JPH09208584A - Amide derivative, pharmaceutical preparation containing the same, and intermediate for synthesizing the same - Google Patents

Amide derivative, pharmaceutical preparation containing the same, and intermediate for synthesizing the same

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Publication number
JPH09208584A
JPH09208584A JP1311396A JP1311396A JPH09208584A JP H09208584 A JPH09208584 A JP H09208584A JP 1311396 A JP1311396 A JP 1311396A JP 1311396 A JP1311396 A JP 1311396A JP H09208584 A JPH09208584 A JP H09208584A
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Japan
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1h
carbon atoms
2h
nitro
branched chain
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Japanese (ja)
Inventor
Takao Iizuka
Takeo Ishii
Ryoichi Nanba
Hitoshi Nishida
竹夫 石井
仁 西田
亮一 難波
貴夫 飯塚
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Terumo Corp
テルモ株式会社
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Priority to JP1311396A priority Critical patent/JPH09208584A/en
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Abstract

PROBLEM TO BE SOLVED: To obtain a new amide derivative having excellent antihistaminic activity and an inhibitory activity against eosinophilic leukocyte infiltration, capable of highly inhibiting both immediate and delayed allergic reactions, thus esp. useful for treating atopic dermatitides.
SOLUTION: This new amide derivative is expressed by formula I (X is H or a halogen; (m) is 1-9; (n) is 2-12), e.g. 1-(3-{[4-(diphenylmethoxy)-1- piperidineacetyl]amino}propyl)-1H-imidazo[4,5-c]quinoline-4-amine. The compound of formula I is obtained by heating a compound of formula II (X' is a halogen) and a compound of formula III in an organic solvent, optionally in the presence of a base. It is preferable that this new compound is used as a formulation for percutaneous administration such as ointment, lotion or cream.
COPYRIGHT: (C)1997,JPO

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、好酸球浸潤抑制作用および抗ヒスタミン作用を有し、アトピー性皮膚炎などの治療剤として有用な新規なアミド誘導体、およびそれを含有する医薬製剤、および合成中間体に関する。 The present invention relates has eosinophilic infiltration inhibitory action and antihistaminic action, novel amide derivatives useful as therapeutic agents, such as atopic dermatitis and pharmaceutical formulations containing them, and synthetic intermediates on.

【0002】 [0002]

【従来の技術】アトピー性皮膚炎の治療には、従来より基本的にステロイド剤の外用と抗ヒスタミン剤あるいは抗アレルギー剤の内服が行われており、その他、減感作療法、アレルゲン(ダニ・食物)除去療法、PUVA Treatment of the Related Art atopic dermatitis, conventionally have been basically conducted oral topical and antihistamines or antiallergic agents steroids, other, desensitization therapy, allergens (Dani food) removal therapy, PUVA
(ソラレン−長波長紫外線照射)療法、細菌ワクチン療法などが試みられている。 (Psoralen - UVA radiation) therapy, such as bacterial vaccine therapy has been attempted. しかし、いずれも決め手となるものではなく、特にステロイド外用剤は、切れ味は良いが長期連投による皮膚の萎縮・毛細血管拡張・潮紅・ However, none of them is decisive, especially topical steroids, the sharpness is good, but flushing atrophy, telangiectasia, of the skin due to long-term Rento -
紫斑・易感染性などの副作用が問題となっている。 Side effects such as bruising, susceptibility to infection has become a problem. 最近、アトピー性皮膚炎治療の方向はステロイドからサイトカイン療法に向かいつつある(中川秀巳,臨床免疫, Recently, the direction of the treatment atopic dermatitis is moving toward the steroids cytokine therapy (Nakagawa Shigerumi, Clinical Immunology,
27[supple 16]597−602,1995,小林祥子ら,臨床免疫,27[supple 16]603−609, 27 [supple 16] 597-602,1995, Sachiko, et al. Kobayashi, Clinical Immunology, 27 [supple 16] 603-609,
1995)。 1995). アトピー性皮膚炎患者においては、Th1 In patients with atopic dermatitis, Th1
ヘルパー細胞とTh2ヘルパー細胞のバランスの不均衡すなわちTh2細胞優位の状態にあり、Th2細胞からのインターロイキン−4やインターロイキン−5などのサイトカインの産性増大の結果、好酸球等の炎症細胞の分化・増殖・浸潤を増強し炎症が惹起されるという説が有力となっている。 Located unbalanced i.e. Th2 cells dominant state of balance of helper cells and Th2 helper cells, interleukin-4 and interleukin-5 results in production-enhancing cytokines such as from Th2 cells, inflammatory cells such as eosinophils theory that enhanced inflammation differentiation and proliferation and infiltration of is induced has become a leading. 従って、Th2細胞優位を抑制するインターフェロンや免疫抑制剤などが試みられているが、まだ、効果や副作用の点で満足できる結果が得られていない。 Accordingly, the like suppresses interferon or immunosuppressive agents Th2 cells dominant has been attempted, not yet, satisfactory results in terms of effect and side effects can not be obtained.

【0003】一般に、感作されたヒトの皮膚に抗原を投与すると投与直後と4〜8時間後に最大となり24〜4 [0003] In general, immediately after administration and the administration of the antigen to the skin of the person that has been sensitized and become a maximum after 4-8 hours 24-4
8時間持続する皮膚反応が生じる。 Skin reaction occurs that lasts 8 hours. 前者を即時型反応、 Former immediate reaction,
後者を遅発型アレルギー反応と呼ぶ。 The latter is referred to as late-onset allergic reactions. 特に遅発型反応は喘息を含むアレルギー疾患の病態と密接な関係があると指摘されている。 Especially late reaction is pointed out that closely related to pathogenesis of allergic diseases including asthma. 遅発型反応のメカニズムは永らく不明であったが、今日ではIgE−肥満細胞が関与するI型アレルギー反応における時間的に遅れた相、すなわち l Although the mechanism of late reactions were Nagaraku unknown today has a time delay in the type I allergic reaction involving IgE- mast cells phases, i.e. l
ate phase reaction of the type I allergyであり、T Is ate phase reaction of the type I allergy, T
h2ヘルパー細胞・好酸球が深く関わっていると考えられるようになった(黒沢元博,臨床免疫,27(5), h2-helper cells, eosinophils now considered to be deeply involved (Motohiro Kurosawa, Clinical Immunology, 27 (5),
564−574,1995)。 564-574,1995). このように、アトピー性皮膚炎は即時型と遅発型の両アレルギー反応が関与する疾患であり、遅発型反応の発症メカニズムも単一ではないと考えられるため、単に肥満細胞からのケミカルメディエーター遊離阻害剤や拮抗剤、あるいは炎症細胞浸潤抑制剤の単独使用では効果が不十分である。 Thus, since the atopic dermatitis is a disease where both allergic reactions of immediate and delayed type are involved, the onset mechanism of late reactions not considered to be a single, simply chemical mediators from mast cells free inhibitors or antagonists, or the effect is insufficient by itself using inflammatory cell infiltration inhibitors. それゆえ、 therefore,
アトピー性皮膚炎の治療には肥満細胞から遊離するケミカルメディエーターのうち特に重要なヒスタミン(ヒスタミンは即時型だけでなく一部遅発型にも関与)と遅発型反応に関与することが知られている好酸球浸潤の両方を抑制する必要があるがそのような化合物は提示されていない。 Treatment of atopic dermatitis is known to be involved in particularly important histamine (histamine also involved in some late not only immediate type) and late reaction of the chemical mediators liberated from mast cells both of which eosinophilic infiltration should be suppressed but such compounds are not presented.

【0004】また、本発明の化合物と類似した化合物が幾つか公知となっている。 [0004] The compounds similar to the compounds of the present invention has a number known. 例えば、1−置換−1H−イミダゾ[4,5−c]キノリン−4−アミン類としては、抗ウイルス剤である1−イソブチル−1H−イミダゾ[4,5−c]キノリン−4−アミン(イミキモド) For example, the 1-substituted -1H- imidazo [4,5-c] quinolin-4-amine, is an antiviral agent 1-isobutyl--1H- imidazo [4,5-c] quinolin-4-amine ( imiquimod)
を始めとしていくつか知られている(欧州特許第145 It is known some as the beginning (European Patent No. 145
340号、米国特許第4689338号、米国特許第4 340, U.S. Patent No. 4,689,338, U.S. Pat. No. 4
698348号、米国特許第4929624号、欧州特許第385630号、米国特許第5346905号等)。 No. 698,348, U.S. Pat. No. 4,929,624, European Patent No. 385,630, U.S. Pat. No. 5,346,905, etc.). しかしながら、それらには抗ヒスタミン作用及び好酸球浸潤抑制作用は開示されていない。 However, them is not disclosed antihistaminic action and eosinophil infiltration suppressive action. また、4− In addition, 4
(ジフェニルメトキシ)−1−ピペリジンアルカン酸類は特開平3−264562号に開示されているが、好酸球浸潤抑制作用は記載されていない。 (Diphenyl-methoxy) -1-piperidine alkanoic acids is disclosed in JP-A-3-264562, eosinophilic infiltration inhibitory action is not described.

【0005】 [0005]

【発明が解決しようとする課題】従って本発明は、十分な抗ヒスタミン作用および好酸球浸潤抑制作用を併せ持ち、アトピー性皮膚炎における主としてヒスタミン関与による即時型アレルギー反応と好酸球及びヒスタミン関与の遅発型アレルギー反応の両方の反応を抑える新規な化合物およびそれを含有する医薬製剤を提供することにある。 [0005] Accordingly, the present invention has both a sufficient antihistaminic action and eosinophil infiltration suppressive action, mainly immediate allergic reaction and eosinophils and histamine involved histamine involved in atopic dermatitis It is to provide novel compounds and pharmaceutical formulations containing it to suppress the reaction of both the late allergic reaction.

【0006】 [0006]

【課題を解決するための手段】上記の課題を解決する本発明は以下の通りである。 To solve the above problems SUMMARY OF THE INVENTION The present invention is as follows. (1)下記式Iで示されるアミド誘導体、およびその医薬的に許容しうる酸付加塩である。 (1) amide derivatives of the following formula I, and a pharmaceutically acceptable acid addition salts.

【0007】 [0007]

【化10】 [Of 10]

【0008】式I中、Xは水素原子またはハロゲン原子を表わし、mは1から9の整数を、nは2から12の整数を示す。 [0008] In formula I, X represents a hydrogen atom or a halogen atom, m is an integer of 1 to 9, n represents an integer of from 2 to 12.

【0009】(2)上記(1)に記載のアミド誘導体を含有する医薬製剤である。 [0009] (2) a pharmaceutical formulation containing an amide derivative according to (1).

【0010】(3)下記式IIで示される式Iのアミド誘導体を合成するための合成中間体である。 [0010] (3) a synthetic intermediate for the synthesis of amide derivatives of formula I represented by the following formula II.

【0011】 [0011]

【化11】 [Of 11]

【0012】式II中、X'はハロゲン原子を表わし、m [0012] In Formula II, X 'represents a halogen atom, m
は1から9の整数を、nは2から12の整数を示す。 An integer of from 1 9, n is an integer of 2 to 12.

【0013】(4)下記式II'で示される式Iのアミド誘導体を合成するための合成中間体である。 [0013] (4) a synthetic intermediate for the synthesis of amide derivatives of formula I represented by the following formula II '.

【0014】 [0014]

【化12】 [Of 12]

【0015】式II'中、nは2から12の整数を示す。 [0015] In the formula II ', n represents an integer of from 2 to 12.

【0016】(5)下記式IIIで示される式Iのアミド誘導体を合成するための合成中間体である。 [0016] (5) it is a synthetic intermediate for the synthesis of amide derivatives of formula I represented by the following formula III.

【0017】 [0017]

【化13】 [Of 13]

【0018】式III中、nは2から12の整数を示す。 [0018] In the formula III, n is an integer of 2 to 12.

【0019】(6)下記式IVで示される式Iのアミド誘導体を合成するための合成中間体である。 [0019] (6) is a synthetic intermediate for the synthesis of amide derivatives of formula I represented by the following formula IV.

【0020】 [0020]

【化14】 [Of 14]

【0021】式IV中、nは2から12の整数を示す。 [0021] In the formula IV, n is an integer of 2 to 12.

【0022】(7)下記式Vで示される式Iのアミド誘導体を合成するための合成中間体である。 [0022] (7) is a synthetic intermediate for the synthesis of amide derivatives of formula I represented by the following formula V.

【0023】 [0023]

【化15】 [Of 15]

【0024】式V中、Rが水素のとき、R'は、炭素数1 [0024] In formula V, when R is hydrogen, R 'is C 1 -C
〜8で分岐鎖を有してもよいアルカノイル基、炭素数1 8 branched chain optionally alkanoyl group optionally having a carbon number of 1
〜8で分岐鎖を有してもよいハロアルカノイル基、炭素数1〜12でベンゼン環上ハロゲン、ニトロあるいはメトキシ置換基を有してもよいフェニルアルカノイル基、 8 branched chain good haloalkanoyl group which may have a benzene ring on silver in 1 to 12 carbon atoms, nitro or phenyl alkanoyl group which may have a methoxy substituent,
炭素数1〜12でベンゼン環上ハロゲン、ニトロあるいはメトキシ置換基を有してもよいフェノキシアルカノイル基、炭素数1〜8で分岐鎖を有してもよいアルコキシカルボニル基、炭素数1〜8で分岐鎖を有してもよいハロアルコキシカルボニル基、あるいは炭素数1〜12でベンゼン環上ハロゲン、ニトロあるいはメトキシ置換基を有してもよいフェニルアルコキシカルボニル基を示す。 Benzene ring on silver in 1 to 12 carbon atoms, nitro or methoxy substituents may phenoxy alkanoyl group which may have a alkoxycarbonyl group which may have a branched chain having 1 to 8 carbon atoms, with 1 to 8 carbon atoms It may have a branched chain haloalkoxycarbonyl group or a benzene ring on silver in 1 to 12 carbon atoms, exhibit a phenyl alkoxycarbonyl group optionally having a nitro or methoxy substituent. また、R、R'が一つになってハロゲン、ニトロあるいはメトキシ置換基を有してもよい芳香族環状イミドを形成する。 Also, R, R 'are taken one halogen, to form an aromatic cyclic imide may have a nitro or methoxy substituent. nは2から12の整数を示す。 n represents an integer of 2 to 12.

【0025】(8)下記式VIで示される式Iのアミド誘導体を合成するための合成中間体である。 [0025] (8) is a synthetic intermediate for the synthesis of amide derivatives of formula I represented by the following formula VI.

【0026】 [0026]

【化16】 [Of 16]

【0027】式VI中、Rが水素のとき、R'は、炭素数1〜8で分岐鎖を有してもよいアルカノイル基、炭素数1〜8で分岐鎖を有してもよいハロアルカノイル基、炭素数1〜12でベンゼン環上ハロゲン、ニトロあるいはメトキシ置換基を有してもよいフェニルアルカノイル基、炭素数1〜12でベンゼン環上ハロゲン、ニトロあるいはメトキシ置換基を有してもよいフェノキシアルカノイル基、炭素数1〜8で分岐鎖を有してもよいアルコキシカルボニル基、炭素数1〜8で分岐鎖を有してもよいハロアルコキシカルボニル基、あるいは炭素数1〜1 [0027] In formula VI, when R is hydrogen, R 'is optionally alkanoyl group which may have a branched chain having 1 to 8 carbon atoms, optionally halo alkanoyl which may have a branched chain having 1 to 8 carbon atoms group, a benzene ring on silver in 1 to 12 carbon atoms, nitro or methoxy substituent a phenyl alkanoyl group which may have a benzene ring on silver in 1 to 12 carbon atoms, which may have a nitro or methoxy substituent phenoxy alkanoyl group, alkoxycarbonyl group which may have a branched chain having 1 to 8 carbon atoms, optionally halo alkoxycarbonyl group optionally having a branched chain having 1 to 8 carbon atoms or carbon atoms, 1 to 1
2でベンゼン環上ハロゲン、ニトロあるいはメトキシ置換基を有してもよいフェニルアルコキシカルボニル基を示す。 Benzene ring on halogen 2 shows a phenyl alkoxycarbonyl group optionally having a nitro or methoxy substituent. また、R、R'が一つになってハロゲン、ニトロあるいはメトキシ置換基を有してもよい芳香族環状イミドを形成する。 Also, R, R 'are taken one halogen, to form an aromatic cyclic imide may have a nitro or methoxy substituent. nは2から12の整数を示す。 n represents an integer of 2 to 12.

【0028】(9)下記式VIIで示される式Iのアミド誘導体を合成するための合成中間体である。 [0028] (9) which is a synthetic intermediate for the synthesis of amide derivatives of formula I represented by the following formula VII.

【0029】 [0029]

【化17】 [Of 17]

【0030】式VII中、Rが水素のとき、R'は、炭素数1〜8で分岐鎖を有してもよいアルカノイル基、炭素数1〜8で分岐鎖を有してもよいハロアルカノイル基、炭素数1〜12でベンゼン環上ハロゲン、ニトロあるいはメトキシ置換基を有してもよいフェニルアルカノイル基、炭素数1〜12でベンゼン環上ハロゲン、ニトロあるいはメトキシ置換基を有してもよいフェノキシアルカノイル基、炭素数1〜8で分岐鎖を有してもよいアルコキシカルボニル基、炭素数1〜8で分岐鎖を有してもよいハロアルコキシカルボニル基、あるいは炭素数1〜1 [0030] In the formula VII, when R is hydrogen, R 'is optionally alkanoyl group which may have a branched chain having 1 to 8 carbon atoms, optionally halo alkanoyl which may have a branched chain having 1 to 8 carbon atoms group, a benzene ring on silver in 1 to 12 carbon atoms, nitro or methoxy substituent a phenyl alkanoyl group which may have a benzene ring on silver in 1 to 12 carbon atoms, which may have a nitro or methoxy substituent phenoxy alkanoyl group, alkoxycarbonyl group which may have a branched chain having 1 to 8 carbon atoms, optionally halo alkoxycarbonyl group optionally having a branched chain having 1 to 8 carbon atoms or carbon atoms, 1 to 1
2でベンゼン環上ハロゲン、ニトロあるいはメトキシ置換基を有してもよいフェニルアルコキシカルボニル基を示す。 Benzene ring on halogen 2 shows a phenyl alkoxycarbonyl group optionally having a nitro or methoxy substituent. また、R、R'が一つになってハロゲン、ニトロあるいはメトキシ置換基を有してもよい芳香族環状イミドを形成する。 Also, R, R 'are taken one halogen, to form an aromatic cyclic imide may have a nitro or methoxy substituent. nは2から12の整数を示す。 n represents an integer of 2 to 12.

【0031】(10)下記式VIIIで示される式Iのアミド誘導体を合成するための合成中間体である。 [0031] (10) is a synthetic intermediate for the synthesis of amide derivatives of formula I represented by the following formula VIII.

【0032】 [0032]

【化18】 [Of 18]

【0033】式VIII中、Rが水素のとき、R'は、炭素数1〜8で分岐鎖を有してもよいアルカノイル基、炭素数1〜8で分岐鎖を有してもよいハロアルカノイル基、 [0033] In the formula VIII, when R is hydrogen, R 'is optionally alkanoyl group which may have a branched chain having 1 to 8 carbon atoms, optionally halo alkanoyl which may have a branched chain having 1 to 8 carbon atoms group,
炭素数1〜12でベンゼン環上ハロゲン、ニトロあるいはメトキシ置換基を有してもよいフェニルアルカノイル基、炭素数1〜12でベンゼン環上ハロゲン、ニトロあるいはメトキシ置換基を有してもよいフェノキシアルカノイル基、炭素数1〜8で分岐鎖を有してもよいアルコキシカルボニル基、炭素数1〜8で分岐鎖を有してもよいハロアルコキシカルボニル基、あるいは炭素数1〜1 Benzene ring on silver in 1 to 12 carbon atoms, nitro or methoxy substituent a phenyl alkanoyl group which may have a benzene ring on silver in 1 to 12 carbon atoms, nitro or methoxy which may have a substituent phenoxy alkanoyl group, alkoxycarbonyl group which may have a branched chain having 1 to 8 carbon atoms, optionally halo alkoxycarbonyl group optionally having a branched chain having 1 to 8 carbon atoms or carbon atoms 1 to 1,
2でベンゼン環上ハロゲン、ニトロあるいはメトキシ置換基を有してもよいフェニルアルコキシカルボニル基を示す。 Benzene ring on halogen 2 shows a phenyl alkoxycarbonyl group optionally having a nitro or methoxy substituent. また、R、R'が一つになってハロゲン、ニトロあるいはメトキシ置換基を有してもよい芳香族環状イミドを形成する。 Also, R, R 'are taken one halogen, to form an aromatic cyclic imide may have a nitro or methoxy substituent. nは2から12の整数を示す。 n represents an integer of 2 to 12.

【0034】式V、式VI、式VIIにおけるR、R'はアミノ基の保護基であり、好適には、アセチル、プロピオニル、ピバロイル、ベンゾイル、メトキシカルボニル、エトキシカルボニル、iso−ブトキシカルボニル、tert− [0034] Formula V, Formula VI, R in formula VII, R 'is a protecting group for amino group, preferably, acetyl, propionyl, pivaloyl, benzoyl, methoxycarbonyl, ethoxycarbonyl, iso- butoxycarbonyl, tert-
ブトキシカルボニル、ベンジルオキシカルボニル、フタルイミドなどが挙げられる。 Butoxycarbonyl, benzyloxycarbonyl, etc. phthalimide and the like.

【0035】式Iの化合物の医薬的に許容しうる酸付加塩としては、塩酸、臭化水素酸、硫酸、硝酸、リン酸、 [0035] Formula Pharmaceutically acceptable acid addition salts of compounds of I, hydrochloric, hydrobromic, sulfuric, nitric, phosphoric acid,
酢酸、乳酸、マレイン酸、フマル酸、クエン酸、リンゴ酸、酒石酸、シュウ酸、メタンスルホン酸、p−トルエンスルホン酸などの塩が挙げられる。 Acetic, lactic, maleic, fumaric acid, citric acid, malic acid, tartaric acid, oxalic acid, methanesulfonic acid, and the like salts p- toluenesulfonic acid. これらは常法により調製される。 They are prepared by a conventional method.

【0036】 [0036]

【発明の実施の形態】本発明の式Iで示される新規なアミド誘導体は、例えば以下のようにして製造することができる。 Novel amide derivatives of formula I of the present invention DETAILED DESCRIPTION OF THE INVENTION, can be produced, for example, as follows.

【0037】 [0037]

【化19】 [Of 19]

【0038】工程(1)において、出発物質である式IX [0038] In step (1), formula IX is the starting material
の2,4−ジクロロ−3−ニトロキノリンは公知物質であり、ガブリエルの方法(Chem.Ber.,1918,51,1500)等によって合成することができる。 2,4-dichloro-3-nitroquinoline are known substances, Gabriel method (Chem.Ber., 1918,51,1500) can be synthesized by such. また、式Xのアルキレンジアミンのモノアミノ保護体も公知の方法(Synth.Co Further, monoamino protection of alkylenediamine of formula X also known methods (Synth.Co
mmun.,1990,20,2559、J.Med.Chem.,1988,31,898、J.Or mmun., 1990,20,2559, J.Med.Chem., 1988,31,898, J.Or
g.Chem.,1981,46,2455、J.Amer.Chem.Soc.,1941,63,852 g.Chem., 1981,46,2455, J.Amer.Chem.Soc., 1941,63,852
等)によって合成することができる。 It can be synthesized by etc). 式IXと式Xの化合物の反応は、適当な溶媒(好ましくはトリエチルアミンやピリジンのような塩基性溶媒)中で加熱することによって行なわれ、式VIIIの化合物を得ることができる。 The reaction of a compound of Formula IX and Formula X can be carried out in a suitable solvent (preferably a basic solvent such as triethylamine or pyridine) performed by heating in, it is possible to obtain a compound of formula VIII.

【0039】工程(2)において、ニトロ基の還元は適当な溶媒(好ましくはアルコール)中で、鉄粉−塩酸あるいは塩化すず[II]によって0℃から還流温度で行うことができる。 [0039] In step (2), reduction of the nitro group with a suitable solvent (preferably an alcohol), iron powder - can be carried out at reflux temperature 0 ℃ with hydrochloric acid or tin chloride [II]. また、パラジウムや白金触媒存在下水素による接触還元によっても式VIIの化合物を得ることができる。 Further, it is possible to obtain a compound of formula VII by catalytic reduction by a palladium or platinum catalyst presence of hydrogen.

【0040】工程(3)において、式VIIの化合物をトリアルキルオルトホルメートと加熱するか、ギ酸金属塩存在下ギ酸中で加熱することによって、式VIの化合物を得ることができる。 [0040] In step (3), or a compound of formula VII is heated with a trialkyl orthoformate, by heating with formic acid metal salt presence in formic acid, can be obtained a compound of formula VI.

【0041】工程(4)において、式VIの化合物のアミノ保護基の脱保護反応は、保護基の種類に応じて適当な反応条件を選択することができる。 [0041] In step (4), the deprotection reaction of the amino protecting group of the compound of formula VI may be selected appropriate reaction conditions depending on the type of protecting group. たとえば、保護基が For example, a protecting group
tert−ブトキシカルボニル(Boc)の場合は適当な溶媒中トリフルオロ酢酸で、ベンジルオキシカルボニル(Z)の場合は臭化水素−酢酸を選択することによって式IVの化合物を得ることができる。 With tert- butoxy appropriate solvent in trifluoroacetic acid in the case of carbonyl (Boc), in the case of benzyloxycarbonyl (Z) hydrogen bromide - to give a compound of formula IV by selecting acetate.

【0042】工程(5)において、適当な溶媒中ベンジルアミンと加熱するか、無溶媒で過剰のベンジルアミンと加熱することによって式Vの化合物を得ることができる。 [0042] In step (5), or heated with a suitable solvent benzylamine, to give a compound of formula V by heating with an excess of benzylamine without solvent.

【0043】工程(6)において、オートクレーブ(耐圧鋼製ボンベ)中で、アルコール溶媒中のアンモニアあるいは濃アンモニア水と加熱して反応させることによって、式IIIの化合物を得ることができる。 [0043] In step (6), in an autoclave (pressure-resistant steel bomb), by reacting by heating with ammonia or concentrated ammonia in an alcohol solvent to give a compound of formula III.

【0044】工程(7)において、炭素担体上の水酸化パラジウムとともにカルボン酸(好ましくは、ギ酸)中で加熱することによって式IIIの化合物を得ることができる。 [0044] In step (7), a carboxylic acid (preferably formic acid) with palladium hydroxide on carbon support to give a compound of formula III by heating in.

【0045】工程(8)において、式IIIの化合物をハロアルカン酸とともに適当な溶媒(たとえば、N,N− [0045] In step (8), an appropriate solvent a compound of formula III with a haloalkane acid (e.g., N, N-
ジメチルホルムアミド)中、適当な縮合剤・縮合方法(たとえば、カルボジイミド、混合酸無水物法、酸クロライド法など)で縮合させることによって式IIの化合物に導くことができる。 In dimethylformamide), an appropriate condensing agent and condensation process (e.g., carbodiimides, mixed acid anhydride method, can be converted into the compound of formula II by condensing an acid chloride method, etc.). また、ハロアルカン酸の代わりに、適当な脱離基(たとえば、メタンスルホニルオキシ、p−トルエンスルホニルオキシなど)で置換されたアルカン酸を用いてもよい。 Further, instead of haloalkane acid, suitable leaving group (e.g., methanesulfonyloxy, p- toluenesulfonyloxy, etc.) may be used alkanoic acids substituted with.

【0046】工程(9)において、式XIの化合物は公知物であり、式IIあるいはII'の化合物とともに適当な溶媒(ベンゼン、トルエン、キシレン、N,N−ジメチルホルムアミド、メタノール、エタノール、n−プロパノール、イソプロパノールなど)中加熱することによって式Iの化合物を得ることができる。 [0046] In step (9), a compound of Formula XI are known compounds, appropriate solvent with a compound of formula II or II '(benzene, toluene, xylene, N, N- dimethylformamide, methanol, ethanol, n- propanol, to give compounds of formula I by heating in isopropanol, etc.). またこの時、適当な塩基(たとえば、炭酸水素ナトリウム、炭酸カリウム、 Further, at this time, a suitable base (e.g., sodium hydrogen carbonate, potassium carbonate,
トリエチルアミンなど)を用いてもよい。 Triethylamine, etc.) may be used.

【0047】本発明の式Iで示されるアミド誘導体及びその医薬的に許容される酸付加塩は、アトピー性皮膚炎治療剤として経口及び非経口に哺乳動物に投与することができる。 The amide derivatives and their pharmaceutically acceptable acid addition salt of formula I of the present invention can be administered to a mammal orally and parenterally as atopic dermatitis therapeutic agent. 経口投与に用いる薬剤組成物の剤形は、錠剤、カプセル剤、散剤、細粒剤、顆粒剤、懸濁剤、乳剤、液剤、シロップなどが挙げられる。 Dosage form of a pharmaceutical composition for use in oral administration include tablets, capsules, powders, fine granules, granules, suspensions, emulsions, solutions, syrups and the like. 非経口投与に用いる剤形は、注射剤、坐剤、吸入剤、点眼剤、点鼻剤、 Dosage forms used for parenteral administration, injections, suppositories, inhalants, eye drops, nasal drops,
軟膏、クリーム、ローション、貼付剤などが挙げられる。 Ointments, creams, lotions, and the like patches. いずれの剤形においても、調製の際に適当な医薬・ In any dosage form, suitable pharmaceutical, in the preparation
製剤的に許容しうる添加物を用いることができる。 It can be used additives which may pharmaceutically acceptable. 添加物としては、賦形剤、結合剤、滑沢剤、崩壊剤、希釈剤、風味剤、着色剤、溶解剤、懸濁剤、乳化剤、保存剤、緩衝剤、等張化剤、軟膏基剤、オイル、溶解補助剤、吸収促進剤、接着剤、噴霧剤などが挙げられる。 The additives, excipients, binding agents, lubricants, disintegrants, diluents, flavoring agents, coloring agents, solubilizers, suspending agents, emulsifiers, preservatives, buffering agents, tonicity agents, ointment bases , oils, solubilizers, absorption enhancers, adhesives, and the like sprays.

【0048】式Iの化合物及びその酸付加塩は、好ましくは軟膏、ローション、クリームなどの経皮投与のための製剤の形をとる。 The compounds and their acid addition salts of formula I, preferably takes ointments, lotions, the form of preparation for transdermal administration, such as creams.

【0049】式Iの化合物及びその酸付加塩は、好酸球浸潤抑制作用及び抗ヒスタミン作用を示すことから、それらの作用が効果を及ぼす他の疾患、たとえばアレルギー性鼻炎、じん麻疹、喘息などに有用であることが示唆される。 The compounds and their acid addition salts of formula I, because they exhibit eosinophil infiltration suppressing action and antihistaminic action, other diseases their action is an effect, for example, allergic rhinitis, urticaria, asthma etc. it is suggested to be useful in.

【0050】 [0050]

【実施例】次に、本発明を実施例によってさらに詳細に説明する。 EXAMPLES As follows is a description of examples of the present invention. なお、実施例にて合成した化合物の分光学的データは、IRスペクトルは日本分光IR−810、 1 Incidentally, spectroscopic data of the compounds synthesized in Examples, IR spectra JASCO IR-810, 1
H−NMRスペクトルは Varian Unity 400 NMR Appara H-NMR spectra Varian Unity 400 NMR Appara
tus により測定した。 It was measured by tus.

【0051】(実施例1) 4−[3−(ベンジルオキシカルボニルアミノ)プロピ [0051] (Example 1) 4- [3- (benzyloxycarbonylamino) propyl
ルアミノ]−2−クロロ−3−ニトロキノリンの合成 2,4−ジクロロ−3−ニトロキノリン0.19g(0. Arylamino] -2-chloro -3-nitroquinoline 2,4-dichloro-3-nitroquinoline 0.19 g (0.
768mmol)及びN−(ベンジルオキシカルボニル)− 768Mmol) and N- (benzyloxycarbonyl) -
1,3−プロパンジアミン0.16g(0.768mmol) 1,3-propane diamine 0.16g (0.768mmol)
をトリエチルアミン5ml中、70℃に加熱して1時間撹拌した。 The triethylamine 5 ml, and stirred for 1 hour and heated to 70 ° C.. トリエチルアミンを減圧下留去した後、塩化メチレンに溶解し、水洗、乾燥(MgSO 4 )後、溶媒を減圧下留去した。 After evaporation of triethylamine under a reduced pressure and dissolved in methylene chloride, washed with water, dried (MgSO 4), and the solvent was evaporated under reduced pressure. 残渣をシリカゲルカラムクロマトグラフィーに付し、n−ヘキサン−酢酸エチル(2:1v/ The residue was subjected to silica gel column chromatography, n- hexane - ethyl acetate (2: 1 v /
v)溶出画分により、4−[3−(ベンジルオキシカルボニルアミノ)プロピルアミノ]−2−クロロ−3−ニトロキノリン0.27g(0.651mmol)を黄色粉末として得た。 v) The elution fraction, 4- [3- (benzyloxycarbonylamino) propylamino] -2-chloro-3-nitroquinoline 0.27 g (0.651 mmol) as a yellow powder. このものの分光学的データは以下の通りである。 Spectroscopic data of the product are as follows.

【0052】 1 H−NMR(CDCl 3 )δ(ppm):1. [0052] 1 H-NMR (CDCl 3) δ (ppm): 1.
79(2H,m),3.35(4H,m),5.02(1 79 (2H, m), 3.35 (4H, m), 5.02 (1
H,br),5.18(2H,s),7.15(1H,b H, br), 5.18 (2H, s), 7.15 (1H, b
r),7.37(5H,m),7.57(1H,t,J=8. r), 7.37 (5H, m), 7.57 (1H, t, J = 8.
0Hz),7.73(1H,t,J=7.8Hz),7.90 0Hz), 7.73 (1H, t, J = 7.8Hz), 7.90
(1H,d,J=8.4Hz),8.21(1H,d,J=8. (1H, d, J = 8.4Hz), 8.21 (1H, d, J = 8.
0Hz) 0Hz)

【0053】(実施例2) 3−アミノ−4−[3−(ベンジルオキシカルボニルア [0053] (Example 2) 3-amino-4- [3- (benzyloxycarbonyl A
ミノ)プロピルアミノ]−2−クロロキノリンの合成 4−[3−(ベンジルオキシカルボニルアミノ)プロピルアミノ]−2−クロロ−3−ニトロキノリン0.27 Mino) propylamino] -2-chloro quinoline 4- [3- (benzyloxycarbonylamino) propylamino] -2-chloro-3-nitroquinoline 0.27
g(0.651mmol)をメタノール10mlに溶解し、濃塩酸1ml及び鉄粉0.22g(0.390mmol)を加え室温で2時間撹拌した。 g and (0.651 mmol) was dissolved in methanol 10 ml, the mixture was stirred for 2 hours at room temperature was added concentrated hydrochloric acid 1ml and iron powder 0.22g of (0.390 mmol). 反応液を飽和炭酸水素ナトリウム水溶液にあけ、酢酸エチルで抽出し、食塩水で洗浄、乾燥(Na 2 SO 4 )後、溶媒を減圧下留去した。 The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate, washed with brine, dried (Na 2 SO 4), and the solvent was evaporated under reduced pressure. 残渣をシリカゲルカラムクロマトグラフィーに付し、クロロホルム−メタノール(300:1v/v)溶出画分により、3 The residue was subjected to silica gel column chromatography using chloroform - methanol (300: 1v / v) elution fraction 3
−アミノ−4−[3−(ベンジルオキシカルボニルアミノ)プロピルアミノ]−2−クロロキノリン0.12g - Amino-4- [3- (benzyloxycarbonylamino) propylamino] -2-chloroquinoline 0.12g
(0.312mmol)を微黄色粉末として得た。 The (0.312 mmol) was obtained as a slightly yellow powder. このものの分光学的データは以下の通りである。 Spectroscopic data of the product are as follows.

【0054】 1 H−NMR(CDCl 3 )δ(ppm):1. [0054] 1 H-NMR (CDCl 3) δ (ppm): 1.
76(2H,m),3.30(2H,m),3.42(2 76 (2H, m), 3.30 (2H, m), 3.42 (2
H,q,J=6.3Hz),4.21(2H,bs),4.44 H, q, J = 6.3Hz), 4.21 (2H, bs), 4.44
(1H,br),4.92(1H,br),5.16(2 (1H, br), 4.92 (1H, br), 5.16 (2
H,s),7.30−7.39(5H,m),7.46(2 H, s), 7.30-7.39 (5H, m), 7.46 (2
H,m),7.89(2H,m) H, m), 7.89 (2H, m)

【0055】(実施例3) 1−[3−(ベンジルオキシカルボニルアミノ)プロピ [0055] (Example 3) 1- [3- (benzyloxycarbonylamino) propyl
ル]−4−クロロ−1H−イミダゾ[4,5−c]キノ ] -4- chloro -1H- imidazo [4,5-c] quinoline
リンの合成 3−アミノ−4−[3−(ベンジルオキシカルボニルアミノ)プロピルアミノ]−2−クロロキノリン0.12 Synthesis 3-Amino-4-phosphorus [3- (benzyloxycarbonylamino) propylamino] -2-chloroquinoline 0.12
g(0.312mmol)にトリエチルオルトホルメート0. g (0.312 mmol) in triethyl orthoformate 0.
52ml(3.12mmol)を加え、100℃に加熱して3. 52ml of (3.12 mmol) was added, 3 and heated to 100 ° C..
5時間撹拌した。 5 hours and the mixture was stirred. 反応液を減圧下濃縮して、1−[3− The reaction solution was concentrated under reduced pressure, 1- [3-
(ベンジルオキシカルボニルアミノ)プロピル]−4− (Benzyloxycarbonylamino) propyl] -4-
クロロ−1H−イミダゾ[4,5−c]キノリン0.12 Chloro -1H- imidazo [4,5-c] quinoline 0.12
g(0.304mmol)を淡黄色固体として得た。 g and (0.304 mmol) as a pale yellow solid. このものの分光学的データは以下の通りである。 Spectroscopic data of the product are as follows.

【0056】 1 H−NMR(CDCl 3 )δ(ppm):2. [0056] 1 H-NMR (CDCl 3) δ (ppm): 2.
24(2H,m),3.36(2H,q,J=6.4Hz), 24 (2H, m), 3.36 (2H, q, J = 6.4Hz),
4.67(2H,t,J=7.0Hz),4.95(1H,b 4.67 (2H, t, J = 7.0Hz), 4.95 (1H, b
r),5.14(2H,s),7.31−7.39(5H, r), 5.14 (2H, s), 7.31-7.39 (5H,
m),7.62(1H,t,J=7.8Hz),7.71(1 m), 7.62 (1H, t, J = 7.8Hz), 7.71 (1
H,t,J=7.8Hz),8.09(1H,s),8.13 H, t, J = 7.8Hz), 8.09 (1H, s), 8.13
(1H,d,J=8.4Hz),8.21(1H,d,J=8. (1H, d, J = 8.4Hz), 8.21 (1H, d, J = 8.
4Hz) 4Hz)

【0057】(実施例4) 1−(3−アミノプロピル)−4−クロロ−1H−イミ [0057] (Example 4) 1- (3-aminopropyl) -4-chloro -1H- Imi
ダゾ[4,5−c]キノリン・酢酸塩の合成 1−[3−(ベンジルオキシカルボニルアミノ)プロピル]−4−クロロ−1H−イミダゾ[4,5−c]キノリン0.12g(0.304mmol)に臭化水素−酢酸[3 Dazo [4,5-c] quinolin-acetate 1- [3- (benzyloxycarbonylamino) propyl] -4-chloro -1H- imidazo [4,5-c] quinoline 0.12 g (0.304 mmol ) in hydrogen bromide - acetic acid [3
3%]3mlを加え、室温で1.5時間撹拌した。 3%] 3 ml and the mixture was stirred for 1.5 hours at room temperature. 反応液を減圧下濃縮し、残渣に1N−水酸化ナトリウム水溶液及び食塩水を加えクロロホルムで5回抽出した。 The reaction solution was concentrated under reduced pressure, and extracted 5 times with chloroform was added to the residue 1N- sodium hydroxide aqueous solution and brine. 乾燥(Na 2 SO 4 )後溶媒を減圧下留去し、残渣をシリカゲルカラムクロマトグラフィーに付し、クロロホルム−メタノール−32%酢酸(12:6:1v/v)溶出画分により、1−(3−アミノプロピル)−4−クロロ−1H Dried (Na 2 SO 4) and the solvent was distilled off under reduced pressure, the residue was subjected to silica gel column chromatography, chloroform - methanol -32% acetic acid by (12:: 6 1v / v ) eluate fractions, 1- ( 3-aminopropyl) -4-chloro -1H
−イミダゾ[4,5−c]キノリン・酢酸塩60mg(0. - imidazo [4,5-c] quinoline-acetate 60 mg (0.
187mmol)を淡黄色固体として得た。 187 mmol) was obtained as a pale yellow solid. このものの分光学的データは以下の通りである。 Spectroscopic data of the product are as follows.

【0058】 1 H−NMR(CD 3 OD)δ(ppm):1. [0058] 1 H-NMR (CD 3 OD ) δ (ppm): 1.
94(3H,s),2.39(2H,m),3.12(2 94 (3H, s), 2.39 (2H, m), 3.12 (2
H,t,J=7.8Hz),4.82(2H,t,J=7.2H H, t, J = 7.8Hz), 4.82 (2H, t, J = 7.2H
z),7.70(2H,m),7.97(1H,d,J=8. z), 7.70 (2H, m), 7.97 (1H, d, J = 8.
0Hz),8.27(1H,d,J=8.0Hz),8.41 0Hz), 8.27 (1H, d, J = 8.0Hz), 8.41
(1H,s) (1H, s)

【0059】(実施例5) 1−(3−アミノプロピル)−1H−イミダゾ[4,5 [0059] (Example 5) 1- (3-aminopropyl)-1H-imidazo [4,5
−c]キノリン−4−アミンの合成 1−(3−アミノプロピル)−4−クロロ−1H−イミダゾ[4,5−c]キノリン・酢酸塩60mg(0.187 -C] quinolin-4-amine 1- (3-aminopropyl) -4-chloro -1H- imidazo [4,5-c] quinoline-acetate 60 mg (0.187
mmol)を耐圧鋼製反応管に入れ、メタノール10ml及び冷却下液体アンモニア5mlを加え、150℃に加熱して1晩撹拌した。 Put mmol) in pressure-resistant steel reaction tube, methanol 10ml and cooled under liquid ammonia 5ml was added and stirred overnight then heated to 0.99 ° C.. 反応液を減圧下濃縮し、残渣を少量の水に溶解し1N−水酸化ナトリウム水溶液0.5mlを加えた。 The reaction solution was concentrated under reduced pressure, the residue was dissolved in a small amount of water 1N- was added aqueous sodium hydroxide 0.5 ml. 析出物を濾取しエタノールから再結晶して、1− Precipitate collected by filtration and recrystallized from ethanol, 1-
(3−アミノプロピル)−1H−イミダゾ[4,5− (3-aminopropyl)-1H-imidazo [4,5
c]キノリン−4−アミン11mg(0.0455mmol) c] quinolin-4-amine 11mg (0.0455mmol)
を淡黄色綿状結晶(mp:243〜245℃(分解)) A pale yellow cotton-like crystals (mp: 243~245 ℃ (decomposition))
として得た。 It was obtained as a. このものの分光学的データは以下の通りである。 Spectroscopic data of the product are as follows.

【0060】IR(KBr)cm -1 :3320,317 [0060] IR (KBr) cm -1: 3320,317
0,1650 1 H−NMR(DMSO−d 6 )δ(ppm):1.93(2 0,1650 1 H-NMR (DMSO- d 6) δ (ppm): 1.93 (2
H,m),2.57(2H,t,J=6.6Hz),4.64 H, m), 2.57 (2H, t, J = 6.6Hz), 4.64
(2H,t,J=7.0Hz),6.55(2H,s),7.2 (2H, t, J = 7.0Hz), 6.55 (2H, s), 7.2
6(1H,t,J=7.2Hz),7.44(1H,t,J= 6 (1H, t, J = 7.2Hz), 7.44 (1H, t, J =
7.4Hz),7.62(1H,d,J=8.0Hz),8.12 7.4Hz), 7.62 (1H, d, J = 8.0Hz), 8.12
(1H,d,J=8.0Hz),8.19(1H,s) (1H, d, J = 8.0Hz), 8.19 (1H, s)

【0061】(実施例6) 4−[3−(tert−ブトキシカルボニルアミノ)プロピ [0061] (Example 6) 4- [3- (tert- butoxycarbonylamino) prop
ルアミノ]−2−クロロ−3−ニトロキノリンの合成 2,4−ジクロロ−3−ニトロキノリン0.59g(2. Arylamino] -2-chloro -3-nitroquinoline 2,4-dichloro-3-nitroquinoline 0.59 g (2.
41mmol)及びN−(tert−ブトキシカルボニル)− 41 mmol) and N- (tert- butoxycarbonyl) -
1,3−プロパンジアミン0.42g(2.41mmol)をトリエチルアミン10ml中、70℃に加熱して1.5時間撹拌した。 1,3-propanediamine 0.42g of (2.41 mmol) of triethylamine 10 ml, and stirred for 1.5 hours and heated to 70 ° C.. 減圧下トリエチルアミンを留去し、残渣を塩化メチレンに溶解し、水洗、乾燥(Na 2 SO 4 )後減圧下濃縮した。 Was distilled off under reduced pressure triethylamine, the residue was dissolved in methylene chloride, washed with water, dried and (Na 2 SO 4), the concentrated under reduced pressure. 残渣をメタノールでトリチュレートして濾取し、4−[3−(tert−ブトキシカルボニルアミノ)プロピルアミノ]−2−クロロ−3−ニトロキノリン0.61g(1.60mmol)を黄色結晶(mp:159 The residue was collected by filtration and triturated with methanol, 4- [3- (tert- butoxycarbonylamino) propylamino] -2-chloro-3-nitroquinoline 0.61g of (1.60 mmol) of yellow crystals (mp: 159
〜161℃)として得た。 ~161 ℃) and was obtained. このものの分光学的データは以下の通りである。 Spectroscopic data of the product are as follows.

【0062】IR(KBr)cm -1 :3310,168 [0062] IR (KBr) cm -1: 3310,168
0,1580 1 H−NMR(CDCl 3 )δ(ppm):1.50(9H, 0,1580 1 H-NMR (CDCl 3 ) δ (ppm): 1.50 (9H,
s),1.77(2H,m),3.27(2H,q,J=6. s), 1.77 (2H, m), 3.27 (2H, q, J = 6.
1Hz),3.36(2H,q,J=6.0Hz),4.82 1Hz), 3.36 (2H, q, J = 6.0Hz), 4.82
(1H,br),7.37(1H,br),7.55(1 (1H, br), 7.37 (1H, br), 7.55 (1
H,t,J=7.8Hz),7.72(1H,t,J=7.7H H, t, J = 7.8Hz), 7.72 (1H, t, J = 7.7H
z),7.89(1H,d,J=8.2Hz),8.27(1 z), 7.89 (1H, d, J = 8.2Hz), 8.27 (1
H,d,J=8.4Hz) H, d, J = 8.4Hz)

【0063】(実施例7) 3−アミノ−4−[3−(tert−ブトキシカルボニルア [0063] (Example 7) 3-Amino-4-[3- (tert-butoxycarbonyl A
ミノ)プロピルアミノ]−2−クロロキノリンの合成 4−[3−(tert−ブトキシカルボニルアミノ)プロピルアミノ]−2−クロロ−3−ニトロキノリン0.27 Mino) propylamino] -2-chloro quinoline 4- [3- (tert- butoxycarbonylamino) propylamino] -2-chloro-3-nitroquinoline 0.27
g(0.70mmol)をエタノール7mlに溶解し、塩化すず[II]・2水和物0.55g(2.45mmol)を加え1 g of (0.70 mmol) was dissolved in ethanol 7 ml, 1 chloride was added tin [II] · 2 hydrate 0.55 g (2.45 mmol)
時間加熱還流した。 It was heated to reflux time. 冷却後反応液を2N−アンモニア水にあけ、クロロホルムで2回抽出し、洗浄(食塩水)、 Open After cooling, the reaction liquid in 2N- aqueous ammonia, and extracted twice with chloroform, washed (brine),
乾燥(Na 2 SO 4 )後、減圧下溶媒を留去した。 After drying (Na 2 SO 4), the solvent was distilled off under reduced pressure. 残渣をシリカゲルカラムクロマトグラフィーに付し、n−ヘキサン−酢酸エチル(1:1v/v)溶出画分により、3− The residue was subjected to silica gel column chromatography, n- hexane - ethyl acetate: (1 1v / v) eluate fractions, 3-
アミノ−4−[3−(tert−ブトキシカルボニルアミノ)プロピルアミノ]−2−クロロキノリン0.15g Amino -4- [3- (tert- butoxycarbonylamino) propyl] -2-chloroquinoline 0.15g
(0.428mmol)を淡黄色結晶として得た。 The (0.428mmol) was obtained as a pale yellow crystal. このものの分光学的データは以下の通りである。 Spectroscopic data of the product are as follows.

【0064】 1 H−NMR(CDCl 3 )δ(ppm):1. [0064] 1 H-NMR (CDCl 3) δ (ppm): 1.
49(9H,s),1.73(2H,m),3.29(2 49 (9H, s), 1.73 (2H, m), 3.29 (2
H,t,J=6.2Hz),3.35(2H,q,J=6.0H H, t, J = 6.2Hz), 3.35 (2H, q, J = 6.0H
z),4.28(2H,bs),4.60(1H,br), z), 4.28 (2H, bs), 4.60 (1H, br),
4.75(1H,br),7.44(2H,m),7.87 4.75 (1H, br), 7.44 (2H, m), 7.87
(1H,d,J=7.6Hz),7.94(1H,d,J=7. (1H, d, J = 7.6Hz), 7.94 (1H, d, J = 7.
6Hz) 6Hz)

【0065】(実施例8) 1−[3−(tert−ブトキシカルボニルアミノ)プ [0065] (Example 8) 1- [3- (tert- butoxycarbonylamino) flop
ロピル]−4−クロロ−1H−イミダゾ[4,5−c] Propyl] -4-chloro -1H- imidazo [4,5-c]
キノリンの合成 3−アミノ−4−[3−(tert−ブトキシカルボニルアミノ)プロピルアミノ]−2−クロロキノリン0.15 Quinoline 3-amino-4-[3- (tert-butoxycarbonylamino) propyl] -2-chloroquinoline 0.15
g(0.428mmol)にトリエチルオルトホルメート0. g (0.428 mmol) in triethyl orthoformate 0.
36ml(2.14mmmol)を加えて、100℃で2時間さらに80℃で1晩撹拌した。 Added 36ml (2.14mmmol), and stirred overnight at 2 hours further 80 ° C. at 100 ° C.. 反応混合物を減圧下濃縮し、残渣をシリカゲルカラムクロマトグラフィーに付し、クロロホルム−メタノール(150:1〜100: The reaction mixture was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography using chloroform - methanol (150: 1 to 100:
1v/v)溶出画分により、1−[3−(tert−ブトキシカルボニルアミノ)プロピル]−4−クロロ−1H−イミダゾ[4,5−c]キノリン0.14g(0.388mmo 1 v / v) elution fraction, 1- [3- (tert- butoxycarbonylamino) propyl] -4-chloro -1H- imidazo [4,5-c] quinoline 0.14g (0.388mmo
l)を白色粉末(mp:155〜156℃)として得た。 l) a white powder (mp: 155~156 ℃) and was obtained. このものの分光学的データは以下の通りである。 Spectroscopic data of the product are as follows.

【0066】IR(KBr)cm -1 :3380,168 [0066] IR (KBr) cm -1: 3380,168
0,1520 1 H−NMR(CDCl 3 )δ(ppm):1.47(9H, 0,1520 1 H-NMR (CDCl 3 ) δ (ppm): 1.47 (9H,
s),2.22(2H,m),3.30(2H,q,J=6. s), 2.22 (2H, m), 3.30 (2H, q, J = 6.
4Hz),4.68(2H,t,J=7.2Hz),4.7(1 4Hz), 4.68 (2H, t, J = 7.2Hz), 4.7 (1
H,br),7.66(1H,t,J=7.6Hz),7.72 H, br), 7.66 (1H, t, J = 7.6Hz), 7.72
(1H,t,J=7.6Hz),8.09(1H,s),8.1 (1H, t, J = 7.6Hz), 8.09 (1H, s), 8.1
6(1H,d,J=8.4Hz),8.21(1H,d,J= 6 (1H, d, J = 8.4Hz), 8.21 (1H, d, J =
8.4Hz) 8.4Hz)

【0067】(実施例9) 1−(3−アミノプロピル)−4−クロロ−1H−イミ [0067] (Example 9) 1- (3-aminopropyl) -4-chloro -1H- Imi
ダゾ[4,5−c]キノリンの合成 1−[3−(tert−ブトキシカルボニルアミノ)プロピル]−4−クロロ−1H−イミダゾ[4,5−c]キノリン50mg(0.139mmol)を塩化メチレン3mlに溶解し、トリフルオロ酢酸0.11ml(1.39mmol)を加え室温で1日撹拌した。 Dazo [4,5-c] quinoline 1- [3- (tert- butoxycarbonylamino) propyl] -4-chloro -1H- imidazo [4,5-c] quinoline 50 mg (0.139 mmol) in methylene chloride It was dissolved in 3 ml, and stirred at room temperature for 1 day added trifluoroacetic acid 0.11 ml (1.39 mmol). 反応液を減圧下濃縮し、残渣に1N−水酸化ナトリウム水溶液1ml及び食塩水を加え、 The reaction mixture was concentrated under reduced pressure, the residue 1N- sodium hydroxide aqueous solution 1ml and brine was added,
クロロホルムで5回抽出し、乾燥(Na 2 SO 4 )後減圧下濃縮した。 And extracted 5 times with chloroform, dried and (Na 2 SO 4), the concentrated under reduced pressure. 残渣をジエチルエーテル(塩化メチレンを少量含む)でトリチュレートして析出物を濾取し、1− The residue was triturated with diethyl ether (containing a small amount of methylene chloride) is filtered off precipitate, 1-
(3−アミノプロピル)−4−クロロ−1H−イミダゾ[4,5−c]キノリン14mg(0.0536mmol)を白色粉末として得た。 (3-aminopropyl) -4-chloro -1H- give imidazo [4,5-c] quinoline 14mg of (0.0536Mmol) as a white powder. このものの分光学的データは以下の通りである。 Spectroscopic data of the product are as follows.

【0068】IR(KBr)cm -1 :3400,159 [0068] IR (KBr) cm -1: 3400,159
0,1510 1 H−NMR(CDCl 3 +CD 3 OD)δ(ppm):2. 0,1510 1 H-NMR (CDCl 3 + CD 3 OD) δ (ppm): 2.
06(2H,m),2.72(2H,t,J=6.8Hz), 06 (2H, m), 2.72 (2H, t, J = 6.8Hz),
2.98(2H,br),4.64(2H,t,J=7.0H 2.98 (2H, br), 4.64 (2H, t, J = 7.0H
z),7.57(1H,t,J=7.6Hz),7.61(1 z), 7.57 (1H, t, J = 7.6Hz), 7.61 (1
H,t,J=7.6Hz),8.03(1Hs),8.05 H, t, J = 7.6Hz), 8.03 (1Hs), 8.05
(1H,d,J=8.0Hz),8.11(1H,d,J=8. (1H, d, J = 8.0Hz), 8.11 (1H, d, J = 8.
0Hz) 0Hz)

【0069】(実施例10) 1−(3−アミノプロピル)−1H−イミダゾ[4,5 [0069] (Example 10) 1- (3-aminopropyl)-1H-imidazo [4,5
−c]キノリン−4−アミンの合成(その2) 1−(3−アミノプロピル)−4−クロロ−1H−イミダゾ[4,5−c]キノリン14mg(0.0536mmol) -C] quinolin-4-amine (2) 1- (3-aminopropyl) -4-chloro -1H- imidazo [4,5-c] quinoline 14 mg (0.0536Mmol)
を耐圧鋼製反応管に入れ、メタノール5ml及び冷却下液体アンモニア3mlを加え、150℃に加熱して1晩撹拌した。 Was placed in a pressure-resistant steel reaction tube, methanol 5ml and cooling under liquid ammonia 3ml was added and stirred overnight then heated to 0.99 ° C.. 反応液を減圧下濃縮し、残渣に1N−水酸化ナトリウム水溶液0.3mlを加え析出物を濾取して、1− The reaction mixture was concentrated under reduced pressure, and the precipitates are collected by filtration was added to the residue 1N- aqueous sodium hydroxide 0.3 ml, 1-
(3−アミノプロピル)−1H−イミダゾ[4,5− (3-aminopropyl)-1H-imidazo [4,5
c]キノリン−4−アミン8mg(0.0331mmol)を得た。 c] quinolin-4-amine 8mg (0.0331mmol). このものの物性値は、実施例5の化合物と一致した。 The property values ​​of the compound was consistent with the compound of Example 5.

【0070】(実施例11) 4−ベンジルアミノ−1−[3−(tert−ブトキシ [0070] (Example 11) 4-benzylamino-1-[3- (tert-butoxy
カルボニルアミノ)プロピル]−1H−イミダゾ[4, Carbonylamino) propyl]-1H-imidazo [4,
5−c]キノリンの合成 1−[3−(tert−ブトキシカルボニルアミノ)プロピル]−4−クロロ−1H−イミダゾ[4,5−c]キノリン30mg(0.0831mmol)にベンジルアミン1ml 5-c] Synthesis 1- [3- (tert- butoxycarbonylamino) quinoline propyl] -4-chloro -1H- imidazo [4,5-c] quinoline 30mg (0.0831mmol) benzylamine 1ml
を加え、150℃に加熱して3時間撹拌した。 And the mixture was stirred for 3 hours and heated to 0.99 ° C.. 減圧下過剰のベンジルアミンを留去し、1N−塩酸と食塩水を加え塩化メチレンで2回抽出した。 Was distilled off under reduced pressure excess benzylamine, and extracted twice with methylene chloride added 1N- hydrochloric acid and brine. 有機相を飽和炭酸水素ナトリウム水溶液で洗浄し、乾燥(Na 2 SO 4 )後、減圧下溶媒を留去した。 The organic phase was washed with saturated aqueous sodium hydrogen carbonate solution, dried (Na 2 SO 4), the solvent was distilled off under reduced pressure. 残渣をシリカゲルカラムクロマトグラフィーに付し、クロロホルム−メタノール(15 The residue was subjected to silica gel column chromatography using chloroform - methanol (15
0:1v/v)溶出画分により、4−ベンジルアミノ−1 0: 1v / v) elution fraction, 4-benzylamino -1
−[3−(tert−ブトキシカルボニルアミノ)プロピル]−1H−イミダゾ[4,5−c]キノリン35mg - [3- (tert-butoxycarbonylamino) propyl]-1H-imidazo [4,5-c] quinoline 35mg
(0.0811mmol)を白色粉末(mp:171〜17 The (0.0811mmol) white powder (mp: one hundred seventy-one to seventeen
2.5℃)として得た。 2.5 ℃) and was obtained. このものの分光学的データは以下の通りである。 Spectroscopic data of the product are as follows.

【0071】IR(KBr)cm -1 :3330,170 [0071] IR (KBr) cm -1: 3330,170
0,1590,1540 1 H−NMR(CDCl 3 )δ(ppm):1.46(9H, 0,1590,1540 1 H-NMR (CDCl 3 ) δ (ppm): 1.46 (9H,
s),2.18(2H,m),3.25(2H,m),4. s), 2.18 (2H, m), 3.25 (2H, m), 4.
57(2H,t,J=7.0Hz),4.64(1H,b 57 (2H, t, J = 7.0Hz), 4.64 (1H, b
r),4.95(2H,d,J=5.2Hz),6.05 r), 4.95 (2H, d, J = 5.2Hz), 6.05
(1H,br),7.26−7.36(4H,m),7.4 (1H, br), 7.26-7.36 (4H, m), 7.4
7(2H,d,J=7.6Hz),7.51(1H,t,J= 7 (2H, d, J = 7.6Hz), 7.51 (1H, t, J =
7.6Hz),7.82(1H,s),7.92(2H,t,J 7.6Hz), 7.82 (1H, s), 7.92 (2H, t, J
=8.0Hz) = 8.0Hz)

【0072】(実施例12) 1−(3−アミノプロピル)−1H−イミダゾ[4,5 [0072] (Example 12) 1- (3-aminopropyl)-1H-imidazo [4,5
−c]キノリン−4−アミンの合成(その3) 4−ベンジルアミノ−1−[3−(tert−ブトキシカルボニルアミノ)プロピル]−1H−イミダゾ[4, -C] quinolin-4-amine (3) 4-benzylamino-1-[3- (tert-butoxycarbonylamino) propyl]-1H-imidazo [4,
5−c]キノリン30mg(0.0695mmol)をギ酸3m 5-c] quinoline 30mg of (0.0695mmol) formic acid 3m
lに溶解し、水酸化パラジウム−炭素[20%]0.1g It was dissolved in l, palladium hydroxide - carbon [20%] 0.1 g
を加え1日加熱還流した。 And daily added and heated under reflux. 反応液を濾過し減圧下溶媒を留去した後、残渣をシリカゲルカラムクロマトグラフィーに付し、クロロホルム−メタノール−32%酢酸(6:3:1v/v)溶出画分より目的物の酢酸塩を得、 The reaction solution was evaporated filtered solvent under reduced pressure, the residue was subjected to silica gel column chromatography, chloroform - methanol -32% acetic acid acetate (6:: 3 1v / v) intended product from elution fractions obtained,
アルカリ処理で結晶を濾取し、1−(3−アミノプロピル)−1H−イミダゾ[4,5−c]キノリン−4−アミン7mg(0.0290mmol)を微褐色粉末として得た。 The crystals were collected by filtration alkali treatment, to give 1- (3-aminopropyl)-1H-imidazo [4,5-c] quinolin-4-amine 7mg (0.0290mmol) as a slightly brown powder. このものの物性値は、実施例5の化合物と一致した。 The property values ​​of the compound was consistent with the compound of Example 5.

【0073】(実施例13) 4−[4−(tert−ブトキシカルボニルアミノ)ブチル [0073] (Example 13) 4- [4- (tert- butoxycarbonylamino) butyl
アミノ]−2−クロロ−3−ニトロキノリンの合成 2,4−ジクロロ−3−ニトロキノリン0.72g(2. Amino] -2-chloro -3-nitroquinoline 2,4-dichloro-3-nitroquinoline 0.72 g (2.
97mmol)及びN−(tert−ブトキシカルボニル)− 97 mmol) and N- (tert- butoxycarbonyl) -
1,4−ジアミノブタン0.56g(2.97mmol)をトリエチルアミン12ml中、70℃に加熱して1.5時間撹拌した。 Triethylamine 12ml 1,4-diaminobutane 0.56 g (2.97 mmol), and stirred for 1.5 hours and heated to 70 ° C.. 減圧下濃縮し、残渣を塩化メチレンに溶解し、水洗、乾燥(MgSO 4 )後、減圧下溶媒を留去した。 And concentrated under reduced pressure, the residue was dissolved in methylene chloride, washed with water, dried (MgSO 4), and the solvent was evaporated under reduced pressure. 残渣をn−ヘキサン−ジエチルエーテル(1:1v/ The residue n- hexane - diethyl ether (1: 1 v /
v)でトリチュレートして濾取し、4−[4−(ter v) and triturated with was filtered off, 4- [4- (ter
t−ブトキシカルボニルアミノ)ブチルアミノ]−2− t- butoxycarbonyl amino) butyl] -2-
クロロ−3−ニトロキノリン0.97g(2.46mmol) Chloro-3-nitroquinoline 0.97 g (2.46 mmol)
を黄色粉末(mp:125〜126.5℃)として得た。 The yellow powder (mp: 125~126.5 ℃) and was obtained. このものの分光学的データは以下の通りである。 Spectroscopic data of the product are as follows.

【0074】IR(KBr)cm -1 :3340,328 [0074] IR (KBr) cm -1: 3340,328
0,1680,1540,1520 1 H−NMR(CDCl 3 )δ(ppm):1.46(9H, 0,1680,1540,1520 1 H-NMR (CDCl 3 ) δ (ppm): 1.46 (9H,
s),1.63(2H,m),1.78(2H,m),3. s), 1.63 (2H, m), 1.78 (2H, m), 3.
19(2H,q,J=6.4Hz),3.47(2H,q,J= 19 (2H, q, J = 6.4Hz), 3.47 (2H, q, J =
6.1Hz),4.68(1H,br),6.41(1H,b 6.1Hz), 4.68 (1H, br), 6.41 (1H, b
r),7.52(1H,t,J=7.7Hz),7.74(1 r), 7.52 (1H, t, J = 7.7Hz), 7.74 (1
H,t,J=7.8Hz),7.91(1H,d,J=8.4H H, t, J = 7.8Hz), 7.91 (1H, d, J = 8.4H
z),8.11(1H,d,J=8.4Hz) z), 8.11 (1H, d, J = 8.4Hz)

【0075】(実施例14) 3−アミノ−4−[4−(tert−ブトキシカルボニルア [0075] (Example 14) 3-Amino-4-[4-(tert-butoxycarbonyl A
ミノ)ブチルアミノ]−2−クロロキノリンの合成 4−[4−(tert−ブトキシカルボニルアミノ)ブチルアミノ]−2−クロロ−3−ニトロキノリン0.5g Mino) butylamino] -2-chloro quinoline 4- [4- (tert- butoxycarbonylamino) butylamino] -2-chloro-3-nitroquinoline 0.5g
(1.27mmol)をエタノール13mlに溶解し、塩化すず[II]・2水和物1.0g(4.43mmol)を加え1時間加熱還流した。 The (1.27 mmol) was dissolved in ethanol 13 ml, and heated to reflux chloride tin [II] · 2 hydrate 1.0 g (4.43 mmol) was added 1 hour. 反応液を2N−アンモニア水にあけ、 The reaction mixture was poured into 2N- aqueous ammonia,
クロロホルムで2回抽出し、洗浄(食塩水)、乾燥(N And extracted twice with chloroform, washed (brine), dried (N
2 SO 4 )後、減圧下溶媒を留去した。 a 2 SO 4) after the solvent was distilled off under reduced pressure. 残渣をシリカゲルカラムクロマトグラフィーに付し、n−ヘキサン−酢酸エチル(2:1v/v)溶出画分により目的物を集め、 The residue was subjected to silica gel column chromatography, n- hexane - ethyl acetate (2: 1v / v) The target product was collected by elution fraction,
溶媒留去後ジエチルエーテルでトリチュレートして、3 Trituration with evaporated after diethyl ether, 3
−アミノ−4−[4−(tert−ブトキシカルボニルアミノ)ブチルアミノ]−2−クロロキノリン0.12g - Amino -4- [4- (tert- butoxycarbonylamino) butyl] -2-chloroquinoline 0.12g
(0.329mmol)を橙色結晶として得た。 The (0.329mmol) was obtained as orange crystals. このものの分光学的データは以下の通りである。 Spectroscopic data of the product are as follows.

【0076】IR(KBr)cm -1 :3270,168 [0076] IR (KBr) cm -1: 3270,168
0,1540,760 1 H−NMR(CDCl 3 )δ(ppm):1.44(9H, 0,1540,760 1 H-NMR (CDCl 3 ) δ (ppm): 1.44 (9H,
s),1.64(4H,m),3.17(2H,q,J=6. s), 1.64 (4H, m), 3.17 (2H, q, J = 6.
0Hz),3.27(2H,t,J=6.6Hz),3.89 0Hz), 3.27 (2H, t, J = 6.6Hz), 3.89
(1H,br),4.15(2H,bs),4.59(1 (1H, br), 4.15 (2H, bs), 4.59 (1
H,br),7.47(2H,m),7.77(1H,d,J H, br), 7.47 (2H, m), 7.77 (1H, d, J
=7.6Hz),7.89(1H,d,J=7.2Hz) = 7.6Hz), 7.89 (1H, d, J = 7.2Hz)

【0077】(実施例15) 1−[4−(tert−ブトキシカルボニルアミノ)ブチ [0077] (Example 15) 1- [4- (tert- butoxycarbonylamino) butyl
ル]−4−クロロ−1H−イミダゾ[4,5−c]キノ ] -4- chloro -1H- imidazo [4,5-c] quinoline
リンの合成 3−アミノ−4−[4−(tert−ブトキシカルボニルアミノ)ブチルアミノ]−2−クロロキノリン0.14g Synthesis 3-Amino-4-phosphorus [4-(tert-butoxycarbonylamino) butyl] -2-chloroquinoline 0.14g
(0.384mmol)にトリエチルオルトホルメート0.3 (0.384 mmol) in triethyl orthoformate 0.3
2ml(1.92mmol)を加え、100℃に加熱して1晩撹拌した。 2ml of (1.92 mmol) was added, and stirred overnight and heated to 100 ° C.. 反応混合物を減圧下濃縮し、残渣をシリカゲルカラムクロマトグラフィーに付し、クロロホルム−メタノール(150:1〜100:1v/v)溶出画分により、1−[4−(tert−ブトキシカルボニルアミノ)ブチル]−4−クロロ−1H−イミダゾ[4,5−c]キノリン0.12g(0.321mmol)を淡橙色粉末(m The reaction mixture was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography using chloroform - methanol (150: 1~100: 1v / v) elution fraction, 1- [4- (tert- butoxycarbonylamino) butyl ] -4-chloro -1H- imidazo [4,5-c] quinoline 0.12 g (0.321 mmol) of a pale orange powder (m
p:148〜150℃)として得た。 p: 148~150 ℃) and was obtained. このものの分光学的データは以下の通りである。 Spectroscopic data of the product are as follows.

【0078】IR(KBr)cm -1 :1695,1510 1 H−NMR(CDCl 3 )δ(ppm):1.42(9H, [0078] IR (KBr) cm -1: 1695,1510 1 H-NMR (CDCl 3) δ (ppm): 1.42 (9H,
s),1.62(2H,m),2.06(2H,m),3. s), 1.62 (2H, m), 2.06 (2H, m), 3.
21(2H,q,J=6.4Hz),4.58(1H,b 21 (2H, q, J = 6.4Hz), 4.58 (1H, b
r),4.65(2H,t,J=7.4Hz),7.66(1 r), 4.65 (2H, t, J = 7.4Hz), 7.66 (1
H,t,J=7.2Hz),7.72(1H,t,J=7.6H H, t, J = 7.2Hz), 7.72 (1H, t, J = 7.6H
z),8.02(1H,s),8.13(1H,d,J=8. z), 8.02 (1H, s), 8.13 (1H, d, J = 8.
4Hz),8.21(1H,d,J=8.2Hz) 4Hz), 8.21 (1H, d, J = 8.2Hz)

【0079】(実施例16) 1−(4−アミノブチル)−4−クロロ−1H−イミダ [0079] (Example 16) 1- (4-aminobutyl) -4-chloro -1H- Imida
ゾ[4,5−c]キノリンの合成 1−[4−(tert−ブトキシカルボニルアミノ)ブチル]−4−クロロ−1H−イミダゾ[4,5−c]キノリン0.10g(0.267mmol)を塩化メチレン6mlに溶解し、トリフルオロ酢酸0.21ml(2.67mmol)を加え室温で1晩撹拌した。 Zone [4,5-c] 1- quinoline [4-(tert-butoxycarbonylamino) butyl] -4-chloro -1H- imidazo [4,5-c] quinoline 0.10g of (0.267 mmol) was dissolved in methylene chloride 6 ml, and stirred overnight at room temperature was added trifluoroacetic acid 0.21 ml (2.67 mmol). 反応液を減圧下濃縮し、残渣に1N−水酸化ナトリウム水溶液2ml及び食塩水を加えてクロロホルムで5回抽出し、乾燥(Na 2 SO 4 )後減圧下濃縮した。 The reaction mixture was concentrated under reduced pressure, added to the residue 1N- sodium hydroxide aqueous solution 2ml and brine and extracted five times with chloroform, dried and (Na 2 SO 4), the concentrated under reduced pressure. 残渣をジエチルエーテル(塩化メチレンを少量含む)でトリチュレートして析出物を濾取し、1 The residue was triturated with diethyl ether (containing a small amount of methylene chloride) is filtered off precipitate, 1
−(4−アミノブチル)−4−クロロ−1H−イミダゾ[4,5−c]キノリン45mg(0.164mmol)を淡橙色粉末として得た。 - (4-aminobutyl) -4-chloro -1H- imidazo [4,5-c] quinoline 45 mg (0.164 mmol) as a pale orange powder. このものの分光学的データは以下の通りである。 Spectroscopic data of the product are as follows.

【0080】IR(KBr)cm -1 :3400,295 [0080] IR (KBr) cm -1: 3400,295
0,1670,1520,1360 1 H−NMR(CDCl 3 )δ(ppm):1.51(2H, 0,1670,1520,1360 1 H-NMR (CDCl 3 ) δ (ppm): 1.51 (2H,
m),1.96(2H,m),2.66(2H,t,J=7. m), 1.96 (2H, m), 2.66 (2H, t, J = 7.
2Hz),3.03(2H,bs),4.53(2H,t,J 2Hz), 3.03 (2H, bs), 4.53 (2H, t, J
=7.4Hz),7.56(1H,t,J=7.4Hz),7.6 = 7.4Hz), 7.56 (1H, t, J = 7.4Hz), 7.6
0(1H,t,J=7.5Hz),7.97(1H,s),8. 0 (1H, t, J = 7.5Hz), 7.97 (1H, s), 8.
02(1H,d,J=6.4Hz),8.04(1H,d,J= 02 (1H, d, J = 6.4Hz), 8.04 (1H, d, J =
6.4Hz) 6.4Hz)

【0081】(実施例17) 1−(4−アミノブチル)−1H−イミダゾ[4,5− [0081] (Example 17) 1- (4-aminobutyl)-1H-imidazo [4,5
c]キノリン−4−アミンの合成 1−(4−アミノブチル)−4−クロロ−1H−イミダゾ[4,5−c]キノリン40mg(0.146mmol)を耐圧鋼製反応管に入れ、メタノール8ml及び冷却下液体アンモニア4mlを加え、150℃に加熱して1晩撹拌した。 c] quinolin-4-1- (4-aminobutyl) amine 4-chloro -1H- imidazo [4,5-c] put quinoline 40mg of (0.146 mmol) in a pressure steel reaction tube, methanol 8ml and cooling under liquid ammonia 4ml was added and stirred overnight then heated to 0.99 ° C.. 反応液を減圧下濃縮し、残渣を少量の水に溶解し、 The reaction solution was concentrated under reduced pressure, the residue is dissolved in a small amount of water,
1N−水酸化ナトリウム水溶液0.5mlを加えた。 1N- was added aqueous sodium hydroxide 0.5 ml. 析出物を濾取しエタノールから再結晶して、1−(4−アミノブチル)−1H−イミダゾ[4,5−c]キノリン− Precipitate collected by filtration and recrystallized from ethanol, 1- (4-aminobutyl)-1H-imidazo [4,5-c] quinoline -
4−アミン14mg(0.0548mmol)を淡黄緑色結晶(mp:227〜230.5℃(分解))として得た。 4- amine 14mg (0.0548mmol) of pale green crystals: was obtained as (mp from 227 to 230.5 ° C. (dec.)).
このものの分光学的データは以下の通りである。 Spectroscopic data of the product are as follows.

【0082】IR(KBr)cm -1 :3340,318 [0082] IR (KBr) cm -1: 3340,318
0,1650,1530,1400 1 H−NMR(DMSO−d 6 )δ(ppm):1.30(2 0,1650,1530,1400 1 H-NMR (DMSO- d 6) δ (ppm): 1.30 (2
H,br),1.39(2H,m),1.89(2H, H, br), 1.39 (2H, m), 1.89 (2H,
m),2.55(2H,t,J=6.8Hz),4.59(2 m), 2.55 (2H, t, J = 6.8Hz), 4.59 (2
H,t,J=7.0Hz),6.56(2H,bs),7.26 H, t, J = 7.0Hz), 6.56 (2H, bs), 7.26
(1H,t,J=7.4Hz),7.44(1H,t,J=7. (1H, t, J = 7.4Hz), 7.44 (1H, t, J = 7.
7Hz),7.62(1H,d,J=8.0Hz),8.05 7Hz), 7.62 (1H, d, J = 8.0Hz), 8.05
(1H,d,J=8.0Hz),8.19(1H,s) (1H, d, J = 8.0Hz), 8.19 (1H, s)

【0083】(実施例18) 4−ベンジルアミノ−1−[4−(tert−ブトキシカル [0083] (Example 18) 4-benzylamino-1-[4- (tert Butokishikaru
ボニルアミノ)ブチル]−1H−イミダゾ[4,5− Boniruamino) butyl]-1H-imidazo [4,5
c]キノリンの合成 1−[4−(tert−ブトキシカルボニルアミノ)ブチル]−4−クロロ−1H−イミダゾ[4,5−c]キノリン70mg(0.187mmol)にベンジルアミン2mlを加え、150℃に加熱して3時間撹拌した。 c] Synthesis 1- [4- (tert- butoxycarbonylamino) quinoline-butyl] -4-chloro -1H- imidazo [4,5-c] benzylamine 2ml added quinoline 70mg (0.187mmol), 150 ℃ and stirred for 3 hours and heated to. 減圧下過剰のベンジルアミンを留去し、1N−塩酸及び食塩水を加え塩化メチレンで2回抽出した。 Was distilled off under reduced pressure excess benzylamine, and extracted twice with methylene chloride added 1N- hydrochloric acid and brine. 有機層を飽和炭酸水素ナトリウム水溶液で洗浄し、乾燥(Na 2 SO 4 )後、減圧下溶媒を留去した。 The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution, dried (Na 2 SO 4), the solvent was distilled off under reduced pressure. 残渣をシリカゲルカラムクロマトグラフィーに付し、クロロホルム−メタノール(15 The residue was subjected to silica gel column chromatography using chloroform - methanol (15
0:1v/v)溶出画分により、4−ベンジルアミノ−1 0: 1v / v) elution fraction, 4-benzylamino -1
−[4−(tert−ブトキシカルボニルアミノ)ブチル] - [4- (tert- butoxycarbonylamino) butyl]
−1H−イミダゾ[4,5−c]キノリン79mg(0.1 -1H- imidazo [4,5-c] quinoline 79 mg (0.1
77mmol)を白色粉末(mp:151〜153.5℃) 77 mmol) of a white powder (mp: 151~153.5 ℃)
として得た。 It was obtained as a. このものの分光学的データは以下の通りである。 Spectroscopic data of the product are as follows.

【0084】IR(KBr)cm -1 :3380,331 [0084] IR (KBr) cm -1: 3380,331
0,2930,1680,1595,1540,124 0,2930,1680,1595,1540,124
5,1160 1 H−NMR(CDCl 3 )δ(ppm):1.42(9H, 5,1160 1 H-NMR (CDCl 3 ) δ (ppm): 1.42 (9H,
s),1.58(2H,m),2.02(2H,m),3. s), 1.58 (2H, m), 2.02 (2H, m), 3.
18(2H,m),4.55(2H,t,J=7.4Hz), 18 (2H, m), 4.55 (2H, t, J = 7.4Hz),
4.55(1H,br),4.95(2H,d,J=5.6H 4.55 (1H, br), 4.95 (2H, d, J = 5.6H
z),6.03(1H,t,J=5.6Hz),7.23−7. z), 6.03 (1H, t, J = 5.6Hz), 7.23-7.
36(4H,m),7.47(2H,d,J=7.6Hz), 36 (4H, m), 7.47 (2H, d, J = 7.6Hz),
7.51(1H,t,J=7.8Hz),7.75(1H, 7.51 (1H, t, J = 7.8Hz), 7.75 (1H,
s),7.90(2H,d,J=8.0Hz) s), 7.90 (2H, d, J = 8.0Hz)

【0085】(実施例19) 1−(4−アミノブチル)−1H−イミダゾ[4,5− [0085] (Example 19) 1- (4-aminobutyl)-1H-imidazo [4,5
c]キノリン−4−アミンの合成 4−ベンジルアミノ−1−[4−(tert−ブトキシカルボニルアミノ)ブチル]−1H−イミダゾ[4,5− c] quinolin-4-amine 4-benzylamino-1-[4- (tert-butoxycarbonylamino) butyl]-1H-imidazo [4,5
c]キノリン67mg(0.150mmol)をギ酸5mlに溶解し、水酸化パラジウム−炭素[20%]0.15gを加え2日間加熱還流した。 c] quinoline 67mg of (0.150 mmol) was dissolved in formic acid 5 ml, palladium hydroxide - carbon [20%] was heated for 2 days under reflux 0.15 g. 反応液を濾過し、減圧下溶媒を留去した後残渣をシリカゲルカラムクロマトグラフィーに付し、クロロホルム−メタノール−32%酢酸(6:3:1v/v)溶出画分より目的物の酢酸塩を得、 The reaction was filtered, the residue was subjected after solvent was evaporated under reduced pressure to silica gel column chromatography using chloroform - methanol -32% acetic acid acetate (6:: 3 1v / v) intended product from elution fractions obtained,
アルカリ処理して固体を濾取し、1−(4−アミノブチル)−1H−イミダゾ[4,5−c]キノリン−4−アミン14mg(0.0548mmol)を微褐色粉末として得た。 And alkali treatment the solid collected by filtration to give 1- (4-aminobutyl)-1H-imidazo [4,5-c] quinolin-4-amine 14mg of (0.0548Mmol) as a slightly brown powder. このものの物性値は、実施例17の化合物と一致した。 The property values ​​of the compound was consistent with the compound of Example 17.

【0086】(実施例20) 1−[3−[[4−(ジフェニルメトキシ)−1−ピペ [0086] (Example 20) 1- [3 - [[4- (diphenyl-methoxy) -1-piperazinyl
リジンアセチル]アミノ]プロピル]−1H−イミダゾ Lysine acetyl] amino] propyl]-1H-imidazo
[4,5−c]キノリン−4−アミンの合成 a) クロロ酢酸0.10g(1.1mmol)及び1−(3 [4,5-c] quinolin-4-a) Synthesis of chloroacetic acid 0.10g of the amine (1.1 mmol) and 1- (3
−アミノプロピル)−1H−イミダゾ[4,5−c]キノリン−4−アミン0.24g(1mmol)をN,N−ジメチルホルムアミド30mlに懸濁し、1−(3−ジメチルアミノプロピル)−3−エチルカルボジイミド・塩酸塩(EDCI)0.29g(1.5mmol)を加えて室温で1 - aminopropyl)-1H-imidazo [4,5-c] quinolin-4-amine 0.24g of (1 mmol) was suspended in N, N- dimethylformamide 30ml, 1- (3- dimethylaminopropyl) -3- 1 at room temperature was added ethyl carbodiimide hydrochloride (EDCI) 0.29g (1.5mmol)
晩撹拌した。 And the mixture was stirred evening. 反応液に水を加え、クロロホルムで1回、 Water was added to the reaction solution, once with chloroform,
クロロホルム−メタノール(10:1v/v)で3回抽出した。 Chloroform - methanol: extracted 3 times with (10 1v / v). 有機層を食塩水で洗浄し、乾燥(Na 2 SO 4 The organic layer was washed with brine, dried (Na 2 SO 4)
後、減圧下溶媒を留去して、1−[3−[(クロロアセチル)アミノ]プロピル]−1H−イミダゾ[4,5− After, the solvent was distilled off under reduced pressure, 1- [3 - [(chloroacetyl) amino] propyl]-1H-imidazo [4,5
c]キノリン−4−アミンの粗生成物を得た。 To give the crude product c] quinolin-4-amine. この化合物は不安定なため、精製せずに次の反応に用いた。 Since this compound is unstable, it was used in the next reaction without purification.

【0087】b) a)で得られた1−[3−[(クロロアセチル)アミノ]プロピル]−1H−イミダゾ[4,5−c]キノリン−4−アミンの粗生成物をエタノール5mlに溶解し、4−(ジフェニルメトキシ)ピペリジン・塩酸塩0.14g(0.472mmol)及び炭酸水素ナトリウム48mg(0.566mmol)を加え、7時間加熱還流した。 [0087] b) obtained in a) 1-- dissolved [3 [(chloroacetyl) amino] propyl]-1H-imidazo [4,5-c] crude quinolin-4-amine in ethanol 5ml and, 4- (diphenylmethoxy) piperidine hydrochloride 0.14 g (0.472 mmol) and sodium bicarbonate 48 mg (0.566 mmol) and the mixture was heated under reflux for 7 hours. 不溶物を濾過して除き、濾液を減圧下濃縮した。 The insoluble was filtered, and the filtrate was concentrated under reduced pressure. 残渣をシリカゲルカラムクロマトグラフィーに付し、クロロホルム−メタノール(30:1〜20: The residue was subjected to silica gel column chromatography using chloroform - methanol (30: 1 to 20:
1v/v)溶出画分により、1−[3−[[4−(ジフェニルメトキシ)−1−ピペリジンアセチル]アミノ]プロピル]−1H−イミダゾ[4,5−c]キノリン−4 By 1 v / v) eluate fractions, 1- [3 - [[4- (diphenyl-methoxy) -1-piperidine acetyl] amino] propyl]-1H-imidazo [4,5-c] quinoline -4
−アミン20mg(0.0364mmol)を淡黄色非晶質として得た。 - give amine 20mg of (0.0364mmol) as a pale yellow amorphous. このものの分光学的データは以下の通りである。 Spectroscopic data of the product are as follows.

【0088】IR(KBr)cm -1 :3320,165 [0088] IR (KBr) cm -1: 3320,165
0,1525,1070,700 1 H−NMR(CDCl 3 )δ(ppm):1.70(2H, 0,1525,1070,700 1 H-NMR (CDCl 3 ) δ (ppm): 1.70 (2H,
m),1.86(2H,m),2.19(2H,m),2. m), 1.86 (2H, m), 2.19 (2H, m), 2.
27(2H,t,J=10.4Hz),2.74(2H, 27 (2H, t, J = 10.4Hz), 2.74 (2H,
m),2.98(2H,s),3.39(2H,q,J=6. m), 2.98 (2H, s), 3.39 (2H, q, J = 6.
5Hz),3.45(1H,m),4.54(2H,t,J= 5Hz), 3.45 (1H, m), 4.54 (2H, t, J =
7.0Hz),5.49(1H,s),5.60(2H,b 7.0Hz), 5.49 (1H, s), 5.60 (2H, b
s),7.21−7.36(10H,m),7.38(1 s), 7.21-7.36 (10H, m), 7.38 (1
H,t,J=7.2Hz),7.51(1H,t,J=7.7H H, t, J = 7.2Hz), 7.51 (1H, t, J = 7.7H
z),7.82(1H,d,J=8.2Hz),7.89(1 z), 7.82 (1H, d, J = 8.2Hz), 7.89 (1
H,s),7.90(1H,d,J=8.0Hz) H, s), 7.90 (1H, d, J = 8.0Hz)

【0089】(実施例21) 1−[3−(アクリルアミノ)プロピル]−1H−イミ [0089] (Example 21) 1- [3- (acylamino) propyl]-1H-Imi
ダゾ[4,5−c]キノリン−4−アミンの合成 1−(3−アミノプロピル)−1H−イミダゾ[4,5 Dazo [4,5-c] quinolin-4-amine 1- (3-aminopropyl)-1H-imidazo [4,5
−c]キノリン−4−アミン0.24g(1mmol)をN, -c] quinolin-4-amine 0.24g of (1 mmol) N,
N−ジメチルホルムアミド30mlに懸濁し、アクリル酸75μl(1.1mmol)及び1−(3−ジメチルアミノプロピル)−3−エチルカルボジイミド・塩酸塩0.29 Were suspended in N- dimethylformamide 30 ml, 75 [mu] l of acrylic acid (1.1 mmol) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride 0.29
g(1.5mmol)を加え室温で3.5時間撹拌した。 g of (1.5 mmol) was added and stirred at room temperature for 3.5 hours. 反応液に水を加え、クロロホルムで1回、クロロホルム−メタノール(10:1v/v)で4回抽出した。 Water was added to the reaction solution, once with chloroform, chloroform - methanol: extracted 4 times with (10 1v / v). 有機層を食塩水で洗浄し、乾燥(Na 2 SO 4 )後、減圧下溶媒を留去した。 The organic layer was washed with brine, dried (Na 2 SO 4), the solvent was distilled off under reduced pressure. 残渣をシリカゲルカラムクロマトグラフィーに付し、クロロホルム−メタノール(8:1v/v)溶出画分により目的物を集め、溶媒留去後少量のクロロホルムでトリチュレートして濾取し、1−[3−(アクリルアミノ)プロピル]−1H−イミダゾ[4,5−c]キノリン−4−アミン0.14g(0.474mmol)を微黄色粉末(mp:173〜175℃)として得た。 The residue was subjected to silica gel column chromatography using chloroform - methanol (8: 1v / v) The target product was collected by elution fractions were collected by filtration and triturated with a small amount of chloroform and then the solvent was distilled off, 1- [3- ( acrylic amino) propyl]-1H-imidazo [4,5-c] quinolin-4-amine 0.14g of (0.474 mmol) slightly yellow powder (mp: 173-175 ° C.) and was obtained. このものの分光学的データは以下の通りである。 Spectroscopic data of the product are as follows.

【0090】IR(KBr)cm -1 :3330,320 [0090] IR (KBr) cm -1: 3330,320
0,1630,1525 1 H−NMR(CDCl 3 )δ(ppm):2.25(2H, 0,1630,1525 1 H-NMR (CDCl 3 ) δ (ppm): 2.25 (2H,
m),3.47(2H,q,J=6.5Hz),4.61(2 m), 3.47 (2H, q, J = 6.5Hz), 4.61 (2
H,t,J=7.0Hz),5.47(2H,bs),5.7 H, t, J = 7.0Hz), 5.47 (2H, bs), 5.7
(1H,br),5.71(1H,d,J=10.4Hz), (1H, br), 5.71 (1H, d, J = 10.4Hz),
6.09(1H,dd,J=16.8,10.4Hz),6.3 6.09 (1H, dd, J = 16.8,10.4Hz), 6.3
2(1H,d,J=16.8Hz),7.33(1H,t,J= 2 (1H, d, J = 16.8Hz), 7.33 (1H, t, J =
7.6Hz),7.53(1H,t,J=7.8Hz),7.83 7.6Hz), 7.53 (1H, t, J = 7.8Hz), 7.83
(1H,d,J=8.4Hz),7.92(1H,s),7.9 (1H, d, J = 8.4Hz), 7.92 (1H, s), 7.9
3(1H,d,J=8.2Hz) 3 (1H, d, J = 8.2Hz)

【0091】(実施例22) 1−[3−[[4−(ジフェニルメトキシ)−1−ピペ [0091] (Example 22) 1- [3 - [[4- (diphenyl-methoxy) -1-piperazinyl
リジンプロパノイル]アミノ]プロピル]−1H−イミ Lysine propanoylamino] amino] propyl]-1H-Imi
ダゾ[4,5−c]キノリン−4−アミンの合成 1−[3−(アクリルアミノ)プロピル]−1H−イミダゾ[4,5−c]キノリン−4−アミン0.12g Dazo [4,5-c] quinolin-4-amine 1- [3- (acylamino) propyl]-1H-imidazo [4,5-c] quinolin-4-amine 0.12g
(0.406mmol)をエタノール10mlに溶解し、4− The (0.406 mmol) was dissolved in ethanol 10 ml, 4-
(ジフェニルメトキシ)ピペリジン・塩酸塩0.13g (Diphenyl-methoxy) piperidine hydrochloride 0.13g
(0.427mmol)及び炭酸水素ナトリウム38mg(0. (0.427 mmol) and sodium bicarbonate 38 mg (0.
447mmol)を加え、1晩加熱還流した。 447Mmol) and the mixture was heated under reflux overnight. 不溶物を濾過して除き、濾液を濃縮し、残渣をアルミナカラムクロマトグラフィーに付した。 The insoluble was filtered, the filtrate was concentrated and residue was subjected to alumina column chromatography. クロロホルム−メタノール(4 Chloroform - methanol (4
0:1v/v)溶出画分により目的物を集め、溶媒留去後エーテルでトリチュレートして濾取し、1−[3− 0: 1v / v) The target product was collected by elution fractions were collected by filtration and triturated with evaporated after ether, 1- [3-
[[4−(ジフェニルメトキシ)−1−ピペリジンプロパノイル]アミノ]プロピル]−1H−イミダゾ[4, [[4- (diphenyl-methoxy) -1-piperidine propanoyl] amino] propyl]-1H-imidazo [4,
5−c]キノリン−4−アミン75mg(0.133mmo 5-c] quinolin-4-amine 75mg (0.133mmo
l)を微黄色粉末(mp:178〜182℃)として得た。 l) The fine yellow powder (mp: 178~182 ℃) and was obtained. このものの分光学的データは以下の通りである。 Spectroscopic data of the product are as follows.

【0092】IR(KBr)cm -1 :3330,320 [0092] IR (KBr) cm -1: 3330,320
0,1640,1530,1080,700 1 H−NMR(CDCl 3 )δ(ppm):1.61(2H, 0,1640,1530,1080,700 1 H-NMR (CDCl 3 ) δ (ppm): 1.61 (2H,
m),1.84(2H,m),2.13(2H,m),2. m), 1.84 (2H, m), 2.13 (2H, m), 2.
20(2H,m),2.38(2H,t,J=6.0Hz), 20 (2H, m), 2.38 (2H, t, J = 6.0Hz),
2.54(2H,t,J=6.0Hz),2.74(2H, 2.54 (2H, t, J = 6.0Hz), 2.74 (2H,
m),5.48(1H,s),7.21−7.54(11 m), 5.48 (1H, s), 7.21-7.54 (11
H,m),7.51(1H,t,J=7.7Hz),7.83 H, m), 7.51 (1H, t, J = 7.7Hz), 7.83
(1H,d,J=8.4Hz),7.91(1H,s),7.9 (1H, d, J = 8.4Hz), 7.91 (1H, s), 7.9
4(1H,d,J=8.4Hz),8.68(1H,br) 4 (1H, d, J = 8.4Hz), 8.68 (1H, br)

【0093】(実施例23) 1−[4−(アクリルアミノ)ブチル]−1H−イミダ [0093] (Example 23) 1- [4- (acylamino) butyl]-1H-Imida
ゾ[4,5−c]キノリン−4−アミンの合成 1−(4−アミノブチル)−1H−イミダゾ[4,5− Zone [4,5-c] quinolin-4-amine 1- (4-aminobutyl)-1H-imidazo [4,5
c]キノリン−4−アミン0.26g(1mmol)をN,N c] quinolin-4-amine 0.26g of (1mmol) N, N
−ジメチルホルムアミド30mlに懸濁し、アクリル酸7 - it was suspended in dimethyl formamide 30 ml, acrylic acid 7
5μl(1.1mmol)及び1−(3−ジメチルアミノプロピル)−3−エチルカルボジイミド・塩酸塩0.29g 5 [mu] l (1.1 mmol) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride 0.29g
(1.5mmol)を加え室温で1晩撹拌した。 (1.5 mmol) and the mixture was stirred overnight at room temperature. 反応液に水を加え、クロロホルムで1回さらにクロロホルム−メタノール(10:1v/v)で4回抽出した。 Water was added to the reaction solution, further chloroform once with chloroform - methanol: extracted 4 times with (10 1v / v). 有機層を食塩水で洗浄し、乾燥(Na 2 SO 4 )後、減圧下溶媒を留去した。 The organic layer was washed with brine, dried (Na 2 SO 4), the solvent was distilled off under reduced pressure. 残渣をシリカゲルカラムクロマトグラフィーに付し、クロロホルム−メタノール(10:1〜8:1v/ The residue was subjected to silica gel column chromatography using chloroform - methanol (10: 1~8: 1v /
v)溶出画分により、1−[4−(アクリルアミノ)ブチル]−1H−イミダゾ[4,5−c]キノリン−4− v) The elution fraction, 1- [4- (acylamino) butyl]-1H-imidazo [4,5-c] quinolin-4
アミン90mg(0.291mmol)を淡黄色粉末(mp:176〜178℃)として得た。 Amine 90 mg (0.291 mmol) of a pale yellow powder (mp: 176~178 ℃) and was obtained. このものの分光学的データは以下の通りである。 Spectroscopic data of the product are as follows.

【0094】IR(KBr)cm -1 :3320,320 [0094] IR (KBr) cm -1: 3320,320
0,1640,1530 1 H−NMR(CDCl 3 )δ(ppm):1.65(2H, 0,1640,1530 1 H-NMR (CDCl 3 ) δ (ppm): 1.65 (2H,
m),2.04(2H,m),3.40(2H,q,J=6. m), 2.04 (2H, m), 3.40 (2H, q, J = 6.
7Hz),4.58(2H,t,J=7.2Hz),5.50 7Hz), 4.58 (2H, t, J = 7.2Hz), 5.50
(2H,br),5.52(1H,br),5.65(1 (2H, br), 5.52 (1H, br), 5.65 (1
H,d,J=10.2Hz),6.03(1H,dd,J=16. H, d, J = 10.2Hz), 6.03 (1H, dd, J = 16.
8,10.4Hz),6.27(1H,d,J=17.0H 8,10.4Hz), 6.27 (1H, d, J = 17.0H
z),7.33(1H,t,J=7.6Hz),7.53(1 z), 7.33 (1H, t, J = 7.6Hz), 7.53 (1
H,t,J=7.7Hz),7.83(1H,s),7.83 H, t, J = 7.7Hz), 7.83 (1H, s), 7.83
(1H,d,J=8.6Hz),7.93(1H,d,J=8. (1H, d, J = 8.6Hz), 7.93 (1H, d, J = 8.
4Hz) 4Hz)

【0095】(実施例24) 1−[4−[[4−(ジフェニルメトキシ)−1−ピペ [0095] (Example 24) 1- [4 - [[4- (diphenyl-methoxy) -1-piperazinyl
リジンプロパノイル]アミノ]ブチル]−1H−イミダ Lysine propanoylamino] amino] butyl]-1H-Imida
ゾ[4,5−c]キノリン−4−アミンの合成 1−[4−(アクリルアミノ)ブチル]−1H−イミダゾ[4,5−c]キノリン−4−アミン85mg(0.27 Zone [4,5-c] 1- quinolin-4-amine [4- (acylamino) butyl]-1H-imidazo [4,5-c] quinolin-4-amine 85 mg (0.27
5mmol)をエタノール7mlに溶解し、4−(ジフェニルメトキシ)ピペリジン・塩酸塩88mg(0.288mmo The 5 mmol) was dissolved in ethanol 7 ml, 4-(diphenylmethoxy) piperidine hydrochloride 88mg (0.288mmo
l)及び炭酸水素ナトリウム25mg(0.302mmol)を加え、1晩加熱還流した。 l) and sodium bicarbonate 25mg and (0.302 mmol), and the mixture was heated under reflux overnight. 不溶物を濾過して除き、濾液を濃縮し、残渣をアルミナカラムクロマトグラフィーに付した。 The insoluble was filtered, the filtrate was concentrated and residue was subjected to alumina column chromatography. クロロホルム−メタノール(50:1v/v)溶出画分により目的物を集め、溶媒留去後エーテルでトリチュレートして濾取し、1−[4−[[4−(ジフェニルメトキシ)−1−ピペリジンプロパノイル]アミノ] Chloroform - methanol (50: 1 v / v) The target product was collected by elution fractions were collected by filtration and triturated with evaporated after ether, 1- [4 - [[4- (diphenyl-methoxy) -1-piperidinepropanoic noil] amino]
ブチル]−1H−イミダゾ[4,5−c]キノリン−4 Butyl]-1H-imidazo [4,5-c] quinoline -4
−アミン48mg(0.0832mmol)を白色粉末(m - White amine 48mg (0.0832mmol) powder (m
p:174〜176℃)として得た。 p: 174~176 ℃) and was obtained. このものの分光学的データは以下の通りである。 Spectroscopic data of the product are as follows.

【0096】IR(KBr)cm -1 :3370,310 [0096] IR (KBr) cm -1: 3370,310
0,2950,1640,1530,1090,75 0,2950,1640,1530,1090,75
0,705 1 H−NMR(CDCl 3 )δ(ppm):1.48−1.6 0,705 1 H-NMR (CDCl 3 ) δ (ppm): 1.48-1.6
3(4H,m),1.77(2H,m),2.01(4H, 3 (4H, m), 1.77 (2H, m), 2.01 (4H,
m),2.30(2H,t,J=6.0Hz),2.44(2 m), 2.30 (2H, t, J = 6.0Hz), 2.44 (2
H,t,J=6.0Hz),2.63(2H,m),3.28 H, t, J = 6.0Hz), 2.63 (2H, m), 3.28
(2H,q,J=6.5Hz),3.37(1H,m),4.5 (2H, q, J = 6.5Hz), 3.37 (1H, m), 4.5
6(2H,t,J=7.2Hz),5.42(2H,bs), 6 (2H, t, J = 7.2Hz), 5.42 (2H, bs),
5.47(1H,s),7.21−7.35(11H, 5.47 (1H, s), 7.21-7.35 (11H,
m),7.51(1H,t,J=7.7Hz),7.81(1 m), 7.51 (1H, t, J = 7.7Hz), 7.81 (1
H,s),7.82(1H,d,J=8.0Hz),7.92 H, s), 7.82 (1H, d, J = 8.0Hz), 7.92
(1H,d,J=8.0Hz),8.58(1H,br) (1H, d, J = 8.0Hz), 8.58 (1H, br)

【0097】(実施例25) 1−[3−[[4−[(4−クロロフェニル)フェニル [0097] (Example 25) 1- [3 - [[4 - [(4-chlorophenyl) phenyl
メトキシ]−1−ピペリジンプロパノイル]アミノ]プ Methoxy] -1-piperidine propanoylamino] amino] flop
ロピル]−1H−イミダゾ[4,5−c]キノリン−4 Propyl]-1H-imidazo [4,5-c] quinoline -4
−アミンの合成 1−[3−(アクリルアミノ)プロピル]−1H−イミダゾ[4,5−c]キノリン−4−アミン50mg(0.1 - Synthesis of amine 1- [3- (acylamino) propyl]-1H-imidazo [4,5-c] quinolin-4-amine 50 mg (0.1
69mmol)をエタノール5mlに溶解し、4−[(4−クロロフェニル)フェニルメトキシ]ピペリジン・塩酸塩60mg(0.178mmol)及び炭酸水素ナトリウム16m The 69 mmol) was dissolved in ethanol 5ml, 4 - [(4- chlorophenyl) phenylmethoxy] piperidine hydrochloride 60 mg (0.178 mmol) and sodium bicarbonate 16m
g(0.186mmol)を加えて1日加熱還流した。 In addition to the g (0.186mmol) was heated to reflux for 1 day. 不溶物を濾過した後、溶媒を留去し、残渣をアルミナカラムクロマトグラフィーに付した。 After the insolubles were filtered, the solvent was evaporated and the residue was subjected to alumina column chromatography. クロロホルム−メタノール(40:1v/v)溶出画分により目的物を集め、溶媒留去後エーテルでトリチュレートして濾取し、1−[3− Chloroform - methanol (40: 1v / v) The target product was collected by elution fractions were collected by filtration and triturated with evaporated after ether, 1- [3-
[[4−[(4−クロロフェニル)フェニルメトキシ] [[4 - [(4-chlorophenyl) phenylmethoxy]
−1−ピペリジンプロパノイル]アミノ]プロピル]− -1-piperidine propanoylamino] amino] propyl] -
1H−イミダゾ[4,5−c]キノリン−4−アミン4 1H- imidazo [4,5-c] quinolin-4-amine 4
0mg(0.0669mmol)を白色粉末(mp:170〜 0mg (0.0669mmol) of a white powder (mp: 170 to
172.5℃)として得た。 172.5 ℃) and was obtained. このものの分光学的データは以下の通りである。 Spectroscopic data of the product are as follows.

【0098】IR(KBr)cm -1 :3320,320 [0098] IR (KBr) cm -1: 3320,320
0,2940,1640,1530,1080 1 H−NMR(CDCl 3 )δ(ppm):1.59(2H, 0,2940,1640,1530,1080 1 H-NMR (CDCl 3 ) δ (ppm): 1.59 (2H,
m),1.81(2H,m),2.13(2H,m),2. m), 1.81 (2H, m), 2.13 (2H, m), 2.
20(2H,m),2.37(2H,t,J=6.0Hz), 20 (2H, m), 2.37 (2H, t, J = 6.0Hz),
2.54(2H,t,J=5.8Hz),2.72(2H, 2.54 (2H, t, J = 5.8Hz), 2.72 (2H,
m),3.37(2H,q,J=6.4Hz),3.40(1 m), 3.37 (2H, q, J = 6.4Hz), 3.40 (1
H,m),4.59(2H,t,J=7.0Hz),5.43 H, m), 4.59 (2H, t, J = 7.0Hz), 5.43
(1H,s),5.45(2H,bs),7.23−7.3 (1H, s), 5.45 (2H, bs), 7.23-7.3
4(10H,m),7.51(1H,t,J=7.6Hz), 4 (10H, m), 7.51 (1H, t, J = 7.6Hz),
7.83(1H,d,J=8.4Hz),7.91(1H, 7.83 (1H, d, J = 8.4Hz), 7.91 (1H,
s),7.94(1H,d,J=8.4Hz),8.59(1 s), 7.94 (1H, d, J = 8.4Hz), 8.59 (1
H,br) H, br)

【0099】(実施例26) 1−[3−(4−クロロルブタノイルアミノ)プロピ [0099] (Example 26) 1- [3- (4-chloro-Le butanoylamino) prop
ル]−1H−イミダゾ[4,5−c]キノリン−4−ア Le]-1H-imidazo [4,5-c] quinolin-4-A
ミンの合成 1−(3−アミノプロピル)−1H−イミダゾ[4,5 Min 1- (3-aminopropyl) of -1H- imidazo [4,5
−c]キノリン−4−アミン0.24g(1mmol)をN, -c] quinolin-4-amine 0.24g of (1 mmol) N,
N−ジメチルホルムアミド30mlに懸濁し、4−クロロ酪酸0.11ml(1.1mmol)及び1−(3−ジメチルアミノプロピル)−3−エチルカルボジイミド・塩酸塩0.29g(1.5mmol)を加え室温で1晩撹拌した。 Rt N- suspended in dimethylformamide 30 ml, 4-chloro-butyric acid 0.11 ml (1.1 mmol) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride 0.29 g (1.5 mmol) was added in the mixture was stirred overnight. 反応液に食塩水を加え、酢酸エチルで3回抽出した。 The brine was added to the reaction solution, and extracted three times with ethyl acetate. 有機層を食塩水で洗浄し、乾燥(Na 2 SO 4 )後、減圧下溶媒を留去した。 The organic layer was washed with brine, dried (Na 2 SO 4), the solvent was distilled off under reduced pressure. 残渣をエーテルさらに水でトリチュレートして濾取し、1−[3−(4−クロロルブタノイルアミノ)プロピル]−1H−イミダゾ[4,5−c]キノリン−4−アミン30mg(0.0867mmol)を淡褐色粉末として得た。 The residue was collected by filtration and triturated with addition of water ether, 1- [3- (4-chloro-Le butanoylamino) propyl]-1H-imidazo [4,5-c] quinolin-4-amine 30 mg (0.0867Mmol ) as a pale brown powder. このものの分光学的データは以下の通りである。 Spectroscopic data of the product are as follows.

【0100】IR(KBr)cm -1 :3330,320 [0100] IR (KBr) cm -1: 3330,320
0,1650,1530 1 H−NMR(DMSO-d 6 )δ(ppm):1.91−2. 0,1650,1530 1 H-NMR (DMSO- d 6) δ (ppm): 1.91-2.
04(4H,m),2.26(2H,t,J=7.4Hz), 04 (4H, m), 2.26 (2H, t, J = 7.4Hz),
3.12(2H,q,J=6.2Hz),3.64(2H,t, 3.12 (2H, q, J = 6.2Hz), 3.64 (2H, t,
J=6.6Hz),4.59(2H,t,J=6.8Hz),6. J = 6.6Hz), 4.59 (2H, t, J = 6.8Hz), 6.
58(2H,br),7.26(1H,t,J=7.4H 58 (2H, br), 7.26 (1H, t, J = 7.4H
z),7.45(1H,t,J=7.8Hz),7.62(1 z), 7.45 (1H, t, J = 7.8Hz), 7.62 (1
H,d,J=8.0Hz),8.03(1H,d,J=7.6H H, d, J = 8.0Hz), 8.03 (1H, d, J = 7.6H
z),8.05(1H,br),8.20(1H,s) z), 8.05 (1H, br), 8.20 (1H, s)

【0101】(実施例27) 1−[3−[[4−(ジフェニルメトキシ)−1−ピペ [0102] (Example 27) 1- [3 - [[4- (diphenyl-methoxy) -1-piperazinyl
リジンブタノイル]アミノ]プロピル]−1H−イミダ Lysine butanoyl] amino] propyl]-1H-Imida
ゾ[4,5−c]キノリン−4−アミンの合成 1−[3−(4−クロロルブタノイルアミノ)プロピル]−1H−イミダゾ[4,5−c]キノリン−4−アミン25mg(0.0722mmol)、4−(ジフェニルメトキシ)ピペリジン・塩酸塩44mg(0.144mmol) Zone [4,5-c] quinolin-4-amine 1- [3- (4-chloro-Le butanoylamino) propyl]-1H-imidazo [4,5-c] quinolin-4-amine 25 mg (0 .0722mmol), 4- (diphenylmethoxy) piperidine hydrochloride 44 mg (0.144 mmol)
及び炭酸カリウム40mg(0.289mmol)をN,N−ジメチルホルムアミド3ml中で、100℃に加熱して8時間撹拌した。 And potassium carbonate 40mg (0.289mmol) N, N- dimethylformamide 3 ml, and stirred for 8 hours by heating to 100 ° C.. 反応液に水を加え、クロロホルムで2回抽出し、乾燥(Na 2 SO 4 )後、減圧下溶媒を留去した。 Water was added to the reaction solution, and extracted twice with chloroform, dried (Na 2 SO 4), the solvent was distilled off under reduced pressure.
残渣をアルミナカラムクロマトグラフィーに付し、クロロホルム−メタノール(150:1〜70:1v/v)溶出画分により目的物を集め、溶媒留去後エーテルでトリチュレートして、1−[3−[[4−(ジフェニルメトキシ)−1−ピペリジンブタノイル]アミノ]プロピル]−1H−イミダゾ[4,5−c]キノリン−4−アミン15mg(0.0260mmol)を白色粉末(mp:1 The residue was subjected to alumina column chromatography, chloroform - methanol (150: 1~70: 1v / v) The target product was collected by elution fractions and triturated with evaporated after ether, 1- [3 - [[ 4- (diphenyl-methoxy) -1-piperidine butanoyl] amino] propyl]-1H-imidazo [4,5-c] white powder quinolin-4-amine 15mg (0.0260mmol) (mp: 1
58〜162.5℃)として得た。 58~162.5 ℃) and was obtained. このものの分光学的データは以下の通りである。 Spectroscopic data of the product are as follows.

【0102】IR(KBr)cm -1 :3200,164 [0102] IR (KBr) cm -1: 3200,164
0,1530,1070,700 1 H−NMR(CDCl 3 )δ(ppm):1.62(2H, 0,1530,1070,700 1 H-NMR (CDCl 3 ) δ (ppm): 1.62 (2H,
m),1.77(4H,m),2.10(2H,m),2. m), 1.77 (4H, m), 2.10 (2H, m), 2.
19(2H,m),2.29(2H,t,J=7.0Hz), 19 (2H, m), 2.29 (2H, t, J = 7.0Hz),
2.34(2H,t,J=6.4Hz),2.69(2H, 2.34 (2H, t, J = 6.4Hz), 2.69 (2H,
m),3.35(2H,q,J=6.5Hz),3.40(1 m), 3.35 (2H, q, J = 6.5Hz), 3.40 (1
H,m),4.58(2H,t,J=7.0Hz),5.45 H, m), 4.58 (2H, t, J = 7.0Hz), 5.45
(2H,bs),5.47(1H,s),7.19−7.3 (2H, bs), 5.47 (1H, s), 7.19-7.3
4(11H,m),7.51(1H,t,J=7.7Hz), 4 (11H, m), 7.51 (1H, t, J = 7.7Hz),
7.82(1H,t,J=8.4Hz),7.92(1H, 7.82 (1H, t, J = 8.4Hz), 7.92 (1H,
s),7.93(1H,d,J=8.2Hz) s), 7.93 (1H, d, J = 8.2Hz)

【0103】(実施例28) 1−[3−(5−クロロルペンタノイルアミノ)プロピ [0103] (Example 28) 1- [3- (5-chloro-Le pentanoylamino) prop
ル]−1H−イミダゾ[4,5−c]キノリン−4−ア Le]-1H-imidazo [4,5-c] quinolin-4-A
ミンの合成 1−(3−アミノプロピル)−1H−イミダゾ[4,5 Min 1- (3-aminopropyl) of -1H- imidazo [4,5
−c]キノリン−4−アミン0.32g(1.33mmol) -c] quinolin-4-amine 0.32g (1.33mmol)
をN,N−ジメチルホルムアミド40mlに懸濁し、5− The N, was suspended in N- dimethylformamide 40 ml, 5-
クロロ吉草酸0.15ml(1.46mmol)及び1−(3− Chloro valerate 0.15 ml (1.46 mmol) and 1- (3
ジメチルアミノプロピル)−3−エチルカルボジイミド・塩酸塩0.38g(1.99mmol)を加え室温で1晩撹拌した。 Dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride 0.38g of (1.99 mmol) was added and stirred overnight at room temperature. 反応液に水を加え、酢酸エチルで2回さらにクロロホルム−メタノール(10:1v/v)で2回抽出した。 Water was added to the reaction solution, 2 times more chloroform ethyl acetate - methanol: was extracted twice with (10 1v / v). 有機層を食塩水で洗浄し、乾燥(Na 2 SO 4 )後、 The organic layer was washed with brine, dried (Na 2 SO 4),
溶媒を減圧下留去した。 The solvent was distilled off under reduced pressure. 残渣をエーテルでトリチュレートして濾取し、1−[3−(5−クロロルペンタノイルアミノ)プロピル]−1H−イミダゾ[4,5−c]キノリン−4−アミン0.16g(0.445mmol)を淡褐色粉末として得た。 The residue was triturated with ether and collected by filtration to give 1- [3- (5-chloro-Le pentanoylamino) propyl]-1H-imidazo [4,5-c] quinolin-4-amine 0.16 g (0.445 mmol ) as a pale brown powder. このものの分光学的データは以下の通りである。 Spectroscopic data of the product are as follows.

【0104】IR(KBr)cm -1 :3470,329 [0104] IR (KBr) cm -1: 3470,329
0,1650,1525,1395 1 H−NMR(DMSO-d 6 )δ(ppm):1.62(2 0,1650,1525,1395 1 H-NMR (DMSO- d 6) δ (ppm): 1.62 (2
H,m),1.70(2H,m),2.00(2H,t,J= H, m), 1.70 (2H, m), 2.00 (2H, t, J =
7.0Hz),2.12(2H,t,J=7.4Hz),3.12 7.0Hz), 2.12 (2H, t, J = 7.4Hz), 3.12
(2H,q,J=6.3Hz),3.62(2H,t,J=6. (2H, q, J = 6.3Hz), 3.62 (2H, t, J = 6.
2Hz),4.59(2H,t,J=6.9Hz),6.61 2Hz), 4.59 (2H, t, J = 6.9Hz), 6.61
(2H,bs),7.26(1H,t,J=7.6Hz),7. (2H, bs), 7.26 (1H, t, J = 7.6Hz), 7.
45(1H,t,J=7.8Hz),7.63(1H,d,J= 45 (1H, t, J = 7.8Hz), 7.63 (1H, d, J =
8.4Hz),7.98(1H,br),8.04(1H,d, 8.4Hz), 7.98 (1H, br), 8.04 (1H, d,
J=8.2Hz),8.21(1H,s) J = 8.2Hz), 8.21 (1H, s)

【0105】(実施例29) 1−[3−[[4−(ジフェニルメトキシ)−1−ピペ [0105] (Example 29) 1- [3 - [[4- (diphenyl-methoxy) -1-piperazinyl
リジンペンタノイル]アミノ]プロピル]−1H−イミ Lysine pentanoyl] amino] propyl]-1H-Imi
ダゾ[4,5−c]キノリン−4−アミンの合成 1−[3−(5−クロロルペンタノイルアミノ)プロピル]−1H−イミダゾ[4,5−c]キノリン−4−アミン50mg(0.139mmol)、4−(ジフェニルメトキシ)ピペリジン・塩酸塩42mg(0.139mmol)及び炭酸カリウム58mg(0.417mmol)をN,N−ジメチルホルムアミド3ml中で、100℃に加熱して7時間撹拌した。 Dazo [4,5-c] quinolin-4-amine 1- [3- (5-chloro-Le pentanoylamino) propyl]-1H-imidazo [4,5-c] quinolin-4-amine 50 mg (0 .139mmol), 4- a (diphenyl methoxy) piperidine hydrochloride 42 mg (0.139 mmol) and potassium carbonate 58 mg (0.417 mmol) N, in N- dimethylformamide 3 ml, and stirred and heated to 100 ° C. 7 hours . 不溶物を濾過して除き、溶媒を減圧下留去した。 The insoluble was filtered, and the solvent was evaporated under reduced pressure. 残渣をアルミナカラムクロマトグラフィーに付し、 The residue was subjected to alumina column chromatography,
クロロホルム−メタノール(100:1〜70:1v/ Chloroform - methanol (100: 1~70: 1v /
v)溶出画分により目的物を集め、溶媒留去後エーテルでトリチュレートして濾取し、1−[3−[[4−(ジフェニルメトキシ)−1−ピペリジンペンタノイル]アミノ]プロピル]−1H−イミダゾ[4,5−c]キノリン−4−アミン20mg(0.0338mmol)を白色粉末(mp:152〜154℃)として得た。 v) The target product was collected by elution fractions were collected by filtration and triturated with evaporated after ether, 1- [3 - [[4- (diphenyl-methoxy) -1-piperidine pentanoyl] amino] propyl]-1H - imidazo [4,5-c] quinolin-4-amine 20mg (0.0338mmol) of a white powder (mp: 152~154 ℃) and was obtained. このものの分光学的データは以下の通りである。 Spectroscopic data of the product are as follows.

【0106】IR(KBr)cm -1 :3330,320 [0106] IR (KBr) cm -1: 3330,320
0,2940,1640,1530,1070,700 1 H−NMR(CDCl 3 )δ(ppm):1.50(2H, 0,2940,1640,1530,1070,700 1 H-NMR (CDCl 3 ) δ (ppm): 1.50 (2H,
m),1.64(2H,m),1.69(2H,m),1.84 m), 1.64 (2H, m), 1.69 (2H, m), 1.84
(2H,m),2.08(2H,m),2.19(2H, (2H, m), 2.08 (2H, m), 2.19 (2H,
m),2.20(2H,t,J=7.4Hz),2.30(2 m), 2.20 (2H, t, J = 7.4Hz), 2.30 (2
H,t,J=7.2Hz),2.70(2H,m),3.36 H, t, J = 7.2Hz), 2.70 (2H, m), 3.36
(2H,q,J=6.5Hz),3.41(1H,m),4.5 (2H, q, J = 6.5Hz), 3.41 (1H, m), 4.5
7(2H,t,J=7.0Hz),5.45(2H,bs), 7 (2H, t, J = 7.0Hz), 5.45 (2H, bs),
5.49(1H,s),5.94(1H,t,J=5.8H 5.49 (1H, s), 5.94 (1H, t, J = 5.8H
z),7.21−7.37(11H,m),7.52(1H, z), 7.21-7.37 (11H, m), 7.52 (1H,
t,J=7.7Hz),7.83(1H,d,J=8.4Hz), t, J = 7.7Hz), 7.83 (1H, d, J = 8.4Hz),
7.90(1H,s),7.92(1H,d,J=8.4Hz) 7.90 (1H, s), 7.92 (1H, d, J = 8.4Hz)

【0107】(実施例30) 1−[3−(6−ブロモヘキサノイルアミノ)プロピ [0107] (Example 30) 1- [3- (6-bromo Hexanoylamino) prop
ル]−1H−イミダゾ[4,5−c]キノリン−4−ア Le]-1H-imidazo [4,5-c] quinolin-4-A
ミンの合成 1−(3−アミノプロピル)−1H−イミダゾ[4,5 Min 1- (3-aminopropyl) of -1H- imidazo [4,5
−c]キノリン−4−アミン0.24g(1mmol)をN, -c] quinolin-4-amine 0.24g of (1 mmol) N,
N−ジメチルホルムアミド30mlに懸濁し、6−ブロモカプロン酸0.21g(1.1mmol)及び1−(3−ジメチルアミノプロピル)−3−エチルカルボジイミド・塩酸塩0.29g(1.5mmol)を加え、室温で1晩撹拌した。 Were suspended in N- dimethylformamide 30 ml, 6- bromocaproate 0.21 g (1.1 mmol) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride 0.29 g (1.5 mmol) was added It was stirred overnight at room temperature. 反応液に食塩水を加え酢酸エチルで2回抽出し、乾燥(Na 2 SO 4 )後、減圧下溶媒を留去した。 To the reaction solution was extracted twice with brine was added ethyl acetate, dried (Na 2 SO 4), the solvent was distilled off under reduced pressure. 残渣をエーテルさらに水でトリチュレートして濾取し、1−[3 The residue was collected by filtration and triturated with addition of water ether, 1- [3
−(6−ブロモヘキサノイルアミノ)プロピル]−1H - (6-bromohexanoyl) propyl]-1H
−イミダゾ[4,5−c]キノリン−4−アミン50mg - imidazo [4,5-c] quinolin-4-amine 50mg
(0.120mmol)を灰白色粉末として得た。 The (0.120 mmol) was obtained as an off-white powder. このものの分光学的データは以下の通りである。 Spectroscopic data of the product are as follows.

【0108】IR(KBr)cm -1 :3330,320 [0108] IR (KBr) cm -1: 3330,320
0,1540,1540,1395 1 H−NMR(DMSO-d 6 )δ(ppm):1.36(2 0,1540,1540,1395 1 H-NMR (DMSO- d 6) δ (ppm): 1.36 (2
H,m),1.52(2H,m),1.70(2H,m), H, m), 1.52 (2H, m), 1.70 (2H, m),
2.00(2H,m),2.10(2H,t,J=7.0H 2.00 (2H, m), 2.10 (2H, t, J = 7.0H
z),3.11(2H,m),3.60(2H,t,J=6. z), 3.11 (2H, m), 3.60 (2H, t, J = 6.
8Hz),4.59(2H,t,J=7.0Hz),6.56 8Hz), 4.59 (2H, t, J = 7.0Hz), 6.56
(2H,bs),7.25(1H,t,J=7.4Hz),7. (2H, bs), 7.25 (1H, t, J = 7.4Hz), 7.
44(1H,t,J=7.4Hz),7.62(1H,d,J= 44 (1H, t, J = 7.4Hz), 7.62 (1H, d, J =
7.8Hz),7.95(1H,br),8.03(1H,d, 7.8Hz), 7.95 (1H, br), 8.03 (1H, d,
J=7.4Hz),8.20(1H,s) J = 7.4Hz), 8.20 (1H, s)

【0109】(実施例31) 1−[3−[[4−(ジフェニルメトキシ)−1−ピペ [0109] (Example 31) 1- [3 - [[4- (diphenyl-methoxy) -1-piperazinyl
リジンヘキサノイル]アミノ]プロピル]−1H−イミ Lysine hexanoyl] amino] propyl]-1H-Imi
ダゾ[4,5−c]キノリン−4−アミンの合成 1−[3−(6−ブロモヘキサノイルアミノ)プロピル]−1H−イミダゾ[4,5−c]キノリン−4−アミン45mg(0.108mmol)、4−(ジフェニルメトキシ)ピペリジン・塩酸塩65mg(0.215mmol)及び炭酸カリウム59mg(0.430mmol)をN,N−ジメチルホルムアミド3ml中、100℃に加熱して8時間撹拌した。 Dazo [4,5-c] quinolin-4-amine 1- [3- (6-bromohexanoyl) propyl]-1H-imidazo [4,5-c] quinolin-4-amine 45 mg (0. 108 mmol), 4-a (diphenyl methoxy) piperidine hydrochloride 65 mg (0.215 mmol) and potassium carbonate 59 mg (0.430 mmol) N, N- dimethylformamide 3 ml, was stirred and heated to 100 ° C. for 8 hours. 反応液に水を加えクロロホルムで2回抽出し、 Water was added to the reaction solution was extracted twice with chloroform,
乾燥(Na 2 SO 4 )後、減圧下溶媒を留去した。 After drying (Na 2 SO 4), the solvent was distilled off under reduced pressure. 残渣をアルミナカラムクロマトグラフィーに付し、クロロホルム−メタノール(150:1〜70:1v/v)溶出画分により目的物を集め、溶媒留去後エーテルでトリチュレートして濾取し、1−[3−[[4−(ジフェニルメトキシ)−1−ピペリジンヘキサノイル]アミノ]プロピル]−1H−イミダゾ[4,5−c]キノリン−4−アミン28mg(0.0462mmol)を微黄色粉末(mp: The residue was subjected to alumina column chromatography, chloroform - methanol (150: 1~70: 1v / v) The target product was collected by elution fractions were collected by filtration and triturated with evaporated after ether, 1- [3 - [[4- (diphenyl-methoxy) -1-piperidine-hexanoyl] amino] propyl]-1H-imidazo [4,5-c] quinolin-4-amine 28 mg (0.0462Mmol) pale yellow powder (mp:
151〜155℃)として得た。 151~155 ℃) and was obtained. このものの分光学的データは以下の通りである。 Spectroscopic data of the product are as follows.

【0110】IR(KBr)cm -1 :3330,294 [0110] IR (KBr) cm -1: 3330,294
0,1630,1540,1070,700 1 H−NMR(CDCl 3 )δ(ppm):1.31(2H, 0,1630,1540,1070,700 1 H-NMR (CDCl 3 ) δ (ppm): 1.31 (2H,
m),1.48(2H,m),1.63(2H,m),1. m), 1.48 (2H, m), 1.63 (2H, m), 1.
70(2H,m),1.86(2H,m),2.07(2 70 (2H, m), 1.86 (2H, m), 2.07 (2
H,m),2.17(2H,t,J=7.6Hz),2.20 H, m), 2.17 (2H, t, J = 7.6Hz), 2.20
(2H,m),2.27(2H,t,J=7.6Hz),2.7 (2H, m), 2.27 (2H, t, J = 7.6Hz), 2.7
1(2H,m),3.37(2H,q,J=6.5Hz),3. 1 (2H, m), 3.37 (2H, q, J = 6.5Hz), 3.
42(1H,m),4.57(2H,t,J=6.8Hz), 42 (1H, m), 4.57 (2H, t, J = 6.8Hz),
5.45(2H,bs),5.50(1H,s),5.62 5.45 (2H, bs), 5.50 (1H, s), 5.62
(1H,t,J=6.0Hz),7.21−7.37(11H, (1H, t, J = 6.0Hz), 7.21-7.37 (11H,
m),7.53(1H,t,J=7.7Hz),7.83(1 m), 7.53 (1H, t, J = 7.7Hz), 7.83 (1
H,d,J=8.4Hz),7.90(1H,s),7.93 H, d, J = 8.4Hz), 7.90 (1H, s), 7.93
(1H,d,J=8.2Hz) (1H, d, J = 8.2Hz)

【0111】(実施例32) 製剤:本発明の化合物を含有する軟膏を以下の方法により調製した。 [0111] (Example 32) Formulation: were prepared by the following method ointment containing the compound of the present invention. 本発明化合物 0.2g ソルビタンモノラウレート(SP−20) 2.0g ミリスチン酸イソプロピル(IPM) 0.4g 白色ワセリン 7.4g 全量 10.0g The compound of the present invention 0.2g Sorbitan monolaurate (SP-20) 2.0g isopropyl myristate (IPM) 0.4 g White petrolatum 7.4g total amount 10.0g

【0112】80℃に加熱したソルビタンモノラウレート(SP−20)2gに本発明化合物0.2gを加え撹拌溶解した。 [0112] Sol was heated to 80 ° C. sorbitan monolaurate (SP-20) The present compound 0.2g mixture was stirred and dissolved to 2g. これにミリスチン酸イソプロピル(IP This in isopropyl myristate (IP
M)0.4gを加えた後、別に加熱溶解(80℃)しておいた白色ワセリン7.4gを加え、撹拌しながら室温冷却した。 After addition of M) 0.4 g, was added to white petrolatum 7.4g which had been separately heated and dissolved (80 ° C.), and cooling to room temperature with stirring.

【0113】(比較例1) 2%イミキモド軟膏の作成 80℃に加熱したイソステアリン酸5gに米国特許49 [0113] (Comparative Example 1) U.S. Patent 2% imiquimod isostearate 5g heated to create 80 ° C. ointment 49
88815に記載の方法で合成したイミキモド0.5g Imiquimod 0.5g synthesized by the method described in 88815
を加え攪拌溶解した。 And the mixture was stirred and dissolved. これに、加熱溶解(80℃)しておいた白色ワセリン19.5gを加え、攪拌しながら室温冷却した。 To this heated and dissolved (80 ° C.) and a white petrolatum 19.5g had been added, was cooling to room temperature with stirring.

【0114】(比較例2) 吉草酸ベタメタゾンの外用剤 0.12%リンデロンV軟膏(シオノギ製薬)をそのまま使用した。 [0114] as it was used (Comparative Example 2) betamethasone valerate for external use agent 0.12% Rinderon V ointment (Shionogi &).

【0115】(実施例33) 抗ヒスタミン作用 (1)試験方法 体重300−600gの雄性、Hartley系モルモット(購入先:ハムリー)を使用した。 [0115] (Example 33) antihistaminic action (1) male test methods weighing 300-600g, Hartley type guinea pigs (purchase: Hamuri) was used. 試験方法はT. The test method is T.
Ishiiら(Naunyn-Schmiedeberg's Arch. Pharmaco Ishii et al. (Naunyn-Schmiedeberg's Arch. Pharmaco
l.,332,219-223,1986)により報告された方法を一部変更したものを用いた。 l., was used, which is a partial modification of the method reported by 332,219-223,1986). モルモットを放血致死させた後、 After the guinea pigs were killed by exsanguination,
甲状軟骨から気管支分岐部までの気管を摘出し栄養液で満たされたシャーレに移す。 It was excised trachea from thyroid cartilage to the bronchial branching unit transferred to a Petri dish filled with nutrient solution. 気管周囲の組織をていねいに取り除いた後、輪状軟骨にそって幅2〜3mmの横切切片を切り出し、その中の2片から気管鎖標本を作成した。 After carefully removing the tissue surrounding the trachea excised transection sections width 2~3mm along the cricoid, created a tracheal chains specimens from two pieces therein. 標本は37℃に加温した栄養液(Krebs bicarbonat Nutrient solution sample was heated to 37 ℃ (Krebs bicarbonat
e液:NaCl 118.1mM,CaCl 2 2.5mM,K e solution: NaCl 118.1mM, CaCl 2 2.5mM, K
2 PO 4 1.2mM,KCl4.6mM,MgSO 4 1.0 H 2 PO 4 1.2mM, KCl4.6mM, MgSO 4 1.0
mM,NaHCO 3 25mM,glucose 11.1mM,p mM, NaHCO 3 25mM, glucose 11.1mM , p
H:7.65)を満たした10mlマグヌス容器中に懸垂し、95%O 2 ,5%CO 2の混合ガスを通気した。 H: 7.65) was suspended in 10ml Magnus vessel filled with, was bubbled through 95% O 2, 5% mixed gas of CO 2. 標本の初期負荷を1gとし、その等尺性張力変化を張力トランスデューサー(NEC San-ei,Type 45196A)及び歪圧力アンプ(NEC San-ei,Type 1236)を介してインク書レクチコーダー(RIKADENKI R-50)上に記録した。 The initial loading of the sample and 1g, its isometric tension change the tension transducer (NEC San-ei, Type 45196A) and strain pressure amplifier (NEC San-ei, Type 1236) ink through a manual rectifying coder (RIKADENKI R -50) was recorded on.

【0116】標本は1時間 incubation してからヒスタミン(10 -5 M)を投与して収縮反応を得た。 [0116] specimens was obtained contractile response by administering histamine (10 -5 M) after 1 hour incubation. これを数回繰り返し、標本の反応が安定になったのち実験に供した。 This is repeated several times, the reaction of the specimens were subjected to the experiment after became stable. 被験化合物を20分間前処置し、被験化合物投与前後のヒスタミンの収縮高から抑制率を求めた。 The test compounds were pre-treated 20 minutes, was determined inhibition rate from contraction height before and after the test compound administration histamine.

【0117】ヒスタミン二塩酸塩は生理食塩水に、イミキモド(1−イソブチル−1H−イミダゾ[4,5− [0117] Histamine dihydrochloride in saline, imiquimod (1-isobutyl--1H- imidazo [4,5
c]キノリン−4−アミン)、塩酸ジフェンヒドラミン及び本発明化合物はDMSO(ジメチルスルホキシド) c] quinolin-4-amine), diphenhydramine hydrochloride and the compound of the present invention DMSO (dimethyl sulfoxide)
に溶解(DMSOのマグヌス容器中での最終濃度は0. 0 final concentration in the Magnus vessel dissolved (DMSO on.
1%)した。 1%) was.

【0118】(2)結果 モルモット気管筋のヒスタミン収縮を50%抑制する被験化合物の濃度(IC 50値)を以下の表1に示す。 [0118] (2) Results of histamine contraction of guinea pig tracheal muscle shows a concentration of 50% inhibition of the test compound (IC 50 value) in Table 1 below. 実施例22、24、27、29及び31の化合物はジフェンヒドラミンと同様にヒスタミン収縮を強く抑制した。 The compounds of Examples 22,24,27,29 and 31 were strongly suppressed in the same manner as histamine contraction and diphenhydramine.

【0119】 [0119]

【表1】 [Table 1]

【0120】(実施例34) 皮膚好酸球浸潤抑制作用 (1)試験方法 動物は4週齢のBalb/cマウス(雄)を日本クレア(株)より購入し1週間の馴化期間の後に実験に供した。 [0120] (Example 34) Skin eosinophilic infiltration inhibitory effect (1) Test method Animals Experiments 4-week-old Balb / c mice (male) after Japan were purchased from CLEA Co. 1 week acclimation period It was subjected to.

【0121】ダニ抗原液の調製 0.9%塩化ナトリウム水溶液20mlにヤケヒョウヒダニ(Dermatophagoidespteronyssinus:International B [0121] D. pteronyssinus to prepare 0.9% aqueous sodium chloride solution 20ml of mite antigen solution (Dermatophagoidespteronyssinus: International B
iologicals,Inc.;Lot.No.14679)1gを添加し、30ml iologicals, Inc;. Lot.No.14679) was added 1 g, 30 ml
のホモジナイズポットに移し、氷冷下、4000〜45 Transferred to a homogenization pot, under ice-cooling, 4000-45
00rpmでホモジナイズした(顕微鏡下でホモジナイズ溶液を観察し、ダニの原形をとどめない程度までホモジナイズした)。 It was homogenized in rpm (observe the homogenized solution under a microscope, and homogenized to the extent that do not have their original form of mite). ホモジナイズした溶液を50mlの遠沈管に移し、室温で3500rpmで5分間遠を行い、上澄を別の遠沈管に移した(溶液A)。 Transfer the homogenized solution to centrifuge tube 50 ml, performed at room temperature for 5 minutes at 3500rpm Centrifuge and transferred supernatant to another centrifuge tube (solution A). この操作を2回繰り返すことによって、溶液B、溶液Cを得た。 By repeating this operation twice to obtain solution B, and solution C. 精製水(RO Purified water (RO
水)で十分洗浄した透析膜(三光純薬(株):Seamless C Water) at sufficiently washed dialysis membrane (Sanko Junyaku (Co.): Seamless C
ellulose Tubinng)に、溶液A,B,Cをそれぞれ封入し、4℃で0.9%塩化ナトリウム水溶液に対して一晩、透析を行った。 The ellulose Tubinng), solution A, B, and C enclosed respectively, overnight against 0.9% sodium chloride solution at 4 ° C., was dialyzed. 透析終了後、溶液A,B,Cのタンパク質量をタンパク定量キット(Protein assay Reagen After completion of the dialysis, the solution A, B, C protein mass protein assay kit (Protein assay Reagen
t BCA Kit:PIERCE,Inc.)で測定し、各々の溶液を50 t BCA Kit:. PIERCE, measured at Inc), each of the solution 50
0μg/mlのタンパク濃度になるように、0.9%塩化ナトリウム水溶液で調製した。 As will become protein concentration of 0 Pg / ml, it was prepared in 0.9% sodium chloride solution. これらの3溶液を混合して15mlのポリプロピレンチューブに10mlずつ分注し、 By mixing these three solutions aliquoted 10ml to 15ml polypropylene tubes minute,
ダニ抗原溶液とした。 It was a mite antigen solution. この溶液は使用時まで−80℃で凍結保存した。 This solution was stored frozen at -80 ℃ until use.

【0122】感作及び惹起 百日せき菌液をダニ抗原溶液に40分の1容量添加したものを感作溶液とした。 [0122] The sensitization and cause pertussis bacterial solution was sensitized solution made by adding 1 volume of 40 minutes to mite antigen solution. 感作はマイジェクター(テルモ社製)を用い、マウスの頸部の皮下にこの溶液を200μl投与することによって行った。 Sensitization with Maijekuta (manufactured by Terumo Corporation), was carried out by the solution 200μl administered to mice subcutaneously in the neck. この感作方法で初回感作を含め7日おきに三回感作を行った。 Was three times sensitization every 7 days, including the first sensitization in this sensitization method.

【0123】惹起は初回感作21日後に、0.9%塩化ナトリウム水溶液で200μg/mlのタンパク濃度に調製したダニ抗原溶液を背部皮内にマイジェクター(テルモ社製)を用いて50μl投与することによって行った。 [0123] elicited first sensitization 21 days later, to 50μl administered using Maijekuta (manufactured by Terumo Corporation) in mite antigen solution dorsal skin was prepared protein concentration of 200 [mu] g / ml in 0.9% sodium chloride solution by went.

【0124】皮膚回収及び病理標本の観察 惹起48時間後に頸椎脱臼によりマウスを屠殺し背部の皮膚を剥ぎ取り、マーキングした部分を中心に1cm四方に皮膚を切断した。 [0124] The skin recovery and cervical dislocation observed induced 48 hours after pathology specimens mice were sacrificed stripped dorsal skin was cut skin 1cm square around the marking portion. 回収した皮膚は10%中性ホルマリン緩衝液(コーニングの15ml遠沈管使用)に入れ1日以上室温に放置して固定した。 Collected skin was fixed by standing at room temperature over 1 day placed in 10% neutral buffered formalin (15ml centrifuge tube using a Corning). 固定した皮膚は、常法にしたがってパラフィン切片作成後、ルナ染色を施した(切り出しは体軸に対し垂直方向に皮膚サンプルの中央と頭側2mm上方の2カ所で行った)。 Fixed skin (Been cut at two locations in the center and head side 2mm above the skin samples in the direction perpendicular to the body axis) in accordance with after creating paraffin sections were subjected to Luna stain conventional method. 標本の観察は光学顕微鏡(400倍)で、1切片1cm当たりの好酸球数を計測した。 Observation of the specimen with an optical microscope (400-fold), and counting the number of eosinophils per section 1 cm. 薬剤(被験化合物)による抑制率は以下の式から算出した。 Inhibition rate by the agent (test compound) was calculated from the following equation.

【0125】抑制率(%)={(基材投与群の好酸球数−被験化合物投与群の好酸球数)/基材投与群の好酸球数)}×100 [0125] inhibitory rate (%) = {(base group administered eosinophil count - test compound number of eosinophils administration group) / number of eosinophils substrate administered group)} × 100

【0126】各被験薬物の調製 実施例32の方法により作製した。 [0126] Prepared by the method of Example 32 of the test drug.

【0127】薬物投与方法 経皮投与(密封包帯法:Occlusive dressing technique [0127] Drug administration methods transdermal administration (occlusive dressing method: Occlusive dressing technique
(ODT)) マウスをエーテル麻酔して背部中央を電気バリカンで皮膚を傷つけないように除毛した。 (ODT)) were shaved so as not to injure the skin with electric clippers dorsal central and ether anesthetized mice. 背部中央の惹起箇所にあたる部分にあらかじめ油性マジックで印を付けた。 Marked in advance permanent marker on a portion corresponding to elicit part of the back center. 薬剤(被験化合物)の塗布は、背部の印をつけた部分を中心に前投与では3cm四方に、惹起後は惹起部分を中心に2cm四方に塗布した。 Coating agents (test compound) in 3cm square at predose be mainly marked back, after the induction was applied to 2cm square around the raised portion. さらに、塗布部を覆うようにラップをのせ伸縮性テープ(Johnson & Johnson MEDICAL IN Further, elastic tape carrying the wrap so as to cover the coating portion (Johnson & Johnson MEDICAL IN
C:エラスコチン)で固定した。 C: Erasukochin) were fixed in. 対照群は基材のみを塗布した。 The control group was applied only to the base material. 投与量は一匹当たり50mgとし、投与スケジュールは以下のように惹起前日より3日間連投した。 The dosage and 50mg per animal, administration schedule was Rento than 3 days previous day caused as follows.

【0128】惹起前日→惹起日(惹起直後)→惹起翌日 (計3回) [0128] (immediately after induced) raised the day before → caused Date → induced the next day (a total of 3 times)

【0129】(2)結果 2%イミキモド軟膏、実施例化合物の2%軟膏、0.1 [0129] (2) Result 2% imiquimod ointment, 2% ointment of Example Compound 0.1
2%吉草酸ベタメタゾン軟膏の各被験薬物のダニ惹起マウス皮膚好酸球浸潤反応に対する抑制効果を表2、3に示す。 The inhibitory effect on ticks induced mouse skin eosinophilic infiltration reaction of each test drug 2% betamethasone valerate ointment shown in Tables 2 and 3. 実施例の化合物の多くは好酸球浸潤を吉草酸ベタメタゾン軟膏と同等以上に抑制した。 Many of the compounds of Examples was suppressed to equal to or more than the betamethasone valerate ointment eosinophilic infiltration.

【0130】 [0130]

【表2】 [Table 2]

【0131】 [0131]

【表3】 [Table 3]

【0132】(実施例35) 2相性耳浮腫抑制作用 (1)試験方法 動物は4週齢のBalb/cマウス(雄)を日本クレア(株)より購入し1週間の馴化期間の後に実験に供した。 [0132] (Example 35) biphasic ear edema suppression effect (1) Test Method animals in experiments 4-week-old Balb / c mice (male) after the CLEA Japan (Ltd.) purchased from one week of acclimatization period It was subjected.

【0133】感作及び惹起 感作及び惹起は澤田らの方法に準じて行った(アレルギー,43(8),p1099,1994)。 [0133] sensitization and induce sensitization and cause was carried out in accordance with the method of Sawada et al. (Allergy, 43 (8), p1099,1994). すなわち、卵白アルブミン(OVA)1μgと水酸化アルミニウムゲル(alum)4 That is, ovalbumin (OVA) 1 [mu] g aluminum hydroxide gel (alum) 4
mgを含む生理食塩液250μlを腹腔内投与して感作した。 Physiological saline 250μl containing mg were sensitized by intraperitoneal administration. さらに、2週間後に同様の方法で追加感作を行った。 In addition, it added sensitization in a similar manner after two weeks. 惹起は2回目の感作10日後にエーテル麻酔下に5 Elicited under ether anesthesia in 10 days after the second sensitization 5
μgOVA(20μl)を耳に皮内注射した。 They were injected intradermally μgOVA the (20μl) to the ear. 惹起においては、注射の影響を除くためOVAの代わりに生理食塩液のみを投与する群を設けた。 In induced, it provided the group administered only physiological saline instead of OVA for excluding the influence of the injection.

【0134】2相性耳浮腫反応の測定 OVAで惹起すると1時間と24時間後にピークとなる耳浮腫反応が生じるので、このときの耳の厚みをダイアルシックネスゲージを用いて測定し、これらの厚みに対する薬物と被験化合物の効果を検討した。 [0134] Since the biphasic ear edema reaction ear edema reaction reaches a peak by eliciting after 1 hour and 24 hours at the measurement OVA occurs, the thickness of the ear at this time was measured using a dial thickness gauge, for these thickness It was studied the effect of the drug and the test compound.

【0135】薬物投与方法 薬物及び被験化合物は1%カルボキシメチルセルロース(CMC)に懸濁し、惹起24時間前と2時間前に経口あるいは腹腔内に投与した。 [0135] Drug administration drugs and test compound was suspended in 1% carboxymethylcellulose (CMC), it was administered to elicit 24 hours before and orally or intraperitoneally two hours prior. 溶媒コントロール群には1 The solvent control group 1
%CMCのみを投与した。 % CMC only was administered. そして以下の式より薬剤(被験化合物)により抑制率を算出した。 And to calculate the inhibition rate by the drug (the test compound) from the following equation.

【0136】抑制率(%)={(OVA惹起薬物投与群の耳の厚み−生食惹起溶媒投与群の耳の厚み)/OVA [0136] inhibitory rate (%) = {(OVA induced drug administration group ear thickness - Thickness of saline induced the solvent administration group ear) / OVA
惹起溶媒投与群の耳の厚み−生食惹起溶媒投与群の耳の厚み)}×100 Induced solvent administration group ear thickness - Thickness of saline induced the solvent administration group ear)} × 100

【0137】(2)結果 表4に示す通り、実施例22の化合物は32mg/kgの経口あるいは腹腔内投与で即時型及び遅発型の耳浮腫反応を同用量のイミキモドよりも強く抑制した。 [0137] (2) Results As shown in Table 4, the compound of Example 22 inhibited stronger than imiquimod same dose ear edema reaction of immediate and delayed type orally or intraperitoneal administration of 32 mg / kg.

【0138】 [0138]

【表4】 [Table 4]

【0139】 [0139]

【発明の効果】上述した通り、本発明により新規なアミド誘導体が得られる。 [Effect of the Invention] As described above, the novel amide derivatives obtained by the present invention. 本発明のアミド誘導体は、抗ヒスタミン効果及び好酸球浸潤抑制効果により、即時型及び遅発型のアレルギー反応を強く抑え、特にアトピー性皮膚炎の治療に有用である。 Amide derivatives of the present invention, the antihistamine effects and eosinophil infiltration suppressing effect, suppress strongly allergic reactions immediate and delayed type are particularly useful in the treatment of atopic dermatitis.

───────────────────────────────────────────────────── フロントページの続き (72)発明者 飯塚 貴夫 神奈川県足柄上郡中井町井ノ口1500番地 テルモ株式会社内 ────────────────────────────────────────────────── ─── of the front page continued (72) inventor Takao Iizuka Kanagawa Prefecture ashigarakami district Nakai-cho, Inokuchi 1500 address Terumo within the Corporation

Claims (10)

    【特許請求の範囲】 [The claims]
  1. 【請求項1】下記式Iで示されるアミド誘導体。 1. A derivative of the following formula I. 【化1】 [Formula 1] 式I中、Xは水素原子またはハロゲン原子を表わし、m Wherein I, X represents a hydrogen atom or a halogen atom, m
    は1から9の整数を、nは2から12の整数を示す。 An integer of from 1 9, n is an integer of 2 to 12.
  2. 【請求項2】請求項1に記載のアミド誘導体を含有する医薬製剤。 2. A pharmaceutical formulation containing an amide derivative of claim 1.
  3. 【請求項3】下記式IIで示される合成中間体。 3. A synthetic intermediate represented by the following formula II. 【化2】 ## STR2 ## 式II中、X'はハロゲン原子を表わし、mは1から9の整数を、nは2から12の整数を示す。 Wherein II, X 'represents a halogen atom, m is an integer of 1 to 9, n represents an integer of from 2 to 12.
  4. 【請求項4】下記式II'で示される合成中間体。 4. A synthetic intermediate represented by the following formula II '. 【化3】 [Formula 3] 式II'中、nは2から12の整数を示す。 Wherein II ', n represents an integer of from 2 to 12.
  5. 【請求項5】下記式IIIで示される合成中間体。 5. A synthetic intermediate represented by the following formula III. 【化4】 [Of 4] 式III中、nは2から12の整数を示す。 Wherein III, n is an integer of 2 to 12.
  6. 【請求項6】下記式IVで示される合成中間体。 6. A synthetic intermediate represented by the following formula IV. 【化5】 [Of 5] 式IV中、nは2から12の整数を示す。 Wherein IV, n is an integer of 2 to 12.
  7. 【請求項7】下記式Vで示される合成中間体。 7. A synthetic intermediate represented by the following formula V. 【化6】 [Omitted] 式V中、Rが水素のとき、R'は、炭素数1〜8で分岐鎖を有してもよいアルカノイル基、炭素数1〜8で分岐鎖を有してもよいハロアルカノイル基、炭素数1〜12でベンゼン環上ハロゲン、ニトロあるいはメトキシ置換基を有してもよいフェニルアルカノイル基、炭素数1〜1 During of Formula V, when R is hydrogen, R 'is optionally alkanoyl group which may have a branched chain having 1 to 8 carbon atoms, optionally halo alkanoyl group which may have a branched chain having 1 to 8 carbon atoms, carbon benzene ring on silver by the number 1 to 12, nitro or methoxy substituent a phenyl alkanoyl group optionally having a carbon number 1 to 1
    2でベンゼン環上ハロゲン、ニトロあるいはメトキシ置換基を有してもよいフェノキシアルカノイル基、炭素数1〜8で分岐鎖を有してもよいアルコキシカルボニル基、炭素数1〜8で分岐鎖を有してもよいハロアルコキシカルボニル基、あるいは炭素数1〜12でベンゼン環上ハロゲン、ニトロあるいはメトキシ置換基を有してもよいフェニルアルコキシカルボニル基を示す。 Benzene ring on halogen 2, nitro or methoxy which may have a substituent phenoxy alkanoyl group, alkoxycarbonyl group which may have a branched chain having 1 to 8 carbon atoms, have a branched chain having 1 to 8 carbon atoms and it shows also good halo alkoxycarbonyl group or a benzene ring on silver in 1 to 12 carbon atoms, phenyl alkoxycarbonyl group optionally having a nitro or methoxy substituent, and. また、 Also,
    R、R'が一つになってハロゲン、ニトロあるいはメトキシ置換基を有してもよい芳香族環状イミドを形成する。 R, R 'are taken one halogen, to form an aromatic cyclic imide may have a nitro or methoxy substituent. nは2から12の整数を示す。 n represents an integer of 2 to 12.
  8. 【請求項8】下記式VIで示される合成中間体。 8. A synthetic intermediate represented by the following formula VI. 【化7】 [Omitted] 式VI中、Rが水素のとき、R'は、炭素数1〜8で分岐鎖を有してもよいアルカノイル基、炭素数1〜8で分岐鎖を有してもよいハロアルカノイル基、炭素数1〜12 Wherein VI, when R is hydrogen, R 'is optionally alkanoyl group which may have a branched chain having 1 to 8 carbon atoms, optionally halo alkanoyl group which may have a branched chain having 1 to 8 carbon atoms, carbon number 1 to 12
    でベンゼン環上ハロゲン、ニトロあるいはメトキシ置換基を有してもよいフェニルアルカノイル基、炭素数1〜 In benzene ring on halogen, nitro or phenyl alkanoyl group which may have a methoxy substituent, 1 carbon atoms
    12でベンゼン環上ハロゲン、ニトロあるいはメトキシ置換基を有してもよいフェノキシアルカノイル基、炭素数1〜8で分岐鎖を有してもよいアルコキシカルボニル基、炭素数1〜8で分岐鎖を有してもよいハロアルコキシカルボニル基、あるいは炭素数1〜12でベンゼン環上ハロゲン、ニトロあるいはメトキシ置換基を有してもよいフェニルアルコキシカルボニル基を示す。 Benzene ring on halogen 12, nitro or methoxy which may have a substituent phenoxy alkanoyl group, alkoxycarbonyl group which may have a branched chain having 1 to 8 carbon atoms, have a branched chain having 1 to 8 carbon atoms and it shows also good halo alkoxycarbonyl group or a benzene ring on silver in 1 to 12 carbon atoms, phenyl alkoxycarbonyl group optionally having a nitro or methoxy substituent, and. また、 Also,
    R、R'が一つになってハロゲン、ニトロあるいはメトキシ置換基を有してもよい芳香族環状イミドを形成する。 R, R 'are taken one halogen, to form an aromatic cyclic imide may have a nitro or methoxy substituent. nは2から12の整数を示す。 n represents an integer of 2 to 12.
  9. 【請求項9】下記式VIIで示される合成中間体。 9. synthetic intermediate represented by the following formula VII. 【化8】 [Of 8] 式VII中、Rが水素のとき、R'は、炭素数1〜8で分岐鎖を有してもよいアルカノイル基、炭素数1〜8で分岐鎖を有してもよいハロアルカノイル基、炭素数1〜12 Wherein VII, when R is hydrogen, R 'is optionally alkanoyl group which may have a branched chain having 1 to 8 carbon atoms, optionally halo alkanoyl group which may have a branched chain having 1 to 8 carbon atoms, carbon number 1 to 12
    でベンゼン環上ハロゲン、ニトロあるいはメトキシ置換基を有してもよいフェニルアルカノイル基、炭素数1〜 In benzene ring on halogen, nitro or phenyl alkanoyl group which may have a methoxy substituent, 1 carbon atoms
    12でベンゼン環上ハロゲン、ニトロあるいはメトキシ置換基を有してもよいフェノキシアルカノイル基、炭素数1〜8で分岐鎖を有してもよいアルコキシカルボニル基、炭素数1〜8で分岐鎖を有してもよいハロアルコキシカルボニル基、あるいは炭素数1〜12でベンゼン環上ハロゲン、ニトロあるいはメトキシ置換基を有してもよいフェニルアルコキシカルボニル基を示す。 Benzene ring on halogen 12, nitro or methoxy which may have a substituent phenoxy alkanoyl group, alkoxycarbonyl group which may have a branched chain having 1 to 8 carbon atoms, have a branched chain having 1 to 8 carbon atoms and it shows also good halo alkoxycarbonyl group or a benzene ring on silver in 1 to 12 carbon atoms, phenyl alkoxycarbonyl group optionally having a nitro or methoxy substituent, and. また、 Also,
    R、R'が一つになってハロゲン、ニトロあるいはメトキシ置換基を有してもよい芳香族環状イミドを形成する。 R, R 'are taken one halogen, to form an aromatic cyclic imide may have a nitro or methoxy substituent. nは2から12の整数を示す。 n represents an integer of 2 to 12.
  10. 【請求項10】下記式VIIIで示される合成中間体。 10. A synthetic intermediate represented by the following formula VIII. 【化9】 [Omitted] 式VIII中、Rが水素のとき、R'は、炭素数1〜8で分岐鎖を有してもよいアルカノイル基、炭素数1〜8で分岐鎖を有してもよいハロアルカノイル基、炭素数1〜1 Wherein VIII, when R is hydrogen, R 'is optionally alkanoyl group which may have a branched chain having 1 to 8 carbon atoms, optionally halo alkanoyl group which may have a branched chain having 1 to 8 carbon atoms, carbon number 1 to 1
    2でベンゼン環上ハロゲン、ニトロあるいはメトキシ置換基を有してもよいフェニルアルカノイル基、炭素数1 Benzene ring on halogen 2, nitro or phenyl alkanoyl group which may have a methoxy substituent, a carbon number 1
    〜12でベンゼン環上ハロゲン、ニトロあるいはメトキシ置換基を有してもよいフェノキシアルカノイル基、炭素数1〜8で分岐鎖を有してもよいアルコキシカルボニル基、炭素数1〜8で分岐鎖を有してもよいハロアルコキシカルボニル基、あるいは炭素数1〜12でベンゼン環上ハロゲン、ニトロあるいはメトキシ置換基を有してもよいフェニルアルコキシカルボニル基を示す。 12 benzene rings on halogen, nitro or methoxy which may have a substituent phenoxy alkanoyl group, alkoxycarbonyl group which may have a branched chain having 1 to 8 carbon atoms, a branched chain having 1 to 8 carbon atoms good haloalkoxycarbonyl group which may have or benzene ring on silver in 1 to 12 carbon atoms, exhibit a phenyl alkoxycarbonyl group optionally having a nitro or methoxy substituent. また、 Also,
    R、R'が一つになってハロゲン、ニトロあるいはメトキシ置換基を有してもよい芳香族環状イミドを形成する。 R, R 'are taken one halogen, to form an aromatic cyclic imide may have a nitro or methoxy substituent. nは2から12の整数を示す。 n represents an integer of 2 to 12.
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Cited By (79)

* Cited by examiner, † Cited by third party
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