JPH085884B2 - 5H-Pyrazolo [4,3-a] quinolidin-5-one derivatives - Google Patents
5H-Pyrazolo [4,3-a] quinolidin-5-one derivativesInfo
- Publication number
- JPH085884B2 JPH085884B2 JP12029788A JP12029788A JPH085884B2 JP H085884 B2 JPH085884 B2 JP H085884B2 JP 12029788 A JP12029788 A JP 12029788A JP 12029788 A JP12029788 A JP 12029788A JP H085884 B2 JPH085884 B2 JP H085884B2
- Authority
- JP
- Japan
- Prior art keywords
- pyrazolo
- general formula
- quinolidin
- group
- present
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
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- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
【発明の詳細な説明】 産業上の利用分野 本発明は抗アレルギー作用を有し、アレルギー性疾
患、例えば気管支喘息、鼻炎、皮膚炎、過敏症等の治療
剤として有用な5H−ピラゾロ〔4,3−ａ〕キノリジン−
５−オン誘導体に関するものである。TECHNICAL FIELD The present invention has 5H-pyrazolo [4, which has an antiallergic effect and is useful as a therapeutic agent for allergic diseases such as bronchial asthma, rhinitis, dermatitis, and hypersensitivity. 3-a] quinolidine-
It relates to a 5-one derivative.
従来の技術 アレルギーに起因する疾患の治療剤として種々の化合
物が用いられているが、それらの中で原因療法的な薬物
としてケミカルメディエーター遊離抑制剤が従来知られ
ている。BACKGROUND ART Various compounds have been used as therapeutic agents for diseases caused by allergies, and among them, chemical mediator release inhibitors have been conventionally known as causative therapeutic drugs.
近年、生体の免疫反応を司るたん白として知られてい
る免疫グロブリン（以下Igという）の一つである免疫グ
ロブリンＥ（以下IgEという）がアレルギー性疾患の起
因物質として作用することが明らかになって以来、IgE
の産生を抑制する薬剤はこれらのアレルギー性疾患の原
因療法的な薬物として注目されるようになり、これまで
いくつかの化合物が見出されている〔日本特許公開公報
昭54-130516号、同62-76号〕。In recent years, it has been revealed that immunoglobulin E (hereinafter referred to as IgE), which is one of the immunoglobulins (hereinafter referred to as Ig) known as proteins that control the immune response of the body, acts as a causative agent of allergic diseases. Since then, IgE
The drug that suppresses the production of is attracting attention as a causative drug for these allergic diseases, and several compounds have been found so far [Japanese Patent Publication No. 54-130516, the same. 62-76].
しかしながら、これらの化合物はいまだ実用に供され
るには至っていない。However, these compounds have not yet been put to practical use.
発明が解決しようとする問題点 Igは生体の免疫反応を司るたん白であり、その中でも
免疫グロブリンＧ（以下IgGという）は特に感染防禦等
において重要な働きをする。Problems to be Solved by the Invention Ig is a protein that controls the immune reaction of a living body, and among them, immunoglobulin G (hereinafter referred to as IgG) plays an important role especially in infection prevention and the like.
従って、アレルギー性疾患治療剤として用いられるIg
E産生抑制剤はIgE以外のIgの産生に対してはあまり影響
を与えないことが重要である。Therefore, Ig used as a therapeutic agent for allergic diseases
It is important that the E production inhibitor does not significantly affect the production of Ig other than IgE.
本発明の目的はこのような選択的なIgE産生抑制作用
を有し、アレルギー性疾患治療剤として有用な5H−ピラ
ゾロ〔4,3−ａ〕キノリジン−５−オン誘導体を提供す
ることである。An object of the present invention is to provide a 5H-pyrazolo [4,3-a] quinolidin-5-one derivative having such selective IgE production inhibitory activity and useful as a therapeutic agent for allergic diseases.
問題点を解決するための手段 本発明者らは選択的IgE産生抑制作用を有し、アレル
ギー性疾患治療剤として有用な化合物を見出すべく鋭意
研究を重ねた結果、ある種の5H−ピラゾロ〔4,3−ａ〕
キノリジン−５−オン誘導体において良好な結果が得ら
れ、その目的を達成できることを見出し、本発明を成す
に至った。Means for Solving the Problems The present inventors have conducted intensive studies to find a compound having a selective IgE production inhibitory action and useful as a therapeutic agent for allergic diseases, and as a result, a certain 5H-pyrazolo (4 , 3-a]
The inventors have found that good results were obtained with the quinolidin-5-one derivative, and that the object could be achieved, and completed the present invention.
すなわち、本発明は、一般式 （式中のR1は低級アルキル基、アリール基またはアラル
キル基であり、R2は水素原子、低級アルキル基またはア
リール基である）で表される5H−ピラゾロ〔4,3−ａ〕
キノリジン−５−オン誘導体を提供するものである。That is, the present invention has the general formula (Wherein R 1 is a lower alkyl group, an aryl group or an aralkyl group, and R 2 is a hydrogen atom, a lower alkyl group or an aryl group) and is represented by 5H-pyrazolo [4,3-a].
A quinolidin-5-one derivative is provided.
本発明において低級アルキル基とは炭素数１〜10の直
鎖状または枝別れ状のアルキル基を意味する。In the present invention, the lower alkyl group means a linear or branched alkyl group having 1 to 10 carbon atoms.
アリール基とは環上に適当な置換基を有することもあ
る芳香族炭素水素基、例えばフェニル基、ナフチル基を
意味し、アラルキル基とは前記したようなアリール基を
置換基として有する低級アルキル基を意味する。The aryl group means an aromatic carbon hydrogen group which may have an appropriate substituent on the ring, for example, a phenyl group or a naphthyl group, and the aralkyl group means a lower alkyl group having the aryl group as a substituent as described above. Means
本発明の前記一般式（Ｉ）で表される化合物は新規化
合物であり、以下のような方法により製造することがで
きる。The compound represented by the general formula (I) of the present invention is a novel compound and can be produced by the following method.
すなわち、一般式 （式中のR1は前記と同じ意味をもつ）で表される4H−キ
ノリジン−４−オン誘導体と、一般式 R2-NHNH2 （III） （式中のR2は前記と同じ意味をもつ）で表されるヒドラ
ジン誘導体とを反応させることにより製造することがで
きる。That is, the general formula (R 1 in the formula has the same meaning as described above) and a 4H-quinolizin-4-one derivative represented by the general formula R 2 —NHNH 2 (III) (wherein R 2 has the same meaning as described above) It can be produced by reacting with a hydrazine derivative represented by
本製造方法において出発原料として用いられる前記一
般式（II）の化合物は、薬学雑誌、89巻、２号、203〜2
08ページ、1969年に記載されている方法と同様な反応に
より製造することができる。The compound of the general formula (II) used as a starting material in the present production method is as described in Pharmaceutical Journal, Vol. 89, No. 2, 203-2.
It can be produced by a reaction similar to the method described on page 08, 1969.
すなわち、一般式 （式中のR1は前記と同じ意味をもつ）で表されるケトン
誘導体と、式 で表されるメチル ２−シアノ−3,3−ジメチルチオア
クリラートとを反応させることにより製造することがで
きる。That is, the general formula (Wherein R 1 has the same meaning as described above), It can be produced by reacting with methyl 2-cyano-3,3-dimethylthioacrylate represented by
前記一般式（II）の化合物の製造において出発原料と
して用いられる前記一般式（IV）で表される化合物は、
ヘルベティカ ヒミカ アクタ（Helv.Chim.Acta）、45
巻、729〜737ページ、1962年に記載の方法と同様な反応
に従って製造することができる。The compound represented by the general formula (IV) used as a starting material in the production of the compound of the general formula (II) is
Helvetica Himika Acta (Helv.Chim.Acta), 45
Vol., P.729-737, 1962.
また、前記式（Ｖ）の化合物はヘミッシュ ベリヒテ
（Chem.Ber.）、95巻、2861〜2870ページ、1962年に記
載の方法により製造することができる。Further, the compound of the formula (V) can be produced by the method described in Hemisch Berichte (Chem. Ber.), Vol. 95, pages 281-2870, 1962.
本発明の製造方法を好適に実施するには、一般式（I
I）の化合物を適当な有機溶媒、例えばジメチルスルホ
キシドに溶解し、これに過剰のヒドラジン誘導体（II
I）を加え、室温ないしやや加温下に１〜数時間攪拌す
る。反応混合液に冷水を加えて析出した結晶をろ取し、
水および適当な有機溶媒で洗浄し、乾燥して目的物を得
る。In order to preferably carry out the production method of the present invention, the general formula (I
The compound of I) is dissolved in a suitable organic solvent such as dimethylsulfoxide, and an excess of the hydrazine derivative (II
I) is added, and the mixture is stirred at room temperature or slightly warmed for 1 to several hours. Cold water was added to the reaction mixture, and the precipitated crystals were collected by filtration,
Wash with water and a suitable organic solvent, and dry to obtain the desired product.
本発明の前記一般式（Ｉ）で表される化合物のIgE産
生抑制作用は、セルラー イムノロジー（Cellular Imm
unology）、58巻、188〜201ページ、1981年に記載され
た方法、すなわちジニトロフェニル化したアスカリスた
ん白（以下DNP-Asという）に対してアドプティブ セカ
ンダリー イミューン レスポンス（adoptive seconda
ry immune response）を示しているBALB/c系マウス脾細
胞を用いたIg産生量測定試験によって確認することがで
きる。The inhibitory effect of the compound represented by the general formula (I) of the present invention on IgE production is as follows.
unology), vol. 58, pp. 188-201, 1981, that is, for the dinitrophenylated Ascaris protein (hereinafter referred to as DNP-As), an adaptive secondary immune response (adoptive seconda).
It can be confirmed by an Ig production measurement test using BALB / c mouse splenocytes exhibiting ry immune response.
また、本発明の前記一般式（Ｉ）の化合物の抗アレル
ギー作用はラットを用いた同種受身アナフィラキシー
（Rat Homologous Passive Cutaneous Anaphylaxis、以
下PCAという）反応においても確認することができる。Further, the antiallergic action of the compound of the general formula (I) of the present invention can be confirmed also in a rat homologous anaphylaxis (Rat Homologous Passive Cutaneous Anaphylaxis, hereinafter referred to as PCA) reaction using rats.
本発明の一般式（Ｉ）の化合物において好ましい化合
物はR2が水素原子、R1が低級アルキル基、特に炭素数１
〜４の直鎖または枝分かれ状の低級アルキル基の化合物
群である。好ましいR1としてはエチル基、ｎ−プロピル
基、イソプロピル基、ｎ−ブチル基、二級ブチル基、三
級ブチル基、イソブチル基などの基をあげることができ
る。Preferred compounds of the general formula (I) of the present invention are those in which R 2 is a hydrogen atom, R 1 is a lower alkyl group, and especially C 1
To 4 straight chain or branched lower alkyl group compounds. Preferred R 1 includes groups such as ethyl group, n-propyl group, isopropyl group, n-butyl group, secondary butyl group, tertiary butyl group and isobutyl group.
本発明の一般式（Ｉ）の化合物を実際の治療に用いる
場合、適当な医薬品添加剤、例えば、賦形剤、結合剤、
滑沢剤、崩壊剤、溶解補助剤、安定化剤等を加えて常法
に従い種々の剤型、例えば散剤、錠剤、カプセル剤、シ
ロップ剤、注射剤などを調整し、経口的あるいは非経口
的に投与する。When the compound of general formula (I) of the present invention is used for the actual treatment, suitable pharmaceutical additives such as excipients, binders,
Add various agents such as powders, tablets, capsules, syrups, and injections by adding lubricants, disintegrants, solubilizers, stabilizers, etc. according to a conventional method, and then orally or parenterally. Administered to.
本発明の一般式（Ｉ）の化合物の投与量または治療有
効量は対象となる患者の年齢、性別、疾患の度合および
治療条件などによって変化するが、人または動物の治療
に用いる場合の１日投与量は、経口投与の場合、概ね0.
1〜10mg/kg、非経口投与の場合、概ね0.02〜5mg/kgであ
る。The dose or therapeutically effective amount of the compound of the general formula (I) of the present invention varies depending on the age, sex, degree of disease and treatment condition of the target patient, but one day when used for treatment of humans or animals The dose is generally 0 for oral administration.
The dose is 1 to 10 mg / kg, and generally 0.02 to 5 mg / kg for parenteral administration.
発明の効果 本発明の一般式（Ｉ）で表される5H−ピラゾロ〔4,3
−ａ〕キノリジン−５−オン誘導体はDNP-Asに対してad
optive secondary immune responseを示しているBALB/c
系マウスの脾細胞を用いたIg産生量測定試験で、10-8〜
10-5g/mlの濃度で約40〜80％程度のIgE産生抑制作用を
示す。EFFECT OF THE INVENTION 5H-pyrazolo [4,3] represented by the general formula (I) of the present invention
-A] quinolidin-5-one derivative is ad
BALB / c showing optive secondary immune response
In a test for measuring Ig production using splenocytes of mouse strains, 10 -8 ~
It exhibits an inhibitory effect on IgE production of about 40-80% at a concentration of 10 -5 g / ml.
また、ウィスター（Wister）系ラットを用いたPCA反
応において、１〜50mg/kgの経口投与で約30〜100％程度
の抑制活性を示す。Further, in the PCA reaction using Wistar rats, the oral administration of 1 to 50 mg / kg shows an inhibitory activity of about 30 to 100%.
実施例 本発明の内容を以下の参考例および実施例を用いてさ
らに詳細に説明する。なお、各参考例および実施例中の
化合物の融点はすべて未補正である。EXAMPLES The contents of the present invention will be described in more detail with reference to the following reference examples and examples. The melting points of the compounds in Reference Examples and Examples are all uncorrected.
参考例 １ １−ブチリル−３−シアノ−２−メチルチオ−4H−キ
ノリジン−４−オン プロピル ２−ピリジルメチル ケトン（56.1g）、
メチル ２−シアノ−3,3−ジメチルチオアクリラート
（70.0g）の混合物を120℃で約16時間加熱攪拌する。反
応混合物をシリカゲルカラムクロマトグラフィーに付
し、塩化メチレン−ジエチルエーテル（5:1,v/v）で溶
出することにより、１−ブチリル−３−シアノ−２−メ
チルチオ−4H−キノリジン−４−オン（50.3g）を淡黄
色結晶として得る。1 H NMR（CDCl3） δ:1.04（t,3H）,1.80（m,2H）,2.73（s,3H）,2.91（t,
2H）,7.33（dt,1H）,7.53（d,1H）,7.76（dt,1H）,9.30
（d,1H） 参考例 ２〜17 参考例１と同様にして下記の化合物を得た。Reference Example 1 1-butyryl-3-cyano-2-methylthio-4H-quinolizin-4-one propyl 2-pyridylmethyl ketone (56.1 g),
A mixture of methyl 2-cyano-3,3-dimethylthioacrylate (70.0 g) is heated with stirring at 120 ° C for about 16 hours. The reaction mixture was subjected to silica gel column chromatography, and eluted with methylene chloride-diethyl ether (5: 1, v / v) to give 1-butyryl-3-cyano-2-methylthio-4H-quinolidin-4-one. (50.3g) is obtained as pale yellow crystals. 1 H NMR (CDCl 3 ) δ: 1.04 (t, 3H), 1.80 (m, 2H), 2.73 (s, 3H), 2.91 (t,
2H), 7.33 (dt, 1H), 7.53 (d, 1H), 7.76 (dt, 1H), 9.30
(D, 1H) Reference Examples 2 to 17 In the same manner as in Reference Example 1, the following compounds were obtained.
実施例 １ ４−シアノ−１−プロピル−5H−ピラゾロ〔4,3−
ａ〕キノリジン−５−オン １−ブチリル−３−シアノ−２−メチルチオ−4H−キ
ノリジン−４−オン（212g、参考例１）のジメチルスル
ホキシド（DMSO、1.5l）溶液にヒドラジン・１水和物
（74ml）を加え、室温で１時間攪拌する。反応液に冷水
2lを加えて析出する結晶をろ取後、結晶を水（1.0l）、
エチルアルコール（0.5l）、ジエチルエーテル（0.5l）
で順次洗浄し、４−シアノ−１−プロピル−5H−ピラゾ
ロ〔4,3−ａ〕キノリジン−５−オン（144g）を淡黄色
結晶として得る。 Example 1 4-Cyano-1-propyl-5H-pyrazolo [4,3-
a] quinolizin-5-one 1-butyryl-3-cyano-2-methylthio-4H-quinolidin-4-one (212 g, Reference Example 1) in dimethyl sulfoxide (DMSO, 1.5 l) was added to a solution of hydrazine monohydrate. (74 ml) is added, and the mixture is stirred at room temperature for 1 hour. Cold water in the reaction solution
2 l was added and the precipitated crystals were collected by filtration, and the crystals were washed with water (1.0 l),
Ethyl alcohol (0.5l), diethyl ether (0.5l)
Then, 4-cyano-1-propyl-5H-pyrazolo [4,3-a] quinolidin-5-one (144 g) is obtained as pale yellow crystals.
融点: 298〜300℃ IR（KBr）:2205,1670,1625,1605cm-1 1 H NMR（DMSO-d6） δ:1.12（t,3H）,1.89（m,2H）,3.17（t,2H）,7.78（t,
1H）,8.38（m,2H）,9.50（d,1H）,13.46（br,1H） 元素分析値：（C14H12N4Oとして） Ｃ％ Ｈ％ Ｎ％ 理論値 66.65 4.79 22.21 測定値 66.78 4.81 22.21 実施例 ２〜25 実施例１と同様にして下記の化合物を得た。Mp: 298~300 ℃ IR (KBr): 2205,1670,1625,1605cm -1 1 H NMR (DMSO-d 6) δ: 1.12 (t, 3H), 1.89 (m, 2H), 3.17 (t, 2H ), 7.78 (t,
1H), 8.38 (m, 2H), 9.50 (d, 1H), 13.46 (br, 1H) Elemental analysis value: (as C 14 H 12 N 4 O) C% H% N% Theoretical value 66.65 4.79 22.21 Measured value 66.78 4.81 22.21 Examples 2 to 25 The following compounds were obtained in the same manner as in Example 1.
フロントページの続き (51)Int.Cl.6 識別記号 庁内整理番号 ＦＩ 技術表示箇所 Ａ６１Ｋ 31/435 ＡＤＡ Continuation of front page (51) Int.Cl. 6 Identification number Office reference number FI technical display location A61K 31/435 ADA
Claims (3)
キル基であり、R2は水素原子、低級アルキル基またはア
リール基である）で表される5H−ピラゾロ〔4,3−ａ〕
キノリジン−５−オン誘導体。1. A general formula (Wherein R 1 is a lower alkyl group, an aryl group or an aralkyl group, and R 2 is a hydrogen atom, a lower alkyl group or an aryl group) and is represented by 5H-pyrazolo [4,3-a].
A quinolidin-5-one derivative.
アルキル基である）で表される5H−ピラゾロ〔4,3−
ａ〕キノリジン−５−オン誘導体。2. General formula (Wherein R 3 is a linear or branched alkyl group having 1 to 4 carbon atoms) represented by 5H-pyrazolo [4,3-
a] Quinolidin-5-one derivative.
オン誘導体。3. A formula 5H-pyrazolo [4,3-a] quinolizin-5 represented by
On derivative.
Priority Applications (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP12029788A JPH085884B2 (en) | 1988-05-17 | 1988-05-17 | 5H-Pyrazolo [4,3-a] quinolidin-5-one derivatives |
| US07/349,778 US4940715A (en) | 1988-05-17 | 1989-05-10 | 5H-pyrazolo[4,3-A] quinolizin-5-one compounds exhibiting therapeutic activities |
| EP19890304940 EP0343832A3 (en) | 1988-05-17 | 1989-05-15 | 5h-pyrazolo(4,3-a)quinolizin-5-one compounds exhibiting therapeutic activities |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP12029788A JPH085884B2 (en) | 1988-05-17 | 1988-05-17 | 5H-Pyrazolo [4,3-a] quinolidin-5-one derivatives |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH01290676A JPH01290676A (en) | 1989-11-22 |
| JPH085884B2 true JPH085884B2 (en) | 1996-01-24 |
Family
ID=14782748
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP12029788A Expired - Lifetime JPH085884B2 (en) | 1988-05-17 | 1988-05-17 | 5H-Pyrazolo [4,3-a] quinolidin-5-one derivatives |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH085884B2 (en) |
-
1988
- 1988-05-17 JP JP12029788A patent/JPH085884B2/en not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| JPH01290676A (en) | 1989-11-22 |
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