マススペクトル m/z : 450 , 452 (M + , 3:1), 210 , 1522 Mass spectrum m / z: 450, 452 ( M +, 3: 1), 210
(BP) NMRスペクトル δ (CDCl 3 ) ppm : 1.65-1.80(4H, (BP) NMR spectrum δ (CDCl 3) ppm: 1.65-1.80 (4H,
m),2.02-2.15(2H,m),2.70-2.85(4H,m),3.03(3H,s),3.30 m), 2.02-2.15 (2H, m), 2.70-2.85 (4H, m), 3.03 (3H, s), 3.30
(2H,q,J=6Hz),4.33(1H,br-s),4.53(2H,s),6.71(2H,d,J= (2H, q, J = 6Hz), 4.33 (1H, br-s), 4.53 (2H, s), 6.71 (2H, d, J =
8.5Hz),7.01(2H,d,J=8.5Hz),7.15-7.38(5H,m),7.22(2H, 8.5Hz), 7.01 (2H, d, J = 8.5Hz), 7.15-7.38 (5H, m), 7.22 (2H,
d,J=7.5Hz),7.24(1H,t,J=7.5Hz),7.31(2H,t,J=7.5Hz) d, J = 7.5Hz), 7.24 (1H, t, J = 7.5Hz), 7.31 (2H, t, J = 7.5Hz)

【0078】参考例50 N−〔4−〔2−〔(2−ジベンジルアミノ−3−ニトロキノリン−4−イル)アミノ〕エチル〕フェニル〕アセトアミド N−〔4−〔2−〔(3−アミノ−2−クロロキノリン−4−イル)アミノ〕エチル〕フェニル〕アセトアミド5.75g及びジベンジルアミン11.9mlの混合物を100℃で10時間攪拌した。 [0078] Reference Example 50 N- [4- [2 - [(2-dibenzylamino-3-nitroquinoline-4-yl) amino] ethyl] phenyl] acetamide N- [4- [2 - [(3- amino-2-chloro-4-yl) amino] ethyl] phenyl] mixture of acetamide 5.75g and dibenzylamine 11.9ml was stirred for 10 hours at 100 ° C.. 反応混合物に水及び10 Water and 10 to the reaction mixture
%塩酸を加え、析出物を濾去し、母液を塩化メチレンで抽出した。 % Hydrochloric acid was added, the precipitate was removed by filtration, was extracted mother liquor with methylene chloride. 抽出液は水洗後脱水し、溶媒を留去した。 The extract was dried after washing with water, the solvent was distilled off. 得られた赤橙色オイル状残渣をカラムクロマトグラフィー〔シリカゲル,酢酸エチル−n-ヘキサン(1:2〜2: The resulting red-orange oily residue was purified by column chromatography [silica gel, ethyl acetate -n- hexane (1: 2 to 2:
1)〕で精製して、赤橙色液体6.37gを得た。 Purification by 1)] to give the red-orange liquid 6.37 g. IRスペクトル ν (liq) cm -1 : 3320 , 1668 IR spectrum ν (liq) cm -1: 3320 , 1668
, 1522 NMRスペクトル δ (CDCl 3 ) ppm : 2.15(3H,s),2. , 1522 NMR spectrum δ (CDCl 3) ppm: 2.15 (3H, s), 2.
88(2H,t,J=7Hz),4.03(2H,q,J=7Hz),4.50(4H,s),7.00-7. 88 (2H, t, J = 7Hz), 4.03 (2H, q, J = 7Hz), 4.50 (4H, s), 7.00-7.
30(13H,m),7.42(2H,d,J=8Hz),7.50-7.60(3H,m),7.92(1 30 (13H, m), 7.42 (2H, d, J = 8Hz), 7.50-7.60 (3H, m), 7.92 (1
H,d,J=8Hz) H, d, J = 8Hz)

【0079】参考例50の方法に従って、表11〜表1 [0079] In accordance with the method of Reference Example 50, Tables 11 1
2に示した参考例51〜54の化合物を得た。 To give the compound of Reference Example 51 to 54 shown in 2.

【0080】 [0080]

【表11】 [Table 11]

【0081】 [0081]

【表12】 [Table 12]

【0082】参考例55 4−〔2−〔(2−N−メチルベンジルアミノ−3−ニトロキノリン−4−イル)アミノ〕エチル〕ベンゼンスルホンアミド 4−〔2−〔(2−クロロ−3−ニトロキノリン−4− [0082] Reference Example 55 4- [2 - [(2-N-methyl-benzylamino-3-nitro-quinolin-4-yl) amino] ethyl] benzenesulfonamide 4- [2 - [(2-chloro-3- nitro-4-
イル)アミノ〕エチル〕ベンゼンスルホンアミド2.4 Yl) amino] ethyl] benzenesulfonamide 2.4
1gをN−メチルベンジルアミン7.6mlに溶解し、1 The 1g was dissolved in N- methyl-benzylamine 7.6 ml, 1
00℃で1時間攪拌した。 And the mixture was stirred for 1 hour at 00 ℃. 反応混合物を室温まで冷却した後、5%塩酸を加え、塩化メチレンで抽出した。 The reaction mixture was cooled to room temperature, 5% hydrochloric acid was added, and extracted with methylene chloride. 抽出液は水及び飽和食塩水で順次洗浄し脱水した後、溶媒を減圧留去した。 Extract was washed sequentially dehydrated with water and saturated brine, and the solvent was evaporated under reduced pressure. 残渣をカラムクロマトグラフィー〔シリカゲル,塩化メチレン−メタノール(50:1〜40: The residue was purified by column chromatography [silica gel, methylene chloride - methanol (50: 1 to 40:
1)〕で精製して、赤橙色結晶2.34gを得た。 And purified by 1)] to give a red-orange crystals 2.34g. メタノールから再結晶して、融点156.0〜157.5℃ Recrystallization from methanol, melting point from 156.0 to 157.5 ° C.
の赤橙色結晶を得た。 To give a red-orange crystals. 元素分析値 C 252752 S 理論値 C, 65.05; H, 5.90; N, 15.17 実験値 C, 64.81; H, 5.91; N, 14.90 Elemental analysis C 25 H 27 N 5 O 2 S theory C, 65.05; H, 5.90; N, 15.17 Found C, 64.81; H, 5.91; N, 14.90

【0083】参考例56 4−〔2−〔(3−アミノ−2−クロロキノリン−4− [0083] Reference Example 56 4- [2 - [(3-amino-2-chloro-4-
イル)アミノ〕エチル〕ベンズアミド 塩化ニッケル・6水和物2.05gをメタノール32ml Yl) amino] ethyl] benzamide nickel hexahydrate 2.05g chloride methanol 32ml
に溶解し、室温下水素化ホウ素ナトリウム1.18gを加えた後、4−〔2−〔(2−クロロ−3−ニトロキノリン−4−イル)アミノ〕エチル〕ベンズアミド6.4 Dissolved in, after it added at room temperature sodium borohydride 1.18 g, 4-[2 - [(2-chloro-3-nitro-4-yl) amino] ethyl] benzamide 6.4
1gのN,N−ジメチルホルムアミド溶液を加えた。 1g of N, was added N- dimethylformamide. 更に、水素化ホウ素ナトリウム0.65gを少量ずつ加えた。 Furthermore, it was added portionwise sodium borohydride 0.65 g. 不溶物を濾去した後、溶媒を減圧留去し、得られた残渣に水,酢酸エチル及びメタノールの混液を加えて抽出した。 After the insoluble material was removed by filtration, the solvent was distilled off under reduced pressure, water to the resulting residue was extracted by adding a mixture of ethyl acetate and methanol. 有機層を飽和食塩水で洗浄し脱水後、溶媒を減圧留去した。 The organic layer was washed with saturated brine, dried and evaporated under reduced pressure. 残渣をカラムクロマトグラフィー〔シリカゲル,塩化メチレン−メタノール(30:1〜10: The residue was purified by column chromatography [silica gel, methylene chloride - methanol (30: 1 to 10:
1)〕で精製し、淡褐色結晶2.88gを得た。 Purification by 1)] to give a pale brown crystals 2.88 g. エタノールから再結晶して、融点220.0〜220.5℃の淡黄色結晶を得た。 Recrystallization from ethanol to give pale yellow crystals of melting point 220.0 to 220.5 ° C.. 元素分析値 C 1817 ClN 4 O 理論値 C, 63.44; H, 5.03; N, 16.44 実験値 C, 63.28; H, 4.93; N, 16.24 Elemental analysis C 18 H 17 ClN 4 O theory C, 63.44; H, 5.03; N, 16.44 Found C, 63.28; H, 4.93; N, 16.24

【0084】参考例56の方法に従って、表13〜表2 [0084] In accordance with the method of Reference Example 56, Tables 13 2
5に示した参考例57〜94の化合物を得た。 5 shown in give the compounds of Reference Examples 57 to 94.

【0085】 [0085]

【表13】 [Table 13]

【0086】 [0086]

【表14】 [Table 14]

【0087】 [0087]

【表15】 [Table 15]

【0088】 [0088]

【表16】 [Table 16]

【0089】 [0089]

【表17】 [Table 17]

【0090】 [0090]

【表18】 [Table 18]

【0091】 [0091]

【表19】 [Table 19]

【0092】 [0092]

【表20】 [Table 20]

【0093】 [0093]

【表21】 [Table 21]

【0094】 [0094]

【表22】 [Table 22]

【0095】 [0095]

【表23】 [Table 23]

【0096】 [0096]

【表24】 [Table 24]

【0097】 [0097]

【表25】 [Table 25]

【0098】参考例95 4−〔2−(4−クロロ−1H−イミダゾ〔4,5− [0098] Reference Example 95 4- [2- (4-chloro -1H- imidazo [4,5
c〕キノリン−1−イル)エチル〕ベンズアミド 4−〔2−〔(3−アミノ−2−クロロキノリン−4− c] quinolin-1-yl) ethyl] benzamide 4- [2 - [(3-amino-2-chloro-4-
イル)アミノ〕エチル〕ベンズアミド2.45gにオルトギ酸エチル10mlを加え、80〜120℃で5時間攪拌した。 Yl) amino] ethyl] benzamide 2.45g ethyl orthoformate 10ml was added and the mixture was stirred for 5 hours at 80 to 120 ° C.. 室温下n-ヘキサンを加え、析出結晶を濾取し、 It added at room temperature n- hexane, and the precipitated crystals were collected by filtration,
イソプロピルエーテルで洗浄して淡褐色結晶2.29g Pale brown crystals 2.29g and washed with isopropyl ether
を得た。 It was obtained. アセトニトリルから再結晶して、融点287. Recrystallization from acetonitrile, mp 287.
0〜288.0℃の無色結晶を得た。 0 to 288.0 to give colorless crystals ° C.. 元素分析値 C 1915 ClN 4 O 理論値 C, 65.05; H, 4.31; N, 15.97 実験値 C, 64.80; H, 4.08; N, 16.15 Elemental analysis C 19 H 15 ClN 4 O theory C, 65.05; H, 4.31; N, 15.97 Found C, 64.80; H, 4.08; N, 16.15

【0099】参考例95の方法に従って、表26〜表3 [0099] In accordance with the method of Reference Example 95, Table 26 to Table 3
4に示した参考例96〜147の化合物を得た。 4 to give compounds of Reference Examples 96 to 147 shown in.

【0100】 [0100]

【表26】 [Table 26]

【0101】 [0101]

【表27】 [Table 27]

【0102】 [0102]

【表28】 [Table 28]

【0103】 [0103]

【表29】 [Table 29]

【0104】 [0104]

【表30】 [Table 30]

【0105】 [0105]

【表31】 [Table 31]

【0106】 [0106]

【表32】 [Table 32]

【0107】 [0107]

【表33】 [Table 33]

【0108】 [0108]

【表34】 [Table 34]

【0109】参考例148 4−〔2−(4−クロロ−2−メチル−1H−イミダゾ〔4,5−c〕キノリン−1−イル)エチル〕−N− [0109] Reference Example 148 4- [2- (4-chloro-2-methyl -1H- imidazo [4,5-c] quinolin-1-yl) ethyl] -N-
(1−エトキシエチリデン)ベンゼンスルホンアミド 4−〔2−〔(3−アミノ−2−クロロキノリン−4− (1-ethoxy-ethylidene) benzenesulfonamide 4- [2 - [(3-amino-2-chloro-4-
イル)アミノ〕エチル〕ベンゼンスルホンアミド2.3 Yl) amino] ethyl] benzenesulfonamide 2.3
4gにオルトギ酸エチル9.4mlを加え、140℃で1 Ethyl orthoformate 9.4ml added to 4g, 1 at 140 ° C.
晩攪拌した。 Evening and the mixture was stirred. 反応液を冷却後、n-ヘキサンを加えてデカント後、残渣をカラムクロマトグラフィー〔シリカゲル,酢酸エチル−n-ヘキサン(1:1〜4:1)〕で精製した。 After cooling the reaction mixture, after decanting the addition of n- hexane and the residue was purified by column chromatography [silica gel, ethyl acetate -n- hexane (1: 1 to 4: 1)] was purified. 酢酸エチルとn-ヘキサンの混液から結晶化して、1.67gの結晶を得た。 Crystallization from a mixture of ethyl acetate and n- hexane to give crystals 1.67 g. 酢酸エチルから再結晶して、融点151.0〜152.0℃の黄色針状晶を得た。 Recrystallization from ethyl acetate gave yellow needles of melting point 151.0-152.0 ° C.. 元素分析値 C 2323 ClN 43 S 理論値 C, 58.65; H, 4.92; N, 11.90 実験値 C, 58.59; H, 4.70; N, 11.71 Elemental analysis C 23 H 23 ClN 4 O 3 S theory C, 58.65; H, 4.92; N, 11.90 Found C, 58.59; H, 4.70; N, 11.71

【0110】参考例148の方法に従って、表35〜表36に示した参考例149〜152の化合物を得た。 [0110] according to the method of Reference Example 148 to give the compound of Reference Example 149-152 shown in Table 35 Table 36.

【0111】 [0111]

【表35】 [Table 35]

【0112】 [0112]

【表36】 [Table 36]

【0113】参考例153 プロピオン酸 4−〔2−(4−クロロ−2−エチル− [0113] Reference Example 153 propionic acid 4- [2- (4-chloro-2-ethyl -
1H−イミダゾ〔4,5−c〕キノリン−1−イル)エチル〕ベンジル 4−〔2−〔(3−アミノ−2−クロロキノリン−4− 1H- imidazo [4,5-c] quinolin-1-yl) ethyl] benzyl 4- [2 - [(3-amino-2-chloro-4-
イル)アミノ〕エチル〕ベンジルアルコール3.00g Yl) amino] ethyl] benzyl alcohol 3.00g
をトルエン75mlに溶解し、プロピオニルクロリド3. Was dissolved in toluene 75 ml, propionyl chloride 3.
1mlを加えた。 It was added to 1ml. 室温で3時間攪拌した後、p-トルエンスルホン酸・1水和物0.17gを加え、6時間還流した後、反応混合物を減圧濃縮し、残渣を塩化メチレンに溶解した後、10%アンモニア水,水及び飽和食塩水で順次洗浄した。 After stirring for 3 hours at room temperature, p- toluenesulfonic acid monohydrate 0.17g was added and after refluxing for 6 hours, the reaction mixture was concentrated under reduced pressure, the residue was dissolved in methylene chloride, 10% aqueous ammonia and washed sequentially with water and brine. 塩化メチレン層は脱水後、溶媒を減圧留去した。 After methylene chloride layer dried, and the solvent was evaporated under reduced pressure. 残渣をカラムクロマトグラフィー〔シリカゲル, The residue was purified by column chromatography [silica gel,
塩化メチレン−メタノール(50:1)〕で精製して、 Methylene chloride - methanol (50: 1)] to give the
淡褐色結晶1.70gを得た。 To give a pale brown crystal 1.70g. イソプロピルアルコールから再結晶して、融点144.0〜145.5℃の淡褐色結晶を得た。 Recrystallization from isopropyl alcohol to give pale brown crystals of melting point 144.0-145.5 ° C.. 元素分析値 C 2424 ClN 32理論値 C, 68.32; H, 5.73; N, 9.96 実験値 C, 68.32; H, 5.74; N, 9.98 Elemental analysis C 24 H 24 ClN 3 O 2 theory C, 68.32; H, 5.73; N, 9.96 Found C, 68.32; H, 5.74; N, 9.98

【0114】参考例153の方法に従って、表37〜表38に示した参考例154〜156の化合物を得た。 [0114] according to the method of Reference Example 153 to give the compound of Reference Example 154-156 shown in Table 37 to Table 38.

【0115】 [0115]

【表37】 [Table 37]

【0116】 [0116]

【表38】 [Table 38]

【0117】参考例157 4−〔2−(2−エトキシメチル−4−ヒドロキシ−1 [0117] Reference Example 157 4- [2- (2-ethoxymethyl-4-hydroxy-1
H−イミダゾ〔4,5−c〕キノリン−1−イル)エチル〕ベンゼンスルホンアミド 4−〔2−〔(3−アミノ−2−クロロキノリン−4− H- imidazo [4,5-c] quinolin-1-yl) ethyl] benzenesulfonamide 4- [2 - [(3-amino-2-chloro-4-
イル)アミノ〕エチル〕ベンゼンスルホンアミド5.9 Yl) amino] ethyl] benzenesulfonamide 5.9
2gにエトキシ酢酸23.7mlを加え、80〜130℃ Ethoxy acetic acid 23.7ml was added to 2 g, 80 to 130 ° C.
で6時間攪拌した。 In the mixture was stirred for 6 hours. 反応後、析出した結晶を濾取し、塩化メチレンで洗浄し、3.90gの結晶を得た。 After the reaction, the precipitated crystals were collected by filtration, washed with methylene chloride to give crystals 3.90 g. N,N N, N
−ジメチルホルムアミドと水の混液から再結晶して、融点300℃以上の無色結晶を得た。 - it was recrystallized from a mixture of dimethylformamide and water, mp 300 ° C. or more colorless crystals. 元素分析値 C 212244・1/2H 2 O 理論値 C, 58.52; H, 5.26; N, 13.00 実験値 C, 58.41; H, 5.00; N, 12.75 Elemental analysis C 21 H 22 N 4 O 4 · 1 / 2H 2 O Theoretical value C, 58.52; H, 5.26; N, 13.00 Found C, 58.41; H, 5.00; N, 12.75

【0118】参考例157の方法に従って、表39〜表46に示した参考例158〜178の化合物を得た。 [0118] according to the method of Reference Example 157 to give the compound of Reference Example 158-178 shown in Table 39 to Table 46.

【0119】 [0119]

【表39】 [Table 39]

【0120】 [0120]

【表40】 [Table 40]

【0121】 [0121]

【表41】 [Table 41]

【0122】 [0122]

【表42】 [Table 42]

【0123】 [0123]

【表43】 [Table 43]

【0124】 [0124]

【表44】 [Table 44]

【0125】 [0125]

【表45】 [Table 45]

【0126】 [0126]

【表46】 [Table 46]

【0127】参考例179 4−〔2−(4−クロロ−2−エトキシメチル−1H− [0127] Reference Example 179 4- [2- (4-chloro-2-ethoxymethyl -1H-
イミダゾ〔4,5−c〕キノリン−1−イル)エチル〕 Imidazo [4,5-c] quinolin-1-yl) ethyl]
ベンゼンスルホンアミド 4−〔2−(2−エトキシメチル−4−ヒドロキシ−1 Benzenesulfonamide 4- [2- (2-ethoxymethyl-4-hydroxy-1
H−イミダゾ〔4,5−c〕キノリン−1−イル)エチル〕ベンゼンスルホンアミド3.03g,トリエチルアミン1.5ml及びトルエン30mlを加えた懸濁液に、室温下、オキシ塩化リン2.8mlを滴下後、120℃で5 H- imidazo [4,5-c] quinolin-1-yl) ethyl] benzenesulfonamide 3.03 g, to a suspension of triethylamine was added 1.5ml and toluene 30 ml, at room temperature, phosphorus oxychloride 2.8ml after the dropwise addition, 5 at 120 ° C.
時間攪拌した。 Time and the mixture was stirred. 反応液を氷水中に注ぎ、析出した結晶を濾取し、得られた結晶をカラムクロマトグラフィー〔シリカゲル,塩化メチレン−メタノール(20:1)〕で精製し、淡褐色結晶1.89gを得た。 The reaction mixture was poured into ice water, and the precipitated crystals were collected by filtration, column resulting crystals chromatography [silica gel, methylene chloride - methanol (20: 1)] to give the pale brown crystals 1.89g . IRスペクトル ν (KBr) cm -1 : 3360 , 1332 IR spectrum ν (KBr) cm -1: 3360 , 1332
, 1160 マススペクトル m/z : 444 (M + ) NMRスペクトル δ (DMSO) ppm: 1.16(3H,t,J=7H , 1160 Mass spectrum m / z: 444 (M + ) NMR spectrum δ (DMSO) ppm: 1.16 ( 3H, t, J = 7H
z),3.30(2H,t,J=8Hz),3.56(2H,q,J=7Hz),4.59(2H,s),4. z), 3.30 (2H, t, J = 8Hz), 3.56 (2H, q, J = 7Hz), 4.59 (2H, s), 4.
99(2H,t,J=8Hz),7.24(2H,br-s),7.41(2H,d,J=8Hz),7.77 99 (2H, t, J = 8Hz), 7.24 (2H, br-s), 7.41 (2H, d, J = 8Hz), 7.77
-7.82(4H,m),8.11-8.13(1H,m),8.45-8.47(1H,m) -7.82 (4H, m), 8.11-8.13 (1H, m), 8.45-8.47 (1H, m)

【0128】参考例179の方法に従って、表47〜表51に示した参考例180〜196の化合物を得た。 [0128] according to the method of Reference Example 179 to give the compound of Reference Example 180-196 shown in Table 47 to Table 51.

【0129】 [0129]

【表47】 [Table 47]

【0130】 [0130]

【表48】 [Table 48]

【0131】 [0131]

【表49】 [Table 49]

【0132】 [0132]

【表50】 [Table 50]

【0133】 [0133]

【表51】 [Table 51]

【0134】参考例197 N−〔4−〔2−(4−ジベンジルアミノ)−2−エトキシメチル−1H−イミダゾ〔4,5−c〕キノリン− [0134] Reference Example 197 N-[4- [2- (4-dibenzylamino) -2-ethoxymethyl -1H- imidazo [4,5-c] quinoline -
1−イル)エチル〕フェニル〕アセトアミド N−〔4−〔2−〔(3−アミノ−2−ジベンジルアミノキノリン−4−イル)アミノ〕エチル〕フェニル〕アセトアミド5.21g及びエトキシ酢酸4.21gの混合物を140℃で10時間攪拌した。 1-yl) ethyl] phenyl] acetamide N- [4- [2 - [(3-amino-2-dibenzylamino-4-yl) amino] ethyl] phenyl] acetamide 5.21g and ethoxy acetate 4.21g and stirred for 10 hours with a mixture of 140 ° C.. 酢酸エチルと10 Ethyl acetate and 10
%水酸化ナトリウム水溶液を反応混合物に加えて分液し、水層を酢酸エチルで抽出した。 % Sodium hydroxide aqueous solution was added to the reaction mixture was separated and the aqueous layer was extracted with ethyl acetate. 酢酸エチル層を合わせて、飽和食塩水で洗浄後脱水し、溶媒を留去した。 The combined ethyl acetate layer, dried and washed with saturated brine and then the solvent was evaporated. 残渣をカラムクロマトグラフィー〔シリカゲル,酢酸エチル−n-ヘキサン(1:2〜1:1)〕で精製し、酢酸エチルとイソプロピルエーテルの混液で洗浄して、淡褐色結晶2.35gを得た。 The residue was purified by column chromatography [silica gel, ethyl acetate -n- hexane (1: 2 to 1: 1)] to give washed with a mixture of ethyl acetate and isopropyl ether to give pale brown crystals 2.35 g. 酢酸エチルから再結晶して、融点171.0〜171.5℃の無色針状晶を得た。 Recrystallization from ethyl acetate gave colorless needles having a melting point of from 171.0 to 171.5 ° C.. 元素分析値 C 373752理論値 C, 76.13; H, 6.39; N, 12.00 実験値 C, 76.23; H, 6.32; N, 11.98 Elemental analysis C 37 H 37 N 5 O 2 theory C, 76.13; H, 6.39; N, 12.00 Found C, 76.23; H, 6.32; N, 11.98

【0135】参考例197の方法に従って、表52〜表56に示した参考例198〜204の化合物を得た。 [0135] according to the method of Reference Example 197 to give the compound of Reference Example 198-204 shown in Table 52 to Table 56.

【0136】 [0136]

【表52】 [Table 52]

【0137】 [0137]

【表53】 [Table 53]

【0138】 [0138]

【表54】 [Table 54]

【0139】 [0139]

【表55】 [Table 55]

【0140】 [0140]

【表56】 [Table 56]

【0141】参考例205 4−〔2−(2−アセトキシメチル−4−ヒドロキシ− [0141] Reference Example 205 4- [2- (2-acetoxymethyl-4-hydroxy -
1H−イミダゾ〔4,5−c〕キノリン−1−イル)エチル〕ベンゼンスルホンアミド 4−〔2−(4−ヒドロキシ−2−ヒドロキシメチル− 1H- imidazo [4,5-c] quinolin-1-yl) ethyl] benzenesulfonamide 4- [2- (4-hydroxy-2-hydroxymethyl -
1H−イミダゾ〔4,5−c〕キノリン−1−イル)エチル〕ベンゼンスルホンアミド7.53gにピリジン2 1H- imidazo [4,5-c] quinolin-1-yl) ethyl] pyridine benzenesulfonamide 7.53 g 2
25ml及び無水酢酸17.8mlを加えて、室温で1時間攪拌した。 It added 25ml and acetic anhydride 17.8 ml, and stirred at room temperature for 1 hour. 反応液を減圧濃縮後、水を加えて析出した結晶を濾取し、水及び酢酸エチルで順次洗浄して、7.8 The reaction mixture was concentrated under reduced pressure, crystals were collected by filtration precipitated by adding water, washed successively with water and ethyl acetate, 7.8
1gの結晶を得た。 To obtain a 1g of crystal. N,N−ジメチルホルムアミドと水の混液から再結晶して、融点275.0〜276.0℃ N, and recrystallized from a mixture of N- dimethylformamide and water, mp 275.0-276.0 ° C.
の淡褐色結晶を得た。 It was obtained as a pale brown crystal. 元素分析値 C 212045 S 理論値 C, 57.26; H, 4.58; N, 12.72 実験値 C, 56.94; H, 4.50; N, 12.63 Elemental analysis C 21 H 20 N 4 O 5 S theory C, 57.26; H, 4.58; N, 12.72 Found C, 56.94; H, 4.50; N, 12.63

【0142】参考例205の方法に従って、表57に示した参考例206の化合物を得た。 [0142] according to the method of Reference Example 205 to give the compound of Reference Example 206 shown in Table 57.

【0143】 [0143]

【表57】 [Table 57]

【0144】参考例207 4−〔2−(2−ヒドロキシメチル−4−フェノキシ− [0144] Reference Example 207 4- [2- (2-hydroxymethyl-4-phenoxy -
1H−イミダゾ〔4,5−c〕キノリン−1−イル)エチル〕ベンゼンスルホンアミド 4−〔2−(2−アセトキシメチル−4−ヒドロキシ− 1H- imidazo [4,5-c] quinolin-1-yl) ethyl] benzenesulfonamide 4- [2- (2-acetoxymethyl-4-hydroxy -
1H−イミダゾ〔4,5−c〕キノリン−1−イル)エチル〕ベンゼンスルホンアミド3.00gとオキシ塩化リン45mlの混合物を1時間還流した。 1H- imidazo [4,5-c] quinolin-1-yl) ethyl] benzenesulfonamide 3.00g and phosphorus oxychloride 45ml was refluxed for 1 hour. 冷却後結晶を濾取し、酢酸エチルで洗浄して、淡褐色結晶2.30gを得た。 Collected by filtration after cooling crystals were washed with ethyl acetate to give pale brown crystals 2.30 g. 得られた淡褐色結晶にフェノール4.71g及び水酸化カリウム1.72gを加えて、120℃で1時間攪拌した。 To the resulting pale brown crystals by the addition of phenol 4.71g and potassium hydroxide 1.72 g, it was stirred for 1 hour at 120 ° C.. 冷却後、10%塩酸及び酢酸エチルを加え、 After cooling, 10% hydrochloric acid and ethyl acetate were added,
不溶物を濾去した後分液し、酢酸エチル層を脱水して減圧濃縮した。 And separated After filtering off the insoluble material, and concentrated under reduced pressure to dehydrate the ethyl acetate layer. 残渣にジエチルエーテルを加え、析出した結晶を濾取して、1.39gの結晶を得た。 Diethyl ether was added to the residue, and the precipitated crystals were collected by filtration to obtain crystals of 1.39 g. N,N−ジメチルホルムアミドと水の混液から再結晶して、融点2 N, and recrystallized from a mixture of N- dimethylformamide and water, mp 2
61.0〜263.0℃の淡褐色結晶を得た。 61.0 to 263.0 to give a pale brown crystals ° C.. 元素分析値 C 252244 S 理論値 C, 63.28; H, 4.67; N, 11.81 実験値 C, 63.24; H, 4.58; N, 11.71 Elemental analysis C 25 H 22 N 4 O 4 S theory C, 63.28; H, 4.67; N, 11.81 Found C, 63.24; H, 4.58; N, 11.71

【0145】参考例207の方法に従って、表58に示した参考例208の化合物を得た。 [0145] according to the method of Reference Example 207 to give the compound of Reference Example 208 shown in Table 58.

【0146】 [0146]

【表58】 [Table 58]

【0147】参考例209 4−〔2−(4−フェノキシ−1H−イミダゾ〔4,5 [0147] Reference Example 209 4- [2- (4-phenoxy -1H- [4,5
−c〕キノリン−1−イル)エチル〕ベンズアミド 4−〔2−(4−クロロ−1H−イミダゾ〔4,5− -c] quinolin-1-yl) ethyl] benzamide 4- [2- (4-chloro -1H- imidazo [4,5
c〕キノリン−1−イル)エチル〕ベンズアミド1.6 c] quinolin-1-yl) ethyl] benzamide 1.6
5gに水酸化カリウム0.81g及びフェノール4.4 Potassium hydroxide 5 g 0.81 g and phenol 4.4
3gを加え、120℃で4.5時間攪拌した。 3g, and the mixture was stirred for 4.5 hours at 120 ° C.. 反応混合物に、水及び10%塩酸を加え、液性をpH8に調整した後、酢酸エチルを加えて析出した結晶を濾取し、淡褐色結晶1.29gを得た。 To the reaction mixture, water and 10% hydrochloric acid were added, after adjusting the liquid to pH 8, and filtered crystals precipitated by adding ethyl acetate to give pale brown crystals 1.29 g. エタノールから再結晶して、融点265.0〜266.0℃の黄色針状晶を得た。 Recrystallization from ethanol gave yellow needles of melting point from 265.0 to 266.0 ° C.. 元素分析値 C 252042理論値 C, 73.51; H, 4.94; N, 13.72 実験値 C, 73.33; H, 4.85; N, 13.43 Elemental analysis C 25 H 20 N 4 O 2 theory C, 73.51; H, 4.94; N, 13.72 Found C, 73.33; H, 4.85; N, 13.43

【0148】参考例209の方法に従って、表59〜表71に示した参考例210〜287の化合物を得た。 [0148] according to the method of Reference Example 209 to give the compound of Reference Example 210-287 shown in Table 59 to Table 71.

【0149】 [0149]

【表59】 [Table 59]

【0150】 [0150]

【表60】 [Table 60]

【0151】 [0151]

【表61】 [Table 61]

【0152】 [0152]

【表62】 [Table 62]

【0153】 [0153]

【表63】 [Table 63]

【0154】 [0154]

【表64】 [Table 64]

【0155】 [0155]

【表65】 [Table 65]

【0156】 [0156]

【表66】 [Table 66]

【0157】 [0157]

【表67】 [Table 67]

【0158】 [0158]

【表68】 [Table 68]

【0159】 [0159]

【表69】 [Table 69]

【0160】 [0160]

【表70】 [Table 70]

【0161】 [0161]

【表71】 [Table 71]

【0162】参考例288 4−〔2−(2−n-ブチル−4−フェノキシ−6,7, [0162] Reference Example 288 4- [2- (2-n- butyl-4-phenoxy -6,7,
8,9−テトラヒドロ−1H−イミダゾ〔4,5−c〕 8,9-tetrahydro -1H- imidazo [4,5-c]
キノリン−1−イル)エチル〕ベンゼンスルホンアミド (1) 4−〔2−(2−n-ブチル−4−クロロ−6,7, Quinolin-1-yl) ethyl] benzenesulfonamide (1) 4- [2-(2-n-butyl-4-chloro -6,7,
8,9−テトラヒドロ−1H−イミダゾ〔4,5−c〕 8,9-tetrahydro -1H- imidazo [4,5-c]
キノリン−1−イル)エチル−N−(1−エトキシペンチリデン)ベンゼンスルホンアミド 4−〔2−〔(3−アミノ−2−クロロ−5,6,7, Quinolin-1-yl) ethyl-N-(1-ethoxy cyclopentylidene) benzenesulfonamide 4- [2 - [(3-amino-2-chloro -5,6,7,
8−テトラヒドロキノリン−4−イル)アミノ〕エチル〕ベンゼンスルホンアミド3.04gにオルト吉草酸トリエチル12mlを加え、120〜140℃で25時間攪拌した。 The orthovalerate triethyl 12ml was added to 8-tetrahydroquinolin-4-yl) amino] ethyl] benzenesulphonamide 3.04 g, it was stirred for 25 hours at 120 to 140 ° C.. n-ヘキサンを加え、オルト吉草酸トリエチルをデカントで除去し、残渣を140℃で19時間攪拌した。 The n- hexane was added to remove the orthovalerate triethyl by decantation, the residue was stirred for 19 hours at 140 ° C.. これをカラムクロマトグラフィー〔シリカゲル,塩化メチレン−メタノール(100:1)〕で精製し、淡褐色結晶1.67gを得た。 Which was purified by column chromatography [silica gel, methylene chloride - methanol (100: 1)] to give the pale brown crystals 1.67 g. (2) 4−〔2−(2−n-ブチル−4−フェノキシ−6, (2) 4- [2-(2-n-butyl-4-phenoxy-6,
7,8,9−テトラヒドロ−1H−イミダゾ〔4,5− 7,8,9- tetrahydro -1H- imidazo [4,5
c〕キノリン−1−イル)エチル〕ベンゼンスルホンアミド 4−〔2−(2−n-ブチル−4−クロロ−6,7,8, c] quinolin-1-yl) ethyl] benzenesulfonamide 4- [2- (2-n- butyl-4-chloro -6,7,8,
9−テトラヒドロ−1H−イミダゾ〔4,5−c〕キノリン−1−イル)エチル−N−(1−エトキシペンチリデン)ベンゼンスルホンアミド1.35gに、水酸化カリウム0.43gとフェノール2.33gを加え、12 9-tetrahydro -1H- imidazo [4,5-c] quinolin-1-yl) ethyl-N-(1-ethoxy cyclopentylidene) benzenesulfonamide 1.35 g, potassium hydroxide 0.43g phenol 2.33g was added, 12
0℃で5時間攪拌した。 The mixture was stirred for 5 hours at 0 ℃. 反応混合物に、水及び10%水酸化ナトリウム水溶液を加え、液性をpH10に調整した後、塩化メチレンを加え抽出した。 To the reaction mixture, water and 10% aqueous sodium hydroxide was added, after adjusting the liquid to pH 10, and extraction was performed with methylene chloride. 抽出液を10%水酸化ナトリウム水溶液,水,飽和食塩水で順次洗浄し脱水後、塩化メチレンを留去した。 Extract 10% sodium hydroxide solution, water, washed successively dehydrated with saturated sodium chloride solution, methylene chloride was distilled off. 残渣をカラムクロマトグラフィー〔シリカゲル,塩化メチレン−メタノール(1 The residue was purified by column chromatography [silica gel, methylene chloride - methanol (1
00:1〜30:1)〕で精製し、微褐色結晶0.68 00: 1 to 30: 1) to give], fine brown crystals 0.68
gを得た。 It was obtained g. 酢酸エチルから再結晶して、融点224.5 Recrystallization from ethyl acetate, melting point 224.5
〜225.5℃の無色結晶を得た。 ~225.5 give colorless crystals ° C.. 元素分析値 C 283243 S 理論値 C, 66.64; H, 6.39; N, 11.10 実験値 C, 66.43; H, 6.41; N, 10.84 Elemental analysis C 28 H 32 N 4 O 3 S theory C, 66.64; H, 6.39; N, 11.10 Found C, 66.43; H, 6.41; N, 10.84

【0163】参考例289 4−〔2−(2−シクロプロピルメチル−4−フェノキシ−1H−イミダゾ〔4,5−c〕キノリン−1−イル)エチル〕ベンジルアルコール (1) シクロプロピル酢酸 4−〔2−(4−クロロ−2 [0163] Reference Example 289 4- [2- (2-cyclopropylmethyl-4-phenoxy -1H- imidazo [4,5-c] quinolin-1-yl) ethyl] benzyl alcohol (1) cyclopropyl acetate 4- [2- (4-chloro-2
−シクロプロピルメチル−1H−イミダゾ〔4,5− - cyclopropylmethyl -1H- imidazo [4,5
c〕キノリン−1−イル)エチル〕ベンジル シクロプロピル酢酸 4−〔2−(2−シクロプロピルメチル−4−ヒドロキシ−1H−イミダゾ〔4,5− c] quinolin-1-yl) ethyl] benzyl cyclopropyl acetate 4- [2- (2-cyclopropylmethyl-4-hydroxy -1H- imidazo [4,5
c〕キノリン−1−イル)エチル〕ベンジル1.33g c] quinolin-1-yl) ethyl] benzyl 1.33g
にオキシ塩化リン20mlを加え、120℃で1時間攪拌した。 Phosphorus oxychloride 20ml was added, and the mixture was stirred for 1 hour at 120 ° C.. 反応液を水中に注ぎ、塩化メチレンを加えて抽出した。 The reaction mixture was poured into water and extracted by addition of methylene chloride. 抽出液を水,飽和食塩水で順次洗浄し脱水後、溶媒を留去した。 The extract was water washed successively dehydrated with saturated brine and then the solvent was evaporated. 残渣をカラムクロマトグラフィー〔シリカゲル,塩化メチレン−メタノール(100:1〜3 The residue was purified by column chromatography [silica gel, methylene chloride - methanol (100: 1-3
0:1)〕で精製し、無色結晶0.36gを得た。 0: 1) to give], colorless crystals 0.36 g. (2) 4−〔2−(2−シクロプロピルメチル−4−フェノキシ−1H−イミダゾ〔4,5−c〕キノリン−1− (2) 4- [2- (2-cyclopropylmethyl-4-phenoxy -1H- imidazo [4,5-c] quinolin-1
イル)エチル〕ベンジルアルコール シクロプロピル酢酸 4−〔2−(4−クロロ−2−シクロプロピルメチル−1H−イミダゾ〔4,5−c〕キノリン−1−イル)エチル〕ベンジル0.25gに、水酸化カリウム0.09gとフェノール0.50gを加え、120℃で4時間攪拌した。 To-yl) ethyl] benzyl alcohol cyclopropyl acetate 4- [2- (4-chloro-2-cyclopropylmethyl -1H- imidazo [4,5-c] quinolin-1-yl) ethyl] benzyl 0.25 g, water potassium oxide 0.09g phenol 0.50g was added, and stirred for 4 hours at 120 ° C.. 反応後、水,10%水酸化ナトリウム水溶液及び酢酸エチルを加え、氷冷下攪拌した。 After the reaction, water, an aqueous 10% sodium and ethyl acetate hydroxide was added, followed by stirring under ice cooling. 析出結晶を濾取し、0.14gの微褐色結晶を得た。 And the precipitated crystals were collected by filtration, to obtain a fine brown crystals of 0.14g. 酢酸エチルから再結晶して、融点185.0〜1 Recrystallization from ethyl acetate, melting point 185.0 to 1
85.5℃の無色結晶0.10gを得た。 Colorless crystals 0.10g of 85.5 ° C.. 元素分析値 C 292732理論値 C, 77.48; H, 6.05; N, 9.35 実験値 C, 77.22; H, 6.09; N, 9.11 Elemental analysis C 29 H 27 N 3 O 2 theory C, 77.48; H, 6.05; N, 9.35 Found C, 77.22; H, 6.09; N, 9.11

【0164】参考例289の方法に従って、表72〜表73に示した参考例290〜291の化合物を得た。 [0164] according to the method of Reference Example 289 to give the compound of Reference Example 290-291 shown in Table 72 to Table 73.

【0165】 [0165]

【表72】 [Table 72]

【0166】 [0166]

【表73】 [Table 73]

【0167】参考例292 4−〔2−〔2−(2−メチルプロピル)−4−フェノキシ−1H−イミダゾ〔4,5−c〕キノリン−1−イル〕エチル〕ベンゼンスルホンアミド (1) 4−〔2−〔4−ヒドロキシ−2−(2−メチルプロピル)−1H−イミダゾ〔4,5−c〕キノリン−1 [0167] Reference Example 292 4- [2- [2- (2-methylpropyl) -4-phenoxy -1H- imidazo [4,5-c] quinolin-1-yl] ethyl] benzenesulfonamide (1) 4 - [2- [4-hydroxy-2- (2-methylpropyl)-1H-imidazo [4,5-c] quinolin -1
−イル〕エチル〕ベンゼンスルホンアミド 4−〔2−〔(3−アミノ−2−クロロキノリン−4− - yl] ethyl] benzenesulfonamide 4- [2 - [(3-amino-2-chloro-4-
イル)アミノ〕エチル〕ベンゼンスルホンアミド8.0 Yl) amino] ethyl] benzenesulfonamide 8.0
0gにイソ吉草酸11.6mlを加え、130℃で24時間攪拌した。 Isovalerate 11.6ml added to 0 g, and stirred for 24 hours at 130 ° C.. 析出結晶を濾取し、塩化メチレンで洗浄して、9.31gの結晶を得た。 And the precipitated crystals were collected by filtration and washed with methylene chloride to give crystals 9.31 g. (2) 4−〔2−〔4−クロロ−2−(2−メチルプロピル)−1H−イミダゾ〔4,5−c〕キノリン−1−イル〕エチル〕ベンゼンスルホンアミド 4−〔2−〔4−ヒドロキシ−2−(2−メチルプロピル)−1H−イミダゾ〔4,5−c〕キノリン−1−イル〕エチル〕ベンゼンスルホンアミド9.00gにオキシ塩化リン135mlを加え、120℃で9時間攪拌した。 (2) 4- [2- [4-chloro-2- (2-methylpropyl)-1H-imidazo [4,5-c] quinolin-1-yl] ethyl] benzenesulfonamide 4- [2- [4 - hydroxy-2- (2-methylpropyl)-1H-imidazo [4,5-c] quinolin-1-yl] ethyl] phosphorus oxychloride 135ml added to benzenesulfonamide 9.00 g, 9 hours at 120 ° C. did. 反応液を減圧濃縮し、酢酸エチルを加えて析出した結晶を濾取し、5.10gの結晶を得た。 The reaction mixture was concentrated under reduced pressure, crystals were collected by filtration precipitated by adding ethyl acetate to obtain crystals of 5.10 g. (3) 4−〔2−〔2−(2−メチルプロピル)−4−フェノキシ−1H−イミダゾ〔4,5−c〕キノリン−1 (3) 4- [2- [2- (2-methylpropyl) -4-phenoxy -1H- imidazo [4,5-c] quinolin -1
−イル〕エチル〕ベンゼンスルホンアミド 4−〔2−〔4−クロロ−2−(2−メチルプロピル) - yl] ethyl] benzenesulfonamide 4- [2- [4-chloro-2- (2-methylpropyl)
−1H−イミダゾ〔4,5−c〕キノリン−1−イル〕 -1H- imidazo [4,5-c] quinolin-1-yl]
エチル〕ベンゼンスルホンアミド4.80gに水酸化カリウム1.86g及びフェノール10.2gを加え、1 Potassium hydroxide 1.86g and phenol 10.2g added to ethyl] benzenesulfonamide 4.80 g, 1
20℃で5時間攪拌した。 The mixture was stirred for 5 hours at 20 ℃. 反応混合物に、水及び10% To the reaction mixture, water and 10%
塩酸を加え、液性をpH8に調整した後、酢酸エチルを加えて析出した結晶を濾取し、淡褐色結晶2.16gを得た。 Hydrochloric acid was added, after adjusting the liquid to pH 8, and filtered crystals precipitated by adding ethyl acetate to give pale brown crystals 2.16 g. 酢酸エチルから再結晶して、融点221.0〜22 Recrystallization from ethyl acetate, melting point 221.0 to 22
2.0℃の淡褐色針状晶を得た。 2.0 to give a pale brown needles ° C.. 元素分析値 C 282843 S 理論値 C, 67.18; H, 5.64; N, 11.19 実験値 C, 67.08; H, 5.47; N, 11.40 Elemental analysis C 28 H 28 N 4 O 3 S theory C, 67.18; H, 5.64; N, 11.19 Found C, 67.08; H, 5.47; N, 11.40

【0168】参考例292の方法に従って、表74に示した参考例293の化合物を得た。 [0168] according to the method of Reference Example 292 to give the compound of Reference Example 293 shown in Table 74.

【0169】 [0169]

【表74】 [Table 74]

【0170】参考例294 1−〔2−(4−シアノフェニル)エチル〕−4−フェノキシ−1H−イミダゾ〔4,5−c〕キノリン 4−〔2−(4−フェノキシ−1H−イミダゾ〔4,5 [0170] Reference Example 294 1- [2- (4-cyanophenyl) ethyl] -4-phenoxy -1H- imidazo [4,5-c] quinoline 4- [2- (4-phenoxy -1H- imidazo [4 , 5
−c〕キノリン−1−イル)エチル〕ベンズアミド1. -c] quinolin-1-yl) ethyl] benzamide 1.
33gをN,N−ジメチルホルムアミド33mlに溶解して、氷冷攪拌下、ピリジン1.05ml及び無水トリフルオロ酢酸0.92mlを加えて、30分間氷冷攪拌した。 By dissolving 33 g N, N- dimethylformamide 33 ml, with stirring under ice cooling, it added pyridine 1.05ml and trifluoroacetic anhydride 0.92 ml, followed by stirring for 30 minutes ice cooling.
反応液に氷水100ml及びジエチルエーテル20mlを加えて攪拌し、析出した結晶を濾取して、0.89gの結晶を得た。 Added ice water 100ml and diethyl ether 20ml reaction solution was stirred, and the precipitated crystals were collected by filtration to obtain crystals of 0.89 g. 酢酸エチルから再結晶して、融点196.0 Recrystallization from ethyl acetate, melting point 196.0
〜198.0℃の淡黄色針状晶を得た。 ~198.0 give pale yellow needles of ° C.. 元素分析値 C 25184 O 理論値 C, 76.91; H, 4.65; N, 14.35 実験値 C, 76.97; H, 4.35; N, 14.45 Elemental analysis C 25 H 18 N 4 O theory C, 76.91; H, 4.65; N, 14.35 Found C, 76.97; H, 4.35; N, 14.45

【0171】参考例295 4−〔2−(4−フェノキシ−1H−イミダゾ〔4,5 [0171] Reference Example 295 4- [2- (4-phenoxy -1H- [4,5
−c〕キノリン−1−イル)エチル〕安息香酸 4−〔2−(4−クロロ−1H−イミダゾ〔4,5− -c] quinolin-1-yl) ethyl] benzoic acid 4- [2- (4-chloro -1H- imidazo [4,5
c〕キノリン−1−イル)エチル〕安息香酸エチル2. c] quinolin-1-yl) ethyl] benzoate 2.
31gにフェノール5.67g及び水酸化カリウム2. Phenol 5.67g and potassium hydroxide 2 to 31 g.
02gを加え、120℃で3時間攪拌した。 02g, and the mixture was stirred for 3 hours at 120 ° C.. 反応混合物に、水及び10%塩酸を加え、液性をpH8に調整した後、酢酸エチルを加えて析出した結晶を濾取し、2.2 The reaction mixture, water and 10% hydrochloric acid were added, after adjusting the liquid to pH 8, and filtered crystals precipitated by adding ethyl acetate, 2.2
9gの結晶を得た。 It was obtained 9g of the crystal. N,N−ジメチルホルムアミドと水の混液から再結晶して、融点265.0〜267.0℃ N, and recrystallized from a mixture of N- dimethylformamide and water, melting point from 265.0 to 267.0 ° C.
の無色結晶を得た。 It was obtained as colorless crystals. 元素分析値 C 251933理論値 C, 73.34; H, 4.68; N, 10.26 実験値 C, 73.34; H, 4.38; N, 10.38 Elemental analysis C 25 H 19 N 3 O 3 theory C, 73.34; H, 4.68; N, 10.26 Found C, 73.34; H, 4.38; N, 10.38

【0172】実施例1 4−〔2−(4−アミノ−1H−イミダゾ〔4,5− [0172] EXAMPLE 1 4- [2- (4-amino -1H- imidazo [4,5
c〕キノリン−1−イル)エチル〕ベンズアミド 4−〔2−(4−フェノキシ−1H−イミダゾ〔4,5 c] quinolin-1-yl) ethyl] benzamide 4- [2- (4-phenoxy -1H- [4,5
−c〕キノリン−1−イル)エチル〕ベンズアミド1. -c] quinolin-1-yl) ethyl] benzamide 1.
09gに酢酸アンモニウム9.87gを加え、140℃ Ammonium acetate 9.87g was added to 09g, 140 ℃
で5時間攪拌した。 In and the mixture was stirred for 5 hours. 反応混合物に、10%水酸化ナトリウム水溶液を加え、液性をpH8に調整した後、析出した結晶を濾取し水洗して、0.82gの淡褐色結晶を得た。 To the reaction mixture, 10% sodium hydroxide aqueous solution was added, and after adjusting the liquid to pH 8, and filtered and washed with water and the precipitated crystals to give pale brown crystals of 0.82 g. エタノールから再結晶して、融点267.0〜26 Recrystallization from ethanol, melting point 267.0 to 26
8.0℃の淡褐色結晶を得た。 8.0 was obtained ℃ of pale brown crystals. 元素分析値 C 19175 O 理論値 C, 68.87; H, 5.17; N, 21.13 実験値 C, 68.58; H, 4.94; N, 20.87 Elemental analysis C 19 H 17 N 5 O theory C, 68.87; H, 5.17; N, 21.13 Found C, 68.58; H, 4.94; N, 20.87

【0173】実施例1の方法に従って、表75〜表78 [0173] according to the method of Example 1, Table 75 Table 78
に示した実施例2〜50の化合物を得た。 To give the compounds of Examples 2 to 50 shown in.

【0174】 [0174]

【表75】 [Table 75]

【0175】 [0175]

【表76】 [Table 76]

【0176】 [0176]

【表77】 [Table 77]

【0177】 [0177]

【表78】 [Table 78]

【0178】実施例51 4−〔2−(4−アミノ−2−メチル−1H−イミダゾ〔4,5−c〕キノリン−1−イル)エチル〕ベンジルアルコール (1) 4−〔2−(4−クロロ−2−メチル−1H−イミダゾ〔4,5−c〕キノリン−1−イル)エチル〕ベンジルアルコール 4−〔2−〔(3−アミノ−2−クロロキノリン−4− [0178] EXAMPLE 51 4- [2- (4-amino-2-methyl -1H- imidazo [4,5-c] quinolin-1-yl) ethyl] benzyl alcohol (1) 4- [2- (4 - chloro-2-methyl -1H- imidazo [4,5-c] quinolin-1-yl) ethyl] benzyl alcohol 4- [2 - [(3-amino-2-chloro-4-
イル)アミノ〕エチル〕ベンジルアルコール2.57g Yl) amino] ethyl] benzyl alcohol 2.57g
にオルト酢酸トリエチル7.2mlを加え、120〜14 The triethyl orthoacetate 7.2ml addition, 120-14
0℃で28時間攪拌した。 And the mixture was stirred for 28 hours at 0 ℃. 反応混合物に、n-ヘキサンを加えデカントで除去した後、残渣をカラムクロマトグラフィー〔シリカゲル,塩化メチレン−メタノール(1: To the reaction mixture was removed by decantation added n- hexane, the residue was purified by column chromatography [silica gel, methylene chloride - methanol (1:
0〜30:1)〕で精製し、淡黄色結晶1.66gを得た。 0-30: 1) to give] to give pale yellow crystals 1.66 g. (2) 4−〔2−(2−メチル−4−フェノキシ−1H− (2) 4- [2- (2-methyl-4-phenoxy -1H-
イミダゾ〔4,5−c〕キノリン−1−イル)エチル〕 Imidazo [4,5-c] quinolin-1-yl) ethyl]
ベンジルアルコール 4−〔2−(4−クロロ−2−メチル−1H−イミダゾ〔4,5−c〕キノリン−1−イル)エチル〕ベンジルアルコール1.50gに水酸化カリウム0.73g及びフェノール4.02gを加え、120℃で6時間攪拌した。 Benzyl alcohol 4- [2- (4-chloro-2-methyl -1H- imidazo [4,5-c] quinolin-1-yl) ethyl] potassium hydroxide benzyl alcohol 1.50 g 0.73 g and phenol 4. 02g, and the mixture was stirred for 6 hours at 120 ° C.. 反応混合物に、水及び10%水酸化ナトリウム水溶液を加え、液性をpH10に調整した後、塩化メチレンを加えて抽出した。 To the reaction mixture, water and 10% aqueous sodium hydroxide was added, after adjusting the liquid to pH 10, and extracted by addition of methylene chloride. 塩化メチレン層を10%水酸化ナトリウム水溶液,水及び飽和食塩水で順次洗浄し、脱水後溶媒を減圧留去し、淡褐色結晶1.20gを得た。 Methylene layer of a 10% aqueous solution of sodium hydroxide chloride, washed sequentially with water and saturated saline, dried, and then the solvent was distilled off under reduced pressure to give a pale brown crystals 1.20 g. (3) 4−〔2−(4−アミノ−2−メチル−1H−イミダゾ〔4,5−c〕キノリン−1−イル)エチル〕ベンジルアルコール 4−〔2−(2−メチル−4−フェノキシ−1H−イミダゾ〔4,5−c〕キノリン−1−イル)エチル〕ベンジルアルコール1.00gに酢酸アンモニウム4.52 (3) 4- [2- (4-amino-2-methyl -1H- imidazo [4,5-c] quinolin-1-yl) ethyl] benzyl alcohol 4- [2- (2-methyl-4-phenoxy -1H- imidazo [4,5-c] quinolin-1-yl) ethyl] ammonium acetate benzyl alcohol 1.00 g 4.52
gを加え、140℃で6時間攪拌した。 g, and the mixture was stirred for 6 hours at 140 ° C.. 反応後、10% After the reaction, 10%
水酸化ナトリウム水溶液を加え液性をpH8に調整した後、塩化メチレンとメタノールの混液(10:1)で抽出した。 After adjusting the added liquid-sodium hydroxide aqueous solution pH 8, methylene and methanol mixture chloride (10: 1). 有機層を減圧濃縮し、残渣にメタノール3.8 The organic layer was concentrated under reduced pressure, methanol 3.8 to the residue
ml及び2規定水酸化ナトリウム水溶液0.2mlを加え、 The ml and 2 N aqueous sodium hydroxide 0.2ml added,
50℃で1時間攪拌した。 And stirred for 1 hour at 50 ° C.. 反応液を氷冷下攪拌し、0. The reaction was stirred under ice-cooling, 0.
26gの結晶を得た。 It was obtained 26g of crystal. エタノールから再結晶して、融点236.0〜237.0℃の無色結晶を得た。 Recrystallization from ethanol gave colorless crystals of melting point from 236.0 to 237.0 ° C.. 元素分析値 C 20204 O 理論値 C, 72.27; H, 6.06; N, 16.86 実験値 C, 72.05; H, 6.07; N, 16.64 Elemental analysis C 20 H 20 N 4 O theory C, 72.27; H, 6.06; N, 16.86 Found C, 72.05; H, 6.07; N, 16.64

【0179】実施例1の方法に従って、表79〜表84 [0179] according to the method of Example 1, Table 79 to Table 84
に示した実施例52〜79の化合物を得た。 To give the compounds of Examples 52 to 79 shown in.

【0180】 [0180]

【表79】 [Table 79]

【0181】 [0181]

【表80】 [Table 80]

【0182】 [0182]

【表81】 [Table 81]

【0183】 [0183]

【表82】 [Table 82]

【0184】 [0184]

【表83】 [Table 83]

【0185】 [0185]

【表84】 [Table 84]

【0186】実施例80 N−〔4−〔2−(4−アミノ−2−エトキシメチル− [0186] EXAMPLE 80 N-[4- [2- (4-amino-2-ethoxymethyl -
1H−イミダゾ〔4,5−c〕キノリン−1−イル)エチル〕フェニル〕アセトアミド N−〔4−〔2−(4−ジベンジルアミノ−2−エトキシメチル−1H−イミダゾ〔4,5−c〕キノリン−1 1H- imidazo [4,5-c] quinolin-1-yl) ethyl] phenyl] acetamide N- [4- [2- (4-dibenzylamino-2-ethoxymethyl--1H- imidazo [4,5-c ] quinoline -1
−イル)エチル〕フェニル〕アセトアミド2.20g, - yl) ethyl] phenyl] acetamide 2.20 g,
パールマンズ試薬4.00g及びギ酸アンモニウム1 Pearlman's reagent 4.00g and ammonium formate 1
4.28gのメタノール70ml懸濁液を53時間還流した。 Methanol 70ml suspension 4.28g was refluxed for 53 hours. 触媒を濾去し、溶媒を減圧留去した。 The catalyst was filtered off, the solvent was distilled off under reduced pressure. 残渣に水及び飽和食塩水を加え、塩化メチレンで抽出した。 The residue water and saturated brine was added, and the mixture was extracted with methylene chloride. 抽出液は脱水後、溶媒を減圧留去した。 The extract was dehydrated, and the solvent was evaporated under reduced pressure. 得られた残渣をイソプロピルエーテルで洗浄して、無色結晶1.24gを得た。 The resulting residue was washed with isopropyl ether to give colorless crystals 1.24 g.
イソプロパノールから再結晶して、融点207.0〜2 Recrystallization from isopropanol, melting point 207.0 to 2
08.0℃の無色結晶を得た。 08.0 to give colorless crystals ° C.. 元素分析値 C 232552・1/2H 2 O 理論値 C, 66.97; H, 6.35; N, 16.98 実験値 C, 66.90; H, 6.28; N, 16.81 Elemental analysis C 23 H 25 N 5 O 2 · 1 / 2H 2 O Theoretical value C, 66.97; H, 6.35; N, 16.98 Found C, 66.90; H, 6.28; N, 16.81

【0187】実施例80の方法に従って、表85〜表8 [0187] according to the method of Example 80, Table 85 Table 8
7に示した実施例81〜84の化合物を得た。 To give the compounds of Examples 81 to 84 shown in 7.

【0188】 [0188]

【表85】 [Table 85]

【0189】 [0189]

【表86】 [Table 86]

【0190】 [0190]

【表87】 [Table 87]

【0191】実施例85 1−〔2−(4−アミノフェニル)エチル〕−1H−イミダゾ〔4,5−c〕キノリン−4−アミン・塩酸塩 N−〔4−〔2−(4−アミノ−1H−イミダゾ〔4, [0191] Example 85 1- [2- (4-aminophenyl) ethyl] -1H- imidazo [4,5-c] quinolin-4-amine hydrochloride N- [4- [2- (4-amino -1H- imidazo [4,
5−c〕キノリン−1−イル)エチル〕フェニル〕アセトアミド8.00gに2規定塩酸40mlを加え、120 2N hydrochloric acid 40ml was added to 5-c] quinolin-1-yl) ethyl] phenyl] acetamide 8.00 g, 120
℃で1時間攪拌した。 And the mixture was stirred for 1 hour at ℃. 反応後、10%水酸化ナトリウム水溶液を加え、液性をpH7に調整した後、析出した結晶を濾取し、カラムクロマトグラフィー〔シリカゲル,塩化メチレン−メタノール(20:1)〕で精製後、エタノール性塩化水素を加え、析出した結晶を濾取して、無色結晶3.50gを得た。 After the reaction, 10% aqueous sodium hydroxide was added and after adjusting the mixture to around pH 7, and the precipitated crystals were collected by filtration, column chromatography [silica gel, methylene chloride - methanol (20: 1)] and recrystallized from ethanol sex hydrogen chloride was added, and the precipitated crystals were collected by filtration to give colorless crystals 3.50 g. メタノールと水の混液から再結晶して、融点275.0〜283.0℃の無色結晶を得た。 Recrystallization from a mixture of methanol and water to give colorless crystals of melting point 275.0-283.0 ° C.. 元素分析値 C 18175・2HCl・1/4H 2 O 理論値 C, 56.78; H, 5.16; N, 18.39 実験値 C, 56.78; H, 5.11; N, 18.22 Elemental analysis C 18 H 17 N 5 · 2HCl · 1 / 4H 2 O Theoretical value C, 56.78; H, 5.16; N, 18.39 Found C, 56.78; H, 5.11; N, 18.22

【0192】実施例85の方法に従って、表88〜表8 [0192] according to the method of Example 85, Table 88 to Table 8
9に示した実施例86〜104の化合物を得た。 To give the compounds of Examples 86 to 104 shown in 9.

【0193】 [0193]

【表88】 [Table 88]

【0194】 [0194]

【表89】 [Table 89]

【0195】実施例105 1−〔2−(4−アミノフェニル)エチル〕−2−n-ブチル−1H−イミダゾ〔4,5−c〕キノリン−4−アミン 1−〔2−〔4−(ジベンジルアミノ)フェニル〕エチル〕−2−n-ブチル−1H−イミダゾ〔4,5−c〕キノリン−4−アミン18.8g,パールマンズ試薬3. [0195] Example 105 1- [2- (4-aminophenyl) ethyl] -2-n-butyl -1H- imidazo [4,5-c] quinolin-4-amine 1- [2- [4- ( dibenzylamino) phenyl] ethyl] -2-n-butyl -1H- imidazo [4,5-c] quinolin-4-amine 18.8 g, Pearlman's reagent 3.
76g,ギ酸アンモニウム33.0g及びメタノール6 76 g, ammonium formate 33.0g and methanol 6
00mlの懸濁液を7時間還流した。 Suspension of 00ml was refluxed for 7 hours. 触媒を濾去し、溶媒を留去した。 The catalyst was filtered off, the solvent was distilled off. 得られた残渣に水を加え、10%水酸化ナトリウム水溶液で液性をpHを9に調整し、塩化メチレンで抽出した。 The resulting residue was added water, the liquid was adjusted to pH 9 with 10% sodium hydroxide solution and extracted with methylene chloride. 抽出液は水洗,脱水後、溶媒を留去して、 The extract was washed with water, dried, and evaporated to remove the solvent,
得られた残渣を酢酸エチルで洗浄し、イソプロパノールから再結晶して、融点191.0〜192.0℃の無色結晶を得た。 The obtained residue was washed with ethyl acetate, and recrystallized from isopropanol to give colorless crystals of melting point 191.0 to 192.0 ° C.. 元素分析値 C 22255理論値 C, 73.51; H, 7.01; N, 19.48 実験値 C, 73.41; H, 6.90; N, 19.22 Elemental analysis C 22 H 25 N 5 theory C, 73.51; H, 7.01; N, 19.48 Found C, 73.41; H, 6.90; N, 19.22

【0196】実施例105の方法に従って、表90に示した実施例106の化合物を得た。 [0196] according to the method of Example 105 to give the compound of Example 106 shown in Table 90.

【0197】 [0197]

【表90】 [Table 90]

【0198】実施例107 1−〔2−(4−アミノフェニル)エチル〕−1,6, [0198] Example 107 1- [2- (4-aminophenyl) ethyl] 1,6,
7,8−テトラヒドロ−シクロペンタ〔b〕イミダゾ〔4,5−d〕ピリジン−4−アミン・塩酸塩 N,N−ジベンジル−1−〔2−〔4−(ジベンジルアミノ)フェニル〕エチル〕−1,6,7,8−テトラヒドロシクロペンタ〔b〕イミダゾ〔4,5−d〕ピリジン−4−アミン0.81g,パールマンズ試薬0.16 7,8-tetrahydro - cyclopenta [b] imidazo [4,5-d] pyridin-4-amine hydrochloride N, N-dibenzyl-1- [2- [4- (dibenzylamino) phenyl] ethyl] - 1,6,7,8-tetrahydrocyclopenta [b] imidazo [4,5-d] pyridin-4-amine 0.81 g, Pearlman's reagent 0.16
g,ギ酸アンモニウム1.56g及びメタノール40ml g, ammonium formate 1.56g and methanol 40ml
の混合物を30.5時間還流した。 Mixture was refluxed for 30.5 hours. 触媒を濾去し、溶媒を留去した。 The catalyst was filtered off, the solvent was distilled off. 残渣に水を加え、10%炭酸カリウム水溶液で液性をpH9に調整し、塩化メチレンを加えた。 Water was added to the residue, the liquid was adjusted to pH9 with 10% aqueous potassium carbonate solution, methylene chloride was added. 析出結晶を濾取し、塩化メチレン層を分取後、水層を更に塩化メチレンで抽出した。 And the precipitated crystals were collected by filtration, after preparative methylene chloride layer was extracted with further methylene chloride and the aqueous layer. 塩化メチレン層は脱水後、溶媒を留去して、無色結晶を得た。 After methylene chloride layer dried, the solvent was evaporated to give colorless crystals. 先の結晶と合わせて常法により塩酸塩として、無色結晶0.41gを得た。 Combined with the previous crystals as the hydrochloride salt by a conventional method, to give colorless crystals 0.41 g. メタノールから再結晶して、融点259.0〜260.0℃ Recrystallization from methanol, mp 259.0-260.0 ° C.
(分解)の無色結晶を得た。 To give colorless crystals (decomposition). 元素分析値 C 17195・2HCl 理論値 C, 55.74; H, 5.78; N, 19.12 実験値 C, 55.76; H, 5.89; N, 19.07 Elemental analysis C 17 H 19 N 5 · 2HCl theory C, 55.74; H, 5.78; N, 19.12 Found C, 55.76; H, 5.89; N, 19.07

【0199】実施例107の方法に従って、表91に示した実施例108〜109の化合物を得た。 [0199] according to the method of Example 107 to give the compounds of Examples 108-109 shown in Table 91.

【0200】 [0200]

【表91】 [Table 91]

【0201】実施例110 1−〔2−(4−ウレイドフェニル)エチル〕−1H− [0201] Example 110 1- [2- (4-ureido-phenyl) ethyl] -1H-
イミダゾ〔4,5−c〕キノリン−4−アミン 1−〔2−(4−アミノフェニル)エチル〕−1H−イミダゾ〔4,5−c〕キノリン−4−アミン800mgを酢酸8mlと水4.8mlの混液に溶解し、室温攪拌下、シアン酸ナトリウム400mgの水4.8ml溶液を加えて、 Imidazo [4,5-c] quinolin-4-amine 1- [2- (4-aminophenyl) ethyl] -1H- imidazo [4,5-c] quinolin-4-amine 800mg acetate 8ml water 4. was dissolved in a mixture of 8 ml, stirring at room temperature, add water 4.8ml solution of sodium cyanate 400mg,
室温で2時間攪拌した。 The mixture was stirred for 2 hours at room temperature. 反応液に10%水酸化ナトリウム水溶液を加え、液性をpH9に調整して結晶を濾取後、 The reaction mixture of 10% aqueous sodium hydroxide was added to the filtration after the crystals by adjusting the liquid to pH 9,
水洗して790mgの結晶を得た。 Washed with water to obtain a crystal of 790mg. エタノールと水の混液から再結晶して、融点300℃以上の微褐色結晶を得た。 Recrystallization from a mixture of ethanol and water to obtain a slightly brown crystals of higher melting point 300 ° C.. 元素分析値 C 19186 O 理論値 C, 65.88; H, 5.24; N, 24.26 実験値 C, 66.00; H, 5.14; N, 24.07 Elemental analysis C 19 H 18 N 6 O theory C, 65.88; H, 5.24; N, 24.26 Found C, 66.00; H, 5.14; N, 24.07

【0202】実施例111 1−〔2−〔4−(N'−メチルチオウレイド)フェニル〕エチル〕−1H−イミダゾ〔4,5−c〕キノリン−4−アミン 1−〔2−(4−アミノフェニル)エチル〕−1H−イミダゾ〔4,5−c〕キノリン−4−アミン800mgにメタノール24ml及びメチルイソチオシアネート0.6 [0202] Example 111 1- [2- [4- (N'-methyl-thioureido) phenyl] ethyl] -1H- imidazo [4,5-c] quinolin-4-amine 1- [2- (4-amino phenyl) ethyl] -1H- imidazo [4,5-c] methanol quinolin-4-amine 800 mg 24 ml and methyl isothiocyanate 0.6
0mlを加え、40℃で15時間攪拌した。 0ml and the mixture was stirred for 15 hours at 40 ° C.. 反応液を冷却後、析出した結晶を濾取して、770mgの結晶を得た。 The reaction solution was cooled, and precipitated crystals were collected by filtration to give crystals of 770 mg.
エタノールと水の混液から再結晶して、融点220.0 Recrystallization from a mixture of ethanol and water, melting point 220.0
〜221.5℃の微褐色結晶を得た。 ~221.5 to obtain a fine brown crystals of ℃. 元素分析値 C 20206 S 理論値 C, 63.81; H, 5.35; N, 22.32 実験値 C, 63.60; H, 5.13; N, 22.05 Elemental analysis C 20 H 20 N 6 S theory C, 63.81; H, 5.35; N, 22.32 Found C, 63.60; H, 5.13; N, 22.05

【0203】実施例112 1−〔2−(4−アセチルフェニル)エチル〕−1H− [0203] Example 112 1- [2- (4-acetylphenyl) ethyl] -1H-
イミダゾ〔4,5−c〕キノリン−4−アミン 2−〔4−〔2−(4−フェノキシ−1H−イミダゾ〔4,5−c〕キノリン−1−イル)エチル〕フェニル〕−2−メチル−1,3−ジオキソラン3.89gに酢酸アンモニウム33.2gを加え、140℃で3時間攪拌した。 Imidazo [4,5-c] quinolin-4-amine 2- [4- [2- (4-phenoxy -1H- imidazo [4,5-c] quinolin-1-yl) ethyl] phenyl] -2-methyl ammonium acetate 33.2g addition to 1,3-dioxolane 3.89 g, was stirred for 3 hours at 140 ° C.. 反応後、10%水酸化ナトリウム水溶液を加え、液性をpH8に調整した後、析出した結晶を濾取して水洗し、淡褐色結晶2.83gを得た。 After the reaction, 10% aqueous sodium hydroxide was added, after adjusting the liquid to pH 8, washed with water and the precipitated crystals were collected by filtration to give pale brown crystals 2.83 g. 塩化メチレンとメタノールの混液から再結晶して、融点267.0〜2 Recrystallization from a mixture of methylene chloride and methanol, mp 267.0 to 2
69.0℃の無色結晶を得た。 69.0 to give colorless crystals ° C.. 元素分析値 C 20184 O 理論値 C, 72.71; H, 5.49; N, 16.96 実験値 C, 72.41; H, 5.34; N, 16.70 Elemental analysis C 20 H 18 N 4 O theory C, 72.71; H, 5.49; N, 16.96 Found C, 72.41; H, 5.34; N, 16.70

【0204】実施例113 1−〔2−〔4−(1−ヒドロキシイミノエチル)フェニル〕エチル〕−1H−イミダゾ〔4,5−c〕キノリン−4−アミン 1−〔2−(4−アセチルフェニル)エチル〕−1H− [0204] Example 113 1- [2- [4- (1-hydroxyimino-ethyl) phenyl] ethyl] -1H- imidazo [4,5-c] quinolin-4-amine 1- [2- (4-acetyl phenyl) ethyl] -1H-
イミダゾ〔4,5−c〕キノリン−4−アミン1.63 Imidazo [4,5-c] quinolin-4-amine 1.63
gに塩酸ヒドロキシルアミン0.38g,酢酸ナトリウム・3水和物1.34g及びエタノール16mlを加え、 g hydroxylamine hydrochloride 0.38 g, sodium trihydrate 1.34g acetic acid and ethanol 16ml addition,
2時間還流した。 It was refluxed for 2 hours. 反応液を減圧濃縮後、水を加え析出結晶を濾取して、1.47gの結晶を得た。 The reaction mixture was concentrated under reduced pressure, and the precipitated crystals were collected by filtration and water was added to obtain crystals of 1.47 g. エタノールと水の混液から再結晶して、融点269.0〜270.5 Recrystallization from a mixture of ethanol and water, melting point 269.0 to 270.5
℃の微褐色結晶を得た。 ℃ to give a fine brown crystals. 元素分析値 C 20195 O 理論値 C, 69.55; H, 5.54; N, 20.28 実験値 C, 69.34; H, 5.54; N, 20.11 Elemental analysis C 20 H 19 N 5 O theory C, 69.55; H, 5.54; N, 20.28 Found C, 69.34; H, 5.54; N, 20.11

【0205】実施例114 1−〔2−〔4−(1−アミノエチル)フェニル〕エチル〕−1H−イミダゾ〔4,5−c〕キノリン−4−アミン 1−〔2−〔4−(1−ヒドロキシイミノエチル)フェニル〕エチル〕−1H−イミダゾ〔4,5−c〕キノリン−4−アミン500mgに10%メタノール性アンモニア150ml及びラネーニッケル1mlを加え、水素50気圧,50℃で80時間攪拌した。 [0205] Example 114 1- [2- [4- (1-aminoethyl) phenyl] ethyl] -1H- imidazo [4,5-c] quinolin-4-amine 1- [2- [4- (1 - hydroxyimino) phenyl] ethyl] -1H- imidazo [4,5-c] 10% methanolic ammonia 150ml and Raney nickel 1ml addition quinolin-4-amine 500mg, hydrogen 50 atm, followed by stirring for 80 hours at 50 ° C. . 反応液を冷却後、溶媒を濾過,減圧濃縮して、300mgの結晶を得た。 After cooling the reaction mixture, the solvent is filtered, concentrated under reduced pressure to give crystals of 300 mg. エタノールから再結晶して、融点222.0〜224.0℃の微褐色結晶を得た。 Recrystallization from ethanol gave slightly brown crystals having a melting point of 222.0 to 224.0 ° C.. 元素分析値 C 20215理論値 C, 72.48; H, 6.39; N, 21.13 実験値 C, 72.46; H, 6.39; N, 20.86 Elemental analysis C 20 H 21 N 5 theory C, 72.48; H, 6.39; N, 21.13 Found C, 72.46; H, 6.39; N, 20.86

【0206】実施例115 4−〔2−(4−アミノ−1H−イミダゾ〔4,5− [0206] Example 115 4- [2- (4-amino -1H- imidazo [4,5
c〕キノリン−1−イル)エチル〕安息香酸エチル 4−〔2−(4−アミノ−1H−イミダゾ〔4,5− c] quinolin-1-yl) ethyl] benzoate 4- [2- (4-amino -1H- imidazo [4,5
c〕キノリン−1−イル)エチル〕安息香酸550mgにエタノール28ml及び濃硫酸2.8mlを加え、5時間還流した。 c] quinolin-1-yl) ethyl] ethanol 28ml and concentrated sulfuric acid 2.8ml was added to the benzoic acid 550 mg, was refluxed for 5 hours. 反応液を減圧濃縮後、水及び10%水酸化ナトリウム水溶液を加え、液性をpH9に調整して析出した結晶を濾取して、淡褐色結晶550mgを得た。 The reaction mixture was concentrated under reduced pressure, water and 10% sodium hydroxide aqueous solution was added, and crystals were collected by filtration precipitated by adjusting the liquid to pH 9, to give a pale brown crystals 550 mg. メタノールから再結晶して、融点180.0〜182.0℃の淡褐色針状晶を得た。 Recrystallization from methanol gave pale brown needles melting 180.0 to 182.0 ° C.. 元素分析値 C 212042理論値 C, 69.98; H, 5.59; N, 15.55 実験値 C, 69.98; H, 5.39; N, 15.62 Elemental analysis C 21 H 20 N 4 O 2 theory C, 69.98; H, 5.59; N, 15.55 Found C, 69.98; H, 5.39; N, 15.62

【0207】試験例1:ヒト細胞におけるインターフェロンα誘導能 以下、本発明化合物の優れた効果を示す一例として、ヒトの細胞におけるインターフェロンα誘導能を表1に示す。 [0207] Test Example 1: The following inducibility interferon α in human cells, as an example showing the excellent effects of the compounds of the present invention, shown in Table 1 the ability to induce interferon α in human cells. 尚、対照薬物は以下の化合物を使用した。 Incidentally, control drug was used the following compounds. 対照薬物A:1−イソブチル−1H−イミダゾ〔4,5 Control drug A: 1-isobutyl--1H- [4,5
−c〕キノリン−4−アミン(一般名:imiquimod ) 対照薬物B:1−(2−フェニルエチル)−1H−イミダゾ〔4,5−c〕キノリン−4−アミン -c] quinolin-4-amine (common name: imiquimod) control drug B: 1-(2-phenylethyl)-1H-imidazo [4,5-c] quinolin-4-amine

【0208】1. [0208] 1. 培養用の血液細胞の調整 ノボ・ヘパリン注1000(ノボ・ノルディスクA/S )を17 Adjustment of blood cells for culture Novo Heparin 1000 (Novo Nordisk A / S) 17
0 μl 含有する50ml遠心管中へ静脈穿刺して全血採取した。 0 [mu] l were whole blood collected by venipuncture into 50ml centrifuge tube containing. 末梢血単核細胞(PBMC)をLeuco PREPTM(Becton D Peripheral blood mononuclear cells (PBMC) Leuco PREPTM (Becton D
ickinson; Reorder No. 2751)細胞分離管によって調整し、2mML−グルタミン(LIFE TECHNOLOGIS; Cat. No. ickinson; Reorder No. 2751) adjusted by a cell separation tube, 2 mM L-glutamine (LIFE TECHNOLOGIS;. Cat No.
25030-016)、ペニシリン−ストレプトマイシン溶液(終濃度penicillin 100U/ml, streptomycin 100μg/m 25030-016), penicillin - streptomycin solution (final concentration penicillin 100U / ml, streptomycin 100μg / m
l、LIFE TECHNOLOGIS; Cat. No. 15145-014)を含有し、10% 牛胎児血清(INTERGEN COMPANY; Cat. No. 102 l, LIFE TECHNOLOGIS;. Cat No. 15145-014) containing 10% fetal bovine serum (INTERGEN COMPANY;. Cat No. 102
0-90)を添加したRPM-1640培地(日水製薬株式会社; Co 0-90) was added and the RPM-1640 medium (Nissui Pharmaceutical Co., Ltd.; Co
de 05918)で、細胞密度1 ×106 個/ml となるように培養した。 In de 05918), it was cultured as a cell density 1 × 106 cells / ml.

【0209】2. [0209] 2. 化合物の調整 化合物は0.1 N 塩酸で1 mg/ml となるよう懸濁してから生理食塩水で希釈し可溶化した。 Compounds modifying compounds was diluted with solubilized with saline from the suspension so as to be 1 mg / ml in 0.1 N hydrochloric acid. 化合物は0.03μg/ml〜 Compounds 0.03μg / ml~
3.0 μg/mlの濃度範囲で試験した。 3.0 was tested in a concentration range of [mu] g / ml. 3. 3. インキュベーション 50μl の試験化合物の溶液又は、溶媒を96穴(平底)Mi The solution of test compound incubation 50μl or solvent 96 (flat bottom) Mi
cro Test III TM (Becton Dickinson; FALCON 3072 ) cro Test III TM (Becton Dickinson; FALCON 3072)
細胞培養用プレートへ添加し、それを含有するウェルに、培地中のPBMCを200 μl 添加した。 Was added to a cell culture plate, the wells containing the same, and the PBMC in medium were added 200 [mu] l. プレートにプラスチック製の蓋をして、5%二酸化炭素雰囲気において37 Plates were plastic lid, 37 in a 5% carbon dioxide atmosphere
℃で二日間インキュベートした。 And incubated for two days at ℃.

【0210】4. [0210] 4. 分離 インキュベーションに続いて、プレートをPLATE SEALER Following the separation incubation, the plates PLATE SEALER
S (Coster Corporation; Cat. No. 3095)で被覆した後、ユニバーサル冷却遠心機(久保田製作所; KUBOTA 5 After coating with; (Cat No. 3095 Coster Corporation.), Universal refrigerated centrifuge (Kubota Corp.; S KUBOTA 5
800 )において4 ℃で5 分間、2000 rpm(740xg, ローター; RS-96SA/6)で遠心分離した。 5 minutes at 4 ° C. in 800), 2000 rpm (740xg, rotor; and centrifuged at RS-96SA / 6). それぞれの培養上清を試料とした。 Each of the culture supernatant was used as a sample.

【0211】5. [0211] 5. インターフェロンαの定量 エンザイムイムノアッセイ法により行った。 It was carried out by a quantitative enzyme immunoassay of interferon α. Cyto scree Cyto scree
n TMヒトインターフェロンα定量キット(BIOSOURCE; C n TM human interferon α quantification kit (BIOSOURCE; C
at. #ASY-05)を使用して、マウス抗ヒトインターフェロンαモノクローナル抗体(第一抗体)が固定してある96 at. # ASY-05) using a mouse anti-human interferon α monoclonal antibody (first antibody) is fixed 96
穴プレートを抗原抗体反応により試料100 μl 中のインターフェロンαと結合させた。 The well plate was combined with interferon α in the sample 100 [mu] l by an antigen-antibody reaction. 次に、ウサギ抗ヒトインターフェロンαポリクローナル抗体(二次抗体)を結合させた後、ペルオキシダーゼで標識した抗ウサギ抗体を結合させた。 Next, after bonding the rabbit anti-human interferon-α polyclonal antibody (secondary antibody) was bound to anti-rabbit antibody labeled with peroxidase. テトラメチルベンジジンを用いて発色させ反応を止めた。 The reaction was stopped developed using tetramethylbenzidine. 次いで、450 nmでの吸光度をV max kine Next, V max kine the absorbance at 450 nm
tic microplate reader (Molecular Devices )により測定した。 It was determined by tic microplate reader (Molecular Devices). 全ての結果はインターフェロンα標準曲線に従って、その値をpg/ml として表現した。 All results according interferon α standard curve and expressed the value as pg / ml. 結果を表92 The results in Table 92
及び表93に示す。 And it is shown in Table 93.

【0212】 [0212]

【表92】 [Table 92]

【0213】 [0213]

【表93】 [Table 93] 本発明化合物は対照薬物に比べ、優れたインターフェロンαの誘導能を示し、リウマチ性関節炎、いぼ、B型肝炎、C型肝炎等のウイルスの関与に起因する疾患、及び癌やその他の腫瘍性疾患の治療に極めて有用である。 The compounds of the present invention compared to the control drug, exhibits excellent ability to induce interferon alpha, rheumatoid arthritis, warts, B hepatitis, diseases caused by the involvement of viruses such as hepatitis C, and cancer and other neoplastic diseases it is extremely useful in the treatment.

【0214】 [0214]

【発明の効果】本発明化合物は、優れたインターフェロン誘導能を有しており、リウマチ性関節炎,いぼ,B型肝炎,C型肝炎等のウイルスの関与に起因する疾患、及び癌やその他の腫瘍性疾患の治療に極めて有用である。 The present invention compounds according to the present invention has excellent interferon-inducing ability, rheumatoid arthritis, warts, B hepatitis, diseases caused by the involvement of viruses such as hepatitis C, and cancer and other tumors it is extremely useful for the treatment of sexual disorders.

───────────────────────────────────────────────────── フロントページの続き (72)発明者 坪内 勝俊 福井県勝山市猪野口37号1 番地1 北陸 製薬株式会社内 ────────────────────────────────────────────────── ─── of the front page continued (72) inventor Katsutoshi Tsubouchi Fukui Prefecture Katsuyama Inokuchi 37 No. 1 address 1 Hokuriku pharmaceutical Co., Ltd. in

Claims (1)

    【特許請求の範囲】 [The claims]
  1. 【請求項1】次の一般式(I) 【化1】 [Claim 1] of the general formula (I) ## STR1 ## (式中、R 1はCOR 7 ,SO 2 NR 89 ,CONR (In the formula, R 1 is COR 7, SO 2 NR 8 R 9, CONR
    89 ,NR 1011 ,C(R 12 )=NOHで示される基,水酸基又はシアノ基を、R 2とR 3は同一又は異なって水素原子又は低級アルキル基を表し、R 4は水素原子あるいは1個又は複数個の水酸基,低級アルコキシ基,環状アルキル基もしくはハロゲン原子で置換されても良い炭素数1〜10個の直鎖状又は分枝鎖状アルキル基を表し、R 5は水素原子又は低級アルキル基を、R 6 8 R 9, NR 10 R 11 , C (R 12) = groups represented by NOH, a hydroxyl group or a cyano group, R 2 and R 3 represents a hydrogen atom or a lower alkyl group the same or different, R 4 is hydrogen atoms or one or more hydroxyl, lower alkoxy group, a cyclic alkyl group or substituted by a halogen atom good number 1-10 straight even or branched alkyl group, R 5 is hydrogen the atom or a lower alkyl group, R 6
    は水素原子,低級アルキル基,低級アルコキシ基又はハロゲン原子を、R 7は水酸基,低級アルキル基又は低級アルコキシ基を表し、R 8とR 9は同一又は異なって水素原子又は低級アルキル基を、R 10は水素原子,低級アルキル基,ベンジル基を表し、R 11は水素原子,低級アルキル基,ベンジル基,低級アルカンスルホニル基,低級アルカノイル基,置換もしくは未置換のカルバモイル基,置換もしくは未置換のチオカルバモイル基又は置換もしくは未置換のベンゼンスルホニル基を表し、R 12は水素原子,低級アルキル基を、mは0〜1の整数、nは1〜3の整数を表し、Xは炭素数1〜3個のアルキレン鎖又はCH=CHで示される炭素鎖を表し、Yは硫黄原子又はCH=CHで示される炭素鎖を表し、実線と点線とで示される結合は It is a hydrogen atom, a lower alkyl group, a lower alkoxy group or a halogen atom, R 7 is a hydroxyl group, a lower alkyl group or a lower alkoxy group, a R 8 and R 9 are the same or different and each represents a hydrogen atom or a lower alkyl radical, R 10 is a hydrogen atom, a lower alkyl group, a benzyl group, R 11 is a hydrogen atom, a lower alkyl group, a benzyl group, a lower alkanesulfonyl group, a lower alkanoyl group, a substituted or unsubstituted carbamoyl group, a substituted or unsubstituted thio a carbamoyl group or a substituted or unsubstituted benzenesulfonyl group, R 12 is a hydrogen atom, a lower alkyl group, m is an integer of 0 to 1, n represents an integer of 1 to 3, X is 1 to 3 carbon atoms number of represents a carbon chain represented by an alkylene chain or CH = CH, Y represents a carbon chain represented by a sulfur atom or CH = CH, bond represented by the solid line and the dotted line 結合又は二重結合を表す。 Bond or a double bond. )で示される1−(置換アリール)アルキル−1H−イミダゾピリジン−4−アミン誘導体、又はその薬理学的に許容しうる塩。 1- (substituted aryl) alkyl -1H- imidazo-4-amine derivative represented by) or a pharmaceutically acceptable salt thereof.
JP25592697A 1997-09-04 1997-09-04 1-(substitutedaryl)alkyl-1h-imidazopyridin-4-amine derivative Pending JPH1180156A (en)

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