JPH09194481A - Condensed tetra-and hetyerocyclic derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject new compound derivative which is a specific condensed tetra- and heterocyclic derivative, having a cyclic imide part in the molecule, excellent antitumor activities and low toxicity and useful as an active ingredient, etc., of an antitumor agent. SOLUTION: This new tetra- and heterocyclic derivative (salt) is represented by formula I rings A and B are each a (substituted)monocyclic aromatic ring; X is a bond, O, S or CH=CH; Y is a group represented by the formula e-f [(e) is a lower alkylene; (f) is an amino group which may be substituted with a lower alkyl group]}, has excellent antitumor activities and low toxicity and is useful as an active ingredient, etc., of an antitumor agent. The compound is obtained by reacting a compound represented by formula II [ring Aa is a (protected)ring A; G is O or S] with a compound represented by formula III [ring Ba is a (protected)ring B; K and L are each an eliminable group; R is a lower alkyl], then amidating the resultant compound, providing a condensed tricyclic compound represented by formula IV and further carrying out the cyclizing reaction of the resultant condensed tricyclic compound represented by formula IV with a compound represented by formula V (D and E are each an eliminable group).

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】本発明は新規な縮合四環式ヘ
テロ環誘導体、その製造法および該化合物を有効成分と
する医薬組成物に関する。TECHNICAL FIELD The present invention relates to a novel fused tetracyclic heterocyclic derivative, a method for producing the same, and a pharmaceutical composition containing the compound as an active ingredient.

【０００２】[0002]

【従来の技術】分子内に環状イミド部分2. Description of the Related Art A cyclic imide moiety in a molecule

【化２】 を有する縮合多環式ヘテロ環系抗腫瘍性物質としては三
環系化合物のアモナフィド［５−アミノ−２−［２−
（ジメチルアミノ）エチル］−１Ｈ−ベンズ［ｄｅ］イ
ソキノリン−１，３（２Ｈ）−ジオン］が最もよく知ら
れているが、これまでに行われた臨床試験において骨髄
毒性が強く、有効率が低いことが報告されている［Drug
s Fut., 17, 832 （1992）］。また、四環系化合物とし
ては、アモナフィドのアミノナフタレン部分をアントラ
センに変換することにより前臨床試験での抗腫瘍活性を
上昇させたアゾナフィド［２−［２’−( ジメチルアミ
ノ）エチル］−１，２−ジヒドロ−３Ｈ−ジベンズ（ｄ
ｅｈ）−イソキノリン−１，３−ジオン］が報告されて
いる( ＷＯ９２００２８１）。上記以外に分子内に環状
イミド部分を有する縮合多環式ヘテロ環系抗腫瘍性物質
としては、２−［２−（ジメチルアミノ）エチル］ピリ
ミド［５，６，１−ｄｅ］アクリジン−１，３，７−ト
リオン［ファルマコ（Farmaco), 47, 1035（1992）］お
よび２，３−ジヒドロ−２−［２−（ジメチルアミノ）
エチル］−１Ｈ，７Ｈ−ナフチリジノ［３，２，１−ｉ
ｊ］キナゾリン−１，３，７（２Ｈ）−トリオン［ジャ
ーナル・オブ・メディシナルケミストリー (J. Med. Ch
em.)，37, 593 （1994）］が報告されているが、いずれ
も前臨床試験で弱い抗腫瘍活性しか示していない。Embedded image Examples of the fused polycyclic heterocyclic antitumor substance having a compound include tricyclic compound amonafide [5-amino-2- [2-
(Dimethylamino) ethyl] -1H-benz [de] isoquinoline-1,3 (2H) -dione] is the most well known, but it has strong bone marrow toxicity in clinical studies conducted so far and its efficacy rate is high. Reported to be low [Drug
S Fut., 17 , 832 (1992)]. Further, as a tetracyclic compound, azonafide [2- [2 '-(dimethylamino) ethyl] -1, which increased antitumor activity in a preclinical test by converting the aminonaphthalene part of amonafide into anthracene, 2-dihydro-3H-dibenz (d
[eh) -isoquinoline-1,3-dione] has been reported (WO9200281). In addition to the above, condensed polycyclic heterocyclic antitumor substances having a cyclic imide moiety in the molecule include 2- [2- (dimethylamino) ethyl] pyrimido [5,6,1-de] acridine-1, 3,7-Trione [Farmaco, 47 , 1035 (1992)] and 2,3-dihydro-2- [2- (dimethylamino)
Ethyl] -1H, 7H-naphthyridino [3,2,1-i
j] Quinazoline-1,3,7 (2H) -trione [Journal of Medicinal Chemistry (J. Med. Ch
em.), 37 , 593 (1994)], but all have shown weak antitumor activity in preclinical studies.

【０００３】[0003]

【発明が解決しようとする課題】本発明は、優れた抗腫
瘍活性を有する新規縮合四環式ヘテロ環誘導体の提供を
目的とする。さらに、該化合物を有効成分とする医薬組
成物をも提供することを目的とする。DISCLOSURE OF THE INVENTION An object of the present invention is to provide a novel fused tetracyclic heterocyclic derivative having excellent antitumor activity. Furthermore, it aims at providing the pharmaceutical composition which uses this compound as an active ingredient.

【０００４】[0004]

【課題を解決するための手段】本発明者らは、上記趣旨
に鑑み、優れた抗腫瘍性物質を求めて鋭意研究を行って
きた結果、新規縮合四環式ヘテロ環誘導体が優れた抗腫
瘍活性を有し、かつ低毒性であることを見出し、本発明
を完成した。[Means for Solving the Problems] In view of the above points, the present inventors have conducted earnest research in search of an excellent antitumor substance, and as a result, the novel fused tetracyclic heterocycle derivative has excellent antitumor properties. The present invention has been completed by finding that it has activity and low toxicity.

【０００５】すなわち、本発明は一般式（Ｉ）That is, the present invention has the general formula (I)

【化３】 Embedded image

【０００６】［式中、Ａ環およびＢ環は、同一または異
なって、置換基を有していてもよい単環式芳香環を意味
する。Ｘは結合、酸素原子、硫黄原子または−ＣＨ＝Ｃ
Ｈ−を意味する。Ｙは式ｅ−ｆ（式中、ｅは低級アルキ
レン基を、ｆは低級アルキル基で置換されていてもよい
アミノ基を意味する）で示される基を意味する］で表わ
される化合物またはその薬理学的に許容される塩に関す
る。[In the formula, A ring and B ring are the same or different and each represents a monocyclic aromatic ring which may have a substituent. X is a bond, an oxygen atom, a sulfur atom or -CH = C
Means H-. Y represents a group represented by the formula ef (wherein e represents a lower alkylene group, and f represents an amino group optionally substituted with a lower alkyl group), or a drug thereof. Regarding a salt that is physically acceptable.

【０００７】上記一般式（Ｉ）のＡ環およびＢ環の定義
において、単環式芳香環とは、窒素原子、酸素原子およ
び硫黄原子のうち少なくとも１個を含んでいてもよい芳
香族５または６員環であり、例えば、ベンゼン、ピリジ
ン、ピラジン、ピリミジン、ピリダジン、フラン、チオ
フェン、ピロール、チアゾールなどを挙げることができ
る。上記環は各々置換基１〜３個を有していてもよく、
置換基が複数個ある場合には、同一または異なっていて
もよい。置換基としては、例えばニトロ基、低級アルキ
ル基、低級アルコキシ基、水酸基、ハロゲン原子、低級
アシル基、低級アルキル化、低級アシル化または低級ア
ルキルスルホニル化されていてもよいアミノ基、芳香族
カルボン酸アミド基、芳香族スルホンアミド基などを挙
げることができる。In the definition of the A ring and the B ring of the above general formula (I), the monocyclic aromatic ring means an aromatic group 5 or 5 which may contain at least one of a nitrogen atom, an oxygen atom and a sulfur atom. It is a 6-membered ring, and examples thereof include benzene, pyridine, pyrazine, pyrimidine, pyridazine, furan, thiophene, pyrrole, and thiazole. The above rings may each have 1 to 3 substituents,
When there are a plurality of substituents, they may be the same or different. Examples of the substituent include a nitro group, a lower alkyl group, a lower alkoxy group, a hydroxyl group, a halogen atom, a lower acyl group, a lower alkylated, a lower acylated or a lower alkylsulfonylated amino group, an aromatic carboxylic acid. Examples thereof include an amide group and an aromatic sulfonamide group.

【０００８】上記一般式（Ｉ）において、Ａ環およびＢ
環が有していてもよい置換基ならびにＹ中のｆの定義中
の低級アルキル基としては、炭素数１〜６の直鎖もしく
は分枝状のアルキル基、例えばメチル基、エチル基、ｎ
−プロピル基、イソプロピル基、ｎ−ブチル基、イソブ
チル基、ｓｅｃ−ブチル基、ｔｅｒｔ−ブチル基、ｎ−
ペンチル基（アミル基）、イソペンチル基、ネオペンチ
ル基、ｔｅｒｔ−ペンチル基、１−メチルブチル基、２
−メチルブチル基、１，２−ジメチルプロピル基、ｎ−
ヘキシル基、イソヘキシル基、１−メチルペンチル基、
２−メチルペンチル基、３−メチルペンチル基、１，１
−ジメチルブチル基、１，２−ジメチルブチル基、２，
２−ジメチルブチル基、１，３−ジメチルブチル基、
２，３−ジメチルブチル基、３，３−ジメチルブチル
基、１−エチルブチル基、２−エチルブチル基、１，
１，２−トリメチルプロピル基、１，２，２−トリメチ
ルプロピル基、１−エチル−１−メチルプロピル基、１
−エチル−２−メチルプロピル基などを挙げることがで
きる。これらのうち好ましい基としては、メチル基、エ
チル基、ｎ−プロピル基、イソプロピル基などを挙げる
ことができ、これらのうち、最も好ましい基としてはメ
チル基、エチル基を挙げることができる。また、Ｙ中の
ｅの定義における低級アルキレン基とは、上記低級アル
キル基から水素１原子を除いた残基を意味する。Ａ環お
よびＢ環が有していてもよい置換基ならびにＹ中のｆの
定義において、アミノ基が２個の低級アルキル基で置換
されている場合には、これらのアルキル基が結合して５
または６員環を形成してもよい。In the above general formula (I), ring A and B
The substituent which the ring may have and the lower alkyl group in the definition of f in Y are a linear or branched alkyl group having 1 to 6 carbon atoms, for example, a methyl group, an ethyl group, n
-Propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, n-
Pentyl group (amyl group), isopentyl group, neopentyl group, tert-pentyl group, 1-methylbutyl group, 2
-Methylbutyl group, 1,2-dimethylpropyl group, n-
Hexyl group, isohexyl group, 1-methylpentyl group,
2-methylpentyl group, 3-methylpentyl group, 1,1
-Dimethylbutyl group, 1,2-dimethylbutyl group, 2,
2-dimethylbutyl group, 1,3-dimethylbutyl group,
2,3-dimethylbutyl group, 3,3-dimethylbutyl group, 1-ethylbutyl group, 2-ethylbutyl group, 1,
1,2-trimethylpropyl group, 1,2,2-trimethylpropyl group, 1-ethyl-1-methylpropyl group, 1
-Ethyl-2-methylpropyl group and the like can be mentioned. Among these, preferable groups include a methyl group, an ethyl group, an n-propyl group, an isopropyl group and the like, and among these, a most preferable group includes a methyl group and an ethyl group. The lower alkylene group in the definition of e in Y means a residue obtained by removing one hydrogen atom from the above lower alkyl group. In the definition of the substituent which ring A and ring B may have and f in Y, when the amino group is substituted with two lower alkyl groups, these alkyl groups are bonded to each other to form 5
Alternatively, a 6-membered ring may be formed.

【０００９】Ａ環およびＢ環が有していてもよい置換基
の定義中の低級アルコキシ基とは、メトキシ基、エトキ
シ基、ｎ−プロポキシ基、イソプロポキシ基、ｎ−ブト
キシ基、イソブトキシ基、ｔｅｒｔ−ブトキシ基など上
記の低級アルキル基から誘導される低級アルコキシ基を
意味するが、これらのうち最も好ましい基としてはメト
キシ基、エトキシ基を挙げることができる。またハロゲ
ン原子としてはフッ素原子、塩素原子、臭素原子などが
挙げられる。低級アシル基としては、炭素数１〜６のホ
ルミル基、アセチル基、プロピオニル基、ブチリル基、
イソブチリル基、バレリル基などが挙げられる。低級ア
ルキルスルホニル化されているアミノ基としては、炭素
数１〜６のメタンスルホンアミド基、エタンスルホンア
ミド基、プロパンスルホンアミド基、ブタンスルホンア
ミド基、ペンタンスルホンアミド基、ヘキサンスルホン
アミド基などが挙げられる。芳香族カルボン酸アミド基
および芳香族スルホンアミド基とは、置換基を有してい
てもよい、例えば、ベンゼン、ピリジン、チオフェン、
フランなどの単環式芳香族カルボン酸アミド基およびス
ルホン酸アミド基を意味する。置換基としては、例えば
低級アルキル基、低級アルコキシ基、水酸基、ハロゲン
原子などを挙げることができる。The lower alkoxy group in the definition of the substituent which ring A and ring B may have is a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, an n-butoxy group, an isobutoxy group, It means a lower alkoxy group derived from the above lower alkyl group such as a tert-butoxy group, and among these, the most preferable group includes a methoxy group and an ethoxy group. Further, examples of the halogen atom include a fluorine atom, a chlorine atom and a bromine atom. The lower acyl group includes a formyl group having 1 to 6 carbon atoms, an acetyl group, a propionyl group, a butyryl group,
Examples thereof include isobutyryl group and valeryl group. Examples of the lower alkylsulfonylated amino group include a methanesulfonamide group having 1 to 6 carbon atoms, an ethanesulfonamide group, a propanesulfonamide group, a butanesulfonamide group, a pentanesulfonamide group, and a hexanesulfonamide group. To be The aromatic carboxylic acid amide group and the aromatic sulfonamide group may have a substituent, for example, benzene, pyridine, thiophene,
It means a monocyclic aromatic carboxylic acid amide group such as furan and a sulfonic acid amide group. Examples of the substituent include a lower alkyl group, a lower alkoxy group, a hydroxyl group and a halogen atom.

【００１０】上記一般式（Ｉ）で示される縮合四環式ヘ
テロ環誘導体は酸と塩を形成する場合もある。本発明は
化合物（Ｉ）の塩をも包含する。酸との塩としては、た
とえば塩酸、臭化水素酸、硫酸等との無機酸塩や酢酸、
乳酸、コハク酸、フマル酸、マレイン酸、クエン酸、安
息香酸、メタンスルホン酸、ｐ−トルエンスルホン酸な
どとの有機酸塩を挙げることができる。また、これら化
合物の水和物はもちろんのこと光学異性体が存在する場
合はそれらすべてが含まれることはいうまでもない。ま
た、本発明化合物は強い抗腫瘍活性を示すが、生体内で
酸化、還元、加水分解、抱合などの代謝を受けて抗腫瘍
活性を示す化合物をも包含する。またさらに、本発明は
生体内で酸化、還元、加水分解などの代謝を受けて本発
明化合物を生成する化合物をも包含する。The fused tetracyclic heterocyclic derivative represented by the above general formula (I) may form a salt with an acid. The present invention also includes a salt of compound (I). As the salt with an acid, for example, an inorganic acid salt with hydrochloric acid, hydrobromic acid, sulfuric acid, or acetic acid,
Examples thereof include organic acid salts with lactic acid, succinic acid, fumaric acid, maleic acid, citric acid, benzoic acid, methanesulfonic acid, p-toluenesulfonic acid and the like. It goes without saying that not only hydrates of these compounds but also all optical isomers are included when they exist. Further, the compound of the present invention also includes a compound which exhibits a strong antitumor activity, but exhibits an antitumor activity by being metabolized in vivo by metabolism such as oxidation, reduction, hydrolysis and conjugation. Furthermore, the present invention also includes a compound which is metabolized in vivo by metabolism such as oxidation, reduction and hydrolysis to produce the compound of the present invention.

【００１１】本発明化合物（Ｉ）は種々の方法によって
製造することができるが、それらのうち代表的な方法を
示せば以下の通りである。The compound (I) of the present invention can be produced by various methods. Among them, typical methods are shown below.

【００１２】１）一般式（II）1) General formula (II)

【化４】 Embedded image

【００１３】（式中、Ａａ環およびＢａ環は各々保護さ
れていてもよいＡ環およびＢ環を意味する。ｘ、ｅおよ
びｆは前記と同じ意味を示す）で表わされる化合物と一
般式（III)(In the formulae, Aa ring and Ba ring mean A ring and B ring which may be protected respectively. X, e and f have the same meanings as described above) and a general formula ( III)

【化５】 Embedded image

【００１４】（式中、ＤおよびＥは同一または異なって
脱離基を意味する）で表わされる化合物を反応させるこ
とにより製造することができる。本反応は一般に、例え
ばジメチルホルムアミド、テトラヒドロフラン、ジオキ
サンなどの非プロトン性の溶媒に化合物（II）を溶解
し、次に２〜３当量の水素化ナトリウムを加えた後、化
合物（III ）を加えることにより行なわれる。化合物
（III ）としては、例えば、ホスゲン、クロロ炭酸エチ
ル、Ｎ，Ｎ’−カルボニルジイミダゾールなどを挙げる
ことができる。反応は通常−50〜 150℃の温度範囲で行
なわれる。得られた生成物において、アミノ基、水酸基
などが保護されている場合には、酸処理、アルカリ処
理、接触還元など通常の脱保護法を行なうことにより、
目的とする化合物（Ｉ）を得ることが可能である。It can be produced by reacting a compound represented by the formula (wherein D and E are the same or different and each represents a leaving group). This reaction is generally carried out by dissolving the compound (II) in an aprotic solvent such as dimethylformamide, tetrahydrofuran or dioxane, and then adding 2-3 equivalents of sodium hydride, and then adding the compound (III). Performed by. Examples of compound (III) include phosgene, ethyl chlorocarbonate, N, N'-carbonyldiimidazole and the like. The reaction is usually performed in the temperature range of -50 to 150 ° C. In the obtained product, when the amino group, hydroxyl group, etc. are protected, by carrying out a usual deprotection method such as acid treatment, alkali treatment, catalytic reduction,
It is possible to obtain the target compound (I).

【００１５】２）一般式（IV）2) General formula (IV)

【化６】 [Chemical 6]

【００１６】（式中、Ａｂ環およびＢｂ環は、どちらか
一方または両方の環にアミノ基を有するＡ環およびＢ環
を意味する）で表わされる化合物を酸性下、亜硝酸ナト
リウムと反応させることによりジアゾニウム塩とし、つ
いで触媒の存在下または非存在下、求核試薬と反応させ
ることにより製造することができる。本反応は通常のザ
ンドマイヤー（Sandmeyer)反応またはそれに準じた反応
条件で行なうことができる。求核試薬としては、例えば
ハロゲン化第一銅、シアン化第一銅、硫酸−硝酸第二銅
−酸化第一銅などが挙げられる。またこれらを組み合わ
せて用いることもできる。Reacting a compound represented by the formula (wherein Ab ring and Bb ring are A ring and B ring having an amino group on either one or both rings) with sodium nitrite under acidic condition To give a diazonium salt, and then reacting with a nucleophile in the presence or absence of a catalyst. This reaction can be carried out under usual Sandmeyer reaction or reaction conditions similar thereto. Examples of the nucleophile include cuprous halide, cuprous cyanide, sulfuric acid-cupric nitrate-cuprous oxide, and the like. Moreover, these can also be used in combination.

【００１７】次に、本発明に用いられる原料化合物（I
I）を製造する方法について説明する。原料化合物（I
I）には、公知化合物および新規化合物が含まれる。新
規化合物の場合、既に報告されている公知化合物の合成
法を応用することにより、または、それらを組み合わせ
ることにより製造することが可能である。Next, the raw material compound (I
The method for producing I) will be described. Raw compound (I
I) includes known compounds and novel compounds. In the case of a new compound, it can be produced by applying a synthetic method of a known compound which has already been reported, or by combining them.

【００１８】製造法１Manufacturing method 1

【化７】 Embedded image

【００１９】（式中、Ａｃ環は、置換基を有していても
よい芳香環ではない単環を意味する。Ａａ、Ｂａ環、ｅ
およびｆは前記と同じ意味を示す。） 一般式（VII ）で表わされる化合物は、フィッシャー(F
ischer）のインドール合成法、ボルシェ（Borsche)のテ
トラヒドロカルバゾール合成法［オーガニック・シンセ
シス（Org. Syn.) IV, 884（1963）］などを応用するこ
とにより製造することができる。即ち、一般式（Ｖ）で
表わされる環式ケトンと一般式（VI）で表わされるｏ−
ヒドラジノ芳香族カルボン酸を例えば酢酸中またはギ酸
中あるいは塩酸、硫酸、塩化亜鉛などの酸触媒存在下エ
タノールなどの中性溶媒中加熱することにより製造する
ことができる。一般式（VIII）で表わされる化合物は、
化合物（VII ）を脱水素剤により脱水素することにより
製造することができる。脱水素剤としては、例えば２，
３−ジクロロ−５，６−ジシアノ−１，４−ベレゾキノ
ン、クロラニル、パラジウム−炭素などを挙げることが
できる。反応は通常室温または加熱下で行なわれる。目
的とする化合物（IIａ) は、化合物（VIII）と化合物
（IX）を縮合させることにより製造することができる。
縮合法としては、例えば、酸クロリド法、活性エステル
法、混合酸無水物法や縮合剤として、１，３−ジシクロ
ヘキシルカルボジイミド、Ｎ，Ｎ’−カルボニルジイミ
ダゾール、ジフェニルホスホリルアジドを用いる方法な
どがある。(In the formulae, the Ac ring means a monocyclic ring which is not an aromatic ring which may have a substituent. Aa, Ba ring, e
And f have the same meaning as described above. ) The compound represented by the general formula (VII) is
It can be produced by applying the indole synthesis method of Ischer, the tetrahydrocarbazole synthesis method of Borsche [Org. Syn. IV , 884 (1963)], and the like. That is, a cyclic ketone represented by the general formula (V) and an o-represented by the general formula (VI).
The hydrazino aromatic carboxylic acid can be produced, for example, by heating in acetic acid or formic acid or in a neutral solvent such as ethanol in the presence of an acid catalyst such as hydrochloric acid, sulfuric acid or zinc chloride. The compound represented by the general formula (VIII) is
It can be produced by dehydrogenating compound (VII) with a dehydrogenating agent. Examples of the dehydrogenating agent include 2,
3-dichloro-5,6-dicyano-1,4-berezoquinone, chloranil, palladium-carbon and the like can be mentioned. The reaction is usually performed at room temperature or under heating. The target compound (IIa) can be produced by condensing the compound (VIII) and the compound (IX).
Examples of the condensation method include an acid chloride method, an active ester method, a mixed acid anhydride method, and a method using 1,3-dicyclohexylcarbodiimide, N, N′-carbonyldiimidazole, diphenylphosphoryl azide as a condensing agent. .

【００２０】製造法２Manufacturing method 2

【化８】 Embedded image

【００２１】（式中、Ｇは酸素原子または硫黄原子を意
味する。ＫおよびＬは脱離基を意味し、Ｒは低級アルキ
ル基を意味する。Ａａ、Ｂａ、ｅおよびｆは前記と同じ
意味を示す。） 一般式（XII ）で表わされる化合物は、一般式（Ｘ）の
化合物と一般式（XI）の化合物を反応させることにより
製造することができる。化合物（XI）中の脱離基Ｋの好
ましい例としてはニトロ基を、Ｌの好ましい例として
は、ハロゲン原子を挙げることができる。反応は、トリ
エチルアミン、酢酸ナトリウム、水酸化ナトリウムなど
の塩基存在下または非存在下加熱することにより行なう
ことができる。目的とする化合物（IIｂ）は、化合物
（XII ）のエステルをアルカリ加水分解により化合物(X
III)に導き、これを製造法１と同様にして化合物（IX）
と縮合させることにより製造することができる。(Wherein G represents an oxygen atom or a sulfur atom. K and L represent a leaving group and R represents a lower alkyl group. Aa, Ba, e and f have the same meanings as described above. The compound represented by the general formula (XII) can be produced by reacting the compound of the general formula (X) with the compound of the general formula (XI). A preferable example of the leaving group K in the compound (XI) is a nitro group, and a preferable example of L is a halogen atom. The reaction can be carried out by heating in the presence or absence of a base such as triethylamine, sodium acetate or sodium hydroxide. The target compound (IIb) is obtained by subjecting the ester of the compound (XII) to alkaline hydrolysis.
III), and in the same manner as in Production method 1, the compound (IX)
It can be produced by condensation with.

【００２２】本発明化合物を医薬として使用する場合
は、経口もしくは非経口的に投与される。投与量は、症
状の程度、患者の年齢、性別、体重、感受性差、投与方
法、投与時期、投与間隔、医薬製剤の性質、調剤、種
類、有効成分の種類等によって異なり特に限定されない
が、通常成人１日あたり１〜3000mg、好ましくは約10〜
2000mg、さらに好ましくは20〜1000mgでありこれを通常
１日１〜３回に分けて投与する。経口用固形製剤を調製
する場合は、主薬に賦形剤さらに必要に応じて結合剤、
崩壊剤、滑沢剤、着色剤、矯味矯臭剤などを加えた後、
常法により錠剤、被覆錠剤、顆粒剤、細粒剤、散剤、カ
プセル剤等とする。賦形剤としては、例えば乳糖、コー
ンスターチ、白糖、ぶどう糖、ソルビット、結晶セルロ
ース、二酸化ケイ素などが、結合剤としては、例えばポ
リビニルアルコール、エチルセルロース、メチルセルロ
ース、アラビアゴム、ヒドロキシプロピルセルロース、
ヒドロキシプロピルメチルセルロース等が、滑沢剤とし
ては、例えばステアリン酸マグネシウム、タルク、シリ
カ等が、着色剤としては医薬品に添加することが許可さ
れているものが、矯味矯臭剤としては、ココア末、ハッ
カ脳、芳香酸、ハッカ油、龍脳、桂皮末等が用いられ
る。これらの錠剤、顆粒剤には糖衣、ゼラチン衣、その
他必要により適宜コーティングすることは勿論差し支え
ない。注射剤を調製する場合には、必要により主薬にｐ
Ｈ調整剤、緩衝剤、懸濁化剤、溶解補助剤、安定化剤、
等張化剤、保存剤などを添加し、常法により静脈、皮
下、筋肉内注射剤とする。その際必要により、常法によ
り凍結乾燥物とすることもある。懸濁化剤としては、例
えばメチルセルロース、ポリソルベート80、ヒドロキシ
エチルセルロース、アラビアゴム、トラガント末、カル
ボキシメチルセルロースナトリウム、ポリオキシエチレ
ンソルビタンモノラウレートなどを挙げることができ
る。溶解補助剤としては、例えばポリオキシエチレン硬
化ヒマシ油、ポリソルベート80、ニコチン酸アミド、ポ
リオキシエチレンソルビタンモノラウレート、マクロゴ
ール、ヒマシ油脂肪酸エチルエステルなどを挙げること
ができる。また安定化剤としては、例えば亜硫酸ナトリ
ウム、メタ亜硫酸ナトリウム等を、保存剤としては、例
えばパラオキシ安息香酸メチル、パラオキシ安息香酸エ
チル、ソルビン酸、フェノール、クレゾール、クロロク
レゾールなどを挙げることができる。When the compound of the present invention is used as a medicine, it is administered orally or parenterally. The dose is not particularly limited, although it varies depending on the degree of symptoms, age of patient, sex, weight, difference in sensitivity, administration method, administration time, administration interval, properties of pharmaceutical preparation, preparation, type, type of active ingredient, etc. Adults 1-3000mg per day, preferably about 10-
The dose is 2000 mg, more preferably 20 to 1000 mg, which is usually administered in 1 to 3 times daily. When preparing a solid preparation for oral use, the main ingredient is an excipient and further a binder, if necessary.
After adding disintegrant, lubricant, coloring agent, flavoring agent, etc.,
Tablets, coated tablets, granules, fine granules, powders, capsules and the like are prepared by a conventional method. Examples of the excipient include lactose, corn starch, sucrose, glucose, sorbitol, crystalline cellulose, silicon dioxide, and the like, and examples of the binder include polyvinyl alcohol, ethyl cellulose, methyl cellulose, gum arabic, hydroxypropyl cellulose,
Hydroxypropyl methylcellulose and the like, lubricants such as magnesium stearate, talc, and silica are those that are permitted to be added to pharmaceuticals as coloring agents, and as flavoring agents, cocoa powder, peppermint Brain, aromatic acid, peppermint oil, dragon brain, cinnamon powder and the like are used. Of course, these tablets and granules may be sugar-coated, gelatin-coated and optionally coated as needed. When preparing an injection, p should be added as the main drug if necessary.
H adjusting agent, buffering agent, suspending agent, solubilizing agent, stabilizing agent,
An isotonic agent, a preservative, etc. are added, and an intravenous, subcutaneous or intramuscular injection is prepared by a conventional method. At that time, if necessary, the product may be freeze-dried by a conventional method. Examples of the suspending agent include methyl cellulose, polysorbate 80, hydroxyethyl cellulose, gum arabic, tragacanth powder, sodium carboxymethyl cellulose, polyoxyethylene sorbitan monolaurate and the like. Examples of the solubilizing agent include polyoxyethylene hydrogenated castor oil, polysorbate 80, nicotinic acid amide, polyoxyethylene sorbitan monolaurate, macrogol, and castor oil fatty acid ethyl ester. Examples of the stabilizer include sodium sulfite, sodium metasulfite and the like, and examples of the preservative include methyl paraoxybenzoate, ethyl paraoxybenzoate, sorbic acid, phenol, cresol, chlorocresol and the like.

【００２３】[0023]

【発明の効果】次に本発明化合物の効果を記述するため
の薬理実験例を示す。 実験例１ Ｐ388 細胞（マウス白血病細胞）に対するin
vitro抗腫瘍試験 10％牛胎児血清、ペニシリン(100単位／ml）、ストレプ
トマイシン(100μg ／ml）、メルカプトエタノール（５
×10^-5Ｍ）およびピルビン酸ナトリウム（１mM）を含む
ＲＰＭＩ1640培地（三光純薬）に浮遊させたＰ388 細胞
を96穴Ｕ底マイクロプレートの各穴に1.25×10³ 個（0.
1ml)ずつ播種し、５％炭酸ガス含有の培養器中37℃で１
日培養した。Next, examples of pharmacological experiments for describing the effects of the compounds of the present invention will be shown. Experimental Example 1 in P388 cells (mouse leukemia cells)
In vitro antitumor test 10% fetal bovine serum, penicillin (100 units / ml), streptomycin (100 μg / ml), mercaptoethanol (5
(× 10 ⁻⁵ M) and sodium pyruvate (1 mM) were added to RPMI1640 medium (Sanko Junyaku Co., Ltd.), and P388 cells were suspended in each well of a 96-well U-bottom microplate at 1.25 × 10 ³ cells (0.
1 ml) and seeded at 37 ℃ in an incubator containing 5% carbon dioxide gas.
Cultured for one day.

【００２４】本発明化合物をジメチルスルホキシドにて
10^-2Ｍの濃度に溶解し、10％牛胎児血清−ＲＰＭＩ1640
培養液で10^-4Ｍあるいは10^-5Ｍの濃度まで希釈した。こ
れを最高濃度として10％牛胎児血清−ＲＰＭＩ1640培養
液にて３倍系列希釈を行った。これを先に述べたＰ388
細胞の培養プレートの各穴に0.1ml ずつ加え、５％炭酸
ガス含有培養器中37℃で３日間培養した。The compound of the present invention was treated with dimethyl sulfoxide.
Dissolve at a concentration of 10 ^-2 M and 10% fetal bovine serum-RPMI1640
The medium was diluted to a concentration of 10 ⁻⁴ M or 10 ⁻⁵ M. Using this as the highest concentration, 3-fold serial dilution was performed with 10% fetal bovine serum-RPMI 1640 culture solution. This is P388 mentioned earlier.
0.1 ml of each was added to each well of the cell culture plate and cultured at 37 ° C. for 3 days in a culture vessel containing 5% carbon dioxide.

【００２５】培養後、ＭＴＴ［３−（４，５−ジメチル
チアゾール−２−イル）−２，５−ジフェニルテトラゾ
リウムブロミド］溶液（3.3mg ／ml）を0.05mlずつ各穴
に加え、さらに２時間培養した。マイクロプレートを遠
心し、各穴から上清を吸引除去後、生成したホルマザン
をジメチルスルホキシド 0.1mlで溶解し、マイクロプレ
ートリーダーで 540nmにおける吸光度を測定し、生細胞
数の指標とした。以下の式より抑制率を算出し、50％抑
制する被検化合物の濃度（ＩＣ₅₀）を求めた。After culturing, 0.05 ml of MTT [3- (4,5-dimethylthiazol-2-yl) -2,5-diphenyltetrazolium bromide] solution (3.3 mg / ml) was added to each well for another 2 hours. Cultured. After centrifuging the microplate and removing the supernatant by suction from each well, the produced formazan was dissolved in 0.1 ml of dimethyl sulfoxide, and the absorbance at 540 nm was measured with a microplate reader, which was used as an index of the number of viable cells. The inhibition rate was calculated from the following formula, and the concentration of the test compound that inhibited 50% (IC ₅₀ ) was determined.

【００２６】[0026]

【数１】 [Equation 1]

【００２７】 Ｔ：被検化合物を添加した穴の吸光度 Ｃ：被検化合物を添加しなかった穴の吸光度 得られたＩＣ₅₀値を表１に示す。T: Absorbance of the hole to which the test compound was added C: Absorbance of the hole to which the test compound was not added The obtained IC ₅₀ values are shown in Table 1.

【００２８】[0028]

【表１】 [Table 1]

【００２９】実験例２ ＫＢ細胞（ヒト鼻咽腔癌細胞）
に対するin vitro抗腫瘍試験 10％牛胎児血清、ペニシリン(100単位／ml）、ストレプ
トマイシン(100μg ／ml）、メルカプトエタノール（５
×10^-5Ｍ）およびピルビン酸ナトリウム（１mM）を含む
ＲＰＭＩ1640培地（三光純薬）に浮遊させたＫＢ細胞を
96穴平底マイクロプレートの各穴に1.25×10³ 個（0.1m
l)ずつ播種し、５％炭酸ガス含有の培養器中37℃で１日
培養した。本発明化合物をジメチルスルホキシドにて10
^-2Ｍの濃度に溶解し、10％牛胎児血清−ＲＰＭＩ1640培
養液で10^-4Ｍあるいは10^-5Ｍの濃度まで希釈した。これ
を最高濃度として10％牛胎児血清−ＲＰＭＩ1640培養液
にて３倍系列希釈を行った。これを先に述べたＫＢ細胞
の培養プレートの各穴に 0.1mlずつ加え、５％炭酸ガス
含有培養器中37℃で３日間培養した。Experimental Example 2 KB cells (human nasopharyngeal carcinoma cells)
In vitro antitumor test against 10% fetal bovine serum, penicillin (100 units / ml), streptomycin (100 μg / ml), mercaptoethanol (5
KB cells suspended in RPMI1640 medium (Sanko Junyaku Co., Ltd.) containing × 10 ^-5 M) and sodium pyruvate (1 mM)
1.25 x 10 ³ (0.1 m
l), and the cells were cultured at 37 ° C. for 1 day in an incubator containing 5% carbon dioxide. The compound of the present invention was treated with dimethyl sulfoxide to give 10
^It was dissolved at a concentration of ^-2 M and diluted with 10% fetal calf serum-RPMI1640 culture medium to a concentration of 10 ^-4 M or 10 ^-5 M. Using this as the highest concentration, 3-fold serial dilution was performed with 10% fetal bovine serum-RPMI 1640 culture solution. 0.1 ml of this was added to each well of the culture plate of KB cells described above, and the mixture was cultured at 37 ° C. for 3 days in a culture vessel containing 5% carbon dioxide.

【００３０】培養後、ＭＴＴ［３−（４，５−ジメチル
チアゾール−２−イル）−２，５−ジフェニルテトラゾ
リウムブロミド］溶液(3.3mg／ml）を0.05mlずつ各穴に
加え、さらに２時間培養した。各穴から上清を吸引除去
後、生成したホルマザンをジメチルスルホキシド 0.1ml
で溶解し、マイクロプレートリーダーで 540nmにおける
吸光度を測定し、生細胞数の指標とした。以下の式より
抑制率を算出し、50％抑制する被検化合物の濃度（ＩＣ
₅₀）を求めた。After culturing, 0.05 ml of MTT [3- (4,5-dimethylthiazol-2-yl) -2,5-diphenyltetrazolium bromide] solution (3.3 mg / ml) was added to each well for another 2 hours. Cultured. After removing the supernatant from each well by suction, remove the formed formazan by adding 0.1 ml of dimethyl sulfoxide.
The cells were lysed and the absorbance at 540 nm was measured with a microplate reader and used as an index of the number of living cells. The inhibition rate was calculated from the following formula, and the concentration of the test compound that inhibited 50% (IC
₅₀ ) asked.

【００３１】[0031]

【数２】 [Equation 2]

【００３２】 Ｔ：被検化合物を添加した穴の吸光度 Ｃ：被検化合物を添加しなかった穴の吸光度 得られたＩＣ₅₀値を表２に示す。T: Absorbance of the hole to which the test compound was added C: Absorbance of the hole to which the test compound was not added The obtained IC ₅₀ values are shown in Table 2.

【００３３】[0033]

【表２】 [Table 2]

【００３４】実験例３ Ｍ5076（マウス細網肉腫）に対
するin vivo 抗腫瘍試験 ＢＤＦ１マウス（６〜７週齢、雌）の体側皮下に１×10
⁶ 個のＭ5076を移植した。本発明の化合物を５％ブドウ
糖液に溶解し、移植した翌日以降に各スケジュールによ
り１日１回腹腔内投与した。対照群には５％ブドウ糖液
を投与した。対照群は１群10匹、薬剤投与群は１群５匹
で実験を行った。移植後21日目に腫瘍を摘出し、腫瘍重
量を測定した。対照群に対する薬剤投与群の腫瘍増殖抑
制率を下記式より求めた。 増殖抑制率（％）＝Ｃ−Ｔ／Ｃ×100 Ｔ；被検化合物投与群の平均腫瘍重量 Ｃ：対照群の平均腫瘍重量 実験結果を表３に示す。Experimental Example 3 In vivo antitumor test against M5076 (mouse reticulosarcoma) BDF1 mice (6 to 7 weeks of age, female) were subcutaneously implanted on the lateral side of the body at 1 × 10 5.
^Six M5076 were transplanted. The compound of the present invention was dissolved in 5% glucose solution, and intraperitoneally administered once a day according to each schedule on and after the day after transplantation. The control group was administered with 5% glucose solution. The experiment was carried out with 10 mice as a control group and 5 mice as a drug administration group. The tumor was excised 21 days after the transplantation and the tumor weight was measured. The tumor growth inhibition rate of the drug-administered group relative to the control group was determined by the following formula. Growth inhibition rate (%) = C−T / C × 100 T; average tumor weight of test compound administration group C: average tumor weight of control group Experimental results are shown in Table 3.

【００３５】[0035]

【表３】 [Table 3]

【００３６】上記実験例から明らかな様に本発明化合物
は優れた抗腫瘍効果を有し、抗腫瘍剤として有用であ
る。As is clear from the above experimental examples, the compound of the present invention has an excellent antitumor effect and is useful as an antitumor agent.

【００３７】[0037]

【実施例】次に本発明化合物の原料化合物の製造を示す
製造例および発明化合物の代表的化合物についての実施
例を挙げるが、本発明がこれらにのみ限定されるもので
はない。EXAMPLES Next, Production Examples showing production of starting compounds of the compounds of the present invention and Examples of representative compounds of the invention compounds will be shown, but the present invention is not limited thereto.

【００３８】製造例１ ９Ｈ−カルバゾール−１−カルボン酸Production Example 1 9H-carbazole-1-carboxylic acid

【化９】 Embedded image

【００３９】２−ヒドラジノ安息香酸塩酸塩 19.8g（0.
105mol) の酢酸（180ml)懸濁液を緩和に沸騰させ、攪拌
下シクロヘキサノン10.4ml（0.100mol) の酢酸（20ml)
溶液を10分要して滴下した。加え終わった後６時間加熱
還流し、放冷後ゆっくりと水（lL) を加えた。沈殿した
成績体を吸引濾取、水で洗浄後乾燥し、５，６，７，８
−テトラヒドロ−９Ｈ−カルバゾール−１−カルボン酸
10.0g（収率46％）を得た。続いて、５，６，７，８−
テトラヒドロ−９Ｈ−カルバゾール−１−カルボン酸4.
3g（20mmol) 及び２，３−ジクロロ−５，６−ジシアノ
−ｐ−ベンゾキノン10g （44mmol）をトルエン（100ml)
に懸濁し、２時間加熱還流した。放冷後沈殿した成績体
を吸引濾取し、シリカゲルカラムクロマトグラフィー
（ジクロロメタン：メタノール＝９：１で溶出）にて精
製し、表題化合物 2.46g（収率58％）を得た。¹ HNMR (DMSO-d₆）δ（ppm)；7.19-7.23(m,1H),7.26(t,J
=7.6Hz,1H),7.40-7.45(m,1H),7.74(d,J=8.0Hz,1H),8.00
(dd,J=0.8,7.6Hz,1H),8.17(d,J=7.6Hz,1H),8.41(dd,J=
0.8,7.6Hz,1H),11.34(br-s,1H),13.18(br-s,1H)2-hydrazinobenzoic acid hydrochloride 19.8 g (0.
A suspension of 105 mol) of acetic acid (180 ml) is gently boiled and stirred with cyclohexanone 10.4 ml (0.100 mol) of acetic acid (20 ml).
The solution was added dropwise over 10 minutes. After the addition was completed, the mixture was heated under reflux for 6 hours, allowed to cool, and water (1 L) was slowly added. The precipitated product is filtered off with suction, washed with water and dried to give 5, 6, 7, 8
-Tetrahydro-9H-carbazole-1-carboxylic acid
10.0 g (yield 46%) was obtained. Then, 5, 6, 7, 8-
Tetrahydro-9H-carbazole-1-carboxylic acid 4.
Toluene (100 ml) was added 3 g (20 mmol) and 2,3-dichloro-5,6-dicyano-p-benzoquinone (10 g, 44 mmol).
And was heated to reflux for 2 hours. After cooling down, the precipitate that precipitated was collected by suction filtration and purified by silica gel column chromatography (eluting with dichloromethane: methanol = 9: 1) to obtain 2.46 g (yield 58%) of the title compound. ¹ HNMR (DMSO-d ₆ ) δ (ppm); 7.19-7.23 (m, 1H), 7.26 (t, J
= 7.6Hz, 1H), 7.40-7.45 (m, 1H), 7.74 (d, J = 8.0Hz, 1H), 8.00
(dd, J = 0.8,7.6Hz, 1H), 8.17 (d, J = 7.6Hz, 1H), 8.41 (dd, J =
0.8,7.6Hz, 1H), 11.34 (br-s, 1H), 13.18 (br-s, 1H)

【００４０】製造例２ ６−アセチル−９Ｈ−カルバゾール−１−カルボン酸Production Example 2 6-Acetyl-9H-carbazole-1-carboxylic acid

【化１０】 Embedded image

【００４１】塩化アルミニウム、無水 880mg（6.6mmol)
のクロロホルム（20ml) 懸濁液に無水酢酸0.21ml（2.2m
mol)を加え、室温にて攪拌した後、氷冷下、製造例１の
化合物 420mg（２mmol）のクロロホルム（20ml) 懸濁液
を一度に加えた。加え終わった後ゆっくりと室温に戻し
終夜攪拌した。これをゆっくりと氷にあけ、１Ｎ塩酸を
加え、塩化アルミニウムを分解した。酢酸エチル及びテ
トラヒドロフランを用いて抽出し、有機層を飽和炭酸水
素ナトリウム水溶液、水、飽和食塩水で洗浄し、無水硫
酸マグネシウムで乾燥後濃縮した。残渣をシリカゲルカ
ラムクロマトグラフィー（ジクロロメタン：エタノール
＝４：１）にて精製し、表題化合物 370mg（収率75％）
を得た。¹ HNMR (DMSO-d₆）δ(ppm）；2.68(s,3H),7.34(t,J=7.6H
z,1H),7.80(d,J=8.8Hz,1H),8.03-8.06(m,1H),8.06(dd,J
=1.6,8.8Hz,1H),8.55(d,J=7.6Hz,1H),8.91(d,J=1.6Hz,1
H),11.73(br-s,1H)Aluminum chloride, anhydrous 880 mg (6.6 mmol)
0.21 ml of acetic anhydride (2.2 m
mol) was added and the mixture was stirred at room temperature, and then a suspension of 420 mg (2 mmol) of the compound of Production Example 1 in chloroform (20 ml) was added all at once under ice cooling. After the addition was completed, the temperature was slowly returned to room temperature and the mixture was stirred overnight. This was slowly poured into ice and 1N hydrochloric acid was added to decompose aluminum chloride. The mixture was extracted with ethyl acetate and tetrahydrofuran, the organic layer was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (dichloromethane: ethanol = 4: 1) to give the title compound (370 mg, yield 75%).
I got ¹ HNMR (DMSO-d ₆ ) δ (ppm); 2.68 (s, 3H), 7.34 (t, J = 7.6H
z, 1H), 7.80 (d, J = 8.8Hz, 1H), 8.03-8.06 (m, 1H), 8.06 (dd, J
= 1.6,8.8Hz, 1H), 8.55 (d, J = 7.6Hz, 1H), 8.91 (d, J = 1.6Hz, 1
H), 11.73 (br-s, 1H)

【００４２】製造例３ Ｎ−［２−（ジメチルアミノ）エチル］−６−ニトロ−
９Ｈ−カルバゾール−１−カルボキサミド（１）および
Ｎ−［２−（ジメチルアミノ）エチル］−３−ニトロ−
９Ｈ−カルバゾール−１−カルボキサミド（２）Production Example 3 N- [2- (dimethylamino) ethyl] -6-nitro-
9H-carbazole-1-carboxamide ( 1 ) and N- [2- (dimethylamino) ethyl] -3-nitro-
9H-carbazole-1-carboxamide ( 2 )

【化１１】 Embedded image

【００４３】カルバゾール−１−カルボン酸2.0g（9.5m
mol)の酢酸（250ml)溶液に冷水浴中、攪拌下、硝酸カリ
ウム 1.01g (10mmol）の濃硫酸（2.5ml)溶液を滴下し
た。室温終夜攪拌した後ゆっくりと水（500ml)を加え、
沈殿した生成物を濾取、水で洗浄後乾燥し、ニトロカル
バゾール−１−カルボン酸の位置異性体混合物2.3gを得
た。これをＮ，Ｎ−ジメチルホルムアミド 100mlに溶解
し、１，１−カルボニルジイミダゾール2.9g（18mmol)
を加え２時間攪拌した。次いでＮ，Ｎ−ジメチルエチレ
ンジアミン４ml（36mmol) を加え終夜攪拌した。水を加
えた後、生成物を酢酸エチルを用いて抽出し、有機層を
水、飽和炭酸水素ナトリウム水溶液、飽和食塩水で洗浄
し濃縮した。残渣をシリカゲルカラムクロマトグラフィ
ー（ジクロロメタン：エタノールで溶出）により分離精
製し、Ｎ−［２−（ジメチルアミノ）エチル］−６−ニ
トロ−９Ｈ−カルバゾール−１−カルボキサミド（１）
を1.46g （収率47.4％）、及びＮ−［２−（ジメチルア
ミノ）エチル］−３−ニトロ−９Ｈ−カルバゾール−１
−カルボキサミド（２）を 210mg（収率 6.8％）得た。 ６−ニトロ体（１，塩酸塩として）¹ HNMR (DMSO-d₆）δ(ppm）；2.85(br-s,6H),3.26-3.38
(m,2H),3.73(q,J=5.6Hz,2H),7.38(t,J=7.6Hz,1H),7.86
(d,J=9.0Hz,1H),8.09(d,J=7.6Hz,1H),8.32(dd,J=2.2,9.
0Hz,1H),8.60(d,J=7.6Hz,1H),9.04(t,J=5.6Hz,1H),9.22
(d,J=2.2Hz,1H),9.93(br-s,1H),12.14(s,1H) ３−ニトロ体（２，塩酸塩として）¹ HNMR (DMSO-d₆）δ(ppm）；2.84(br-s,6H),3.20-3.40
(m,2H),3.65-3.80(m,2H),7.31(t,J=7.6Hz,1H),7.52(t,J
=7.6Hz,1H),7.81(d,J=7.6Hz,1H),8.41(d,J=7.6Hz,1H),
8.90(d,J=2.0Hz,1H),9.20-9.28(m,1H),9.35(d,J=2.0Hz,
1H),9.64-9.86(m,1H),12.14(br-s,1H)Carbazole-1-carboxylic acid 2.0 g (9.5 m
To a solution of (mol) in acetic acid (250 ml) was added dropwise a solution of 1.01 g (10 mmol) of potassium nitrate in concentrated sulfuric acid (2.5 ml) in a cold water bath with stirring. After stirring overnight at room temperature, slowly add water (500 ml),
The precipitated product was collected by filtration, washed with water and dried to give 2.3 g of a mixture of regioisomers of nitrocarbazole-1-carboxylic acid. This was dissolved in 100 ml of N, N-dimethylformamide, and 2.9 g (18 mmol) of 1,1-carbonyldiimidazole
Was added and stirred for 2 hours. Next, 4 ml (36 mmol) of N, N-dimethylethylenediamine was added and the mixture was stirred overnight. After adding water, the product was extracted with ethyl acetate, and the organic layer was washed with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and concentrated. The residue was separated and purified by silica gel column chromatography (eluting with dichloromethane: ethanol), and N- [2- (dimethylamino) ethyl] -6-nitro-9H-carbazole-1-carboxamide ( 1 ).
Of 1.46 g (yield 47.4%), and N- [2- (dimethylamino) ethyl] -3-nitro-9H-carbazole-1.
-210 mg (yield 6.8%) of carboxamide ( 2 ) was obtained. 6-nitro form ( 1 , as hydrochloride) ¹ HNMR (DMSO-d ₆ ) δ (ppm); 2.85 (br-s, 6H), 3.26-3.38
(m, 2H), 3.73 (q, J = 5.6Hz, 2H), 7.38 (t, J = 7.6Hz, 1H), 7.86
(d, J = 9.0Hz, 1H), 8.09 (d, J = 7.6Hz, 1H), 8.32 (dd, J = 2.2,9.
0Hz, 1H), 8.60 (d, J = 7.6Hz, 1H), 9.04 (t, J = 5.6Hz, 1H), 9.22
(d, J = 2.2Hz, 1H), 9.93 (br-s, 1H), 12.14 (s, 1H) 3-nitro compound ( 2 , as hydrochloride) ¹ HNMR (DMSO-d ₆ ) δ (ppm); 2.84 (br-s, 6H), 3.20-3.40
(m, 2H), 3.65-3.80 (m, 2H), 7.31 (t, J = 7.6Hz, 1H), 7.52 (t, J
= 7.6Hz, 1H), 7.81 (d, J = 7.6Hz, 1H), 8.41 (d, J = 7.6Hz, 1H),
8.90 (d, J = 2.0Hz, 1H), 9.20-9.28 (m, 1H), 9.35 (d, J = 2.0Hz,
1H), 9.64-9.86 (m, 1H), 12.14 (br-s, 1H)

【００４４】実施例１ ２−［２−（ジメチルアミノ）エチル］−１Ｈ−ピリミ
ド［５，６，１−ｊｋ］カルバゾール−１，３（２Ｈ）
−ジオン 塩酸塩Example 1 2- [2- (Dimethylamino) ethyl] -1H-pyrimido [5,6,1-jk] carbazole-1,3 (2H)
-Dione hydrochloride

【化１２】 Embedded image

【００４５】製造例１の化合物 1.06g（５mmol）をＮ，
Ｎ−ジメチルホルムアミド（50ml)に溶解し、Ｎ，Ｎ’
−カルボニルジイミダゾール 1.62g（10mmol）を加え室
温にて30分間攪拌した。続いてＮ，Ｎ−ジメチルエチレ
ンジアミン 2.2ml（20mmol）を加え終夜攪拌した。溶媒
を減圧留去した後、水を加え、酢酸エチル及びテトラヒ
ドロフランを用いて抽出した。有機層を飽和炭酸水素ナ
トリウム水溶液、水、飽和食塩水で洗浄し、無水硫酸マ
グネシウムで乾燥後濃縮した。残渣をシリカゲルカラム
クロマトグラフィー（ジクロロメタン：メタノール＝2
0：１で溶出）にて精製し、Ｎ−［２−（ジメチルアミ
ノ）エチル］−９Ｈ−カルバゾール−１−カルボキサミ
ド1.4g（定量的）を得た。このＮ−［２−（ジメチルア
ミノ）エチル］−９Ｈ−カルバゾール−１−カルボキサ
ミド 350mg（1.24mmol）をＮ，Ｎ−ジメチルホルムアミ
ド（20ml) に溶解し、窒素気流下、水素化ナトリウム
（油性)110mg（2.74mmol) を加え、30分後、氷冷下クロ
ロぎ酸エチル0.12ml（1.25mmol) を加え、30分間攪拌し
た。１Ｎ塩酸を加え酸性とし、溶媒を減圧留去した後、
飽和炭酸水素ナトリウム水溶液を加え弱アルカリ性とし
て、酢酸エチル及びテトラヒドロフランを用いて抽出し
た。有機層を水、飽和食塩水で洗浄し、無水硫酸マグネ
シウムで乾燥後濃縮した。これにエタノール＋１Ｎ塩酸
を加え終夜攪拌した。析出した結晶を濾取し表題化合物
200mg（収率47％）を得た。¹ HNMR (DMSO-d₆）δ（ppm)；2.90(br-s,6H),3.44-3.49
(m,2H),4.41(t,J=5.6Hz,2H),7.55-7.60(m,1H),7.67-7.7
2(m,2H),8.10(dd,J=0.8,7.6Hz,1H),8.34-8.37(m,1H),8.
38-8.41(m,1H),8.58(dd,J=0.8,7.6Hz,1H),9.62(br-s,1
H) 1.06 g (5 mmol) of the compound of Preparation Example 1 was added to N,
Dissolved in N-dimethylformamide (50 ml) to give N, N '
-Carbonyldiimidazole (1.62 g, 10 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. Then, 2.2 ml (20 mmol) of N, N-dimethylethylenediamine was added and stirred overnight. The solvent was distilled off under reduced pressure, water was added, and the mixture was extracted with ethyl acetate and tetrahydrofuran. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography (dichloromethane: methanol = 2).
Purification by elution at 0: 1) gave 1.4 g (quantitative) of N- [2- (dimethylamino) ethyl] -9H-carbazole-1-carboxamide. 350 mg (1.24 mmol) of this N- [2- (dimethylamino) ethyl] -9H-carbazole-1-carboxamide was dissolved in N, N-dimethylformamide (20 ml), and 110 mg of sodium hydride (oil-based) under a nitrogen stream. (2.74 mmol) was added, and after 30 minutes, 0.12 ml (1.25 mmol) of ethyl chloroformate was added under ice cooling, and the mixture was stirred for 30 minutes. After 1N hydrochloric acid was added to acidify and the solvent was distilled off under reduced pressure,
A saturated aqueous sodium hydrogen carbonate solution was added to make the mixture weakly alkaline, and the mixture was extracted with ethyl acetate and tetrahydrofuran. The organic layer was washed with water and saturated saline, dried over anhydrous magnesium sulfate and concentrated. Ethanol + 1N hydrochloric acid was added thereto, and the mixture was stirred overnight. The precipitated crystals were collected by filtration to give the title compound
200 mg (47% yield) were obtained. ¹ HNMR (DMSO-d ₆ ) δ (ppm); 2.90 (br-s, 6H), 3.44-3.49
(m, 2H), 4.41 (t, J = 5.6Hz, 2H), 7.55-7.60 (m, 1H), 7.67-7.7
2 (m, 2H), 8.10 (dd, J = 0.8,7.6Hz, 1H), 8.34-8.37 (m, 1H), 8.
38-8.41 (m, 1H), 8.58 (dd, J = 0.8,7.6Hz, 1H), 9.62 (br-s, 1
H)

【００４６】実施例２ ８−アセチル−２−［２−（ジメチルアミノ）エチル］
−１Ｈ−ピリミド［５，６，１−ｊｋ］カルバゾール−
１，３（２Ｈ）−ジオン 塩酸塩Example 2 8-Acetyl-2- [2- (dimethylamino) ethyl]
-1H-pyrimido [5,6,1-jk] carbazole-
1,3 (2H) -dione hydrochloride

【化１３】 Embedded image

【００４７】製造例２の化合物 300mg (1.2mmol)をＮ，
Ｎ−ジメチルホルムアミド（20ml)に溶解し、Ｎ，Ｎ’
−カルボニルジイミダゾール 400mg (2.4mmol)を加え室
温にて30分間攪拌した。続いてＮ，Ｎ−ジメチルエチレ
ンジアミン0.53ml（4.8mmol）を加え終夜攪拌した。溶
媒を減圧留去した後、水を加え、酢酸エチルを用いて抽
出した。有機層を飽和炭酸水素ナトリウム水溶液、水、
飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥後濃
縮した。残渣をエタノールに溶解し、ヘキサンを加えて
結晶化させ、Ｎ−［２−（ジメチルアミノ）エチル］−
８−アセチル−９Ｈ−カルバゾール−１−カルボキサミ
ド 180mgを得た。これをＮ，Ｎ−ジメチルホルムアミド
（10ml) に溶解し、窒素気流下、水素化ナトリウム（油
性）56mg（1.4mmol)を加え、30分後、氷冷下クロロぎ酸
エチル0.14ml（1.4mmol)を加え、10分間攪拌した。１Ｎ
塩酸を加え酸性とし、溶媒を減圧留去した後、飽和炭酸
水素ナトリウム水溶液を加え弱アルカリ性として、酢酸
エチルを用いて抽出した。有機層を水、飽和食塩水で洗
浄し、無水硫酸マグネシウムで乾燥後濃縮した。残渣を
シリカゲルカラムクロマトグラフィー（ジクロロメタ
ン: エタノール＝９：１で溶出）にて精製した。これを
エタノールに懸濁し、１Ｎ塩酸を加え終夜攪拌した。析
出した結晶を濾取し表題化合物 125mg（収率27％）を得
た。融点；240 ℃より湿潤し始め、258 ℃より着色し始
め、270 ℃にて1/2 が湿潤着色し、281 〜 284℃にて全
体が浸潤、褐色に着色しガスを発生し分解した。 ＦＡＢ質量分析ｍ／ｚ；350(MH⁺)¹ HNMR (DMSO-d₆）δ(ppm）；2.75(s,3H),2.90-2.94(m,6
H),3.48-3.52(m,2H),4.42(t,J=5.6Hz,2H),7.75(t,J=8.0
Hz,1H),8.16(d,J=8.0Hz,1H),8.31(dd,J=1.6,8.8Hz,1H),
8.49(d,J=8.8Hz,1H),8.73(d,J=8.0Hz,1H),9.05(d,J=1.6
Hz,1H),9.44(br-s,1H) 300 mg (1.2 mmol) of the compound of Preparation Example 2 was added to N,
Dissolved in N-dimethylformamide (20 ml) to give N, N '
-Carbonyldiimidazole (400 mg, 2.4 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. Then, 0.53 ml (4.8 mmol) of N, N-dimethylethylenediamine was added and stirred overnight. The solvent was distilled off under reduced pressure, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate, water,
The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was dissolved in ethanol, hexane was added for crystallization, and N- [2- (dimethylamino) ethyl]-
180 mg of 8-acetyl-9H-carbazole-1-carboxamide was obtained. This was dissolved in N, N-dimethylformamide (10 ml), and under a nitrogen stream, 56 mg (1.4 mmol) of sodium hydride (oil) was added, and after 30 minutes, 0.14 ml (1.4 mmol) of ethyl chloroformate under ice cooling. Was added and stirred for 10 minutes. 1N
Hydrochloric acid was added to make the mixture acidic, the solvent was distilled off under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added to make the mixture weakly alkaline, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (dichloromethane: ethanol = 9: 1). This was suspended in ethanol, 1N hydrochloric acid was added, and the mixture was stirred overnight. The precipitated crystals were collected by filtration to give the title compound (125 mg, yield 27%). Melting point: Wetting started at 240 ° C., coloring started at 258 ° C., 1/2 wet coloring at 270 ° C., whole infiltrated at 281 to 284 ° C., colored brown, and gas was generated to decompose. FAB mass spectrometry m / z; 350 (MH ⁺ ) ¹ HNMR (DMSO-d ₆ ) δ (ppm); 2.75 (s, 3H), 2.90-2.94 (m, 6)
H), 3.48-3.52 (m, 2H), 4.42 (t, J = 5.6Hz, 2H), 7.75 (t, J = 8.0
Hz, 1H), 8.16 (d, J = 8.0Hz, 1H), 8.31 (dd, J = 1.6,8.8Hz, 1H),
8.49 (d, J = 8.8Hz, 1H), 8.73 (d, J = 8.0Hz, 1H), 9.05 (d, J = 1.6
Hz, 1H), 9.44 (br-s, 1H)

【００４８】実施例３ ２−［２−（ジメチルアミノ）エチル］−８−ニトロ−
１Ｈ−ピリミド［５，６，１−ｊｋ］カルバゾール−
１，３（２Ｈ）−ジオン 塩酸塩Example 3 2- [2- (Dimethylamino) ethyl] -8-nitro-
1H-pyrimido [5,6,1-jk] carbazole-
1,3 (2H) -dione hydrochloride

【化１４】 Embedded image

【００４９】製造例３のＮ−［２−（ジメチルアミノ）
エチル］−６−ニトロ−９Ｈ−カルバゾール−１−カル
ボキサミド 5.82gをＮ，Ｎ−ジメチルホルムアミド(200
ml）に溶解し、窒素気流下、水素化ナトリウム（油性）
1.75g （40mmol) を加え、１時間攪拌後、氷冷下クロロ
ぎ酸エチル 3.8ml (40mmol）のジクロロメタン（10ml)
溶液を加え、30分間攪拌した。１Ｎ塩酸を加え酸性に
し、析出した沈殿を濾取した。エタノールを加え加熱
し、冷後沈殿を濾取し、表題化合物 5.54g（収率36％）
を得た。¹ HNMR (DMSO-d₆）δ(ppm）；2.89(br-s,6H),3.46-3.50
(m,2H),4.43(t,J=5.6Hz,2H),7.76(t,J=7.6Hz,1H),8.19
(d,J=7.6Hz,1H),8.53-8.60(m,2H),8.80(d,J=7.6Hz,1H),
9.38(d,J=2.0Hz,1H),10.18(br-s,1H) N- [2- (dimethylamino) of Production Example 3
5.82 g of ethyl] -6-nitro-9H-carbazole-1-carboxamide was added to N, N-dimethylformamide (200
ml), and under a nitrogen stream, sodium hydride (oil-based)
After adding 1.75g (40mmol) and stirring for 1 hour, under ice cooling, ethyl chloroformate 3.8ml (40mmol) in dichloromethane (10ml)
The solution was added and stirred for 30 minutes. 1N Hydrochloric acid was added to acidify, and the deposited precipitate was collected by filtration. Ethanol was added and heated, and after cooling, the precipitate was collected by filtration and the title compound 5.54 g (yield 36%)
I got ¹ HNMR (DMSO-d ₆ ) δ (ppm); 2.89 (br-s, 6H), 3.46-3.50
(m, 2H), 4.43 (t, J = 5.6Hz, 2H), 7.76 (t, J = 7.6Hz, 1H), 8.19
(d, J = 7.6Hz, 1H), 8.53-8.60 (m, 2H), 8.80 (d, J = 7.6Hz, 1H),
9.38 (d, J = 2.0Hz, 1H), 10.18 (br-s, 1H)

【００５０】実施例４ ８−アミノ−２−［２−（ジメチルアミノ）エチル］−
１Ｈ−ピリミド［５，６，１−ｊｋ］カルバゾール−
１，３（２Ｈ）−ジオン 塩酸塩Example 4 8-Amino-2- [2- (dimethylamino) ethyl]-
1H-pyrimido [5,6,1-jk] carbazole-
1,3 (2H) -dione hydrochloride

【化１５】 Embedded image

【００５１】実施例３の化合物 5.54g (14mmol) を酢酸
（200ml)及び１Ｎ塩酸に懸濁し、10％パラジウム炭素
（50％含水) 550mg を加え常圧水素気流下室温にて終夜
攪拌した。触媒を濾去し、溶媒を減圧留去した後、水、
飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルを用
いて抽出した。有機層を水、飽和食塩水で洗浄し、無水
硫酸マグネシウムで乾燥後濃縮乾固した。エタノールを
加え加熱し、冷後沈殿を濾取し、表題化合物の遊離塩基
3.74g (収率81％）を得た。このうち 430mg (1.3mmol)
をエタノール（20ml) に懸濁し、１Ｎ塩酸（1.5ml)を加
え終夜攪拌した。析出した結晶を濾取し表題化合物 480
mg（定量的）を得た。¹ HNMR (DMSO-d₆）δ（ppm)；2.91(br-s,6H),3.44-3.50
(m,2H),4.39(t,J=5.6Hz,2H),7.04-7.08(m,1H),7.54-7.5
6(m,1H),7.63(t,J=7.6Hz,1H),8.05(dd,J=0.8,7.6Hz,1
H),8.12(d,J=8.8Hz,1H),8.44(dd,J=0.8,7.6Hz,1H),9.60
(br-s,1H) 5.54 g (14 mmol) of the compound of Example 3 was suspended in acetic acid (200 ml) and 1N hydrochloric acid, 10% palladium carbon (containing 50% water) (550 mg) was added, and the mixture was stirred overnight at room temperature under a hydrogen atmosphere at atmospheric pressure. After removing the catalyst by filtration and distilling off the solvent under reduced pressure, water,
A saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated to dryness. Ethanol was added and heated, and after cooling, the precipitate was collected by filtration and used as the free base of the title compound.
3.74 g (yield 81%) was obtained. Of this, 430 mg (1.3 mmol)
Was suspended in ethanol (20 ml), 1N hydrochloric acid (1.5 ml) was added, and the mixture was stirred overnight. The precipitated crystals were collected by filtration to give the title compound 480
mg (quantitative) was obtained. ¹ HNMR (DMSO-d ₆ ) δ (ppm); 2.91 (br-s, 6H), 3.44-3.50
(m, 2H), 4.39 (t, J = 5.6Hz, 2H), 7.04-7.08 (m, 1H), 7.54-7.5
6 (m, 1H), 7.63 (t, J = 7.6Hz, 1H), 8.05 (dd, J = 0.8,7.6Hz, 1
H), 8.12 (d, J = 8.8Hz, 1H), 8.44 (dd, J = 0.8,7.6Hz, 1H), 9.60
(br-s, 1H)

【００５２】実施例５ ８−アセチルアミノ−２−［２−（ジメチルアミノ）エ
チル］−１Ｈ−ピリミド［５，６，１−ｊｋ］カルバゾ
ール−１，３（２Ｈ）−ジオン 塩酸塩Example 5 8-Acetylamino-2- [2- (dimethylamino) ethyl] -1H-pyrimido [5,6,1-jk] carbazole-1,3 (2H) -dione hydrochloride

【化１６】 Embedded image

【００５３】実施例４の化合物の遊離塩基 1.61g（５mm
ol）をピリジン（15ml）に懸濁し、無水酢酸（15ml）を
加え室温にて３時間攪拌した後、酢酸エチルを加え沈殿
を濾取した。これをエタノールに懸濁し、１Ｎ塩酸を加
え攪拌し、析出した結晶を濾取し表題化合物 1.81g（収
率90％）を得た。これに水、飽和炭酸水素ナトリウム水
溶液を加え、酢酸エチル及びテトラヒドロフランを用い
て抽出した。有機層を水、飽和食塩水で洗浄し、無水硫
酸マグネシウムで乾燥後濃縮乾固した。これをエタノー
ルに懸濁し、沈殿を濾取した後、更にエタノール及び１
Ｎ塩酸を加え攪拌し、析出した結晶を濾取し表題化合物
1.37g （収率68％）を得た。融点； 255℃より湿潤着色
し始め、 267℃にて1/2 、 269℃にて全体が浸潤、褐色
に着色し分解した。 ＦＡＢ質量分析ｍ／ｚ；365(MH⁺)¹ HNMR (DMSO-d₆）δ（ppm)；2.12(s,3H),2.92(br-s,6
H),3.45-3.52(m,2H),4.40(t,J=5.6Hz,2H),7.67(t,J=7.6
Hz,1H),7.74(dd,J=2.0,8.8Hz,1H),8.10(dd,J=0.8,7.6H
z,1H),8.30(d,J=8.8Hz,1H),8.53(dd,J=0.8,7.6Hz,1H),
8.62(d,J=2.0Hz,1H),9.29(br-s,1H),10.32(s,1H) 1.61 g (5 mm) of the free base of the compound of Example 4
ol) was suspended in pyridine (15 ml), acetic anhydride (15 ml) was added and the mixture was stirred at room temperature for 3 hours, ethyl acetate was added and the precipitate was collected by filtration. This was suspended in ethanol, 1N hydrochloric acid was added, and the mixture was stirred, and the precipitated crystals were collected by filtration to give the title compound (1.81 g, yield 90%). Water and saturated aqueous sodium hydrogen carbonate solution were added to this, and the mixture was extracted with ethyl acetate and tetrahydrofuran. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated to dryness. This was suspended in ethanol, the precipitate was collected by filtration, and then ethanol and 1
N hydrochloric acid was added and stirred, and the precipitated crystals were collected by filtration to give the title compound.
1.37 g (68% yield) was obtained. Melting point: Wet coloring started at 255 ° C., 1/2 at 267 ° C., whole infiltrated at 269 ° C., colored brown and decomposed. FAB mass spectrometry m / z; 365 (MH ⁺ ) ¹ HNMR (DMSO-d ₆ ) δ (ppm); 2.12 (s, 3H), 2.92 (br-s, 6)
H), 3.45-3.52 (m, 2H), 4.40 (t, J = 5.6Hz, 2H), 7.67 (t, J = 7.6
Hz, 1H), 7.74 (dd, J = 2.0,8.8Hz, 1H), 8.10 (dd, J = 0.8,7.6H
z, 1H), 8.30 (d, J = 8.8Hz, 1H), 8.53 (dd, J = 0.8,7.6Hz, 1H),
8.62 (d, J = 2.0Hz, 1H), 9.29 (br-s, 1H), 10.32 (s, 1H)

【００５４】実施例６ ２−［２−（ジメチルアミノ）エチル］−８−ヒドロキ
シ−１Ｈ−ピリミド［５，６，１−ｊｋ］カルバゾール
−１，３（２Ｈ）−ジオン 塩酸塩Example 6 2- [2- (Dimethylamino) ethyl] -8-hydroxy-1H-pyrimido [5,6,1-jk] carbazole-1,3 (2H) -dione hydrochloride

【化１７】 Embedded image

【００５５】実施例４の化合物の硫酸塩をジアゾニウム
塩経由で水酸化することにより表題化合物を得た。¹ HNMR (DMSO-d₆）δ（ppm)；2.87(br-s,6H),3.36-3.48
(m,2H),4.32-4.40(m,2H),7.09(dd,J=2.4,8.8Hz,1H),7.6
2(t,J=7.6Hz,1H),7.63(d,J=2.4Hz,1H),8.04(d,J=7.6Hz,
1H),8.15(d,J=8.8Hz,1H),8.48(d,J=7.6Hz,1H),9.30(br-
s,1H),9.84(s,1H) The title compound was obtained by hydroxylating the sulfate salt of the compound of Example 4 via the diazonium salt. ¹ HNMR (DMSO-d ₆ ) δ (ppm); 2.87 (br-s, 6H), 3.36-3.48
(m, 2H), 4.32-4.40 (m, 2H), 7.09 (dd, J = 2.4,8.8Hz, 1H), 7.6
2 (t, J = 7.6Hz, 1H), 7.63 (d, J = 2.4Hz, 1H), 8.04 (d, J = 7.6Hz,
1H), 8.15 (d, J = 8.8Hz, 1H), 8.48 (d, J = 7.6Hz, 1H), 9.30 (br-
s, 1H), 9.84 (s, 1H)

【００５６】実施例７ ８−クロロ−２−［２−（ジメチルアミノ）エチル］−
１Ｈ−ピリミド［５，６，１−ｊｋ］カルバゾール−
１，３（２Ｈ）−ジオン 塩酸塩Example 7 8-Chloro-2- [2- (dimethylamino) ethyl]-
1H-pyrimido [5,6,1-jk] carbazole-
1,3 (2H) -dione hydrochloride

【化１８】 Embedded image

【００５７】実施例４の化合物の硫酸塩をジアゾニウム
塩経由でザンドマイヤー (Sandmeyer)反応を行い塩素化
することにより表題化合物を得た。¹ HNMR (DMSO-d₆）δ(ppm）；2.28(br-s,6H),3.42-3.48
(m,2H),4.40(t,J=5.8Hz,2H),7.71(t,J=7.6Hz,1H),7.73
(dd,J=2.0,8.6Hz,1H),8.13(dd,J=0.8,7.6Hz,1H),8.36
(d,J=8.6Hz,1H),8.53(d,J=2.0Hz,1H),8.60(dd,J=0.8,7.
6Hz,1H),9.89(br-s,1H） The title compound was obtained by subjecting the sulfate salt of the compound of Example 4 to chlorination by a Sandmeyer reaction via a diazonium salt. ¹ HNMR (DMSO-d ₆ ) δ (ppm); 2.28 (br-s, 6H), 3.42-3.48
(m, 2H), 4.40 (t, J = 5.8Hz, 2H), 7.71 (t, J = 7.6Hz, 1H), 7.73
(dd, J = 2.0,8.6Hz, 1H), 8.13 (dd, J = 0.8,7.6Hz, 1H), 8.36
(d, J = 8.6Hz, 1H), 8.53 (d, J = 2.0Hz, 1H), 8.60 (dd, J = 0.8,7.
6Hz, 1H), 9.89 (br-s, 1H)

【００５８】実施例８ ２−［２−（ジメチルアミノ）エチル］−８−メチル−
１Ｈ−ピリミド［５，６，１−ｊｋ］カルバゾール−
１，３（２Ｈ）−ジオン 塩酸塩Example 8 2- [2- (Dimethylamino) ethyl] -8-methyl-
1H-pyrimido [5,6,1-jk] carbazole-
1,3 (2H) -dione hydrochloride

【化１９】 Embedded image

【００５９】６−メチル−９Ｈ−カルバゾール−１−カ
ルボン酸から実施例１と同様にして表題化合物を得た。¹ HNMR (DMSO-d₆）δ（ppm)；2.51(s,3H),2.88(br-s,6
H),3.42-3.47(m,2H),4.38(t,J=5.8Hz,2H),7.47-7.50(m,
1H),7.65(t,J=7.6Hz,1H),8.05(dd,J=0.8,7.6Hz,1H),8.1
2-8.14(m,1H),8.23(d,J=8.8Hz,1H),8.49(dd,J=0.8,7.6H
z,1H),9.65(br-s,1H) The title compound was obtained from 6-methyl-9H-carbazole-1-carboxylic acid in the same manner as in Example 1. ¹ HNMR (DMSO-d ₆ ) δ (ppm); 2.51 (s, 3H), 2.88 (br-s, 6
H), 3.42-3.47 (m, 2H), 4.38 (t, J = 5.8Hz, 2H), 7.47-7.50 (m,
1H), 7.65 (t, J = 7.6Hz, 1H), 8.05 (dd, J = 0.8,7.6Hz, 1H), 8.1
2-8.14 (m, 1H), 8.23 (d, J = 8.8Hz, 1H), 8.49 (dd, J = 0.8,7.6H
z, 1H), 9.65 (br-s, 1H)

【００６０】実施例９ ２−［２−（ジメチルアミノ）エチル］−８−メトキシ
−１Ｈ−ピリミド［５，６，１−ｊｋ］カルバゾール−
１，３（２Ｈ）−ジオン 塩酸塩Example 9 2- [2- (Dimethylamino) ethyl] -8-methoxy-1H-pyrimido [5,6,1-jk] carbazole-
1,3 (2H) -dione hydrochloride

【化２０】 Embedded image

【００６１】６−メトキシ−９Ｈ−カルバゾール−１−
カルボン酸から実施例１と同様にして表題化合物を得
た。¹ HNMR (DMSO-d₆）δ（ppm)；2.92(br-s,6H),3.46-3.51
(m,2H),3.92(s,3H),4.40(t,J=5.6Hz,2H),7.27(dd,J=2.
6,9.0Hz,1H),7.68(t,J=7.6Hz,1H),7.97(d,J=2.6Hz,1H),
8.09(dd,J=0.8,7.6Hz,1H),8.26(d,J=9.0Hz,1H),8.57(d
d,J=0.8,7.6Hz,1H),9.43(br-s,1H) 6-methoxy-9H-carbazole-1-
The title compound was obtained from the carboxylic acid in the same manner as in Example 1. ¹ HNMR (DMSO-d ₆ ) δ (ppm); 2.92 (br-s, 6H), 3.46-3.51
(m, 2H), 3.92 (s, 3H), 4.40 (t, J = 5.6Hz, 2H), 7.27 (dd, J = 2.
6,9.0Hz, 1H), 7.68 (t, J = 7.6Hz, 1H), 7.97 (d, J = 2.6Hz, 1H),
8.09 (dd, J = 0.8,7.6Hz, 1H), 8.26 (d, J = 9.0Hz, 1H), 8.57 (d
d, J = 0.8,7.6Hz, 1H), 9.43 (br-s, 1H)

【００６２】実施例１０ ２−［２−（ジメチルアミノ）エチル］−５−ニトロ−
１Ｈ−ピリミド［５，６，１−ｊｋ］カルバゾール−
１，３（２Ｈ）−ジオン 塩酸塩Example 10 2- [2- (Dimethylamino) ethyl] -5-nitro-
1H-pyrimido [5,6,1-jk] carbazole-
1,3 (2H) -dione hydrochloride

【化２１】 [Chemical 21]

【００６３】製造例３のＮ−［２−（ジメチルアミノ）
エチル］−３−ニトロ−９Ｈ−カルバゾール−１−カル
ボキサミドを実施例３と同様にして表題化合物を得た。 ¹ HNMR (DMSO-d₆）δ（ppm)；2.83(br-s,6H),3.28-3.46
(m,2H),4.36-4.44(m,2H),7.63-7.68(m,1H),7.77-7.82
(m,1H),8.41-8.44(m,1H),8.59-8.62(m,1H),8.78(d,J=2.
0Hz,1H),9.57(d,J=2.0Hz,1H),9.60-9.88(m,1H） N- [2- (dimethylamino) of Production Example 3
Ethyl] -3-nitro-9H-carbazole-1-cal
The title compound was obtained using voxamide in the same manner as in Example 3. ¹ HNMR (DMSO-d₆) Δ (ppm); 2.83 (br-s, 6H), 3.28-3.46
(m, 2H), 4.36-4.44 (m, 2H), 7.63-7.68 (m, 1H), 7.77-7.82
(m, 1H), 8.41-8.44 (m, 1H), 8.59-8.62 (m, 1H), 8.78 (d, J = 2.
0Hz, 1H), 9.57 (d, J = 2.0Hz, 1H), 9.60-9.88 (m, 1H)

【００６４】実施例１１ ５−アミノ−２−［２−（ジメチルアミノ）エチル］−
１Ｈ−ピリミド［５，６，１−ｊｋ］カルバゾール−
１，３（２Ｈ）−ジオン 二塩酸塩Example 11 5-Amino-2- [2- (dimethylamino) ethyl]-
1H-pyrimido [5,6,1-jk] carbazole-
1,3 (2H) -dione dihydrochloride

【化２２】 Embedded image

【００６５】実施例１０の化合物を実施例４と同様にし
て表題化合物を得た。¹ HNMR (DMSO-d₆）δ（ppm)；2.84-2.94(m,6H),3.42-3.5
2(m,2H),4.40(t,J=5.6Hz,2H),7.54-7.59(m,1H),7.67-7.
73(m,1H),7.86(d,J=1.6Hz,1H),8.23(d,J=1.6Hz,1H),8.3
2-8.38(m,2H),10.05(br-s,1H) The title compound was obtained by treating the compound of Example 10 in the same manner as in Example 4. ¹ HNMR (DMSO-d ₆ ) δ (ppm); 2.84-2.94 (m, 6H), 3.42-3.5
2 (m, 2H), 4.40 (t, J = 5.6Hz, 2H), 7.54-7.59 (m, 1H), 7.67-7.
73 (m, 1H), 7.86 (d, J = 1.6Hz, 1H), 8.23 (d, J = 1.6Hz, 1H), 8.3
2-8.38 (m, 2H), 10.05 (br-s, 1H)

【００６６】実施例１２ ５−アセチルアミノ−２−［２−（ジメチルアミノ）エ
チル］−１Ｈ−ピリミド［５，６，１−ｊｋ］カルバゾ
ール−１，３（２Ｈ）−ジオン 塩酸塩Example 12 5-Acetylamino-2- [2- (dimethylamino) ethyl] -1H-pyrimido [5,6,1-jk] carbazole-1,3 (2H) -dione hydrochloride

【化２３】 Embedded image

【００６７】実施例１１の化合物を実施例５と同様にし
て表題化合物を得た。¹ HNMR (DMSO-d₆）δ（ppm)；2.15(s,3H),2.89-2.94(m,6
H),3.45-3.51(m,2H),4.40(t,J=5.8Hz,2H),7.54-7.58(m,
1H),7.67-7.72(m,1H),8.30(d,J=7.6Hz,1H),8.34-8.38
(m,2H),8.66(d,J=1.6Hz,1H),9.57(br-s,1H),10.53(s,1
H) The title compound was obtained by treating the compound of Example 11 in the same manner as in Example 5. ¹ HNMR (DMSO-d ₆ ) δ (ppm); 2.15 (s, 3H), 2.89-2.94 (m, 6
H), 3.45-3.51 (m, 2H), 4.40 (t, J = 5.8Hz, 2H), 7.54-7.58 (m,
1H), 7.67-7.72 (m, 1H), 8.30 (d, J = 7.6Hz, 1H), 8.34-8.38
(m, 2H), 8.66 (d, J = 1.6Hz, 1H), 9.57 (br-s, 1H), 10.53 (s, 1
H)

【００６８】実施例１３ ２−［２−（ジメチルアミノ）エチル］−１Ｈ−ピリミ
ド［５，６，１−ｋｌ］フェノチアジン−１，３（２
Ｈ）−ジオン 塩酸塩Example 13 2- [2- (Dimethylamino) ethyl] -1H-pyrimido [5,6,1-kl] phenothiazine-1,3 (2
H) -dione hydrochloride

【化２４】 Embedded image

【００６９】１０Ｈ−フェノチアジン−１−カルボン酸
228mg（0.937 ミリモル）をクロロホルム５mlに懸濁
し、氷冷攪拌下、三塩化リン２ml、Ｎ，Ｎ−ジメチルホ
ルムアミド 0.4mlを順次滴下した。氷冷下、30分攪拌し
た後、更に室温で 3.5時間攪拌を続けた。反応混合物を
減圧下、溶媒を完全に留去し、得られた残渣をトルエン
５mlに溶解して、氷冷攪拌下、Ｎ，Ｎ−ジメチルエチレ
ンジアミン１mlのクロロホルム20ml溶液に滴下した。反
応混合物を徐々に室温にもどし、一晩攪拌を続けた。反
応混合物に飽和炭酸水素ナトリウム水溶液を加え、有機
層を分取し、水、飽和食塩水で順次洗浄後、無水硫酸マ
グネシウムで乾燥した。濾過後、溶媒を留去することに
より、Ｎ−［２−（ジメチルアミノ）エチル］−10Ｈ−
フェノチアジン−１−カルボキサミド 290mgを得た。Ｎ
−［２−（ジメチルアミノ）エチル］−10Ｈ−フェノチ
アジン−1 −カルボキサミド 100mg、トリエチルアミン
0.2mlをジクロロメタン５mlに溶解し、室温攪拌下、ク
ロロぎ酸エチル0.06mlを加え２時間攪拌を続けた。反応
混合物に飽和炭酸水素ナトリウム水溶液を加え、有機層
を分取し、水、飽和食塩水で洗浄後、無水硫酸マグネシ
ウムで乾燥した。濾過後、溶媒を留去し、得られた残渣
をＮ，Ｎ−ジメチルホルムアミド５mlに溶解し、110 〜
120 ℃で40分間加熱攪拌した。反応混合物を室温にもど
し、減圧下、溶媒を留去し、得られた残渣をシリカゲル
カラムクロマトグラフィーで精製することにより、表題
化合物の遊離塩基90mgを得た。これを常法により塩酸塩
とした後、エタノールから再結晶することにより、表題
化合物76mgを得た。 ＦＡＢ質量分析ｍ／ｚ；342(MH⁺)¹ HNMR (DMSO-d₆）δ（ppm)；2.90(s,6H),3.48(br-t,J=
5.6Hz,2H),4.34(t,J=5.6Hz,2H),7.29(td,J=1.2,7.6Hz,1
H),7.35(td,J=1.6,7.6Hz,1H),7.41(t,J=7.6Hz,1H),7.43
(dd,J=1.6,7.6Hz,1H),7.70(dd,J=1.6,7.2Hz,1H),7.78(d
d,J=1.2,8.4Hz,1H),7.88(dd,J=1.2,8.0Hz,1H) 10H-phenothiazine-1-carboxylic acid
228 mg (0.937 mmol) was suspended in 5 ml of chloroform, and phosphorus trichloride (2 ml) and N, N-dimethylformamide (0.4 ml) were sequentially added dropwise under ice-cooling stirring. After stirring under ice cooling for 30 minutes, the stirring was continued at room temperature for 3.5 hours. The solvent was completely distilled off from the reaction mixture under reduced pressure, the obtained residue was dissolved in 5 ml of toluene, and the mixture was added dropwise to a solution of 1 ml of N, N-dimethylethylenediamine in 20 ml of chloroform under stirring with ice cooling. The reaction mixture was allowed to come to room temperature gradually and stirring was continued overnight. A saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture, the organic layer was separated, washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off to give N- [2- (dimethylamino) ethyl] -10H-.
290 mg of phenothiazine-1-carboxamide was obtained. N
-[2- (Dimethylamino) ethyl] -10H-phenothiazine-1-carboxamide 100 mg, triethylamine
0.2 ml was dissolved in 5 ml of dichloromethane, 0.06 ml of ethyl chloroformate was added with stirring at room temperature, and stirring was continued for 2 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, the organic layer was separated, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off, and the resulting residue was dissolved in 5 ml of N, N-dimethylformamide to give 110-
The mixture was heated and stirred at 120 ° C for 40 minutes. The reaction mixture was returned to room temperature, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to give 90 mg of the free base of the title compound. This was converted into a hydrochloride by a conventional method and then recrystallized from ethanol to obtain 76 mg of the title compound. FAB mass spectrometry m / z; 342 (MH ⁺ ) ¹ HNMR (DMSO-d ₆ ) δ (ppm); 2.90 (s, 6H), 3.48 (br-t, J =
5.6Hz, 2H), 4.34 (t, J = 5.6Hz, 2H), 7.29 (td, J = 1.2,7.6Hz, 1
H), 7.35 (td, J = 1.6,7.6Hz, 1H), 7.41 (t, J = 7.6Hz, 1H), 7.43
(dd, J = 1.6,7.6Hz, 1H), 7.70 (dd, J = 1.6,7.2Hz, 1H), 7.78 (d
d, J = 1.2,8.4Hz, 1H), 7.88 (dd, J = 1.2,8.0Hz, 1H)

【００７０】実施例１４ ２−［２−（ジメチルアミノ）エチル］−１Ｈ−ベンゾ
［ｂ］ピリミド［５，６，１−ｊｋ］［１］ベンズアゼ
ピン−１，３（２Ｈ）−ジオン 塩酸塩Example 14 2- [2- (Dimethylamino) ethyl] -1H-benzo [b] pyrimido [5,6,1-jk] [1] benzazepine-1,3 (2H) -dione hydrochloride

【化２５】 Embedded image

【００７１】５Ｈ−ジベンズ［ｂ，ｆ］アゼピン−４−
カルボン酸を実施例１と同様にして表題化合物を得た。¹ HNMR (DMSO-d₆）δ（ppm)；2.85(s,3H),2.92(s,3H),3.
40-3.50(m,2H),4.26-4.32(m,2H),6.73(d,J=11.4Hz,1H).
6.94(d,J=11.4Hz,1H),7.28-7.44(m,5H),7.61(d,J=8.4H
z,1H),7.93(d,J=8.4Hz,1H),9.84(br-s,1H)5H-dibenz [b, f] azepine-4-
The carboxylic acid was treated in the same manner as in Example 1 to obtain the title compound. ¹ HNMR (DMSO-d ₆ ) δ (ppm); 2.85 (s, 3H), 2.92 (s, 3H), 3.
40-3.50 (m, 2H), 4.26-4.32 (m, 2H), 6.73 (d, J = 11.4Hz, 1H).
6.94 (d, J = 11.4Hz, 1H), 7.28-7.44 (m, 5H), 7.61 (d, J = 8.4H
z, 1H), 7.93 (d, J = 8.4Hz, 1H), 9.84 (br-s, 1H)

【００７２】実施例１５ ５−アセチルアミノ−２−［２−（ジメチルアミノ）エ
チル］−１Ｈ−ピリド［３，２−ｂ］ピリミド［５，
６，１−ｅｄ］［１，４］ベンゾオキサジン−１，３
（２Ｈ）−ジオン 塩酸塩Example 15 5-Acetylamino-2- [2- (dimethylamino) ethyl] -1H-pyrido [3,2-b] pyrimido [5,5]
6,1-ed] [1,4] benzoxazine-1,3
(2H) -dione hydrochloride

【化２６】 Embedded image

【００７３】１０Ｈ−ピリド［３，２−ｂ］［１，４］
ベンゾオキサジン−７−ニトロ−９−カルボン酸を実施
例１，１１，１２と同様にして表題化合物を得た。¹ HNMR (DMSO-d₆）δ（ppm)；2.06(s,3H),2.85(s,6H),3.
37(q,J=5.2,11.2Hz,2H),4.28(t,J=5.6Hz,2H),7.28(dd,J
=4.4,8.0Hz,1H),7.57(dd,J=1.2,8.0Hz,1H),7.64(d,J=2.
4Hz,1H),7.91(d,J=2.4,1H),8.10(dd,J=1.6,4.4Hz,1H),
9.82(br-s,1H),10.5(s,1H)10H-pyrido [3,2-b] [1,4]
The title compound was obtained in the same manner as in Examples 1, 11, and 12 using benzoxazine-7-nitro-9-carboxylic acid. ¹ HNMR (DMSO-d ₆ ) δ (ppm); 2.06 (s, 3H), 2.85 (s, 6H), 3.
37 (q, J = 5.2,11.2Hz, 2H), 4.28 (t, J = 5.6Hz, 2H), 7.28 (dd, J
= 4.4,8.0Hz, 1H), 7.57 (dd, J = 1.2,8.0Hz, 1H), 7.64 (d, J = 2.
4Hz, 1H), 7.91 (d, J = 2.4,1H), 8.10 (dd, J = 1.6,4.4Hz, 1H),
9.82 (br-s, 1H), 10.5 (s, 1H)

【００７４】実施例１６ ９−アセチルアミノ−２−［２−（ジメチルアミノ）エ
チル］−１Ｈ−ピリミド［５，６，１−ｋｌ］フェノキ
サジン−１，３（２Ｈ）ジオン 塩酸塩Example 16 9-Acetylamino-2- [2- (dimethylamino) ethyl] -1H-pyrimido [5,6,1-kl] phenoxazine-1,3 (2H) dione hydrochloride

【化２７】 Embedded image

【００７５】７−ニトロ−１０Ｈ−フェノキサジン−１
−カルボン酸を実施例１，４，５と同様にして表題化合
物を得た。¹ HNMR (DMSO-d₆）δ（ppm)；2.06(s,3H),2.88(s,6H),3.
38-3.44(m,2H),4.32(t,J=5.6Hz,2H),7.19(dd,J=1.2,9.6
Hz,1H),7.31(td,J=1.6,7.6Hz,1H),7.39(dt,J=1.6,7.6H
z,1H),7.55(d,J=1.6Hz,1H),7.64(dt,J=1.6,7.6Hz,1H),
8.44(dd,J=1.6,9.6Hz,1H),9.80(br-s,1H),10.30(s,1H）7-Nitro-10H-phenoxazine-1
Using the same carboxylic acid as in Examples 1, 4 and 5, the title compound was obtained. ¹ HNMR (DMSO-d ₆ ) δ (ppm); 2.06 (s, 3H), 2.88 (s, 6H), 3.
38-3.44 (m, 2H), 4.32 (t, J = 5.6Hz, 2H), 7.19 (dd, J = 1.2,9.6
Hz, 1H), 7.31 (td, J = 1.6,7.6Hz, 1H), 7.39 (dt, J = 1.6,7.6H
z, 1H), 7.55 (d, J = 1.6Hz, 1H), 7.64 (dt, J = 1.6,7.6Hz, 1H),
8.44 (dd, J = 1.6,9.6Hz, 1H), 9.80 (br-s, 1H), 10.30 (s, 1H)

【００７６】実施例１７ ２−［２−（ジメチルアミノ）エチル］−８−メタンス
ルホニルアミノ−１Ｈ−ピリミド［５，６，１−ｊｋ］
カルバゾール−１，３（２Ｈ）−ジオン 塩酸塩Example 17 2- [2- (Dimethylamino) ethyl] -8-methanesulfonylamino-1H-pyrimido [5,6,1-jk]
Carbazole-1,3 (2H) -dione hydrochloride

【化２８】 Embedded image

【００７７】実施例５と同様にして表題化合物を得た。¹ HNMR (DMSO-d₆）δ（ppm)；2.90(br-s,6H),3.05(s,3
H),3.42-3.52(m,2H),4.35-4.42(m,2H),7.47-7.55(m,1
H),7.67(t,J=7.6Hz,1H),8.06-8.16(m,2H),8.32(d,J=8.8
Hz,1H),8.57(d,J=7.6Hz,1H),9.35(br-s,1H),10.01(s,1
H）The title compound was obtained in the same manner as in Example 5. ¹ HNMR (DMSO-d ₆ ) δ (ppm); 2.90 (br-s, 6H), 3.05 (s, 3
H), 3.42-3.52 (m, 2H), 4.35-4.42 (m, 2H), 7.47-7.55 (m, 1
H), 7.67 (t, J = 7.6Hz, 1H), 8.06-8.16 (m, 2H), 8.32 (d, J = 8.8
Hz, 1H), 8.57 (d, J = 7.6Hz, 1H), 9.35 (br-s, 1H), 10.01 (s, 1
H)

【００７８】実施例１８ ２−［２−（ジメチルアミノ）エチル］−８−（２−チ
オフェンカルボニルアミノ）−１Ｈ−ピリミド［５，
６，１−ｊｋ］カルバゾール−１，３（２Ｈ）−ジオン
塩酸塩Example 18 2- [2- (Dimethylamino) ethyl] -8- (2-thiophenecarbonylamino) -1H-pyrimido [5,5]
6,1-jk] carbazole-1,3 (2H) -dione hydrochloride

【化２９】 Embedded image

【００７９】実施例５と同様にして表題化合物を得た。¹ HNMR (DMSO-d₆）δ（ppm)；2.91(br-s,6H),3.44-3.52
(m,2H),4.39(t,J=5.6Hz,2H),7.25(dd,J=4.0,5.0Hz,1H),
7.68(t,J=7.6Hz,1H),7.89(dd,J=1.2,5.0Hz,1H),7.93(d
d,J=2.0,8.8Hz,1H),8.10(dd,J=0.8,7.6Hz,1H),8.11(dd,
J=1.2,4.0Hz,1H),8.34(d,J=8.8Hz,1H),8.54(dd,J=0.8,
7.6Hz,1H),8.72(d,J=2.0Hz,1H),9.42(br-s,1H),10.61
(s,1H）The title compound was obtained in the same manner as in Example 5. ¹ HNMR (DMSO-d ₆ ) δ (ppm); 2.91 (br-s, 6H), 3.44-3.52
(m, 2H), 4.39 (t, J = 5.6Hz, 2H), 7.25 (dd, J = 4.0,5.0Hz, 1H),
7.68 (t, J = 7.6Hz, 1H), 7.89 (dd, J = 1.2,5.0Hz, 1H), 7.93 (d
d, J = 2.0,8.8Hz, 1H), 8.10 (dd, J = 0.8,7.6Hz, 1H), 8.11 (dd,
J = 1.2,4.0Hz, 1H), 8.34 (d, J = 8.8Hz, 1H), 8.54 (dd, J = 0.8,
7.6Hz, 1H), 8.72 (d, J = 2.0Hz, 1H), 9.42 (br-s, 1H), 10.61
(s, 1H)

【００８０】実施例１９ ２−［２−（ジメチルアミノ）エチル］−８−（２−チ
オフェンスルホンニルアミノ）−１Ｈ−ピリミド［５，
６，１−ｊｋ］カルバゾール−１，３（２Ｈ）−ジオン
塩酸塩Example 19 2- [2- (Dimethylamino) ethyl] -8- (2-thiophenesulfonylamino) -1H-pyrimido [5
6,1-jk] carbazole-1,3 (2H) -dione hydrochloride

【化３０】 Embedded image

【００８１】実施例５と同様にして表題化合物を得た。 （遊離塩基)¹HNMR（CDCl₃)δ（ppm)；2.90(br-s,6H),3.
42-3.52(m,2H),4.38(t,J=5.6Hz,2H),7.09(dd,J=3.7,4.9
Hz,1H),7.38(dd,J=2.2,8.8Hz,11H),7.55(dd,J=1.3,3.7H
z,1H),7.67(t,J=7.7Hz,1H),7.87(dd,J=1.3,4.9Hz,1H),
8.08(d,J=2.2Hz,1H),8.11(dd,J=0.7,7.7Hz,1H),8.27(d,
J=8.8Hz,1H),8.58(dd,J=0.7,7.7Hz,1H),9.31(br-s,1H),
10.66(s,1H)The title compound was obtained in the same manner as in Example 5. (Free base) ¹ HNMR (CDCl ₃ ) δ (ppm); 2.90 (br-s, 6H), 3.
42-3.52 (m, 2H), 4.38 (t, J = 5.6Hz, 2H), 7.09 (dd, J = 3.7,4.9
Hz, 1H), 7.38 (dd, J = 2.2,8.8Hz, 11H), 7.55 (dd, J = 1.3,3.7H
z, 1H), 7.67 (t, J = 7.7Hz, 1H), 7.87 (dd, J = 1.3,4.9Hz, 1H),
8.08 (d, J = 2.2Hz, 1H), 8.11 (dd, J = 0.7,7.7Hz, 1H), 8.27 (d,
J = 8.8Hz, 1H), 8.58 (dd, J = 0.7,7.7Hz, 1H), 9.31 (br-s, 1H),
10.66 (s, 1H)

【００８２】実施例２０ ８−アセチルアミノ−２−［２−（ジメチルアミノ）エ
チル］−９−メチル−１Ｈ−ピリミド［５，６，１−ｊ
ｋ］カルバゾール−１，３（２Ｈ）−ジオン塩酸塩Example 20 8-Acetylamino-2- [2- (dimethylamino) ethyl] -9-methyl-1H-pyrimido [5,6,1-j
k] carbazole-1,3 (2H) -dione hydrochloride

【化３１】 Embedded image

【００８３】実施例５と同様にして表題化合物を得た。¹ HNMR (DMSO-d₆）δ（ppm)；2.14(s,3H),2.44(s,3H),2.
88-2.96(m,6H),3.46-3.53(m,2H),4.40(t,J=5.5Hz,2H),
7.66(t,J=7.6Hz,1H),8.07(d,J=7.6Hz,1H),8.23(s,1H),
8.33(s,1H),8.51(d,J=7.6Hz,1H),9.41(br-s,1H),9.58
(s,1H)The title compound was obtained in the same manner as in Example 5. ¹ HNMR (DMSO-d ₆ ) δ (ppm); 2.14 (s, 3H), 2.44 (s, 3H), 2.
88-2.96 (m, 6H), 3.46-3.53 (m, 2H), 4.40 (t, J = 5.5Hz, 2H),
7.66 (t, J = 7.6Hz, 1H), 8.07 (d, J = 7.6Hz, 1H), 8.23 (s, 1H),
8.33 (s, 1H), 8.51 (d, J = 7.6Hz, 1H), 9.41 (br-s, 1H), 9.58
(s, 1H)

【００８４】実施例２１ ２−［２−（ジメチルアミノ）エチル］−８−オクタノ
イルアミノ−１Ｈ−ピリミド［５，６，１−ｊｋ］カル
バゾール−１，３（２Ｈ）−ジオン 塩酸塩Example 21 2- [2- (Dimethylamino) ethyl] -8-octanoylamino-1H-pyrimido [5,6,1-jk] carbazole-1,3 (2H) -dione hydrochloride

【化３２】 Embedded image

【００８５】実施例５と同様にして表題化合物を得た。¹ HNMR (DMSO-d₆）δ（ppm)；0.88(t,J=6.8Hz,3H),1.22-
1.40(m,8H),1.59-1.70(m,2H),2.38(t,J=7.3Hz,2H),2.89
-2.96(m,6H),3.50(t,J=6.0Hz,2H),4.40(t,J=6.0Hz,2H),
7.68(t,J=7.6Hz,1H),7.75(dd,J=2.0,8.8Hz,1H),8.10(d,
J=7.6Hz,1H),8.30(d,J=8.8Hz,1H),8.53(d,J=7.6Hz,1H),
8.66(d,J=2.0Hz,1H),9.31(br-s,1H),10.25(s,1H)The title compound was obtained in the same manner as in Example 5. ¹ HNMR (DMSO-d ₆ ) δ (ppm); 0.88 (t, J = 6.8Hz, 3H), 1.22-
1.40 (m, 8H), 1.59-1.70 (m, 2H), 2.38 (t, J = 7.3Hz, 2H), 2.89
-2.96 (m, 6H), 3.50 (t, J = 6.0Hz, 2H), 4.40 (t, J = 6.0Hz, 2H),
7.68 (t, J = 7.6Hz, 1H), 7.75 (dd, J = 2.0,8.8Hz, 1H), 8.10 (d,
J = 7.6Hz, 1H), 8.30 (d, J = 8.8Hz, 1H), 8.53 (d, J = 7.6Hz, 1H),
8.66 (d, J = 2.0Hz, 1H), 9.31 (br-s, 1H), 10.25 (s, 1H)

【００８６】実施例２２ ２−［２−（ジメチルアミノ）エチル］−８−（１−ピ
ロリル）−１Ｈ−ピリミド［５，６，１−ｊｋ］カルバ
ゾール−１，３（２Ｈ）−ジオン 塩酸塩Example 22 2- [2- (Dimethylamino) ethyl] -8- (1-pyrrolyl) -1H-pyrimido [5,6,1-jk] carbazole-1,3 (2H) -dione hydrochloride

【化３３】 Embedded image

【００８７】実施例４の化合物の遊離塩基96mg（0.3mmo
l)を酢酸（10ml) に溶解し、２，５−ジメトキシテトラ
ヒドロフラン39μl （0.3ml)を加え、30分間加熱還流し
た。放冷後溶媒を留去し、炭酸水素ナトリウム水溶液を
加え、酢酸エチルを用いて抽出した。有機層を水、飽和
食塩水で洗浄し無水硫酸マグネシウムで乾燥した。溶媒
を留去し残渣にヘキサン＋エタノールを加え結晶化させ
表題化合物の遊離塩基を85mg（75％）得た。これをエタ
ノールに懸濁し、１Ｎ塩酸を加え塩酸塩として表題化合
物80mg（65％）を得た。 （遊離塩基)¹HNMR（DMSO-d₆)δ（ppm)；2.23(s,6H),2.5
6(t,J=6.9Hz,2H),4.16(t,J=6.9Hz,2H),6.35(t,J=2.2Hz,
2H),7.52(t,J=2.2Hz,2H),7.69(t,J=7.7Hz,1H),7.89(dd,
J=2.2,8.8Hz,1H),8.10(dd,J=0.9,7.7Hz,1H),8.39(d,J=
8.8Hz,1H),8.56(dd,J=0.9,7.7Hz,1H),8.60(d,J=2.2Hz,1
H)96 mg of the free base of the compound of Example 4 (0.3 mmo
l) was dissolved in acetic acid (10 ml), 39 μl of 2,5-dimethoxytetrahydrofuran (0.3 ml) was added, and the mixture was heated under reflux for 30 minutes. After allowing to cool, the solvent was evaporated, an aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline and dried over anhydrous magnesium sulfate. The solvent was evaporated, and hexane + ethanol was added to the residue for crystallization to give 85 mg (75%) of the free base of the title compound. This was suspended in ethanol and 1N hydrochloric acid was added to give 80 mg (65%) of the title compound as a hydrochloride salt. (Free base) ¹ HNMR (DMSO-d ₆ ) δ (ppm); 2.23 (s, 6H), 2.5
6 (t, J = 6.9Hz, 2H), 4.16 (t, J = 6.9Hz, 2H), 6.35 (t, J = 2.2Hz,
2H), 7.52 (t, J = 2.2Hz, 2H), 7.69 (t, J = 7.7Hz, 1H), 7.89 (dd,
J = 2.2,8.8Hz, 1H), 8.10 (dd, J = 0.9,7.7Hz, 1H), 8.39 (d, J =
8.8Hz, 1H), 8.56 (dd, J = 0.9,7.7Hz, 1H), 8.60 (d, J = 2.2Hz, 1
H)

【００８８】実施例２３ ８−ジメチルアミノ−２−［２−（ジメチルアミノ）エ
チル］−１Ｈ−ピリミド［５，６，１−ｊｋ］カルバゾ
ール−１，３（２Ｈ）−ジオン 二塩酸塩Example 23 8-Dimethylamino-2- [2- (dimethylamino) ethyl] -1H-pyrimido [5,6,1-jk] carbazole-1,3 (2H) -dione dihydrochloride

【化３４】 Embedded image

【００８９】実施例４の遊離塩基36mg（１mmol）をエタ
ノールに懸濁し、ホルムアルデヒド水溶液（37％）１m
l、１Ｎ塩酸１ml、10％パラジウム炭素５mgを加え、水
素零囲気下還元的アルキル化を行った。反応液を濾過
し、濾液を濃縮後、炭酸水素ナトリウム水を加え中和し
た後、酢酸エチルを用いて抽出した。水で洗浄後濃縮
し、残渣にエタノール及び１Ｎ塩酸を加えて、表題化合
物を20mg（51％）得た。¹ HNMR (DMSO-d₆+D₂O）δ（ppm)；2.93(br-s,6H),3.14(b
r-s,6H),3.46-3.54(m,2H),4.37-4.45(m,2H),7.34-7.48
(m,1H),7.70(t,J=7.6HZ,1H),7.96-8.07(m,1H),8.11(d,J
=7.6Hz,1H),8.24-8.32(m,1H),8.55(d,J=7.6Hz,1H)36 mg (1 mmol) of the free base of Example 4 was suspended in ethanol and formaldehyde aqueous solution (37%) 1 m
1, 1N hydrochloric acid (1 ml) and 10% palladium on carbon (5 mg) were added, and reductive alkylation was carried out under zero hydrogen atmosphere. The reaction solution was filtered, the filtrate was concentrated, aqueous sodium hydrogen carbonate was added for neutralization, and the mixture was extracted with ethyl acetate. After washing with water and concentration, ethanol and 1N hydrochloric acid were added to the residue to give the title compound (20 mg, 51%). ¹ HNMR (DMSO-d ₆ + D ₂ O) δ (ppm); 2.93 (br-s, 6H), 3.14 (b
rs, 6H), 3.46-3.54 (m, 2H), 4.37-4.45 (m, 2H), 7.34-7.48
(m, 1H), 7.70 (t, J = 7.6HZ, 1H), 7.96-8.07 (m, 1H), 8.11 (d, J
= 7.6Hz, 1H), 8.24-8.32 (m, 1H), 8.55 (d, J = 7.6Hz, 1H)

【００９０】実施例２４ ８−ブチリル−２−［２−（ジメチルアミノ）エチル］
−１Ｈ−ピリミド［５，６，１−ｊｋ］カルバゾール−
１，３（２Ｈ）−ジオン 塩酸塩Example 24 8-Butyryl-2- [2- (dimethylamino) ethyl]
-1H-pyrimido [5,6,1-jk] carbazole-
1,3 (2H) -dione hydrochloride

【化３５】 Embedded image

【００９１】製造例２、実施例２と同様にして表題化合
物を得た。¹ HNMR (DMSO-d₆）δ（ppm)；1.00(t,J=7.4Hz,3H),1.67-
1.78(m,2H),2.89(br-s,6H),3.18(t,J=7.1Hz,2H),3.38-
3.55(m,2H),4.41(t,J=5.7Hz,2H),7.75(t,J=7.7Hz,1H),
8.15(dd,J=0.5,7.7Hz,1H),8.31(dd,J=1.6,8.6Hz,1H),8.
48(d,J=8.6Hz,1H),8.73(dd,J=0.5,7.7Hz,1H),9.04(d,J=
1.6Hz,1H),9.54(br-s,1H） The title compound was obtained in the same manner as in Production Example 2 and Example 2. ¹ HNMR (DMSO-d ₆ ) δ (ppm); 1.00 (t, J = 7.4Hz, 3H), 1.67-
1.78 (m, 2H), 2.89 (br-s, 6H), 3.18 (t, J = 7.1Hz, 2H), 3.38-
3.55 (m, 2H), 4.41 (t, J = 5.7Hz, 2H), 7.75 (t, J = 7.7Hz, 1H),
8.15 (dd, J = 0.5,7.7Hz, 1H), 8.31 (dd, J = 1.6,8.6Hz, 1H), 8.
48 (d, J = 8.6Hz, 1H), 8.73 (dd, J = 0.5,7.7Hz, 1H), 9.04 (d, J =
1.6Hz, 1H), 9.54 (br-s, 1H)

───────────────────────────────────────────────────── フロントページの続き (51)Int.Cl.⁶ 識別記号 庁内整理番号 ＦＩ 技術表示箇所 Ａ６１Ｋ 31/55 Ａ６１Ｋ 31/55 Ｃ０７Ｄ 498/04 Ｃ０７Ｄ 498/14 498/14 513/04 ３８１ 513/04 ３８１ 498/04 １１２Ｔ (72)発明者 鎌田 淳一 茨城県つくば市天久保２−23−５、メゾン 学園306 (72)発明者 吉松 賢太郎 茨城県土浦市乙戸南２−９−44 (72)発明者 長洲 毅志 茨城県土浦市永国852−13 (72)発明者 中村 勝次 茨城県つくば市松代１−14−10、クレスト 松代Ａ−202 (72)発明者 上仲 俊光 茨城県牛久市栄町２−７−１−203 (72)発明者 飯島 温美 茨城県新治郡新治村本郷34−４ (72)発明者 吉野 博 千葉県我孫子市つくし野２−４−７ (72)発明者 小柳 望 茨城県つくば市東光台１−10−５ (72)発明者 紀藤 恭輔 茨城県つくば市東光台１−10−８─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical display location A61K 31/55 A61K 31/55 C07D 498/04 C07D 498/14 498/14 513/04 381 513 / 04 381 498/04 112T (72) Inventor Junichi Kamada 2-23-5 Amakubo, Tsukuba City, Ibaraki Prefecture, Maison Gakuen 306 (72) Inventor Kentaro Yoshimatsu 2-9-44 Otodo Minami, Tsuchiura City, Ibaraki Prefecture (72) Invention Takeshi Nagasu 852-13 Nagakuni, Tsuchiura City, Ibaraki Prefecture 852-13 (72) Katsuji Nakamura 1-14-10 Matsushiro, Tsukuba City, Ibaraki Prefecture, A-202 Crest Matsushiro A-202 (72) Toshimitsu Kaminaka 2-Sakaecho, Ushiku City, Ibaraki Prefecture 7-1-203 (72) Inventor Atsumi Iijima 34-4 Hongo, Shinji-mura, Shinji-gun, Ibaraki Prefecture (72) Inventor Hiroshi Yoshino 2-4-7 Tsukushino, Abiko-shi, Chiba Inventor Nozomu Koyanagi Tsukuba, Ibaraki Prefecture City toko 1-10-5 (72) Inventor Kyosuke Kito 1-10-8 Tokodai, Tsukuba, Ibaraki

Claims (4)

【特許請求の範囲】[Claims] 【請求項１】 一般式（Ｉ） 【化１】 ［式中、Ａ環およびＢ環は、同一または異なって、置換
基を有していてもよい単環式芳香環を意味する。Ｘは結
合、酸素原子、硫黄原子または−ＣＨ＝ＣＨ−を意味す
る。Ｙは式ｅ−ｆ（式中、ｅは低級アルキレン基を、ｆ
は低級アルキル基で置換されていてもよいアミノ基を意
味する）で示される基を意味する］で表わされる化合物
またはその薬理学的に許容される塩。1. A compound of the general formula (I) [In the formula, A ring and B ring are the same or different and mean a monocyclic aromatic ring which may have a substituent. X means a bond, an oxygen atom, a sulfur atom or -CH = CH-. Y is of the formula ef (wherein e is a lower alkylene group, f
Means an amino group which may be substituted with a lower alkyl group), or a pharmaceutically acceptable salt thereof. 【請求項２】 Ｘが結合である請求項１記載の化合物ま
たはその薬理学的に許容される塩。2. The compound according to claim 1, wherein X is a bond, or a pharmaceutically acceptable salt thereof. 【請求項３】 Ａ環およびＢ環が、同一または異なった
置換基を有していてもよいベンゼンである請求項１記載
の化合物またはその薬理学的に許容される塩。3. The compound according to claim 1, wherein ring A and ring B are benzene which may have the same or different substituents, or a pharmaceutically acceptable salt thereof. 【請求項４】 請求項１〜３いずれか一項記載の縮合四
環式ヘテロ環誘導体、あるいはその薬理学的に許容され
る塩を有効成分とする抗腫瘍剤。4. An antitumor agent comprising the fused tetracyclic heterocyclic derivative according to any one of claims 1 to 3 or a pharmacologically acceptable salt thereof as an active ingredient.