JP2000204080A - Phthalazine derivative and therapeutic agent for impotence - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a new compound useful as a preventive and therapeutic agent for impotence, a preventive and therapeutic agent for female sexual function insufficiency or dysmenorrhea and a preventive and therapeutic agent for hypertension, etc. SOLUTION: This compound is represented by formula I [R1 and R2 are each a Halogen or the like; X is cyano or the like; Y is a group of formula II or the like; ring A is a 4 to 8 membered amine ring substitutable with methyl and containing double bond; D is a single bond or the like; R is H or the like; (m) is 0-3; W is amino or the like; (l) is 1-3], preferably 4-[(3-chloro-4- methoxybenzyl)amino]-1-(3-pyridyl)-6-phthalazinecarbonitrile or the like. The compound of formula I is obtained by coupling, e.g. a compound of formula III (Hal is a halogen) [e.g. 1-chloro-4-(3-chloro-4-methoxybenzyl)amino-6 cyanophthalazine] to the corresponding trialkyltin derivative such as a heteroaryl [e.g. 3-(1,1,1-tri-n-butylstanyl)pyridine] in the presence of a catalyst.

Description

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

【０００１】[0001]

【産業上の利用分野】本発明は、フタラジン誘導体に関
する。更に詳しくは男性の***機能不全症予防・治療剤
ならびに女性の性的機能不全または月経困難症の予防・
治療剤に関する。さらには高血圧症、肺高血圧症、狭心
症などの心疾患、糖尿病、または腎炎の予防・治療剤に
関する。The present invention relates to phthalazine derivatives. More specifically, agents for the prevention and treatment of erectile dysfunction in men and the prevention and
Related to therapeutic agents. Furthermore, the present invention relates to a prophylactic / therapeutic agent for heart diseases such as hypertension, pulmonary hypertension, and angina, diabetes, and nephritis.

【０００２】[0002]

【従来技術】***機能不全症の潜在的患者は、我が国に
おいては約300万人といわれて、米国においては2000万
人で50代の男性の15％、60代の男性の約1／3が本疾患に
該当すると報告されている。高齢化社会を迎え、セック
スが快楽、情動行動と考えられ、より高質な生活が求め
られる中で、今後***機能不全症は医療上の問題だけで
なく、社会的な問題になることが予想される。本疾患
は、陰茎そのものの神経、血管、筋肉あるいは性ホルモ
ンなどの障害による器質性と、精神的あるいは心理的原
因などによる機能性（心因性）の二つに分類される。勃
起には、陰茎動脈血流の増加、陰茎静脈からの血液漏出
の抑制、および海綿体組織の弛緩の三条件が必要とさ
れ、いずれかひとつでも阻害されると***機能不全が起
こる。BACKGROUND ART Potential patients with erectile dysfunction are said to be about 3 million in Japan, and 20 million in the United States, 15% of men in their 50s and about 1/3 of men in their 60s. It has been reported to fall under this disease. In an aging society, sex is considered a pleasure and emotional behavior, and a higher quality of life is required.In the future, erectile dysfunction is expected to become a social problem as well as a medical problem in the future Is done. This disease is classified into two types: organic due to disorders of the penis itself such as nerves, blood vessels, muscles, and sex hormones, and functional (psychogenic) due to mental or psychological causes. Erection requires three conditions: increased penile arterial blood flow, suppression of blood leakage from the penile vein, and relaxation of the corpus cavernosum tissue, and inhibition of any one of them results in erectile dysfunction.

【０００３】現在、泌尿器科で実施されている***機能
不全症の治療法は、薬物療法と陰茎補綴具による手術的
陰茎補綴法である。薬物療法として、塩酸パパベリンや
プロスタグランジンE1の陰茎海綿体内への注射などが可
能であるが、日本では患者自身で注射はできず、セック
スのたびに医者に行くことができないため、現在ではあ
まり行われていない。さらに、塩酸パパベリンの注射は
稀ではあるが、陰茎持続***症という痛みを伴う症状を
起こすことがある。このように、現在ある薬物による治
療法は実用的でなく、臨床上、実用性の高い薬物療法が
切望されている。[0003] The current treatments for erectile dysfunction in urology are drug treatment and surgical penile prosthesis using a penile prosthesis. As pharmacological therapy, injection of papaverine hydrochloride or prostaglandin E1 into the corpus cavernosum is possible, but in Japan it is not possible to inject by yourself and go to the doctor every time you have sex. Not done. In addition, injections of papaverine hydrochloride, though rare, can cause the painful symptoms of priapism of the penis. As described above, the existing drug treatment is not practical, and a clinically practical drug therapy has been eagerly desired.

【０００４】[0004]

【発明が解決しようとする課題】1984年、バウマン（Bo
wman）とドルモンド（Drummond）はウシの陰茎後引筋に
おいて、選択的なサイクリック GMP ホスフォジエステ
ラーゼ阻害薬、M&B22948（ザプリナスト）が組織中のサ
イクリックGMPを増加し、弛緩することを報告した（Cyc
lic GMP mediates neurogenic relaxation in the bovi
ne retractor penis muscle, Br. J. Pharmacol.，81，
665-674, 1984）。その後、他の研究者により、組織中
のサイクリックGMPを増加することによる陰茎海綿体の
弛緩作用について報告が相次いで行われた（Int. J. Im
potence Res., 4，85-93，1992； J. Urol., 147，1650
-1655，1992；N. Engl. J. Med., 326，90-94，199
2）。しかし、これらの研究で使用されている化合物
は、作用が弱いなど、臨床上使用するには満足のいくも
のではない。[Problems to be Solved by the Invention] In 1984, Bauman (Bo
wman) and Drummond report that a selective cyclic GMP phosphodiesterase inhibitor, M & B 22948 (Zaprinast), increases and relaxes cyclic GMP in tissues in bovine penile retractor muscle (Cyc
lic GMP mediates neurogenic relaxation in the bovi
ne retractor penis muscle, Br. J. Pharmacol., 81,
665-674, 1984). Subsequently, other investigators reported on the relaxing effect of the corpus cavernosum by increasing cyclic GMP in tissues (Int. J. Im.
potence Res., 4, 85-93, 1992; J. Urol., 147, 1650
-1655, 1992; N. Engl. J. Med., 326, 90-94, 199.
2). However, the compounds used in these studies are not satisfactory for clinical use due to their weak effects.

【０００５】ホスホジエステラーゼ タイプ５の阻害剤
は女性の性的機能障害にも有効である。ホスホジエステ
ラーゼ タイプ５の阻害作用を有するフタラジン誘導体
はＷＯ９６０５１７６（特許公開公報平８−２２５５４
１）に開示されているが、窒素原子含有スピロ化合物、
ビシクロ環および６員式ヘテロ環誘導体に関する開示は
なく、また***機能不全症予防・治療に関する記載は全
く無い。[0005] Inhibitors of phosphodiesterase type 5 are also effective against female sexual dysfunction. Phthalazine derivatives having an inhibitory effect on phosphodiesterase type 5 are disclosed in WO9605176 (Patent Publication 8-22554).
1) a spiro compound containing a nitrogen atom,
There is no disclosure about bicyclo ring and 6-membered hetero ring derivative, and there is no description about prevention and treatment of erectile dysfunction.

【０００６】[0006]

【課題を解決するための手段】種々検討重ねた結果、一
般式（I）に示すフタラジン誘導体がサイクリックGMPの
分解酵素であるホスホジエステラーゼ タイプ ５に対
し高い選択性と強力な阻害作用を有し、かつ陰茎海綿体
に対し強力な弛緩作用を示すと共に、生体内での利用率
は上昇し、また高い安全性を有することを見出し本発明
を完成した。As a result of various studies, it has been found that the phthalazine derivative represented by the general formula (I) has high selectivity and a strong inhibitory effect on phosphodiesterase type 5 which is a cyclic GMP-degrading enzyme, In addition to showing a strong relaxing action on the corpus cavernosum of the penis, the in vivo utilization rate was increased, and the present invention was found to have high safety, and the present invention was completed.

【０００７】本発明は特開平８−２２５５４１に具体的
に開示されていないフタラジン誘導体および全く示唆さ
れていないフタラジン誘導体、さらには一部の誘導体の
製造方法に関するものである。 一般式（I）The present invention relates to a phthalazine derivative which is not specifically disclosed in JP-A-8-225541, a phthalazine derivative which is not suggested at all, and a method for producing some derivatives. General formula (I)

【０００８】[0008]

【化１９】 Embedded image

【０００９】｛式中、R¹およびR²は同一または相異なっ
て、ハロゲン原子、ハロゲン原子で置換されていてもよ
いC1〜C4アルキル基、ハロゲン原子で置換されていても
よいC1〜C4アルコキシ基またはシアノ基を意味する。X
はシアノ基、ニトロ基、ハロゲン原子、チオカルバモイ
ル基、C1〜C4アルキル基・アリールC1〜C4アルキル基ま
たはカルボキシC1〜C4アルキル基で置換されていてもよ
いヒドロキシイミノ基、または下記置換基群Aから選ば
れる１〜３個の置換基で置換されていてもよいヘテロア
リール基を意味する。In the formula, R ¹ and R ² are the same or different and each is a halogen atom, a C ¹ -C 4 alkyl group optionally substituted with a halogen atom, a C ¹ -C 4 alkoxy optionally substituted with a halogen atom. Group or cyano group. X
Is a hydroxyimino group which may be substituted with a cyano group, a nitro group, a halogen atom, a thiocarbamoyl group, a C1-C4 alkyl group / aryl C1-C4 alkyl group or a carboxy C1-C4 alkyl group, or the following substituent group A A heteroaryl group which may be substituted with 1 to 3 substituents selected from

【００１０】Yは i)式（II）Y is i) Formula (II)

【００１１】[0011]

【化２０】 Embedded image

【００１２】（式中、環Aはメチル基で置換されていて
もよく、二重結合を有していてもよい4〜8員式アミン環
を、Dは単結合または酸素原子を、R³は水素原子、C1〜C
4アルキル基またはハロゲン原子を、mは０または１〜３
の整数を意味する。Wはアミノ基、水酸基、シアノ基、
保護基を有していてもよいカルボキシル基またはC1〜C4
アルコキシ基を意味する。）で示される基、 ii)式（III）(Wherein ring A is a 4- to 8-membered amine ring which may be substituted with a methyl group and may have a double bond, D is a single bond or an oxygen atom, R ³ Is a hydrogen atom, C1-C
4 alkyl groups or halogen atoms, m is 0 or 1-3
Means an integer. W is an amino group, a hydroxyl group, a cyano group,
Carboxyl group or C1 to C4 which may have a protecting group
It means an alkoxy group. Ii) a group represented by the formula (III)

【００１３】[0013]

【化２１】 Embedded image

【００１４】（式中、環Bは二重結合を有していてもよ
い4〜8員式アミン環を、nおよびpは同一または相異なっ
て０または１〜３の整数を意味する。）で示される基、 iii)式（IV）(Wherein, ring B is a 4- to 8-membered amine ring optionally having a double bond, and n and p are the same or different and represent an integer of 0 or 1 to 3.) Iii) Formula (IV)

【００１５】[0015]

【化２２】 Embedded image

【００１６】｛式中、環Gは二重結合を有していてもよ
い4〜8員式アミン環を示し、Eは水酸基、ハロゲン原
子、C1〜C4アルキル基またはC1〜C4アルコキシ基を、J
は式-(CHR⁴)q-Q（式中、R⁴は水素原子またはC1〜C4アル
キル基を、Qは水酸基、ハロゲン原子、保護基を有して
いてもよいカルボキシル基、カルバモイル基または窒素
原子以外のヘテロ原子を含まないアゾリル基を、qは０
または１〜４の整数を意味する。）示す。またはEとJは
結合している炭素原子と一緒になって３から６員式の環
を形成してもよく、この環はヘテロ原子を有していてよ
い。またこの環は置換基を有していてもよい。で示｝さ
れる基、 iv)式（V）In the formula, ring G represents a 4- to 8-membered amine ring which may have a double bond, E represents a hydroxyl group, a halogen atom, a C1-C4 alkyl group or a C1-C4 alkoxy group, J
Is of the formula-(CHR ⁴ ) qQ (wherein R ⁴ is a hydrogen atom or a C1-C4 alkyl group, Q is a hydroxyl group, a halogen atom, a carboxyl group which may have a protecting group, a carbamoyl group or a nitrogen atom other than An azolyl group not containing a hetero atom, q is 0
Or an integer of 1 to 4. ). Alternatively, E and J, together with the carbon atom to which they are attached, may form a 3- to 6-membered ring, which may have a heteroatom. This ring may have a substituent. Iv) Formula (V)

【００１７】[0017]

【化２３】 Embedded image

【００１８】（式中、Mは単結合、または水酸基・カル
ボキシル基・C1〜C4アルキル基またはC1〜C4アルコキシ
基で置換されていてもよいC1〜C4アルキレン基を意味す
る。環KはMと一緒になって５ないし８員式アミン環を意
味する。環Lは置換基を有していてもよく、酸素原子を
有していてもよい、５〜８員式アルキル環を示す。）で
示される基、 v）式（VI）(Wherein, M represents a single bond or a C1-C4 alkylene group which may be substituted with a hydroxyl group, a carboxyl group, a C1-C4 alkyl group or a C1-C4 alkoxy group. Taken together means a 5- to 8-membered amine ring, wherein ring L represents a 5- to 8-membered alkyl ring which may have a substituent and may have an oxygen atom. The group shown, v) formula (VI)

【００１９】[0019]

【化２４】 Embedded image

【００２０】（式中、環Pは５〜７員式アミン環、R⁵は
水素原子、またはハロゲン原子・水酸基またはカルボキ
シル基で置換されていてもよいC1〜C4アルキル基を意味
する。）で示される基、 vi)置換基を有していてもよい、アルキニル基、アルケ
ニル基またはアルキル基、 vii)下記置換基群Aから選ばれる１〜３個の置換基で置
換されていてもよいフェニル基、または、 viii）下記置換基群Aから選ばれる１〜３個の置換基で
置換されていてもよいピリジル基、ピリミジル基、チエ
ニル基、チアゾリル基またはフリール基を意味する。 [置換基群A]ハロゲン原子・シアノ基・ニトロ基または
水酸基で置換されていてもよいC1〜C4アルキル基、ハロ
ゲン原子・シアノ基・ニトロ基または水酸基で置換され
ていてもよいC1〜C4アルコキシ基、シアノ基、ニトロ
基、保護基を有していてもよいカルボキシル基、保護基
を有していてもよい水酸基、；低級アルキル基で置換さ
れていてもよいカルバモイル基、ハロゲン原子、C1〜C4
アシル基・C1〜C4アルキルスルホニル基または置換基を
有していてもよいアリールスルホニル基で置換されてい
てもよいアミノ基。(Wherein, ring P is a 5- to 7-membered amine ring, R ⁵ is a hydrogen atom or a C 1 -C 4 alkyl group optionally substituted with a halogen atom, a hydroxyl group or a carboxyl group). A) an alkynyl group, an alkenyl group or an alkyl group which may have a substituent, vii) phenyl optionally substituted with 1 to 3 substituents selected from the following substituent group A Or viii) a pyridyl group, a pyrimidyl group, a thienyl group, a thiazolyl group or a freel group which may be substituted with 1 to 3 substituents selected from the following substituent group A. [Substituent group A] a C1-C4 alkyl group optionally substituted with a halogen atom / cyano group / nitro group or a hydroxyl group, a C1-C4 alkoxy optionally substituted with a halogen atom / cyano group / nitro group or a hydroxyl group Group, cyano group, nitro group, carboxyl group which may have a protecting group, hydroxyl group which may have a protecting group; carbamoyl group which may be substituted by a lower alkyl group, a halogen atom, C1 to C4
An acyl group, an amino group which may be substituted with a C1-C4 alkylsulfonyl group or an optionally substituted arylsulfonyl group.

【００２１】lは１〜３の整数を意味する。但し、lが１
または２、Xがシアノ基、ニトロ基またはクロロ原子、R
¹がクロロ原子、R²がメトキシ基、環Aが５または６員式
アミン環、Dが単結合、mが０でWが保護基を有していて
もよいカルボキシル基またはC1〜C4アルコキシ基の場
合；lが１、R¹がクロロ原子、R²がメトキシ基、環Aが飽
和の５または６員式アミン環、Dが単結合でWが水酸基の
場合；lが１で環Bが５または６員式アミン環でｎおよび
ｐが共に０の場合；lが１でEおよびQが水酸基で、qが０
の場合；およびlが１でXがクロロ原子でYがメトキシ基
で置換されたフェニル基である場合を除く。｝で示され
るフタラジン誘導体または薬理学的に許容される塩、ま
たはそれらの水和物。L represents an integer of 1 to 3. Where l is 1
Or 2, X is a cyano group, a nitro group or a chloro atom, R
¹ is a chloro atom, R ² is a methoxy group, ring A is a 5- or 6-membered amine ring, D is a single bond, m is 0, and W is a carboxyl group or a C1-C4 alkoxy group which may have a protecting group. When l is 1, R ¹ is a chloro atom, R ² is a methoxy group, ring A is a saturated 5- or 6-membered amine ring, D is a single bond and W is a hydroxyl group; l is 1 and ring B is A 5- or 6-membered amine ring wherein n and p are both 0; l is 1, E and Q are hydroxyl groups, and q is 0
And the case where l is 1, X is a chloro atom and Y is a phenyl group substituted with a methoxy group is excluded. A phthalazine derivative or a pharmacologically acceptable salt thereof, or a hydrate thereof,

【００２２】さらに、以下の一般式（VII）も陰茎海綿
体に対し強力な弛緩作用を示すと共に、生体内での利用
率は上昇し、また高い安全性を有することを見出して、
本発明を完成させた。 一般式（VII）Further, they have found that the following general formula (VII) also has a strong relaxing action on the corpus cavernosum, increases the in vivo utilization rate, and has high safety.
The present invention has been completed. General formula (VII)

【００２３】[0023]

【化２５】 Embedded image

【００２４】｛式中、l’は１〜３の整数を意味する。R
⁶はハロゲン原子、ハロゲン原子で置換されていてもよ
いC1〜C4アルキル基またはシアノ基を意味する。X1はシ
アノ基、ニトロ基またはハロゲン原子を意味する。Y1は i)式（VIII）In the formula, l ′ represents an integer of 1 to 3. R
⁶ represents a halogen atom, a C1-C4 alkyl group optionally substituted with a halogen atom, or a cyano group. X1 represents a cyano group, a nitro group or a halogen atom. Y1 is i) Formula (VIII)

【００２５】[0025]

【化２６】 Embedded image

【００２６】（式中、環A1は５または６員式アミン環
を、m1は０または１〜３の整数を意味し、Zはアミノ
基、保護基を有していてもよい水酸基、保護基を有して
いてもよいカルボキシル基、C1〜C4アルコキシ基または
シアノ基を意味する。）で示される基、 ii)式（IX）(Wherein, ring A1 is a 5- or 6-membered amine ring, m1 is an integer of 0 or 1-3, Z is an amino group, a hydroxyl group which may have a protecting group, a protecting group A carboxyl group, a C1-C4 alkoxy group or a cyano group which may have: ii) a group represented by the formula (IX):

【００２７】[0027]

【化２７】 Embedded image

【００２８】（式中、環B1は５または６員式アミン環
を、n1およびp1は０または１〜３の整数を意味する。）
で示される基、 iii)モルホリノ基または硫黄原子が酸化されていてもよ
いチオモルホリノ基、 iv)下記置換基群Aから選ばれる１〜３個の置換基で置換
されていてもよいフェニル基、 v）下記置換基群Aから選ばれる１〜３個の置換基で置換
されていてもよいピリジル基、ピリミジル基、チエニル
基またはフリール基であるヘテロアリール基、または、 vi)式-N(R⁷)-(CH₂)s-Het （式中、R⁷は低級アルキル基を、Hetは下記の置換基群A
1から選ばれる１から３個の置換基で置換されていても
よいピリジル基またはピリミジル基を意味する。sは０
または１〜３の整数を意味する。） [置換基群A1]ハロゲン原子・シアノ基・ニトロ基または
水酸基で置換されていてもよい低級アルキル基、ハロゲ
ン原子・シアノ基・ニトロ基または水酸基で置換されて
いてもよい低級アルコキシ基、シアノ基、ニトロ基、保
護基を有していてもよいカルボキシル基、保護基を有し
ていてもよい水酸基、低級アルキル基で置換されていて
もよいカルバモイル基、ハロゲン原子、アルキル基・ア
ルコキシ基・ハロゲン原子またはアミノ基フェニル
基。｝で示されるフタラジン誘導体または薬理学的に許
容される塩、またはそれらの水和物を有効成分とする勃
起機能不全症治療剤。(Wherein, ring B1 represents a 5- or 6-membered amine ring, and n1 and p1 represent 0 or an integer of 1 to 3).
Iii) a morpholino group or a thiomorpholino group in which a sulfur atom may be oxidized, iv) a phenyl group optionally substituted with 1 to 3 substituents selected from the following substituent group A, v) a pyridyl group, a pyrimidyl group, a thienyl group or a heteroaryl group which is a freel group which may be substituted with 1 to 3 substituents selected from the following substituent group A, or vi) a formula -N (R ⁷ )-(CH ₂ ) s-Het (wherein, R ⁷ represents a lower alkyl group, and Het represents the following substituent group A
It means a pyridyl group or a pyrimidyl group which may be substituted with 1 to 3 substituents selected from 1. s is 0
Or an integer of 1 to 3. [Substituent group A1] A lower alkyl group optionally substituted with a halogen atom / cyano group / nitro group or a hydroxyl group, a lower alkoxy group optionally substituted with a halogen atom / cyano group / nitro group or a hydroxyl group, cyano Group, nitro group, carboxyl group which may have a protecting group, hydroxyl group which may have a protecting group, carbamoyl group which may be substituted by a lower alkyl group, halogen atom, alkyl group / alkoxy group A halogen atom or an amino phenyl group. A therapeutic agent for erectile dysfunction, comprising as an active ingredient a phthalazine derivative or a pharmacologically acceptable salt thereof, or a hydrate thereof.

【００２９】本発明で示される定義において、X、R¹、R
²、R³、R⁴、R⁵、E、Q、置換基群AおよびA1等に見られる
ハロゲン原子とはフッ素原子、塩素原子、臭素原子、ヨ
ウ素原子を意味する。R¹、R²、R³、R⁴、R⁵、R⁶、R⁷、置
換基群AおよびA1等にみられるC1〜C4アルキル基とは、
炭素数1-4の直鎖状または分枝状のアルキル基、例えば
メチル，エチル、n-プロピル、イソプロピル、n-ブチ
ル、イソブチル、1-メチルプロピル、tert-ブチルを意
味する。R¹、R²、および置換基群AおよびA1等にみられ
るC1〜C4アルコキシ基とは、上記C1〜C4アルキル基から
誘導される基を意味する。例えば、メトキシ基、エトキ
シ基、プロポキシ基などを意味する。In the definitions given in the present invention, X, R ¹ , R
Halogen atoms found in ² , R ³ , R ⁴ , R ⁵ , E, Q, substituent groups A and A1, and the like mean a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , a substituent group A and a C1 to C4 alkyl group found in A1 and the like,
It means a linear or branched alkyl group having 1 to 4 carbon atoms, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, 1-methylpropyl, tert-butyl. R ¹ , R ² , and the C1-C4 alkoxy group found in the substituent groups A and A1 and the like mean a group derived from the above C1-C4 alkyl group. For example, it means a methoxy group, an ethoxy group, a propoxy group and the like.

【００３０】Q、W、置換基群AおよびA1等にみられる保
護基を有していてもよいカルボキシル基における保護基
とは、例えば、メチル基、エチル基、tert-ブチル基等
の低級アルキル基やp-メトキシベンジル、p-ニトロベン
ジル、3,4-ジメトキシベンジル、ジフェニルメチル、ト
リチル、フェネチル等の置換基を有していてもよいフェ
ニル基で置換された低級アルキル基、2,2,2-トリクロロ
エチル、2-ヨードエチルなどのハロゲン化低級アルキル
基、ピバロイルオキシメチル、アセトキシメチル、プオ
ピオニルオキシメチル、ブチリルオキシメチル、バレリ
ルオキシメチル、1-アセトキシエチル、2-アセトキシエ
チル、1-ピバロイルオキシエチル、2-ピバロイルオキシ
エチルなどの低級アルカノイルオキシ低級アルキル基、
パルミトイルオキシエチル、ヘプタデカノイルオキシメ
チル、1-パルミトイルオキシエチルなどの高級アルカノ
イルオキシ低級アルキル基、メトキシカルボニルオキシ
メチル、1-ブトキシカルボニルオキシエチル、1-（イソ
プロポキシカルボニルオキシ）エチル等の低級アルコキ
シカルボニルオキシ低級アルキル基、カルボキシメチ
ル、2-カルボキシエチルなどのカルボキシ低級アルキル
基、3-フタリジル等のヘテロアリール基、4-グリシルオ
キシベンゾイルオキシメチルなどの置換基を有していて
もよいベンゾイルオキシ低級アルキル基、（5-メチル-2
-オキソ-1,3-ジオキソレン-4-イル）メチルなどの（置
換ジオキソレン）低級アルキル基、1-シクロヘキシルア
セチルオキシエチルなどのシクロアルキル置換低級アル
カノイルオキシ低級アルキル基、1-シクロヘキシルオキ
シカルボニルオキシエチルなどのシクロアルキルオキシ
カルボニルオキシ低級アルキル基などを挙げることがで
きる。要するに生体内で何らかの手段で分解されて、カ
ルボン酸となりうるものであれば、いかなるものもカル
ボキシル基の保護基となり得る。Protecting groups in the carboxyl group which may have a protecting group, such as Q, W and substituent groups A and A1, are, for example, lower alkyl groups such as methyl group, ethyl group and tert-butyl group. Group or p-methoxybenzyl, p-nitrobenzyl, 3,4-dimethoxybenzyl, diphenylmethyl, trityl, lower alkyl group substituted with a phenyl group which may have a substituent such as phenethyl, 2,2, Halogenated lower alkyl groups such as 2-trichloroethyl and 2-iodoethyl, pivaloyloxymethyl, acetoxymethyl, popionyloxymethyl, butyryloxymethyl, valeryloxymethyl, 1-acetoxyethyl, 2-acetoxyethyl Lower alkanoyloxy lower alkyl groups such as 1-pivaloyloxyethyl and 2-pivaloyloxyethyl,
Higher alkanoyloxy lower alkyl groups such as palmitoyloxyethyl, heptadecanoyloxymethyl and 1-palmitoyloxyethyl; lower alkoxycarbonyl such as methoxycarbonyloxymethyl, 1-butoxycarbonyloxyethyl and 1- (isopropoxycarbonyloxy) ethyl Oxy lower alkyl groups, carboxymethyl, carboxy lower alkyl groups such as 2-carboxyethyl, heteroaryl groups such as 3-phthalidyl, and optionally substituted benzoyloxy lower groups such as 4-glycyloxybenzoyloxymethyl Alkyl group, (5-methyl-2
(Substituted dioxolen) lower alkyl groups such as -oxo-1,3-dioxolen-4-yl) methyl, cycloalkyl-substituted lower alkanoyloxy lower alkyl groups such as 1-cyclohexylacetyloxyethyl, 1-cyclohexyloxycarbonyloxyethyl And cycloalkyloxycarbonyloxy lower alkyl groups. In short, any substance that can be decomposed in vivo by some means to become a carboxylic acid can be a protecting group for a carboxyl group.

【００３１】また、置換基群AおよびA1等にみられる保
護基を有していてもよい水酸基における保護基とは、例
えばホルミル基、アセチル基，ベンゾイル基等のアシル
基；2-メトキシエトキシメチル基などの低級アルコキシ
メチル基等を挙げることができる。要するに生体内で何
らかの手段で分解されて、水酸基となりうるものであれ
ば、いかなるものも水酸基の保護基となり得る。The protecting group in the optionally substituted hydroxyl group which is found in the substituent groups A and A1 is, for example, an acyl group such as a formyl group, an acetyl group or a benzoyl group; 2-methoxyethoxymethyl And a lower alkoxymethyl group such as a group. In short, any substance that can be decomposed by some means in a living body to become a hydroxyl group can be a protecting group for the hydroxyl group.

【００３２】Qにおける窒素原子以外のヘテロ原子を含
まないアゾリル基とはピロール、ピラゾール、イミダゾ
ール、トリアゾール、テトラゾール、インダゾール、ベ
ンゾイミダゾール、ベンゾトリアゾールから導かれる基
を意味する。The azolyl group containing no hetero atom other than the nitrogen atom in Q means a group derived from pyrrole, pyrazole, imidazole, triazole, tetrazole, indazole, benzimidazole, and benzotriazole.

【００３３】式（IV）において、EとJとが結合している
炭素原子と一緒になって形成する環と環Gとでできる化
合物はスピロ化合物である。EとJとが結合している炭素
原子と一緒になって形成する環としては、シクロブタ
ン、シクロペンタン、シクロヘキサン、オキシラン、テ
トラヒドロフラン、テトラヒドロピラン、ブチロラクト
ン、ブチロラクタムなどを挙げることができる。また、
これらの環上の置換基としては、水酸基、前記の保護基
を有していてもよいカルボキシル基、ヒドロキシメチル
基・ヒドロキシエチル基等の水酸基で置換されていても
よいC1〜C4アルキル基、カルボニル基、フッ素・クロロ
原子等のハロゲン原子などを挙げることができる。In the formula (IV), the compound formed by the ring G and the ring formed together with the carbon atom to which E and J are bonded is a spiro compound. Examples of the ring formed together with the carbon atom to which E and J are bonded include cyclobutane, cyclopentane, cyclohexane, oxirane, tetrahydrofuran, tetrahydropyran, butyrolactone, butyrolactam, and the like. Also,
As a substituent on these rings, a hydroxyl group, a carboxyl group which may have the above-mentioned protecting group, a C1 to C4 alkyl group which may be substituted with a hydroxyl group such as a hydroxymethyl group / hydroxyethyl group, a carbonyl group And halogen atoms such as fluorine and chloro atoms.

【００３４】式（V）において、MがC1〜C4アルキレン基
である場合に環Kと環Lで形成されビシクロ環は架橋環で
あることを意味する。環L上の置換基としては、水酸
基、前記の保護基を有していてもよいカルボキシル基、
ヒドロキシメチル基・ヒドロキシエチル基等の水酸基で
置換されていてもよいC1〜C4アルキル基、カルボキシメ
チル基・カルボキシエチル基等のカルボキシル基で置換
されていてもよいC1〜C4アルキル基カルボニル基、フッ
素・クロロ原子等のハロゲン原子、ビニル基等を挙げる
ことができる。In the formula (V), when M is a C1-C4 alkylene group, it means that the bicyclo ring formed by the ring K and the ring L is a bridged ring. As a substituent on the ring L, a hydroxyl group, a carboxyl group which may have the above-mentioned protecting group,
A C1-C4 alkyl group which may be substituted with a hydroxyl group such as a hydroxymethyl group / hydroxyethyl group, a C1-C4 alkyl group which may be substituted with a carboxyl group such as a carboxymethyl group / carboxyethyl group, carbonyl group, fluorine -Examples include a halogen atom such as a chloro atom, and a vinyl group.

【００３５】Yが置換基を有していてもよい、アルキニ
ル基、アルケニル基またはアルキル基における置換基と
は、メチル基・エチル基・プロピル基・イソプロピル基
・ブチル基・イソブチル基・sec-ブチル基・tert-ブチ
ル基などのC1〜C4アルキル基、シクロプロパン・シクロ
ブタン・シクロペンタン・シクロヘキサン等のシクロア
ルカンから導かれる基、メトキシ基・エトキシ基・プロ
ポキシ基などの、前記C1〜C4アルキル基から誘導される
C1〜C4アルコキシ基、水酸基、C1〜C4アルキル基で置換
されていてもよいアミノ基、水酸基で置換されていても
よいアジリジン・アゼチジン、ピロリジン・ピペリジン
などの環状アミン、ヒドロキシC1〜C4アルキル基、ヒド
ロキシC1〜C4アルコキシ基、カルボキシアルコキシ基、
フッ素原子・クロロ原子等のハロゲン原子等を意味す
る。The substituent in the alkynyl group, alkenyl group or alkyl group which Y may have a substituent means a methyl group / ethyl group / propyl group / isopropyl group / butyl group / isobutyl group / sec-butyl group C1-C4 alkyl groups such as groups and tert-butyl groups, groups derived from cycloalkanes such as cyclopropane, cyclobutane, cyclopentane and cyclohexane, methoxy groups, ethoxy groups, and propoxy groups; Be guided
C1-C4 alkoxy group, hydroxyl group, amino group which may be substituted with a C1-C4 alkyl group, aziridine / azetidine which may be substituted with a hydroxyl group, cyclic amine such as pyrrolidine / piperidine, hydroxy C1-C4 alkyl group, Hydroxy C1-C4 alkoxy group, carboxyalkoxy group,
It means a halogen atom such as a fluorine atom and a chloro atom.

【００３６】Xにおけるヘテロアリール基としては、ピ
ロール、ピラゾール、イミダゾール、トリアゾール、テ
トラゾール、インダゾール、ベンゾイミダゾール、ベン
ゾトリアゾール、チアゾール、イソチアゾール、チアジ
アゾール、ベンゾチアジアゾール、ピリジン、ピリミジ
ン、トリアジン、キノリン、イソキノリン、ナフチリジ
ン、フタラジンなどから導かれる基を挙げることができ
る。Examples of the heteroaryl group in X include pyrrole, pyrazole, imidazole, triazole, tetrazole, indazole, benzimidazole, benzotriazole, thiazole, isothiazole, thiadiazole, benzothiadiazole, pyridine, pyrimidine, triazine, quinoline, isoquinoline, naphthyridine. And groups derived from phthalazine and the like.

【００３７】本発明において、薬理学的に許容される塩
とは、例えば、塩酸塩、硫酸塩、臭化水素酸塩、リン酸
塩などの無機酸塩、蟻酸塩、酢酸塩、マレイン酸塩、フ
マル酸塩、酒石酸塩、メタンスルホン酸塩、ベンゼンス
ルホン酸塩、トルエンスルホン酸塩などの有機酸塩を挙
げることができる。本発明において不斉原子を有する化
合物はその光学活性生体も本発明に包含されることは言
うまでもない。In the present invention, the pharmacologically acceptable salt includes, for example, inorganic acid salts such as hydrochloride, sulfate, hydrobromide and phosphate, formate, acetate and maleate. , Fumarate, tartrate, methanesulfonate, benzenesulfonate, toluenesulfonate and the like. It goes without saying that the compound having an asymmetric atom in the present invention includes its optically active organism.

【００３８】さらに、本発明には生体内で代謝されて生
成する本発明化合物および本発明化合物が代謝されて生
成する化合物も含まれる。これらのフタラジン誘導体ま
たはその薬理的に許容される塩、またはそれらの水和物
は経口吸収性および持続性にすぐれているので、陰茎海
綿体または陰部へ直接注射するなく、経皮、静脈内およ
び経口投与による治療が可能であり、***機能不全症予
防・治療剤、および女性の性的機能不全または月経困難
症の予防・治療剤として望ましいものである。PDE5阻害
剤が高血圧症、肺高血圧症、狭心症等の心疾患、糖尿病
や腎炎の予防・治療に有効であることはＷＯ９６０５１
７６やＷＯ９９００３５９に記載されている。Further, the present invention includes the compound of the present invention produced by metabolism in a living body and the compound produced by metabolizing the compound of the present invention. These phthalazine derivatives or their pharmaceutically acceptable salts, or their hydrates, have excellent oral absorption and long-lasting properties, so that they are not directly injected into the corpus cavernosum or genital area, but are transdermal, intravenous and It can be treated by oral administration and is desirable as a prophylactic / therapeutic agent for erectile dysfunction and a prophylactic / therapeutic agent for female sexual dysfunction or dysmenorrhea. WO96051 shows that PDE5 inhibitors are effective for the prevention and treatment of heart diseases such as hypertension, pulmonary hypertension and angina, diabetes and nephritis.
76 and WO9900359.

【００３９】本発明化合物の投与量は、特に限定されな
いが、通常成人１回あたり、静脈内投与により使用する
場合は、５μｇ−１００ｍｇ、好ましくは１０−１００
０μｇを、経口投与により使用する場合は、１−１００
０ｍｇ、好ましくは５−１００ｍｇを用いる。The dose of the compound of the present invention is not particularly limited, but is usually 5 μg to 100 mg, preferably 10 to 100 mg when used by intravenous administration per adult once.
When 0 μg is used by oral administration, 1-100
Use 0 mg, preferably 5-100 mg.

【００４０】[0040]

【発明の実施の形態】製造方法１ 本発明フタラジン誘導体またはその薬理的に許容される
塩の類似の化合物の製造方法はＷＯ９６０５１７６（特
許公開公報平８−２２５５４１）に記載されており、本
発明フタラジン誘導体も同様にして以下のよう製造され
る。BEST MODE FOR CARRYING OUT THE INVENTION Production method 1 A method for producing a phthalazine derivative of the present invention or a similar compound of a pharmaceutically acceptable salt thereof is described in WO9605176 (Patent Publication No. 8-225541). Derivatives are similarly prepared as follows.

【００４１】[0041]

【化２８】 Embedded image

【００４２】式（X）で示される化合物を溶媒中HY²と反
応させて式（XII）を得る反応である。反応溶媒はN-メ
チル-2-ピロリジノンなどが好ましいが、反応に関与し
ないあらゆる溶媒を用いることができる。HYは化合物
（X）に対して過剰量用いるか、あるいは、ジイソプロ
ピルエチルアミンなどの有機塩基、炭酸カリウム、炭酸
ナトリウム、炭酸水素ナトリウムなどの塩を用いること
により、良い結果が得られることがある。反応温度は、
室温から溶媒の沸点であるが、好ましくは１００℃以上
に加熱する。In this reaction, the compound represented by the formula (X) is reacted with HY ² in a solvent to obtain the formula (XII). The reaction solvent is preferably N-methyl-2-pyrrolidinone or the like, but any solvent not involved in the reaction can be used. Good results may be obtained by using an excess amount of HY relative to compound (X) or by using an organic base such as diisopropylethylamine or a salt such as potassium carbonate, sodium carbonate or sodium hydrogen carbonate. The reaction temperature is
The temperature is from room temperature to the boiling point of the solvent, but preferably 100 ° C. or higher.

【００４３】ＷＯ９６０５１７６（特許公開公報平８−
２２５５４１）に記載のないWがシアノ基である化合物
の製造に必要なHY²の合成は次のように行われる。[0043] WO9605176 (Patent Publication 8-
The synthesis of HY ² required for the production of a compound in which W is a cyano group not described in 225541) is carried out as follows.

【００４４】[0044]

【化２９】 Embedded image

【００４５】また、上記公報には具体的な記載のない、
前記定義におけるWがアミノ基の場合はアミノ基が保護
基されたHY²を下記のように合成し、上記は工程終了後
脱保護することにより製造される。Further, there is no specific description in the above publication,
When W in the above definition is an amino group, HY ² in which the amino group is protected is synthesized as follows, and the above is produced by deprotection after the step.

【００４６】[0046]

【化３０】 Embedded image

【００４７】一般式（I）においてYが一般式（IV）およ
び一般式（V）である場合のHY²は、ＷＯ９８０６７２０
に開示されている化合物を用いるか、またそこに開示さ
れている方法を利用することにより製造することができ
る。 １）例えば、一般式（IV）で示される一部の化合物は以
下の方法により製造される。In the general formula (I), when Y is the general formula (IV) or the general formula (V), HY ² is as described in WO98067720.
Or by utilizing the methods disclosed therein. 1) For example, some compounds represented by the general formula (IV) are produced by the following method.

【００４８】[0048]

【化３１】 Embedded image

【００４９】（式中、G1は４〜８員式アミン環を、Q1は
ピロリル、ピラゾリル、イミダゾリル、トリアゾリル、
テトラゾリル、インダゾリル、ベンゾイミダゾリル、ベ
ンゾトリアゾリル基またはフッ素原子を、Proは窒素原
子の保護基を意味する。） トルエン、キシレン、テトラヒドロフラン等の溶媒中、
メチルトリフェニルスルホニウムブロミドをカリウムte
rt-ブトキシド、ブチルリチウム等の塩基で処理し、式
（a）で示されるケトン体と反応させると、式（b）で示
される化合物を得ることができる。反応温度は−７８℃
から室温が好ましい。(Wherein G1 represents a 4- to 8-membered amine ring, Q1 represents pyrrolyl, pyrazolyl, imidazolyl, triazolyl,
A tetrazolyl, indazolyl, benzimidazolyl, benzotriazolyl group or a fluorine atom, and Pro means a protecting group for a nitrogen atom. ) In solvents such as toluene, xylene and tetrahydrofuran,
Methyltriphenylsulfonium bromide to potassium te
The compound represented by the formula (b) can be obtained by treating with a base such as rt-butoxide and butyllithium and reacting with a ketone represented by the formula (a). Reaction temperature is -78 ° C
To room temperature is preferred.

【００５０】化合物（b）にジエチルエーテル、ジメト
キシエタン、テトラヒドロフラン等の溶媒中でトリクロ
ロアセチルクロリドと反応させてジクロロシクロブタノ
ン体（f）（またはジアセチルクロリドと反応させると
モノクロロ体が得られる。このモノクロロ体はトリクロ
ロアセチルクロリドと反応後、酢酸で処理しても得られ
る。）を得た後、亜鉛末等の還元剤で処理することによ
り式（g）で示されるシクロブタノン体を得ることがで
きる。反応温度は１０から５０℃が好ましい。化合物
（g）をジクロロメタン等の溶媒中炭酸水素ナトリウム
等の存在下に、3-クロロ過安息香酸等の過酸化物を作用
させると、式（h）で示されるラクトン体を得ることが
できる。反応温度としては室温から４０℃の範囲が好ま
しい。化合物（b）をジクロロケテンおよびジアゾメタ
ン、あるいは化合物（g）をジアゾメタンで処理すると
式（g）においてシクロペンタノン体が得られる。また
このシクロペンタノン体をジアゾメタンで処理するとシ
クロヘキサノン体が得られる。The compound (b) is reacted with trichloroacetyl chloride in a solvent such as diethyl ether, dimethoxyethane, or tetrahydrofuran to react with dichlorocyclobutanone (f) (or diacetyl chloride) to obtain a monochloro form. Can be obtained by reacting with trichloroacetyl chloride and then treating with acetic acid.) To obtain a cyclobutanone compound represented by the formula (g) by treating with a reducing agent such as zinc dust. The reaction temperature is preferably from 10 to 50 ° C. When compound (g) is reacted with a peroxide such as 3-chloroperbenzoic acid in the presence of sodium bicarbonate or the like in a solvent such as dichloromethane or the like, a lactone compound represented by the formula (h) can be obtained. The reaction temperature is preferably in the range from room temperature to 40 ° C. When the compound (b) is treated with dichloroketene and diazomethane, or the compound (g) is treated with diazomethane, a cyclopentanone compound is obtained in the formula (g). When the cyclopentanone is treated with diazomethane, a cyclohexanone is obtained.

【００５１】化合物（b）を溶媒中フタル酸モノ過酸マ
グネシウム等の過酸で処理すると式（c）で示されるエ
ポキシド体が得られる。このエポキシド体（c）をジメ
チルホルムアミド等の溶媒中、ヘテロ原子として窒素原
子のみからなるアゾールのナトリウム塩と反応させる
と、対応する式（d）で示される化合物（Q1が1-イミダ
ゾリル基、1-トリアゾリル基等）が得られる。また、Bu
₄N・H₂F₃存在下に１００から１５０℃でフッ化水素カリ
ウムで処理すると式（d）で示される化合物においてQ1
がフルオロ原子であるフルオロメチル体が得られる。When the compound (b) is treated with a peracid such as magnesium monophthalate in a solvent, an epoxide represented by the formula (c) is obtained. When this epoxide (c) is reacted with a sodium salt of an azole comprising only a nitrogen atom as a hetero atom in a solvent such as dimethylformamide, the corresponding compound represented by the formula (d) (Q1 is a 1-imidazolyl group, 1 -Triazolyl group). Also, Bu
_When treated with potassium hydrogen fluoride at 100 to 150 ° C. in the presence of ₄ N · H ₂ F ₃ , the compound represented by the formula (d) has Q1
Is a fluoromethyl form.

【００５２】一方、化合物（c）を−１０から１０℃で
塩化メチレン等の溶媒中フッ化水素ピリジンと処理する
と、式（e）で示されるフルオロ体が得られる。 ２）一般式（V）で示されるの化合物のうち、Mが水酸基
で置換されているメチレンの場合は、例えば以下の方法
により製造される。On the other hand, when the compound (c) is treated with hydrogen fluoride pyridine in a solvent such as methylene chloride at -10 to 10 ° C., a fluoro compound represented by the formula (e) is obtained. 2) Among the compounds represented by the general formula (V), when M is methylene substituted with a hydroxyl group, the compound is produced, for example, by the following method.

【００５３】[0053]

【化３２】 Embedded image

【００５４】環Lが酸素原子を含む場合も同様に製造す
ることができる。 製造方法２ 一般式（I）において、Yが置換基を有していてもよいア
ルキニル基、アルケニル基、アルキル基である化合物は
以下の方法により製造することができる。When the ring L contains an oxygen atom, it can be produced in the same manner. Production Method 2 In the general formula (I), a compound in which Y is an alkynyl group, an alkenyl group, or an alkyl group which may have a substituent can be produced by the following method.

【００５５】[0055]

【化３３】 Embedded image

【００５６】（式中、Halはハロゲン原子を、R⁸は置換
基を有していてもよいC1〜C4アルキル基、または置換基
を有していてもよいシクロアルキル基またはシクロアル
キルアルキル基を意味する。R¹、R²、lおよびXは前記を
意味する。） 一般式（X）とアルキン誘導体との反応は、触媒量のジ
クロロビストリフェニルホスフィンパラジウム(II)とヨ
ウ化第一銅および3級アミン存在下で室温あるいは加熱
下で行われる。使用される溶媒としてはジメチルホルム
アミドまたは1-メチルピロリジノンなどを挙げることが
できる。使用する3級アミンとしてはトリエチルアミ
ン、ジイソプロピルエチルアミン、DBU、ジメチルアニ
リンなどである。反応温度は0〜150℃が好適である。(Wherein, Hal represents a halogen atom, R ⁸ represents a C1-C4 alkyl group which may have a substituent, or a cycloalkyl group or a cycloalkylalkyl group which may have a substituent. R ¹ , R ² , l and X have the same meanings as defined above.) The reaction between the general formula (X) and the alkyne derivative is carried out by reacting a catalytic amount of dichlorobistriphenylphosphine palladium (II) with cuprous iodide and The reaction is performed at room temperature or under heating in the presence of a tertiary amine. Examples of the solvent used include dimethylformamide and 1-methylpyrrolidinone. The tertiary amine used includes triethylamine, diisopropylethylamine, DBU, dimethylaniline and the like. The reaction temperature is preferably from 0 to 150 ° C.

【００５７】式（XIII）で示されるアルキン化合物から
式（XIV）で示されるアルケン化合物および式（XV）で
示されるアルカン化合物への変換はリンドラー触媒やPd
-C触媒存在下に接触還元等により行われる。 製造方法３ また、Yが置換基を有していてもよいアリール基または
ヘテロアリール基であるY3のフタラジン誘導体は以下の
ようにして製造される。The conversion of the alkyne compound represented by the formula (XIII) into the alkene compound represented by the formula (XIV) and the alkane compound represented by the formula (XV) can be carried out using a Lindlar catalyst or Pd.
It is carried out by catalytic reduction in the presence of a -C catalyst. Production Method 3 Further, a phthalazine derivative of Y3 in which Y is an aryl group or a heteroaryl group which may have a substituent is produced as follows.

【００５８】[0058]

【化３４】 Embedded image

【００５９】反応は０価または２価のパラジウム錯体を
用い、式（X）で示される1-ハロゲノキナゾリン誘導体
と対応するアリール基またはヘテロアリール基のボロン
酸、ジアルコキシボランまたはトリアルキルスズ誘導体
をカップリングさせることにより行われる。アリール基
またはヘテロアリール基のボロン酸、ジアルコキシボラ
ンまたはトリアルキルスズ誘導体とパラジウム錯体を有
機溶媒と炭酸ナトリウム水溶液の二相系溶媒に溶解また
は懸濁し、窒素気流下、室温から溶媒の沸点でおよそ1
−24時間反応させる。パラジウム錯体としては反応を進
行させるあらゆるパラジウム錯体を用いることができる
が、テトラキス（トリフェニルフォスフィン）パラジウ
ムなどが好ましい。有機溶媒としては反応に影響を与え
ないあらゆるものを用いることができるが、キシレン、
トルエン、テトラヒドロフラン、またはそれらの混合溶
媒が好ましい。 製造方法４ 一般式（Ｉ）において、Xがシアノ基である化合物（XVI
I）を用いて公知の反応を組み合わせ、下記の反応式中
に示される化合物を製造することができる。The reaction is carried out using a zero-valent or divalent palladium complex, and a 1-halogenoquinazoline derivative represented by the formula (X) and a boronic acid, dialkoxyborane or trialkyltin derivative of the corresponding aryl group or heteroaryl group are reacted. This is performed by coupling. A boronic acid of an aryl group or a heteroaryl group, a dialkoxyborane or a trialkyltin derivative and a palladium complex are dissolved or suspended in a biphasic solvent of an organic solvent and an aqueous solution of sodium carbonate. 1
Incubate for 24 hours. As the palladium complex, any palladium complex that promotes the reaction can be used, but tetrakis (triphenylphosphine) palladium or the like is preferable. Any organic solvent that does not affect the reaction can be used, but xylene,
Toluene, tetrahydrofuran, or a mixed solvent thereof is preferred. Production Method 4 In the general formula (I), a compound (XVI) wherein X is a cyano group
The compounds shown in the following reaction formulas can be produced by combining known reactions using I).

【００６０】[0060]

【化３５】 Embedded image

【００６１】（式中、R⁹は水素原子、ハロゲン原子で置
換されていてもよいC1〜C4アルキル基、アリールC1〜C4
アルキル基またはカルボキシC1〜C4アルキル基を意味
し、R¹⁰はC1〜C4アルキル基を意味する。R¹、R²、lおよ
びYは前記を意味する。） 製造方法５ 一般式（Ｉ）において、Xがヘテロアリール基である一
部の化合物については、製造方法３と同様の方法で製造
することができる。(Wherein R ⁹ is a hydrogen atom, a C1-C4 alkyl group optionally substituted by a halogen atom, an aryl C1-C4
Means an alkyl group or a carboxy C1~C4 alkyl group, R ¹⁰ denotes a C1~C4 alkyl group. R ¹ , R ² , l and Y are as defined above. Production Method 5 Some compounds in which X is a heteroaryl group in the general formula (I) can be produced in the same manner as in Production Method 3.

【００６２】[0062]

【化３６】 Embedded image

【００６３】（式中、Halはハロゲン原子を、Het¹はヘ
テロアリール基を意味し、R¹、R²、lおよびYは前記を意
味する。） ハロゲン原子としてはブロム原子またはヨウ素原子が好
ましい。また、一般式（Ｉ）において、窒素原子以外の
ヘテロ原子を有しないアゾリル基である化合物の製造
は、あらかじめ対応する一般式（X）で示される化合物
を製造した後、前記製造方法１に準じて行われる。対応
する一般式（X）で示される化合物は、例えば、4-フル
オロフタル酸ジメチルを窒素原子以外のヘテロ原子を含
まないアゾールと処理して4-アゾリルフタル酸ジメチル
を得、続いてヒドラジンと処理して6-アゾリル-2,3-ジ
ヒドロ-1,4-フタラジンジオンを得た後、ＷＯ９６０５
１７６に開示の方法により製造される。 製造方法６ 一般式（I）においてYが一般式（VI）で示される化合物
は、下記の一般式（XXIV）で示される化合物から公知の
方法によるオキシム化により製造される。(In the formula, Hal represents a halogen atom, Het ¹ represents a heteroaryl group, and R ¹ , R ² , l and Y represent the same as above.) As the halogen atom, a bromo atom or an iodine atom is preferable. . In the general formula (I), the compound which is an azolyl group having no hetero atom other than a nitrogen atom is prepared according to the above-mentioned production method 1 after preparing the corresponding compound represented by the general formula (X) in advance. Done. The corresponding compound represented by the general formula (X) can be obtained, for example, by treating dimethyl 4-fluorophthalate with an azole containing no heteroatom other than a nitrogen atom to obtain dimethyl 4-azolylphthalate, followed by treatment with hydrazine. To obtain 6-azolyl-2,3-dihydro-1,4-phthalazinedione,
176. Production Method 6 In the general formula (I), the compound represented by the general formula (VI) where Y is produced from the compound represented by the following general formula (XXIV) by oximation by a known method.

【００６４】[0064]

【化３７】 Embedded image

【００６５】（式中、R¹、R²、R⁵、lおよびXは前記を意
味する。）(Wherein, R ¹ , R ² , R ⁵ , 1 and X are as defined above)

【００６６】[0066]

【発明の効果】以下に実験例により本化合物の効果を示
す。The effects of the present compound will be described below with reference to experimental examples.

【００６７】[0067]

【実験例】１）ブタ血小板より得たcGMP-PDEを用いた酵
素阻害作用 ブタ血小板より調製したcGMP-PDEの酵素活性をトンプソ
ン（Tompson）等の方法に準じて1mM EGTA存在下に1μM
cGMPを基質とし,被験化合物をDMSOに溶解して反応液に
加えて阻害活性を測定した。尚、反応液中のDMSOの最終
濃度は1%以下とした。cGMP-PDEの調製は次のように行っ
た。ブタ血小板をバッファーA（20mM Tris/HCl、2mM 酢
酸マグネシウム、10mM 2-メルカプトエタノール、0.1mM
EGTA、pH7.4）に加えソニケートした。懸濁液を100000
xgで60分間遠心分離し、得られた上清を、DEAE-Toyopea
rl 650S（Toso, Tokyo, Japan）カラムにかけた。バッ
ファーAでカラムを洗浄した後、バッファーAの0.075-0.
25M NaClグラジェントで溶出し、cGMP-PDE画分を得た。
得られた画分を透析、濃縮して保存した。[Experimental example] 1) Enzyme using cGMP-PDE obtained from porcine platelets
Elemental inhibitory activity The enzyme activity of cGMP-PDE prepared from porcine platelets was determined to be 1 μM in the presence of 1 mM EGTA according to the method of Tompson et al.
Using cGMP as a substrate, a test compound was dissolved in DMSO and added to the reaction solution to measure the inhibitory activity. Note that the final concentration of DMSO in the reaction solution was 1% or less. The preparation of cGMP-PDE was performed as follows. Porcine platelets were washed with buffer A (20 mM Tris / HCl, 2 mM magnesium acetate, 10 mM 2-mercaptoethanol, 0.1 mM
(EGTA, pH 7.4) and sonicated. 100000 suspension
centrifuged at xg for 60 minutes, and the resulting supernatant was used for DEAE-Toyopea
rl 650S (Toso, Tokyo, Japan) column. After washing the column with buffer A, 0.075-0.
Elution was performed with a 25 M NaCl gradient to obtain a cGMP-PDE fraction.
The obtained fraction was dialyzed, concentrated and stored.

【００６８】[0068]

【表１】 [Table 1]

【００６９】２）ウサギ摘出陰茎海綿体標本におけるニ
トロプルシッドによる弛緩作用に対するPDE5阻害化合物
の増強作用 NZW系ウサギ（約3.0 kg）はペントバルビタール（50 mg
/kg）の静脈内投与により致死せしめ、陰茎を摘出し
た。摘出後、白膜等の周囲組織を除き海綿体を露出し、
約10 x 1.5 x 1.5 mmの標本を作成した。この標本を37
℃において10mlのKrebs-Henseleit溶液（NaCl:118.4mM,
KCl:4.7mM, CaCl₂:2.5mM, MgSO₄:1.3mM, KH₂PO₄:1.2m
M, NaHCO₃:25.0mM, glucose:11.0mM, EDTA:0.026mM, in
domethacin:0.001mM）を満たしたマグヌス管に懸垂し、
混合ガス（95%O₂ + 5%CO₂）を通気し、2gの負荷のもと
に収縮張力の変化を等尺性に記録し測定した。収縮を安
定させるため、KCl添加（最終濃度100 mM）による収縮
と洗浄を２回繰り返し、さらにフェニレフリン添加（最
終濃度10 mM）による収縮と洗浄を行った。再度、10ml
のKrebs-Henseleit溶液で満たし、L-N^G-ニトロアルギニ
ンメチルエステル（最終濃度100 mM）を添加により内因
性の一酸化窒素の生成を阻害した。フェニレフリン添加
（最終濃度10 mM）により収縮を惹起させ、3、30または
300 nMとなるよう薬物溶液を添加した。この時、媒体と
してジメチルスルホキシドを用いた。薬物添加15分後に
ニトロプルシッド（最終濃度300 mM）を加え、標本を弛
緩させた。さらに、パパベリン添加（最終濃度100 mM）
により最大弛緩を求めた。実験終了後、パパベリン添加
時の発生張力を基線とし、チャート上におけるニトロプ
ルシッド添加による弛緩をデジマチックキャリパを用い
て計測し、弛緩率を求めた。 2) D in rabbit isolated penis corpus cavernosum specimen
PDE5 inhibitory compounds on the relaxing action of troprusid
Potentiation NZW rabbits (approximately 3.0 kg) is pentobarbital (50 mg
/ kg), and the penis was excised. After excision, exposing the corpus cavernosum excluding surrounding tissues such as white membrane,
Approximately 10 x 1.5 x 1.5 mm specimens were made. 37
10 ml of Krebs-Henseleit solution (NaCl: 118.4 mM,
_{KCl: 4.7mM, CaCl 2: 2.5mM} , MgSO 4: 1.3mM, KH 2 PO 4: 1.2m
M, NaHCO ₃ : 25.0mM, glucose: 11.0mM, EDTA: 0.026mM, in
domethacin: 0.001mM)
A mixed gas (95% O ₂ + 5% CO ₂ ) was ventilated, and the change in contraction tension was isometrically recorded and measured under a load of 2 g. In order to stabilize the contraction, contraction and washing with KCl addition (final concentration 100 mM) were repeated twice, and further contraction and washing with phenylephrine addition (final concentration 10 mM) were performed. Again, 10ml
Filled with Krebs-Henseleit solution, LN ^G - inhibited the production of endogenous nitric oxide by the addition of nitroarginine methyl ester (final concentration 100 mM). Addition of phenylephrine (final concentration 10 mM) induces contraction, resulting in 3, 30 or
The drug solution was added to 300 nM. At this time, dimethyl sulfoxide was used as a medium. 15 minutes after drug addition, nitroprusside (final concentration 300 mM) was added to relax the specimen. In addition, add papaverine (final concentration 100 mM)
To determine the maximum relaxation. After completion of the experiment, the relaxation caused by the addition of nitroprusside on the chart was measured using a digimatic caliper using the tension generated when papaverine was added as a baseline, and the relaxation rate was determined.

【００７０】[0070]

【表２】 [Table 2]

【００７１】表中の数値は3、30及び300 nMの化合物で
前処理した標本におけるニトロプルシッド添加後の弛緩
率について%で示し、２例の平均値を記載した。また、E
C₅₀値はフェニレフリンで惹起した収縮に対する50%弛緩
を生じさせる化合物濃度を示し、２例の弛緩曲線から回
帰分析により算出した。ニトロプルッシドから生成した
一酸化窒素が、グアニレートサイクラーゼを活性化し、
GTPからのcGMPの生成を促進して陰茎海綿体を弛緩し
た。PDE5阻害剤はcGMPの分解を抑制することによりこの
弛緩作用を増強した。The numerical values in the table are shown in% for the relaxation rate after addition of nitroprusside in the samples pretreated with the compounds of 3, 30 and 300 nM, and the average value of two cases is described. Also, E
The C ₅₀ value indicates the concentration of the compound that causes 50% relaxation with respect to the contraction induced by phenylephrine, and was calculated by regression analysis from the relaxation curves of two cases. Nitric oxide generated from nitroprusside activates guanylate cyclase,
It promoted the production of cGMP from GTP and relaxed the corpus cavernosum. PDE5 inhibitors enhanced this relaxation by suppressing the degradation of cGMP.

【００７２】以上のように、本発明化合物はPDE5阻害作
用を有し、濃度依存的にウサギ摘出陰茎海綿体標本にお
けるニトロプルシッドによる弛緩作用を増強することが
示された。即ち、本発明化合物は***機能不全症の予防
・治療剤として有用である。本発明の理解を容易にする
ために製造例および実施例を示すが、本発明がこれらの
化合物に限定されるものでないことは言うまでもない。 製造例１ 4-(3-クロロ-4-メトキシベンジル)アミノ-6-シアノ-1-
[(3R)-3-ヒドロキシピペリジノ]フタラジン塩酸塩As described above, it was shown that the compound of the present invention has a PDE5 inhibitory effect and enhances the relaxation effect of nitroprusside in a rabbit isolated penis corpus cavernosum specimen in a concentration-dependent manner. That is, the compound of the present invention is useful as an agent for preventing or treating erectile dysfunction. Production Examples and Examples are shown to facilitate understanding of the present invention, but it goes without saying that the present invention is not limited to these compounds. Production Example 1 4- (3-chloro-4-methoxybenzyl) amino-6-cyano-1-
[(3R) -3-hydroxypiperidino] phthalazine hydrochloride

【００７３】[0073]

【化３８】 Embedded image

【００７４】1-クロロ-4-(3-クロロ-4-メトキシベンジ
ル)アミノ-6-シアノフタラジン1.0g、(R)-(+)-3-ヒドロ
キシピペリジン塩酸塩1.92g、ジイソプロピルエチルア
ミン1.80g、1-メチル-2-ピロリドン12mLの混合物を170
℃で1時間１５分攪拌した。冷後、反応液に酢酸エチル
を加え、水及び飽和食塩水で洗浄した。無水硫酸ナトリ
ウムで乾燥後、減圧下溶媒留去し、残渣をシリカゲルカ
ラムクロマトグラフィーで精製した。得られたフリー体
を酢酸エタノール−水に懸濁し、1Ｎ塩酸水溶液を加え
加熱溶解した。冷後、析出した結晶をろ取し標記化合物
を黄色の粉末として860mg得た。 MASS(ESI):424.1(MH⁺)¹ H-NMR(400MHz, DMSO-d₆)δ;1.39-1.50(1H, m), 1.65-
1.78(1H, m), 1.75-1.98(2H, m), 2.82-2.91(1H, m),
2.93-3.02(1H, m), 3.33-3.48(2H, m), 3.79-3.88(1H,
m), 3.85(3H, s), 4.72(2H, br), 7.16(1H, d, J=8.4H
z), 7.47(1H, dd, J=8.4, 1.6Hz), 7.62(1H, d, J=1.6H
z), 8.31(1H, d, J=8.4Hz), 8.48(1H, d, J=8.4Hz),9.3
8-9.46(1H, m), 10.27(1H, br) 製造例２ 4-(3-クロロ-4-メトキシベンジル)アミノ-6-シアノ-1-
[(3S)-3-ヒドロキシピロリジノ]フタラジン塩酸塩1-chloro-4- (3-chloro-4-methoxybenzyl) amino-6-cyanophthalazine 1.0 g, (R)-(+)-3-hydroxypiperidine hydrochloride 1.92 g, diisopropylethylamine 1.80 g, 1 -Methyl-2-pyrrolidone
The mixture was stirred at ℃ for 1 hour and 15 minutes. After cooling, ethyl acetate was added to the reaction solution, which was washed with water and saturated saline. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography. The obtained free form was suspended in acetic acid-ethanol / water, and a 1N aqueous hydrochloric acid solution was added thereto to dissolve by heating. After cooling, the precipitated crystals were collected by filtration to give 860 mg of the title compound as a yellow powder. MASS (ESI): 424.1 (MH +) 1 H-NMR (400MHz, DMSO-d 6) δ; 1.39-1.50 (1H, m), 1.65-
1.78 (1H, m), 1.75-1.98 (2H, m), 2.82-2.91 (1H, m),
2.93-3.02 (1H, m), 3.33-3.48 (2H, m), 3.79-3.88 (1H,
m), 3.85 (3H, s), 4.72 (2H, br), 7.16 (1H, d, J = 8.4H
z), 7.47 (1H, dd, J = 8.4, 1.6Hz), 7.62 (1H, d, J = 1.6H
z), 8.31 (1H, d, J = 8.4Hz), 8.48 (1H, d, J = 8.4Hz), 9.3
8-9.46 (1H, m), 10.27 (1H, br) Production Example 2 4- (3-chloro-4-methoxybenzyl) amino-6-cyano-1-
[(3S) -3-hydroxypyrrolidino] phthalazine hydrochloride

【００７５】[0075]

【化３９】 Embedded image

【００７６】製造例１の(R)-(+)-3-ヒドロキシピペリジ
ン塩酸塩の代わりに(S)-3-ヒドロキシピロリジンを用い
て標記化合物を得た。 MASS(ESI)；410.0(MH⁺)¹ H-NMR(400 MHz, DMSO-d₆)δ;1.94-2.10 (2H, m), 3.50
-3.62 (1H, m), 3.42-3.68 (1H, m), 3.83 (3H, s), 3.
93-4.10 (2H, m), 4.43-4.50 (1H, m), 4.50-4.64 (2H,
m), 5.30 (1H, br), 7.13 (1H, d, J= 8.4 Hz), 7.34-
7.44 (1H, m), 7.48-7.56 (1H, m), 8.38-8.46 (1H,
m), 8.62-8.74 (1H, m), 9.10-9.32 (1H, m) .製造例３ 4-(3-クロロ-4-メトキシベンジル)アミノ-6-シアノ-1-
[(2S)-2-ヒドロキシメチルピロリジノ]フタラジン塩酸
塩The title compound was obtained by using (S) -3-hydroxypyrrolidine instead of (R)-(+)-3-hydroxypiperidine hydrochloride of Production Example 1. MASS (ESI); 410.0 (MH ⁺ ) ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ; 1.94-2.10 (2H, m), 3.50
-3.62 (1H, m), 3.42-3.68 (1H, m), 3.83 (3H, s), 3.
93-4.10 (2H, m), 4.43-4.50 (1H, m), 4.50-4.64 (2H, m
m), 5.30 (1H, br), 7.13 (1H, d, J = 8.4 Hz), 7.34-
7.44 (1H, m), 7.48-7.56 (1H, m), 8.38-8.46 (1H,
m), 8.62-8.74 (1H, m), 9.10-9.32 (1H, m) Production Example 3 4- (3-chloro-4-methoxybenzyl) amino-6-cyano-1-
[(2S) -2-hydroxymethylpyrrolidino] phthalazine hydrochloride

【００７７】[0077]

【化４０】 Embedded image

【００７８】製造例１の(R)-(+)-3-ヒドロキシピペリジ
ン塩酸塩の代わりに(S)-2-ヒドロキシメチルピロリジン
を用いて標記化合物を得た。 MASS(ESI)；424.1(MH⁺)¹ H-NMR(400 MHz, DMSO-d₆)δ;1.60-2.39 (4H, m), 3.44
-3.53 (1H, m), 3.83 (3H, s), 3.89-3.99 (1H, m), 4.
34-4.70 (3H, m), 7.12-7.16 (1H, m), 7.38-7.46 (1H,
m), 7.52-7.59 (1H, m), 8.40-8.43 (1H, m), 8.43-8.
60 (1H, m), 9.23-9.30 (1H, m) 製造例４ 4-(3-クロロ-4-メトキシベンジル)アミノ-6-シアノ-1-
(3-ヒドロキシメチルピペリジノ)フタラジン塩酸塩The title compound was obtained by using (S) -2-hydroxymethylpyrrolidine instead of (R)-(+)-3-hydroxypiperidine hydrochloride of Production Example 1. MASS (ESI); 424.1 (MH ⁺ ) ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ; 1.60-2.39 (4H, m), 3.44
-3.53 (1H, m), 3.83 (3H, s), 3.89-3.99 (1H, m), 4.
34-4.70 (3H, m), 7.12-7.16 (1H, m), 7.38-7.46 (1H,
m), 7.52-7.59 (1H, m), 8.40-8.43 (1H, m), 8.43-8.
60 (1H, m), 9.23-9.30 (1H, m) Production Example 4 4- (3-chloro-4-methoxybenzyl) amino-6-cyano-1-
(3-Hydroxymethylpiperidino) phthalazine hydrochloride

【００７９】[0079]

【化４１】 Embedded image

【００８０】製造例１の(R)-(+)-3-ヒドロキシピペリジ
ン塩酸塩の代わりに3-ヒドロキシメチルピペリジンを用
いて標記化合物を得た。 MASS(ESI)；438.2(MH⁺)¹ H-NMR(400 MHz, DMSO-d₆)δ;1.13-1.28 (1H, m), 1.70
-1.86 (3H, m), 1.87-1.99 (1H, m), 2.67-2.75 (1H,
m), 2.86-2.95 (1H, m), 3.33-3.50 (3H, m), 3.51-3.6
0 (1H, m), 3.16 (3H, s), 3.85 (3H, s), 4.71 (2H, b
r s), 7.16 (1H, d, J= 8.4 Hz), 7.44 (1H, dd, J =
8.4, 0.8 Hz), 7.59 (1H, d, J = 0.8 Hz),8.23 (1H,
d, J = 8.8 Hz), 8.45 (1H, dd, J = 8.8, 0.4 Hz), 9.
28-9.35 (1H,m), 9.95 (1H, br), 14.00 (1H, br) 製造例５ 4-(3-クロロ-4-メトキシフェネチル)アミノ-6-シアノ-1
-(3-ヒドロキシメチルピペリジノ)フタラジン塩酸塩The title compound was obtained by using 3-hydroxymethylpiperidine instead of (R)-(+)-3-hydroxypiperidine hydrochloride of Production Example 1. MASS (ESI); 438.2 (MH ⁺ ) ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ; 1.13-1.28 (1H, m), 1.70
-1.86 (3H, m), 1.87-1.99 (1H, m), 2.67-2.75 (1H, m
m), 2.86-2.95 (1H, m), 3.33-3.50 (3H, m), 3.51-3.6
0 (1H, m), 3.16 (3H, s), 3.85 (3H, s), 4.71 (2H, b
rs), 7.16 (1H, d, J = 8.4 Hz), 7.44 (1H, dd, J =
8.4, 0.8 Hz), 7.59 (1H, d, J = 0.8 Hz), 8.23 (1H,
d, J = 8.8 Hz), 8.45 (1H, dd, J = 8.8, 0.4 Hz), 9.
28-9.35 (1H, m), 9.95 (1H, br), 14.00 (1H, br) Production Example 5 4- (3-chloro-4-methoxyphenethyl) amino-6-cyano-1
-(3-hydroxymethylpiperidino) phthalazine hydrochloride

【００８１】[0081]

【化４２】 Embedded image

【００８２】製造例４の1-クロロ-4-(3-クロロ-4-メト
キシベンジル)アミノ-6-シアノフタラジンの代わりに1-
クロロ-4-(3-クロロ-4-メトキシフェネチル)アミノ-6-
シアノフタラジンを用いて標記化合物を得た。 MASS(ESI)；452.3(MH⁺)¹ H-NMR(400 MHz, DMSO-d₆)δ;1.70-1.90 (2H, m), 1.90
-2.05 (2H, m), 2.70 (1H, br.t), 2.88 (1H,br.t), 2.
95-3.08 (2H, m), 3.25-3.63 (2H, m), 3.78 (2H, m),
3.83 (3H, s), 7.09 (1H, d, J= 8.6 Hz), 7.29 (1H,
d, J= 8.6 Hz), 7.47 (1H, s), 8.25 (1H, d, J= 8.6 H
z), 8.49 (1H, d, J= 8.6 Hz), 9.48 (1H,s) 製造例６ 4-(3-クロロ-4-メトキシフェネチル)アミノ-6-シアノ-1
-(4-ヒドロキシメチルピペリジノ)フタラジンIn Preparation Example 4, 1-chloro-4- (3-chloro-4-methoxybenzyl) amino-6-cyanophthalazine was replaced with 1-chloro-4- (3-chloro-4-methoxybenzyl) amino-6-cyanophthalazine
Chloro-4- (3-chloro-4-methoxyphenethyl) amino-6-
The title compound was obtained using cyanophthalazine. MASS (ESI); 452.3 (MH ⁺ ) ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ; 1.70-1.90 (2H, m), 1.90
-2.05 (2H, m), 2.70 (1H, br.t), 2.88 (1H, br.t), 2.
95-3.08 (2H, m), 3.25-3.63 (2H, m), 3.78 (2H, m),
3.83 (3H, s), 7.09 (1H, d, J = 8.6 Hz), 7.29 (1H,
d, J = 8.6 Hz), 7.47 (1H, s), 8.25 (1H, d, J = 8.6 H
z), 8.49 (1H, d, J = 8.6 Hz), 9.48 (1H, s) Production Example 6 4- (3-chloro-4-methoxyphenethyl) amino-6-cyano-1
-(4-hydroxymethylpiperidino) phthalazine

【００８３】[0083]

【化４３】 Embedded image

【００８４】製造例5の3-ヒドロキシメチルピペリジン
の代わりに4-ヒドロキシメチルピペリジンを用いて標記
化合物を得た。 MASS(ESI)；452.3(MH⁺)¹ H-NMR(400 MHz, CDCl₃)δ;1.51-1.65 (2H, m), 1.79-
1.85 (1H, m), 1.93 (2H,m), 2.99-3.09 (4H, m), 3.56
-3.68 (4H, m), 3.90 (3H, s), 3.85-3.99 (2H,m), 4.9
4 (1H, br t), 6.88 (1H, d, J= 8.4 Hz), 7.13 (1H, d
d, J= 2.2, 8.4Hz), 7.28 (1H,d, J= 2.2 Hz), 7.94 (1
H, d, J= 8.4 Hz), 7.98 (1H, s), 8.13(1H, d, J= 8.4
Hz) 製造例７ 4-(3-クロロ-4-メトキシベンジル)アミノ-6-シアノ-1-
[メチル(2-ピリジルメチル)アミノ]フタラジン・二塩酸
塩The title compound was obtained by using 4-hydroxymethylpiperidine instead of 3-hydroxymethylpiperidine of Production Example 5. MASS (ESI); 452.3 (MH ⁺ ) ¹ H-NMR (400 MHz, CDCl ₃ ) δ; 1.51-1.65 (2H, m), 1.79-
1.85 (1H, m), 1.93 (2H, m), 2.99-3.09 (4H, m), 3.56
-3.68 (4H, m), 3.90 (3H, s), 3.85-3.99 (2H, m), 4.9
4 (1H, br t), 6.88 (1H, d, J = 8.4 Hz), 7.13 (1H, d
d, J = 2.2, 8.4 Hz), 7.28 (1H, d, J = 2.2 Hz), 7.94 (1
H, d, J = 8.4 Hz), 7.98 (1H, s), 8.13 (1H, d, J = 8.4
Hz) Production Example 7 4- (3-chloro-4-methoxybenzyl) amino-6-cyano-1-
[Methyl (2-pyridylmethyl) amino] phthalazine dihydrochloride

【００８５】[0085]

【化４４】 Embedded image

【００８６】製造例１の(R)-(+)-3-ヒドロキシピペリジ
ン塩酸塩の代わりにN-メチル-[(2-ピリジル)メチル]ア
ミンを用いて同様に処理し標記化合物を得た。 MASS(ESI)；445.3(MH⁺)¹ H-NMR(400 MHz, DMSO-d₆)δ;2.95 (3H, s), 3.85 (3H,
s), 4.73-4.79 (4H, m), 7.16 (1H, d, J= 8.4 Hz),
7.49 (1H, dd, J = 8.4, 2.0 Hz), 7.64 (1H, d,J = 2.
0 Hz), 7.65-7.72 (1H, m), 7.83-7.87 (1H, m), 8.18-
8.26 (1H, m), 8.52 (1H, dd, J = 8.4, 1.2 Hz), 8.60
(1H, d, J = 8.4 Hz), 8.74 (1H, d, J =4.8 Hz), 9.5
3-9.55 (1H, m), 10.64 (1H, br) 製造例８ 4-(3-クロロ-4-メトキシベンジル)アミノ-6-シアノ-1-
[N-メチル-[2-(2-ピリジル)エチル]アミノ]フタラジン
・二塩酸塩The same treatment was carried out using N-methyl-[(2-pyridyl) methyl] amine in place of (R)-(+)-3-hydroxypiperidine hydrochloride in Production Example 1 to obtain the title compound. MASS (ESI); 445.3 (MH ⁺ ) ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ; 2.95 (3H, s), 3.85 (3H,
s), 4.73-4.79 (4H, m), 7.16 (1H, d, J = 8.4 Hz),
7.49 (1H, dd, J = 8.4, 2.0 Hz), 7.64 (1H, d, J = 2.
0 Hz), 7.65-7.72 (1H, m), 7.83-7.87 (1H, m), 8.18-
8.26 (1H, m), 8.52 (1H, dd, J = 8.4, 1.2 Hz), 8.60
(1H, d, J = 8.4 Hz), 8.74 (1H, d, J = 4.8 Hz), 9.5
3-9.55 (1H, m), 10.64 (1H, br) Production Example 8 4- (3-chloro-4-methoxybenzyl) amino-6-cyano-1-
[N-methyl- [2- (2-pyridyl) ethyl] amino] phthalazine dihydrochloride

【００８７】[0087]

【化４５】 Embedded image

【００８８】製造例７のN-メチル-[(2-ピリジル)メチ
ル]アミンの代わりにN-メチル-[2-(2-ピリジル)エチル]
アミンを用いて同様に処理し標記化合物を得た。 MASS(ESI)；459.2(MH⁺)¹ H-NMR(400 MHz, DMSO-d₆)δ;3.00 (3H, s), 3.35 (2H,
t, J = 6.4 Hz), 3.76(2H, t, J = 6.4 Hz), 3.85 (3
H, s), 4.73-4.77 (2H, m), 7.18 (1H, d, J= 8.4 Hz),
7.50 (1H, d, J = 8.4 Hz), 7.53-7.64 (1H, m), 7.65
(1H, s), 7.68-7.77 (1H, m), 8.10-8.30 (1H, m), 8.
16 (1H, d, J = 8.6 Hz), 8.44 (1H, d, J= 8.6 Hz),
8.55 -8.61 (1H, m), 9.45-9.51 (1H, m), 10.53 (1H,
br) 製造例９ 4-(3-クロロ-4-メトキシフェネチル)アミノ-6-シアノ-1
-(4-メトキシピペリジノ)フタラジン塩酸塩Instead of N-methyl-[(2-pyridyl) methyl] amine in Preparation Example 7, N-methyl- [2- (2-pyridyl) ethyl]
The same treatment was carried out using an amine to obtain the title compound. MASS (ESI); 459.2 (MH ⁺ ) ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ; 3.00 (3H, s), 3.35 (2H,
t, J = 6.4 Hz), 3.76 (2H, t, J = 6.4 Hz), 3.85 (3
H, s), 4.73-4.77 (2H, m), 7.18 (1H, d, J = 8.4 Hz),
7.50 (1H, d, J = 8.4 Hz), 7.53-7.64 (1H, m), 7.65
(1H, s), 7.68-7.77 (1H, m), 8.10-8.30 (1H, m), 8.
16 (1H, d, J = 8.6 Hz), 8.44 (1H, d, J = 8.6 Hz),
8.55 -8.61 (1H, m), 9.45-9.51 (1H, m), 10.53 (1H,
br) Production Example 9 4- (3-chloro-4-methoxyphenethyl) amino-6-cyano-1
-(4-Methoxypiperidino) phthalazine hydrochloride

【００８９】[0089]

【化４６】 Embedded image

【００９０】製造例５の3-ヒドロキシピペリジンの代わ
りに4-メトキシピペリジン塩酸塩を用いて同様に処理し
標記化合物を得た。 MASS(ESI)；452.2(MH⁺)¹ H-NMR(400 MHz, DMSO-d₆)δ;1.66-1.76 (2H, m), 2.00
-2.08 (2H, m), 2.91-2.97 (2H, m), 2.99-3.07 (2H,
m), 3.29 (3H, s), 3.37-3.49 (3H, m), 3.70-3.77 (2
H, m), 3.81 (3H, s), 7.07 (1H, d, J = 8.6 Hz), 7.2
6 (1H, dd, J = 8.6, 2.0 Hz), 7.43 (1H, d, J = 2.0
Hz), 8.24 (1H, d, J = 8.3 Hz), 8.45 (1H,dd, J = 8.
3, 1.6 Hz), 9.22 (1H, d, J = 1.6 Hz) 製造例１０ 4-(3-クロロ-4-メトキシベンジル)アミノ-6-シアノ-1-
(4-メトキシフェニル)フタラジン塩酸塩The same treatment was carried out using 4-methoxypiperidine hydrochloride instead of 3-hydroxypiperidine in Preparation Example 5 to obtain the title compound. MASS (ESI); 452.2 (MH ⁺ ) ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ; 1.66-1.76 (2H, m), 2.00
-2.08 (2H, m), 2.91-2.97 (2H, m), 2.99-3.07 (2H,
m), 3.29 (3H, s), 3.37-3.49 (3H, m), 3.70-3.77 (2
H, m), 3.81 (3H, s), 7.07 (1H, d, J = 8.6 Hz), 7.2
6 (1H, dd, J = 8.6, 2.0 Hz), 7.43 (1H, d, J = 2.0
Hz), 8.24 (1H, d, J = 8.3 Hz), 8.45 (1H, dd, J = 8.
3, 1.6 Hz), 9.22 (1H, d, J = 1.6 Hz) Production Example 10 4- (3-chloro-4-methoxybenzyl) amino-6-cyano-1-
(4-Methoxyphenyl) phthalazine hydrochloride

【００９１】[0091]

【化４７】 Embedded image

【００９２】1-クロロ-4-(3-クロロ-4-メトキシベンジ
ル)アミノ-6-シアノフタラジン1.0gと4-メトキシフェニ
ルほう酸423mgとトルエン30mL、テトラヒドロフラン30m
L、2M炭酸ナトリウム水溶液30mLの混合物に窒素雰囲気
下、テトラキス(トリフェニルホスフィン)パラジウム
(0)423mgを加え、80℃で２時間さらに、100℃で15.5時
間攪拌した。反応液を室温に戻し、塩化アンモニウム水
溶液と酢酸エチルを加え、抽出した。有機層をアンモニ
ア水、水、飽和食塩水で洗浄し、無水硫酸ナトリウムで
乾燥した。減圧下溶媒を留去し、残渣をシリカゲルカラ
ムクロマトグラフィーで精製した。得られたカップリン
グ体を酢酸エチル−エタノールに溶解し、4N塩酸−酢酸
エチル溶液を加え、析出した結晶をろ取し標記化合物を
黄色の粉末として460mg得た。 MASS(ESI)；431.2 (MH⁺)¹ H-NMR(400 MHz, DMSO-d₆)δ; 3.85 (3H, s), 3.87 (3
H, s), 4.82-4.85 (2H, m), 7.16-7.21 (3H, m), 7.49
(1H, dd, J = 8.6, 2.2 Hz), 7.60-7.63 (3H, m),8.08
(1H, d, J = 8.4 Hz), 8.45 (1H, dd, J = 8.4, 1.4 H
z), 9.45-9.49 (1H, m), 10.39 (1H, br) 製造例１１ 4-[(3-クロロ-4-メトキシベンジル)アミノ]-1-(4-ヒド
ロキシ-3-メチルピペリジノ)-6-フタラジンカルボニト
リル塩酸塩 製造例1の(R)-(+)-3-ヒドロキシピペリジン塩酸塩の代
わりに4-ヒドロキシ-3-メチルピペリジンを用いて同様
に処理し標記化合物を得た。¹ H NMR (DMSO-d₆) δ 0.94 (3H, t, J = 8.0 Hz), 1.59
-2.03 (3H, m), 2.74-3.96 (5H, m), 3.83 (3H, s), 4.
68 (2H, d, J = 5.2 Hz), 7.15 (1H, d, J = 8.4Hz),
7.43 (1H, d, J = 8.0 Hz), 7.58 (1H, s), 8.23 (1H,
t, J = 8.0 Hz),8.45 (1H, d, J = 8.4 Hz), 9.29 (1H,
s) 製造例１２ 4-[(3-クロロ-4-メトキシベンジル)アミノ]-1-(4-ヒド
ロキシ-3,3,5,5-テトラメチルピペリジノ)-6-フタラジ
ンカルボニトリル塩酸塩 製造例1の(R)-(+)-3-ヒドロキシピペリジン塩酸塩の代
わりに4-ヒドロキシ-3,3,5,5-テトラメチルピペリジン
を用いて同様に処理し標記化合物を得た。¹ H NMR (DMSO-d₆) δ; 0.91 (6H, s), 1.15 (6H, s),
2.57 (1H, d, J = 12.4 Hz), 2.95 (1H, s), 3.21 (2H,
d, J = 12.0 Hz), 3.83 (3H, s), 4.47 (2H, d,J = 5.
6 Hz), 7.14 (1H, d, J = 8.4 Hz), 7.47 (1H, d, J =
8.8 Hz), 7.63 (1H, s), 8.29 (1H, d, J = 8.4 Hz),
8.55 (1H, d, J = 8.4 Hz), 9.52 (1H, s),10.63 (1H,
brs) 中間体製造例１ 1-クロロ-4-[[(4-メトキシ-3-トリフルオロメチル)ベン
ジル]アミノ]-6-フタラジンカルボニトリル1.0 g of 1-chloro-4- (3-chloro-4-methoxybenzyl) amino-6-cyanophthalazine, 423 mg of 4-methoxyphenylboronic acid, 30 mL of toluene, 30 m of tetrahydrofuran
L, 2M sodium carbonate aqueous solution 30mL mixture under a nitrogen atmosphere, tetrakis (triphenylphosphine) palladium
(0) 423 mg was added, and the mixture was stirred at 80 ° C for 2 hours and further at 100 ° C for 15.5 hours. The reaction solution was returned to room temperature, and an aqueous ammonium chloride solution and ethyl acetate were added thereto for extraction. The organic layer was washed with aqueous ammonia, water, and saturated saline, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography. The obtained coupling compound was dissolved in ethyl acetate-ethanol, a 4N hydrochloric acid-ethyl acetate solution was added, and the precipitated crystals were collected by filtration to obtain 460 mg of the title compound as yellow powder. MASS (ESI); 431.2 (MH ⁺ ) ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ; 3.85 (3H, s), 3.87 (3
H, s), 4.82-4.85 (2H, m), 7.16-7.21 (3H, m), 7.49
(1H, dd, J = 8.6, 2.2 Hz), 7.60-7.63 (3H, m), 8.08
(1H, d, J = 8.4 Hz), 8.45 (1H, dd, J = 8.4, 1.4 H
z), 9.45-9.49 (1H, m), 10.39 (1H, br) Production Example 11 4-[(3-chloro-4-methoxybenzyl) amino] -1- (4-hydroxy-3-methylpiperidino) -6 -Phthalazinecarbonitrile hydrochloride The same treatment was carried out using 4-hydroxy-3-methylpiperidine instead of (R)-(+)-3-hydroxypiperidine hydrochloride of Production Example 1 to obtain the title compound. ¹ H NMR (DMSO-d ₆ ) δ 0.94 (3H, t, J = 8.0 Hz), 1.59
-2.03 (3H, m), 2.74-3.96 (5H, m), 3.83 (3H, s), 4.
68 (2H, d, J = 5.2 Hz), 7.15 (1H, d, J = 8.4Hz),
7.43 (1H, d, J = 8.0 Hz), 7.58 (1H, s), 8.23 (1H,
t, J = 8.0 Hz), 8.45 (1H, d, J = 8.4 Hz), 9.29 (1H,
s) Production Example 12 4-[(3-chloro-4-methoxybenzyl) amino] -1- (4-hydroxy-3,3,5,5-tetramethylpiperidino) -6-phthalazinecarbonitrile hydrochloride Salt In the same manner as in Production Example 1 except that (R)-(+)-3-hydroxypiperidine hydrochloride was replaced with 4-hydroxy-3,3,5,5-tetramethylpiperidine, the title compound was obtained. ¹ H NMR (DMSO-d ₆ ) δ; 0.91 (6H, s), 1.15 (6H, s),
2.57 (1H, d, J = 12.4 Hz), 2.95 (1H, s), 3.21 (2H,
d, J = 12.0 Hz), 3.83 (3H, s), 4.47 (2H, d, J = 5.
6 Hz), 7.14 (1H, d, J = 8.4 Hz), 7.47 (1H, d, J =
8.8 Hz), 7.63 (1H, s), 8.29 (1H, d, J = 8.4 Hz),
8.55 (1H, d, J = 8.4 Hz), 9.52 (1H, s), 10.63 (1H,
brs) Intermediate Preparation Example 1 1-Chloro-4-[[(4-methoxy-3-trifluoromethyl) benzyl] amino] -6-phthalazinecarbonitrile

【００９３】[0093]

【化４８】 Embedded image

【００９４】2-トリフルオロメチルフェノール10 g、炭
酸カリウム17 g、アセトン150 mL、ヨードメタン7.7 mL
の混合物を２時間加熱還流した。冷後、不溶物を濾去
し、濾液を減圧下濃縮した。残渣を酢酸エチルに溶解
し、水及び飽和食塩水で洗浄した。無水硫酸マグネシウ
ムで乾燥、濾過、減圧下濃縮し、2-トリフルオロメチル
アニソールを12.15 g得た。10 g of 2-trifluoromethylphenol, 17 g of potassium carbonate, 150 mL of acetone, 7.7 mL of iodomethane
Was heated to reflux for 2 hours. After cooling, insoluble materials were removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate and washed with water and saturated saline. The extract was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain 12.15 g of 2-trifluoromethylanisole.

【００９５】2-トリフルオロメチルアニソール8.5 gと
ヘキサメチレンテトラミン7.0 gの混合物をトリフルオ
ロ酢酸80 mL中９０℃で１．５時間撹拌した。反応液を
減圧下濃縮した。残渣を酢酸エチルに溶解し、氷冷した
飽和重曹水に滴下した。酢酸エチル層を分取し、飽和食
塩水で洗浄した。無水硫酸マグネシウムで乾燥、濾過、
減圧下濃縮した。残渣をシリカゲルカラムクロマトグラ
フィーで精製し、3-トリフルオロメチル-p-アニスアル
デヒドを5.8 g得た。A mixture of 8.5 g of 2-trifluoromethylanisole and 7.0 g of hexamethylenetetramine was stirred in 80 mL of trifluoroacetic acid at 90 ° C. for 1.5 hours. The reaction solution was concentrated under reduced pressure. The residue was dissolved in ethyl acetate and added dropwise to ice-cooled saturated aqueous sodium hydrogen carbonate. The ethyl acetate layer was separated and washed with saturated saline. Dry over anhydrous magnesium sulfate, filter,
It was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 5.8 g of 3-trifluoromethyl-p-anisaldehyde.

【００９６】3-トリフルオロメチル-p-アニスアルデヒ
ド5.8 g、ホルムアミド8.6 mL、ぎ酸13.6 mLの混合物を
１３０℃で９時間撹拌した。冷後、水と酢酸エチルを加
えた。酢酸エチル層を分取し、飽和食塩水で洗浄した。
無水硫酸マグネシウムで乾燥、濾過、減圧下濃縮した。
残渣をシリカゲルカラムクロマトグラフィーで精製し、
N-[4-メトキシ-3-(トリフルオロメチル)ベンジル]ホル
ムアミドを3.8 g得た。A mixture of 5.8 g of 3-trifluoromethyl-p-anisaldehyde, 8.6 mL of formamide and 13.6 mL of formic acid was stirred at 130 ° C. for 9 hours. After cooling, water and ethyl acetate were added. The ethyl acetate layer was separated and washed with saturated saline.
The extract was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure.
The residue was purified by silica gel column chromatography,
3.8 g of N- [4-methoxy-3- (trifluoromethyl) benzyl] formamide was obtained.

【００９７】N-[4-メトキシ-3-(トリフルオロメチル)ベ
ンジル]ホルムアミドを3.8 gをエタノール20 mLに溶解
し、濃塩酸2 mLを加え、３時間加熱還流した。冷後、ジ
エチルエーテルを加え、析出した結晶を濾取し、4-メト
キシ-3-(トリフルオロメチル)ベンジルアミン 塩酸塩
を2.5 g得た。1,4-ジクロロフタラジン-6-カルボニトリ
ル2.2 g、4-メトキシ-3-(トリフルオロメチル)ベンジル
アミン 塩酸塩を2.5 g、1-メチル-2-ピロリジノン25 m
Lの混合物にDBU 3.7 gを加え、室温で１．２５時間撹拌
した。反応液に酢酸エチルを加え、水及び飽和食塩水で
洗浄した。無水硫酸ナトリウムで乾燥、濾過、減圧下濃
縮した。残渣をシリカゲルカラムクロマトグラフィーで
精製し、より極性の低い生成物として標記化合物を1.66
g得た。¹ H NMR (DMSO-d₆) δ 3.86 (3H, s), 4.74 (2H, d, J =
5.2 Hz), 7.22 (1H, d,J = 9.6 Hz), 7.67-7.71 (2H,
m), 8.20 (1H, d, J = 8.4 Hz), 8.35 (1H, dd,J = 8.
4, 1.4 Hz), 8.50 (1H, t, J = 5.2 Hz), 8.99 (1H, d,
J = 1.4 Hz) 同様の方法により市販の2-ヨードアニソールより1-クロ
ロ-4-[(3-ヨード-4-メトキシベンジル)アミノ]-6-フタ
ラジンカルボニトリルを、3-ブロモ-p-アニスアルデヒ
ドより4-[(3-ブロモ-4-メトキシベンジル)アミノ]-1-ク
ロロ-6-フタラジンカルボニトリルを、3-フルオロ-p-ア
ニスアルデヒドより1-クロロ-4-[(3-フルオロ-4-メトキ
シベンジル)アミノ]-6-フタラジンカルボニトリルを、3
-メチル-p-アニスアルデヒドより1-クロロ-4-[(4-メト
キシ−３−メチルベンジル)アミノ]-6-フタラジンカル
ボニトリルを得た。 中間体製造例２ 1-クロロ-4-[(3-ヨード-4-メトキシベンジル)アミノ]-6
-フタラジンカルボニトリル¹ H NMR (DMSO-d₆) δ; 3.80 (3H, s), 4.67 (2H, d, J
= 5.2 Hz), 6.96 (1H, d, J = 8.4 Hz), 7.42 (1H, dd,
J = 8.4, 2.0 Hz), 7.83 (1H, d, J = 2.0 Hz),8.18
(1H, d, J = 8.4 Hz), 8.34 (1H, dd, J = 8.4, 1.2 H
z), 8.45 (1H, t,J = 5.2 Hz), 8.99 (1H, d, J = 1.2
Hz) 中間体製造例３ 4-[(3-ブロモ-4-メトキシベンジル)アミノ]-1-クロロ-6
-フタラジンカルボニトリル¹ H NMR (DMSO-d₆) δ 3.82 (3H, s), 4.70 (2H, d, J =
5.2 Hz), 7.07 (1H, d,J = 8.4 Hz), 7.41 (1H, dd, J
= 8.4, 2.0 Hz), 7.63 (1H, d, J = 2.0 Hz),8.20 (1
H, d, J = 8.4 Hz), 8.34 (1H, dd, J = 8.4, 1.2 Hz),
8.47 (1H, t, J= 5.2 Hz), 8.99 (1H, d, J = 1.2 Hz) 中間体製造例４ 1-クロロ-4-[(3-フルオロ-4-メトキシベンジル)アミノ]
-6-フタラジンカルボニトリル¹ H NMR (DMSO-d₆) δ; 3.81 (3H, s), 4.70(2H, d, J =
5.4 Hz), 7.11 (1H, t,J = 8.8 Hz), 7.19 (1H, d, J
= 8.8 Hz), 7.26 (1H, dd, J = 12.8, 2.0 Hz),8.20 (1
H, d, J = 8.4 Hz), 8.35 (1H, dd, J = 8.4, 0.8 Hz),
8.46 (1H, t,J = 5.4 Hz), 9.01 (1H, d, J = 0.8 Hz) 中間体製造例５ 1-クロロ-4-[(3-シアノ-4-メトキシベンジル)アミノ]-6
-フタラジンカルボニトリル 4-メトキシベンジルクロリド20 g、フタルイミドカリウ
ム26 g、ジメチルホルムアミド100 mLの混合物を５０℃
で５時間撹拌した。冷後、反応液を氷水に注ぎ、沈殿物
を濾取した。これを水で洗浄し、乾燥しN-(4-メトキシ
ベンジル)フタルイミドを31 g得た。3.8 g of N- [4-methoxy-3- (trifluoromethyl) benzyl] formamide was dissolved in 20 mL of ethanol, 2 mL of concentrated hydrochloric acid was added, and the mixture was heated under reflux for 3 hours. After cooling, diethyl ether was added, and the precipitated crystals were collected by filtration to obtain 2.5 g of 4-methoxy-3- (trifluoromethyl) benzylamine hydrochloride. 2.2 g of 1,4-dichlorophthalazine-6-carbonitrile, 2.5 g of 4-methoxy-3- (trifluoromethyl) benzylamine hydrochloride, 25 m of 1-methyl-2-pyrrolidinone
3.7 g of DBU was added to the mixture of L, and the mixture was stirred at room temperature for 1.25 hours. Ethyl acetate was added to the reaction solution, and the mixture was washed with water and saturated saline. The extract was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 1.66 of the title compound as a less polar product.
g obtained. ¹ H NMR (DMSO-d ₆ ) δ 3.86 (3H, s), 4.74 (2H, d, J =
5.2 Hz), 7.22 (1H, d, J = 9.6 Hz), 7.67-7.71 (2H,
m), 8.20 (1H, d, J = 8.4 Hz), 8.35 (1H, dd, J = 8.
4, 1.4 Hz), 8.50 (1H, t, J = 5.2 Hz), 8.99 (1H, d,
J = 1.4 Hz) In the same manner, 1-chloro-4-[(3-iodo-4-methoxybenzyl) amino] -6-phthalazinecarbonitrile was converted from commercially available 2-iodoanisole with 3-bromo-p- 4-[(3-bromo-4-methoxybenzyl) amino] -1-chloro-6-phthalazinecarbonitrile from anisaldehyde and 1-chloro-4-[(3- Fluoro-4-methoxybenzyl) amino] -6-phthalazinecarbonitrile,
1-Chloro-4-[(4-methoxy-3-methylbenzyl) amino] -6-phthalazinecarbonitrile was obtained from -methyl-p-anisaldehyde. Intermediate Production Example 2 1-Chloro-4-[(3-iodo-4-methoxybenzyl) amino] -6
-Phthalazinecarbonitrile ¹ H NMR (DMSO-d ₆ ) δ; 3.80 (3H, s), 4.67 (2H, d, J
= 5.2 Hz), 6.96 (1H, d, J = 8.4 Hz), 7.42 (1H, dd,
J = 8.4, 2.0 Hz), 7.83 (1H, d, J = 2.0 Hz), 8.18
(1H, d, J = 8.4 Hz), 8.34 (1H, dd, J = 8.4, 1.2 H
z), 8.45 (1H, t, J = 5.2 Hz), 8.99 (1H, d, J = 1.2
Hz) Intermediate Production Example 3 4-[(3-bromo-4-methoxybenzyl) amino] -1-chloro-6
-Phthalazinecarbonitrile ¹ H NMR (DMSO-d ₆ ) δ 3.82 (3H, s), 4.70 (2H, d, J =
5.2 Hz), 7.07 (1H, d, J = 8.4 Hz), 7.41 (1H, dd, J
= 8.4, 2.0 Hz), 7.63 (1H, d, J = 2.0 Hz), 8.20 (1
H, d, J = 8.4 Hz), 8.34 (1H, dd, J = 8.4, 1.2 Hz),
8.47 (1H, t, J = 5.2 Hz), 8.99 (1H, d, J = 1.2 Hz) Intermediate Production Example 4 1-Chloro-4-[(3-fluoro-4-methoxybenzyl) amino]
-6-phthalazinecarbonitrile ¹ H NMR (DMSO-d ₆ ) δ; 3.81 (3H, s), 4.70 (2H, d, J =
5.4 Hz), 7.11 (1H, t, J = 8.8 Hz), 7.19 (1H, d, J
= 8.8 Hz), 7.26 (1H, dd, J = 12.8, 2.0 Hz), 8.20 (1
H, d, J = 8.4 Hz), 8.35 (1H, dd, J = 8.4, 0.8 Hz),
8.46 (1H, t, J = 5.4 Hz), 9.01 (1H, d, J = 0.8 Hz) Intermediate Production Example 5 1-Chloro-4-[(3-cyano-4-methoxybenzyl) amino] -6
-Phthalazinecarbonitrile 4-methoxybenzyl chloride 20 g, phthalimide potassium 26 g, dimethylformamide 100 mL
For 5 hours. After cooling, the reaction solution was poured into ice water, and the precipitate was collected by filtration. This was washed with water and dried to obtain 31 g of N- (4-methoxybenzyl) phthalimide.

【００９８】N-(4-メトキシベンジル)フタルイミド31 g
とトリフルオロ酢酸100 mLの混合物にヘキサメチレンテ
トラミン18 gを少量ずつ加え、室温で１時間撹拌後、４
時間加熱還流した。反応液を０℃に冷却し、水を加え
た。炭酸カリウムを加え、析出した結晶を濾取した。結
晶を乾燥しN-(3-ホルミル-4-トキシベンジル)フタルイ
ミドを20 g得た。N- (4-methoxybenzyl) phthalimide 31 g
18 g of hexamethylenetetramine was added little by little to a mixture of trifluoroacetic acid and 100 mL, and stirred at room temperature for 1 hour.
Heated to reflux for an hour. The reaction was cooled to 0 ° C. and water was added. Potassium carbonate was added, and the precipitated crystals were collected by filtration. The crystals were dried to obtain 20 g of N- (3-formyl-4-toxylbenzyl) phthalimide.

【００９９】N-(3-ホルミル-4-メトキシベンジル)フタ
ルイミド20 gとテトラヒドロフラン200 mLの混合物にヒ
ドロキシルアミン 塩酸塩5.2 g、酢酸ナトリウム12.2
g、水50 mLを加え室温で１時間撹拌した。６０℃で１時
間撹拌し、減圧下濃縮した。残渣に水を加え、不溶物を
濾取した。ジエチルエーテルで洗浄し、N-(3-ヒドロキ
シイミノ-4-メトキシベンジル)フタルイミドを20 g得
た。To a mixture of 20 g of N- (3-formyl-4-methoxybenzyl) phthalimide and 200 mL of tetrahydrofuran, 5.2 g of hydroxylamine hydrochloride, 12.2 g of sodium acetate
g and 50 mL of water were added, and the mixture was stirred at room temperature for 1 hour. The mixture was stirred at 60 ° C. for 1 hour and concentrated under reduced pressure. Water was added to the residue, and insolubles were collected by filtration. After washing with diethyl ether, 20 g of N- (3-hydroxyimino-4-methoxybenzyl) phthalimide was obtained.

【０１００】N-(3-ヒドロキシイミノ-4-メトキシベンジ
ル)フタルイミド20 gとキシレン200mLの混合物に無水酢
酸6.7 mLを加え、１０時間加熱還流した。室温に戻し、
析出している結晶を濾取し、キシレンで洗浄し、 N-(3-
シアノ-4-メトキシベンジル)フタルイミドを15 g得た。
N-(3-シアノ-4-メトキシベンジル)フタルイミド15 gと
エタノール200 mLの混合物にヒドラジン一水和物3.9 g
を加え、３時間加熱還流した。冷後、不溶物を濾去し
た。濾液を減圧下濃縮し、残渣に１N水酸化ナトリウム
水溶液を加え、ジクロロメタンで抽出した。抽出液を無
水硫酸マグネシウムで乾燥、濾過した。濾液を減圧下濃
縮し、３−シアノ−４−メトキシベンジルアミンを8.0
g得た。6.7 mL of acetic anhydride was added to a mixture of 20 g of N- (3-hydroxyimino-4-methoxybenzyl) phthalimide and 200 mL of xylene, and the mixture was heated under reflux for 10 hours. Return to room temperature,
The precipitated crystals are collected by filtration, washed with xylene, and treated with N- (3-
15 g of cyano-4-methoxybenzyl) phthalimide were obtained.
Hydrazine monohydrate (3.9 g) was added to a mixture of 15 g of N- (3-cyano-4-methoxybenzyl) phthalimide and 200 mL of ethanol.
Was added and heated under reflux for 3 hours. After cooling, insolubles were removed by filtration. The filtrate was concentrated under reduced pressure, a 1N aqueous sodium hydroxide solution was added to the residue, and the mixture was extracted with dichloromethane. The extract was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and 3-cyano-4-methoxybenzylamine was added to 8.0%.
g obtained.

【０１０１】1,4-ジクロロフタラジン-6-カルボニトリ
ル、3-シアノ-4-メトキシベンジルアミンをDBU存在下1-
メチル-2-ピロリジノン中室温で撹拌することにより、
より極性の低い生成物として1-クロロ-4-[(3-シアノ-4-
メトキシベンジル)アミノ]-6-フタラジンカルボニトリ
ルを得た。¹ H NMR (DMSO-d₆) δ; 3.87 (3H, s), 4.70 (2H, d, J
= 5.6 Hz), 7.20 (1H, d, J = 8.4 Hz), 7.70 (1H, dd,
J = 2.4, 8.4 Hz), 7.75 (1H, d, J = 2.4 Hz),8.19
(1H, d, J = 8.4 Hz), 8.34 (1H, dd, J = 1.2, 8.4 H
z), 8.48 (1H, t,J = 5.6 Hz), 8.97 (1H, s) 中間体製造例６ 1-クロロ-4-[(3-エチル-4-メトキシベンジル)アミノ]-6
-フタラジンカルボニトリル メチルトリフェニルホスホニウムブロミド12.7 gのテト
ラヒドロフラン80 mL溶液に０℃でカリウム−ｔ−ブト
キシド3.99 gを加え、N-(3-ホルミル-4-メトキシベンジ
ル)フタルイミド７gを加え、室温で１時間撹拌した。反
応液をセライト濾過し、減圧下濃縮した。残渣シリカゲ
ルカラムクロマトグラフィーで精製し、N-メ(4-メトキ
シ-3-ビニルベンジル)フタルイミドを2.75 g得た。1,4-Dichlorophthalazine-6-carbonitrile and 3-cyano-4-methoxybenzylamine were reacted with 1-
By stirring at room temperature in methyl-2-pyrrolidinone,
As a less polar product, 1-chloro-4-[(3-cyano-4-
Methoxybenzyl) amino] -6-phthalazinecarbonitrile was obtained. ¹ H NMR (DMSO-d ₆ ) δ; 3.87 (3H, s), 4.70 (2H, d, J
= 5.6 Hz), 7.20 (1H, d, J = 8.4 Hz), 7.70 (1H, dd,
J = 2.4, 8.4 Hz), 7.75 (1H, d, J = 2.4 Hz), 8.19
(1H, d, J = 8.4 Hz), 8.34 (1H, dd, J = 1.2, 8.4 H
z), 8.48 (1H, t, J = 5.6 Hz), 8.97 (1H, s) Intermediate Production Example 6 1-chloro-4-[(3-ethyl-4-methoxybenzyl) amino] -6
To a solution of 12.7 g of -phthalazinecarbonitrile methyltriphenylphosphonium bromide in 80 mL of tetrahydrofuran was added 3.99 g of potassium-t-butoxide at 0 ° C, and 7 g of N- (3-formyl-4-methoxybenzyl) phthalimide was added. Stir for 1 hour. The reaction solution was filtered through celite and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 2.75 g of N-meth (4-methoxy-3-vinylbenzyl) phthalimide.

【０１０２】N-(4-メトキシ-3-ビニルベンジル)フタル
イミド2.75 gをテトラヒドロフラン50 mLに溶解し、10%
Pd-C 0.1 gを加え、水素雰囲気下４０分撹拌した。セ
ライト濾過し、濾液を減圧下濃縮した。残渣をシリカゲ
ルカラムクロマトグラフィーで精製し、N-(3-エチル-4-
メトキシベンジル)フタルイミドを2.55 g得た。N-(3-エ
チル-4-メトキシベンジル)フタルイミド2.55 gとエタノ
ール60 mLの混合物にヒドラジン一水和物0.84 mLを加
え、１時間加熱還流した。冷後、減圧下濃縮し、残渣に
２N水酸化ナトリウム水溶液を加え、ジクロロメタンで
抽出した。抽出液を無水硫酸マグネシウムで乾燥、濾過
した。濾液を減圧下濃縮し、酢酸エチルを加え、不溶物
を濾過した。４Ｎ塩酸（酢酸エチル溶液）を加え、析出
した結晶を濾取し、3-エチル-4-メトキシベンジルアミ
ン 塩酸塩を1.75 g得た。Dissolve 2.75 g of N- (4-methoxy-3-vinylbenzyl) phthalimide in 50 mL of tetrahydrofuran and add 10%
0.1 g of Pd-C was added, and the mixture was stirred under a hydrogen atmosphere for 40 minutes. The mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, and N- (3-ethyl-4-
2.55 g of (methoxybenzyl) phthalimide was obtained. To a mixture of 2.55 g of N- (3-ethyl-4-methoxybenzyl) phthalimide and 60 mL of ethanol was added 0.84 mL of hydrazine monohydrate, and the mixture was heated under reflux for 1 hour. After cooling, the mixture was concentrated under reduced pressure, 2N aqueous sodium hydroxide solution was added to the residue, and the mixture was extracted with dichloromethane. The extract was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, ethyl acetate was added, and the insolubles were filtered. 4N Hydrochloric acid (ethyl acetate solution) was added, and the precipitated crystals were collected by filtration to obtain 1.75 g of 3-ethyl-4-methoxybenzylamine hydrochloride.

【０１０３】1,4-ジクロロフタラジン-6-カルボニトリ
ル、3-エチル-4-メトキシベンジルアミン 塩酸塩をDBU
存在下1-メチル-2-ピロリジノン中室温で撹拌すること
により、より極性の低い生成物として1-クロロ-4-[(3-
エチル-4-メトキシベンジル)アミノ]-6-フタラジンカル
ボニトリルを得た。¹ H NMR (CDCl₃) δ; 1.14 (3H, t, J = 7.5 Hz), 2.60
(2H, q, J = 7.5 Hz), 3.81 (3H, s), 4.84 (2H, s),
6.80 (1H, d, J = 8.2 Hz), 7.25 (1H, d, J = 2.0 H
z), 7.30 (1H, dd, J = 2.0, 8.2 Hz), 8.06 (1H, d, J
= 9.0 Hz), 8.27 (1H, d, J = 9.0 Hz), 8.42 (1H, m) 中間体製造例７ 1-クロロ-4-[(3-クロロ-4-メチルベンジル)アミノ]-6-
フタラジンカルボニトリル 水素化リチウムアルミニウ
ム453 mgのテトラヒドロフラン40 mL溶液に窒素雰囲気
下３−クロロ−４−メチルベンゾニトリル2.0 gのテト
ラヒドロフラン15mL溶液を滴下した。２時間１０分加熱
還流した。氷冷し、１０℃以下に保つように水0.45 m
L、１５％水酸化ナトリウム水溶液0.45 mL、水1.35 mL
を滴下した。セライト濾過し、濾液に無水硫酸ナトリウ
ムを加え乾燥した。NH-formシリカゲルで濾過し、濾液
を減圧下濃縮し、３−クロロ−４−メチルベンジルアミ
ンを1.74 g得た。1,4-dichlorophthalazine-6-carbonitrile and 3-ethyl-4-methoxybenzylamine hydrochloride were added to DBU
By stirring at room temperature in 1-methyl-2-pyrrolidinone in the presence, 1-chloro-4-[(3-
Ethyl-4-methoxybenzyl) amino] -6-phthalazinecarbonitrile was obtained. ¹ H NMR (CDCl ₃ ) δ; 1.14 (3H, t, J = 7.5 Hz), 2.60
(2H, q, J = 7.5 Hz), 3.81 (3H, s), 4.84 (2H, s),
6.80 (1H, d, J = 8.2 Hz), 7.25 (1H, d, J = 2.0 H
z), 7.30 (1H, dd, J = 2.0, 8.2 Hz), 8.06 (1H, d, J
= 9.0 Hz), 8.27 (1H, d, J = 9.0 Hz), 8.42 (1H, m) Intermediate Preparation Example 7 1-Chloro-4-[(3-chloro-4-methylbenzyl) amino] -6-
Phthalazinecarbonitrile To a solution of 453 mg of lithium aluminum hydride in 40 mL of tetrahydrofuran, a solution of 2.0 g of 3-chloro-4-methylbenzonitrile in 15 mL of tetrahydrofuran was added dropwise under a nitrogen atmosphere. The mixture was heated under reflux for 2 hours and 10 minutes. Cool on ice and keep the temperature below 10 ℃ 0.45 m
L, 15% aqueous solution of sodium hydroxide 0.45 mL, water 1.35 mL
Was added dropwise. The mixture was filtered through celite, and anhydrous sodium sulfate was added to the filtrate, followed by drying. The mixture was filtered through NH-form silica gel, and the filtrate was concentrated under reduced pressure to obtain 1.74 g of 3-chloro-4-methylbenzylamine.

【０１０４】1,4-ジクロロフタラジン-6-カルボニトリ
ル、3-クロロ-4-メチルベンジルアミンをDBU存在下1-メ
チル-2-ピロリジノン中室温で撹拌することにより、よ
り極性の低い生成物として標記化合物を得た。¹ H NMR (DMSO-d₆) δ; 2.29 (3H, s), 4.73 (2H, d, J
= 5.2 Hz), 7.28-7.32 (2H, m), 7.45 (1H, d, J = 0.8
Hz), 8.20 (1H, dd, J = 8.4, 0.4 Hz), 8.34 (1H, d,
J = 8.4, 1.6 Hz), 8.52 (1H, t, J = 5.2 Hz), 9.00
(1H, m) 中間体製造例８ 1-クロロ-4-[(4-クロロ-3-メトキシベンジル)アミノ]-6
-フタラジンカルボニトリル ＷＯ９５１８０９７に記載の方法により合成した4-クロ
ロ-3-メトキシベンジルアミンベンジルアミン 塩酸
塩、1,4-ジクロロフタラジン-6-カルボニトリルをDBU存
在下1-メチル-2-ピロリジノン中室温で撹拌することに
より、より極性の低い生成物として1-クロロ-4-[(4-ク
ロロ-3-メトキシベンジル)アミノ]-6-フタラジンカルボ
ニトリルを得た。¹ H NMR (DMSO-d₆) δ; 3.86 (3H, s), 4.76 (2H, d, J
= 5.5 Hz), 4.74 (1H, d, J = 4.2 Hz), 6.99 (1H, dd,
J = 1.8, 8.1 Hz), 7.22 (1H, d, J = 1.8 Hz),7.35
(1H, d, J = 8.1 Hz), 8.21 (1H, d, J = 8.6 Hz), 8.3
6 (1H, d, J = 8.6 Hz), 8.52 (1H, t, J = 5.5 Hz),
9.03(1H, s) 中間体製造例９ 1-クロロ-4-[(3,4-ジクロロベンジル)アミノ]-6-フタラ
ジンカルボニトリル¹ H NMR (DMSO-d₆) δ; 4.76 (2H, d, J = 5.4 Hz), 7.4
0 (1H, dd, J = 8.4, 1.8 Hz), 7.58 (1H, d, J = 8.4
Hz), 7.68 (1H, d, J = 1.8 Hz), 8.21 (1H, dd,J = 8.
4, 0.4 Hz), 8.36 (1H, dd, J = 8.4, 1.6 Hz), 8.57
(1H, t, J = 5.4Hz), 8.99 (1H, d, J = 1.6 Hz) 中間体製造例１０ 4-フルオロ-4-ヒドロキシメチル-1-ピペリジンカルボン
酸ベンジルBy stirring 1,4-dichlorophthalazine-6-carbonitrile, 3-chloro-4-methylbenzylamine in 1-methyl-2-pyrrolidinone in the presence of DBU at room temperature, the less polar product To give the title compound. ¹ H NMR (DMSO-d ₆ ) δ; 2.29 (3H, s), 4.73 (2H, d, J
= 5.2 Hz), 7.28-7.32 (2H, m), 7.45 (1H, d, J = 0.8
Hz), 8.20 (1H, dd, J = 8.4, 0.4 Hz), 8.34 (1H, d,
J = 8.4, 1.6 Hz), 8.52 (1H, t, J = 5.2 Hz), 9.00
(1H, m) Intermediate Production Example 8 1-Chloro-4-[(4-chloro-3-methoxybenzyl) amino] -6
-Phthalazinecarbonitrile 4-chloro-3-methoxybenzylaminebenzylamine hydrochloride synthesized by the method described in WO9518097, 1,4-dichlorophthalazine-6-carbonitrile was reacted with 1-methyl-2-pyrrolidinone in the presence of DBU Stirring at medium room temperature provided 1-chloro-4-[(4-chloro-3-methoxybenzyl) amino] -6-phthalazinecarbonitrile as a less polar product. ¹ H NMR (DMSO-d ₆ ) δ; 3.86 (3H, s), 4.76 (2H, d, J
= 5.5 Hz), 4.74 (1H, d, J = 4.2 Hz), 6.99 (1H, dd,
J = 1.8, 8.1 Hz), 7.22 (1H, d, J = 1.8 Hz), 7.35
(1H, d, J = 8.1 Hz), 8.21 (1H, d, J = 8.6 Hz), 8.3
6 (1H, d, J = 8.6 Hz), 8.52 (1H, t, J = 5.5 Hz),
9.03 (1H, s) Intermediate Production Example 9 1-Chloro-4-[(3,4-dichlorobenzyl) amino] -6-phthalazinecarbonitrile ¹ H NMR (DMSO-d ₆ ) δ; 4.76 (2H, d, J = 5.4 Hz), 7.4
0 (1H, dd, J = 8.4, 1.8 Hz), 7.58 (1H, d, J = 8.4
Hz), 7.68 (1H, d, J = 1.8 Hz), 8.21 (1H, dd, J = 8.
4, 0.4 Hz), 8.36 (1H, dd, J = 8.4, 1.6 Hz), 8.57
(1H, t, J = 5.4 Hz), 8.99 (1H, d, J = 1.6 Hz) Intermediate Production Example 10 Benzyl 4-fluoro-4-hydroxymethyl-1-piperidinecarboxylate

【０１０５】[0105]

【化４９】 Embedded image

【０１０６】tert-ブトキシカリウム16.1 gとテトラヒ
ドロフラン500 mLの混合物にメチルトルフェニルホスホ
ニウムブロミド51.1 gを加え、１時間２０分室温で撹拌
した。4-オキソ-1-ピペリジンカルボン酸ベンジル16.1
gを加え、２時間４０分室温で撹拌した。反応液を減圧
下濃縮しジエチルエーテルを加え、セライト濾過した。
濾液を水及び飽和食塩水で洗浄し無水硫酸マグネシウム
で乾燥、濾過した。濾液を減圧下濃縮し、残渣をシリカ
ゲルカラムクロマトグラフィーに付し4-メチレン-1-ピ
ペリジンカルボン酸ベンジルを25.5 g得た。To a mixture of 16.1 g of potassium tert-butoxide and 500 mL of tetrahydrofuran was added 51.1 g of methyltoluphenylphosphonium bromide, and the mixture was stirred at room temperature for 1 hour and 20 minutes. Benzyl 4-oxo-1-piperidinecarboxylate 16.1
g was added and stirred at room temperature for 2 hours and 40 minutes. The reaction solution was concentrated under reduced pressure, diethyl ether was added, and the mixture was filtered through celite.
The filtrate was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography to obtain 25.5 g of benzyl 4-methylene-1-piperidinecarboxylate.

【０１０７】4-メチレン-1-ピペリジンカルボン酸ベン
ジル14.7 gをメタノール300 mLに溶解し、フタル酸モノ
過酸マグネシウム塩20.4 g及び重曹13.3 gを加え、室温
で７．５時間撹拌した。反応液を減圧下濃縮した。残渣
に酢酸エチルを加え、水及び飽和食塩水で洗浄し、無水
硫酸マグネシウムで乾燥、濾過した。濾液を減圧下濃縮
し、シリカゲルカラムクロマトグラフィーに付し、1-オ
キサ-6-アザスピロ[2.5]オクタン-6-カルボン酸ベンジ
ルを11.3 g得た。14.7 g of benzyl 4-methylene-1-piperidinecarboxylate was dissolved in 300 mL of methanol, 20.4 g of magnesium phthalate monoperoxide and 13.3 g of sodium bicarbonate were added, and the mixture was stirred at room temperature for 7.5 hours. The reaction solution was concentrated under reduced pressure. Ethyl acetate was added to the residue, washed with water and saturated saline, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure and subjected to silica gel column chromatography to obtain 11.3 g of benzyl 1-oxa-6-azaspiro [2.5] octane-6-carboxylate.

【０１０８】ふっ化水素ピリジン5 mLと塩化メチレン20
mLの混合物を冷却し、1-オキサ-6-アザスピロ[2.5]オ
クタン-6-カルボン酸ベンジル4.95 gの塩化メチレン10
mL溶液を内温が０℃以下になるように２５分で滴下し
た。氷冷下３５分撹拌した。反応液を飽和重曹水と氷の
混合物中に注いだ。有機層を分取し、無水硫酸マグネシ
ウムで乾燥、濾過した。濾液を減圧下濃縮し、シリカゲ
ルカラムクロマトグラフィーに付し、標記化合物を2.84
g得た。 中間体製造例１１ 4-ヒドロキシ-4-(1H-1-イミダゾリルメチル)-1-ピペリ
ジンカルボン酸tert-ブチル5 ml of pyridine hydrofluoride and 20 ml of methylene chloride
Cool the mixture of mL and benzyl 1-oxa-6-azaspiro [2.5] octane-6-carboxylate 4.95 g of methylene chloride 10
The mL solution was added dropwise over 25 minutes so that the internal temperature was 0 ° C. or lower. The mixture was stirred for 35 minutes under ice cooling. The reaction solution was poured into a mixture of saturated aqueous sodium hydrogen carbonate and ice. The organic layer was separated, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure and subjected to silica gel column chromatography to give the title compound as 2.84.
g obtained. Intermediate Production Example 11 tert-butyl 4-hydroxy-4- (1H-1-imidazolylmethyl) -1-piperidinecarboxylate

【０１０９】[0109]

【化５０】 Embedded image

【０１１０】4-メチレン-1-ピペリジンカルボン酸tert-
ブチル13.5 gをメタノール300 mLに溶解し、フタル酸モ
ノ過酸マグネシウム塩28.3 g及び重曹8.62 gを加え、室
温で１日撹拌した。反応液をセライト濾過し、濾液を減
圧下濃縮した。残渣に酢酸エチルを加え、水及び飽和食
塩水で洗浄し、無水硫酸マグネシウムで乾燥、濾過し
た。濾液を減圧下濃縮し、シリカゲルカラムクロマトグ
ラフィーに付し、1-オキサ-6-アザスピロ[2.5]オクタン
-6-カルボン酸tert-ブチルを12.2 g得た。4-methylene-1-piperidinecarboxylic acid tert-
13.5 g of butyl was dissolved in 300 mL of methanol, 28.3 g of magnesium phthalate monoperoxide and 8.62 g of sodium bicarbonate were added, and the mixture was stirred at room temperature for 1 day. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure. Ethyl acetate was added to the residue, washed with water and saturated saline, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure and subjected to silica gel column chromatography to give 1-oxa-6-azaspiro [2.5] octane.
12.2 g of tert-butyl-6-carboxylate was obtained.

【０１１１】1-オキサ-6-アザスピロ[2.5]オクタン-6-
カルボン酸tert-ブチル4.25 gをジメチルホルムアミド3
0 mLに溶解し、イミダゾールナトリウム5.38 gを加え、
６０℃で３時間４０分撹拌した。冷後、反応液に酢酸エ
チルを加え、水で３回、飽和食塩水で洗浄し、無水硫酸
マグネシウムで乾燥、濾過した。濾液を減圧下濃縮し、
シリカゲルカラムクロマトグラフィーに付し、4-ヒドロ
キシ-4-(1H-1-イミダゾリルメチル)-1-ピペリジンカル
ボン酸tert-ブチルを4.93 g得た。 中間体製造例１２ 4-ヒドロキシ-4-(1H-1,2,4-トリアゾール-1-イルメチ
ル)-1-ピペリジンカルボン酸tert-ブチル 中間体製造例１１のイミダゾールナトリウムの代わりに
1,2,4-トリアゾールナトリウムを用いて、標記化合物を
得た。 中間体製造例１３ 4-フルオロメチル-4-ヒドロキシ-1-ピペリジンカルボン
酸ベンジル 1-オキサ-6-アザスピロ[2.5]オクタン-6-カルボン酸ベ
ンジル5 gにふっ化水素カリウム3.2 g、テトラ−n−ブ
チルアンモニウムジハイドロジェントリフルオリド610
mgを加え、１２０℃で７時間撹拌した。冷後、塩化メチ
レンを加え、セライト濾過した。濾液を減圧下濃縮し、
残渣をシリカゲルカラムクロマトグラフィーに付し、標
記化合物を4.7 g得た。 中間体製造例１４ 4-ヒドロキシ-4-ピペリジンカルボキサミド塩酸塩 濃硫酸18 mLと水1.8 mLの混合液を０℃に冷却し、1-ベ
ンジル-4-ヒドロキシ-4-ピペリジンカルボニトリル塩酸
塩5 gを少量ずつ加えた。濃硫酸25 mLと水2.5 mLの混合
液を加え、室温で２時間撹拌した。フリーザー中に一夜
放置した。反応液を氷に注ぎ、水酸化ナトリウム47 gを
少量ずつ加えた。テトラヒドロフラン、酢酸エチル
（１：１）の混合溶媒で３回抽出した。抽出液を飽和食
塩水で洗浄し、無水硫酸マグネシウムで乾燥、濾過し
た。濾液を減圧下濃縮し、シリカゲルカラムクロマトグ
ラフィーに付し、1-ベンジル-4-ヒドロキシ-4-ピペリジ
ンカルボキサミドを3.19 g得た。1-oxa-6-azaspiro [2.5] octane-6-
4.25 g of tert-butyl carboxylate was added to dimethylformamide 3
Dissolve in 0 mL, add imidazole sodium 5.38 g,
The mixture was stirred at 60 ° C for 3 hours and 40 minutes. After cooling, ethyl acetate was added to the reaction solution, which was washed three times with water and saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate is concentrated under reduced pressure,
The residue was subjected to silica gel column chromatography to obtain 4.93 g of tert-butyl 4-hydroxy-4- (1H-1-imidazolylmethyl) -1-piperidinecarboxylate. Intermediate Preparation Example 12 tert-butyl 4-hydroxy-4- (1H-1,2,4-triazol-1-ylmethyl) -1-piperidinecarboxylate Instead of imidazole sodium of Intermediate Preparation Example 11
The title compound was obtained using sodium 1,2,4-triazole. Intermediate Production Example 13 Benzyl 4-fluoromethyl-4-hydroxy-1-piperidinecarboxylate 1 g of benzyl 1-oxa-6-azaspiro [2.5] octane-6-carboxylate 3.2 g of potassium hydrogen fluoride and tetra-n -Butyl ammonium dihydrogen trifluoride 610
mg was added and stirred at 120 ° C. for 7 hours. After cooling, methylene chloride was added, and the mixture was filtered through celite. The filtrate is concentrated under reduced pressure,
The residue was subjected to silica gel column chromatography to obtain 4.7 g of the title compound. Intermediate Production Example 14 4-Hydroxy-4-piperidinecarboxamide hydrochloride A mixture of 18 mL of concentrated sulfuric acid and 1.8 mL of water was cooled to 0 ° C., and 5 g of 1-benzyl-4-hydroxy-4-piperidinecarbonitrile hydrochloride was added. Was added in small portions. A mixture of 25 mL of concentrated sulfuric acid and 2.5 mL of water was added, and the mixture was stirred at room temperature for 2 hours. Left overnight in freezer. The reaction solution was poured into ice, and 47 g of sodium hydroxide was added little by little. Extraction was performed three times with a mixed solvent of tetrahydrofuran and ethyl acetate (1: 1). The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and subjected to silica gel column chromatography to obtain 3.19 g of 1-benzyl-4-hydroxy-4-piperidinecarboxamide.

【０１１２】1-ベンジル-4-ヒドロキシ-4-ピペリジンカ
ルボキサミド3.19 gをメタノール150mLに溶解し、20%含
水水酸化パラジウム 1.5 gを加えた。４気圧水素雰囲気
下４時間震とうした。反応液をセライト濾過し、濾液を
に4N HCl-ジオキサン5 mLを加え、減圧下濃縮した。結
晶性残渣をジイソプロピルエーテルで洗浄濾取し、標記
化合物を1.96 g得た。 中間体製造例１５ N-(3-クロロ-4-メトキシベンジル)-N-[4-クロロ-7-(1H-
1-ピラゾリル)-1-フタラジニル]アミン3.19 g of 1-benzyl-4-hydroxy-4-piperidinecarboxamide was dissolved in 150 mL of methanol, and 1.5 g of 20% aqueous palladium hydroxide was added. It was shaken for 4 hours under a 4 atm hydrogen atmosphere. The reaction solution was filtered through celite, and the filtrate was added with 4N HCl-dioxane (5 mL) and concentrated under reduced pressure. The crystalline residue was washed with diisopropyl ether and collected by filtration to give 1.96 g of the title compound. Intermediate Production Example 15 N- (3-chloro-4-methoxybenzyl) -N- [4-chloro-7- (1H-
1-Pyrazolyl) -1-phthalazinyl] amine

【０１１３】[0113]

【化５１】 Embedded image

【０１１４】4-フルオロフタル酸無水物100ｇとメタノ
ール1500 mLの混合物に塩化チオニル110 mLを３０分で
滴下した。８時間加熱還流し、減圧下濃縮した。残渣に
氷水を加え、酢酸エチルで抽出した。抽出液を飽和食塩
水で洗浄し、無水硫酸マグネシウムで乾燥、濾過した。
濾液を減圧下濃縮し、4-フルオロフタル酸ジメチルを12
5 g得た。To a mixture of 100 g of 4-fluorophthalic anhydride and 1500 mL of methanol, 110 mL of thionyl chloride was added dropwise over 30 minutes. The mixture was heated under reflux for 8 hours and concentrated under reduced pressure. Ice water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and filtered.
The filtrate was concentrated under reduced pressure, and dimethyl 4-fluorophthalate was added to 12
5 g were obtained.

【０１１５】ピラゾール44 gの1-メチル-2-ピロリジノ
ン200 mL溶液に油性水素化ナトリウム26 gを４０分で加
えた。4-フルオロフタル酸ジメチル125 gを３０分で加
え、室温で２時間撹拌した。反応液を０℃に冷却し、氷
水に加えた。酢酸エチルで抽出し、飽和重曹水、飽和食
塩水で洗浄した。無水硫酸マグネシウムで乾燥、濾過し
た。濾液を減圧下濃縮し、得られた結晶性残渣にジエチ
ルエーテルを加え濾取し、4-(1H-1-ピラゾリル）フタル
酸ジメチルを77ｇ得た。26 g of oily sodium hydride was added to a solution of 44 g of pyrazole in 200 mL of 1-methyl-2-pyrrolidinone in 40 minutes. 125 g of dimethyl 4-fluorophthalate was added over 30 minutes, and the mixture was stirred at room temperature for 2 hours. The reaction was cooled to 0 ° C. and added to ice water. The mixture was extracted with ethyl acetate, and washed with saturated aqueous sodium hydrogen carbonate and saturated saline. The extract was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and diethyl ether was added to the obtained crystalline residue, followed by filtration to obtain 77 g of dimethyl 4- (1H-1-pyrazolyl) phthalate.

【０１１６】4-(1H-1-ピラゾリル）フタル酸ジメチル77
gとエタノール500ｍＬの混合物にヒドラジン１水和物2
2 mLを加え、６時間加熱還流した。冷後、沈殿物を濾取
し、6-(1H-1-ピラゾリル)-1,4-フタラジンジオンを36 g
得た。6-(1H-1-ピラゾリル)-1,4-フタラジンジオン5.0
gとオキシ塩化リン20 mLの混合物にジイソプロピルエチ
ルアミン15 mLを加え、１１０℃で０．５時間撹拌し
た。反応液を０℃に冷却し、酢酸エチルを加え、更に氷
及び水を少量ずつ加えた。０℃で０．５時間撹拌し、不
溶物を濾去した。酢酸エチル層を分取し、飽和食塩水で
洗浄、無水硫酸マグネシウムで乾燥、濾過した。濾液を
減圧下濃縮し、得られた結晶性残渣に酢酸エチルを加え
濾取し、1,4-ジクロロ-6-(1H-1-ピラゾリル）フタラジ
ンを3.8 g得た。Dimethyl 4- (1H-1-pyrazolyl) phthalate 77
g and 500 mL of ethanol in a mixture of hydrazine monohydrate 2
2 mL was added, and the mixture was heated under reflux for 6 hours. After cooling, the precipitate was collected by filtration, and 36 g of 6- (1H-1-pyrazolyl) -1,4-phthalazinedione was added.
Obtained. 6- (1H-1-pyrazolyl) -1,4-phthalazinedione 5.0
15 mL of diisopropylethylamine was added to a mixture of g and phosphorus oxychloride (20 mL), and the mixture was stirred at 110 ° C for 0.5 hour. The reaction solution was cooled to 0 ° C., ethyl acetate was added, and ice and water were added little by little. The mixture was stirred at 0 ° C for 0.5 hour, and insoluble materials were removed by filtration. The ethyl acetate layer was separated, washed with brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and ethyl acetate was added to the obtained crystalline residue, followed by filtration to obtain 3.8 g of 1,4-dichloro-6- (1H-1-pyrazolyl) phthalazine.

【０１１７】1,4-ジクロロ-6-(1H-1-ピラゾリル）フタ
ラジン8 g、3-クロロ-4-メトキシベンジルアミン 塩酸
塩を9.5 g、1-メチル-2-ピロリジノン30 mLの混合物にD
BU 14 mLを加え、室温で１時間撹拌した。更に６０℃で
３時間撹拌した。反応液を０℃に冷却し、酢酸エチルを
加え、水及び飽和食塩水で洗浄した。無水硫酸マグネシ
ウムで乾燥、濾過し濾液を減圧下濃縮した。残渣をシリ
カゲルカラムクロマトグラフィーで精製し、より極性の
低い生成物として標記化合物を2.6 g得た。¹ H NMR (DMSO-d₆) δ; 3.80 (3H, s), 4.68 (2H, d, J
= 6.0 Hz), 6.70 (1H, t, J = 2.0 Hz), 7.09 (1H, d,
J = 8.8 Hz), 7.35 (1H, dd, J = 2.0, 8.4 Hz),7.47
(1H, d, J = 2.0 Hz), 7.91 (1H, d, J = 2.0 Hz), 8.1
8 (1H, d, J = 9.2 Hz), 8.32 (1H, t , J = 5.6 Hz),
8.50 (1H, dd, J = 2.0, 8.8 Hz), 8.68 (1H, d, J =
2.4 Hz), 8.78 (1H, d, J = 2.0 Hz) 中間体製造例１６ N-(3-クロロ-4-メトキシベンジル)-N-[4-クロロ-7-(1H-
1,2,3-トリアゾール-1-イル)-1-フタラジニル]アミン ピラゾールの代わりに1,2,3-トリアゾールを用い実施例
１５と同様にして標記化合物を得た。¹ H NMR (CD₃OD) δ; 3.82 (3H, s), 4.72 (2H, s), 6.9
7 (1H, d, J = 8.4 Hz),7.34 (1H, dd, J = 1.6, 8.4 H
z), 7.44 (1H, d, J = 1.6 Hz), 7.99 (1H, d,J = 1.2
Hz), 8.34 (1H, d, J = 8.8 Hz), 8.52 (1H, dd, J =
1.6, 8.8 Hz), 8.72 (1H, d, J = 1.2 Hz), 8.81 (1H,
d, J = 2 Hz) 中間体製造例１７ 6-ブロモ-1-クロロ-4-[(3-クロロ-4-メトキシベンジル)
アミノ]フタラジン 4-ブロモフタル酸無水物20 g とエタノール400ｍＬの混
合物にヒドラジン１水和物96.9 mLを加え、８時間加熱
還流した。冷後、沈殿物を濾取し、6-ブロモ-1,4-フタ
ラジンジオンを28 g得た。A mixture of 8 g of 1,4-dichloro-6- (1H-1-pyrazolyl) phthalazine, 9.5 g of 3-chloro-4-methoxybenzylamine hydrochloride and 30 mL of 1-methyl-2-pyrrolidinone was added with D.
14 mL of BU was added, and the mixture was stirred at room temperature for 1 hour. The mixture was further stirred at 60 ° C. for 3 hours. The reaction solution was cooled to 0 ° C., ethyl acetate was added, and the mixture was washed with water and saturated saline. The extract was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 2.6 g of the title compound as a less polar product. ¹ H NMR (DMSO-d ₆ ) δ; 3.80 (3H, s), 4.68 (2H, d, J
= 6.0 Hz), 6.70 (1H, t, J = 2.0 Hz), 7.09 (1H, d,
J = 8.8 Hz), 7.35 (1H, dd, J = 2.0, 8.4 Hz), 7.47
(1H, d, J = 2.0 Hz), 7.91 (1H, d, J = 2.0 Hz), 8.1
8 (1H, d, J = 9.2 Hz), 8.32 (1H, t, J = 5.6 Hz),
8.50 (1H, dd, J = 2.0, 8.8 Hz), 8.68 (1H, d, J =
2.4 Hz), 8.78 (1H, d, J = 2.0 Hz) Intermediate Production Example 16 N- (3-chloro-4-methoxybenzyl) -N- [4-chloro-7- (1H-
[1,2,3-Triazol-1-yl) -1-phthalazinyl] amine The title compound was obtained in the same manner as in Example 15 except that 1,2,3-triazole was used instead of pyrazole. ¹ H NMR (CD ₃ OD) δ; 3.82 (3H, s), 4.72 (2H, s), 6.9
7 (1H, d, J = 8.4 Hz), 7.34 (1H, dd, J = 1.6, 8.4 H
z), 7.44 (1H, d, J = 1.6 Hz), 7.99 (1H, d, J = 1.2
Hz), 8.34 (1H, d, J = 8.8 Hz), 8.52 (1H, dd, J =
1.6, 8.8 Hz), 8.72 (1H, d, J = 1.2 Hz), 8.81 (1H,
d, J = 2 Hz) Intermediate Production Example 17 6-bromo-1-chloro-4-[(3-chloro-4-methoxybenzyl)
[Amino] phthalazine 96.9 mL of hydrazine monohydrate was added to a mixture of 20 g of 4-bromophthalic anhydride and 400 mL of ethanol, and the mixture was refluxed for 8 hours. After cooling, the precipitate was collected by filtration to obtain 28 g of 6-bromo-1,4-phthalazinedione.

【０１１８】6-ブロモ-1,4-フタラジンジオン6.8 gとオ
キシ塩化リン15 mLの混合物にジイソプロピルエチルア
ミン15 mLを加え、１．５時間加熱還流した。冷後、反
応液を氷水に注ぎ良く撹拌し、塩化メチレンで抽出し
た。水層を酢酸エチルで抽出した。合わせた抽出液を無
水硫酸マグネシウムで乾燥、濾過した。濾液を減圧下濃
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、6-ブロモ-1,4-ジクロロフタラジンを4.3 g得た。To a mixture of 6.8 g of 6-bromo-1,4-phthalazinedione and 15 mL of phosphorus oxychloride was added 15 mL of diisopropylethylamine, and the mixture was heated under reflux for 1.5 hours. After cooling, the reaction solution was poured into ice water, stirred well, and extracted with methylene chloride. The aqueous layer was extracted with ethyl acetate. The combined extracts were dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography to obtain 6 g of 6-bromo-1,4-dichlorophthalazine.

【０１１９】6-ブロモ-1,4-ジクロロフタラジン3.8 g、
3-クロロ-4-メトキシベンジルアミン塩酸塩を3.5 g、1-
メチル-2-ピロリジノン30 mLの混合物にDBU 5.2 mLを加
え、１００℃で３時間撹拌した。冷後、反応液に水を加
え酢酸エチルで抽出した。抽出液を飽和食塩水で洗浄し
た。無水硫酸マグネシウムで乾燥、濾過し濾液を減圧下
濃縮した。残渣をシリカゲルカラムクロマトグラフィー
で精製し、より極性の低い生成物として標記化合物を1.
8 g得た。 中間体製造例１８ 1-(1,1-ジメチル-2-プロピニル)-4-ピペリジノール 4-ヒドロキシピペリジン7.3 gのジエチルエーテル5 m
L、水2.5 mLの混合溶液に、窒素雰囲気下塩化第一銅24
mg、銅粉15 mgを加えた。氷冷し、内温が１７〜２２℃
で3-クロロ-3-メチル-1-ブチン2.7 mLのジエチルエーテ
ル2.5 mL溶液を滴下した。室温で一夜撹拌した。水を加
え、ジエチルエーテルで５回抽出した。有機層を合わせ
炭酸カリウムで次いで水酸化カリウムで乾燥し、濾過し
た。濾液を常圧で濃縮し、得られた結晶性残渣を酢酸エ
チル−ヘキサンを加え濾取し、を2.54 g得た。 中間体製造例１９ 1-(1,1-ジメチル-2-プロピニル)ピロリジン ピロリジンと3-クロロ-3-メチル-1-ブチンより中間体製
造例１８と同様にして、標記化合物を得た。 中間体製造例２０ (2R)-1-オキサ-8-アザスピロ[4.5]デカ-2-イルメタノー
ル (5S)-5-(ヒドロキシメチル)テトラヒドロ-2-フラノン10
5.5gをピリジン1.2lに溶解し、トリチルクロリド380gを
室温で加え、80℃で一夜撹拌した。反応終了後、冷却し
水を加え、酢酸エチルで抽出し、飽和食塩水で洗浄し
た。溶媒を除き、クロロホルム300mlに溶かし、シリカ
ゲル600mlを加えてから溶媒を除いた。シリカゲルカラ
ムクロマトグラフィーで精製して(5S)-5-[(トリチルオ
キシ)メチル]テトラヒドロ-2-フラノン149.3gを得た。3.8 g of 6-bromo-1,4-dichlorophthalazine,
3.5 g of 3-chloro-4-methoxybenzylamine hydrochloride, 1-
5.2 mL of DBU was added to a mixture of 30 mL of methyl-2-pyrrolidinone, and the mixture was stirred at 100 ° C for 3 hours. After cooling, water was added to the reaction solution, which was extracted with ethyl acetate. The extract was washed with saturated saline. The extract was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound as a less polar product, 1.
8 g were obtained. Intermediate Production Example 18 1- (1,1-dimethyl-2-propynyl) -4-piperidinol 4-hydroxypiperidine 7.3 g of diethyl ether 5 m
L, 2.5 mL of water in a mixed solution under a nitrogen atmosphere, cuprous chloride 24
mg and 15 mg of copper powder were added. Ice-cooled, internal temperature 17-22 ℃
Then, a solution of 2.7 mL of 3-chloro-3-methyl-1-butyne in 2.5 mL of diethyl ether was added dropwise. Stirred overnight at room temperature. Water was added, and the mixture was extracted five times with diethyl ether. The organic layers were combined, dried over potassium carbonate and then over potassium hydroxide, and filtered. The filtrate was concentrated under normal pressure, and the obtained crystalline residue was added with ethyl acetate-hexane and collected by filtration to obtain 2.54 g. Intermediate Production Example 19 1- (1,1-Dimethyl-2-propynyl) pyrrolidine The title compound was obtained from pyrrolidine and 3-chloro-3-methyl-1-butyne in the same manner as in Intermediate Production Example 18. Intermediate Production Example 20 (2R) -1-oxa-8-azaspiro [4.5] dec-2-ylmethanol (5S) -5- (hydroxymethyl) tetrahydro-2-furanone 10
5.5 g was dissolved in 1.2 l of pyridine, 380 g of trityl chloride was added at room temperature, and the mixture was stirred at 80 ° C. overnight. After completion of the reaction, the reaction mixture was cooled, added with water, extracted with ethyl acetate, and washed with saturated saline. The solvent was removed, the residue was dissolved in 300 ml of chloroform, 600 ml of silica gel was added, and the solvent was removed. Purification by silica gel column chromatography provided 149.3 g of (5S) -5-[(trityloxy) methyl] tetrahydro-2-furanone.

【０１２０】(5S)-5-[(トリチルオキシ)メチル]テトラ
ヒドロ-2-フラノン26.9gをTHF200mlに溶かし、１Ｍビニ
ルマグネシウムブロミドTHF溶液300mlを室温で加え、加
熱環流下1.5時間撹拌した。反応終了後、氷冷下で飽和
塩化アンモニウム水溶液を加え、酢酸エチルで抽出し、
飽和食塩水で２回洗浄した。溶媒を除き、シリカゲルカ
ラムクロマトグラフィーで精製して(2S)-1-(トリチルオ
キシ)-5-ビニル-6-ヘプテン-2,5-ジオール13.0gを得
た。26.9 g of (5S) -5-[(trityloxy) methyl] tetrahydro-2-furanone was dissolved in 200 ml of THF, 300 ml of a 1M vinylmagnesium bromide THF solution was added at room temperature, and the mixture was stirred under reflux with heating for 1.5 hours. After completion of the reaction, a saturated aqueous ammonium chloride solution was added under ice cooling, and the mixture was extracted with ethyl acetate.
Washed twice with saturated saline. After removing the solvent, the residue was purified by silica gel column chromatography to obtain 13.0 g of (2S) -1- (trityloxy) -5-vinyl-6-heptene-2,5-diol.

【０１２１】(2S)-1-(トリチルオキシ)-5-ビニル-6-ヘ
プテン-2,5-ジオール体13.0gおよびトルエンスルホニル
クロリド57.2gをピリジン200mlに溶かし、80℃で一夜撹
拌した。反応終了後、水を加え、室温で10分間撹拌し
た。酢酸エチルで２回抽出した後、飽和食塩水で洗浄
し、硫酸マグネシウムで乾燥した。溶媒を除き、トルエ
ンに溶かして再び溶媒を除いた後、シリカゲルカラムク
ロマトグラフィーで精製して(5R)-5-[(トリチルオキシ)
メチル]-2,2-ジビニルテトラヒドロフラン5.88gを得
た。13.0 g of (2S) -1- (trityloxy) -5-vinyl-6-heptene-2,5-diol and 57.2 g of toluenesulfonyl chloride were dissolved in 200 ml of pyridine and stirred at 80 ° C. overnight. After completion of the reaction, water was added, and the mixture was stirred at room temperature for 10 minutes. After extracting twice with ethyl acetate, the extract was washed with saturated saline and dried over magnesium sulfate. After removing the solvent, dissolving in toluene and removing the solvent again, the residue was purified by silica gel column chromatography to give (5R) -5-[(trityloxy)
Methyl] -2,2-divinyltetrahydrofuran (5.88 g) was obtained.

【０１２２】(5R)-5-[(トリチルオキシ)メチル]-2,2-ジ
ビニルテトラヒドロフラン体4.68g、0.5M 9-BBN100mlお
よび9-BBNdimer6.1gをTHF100mlにけんだくさせ、加熱環
流下、30時間撹拌した。冷後30%過酸化水素水50mlと3N
水酸化ナトリウム50mlを氷冷下で加え、50℃で２０時間
撹拌した。反応終了後、室温に戻し酢酸エチルで抽出
し、飽和食塩水で洗浄し、硫酸マグネシウムで乾燥し
た。溶媒を除き、シリカゲルカラムクロマトグラフィー
で精製した後、シリカゲルカラムクロマトグラフィーで
精製して2-(5R)-2-(2-ヒドロキシエチル)-5-[(トリチル
オキシ)メチル]テトラヒドロ-2-フラニル-1-エタノール
2.68gを得た。(5R) -5-[(Trityloxy) methyl] -2,2-divinyltetrahydrofuran 4.68 g, 0.5 M 9-BBN100 ml and 9-BBNdimer 6.1 g were stirred in THF 100 ml, and heated under reflux. Stirred for hours. After cooling, 50 ml of 30% hydrogen peroxide solution and 3N
50 ml of sodium hydroxide was added under ice cooling, and the mixture was stirred at 50 ° C. for 20 hours. After the completion of the reaction, the mixture was returned to room temperature, extracted with ethyl acetate, washed with saturated saline, and dried over magnesium sulfate. After removing the solvent and purifying by silica gel column chromatography, purifying by silica gel column chromatography and purifying by 2- (5R) -2- (2-hydroxyethyl) -5-[(trityloxy) methyl] tetrahydro-2-furanyl -1-ethanol
2.68 g were obtained.

【０１２３】2-(5R)-2-(2-ヒドロキシエチル)-5-[(トリ
チルオキシ)メチル]テトラヒドロ-2-フラニル-1-エタノ
ール2.68gおよびピリジン12mlをジクロロメタン30mlに
溶かし、トルエンスルホニルクロリド11.82gを氷冷下で
加え、2.5時間撹拌した。反応終了後、ピリジン30mlを
加え濃縮し、再び氷冷下でピリジンと水を加えて15分間
撹拌した。酢酸エチルで抽出し、飽和食塩水で洗浄した
後硫酸マグネシウムで乾燥した。溶媒を留去し、トルエ
ンを加えてから再び溶媒を留去した後、シリカゲルカラ
ムクロマトグラフィーで精製して2-(5R)-2-[2-[(4-メチ
ルフェニル)フルホニル]オキシエチル]-5-[(トリチルオ
キシ)メチル]テトラヒドロ-2-フラニルエチル 4-メチル
-1-ベンゼンスルホナート4.17gを得た。2.68 g of 2- (5R) -2- (2-hydroxyethyl) -5-[(trityloxy) methyl] tetrahydro-2-furanyl-1-ethanol and 12 ml of pyridine were dissolved in 30 ml of dichloromethane, and toluenesulfonyl chloride was dissolved. 11.82 g was added under ice cooling, and the mixture was stirred for 2.5 hours. After completion of the reaction, 30 ml of pyridine was added and concentrated, and pyridine and water were added again under ice-cooling, followed by stirring for 15 minutes. The mixture was extracted with ethyl acetate, washed with saturated saline, and dried over magnesium sulfate. The solvent was distilled off, toluene was added, and then the solvent was distilled off again. The residue was purified by silica gel column chromatography to give 2- (5R) -2- [2-[(4-methylphenyl) furonyl] oxyethyl]-. 5-[(trityloxy) methyl] tetrahydro-2-furanylethyl 4-methyl
4.17 g of 1-benzenesulfonate was obtained.

【０１２４】2-(5R)-2-[2-[(4-メチルフェニル)フルホ
ニル]オキシエチル]-5-[(トリチルオキシ)メチル]テト
ラヒドロ-2-フラニルエチル 4-メチル-1-ベンゼンスル
ホナート4.17gおよびベンジルアミン5.36gをDMF80mlに
溶かし、110℃で11.5時間撹拌した。反応終了後水を加
え、酢酸エチルで抽出し、飽和食塩水と飽和重曹水で２
回洗浄した。硫酸マグネシウムで乾燥した後、溶媒を除
き、シリカゲルカラムクロマトグラフィーで精製して(2
R)-8-ベンジル-2-[(トリチルオキシ)メチル]-1-オキサ-
8-アザスピロ[4.5]デカン2.1gを得た。2- (5R) -2- [2-[(4-methylphenyl) fluonyl] oxyethyl] -5-[(trityloxy) methyl] tetrahydro-2-furanylethyl 4-methyl-1-benzenesulfonate 4.17 g and benzylamine 5.36 g were dissolved in DMF80 ml and stirred at 110 ° C. for 11.5 hours. After completion of the reaction, water was added, extracted with ethyl acetate, and extracted with saturated saline and saturated aqueous sodium hydrogen carbonate.
Washed twice. After drying over magnesium sulfate, the solvent was removed and the residue was purified by silica gel column chromatography (2
R) -8-benzyl-2-[(trityloxy) methyl] -1-oxa-
2.1 g of 8-azaspiro [4.5] decane was obtained.

【０１２５】(2R)-8-ベンジル-2-[(トリチルオキシ)メ
チル]-1-オキサ-8-アザスピロ[4.5]デカン2.10gをTHF20
mlに溶かし、氷冷下、4N塩酸1,4-ジオキサン溶液8mlを
加え、１時間撹拌した。反応終了後、水および飽和重曹
水を加え、酢酸エチルで２回抽出し、飽和重曹水および
飽和食塩水で洗浄した後、硫酸マグネシウムで乾燥し
た。溶媒を除き、シリカゲルカラムクロマトグラフィー
で精製して[(2R)-8-ベンジル-1-オキサ-8-アザスピロ
[4.5]デカ-2-イル]メタノール1.03gを得た。2.10 g of (2R) -8-benzyl-2-[(trityloxy) methyl] -1-oxa-8-azaspiro [4.5] decane was added to THF 20
Then, 8 ml of 4N hydrochloric acid 1,4-dioxane solution was added thereto under ice cooling, and the mixture was stirred for 1 hour. After completion of the reaction, water and saturated aqueous sodium bicarbonate were added, extracted twice with ethyl acetate, washed with saturated aqueous sodium bicarbonate and saturated saline, and dried over magnesium sulfate. After removing the solvent, the residue was purified by silica gel column chromatography and [(2R) -8-benzyl-1-oxa-8-azaspiro
[4.5] Dec-2-yl] methanol (1.03 g) was obtained.

【０１２６】[(2R)-8-ベンジル-1-オキサ-8-アザスピロ
[4.5]デカ-2-イル]メタノール1.03gおよび10%パラジウ
ムカーボン0.45gをエタノール30mlにけんだくさせ、１
気圧の水素雰囲気下、室温で18時間撹拌した。不溶物を
濾去し、溶媒を除き、乾燥させて標記化合物0.76gを得
た。 中間体実施例２１ 4-オキソ-1-ピペリジンカルボン酸tert-ブチル25.0 gを
ジエチルエーテル800mL溶液を氷−メタノールで冷却
し、アリルマグネシウムブロミド（１Ｍinジエチルエー
テル）溶液138 mLを滴下した。３時間１０分撹拌した。
反応液を飽和塩化アンモニウム水溶液と氷の混合物に注
いだ。ジエチルエーテル層を分取し、飽和食塩水で洗浄
した。無水硫酸マグネシウムで乾燥し、濾過した。濾液
を減圧下濃縮し、残渣をシリカゲルカラムクロマトグラ
フィーで精製し、4-アリル-4-ヒドロキシ-1-ピペリジン
カルボン酸tert-ブチルを15.9 g得た。[(2R) -8-benzyl-1-oxa-8-azaspiro
[4.5] Dec-2-yl] 1.03 g of methanol and 0.45 g of 10% palladium carbon were mixed in 30 ml of ethanol, and 1
The mixture was stirred at room temperature under a hydrogen atmosphere at atmospheric pressure for 18 hours. The insoluble material was removed by filtration, the solvent was removed, and the residue was dried to obtain 0.76 g of the title compound. Intermediate Example 21 A solution of 25.0 g of tert-butyl 4-oxo-1-piperidinecarboxylate in 800 mL of diethyl ether was cooled with ice-methanol, and 138 mL of an allylmagnesium bromide (1M in diethyl ether) solution was added dropwise. Stir for 3 hours 10 minutes.
The reaction was poured into a mixture of saturated aqueous ammonium chloride and ice. The diethyl ether layer was separated and washed with saturated saline. Dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 15.9 g of tert-butyl 4-allyl-4-hydroxy-1-piperidinecarboxylate.

【０１２７】4-アリル-4-ヒドロキシ-1-ピペリジンカル
ボン酸tert-ブチル9.83g をテトラヒドロフラン-水(9:
1) 60ml に溶解し、四酸化オスミウムtert-ブチルアル
コール溶液(2.5wt%, 2ml)とN-メチルモルホリン-N-オキ
シド6.68gを加え、室温にて終夜撹拌した。反応液を減
圧下に濃縮し、残渣を酢酸エチルと水に分配し、飽和塩
化ナトリウム溶液にて洗浄し、硫酸マグネシウムにて乾
燥した。濾過後、溶媒を減圧下で留去し、得られた残渣
をシリカゲルカラムクロマトグラフィー（酢酸エチル-
メタノール）にて精製し、tert-butyl 4-(2,3-ジヒドロ
キシプロピル)-4-ヒドロキシ-1-ピペリジンカルボン酸t
ert-ブチルを9.11g 得た。9.83 g of tert-butyl 4-allyl-4-hydroxy-1-piperidinecarboxylate was added to tetrahydrofuran-water (9:
1) Dissolved in 60 ml, added osmium tetroxide tert-butyl alcohol solution (2.5 wt%, 2 ml) and 6.68 g of N-methylmorpholine-N-oxide and stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure, the residue was partitioned between ethyl acetate and water, washed with a saturated sodium chloride solution, and dried over magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (ethyl acetate-
Methanol) and purified with tert-butyl 4- (2,3-dihydroxypropyl) -4-hydroxy-1-piperidinecarboxylic acid t
9.11 g of ert-butyl was obtained.

【０１２８】4-(2,3-ジヒドロキシプロピル)-4-ヒドロ
キシ-1-ピペリジンカルボン酸tert-ブチル9.11g をピリ
ジン 40ml に溶解し、クロロトリフェニルメタン10.0g
を加え室温にて終夜撹拌した。反応液を酢酸エチルと水
に分配し、２規定塩酸、水、飽和炭酸水素ナトリウム溶
液、飽和塩化ナトリウム溶液にて洗浄し、硫酸マグネシ
ウムにて乾燥した。濾過後、溶媒を減圧下で留去し、得
られた残渣をシリカゲルカラムクロマトグラフィー（ヘ
キサン-酢酸エチル）にて精製し、4-[3-(tert-ブトキ
シ)-2-ヒドロキシプロピル]-4-ヒドロキシ-1-ピペリジ
ンカルボン酸tert-ブチル を10.3g得た。9.11 g of tert-butyl 4- (2,3-dihydroxypropyl) -4-hydroxy-1-piperidinecarboxylate was dissolved in 40 ml of pyridine, and 10.0 g of chlorotriphenylmethane was dissolved.
Was added and stirred at room temperature overnight. The reaction solution was partitioned between ethyl acetate and water, washed with 2N hydrochloric acid, water, a saturated sodium hydrogen carbonate solution and a saturated sodium chloride solution, and dried over magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give 4- [3- (tert-butoxy) -2-hydroxypropyl] -4 10.3 g of tert-butyl-hydroxy-1-piperidinecarboxylate was obtained.

【０１２９】4-[3-(tert-ブトキシ)-2-ヒドロキシプロ
ピル]-4-ヒドロキシ-1-ピペリジンカルボン酸tert-ブチ
ル2.59g をジメチルホルムアミド10ml に溶解し、水素
化ナトリウム400mgとベンジルクロリド823mgを加え、室
温にて20分間撹拌した。反応液を氷水に注ぎ、酢酸エチ
ルで抽出し、水、飽和塩化ナトリウム溶液にて洗浄し、
硫酸マグネシウムにて乾燥した。濾過後、溶媒を減圧下
で留去し、得られた残渣をシリカゲルカラムクロマトグ
ラフィー（ヘキサン-酢酸エチル）にて精製し、4-[2-
(ベンジルオキシ)-3-(tert-ブトキシ)プロピル]-4-ヒド
ロキシ-1-ピペリジンカルボン酸tert-ブチル を2.66g
得た。2.59 g of tert-butyl 4- [3- (tert-butoxy) -2-hydroxypropyl] -4-hydroxy-1-piperidinecarboxylate was dissolved in 10 ml of dimethylformamide, and 400 mg of sodium hydride and 823 mg of benzyl chloride were added. Was added and stirred at room temperature for 20 minutes. The reaction solution was poured into ice water, extracted with ethyl acetate, washed with water and saturated sodium chloride solution,
It was dried over magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give 4- [2-
2.66 g of (tert-butyl (benzyloxy) -3- (tert-butoxy) propyl] -4-hydroxy-1-piperidinecarboxylate
Obtained.

【０１３０】4-[2-(ベンジルオキシ)-3-(tert-ブトキ
シ)プロピル]-4-ヒドロキシ-1-ピペリジンカルボン酸te
rt-ブチル2.36g をアセトニトリル40ml に溶解し、セリ
ウムアンモニウムナイトレイト426mgを加え室温にて終
夜撹拌した。反応液にシリカゲルを加え、減圧下に濃縮
した。吸着シリカゲルを非吸着シリカゲルカラムに充填
し、ヘキサン-酢酸エチルにて精製し、4-[2-(ベンジル
オキシ)-3-ヒドロキシプロピル]-4-ヒドロキシ-1-ピペ
リジンカルボン酸tert-ブチルを 547mg 得た。4- [2- (benzyloxy) -3- (tert-butoxy) propyl] -4-hydroxy-1-piperidinecarboxylic acid te
2.36 g of rt-butyl was dissolved in 40 ml of acetonitrile, and 426 mg of cerium ammonium nitrate was added, followed by stirring at room temperature overnight. Silica gel was added to the reaction solution, and concentrated under reduced pressure. The adsorption silica gel is packed in a non-adsorption silica gel column, purified with hexane-ethyl acetate, and 547 mg of tert-butyl 4- [2- (benzyloxy) -3-hydroxypropyl] -4-hydroxy-1-piperidinecarboxylate is added. Obtained.

【０１３１】4-[2-(ベンジルオキシ)-3-ヒドロキシプロ
ピル]-4-ヒドロキシ-1-ピペリジンカルボン酸tert-ブチ
ル4.81g をピリジン ２0ml に溶解し、トシルクロリド
2.76gを加え室温にて2時間撹拌した。さらにトシルクロ
リド1.00gを加え、室温で30分間、50℃で35分間撹拌し
た。反応液を酢酸エチルと水に分配し、1規定塩酸、飽
和炭酸水素ナトリウム溶液、飽和塩化ナトリウム溶液に
て洗浄し、硫酸マグネシウムにて乾燥した。濾過後、溶
媒を減圧下で留去し、得られた残渣をシリカゲルカラム
クロマトグラフィー（ヘキサン-酢酸エチル）にて精製
し、3-(ベンジルオキシ)-1-オキサ-8-アザスピロ[4.5]
デカン-8-カルボン酸tert-ブチルを3.72gを得た。Dissolve 4.81 g of tert-butyl 4- [2- (benzyloxy) -3-hydroxypropyl] -4-hydroxy-1-piperidinecarboxylate in 20 ml of pyridine and add tosyl chloride
2.76 g was added and the mixture was stirred at room temperature for 2 hours. Further, 1.00 g of tosyl chloride was added, followed by stirring at room temperature for 30 minutes and at 50 ° C. for 35 minutes. The reaction solution was partitioned between ethyl acetate and water, washed with 1N hydrochloric acid, a saturated sodium hydrogen carbonate solution and a saturated sodium chloride solution, and dried over magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give 3- (benzyloxy) -1-oxa-8-azaspiro [4.5]
3.72 g of tert-butyl decane-8-carboxylate was obtained.

【０１３２】3-(ベンジルオキシ)-1-オキサ-8-アザスピ
ロ[4.5]デカン-8-カルボン酸tert-ブチル6.47g をテト
ラヒドロフラン100ml に溶解し、パラジウム炭素1.3gを
加え、水素雰囲気下で終夜撹拌した。反応液から触媒を
濾取し、パラジウム炭素1.3gを加え、水素雰囲気下にて
終夜撹拌した。反応液から触媒を濾取し、パラジウム炭
素2.6gを加え水素雰囲気下4.2気圧で終夜撹拌した。反
応液から触媒を濾取し、溶媒を減圧下で留去し、得られ
た残渣をシリカゲルカラムクロマトグラフィー（酢酸エ
チル-メタノール）にて精製し、3-ヒドロキシ-1-オキサ
-8-アザスピロ[4.5]デカン-8-カルボン酸tert-ブチル
を4.27g 得た。 中間体製造例２２ (anti)-3-オキサ-9-アザビシクロ[3.3.1]ノナン-7-オー
ル塩酸塩 水素化アルミニウムリチウム2.0gをテトラヒドロフラン
200mlに懸濁し氷冷下、9-メチル-3-オキサ-9-アザビシ
クロ[3.3.1]ノナン-7-オン 14.17gをテトラヒドロフラ
ン20mlに溶解した溶液を滴下した。35分撹拌した後、反
応液に水2.0ml、15%水酸化ナトリウム水溶液2.0ml、水
6.0mlを順次加え室温で撹拌した。反応液を濾過し、溶
媒を減圧下で留去した。残査を酢酸エチルに溶解しアル
ミナで濾過した。溶媒を減圧下で濃縮し、(anti)- 9-メ
チル-3-オキサ-9-アザビシクロ[3.3.1]ノナン-7-オール
を黄色蝋状物として10.00g得た。6.47 g of tert-butyl 3- (benzyloxy) -1-oxa-8-azaspiro [4.5] decane-8-carboxylate was dissolved in 100 ml of tetrahydrofuran, 1.3 g of palladium on carbon was added, and the mixture was placed under a hydrogen atmosphere overnight. Stirred. The catalyst was filtered from the reaction solution, 1.3 g of palladium carbon was added, and the mixture was stirred overnight under a hydrogen atmosphere. The catalyst was filtered off from the reaction solution, 2.6 g of palladium carbon was added, and the mixture was stirred overnight at 4.2 atm under a hydrogen atmosphere. The catalyst was filtered off from the reaction solution, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate-methanol) to give 3-hydroxy-1-oxal.
Tert-butyl -8-azaspiro [4.5] decane-8-carboxylate
4.27 g was obtained. Intermediate Production Example 22 (anti) -3-oxa-9-azabicyclo [3.3.1] nonan-7-ol hydrochloride 2.0 g of lithium aluminum hydride in tetrahydrofuran
A suspension prepared by dissolving 14.17 g of 9-methyl-3-oxa-9-azabicyclo [3.3.1] nonan-7-one in 20 ml of tetrahydrofuran was added dropwise to the suspension in ice and cooled with ice. After stirring for 35 minutes, 2.0 ml of water, 2.0 ml of 15% aqueous sodium hydroxide solution, and water were added to the reaction solution.
6.0 ml were sequentially added and the mixture was stirred at room temperature. The reaction solution was filtered, and the solvent was distilled off under reduced pressure. The residue was dissolved in ethyl acetate and filtered through alumina. The solvent was concentrated under reduced pressure to obtain 10.00 g of (anti) -9-methyl-3-oxa-9-azabicyclo [3.3.1] nonan-7-ol as a yellow wax.

【０１３３】(anti)- 9-メチル-3-オキサ-9-アザビシク
ロ[3.3.1]ノナン-7-オール 10.0gをテトラヒドロフラン
100mlに溶解しトリエチルアミン10.7ml、無水酢酸7.2ml
および4-ジメチルアミノピリジン0.77gを加え50℃で終
夜撹拌した。反応液を減圧下で濃縮し、残査を酢酸エチ
ルに溶解しアルミナで濾過した。濾液を濃縮しアルミナ
カラムクロマトグラフィー（溶媒；n-ヘキサン：酢酸エ
チル）で精製し、(anti)-9-メチル-3-オキサ-9-アザビ
シクロ[3.3.1]ノナン-7-イル アセタート を淡黄色油状
物として8.68g得た。10.0 g of (anti) -9-methyl-3-oxa-9-azabicyclo [3.3.1] nonan-7-ol was added to tetrahydrofuran
Dissolve in 100 ml, triethylamine 10.7 ml, acetic anhydride 7.2 ml
And 0.77 g of 4-dimethylaminopyridine were added and the mixture was stirred at 50 ° C. overnight. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate and filtered through alumina. The filtrate was concentrated and purified by alumina column chromatography (solvent; n-hexane: ethyl acetate), and (anti) -9-methyl-3-oxa-9-azabicyclo [3.3.1] nonan-7-yl acetate was eluted. 8.68 g were obtained as a yellow oil.

【０１３４】(anti)-9-メチル-3-オキサ-9-アザビシク
ロ[3.3.1]ノナン-7-イル アセタート8.68gを１，２−ジ
クロロエタン40mlに溶解し、クロロぎ酸ビニル 7.0mlを
加え室温で30分撹拌した後、2時間35分加熱還流した。
反応液を減圧下で濃縮後、シリカゲルカラムクロマトグ
ラフィー（溶媒；n-ヘキサン：酢酸エチル）で精製し、
(anti)-3-オキサ-9-ビニルオキシカルボニル-9-アザビ
シクロ[3.3.1]ノナン-7-イル アセタートを淡黄色油状
物として8.96g得た。8.68 g of (anti) -9-methyl-3-oxa-9-azabicyclo [3.3.1] nonan-7-yl acetate was dissolved in 40 ml of 1,2-dichloroethane, and 7.0 ml of vinyl chloroformate was added. After stirring at room temperature for 30 minutes, the mixture was heated under reflux for 2 hours and 35 minutes.
The reaction solution was concentrated under reduced pressure, and purified by silica gel column chromatography (solvent; n-hexane: ethyl acetate).
8.96 g of (anti) -3-oxa-9-vinyloxycarbonyl-9-azabicyclo [3.3.1] nonan-7-yl acetate was obtained as a pale yellow oil.

【０１３５】(anti)-3-オキサ-9-ビニルオキシカルボニ
ル-9-アザビシクロ[3.3.1]ノナン-7-イル アセタート
8.96gをメタノール45mlに溶解し、水30mlおよび炭酸カ
リウム7.3gを加え室温で1時間30分撹拌し、更に50℃で3
0分撹拌した。反応液を減圧下で濃縮後、飽和食塩水を
加え酢酸エチルで抽出した。無水硫酸マグネシウムで乾
燥後、減圧下で溶媒を留去し、(anti)-3-オキサ-9-ビニ
ルオキシカルボニル-9-アザビシクロ[3.3.1]ノナン-7-
オールを淡黄色油状物として7.37g得た。(Anti) -3-oxa-9-vinyloxycarbonyl-9-azabicyclo [3.3.1] nonan-7-yl acetate
8.96 g was dissolved in 45 ml of methanol, 30 ml of water and 7.3 g of potassium carbonate were added, and the mixture was stirred at room temperature for 1 hour and 30 minutes.
Stirred for 0 minutes. After the reaction solution was concentrated under reduced pressure, a saturated saline solution was added, and the mixture was extracted with ethyl acetate. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to give (anti) -3-oxa-9-vinyloxycarbonyl-9-azabicyclo [3.3.1] nonane-7-
7.37 g of all was obtained as a pale yellow oil.

【０１３６】(anti)-3-オキサ-9-ビニルオキシカルボニ
ル-9-アザビシクロ[3.3.1]ノナン-7-オール 7.37gに4N-
塩化水素-ジオキサン溶液17mlを加え室温で30分撹拌し
た。反応液にエタノール40mlを加え1時間加熱還流し
た。溶媒を減圧下で留去し、残査に酢酸エチルを加え析
出物を濾取し、標記化合物を白色針状晶として5.55g得
た。 中間体製造例２３ (syn)-3-アザビシクロ[3.2.1]オクタン-8-オール塩酸塩 3-メチル-3-アザビシクロ[3.2.1]オクタン-8-オンより
中間体製造法２２と同様にして標記化合物を得た。 中間体製造例２４ (anti)-3-オキサ-7-アザビシクロ[3.3.1]ノナン-9-オー
ル塩酸塩 7-メチル-3-オキサ-7-アザビシクロ[3.3.1]ノナン-9-オ
ンより中間体製造法２２と同様にして標記化合物を得
た。 中間体製造例２５ (anti)-9-アザビシクロ[3.3.1]ノナン-3-オール塩酸塩 9-メチル-9-アザビシクロ[3.3.1]ノナン-3-オンより中
間体製造法２２と同様にして標記化合物を得た。 中間体製造例２６ (exo)-8-アザビシクロ[3.2.1]オクタン-3-オール塩酸塩 (exo)-8-メチル-8-アザビシクロ[3.2.1]オクタン-3-オ
ールよりアセチル化後、中間体製造例２２と同様にして
標記化合物を得た。 中間体製造例２７ (endo)-8-アザビシクロ[3.2.1]オクタン-3-オール塩酸
塩 (endo)-8-メチル-8-アザビシクロ[3.2.1]オクタン-3-オ
ールよりアセチル化後、中間体製造例２２と同様にして
標記化合物を得た。 中間体製造例２８ (anti)-3-アザビシクロ[3.3.1]ノナン-9-オール塩酸塩 水素化アルミニウムリチウム1.0gをテトラヒドロフラン
100mlに懸濁し氷冷下、3-メチル-3-アザビシクロ[3.3.
1]ノナン-9-オン 7.00gをテトラヒドロフラン20mlに溶
解した溶液を滴下した。50分撹拌した後、反応液に水1.
0ml、15%水酸化ナトリウム水溶液1.0ml、水3.0mlを順次
加え室温で撹拌した。反応液を濾過後、溶媒を減圧下で
留去し、淡黄色油状物7.08gを得た。これをテトラヒド
ロフラン90mlに溶解しトリエチルアミン9.55mlを加え,
氷冷下撹拌した。無水酢酸6.46mlおよび4-ジメチルアミ
ノピリジン0.56gを加え室温で14時間撹拌した。メタノ
ール約20mlを加え反応液を減圧下で濃縮し、残査に炭酸
カリウム水溶液を加え酢酸エチルで抽出した。有機層を
水、飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥し
た。溶媒を減圧下で留去後、シリカゲルカラムクロマト
グラフィー（溶媒；n-ヘキサン：酢酸エチル）で精製
し、より極性の低い生成物として(anti)-3-メチル-3-ア
ザビシクロ[3.3.1]ノナン-9-イル アセタート （無色
油状物）を3.33g得た。また、より極性の高い生成物と
して(syn)-3-メチル-3-アザビシクロ[3.3.1]ノナン-9-
イル アセタート （淡橙色油状物）を2.06g得た。(Anti) -3-oxa-9-vinyloxycarbonyl-9-azabicyclo [3.3.1] nonan-7-ol 4N-
17 ml of a hydrogen chloride-dioxane solution was added, and the mixture was stirred at room temperature for 30 minutes. 40 ml of ethanol was added to the reaction solution, and the mixture was heated under reflux for 1 hour. The solvent was distilled off under reduced pressure, ethyl acetate was added to the residue, and the precipitate was collected by filtration to obtain 5.55 g of the title compound as white needles. Intermediate Production Example 23 (syn) -3-Azabicyclo [3.2.1] octan-8-ol hydrochloride In the same manner as in Intermediate Production Method 22 from 3-methyl-3-azabicyclo [3.2.1] octan-8-one To give the title compound. Intermediate Production Example 24 (anti) -3-oxa-7-azabicyclo [3.3.1] nonan-9-ol hydrochloride From 7-methyl-3-oxa-7-azabicyclo [3.3.1] nonan-9-one The title compound was obtained in the same manner as in Intermediate Production Method 22. Intermediate Production Example 25 (anti) -9-Azabicyclo [3.3.1] nonan-3-ol hydrochloride In the same manner as in Intermediate Production Method 22 from 9-methyl-9-azabicyclo [3.3.1] nonan-3-one To give the title compound. Intermediate Production Example 26 (exo) -8-Azabicyclo [3.2.1] octan-3-ol hydrochloride After acetylation from (exo) -8-methyl-8-azabicyclo [3.2.1] octan-3-ol, The title compound was obtained in the same manner as in Intermediate Production Example 22. Intermediate Production Example 27 (endo) -8-Azabicyclo [3.2.1] octan-3-ol hydrochloride After acetylation from (endo) -8-methyl-8-azabicyclo [3.2.1] octan-3-ol, The title compound was obtained in the same manner as in Intermediate Production Example 22. Intermediate Production Example 28 (anti) -3-Azabicyclo [3.3.1] nonan-9-ol hydrochloride 1.0 g of lithium aluminum hydride in tetrahydrofuran
Suspended in 100 ml and cooled with ice, 3-methyl-3-azabicyclo [3.3.
1] A solution of 7.00 g of nonan-9-one dissolved in 20 ml of tetrahydrofuran was added dropwise. After stirring for 50 minutes, add water 1.
0 ml, a 15% aqueous solution of sodium hydroxide 1.0 ml, and water 3.0 ml were sequentially added, followed by stirring at room temperature. After filtering the reaction solution, the solvent was distilled off under reduced pressure to obtain 7.08 g of a pale yellow oil. This was dissolved in 90 ml of tetrahydrofuran, and 9.55 ml of triethylamine was added.
The mixture was stirred under ice cooling. 6.46 ml of acetic anhydride and 0.56 g of 4-dimethylaminopyridine were added, and the mixture was stirred at room temperature for 14 hours. About 20 ml of methanol was added, the reaction solution was concentrated under reduced pressure, an aqueous potassium carbonate solution was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (solvent; n-hexane: ethyl acetate), and as a less polar product (anti) -3-methyl-3-azabicyclo [3.3.1] 3.3 g of nonan-9-yl acetate (colorless oil) was obtained. Also, a more polar product (syn) -3-methyl-3-azabicyclo [3.3.1] nonane-9-
2.06 g of il acetate (light orange oil) was obtained.

【０１３７】(anti)-3-メチル-3-アザビシクロ[3.3.1]
ノナン-9-イル アセタート 2.06gを１，２−ジクロロエ
タン10mlに溶解し、クロロぎ酸ビニル 2.07mlを加え室
温で50分撹拌した後、5時間25分加熱還流した。反応液
を減圧下で濃縮し、残査に水を加え酢酸エチルで抽出し
た。有機層を1N-塩酸、飽和重曹水、飽和食塩水で洗浄
し、無水硫酸マグネシウムで乾燥した。溶媒を減圧下で
留去し、(anti)-3-ビニルオキシカルボニル-3-アザビシ
クロ[3.3.1]ノナン-9-イル アセタートを淡橙色油状物
として2.51g得た。(Anti) -3-Methyl-3-azabicyclo [3.3.1]
2.06 g of nonan-9-yl acetate was dissolved in 10 ml of 1,2-dichloroethane, and 2.07 ml of vinyl chloroformate was added. After stirring at room temperature for 50 minutes, the mixture was heated under reflux for 5 hours and 25 minutes. The reaction solution was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with 1N-hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated saline, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 2.51 g of (anti) -3-vinyloxycarbonyl-3-azabicyclo [3.3.1] nonan-9-yl acetate as a pale orange oil.

【０１３８】(anti)-3-ビニルオキシカルボニル-3-アザ
ビシクロ[3.3.1]ノナン-9-イル アセタート 4.02gをエ
タノール36mlに溶解し、1N-水酸化ナトリウム水溶液18m
lを加え室温で1時間50分撹拌した。反応液を減圧下で濃
縮し、残査に水を加え酢酸エチルで抽出した。有機層を
水、飽和重曹水、飽和食塩水で洗浄し、無水硫酸マグネ
シウムで乾燥した。溶媒を減圧下で留去後、シリカゲル
カラムクロマトグラフィー（溶媒；n-ヘキサン：酢酸エ
チル）で精製し、(anti)-3-ビニルオキシカルボニル-3-
アザビシクロ[3.3.1]ノナン-9-オールを微黄色油状物と
して3.09g得た。4.02 g of (anti) -3-vinyloxycarbonyl-3-azabicyclo [3.3.1] nonan-9-yl acetate was dissolved in 36 ml of ethanol, and 18 ml of a 1N aqueous solution of sodium hydroxide was dissolved.
l was added and the mixture was stirred at room temperature for 1 hour and 50 minutes. The reaction solution was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, saturated aqueous sodium hydrogen carbonate, and saturated saline, and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (solvent; n-hexane: ethyl acetate) to give (anti) -3-vinyloxycarbonyl-3-
3.09 g of azabicyclo [3.3.1] nonan-9-ol was obtained as a pale yellow oil.

【０１３９】(anti)-3-ビニルオキシカルボニル-3-アザ
ビシクロ[3.3.1]ノナン-9-オール 3.09gに4N-塩化水素-
ジオキサン溶液7mlを加え室温で50分撹拌した。反応液
を減圧下で濃縮し、残査にエタノール30mlを加え50分加
熱還流した。溶媒を減圧下で留去し、残査に酢酸エチル
を加え析出物を濾取し、標記化合物を微乳白色粉末とし
て2.41g得た。 中間体製造例２９ (syn)-3-アザビシクロ[3.3.1]ノナン-9-オール酸塩 (syn)-3-メチル-3-アザビシクロ[3.3.1]ノナン-9-イル
アセタートより中間体製造例２８と同様にして標記化合
物を得た。 中間体製造例３０ (anti)-2-(3-アザビシクロ[3.3.1]ノン-9-イル)-1-エタ
ノール 塩酸塩 水素化アルミニウムリチウム1.0gをテトラヒドロフラン
30mlに懸濁し氷冷下、(anti)-メチル (3-アザビシクロ
[3.3.1]ノン-9-イル)アセタート 3.24gをテトラヒドロ
フラン25mlに懸濁したものを滴下した。35分撹拌した
後、反応液に水1.0ml、15%水酸化ナトリウム水溶液1.0m
l、水3.0mlを順次加え室温で撹拌した。セライトおよび
無水硫酸ナトリウムを加え濾過し、溶媒を減圧下で留去
した。残査を酢酸エチルに溶解し、4N-塩化水素-酢酸エ
チル溶液5mlを加え析出物を濾取し、標記化合物を白色
粉末として2.29g得た。 中間体製造例３１ 1-クロロ-4-[(4-メトキシ-3-メチルベンジル)アミノ]-6
-フタラジンカルボニトリル¹ H NMR (DMSO-d₆) δ; 2.10 (3H, s), 3.73 (3H, s),
4.64 (2H, d, J = 5.4 Hz), 6.85 (1H, d, J = 8.0 H
z), 7.17-7.21 (2H, m), 8.15 (1H, d, J = 8.6 Hz),
8.31 (1H, dd, J = 8.6, 1.2 Hz), 8.35 (1H, t, J =
5.4 Hz), 9.00 (1H, d,J = 1.2 Hz) 実施例１ 4-(3-クロロ-4-メトキシベンジル）アミノ-6-シアノ-1-
(3-ピリジル)フタラジン・二塩酸塩(Anti) -3-vinyloxycarbonyl-3-azabicyclo [3.3.1] nonan-9-ol To 3.09 g of 4N-hydrogen chloride-
7 ml of a dioxane solution was added, and the mixture was stirred at room temperature for 50 minutes. The reaction solution was concentrated under reduced pressure, 30 ml of ethanol was added to the residue, and the mixture was heated under reflux for 50 minutes. The solvent was distilled off under reduced pressure, ethyl acetate was added to the residue, and the precipitate was collected by filtration to obtain 2.41 g of the title compound as a fine milky white powder. Intermediate Production Example 29 (syn) -3-Azabicyclo [3.3.1] nonan-9-yl (syn) -3-methyl-3-azabicyclo [3.3.1] nonan-9-yl
The title compound was obtained from acetate in the same manner as in Intermediate Production Example 28. Intermediate Production Example 30 (anti) -2- (3-Azabicyclo [3.3.1] non-9-yl) -1-ethanol hydrochloride 1.0 g of lithium aluminum hydride in tetrahydrofuran
Suspend in 30 ml and cool with (anti) -methyl (3-azabicyclo
[3.3.1] Non-9-yl) acetate A suspension of 3.24 g in 25 ml of tetrahydrofuran was added dropwise. After stirring for 35 minutes, the reaction solution was water 1.0 ml, 15% aqueous sodium hydroxide solution 1.0 m
l and water (3.0 ml) were sequentially added, followed by stirring at room temperature. Celite and anhydrous sodium sulfate were added, the mixture was filtered, and the solvent was distilled off under reduced pressure. The residue was dissolved in ethyl acetate, 5 ml of a 4N-hydrogen chloride-ethyl acetate solution was added, and the precipitate was collected by filtration to obtain 2.29 g of the title compound as a white powder. Intermediate Production Example 31 1-Chloro-4-[(4-methoxy-3-methylbenzyl) amino] -6
-Phthalazinecarbonitrile ¹ H NMR (DMSO-d ₆ ) δ; 2.10 (3H, s), 3.73 (3H, s),
4.64 (2H, d, J = 5.4 Hz), 6.85 (1H, d, J = 8.0 H
z), 7.17-7.21 (2H, m), 8.15 (1H, d, J = 8.6 Hz),
8.31 (1H, dd, J = 8.6, 1.2 Hz), 8.35 (1H, t, J =
(5.4 Hz), 9.00 (1H, d, J = 1.2 Hz) Example 1 4- (3-chloro-4-methoxybenzyl) amino-6-cyano-1-
(3-pyridyl) phthalazine dihydrochloride

【０１４０】[0140]

【化５２】 Embedded image

【０１４１】3-ブロモピリジン2.53gの無水ジエチルエ
ーテル50mL溶液に-70℃以下で、ｎ-ブチルリチウム1.6M
ヘキサン溶液10mLを滴下し、30分間攪拌した。この混合
物にトリ-ｎ-ブチルすずクロリド5.21gの無水ジエチル
エーテル10mL溶液を加えた。反応液を１時間で室温にし
た。反応液を飽和食塩水に注ぎ、有機層を飽和食塩水で
洗浄した。無水硫酸マグネシウムで乾燥後、減圧下濃縮
し、3-(1,1,1-トリ-n-ブチルスタニル)ピリジンを黄色
油状物として得た。A solution of 2.53 g of 3-bromopyridine in 50 mL of anhydrous diethyl ether at -70 ° C. or lower was treated with 1.6M n-butyllithium.
A hexane solution (10 mL) was added dropwise, and the mixture was stirred for 30 minutes. To this mixture was added a solution of 5.21 g of tri-n-butyltin chloride in 10 mL of anhydrous diethyl ether. The reaction was brought to room temperature for 1 hour. The reaction solution was poured into saturated saline, and the organic layer was washed with saturated saline. After drying over anhydrous magnesium sulfate, the mixture was concentrated under reduced pressure to give 3- (1,1,1-tri-n-butylstannyl) pyridine as a yellow oil.

【０１４２】1-クロロ-4-(3-クロロ-4-メトキシベンジ
ル)アミノ-6-シアノフタラジン1.80g、テトラキス（ト
リフェニルホスフィン）パラジウム579mg、キシレン25m
Lと1-メチル-2-ピロリドン3mLの混合物を激しく攪拌
し、加熱還流させ、これに上で得た3-(1,1,1-トリ-n-ブ
チルスタニル)ピリジンのキシレン25mL溶液を１時間で
滴下した。反応液をさらに１５分間加熱還流した。反応
液を室温に戻し、水で３回、飽和食塩水で１回洗浄し
た。シリカゲルカラムクロマトグラフィーで精製し、カ
ップリング体を得た。これをテトラヒドロフランとメタ
ノールの混合溶媒に懸濁し、４Ｎ塩酸−酢酸エチル溶液
を加え、減圧下濃縮した。酢酸エチル-メタノールより
再結晶し、表記化合物を無色の粉末として1.80g得た。 MASS(ESI)；402.0(MH⁺)¹ H-NMR(400 MHz, DMSO-d₆)δ; 3.85 (3H, s), 4.06 (2
H, br), 4.89 (2H, br),7.18 (1H, d, J= 8.0 Hz), 7.5
3 (1H, dd, J = 8.0, 1.2 Hz), 7.67 (1H, d, J= 1.2 H
z), 7.81-7.90 (1H, m), 8.07 (1H, dd, J = 8.8, 0.4
Hz), 8.38-8.45(1H, m), 8.46 (1H, dd, J = 8.8, 1.4
Hz), 8.90-9.00 (2H, m), 9.57 (1H, dd, J = 1.4, 0.4
Hz), 10.76 (1H, br) 実施例２ 4-(3-クロロ-4-メトキシベンジル)アミノ-6-シアノ-1-
(2-ピリジル)フタラジン・二塩酸塩1-chloro-4- (3-chloro-4-methoxybenzyl) amino-6-cyanophthalazine 1.80 g, tetrakis (triphenylphosphine) palladium 579 mg, xylene 25 m
A mixture of L and 3 mL of 1-methyl-2-pyrrolidone was vigorously stirred and heated to reflux, and a solution of 3- (1,1,1-tri-n-butylstannyl) pyridine obtained above in 25 mL of xylene was added for 1 hour. Was dropped. The reaction was heated at reflux for a further 15 minutes. The reaction solution was returned to room temperature, and washed three times with water and once with a saturated saline solution. Purification was performed by silica gel column chromatography to obtain a coupled product. This was suspended in a mixed solvent of tetrahydrofuran and methanol, 4N hydrochloric acid-ethyl acetate solution was added, and the mixture was concentrated under reduced pressure. Recrystallization from ethyl acetate-methanol gave 1.80 g of the title compound as a colorless powder. MASS (ESI); 402.0 (MH ⁺ ) ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ; 3.85 (3H, s), 4.06 (2
H, br), 4.89 (2H, br), 7.18 (1H, d, J = 8.0 Hz), 7.5
3 (1H, dd, J = 8.0, 1.2 Hz), 7.67 (1H, d, J = 1.2 H
z), 7.81-7.90 (1H, m), 8.07 (1H, dd, J = 8.8, 0.4
Hz), 8.38-8.45 (1H, m), 8.46 (1H, dd, J = 8.8, 1.4
Hz), 8.90-9.00 (2H, m), 9.57 (1H, dd, J = 1.4, 0.4
Hz), 10.76 (1H, br) Example 2 4- (3-chloro-4-methoxybenzyl) amino-6-cyano-1-
(2-pyridyl) phthalazine dihydrochloride

【０１４３】[0143]

【化５３】 Embedded image

【０１４４】実施例１の3-ブロモピリジンの代わりに2-
ブロモピリジンを用いて同様にして標記化合物を得た。 MASS(ESI)；402.0(MH⁺)¹ H-NMR(400 MHz, DMSO-d₆)δ; 3.83 (3H, s), 4.86-4.9
0 (2H, m), 7.16 (1H, d, J = 8.6 Hz), 7.52 (1H, dd,
J = 8.6, 2.1 Hz), 7.63-7.69 (2H, m), 7.97 (1H, d,
J = 8.5 Hz), 8.08-8.13 (1H, m), 8.47 (1H, dd, J =
8.5, 1.4 Hz), 8.72-8.83 (2H, m), 9.56 (1H, d, J =
1.4 Hz), 10.82-10.92 (1H, m). 実施例３ 4-(3-クロロ-4-メトキシベンジル）アミノ-6-シアノ-1-
(4-シアノピペリジノ)フタラジン塩酸塩Instead of 3-bromopyridine in Example 1,
The title compound was obtained in the same manner using bromopyridine. MASS (ESI); 402.0 (MH ⁺ ) ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ; 3.83 (3H, s), 4.86-4.9
0 (2H, m), 7.16 (1H, d, J = 8.6 Hz), 7.52 (1H, dd,
J = 8.6, 2.1 Hz), 7.63-7.69 (2H, m), 7.97 (1H, d,
J = 8.5 Hz), 8.08-8.13 (1H, m), 8.47 (1H, dd, J =
8.5, 1.4 Hz), 8.72-8.83 (2H, m), 9.56 (1H, d, J =
1.4 Hz), 10.82-10.92 (1H, m). Example 3 4- (3-chloro-4-methoxybenzyl) amino-6-cyano-1-
(4-cyanopiperidino) phthalazine hydrochloride

【０１４５】[0145]

【化５４】 Embedded image

【０１４６】4-ピペリジンカルボキサミド15g、塩化ベ
ンジル16.3g、炭酸カリウム32.3gとN,N-ジメチルホルム
アミド200mLの混合物を80℃で4時間攪拌した。反応液を
室温に戻し、水酸化ナトリウム水溶液を加え、酢酸エチ
ルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸
ナトリウムで乾燥後、減圧下濃縮した。得られた結晶性
残渣をヘキサン-酢酸エチルで洗浄し、ろ取した。白色
鱗片状結晶として、1-ベンジル-4-ピペリジンカルボキ
サミド12.7g得た。A mixture of 15 g of 4-piperidinecarboxamide, 16.3 g of benzyl chloride, 32.3 g of potassium carbonate and 200 mL of N, N-dimethylformamide was stirred at 80 ° C. for 4 hours. The reaction solution was returned to room temperature, an aqueous sodium hydroxide solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained crystalline residue was washed with hexane-ethyl acetate and collected by filtration. 12.7 g of 1-benzyl-4-piperidinecarboxamide was obtained as white scaly crystals.

【０１４７】1-ベンジル-4-ピペリジンカルボキサミド1
2.7gとオキシ塩化リン60mLの混合物に氷冷下、N,N-ジメ
チルホルムアミド5mLを加え、室温で、1.5時間攪拌し
た。減圧下濃縮し、残渣を酢酸エチルに溶解し、水酸化
ナトリウム水溶液、飽和食塩水で洗浄した。無水硫酸ナ
トリウムで乾燥後、減圧下濃縮し、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し、1-ベンジ
ル-4-ピペリジンカルボニトリルを11.0g得た。1-benzyl-4-piperidinecarboxamide 1
To a mixture of 2.7 g and phosphorus oxychloride (60 mL) was added N, N-dimethylformamide (5 mL) under ice-cooling, followed by stirring at room temperature for 1.5 hours. After concentration under reduced pressure, the residue was dissolved in ethyl acetate and washed with an aqueous sodium hydroxide solution and saturated saline. After drying over anhydrous sodium sulfate, the mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to obtain 11.0 g of 1-benzyl-4-piperidinecarbonitrile.

【０１４８】1-ベンジル-4-ピペリジンカルボニトリル1
1.0gを1,2-ジクロロエタン100mLに溶解し、氷冷下、ク
ロロ蟻酸1-クロロエチル7.1mLを加え、室温で15分間攪
拌後、1時間20分加熱還流した。減圧下濃縮後、メタノ
ール50mLを加え、1時間加熱還流した。減圧下濃縮し、
酢酸エチルで結晶性残渣を洗浄ろ取し、4-ピペリジンカ
ルボニトリル塩酸塩を白色結晶として8.0g得た。1-benzyl-4-piperidinecarbonitrile 1
1.0 g was dissolved in 1,2-dichloroethane (100 mL), and thereto was added 1-chloroethyl chloroformate (7.1 mL) under ice-cooling. The mixture was stirred at room temperature for 15 minutes, and then heated under reflux for 1 hour and 20 minutes. After concentration under reduced pressure, 50 mL of methanol was added, and the mixture was heated under reflux for 1 hour. Concentrate under reduced pressure,
The crystalline residue was washed with ethyl acetate and collected by filtration to obtain 8.0 g of 4-piperidinecarbonitrile hydrochloride as white crystals.

【０１４９】このようにして得た4-ピペリジンカルボニ
トリル塩酸塩1.2gおよび1-クロロ-4-(3-クロロ-4-メト
キシベンジル)アミノ-6-シアノフタラジン1.0g、ジイソ
プロピルエチルアミン1.8g、1-メチル-2-ピロリドン10m
Lの混合物を170℃で２時間３０分攪拌した。冷後、反応
液に酢酸エチルを加え、水及び飽和食塩水で洗浄した。
無水硫酸ナトリウムで乾燥後、減圧下溶媒留去し、残さ
をシリカゲルカラムクロマトグラフィーで精製した。得
られたフリー体を酢酸エチルに溶解し、４Ｎ塩酸−酢酸
エチル溶液を加え、析出した結晶をろ取し標記化合物を
黄色の粉末として880ｍg得た。 MASS(ESI)；433.2(MH⁺)¹ H-NMR(400 MHz, DMSO-d₆)δ; 1.98-2.17(4H, m), 3.10
-3.33 (5H, m), 3.86 (3H, s), 4.70-4.74 (2H, m), 7.
17 (1H, d, J= 8.4 Hz), 7.45 (1H, dd, J = 8.4, 2.0
Hz), 7.61 (1H, d, J = 2.0 Hz), 8.27 (1H, d, J = 8.
4 Hz), 8.47 (1H,dd, J = 8.4, 0.8 Hz), 9.34-9.38 (1
H, m), 10.28 (1H, br) 実施例４ 4-(3-クロロ-4-メトキシフェネチル)アミノ-6-シアノ-1
-(4-シアノピペリジノ)フタラジン塩酸塩1.2 g of 4-piperidinecarbonitrile hydrochloride thus obtained, 1.0 g of 1-chloro-4- (3-chloro-4-methoxybenzyl) amino-6-cyanophthalazine, 1.8 g of diisopropylethylamine, 1-g Methyl-2-pyrrolidone 10m
The L mixture was stirred at 170 ° C. for 2 hours 30 minutes. After cooling, ethyl acetate was added to the reaction solution, which was washed with water and saturated saline.
After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography. The obtained free compound was dissolved in ethyl acetate, a 4N hydrochloric acid-ethyl acetate solution was added, and the precipitated crystals were collected by filtration to obtain 880 mg of the title compound as a yellow powder. MASS (ESI); 433.2 (MH ⁺ ) ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ; 1.98-2.17 (4H, m), 3.10
-3.33 (5H, m), 3.86 (3H, s), 4.70-4.74 (2H, m), 7.
17 (1H, d, J = 8.4 Hz), 7.45 (1H, dd, J = 8.4, 2.0
Hz), 7.61 (1H, d, J = 2.0 Hz), 8.27 (1H, d, J = 8.
4 Hz), 8.47 (1H, dd, J = 8.4, 0.8 Hz), 9.34-9.38 (1
H, m), 10.28 (1H, br) Example 4 4- (3-chloro-4-methoxyphenethyl) amino-6-cyano-1
-(4-cyanopiperidino) phthalazine hydrochloride

【０１５０】[0150]

【化５５】 Embedded image

【０１５１】実施例３の1-クロロ-4-(3-クロロ-4-メト
キシベンジル)アミノ-6-シアノフタラジンの代わり1-ク
ロロ-4-(3-クロロ-4-メトキシフェネチル)アミノ-6-シ
アノフタラジンを用い、標記化合物を得た。 MASS(ESI)；447.1(MH⁺)¹ H-NMR(400 MHz, DMSO-d₆)δ;1.97-2.18 (4H, m), 2.94
-3.00 (2H, m), 3.11-3.23 (3H, m), 3.33-3.40 (2H,
m), 3.72-3.80 (2H, m), 3.82 (3H, s), 7.09 (1H, d,
J= 8.4 Hz), 7.27 (1H, dd, J = 8.4, 2.0 Hz), 7.44
(1H, d, J = 2.0 Hz), 8.28 (1H, d, J = 8.4 Hz), 8.4
7 (1H, dd, J = 8.4, 0.8 Hz), 9.23-9.28 (1H, m), 9.
85 (1H, br) 実施例５ 1-(4-アミノピペリジノ)-4-(3-クロロ-4-メトキシベン
ジル)アミノ-6-シアノフタラジン・二塩酸塩Instead of 1-chloro-4- (3-chloro-4-methoxybenzyl) amino-6-cyanophthalazine in Example 3, 1-chloro-4- (3-chloro-4-methoxyphenethyl) amino-6- The title compound was obtained using cyanophthalazine. MASS (ESI); 447.1 (MH ⁺ ) ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ; 1.97-2.18 (4H, m), 2.94
-3.00 (2H, m), 3.11-3.23 (3H, m), 3.33-3.40 (2H, m
m), 3.72-3.80 (2H, m), 3.82 (3H, s), 7.09 (1H, d,
J = 8.4 Hz), 7.27 (1H, dd, J = 8.4, 2.0 Hz), 7.44
(1H, d, J = 2.0 Hz), 8.28 (1H, d, J = 8.4 Hz), 8.4
7 (1H, dd, J = 8.4, 0.8 Hz), 9.23-9.28 (1H, m), 9.
85 (1H, br) Example 5 1- (4-Aminopiperidino) -4- (3-chloro-4-methoxybenzyl) amino-6-cyanophthalazine dihydrochloride

【０１５２】[0152]

【化５６】 Embedded image

【０１５３】1-クロロ-4-(3-クロロ-4-メトキシベンジ
ル)アミノ-6-シアノフタラジン10.0ｇを1-メチル-2-ピ
ロリドン50mLに溶解し、4-ヒドロキシピペリジン43.32
g、ジイソプロピルエチルアミン10mLを加え、170℃で8
時間加熱した。冷後、酢酸エチルを加え、水で３回、飽
和食塩水で1回洗浄した。無水硫酸マグネシウムで乾燥
した後、減圧下溶媒を留去した。残渣をシリカゲルカラ
ムクロマトグラフィーで精製し、1-(4-ヒドロキシピペ
リジノ)-4-(3-クロロ-4-メトキシベンジル)アミノ-6-シ
アノフタラジンを黄色結晶として10.1g得た。1-Chloro-4- (3-chloro-4-methoxybenzyl) amino-6-cyanophthalazine 10.0 g was dissolved in 1-methyl-2-pyrrolidone 50 mL, and 4-hydroxypiperidine 43.32 was dissolved.
g, 10 mL of diisopropylethylamine, and
Heated for hours. After cooling, ethyl acetate was added, and the mixture was washed three times with water and once with saturated saline. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain 10.1 g of 1- (4-hydroxypiperidino) -4- (3-chloro-4-methoxybenzyl) amino-6-cyanophthalazine as yellow crystals.

【０１５４】次に1-(4-ヒドロキシピペリジノ)-4-(3-ク
ロロ-4-メトキシベンジル)アミノ-6-シアノフタラジン
4.2g、フタルイミド2.94g、トリフェニルホスフィン5.2
4gのテトラヒドロフラン100mL溶液に、氷冷下ジエチル
アゾジカルボキシラート3.48gのテトラヒドロフラン30m
L溶液を30分で滴下し、４℃で２４時間攪拌した。反応
液を減圧下濃縮し、水と酢酸エチルを加え、不溶物をろ
去した。有機層を濃縮し、残渣をシリカゲルカラムクロ
マトグラフィーで精製し、4-(3-クロロ-4-メトキシベン
ジル)アミノ-6-シアノ-1-(4-フタルイミドピペリジノ)
フタラジンを4.85g得た。Next, 1- (4-hydroxypiperidino) -4- (3-chloro-4-methoxybenzyl) amino-6-cyanophthalazine
4.2 g, phthalimide 2.94 g, triphenylphosphine 5.2
4 g of tetrahydrofuran 100 mL solution, diethyl azodicarboxylate 3.48 g of tetrahydrofuran 30 m under ice-cooling
The L solution was added dropwise over 30 minutes, and the mixture was stirred at 4 ° C. for 24 hours. The reaction solution was concentrated under reduced pressure, water and ethyl acetate were added, and the insoluble material was removed by filtration. The organic layer is concentrated, the residue is purified by silica gel column chromatography, and 4- (3-chloro-4-methoxybenzyl) amino-6-cyano-1- (4-phthalimidopiperidino)
4.85 g of phthalazine was obtained.

【０１５５】この4-(3-クロロ-4-メトキシベンジル)ア
ミノ-6-シアノ-1-(4-フタルイミドピペリジノ)フタラジ
ンを4.85g、ヒドラジン１水和物4mLとエタノール40mLの
混合物を１時間加熱還流した。反応液を減圧下濃縮し、
酢酸エチルに溶解し、1N塩酸を加え、pH=3とし、不溶物
をろ去した。ろ液の水層を1N水酸化ナトリウム水溶液で
pH=11とし、酢酸エチルで抽出した。有機層を飽和食塩
水で洗浄し、無水硫酸ナトリウムで乾燥し、減圧下濃縮
後、シリカゲルカラムクロマトグラフィーで精製し、生
成物をエタノール−水に懸濁し、1Ｎ塩酸水溶液を加え
加熱溶解した。冷後、析出した結晶をろ取し表記化合物
を黄色の粉末として440ｍｇ得た。 MASS(FAB)；423(MH⁺)¹ H-NMR(400 MHz, DMSO-d₆)δ;1.78-1.92 (2H, m), 2.03
-2.11 (2H, m), 2.90-3.0 (2H, m), 3.20-3.34 (1H,
m), 3.54-3.63 (2H, m), 3.82 (3H, s), 4.70 (2H,d, J
= 5.6 Hz), 7.13 (1H, d, J= 8.4 Hz), 7.47 (1H, dd,
J = 8.4, 2.0 Hz), 7.62 (1H, d, J = 2.0 Hz), 8.17
(1H, d, J = 8.4 Hz), 8.35-8.45 (2H, m),8.47 (1H, d
d, J = 8.4, 1.0 Hz), 9.54 (1H, d, J = 1.0 Hz), 10.
63 (1H, br )実施例６ 4-(3-クロロ-4-メトキシベンジル)アミノ-6-シアノ-1-
[4-ヒドロキシ-4-(ヒドロキシメチル)ピペリジノ]フタ
ラジン塩酸塩A mixture of 4.85 g of this 4- (3-chloro-4-methoxybenzyl) amino-6-cyano-1- (4-phthalimidopiperidino) phthalazine, 4 mL of hydrazine monohydrate and 40 mL of ethanol was added to the mixture. Heated to reflux for an hour. The reaction solution was concentrated under reduced pressure,
It was dissolved in ethyl acetate, 1N hydrochloric acid was added to adjust the pH to 3, and the insoluble matter was removed by filtration. The aqueous layer of the filtrate is treated with a 1N aqueous sodium hydroxide solution.
The mixture was adjusted to pH = 11 and extracted with ethyl acetate. The organic layer was washed with a saturated saline solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, purified by silica gel column chromatography, and the product was suspended in ethanol-water. After cooling, the precipitated crystals were collected by filtration to give 440 mg of the title compound as a yellow powder. MASS (FAB); 423 (MH ⁺ ) ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ; 1.78-1.92 (2H, m), 2.03
-2.11 (2H, m), 2.90-3.0 (2H, m), 3.20-3.34 (1H,
m), 3.54-3.63 (2H, m), 3.82 (3H, s), 4.70 (2H, d, J
= 5.6 Hz), 7.13 (1H, d, J = 8.4 Hz), 7.47 (1H, dd,
J = 8.4, 2.0 Hz), 7.62 (1H, d, J = 2.0 Hz), 8.17
(1H, d, J = 8.4 Hz), 8.35-8.45 (2H, m), 8.47 (1H, d
d, J = 8.4, 1.0 Hz), 9.54 (1H, d, J = 1.0 Hz), 10.
63 (1H, br) Example 6 4- (3-chloro-4-methoxybenzyl) amino-6-cyano-1-
[4-hydroxy-4- (hydroxymethyl) piperidino] phthalazine hydrochloride

【０１５６】[0156]

【化５７】 Embedded image

【０１５７】60％水素化ナトリウム7.9gをヘキサンで洗
浄後、減圧下乾燥した。ジメチルスルホキシド100mLを
加え、窒素雰囲気下、80〜100℃で30分間攪拌した。氷
冷し、テトラヒドロフラン180mLを加え、ヨウ化トリメ
チルスルホニウム43.7gのジメチルスルホキシド150mL溶
液を滴下した。氷冷下30分間攪拌後1-ベンジル-4-ピペ
リドン15gを加え、氷冷下30分間攪拌した後、室温で6時
間攪拌した。反応液に、水を加え、酢酸エチルで抽出し
た。有機層を飽和食塩水で洗浄後、無水硫酸ナトリウム
で乾燥した。シリカゲルカラムクロマトグラフィーで精
製し、6-ベンジル-1-オキソ-6-アザスピロ[2.5]オクタ
ンを6.8g得た。7.9 g of 60% sodium hydride was washed with hexane and dried under reduced pressure. 100 mL of dimethyl sulfoxide was added, and the mixture was stirred at 80 to 100 ° C. for 30 minutes under a nitrogen atmosphere. After cooling with ice, 180 mL of tetrahydrofuran was added, and a solution of 43.7 g of trimethylsulfonium iodide in 150 mL of dimethyl sulfoxide was added dropwise. After stirring for 30 minutes under ice cooling, 15 g of 1-benzyl-4-piperidone was added, and the mixture was stirred for 30 minutes under ice cooling, and then stirred at room temperature for 6 hours. Water was added to the reaction solution, which was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. Purification by silica gel column chromatography gave 6.8 g of 6-benzyl-1-oxo-6-azaspiro [2.5] octane.

【０１５８】この6-ベンジル-1-オキソ-6-アザスピロ
[2.5]オクタン6.8gのテトラヒドルフラン100mL溶液に、
水100mLと過塩素酸10mLを加え、室温で7時間攪拌した。
氷冷し、炭酸ナトリウム水溶液を加え、pH=7とし、減圧
下濃縮した。残渣に酢酸エチルを加え、不要物をろ去し
た。ろ液を減圧下濃縮後、シリカゲルカラムクロマトグ
ラフィーで精製し、1-ベンジル-4-(ヒドロキシメチル)-
4-ピペリジノールを4g得た。This 6-benzyl-1-oxo-6-azaspiro
[2.5] To a solution of 6.8 g of octane in 100 mL of tetrahydrofuran,
100 mL of water and 10 mL of perchloric acid were added, and the mixture was stirred at room temperature for 7 hours.
After cooling with ice, an aqueous solution of sodium carbonate was added to adjust the pH to 7, and the mixture was concentrated under reduced pressure. Ethyl acetate was added to the residue, and unnecessary substances were removed by filtration. The filtrate was concentrated under reduced pressure, and purified by silica gel column chromatography to give 1-benzyl-4- (hydroxymethyl)-
4 g of 4-piperidinol was obtained.

【０１５９】次に1-ベンジル-4-(ヒドロキシメチル)-4-
ピペリジノール1.46gをメタノール30mLに溶解し、酢酸1
0mLおよび10%Pd-Cを加え、４気圧で水素添加した。反応
液を、セライトでろ過し、ろ液を減圧下濃縮し、メタノ
ールに溶解し、4N塩酸-酢酸エチル溶液を加え、濃縮し
た。メタノール-酢酸エチルより結晶化させろ取し、4-
(ヒドロキシメチル)-4-ピペリジノール塩酸塩を880mg得
た。Next, 1-benzyl-4- (hydroxymethyl) -4-
Dissolve 1.46 g of piperidinol in 30 mL of methanol and add acetic acid 1
0 mL and 10% Pd-C were added and hydrogenated at 4 atm. The reaction solution was filtered through celite, the filtrate was concentrated under reduced pressure, dissolved in methanol, 4N hydrochloric acid-ethyl acetate solution was added, and the mixture was concentrated. Crystallize from methanol-ethyl acetate and collect by filtration.
880 mg of (hydroxymethyl) -4-piperidinol hydrochloride was obtained.

【０１６０】実施例３と同様にこの4-(ヒドロキシメチ
ル)-4-ピペリジノール塩酸塩と1-クロロ-4-(3-クロロ-4
-メトキシベンジル)アミノ-6-シアノフタラジンとを反
応させて標記化合物を得た。 MASS(FAB)；454.2(MH⁺)¹ H-NMR(400 MHz, DMSO-d₆)δ;1.46-1.54 (2H, m), 1.82
-1.94 (2H, m), 3.16-3.30 (6H, m), 3.84 (3H, s), 4.
68-4.72 (2H, m), 7.15 (1H, d, J = 8.6 Hz), 7.44 (1
H, dd, J = 8.6, 2.0 Hz), 7.59 (1H, d, J = 2.0 Hz),
8.22 (1H, d, J= 8.6 Hz), 8.45 (1H, dd, J = 8.6,
1.0 Hz), 9.36 (1H, d, J = 1.0 Hz) 実施例７ 4-(3-クロロ-4-メトキシベンジル)アミノ-6-シアノ-1-
[(2S)-2-(メトキシメチル)ピロリジノ]フタラジン塩酸
塩As in Example 3, 4- (hydroxymethyl) -4-piperidinol hydrochloride and 1-chloro-4- (3-chloro-4
Reaction with (-methoxybenzyl) amino-6-cyanophthalazine provided the title compound. MASS (FAB); 454.2 (MH ⁺ ) ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ; 1.46-1.54 (2H, m), 1.82
-1.94 (2H, m), 3.16-3.30 (6H, m), 3.84 (3H, s), 4.
68-4.72 (2H, m), 7.15 (1H, d, J = 8.6 Hz), 7.44 (1
H, dd, J = 8.6, 2.0 Hz), 7.59 (1H, d, J = 2.0 Hz),
8.22 (1H, d, J = 8.6 Hz), 8.45 (1H, dd, J = 8.6,
1.0 Hz), 9.36 (1H, d, J = 1.0 Hz) Example 7 4- (3-chloro-4-methoxybenzyl) amino-6-cyano-1-
[(2S) -2- (methoxymethyl) pyrrolidino] phthalazine hydrochloride

【０１６１】[0161]

【化５８】 Embedded image

【０１６２】製造例１の(Ｒ)-(+)-3-ヒドロキシピペリ
ジン塩酸塩の代わりに(S)-2-メトキシメチルピロリジン
を用いて標記化合物を得た。 MASS(ESI)；438.1(MH⁺)¹ H-NMR(400 MHz, DMSO-d₆)δ;1.81-1.89 (2H, m), 1.95
-2.03 (1H, m), 2.15-2.24 (1H, m), 3.16 (3H, s), 3.
28-3.37 (1H, m), 3.46-3.58 (2H, m), 3.84 (3H, s),
3.87-3.98 (1H, m), 4.44-4.57 (1H, m), 4.62-4.78 (2
H, m), 7.15 (1H,d, J= 8.6 Hz), 7.47 (1H, dd, J =
8.6, 0.4 Hz), 7.61 (1H, d, J = 0.4 Hz), 8.41-8.51
(2H, m), 9.42-9.60 (1H, m), 10.50 (1H, br), 13.79
(1H, br) 実施例８ 4-(3-クロロ-4-メトキシベンジル)アミノ-6-シアノ-1-
フェニルフタラジン塩酸塩The title compound was obtained by using (S) -2-methoxymethylpyrrolidine instead of (R)-(+)-3-hydroxypiperidine hydrochloride of Preparation Example 1. MASS (ESI); 438.1 (MH ⁺ ) ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ; 1.81-1.89 (2H, m), 1.95
-2.03 (1H, m), 2.15-2.24 (1H, m), 3.16 (3H, s), 3.
28-3.37 (1H, m), 3.46-3.58 (2H, m), 3.84 (3H, s),
3.87-3.98 (1H, m), 4.44-4.57 (1H, m), 4.62-4.78 (2
H, m), 7.15 (1H, d, J = 8.6 Hz), 7.47 (1H, dd, J =
8.6, 0.4 Hz), 7.61 (1H, d, J = 0.4 Hz), 8.41-8.51
(2H, m), 9.42-9.60 (1H, m), 10.50 (1H, br), 13.79
(1H, br) Example 8 4- (3-chloro-4-methoxybenzyl) amino-6-cyano-1-
Phenylphthalazine hydrochloride

【０１６３】[0163]

【化５９】 Embedded image

【０１６４】製造例１０のメトキシフェニルホウ酸の代
わりにフェニルホウ酸を用いて同様にして標記化合物を
得た。 MASS(ESI)；401.1(MH⁺)¹ H-NMR(400 MHz, DMSO-d₆)δ;3.84 (3H, s), 4.81-4.85
(2H, m), 7.15 (1H, d,J = 8.6 Hz), 7.48 (1H, dd, J
= 8.6, 2.1 Hz), 7.60-7.66 (6H, m), 8.00 (1H, d, J
= 8.6 Hz), 8.41 (1H, dd, J = 8.6, 0.9 Hz), 9.42
(1H, d, J = 0.9Hz) 実施例９ 4-[(3-クロロ-4-メトキシベンジル)アミノ]-1-(2-ヒド
ロキシ-7-アザスピロ[3.5]ノン-7-イル)-6-フタラジン
カルボニトリル塩酸塩The title compound was obtained in the same manner as in Preparation Example 10 except that phenylboric acid was used instead of methoxyphenylboric acid. MASS (ESI); 401.1 (MH ⁺ ) ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ; 3.84 (3H, s), 4.81-4.85
(2H, m), 7.15 (1H, d, J = 8.6 Hz), 7.48 (1H, dd, J
= 8.6, 2.1 Hz), 7.60-7.66 (6H, m), 8.00 (1H, d, J
= 8.6 Hz), 8.41 (1H, dd, J = 8.6, 0.9 Hz), 9.42
(1H, d, J = 0.9 Hz) Example 9 4-[(3-chloro-4-methoxybenzyl) amino] -1- (2-hydroxy-7-azaspiro [3.5] non-7-yl) -6 -Phthalazinecarbonitrile hydrochloride

【０１６５】[0165]

【化６０】 Embedded image

【０１６６】tert-ブトキシカリウム14.8 gとテトラヒ
ドロフラン300 mLの混合物にメチルトルフェニルホスホ
ニウムブロミド47.2 g、4-オキソ-1-ピペリジンカルボ
ン酸tert-ブチル21.9 gを加え、４０分室温で撹拌し
た。反応液を減圧下濃縮しジエチルエーテルを加え、セ
ライト濾過した。濾液を水及び飽和食塩水で洗浄し無水
硫酸マグネシウムで乾燥、濾過した。濾液を減圧下濃縮
し、残渣をシリカゲルカラムクロマトグラフィーに付し
4-メチレン-1-ピペリジンカルボン酸tert-ブチルを20.8
g得た。To a mixture of 14.8 g of potassium tert-butoxide and 300 mL of tetrahydrofuran were added 47.2 g of methyltoluphenylphosphonium bromide and 21.9 g of tert-butyl 4-oxo-1-piperidinecarboxylate, and the mixture was stirred at room temperature for 40 minutes. The reaction solution was concentrated under reduced pressure, diethyl ether was added, and the mixture was filtered through celite. The filtrate was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography.
20.8 tert-butyl 4-methylene-1-piperidinecarboxylate
g obtained.

【０１６７】亜鉛・銅合金157.2 gとジエチルエーテル5
00 mLの混合物に4-メチレン-1-ピペリジンカルボン酸te
rt-ブチル49.3 gを加え、塩化トリクロロアセチル181.8
gのジメトキシエタン900 mL溶液を５．５時間で滴下し
た。３０分撹拌後、冷却し、０℃以下で、飽和重曹水を
加えた。混合液をセライト濾過し、減圧下濃縮した。残
渣を酢酸エチルで抽出した。抽出液を飽和食塩水で洗浄
し、無水硫酸マグネシウムで乾燥、濾過した。濾液を減
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、1,1-ジクロロ-2-オキソ-7-アザスピロ[3.5]
ノナン-7-カルボン酸tert-ブチルを62.5 g得た。157.2 g of zinc-copper alloy and diethyl ether 5
4-methylene-1-piperidinecarboxylic acid te
49.3 g of rt-butyl was added, and trichloroacetyl chloride 181.8 g was added.
A solution of g in 900 mL of dimethoxyethane was added dropwise over 5.5 hours. After stirring for 30 minutes, the mixture was cooled, and a saturated aqueous solution of sodium bicarbonate was added at 0 ° C or lower. The mixture was filtered through celite and concentrated under reduced pressure. The residue was extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography to give 1,1-dichloro-2-oxo-7-azaspiro [3.5]
62.5 g of tert-butyl nonane-7-carboxylate was obtained.

【０１６８】1,1-ジクロロ-2-オキソ-7-アザスピロ[3.
5]ノナン-7-カルボン酸tert-ブチル62.5 gと飽和塩化ア
ンモニウムメタノール溶液500 mLの混合物に亜鉛粉末10
6.1 gを加えた。１時間２０分室温で撹拌し、セライト
濾過した。濾液を減圧下濃縮し、酢酸エチル１Ｎ塩酸を
加え、有機層を分取した。抽出液を水、飽和重曹水及び
飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥、濾
過した。濾液を減圧下濃縮し、残渣をシリカゲルカラム
クロマトグラフィーに付し2-オキソ-7-アザスピロノ[3.
5]ノナン-7-カルボン酸tert-ブチルを38.9 g得た。1,1-dichloro-2-oxo-7-azaspiro [3.
5] Zinc powder 10 in a mixture of 62.5 g of tert-butyl nonane-7-carboxylate and 500 mL of a saturated ammonium chloride methanol solution
6.1 g was added. The mixture was stirred at room temperature for 1 hour and 20 minutes, and filtered through celite. The filtrate was concentrated under reduced pressure, ethyl acetate 1N hydrochloric acid was added, and the organic layer was separated. The extract was washed with water, saturated aqueous sodium hydrogen carbonate and saturated saline, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography to give 2-oxo-7-azaspirono [3.
5] 38.9 g of tert-butyl nonane-7-carboxylate was obtained.

【０１６９】エタノール 300ml を氷冷し、水素化ホウ
素ナトリウム 6.13g を溶解させた。2-オキソ-7-アザス
ピロ[3.5]ノナン-7-カルボン酸tert-ブチル38.9gのエタ
ノール 100ml 溶液を２５分間かけて滴下した。反応液
を、飽和塩化アンモニウム水溶液にて処理し、減圧下で
濃縮した。残渣を酢酸エチルと水に分配し、酢酸エチル
層を飽和塩化ナトリウム水溶液にて洗浄し、硫酸マグネ
シウムにより乾燥した。濾過後、溶媒を減圧下に留去
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（ヘキサン-酢酸エチル）にて精製し、 2-ヒドロキシ
-7-アザスピロ[3.5]ノナン-7-カルボン酸tert-ブチル3
6.6ｇを得た。¹ H-NMR (CDCl₃)δ; 1.45 (9H, s), 1.43-1.57 (4H, m),
1.65-1.72 (2H, m), 3.27-3.35 (4H, m), 4.32 (1H, q
uint, J = 7.2 Hz) 2-ヒドロキシ-7-アザスピロ[3.5]ノナン-7-カルボン酸t
ert-ブチル 6.22g をテトラヒドロフラン 20ml に溶解
させ、この溶液に４規定塩化水素-ジオキサン溶液 80ml
を加え、室温にて1時間撹拌した。反応液を減圧下に濃
縮し、得られた残渣を1-メチル-2-ピロリジノン 20ml
に溶解させ、1-クロロ-4-[(3-クロロ-4-メトキシベンジ
ル)アミノ]-6-フタラジンカルボニトリル 4.67g 、ジイ
ソプロピルエチルアミン 6.72g を加え、160℃にて9時
間撹拌した。反応液を室温に戻し、酢酸エチルと水に分
配し、水層を酢酸エチルで抽出した。酢酸エチル層を合
わせて、水（5回）、飽和食塩水で順次洗浄し、硫酸マ
グネシウムで乾燥した。濾過後、溶媒を減圧下に留去
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（酢酸エチル-メタノール）にて精製し、 得られた粗
結晶をジエチルエーテル中で破砕洗浄し、黄色結晶4.86
ｇを得た。このものをエタノール 150ml に溶解し、４
規定塩化水素-ジオキサン溶液 15ml を加え、溶媒を減
圧下留去した。残渣をエタノール 150ml に溶解し、80
℃に加熱し、含水エタノールより別途合成した結晶にて
種づけを行い、結晶化が始まった時点で加熱を停止し
た。室温まで放冷した後、濾取及びエタノール洗浄を行
い、標記化合物 4.35g を得た。Ethanol (300 ml) was ice-cooled, and sodium borohydride (6.13 g) was dissolved. A solution of 38.9 g of tert-butyl 2-oxo-7-azaspiro [3.5] nonane-7-carboxylate in 100 ml of ethanol was added dropwise over 25 minutes. The reaction solution was treated with a saturated aqueous solution of ammonium chloride and concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water, and the ethyl acetate layer was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give 2-hydroxy
Tert-butyl 3-7-azaspiro [3.5] nonane-7-carboxylate
6.6 g were obtained. ¹ H-NMR (CDCl ₃ ) δ; 1.45 (9H, s), 1.43-1.57 (4H, m),
1.65-1.72 (2H, m), 3.27-3.35 (4H, m), 4.32 (1H, q
uint, J = 7.2 Hz) 2-hydroxy-7-azaspiro [3.5] nonane-7-carboxylic acid t
Dissolve 6.22 g of ert-butyl in 20 ml of tetrahydrofuran, and add 4 ml of 4N hydrogen chloride-dioxane solution
Was added and stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the obtained residue was 1-methyl-2-pyrrolidinone 20 ml.
And 4.67 g of 1-chloro-4-[(3-chloro-4-methoxybenzyl) amino] -6-phthalazinecarbonitrile and 6.72 g of diisopropylethylamine were added thereto, followed by stirring at 160 ° C. for 9 hours. The reaction solution was returned to room temperature, partitioned between ethyl acetate and water, and the aqueous layer was extracted with ethyl acetate. The ethyl acetate layers were combined, washed sequentially with water (5 times) and saturated saline, and dried over magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate-methanol). The obtained crude crystals were crushed and washed in diethyl ether to obtain yellow crystals (4.86).
g was obtained. Dissolve this in 150 ml of ethanol and add 4
15 ml of a normal hydrogen chloride-dioxane solution was added, and the solvent was distilled off under reduced pressure. Dissolve the residue in 150 ml of ethanol,
The mixture was heated to ° C. and seeded with crystals separately synthesized from aqueous ethanol, and the heating was stopped when crystallization started. After allowing to cool to room temperature, the crystals were collected by filtration and washed with ethanol to obtain 4.35 g of the title compound.

【０１７０】¹H-NMR (DMSO-d₆)δ; 1.58-1.66 (2H, m),
1.68-1.76 (4H, m), 2.14-2.22 (2H, m), 3.05-3.16
(4H, m), 3.83 (3H, s), 4.12 (1H, t, J = 7.2 Hz),
4.72 (2H, d, J = 5.6 Hz), 7.14 (1H, d, J = 8.8 H
z), 7.45 (1H, dd, J = 8.8, 2.0Hz), 7.60 (1H, d, J
= 2.0 Hz), 8.20 (1H, d, J = 8.4 Hz), 8.44 (1H, dd,
J = 8.4, 1.2 Hz), 9.46 (1H, s) 実施例１０ 4-[(3-クロロ-4-メトキシベンジル)アミノ]-1-(4-ピリ
ジル)-6-フタラジンカルボニトリル ¹ H-NMR (DMSO-d ₆ ) δ; 1.58-1.66 (2H, m),
1.68-1.76 (4H, m), 2.14-2.22 (2H, m), 3.05-3.16
(4H, m), 3.83 (3H, s), 4.12 (1H, t, J = 7.2 Hz),
4.72 (2H, d, J = 5.6 Hz), 7.14 (1H, d, J = 8.8 H
z), 7.45 (1H, dd, J = 8.8, 2.0Hz), 7.60 (1H, d, J
= 2.0 Hz), 8.20 (1H, d, J = 8.4 Hz), 8.44 (1H, dd,
J = 8.4, 1.2 Hz), 9.46 (1H, s) Example 10 4-[(3-chloro-4-methoxybenzyl) amino] -1- (4-pyridyl) -6-phthalazinecarbonitrile

【０１７１】[0171]

【化６１】 Embedded image

【０１７２】実施例１と同様にして標記化合物を得た。¹ H NMR (DMSO-d₆) δ; 3.80 (3H, s), 4.76 (2H, d, J
= 5.5 Hz), 7.10 (1H, d, J = 8.8 Hz), 7.38 (1H, dd,
J = 8.8, 2.4 Hz), 7.50 (1H, d, J = 2.4 Hz),7.64
(2H, d, J = 5.6 Hz), 7.94 (1H, d, J = 8.8 Hz), 8.2
0 (1H, d, J = 8.8 Hz), 8.52 (1H, dd, J =5.5, 5.5 H
z), 8.73 (2H, d, J = 5.6 Hz), 9.02(1H,s) 実施例１１ 4-[(3-クロロ-4-メトキシベンジル)アミノ]-1-(3-オキ
ソ-2-オキサ-8-アザスピロ[4.5]デセ-8-イル)-6-フタラ
ジンカルボニトリルThe title compound was obtained in the same manner as in Example 1. ¹ H NMR (DMSO-d ₆ ) δ; 3.80 (3H, s), 4.76 (2H, d, J
= 5.5 Hz), 7.10 (1H, d, J = 8.8 Hz), 7.38 (1H, dd,
J = 8.8, 2.4 Hz), 7.50 (1H, d, J = 2.4 Hz), 7.64
(2H, d, J = 5.6 Hz), 7.94 (1H, d, J = 8.8 Hz), 8.2
0 (1H, d, J = 8.8 Hz), 8.52 (1H, dd, J = 5.5, 5.5 H
z), 8.73 (2H, d, J = 5.6 Hz), 9.02 (1H, s) Example 11 4-[(3-chloro-4-methoxybenzyl) amino] -1- (3-oxo-2-oxa -8-Azaspiro [4.5] dec-8-yl) -6-phthalazinecarbonitrile

【０１７３】[0173]

【化６２】 Embedded image

【０１７４】2-オキソ-7-アザスピロ[3.5]ノナン-7-カ
ルボン酸tert-ブチル37.8 gのメタノール567 mL溶液を
氷水で冷却し、３０％過酸化水素水43 gを滴下した。１
N水酸化ナトリウム水溶液63 mLを滴下した。室温で２時
間撹拌した。反応液に酢酸エチル1000 mL、水600 mL、
飽和チオ硫酸ナトリウム、５水和物水溶液100 mLを加
え、有機層を分取した。抽出液を飽和食塩水で洗浄し、
無水硫酸マグネシウムで乾燥、濾過した。濾液を減圧下
濃縮し、3-オキソ-2-オキサ-8-アザスピロ[4.5]デカン-
8-カルボン酸tert-ブチルを28.4 g得た。A solution of 37.8 g of tert-butyl 2-oxo-7-azaspiro [3.5] nonane-7-carboxylate in 567 mL of methanol was cooled with ice water, and 43 g of 30% hydrogen peroxide was added dropwise. 1
63 mL of an aqueous solution of N sodium hydroxide was added dropwise. Stirred at room temperature for 2 hours. Ethyl acetate 1000 mL, water 600 mL,
100 mL of saturated sodium thiosulfate pentahydrate aqueous solution was added, and the organic layer was separated. Wash the extract with saturated saline,
The extract was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to give 3-oxo-2-oxa-8-azaspiro [4.5] decane-
28.4 g of tert-butyl 8-carboxylate was obtained.

【０１７５】3-オキソ-2-オキサ-8-アザスピロ[4.5]デ
カン-8-カルボン酸tert-ブチル1.16gをメタノール2.3 m
Lに溶解し、4N塩酸−酢酸エチル4.6 mLを加え、１時間
室温で撹拌した。酢酸エチル5 mL加え、析出している結
晶を濾取し3-オキソ-2-オキサ-8-アザスピロ[4.5]デカ
ン塩酸塩を700 mg得た。1-クロロ-4-[(3-クロロ-4-メト
キシベンジル)アミノ]-6-フタラジンカルボニトリル657
mg、3-オキソ-2-オキサ-8-アザスピロ[4.5]デカン塩酸
塩700 mg、ジエチルアニリン0.44 mL、ヨウ化ナトリウ
ム137 mgおよび1-メチル-2-ピロリジノン1.7 mLの混合
物を１３０℃で１５時間４０分撹拌した。冷後、反応液
にテトラヒドロフラン40 mL、酢酸エチル100 mLおよび1
-メチル-2-ピロリジノン15 mLを加え希釈し、飽和重曹
水、飽和食塩水で洗浄した。無水硫酸マグネシウムで乾
燥し濾過した。濾液を減圧下濃縮し、残渣をシリカゲル
カラムクロマトグラフィー精製し4-[(3-クロロ-4-メト
キシベンジル)アミノ]-1-(3-オキソ-2-オキサ-8-アザス
ピロ[4.5]デセ-8-イル)-6-フタラジンカルボニトリルを
713 mg得た。¹ H NMR(CDCl₃) δ; 1.88-2.01 (4H, m), 2.53 (2H, s),
3.22-3.40 (4H, m), 3.90 (3H, s), 4.20 (2H, s), 4.
77 (2H, d, J = 5.2 Hz), 5.20 (1H, t, J = 5.2Hz),
6.92 (1H, d, J = 8.4 Hz), 7.32 (1H, dd, J = 8.4,
2.0 Hz), 7.46 (1H, d, J = 2.0 Hz), 7.96 (1H, dd, J
= 8.4, 2.0 Hz), 8.11 (1H, d, J = 8.4 Hz), 8.14 (1
H, d, J = 0.8 Hz) 実施例１２ 4-[(3-クロロ-4-メトキシベンジル)アミノ]-1-(2-オキ
ソ-7-アザスピロ[3.5]ノン-7-イル)-6-フタラジンカル
ボニトリルTo a solution of 1.16 g of tert-butyl 3-oxo-2-oxa-8-azaspiro [4.5] decane-8-carboxylate in 2.3 m of methanol
The mixture was dissolved in L, and 4N hydrochloric acid-ethyl acetate (4.6 mL) was added, followed by stirring at room temperature for 1 hour. 5 mL of ethyl acetate was added, and the precipitated crystals were collected by filtration to obtain 700 mg of 3-oxo-2-oxa-8-azaspiro [4.5] decane hydrochloride. 1-chloro-4-[(3-chloro-4-methoxybenzyl) amino] -6-phthalazinecarbonitrile 657
mg, 3-oxo-2-oxa-8-azaspiro [4.5] decane hydrochloride 700 mg, diethylaniline 0.44 mL, a mixture of sodium iodide 137 mg and 1-methyl-2-pyrrolidinone 1.7 mL at 130 ° C. for 15 hours. Stir for 40 minutes. After cooling, add 40 mL of tetrahydrofuran, 100 mL of ethyl acetate and 1 mL of
-Methyl-2-pyrrolidinone (15 mL) was added for dilution, and the mixture was washed with saturated aqueous sodium hydrogen carbonate and saturated saline. It was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give 4-[(3-chloro-4-methoxybenzyl) amino] -1- (3-oxo-2-oxa-8-azaspiro [4.5] -8-yl) -6-phthalazinecarbonitrile
713 mg were obtained. _{^{1 H NMR (CDCl 3) δ}} ; 1.88-2.01 (4H, m), 2.53 (2H, s),
3.22-3.40 (4H, m), 3.90 (3H, s), 4.20 (2H, s), 4.
77 (2H, d, J = 5.2 Hz), 5.20 (1H, t, J = 5.2 Hz),
6.92 (1H, d, J = 8.4 Hz), 7.32 (1H, dd, J = 8.4,
2.0 Hz), 7.46 (1H, d, J = 2.0 Hz), 7.96 (1H, dd, J
= 8.4, 2.0 Hz), 8.11 (1H, d, J = 8.4 Hz), 8.14 (1
(H, d, J = 0.8 Hz) Example 12 4-[(3-chloro-4-methoxybenzyl) amino] -1- (2-oxo-7-azaspiro [3.5] non-7-yl) -6- Phthalazine carbonitrile

【０１７６】[0176]

【化６３】 Embedded image

【０１７７】4-[(3-クロロ-4-メトキシベンジル)アミ
ノ]-1-(2-ヒドロキシ-7-アザスピロ[3.5]ノン-7-イル)-
6-フタラジンカルボニトリル500 mgをジクロロメタン20
mLとテトラヒドロフラン10 mL中に懸濁し、1,1,1-トリ
アセトキシ-1,1-ジヒドロ-1,2-ベンズヨードキソール−
３（１Ｈ）−オン690 mg加え、室温で１５分撹拌した。
反応液に酢酸エチル、飽和重曹水30 mLと飽和チオ硫酸
ナトリウム、５水和物水溶液2 mLを加えた。有機層を分
取し、水層を酢酸エチルで抽出した。抽出液を合わせ、
飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥、濾
過した。濾液を減圧下濃縮し、残渣をシリカゲルカラム
クロマトグラフィーで精製し、エタノール中で結晶化さ
せ、ヘキサンを加え濾取し、4-[(3-クロロ-4-メトキシ
ベンジル)アミノ]-1-(2-オキソ-7-アザスピロ[3.5]ノン
-7-イル)-6-フタラジンカルボニトリルを420 mg得た。¹ H NMR(DMSO-d₆) δ; 1.90 (4H, m), 2.86 (4H, m), 3.
09 (4H, s), 3.80 (3H,s), 4.62 (2H, d, J = 5.6 Hz),
7.07 (1H, d, J = 8.5 Hz), 7.33 (1H, d, J =8.5 H
z), 7.44 (1H, s), 7.89 (1H, t, J = 5.6 Hz), 8.09
(1H, d, J = 8.0 Hz), 8.19 (1H, d, J = 8.0 Hz), 8.8
8 (1H, s) 実施例１３ 4-[(3-クロロ-4-メトキシベンジル)アミノ]-1-[4-ヒド
ロキシ-4-(1H-1-イミダゾリルメチル)ピペリジノ]-6-フ
タラジンカルボニトリル・二塩酸塩4-[(3-chloro-4-methoxybenzyl) amino] -1- (2-hydroxy-7-azaspiro [3.5] non-7-yl)-
6-phthalazinecarbonitrile 500 mg in dichloromethane 20
suspended in 10 mL of tetrahydrofuran and 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-
690 mg of 3 (1H) -one was added, and the mixture was stirred at room temperature for 15 minutes.
Ethyl acetate, 30 mL of saturated aqueous sodium bicarbonate and 2 mL of aqueous saturated sodium thiosulfate pentahydrate were added to the reaction solution. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. Combine the extracts,
The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and filtered. The filtrate is concentrated under reduced pressure, the residue is purified by silica gel column chromatography, crystallized in ethanol, hexane is added and collected by filtration, and 4-[(3-chloro-4-methoxybenzyl) amino] -1- ( 2-oxo-7-azaspiro [3.5] non
420 mg of -7-yl) -6-phthalazinecarbonitrile was obtained. ¹ H NMR (DMSO-d ₆ ) δ; 1.90 (4H, m), 2.86 (4H, m), 3.
09 (4H, s), 3.80 (3H, s), 4.62 (2H, d, J = 5.6 Hz),
7.07 (1H, d, J = 8.5 Hz), 7.33 (1H, d, J = 8.5 H
z), 7.44 (1H, s), 7.89 (1H, t, J = 5.6 Hz), 8.09
(1H, d, J = 8.0 Hz), 8.19 (1H, d, J = 8.0 Hz), 8.8
8 (1H, s) Example 13 4-[(3-chloro-4-methoxybenzyl) amino] -1- [4-hydroxy-4- (1H-1-imidazolylmethyl) piperidino] -6-phthalazinecarbo Nitrile dihydrochloride

【０１７８】[0178]

【化６４】 Embedded image

【０１７９】¹H NMR (DMSO-d₆) δ; 1.49 (2H, d, J =
12.4 Hz), 1.82-1.93 (2H, m), 3.13(2H, t, J = 10.8
Hz), 3.37 (2H, d, J = 12.4Hz), 3.82 (3H, s), 4.30
(2H,s), 4.74 (2H, d, J = 5.6 Hz), 7.13 (1H, d, J =
8.8 Hz), 7.48 (1H, dd, J= 2.0, 8.4 Hz), 7.63 (1H,
d, J = 2.0 Hz), 7.66-7.71 (2H, m), 8.18 (1H, d, J
= 8.4 Hz), 8.48 (1H, d, J = 8.4 Hz), 9.10 (1H,
s), 9.60 (1H, s). 実施例１4 4-[(3-クロロ-4-メトキシベンジル)アミノ]-1-[4-ヒド
ロキシ-4-(1H-1,2,4-トリアゾール-1-イルメチル)ピペ
リジノ]-6-フタラジンカルボニトリル・二塩酸塩 ¹ H NMR (DMSO-d ₆ ) δ; 1.49 (2H, d, J =
12.4 Hz), 1.82-1.93 (2H, m), 3.13 (2H, t, J = 10.8
Hz), 3.37 (2H, d, J = 12.4Hz), 3.82 (3H, s), 4.30
(2H, s), 4.74 (2H, d, J = 5.6 Hz), 7.13 (1H, d, J =
8.8 Hz), 7.48 (1H, dd, J = 2.0, 8.4 Hz), 7.63 (1H,
d, J = 2.0 Hz), 7.66-7.71 (2H, m), 8.18 (1H, d, J
= 8.4 Hz), 8.48 (1H, d, J = 8.4 Hz), 9.10 (1H,
s), 9.60 (1H, s). Example 14 4-[(3-chloro-4-methoxybenzyl) amino] -1- [4-hydroxy-4- (1H-1,2,4-triazole-1 -Ylmethyl) piperidino] -6-phthalazinecarbonitrile dihydrochloride

【０１８０】[0180]

【化６５】 Embedded image

【０１８１】¹H NMR (DMSO-d₆) δ; 1.54 (2H, d, J =
12.8 Hz), 1.82-1.92 (2H, m), 3.15(2H, t, J = 11.2
Hz), 3.35 (2H, d, J = 12.8Hz), 3.82 (3H, s), 4.29
(2H,s), 4.73 (2H, d, J = 6.0 Hz), 7.13 (1H, d, J =
8.4 Hz), 7.48 (1H, dd, J= 2.0, 8.4 Hz), 7.62 (1H,
d, J = 2.0 Hz), 8.20 (1H, d, J = 8.4 Hz), 8.21(1
H, s), 8.45 (1H, dd, J = 1.2, 8.4 Hz), 8.79 (1H,
s), 9.56 (1H, s), 10.75 (1H, br.s) 実施例１５ 1-[4-[(3-クロロ-4-メトキシベンジル)アミノ]-6-(1H-
1,2,3,4-テロラアゾール-5-イル)-1-フタラジニル]-4-
ピペリジノール ¹ H NMR (DMSO-d ₆ ) δ; 1.54 (2H, d, J =
12.8 Hz), 1.82-1.92 (2H, m), 3.15 (2H, t, J = 11.2
Hz), 3.35 (2H, d, J = 12.8Hz), 3.82 (3H, s), 4.29
(2H, s), 4.73 (2H, d, J = 6.0 Hz), 7.13 (1H, d, J =
8.4 Hz), 7.48 (1H, dd, J = 2.0, 8.4 Hz), 7.62 (1H,
d, J = 2.0 Hz), 8.20 (1H, d, J = 8.4 Hz), 8.21 (1
H, s), 8.45 (1H, dd, J = 1.2, 8.4 Hz), 8.79 (1H,
s), 9.56 (1H, s), 10.75 (1H, br.s) Example 15 1- [4-[(3-chloro-4-methoxybenzyl) amino] -6- (1H-
1,2,3,4-teloraazol-5-yl) -1-phthalazinyl] -4-
Piperidinol

【０１８２】[0182]

【化６６】 Embedded image

【０１８３】4-[(3-クロロ-4-メトキシベンジル)アミ
ノ]-1-(4-ヒドロキシピペリジノ)-6-フタラジンカルボ
ニトリル1.0 g、トリエチルアミン塩酸塩1.2 g、1-メチ
ル-2-ピロリジノン20 mLの混合物にアジ化ナトリウム0.
55 gを加え、１００℃で８時間撹拌した。反応液を室温
に戻し、水を加え、析出した結晶を濾取し、標記化合物
を1.0 g得た。¹ H NMR (DMSO-d₆) δ; 1.58-1.7 (2H, m), 1.8-1.97
(2H, m), 2.8-2.98 (2H,m), 3.3-3.43 (2H, m), 3.6-3.
7 (1H, m), 3.79 (3H, s), 4.6 (2H, s), 7.06 (1H, d,
J = 8 Hz), 7.34 (1H, d, J = 8 Hz), 7.45 (1H, s),
7.95 (1H, d, J =8 Hz), 8.45 (1H, d, J = 8 Hz), 8.8
9 (1H, s) 実施例１６ 1-[4-[(3-クロロ-4-メトキシベンジル)アミノ]-6-(1-メ
チル-1H-1,2,3,4-テロラアゾール-5-イル)-1-フタラジ
ニル]-4-ピペリジノール4-[(3-chloro-4-methoxybenzyl) amino] -1- (4-hydroxypiperidino) -6-phthalazinecarbonitrile 1.0 g, triethylamine hydrochloride 1.2 g, 1-methyl-2 -Sodium azide in a mixture of 20 mL of pyrrolidinone.
55 g was added, and the mixture was stirred at 100 ° C. for 8 hours. The reaction solution was returned to room temperature, water was added, and the precipitated crystals were collected by filtration to obtain 1.0 g of the title compound. ¹ H NMR (DMSO-d ₆ ) δ; 1.58-1.7 (2H, m), 1.8-1.97
(2H, m), 2.8-2.98 (2H, m), 3.3-3.43 (2H, m), 3.6-3.
7 (1H, m), 3.79 (3H, s), 4.6 (2H, s), 7.06 (1H, d,
J = 8 Hz), 7.34 (1H, d, J = 8 Hz), 7.45 (1H, s),
7.95 (1H, d, J = 8 Hz), 8.45 (1H, d, J = 8 Hz), 8.8
9 (1H, s) Example 16 1- [4-[(3-chloro-4-methoxybenzyl) amino] -6- (1-methyl-1H-1,2,3,4-teloraazol-5-yl ) -1-Phthalazinyl] -4-piperidinol

【０１８４】[0184]

【化６７】 Embedded image

【０１８５】1-[4-[(3-クロロ-4-メトキシベンジル)ア
ミノ]-6-(1H-1,2,3,4-テロラアゾール-5-イル)-1-フタ
ラジニル]-4-ピペリジノール0.25 g、炭酸カリウム1.2
g及びジメチルホルムアミド5 mLの混合物にヨウ化メチ
ル0.037 mLを加え、室温で３時間撹拌した。反応液に水
を加え、析出した不溶物を濾取した。シリカゲルカラム
クロマトグラフィーで精製し標記化合物を50 mg得た。¹ H NMR (DMSO-d₆) δ; 1.6-1.7 (2H, m), 1.85-1.95 (2
H, m), 2.85-2.95 (2H,m), 3.25-3.45 (2H, m), 3.6-3.
7 (1H, m), 3.80 (3H, s), 4.48 (3H, s), 4.61(2H, d,
J = 5.6 Hz), 4.73 (1H, d, J = 4.0 Hz), 7.07 (1H,
d, J = 8.4 Hz), 7.34 (1H, dd, J = 2.0, 8.4 Hz), 7.
44 (1H, d, J = 2.0 Hz), 8.07 (1H, t,J = 5.6 Hz),
8.10 (1H, d, J = 8.4 Hz), 8.47 (1H, d, J = 8.8 H
z), 9.00 (1H, s) 実施例１７ 4-[(3-クロロ-4-メトキシベンジル)アミノ]-1-(4-ヒド
ロキシピペリジノ)-6-フタラジンカルボチアミド1- [4-[(3-chloro-4-methoxybenzyl) amino] -6- (1H-1,2,3,4-tellorazol-5-yl) -1-phthalazinyl] -4-piperidinol 0.25 g, potassium carbonate 1.2
g and dimethylformamide (5 mL) were added to methyl iodide (0.037 mL), and the mixture was stirred at room temperature for 3 hours. Water was added to the reaction solution, and the precipitated insolubles were collected by filtration. Purification by silica gel column chromatography gave 50 mg of the title compound. ¹ H NMR (DMSO-d ₆ ) δ; 1.6-1.7 (2H, m), 1.85-1.95 (2
H, m), 2.85-2.95 (2H, m), 3.25-3.45 (2H, m), 3.6-3.
7 (1H, m), 3.80 (3H, s), 4.48 (3H, s), 4.61 (2H, d,
J = 5.6 Hz), 4.73 (1H, d, J = 4.0 Hz), 7.07 (1H,
d, J = 8.4 Hz), 7.34 (1H, dd, J = 2.0, 8.4 Hz), 7.
44 (1H, d, J = 2.0 Hz), 8.07 (1H, t, J = 5.6 Hz),
8.10 (1H, d, J = 8.4 Hz), 8.47 (1H, d, J = 8.8 H
z), 9.00 (1H, s) Example 17 4-[(3-chloro-4-methoxybenzyl) amino] -1- (4-hydroxypiperidino) -6-phthalazinecarbothiamide

【０１８６】[0186]

【化６８】 Embedded image

【０１８７】4-[(3-クロロ-4-メトキシベンジル)アミ
ノ]-1-(ヒドロキシピペリジノ)-6-フタラジンカルボニ
トリル2.0 g、水1 mL、イソプロパノール2 mLの混合物
にジチオりん酸ジエチル3.7 mLを加え、１時間加熱還流
した。冷後、反応液に水を加え、析出した結晶を濾取し
た。濾液を酢酸エチルで抽出し、飽和食塩水で洗浄し
た。無水硫酸ナトリウムで乾燥、濾過した。濾液を減圧
下濃縮し、得られた結晶性残渣を上記で濾取した結晶と
合わせ標記化合物を1.5 g得た。¹ H NMR (DMSO-d₆) δ; 1.6-1.7 (2H, m), 1.85-2.00 (2
H, m), 2.90-3.1 (2H, m), 3.3-3.5 (2H, m), 3.6-3.8
(1H, m), 3.81 (3H, s), 4.68 (2H, d, J = 4 Hz), 7.1
3 (1H, d, J = 8 Hz), 7.40 (1H, d, J = 8 Hz), 7.54
(1H, s), 8.08 (1H, d, J = 8 Hz), 8.3-8.4 (1H, m),
8.9-9.1 (1H, m), 9.88 (1H, s), 10.33 (1H, s) 実施例１８ 1-[4-[(3-ブロモ-4-メトキシベンジル)アミノ]-6-(4-メ
チル-1,3-チアゾール-2-イル)-1-フタラジニル]-4-ピペ
リジノールDithiophosphoric acid was added to a mixture of 4-[(3-chloro-4-methoxybenzyl) amino] -1- (hydroxypiperidino) -6-phthalazinecarbonitrile (2.0 g), water (1 mL) and isopropanol (2 mL). 3.7 mL of diethyl was added, and the mixture was heated under reflux for 1 hour. After cooling, water was added to the reaction solution, and the precipitated crystals were collected by filtration. The filtrate was extracted with ethyl acetate and washed with saturated saline. Dry over anhydrous sodium sulfate and filter. The filtrate was concentrated under reduced pressure, and the obtained crystalline residue was combined with the crystals collected by filtration above to give 1.5 g of the title compound. ¹ H NMR (DMSO-d ₆ ) δ; 1.6-1.7 (2H, m), 1.85-2.00 (2
H, m), 2.90-3.1 (2H, m), 3.3-3.5 (2H, m), 3.6-3.8
(1H, m), 3.81 (3H, s), 4.68 (2H, d, J = 4 Hz), 7.1
3 (1H, d, J = 8 Hz), 7.40 (1H, d, J = 8 Hz), 7.54
(1H, s), 8.08 (1H, d, J = 8 Hz), 8.3-8.4 (1H, m),
8.9-9.1 (1H, m), 9.88 (1H, s), 10.33 (1H, s) Example 18 1- [4-[(3-bromo-4-methoxybenzyl) amino] -6- (4-methyl -1,3-thiazol-2-yl) -1-phthalazinyl] -4-piperidinol

【０１８８】[0188]

【化６９】 Embedded image

【０１８９】4-[(3-クロロ-4-メトキシベンジル)アミ
ノ]-1-(4-ヒドロキシピペリジノ)-6-フタラジンカルボ
チアミド1.5 gをジメチルホルムアミド50 mLに溶解し、
クロロアセトン1.1 mLを加え、１００℃で４時間撹拌し
た。冷後、反応液に水を加え、デカンテーションで水層
を除いた。残渣を減圧乾燥後、シリカゲルカラムクロマ
トグラフィーで精製し標記化合物を200 mg得た。¹ H NMR (DMSO-d₆) δ; 1.6-1.7 (2H, m), 1.85-1.95 (2
H, m), 2.47 (3H, s), 2.83-2.94 (2H, m), 3.3-3.4 (2
H, m), 3.6-3.7 (1H, m), 3.80 (3H, s), 4.63 (2H, d,
J = 5.6 Hz), 4.72 (1H, d, J = 4.0 Hz), 7.07 (1H,
d, J = 8.4 Hz),7.34 (1H, dd, J = 2.0, 8.4 Hz), 7.4
4 (1H, d, J = 2.0 Hz), 7.48 (1H, s),7.96-8.04 (1H,
m), 8.01 (1H, d, J = 8.4 Hz), 8.36 (1H, dd, J =
1.6, 8.4Hz), 8.76 (1H, d, J = 1.6Hz) 実施例１９ 1-[4-[(3-クロロ-4-メトキシベンジル)アミノ]-6-(2-チ
エニル)-1-フタラジニル]-4-ピペリジノール塩酸塩1.5 g of 4-[(3-chloro-4-methoxybenzyl) amino] -1- (4-hydroxypiperidino) -6-phthalazinecarboticamide was dissolved in 50 mL of dimethylformamide.
1.1 mL of chloroacetone was added, and the mixture was stirred at 100 ° C for 4 hours. After cooling, water was added to the reaction solution, and the aqueous layer was removed by decantation. The residue was dried under reduced pressure, and purified by silica gel column chromatography to obtain 200 mg of the title compound. ¹ H NMR (DMSO-d ₆ ) δ; 1.6-1.7 (2H, m), 1.85-1.95 (2
H, m), 2.47 (3H, s), 2.83-2.94 (2H, m), 3.3-3.4 (2
H, m), 3.6-3.7 (1H, m), 3.80 (3H, s), 4.63 (2H, d,
J = 5.6 Hz), 4.72 (1H, d, J = 4.0 Hz), 7.07 (1H,
d, J = 8.4 Hz), 7.34 (1H, dd, J = 2.0, 8.4 Hz), 7.4
4 (1H, d, J = 2.0 Hz), 7.48 (1H, s), 7.96-8.04 (1H,
m), 8.01 (1H, d, J = 8.4 Hz), 8.36 (1H, dd, J =
1.6, 8.4 Hz), 8.76 (1H, d, J = 1.6 Hz) Example 19 1- [4-[(3-chloro-4-methoxybenzyl) amino] -6- (2-thienyl) -1-phthalazinyl ] -4-Piperidinol hydrochloride

【０１９０】[0190]

【化７０】 Embedded image

【０１９１】1-[6-ブロモ-4-[(3-ブロモ-4-メトキシベ
ンジル)アミノ]-1-フタラジニル]-4-ピペリジノール200
mgとトルエン2 mLの混合物にテトラキス（トリフェニ
ルホスフィン）パラジウム（０）24 mg、2-(トリブチル
スタニル)チオフェン1.4 mLを加えた。２時間加熱還流
した。冷後、反応液を氷水に注ぎ酢酸エチルで抽出し
た。抽出液を無水硫酸マグネシウムで乾燥、濾過した。
濾液を減圧下濃縮し、残渣をシリカゲルカラムクロマト
グラフィーにより精製した。４Ｎ塩酸−酢酸エチルによ
り塩酸塩とすることにより標記化合物を73 mg得た。¹ H NMR (DMSO-d₆) δ; 1.67 (2H, m), 1.92 (2H, m),
3.00 (2H, m), 3.45 (2H,m), 3.74 (1H, m), 3.82 (3H,
s), 4.73 (2H, m), 7.13 (1H, d, J = 7.2 Hz),7.27
(1H, s), 7.46 (1H, d, J = 7.2 Hz), 7.61 (1H, s),
7.79 (1H, d, J =5.6 Hz), 8.03 (1H, d, J = 5.6 Hz),
8.09 (1H, d, J = 8.8 Hz), 8.34 (1H, d, J = 8.8 H
z), 9.20 (1H, brs) 実施例２０ 4-[(3-クロロ-4-メトキシベンジル)アミノ]-1-(4-ヒド
ロキシピペリジノ)-6-フタラジンカルバルデヒド オキ
シム塩酸塩1- [6-bromo-4-[(3-bromo-4-methoxybenzyl) amino] -1-phthalazinyl] -4-piperidinol 200
24 mg of tetrakis (triphenylphosphine) palladium (0) and 1.4 mL of 2- (tributylstannyl) thiophene were added to a mixture of mg and 2 mL of toluene. The mixture was heated under reflux for 2 hours. After cooling, the reaction solution was poured into ice water and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and filtered.
The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography. 73 mg of the title compound was obtained by making the hydrochloride with 4N hydrochloric acid-ethyl acetate. ¹ H NMR (DMSO-d ₆ ) δ; 1.67 (2H, m), 1.92 (2H, m),
3.00 (2H, m), 3.45 (2H, m), 3.74 (1H, m), 3.82 (3H,
s), 4.73 (2H, m), 7.13 (1H, d, J = 7.2 Hz), 7.27
(1H, s), 7.46 (1H, d, J = 7.2 Hz), 7.61 (1H, s),
7.79 (1H, d, J = 5.6 Hz), 8.03 (1H, d, J = 5.6 Hz),
8.09 (1H, d, J = 8.8 Hz), 8.34 (1H, d, J = 8.8 H
z), 9.20 (1H, brs) Example 20 4-[(3-chloro-4-methoxybenzyl) amino] -1- (4-hydroxypiperidino) -6-phthalazinecarbaldehyde oxime hydrochloride

【０１９２】[0192]

【化７１】 Embedded image

【０１９３】4-[(3-クロロ-4-メトキシベンジル)アミ
ノ]-1-(4-ヒドロキシピペリジノ)-6-フタラジンカルボ
ニトリル10.0 gおよびｔ−ブチルジメチルクロロシラン
5.3 gをジメチルホルムアミド80 mLに溶解し、イミダゾ
ール4.8 gを加えた。室温で一夜撹拌した。反応液に酢
酸エチルを加え、水で一回、飽和食塩水で二回洗浄し
た。無水硫酸マグネシウムで乾燥し、濾過した。濾液を
減圧下濃縮し、1-[4-[[1-(tert-ブチル)-1,1-ジメチル
シリル]オキシ]ピペリジノ]-4-[(3-クロロ-4-メトキシ
ベンジル)アミノ]-6-フタラジンカルボニトリルを11.7
g得た。4-[(3-chloro-4-methoxybenzyl) amino] -1- (4-hydroxypiperidino) -6-phthalazinecarbonitrile 10.0 g and t-butyldimethylchlorosilane
5.3 g was dissolved in dimethylformamide (80 mL), and imidazole (4.8 g) was added. Stirred overnight at room temperature. Ethyl acetate was added to the reaction solution, and the mixture was washed once with water and twice with a saturated saline solution. Dried over anhydrous magnesium sulfate and filtered. The filtrate is concentrated under reduced pressure, and 1- [4-[[1- (tert-butyl) -1,1-dimethylsilyl] oxy] piperidino] -4-[(3-chloro-4-methoxybenzyl) amino]- 6-phthalazine carbonitrile 11.7
g obtained.

【０１９４】1-[4-[[1-(tert-ブチル)-1,1-ジメチルシ
リル]オキシ]ピペリジノ]-4-[(3-クロロ-4-メトキシベ
ンジル)アミノ]-6-フタラジンカルボニトリル11.7 gを
塩化メチレン150 mLに溶解し、冷却した。−７８℃で１
Ｍ水素化ジイソブチルアルミニウムのトルエン溶液44 m
Lを加えた。室温に戻し、一夜撹拌した。飽和塩化アン
モニウム水溶液100 mLを加え、室温で０．５時間撹拌し
た。10%硫酸40 mLを加え、酢酸エチルで抽出した。抽出
液を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥
し、濾過した。濾液を減圧下濃縮し、残渣をシリカゲル
カラムクロマトグラフィーで精製し、1-[4-[[1-(tert-
ブチル)-1,1-ジメチルシリル]オキシ]ピペリジノ]-4-
[(3-クロロ-4-メトキシベンジル)アミノ]-6-フタラジン
カルボアルデヒドを5.3 g得た。1- [4-[[1- (tert-butyl) -1,1-dimethylsilyl] oxy] piperidino] -4-[(3-chloro-4-methoxybenzyl) amino] -6-phthalazine 11.7 g of carbonitrile was dissolved in 150 mL of methylene chloride and cooled. 1 at -78 ° C
M diisobutylaluminum hydride in toluene 44 m
L was added. It returned to room temperature and stirred overnight. 100 mL of a saturated ammonium chloride aqueous solution was added, and the mixture was stirred at room temperature for 0.5 hour. 40 mL of 10% sulfuric acid was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, the residue was purified by silica gel column chromatography, and 1- [4-[[1- (tert-
Butyl) -1,1-dimethylsilyl] oxy] piperidino] -4-
[(3-chloro-4-methoxybenzyl) amino] -6-phthalazinecarbaldehyde was obtained in an amount of 5.3 g.

【０１９５】1-[4-[[1-(tert-ブチル)-1,1-ジメチルシ
リル]オキシ]ピペリジノ]-4-[(3-クロロ-4-メトキシベ
ンジル)アミノ]-6-フタラジンカルボアルデヒド1.5 gと
ヒドロキシルアミン塩酸塩0.35 gをメタノール50 mLに
溶解し、２時間加熱還流した。冷後、水を加え、酢酸エ
チルで抽出した。抽出液を飽和食塩水で洗浄し、無水硫
酸マグネシウムで乾燥し、濾過した。濾液を減圧下濃縮
し、残渣をシリカゲルカラムクロマトグラフィーで精製
し、1-[4-[[1-(tert-ブチル)-1,1-ジメチルシリル]オキ
シ]ピペリジノ]-4-[(3-クロロ-4-メトキシベンジル)ア
ミノ]-6-フタラジンカルバルデヒド オキシムを1.18 g
得た。1- [4-[[1- (tert-butyl) -1,1-dimethylsilyl] oxy] piperidino] -4-[(3-chloro-4-methoxybenzyl) amino] -6-phthalazine 1.5 g of carbaldehyde and 0.35 g of hydroxylamine hydrochloride were dissolved in 50 mL of methanol and heated under reflux for 2 hours. After cooling, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, the residue was purified by silica gel column chromatography, and 1- [4-[[1- (tert-butyl) -1,1-dimethylsilyl] oxy] piperidino] -4-[(3- 1.18 g of chloro-4-methoxybenzyl) amino] -6-phthalazinecarbaldehyde oxime
Obtained.

【０１９６】1-[4-[[1-(tert-ブチル)-1,1-ジメチルシ
リル]オキシ]ピペリジノ]-4-[(3-クロロ-4-メトキシベ
ンジル)アミノ]-6-フタラジンカルボアルデヒド オキシ
ム1.18 gのテトラヒドロフラン30 mL溶液にテトラブチ
ルアンモニウムフルオリドのテトラヒドロフラン１Ｍ溶
液を加えた。室温で一夜撹拌した。反応液に水を加え、
酢酸エチルで抽出した。抽出液を飽和食塩水で洗浄し、
無水硫酸マグネシウムで乾燥し、濾過した。濾液を減圧
下濃縮し、結晶性残渣を酢酸エチルで洗浄し、ろ取し標
記化合物を0.34 g得た。常法により塩酸塩とした。¹ H NMR (DMSO-d₆) δ; 1.58-1.70 (2H, m), 1.86-1.95
(2H, m), 2.92-3.02 (2H, m), 3.08-3.22 (2H, m), 3.6
4-3.73 (1H, m), 3.82 (3H, s), 4.61-4.68 (2H,m), 4.
77-4.79 (1H, m), 7.10 (1H, d, J = 8 Hz), 7.38 (1H,
d, J = 8 Hz),7.51 (1H, s), 8.06 (1H, d, J = 8 H
z), 8.23 (1H, d, J = 8 Hz), 8.28 (1H,s), 8.69-8.76
(1H, m) 実施例２１ 4-[(3-クロロ-4-メトキシベンジル)アミノ]-1-[(2R)-2-
(ヒドロキシメチル)-1-オキサ-8-アザスピロ[4.5]デカ-
8-イル]-6-フタラジンカルボニトリル塩酸塩1- [4-[[1- (tert-butyl) -1,1-dimethylsilyl] oxy] piperidino] -4-[(3-chloro-4-methoxybenzyl) amino] -6-phthalazine To a solution of 1.18 g of carbaldehyde oxime in 30 mL of tetrahydrofuran was added a 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran. Stirred overnight at room temperature. Add water to the reaction solution,
Extracted with ethyl acetate. Wash the extract with saturated saline,
Dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the crystalline residue was washed with ethyl acetate and collected by filtration to obtain 0.34 g of the title compound. It was converted into a hydrochloride by a conventional method. ¹ H NMR (DMSO-d ₆ ) δ; 1.58-1.70 (2H, m), 1.86-1.95
(2H, m), 2.92-3.02 (2H, m), 3.08-3.22 (2H, m), 3.6
4-3.73 (1H, m), 3.82 (3H, s), 4.61-4.68 (2H, m), 4.
77-4.79 (1H, m), 7.10 (1H, d, J = 8 Hz), 7.38 (1H,
d, J = 8 Hz), 7.51 (1H, s), 8.06 (1H, d, J = 8 H
z), 8.23 (1H, d, J = 8 Hz), 8.28 (1H, s), 8.69-8.76
(1H, m) Example 21 4-[(3-chloro-4-methoxybenzyl) amino] -1-[(2R) -2-
(Hydroxymethyl) -1-oxa-8-azaspiro [4.5] deca-
8-yl] -6-phthalazinecarbonitrile hydrochloride

【０１９７】[0197]

【化７２】 Embedded image

【０１９８】1-クロロ-4-[(3-クロロ-4-メトキシベンジ
ル)アミノ]-6-フタラジンカルボニトリル1.08gおよび(2
R)-1-オキサ-8-アザスピロ[4.5]デカ-2-イルメタノール
0.76gをN-メチル-2-ピロリドン20mlに溶かし、160℃で
５時間撹拌した。反応終了後、室温に戻し水および飽和
重曹水を加え、酢酸エチルで抽出し、飽和食塩水で３回
洗浄した。硫酸マグネシウムで乾燥後、溶媒を除き、シ
リカゲルカラムクロマトグラフィーで精製して結晶性化
合物0.60gを得た。1.08 g of 1-chloro-4-[(3-chloro-4-methoxybenzyl) amino] -6-phthalazinecarbonitrile and (2
R) -1-oxa-8-azaspiro [4.5] dec-2-ylmethanol
0.76 g was dissolved in 20 ml of N-methyl-2-pyrrolidone and stirred at 160 ° C. for 5 hours. After completion of the reaction, the mixture was returned to room temperature, water and saturated aqueous sodium hydrogencarbonate were added, extracted with ethyl acetate, and washed three times with saturated saline. After drying over magnesium sulfate, the solvent was removed and purification was performed by silica gel column chromatography to obtain 0.60 g of a crystalline compound.

【０１９９】これをエタノール20mlに溶かし、1N塩酸エ
タノール溶液1.40mlを室温で加え,10分間撹拌した。溶
媒を除き、ジイソプロピルエーテルで処理した後、乾燥
させて標記化合物555mgを得た。¹ H NMR (DMSO-d₆) δ; 1.67-1.98 (8H, m), 3.15-3.40
(6H, m), 3.82 (3H, s),3.90-3.98 (1H, m), 4.68-4.77
(2H, m), 7.14(1H, d, J = 9Hz), 7.46 (1H, dd, J =
2, 9Hz), 7.62 (1H, d, J = 2Hz), 8.23 (1H, d, J = 9
Hz), 8.45 (1H,d, J = 9Hz), 9.50 (1H, s) 実施例２２ (anti)-4-[(3-クロロ-4-メトキシベンジル)アミノ]-1-
(7-ヒドロキシ-3-オキサ-9-アザビシクロ[3.3.1]ノン-9
-イル)-6-フタラジンカルボニトリル塩酸塩This was dissolved in 20 ml of ethanol, and 1.40 ml of a 1N ethanol solution of hydrochloric acid was added at room temperature, followed by stirring for 10 minutes. After removing the solvent, the residue was treated with diisopropyl ether and dried to obtain 555 mg of the title compound. ¹ H NMR (DMSO-d ₆ ) δ; 1.67-1.98 (8H, m), 3.15-3.40
(6H, m), 3.82 (3H, s), 3.90-3.98 (1H, m), 4.68-4.77
(2H, m), 7.14 (1H, d, J = 9Hz), 7.46 (1H, dd, J =
2, 9Hz), 7.62 (1H, d, J = 2Hz), 8.23 (1H, d, J = 9
Hz), 8.45 (1H, d, J = 9 Hz), 9.50 (1H, s) Example 22 (anti) -4-[(3-chloro-4-methoxybenzyl) amino] -1-
(7-hydroxy-3-oxa-9-azabicyclo [3.3.1] non-9
-Yl) -6-phthalazinecarbonitrile hydrochloride

【０２００】[0200]

【化７３】 Embedded image

【０２０１】1-クロロ-4-[(3-クロロ-4-メトキシベンジ
ル)アミノ]-6-フタラジンカルボニトリル 1.5g、(anti)
-3-オキサ-9-アザビシクロ[3.3.1]ノナン-7-オール 塩
酸塩1.13g、ジイソプロピルエチルアミン2.16mlをN-メ
チル-2-ピロリドン8mlに加え170℃で9時間15分撹拌し
た。反応液に水を加え酢酸エチルで抽出し、有機層を
水、飽和食塩水で洗浄した。無水硫酸マグネシウムで乾
燥後、溶媒を減圧下で留去した。シリカゲルカラムクロ
マトグラフィー（溶媒；ジクロロメタン：メタノール）
で精製し、黄色油状物0.085gを得た。1-chloro-4-[(3-chloro-4-methoxybenzyl) amino] -6-phthalazinecarbonitrile 1.5 g, (anti)
1.13 g of 3-oxa-9-azabicyclo [3.3.1] nonan-7-ol hydrochloride and 2.16 ml of diisopropylethylamine were added to 8 ml of N-methyl-2-pyrrolidone, and the mixture was stirred at 170 ° C. for 9 hours and 15 minutes. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. Silica gel column chromatography (solvent; dichloromethane: methanol)
Then, 0.085 g of a yellow oily substance was obtained.

【０２０２】これを酢酸エチルに溶解し、4N-塩化水素-
酢酸エチル溶液0.05mlを加え室温で撹拌した。析出物を
濾取し、標記化合物を0.075g得た。¹ H NMR (DMSO-d₆) δ; 1.69-1.78 (2H, m), 2.46-2.56
(2H, m), 3.77-3.84 (2H, m), 3.86 (3H, s), 3.86-3.9
5 (3H, m), 4.04-4.12 (2H, m), 4.74 (2H, s),7.17 (1
H, d, J = 8.4 Hz), 7.46 (1H, dd, J= 2.2, 8.4 Hz),
7.61 (1H, d, J= 2.2 Hz), 8.13 (1H, d, J = 8.4 Hz),
8.45 (1H, d, J = 8.4 Hz), 9.39 (1H,m)実施例２３ (anti)-4-[(3-クロロ-4-メトキシベンジル)アミノ]-1-
(9-ヒドロキシ-3-アザビシクロ[3.3.1]ノン-3-イル)-6-
フタラジンカルボニトリル塩酸塩This was dissolved in ethyl acetate and 4N-hydrogen chloride-
Ethyl acetate solution (0.05 ml) was added and the mixture was stirred at room temperature. The precipitate was collected by filtration to give the title compound (0.075 g). ¹ H NMR (DMSO-d ₆ ) δ; 1.69-1.78 (2H, m), 2.46-2.56
(2H, m), 3.77-3.84 (2H, m), 3.86 (3H, s), 3.86-3.9
5 (3H, m), 4.04-4.12 (2H, m), 4.74 (2H, s), 7.17 (1
H, d, J = 8.4 Hz), 7.46 (1H, dd, J = 2.2, 8.4 Hz),
7.61 (1H, d, J = 2.2 Hz), 8.13 (1H, d, J = 8.4 Hz),
8.45 (1H, d, J = 8.4 Hz), 9.39 (1H, m) Example 23 (anti) -4-[(3-chloro-4-methoxybenzyl) amino] -1-
(9-hydroxy-3-azabicyclo [3.3.1] non-3-yl) -6-
Phthalazine carbonitrile hydrochloride

【０２０３】[0203]

【化７４】 Embedded image

【０２０４】1-クロロ-4-[(3-クロロ-4-メトキシベンジ
ル)アミノ]-6-フタラジンカルボニトリル 1.5g、(anti)
-3-アザビシクロ[3.3.1]ノナン-9-オール 塩酸塩 1.12
g、ジイソプロピルエチルアミン2.18mlをN-メチル-2-ピ
ロリドン8mlに加え170℃で9時間撹拌した。反応液に水
を加え酢酸エチルで抽出し、有機層を水、飽和食塩水で
洗浄した。無水硫酸マグネシウムで乾燥後、溶媒を減圧
下で留去した。ジクロロメタンを加え不溶物を濾取し淡
黄色粉末1.23gを得た。これを酢酸エチルに懸濁し、4N-
塩化水素-酢酸エチル溶液0.7mlを加え室温で撹拌した。
析出物を濾取し、標記化合物を淡色粉末として1.28g得
た。¹ H NMR (DMSO-d₆) δ; 1.54 (1H, m), 1.66-1.75 (2H,
m), 1.86-1.93 (2H, m),2.11-2.23 (2H, m), 2.38 (1H,
m), 3.15-3.24 (2H, m), 3.62-3.70 (2H, m),3.75 (1
H, m), 3.85 (3H, s), 4.74 (2H, s), 7.16 (1H, d, J
= 8.4 Hz), 7.47(1H, dd, J = 1.8, 8.4 Hz), 7.62 (1
H, d, J = 1.8 Hz), 8.23 (1H, d, J = 8.4 Hz), 8.56
(1H, dd, J = 1.3, 8.4 Hz), 9.49 (1H, m). 実施例２４ (anti)-4-[(3-クロロ-4-メトキシベンジル)アミノ]-1-
[9-(2-ヒドロキシエチル)-3-アザビシクロ[3.3.1]ノン-
3-イル]-6-フタラジンカルボニトリル塩酸塩1.5 g of 1-chloro-4-[(3-chloro-4-methoxybenzyl) amino] -6-phthalazinecarbonitrile, (anti)
-3-Azabicyclo [3.3.1] nonan-9-ol hydrochloride 1.12
g and 2.18 ml of diisopropylethylamine were added to 8 ml of N-methyl-2-pyrrolidone and stirred at 170 ° C. for 9 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. Dichloromethane was added, and the insolubles were collected by filtration to obtain 1.23 g of a pale yellow powder. This was suspended in ethyl acetate, and 4N-
0.7 ml of a hydrogen chloride-ethyl acetate solution was added, and the mixture was stirred at room temperature.
The precipitate was collected by filtration to give the title compound (1.28 g) as a pale-colored powder. ¹ H NMR (DMSO-d ₆ ) δ; 1.54 (1H, m), 1.66-1.75 (2H,
m), 1.86-1.93 (2H, m), 2.11-2.23 (2H, m), 2.38 (1H,
m), 3.15-3.24 (2H, m), 3.62-3.70 (2H, m), 3.75 (1
H, m), 3.85 (3H, s), 4.74 (2H, s), 7.16 (1H, d, J
= 8.4 Hz), 7.47 (1H, dd, J = 1.8, 8.4 Hz), 7.62 (1
H, d, J = 1.8 Hz), 8.23 (1H, d, J = 8.4 Hz), 8.56
(1H, dd, J = 1.3, 8.4 Hz), 9.49 (1H, m). Example 24 (anti) -4-[(3-chloro-4-methoxybenzyl) amino] -1-
[9- (2-hydroxyethyl) -3-azabicyclo [3.3.1] non-
3-yl] -6-phthalazinecarbonitrile hydrochloride

【０２０５】[0205]

【化７５】 Embedded image

【０２０６】1-クロロ-4-[(3-クロロ-4-メトキシベンジ
ル)アミノ]-6-フタラジンカルボニトリル 1.5g、(anti)
-2-(3-アザビシクロ[3.3.1] ノン-9-イル)-1-エタノー
ル塩酸塩 1.29g、ジイソプロピルエチルアミン2.18mlを
N-メチル-2-ピロリドン8mlに加え170℃で8時間40分撹拌
した。反応液に水を加え酢酸エチルで抽出し、有機層を
水、飽和食塩水で洗浄した。無水硫酸マグネシウムで乾
燥後、溶媒を減圧下で留去した。シリカゲルカラムクロ
マトグラフィー（溶媒；ジクロロメタン：メタノール）
で精製後、ジクロロメタン-酢酸エチル-エーテルで結晶
化させ淡黄色粉末1.12gを得た。これをアセトンに懸濁
し、4N-塩化水素-酢酸エチル溶液2ml、酢酸エチルを加
え室温で撹拌した。析出物を濾取し、標記化合物を淡黄
色粉末として0.98g得た。¹ H NMR (DMSO-d₆) δ; 1.61 (1H, m), 1.66-1.73 (2H,
m), 1.73-1.87 (5H, m),1.88-2.00 (2H, m), 2.42 (1H,
m), 3.14-3.23 (2H, m), 3.49 (2H, t, J = 6.4 Hz),
3.67-3.76 (2H, m), 3.85 (3H, s), 4.73 (2H, s), 7.
16( 1H, d, J =8.6 Hz), 7.47 (1H, dd, J = 1.6, 8.6
Hz), 7.62 (1H, d, J = 1.6 Hz), 8.24(1H, d, J = 8.4
Hz), 8.55 (1H, dd, J = 1.3, 8.4 Hz), 9.46 (1H, m) 実施例２５ 1-(3-アミノ-3-メチル-1-ブチニル)-4-[(3-クロロ-4-メ
トキシベンジル)アミノ]-6-フタラジンカルボニトリル
塩酸塩1.5 g of 1-chloro-4-[(3-chloro-4-methoxybenzyl) amino] -6-phthalazinecarbonitrile, (anti)
1.29 g of -2- (3-azabicyclo [3.3.1] non-9-yl) -1-ethanol hydrochloride and 2.18 ml of diisopropylethylamine
The mixture was added to 8 ml of N-methyl-2-pyrrolidone and stirred at 170 ° C. for 8 hours and 40 minutes. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. Silica gel column chromatography (solvent; dichloromethane: methanol)
Then, the residue was crystallized from dichloromethane-ethyl acetate-ether to obtain 1.12 g of a pale yellow powder. This was suspended in acetone, 2 ml of a 4N hydrogen chloride-ethyl acetate solution and ethyl acetate were added, and the mixture was stirred at room temperature. The precipitate was collected by filtration to give the title compound (0.98 g) as a pale-yellow powder. ¹ H NMR (DMSO-d ₆ ) δ; 1.61 (1H, m), 1.66-1.73 (2H,
m), 1.73-1.87 (5H, m), 1.88-2.00 (2H, m), 2.42 (1H,
m), 3.14-3.23 (2H, m), 3.49 (2H, t, J = 6.4 Hz),
3.67-3.76 (2H, m), 3.85 (3H, s), 4.73 (2H, s), 7.
16 (1H, d, J = 8.6 Hz), 7.47 (1H, dd, J = 1.6, 8.6
Hz), 7.62 (1H, d, J = 1.6 Hz), 8.24 (1H, d, J = 8.4
Hz), 8.55 (1H, dd, J = 1.3, 8.4 Hz), 9.46 (1H, m) Example 25 1- (3-Amino-3-methyl-1-butynyl) -4-[(3-chloro- 4-methoxybenzyl) amino] -6-phthalazinecarbonitrile hydrochloride

【０２０７】[0207]

【化７６】 Embedded image

【０２０８】1-クロロ-4-[(3-クロロ-4-メトキシベンジ
ル)アミノ]-6-フタラジンカルボニトリル500 mg、ヨウ
化第一銅53 mg、ジクロロビス（トリフェニルホスフィ
ン）パラジウム（II）98 mg、3-アミノ-3-メチル-1-ブ
チン347 mg、ジメチルホルムアミド10 mLの混合物にト
リエチルアミン0.39 mLを加え、窒素雰囲気下８０℃で
３時間撹拌した。冷後、反応液に酢酸エチルを加え、水
及び濃アンモニア水を加え、有機層を分取した。有機層
を、希アンモニア水及び飽和食塩水で洗浄し、無水硫酸
ナトリウムで乾燥した。濾過し、濾液を減圧下濃縮し
た。残渣をNH-formシリカゲルカラムクロマトグラフィ
ーで精製し、標記化合物を446 mg得た。常法により塩酸
塩とした。¹ H NMR (DMSO-d₆) δ; 1.75 (6H, s), 3.82 (3H, s),
4.76 (2H, d, J = 5.6 Hz), 7.10 (1H, d, J = 8.4 H
z), 7.37 (1H, dd, J = 8.4, 2.2 Hz), 7.50 (1H, d, J
= 2.2 Hz), 8.31 (1H, dd, J = 8.4, 1.4 Hz), 8.35
(1H, d, J = 8.4 Hz),8.83 (1H, t, J = 5.6 Hz), 8.92
-9.05 (3H, m), 9.07 (1H, br) 実施例２６ 4-[(3-クロロ-4-メトキシベンジル)アミノ]-1-[4-(メト
キシイミノ)ピペリジノ]-6-フタラジンカルボニトリル
塩酸塩1-chloro-4-[(3-chloro-4-methoxybenzyl) amino] -6-phthalazinecarbonitrile 500 mg, cuprous iodide 53 mg, dichlorobis (triphenylphosphine) palladium (II) 0.39 mL of triethylamine was added to a mixture of 98 mg, 347 mg of 3-amino-3-methyl-1-butyne and 10 mL of dimethylformamide, and the mixture was stirred at 80 ° C. for 3 hours under a nitrogen atmosphere. After cooling, ethyl acetate was added to the reaction solution, water and concentrated aqueous ammonia were added, and the organic layer was separated. The organic layer was washed with diluted aqueous ammonia and saturated saline, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by NH-form silica gel column chromatography to obtain 446 mg of the title compound. It was converted into a hydrochloride by a conventional method. ¹ H NMR (DMSO-d ₆ ) δ; 1.75 (6H, s), 3.82 (3H, s),
4.76 (2H, d, J = 5.6 Hz), 7.10 (1H, d, J = 8.4 H
z), 7.37 (1H, dd, J = 8.4, 2.2 Hz), 7.50 (1H, d, J
= 2.2 Hz), 8.31 (1H, dd, J = 8.4, 1.4 Hz), 8.35
(1H, d, J = 8.4 Hz), 8.83 (1H, t, J = 5.6 Hz), 8.92
-9.05 (3H, m), 9.07 (1H, br) Example 26 4-[(3-chloro-4-methoxybenzyl) amino] -1- [4- (methoxyimino) piperidino] -6-phthalazinecarbo Nitrile hydrochloride

【０２０９】[0209]

【化７７】 Embedded image

【０２１０】4-[(3-クロロ-4-メトキシベンジル)アミ
ノ]-1-[4-オキソピペリジノ]-6-フタラジンカルボニト
リル1.19 g、塩酸メトキシアミン354 mg、炭酸ナトリウ
ム1.2g及びエタノール10 mLの混合物を２時間加熱還流
した。冷後、反応液に食塩水を加え、酢酸エチルで抽出
した。無水硫酸ナトリウムで乾燥し、濾過した。濾液を
減圧下濃縮し、残渣をシリカゲルカラムクロマトグラフ
ィーで精製し、4-[(3-クロロ-4-メトキシベンジル)アミ
ノ]-1-[4-(メトキシイミノ)ピペリジノ]-6-フタラジン
カルボニトリルを620 mg得た。これをメタノールとエタ
ノールの混合溶媒に溶解し、４Ｎ塩酸−酢酸エチル0.35
mLを加え再結晶し、4-[(3-クロロ-4-メトキシベンジ
ル)アミノ]-1-[4-(メトキシイミノ)ピペリジノ]-6-フタ
ラジンカルボニトリル塩酸塩388 mgを得た。¹ H NMR (DMSO-d₆) δ; 2.50-2.55 (2H, m), 2.74-2.80
(2H, m), 3.29-3.35 (4H, m), 3.77 (3H, s), 3.85 (3
H, s), 4.72 (2H, br), 7.16 (1H, d, J = 8.4 Hz), 7.
45 (1H, dd, J = 8.4, 2.0 Hz), 7.60 (1H, d, J = 2.0
Hz), 8.33 (1H, d, J = 8.8 Hz), 8.48 (1H, dd, J =
8.8, 0.8 Hz), 9.35 (1H, d, J = 0.8 Hz),10.19 (1H,
br) 対応する原料を用いて、製造例あるいは実施例の方法と
同様にして、以下の化合物を合成した。 実施例２７ 4-[(3-クロロ-4-メチルベンジル)アミノ]-1-(4-ヒドロ
キシピペリジノ)-6-フタラジンカルボニトリル 塩酸塩4-[(3-chloro-4-methoxybenzyl) amino] -1- [4-oxopiperidino] -6-phthalazinecarbonitrile 1.19 g, methoxyamine hydrochloride 354 mg, sodium carbonate 1.2 g and ethanol 10 mL Was heated to reflux for 2 hours. After cooling, brine was added to the reaction solution, which was extracted with ethyl acetate. Dried over anhydrous sodium sulfate and filtered. The filtrate is concentrated under reduced pressure, the residue is purified by silica gel column chromatography, and 4-[(3-chloro-4-methoxybenzyl) amino] -1- [4- (methoxyimino) piperidino] -6-phthalazinecarbohydrate is used. 620 mg of nitrile were obtained. This was dissolved in a mixed solvent of methanol and ethanol, and 4N hydrochloric acid-ethyl acetate 0.35
mL was added and recrystallized to obtain 388 mg of 4-[(3-chloro-4-methoxybenzyl) amino] -1- [4- (methoxyimino) piperidino] -6-phthalazinecarbonitrile hydrochloride. ¹ H NMR (DMSO-d ₆ ) δ; 2.50-2.55 (2H, m), 2.74-2.80
(2H, m), 3.29-3.35 (4H, m), 3.77 (3H, s), 3.85 (3
H, s), 4.72 (2H, br), 7.16 (1H, d, J = 8.4 Hz), 7.
45 (1H, dd, J = 8.4, 2.0 Hz), 7.60 (1H, d, J = 2.0
Hz), 8.33 (1H, d, J = 8.8 Hz), 8.48 (1H, dd, J =
8.8, 0.8 Hz), 9.35 (1H, d, J = 0.8 Hz), 10.19 (1H,
br) Using the corresponding starting materials, the following compounds were synthesized in the same manner as in the Production Examples or Examples. Example 27 4-[(3-chloro-4-methylbenzyl) amino] -1- (4-hydroxypiperidino) -6-phthalazinecarbonitrile hydrochloride

【０２１１】[0211]

【化７８】 Embedded image

【０２１２】¹H NMR (DMSO-d₆) δ; 1.62-1.73 (2H,
m), 1.90-1.99 (2H, m), 2.32(3H, s),2.98-3.08 (2H,
m), 3.42-3.50 (2H, m), 3.72-3.80 (1H, m), 4.76 (2
H, d, J= 5.6 Hz), 7.36 (2H, s), 7.57 (1H, s), 8.23
(1H, d, J = 8.4 Hz), 8.47 (1H, dd, J = 8.4, 1.2 H
z), 9.37 (1H, d, J = 1.2 Hz), 10.21 (1H, br) 実施例２８ 4-[(3-クロロ-4-メトキシベンジル)アミノ]-1-(5-ヒド
ロキシペルヒドロシクロペンタ[c]ピロール-2-イル)-6-
フタラジンカルボニトリル ¹ H NMR (DMSO-d ₆ ) δ; 1.62-1.73 (2H,
m), 1.90-1.99 (2H, m), 2.32 (3H, s), 2.98-3.08 (2H,
m), 3.42-3.50 (2H, m), 3.72-3.80 (1H, m), 4.76 (2
H, d, J = 5.6 Hz), 7.36 (2H, s), 7.57 (1H, s), 8.23
(1H, d, J = 8.4 Hz), 8.47 (1H, dd, J = 8.4, 1.2 H
z), 9.37 (1H, d, J = 1.2 Hz), 10.21 (1H, br) Example 28 4-[(3-chloro-4-methoxybenzyl) amino] -1- (5-hydroxyperhydrocyclopenta [c] pyrrole-2-yl) -6-
Phthalazine carbonitrile

【０２１３】[0213]

【化７９】 Embedded image

【０２１４】¹H NMR (DMSO-d₆) δ; 1.40-1.49 (2H,
m), 2.02-2.12 (2H, m), 2.55-2.64 (2H, m), 3.24 (4
H, d, J = 4.0 Hz), 3.80 (3H, s), 3.94-4.04 (1H,
m), 4.61 (2H, d, J = 5.2 Hz), 4.72 (1H, d, J = 5.6
Hz), 7.07 (1H, d, J = 8.4 Hz), 7.32 (1H, dd, J =
2.0, 8.4 Hz), 7.77-7.83 (1H, m), 8.14-8.23 (2H,
m), 8.66 (1H, d, J = 0.8 Hz) 実施例２９ 4-[(3-クロロ-4-メトキシベンジル)アミノ]-1-[4-(2-ヒ
ドロキシエチル)-1,2,3,6-テトラヒドロ-1-ピリジニル]
-6-フタラジンカルボニトリル[0214] _{^{1 H NMR (DMSO-d 6}} ) δ; 1.40-1.49 (2H,
m), 2.02-2.12 (2H, m), 2.55-2.64 (2H, m), 3.24 (4
H, d, J = 4.0 Hz), 3.80 (3H, s), 3.94-4.04 (1H,
m), 4.61 (2H, d, J = 5.2 Hz), 4.72 (1H, d, J = 5.6
Hz), 7.07 (1H, d, J = 8.4 Hz), 7.32 (1H, dd, J =
2.0, 8.4 Hz), 7.77-7.83 (1H, m), 8.14-8.23 (2H,
m), 8.66 (1H, d, J = 0.8 Hz) Example 29 4-[(3-chloro-4-methoxybenzyl) amino] -1- [4- (2-hydroxyethyl) -1,2,3 , 6-Tetrahydro-1-pyridinyl]
-6-phthalazinecarbonitrile

【０２１５】[0215]

【化８０】 Embedded image

【０２１６】¹H NMR (DMSO-d₆) δ; 2.15-2.22 (2H,
m), 2.27-2.39 (2H,m), 3.20 (2H, t, J= 5.6 Hz), 3.4
8-3.60 (2H, m), 3.69 (2H, s), 3.80 (3H, s), 4.47
(1H, t,J = 5.6 Hz), 4.61 (2H, d, J = 5.6 Hz), 5.55
(1H, d, J = 0.4 Hz), 7.08 (1H, d, J = 8.4 Hz), 7.
33 (1H, dd, J = 2.0, 8.4 Hz), 7.44 (1H, d, J = 2.0
Hz), 7.83-7.89 (1H, m), 8.04 (1H, d, J = 8.4 Hz),
8.08 (1H, dd, J = 1.2,8.4 Hz), 8.87 (1H, t, J = 0.
4 Hz) 実施例３０ 4-[(3-クロロ-4-メトキシベンジル)アミノ]-1-[3-(ヒド
ロキシメチル)テトラヒドロ-1H-1-ピロリル]-6-フタラ
ジンカルボニトリル ¹ H NMR (DMSO-d ₆ ) δ; 2.15-2.22 (2H,
m), 2.27-2.39 (2H, m), 3.20 (2H, t, J = 5.6 Hz), 3.4
8-3.60 (2H, m), 3.69 (2H, s), 3.80 (3H, s), 4.47
(1H, t, J = 5.6 Hz), 4.61 (2H, d, J = 5.6 Hz), 5.55
(1H, d, J = 0.4 Hz), 7.08 (1H, d, J = 8.4 Hz), 7.
33 (1H, dd, J = 2.0, 8.4 Hz), 7.44 (1H, d, J = 2.0
Hz), 7.83-7.89 (1H, m), 8.04 (1H, d, J = 8.4 Hz),
8.08 (1H, dd, J = 1.2,8.4 Hz), 8.87 (1H, t, J = 0.
4 Hz) Example 30 4-[(3-chloro-4-methoxybenzyl) amino] -1- [3- (hydroxymethyl) tetrahydro-1H-1-pyrrolyl] -6-phthalazinecarbonitrile

【０２１７】[0219]

【化８１】 Embedded image

【０２１８】¹H NMR (DMSO-d₆) δ; 1.59-1.70 (1H,
m), 1.83-2.02 (2H, m), 2.31-2.41 (1H, m), 3.34-3.6
0 (5H, m), 4.58 (2H, J = 5.6 Hz), 4.67 (1H, t, J =
5.6 Hz), 7.07 (1H, d, J = 8.4 Hz), 7.32 (1H, dd,
J = 2.0, 8.4 Hz), 7.43 (1H, d,J = 2.0 Hz), 7.56-7.
62 (1H, m), 8.14 (1H, dd, J = 1.6, 8.8 Hz), 8.23
(1H, d, J = 8.8 Hz), 8.82 (1H, d, J = 1.2 Hz) 実施例３１ 4-[(3-クロロ-4-メトキシベンジル)アミノ]-1-[4-(ヒド
ロキシメチル)-1,2,3,6-テトラヒドロ-1-ピリジニル]-6
-フタラジンカルボニトリル ¹ H NMR (DMSO-d ₆ ) δ; 1.59-1.70 (1H,
m), 1.83-2.02 (2H, m), 2.31-2.41 (1H, m), 3.34-3.6
0 (5H, m), 4.58 (2H, J = 5.6 Hz), 4.67 (1H, t, J =
5.6 Hz), 7.07 (1H, d, J = 8.4 Hz), 7.32 (1H, dd,
J = 2.0, 8.4 Hz), 7.43 (1H, d, J = 2.0 Hz), 7.56-7.
62 (1H, m), 8.14 (1H, dd, J = 1.6, 8.8 Hz), 8.23
(1H, d, J = 8.8 Hz), 8.82 (1H, d, J = 1.2 Hz) Example 31 4-[(3-chloro-4-methoxybenzyl) amino] -1- [4- (hydroxymethyl) -1,2,3,6-tetrahydro-1-pyridinyl] -6
-Phthalazine carbonitrile

【０２１９】[0219]

【化８２】 Embedded image

【０２２０】¹H NMR (DMSO-d₆) δ; 2.28 (2H, brs),
3.19-3.26 (2H, m), 3.73 (2H, br.s),3.80 (3H, s),
3.89 (2H, d, J = 4.4 Hz), 4.62 (2H, d, J = 5.6 H
z), 4.78(1H, t, J = 5.6 Hz), 5.72 (1H, br.s), 7.08
(1H, d, J = 8.4 Hz), 7.33 (1H, dd, J = 2.0, 8.4 H
z), 7.44 (1H, d, J = 2.0 Hz), 7.87 (1H, t, J = 5.6
Hz), 8.05 (1H, d, J = 8.4 Hz), 8.18 (1H, dd, J =
1.2, 8.4 Hz), 8.87 (1H,d, J = 1.2 Hz) 実施例３２ 2-[1-[4-[(3-クロロ-4-メトキシベンジル)アミノ]-6-シ
アノ-1-フタラジニル]-4-ピペリジニル]プロピオン酸塩
酸塩 ¹ H NMR (DMSO-d ₆ ) δ; 2.28 (2H, brs),
3.19-3.26 (2H, m), 3.73 (2H, br.s), 3.80 (3H, s),
3.89 (2H, d, J = 4.4 Hz), 4.62 (2H, d, J = 5.6 H
z), 4.78 (1H, t, J = 5.6 Hz), 5.72 (1H, br.s), 7.08
(1H, d, J = 8.4 Hz), 7.33 (1H, dd, J = 2.0, 8.4 H
z), 7.44 (1H, d, J = 2.0 Hz), 7.87 (1H, t, J = 5.6
Hz), 8.05 (1H, d, J = 8.4 Hz), 8.18 (1H, dd, J =
Example 32 2- [1- [4-[(3-chloro-4-methoxybenzyl) amino] -6-cyano-1-phthalazinyl] 1.2, 8.4 Hz), 8.87 (1H, d, J = 1.2 Hz) -4-piperidinyl] propionate hydrochloride

【０２２１】[0221]

【化８３】 Embedded image

【０２２２】¹H NMR (DMSO-d₆) δ; 1.08 (3H, d, J =
6.8 Hz), 1.46-1.64 (2H, m), 1.66-1.83 (3H, m), 2.2
2-2.32 (1H, m), 2.78-2.90(2H, m), 3.54-3.64 (2H,
m), 3.83 (3H, s), 4.72 ( 2H, d, J = 6.0 Hz), 7.14
(1H, d, J = 8.4 Hz), 7.46 (1H, dd, J = 2.0, 8.4 H
z), 7.61(1H, d, J = 2.0 Hz), 8.22 (1H, d, J = 8.4
Hz), 8.45 (1H, dd, J = 1.6, 8.4 Hz), 9.49 (1H, s) 実施例３３ 2-[1-[4-[(3-クロロ-4-メトキシベンジル)アミノ]-6-シ
アノ-1-フタラジニル]-1,2,3,6-テトラヒドロ-4-ピリジ
ニル]酢酸塩酸塩 ¹ H NMR (DMSO-d ₆ ) δ; 1.08 (3H, d, J =
6.8 Hz), 1.46-1.64 (2H, m), 1.66-1.83 (3H, m), 2.2
2-2.32 (1H, m), 2.78-2.90 (2H, m), 3.54-3.64 (2H, m
m), 3.83 (3H, s), 4.72 (2H, d, J = 6.0 Hz), 7.14
(1H, d, J = 8.4 Hz), 7.46 (1H, dd, J = 2.0, 8.4 H
z), 7.61 (1H, d, J = 2.0 Hz), 8.22 (1H, d, J = 8.4
Hz), 8.45 (1H, dd, J = 1.6, 8.4 Hz), 9.49 (1H, s) Example 33 2- [1- [4-[(3-chloro-4-methoxybenzyl) amino] -6- Cyano-1-phthalazinyl] -1,2,3,6-tetrahydro-4-pyridinyl] acetic acid hydrochloride

【０２２３】[0223]

【化８４】 Embedded image

【０２２４】¹H NMR (DMSO-d₆) δ; 2.38-2.44 (2H,
m), 3.04 (2H, s), 3.79-3.83 (2H, m),3.83 (3H, s),
4.72 (2H, t, J = 2.8 Hz), 5.63-5.68 (1H, m), 7.15
(1H, d,J = 8.8 Hz), 7.46 (1H, dd, J = 2.4, 8.4 H
z), 7.61 (1H, d, J = 2.4 Hz),8.21 (1H, d, J = 8.8
Hz), 8.46 (1H, dd, J = 1.2, 8.4 Hz), 9.45 (1H, s). 実施例３４ 2-[1-[4-[(3-クロロ-4-メトキシベンジル)アミノ]-6-シ
アノ-1-フタラジニル]-4-ピペリジニル]-2-フルオロ酢
酸塩酸塩[0224] _{^{1 H NMR (DMSO-d 6}} ) δ; 2.38-2.44 (2H,
m), 3.04 (2H, s), 3.79-3.83 (2H, m), 3.83 (3H, s),
4.72 (2H, t, J = 2.8 Hz), 5.63-5.68 (1H, m), 7.15
(1H, d, J = 8.8 Hz), 7.46 (1H, dd, J = 2.4, 8.4 H
z), 7.61 (1H, d, J = 2.4 Hz), 8.21 (1H, d, J = 8.8
Hz), 8.46 (1H, dd, J = 1.2, 8.4 Hz), 9.45 (1H, s). Example 34 2- [1- [4-[(3-chloro-4-methoxybenzyl) amino] -6 -Cyano-1-phthalazinyl] -4-piperidinyl] -2-fluoroacetic acid hydrochloride

【０２２５】[0225]

【化８５】 Embedded image

【０２２６】¹H NMR (DMSO-d₆) δ; 1.60-1.90 (4H,
m), 2.03-2.20 (1H, m), 2.83-2.98 (2H, m), 3.58-3.6
5 (2H, m), 3.83 (3H, s), 4.73 (2H, t, J = 2.8 Hz),
4.98 (1H, dd, J = 4.0, 48.4 Hz), 7.14 (1H, d, J =
8.4 Hz), 7.46 (1H, dd, J = 2.0, 8.4 Hz), 7.61 (1
H, d, J = 2.4 Hz), 8.23 (1H, d, J = 8.4 Hz), 8.44
(1H, dd, J = 1.2, 8.4 Hz), 8.46 (1H, s) 実施例３５ 2-[1-[4-[(3-クロロ-4-メトキシベンジル)アミノ]-6-シ
アノ-1-フタラジニル]-4-ピペリジル]酢酸塩酸塩 ¹ H NMR (DMSO-d ₆ ) δ; 1.60-1.90 (4H,
m), 2.03-2.20 (1H, m), 2.83-2.98 (2H, m), 3.58-3.6
5 (2H, m), 3.83 (3H, s), 4.73 (2H, t, J = 2.8 Hz),
4.98 (1H, dd, J = 4.0, 48.4 Hz), 7.14 (1H, d, J =
8.4 Hz), 7.46 (1H, dd, J = 2.0, 8.4 Hz), 7.61 (1
H, d, J = 2.4 Hz), 8.23 (1H, d, J = 8.4 Hz), 8.44
(1H, dd, J = 1.2, 8.4 Hz), 8.46 (1H, s) Example 35 2- [1- [4-[(3-chloro-4-methoxybenzyl) amino] -6-cyano-1- Phthalazinyl] -4-piperidyl] acetic acid hydrochloride

【０２２７】[0227]

【化８６】 Embedded image

【０２２８】¹H NMR (DMSO-d₆) δ; 1.44-1.57 (2H,
m), 1.79-1.84 (2H, m), 1.85-1.96 (1H, m), 2.25 (2
H, d, J = 6.8 Hz), 2.89 (2H, t, J = 12.0 Hz), 3.55
(2H, d,J = 12.0 Hz), 3.84 (3H, s), 4.70 (2H, d, J
= 6.0 Hz), 7.15 (1H, d, J = 8.8 Hz), 7.44 (1H, d
d, J = 2.0, 8.4 Hz), 7.94 (1H, d, J = 2.0 Hz), 8.2
1 (1H, d, J = 8.4 Hz), 8.46 (1H, dd, J = 1.6, 8.8
Hz), 9.37 (1H, s). 実施例３６ 4-[(3-クロロ-4-メトキシベンジル)アミノ]-1-[4-(1-フ
ルオロ-2-ヒドロキシエチル)ピペリジノ]-6-フタラジン
カルボニトリル塩酸塩 ¹ H NMR (DMSO-d ₆ ) δ; 1.44-1.57 (2H,
m), 1.79-1.84 (2H, m), 1.85-1.96 (1H, m), 2.25 (2
H, d, J = 6.8 Hz), 2.89 (2H, t, J = 12.0 Hz), 3.55
(2H, d, J = 12.0 Hz), 3.84 (3H, s), 4.70 (2H, d, J
= 6.0 Hz), 7.15 (1H, d, J = 8.8 Hz), 7.44 (1H, d
d, J = 2.0, 8.4 Hz), 7.94 (1H, d, J = 2.0 Hz), 8.2
1 (1H, d, J = 8.4 Hz), 8.46 (1H, dd, J = 1.6, 8.8
Hz), 9.37 (1H, s). Example 36 4-[(3-chloro-4-methoxybenzyl) amino] -1- [4- (1-fluoro-2-hydroxyethyl) piperidino] -6-lid Razine carbonitrile hydrochloride

【０２２９】[0229]

【化８７】 Embedded image

【０２３０】¹H NMR (DMSO-d₆) δ; 1.56-1.78 (3H,
m), 1.83-1.99 (2H, m), 2.80-2.91 (2H, m), 3.51-3.6
9 (4H, m), 3.83 (3H, s), 4.25-4.31 (1/2H, m), 4.37
-4.43 (1/2H, m), 4.73 (2H, d, J = 5.6 Hz), 7.14 (1
H, d, J = 8.4 Hz), 7.47 (1H, dd, J = 2.0, 8.4 Hz),
7.62 (1H, d, J = 2.0 Hz), 8.22 (1H, d, J = 8.4 H
z),8.45 (1H, dd, J = 1.2, 8.4 Hz), 9.52 (1H, s), 1
0.58 (1H, s) 実施例３７ 4-[(3-クロロ-4-メトキシベンジル)アミノ]-1-[4-(2-ヒ
ドロキシエトキシ)ピペリジノ]-6-フタラジンカルボニ
トリル塩酸塩 ¹ H NMR (DMSO-d ₆ ) δ; 1.56-1.78 (3H,
m), 1.83-1.99 (2H, m), 2.80-2.91 (2H, m), 3.51-3.6
9 (4H, m), 3.83 (3H, s), 4.25-4.31 (1 / 2H, m), 4.37
-4.43 (1 / 2H, m), 4.73 (2H, d, J = 5.6 Hz), 7.14 (1
H, d, J = 8.4 Hz), 7.47 (1H, dd, J = 2.0, 8.4 Hz),
7.62 (1H, d, J = 2.0 Hz), 8.22 (1H, d, J = 8.4 H
z), 8.45 (1H, dd, J = 1.2, 8.4 Hz), 9.52 (1H, s), 1
0.58 (1H, s) Example 37 4-[(3-Chloro-4-methoxybenzyl) amino] -1- [4- (2-hydroxyethoxy) piperidino] -6-phthalazinecarbonitrile hydrochloride

【０２３１】[0231]

【化８８】 Embedded image

【０２３２】¹H NMR (DMSO-d₆) δ; 1.68-1.77 (4H,
m), 1.98-2.07 (2H, m), 2.98-3.07 (2H, m), 3.44-3.5
2 (2H, m), 3.56-3.62 (3H, m), 3.83 (3H, s), 4.74
(2H, d, J= 5.6 Hz), 7.13 (1H, d, J = 8.4 Hz), 7.48
(1H, dd, J = 2.0, 8.4 Hz), 7.627 (1H, d, J = 2.0
Hz), 8.23 (1H, d, J = 8.4 Hz), 8.45 (1H, dd, J =
1.6, 8.4 Hz), 9.57 (1H, s), 10.68 (1H, brs) 実施例３８ 2-[[1-[4-[(3-クロロ-4-メトキシベンジル)アミノ]-6-
シアノ-1-フタラジニル]-4-ピペリジル]オキシ]酢酸塩
酸塩[0232] _{^{1 H NMR (DMSO-d 6}} ) δ; 1.68-1.77 (4H,
m), 1.98-2.07 (2H, m), 2.98-3.07 (2H, m), 3.44-3.5
2 (2H, m), 3.56-3.62 (3H, m), 3.83 (3H, s), 4.74
(2H, d, J = 5.6 Hz), 7.13 (1H, d, J = 8.4 Hz), 7.48
(1H, dd, J = 2.0, 8.4 Hz), 7.627 (1H, d, J = 2.0
Hz), 8.23 (1H, d, J = 8.4 Hz), 8.45 (1H, dd, J =
1.6, 8.4 Hz), 9.57 (1H, s), 10.68 (1H, brs) Example 38 2-[[1- [4-[(3-chloro-4-methoxybenzyl) amino] -6-
Cyano-1-phthalazinyl] -4-piperidyl] oxy] acetic acid hydrochloride

【０２３３】[0233]

【化８９】 Embedded image

【０２３４】¹H NMR (DMSO-d₆) δ; 1.69-1.82 (2H,
m), 1.99-2.10 (2H, m), 2.98-3.09 (2H, m), 3.60-3.6
8 (1H, m), 3.83 (3H, s), 4.08 (2H, s), 4.72 (2H,
d, J = 5.6 Hz), 7.14 (1H, d, J = 8.4Hz), 7.46 (1H,
dd, J = 2.4, 8.4 Hz), 7.61 (1H, d, J = 2.0 Hz),
8.24 (1H, d, J = 8.4 Hz), 8.46 (1H, dd, J = 1.2,
8.4 Hz), 9.46 (1H, s), 10.46 (1H, brs) 実施例３９ 4-[(3-クロロ-4-メトキシベンジル)アミノ]-1-[4-(2-ヒ
ドロキシ-1-メチルエチル)ピペリジノ]-6-フタラジンカ
ルボニトリル ¹ H NMR (DMSO-d ₆ ) δ; 1.69-1.82 (2H,
m), 1.99-2.10 (2H, m), 2.98-3.09 (2H, m), 3.60-3.6
8 (1H, m), 3.83 (3H, s), 4.08 (2H, s), 4.72 (2H,
d, J = 5.6 Hz), 7.14 (1H, d, J = 8.4 Hz), 7.46 (1H,
dd, J = 2.4, 8.4 Hz), 7.61 (1H, d, J = 2.0 Hz),
8.24 (1H, d, J = 8.4 Hz), 8.46 (1H, dd, J = 1.2,
8.4 Hz), 9.46 (1H, s), 10.46 (1H, brs) Example 39 4-[(3-chloro-4-methoxybenzyl) amino] -1- [4- (2-hydroxy-1-methylethyl ) Piperidino] -6-phthalazinecarbonitrile

【０２３５】[0235]

【化９０】 Embedded image

【０２３６】¹H NMR (DMSO-d₆) δ; 0.85 (3H, d, J =
6.4Hz), 1.40-1.59 (4H, m), 1.64-1.73 (2H, m), 2.68
-2.79 (2H, m), 3.33-3.47 (4H, m), 3.78 (3H, m), 4.
40 (1H, t, J = 5.2 Hz), 4.60 (2H, d, J = 5.6 Hz),
7.06 (1H, d, J = 8.4 Hz), 7.31 (1H, dd, J = 2.0,
8.4 Hz), 7.42 (1H, d, J = 2.0 Hz), 7.85 (1H, t, J
=6.0 Hz), 8.03 (1H, d, J = 8.4 Hz), 8.16 (1H, dd,
J = 1.6, 8.4 Hz), 8.85(1H, d, J = 0.8 Hz) 実施例４０ 2-[7-[4-[(3-クロロ-4-メトキシベンジル)アミノ]-6-シ
アノ-1-フタラジニリル]-7-アザスピロ[3.5]ノン-2-イ
ル]酢酸塩酸塩[0236] _{^{1 H NMR (DMSO-d 6}} ) δ; 0.85 (3H, d, J =
6.4Hz), 1.40-1.59 (4H, m), 1.64-1.73 (2H, m), 2.68
-2.79 (2H, m), 3.33-3.47 (4H, m), 3.78 (3H, m), 4.
40 (1H, t, J = 5.2 Hz), 4.60 (2H, d, J = 5.6 Hz),
7.06 (1H, d, J = 8.4 Hz), 7.31 (1H, dd, J = 2.0,
8.4 Hz), 7.42 (1H, d, J = 2.0 Hz), 7.85 (1H, t, J
= 6.0 Hz), 8.03 (1H, d, J = 8.4 Hz), 8.16 (1H, dd,
J = 1.6, 8.4 Hz), 8.85 (1H, d, J = 0.8 Hz) Example 40 2- [7- [4-[(3-chloro-4-methoxybenzyl) amino] -6-cyano-1- Phthalazinyl] -7-azaspiro [3.5] non-2-yl] acetic acid hydrochloride

【０２３７】[0237]

【化９１】 Embedded image

【０２３８】¹H NMR (DMSO-d₆) δ; 1.45-1.53 (2H,
m), 1.66-1.73 (2H, m), 1.77-1.84 (2H, m), 1.96-2.0
4 (2H, m), 2.34 (2H, d, J = 7.6 Hz), 3.02 (2H, br.
s), 3.11(2H, br.s), 3.82 (3H, s), 4.67 (2H, s), 7.
11 (1H, d, J = 8.4 Hz), 7.40(1H, dd, J = 2.0, 8.4
Hz), 7.54 (1H, d, J = 2.0 Hz), 8.15 (1H, d, J = 8.
8 Hz), 8.34 (1H, d, J = 8.8 Hz), 9.24 (1H, s) 実施例４１ 4-[(3-クロロ-4-メトキシベンジル)アミノ]-1-[2-(ヒド
ロキシメチル)ペルヒドロ[1,3]ジオキソロ[4,5-c]ピロ
ール-5-イル]-6-フタラジンカルボニトリル塩酸塩 ¹ H NMR (DMSO-d ₆ ) δ; 1.45-1.53 (2H,
m), 1.66-1.73 (2H, m), 1.77-1.84 (2H, m), 1.96-2.0
4 (2H, m), 2.34 (2H, d, J = 7.6 Hz), 3.02 (2H, br.
s), 3.11 (2H, br.s), 3.82 (3H, s), 4.67 (2H, s), 7.
11 (1H, d, J = 8.4 Hz), 7.40 (1H, dd, J = 2.0, 8.4
Hz), 7.54 (1H, d, J = 2.0 Hz), 8.15 (1H, d, J = 8.
8 Hz), 8.34 (1H, d, J = 8.8 Hz), 9.24 (1H, s) Example 41 4-[(3-chloro-4-methoxybenzyl) amino] -1- [2- (hydroxymethyl) Perhydro [1,3] dioxolo [4,5-c] pyrrole-5-yl] -6-phthalazinecarbonitrile hydrochloride

【０２３９】[0239]

【化９２】 Embedded image

【０２４０】¹H NMR (DMSO-d₆) δ; 3.54-3.67 (2H,
m), 3.80-3.92 (2H, m), 4.16 (2/3H, brs), 4.29 (4/3
H, brs), 4.54 (1H, t, J = 5.2 Hz), 4.54-4.62 (1H,
m), 5.16-5.32 (2H, m), 7.11 (1H, d, J = 8.4 Hz),
7.34-7.40 (1H, m), 7.50 (1H, s), 8.37 (1H, d, J =
8.4 Hz), 8.48-8.58 (1H, m), 9.12-9.21 (1H, m) 実施例４２ 4-[(3-クロロ-4-メトキシベンジル)アミノ]-1-[4-(1-ヒ
ドロキシエチル)ピペリジノ]-6-フタラジンカルボニト
リル塩酸塩 ¹ H NMR (DMSO-d ₆ ) δ; 3.54-3.67 (2H,
m), 3.80-3.92 (2H, m), 4.16 (2 / 3H, brs), 4.29 (4/3
H, brs), 4.54 (1H, t, J = 5.2 Hz), 4.54-4.62 (1H,
m), 5.16-5.32 (2H, m), 7.11 (1H, d, J = 8.4 Hz),
7.34-7.40 (1H, m), 7.50 (1H, s), 8.37 (1H, d, J =
8.4 Hz), 8.48-8.58 (1H, m), 9.12-9.21 (1H, m) Example 42 4-[(3-chloro-4-methoxybenzyl) amino] -1- [4- (1-hydroxyethyl ) Piperidino] -6-phthalazinecarbonitrile hydrochloride

【０２４１】[0241]

【化９３】 Embedded image

【０２４２】¹H NMR (DMSO-d₆) δ; 1.07 (3H, d, J =
6.0 Hz), 1.34-1.60 (3H, m), 1.65-1.76 (2H, m), 1.8
6-1.94 (2H, m), 2.75-2.86 (2H, m), 3.55-3.63 (2H,
m), 3.82 (3H, s), 4.73 (2H, d, J = 5.6 Hz), 7.13
(1H, d, J = 8.8 Hz), 7.48 (1H, dd, J = 2.0, 8.8 H
z), 7.63 (1H, d, J = 2.0 Hz), 8.20 (1H, d, J = 8.4
Hz), 8.45 (1H, dd, J = 1.2, 8.4 Hz), 9.56 (1H,
s), 10.69 (1H, br.s) 実施例４３） 4-[(3-クロロ-4-メトキシベンジル)アミノ]-1-[4-フル
オロ-4-(ヒドロキシメチル)ピペリジノ]-6-フタラジン
カルボニトリル塩酸塩 ¹ H NMR (DMSO-d ₆ ) δ; 1.07 (3H, d, J =
6.0 Hz), 1.34-1.60 (3H, m), 1.65-1.76 (2H, m), 1.8
6-1.94 (2H, m), 2.75-2.86 (2H, m), 3.55-3.63 (2H, m
m), 3.82 (3H, s), 4.73 (2H, d, J = 5.6 Hz), 7.13
(1H, d, J = 8.8 Hz), 7.48 (1H, dd, J = 2.0, 8.8 H
z), 7.63 (1H, d, J = 2.0 Hz), 8.20 (1H, d, J = 8.4
Hz), 8.45 (1H, dd, J = 1.2, 8.4 Hz), 9.56 (1H,
s), 10.69 (1H, br.s) Example 43) 4-[(3-chloro-4-methoxybenzyl) amino] -1- [4-fluoro-4- (hydroxymethyl) piperidino] -6-phthal Razine carbonitrile hydrochloride

【０２４３】[0243]

【化９４】 Embedded image

【０２４４】¹H NMR (DMSO-d₆) δ; 1.69-1.77 (2H,
m), 1.83-2.08 (2H, m), 3.05-3.16 (2H, m), 3.48 (2
H, d, J = 20.0 Hz), 3.82 (3H, s), 4.74 (2H, d, J =
5.6 Hz),7.14 (1H, d, J = 8.8 Hz), 7.48 (1H, dd, J
= 2.0, 8.8 Hz), 7.63 (1H, d,J = 2.0 Hz), 8.26 (1
H, d, J = 8.4 Hz), 8.46 (1H, dd, J = 1.2, 8.4 Hz),
9.57 (1H, s), 10.73 (1H, br.s) 実施例４４ 4-[(3-クロロ-4-メトキシベンジル)アミノ]-1-[4-(ヒド
ロキシメチル)-4-メトキシピペリジノ]-6-フタラジンカ
ルボニトリル塩酸塩 ¹ H NMR (DMSO-d ₆ ) δ; 1.69-1.77 (2H,
m), 1.83-2.08 (2H, m), 3.05-3.16 (2H, m), 3.48 (2
H, d, J = 20.0 Hz), 3.82 (3H, s), 4.74 (2H, d, J =
5.6 Hz), 7.14 (1H, d, J = 8.8 Hz), 7.48 (1H, dd, J
= 2.0, 8.8 Hz), 7.63 (1H, d, J = 2.0 Hz), 8.26 (1
H, d, J = 8.4 Hz), 8.46 (1H, dd, J = 1.2, 8.4 Hz),
9.57 (1H, s), 10.73 (1H, br.s) Example 44 4-[(3-chloro-4-methoxybenzyl) amino] -1- [4- (hydroxymethyl) -4-methoxypiperidino ] -6-Phthalazinecarbonitrile hydrochloride

【０２４５】[0245]

【化９５】 Embedded image

【０２４６】¹H NMR (DMSO-d₆) δ; 1.71-1.86 (4H,m),
3.04-3.16 (2H,m), 3.16 (3H, s), 3.41 (2H, s), 3.8
3 (3H, s), 4.72 (2H, d, J = 5.6 Hz), 7.14 (1H, d,
J = 8.4 Hz), 7.46 (1H, dd, J = 2.0, 8.4 Hz), 7.61
(1H, d, J = 2.0 Hz), 8.23 (1H, d, J = 8.8 Hz), 8.4
4 (1H, dd, J = 1.2, 8.8 Hz), 9.48 (1H, s), 10.46
(1H, brs) 実施例４５ 4-[(3-クロロ-4-メトキシベンジル)アミノ]-1-(2-ヒド
ロキシ-6-アザスピロ[3.4]オクト-6-イル)-6-フタラジ
ンカルボニトリル塩酸塩 ¹ H NMR (DMSO-d ₆ ) δ; 1.71-1.86 (4H, m),
3.04-3.16 (2H, m), 3.16 (3H, s), 3.41 (2H, s), 3.8
3 (3H, s), 4.72 (2H, d, J = 5.6 Hz), 7.14 (1H, d,
J = 8.4 Hz), 7.46 (1H, dd, J = 2.0, 8.4 Hz), 7.61
(1H, d, J = 2.0 Hz), 8.23 (1H, d, J = 8.8 Hz), 8.4
4 (1H, dd, J = 1.2, 8.8 Hz), 9.48 (1H, s), 10.46
(1H, brs) Example 45 4-[(3-Chloro-4-methoxybenzyl) amino] -1- (2-hydroxy-6-azaspiro [3.4] oct-6-yl) -6-phthalazinecarbonitrile Hydrochloride

【０２４７】[0247]

【化９６】 Embedded image

【０２４８】¹H NMR (DMSO-d₆) δ; 1.00-1.08 (2H,
m), 1.82-2.04 (4H, m), 2.19-2.35 (2H, m), 3.32-3.4
5 (2H, m), 3.55-3.60 (2H, m), 3.80 (3H, s), 4.04-
4.19 (1H,m), 4.56 (2H, br.s), 7.10 (1H, d, J = 8.4
Hz), 7.37 (1H, br.s), 7.50 (1H, br.s), 8.38 (1H,
d, J = 8.4 Hz), 8.45-8.73 (1H, m) 実施例４６ 4-[(3-クロロ-4-メトキシベンジル)アミノ]-1-[3-(ヒド
ロキシメチル)-2,5-ジヒドロ-1H-1-ピロリル]-6-フタラ
ジンカルボニトリル塩酸塩 ¹ H NMR (DMSO-d ₆ ) δ; 1.00-1.08 (2H,
m), 1.82-2.04 (4H, m), 2.19-2.35 (2H, m), 3.32-3.4
5 (2H, m), 3.55-3.60 (2H, m), 3.80 (3H, s), 4.04-
4.19 (1H, m), 4.56 (2H, br.s), 7.10 (1H, d, J = 8.4
Hz), 7.37 (1H, br.s), 7.50 (1H, br.s), 8.38 (1H, br.s)
d, J = 8.4 Hz), 8.45-8.73 (1H, m) Example 46 4-[(3-chloro-4-methoxybenzyl) amino] -1- [3- (hydroxymethyl) -2,5-dihydro -1H-1-pyrrolyl] -6-phthalazinecarbonitrile hydrochloride

【０２４９】[0249]

【化９７】 Embedded image

【０２５０】¹H NMR (DMSO-d₆) δ; 3.82 (3H, s), 4.1
2 (2H, s), 4.45-4.83 (6H, m), 5.84(1H, brs), 7.11
(1H, d, J = 9 Hz,), 7.33-7.56 (2H, m), 8.45 (1H,
d, J =9 Hz), 8.66-9.14 (2H, m) 実施例４７ 4-[(3-クロロ-4-メトキシベンジル)アミノ]-1-[(3R,4S)
-3,4-ジ(ヒドロキシメチル)テトラヒドロ-1H-1-ピロリ
ル]-6-フタラジンカルボニトリル塩酸塩[0250] _{^{1 H NMR (DMSO-d 6}} ) δ; 3.82 (3H, s), 4.1
2 (2H, s), 4.45-4.83 (6H, m), 5.84 (1H, brs), 7.11
(1H, d, J = 9 Hz,), 7.33-7.56 (2H, m), 8.45 (1H,
d, J = 9 Hz), 8.66-9.14 (2H, m) Example 47 4-[(3-chloro-4-methoxybenzyl) amino] -1-[(3R, 4S)
-3,4-di (hydroxymethyl) tetrahydro-1H-1-pyrrolyl] -6-phthalazinecarbonitrile hydrochloride

【０２５１】[0251]

【化９８】 Embedded image

【０２５２】¹H NMR (DMSO-d₆) δ; 2.50-2.57 (2H,
m), 3.38-3.49 (2H, m), 3.56-3.60 (2H, m), 3.76-3.8
7 (4H, m), 3.81 (3H, s), 4.55 (2H, brs), 7.10 (1H,
d, J =8.4 Hz), 7.36 (1H, d, J = 7.6 Hz), 7.49 (1
H,s), 8.41 (1H, d, J = 8.4 Hz), 8.68 (1H, d, J =
8.4 Hz), 9.13 (1H, s) 実施例４８ 1-[4-[(3-クロロ-4-メトキシベンジル)アミノ]-6-シア
ノ-1-フタラジニル]-4-ヒドロキシ-4-ピペリジンカルボ
キサミド塩酸塩[0252] _{^{1 H NMR (DMSO-d 6}} ) δ; 2.50-2.57 (2H,
m), 3.38-3.49 (2H, m), 3.56-3.60 (2H, m), 3.76-3.8
7 (4H, m), 3.81 (3H, s), 4.55 (2H, brs), 7.10 (1H,
d, J = 8.4 Hz), 7.36 (1H, d, J = 7.6 Hz), 7.49 (1
H, s), 8.41 (1H, d, J = 8.4 Hz), 8.68 (1H, d, J =
8.4 Hz), 9.13 (1H, s) Example 48 1- [4-[(3-Chloro-4-methoxybenzyl) amino] -6-cyano-1-phthalazinyl] -4-hydroxy-4-piperidinecarboxamide hydrochloride salt

【０２５３】[0253]

【化９９】 Embedded image

【０２５４】¹H NMR (DMSO-d₆) δ; 1.56-1.64 (2H,
m), 2.16-2.28 (2H, m), 3.12-3.24 (2H, m), 3.32-3.4
8 (2H, m),3.54 (1H, brs), 3.83 (3H, s), 4.10-4.30
(1H, m),4.74 (2H, s), 7.13 (1H, d, J = 8.4 Hz), 7.
15 (1H, brs), 7.31 (1H, brs),7.48 (1H, d, J = 8.4
Hz), 7.64 (1H, s), 8.26 (1H, d, J = 8.4 Hz), 8.44
(1H, d, J = 8.4 Hz), 9.52-9.60 (1H, m) 実施例４９ [4-[(3-クロロ-4-メトキシベンジル)アミノ]-1-[4-(フ
ルオロメチル)-4-ヒドロキシピペリジノ]-6-フタラジン
カルボニトリル塩酸塩 ¹ H NMR (DMSO-d ₆ ) δ; 1.56-1.64 (2H,
m), 2.16-2.28 (2H, m), 3.12-3.24 (2H, m), 3.32-3.4
8 (2H, m), 3.54 (1H, brs), 3.83 (3H, s), 4.10-4.30
(1H, m), 4.74 (2H, s), 7.13 (1H, d, J = 8.4 Hz), 7.
15 (1H, brs), 7.31 (1H, brs), 7.48 (1H, d, J = 8.4
Hz), 7.64 (1H, s), 8.26 (1H, d, J = 8.4 Hz), 8.44
(1H, d, J = 8.4 Hz), 9.52-9.60 (1H, m) Example 49 [4-[(3-chloro-4-methoxybenzyl) amino] -1- [4- (fluoromethyl) -4 -Hydroxypiperidino] -6-phthalazinecarbonitrile hydrochloride

【０２５５】[0255]

【化１００】 Embedded image

【０２５６】¹H NMR (DMSO-d₆) δ; 1.54-1.64 (2H,
m), 1.80-1.92 (2H, m), 3.18-3.26 (2H, m), 3.32-3.4
4 (4H, m), 3.83 (3H, s), 4.22 (2H, d, J = 7.6 Hz),
4.72 (1H, d, J = 6.0 Hz), 7.14 (1H, d, J = 8.4 H
z), 7.48 (1H, dd, J = 8.4,1.6 Hz), 7.62 (1H, d, J
= 1.6 Hz), 8.23 (1H, d, J = 8.4 Hz), 8.45 (1H, d,
J =8.4 Hz), 9.45 (1H, brs) 実施例５０ 4-[(3-クロロ-4-メトキシベンジル)アミノ]-1-(4-ヒド
ロキシイミノピペリジノ)-6-フタラジンカルボニトリル
塩酸塩 ¹ H NMR (DMSO-d ₆ ) δ; 1.54-1.64 (2H,
m), 1.80-1.92 (2H, m), 3.18-3.26 (2H, m), 3.32-3.4
4 (4H, m), 3.83 (3H, s), 4.22 (2H, d, J = 7.6 Hz),
4.72 (1H, d, J = 6.0 Hz), 7.14 (1H, d, J = 8.4 H
z), 7.48 (1H, dd, J = 8.4, 1.6 Hz), 7.62 (1H, d, J
= 1.6 Hz), 8.23 (1H, d, J = 8.4 Hz), 8.45 (1H, d,
J = 8.4 Hz), 9.45 (1H, brs) Example 50 4-[(3-chloro-4-methoxybenzyl) amino] -1- (4-hydroxyiminopiperidino) -6-phthalazinecarbonitrile hydrochloride salt

【０２５７】[0257]

【化１０１】 Embedded image

【０２５８】¹H NMR (DMSO-d₆) δ; 2.50-2.52 (2H,
m), 2.74-2.80 (2H, m), 3.26-3.35 (4H, m), 3.85 (3
H, s), 4.71 (2H, br), 7.17 (1H, d, J = 8.8 Hz), 7.
45 (1H, dd, J = 8.8, 2.0 Hz), 7.60 (1H, d, J = 2.0
Hz), 8.34 (1H, d, J = 8.4 Hz),8.49 (1H, dd, J =
8.4, 0.4 Hz), 9.34 (1H, d, J = 0.4 Hz), 10.53 (1H,
br) 実施例５１ (anti)-2-[3-[4-[(3-クロロ-4-メトキシベンジル)アミ
ノ]-6-シアノ-1-フタラジニル]-3-アザビシクロ[3.3.1]
ノン-9-イル]酢酸塩酸塩 ¹ H NMR (DMSO-d ₆ ) δ; 2.50-2.52 (2H,
m), 2.74-2.80 (2H, m), 3.26-3.35 (4H, m), 3.85 (3
H, s), 4.71 (2H, br), 7.17 (1H, d, J = 8.8 Hz), 7.
45 (1H, dd, J = 8.8, 2.0 Hz), 7.60 (1H, d, J = 2.0
Hz), 8.34 (1H, d, J = 8.4 Hz), 8.49 (1H, dd, J =
8.4, 0.4 Hz), 9.34 (1H, d, J = 0.4 Hz), 10.53 (1H,
br) Example 51 (anti) -2- [3- [4-[(3-chloro-4-methoxybenzyl) amino] -6-cyano-1-phthalazinyl] -3-azabicyclo [3.3.1]
Non-9-yl] acetic acid hydrochloride

【０２５９】[0259]

【化１０２】 Embedded image

【０２６０】¹H NMR (DMSO-d₆) δ; 1.62 (1H, m), 1.7
5-2.00 (4H, m), 2.12 (1H, m), 2.52(2H, d, J = 8.1
Hz), 3.16-3.24 (2H, m), 3.68-3.76 (2H, m), 3.85 (3
H, s), 4.74 (2H, s), 7.16 (1H, d, J = 8.6 Hz), 7.4
8 (1H, dd, J = 1.8, 8.6 Hz), 7.62 (1H, d, J = 1.8H
z), 8.23 (1H, d, J = 8.4 Hz), 8.55 (1H, dd, J = 1.
3, 8.4 Hz), 9.48 (1H, m). 実施例５２ (endo)-4-[(3-クロロ-4-メトキシベンジル)アミノ]-1-
(3-ヒドロキシ-8-アザビシクロ[3.2.1]オクト-8-イル)-
6-フタラジンカルボニトリル塩酸塩[0260] _{^{1 H NMR (DMSO-d 6}} ) δ; 1.62 (1H, m), 1.7
5-2.00 (4H, m), 2.12 (1H, m), 2.52 (2H, d, J = 8.1
Hz), 3.16-3.24 (2H, m), 3.68-3.76 (2H, m), 3.85 (3
H, s), 4.74 (2H, s), 7.16 (1H, d, J = 8.6 Hz), 7.4
8 (1H, dd, J = 1.8, 8.6 Hz), 7.62 (1H, d, J = 1.8H
z), 8.23 (1H, d, J = 8.4 Hz), 8.55 (1H, dd, J = 1.
Example 52 (endo) -4-[(3-chloro-4-methoxybenzyl) amino] -1- (3, 8.4 Hz), 9.48 (1H, m).
(3-hydroxy-8-azabicyclo [3.2.1] oct-8-yl)-
6-phthalazinecarbonitrile hydrochloride

【０２６１】[0261]

【化１０３】 Embedded image

【０２６２】¹H NMR (DMSO-d₆) δ; 1.81-1.88 (2H,
m), 1.90-1.98 (2H, m), 2.19-2.30 (4H, m), 3.85 (3
H, s), 4.04 (1H, m), 4.16-4.26 (2H, m), 4.71 (2H,
s), 7.16(1H, d, J = 8.6 Hz), 7.46 (1H, d, J = 8.6
Hz), 7.61 (1H, s), 8.29 (1H, d, J = 8.4 Hz), 8.47
(1H, dd, J = 1.3, 8.4 Hz), 9.44 (1H,m) 実施例５３ (syn)-4-[(3-クロロ-4-メトキシベンジル)アミノ]-1-(9
-ヒドロキシ-3-アザビシクロ[3.3.1]ノン-3-イル)-6-フ
タラジンカルボニトリル 塩酸塩 ¹ H NMR (DMSO-d ₆ ) δ; 1.81-1.88 (2H,
m), 1.90-1.98 (2H, m), 2.19-2.30 (4H, m), 3.85 (3
H, s), 4.04 (1H, m), 4.16-4.26 (2H, m), 4.71 (2H,
s), 7.16 (1H, d, J = 8.6 Hz), 7.46 (1H, d, J = 8.6
Hz), 7.61 (1H, s), 8.29 (1H, d, J = 8.4 Hz), 8.47
(1H, dd, J = 1.3, 8.4 Hz), 9.44 (1H, m) Example 53 (syn) -4-[(3-chloro-4-methoxybenzyl) amino] -1- (9
-Hydroxy-3-azabicyclo [3.3.1] non-3-yl) -6-phthalazinecarbonitrile hydrochloride

【０２６３】[0263]

【化１０４】 Embedded image

【０２６４】¹H NMR (DMSO-d₆) δ; 1.53 (1H,m), 1.74
-1.86 (2H, m), 1.87-1.93 (2H, m),2.05-2.14 (2H,
m), 2.37 (1H, m), 3.28-3.44 (2H, m), 3.41-3.61 (2
H, m), 3.68 (1H, m), 3.85 (3H, s), 4.73 (2H, s),
7.15 (1H, d, J = 8.6 Hz), 7.47(1H, d, J = 8.6 Hz),
7.62 (1H, s), 8.22 (1H, d, J = 8.6 Hz), 8.54 (1H,
d, J = 8.6 Hz), 9.48 (1H, m) 実施例５４ (syn)-4-[(3-クロロ-4)アミノ]-1-(8-ヒドロキシ-3-ア
ザビシクロ[3.2.1]オクト-3-イル)-6-フタラジンカルボ
ニトリル塩酸塩[0264] _{^{1 H NMR (DMSO-d 6}} ) δ; 1.53 (1H, m), 1.74
-1.86 (2H, m), 1.87-1.93 (2H, m), 2.05-2.14 (2H, m
m), 2.37 (1H, m), 3.28-3.44 (2H, m), 3.41-3.61 (2
H, m), 3.68 (1H, m), 3.85 (3H, s), 4.73 (2H, s),
7.15 (1H, d, J = 8.6 Hz), 7.47 (1H, d, J = 8.6 Hz),
7.62 (1H, s), 8.22 (1H, d, J = 8.6 Hz), 8.54 (1H,
d, J = 8.6 Hz), 9.48 (1H, m) Example 54 (syn) -4-[(3-chloro-4) amino] -1- (8-hydroxy-3-azabicyclo [3.2.1] oct -3-yl) -6-phthalazinecarbonitrile hydrochloride

【０２６５】[0265]

【化１０５】 Embedded image

【０２６６】¹H NMR (DMSO-d₆) δ; 1.75-1.96 (4H,
m), 2.02-2.09 (2H, m), 3.06-3.18 (2H, m), 3.50-3.6
0 (2H, m), 3.86 (3H, s), 3.91 (1H, t, J = 4.8 Hz),
4.73 (2H, s), 7.16 (1H, d, J = 8.6 Hz), 7.47 (1H,
d, J = 8.6 Hz), 7.61 (1H, s),8.36 (1H, d, J = 8.6
Hz), 8.48 (1H, dd, J = 1.5, 8.6 Hz), 9.43 (1H,
m). 実施例５５ (exo)-4-[(3-クロロ-4-メトキシベンジル)アミノ]-1-(3
-ヒドロキシ-8-アザビシクロ[3.2.1]オクト-8-イル)-6-
フタラジンカルボニトリル塩酸塩 ¹ H NMR (DMSO-d ₆ ) δ; 1.75-1.96 (4H,
m), 2.02-2.09 (2H, m), 3.06-3.18 (2H, m), 3.50-3.6
0 (2H, m), 3.86 (3H, s), 3.91 (1H, t, J = 4.8 Hz),
4.73 (2H, s), 7.16 (1H, d, J = 8.6 Hz), 7.47 (1H,
d, J = 8.6 Hz), 7.61 (1H, s), 8.36 (1H, d, J = 8.6
Hz), 8.48 (1H, dd, J = 1.5, 8.6 Hz), 9.43 (1H,
m). Example 55 (exo) -4-[(3-chloro-4-methoxybenzyl) amino] -1- (3
-Hydroxy-8-azabicyclo [3.2.1] oct-8-yl) -6-
Phthalazine carbonitrile hydrochloride

【０２６７】[0267]

【化１０６】 Embedded image

【０２６８】¹H NMR (DMSO-d₆) δ; 1.68-1.83 (2H,
m), 1.90-2.02 (4H, m), 3.85 (3H, s),3.97 (1H, m),
4.18-4.28 (2H, m), 4.70 (2H, s), 7.15 (1H, d, J =
8.6 Hz), 7.44 (1H, d, J = 8.6 Hz), 7.59 (1H, s),
8.29 (1H, d, J = 8.6 Hz), 8.45(1H, d, J = 8.6 Hz),
9.36 (1H, m) 実施例５６ (anti)-4-[(3-クロロ-4-メトキシベンジル)アミノ]-1-
(9-ヒドロキシ-3-オキサ-7-アザビシクロ[3.3.1]ノン-7
-イル)-6-フタラジンカルボニトリル 塩酸塩[0268] _{^{1 H NMR (DMSO-d 6}} ) δ; 1.68-1.83 (2H,
m), 1.90-2.02 (4H, m), 3.85 (3H, s), 3.97 (1H, m),
4.18-4.28 (2H, m), 4.70 (2H, s), 7.15 (1H, d, J =
8.6 Hz), 7.44 (1H, d, J = 8.6 Hz), 7.59 (1H, s),
8.29 (1H, d, J = 8.6 Hz), 8.45 (1H, d, J = 8.6 Hz),
9.36 (1H, m) Example 56 (anti) -4-[(3-chloro-4-methoxybenzyl) amino] -1-
(9-hydroxy-3-oxa-7-azabicyclo [3.3.1] non-7
-Yl) -6-phthalazinecarbonitrile hydrochloride

【０２６９】[0269]

【化１０７】 Embedded image

【０２７０】¹H NMR (DMSO-d₆) δ; 1.69-1.76 (2H,
m), 3.24-3.38 (2H, m), 3.73-3.83 (2H, m), 3.85 (3
H, s) 3.85-3.93 (2H, m), 4.11-4.20 (2H, m), 4.73
(2H, s), 7.16 (1H, d, J = 8.6 Hz), 7.47 (1H, d, J
= 8.6 Hz), 7.62 (1H, s), 8.36 (1H,d, J = 8.4 Hz),
8.52 (1H, d, J = 8.4 Hz), 9.43 (1H, m) 実施例５７ (anti)-4-[(3-クロロ-4-メトキシベンジル)アミノ]-1-
(3-ヒドロキシ-9-アザビシクロ[3.3.1]ノン-9-イル)-6-
フタラジンカルボニトリル塩酸塩 ¹ H NMR (DMSO-d ₆ ) δ; 1.69-1.76 (2H,
m), 3.24-3.38 (2H, m), 3.73-3.83 (2H, m), 3.85 (3
H, s) 3.85-3.93 (2H, m), 4.11-4.20 (2H, m), 4.73
(2H, s), 7.16 (1H, d, J = 8.6 Hz), 7.47 (1H, d, J
= 8.6 Hz), 7.62 (1H, s), 8.36 (1H, d, J = 8.4 Hz),
8.52 (1H, d, J = 8.4 Hz), 9.43 (1H, m) Example 57 (anti) -4-[(3-chloro-4-methoxybenzyl) amino] -1-
(3-hydroxy-9-azabicyclo [3.3.1] non-9-yl) -6-
Phthalazine carbonitrile hydrochloride

【０２７１】[0271]

【化１０８】 Embedded image

【０２７２】¹H NMR (DMSO-d₆) δ; 1.38-1.54 (4H,
m), 1.59 (1H, m), 1.90-2.02 (2H, m),2.22-2.45 (3H,
m), 3.86 (3H, s), 3.87 (1H, m), 4.08-4.17 (2H,
m), 4.69(2H, s), 7.16 (1H, d, J = 8.6 Hz), 7.44 (1
H, d, J = 8.6 Hz), 7.58 (1H, s), 8.07 (1H, d, J =
8.6 Hz), 8.44 (1H, d, J = 8.6 Hz), 9.29 (1H, m) 実施例５８ N¹-[3-[4-[(3-クロロ-4-メトキシベンジル)アミノ]-６
−シアノ-1-フタラジニル]フェニル]アセタミド ¹ H NMR (DMSO-d ₆ ) δ; 1.38-1.54 (4H,
m), 1.59 (1H, m), 1.90-2.02 (2H, m), 2.22-2.45 (3H,
m), 3.86 (3H, s), 3.87 (1H, m), 4.08-4.17 (2H,
m), 4.69 (2H, s), 7.16 (1H, d, J = 8.6 Hz), 7.44 (1
H, d, J = 8.6 Hz), 7.58 (1H, s), 8.07 (1H, d, J =
8.6 Hz), 8.44 (1H, d, J = 8.6 Hz), 9.29 (1H, m) Example ^{58 N 1 - [3- [4} - [(3- chloro-4-methoxybenzyl) amino] -6
-Cyano-1-phthalazinyl] phenyl] acetamide

【０２７３】[0273]

【化１０９】 Embedded image

【０２７４】¹H NMR (DMSO-d₆) δ; 2.05 (3H, s), 3.8
1 (3H, s), 4.76 (2H, d, J = 6.0 Hz), 7.09 (1H, d,
J = 8.4 Hz), 7.24 (1H, d, J = 8.0 Hz), 7.38 (1H, d
d, J =8.0, 1.6 Hz), 7.45 (1H, dd, J = 8.4, 8.0 H
z), 7.50 (1H, d, J = 1.6 Hz),7.67 (1H, d, J = 8.0
Hz), 7.86 (1H, m), 7.92 (1H, d, J = 8.4 Hz), 8.17
(1H, dd, J = 8.4, 1.6 Hz), 8.35 (1H, dd, J = 6.0,
6.0 Hz), 9.00 (1H, s),10.09 (1H, s) 実施例５９ 1-(3-アミノフェニル)-4-[(3-クロロ-4-メトキシベンジ
ル)アミノ]-６−フタラジンカルボニトリル・二塩酸塩 ¹ H NMR (DMSO-d ₆ ) δ; 2.05 (3H, s), 3.8
1 (3H, s), 4.76 (2H, d, J = 6.0 Hz), 7.09 (1H, d,
J = 8.4 Hz), 7.24 (1H, d, J = 8.0 Hz), 7.38 (1H, d
d, J = 8.0, 1.6 Hz), 7.45 (1H, dd, J = 8.4, 8.0 H
z), 7.50 (1H, d, J = 1.6 Hz), 7.67 (1H, d, J = 8.0
Hz), 7.86 (1H, m), 7.92 (1H, d, J = 8.4 Hz), 8.17
(1H, dd, J = 8.4, 1.6 Hz), 8.35 (1H, dd, J = 6.0,
6.0 Hz), 9.00 (1H, s), 10.09 (1H, s) Example 59 1- (3-Aminophenyl) -4-[(3-chloro-4-methoxybenzyl) amino] -6-phthalazinecarbo Nitrile dihydrochloride

【０２７５】[0275]

【化１１０】 Embedded image

【０２７６】¹H NMR (DMSO-d₆) δ; 3.83 (3H, s), 4.8
9 (2H, brs), 7.16 (1H, d, J = 8.6Hz), 7.38-7.44 (3
H, m), 7.53 (1H, dd, J = 8.6, 2.0 Hz) , 7.58-7.62
(2H,m), 7.68 (1H, d, J = 2.0 Hz), 8.02 (1H, d, J =
8.4 Hz), 8.45 (1H, d, J =8.4 Hz), 9.65 (1H, s) 実施例６０ N-[3-[4-[(3-クロロ-4-メトキシベンジル)アミノ]-６-
シアノ-1-フタラジニル]フェニル]メタンスルホンアミ
ド塩酸塩 ¹ H NMR (DMSO-d ₆ ) δ; 3.83 (3H, s), 4.8
9 (2H, brs), 7.16 (1H, d, J = 8.6Hz), 7.38-7.44 (3
H, m), 7.53 (1H, dd, J = 8.6, 2.0 Hz), 7.58-7.62
(2H, m), 7.68 (1H, d, J = 2.0 Hz), 8.02 (1H, d, J =
8.4 Hz), 8.45 (1H, d, J = 8.4 Hz), 9.65 (1H, s) Example 60 N- [3- [4-[(3-chloro-4-methoxybenzyl) amino] -6-
Cyano-1-phthalazinyl] phenyl] methanesulfonamide hydrochloride

【０２７７】[0277]

【化１１１】 Embedded image

【０２７８】¹H NMR (DMSO-d₆) δ; 3.06 (3H, s), 3.8
4 (3H, s), 4.86 (2H, d, J = 5.6 Hz), 7.15 (1H, d,
J = 8.4 Hz), 7.35 (1H, d, J = 7.6 Hz), 7.43 (1H,
d, J =7.6 Hz), 7.50 (1H, brs), 7.53 (1H, dd, J =
8.4, 2.0 Hz), 7.55 (1H, dd, J= 7.6, 7.6 Hz), 7.66
(1H, d, J = 2.0 Hz), 8.03 (1H, d, J = 8.8 Hz), 8.4
4 (1H, d, J = 8.8 Hz), 9.60 (1H, brs), 10.14 (1H,
brs) 実施例６１ 4-[(3-クロロ-4-メトキシベンジル)アミノ]-1-[4-(メチ
ルスルフィニル)フェニル]-6-フタラジンカルボニトリ
ル塩酸塩 ¹ H NMR (DMSO-d ₆ ) δ; 3.06 (3H, s), 3.8
4 (3H, s), 4.86 (2H, d, J = 5.6 Hz), 7.15 (1H, d,
J = 8.4 Hz), 7.35 (1H, d, J = 7.6 Hz), 7.43 (1H,
d, J = 7.6 Hz), 7.50 (1H, brs), 7.53 (1H, dd, J =
8.4, 2.0 Hz), 7.55 (1H, dd, J = 7.6, 7.6 Hz), 7.66
(1H, d, J = 2.0 Hz), 8.03 (1H, d, J = 8.8 Hz), 8.4
4 (1H, d, J = 8.8 Hz), 9.60 (1H, brs), 10.14 (1H,
brs) Example 61 4-[(3-chloro-4-methoxybenzyl) amino] -1- [4- (methylsulfinyl) phenyl] -6-phthalazinecarbonitrile hydrochloride

【０２７９】[0279]

【化１１２】 Embedded image

【０２８０】¹H NMR (DMSO-d₆) δ; 2.84 (3H, s), 3.8
3 (3H, s), 4.87 (2H, brs), 7.16 (1H, d, J = 8.4 H
z), 7.51 (1H, d, J = 8.4 Hz), 7.66 (1H, brs), 7.83
(2H, d, J = 8.4 Hz), 7.92 (2H, d, J = 8.4 Hz), 8.
00 (1H, d, J =8.4 Hz), 8.43 (1H, d, J = 8.4 Hz),
9.52-9.60 (1H, m) 実施例６２ 4-[(3-クロロ-4-メトキシベンジル)アミノ]-1-[4-(メチ
ルスルホニル)フェニル]-6-フタラジンカルボニトリル
塩酸塩 ¹ H NMR (DMSO-d ₆ ) δ; 2.84 (3H, s), 3.8
3 (3H, s), 4.87 (2H, brs), 7.16 (1H, d, J = 8.4 H
z), 7.51 (1H, d, J = 8.4 Hz), 7.66 (1H, brs), 7.83
(2H, d, J = 8.4 Hz), 7.92 (2H, d, J = 8.4 Hz), 8.
00 (1H, d, J = 8.4 Hz), 8.43 (1H, d, J = 8.4 Hz),
9.52-9.60 (1H, m) Example 62 4-[(3-chloro-4-methoxybenzyl) amino] -1- [4- (methylsulfonyl) phenyl] -6-phthalazinecarbonitrile hydrochloride

【０２８１】[0281]

【化１１３】 Embedded image

【０２８２】¹H NMR (DMSO-d₆) δ; 3.31 (3H, s), 3.8
2 (3H, s), 4.80 (2H, brs), 7.12 (1H, d, J = 8.8 H
z), 7.43 (1H, dd, J = 8.8, 2.0 Hz), 7.56 (1H, d, J
= 2.0Hz), 7.90 (2H, d, J = 8.0 Hz), 7.93 (1H, d,
J = 8.4 Hz), 8.11 (2H, d, J= 8.0 Hz), 8.28 (1H, d,
J = 8.4 Hz), 9.19-9.22 (1H, m) 実施例６３ 4-[(3-クロロ-4-メトキシベンジル)アミノ]-1-(4-ホル
ミルフェニル)-6-フタラジンカルボニトリル塩酸塩 ¹ H NMR (DMSO-d ₆ ) δ; 3.31 (3H, s), 3.8
2 (3H, s), 4.80 (2H, brs), 7.12 (1H, d, J = 8.8 H
z), 7.43 (1H, dd, J = 8.8, 2.0 Hz), 7.56 (1H, d, J
= 2.0Hz), 7.90 (2H, d, J = 8.0 Hz), 7.93 (1H, d,
J = 8.4 Hz), 8.11 (2H, d, J = 8.0 Hz), 8.28 (1H, d,
J = 8.4 Hz), 9.19-9.22 (1H, m) Example 63 4-[(3-chloro-4-methoxybenzyl) amino] -1- (4-formylphenyl) -6-phthalazinecarbonitrile hydrochloride

【０２８３】[0283]

【化１１４】 Embedded image

【０２８４】¹H NMR (DMSO-d₆) δ; 3.84 (3H, s), 4.8
6 (2H, brs), 7.16 (1H, d, J = 8.4Hz), 7.51 (1H, d,
J = 8.4 Hz), 7.66 (1H, brs), 7.86 (2H, d, J = 8.0
Hz),7.99 (1H, d, J = 8.8 Hz), 8,13 (2H, d, J = 8.
0 Hz), 8.42 (1H, d, J = 8.8 Hz), 9.48-9.53 (1H,
m), 10.15 (1H, s) 実施例６４ 4-[(3-クロロ-4-メトキシベンジル)アミノ]-1-[4-(ヒド
ロキシメチル)フェニル]-6-フタラジンカルボニトリル
塩酸塩[0284] _{^{1 H NMR (DMSO-d 6}} ) δ; 3.84 (3H, s), 4.8
6 (2H, brs), 7.16 (1H, d, J = 8.4Hz), 7.51 (1H, d,
J = 8.4 Hz), 7.66 (1H, brs), 7.86 (2H, d, J = 8.0
Hz), 7.99 (1H, d, J = 8.8 Hz), 8,13 (2H, d, J = 8.
0 Hz), 8.42 (1H, d, J = 8.8 Hz), 9.48-9.53 (1H,
m), 10.15 (1H, s) Example 64 4-[(3-Chloro-4-methoxybenzyl) amino] -1- [4- (hydroxymethyl) phenyl] -6-phthalazinecarbonitrile hydrochloride

【０２８５】[0285]

【化１１５】 Embedded image

【０２８６】¹H NMR (DMSO-d₆) δ; 3.84 (3H, s), 4.6
2 (2H, s), 4.84 (2H, brs), 7.16 (1H, d, J = 8.4 H
z), 7.49 (1H, dd, J = 8.4, 2.0 Hz), 7.55 (2H, d, J
= 8.0Hz), 7.60 (2H, d, J = 8.0 Hz), 7.65 (1H, d,
J = 2.0 Hz), 8.02 (1H, d, J= 8.4 Hz), 8.43 (1H, d,
J = 8.4 Hz), 9.50-9.58 (1H, m) 実施例６５ 4-[4-[(3-クロロ-4-メトキシベンジル)アミノ]-6-シア
ノ-1-フタラジニル]安息香酸 ¹ H NMR (DMSO-d ₆ ) δ; 3.84 (3H, s), 4.6
2 (2H, s), 4.84 (2H, brs), 7.16 (1H, d, J = 8.4 H
z), 7.49 (1H, dd, J = 8.4, 2.0 Hz), 7.55 (2H, d, J
= 8.0Hz), 7.60 (2H, d, J = 8.0 Hz), 7.65 (1H, d,
J = 2.0 Hz), 8.02 (1H, d, J = 8.4 Hz), 8.43 (1H, d,
J = 8.4 Hz), 9.50-9.58 (1H, m) Example 65 4- [4-[(3-chloro-4-methoxybenzyl) amino] -6-cyano-1-phthalazinyl] benzoic acid

【０２８７】[0287]

【化１１６】 Embedded image

【０２８８】¹H NMR (DMSO-d₆) δ; 3.84 (3H, s), 4.7
6 (2H, d, J = 6.0 Hz), 7.10 (1H, d, J = 8.8 Hz),
7.38 (1H, dd, J = 8.8, 2.0 Hz), 7.50 (1H, d, J =
2.0 Hz),7.72 (2H, d, J = 8.4 Hz), 7.91 (1H, d, J =
8.8 Hz), 8.08 (2H, d, J = 8.4 Hz), 8.19 (1H, dd,
J = 8.4, 1.6 Hz), 8.44 (1H, dd, J = 6.0, 6.0 Hz),
9.01 (1H, d, J = 1.6 Hz) 実施例６６ 4-[(3-クロロ-4-メトキシベンジル)アミノ]-1-(1,3-チ
アゾール-2-イル)-6-フタラジンカルボニトリル塩酸塩 ¹ H NMR (DMSO-d ₆ ) δ; 3.84 (3H, s), 4.7
6 (2H, d, J = 6.0 Hz), 7.10 (1H, d, J = 8.8 Hz),
7.38 (1H, dd, J = 8.8, 2.0 Hz), 7.50 (1H, d, J =
2.0 Hz), 7.72 (2H, d, J = 8.4 Hz), 7.91 (1H, d, J =
8.8 Hz), 8.08 (2H, d, J = 8.4 Hz), 8.19 (1H, dd,
J = 8.4, 1.6 Hz), 8.44 (1H, dd, J = 6.0, 6.0 Hz),
9.01 (1H, d, J = 1.6 Hz) Example 66 4-[(3-Chloro-4-methoxybenzyl) amino] -1- (1,3-thiazol-2-yl) -6-phthalazinecarbonitrile Hydrochloride

【０２８９】[0289]

【化１１７】 Embedded image

【０２９０】¹H NMR (DMSO-d₆) δ; 3.80 (3H, s), 4.8
2 (2H, s), 7.13 (1H, d, J = 8.4 Hz), 7.42 (1H, d,
J = 8.4 Hz), 7.57 (1H, s), 7.94 (1H, d, J = 3.6 H
z), 8.11 (1H, d, J = 3.6 Hz), 8.46 (1H, d, J = 8.4
Hz), 9.20-9.26 (1H, m), 9.70(1H, d, J = 8.4 Hz) 実施例６７ 4-[(3-クロロ-4-メトキシベンジル)アミノ]-1-(3-ヒド
ロキシ-3-メチル-1-ブチニル)-6-フタラジンカルボニト
リル塩酸塩 ¹ H NMR (DMSO-d ₆ ) δ; 3.80 (3H, s), 4.8
2 (2H, s), 7.13 (1H, d, J = 8.4 Hz), 7.42 (1H, d,
J = 8.4 Hz), 7.57 (1H, s), 7.94 (1H, d, J = 3.6 H
z), 8.11 (1H, d, J = 3.6 Hz), 8.46 (1H, d, J = 8.4
Hz), 9.20-9.26 (1H, m), 9.70 (1H, d, J = 8.4 Hz) Example 67 4-[(3-chloro-4-methoxybenzyl) amino] -1- (3-hydroxy-3 -Methyl-1-butynyl) -6-phthalazinecarbonitrile hydrochloride

【０２９１】[0291]

【化１１８】 Embedded image

【０２９２】¹H NMR (DMSO-d₆) δ; 1.57 (6H, s), 3.8
4 (3H, s), 4.84 (2H, s), 7.15 (1H,d, J = 8.8 Hz),
7.46 (1H, dd, J = 8.8, 2.0 Hz), 7.61 (1H, d, J =
2.0 Hz), 8.34 (1H, d, J = 8.4 Hz), 8.52 (1H, dd, J
= 8.4, 0.4 Hz), 9.04 (1H, d, J = 0.4 Hz), 10.36
(1H, br) 実施例６８ 4-[(3-クロロ-4-メトキシベンジル)アミノ]-1-(3-ヒド
ロキシ-1-プロピニル)-6-フタラジンカルボニトリル塩
酸塩 ¹ H NMR (DMSO-d ₆ ) δ; 1.57 (6H, s), 3.8
4 (3H, s), 4.84 (2H, s), 7.15 (1H, d, J = 8.8 Hz),
7.46 (1H, dd, J = 8.8, 2.0 Hz), 7.61 (1H, d, J =
2.0 Hz), 8.34 (1H, d, J = 8.4 Hz), 8.52 (1H, dd, J
= 8.4, 0.4 Hz), 9.04 (1H, d, J = 0.4 Hz), 10.36
Example 68 4-[(3-Chloro-4-methoxybenzyl) amino] -1- (3-hydroxy-1-propynyl) -6-phthalazinecarbonitrile hydrochloride

【０２９３】[0293]

【化１１９】 Embedded image

【０２９４】¹H NMR (DMSO-d₆) δ; 3.84 (3H, s), 4.4
9 (2H, s), 4.81 (2H, d, J = 4.0 Hz), 7.14 (1H, d,
J = 8.4 Hz), 7.43 (1H, dd, J = 8.4, 2.4 Hz), 7.58
(1H, d, J = 2.4 Hz), 8.35 (1H, d, J = 8.8 Hz), 8.4
8 (1H, dd, J = 8.8, 0.8 Hz),9.28 (1H, d, J = 0.8 H
z), 9.92 (1H, br) 実施例６９ 4-[(3-クロロ-4-メトキシベンジル)アミノ]-1-[3,4-ジ
ヒドロキシ-3-(ヒドロキシメチル)-1-ブチニル]-6-フタ
ラジンカルボニトリル ¹ H NMR (DMSO-d ₆ ) δ; 3.84 (3H, s), 4.4
9 (2H, s), 4.81 (2H, d, J = 4.0 Hz), 7.14 (1H, d,
J = 8.4 Hz), 7.43 (1H, dd, J = 8.4, 2.4 Hz), 7.58
(1H, d, J = 2.4 Hz), 8.35 (1H, d, J = 8.8 Hz), 8.4
8 (1H, dd, J = 8.8, 0.8 Hz), 9.28 (1H, d, J = 0.8 H
z), 9.92 (1H, br) Example 69 4-[(3-chloro-4-methoxybenzyl) amino] -1- [3,4-dihydroxy-3- (hydroxymethyl) -1-butynyl] -6 -Phthalazine carbonitrile

【０２９５】[0295]

【化１２０】 Embedded image

【０２９６】¹H NMR (DMSO-d₆) δ; 3.54-3.66 (4H,
m), 3.82 (3H, s), 4.76 (2H, d, J = 5.2 Hz), 4.98
(2H, t, J = 5.2 Hz), 5.62 (1H, s), 7.10 (1H, d, J
= 8.8 Hz), 7.36 (1H, dd, J = 8.8, 2.0 Hz), 7.49 (1
H, d, J = 2.0 Hz), 8.29-8.34 (1H, m), 8.51 (1H, t,
J = 5.2 Hz), 8.96 (1H, s) 実施例７０ 4-[(3-クロロ-4-メトキシベンジル)アミノ]-1-[3-(ジメ
チルアミノ)-1-プロピニル]-6-フタラジンカルボニトリ
ル・二塩酸塩 ¹ H NMR (DMSO-d ₆ ) δ; 3.54-3.66 (4H,
m), 3.82 (3H, s), 4.76 (2H, d, J = 5.2 Hz), 4.98
(2H, t, J = 5.2 Hz), 5.62 (1H, s), 7.10 (1H, d, J
= 8.8 Hz), 7.36 (1H, dd, J = 8.8, 2.0 Hz), 7.49 (1
H, d, J = 2.0 Hz), 8.29-8.34 (1H, m), 8.51 (1H, t,
J = 5.2 Hz), 8.96 (1H, s) Example 70 4-[(3-chloro-4-methoxybenzyl) amino] -1- [3- (dimethylamino) -1-propynyl] -6-phthalazine Carbonitrile dihydrochloride

【０２９７】[0297]

【化１２１】 Embedded image

【０２９８】¹H NMR (DMSO-d₆) δ; 2.91 (6H, s), 3.8
3 (3H, s), 4.52 (2H, s), 4.83 (2H,d, J = 4.8 Hz),
7.13 (1H, d, J = 8.8 Hz), 7.42 (1H, dd, J = 8.8,
2.0 Hz), 7.56 (1H, d, J = 2.0 Hz), 8.40 (1H, dd, J
= 8.4, 1.4 Hz), 8.46 (1H, d, J = 8.4 Hz), 9.27 (1
H, d, J = 1.4 Hz), 9.76 (1H, br), 11.39 (1H, br) 実施例７１ 2-[[3-[4-[(3-クロロ-4-メトキシベンジル)アミノ]-6-
シアノ-1-フタラジニル]-1,1-ジメチル-2-プロピニル]
オキシ]酢酸塩酸塩[0298] _{^{1 H NMR (DMSO-d 6}} ) δ; 2.91 (6H, s), 3.8
3 (3H, s), 4.52 (2H, s), 4.83 (2H, d, J = 4.8 Hz),
7.13 (1H, d, J = 8.8 Hz), 7.42 (1H, dd, J = 8.8,
2.0 Hz), 7.56 (1H, d, J = 2.0 Hz), 8.40 (1H, dd, J
= 8.4, 1.4 Hz), 8.46 (1H, d, J = 8.4 Hz), 9.27 (1
H, d, J = 1.4 Hz), 9.76 (1H, br), 11.39 (1H, br) Example 71 2-[[3- [4-[(3-chloro-4-methoxybenzyl) amino] -6 -
Cyano-1-phthalazinyl] -1,1-dimethyl-2-propynyl]
Oxy] acetic acid hydrochloride

【０２９９】[0299]

【化１２２】 Embedded image

【０３００】¹H NMR (DMSO-d₆) δ; 1.62 (6H, s), 3.8
4 (3H, s), 4.21-4.24 (2H, m), 4.77-4.82 (2H, br),
7.11-7.15 (1H, m), 7.38-7.42 (1H, m), 7.51-7.55 (1
H, m),8.19-8.24 (1H, m), 8.38-8.42 (1H, m), 9.12-
9.16 (1H, m) 実施例７２ 4-[(3-クロロ-4-メトキシベンジル)アミノ]-1-[3-(2-ヒ
ドロキシエトキシ)-3-メチル-1-ブチニル]-6-フタラジ
ンカルボニトリル塩酸塩 ¹ H NMR (DMSO-d ₆ ) δ; 1.62 (6H, s), 3.8
4 (3H, s), 4.21-4.24 (2H, m), 4.77-4.82 (2H, br),
7.11-7.15 (1H, m), 7.38-7.42 (1H, m), 7.51-7.55 (1
H, m), 8.19-8.24 (1H, m), 8.38-8.42 (1H, m), 9.12-
9.16 (1H, m) Example 72 4-[(3-chloro-4-methoxybenzyl) amino] -1- [3- (2-hydroxyethoxy) -3-methyl-1-butynyl] -6-phthalazine Carbonitrile hydrochloride

【０３０１】[0301]

【化１２３】 Embedded image

【０３０２】¹H NMR (DMSO-d₆) δ; 1.61 (6H, s), 3.5
5 (2H, t, J = 5.6 Hz), 3.65 (2H, t, J = 5.6 Hz),
3.84 (3H, s), 4.85 (2H, d, J = 4.8 Hz), 7.14 (1H,
d, J =8.6 Hz), 7.46 (1H, dd, J = 8.6, 2.2 Hz), 7.6
1 (1H, d, J = 2.2 Hz), 8.30(1H, d, J = 8.4 Hz), 8.
48 (1H, dd, J = 8.4, 1.6 Hz), 9.42 (1H, d, J = 1.6
Hz), 10.41 (1H, br) 実施例７３ 4-[(3-クロロ-4-メトキシベンジル)アミノ]-1-[3-(4-ヒ
ドロキシピペリジノ)-3-メチル-1-ブチニル]-6-フタラ
ジンカルボニトリル・二塩酸塩 ¹ H NMR (DMSO-d ₆ ) δ; 1.61 (6H, s), 3.5
5 (2H, t, J = 5.6 Hz), 3.65 (2H, t, J = 5.6 Hz),
3.84 (3H, s), 4.85 (2H, d, J = 4.8 Hz), 7.14 (1H,
d, J = 8.6 Hz), 7.46 (1H, dd, J = 8.6, 2.2 Hz), 7.6
1 (1H, d, J = 2.2 Hz), 8.30 (1H, d, J = 8.4 Hz), 8.
48 (1H, dd, J = 8.4, 1.6 Hz), 9.42 (1H, d, J = 1.6
Hz), 10.41 (1H, br) Example 73 4-[(3-chloro-4-methoxybenzyl) amino] -1- [3- (4-hydroxypiperidino) -3-methyl-1-butynyl] -6-phthalazinecarbonitrile dihydrochloride

【０３０３】[0303]

【化１２４】 Embedded image

【０３０４】¹H NMR (DMSO-d₆) d 1.79-2.04 (10H, m),
2.12-2.23 (1H, m), 3.04-3.19 (1H,m), 3.26-3.37 (2
H, m), 3.54-3.77 (1H, m), 3.82 (3H, s), 4.83 (2H,
d, J= 5.6 Hz), 7.12 (1H, d, J = 8.4 Hz), 7.43 (1H,
dd, J = 8.4, 1.2 Hz), 7.56 (1H, d, J = 1.2 Hz),
8.38 (1H, dd, J = 8.4, 0.8 Hz), 8.43 (1H, d, J =8.
4 Hz), 9.30 (1H, d, J = 0.8 Hz), 9.91 (1H, br), 1
1.40-11.66 (1H, m) 実施例７４ 4-[(3-クロロ-4-メトキシベンジル)アミノ]-1-(3-メチ
ル-3-テトラヒドロ-1H-1-ピロリル-1-ブチニル)-6-フタ
ラジンカルボニトリル・二塩酸塩 ¹ H NMR (DMSO-d ₆ ) d 1.79-2.04 (10H, m),
2.12-2.23 (1H, m), 3.04-3.19 (1H, m), 3.26-3.37 (2
H, m), 3.54-3.77 (1H, m), 3.82 (3H, s), 4.83 (2H,
d, J = 5.6 Hz), 7.12 (1H, d, J = 8.4 Hz), 7.43 (1H,
dd, J = 8.4, 1.2 Hz), 7.56 (1H, d, J = 1.2 Hz),
8.38 (1H, dd, J = 8.4, 0.8 Hz), 8.43 (1H, d, J = 8.
4 Hz), 9.30 (1H, d, J = 0.8 Hz), 9.91 (1H, br), 1
1.40-11.66 (1H, m) Example 74 4-[(3-chloro-4-methoxybenzyl) amino] -1- (3-methyl-3-tetrahydro-1H-1-pyrrolyl-1-butynyl) -6 -Phthalazinecarbonitrile dihydrochloride

【０３０５】[0305]

【化１２５】 Embedded image

【０３０６】¹H NMR (DMSO-d₆) δ; 1.85 (6H, s), 1.9
0-2.08 (4H, m), 3.30-3.42 (2H, m),3.60-3.72 (2H,
m), 3.83 (3H, s), 4.80 (2H, d, J = 5.2 Hz), 7.11
(1H, d,J = 8.4 Hz), 7.39 (1H, dd, J = 8.4, 2.0 H
z), 7.52 (1H, d, J = 2.0 Hz),8.28 (1H, d, J = 8.4
Hz), 8.36 (1H, dd, J = 8.4, 0.8 Hz), 9.14 (1H, d,
J= 0.8 Hz), 9.33 (1H, br), 11.89 (1H, m) 実施例７５ 1-(4-ヒドロキシピペリジノ)-4-[[4-メトキシ-3-(トリ
フルオロメチル)ベンジル]アミノ]-6-フタラジンカルボ
ニトリル塩酸塩 ¹ H NMR (DMSO-d ₆ ) δ; 1.85 (6H, s), 1.9
0-2.08 (4H, m), 3.30-3.42 (2H, m), 3.60-3.72 (2H,
m), 3.83 (3H, s), 4.80 (2H, d, J = 5.2 Hz), 7.11
(1H, d, J = 8.4 Hz), 7.39 (1H, dd, J = 8.4, 2.0 H
z), 7.52 (1H, d, J = 2.0 Hz), 8.28 (1H, d, J = 8.4
Hz), 8.36 (1H, dd, J = 8.4, 0.8 Hz), 9.14 (1H, d,
J = 0.8 Hz), 9.33 (1H, br), 11.89 (1H, m) Example 75 1- (4-hydroxypiperidino) -4-[[4-methoxy-3- (trifluoromethyl) benzyl] Amino] -6-phthalazinecarbonitrile hydrochloride

【０３０７】[0307]

【化１２６】 Embedded image

【０３０８】¹H NMR (DMSO-d₆) δ; 1.62-1.73 (2H,
m), 1.90-1.99 (2H, m), 2.97-3.07 (2H, m), 3.40-3.5
2 (2H, m), 3.72-3.80 (1H, m), 3.89 (3H, s), 4.80
(2H, d, J= 5.6 Hz), 7.28 (1H, d, J = 8.4 Hz), 7.81
-7.85 (2H, m), 8.24 (1H, d, J= 8.4 Hz), 8.47 (1H,
dd, J = 8.4, 1.2 Hz), 9.53 (1H, d, J = 1.2 Hz), 1
0.29 (1H, br), 14.02 (1H, br) 実施例７６ 1-(4-ヒドロキシピペリジノ)-4-[(3-ヨード-4-メトキシ
ベンジル)アミノ]-6-フタラジンカルボニトリル塩酸塩 ¹ H NMR (DMSO-d ₆ ) δ; 1.62-1.73 (2H,
m), 1.90-1.99 (2H, m), 2.97-3.07 (2H, m), 3.40-3.5
2 (2H, m), 3.72-3.80 (1H, m), 3.89 (3H, s), 4.80
(2H, d, J = 5.6 Hz), 7.28 (1H, d, J = 8.4 Hz), 7.81
-7.85 (2H, m), 8.24 (1H, d, J = 8.4 Hz), 8.47 (1H,
dd, J = 8.4, 1.2 Hz), 9.53 (1H, d, J = 1.2 Hz), 1
0.29 (1H, br), 14.02 (1H, br) Example 76 1- (4-hydroxypiperidino) -4-[(3-iodo-4-methoxybenzyl) amino] -6-phthalazinecarbonitrile hydrochloride salt

【０３０９】[0309]

【化１２７】 Embedded image

【０３１０】¹H NMR (DMSO-d₆) δ; 1.62-1.73 (2H,
m), 1.90-2.00 (2H, m), 2.98-3.08 (2H, m), 3.40-3.5
0 (2H, m), 3.72-3.80 (1H, m), 3.82 (3H, s), 4.68
(2H, d, J= 4.8 Hz), 7.02 (1H, d, J = 8.8 Hz), 7.50
(1H, dd, J = 8.8, 2.2 Hz), 7.93 (1H, d, J = 2.2 H
z), 8.24 (1H, d, J = 8.6 Hz), 8.46 (1H, dd, J = 8.
6,0.8 Hz), 9.32 (1H, d, J = 0.8 Hz), 10.05 (1H, b
r) 実施例７７ 4-[(3-ブロモ-4-メトキシベンジル)アミノ]-1-(4-ヒド
ロキシピペリジノ)-6-フタラジンカルボニトリル塩酸塩 ¹ H NMR (DMSO-d ₆ ) δ; 1.62-1.73 (2H,
m), 1.90-2.00 (2H, m), 2.98-3.08 (2H, m), 3.40-3.5
0 (2H, m), 3.72-3.80 (1H, m), 3.82 (3H, s), 4.68
(2H, d, J = 4.8 Hz), 7.02 (1H, d, J = 8.8 Hz), 7.50
(1H, dd, J = 8.8, 2.2 Hz), 7.93 (1H, d, J = 2.2 H
z), 8.24 (1H, d, J = 8.6 Hz), 8.46 (1H, dd, J = 8.
6,0.8 Hz), 9.32 (1H, d, J = 0.8 Hz), 10.05 (1H, b
r) Example 77 4-[(3-bromo-4-methoxybenzyl) amino] -1- (4-hydroxypiperidino) -6-phthalazinecarbonitrile hydrochloride

【０３１１】[0311]

【化１２８】 Embedded image

【０３１２】¹H NMR (DMSO-d₆) δ; 1.62-1.73 (2H,
m), 1.90-1.99 (2H, m), 2.98-3.07 (2H, m), 3.39-3.5
0 (2H, m), 3.72-3.80 (1H, m), 3.84 (3H, s), 4.71
(2H, d, J= 4.8 Hz), 7.13 (1H, d, J = 8.6 Hz), 7.49
(1H, dd, J = 8.6, 2.2 Hz), 7.75 (1H, d, J = 2.2 H
z), 8.24 (1H, d, J = 8.4 Hz), 8.46 (1H, dd, J = 8.
4,0.8 Hz), 9.34 (1H, d, J = 0.8 Hz), 10.11 (1H, b
r) 実施例７８ 4-[(3-ブロモ-4-メトキシベンジル)アミノ]-1-[3-(ヒド
ロキシメチル)テトラヒドロ-1H-1-ピロリル]-6-フタラ
ジンカルボニトリル塩酸塩 ¹ H NMR (DMSO-d ₆ ) δ; 1.62-1.73 (2H,
m), 1.90-1.99 (2H, m), 2.98-3.07 (2H, m), 3.39-3.5
0 (2H, m), 3.72-3.80 (1H, m), 3.84 (3H, s), 4.71
(2H, d, J = 4.8 Hz), 7.13 (1H, d, J = 8.6 Hz), 7.49
(1H, dd, J = 8.6, 2.2 Hz), 7.75 (1H, d, J = 2.2 H
z), 8.24 (1H, d, J = 8.4 Hz), 8.46 (1H, dd, J = 8.
4,0.8 Hz), 9.34 (1H, d, J = 0.8 Hz), 10.11 (1H, b
r) Example 78 4-[(3-bromo-4-methoxybenzyl) amino] -1- [3- (hydroxymethyl) tetrahydro-1H-1-pyrrolyl] -6-phthalazinecarbonitrile hydrochloride

【０３１３】[0313]

【化１２９】 Embedded image

【０３１４】¹H NMR (DMSO-d₆) δ; 1.72-1.86 (1H,
m), 1.99-2.12 (1H, m), 2.39-2.51 (1H, m), 3.42 (1
H, dd, J = 7.2, 10.8 Hz), 3.48 (1H, dd, J = 6.0, 1
0.8 Hz),3.60-3.90 (4H, m), 3.80 (3H, s), 7.06 (1H,
d, J = 8.4 Hz), 7.38-7.46 (1H, m), 7.64 (1H, s),
8.40 (1H, dd, J = 1.6, 8.8 Hz), 8.65 (1H, d, J =
8.0Hz), 9.18 (1H, s) 実施例７９ 4-[(3-ブロモ-4-メトキシベンジル)アミノ]-1-[(3S)-3-
(ヒドロキシメチル)テトラヒドロ-1H-1-ピロリル]-6-フ
タラジンカルボニトリル塩酸塩 ¹ H NMR (DMSO-d ₆ ) δ; 1.72-1.86 (1H,
m), 1.99-2.12 (1H, m), 2.39-2.51 (1H, m), 3.42 (1
H, dd, J = 7.2, 10.8 Hz), 3.48 (1H, dd, J = 6.0, 1
0.8 Hz), 3.60-3.90 (4H, m), 3.80 (3H, s), 7.06 (1H,
d, J = 8.4 Hz), 7.38-7.46 (1H, m), 7.64 (1H, s),
8.40 (1H, dd, J = 1.6, 8.8 Hz), 8.65 (1H, d, J =
8.0Hz), 9.18 (1H, s) Example 79 4-[(3-bromo-4-methoxybenzyl) amino] -1-[(3S) -3-
(Hydroxymethyl) tetrahydro-1H-1-pyrrolyl] -6-phthalazinecarbonitrile hydrochloride

【０３１５】[0315]

【化１３０】 Embedded image

【０３１６】¹H NMR (DMSO-d₆) δ; 1.58-1.76 (3H,
m), 1.92-2.02 (2H, m), 2.29-2.42 (2H, m), 3.42-3.6
0 (2H, m), 3.78 (3H, s), 4.58 (2H, J = 6.0 Hz), 4.
69 (1H,t, J = 5.6 Hz), 7.03 (1H, d, J = 8.4 Hz),
7.36 (1H, dd, J = 2.0, 8.4 Hz), 7.57 (1H, d, J =
2.0 Hz), 7.59 (1H, d, J = 6.0 Hz), 8.13 (1H, dd, J
=1.2, 8.8 Hz), 8.22 (1H, d, J = 8.8 Hz), 8.81 (1
H, d, J = 0.8 Hz) 実施例８０ 4-[(3-ブロモ-4-メトキシベンジル)アミノ]-1-[(3R)-3-
(ヒドロキシメチル)テトラヒドロ-1H-1-ピロリル]-6-フ
タラジンカルボニトリル塩酸塩 ¹ H NMR (DMSO-d ₆ ) δ; 1.58-1.76 (3H,
m), 1.92-2.02 (2H, m), 2.29-2.42 (2H, m), 3.42-3.6
0 (2H, m), 3.78 (3H, s), 4.58 (2H, J = 6.0 Hz), 4.
69 (1H, t, J = 5.6 Hz), 7.03 (1H, d, J = 8.4 Hz),
7.36 (1H, dd, J = 2.0, 8.4 Hz), 7.57 (1H, d, J =
2.0 Hz), 7.59 (1H, d, J = 6.0 Hz), 8.13 (1H, dd, J
= 1.2, 8.8 Hz), 8.22 (1H, d, J = 8.8 Hz), 8.81 (1
(H, d, J = 0.8 Hz) Example 80 4-[(3-bromo-4-methoxybenzyl) amino] -1-[(3R) -3-
(Hydroxymethyl) tetrahydro-1H-1-pyrrolyl] -6-phthalazinecarbonitrile hydrochloride

【０３１７】[0317]

【化１３１】 Embedded image

【０３１８】¹H NMR (DMSO-d₆) δ; 1.72-1.86 (1H,
m), 1.99-2.12 (1H, m), 2.39-2.51 (1H, m), 3.42 (1
H, dd, J = 7.2, 10.8 Hz), 3.48 (1H, dd, J = 6.0, 1
0.8 Hz),3.60-3.90 (4H, m), 3.80 (3H, s), 7.06 (1H,
d, J = 8.8 Hz), 7.38-7.46 (1H, m), 7.65 (1H, s),
8.40 (1H, d, J = 8.8 Hz), 8.59-8.68 (1H, m), 9.26
(1H, s) 実施例８１ 4-[(3-ブロモ-4-メトキシベンジル)アミノ]-1-[4-(2-ヒ
ドロキシエチル)ピペリジノ]-6-フタラジンカルボニト
リル塩酸塩 ¹ H NMR (DMSO-d ₆ ) δ; 1.72-1.86 (1H,
m), 1.99-2.12 (1H, m), 2.39-2.51 (1H, m), 3.42 (1
H, dd, J = 7.2, 10.8 Hz), 3.48 (1H, dd, J = 6.0, 1
0.8 Hz), 3.60-3.90 (4H, m), 3.80 (3H, s), 7.06 (1H,
d, J = 8.8 Hz), 7.38-7.46 (1H, m), 7.65 (1H, s),
8.40 (1H, d, J = 8.8 Hz), 8.59-8.68 (1H, m), 9.26
(1H, s) Example 81 4-[(3-bromo-4-methoxybenzyl) amino] -1- [4- (2-hydroxyethyl) piperidino] -6-phthalazinecarbonitrile hydrochloride

【０３１９】[0319]

【化１３２】 Embedded image

【０３２０】¹H NMR (DMSO-d₆) δ; 1.68-1.77 (2H,
m), 1.96-2.07 (2H, m), 3.02 (2H, t,J = 12.0 Hz),
3.38-3.59 (6H, m), 3.80 (3H, s), 3.81-3.99 (3H,
m), 4.72 (2H, d, J = 6.0 Hz), 7.10 (1H, d, J = 8.6
Hz), 7.49 (1H, d, J = 8.6 Hz),7.76 (1H, s), 8.22
(1H, d, J = 8.6 Hz), 8.45 (1H, d, J = 8.6 Hz), 9.5
0 (1H, s) 実施例８２ 4-[(3-ブロモ-4-メトキシベンジル)アミノ]-1-(2-ヒド
ロキシ-7-アザスピロ[3.5]ノン-7-イル)-6-フタラジン
カルボニトリル塩酸塩 ¹ H NMR (DMSO-d ₆ ) δ; 1.68-1.77 (2H,
m), 1.96-2.07 (2H, m), 3.02 (2H, t, J = 12.0 Hz),
3.38-3.59 (6H, m), 3.80 (3H, s), 3.81-3.99 (3H,
m), 4.72 (2H, d, J = 6.0 Hz), 7.10 (1H, d, J = 8.6
Hz), 7.49 (1H, d, J = 8.6 Hz), 7.76 (1H, s), 8.22
(1H, d, J = 8.6 Hz), 8.45 (1H, d, J = 8.6 Hz), 9.5
0 (1H, s) Example 82 4-[(3-Bromo-4-methoxybenzyl) amino] -1- (2-hydroxy-7-azaspiro [3.5] non-7-yl) -6-phthalazinecarbo Nitrile hydrochloride

【０３２１】[0321]

【化１３３】 Embedded image

【０３２２】¹H NMR (DMSO-d₆) δ; 1.58-1.66 (2H,
m), 1.68-1.76 (4H, m), 2.14-2.23 (2H, m), 3.08 (2
H, br.s), 3.13 (2H, br.s), 4.08-4.17 (1H, m), 4.73
(1H, d,J = 5.6 Hz), 7.10 (1H, d, J = 8.4 Hz), 7.5
2 (1H, dd, J = 2.0, 8.4 Hz), 7.70 (1H, d, J = 2.0
Hz), 8.20 (1H, d, J = 8.4 Hz), 8.44 (1H, dd, J =
1.6, 8.4 Hz), 9.55 (1H, s) 実施例８３ 4-[(3-ブロモ-4-メトキシベンジル)アミノ]-1-[4-フル
オロ-4-(ヒドロキシメチル)ピペリジノ]-6-フタラジン
カルボニトリル塩酸塩 ¹ H NMR (DMSO-d ₆ ) δ; 1.58-1.66 (2H,
m), 1.68-1.76 (4H, m), 2.14-2.23 (2H, m), 3.08 (2
H, br.s), 3.13 (2H, br.s), 4.08-4.17 (1H, m), 4.73
(1H, d, J = 5.6 Hz), 7.10 (1H, d, J = 8.4 Hz), 7.5
2 (1H, dd, J = 2.0, 8.4 Hz), 7.70 (1H, d, J = 2.0
Hz), 8.20 (1H, d, J = 8.4 Hz), 8.44 (1H, dd, J =
1.6, 8.4 Hz), 9.55 (1H, s) Example 83 4-[(3-Bromo-4-methoxybenzyl) amino] -1- [4-fluoro-4- (hydroxymethyl) piperidino] -6-phthal Razine carbonitrile hydrochloride

【０３２３】[0323]

【化１３４】 Embedded image

【０３２４】¹H NMR (DMSO-d₆) δ; 1.87-2.10 (4H,
m), 3.08-3.17 (2H, m), 3.40-3.49 (2H, m), 3.55 (2
H, d, J = 12 Hz), 3.84 (3H, s), 4.74 (2H, d, J =
5.2 Hz), 7.13 (1H, d, J = 8.6 Hz), 7.52 (1H, dd, J
= 8.6, 2.2 Hz), 7.78 (1H, d, J= 2.2 Hz), 8.28 (1
H, d, J = 8.4 Hz), 8.48 (1H, dd, J = 8.4, 1.2 Hz),
9.47 (1H, br), 10.43 (1H, br), 14.00 (1H, br) 実施例８４ 4-[(3-ブロモ-4-メトキシベンジル)アミノ]-1-[4-(ヒド
ロキシメチル)ピペリジノ]-6-フタラジンカルボニトリ
ル塩酸塩 ¹ H NMR (DMSO-d ₆ ) δ; 1.87-2.10 (4H,
m), 3.08-3.17 (2H, m), 3.40-3.49 (2H, m), 3.55 (2
H, d, J = 12 Hz), 3.84 (3H, s), 4.74 (2H, d, J =
5.2 Hz), 7.13 (1H, d, J = 8.6 Hz), 7.52 (1H, dd, J
= 8.6, 2.2 Hz), 7.78 (1H, d, J = 2.2 Hz), 8.28 (1
H, d, J = 8.4 Hz), 8.48 (1H, dd, J = 8.4, 1.2 Hz),
9.47 (1H, br), 10.43 (1H, br), 14.00 (1H, br) Example 84 4-[(3-bromo-4-methoxybenzyl) amino] -1- [4- (hydroxymethyl) piperidino] -6-phthalazinecarbonitrile hydrochloride

【０３２５】[0325]

【化１３５】 Embedded image

【０３２６】¹H NMR (DMSO-d₆) δ; 1.41-1.52 (2H,
m), 1.58-1.69 (1H, m), 1.79-1.86 (2H, m), 2.85-2.9
4 (2H, m), 3.35-3.40 (2H, m), 3.59 (2H, d, J = 12.
8 Hz), 3.84 (3H, s), 4.71 (2H, d, J = 5.2 Hz), 7.1
3 (1H, d, J = 8.4 Hz), 7.50 (1H, dd, J = 8.4, 2.0
Hz), 7.76 (1H, d, J = 2.0 Hz), 8.22 (1H, d, J = 8.
4Hz), 8.47 (1H, dd, J = 8.4, 0.8 Hz), 9.38 (1H, b
r), 10.21 (1H, br) 実施例８５ (endo)-4-[(3-ブロモ-4-メトキシベンジル)アミノ]-1-
(3-ヒドロキシ-8-アザビシクロ[3.2.1]オクト-8-イル)-
6-フタラジンカルボニトリル ¹ H NMR (DMSO-d ₆ ) δ; 1.41-1.52 (2H,
m), 1.58-1.69 (1H, m), 1.79-1.86 (2H, m), 2.85-2.9
4 (2H, m), 3.35-3.40 (2H, m), 3.59 (2H, d, J = 12.
8 Hz), 3.84 (3H, s), 4.71 (2H, d, J = 5.2 Hz), 7.1
3 (1H, d, J = 8.4 Hz), 7.50 (1H, dd, J = 8.4, 2.0
Hz), 7.76 (1H, d, J = 2.0 Hz), 8.22 (1H, d, J = 8.
4Hz), 8.47 (1H, dd, J = 8.4, 0.8 Hz), 9.38 (1H, b
r), 10.21 (1H, br) Example 85 (endo) -4-[(3-bromo-4-methoxybenzyl) amino] -1-
(3-hydroxy-8-azabicyclo [3.2.1] oct-8-yl)-
6-phthalazine carbonitrile

【０３２７】[0327]

【化１３６】 Embedded image

【０３２８】¹H NMR (DMSO-d₆) δ; 1.70-1.95 (4H,
m), 2.14-2.28 (4H, m), 3.82 (3H, s),4.15 (1H, m),
4.09 (2H, m), 4.49 (1H, d, J = 2.2 Hz), 4.62 (2H,
d, J =5.5 Hz), 7.05 (1H, d, J = 8.6 Hz), 7.38 (1H,
dd, J = 2.2, 8.6 Hz), 7.60(1H, d, J = 2.2 Hz), 7.
72 (1H, t, J = 5.5 Hz), 8.11 (1H, d, J = 8.6 Hz),
8.18 (1H, dd, J = 1.5, 8.6 Hz), 8.87 (1H, d, J =
1.5 Hz) 実施例８６ 1-(4-ヒドロキシピペリジノ)-4-[(4-メトキシ-3-メチル
ベンジル)アミノ]-6-フタラジンカルボニトリル塩酸塩 ¹ H NMR (DMSO-d ₆ ) δ; 1.70-1.95 (4H,
m), 2.14-2.28 (4H, m), 3.82 (3H, s), 4.15 (1H, m),
4.09 (2H, m), 4.49 (1H, d, J = 2.2 Hz), 4.62 (2H,
d, J = 5.5 Hz), 7.05 (1H, d, J = 8.6 Hz), 7.38 (1H,
dd, J = 2.2, 8.6 Hz), 7.60 (1H, d, J = 2.2 Hz), 7.
72 (1H, t, J = 5.5 Hz), 8.11 (1H, d, J = 8.6 Hz),
8.18 (1H, dd, J = 1.5, 8.6 Hz), 8.87 (1H, d, J =
(1.5 Hz) Example 86 1- (4-hydroxypiperidino) -4-[(4-methoxy-3-methylbenzyl) amino] -6-phthalazinecarbonitrile hydrochloride

【０３２９】[0329]

【化１３７】 Embedded image

【０３３０】¹H NMR (DMSO-d₆) δ; 1.62-1.73 (2H,
m), 1.90-1.99 (2H, m), 2.15(3H, s),2.98-3.07 (2H,
m), 3.42-3.50 (2H, m), 3.72-3.80 (1H, m), 3.78 (3
H, s), 4.67-4.70 (2H, m), 6.94 (1H, d, J = 8.2 H
z), 7.28 (1H, d, J = 2.0 Hz), 7.31 (1H, dd, J = 8.
2, 2.0 Hz), 8.23 (1H, d, J = 8.4 Hz), 8.47 (1H, d
d, J= 8.4, 1.2 Hz), 9.45 (1H, d, J = 1.2 Hz), 10.3
9 (1H, br) 実施例８７ 1-(2-ヒドロキシ-7-アザスピロ[3.5]ノン-7-イル)-4-
[(4-メトキシ-3-メチルベンジル)アミノ]-6-フタラジン
カルボニトリル塩酸塩 ¹ H NMR (DMSO-d ₆ ) δ; 1.62-1.73 (2H,
m), 1.90-1.99 (2H, m), 2.15 (3H, s), 2.98-3.07 (2H,
m), 3.42-3.50 (2H, m), 3.72-3.80 (1H, m), 3.78 (3
H, s), 4.67-4.70 (2H, m), 6.94 (1H, d, J = 8.2 H
z), 7.28 (1H, d, J = 2.0 Hz), 7.31 (1H, dd, J = 8.
2, 2.0 Hz), 8.23 (1H, d, J = 8.4 Hz), 8.47 (1H, d
d, J = 8.4, 1.2 Hz), 9.45 (1H, d, J = 1.2 Hz), 10.3
9 (1H, br) Example 87 1- (2-hydroxy-7-azaspiro [3.5] non-7-yl) -4-
[(4-methoxy-3-methylbenzyl) amino] -6-phthalazinecarbonitrile hydrochloride

【０３３１】[0331]

【化１３８】 Embedded image

【０３３２】¹H NMR (DMSO-d₆) δ; 1.57-1.66 (2H,
m), 1.67-1.8 (4H, m), 2.11 (3H, s),2.14-2.23 (2H,
m), 3.07 (2H, br.s), 3.12 (2H, br.s), 3.55-3.61 (1
H, m),4.07-4.17 (1H, m), 4.69 (1H, d, J = 5.2 Hz),
6.91 (1H, d, J = 8.4 Hz), 7.29 (1H, s), 7.31 (1H,
dd, J = 2.0, 8.4 Hz), 8.19 (1H, d, J = 8.4 Hz),
8.44 (1H, dd, J = 1.2, 8.4 Hz), 9.56 (1H, s), 10.5
9 (1H, brs) 実施例８８ 1-[4-フルオロ-4-(ヒドロキシメチル)ピペリジノ]-4-
[(4-メトキシ-3-メチルベンジル)アミノ]-6-フタラジン
カルボニトリル塩酸塩 ¹ H NMR (DMSO-d ₆ ) δ; 1.57-1.66 (2H,
m), 1.67-1.8 (4H, m), 2.11 (3H, s), 2.14-2.23 (2H,
m), 3.07 (2H, br.s), 3.12 (2H, br.s), 3.55-3.61 (1
H, m), 4.07-4.17 (1H, m), 4.69 (1H, d, J = 5.2 Hz),
6.91 (1H, d, J = 8.4 Hz), 7.29 (1H, s), 7.31 (1H,
dd, J = 2.0, 8.4 Hz), 8.19 (1H, d, J = 8.4 Hz),
8.44 (1H, dd, J = 1.2, 8.4 Hz), 9.56 (1H, s), 10.5
9 (1H, brs) Example 88 1- [4-Fluoro-4- (hydroxymethyl) piperidino] -4-
[(4-methoxy-3-methylbenzyl) amino] -6-phthalazinecarbonitrile hydrochloride

【０３３３】[0333]

【化１３９】 Embedded image

【０３３４】¹H NMR (DMSO-d₆) δ; 1.88-2.10 (4H,
m), 2.15 (3H, s), 3.08-3.17 (2H, m),3.40-3.50 (2H,
m), 3.51 (2H, d, J = 19.6 Hz), 3.78 (3H, s), 4.68
(2H, d, J = 5.2 Hz), 6.94 (1H, d, J = 8.0 Hz), 7.
28-7.33 (2H, m), 8.28 (1H, d,J = 8.4 Hz), 8.47 (1
H, dd, J = 8.4, 1.4 Hz), 9.42 (1H, dd, J = 1.4 H
z),10.26 (1H, br), 13.96 (1H, br) 実施例８９ 1-[4-(ヒドロキシメチル)ピペリジノ]-4-[(3-メトキシ-
4-メチルベンジル)アミノ]-6-フタラジンカルボニトリ
ル塩酸塩 ¹ H NMR (DMSO-d ₆ ) δ; 1.88-2.10 (4H,
m), 2.15 (3H, s), 3.08-3.17 (2H, m), 3.40-3.50 (2H,
m), 3.51 (2H, d, J = 19.6 Hz), 3.78 (3H, s), 4.68
(2H, d, J = 5.2 Hz), 6.94 (1H, d, J = 8.0 Hz), 7.
28-7.33 (2H, m), 8.28 (1H, d, J = 8.4 Hz), 8.47 (1
H, dd, J = 8.4, 1.4 Hz), 9.42 (1H, dd, J = 1.4 H
z), 10.26 (1H, br), 13.96 (1H, br) Example 89 1- [4- (hydroxymethyl) piperidino] -4-[(3-methoxy-
4-methylbenzyl) amino] -6-phthalazinecarbonitrile hydrochloride

【０３３５】[0335]

【化１４０】 Embedded image

【０３３６】¹H NMR (DMSO-d₆) δ; 1.41-1.52 (2H,
m), 1.58-1.68 (1H, m), 1.79-1.87 (2H, m), 2.15 (3
H, s), 2.82-2.93 (2H, m), 3.30-3.40 (2H, m), 3.58
(2H, d, J= 12.8 Hz), 3.78 (3H, s), 4.67 (2H, d, J
= 5.2 Hz), 6.94 (1H, d, J = 8.8 Hz), 7.26-7.32 (2
H, m), 8.22 (1H, d, J = 8.4 Hz), 8.47 (1H, dd, J =
8.4, 0.8 Hz), 9.36 (1H, br), 10.09 (1H, br) 実施例９０ (endo)-1-(3-ヒドロキシ-8-アザビシクロ[3.2.1]オクト
-8-イル)-4-[(4-メトキシ-3-メチルベンジル)アミノ]-6
-フタラジンカルボニトリル ¹ H NMR (DMSO-d ₆ ) δ; 1.41-1.52 (2H,
m), 1.58-1.68 (1H, m), 1.79-1.87 (2H, m), 2.15 (3
H, s), 2.82-2.93 (2H, m), 3.30-3.40 (2H, m), 3.58
(2H, d, J = 12.8 Hz), 3.78 (3H, s), 4.67 (2H, d, J
= 5.2 Hz), 6.94 (1H, d, J = 8.8 Hz), 7.26-7.32 (2
H, m), 8.22 (1H, d, J = 8.4 Hz), 8.47 (1H, dd, J =
8.4, 0.8 Hz), 9.36 (1H, br), 10.09 (1H, br) Example 90 (endo) -1- (3-hydroxy-8-azabicyclo [3.2.1] oct
-8-yl) -4-[(4-methoxy-3-methylbenzyl) amino] -6
-Phthalazine carbonitrile

【０３３７】[0337]

【化１４１】 Embedded image

【０３３８】¹H NMR (DMSO-d₆) δ; 1.79-1.93 (4H,
m), 2.13 (3H, s), 2.13-2.27 (4H, m),3.75 (3H, s),
4.03 (1H, m), 4.08 (2H, m), 4.49 (1H, d, J = 2.2 H
z), 4.59 (2H, d, J = 5.3 Hz), 6.87 (1H, d, J = 7.9
Hz), 7.16-7.22 (2H, m), 7.61(1H, t, J = 5.3 Hz),
8.11 (1H, d, J = 8.4 Hz), 8.17 (1H, dd, J = 1.5,
8.4 Hz), 8.90 (1H, d, J = 1.5 Hz) 実施例９１ 1-[3-(ヒドロキシメチル)テトラヒドロ-1H-1-ピロリル]
-4-[(4-メトキシ-3-メチルベンジル)アミノ]-6-フタラ
ジンカルボニトリル ¹ H NMR (DMSO-d ₆ ) δ; 1.79-1.93 (4H,
m), 2.13 (3H, s), 2.13-2.27 (4H, m), 3.75 (3H, s),
4.03 (1H, m), 4.08 (2H, m), 4.49 (1H, d, J = 2.2 H
z), 4.59 (2H, d, J = 5.3 Hz), 6.87 (1H, d, J = 7.9
Hz), 7.16-7.22 (2H, m), 7.61 (1H, t, J = 5.3 Hz),
8.11 (1H, d, J = 8.4 Hz), 8.17 (1H, dd, J = 1.5,
(8.4 Hz), 8.90 (1H, d, J = 1.5 Hz) Example 91 1- [3- (hydroxymethyl) tetrahydro-1H-1-pyrrolyl]
-4-[(4-methoxy-3-methylbenzyl) amino] -6-phthalazinecarbonitrile

【０３３９】[0339]

【化１４２】 Embedded image

【０３４０】¹H NMR (DMSO-d₆) δ; 1.67 (1H, m), 2.0
0 (1H, m), 2.16 (3H, s), 2.38 (1H,m), 3.36-3.61 (6
H, m), 3.75 (3H, s), 4.58 (2H, d, J = 5.5 Hz), 4.6
8 (1H, t, J = 5.5 Hz), 6.86 (1H, d, J = 8.1 Hz),
7.16-7.22 (2H, m), 7.50 (1H,t, J = 5.3 Hz), 8.15
(1H, dd, J = 1.5, 8.6 Hz), 8.24 (1H, dd, J = 8.6 H
z), 8.88 (1H, d, J = 1.5 Hz) 実施例９２ 4-[(3-フルオロ-4-メトキシベンジル)アミノ]-1-(4-ヒ
ドロキシピペリジノ)-6-フタラジンカルボニトリル ¹ H NMR (DMSO-d ₆ ) δ; 1.67 (1H, m), 2.0
0 (1H, m), 2.16 (3H, s), 2.38 (1H, m), 3.36-3.61 (6
H, m), 3.75 (3H, s), 4.58 (2H, d, J = 5.5 Hz), 4.6
8 (1H, t, J = 5.5 Hz), 6.86 (1H, d, J = 8.1 Hz),
7.16-7.22 (2H, m), 7.50 (1H, t, J = 5.3 Hz), 8.15
(1H, dd, J = 1.5, 8.6 Hz), 8.24 (1H, dd, J = 8.6 H
z), 8.88 (1H, d, J = 1.5 Hz) Example 92 4-[(3-fluoro-4-methoxybenzyl) amino] -1- (4-hydroxypiperidino) -6-phthalazinecarbonitrile

【０３４１】[0341]

【化１４３】 Embedded image

【０３４２】¹H NMR (DMSO-d₆) δ; 1.60-1.73 (2H,
m), 1.88-1.97 (2H, m), 2.86-2.94 (2H, m), 3.42-3.5
0 (2H, m), 3.64-3.71 (1H, m), 3.80 (3H, s), 4.62
(2H, d, J= 5.4 Hz), 4.77 (1H, d, J = 2.0 Hz), 7.09
(1H, t, J = 8.2 Hz), 7.18 (1H, d, J = 8.2 Hz), 7.
23 (1H, dd, J = 12.0, 2.0 Hz), 7.84 (1H, t, J = 5.
4Hz), 8.04 (1H, d, J = 8.4 Hz), 8.20 (1H, dd, J =
8.4, 1.2 Hz), 8.89 (1H,d, J = 1.2 Hz) 実施例９３ 4-[(4-クロロ-3-メトキシベンジル)アミノ]-1-(4-ヒド
ロキシピペリジノ)-6-フタラジンカルボニトリル ¹ H NMR (DMSO-d ₆ ) δ; 1.60-1.73 (2H,
m), 1.88-1.97 (2H, m), 2.86-2.94 (2H, m), 3.42-3.5
0 (2H, m), 3.64-3.71 (1H, m), 3.80 (3H, s), 4.62
(2H, d, J = 5.4 Hz), 4.77 (1H, d, J = 2.0 Hz), 7.09
(1H, t, J = 8.2 Hz), 7.18 (1H, d, J = 8.2 Hz), 7.
23 (1H, dd, J = 12.0, 2.0 Hz), 7.84 (1H, t, J = 5.
4Hz), 8.04 (1H, d, J = 8.4 Hz), 8.20 (1H, dd, J =
8.4, 1.2 Hz), 8.89 (1H, d, J = 1.2 Hz) Example 93 4-[(4-chloro-3-methoxybenzyl) amino] -1- (4-hydroxypiperidino) -6-phthal Razine carbonitrile

【０３４３】[0343]

【化１４４】 Embedded image

【０３４４】¹H NMR (DMSO-d₆) δ; 1.60-1.72 (2H,
m), 1.87-1.96 (2H, m), 2.86-2.95 (2H, m), 3.31-3.3
9 (2H, m), 3.68 (1H, m), 3.84 (3H, s), 4.72 (2H,
d, J = 5.5 Hz), 4.74 (1H, d, J = 4.2 Hz), 6.98 (1
H, dd, J = 1.8, 8.1 Hz), 7.20 (1H, d, J = 1.8 Hz),
7.34 (1H, d, J = 8.1 Hz), 7.92 (1H, t, J = 5.5 H
z), 8.07 (1H, d, J = 8.6 Hz), 8.21 (1H, dd, J = 1.
5, 8.6 Hz), 8.92 (1H, d, J= 1.5 Hz) 実施例９４ 4-[(3-シアノ-4-メトキシベンジル)アミノ]-1-(4-ヒド
ロキシピペリジノ)-6-フタラジンカルボニトリル塩酸塩 ¹ H NMR (DMSO-d ₆ ) δ; 1.60-1.72 (2H,
m), 1.87-1.96 (2H, m), 2.86-2.95 (2H, m), 3.31-3.3
9 (2H, m), 3.68 (1H, m), 3.84 (3H, s), 4.72 (2H,
d, J = 5.5 Hz), 4.74 (1H, d, J = 4.2 Hz), 6.98 (1
H, dd, J = 1.8, 8.1 Hz), 7.20 (1H, d, J = 1.8 Hz),
7.34 (1H, d, J = 8.1 Hz), 7.92 (1H, t, J = 5.5 H
z), 8.07 (1H, d, J = 8.6 Hz), 8.21 (1H, dd, J = 1.
5,8.6 Hz), 8.92 (1H, d, J = 1.5 Hz) Example 94 4-[(3-cyano-4-methoxybenzyl) amino] -1- (4-hydroxypiperidino) -6-phthal Razine carbonitrile hydrochloride

【０３４５】[0345]

【化１４５】 Embedded image

【０３４６】¹H NMR (DMSO-d₆) δ; 1.6-1.73 (2H, m),
1.88-2.0 (2H, m), 2.95-3.08 (2H,m), 3.4-3.7 (2H,
m), 3.7-3.8 (1H, m), 3.90 (3H, s), 4.74 (2H, d, J
= 5.6Hz), 7.27 (1H, d, J = 9.2 Hz), 7.79 (1H, dd,
J = 2.0, 8.8 Hz), 7.87 (1H, d, J = 2.0 Hz), 8.24
(1H, d, J = 8.4 Hz), 8.47 (1H, dd, J = 1.2, 8.4 H
z), 9.38 (1H, s) 実施例９５ (endo)-4-[(3-シアノ-4-メトキシベンジル)アミノ]-1-
(3-ヒドロキシ-8-アザビシクロ[3.2.1]オクト-8-イル)-
6-フタラジンカルボニトリル塩酸塩 ¹ H NMR (DMSO-d ₆ ) δ; 1.6-1.73 (2H, m),
1.88-2.0 (2H, m), 2.95-3.08 (2H, m), 3.4-3.7 (2H, m
m), 3.7-3.8 (1H, m), 3.90 (3H, s), 4.74 (2H, d, J
= 5.6Hz), 7.27 (1H, d, J = 9.2 Hz), 7.79 (1H, dd,
J = 2.0, 8.8 Hz), 7.87 (1H, d, J = 2.0 Hz), 8.24
(1H, d, J = 8.4 Hz), 8.47 (1H, dd, J = 1.2, 8.4 H
z), 9.38 (1H, s) Example 95 (endo) -4-[(3-cyano-4-methoxybenzyl) amino] -1-
(3-hydroxy-8-azabicyclo [3.2.1] oct-8-yl)-
6-phthalazinecarbonitrile hydrochloride

【０３４７】[0347]

【化１４６】 Embedded image

【０３４８】¹H NMR (DMSO-d₆) δ; 1.9-1.96 (4H, m),
2.17-2.29 (4H, m), 3.91 (3H, s),4.04 (1H, m), 4.1
5 (2H, m), 4.68 (2H, s), 7.25 (1H, d, J = 8.6 Hz),
7.74(1H, d, J = 8.6 Hz), 7.80 (1H, s), 8.21 (1H,
d, J = 8.6 Hz), 8.34 (1H,m), 9.07 (1H, m) 実施例９６ 4-[(3-シアノ-4-メトキシベンジル)アミノ]-1-[3-(ヒド
ロキシメチル)テトラヒドロ-1H-1-ピロリル]-6-フタラ
ジンカルボニトリル塩酸塩 ¹ H NMR (DMSO-d ₆ ) δ; 1.9-1.96 (4H, m),
2.17-2.29 (4H, m), 3.91 (3H, s), 4.04 (1H, m), 4.1
5 (2H, m), 4.68 (2H, s), 7.25 (1H, d, J = 8.6 Hz),
7.74 (1H, d, J = 8.6 Hz), 7.80 (1H, s), 8.21 (1H,
d, J = 8.6 Hz), 8.34 (1H, m), 9.07 (1H, m) Example 96 4-[(3-cyano-4-methoxybenzyl) amino] -1- [3- (hydroxymethyl) tetrahydro -1H-1-pyrrolyl] -6-phthalazinecarbonitrile hydrochloride

【０３４９】[0349]

【化１４７】 Embedded image

【０３５０】¹H NMR (DMSO-d₆) δ; 1.84 (1H, m), 2.0
9 (1H, m), 2.48 (1H, m), 3.40-3.55(2H, m), 3.64-3.
90 (4H, m), 3.91 (3H, s), 4.59 (2H, m), 7.24 (1H,
d, J= 8.8 Hz), 7.74 (1H, d, J = 8.8 Hz), 7.79 (1H,
s), 8.42 (1H, d, J = 9.3Hz), 8.70 (1H, m), 9.15
(1H, m) 実施例９７ 4-[(3-エチル-4-メトキシベンジル)アミノ]-1-(4-ヒド
ロキシピペリジノ)-6-フタラジンカルボニトリル塩酸塩 ¹ H NMR (DMSO-d ₆ ) δ; 1.84 (1H, m), 2.0
9 (1H, m), 2.48 (1H, m), 3.40-3.55 (2H, m), 3.64-3.
90 (4H, m), 3.91 (3H, s), 4.59 (2H, m), 7.24 (1H,
d, J = 8.8 Hz), 7.74 (1H, d, J = 8.8 Hz), 7.79 (1H,
s), 8.42 (1H, d, J = 9.3Hz), 8.70 (1H, m), 9.15
(1H, m) Example 97 4-[(3-ethyl-4-methoxybenzyl) amino] -1- (4-hydroxypiperidino) -6-phthalazinecarbonitrile hydrochloride

【０３５１】[0351]

【化１４８】 Embedded image

【０３５２】¹H NMR (DMSO-d₆) δ; 1.14 (3H, t, J =
7.5 Hz), 1.63-1.74 (2H, m), 1.90-2.01 (2H, m), 2.5
7 (2H, q, J = 7.5 Hz), 2.97-3.08 (2H, m), 3.40-3.5
4 (2H,m), 3.75 (1H, m), 3.79 (3H, s), 4.69 (2H,
s), 6.95 (1H, d, J = 8.2 Hz),7.26-7.35 (2H, m), 8.
25 (1H, d, J = 8.6 Hz), 8.48 (1H, dd, J = 1.3, 8.6
Hz), 9.44 (1H, m) 実施例９８ 4-[(3-クロロ-4-メトキシフェネチル)アミノ]-1-(2-ヒ
ドロキシ-7-アザスピロ[3.5]ノン-7-イル)-6-フタラジ
ンカルボニトリル塩酸塩 ¹ H NMR (DMSO-d ₆ ) δ; 1.14 (3H, t, J =
7.5 Hz), 1.63-1.74 (2H, m), 1.90-2.01 (2H, m), 2.5
7 (2H, q, J = 7.5 Hz), 2.97-3.08 (2H, m), 3.40-3.5
4 (2H, m), 3.75 (1H, m), 3.79 (3H, s), 4.69 (2H,
s), 6.95 (1H, d, J = 8.2 Hz), 7.26-7.35 (2H, m), 8.
25 (1H, d, J = 8.6 Hz), 8.48 (1H, dd, J = 1.3, 8.6
Hz), 9.44 (1H, m) Example 98 4-[(3-chloro-4-methoxyphenethyl) amino] -1- (2-hydroxy-7-azaspiro [3.5] non-7-yl) -6- Phthalazine carbonitrile hydrochloride

【０３５３】[0353]

【化１４９】 Embedded image

【０３５４】¹H NMR (DMSO-d₆) d 1.58-1.66 (2H, m),
1.67-1.78 (4H, m), 2.14-2.23 (2H,m), 2.92-3.01 (2
H, m), 3.07 (2H, s), 3.11 (2H, s), 3.70-3.82 (3H,
m), 3.80 (3H, s), 4.08-4.18 (1H, m), 7.06 (1H, d,
J = 8.4 Hz), 7.26 (1H, dd, J= 2.0, 8.4 Hz), 7.43
(1H, d, J = 2.0 Hz), 8.19 (1H, d, J = 8.4 Hz), 8.4
4 (1H, dd, J = 1.2, 8.4 Hz), 9.55 (1H, s), 10.47
(1H, br.s), 13.9 (1H, brs) 実施例９９ 4-[(3-クロロ-4-メトキシフェネチル)アミノ]-1-[4-(2-
ヒドロキシエトキシ)ピペリジノ]-6-フタラジンカルボ
ニトリル塩酸塩 ¹ H NMR (DMSO-d ₆ ) d 1.58-1.66 (2H, m),
1.67-1.78 (4H, m), 2.14-2.23 (2H, m), 2.92-3.01 (2
H, m), 3.07 (2H, s), 3.11 (2H, s), 3.70-3.82 (3H,
m), 3.80 (3H, s), 4.08-4.18 (1H, m), 7.06 (1H, d,
J = 8.4 Hz), 7.26 (1H, dd, J = 2.0, 8.4 Hz), 7.43
(1H, d, J = 2.0 Hz), 8.19 (1H, d, J = 8.4 Hz), 8.4
4 (1H, dd, J = 1.2, 8.4 Hz), 9.55 (1H, s), 10.47
(1H, br.s), 13.9 (1H, brs) Example 99 4-[(3-chloro-4-methoxyphenethyl) amino] -1- [4- (2-
Hydroxyethoxy) piperidino] -6-phthalazinecarbonitrile hydrochloride

【０３５５】[0355]

【化１５０】 Embedded image

【０３５６】¹H NMR (DMSO-d₆) δ; 1.68-1.77 (2H,
m), 2.00-2.06 (2H, m), 2.76 (2H, t,J = 8.0 Hz), 3.
03 (2H, t, J = 12.0 Hz), 3.32 (10H, m), 3.75 (2H,
d, J =8.0 Hz), 3.81 (3H, s), 7.07 (1H, d, J = 8.6
Hz), 7.25 (1H, d, J = 8.6 Hz), 7.43 (1H, s), 8.24
(1H, d, J = 8.6 Hz), 8.45 (1H, d, J = 8.6 Hz), 9.3
2 (1H, s) 実施例１００ 4-[(3-クロロ-4-メトキシフェネチル)アミノ]-1-[4-フ
ルオロ-4-(ヒドロキシメチル)ピペリジノ]-6-フタラジ
ンカルボニトリル ¹ H NMR (DMSO-d ₆ ) δ; 1.68-1.77 (2H,
m), 2.00-2.06 (2H, m), 2.76 (2H, t, J = 8.0 Hz), 3.
03 (2H, t, J = 12.0 Hz), 3.32 (10H, m), 3.75 (2H,
d, J = 8.0 Hz), 3.81 (3H, s), 7.07 (1H, d, J = 8.6
Hz), 7.25 (1H, d, J = 8.6 Hz), 7.43 (1H, s), 8.24
(1H, d, J = 8.6 Hz), 8.45 (1H, d, J = 8.6 Hz), 9.3
2 (1H, s) Example 100 4-[(3-chloro-4-methoxyphenethyl) amino] -1- [4-fluoro-4- (hydroxymethyl) piperidino] -6-phthalazinecarbonitrile

【０３５７】[0357]

【化１５１】 Embedded image

【０３５８】¹H NMR (DMSO-d₆) δ; 1.82-2.06 (4H,
m), 2.83-2.94 (2H, m), 3.04-3.14 (2H, m), 3.24-3.3
0 (1H, m), 3.49 (2H, dd, J = 10.2, 6.0 Hz), 3.54-
3.60 (1H,m), 3.64-3.70 (2H, m), 3.80 (3H, s), 5.03
(1H, dd, J = 6.0, 6.0 Hz), 7.05 (1H, d, J = 12.6
Hz), 7.19 (1H, dd, J = 12.6, 2.0 Hz), 7.32 (1H, d,
J= 2.0 Hz), 7.40-7.45 (1H, m), 8.08 (1H, d, J =
8.4 Hz), 8.18 (1H, d, J= 8.4 Hz), 8.82 (1H, brs) 実施例１０１ (endo)-4-[(3-クロロ-4-メトキシフェネチル)アミノ]-1
-(3-ヒドロキシ-8-アザビシクロ[3.2.1]オクト-8-イル)
-6-フタラジンカルボニトリル ¹ H NMR (DMSO-d ₆ ) δ; 1.82-2.06 (4H,
m), 2.83-2.94 (2H, m), 3.04-3.14 (2H, m), 3.24-3.3
0 (1H, m), 3.49 (2H, dd, J = 10.2, 6.0 Hz), 3.54-
3.60 (1H, m), 3.64-3.70 (2H, m), 3.80 (3H, s), 5.03
(1H, dd, J = 6.0, 6.0 Hz), 7.05 (1H, d, J = 12.6
Hz), 7.19 (1H, dd, J = 12.6, 2.0 Hz), 7.32 (1H, d,
J = 2.0 Hz), 7.40-7.45 (1H, m), 8.08 (1H, d, J =
(8.4 Hz), 8.18 (1H, d, J = 8.4 Hz), 8.82 (1H, brs) Example 101 (endo) -4-[(3-chloro-4-methoxyphenethyl) amino] -1
-(3-Hydroxy-8-azabicyclo [3.2.1] oct-8-yl)
-6-phthalazinecarbonitrile

【０３５９】[0359]

【化１５２】 Embedded image

【０３６０】¹H NMR (DMSO-d₆) δ; 1.78-1.94 (4H,
m), 2.14-2.28 (4H, m), 2.92 (2H, t,J = 7.0 Hz), 3.
67 (2H, q, J = 7.0 Hz), 3.82 (3H, s), 4.04 (1H,
m), 4.09(2H, m), 4.49 (1H, d, J = 1.8 Hz), 7.06 (1
H, d, J = 8.4 Hz), 7.20 (1H, dd, J = 2.2, 8.4 Hz),
7.27 (1H, m), 7.33 (1H, d, J = 2.2 Hz), 8.11 (1H,
d, J = 8.6 Hz), 8.17 (1H, dd, J = 1.5, 8.6 Hz),
8.80 (1H, d, J = 1.5 Hz) 実施例１０２ 4-[(3-クロロ-4-メトキシフェネチル)アミノ]-1-[3-(ヒ
ドロキシメチル)テトラヒドロ-1H-1-ピロリル]-6-フタ
ラジンカルボニトリル ¹ H NMR (DMSO-d ₆ ) δ; 1.78-1.94 (4H,
m), 2.14-2.28 (4H, m), 2.92 (2H, t, J = 7.0 Hz), 3.
67 (2H, q, J = 7.0 Hz), 3.82 (3H, s), 4.04 (1H,
m), 4.09 (2H, m), 4.49 (1H, d, J = 1.8 Hz), 7.06 (1
H, d, J = 8.4 Hz), 7.20 (1H, dd, J = 2.2, 8.4 Hz),
7.27 (1H, m), 7.33 (1H, d, J = 2.2 Hz), 8.11 (1H,
d, J = 8.6 Hz), 8.17 (1H, dd, J = 1.5, 8.6 Hz),
8.80 (1H, d, J = 1.5 Hz) Example 102 4-[(3-chloro-4-methoxyphenethyl) amino] -1- [3- (hydroxymethyl) tetrahydro-1H-1-pyrrolyl] -6- Phthalazine carbonitrile

【０３６１】[0361]

【化１５３】 Embedded image

【０３６２】¹H NMR (DMSO-d₆) δ; 1.68 (1H, m), 2.0
0 (1H, m), 2.40 (1H, m), 2.92 (2H,t, J = 7.5 Hz),
3.37-3.70 (8H, m), 3.82 (3H, s), 4.69 (1H, d, J =
5.3 Hz), 7.06 (1H, d, J = 8.6 Hz), 7.16 (1H, m),
7.20 (1H, dd, J = 2.0, 8.6Hz), 7.33 (1H, d, J = 2.
0 Hz), 8.15 (1H, dd, J = 1.3, 8.6 Hz), 8.25 (1H,
d, J = 8.6 Hz), 8.78 (1H,m) 実施例１０３ 4-[(3,4-ジクロロベンジル)アミノ]-1-(4-ヒドロキシピ
ペリジノ)-6-フタラジンカルボニトリル塩酸塩 ¹ H NMR (DMSO-d ₆ ) δ; 1.68 (1H, m), 2.0
0 (1H, m), 2.40 (1H, m), 2.92 (2H, t, J = 7.5 Hz),
3.37-3.70 (8H, m), 3.82 (3H, s), 4.69 (1H, d, J =
5.3 Hz), 7.06 (1H, d, J = 8.6 Hz), 7.16 (1H, m),
7.20 (1H, dd, J = 2.0, 8.6Hz), 7.33 (1H, d, J = 2.
0 Hz), 8.15 (1H, dd, J = 1.3, 8.6 Hz), 8.25 (1H,
d, J = 8.6 Hz), 8.78 (1H, m) Example 103 4-[(3,4-dichlorobenzyl) amino] -1- (4-hydroxypiperidino) -6-phthalazinecarbonitrile hydrochloride

【０３６３】[0363]

【化１５４】 Embedded image

【０３６４】¹H NMR (DMSO-d₆) δ; 1.61-1.72 (2H,
m), 1.90-2.00 (2H, m), 3.01-3.18 (2H, m), 3.40-3.5
2 (2H, m), 3.72-3.80 (1H, m), 4.75 (2H, d, J = 5.2
Hz), 7.49 (1H, dd, J = 8.6, 2.0 Hz), 7.66 (1H, d,
J = 8.6 Hz), 7.79 (1H, d, J =2.0 Hz), 8.25 (1H,
d, J = 8.6 Hz), 8.47 (1H, dd, J = 8.6, 1.0 Hz), 9.
36(1H, d, J = 1.0 Hz), 10.24 (1H, br) 実施例１０４ 1-[6-ブロモ-4-[(3-クロロ-4-メトキシベンジル)アミ
ノ]-1-フタラジニル]-4-ピペリジノール塩酸塩 ¹ H NMR (DMSO-d ₆ ) δ; 1.61-1.72 (2H,
m), 1.90-2.00 (2H, m), 3.01-3.18 (2H, m), 3.40-3.5
2 (2H, m), 3.72-3.80 (1H, m), 4.75 (2H, d, J = 5.2
Hz), 7.49 (1H, dd, J = 8.6, 2.0 Hz), 7.66 (1H, d,
J = 8.6 Hz), 7.79 (1H, d, J = 2.0 Hz), 8.25 (1H,
d, J = 8.6 Hz), 8.47 (1H, dd, J = 8.6, 1.0 Hz), 9.
36 (1H, d, J = 1.0 Hz), 10.24 (1H, br) Example 104 1- [6-bromo-4-[(3-chloro-4-methoxybenzyl) amino] -1-phthalazinyl] -4 -Piperidinol hydrochloride

【０３６５】[0365]

【化１５５】 Embedded image

【０３６６】¹H NMR (DMSO-d₆) δ; 1.59-1.68 (2H,
m), 1.85-1.94 (2H, m), 2.94-3.08 (2H, m), 3.45-3.5
5 (2H, m), 3.70-3.76 (1H, m), 3.83 (3H, s), 4.69
(2H, d, J= 4.8 Hz), 7.14 (1H, d, J = 8.4 Hz), 7.44
(1H, d, J = 8.4 Hz), 7.59 (1H, s), 8.01 (1H, d, J
= 8.8 Hz), 8.26 (1H, d, J = 8.8 Hz), 9.18 (1H, s) 実施例１０５ 1-[4-[(3-クロロ-4-メトキシベンジル)アミノ]-6-(1H-1
-ピラゾリル)-1-フタラジニル]-4-ピペリジノール塩酸
塩 ¹ H NMR (DMSO-d ₆ ) δ; 1.59-1.68 (2H,
m), 1.85-1.94 (2H, m), 2.94-3.08 (2H, m), 3.45-3.5
5 (2H, m), 3.70-3.76 (1H, m), 3.83 (3H, s), 4.69
(2H, d, J = 4.8 Hz), 7.14 (1H, d, J = 8.4 Hz), 7.44
(1H, d, J = 8.4 Hz), 7.59 (1H, s), 8.01 (1H, d, J
= 8.8 Hz), 8.26 (1H, d, J = 8.8 Hz), 9.18 (1H, s) Example 105 1- [4-[(3-chloro-4-methoxybenzyl) amino] -6- (1H- 1
-Pyrazolyl) -1-phthalazinyl] -4-piperidinol hydrochloride

【０３６７】[0367]

【化１５６】 Embedded image

【０３６８】¹H NMR (DMSO-d₆) δ; 1.6-1.75 (2H, m),
1.85-2.0 (2H, m), 2.95-3.1 (2H, m), 3.3-3.55 (2H,
m), 3.7-3.8 (1H, m), 3.82 (3H, s), 4.68-4.77 (2H,
m), 6.72 (1H, m), 7.14 (1H, d, J = 8.4 Hz), 7.48
(1H, d, J = 7.6 Hz), 7.63 (1H, s), 7.93 (1H, d, J
= 1.6Hz), 8.22 (1H, d, J = 8.8 Hz), 8.61 (1H, dd,J
= 1.6, 8.8 Hz), 8.97 (1H, s), 9.46 (1H, m) 実施例１０６ 7-[4-[(3-クロロ-4-メトキシベンジル)アミノ]-6-(1H-1
-ピラゾリル)-1-フタラジニル]-7-アザスピロ[3.5]ノナ
ン-2-オール塩酸塩 ¹ H NMR (DMSO-d ₆ ) δ; 1.6-1.75 (2H, m),
1.85-2.0 (2H, m), 2.95-3.1 (2H, m), 3.3-3.55 (2H, m
m), 3.7-3.8 (1H, m), 3.82 (3H, s), 4.68-4.77 (2H,
m), 6.72 (1H, m), 7.14 (1H, d, J = 8.4 Hz), 7.48
(1H, d, J = 7.6 Hz), 7.63 (1H, s), 7.93 (1H, d, J
= 1.6Hz), 8.22 (1H, d, J = 8.8 Hz), 8.61 (1H, dd, J
= 1.6, 8.8 Hz), 8.97 (1H, s), 9.46 (1H, m) Example 106 7- [4-[(3-chloro-4-methoxybenzyl) amino] -6- (1H-1
-Pyrazolyl) -1-phthalazinyl] -7-azaspiro [3.5] nonan-2-ol hydrochloride

【０３６９】[0369]

【化１５７】 Embedded image

【０３７０】¹H NMR (DMSO-d₆) δ; 1.55-1.68 (2H,
m), 1.68-1.80 (4H, m), 2.14-2.25 (2H, m), 3.0-3.2
(4H, m), 3.82 (3H, s), 4.14 (1H, hep, J = 7.2 Hz),
4.72 (2H, m), 6.72 (1H, t, J = 2 Hz), 7.14 (1H,
d, J = 8.4Hz), 7.47 (1H, d, J =8.4 Hz), 7.62 (1H,
s), 7.93 (1H, d, J = 1.6Hz), 8.20 (1H, d, J = 9.2
Hz), 8.60 (1H, dd, J = 2.0, 9.2 Hz), 8.94 (1H, d,
J = 2.4 Hz), 9.43 (1H,s)実施例１０７ [1-[4-[(3-クロロ-4-メトキシベンジル)アミノ]-6-(1H-
1-ピラゾリル)-1-フタラジニル]-4-フルオロ-4-ピペリ
ジニル]メタノール塩酸塩 ¹ H NMR (DMSO-d ₆ ) δ; 1.55-1.68 (2H,
m), 1.68-1.80 (4H, m), 2.14-2.25 (2H, m), 3.0-3.2
(4H, m), 3.82 (3H, s), 4.14 (1H, hep, J = 7.2 Hz),
4.72 (2H, m), 6.72 (1H, t, J = 2 Hz), 7.14 (1H,
d, J = 8.4 Hz), 7.47 (1H, d, J = 8.4 Hz), 7.62 (1H,
s), 7.93 (1H, d, J = 1.6Hz), 8.20 (1H, d, J = 9.2
Hz), 8.60 (1H, dd, J = 2.0, 9.2 Hz), 8.94 (1H, d,
J = 2.4 Hz), 9.43 (1H, s) Example 107 [1- [4-[(3-chloro-4-methoxybenzyl) amino] -6- (1H-
1-pyrazolyl) -1-phthalazinyl] -4-fluoro-4-piperidinyl] methanol hydrochloride

【０３７１】[0371]

【化１５８】 Embedded image

【０３７２】¹H NMR (DMSO-d₆) δ; 1.85-2.0 (2H, m),
1.95-2.1 (2H, m), 3.05-3.2 (2H, m), 3.4-3.6 (2H,
m), 3.51 (2H, d, J = 20 Hz), 3.83 (3H, s), 4.74 (2
H, d,J = 5.2 Hz), 6.72 (1H, t, J = 1.6 Hz), 7.14
(1H, d, J = 8.8Hz), 7.48 (1H, d, J = 8.4 Hz), 7.64
(1H, s), 7.93 (1H, d, J = 1.6Hz), 8.25 (1H, d, J=
9.2 Hz), 8.61 (1H, dd, J = 2.0, 9.2 Hz), 8.95 (1
H, s), 9.44 (1H, s) 実施例１０８ 1-[4-[(3-ブロモ-4-メトキシベンジル)アミノ]-6-(1H-1
-ピラゾリル)-1-フタラジニル]-4-ピペリジノール塩酸
塩 ¹ H NMR (DMSO-d ₆ ) δ; 1.85-2.0 (2H, m),
1.95-2.1 (2H, m), 3.05-3.2 (2H, m), 3.4-3.6 (2H,
m), 3.51 (2H, d, J = 20 Hz), 3.83 (3H, s), 4.74 (2
H, d, J = 5.2 Hz), 6.72 (1H, t, J = 1.6 Hz), 7.14
(1H, d, J = 8.8 Hz), 7.48 (1H, d, J = 8.4 Hz), 7.64
(1H, s), 7.93 (1H, d, J = 1.6Hz), 8.25 (1H, d, J =
9.2 Hz), 8.61 (1H, dd, J = 2.0, 9.2 Hz), 8.95 (1
H, s), 9.44 (1H, s) Example 108 1- [4-[(3-bromo-4-methoxybenzyl) amino] -6- (1H-1
-Pyrazolyl) -1-phthalazinyl] -4-piperidinol hydrochloride

【０３７３】[0373]

【化１５９】 Embedded image

【０３７４】¹H NMR (DMSO-d₆) δ; 1.6-1.74 (2H, m),
1.87-2.0 (2H, m), 2.9-3.1 (2H, m), 3.4-3.55 (2H,
m), 3.7-3.8 (1H, m), 3.81 (3H, s), 4.65-4.8 (2H,
m), 6.72 (1H, m), 7.10 (1H, d, J = 8.8 Hz), 7.53
(1H, d, J = 8.0 Hz), 7.79 (1H,s), 7.93 (1H, d, J =
1.2 Hz), 8.21 (1H, d, J = 8.8 Hz), 8.61 (1H, d, J
= 8.8 Hz), 9.00 (1H, d, J = 2.8 Hz), 9.51 (1H, s) 実施例１０９ 1-[4-[(3-クロロ-4-メトキシベンジル)アミノ]-6-(1H-
1,2,3-トリアゾール-1-イル)-1-フタラジニル]-4-ピペ
リジノール塩酸塩 ¹ H NMR (DMSO-d ₆ ) δ; 1.6-1.74 (2H, m),
1.87-2.0 (2H, m), 2.9-3.1 (2H, m), 3.4-3.55 (2H, m
m), 3.7-3.8 (1H, m), 3.81 (3H, s), 4.65-4.8 (2H,
m), 6.72 (1H, m), 7.10 (1H, d, J = 8.8 Hz), 7.53
(1H, d, J = 8.0 Hz), 7.79 (1H, s), 7.93 (1H, d, J =
1.2 Hz), 8.21 (1H, d, J = 8.8 Hz), 8.61 (1H, d, J
= 8.8 Hz), 9.00 (1H, d, J = 2.8 Hz), 9.51 (1H, s) Example 109 1- [4-[(3-chloro-4-methoxybenzyl) amino] -6- (1H-
1,2,3-Triazol-1-yl) -1-phthalazinyl] -4-piperidinol hydrochloride

【０３７５】[0375]

【化１６０】 Embedded image

【０３７６】¹H NMR (DMSO-d₆) δ; 1.62-1.75 (2H,
m), 1.9-2.0 (2H, m), 3.0-3.1 (2H, m), 3.3-3.58 (2
H, m), 3.7-3.8 (1H, m), 3.83 (3H, s), 4.73 (2H, d,
J = 5.6Hz), 7.15 (1H, d, J = 8.8 Hz), 7.46 (1H,
d, J = 8.4 Hz), 7.62 (1H, s), 8.13 (1H, m), 8.32
(1H, d, J = 8.8 Hz), 8.68 (1H, d, J = 9.2 Hz), 9.1
7 (1H, s), 9.56 (1H, s) 実施例１１０ 4-[(3-クロロ-4-メトキシベンジル)アミノ]-1-(4-ヒド
ロキシピペリジノ)-6-フタラジンカルバルデヒド O6-メ
チルオキシム塩酸塩 ¹ H NMR (DMSO-d ₆ ) δ; 1.62-1.75 (2H,
m), 1.9-2.0 (2H, m), 3.0-3.1 (2H, m), 3.3-3.58 (2
H, m), 3.7-3.8 (1H, m), 3.83 (3H, s), 4.73 (2H, d,
J = 5.6 Hz), 7.15 (1H, d, J = 8.8 Hz), 7.46 (1H,
d, J = 8.4 Hz), 7.62 (1H, s), 8.13 (1H, m), 8.32
(1H, d, J = 8.8 Hz), 8.68 (1H, d, J = 9.2 Hz), 9.1
7 (1H, s), 9.56 (1H, s) Example 110 4-[(3-chloro-4-methoxybenzyl) amino] -1- (4-hydroxypiperidino) -6-phthalazine carbaldehyde O6 -Methyloxime hydrochloride

【０３７７】[0377]

【化１６１】 Embedded image

【０３７８】¹H NMR (DMSO-d₆) δ; 1.60-1.70 (2H,
m), 1.87-1.70 (2H, m), 2.96-3.05 (2H, m), 3.30-3.5
0 (2H, m), 3.68-3.78 (1H, m), 3.83 (3H, s), 3.99
(3H, s),4.66-4.73 (2H, m), 7.14 (1H, d, J = 8 Hz),
7.42 (1H, dd, J = 2, 8 Hz), 7.57 (1H, d, J = 2 H
z), 8.13 (1H, d, J = 8 Hz), 8.28 (1H, d, J = 8 H
z), 8.39 (1H, s), 8.94 (1H, brs) 実施例１１１ 4-[(3-クロロ-4-メトキシベンジル)アミノ]-1-(4-ヒド
ロキシピペリジノ)-6-フタラジンカルバルデヒド O6-エ
チルオキシム塩酸塩 ¹ H NMR (DMSO-d ₆ ) δ; 1.60-1.70 (2H,
m), 1.87-1.70 (2H, m), 2.96-3.05 (2H, m), 3.30-3.5
0 (2H, m), 3.68-3.78 (1H, m), 3.83 (3H, s), 3.99
(3H, s), 4.66-4.73 (2H, m), 7.14 (1H, d, J = 8 Hz),
7.42 (1H, dd, J = 2, 8 Hz), 7.57 (1H, d, J = 2 H
z), 8.13 (1H, d, J = 8 Hz), 8.28 (1H, d, J = 8 H
z), 8.39 (1H, s), 8.94 (1H, brs) Example 111 4-[(3-chloro-4-methoxybenzyl) amino] -1- (4-hydroxypiperidino) -6-phthalazine Carbaldehyde O6-ethyl oxime hydrochloride

【０３７９】[0379]

【化１６２】 Embedded image

【０３８０】¹H NMR (DMSO-d₆) δ; 1.28 (3H, t, J =
6 Hz), 1.60-1.73 (2H, m), 1.87-1.98 (2H, m), 2.94-
3.06 (2H, m), 3.39-3.52 (2H, m), 3.68-3.78 (1H,
m), 3.83(3H, s), 4.25 (2H, q, J = 6 Hz), 4.67-4.74
(2H, m), 7.13 (1H, d, J = 9Hz), 7.42 (1H, d, J =
9 Hz), 7.58 (1H, s), 8.13 (1H, d, J = 8 Hz), 8.30
(1H, d, J = 8 Hz), 8.39 (1H, s), 8.97 (1H, s) 実施例１１２ 4-[(3-クロロ-4-メトキシベンジル)アミノ]-1-(4-ヒド
ロキシピペリジノ)-6-フタラジンカルバルデヒド O6-ベ
ンジルオキシム塩酸塩 ¹ H NMR (DMSO-d ₆ ) δ; 1.28 (3H, t, J =
6 Hz), 1.60-1.73 (2H, m), 1.87-1.98 (2H, m), 2.94-
3.06 (2H, m), 3.39-3.52 (2H, m), 3.68-3.78 (1H,
m), 3.83 (3H, s), 4.25 (2H, q, J = 6 Hz), 4.67-4.74
(2H, m), 7.13 (1H, d, J = 9Hz), 7.42 (1H, d, J =
9 Hz), 7.58 (1H, s), 8.13 (1H, d, J = 8 Hz), 8.30
(1H, d, J = 8 Hz), 8.39 (1H, s), 8.97 (1H, s) Example 112 4-[(3-chloro-4-methoxybenzyl) amino] -1- (4-hydroxypi Peridino) -6-phthalazinecarbaldehyde O6-benzyloxime hydrochloride

【０３８１】[0381]

【化１６３】 Embedded image

【０３８２】¹H NMR (DMSO-d₆) δ; 1.59-1.71 (2H,
m), 1.87-1.96 (2H, m), 2.94-3.05 (2H, m), 3.37-3.5
1 (2H, m), 3.68-3.78 (1H, m), 3.82 (3H, s), 4.67-
4.76 (2H,m), 5.27 (2H, s), 7.13 (1H, d, J = 9 Hz),
7.29-7.48 (6H, m), 7.59 (1H,s), 8.12 (1H, d, J =
9 Hz), 8.29 (1H, d, J = 9 Hz), 8.45 (1H, s), 9.04
(1H, brs) 実施例１１３ 4-[(3-クロロ-4-メトキシベンジル)アミノ]-1-[3-フル
オロ-3-(ヒドロキシメチル)テトラヒドロ-1H-1-ピロリ
ル]-6-フタラジンカルボニトリル塩酸塩 ¹ H NMR (DMSO-d ₆ ) δ; 1.59-1.71 (2H,
m), 1.87-1.96 (2H, m), 2.94-3.05 (2H, m), 3.37-3.5
1 (2H, m), 3.68-3.78 (1H, m), 3.82 (3H, s), 4.67-
4.76 (2H, m), 5.27 (2H, s), 7.13 (1H, d, J = 9 Hz),
7.29-7.48 (6H, m), 7.59 (1H, s), 8.12 (1H, d, J =
9 Hz), 8.29 (1H, d, J = 9 Hz), 8.45 (1H, s), 9.04
(1H, brs) Example 113 4-[(3-chloro-4-methoxybenzyl) amino] -1- [3-fluoro-3- (hydroxymethyl) tetrahydro-1H-1-pyrrolyl] -6-phthalazine Carbonitrile hydrochloride

【０３８３】[0383]

【化１６４】 Embedded image

【０３８４】¹H NMR (DMSO-d₆) δ; 2.09-2.28 (2H,
m), 3.50-4.05 (6H, m), 3.81 (3H, s),4.66 (2H, s),
7.11 (1H, d, J = 8.0 Hz), 7.43 (1H, d, J = 8.0 H
z), 7.58(1H, s), 8.43 (1H, d, J = 8.4 Hz), 8.53 (1
H, s), 9.45 (1H, s) 実施例１１４ 4-[(3-クロロ-4-メトキシベンジル)アミノ]-1-(3-ヒド
ロキシ-1-オキサ-8-アザスピロ[4.5]デカ-8-イル)-6-フ
タラジンカルボニトリル塩酸塩 ¹ H NMR (DMSO-d ₆ ) δ; 2.09-2.28 (2H,
m), 3.50-4.05 (6H, m), 3.81 (3H, s), 4.66 (2H, s),
7.11 (1H, d, J = 8.0 Hz), 7.43 (1H, d, J = 8.0 H
z), 7.58 (1H, s), 8.43 (1H, d, J = 8.4 Hz), 8.53 (1
H, s), 9.45 (1H, s) Example 114 4-[(3-Chloro-4-methoxybenzyl) amino] -1- (3-hydroxy-1-oxa-8-azaspiro [4.5] deca-8 -Yl) -6-phthalazinecarbonitrile hydrochloride

【０３８５】[0385]

【化１６５】 Embedded image

【０３８６】¹H NMR (DMSO-d₆) δ; 1.65-1.85 (3H,
m), 1.87-2.01(2H, m), 3.16-3.63 (8H,m), 3.82 (3H,
s), 4.32 (1H, s), 4.73 (2H, d, J = 4.8 Hz), 7.13
(1H, d,J = 8.4 Hz), 7.48 (1H, d, J = 8.0 Hz), 7.62
(1H, s), 8.23 (1H, d, J = 8.0 Hz), 8.44 (1H, d, J
= 8.0 Hz), 9.57 (1H, s), 10.78 (1H, s) 実施例１１５ 4-[(3-クロロ-4-メトキシベンジル)アミノ]-1-[2-(1-ヒ
ドロキシシクロペンチル)-1-エチニル]-6-フタラジンカ
ルボニトリル ¹ H NMR (DMSO-d ₆ ) δ; 1.65-1.85 (3H,
m), 1.87-2.01 (2H, m), 3.16-3.63 (8H, m), 3.82 (3H,
s), 4.32 (1H, s), 4.73 (2H, d, J = 4.8 Hz), 7.13
(1H, d, J = 8.4 Hz), 7.48 (1H, d, J = 8.0 Hz), 7.62
(1H, s), 8.23 (1H, d, J = 8.0 Hz), 8.44 (1H, d, J
= 8.0 Hz), 9.57 (1H, s), 10.78 (1H, s) Example 115 4-[(3-chloro-4-methoxybenzyl) amino] -1- [2- (1-hydroxycyclopentyl) -1 -Ethynyl] -6-phthalazinecarbonitrile

【０３８７】[0387]

【化１６６】 Embedded image

【０３８８】NMR(DMSO-d₆)δ; 1.69-1.86 (4H, m), 1.9
7-2.04 (4H, m), 3.82 (3H, s), 4.75(2H, d, J = 5.4
Hz), 5.60 (1H, s), 7.10 (1H, d, J = 8.8 Hz), 7.36
(1H,dd, J = 8.8, 1.2 Hz), 7.49 (1H, d, J = 1.2 H
z), 8.19 (1H, d, J = 8.8 Hz), 8.31 (1H, dd, J = 8.
8, 0.6 Hz), 8.52 (1H, t, J = 5.4 Hz), 8.97 (1H, d,
J = 0.6 Hz) 実施例１１６ 4-[(3-クロロ-4-メトキシベンジル)アミノ]-1-[2-(1-ヒ
ドロキシシクロペンチル)エチル]-6-フタラジンカルボ
ニトリル 塩酸塩NMR (DMSO-d ₆ ) δ; 1.69-1.86 (4H, m), 1.9
7-2.04 (4H, m), 3.82 (3H, s), 4.75 (2H, d, J = 5.4
Hz), 5.60 (1H, s), 7.10 (1H, d, J = 8.8 Hz), 7.36
(1H, dd, J = 8.8, 1.2 Hz), 7.49 (1H, d, J = 1.2 H
z), 8.19 (1H, d, J = 8.8 Hz), 8.31 (1H, dd, J = 8.
8, 0.6 Hz), 8.52 (1H, t, J = 5.4 Hz), 8.97 (1H, d,
J = 0.6 Hz) Example 116 4-[(3-chloro-4-methoxybenzyl) amino] -1- [2- (1-hydroxycyclopentyl) ethyl] -6-phthalazinecarbonitrile hydrochloride

【０３８９】[0389]

【化１６７】 Embedded image

【０３９０】4-[(3-クロロ-4-メトキシベンジル)アミ
ノ]-1-[2-(1-ヒドロキシシクロペンチル)-１-エチニル]
-6-フタラジンカルボニトリル690 mgをテトラヒドロフ
ラン200mLに溶解し、１０％Pd-C 50 mgを加え、水素雰
囲気下０．５時間撹拌した。セライト濾過し、濾液を減
圧下濃縮した。残渣をシリカゲルカラムクロマトグラフ
ィーで精製し、4-[(3-クロロ-4-メトキシベンジル)アミ
ノ]-1-[2-(1-ヒドロキシシクロペンチル)エチル]-6-フ
タラジンカルボニトリルを400 mg得た。常法により塩酸
塩とした。¹ H NMR (DMSO-d₆) δ; 1.47-1.78 (8H, m), 1.89-1.94
(2H, m), 3.24-3.33 (2H, m), 3.84 (3H, s), 4.74 (2
H, d, J = 4.4 Hz), 7.15 (1H, d, J = 8.4 Hz),7.45
(1H, dd, J = 8.4, 2.0 Hz), 7.60 (1H, d, J = 2.0 H
z), 8.46 (1H, d, J= 8.8 Hz), 8.55 (1H, dd, J = 8.
8, 1.2 Hz), 9.40 (1H, br) 同様にして以下の化合物を得た。 実施例１１７ 4-[(3-クロロ-4-メトキシベンジル)アミノ]-1-(3-ヒド
ロキシ-3-メチルブチル)-6-フタラジンカルボニトリル
塩酸塩4-[(3-chloro-4-methoxybenzyl) amino] -1- [2- (1-hydroxycyclopentyl) -1-ethynyl]
690 mg of -6-phthalazinecarbonitrile was dissolved in 200 mL of tetrahydrofuran, 50 mg of 10% Pd-C was added, and the mixture was stirred for 0.5 hour under a hydrogen atmosphere. The mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 400 mg of 4-[(3-chloro-4-methoxybenzyl) amino] -1- [2- (1-hydroxycyclopentyl) ethyl] -6-phthalazinecarbonitrile. Was. It was converted into a hydrochloride by a conventional method. ¹ H NMR (DMSO-d ₆ ) δ; 1.47-1.78 (8H, m), 1.89-1.94
(2H, m), 3.24-3.33 (2H, m), 3.84 (3H, s), 4.74 (2
H, d, J = 4.4 Hz), 7.15 (1H, d, J = 8.4 Hz), 7.45
(1H, dd, J = 8.4, 2.0 Hz), 7.60 (1H, d, J = 2.0 H
z), 8.46 (1H, d, J = 8.8 Hz), 8.55 (1H, dd, J = 8.
8, 1.2 Hz), 9.40 (1H, br) The following compounds were obtained in the same manner. Example 117 4-[(3-chloro-4-methoxybenzyl) amino] -1- (3-hydroxy-3-methylbutyl) -6-phthalazinecarbonitrile hydrochloride

【０３９１】[0391]

【化１６８】 Embedded image

【０３９２】¹H NMR (DMSO-d₆) δ; 1.17 (6H, s), 1.7
3-1.80 (2H, m), 3.17-3.24 (2H, m),3.80 (3H, s), 4.
78 (2H, d, J = 4.4 Hz), 7.10 (1H, d, J = 8.4 Hz),
7.48(1H, dd, J = 8.4, 1.8 Hz), 7.62 (1H, d, J = 1.
8 Hz), 8.43 (1H, d, J = 8.6 Hz), 8.51 (1H, dd, J =
8.6, 1.2 Hz), 9.63 (1H, br), 10.30 (1H, br). 実施例１１８ 1-(3-アミノ-3-メチルブチル)-4-[(3-クロロ-4-メトキ
シベンジル)アミノ]-6-フタラジンカルボニトリル・二
塩酸塩[0392] _{^{1 H NMR (DMSO-d 6}} ) δ; 1.17 (6H, s), 1.7
3-1.80 (2H, m), 3.17-3.24 (2H, m), 3.80 (3H, s), 4.
78 (2H, d, J = 4.4 Hz), 7.10 (1H, d, J = 8.4 Hz),
7.48 (1H, dd, J = 8.4, 1.8 Hz), 7.62 (1H, d, J = 1.
8 Hz), 8.43 (1H, d, J = 8.6 Hz), 8.51 (1H, dd, J =
8.6, 1.2 Hz), 9.63 (1H, br), 10.30 (1H, br). Example 118 1- (3-amino-3-methylbutyl) -4-[(3-chloro-4-methoxybenzyl) amino] -6-phthalazinecarbonitrile dihydrochloride

【０３９３】[0393]

【化１６９】 Embedded image

【０３９４】¹H NMR (DMSO-d₆) δ; 1.37 (6H, s), 2.0
0-2.19 (2H, m), 3.21-3.56 (2H, m),3.84 (3H, s), 4.
78 (2H, d, J = 4.4 Hz), 7.15 (1H, d, J = 8.4 Hz),
7.46(1H, d, J = 8.4 Hz), 7.61 (1H, s), 8.15-8.29
(4H, m), 8.48 (1H, d, J = 8.8 Hz), 8.56 (1H, d, J
= 8.8 Hz), 9.38 (1H, br) 実施例１１９ 4-[(3-クロロ-4-メトキシベンジル)アミノ]-1-[3-(ジメ
チルアミノ)プロピル]-6-フタラジンカルボニトリル・
二塩酸塩 ¹ H NMR (DMSO-d ₆ ) δ; 1.37 (6H, s), 2.0
0-2.19 (2H, m), 3.21-3.56 (2H, m), 3.84 (3H, s), 4.
78 (2H, d, J = 4.4 Hz), 7.15 (1H, d, J = 8.4 Hz),
7.46 (1H, d, J = 8.4 Hz), 7.61 (1H, s), 8.15-8.29
(4H, m), 8.48 (1H, d, J = 8.8 Hz), 8.56 (1H, d, J
= 8.8 Hz), 9.38 (1H, br) Example 119 4-[(3-Chloro-4-methoxybenzyl) amino] -1- [3- (dimethylamino) propyl] -6-phthalazinecarbonitrile
Dihydrochloride

【０３９５】[0395]

【化１７０】 Embedded image

【０３９６】¹H NMR (DMSO-d₆) d 2.11-2.19 (2H, m),
2.74 (3H, s), 2.75 (3H, s), 3.16-3.29 (4H, m), 3.8
5 (3H, s), 4.80 (2H, d, J = 5.2 Hz), 7.16 (1H, d,
J = 8.4 Hz), 7.48 (1H, dd, J = 8.4, 2.0 Hz), 7.63
(1H, d, J = 2.0 Hz), 8.49 (1H, d, J = 8.4 Hz), 8.5
6 (1H, dd, J = 8.4, 1.4 Hz), 9.47 (1H, d, J = 1.4H
z), 10.56 (2H, br) ¹ H NMR (DMSO-d ₆ ) d 2.11-2.19 (2H, m),
2.74 (3H, s), 2.75 (3H, s), 3.16-3.29 (4H, m), 3.8
5 (3H, s), 4.80 (2H, d, J = 5.2 Hz), 7.16 (1H, d,
J = 8.4 Hz), 7.48 (1H, dd, J = 8.4, 2.0 Hz), 7.63
(1H, d, J = 2.0 Hz), 8.49 (1H, d, J = 8.4 Hz), 8.5
6 (1H, dd, J = 8.4, 1.4 Hz), 9.47 (1H, d, J = 1.4H
z), 10.56 (2H, br)

───────────────────────────────────────────────────── フロントページの続き (51)Int.Cl.⁷ 識別記号 ＦＩ テーマコート゛(参考） Ｃ０７Ｄ 401/04 ２３７ Ｃ０７Ｄ 401/04 ２３７ 401/06 401/06 401/14 401/14 403/04 ２０７ 403/04 ２０７ 409/14 409/14 417/04 417/04 417/14 417/14 491/056 491/056 491/107 491/107 498/08 498/08 (72)発明者 鎌田 厚 茨城県牛久市神谷２−７−30 (72)発明者 宮澤 修平 茨城県北相馬郡守谷町松ヶ丘２−39−26 (72)発明者 直江 吉充 茨城県つくば市上横場2574−20−Ｂ102 (72)発明者 金子敏彦 茨城県牛久市田宮町1082−70 (72)発明者 塚田 格 茨城県牛久市南３−11−13 (72)発明者 長倉 廷 茨城県つくば市稲荷前９−７−105 (72)発明者 石原 浩樹 茨城県つくば市大字緑が丘42−10 (72)発明者 児玉 耕太郎 茨城県土浦市中高津２−12−２ (72)発明者 足立 秀之 茨城県稲敷郡阿見町中央７−７−18 Ｆターム(参考） 4C063 AA01 AA03 BB01 BB02 BB03 BB09 CC28 CC41 CC47 CC62 CC92 DD03 DD08 DD10 DD11 DD12 DD17 DD22 DD28 EE01 4C072 AA03 BB02 CC01 CC11 EE07 FF07 GG07 HH07 JJ03 UU01 4C086 AA01 AA02 AA03 AA04 BC41 BC60 BC62 BC82 CB22 GA04 GA07 GA08 GA10 GA12 MA01 MA04 NA14 ZA40 ZA42 ZA81 ZC20 ZC35 ──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme court ゛ (Reference) C07D 401/04 237 C07D 401/04 237 401/06 401/06 401/14 401/14 403/04 207 403 / 04 207 409/14 409/14 417/04 417/04 417/14 417/14 491/056 491/056 491/107 491/107 498/08 498/08 (72) Inventor Atsushi Kamata Ushiku, Ibaraki 2-7-30 Kamiya (72) Inventor Shuhei Miyazawa 2-39-26, Matsugaoka, Moriya-cho, Kitasoma-gun, Ibaraki Prefecture (72) Inventor Yoshimitsu Naoe 2574-20-B102, 2574-20-B102 Tsukuba, Ibaraki Prefecture (72) Invention Person Toshihiko Kaneko 1082-70, Tamiya-cho, Ushiku City, Ibaraki Prefecture (72) Inventor, Tadashi Tsukada 3-11-13 Minami, Ushiku City, Ibaraki Prefecture (72) Court of Inventor Court, Nagakura 9-7-105, Inarizen, Tsukuba City, Ibaraki Prefecture (72) Inventor Hiroki Ishihara 42-10 Midorigaoka, Tsukuba, Ibaraki Prefecture (72) Inventor Kotaro Kodama Sat, Ibaraki 2-12-2 Nakatakatsu, Ichino (72) Inventor Hideyuki Adachi 7-7-18 Chuo, Ami-cho, Inashiki-gun, Ibaraki F-term (reference) 4C063 AA01 AA03 BB01 BB02 BB03 BB09 CC28 CC41 CC47 CC62 CC92 DD03 DD08 DD10 DD11 DD12 DD17 DD22 DD28 EE01 4C072 AA03 BB02 CC01 CC11 EE07 FF07 GG07 HH07 JJ03 UU01 4C086 AA01 AA02 AA03 AA04 BC41 BC60 BC62 BC82 CB22 GA04 GA07 GA08 GA10 GA12 MA01 MA04 NA14 ZA40 ZA42 ZA81 ZC20 ZC35

Claims (29)

【特許請求の範囲】[Claims] 【請求項１】一般式（I） 【化１】 ｛式中、 R¹およびR²は同一または相異なって、ハロゲン原子、ハ
ロゲン原子で置換されていてもよいC1〜C4アルキル基、
ハロゲン原子で置換されていてもよいC1〜C4アルコキシ
基またはシアノ基を意味する。Xはシアノ基、ニトロ
基、ハロゲン原子、チオカルバモイル基、C1〜C4アルキ
ル基・アリールC1〜C4アルキル基またはカルボキシC1〜
C4アルキル基で置換されていてもよいヒドロキシイミノ
基、または下記置換基群Aから選ばれる１〜３個の置換
基で置換されていてもよいヘテロアリール基を意味す
る。Yは i)式（II） 【化２】 （式中、環Aはメチル基で置換されていてもよく、二重
結合を有していてもよい4〜8員式アミン環を、Dは単結
合または酸素原子を、R³は水素原子、C1〜C4アルキル基
またはハロゲン原子を、mは０または１〜３の整数を意
味する。Wはアミノ基、水酸基、シアノ基、保護基を有
していてもよいカルボキシル基またはC1〜C4アルコキシ
基を意味する。）で示される基、 ii)式（III） 【化３】 （式中、環Bは二重結合を有していてもよい4〜8員式ア
ミン環を、nおよびpは同一または相異なって０または１
〜３の整数を意味する。）で示される基、 iii)式（IV） 【化４】 ｛式中、環Gは二重結合を有していてもよい4〜8員式ア
ミン環を示し、Eは水酸基、ハロゲン原子、C1〜C4アル
キル基またはC1〜C4アルコキシ基を、Jは式-(CHR⁴)q-Q
（式中、R⁴は水素原子またはC1〜C4アルキル基を、Qは
水酸基、ハロゲン原子、保護基を有していてもよいカル
ボキシル基、カルバモイル基または窒素原子以外のヘテ
ロ原子を含まないアゾリル基を、qは０または１〜４の
整数を意味する。）示す。またはEとJは結合している炭
素原子と一緒になって３から６員式の環を形成してもよ
く、この環はヘテロ原子を有していてよい。またこの環
は置換基を有していてもよい。｝で示される基、 iv)式（V） 【化５】 （式中、Mは単結合、または水酸基・カルボキシル基・C
1〜C4アルキル基またはC1〜C4アルコキシ基で置換され
ていてもよいC1〜C4アルキレン基を意味する。環KはMと
一緒になって５ないし８員式アミン環を意味する。環L
は置換基を有していてもよく、酸素原子を有していても
よい、５〜８員式アルキル環を示す。）で示される基、 v）式（VI） 【化６】 （式中、環Pは５〜７員式アミン環、R⁵は水素原子、ま
たはハロゲン原子・水酸基またはカルボキシル基で置換
されていてもよいC1〜C4アルキル基を意味する。）で示
される基、 vi)置換基を有していてもよい、アルキニル基、アルケ
ニル基またはアルキル基、 vii)下記置換基群Aから選ばれる１〜３個の置換基で置
換されていてもよいフェニル基、または、 viii）下記置換基群Aから選ばれる１〜３個の置換基で
置換されていてもよいピリジル基、ピリミジル基、チエ
ニル基、チアゾリル基またはフリール基を意味する。 [置換基群A]ハロゲン原子・シアノ基・ニトロ基または
水酸基で置換されていてもよいC1〜C4アルキル基、ハロ
ゲン原子・シアノ基・ニトロ基または水酸基で置換され
ていてもよいC1〜C4アルコキシ基、シアノ基、ニトロ
基、保護基を有していてもよいカルボキシル基、保護基
を有していてもよい水酸基、低級アルキル基で置換され
ていてもよいカルバモイル基、ハロゲン原子、C1〜C4ア
シル基・C1〜C4アルキルスルホニル基または置換基を有
していてもよいアリールスルホニル基で置換されていて
もよいアミノ基。lは１〜３の整数を意味する。但し、l
が１または２、Xがシアノ基、ニトロ基またはクロロ原
子、R¹がクロロ原子、R²がメトキシ基、環Aが飽和の５
または６員式アミン環、Dが単結合、mが０でWが保護基
を有していてもよいカルボキシル基またはC1〜C4アルコ
キシ基の場合；lが１、R¹がクロロ原子、R²がメトキシ
基、環Aが飽和の５または６員式アミン環、Dが単結合で
Wが水酸基の場合；lが１で環Bが５または６員式アミン
環でｎおよびｐが共に０の場合；lが１でEおよびQが水
酸基で、qが０の場合；およびlが１でXがクロロ原子でY
がメトキシ基で置換されたフェニル基である場合を除
く。｝で示されるフタラジン誘導体または薬理学的に許
容される塩、またはそれらの水和物。1. A compound of the general formula (I) In the formula, R ¹ and R ² are the same or different, and are a halogen atom, a C1-C4 alkyl group optionally substituted with a halogen atom,
It means a C1-C4 alkoxy group or a cyano group which may be substituted with a halogen atom. X is a cyano group, a nitro group, a halogen atom, a thiocarbamoyl group, a C1-C4 alkyl group, an aryl C1-C4 alkyl group or a carboxy C1-
It means a hydroxyimino group which may be substituted with a C4 alkyl group, or a heteroaryl group which may be substituted with 1 to 3 substituents selected from the following substituent group A. Y is i) Formula (II) (Wherein, ring A is a 4- to 8-membered amine ring which may be substituted with a methyl group and may have a double bond, D is a single bond or an oxygen atom, and R ³ is a hydrogen atom , A C1-C4 alkyl group or a halogen atom, m represents an integer of 0 or 1-3, W represents an amino group, a hydroxyl group, a cyano group, a carboxyl group which may have a protecting group or a C1-C4 alkoxy group. Ii) a group represented by the formula (III): (Wherein, ring B is a 4- to 8-membered amine ring optionally having a double bond, n and p are the same or different and are 0 or 1
Means an integer of Iii) a group represented by the formula (IV): In the formula, ring G represents a 4- to 8-membered amine ring which may have a double bond, E is a hydroxyl group, a halogen atom, a C1-C4 alkyl group or a C1-C4 alkoxy group, and J is a compound represented by the formula -(CHR ⁴ ) qQ
(Wherein, R ⁴ represents a hydrogen atom or a C1-C4 alkyl group, Q represents a hydroxyl group, a halogen atom, a carboxyl group which may have a protecting group, a carbamoyl group, or an azolyl group containing no heteroatom other than a nitrogen atom. Represents q or an integer of 1 to 4.) Alternatively, E and J, together with the carbon atom to which they are attached, may form a 3- to 6-membered ring, which may have a heteroatom. This ring may have a substituent. A group represented by｝, iv) Formula (V) (Where M is a single bond, or a hydroxyl group, a carboxyl group, or C
It means a C1-C4 alkylene group which may be substituted with a 1-C4 alkyl group or a C1-C4 alkoxy group. Ring K together with M represents a 5- to 8-membered amine ring. Ring L
Represents a 5- to 8-membered alkyl ring which may have a substituent and may have an oxygen atom. A) a group represented by the formula: v) Formula (VI) (Wherein, ring P represents a 5- to 7-membered amine ring, and R ⁵ represents a hydrogen atom, or a C 1 -C 4 alkyl group optionally substituted with a halogen atom, a hydroxyl group or a carboxyl group.) Vi) optionally substituted alkynyl group, alkenyl group or alkyl group, vii) phenyl group optionally substituted with 1 to 3 substituents selected from the following substituent group A, or Viii) a pyridyl group, a pyrimidyl group, a thienyl group, a thiazolyl group or a freel group which may be substituted with 1 to 3 substituents selected from the following substituent group A. [Substituent group A] a C1-C4 alkyl group optionally substituted with a halogen atom / cyano group / nitro group or a hydroxyl group, a C1-C4 alkoxy optionally substituted with a halogen atom / cyano group / nitro group or a hydroxyl group Group, cyano group, nitro group, carboxyl group optionally having a protecting group, hydroxyl group optionally having a protecting group, carbamoyl group optionally substituted with a lower alkyl group, a halogen atom, C1 to C4 An acyl group, an amino group which may be substituted with a C1-C4 alkylsulfonyl group or an optionally substituted arylsulfonyl group. l means an integer of 1 to 3. Where l
Is 1 or 2, X is cyano, nitro or chloro, R ¹ is chloro, R ² is methoxy, and ring A is saturated
Or 6-membered amine ring, D is a single bond, when m is a carboxyl group which or C1~C4 alkoxy group which may have a W protecting group 0; l is 1, R ¹ is chloro atom, R ² Is a methoxy group, ring A is a saturated 5- or 6-membered amine ring, D is a single bond
W is a hydroxyl group; l is 1 and ring B is a 5- or 6-membered amine ring and n and p are both 0; l is 1 and E and Q are hydroxyl groups and q is 0; X is chloro and Y is 1.
Is a phenyl group substituted by a methoxy group. A phthalazine derivative or a pharmacologically acceptable salt thereof, or a hydrate thereof, 【請求項２】R¹がハロゲン原子、ハロゲン原子で置換さ
れていてもよいC1〜C4アルキル基またはシアノ基で、R²
がハロゲン原子またはC1〜C4アルコキシ基である請求項
１記載のフタラジン誘導体またはその薬理学的に許容さ
れる塩、またはそれらの水和物。In wherein R ¹ is a halogen atom, a halogen atom with optionally substituted C1~C4 alkyl group or a cyano group, R ²
Is a halogen atom or a C1 to C4 alkoxy group, the phthalazine derivative or a pharmaceutically acceptable salt thereof, or a hydrate thereof. 【請求項３】Yが式（II） 【化７】 （式中、環A、D、R³、Wおよびmは前記を意味する。）で
ある請求項１または２に記載のフタラジン誘導体または
その薬理学的に許容される塩、またはそれらの水和物。(3) Y is a compound represented by the formula (II): (Wherein rings A, D, R ³ , W and m are as defined above). The phthalazine derivative according to claim 1 or 2, a pharmaceutically acceptable salt thereof, or a hydration thereof. object. 【請求項４】Yが式（III） 【化８】 （式中、環B、nおよびpは前記を意味する。）である請
求項１または２に記載のフタラジン誘導体またはその薬
理学的に許容される塩、またはそれらの水和物。(4) Y is a compound represented by the formula (III): (Wherein ring B, n and p mean the same as above). The phthalazine derivative or a pharmacologically acceptable salt thereof or the hydrate thereof according to claim 1 or 2. 【請求項５】Yが式（IV） 【化９】 （式中、環G、EおよびJは前記を意味する。）である請
求項１または２に記載のフタラジン誘導体またはその薬
理学的に許容される塩、またはそれらの水和物。(5) Y is a compound represented by the formula (IV): (Wherein rings G, E and J are as defined above). The phthalazine derivative or a pharmacologically acceptable salt thereof or a hydrate thereof according to claim 1 or 2. 【請求項６】Yが式（V） 【化１０】 （式中、M、環Kおよび環Lは前記を意味する。）である
請求項１または２に記載のフタラジン誘導体またはその
薬理学的に許容される塩、またはそれらの水和物。(6) Y is a compound represented by the formula (V): (Wherein M, ring K and ring L mean the same). The phthalazine derivative or a pharmaceutically acceptable salt thereof or the hydrate thereof according to claim 1 or 2. 【請求項７】Yが式（VI） 【化１１】 （式中、環PおよびR⁵は前記を意味する。）である請求
項１または２に記載のフタラジン誘導体またはその薬理
学的に許容される塩、またはそれらの水和物。7. Y is a compound of the formula (VI) (Wherein rings P and R ⁵ are as defined above). The phthalazine derivative or a pharmacologically acceptable salt thereof, or a hydrate thereof according to claim 1 or 2. 【請求項８】Yが置換基を有していてもよい、アルキニ
ル基、アルケニル基またはアルキル基である請求項１ま
たは２に記載のフタラジン誘導体またはその薬理学的に
許容される塩、またはそれらの水和物。8. The phthalazine derivative according to claim 1, wherein Y is an alkynyl group, an alkenyl group or an alkyl group which may have a substituent, or a pharmaceutically acceptable salt thereof, or a salt thereof. Hydrate. 【請求項９】Yが前記置換基群Aで置換されていてもよい
フェニル基である請求項１または２に記載のフタラジン
誘導体またはその薬理学的に許容される塩、またはそれ
らの水和物。9. The phthalazine derivative according to claim 1, wherein Y is a phenyl group which may be substituted with the substituent group A, a pharmaceutically acceptable salt thereof, or a hydrate thereof. . 【請求項１０】Yが前記置換基群Aで置換されていてもよ
いピリジル基、ピリミジル基、チエニル基、チアゾリル
基またはフリール基である請求項１または２に記載のフ
タラジン誘導体またはその薬理学的に許容される塩、ま
たはそれらの水和物。10. The phthalazine derivative according to claim 1, wherein Y is a pyridyl group, a pyrimidyl group, a thienyl group, a thiazolyl group or a freel group which may be substituted with the substituent group A, or a pharmacologically active substance thereof. Or a hydrate thereof. 【請求項１１】Yが式（II）で示される基であって、環A
が二重結合を有していてもよい4〜8員式アミン環、Wが
水酸基、mが０または１〜３の整数で、 i）Dが単結合でR³がハロゲン原子、または ii）Dが酸素原子で、R³が水素原子である請求項１〜３
のいずれか一項に記載のフタラジン誘導体またはその薬
理学的に許容される塩、またはそれらの水和物。(11) Y is a group represented by the formula (II),
Is a 4- to 8-membered amine ring which may have a double bond, W is a hydroxyl group, m is 0 or an integer of 1 to 3, i) D is a single bond and R ³ is a halogen atom, or ii) D is an oxygen atom, and R ³ is a hydrogen atom.
The phthalazine derivative according to any one of the above, a pharmacologically acceptable salt thereof, or a hydrate thereof. 【請求項１２】Yが式（III）で示される基であって、環
Bが６員式アミノ環、nは０または１、pは１である請求
項１、２または４のいずれか一項に記載のフタラジン誘
導体またはその薬理学的に許容される塩、またはそれら
の水和物。(12) Y is a group represented by the formula (III),
The phthalazine derivative according to any one of claims 1, 2 or 4, or a pharmaceutically acceptable salt thereof, or a salt thereof, wherein B is a 6-membered amino ring, n is 0 or 1, and p is 1. Hydrate. 【請求項１３】Yが式（IV）で示される基であって、Eと
Jは結合している炭素原子と一緒になって、ヘテロ原子
を有していてもよく、置換基を有していてもよい３から
６員式環を形成し、環Gが二重結合を有していてもよい
４から８員式アミン環である請求項１、２または５のい
ずれか一項に記載のフタラジン誘導体またはその薬理学
的に許容される塩、またはそれらの水和物。13. Y is a group represented by the formula (IV), wherein E and
J together with the bonding carbon atom forms a 3- to 6-membered ring which may have a hetero atom and may have a substituent, and ring G has a double bond. The phthalazine derivative according to any one of claims 1, 2 or 5, which is a 4- to 8-membered amine ring which may have, a pharmacologically acceptable salt thereof, or a hydrate thereof. 【請求項１４】Yが式（IV）で示される基であって、Eは
水酸基、ハロゲン原子、C1〜C4アルキル基またはC1〜C4
アルコキシ基で、Jは式-(CHR⁴)q-Q（式中、R ⁴は水素原
子またはC1〜C4アルキル基を、Qは水酸基、ハロゲン原
子、保護基を有していてもよいカルボキシル基、カルバ
モイル基または窒素原子以外のヘテロ原子を含まないア
ゾリル基、qは０または１〜４の整数であり、環Gが二重
結合を有していてもよい４〜８員式アミン環である請求
項１、２または５のいずれか一項に記載のフタラジン誘
導体またはその薬理学的に許容される塩、またはそれら
の水和物。(14) Y is a group represented by the formula (IV), wherein E is
Hydroxyl group, halogen atom, C1-C4 alkyl group or C1-C4
An alkoxy group, J is of the formula-(CHR^Four) q-Q (where R ^FourIs hydrogen field
Q represents a hydroxyl group or a halogen atom,
, A carboxyl group which may have a protecting group,
Moyl or heteroatoms other than nitrogen
Zolyl group, q is 0 or an integer of 1-4, and ring G is double
A 4- to 8-membered amine ring optionally having a bond
Item 6. The phthalazine derivative according to any one of items 1, 2 or 5.
Conductors or pharmacologically acceptable salts thereof, or those
Hydrate. 【請求項１５】Yが式（V）で示される基であって、環K
および環LMは前記を意味し、Mが水酸基・カルボキシル
基・ヒドロキシC1〜C4アルキレン基またはカルボキシC1
〜C4アルキレン基で置換されたC1〜C4アルキレン基であ
る請求項１、２または６のいずれか一項に記載のフタラ
ジン誘導体またはその薬理学的に許容される塩、または
それらの水和物。(15) Y is a group represented by the formula (V),
And ring LM mean the above, and M is a hydroxyl group, a carboxyl group, a hydroxy C1-C4 alkylene group or a carboxy C1.
The phthalazine derivative according to any one of claims 1, 2 or 6, which is a C1-C4 alkylene group substituted with a -C4 alkylene group, a pharmacologically acceptable salt thereof, or a hydrate thereof. 【請求項１６】Yが置換基を有していてもよいアルキニ
ル基であって、三重結合が１個である請求項１、２また
は８のいずれか一項に記載のフタラジン誘導体またはそ
の薬理学的に許容される塩、またはそれらの水和物。16. The phthalazine derivative or the pharmacology thereof according to claim 1, wherein Y is an alkynyl group which may have a substituent and has one triple bond. Pharmaceutically acceptable salts or hydrates thereof. 【請求項１７】化合物が以下に示す化合物群から選ばれ
る請求項１〜１５のいずれか一項に記載の縮合フタラジ
ン誘導体またはその薬理学的に許容される塩、またはそ
れらの水和物。 １）1-(4-アミノピペリジノ)-4-[(3-クロロ-4-メトキシ
ベンジル)アミノ]-6-フタラジンカルボニトリル ２）4-[(3-クロロ-4-メトキシベンジル)アミノ]-1-[(4-
ヒドロキシ-4-ヒドロキシメチル)ピペリジノ]-6-フタラ
ジンカルボニトリル ３）4-[(3-クロロ-4-メトキシベンジル)アミノ]-1-(4-
シアノピペリジノ)-6-フタラジンカルボニトリル ４）4-[(3-クロロ-4-メトキシベンジル)アミノ]-1-(4-
シアノフェニル)-6-フタラジンカルボニトリル ５）4-[4-[(3-クロロ-4-メトキシベンジル)アミノ]-6-
シアノフタラジン-1-イル]フェニルカルボキサミド ６）4-[(3-クロロ-4-メトキシフェネチル)アミノ]-1-(4
-シアノピペリジノ)-6-フタラジンカルボニトリル ７）4-[(3-クロロ-4-メトキシベンジル)アミノ]-1-(2-
ピリジル)-6-フタラジンカルボニトリル ８）4-[(3-クロロ-4-メトキシベンジル)アミノ]-1-(3-
ピリジル)-6-フタラジンカルボニトリル ９）4-[(3-クロロ-4-メトキシベンジル)アミノ]-1-(4-
ピリジル)-6-フタラジンカルボニトリル １０）4-[(3-クロロ-4-メトキシフェネチル)アミノ]-1-
(2-ピリジル)-6-フタラジンカルボニトリル １１）4-[(3-クロロ-4-メトキシフェネチルアミノ)]-1-
(3-ピリジル)-6-フタラジンカルボニトリル １２）4-[(3-クロロ-4-メトキシフェネチル)アミノ]-1-
(4-ピリジル)-6-フタラジンカルボニトリル １３）4-[(3-クロロ-4-メトキシベンジル)アミノ]-1-(2
-ヒドロキシ-7-アザスピロ[3.5]ノン-7-イル)-6-フタラ
ジンカルボニトリル １４）4-[(3-クロロ-4-メトキフェネチル)アミノ]-1-(2
-ヒドロキシ-7-アザスピロ[3.5]ノン-7-イル)-6-フタラ
ジンカルボニトリル １５）4-[(3-ブロモ-4-メトキシベンジル)アミノ]-1-(2
-ヒドロキシ-7-アザスピロ[3.5]ノン-7-イル)-6-フタラ
ジンカルボニトリル １６）4-[(3-クロロ-4-メトキシベンジル)アミノ]-1-(2
-ヒドロキシ-6-アザスピロ[3.4]オクト-6-イル)-6-フタ
ラジンカルボニトリル １７）4-[(3-クロロ-4-メトキシベンジル)アミノ]-1-[4
-(1-フルオロ-2-ヒドロキシエチル)ピペリジノ]-6-フタ
ラジンカルボニトリル １８）4-[(3-クロロ-4-メトキシベンジル)アミノ]-1-[4
-フルオロ-4-(ヒドロキシメチル)ピペリジノ]-6-フタラ
ジンカルボニトリル １９）4-[(3-クロロ-4-メトキシベンジル)アミノ]-1-[4
-(ヒドロキシメチル)-4-メトキシピペリジノ]-6-フタラ
ジンカルボニトリル ２０）4-[(3-クロロ-4-メトキシベンジル)アミノ]-1-[4
-(ヒドロキシエトキシ)ピペリジノ]-6-フタラジンカル
ボニトリル ２１）4-[(3-クロロ-4-メトキシベンジル)アミノ]-1-(3
-ヒドロキシ-3-メチル-1-ブチニル)-6-フタラジンカル
ボニトリル ２２）1-(3-アミノ-3-メチル-1-ブチニル)-4-[(3-クロ
ロ-4-メトキシベンジル)アミノ]-6-フタラジンカルボニ
トリル ２３）4-[(3-クロロ-4-メトキシベンジル)アミノ]-1-(3
-ヒドロキシ-3-メチルブチル)-6-フタラジンカルボニト
リル ２４）4-[(3-クロロ-4-メトキシベンジル)アミノ]-1-(4
-ヒドロキシイミノピペリジノ)-6-フタラジンカルボニ
トリル ２５）4-[(3-ブロモ-4-メトキシベンジル)アミノ]-1-(4
-ヒドロキシピペリジノ)-6-フタラジンカルボニトリル ２６）1-(4-ヒドロキシピペリジノ)-4-[(4-メトキシ-3-
メチルベンジル)アミノ]-6-フタラジンカルボニトリル ２７）1-(4-ヒドロキシピペリジノ)-4-[[4-メトキシ-3-
(トリフルオロメチル）ベンジル]アミノ]-6-フタラジン
カルボニトリル ２８）1-(4-ヒドロキシピペリジノ)-4-[(3-ヨード-4-メ
トキシベンジル)アミノ]-6-フタラジンカルボニトリル ２９）1-[4-フルオロ-4-(ヒドロキシメチル)ピペリジ
ノ]-4-[(4-メトキシ-3-メチルベンジル)アミノ]-6-フタ
ラジンカルボニトリル ３０）4-[(3-ブロモ-4-メトキシベンジル)アミノ]-1-[4
-(ヒドロキシメチル)ピペリジノ]-6-フタラジンカルボ
ニトリル ３１）4-[(3-クロロ-4-メトキシベンジル)アミノ]-1-[4
-(フルオロメチル)-4-ヒドロキシピペリジノ]-6-フタラ
ジンカルボニトリル ３２）4-[(3-クロロ-4-メトキシベンジル)アミノ]-1-(4
-ヒドロキシピペリジノ)-6-フタラジンカルバルデヒド
O6-メチルオキシム ３３）1-[4-[(3-クロロ-4-メトキシベンジル)アミノ]-6
-(1H-1-ピラゾリル)-1-フタラジニル]-4-ピペリジノー
ル ３４）4-[(3-シアノ-4-メトキシベンジル)アミノ]-1-(4
-ヒドロキシピペリジノ)-6-フタラジンカルボニトリル ３５）(endo)-4-[(3-クロロ-4-メトキシベンジル)アミ
ノ]-1-(3-ヒドロキシ-8-アザビシクロ[3.2.1]オクト-8-
イル)-6-フタラジンカルボニトリル ３６）(syn)-4-[(3-クロロ-4-メトキシベンジル)アミ
ノ]-1-(9-ヒドロキシ-3-アザビシクロ[3.3.1]ノン-3-イ
ル)-6-フタラジンカルボニトリル17. The condensed phthalazine derivative according to any one of claims 1 to 15, wherein the compound is selected from the following compounds, or a pharmaceutically acceptable salt thereof, or a hydrate thereof. 1) 1- (4-aminopiperidino) -4-[(3-chloro-4-methoxybenzyl) amino] -6-phthalazinecarbonitrile 2) 4-[(3-chloro-4-methoxybenzyl) amino]- 1-[(4-
Hydroxy-4-hydroxymethyl) piperidino] -6-phthalazinecarbonitrile 3) 4-[(3-chloro-4-methoxybenzyl) amino] -1- (4-
Cyanopiperidino) -6-phthalazinecarbonitrile 4) 4-[(3-chloro-4-methoxybenzyl) amino] -1- (4-
Cyanophenyl) -6-phthalazinecarbonitrile 5) 4- [4-[(3-chloro-4-methoxybenzyl) amino] -6-
Cyanophthalazin-1-yl] phenylcarboxamide 6) 4-[(3-chloro-4-methoxyphenethyl) amino] -1- (4
-Cyanopiperidino) -6-phthalazinecarbonitrile 7) 4-[(3-chloro-4-methoxybenzyl) amino] -1- (2-
Pyridyl) -6-phthalazinecarbonitrile 8) 4-[(3-chloro-4-methoxybenzyl) amino] -1- (3-
Pyridyl) -6-phthalazinecarbonitrile 9) 4-[(3-chloro-4-methoxybenzyl) amino] -1- (4-
Pyridyl) -6-phthalazinecarbonitrile 10) 4-[(3-chloro-4-methoxyphenethyl) amino] -1-
(2-pyridyl) -6-phthalazinecarbonitrile 11) 4-[(3-chloro-4-methoxyphenethylamino)]-1-
(3-pyridyl) -6-phthalazinecarbonitrile 12) 4-[(3-chloro-4-methoxyphenethyl) amino] -1-
(4-pyridyl) -6-phthalazinecarbonitrile 13) 4-[(3-chloro-4-methoxybenzyl) amino] -1- (2
-Hydroxy-7-azaspiro [3.5] non-7-yl) -6-phthalazinecarbonitrile 14) 4-[(3-chloro-4-methoxyphenethyl) amino] -1- (2
-Hydroxy-7-azaspiro [3.5] non-7-yl) -6-phthalazinecarbonitrile 15) 4-[(3-bromo-4-methoxybenzyl) amino] -1- (2
-Hydroxy-7-azaspiro [3.5] non-7-yl) -6-phthalazinecarbonitrile 16) 4-[(3-chloro-4-methoxybenzyl) amino] -1- (2
-Hydroxy-6-azaspiro [3.4] oct-6-yl) -6-phthalazinecarbonitrile 17) 4-[(3-chloro-4-methoxybenzyl) amino] -1- [4
-(1-Fluoro-2-hydroxyethyl) piperidino] -6-phthalazinecarbonitrile 18) 4-[(3-chloro-4-methoxybenzyl) amino] -1- [4
-Fluoro-4- (hydroxymethyl) piperidino] -6-phthalazinecarbonitrile 19) 4-[(3-chloro-4-methoxybenzyl) amino] -1- [4
-(Hydroxymethyl) -4-methoxypiperidino] -6-phthalazinecarbonitrile 20) 4-[(3-chloro-4-methoxybenzyl) amino] -1- [4
-(Hydroxyethoxy) piperidino] -6-phthalazinecarbonitrile 21) 4-[(3-chloro-4-methoxybenzyl) amino] -1- (3
-Hydroxy-3-methyl-1-butynyl) -6-phthalazinecarbonitrile 22) 1- (3-Amino-3-methyl-1-butynyl) -4-[(3-chloro-4-methoxybenzyl) amino ] -6-phthalazinecarbonitrile 23) 4-[(3-chloro-4-methoxybenzyl) amino] -1- (3
-Hydroxy-3-methylbutyl) -6-phthalazinecarbonitrile 24) 4-[(3-Chloro-4-methoxybenzyl) amino] -1- (4
-Hydroxyiminopiperidino) -6-phthalazinecarbonitrile 25) 4-[(3-bromo-4-methoxybenzyl) amino] -1- (4
-Hydroxypiperidino) -6-phthalazinecarbonitrile 26) 1- (4-Hydroxypiperidino) -4-[(4-methoxy-3-
Methylbenzyl) amino] -6-phthalazinecarbonitrile 27) 1- (4-hydroxypiperidino) -4-[[4-methoxy-3-
(Trifluoromethyl) benzyl] amino] -6-phthalazinecarbonitrile 28) 1- (4-hydroxypiperidino) -4-[(3-iodo-4-methoxybenzyl) amino] -6-phthalazinecarbo Nitrile 29) 1- [4-Fluoro-4- (hydroxymethyl) piperidino] -4-[(4-methoxy-3-methylbenzyl) amino] -6-phthalazinecarbonitrile 30) 4-[(3-bromo -4-methoxybenzyl) amino] -1- [4
-(Hydroxymethyl) piperidino] -6-phthalazinecarbonitrile 31) 4-[(3-chloro-4-methoxybenzyl) amino] -1- [4
-(Fluoromethyl) -4-hydroxypiperidino] -6-phthalazinecarbonitrile 32) 4-[(3-chloro-4-methoxybenzyl) amino] -1- (4
-Hydroxypiperidino) -6-phthalazine carbaldehyde
O6-Methyloxime 33) 1- [4-[(3-chloro-4-methoxybenzyl) amino] -6
-(1H-1-pyrazolyl) -1-phthalazinyl] -4-piperidinol 34) 4-[(3-cyano-4-methoxybenzyl) amino] -1- (4
-Hydroxypiperidino) -6-phthalazinecarbonitrile 35) (endo) -4-[(3-chloro-4-methoxybenzyl) amino] -1- (3-hydroxy-8-azabicyclo [3.2.1] Oct-8-
Yl) -6-phthalazinecarbonitrile 36) (syn) -4-[(3-chloro-4-methoxybenzyl) amino] -1- (9-hydroxy-3-azabicyclo [3.3.1] non-3- Yl) -6-phthalazinecarbonitrile 【請求項１８】化合物が以下に示す化合物群から選ばれ
る請求項１〜１６のいずれか一項に記載の縮合フタラジ
ン誘導体またはその薬理学的に許容される塩、またはそ
れらの水和物。 １）4-[(3-クロロ-4-メトキシベンジル)アミノ]-1-(2-
ピリジル)-6-フタラジンカルボニトリル ２）4-[(3-クロロ-4-メトキシベンジル)アミノ]-1-(3-
ピリジル)-6-フタラジンカルボニトリル ３）4-[(3-クロロ-4-メトキシベンジル)アミノ]-1-(4-
ピリジル)-6-フタラジンカルボニトリル ４）4-[(3-クロロ-4-メトキシフェネチル)アミノ]-1-(2
-ピリジル)-6-フタラジンカルボニトリル ５）4-[(3-クロロ-4-メトキシフェネチルアミノ)]-1-(3
-ピリジル)-6-フタラジンカルボニトリル ６）4-[(3-クロロ-4-メトキシフェネチル)アミノ]-1-(4
-ピリジル)-6-フタラジンカルボニトリル ７）4-[(3-クロロ-4-メトキシベンジル)アミノ]-1-(2-
ヒドロキシ-7-アザスピロ[3.5]ノン-7-イル)-6-フタラ
ジンカルボニトリル ８）4-[(3-クロロ-4-メトキフェネチル)アミノ]-1-(2-
ヒドロキシ-7-アザスピロ[3.5]ノン-7-イル)-6-フタラ
ジンカルボニトリル ９）4-[(3-ブロモ-4-メトキシベンジル)アミノ]-1-(2-
ヒドロキシ-7-アザスピロ[3.5]ノン-7-イル)-6-フタラ
ジンカルボニトリル １０）4-[(3-クロロ-4-メトキシベンジル)アミノ]-1-(2
-ヒドロキシ-6-アザスピロ[3.4]オクト-6-イル)-6-フタ
ラジンカルボニトリル １１）4-[(3-クロロ-4-メトキシベンジル)アミノ]-1-[4
-(1-フルオロ-2-ヒドロキシエチル)ピペリジノ]-6-フタ
ラジンカルボニトリル １２）4-[(3-クロロ-4-メトキシベンジル)アミノ]-1-[4
-フルオロ-4-(ヒドロキシメチル)ピペリジノ]-6-フタラ
ジンカルボニトリル １３）4-[(3-クロロ-4-メトキシベンジル)アミノ]-1-[4
-(ヒドロキシメチル)-4-メトキシピペリジノ]-6-フタラ
ジンカルボニトリル １４）4-[(3-クロロ-4-メトキシベンジル)アミノ]-1-[4
-(ヒドロキシエトキシ)ピペリジノ]-6-フタラジンカル
ボニトリル １５）4-[(3-クロロ-4-メトキシベンジル)アミノ]-1-(3
-ヒドロキシ-3-メチル-1-ブチニル)-6-フタラジンカル
ボニトリル １６）1-(3-アミノ-3-メチル-1-ブチニル)-4-[(3-クロ
ロ-4-メトキシベンジル)アミノ]-6-フタラジンカルボニ
トリル １７）4-[(3-クロロ-4-メトキシベンジル)アミノ]-1-(3
-ヒドロキシ-3-メチルブチル)-6-フタラジンカルボニト
リル １８）4-[(3-クロロ-4-メトキシベンジル)アミノ]-1-(4
-ヒドロキシイミノピペリジノ)-6-フタラジンカルボニ
トリル １９）4-[(3-ブロモ-4-メトキシベンジル)アミノ]-1-(4
-ヒドロキシピペリジノ)-6-フタラジンカルボニトリル ２０）1-(4-ヒドロキシピペリジノ)-4-[(4-メトキシ-3-
メチルベンジル)アミノ]-6-フタラジンカルボニトリル ２１）1-[4-フルオロ-4-(ヒドロキシメチル)ピペリジ
ノ]-4-[(4-メトキシ-3-メチルベンジル)アミノ]-6-フタ
ラジンカルボニトリル ２２）4-[(3-クロロ-4-メトキシベンジル)アミノ]-1-[4
-(フルオロメチル)-4-ヒドロキシピペリジノ]-6-フタラ
ジンカルボニトリル ２３）4-[(3-クロロ-4-メトキシベンジル)アミノ]-1-(4
-ヒドロキシピペリジノ)-6-フタラジンカルバルデヒド
O6-メチルオキシム ２４）1-[4-[(3-クロロ-4-メトキシベンジル)アミノ]-6
-(1H-1-ピラゾリル)-1-フタラジニル]-4-ピペリジノー
ル ２５）4-[(3-シアノ-4-メトキシベンジル)アミノ]-1-(4
-ヒドロキシピペリジノ)-6-フタラジンカルボニトリル ２６）(endo)-4-[(3-クロロ-4-メトキシベンジル)アミ
ノ]-1-(3-ヒドロキシ-8-アザビシクロ[3.2.1]オクト-8-
イル)-6-フタラジンカルボニトリル ２７）(syn)-4-[(3-クロロ-4-メトキシベンジル)アミ
ノ]-1-(9-ヒドロキシ-3-アザビシクロ[3.3.1]ノン-3-イ
ル)-6-フタラジンカルボニトリル18. The fused phthalazine derivative according to any one of claims 1 to 16, wherein the compound is selected from the group consisting of the following compounds, a pharmaceutically acceptable salt thereof, or a hydrate thereof. 1) 4-[(3-chloro-4-methoxybenzyl) amino] -1- (2-
Pyridyl) -6-phthalazinecarbonitrile 2) 4-[(3-chloro-4-methoxybenzyl) amino] -1- (3-
Pyridyl) -6-phthalazinecarbonitrile 3) 4-[(3-chloro-4-methoxybenzyl) amino] -1- (4-
Pyridyl) -6-phthalazinecarbonitrile 4) 4-[(3-chloro-4-methoxyphenethyl) amino] -1- (2
-Pyridyl) -6-phthalazinecarbonitrile 5) 4-[(3-chloro-4-methoxyphenethylamino)]-1- (3
-Pyridyl) -6-phthalazinecarbonitrile 6) 4-[(3-chloro-4-methoxyphenethyl) amino] -1- (4
-Pyridyl) -6-phthalazinecarbonitrile 7) 4-[(3-chloro-4-methoxybenzyl) amino] -1- (2-
Hydroxy-7-azaspiro [3.5] non-7-yl) -6-phthalazinecarbonitrile 8) 4-[(3-chloro-4-methoxyphenethyl) amino] -1- (2-
Hydroxy-7-azaspiro [3.5] non-7-yl) -6-phthalazinecarbonitrile 9) 4-[(3-bromo-4-methoxybenzyl) amino] -1- (2-
Hydroxy-7-azaspiro [3.5] non-7-yl) -6-phthalazinecarbonitrile 10) 4-[(3-chloro-4-methoxybenzyl) amino] -1- (2
-Hydroxy-6-azaspiro [3.4] oct-6-yl) -6-phthalazinecarbonitrile 11) 4-[(3-chloro-4-methoxybenzyl) amino] -1- [4
-(1-Fluoro-2-hydroxyethyl) piperidino] -6-phthalazinecarbonitrile 12) 4-[(3-chloro-4-methoxybenzyl) amino] -1- [4
-Fluoro-4- (hydroxymethyl) piperidino] -6-phthalazinecarbonitrile 13) 4-[(3-chloro-4-methoxybenzyl) amino] -1- [4
-(Hydroxymethyl) -4-methoxypiperidino] -6-phthalazinecarbonitrile 14) 4-[(3-chloro-4-methoxybenzyl) amino] -1- [4
-(Hydroxyethoxy) piperidino] -6-phthalazinecarbonitrile 15) 4-[(3-chloro-4-methoxybenzyl) amino] -1- (3
-Hydroxy-3-methyl-1-butynyl) -6-phthalazinecarbonitrile 16) 1- (3-Amino-3-methyl-1-butynyl) -4-[(3-chloro-4-methoxybenzyl) amino ] -6-phthalazinecarbonitrile 17) 4-[(3-chloro-4-methoxybenzyl) amino] -1- (3
-Hydroxy-3-methylbutyl) -6-phthalazinecarbonitrile 18) 4-[(3-chloro-4-methoxybenzyl) amino] -1- (4
-Hydroxyiminopiperidino) -6-phthalazinecarbonitrile 19) 4-[(3-bromo-4-methoxybenzyl) amino] -1- (4
-Hydroxypiperidino) -6-phthalazinecarbonitrile 20) 1- (4-Hydroxypiperidino) -4-[(4-methoxy-3-
Methylbenzyl) amino] -6-phthalazinecarbonitrile 21) 1- [4-Fluoro-4- (hydroxymethyl) piperidino] -4-[(4-methoxy-3-methylbenzyl) amino] -6-phthalazine Carbonitrile 22) 4-[(3-chloro-4-methoxybenzyl) amino] -1- [4
-(Fluoromethyl) -4-hydroxypiperidino] -6-phthalazinecarbonitrile 23) 4-[(3-chloro-4-methoxybenzyl) amino] -1- (4
-Hydroxypiperidino) -6-phthalazine carbaldehyde
O6-Methyloxime 24) 1- [4-[(3-chloro-4-methoxybenzyl) amino] -6
-(1H-1-pyrazolyl) -1-phthalazinyl] -4-piperidinol 25) 4-[(3-cyano-4-methoxybenzyl) amino] -1- (4
-Hydroxypiperidino) -6-phthalazinecarbonitrile 26) (endo) -4-[(3-chloro-4-methoxybenzyl) amino] -1- (3-hydroxy-8-azabicyclo [3.2.1] Oct-8-
Yl) -6-phthalazinecarbonitrile 27) (syn) -4-[(3-chloro-4-methoxybenzyl) amino] -1- (9-hydroxy-3-azabicyclo [3.3.1] non-3- Yl) -6-phthalazinecarbonitrile 【請求項１９】請求項１〜１８のいずれか一項に記載の
フタラジン誘導体または薬理学的に許容される塩、また
はそれらの水和物を有効成分とする***機能不全予防・
治療剤。19. A method for preventing erectile dysfunction comprising the phthalazine derivative according to any one of claims 1 to 18, a pharmacologically acceptable salt thereof, or a hydrate thereof as an active ingredient.
Therapeutic agent. 【請求項２０】一般式（VII） 【化１２】 ｛式中、l’は１〜３の整数を意味する。R⁶はハロゲン
原子、ハロゲン原子で置換されていてもよいC1〜C4アル
キル基またはシアノ基を意味する。X¹はシアノ基、ニト
ロ基またはハロゲン原子を意味する。Y¹は i)式（VIII） 【化１３】 （式中、環A1は５または６員式アミン環を、m1は０また
は１〜３の整数を意味し、Zはアミノ基、保護基を有し
ていてもよい水酸基、保護基を有していてもよいカルボ
キシル基、C1〜C4アルコキシ基またはシアノ基を意味す
る。）で示される基、 ii)式（IX） 【化１４】 （式中、環B1は５または６員式アミン環を、n1およびp1
は０または１〜３の整数を意味する。）で示される基、 iii)モルホリノ基または硫黄原子が酸化されていてもよ
いチオモルホリノ基、 iv)下記置換基群A1から選ばれる１〜３個の置換基で置
換されていてもよいフェニル基、 v）下記置換基群Aから選ばれる１〜３個の置換基で置換
されていてもよいピリジル基、ピリミジル基、チエニル
基またはフリール基であるヘテロアリール基、または、 vi)式-N(R⁷)-(CH₂)s-Het （式中、R⁷はC1〜C4アルキル基を、Hetは下記の置換基
群Aから選ばれる１から３個の置換基で置換されていて
もよいピリジル基またはピリミジル基を意味する。sは
０または１〜３の整数を意味する。） [置換基群A1]ハロゲン原子・シアノ基・ニトロ基または
水酸基で置換されていてもよい低級アルキル基、ハロゲ
ン原子・シアノ基・ニトロ基または水酸基で置換されて
いてもよい低級アルコキシ基、シアノ基、ニトロ基、保
護基を有していてもよいカルボキシル基、保護基を有し
ていてもよい水酸基、低級アルキル基で置換されていて
もよいカルバモイル基、ハロゲン原子、アルキル基・ア
ルコキシ基・ハロゲン原子またはアミノ基フェニル
基。｝で示されるフタラジン誘導体または薬理学的に許
容される塩、またはそれらの水和物を有効成分とする勃
起機能不全症治療剤。20. A compound of the general formula (VII) In the formula, l ′ represents an integer of 1 to 3. R ⁶ represents a halogen atom, a C1-C4 alkyl group optionally substituted with a halogen atom, or a cyano group. X ¹ represents a cyano group, a nitro group or a halogen atom. Y ¹ is i) Formula (VIII) (Wherein, ring A1 represents a 5- or 6-membered amine ring, m1 represents an integer of 0 or 1 to 3, and Z represents an amino group, a hydroxyl group which may have a protecting group, or a protecting group. A carboxyl group, a C1-C4 alkoxy group or a cyano group, which may be optionally selected, ii) a group represented by the formula (IX): (Wherein ring B1 is a 5- or 6-membered amine ring, n1 and p1
Represents an integer of 0 or 1 to 3. Iii) a morpholino group or a thiomorpholino group whose sulfur atom may be oxidized; iv) a phenyl group optionally substituted with 1 to 3 substituents selected from the following substituent group A1 , V) a heteroaryl group which is a pyridyl group, a pyrimidyl group, a thienyl group or a freel group which may be substituted with 1 to 3 substituents selected from the following substituent group A, or vi) a formula -N ( R ⁷ )-(CH ₂ ) s-Het (wherein, R ⁷ is a C1-C4 alkyl group, and Het may be substituted with 1 to 3 substituents selected from Substituent Group A below. Represents a pyridyl group or a pyrimidyl group, and s represents an integer of 0 or 1 to 3.) [Substituent group A1] A lower alkyl group which may be substituted with a halogen atom, a cyano group, a nitro group or a hydroxyl group, Even if substituted with a halogen atom, cyano group, nitro group or hydroxyl group A lower alkoxy group, a cyano group, a nitro group, a carboxyl group optionally having a protecting group, a hydroxyl group optionally having a protecting group, a carbamoyl group optionally substituted with a lower alkyl group, a halogen atom, Alkyl group / alkoxy group / halogen atom or amino group phenyl group. A therapeutic agent for erectile dysfunction, comprising as an active ingredient a phthalazine derivative or a pharmacologically acceptable salt thereof, or a hydrate thereof. 【請求項２１】Y¹が i)式（VIII） 【化１５】 （式中、環A1、Zおよびm1は前記を意味する。）で示さ
れる基、 ii)式（III） 【化１６】 （式中、環B1、n1およびp1は前記を意味する。）で示さ
れる基、または iii)硫黄原子が酸化されていてもよいチオモルホリノ基
で示される基である請求項２０に記載のフタラジン誘導
体またはその薬理学的に許容される塩、またはそれらの
水和物を有効成分とするの***機能不全予防・治療剤。(21) Y ¹ is i) a compound of the formula (VIII) (Wherein rings A1, Z and m1 are as defined above), ii) a group represented by the formula (III): 21. The phthalazine according to claim 20, which is a group represented by the formula (wherein, rings B1, n1 and p1 represent the same as described above), or iii) a group represented by a thiomorpholino group in which a sulfur atom may be oxidized. An agent for preventing or treating erectile dysfunction, comprising a derivative or a pharmacologically acceptable salt thereof, or a hydrate thereof as an active ingredient. 【請求項２２】Y¹が前記置換基群A1から選ばれる１〜３
個の置換基で置換されていてもよいフェニル基、または
ピリジル基、ピリミジル基、チエニル基またはフリール
基であるヘテロアリール基であるフタラジン誘導体また
は薬理学的に許容される塩、またはそれらの水和物を有
効成分とする請求項２０に記載の***機能不全症予防・
治療剤。22. 1-3 Y ¹ is selected from the substituent group A1
Phthalazine derivative or a pharmacologically acceptable salt, or a hydration thereof, which is a phenyl group which may be substituted with a plurality of substituents, or a heteroaryl group which is a pyridyl group, a pyrimidyl group, a thienyl group or a freel group. The erectile dysfunction prevention and prevention according to claim 20, wherein the substance is an active ingredient.
Therapeutic agent. 【請求項２３】Yが式-N(R⁷)-(CH₂)s-Het （式中、Hetは前記置換基群Aから選ばれる１〜３個の置
換基で置換されていてもよいピリジル基を意味する。R⁷
およびsは前記を意味する。）であるフタラジン誘導体
または薬理学的に許容される塩、またはそれらの水和物
を有効成分とする請求項２０に記載の***機能不全症予
防・治療剤。(23) Y is a group represented by the formula -N (R ⁷ )-(CH ₂ ) s-Het (where Het may be substituted with 1 to 3 substituents selected from the above-mentioned substituent group A) Represents a pyridyl group, R ⁷
And s mean the above. 21. The prophylactic / therapeutic agent for erectile dysfunction according to claim 20, comprising a phthalazine derivative or a pharmacologically acceptable salt thereof or a hydrate thereof as an active ingredient. 【請求項２４】化合物が以下に示す請求項２０〜２３の
いずれか一項に記載のフタラジン誘導体またはその薬理
学的に許容される塩、またはそれらの水和物を有効成分
とする***機能不全症治療剤。 １）4-(3-クロロ-4-メトキシベンジル)アミノ-6-シアノ
-1-(3-ヒドロキシメチルピペリジノ)フタラジン ２）4-(3-クロロ-4-メトキシベンジル)アミノ-6-シアノ
-1-(3,4-ジヒドロキシピペリジノ)フタラジン ３）4-(4-アミノピペリジノ)-1-(3-クロロ-4-メトキシ
ベンジル)アミノ-6-シアノフタラジン ４）4-(3-クロロ-4-メトキシベンジル)アミノ-6-シアノ
-1-(4-メトキシピペリジノ)フタラジン ５）4-(3-クロロ-4-メトキシベンジル)アミノ-6-シアノ
-1-(4-ヒドロキシ-4-ヒドロキシメチルピペリジノ)フタ
ラジン ６）4-(3-クロロ-4-メトキシベンジル)アミノ-6-シアノ
-1-(4,4-ジヒドロキシメチルピペリジノ)フタラジン ７）4-(3-クロロ-4-メトキシベンジル)アミノ-6-シアノ
-1-(4-シアノピペリジノ)フタラジン ８）4-(3-クロロ-4-メトキシベンジル)アミノ-6-シアノ
-1-[(3R)-ヒドロキシピロリジノ]フタラジン ９）4-(3-クロロ-4-メトキシベンジル)アミノ-6-シアノ
-1-(3-ヒドロキシメチルピロリジノ)フタラジン １０）4-(3-クロロ-4-メトキシベンジル)アミノ-6-シア
ノ-1-(3,4-ジヒドロキシピロリジノ)フタラジン １１）4-(3-クロロ-4-メトキシベンジル)アミノ-6-シア
ノ-1-(2-メトキシメチルピロリジノ)フタラジン １２）4-[4-(3-クロロ-4-メトキシベンジルアミノ)-6-
シアノフタラジン-1-イル]チオモルホリン 1-オキサイ
ド １３）4-(3-クロロ-4-メトキシベンジル)アミノ-6-シア
ノ-1-(4-メトキシフェニル)フタラジン １４）4-(3-クロロ-4-メトキシベンジル)アミノ-6-シア
ノ-1-(4-シアノフェニル)フタラジン １５）4-[4-(3-クロロ-4-メトキシベンジルアミノ)-6-
シアノフタラジン-1-イル]フェニル-4-カルボキサミド １６）4-(3-クロロ-4-メトキシベンジル)アミノ-6-シア
ノ-1-(2-ピリジルメチル)アミノフタラジン １７）4-(3-クロロ-4-メトキシベンジル)アミノ-6-シア
ノ-1-[N-メチル-N-(2-ピリジルメチル)アミノ]フタラジ
ン １８）4-(3-クロロ-4-メトキシフェネチル)アミノ-6-シ
アノ-1-(4-シアノピペリジノ)フタラジン １９）4-(3-クロロ-4-メトキシフェネチル)アミノ-6-シ
アノ-1-(3-ヒドロキシメチルピペリジノ)フタラジン ２０）4-(3-クロロ-4-メトキシフェネチル)アミノ-6-シ
アノ-1-(4-ヒドロキシメチルピペリジノ)フタラジン ２１）4-(3-クロロ-4-メトキシベンジル)アミノ-6-シア
ノ-1-フェニルフタラジン ２２）4-(3-クロロ-4-メトキシベンジル)-6-シアノ-1-
(2-ピリジル)フタラジン ２３）4-(3-クロロ-4-メトキシベンジル)-6-シアノ-1-
(3-ピリジル)フタラジン ２４）4-(3-クロロ-4-メトキシベンジル)-6-シアノ-1-
(4-ピリジル)フタラジン ２５）4-(3-クロロ-4-メトキシフェネチル)-6-シアノ-1
-(2-ピリジル)フタラジン ２６）4-(3-クロロ-4-メトキシフェネチル)-6-シアノ-1
-(3-ピリジル)フタラジン ２７）4-(3-クロロ-4-メトキシフェネチル)-6-シアノ-1
-(4-ピリジル)フタラジン24. An erectile dysfunction comprising a phthalazine derivative according to any one of claims 20 to 23 or a pharmacologically acceptable salt thereof, or a hydrate thereof as an active ingredient, wherein the compound is shown below. Therapeutic agent. 1) 4- (3-chloro-4-methoxybenzyl) amino-6-cyano
-1- (3-hydroxymethylpiperidino) phthalazine 2) 4- (3-chloro-4-methoxybenzyl) amino-6-cyano
-1- (3,4-dihydroxypiperidino) phthalazine 3) 4- (4-aminopiperidino) -1- (3-chloro-4-methoxybenzyl) amino-6-cyanophthalazine 4) 4- (3-chloro- 4-methoxybenzyl) amino-6-cyano
-1- (4-methoxypiperidino) phthalazine 5) 4- (3-chloro-4-methoxybenzyl) amino-6-cyano
-1- (4-hydroxy-4-hydroxymethylpiperidino) phthalazine 6) 4- (3-chloro-4-methoxybenzyl) amino-6-cyano
-1- (4,4-dihydroxymethylpiperidino) phthalazine 7) 4- (3-chloro-4-methoxybenzyl) amino-6-cyano
-1- (4-cyanopiperidino) phthalazine 8) 4- (3-chloro-4-methoxybenzyl) amino-6-cyano
-1-[(3R) -hydroxypyrrolidino] phthalazine 9) 4- (3-chloro-4-methoxybenzyl) amino-6-cyano
-1- (3-hydroxymethylpyrrolidino) phthalazine 10) 4- (3-chloro-4-methoxybenzyl) amino-6-cyano-1- (3,4-dihydroxypyrrolidino) phthalazine 11) 4- (3 -Chloro-4-methoxybenzyl) amino-6-cyano-1- (2-methoxymethylpyrrolidino) phthalazine 12) 4- [4- (3-chloro-4-methoxybenzylamino) -6-
Cyanophthalazin-1-yl] thiomorpholine 1-oxide 13) 4- (3-chloro-4-methoxybenzyl) amino-6-cyano-1- (4-methoxyphenyl) phthalazine 14) 4- (3-chloro-4 -Methoxybenzyl) amino-6-cyano-1- (4-cyanophenyl) phthalazine 15) 4- [4- (3-chloro-4-methoxybenzylamino) -6-
Cyanophthalazin-1-yl] phenyl-4-carboxamide 16) 4- (3-chloro-4-methoxybenzyl) amino-6-cyano-1- (2-pyridylmethyl) aminophthalazine 17) 4- (3-chloro -4-methoxybenzyl) amino-6-cyano-1- [N-methyl-N- (2-pyridylmethyl) amino] phthalazine 18) 4- (3-chloro-4-methoxyphenethyl) amino-6-cyano- 1- (4-cyanopiperidino) phthalazine 19) 4- (3-chloro-4-methoxyphenethyl) amino-6-cyano-1- (3-hydroxymethylpiperidino) phthalazine 20) 4- (3-chloro-4 -Methoxyphenethyl) amino-6-cyano-1- (4-hydroxymethylpiperidino) phthalazine 21) 4- (3-chloro-4-methoxybenzyl) amino-6-cyano-1-phenylphthalazine 22) 4 -(3-chloro-4-methoxybenzyl) -6-cyano-1-
(2-pyridyl) phthalazine 23) 4- (3-chloro-4-methoxybenzyl) -6-cyano-1-
(3-pyridyl) phthalazine 24) 4- (3-chloro-4-methoxybenzyl) -6-cyano-1-
(4-pyridyl) phthalazine 25) 4- (3-chloro-4-methoxyphenethyl) -6-cyano-1
-(2-pyridyl) phthalazine 26) 4- (3-chloro-4-methoxyphenethyl) -6-cyano-1
-(3-pyridyl) phthalazine 27) 4- (3-chloro-4-methoxyphenethyl) -6-cyano-1
-(4-pyridyl) phthalazine 【請求項２５】請求項１〜２４のいずれか一項に記載の
フタラジン誘導体またはその薬理学的に許容される塩、
またはそれらの水和物を有効成分とする女性の性的機能
不全または月経困難症の予防・治療剤。(25) the phthalazine derivative or the pharmaceutically acceptable salt thereof according to any one of (1) to (24);
Alternatively, a prophylactic / therapeutic agent for female sexual dysfunction or dysmenorrhea, comprising a hydrate thereof as an active ingredient. 【請求項２６】***機能不全症治療剤を製造するための
請求項１〜２４のいずれか一項に記載のフタラジン誘導
体またはその薬理学的に許容される塩、またはそれらの
水和物の使用。26. Use of the phthalazine derivative according to any one of claims 1 to 24, a pharmaceutically acceptable salt thereof, or a hydrate thereof for producing a therapeutic agent for erectile dysfunction. . 【請求項２７】一般式（X） 【化１７】 （式中、Halはハロゲン原子を意味し、R¹、R²、lおよび
Xは前記を意味する。）と式Y³-B(OH)₂（式中、Y³は前記
置換基群Aから選ばれる置換基を有していてもよいフェ
ニル基、ピリジル基、ピリミジル基、チエニル基または
フリル基を意味する。）とを反応させて一般式（XI） 【化１８】 (式中、X、Y³、R¹、R²およびlは前記を意味する。）を
製造する方法。27. The general formula (X) (Wherein Hal represents a halogen atom, and R ¹ , R ² , l and
X means the above. ) And a formula Y ³ -B (OH) ₂ (wherein Y ³ represents a phenyl group, a pyridyl group, a pyrimidyl group, a thienyl group or a furyl group which may have a substituent selected from the substituent group A) With the general formula (XI) (Wherein X, Y ³ , R ¹ , R ² and 1 have the same meaning as described above). 【請求項２８】請求項１〜２０のいずれか一項に記載の
フタラジン誘導体またはその薬理学的に許容される塩、
またはそれらの水和物からなるPDE5阻害剤を有効成分と
する高血圧症、肺高血圧症、狭心症、糖尿病、または腎
炎の予防・治療剤。28. The phthalazine derivative according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof,
Or a prophylactic / therapeutic agent for hypertension, pulmonary hypertension, angina pectoris, diabetes mellitus or nephritis, comprising a PDE5 inhibitor comprising a hydrate thereof as an active ingredient. 【請求項２９】請求項１〜２０のいずれか一項に記載の
フタラジン誘導体またはその薬理学的に許容される塩、
またはそれらの水和物が有効な疾患の予防・治療剤。29. The phthalazine derivative or the pharmaceutically acceptable salt thereof according to any one of claims 1 to 20,
Or a prophylactic / therapeutic agent for diseases for which their hydrate is effective.