JPH05105626A - Anti-viral agent - Google Patents
Anti-viral agentInfo
- Publication number
- JPH05105626A JPH05105626A JP29624391A JP29624391A JPH05105626A JP H05105626 A JPH05105626 A JP H05105626A JP 29624391 A JP29624391 A JP 29624391A JP 29624391 A JP29624391 A JP 29624391A JP H05105626 A JPH05105626 A JP H05105626A
- Authority
- JP
- Japan
- Prior art keywords
- hiv
- naphthalenedisulfonic acid
- viral agent
- effect
- viral
- 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.)
- Pending
Links
Landscapes
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Description
【０００１】[0001]
【産業上の利用分野】本発明は抗ウイルス剤に関するも
のであり、特に抗ヒト免疫不全症ウイルス（以下、「Ｈ
ＩＶ」と略称する）に関し、エイズの予防、治療をめざ
したものである。さらに詳細にはアルキルアミド基を有
するナフタレンジスルホン酸化合物およびそのスルホン
酸塩を有効成分とする抗ウイルス剤に関する。BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to an antiviral agent, particularly anti-human immunodeficiency virus (hereinafter referred to as "H
IV)) is aimed at the prevention and treatment of AIDS. More specifically, it relates to a naphthalenedisulfonic acid compound having an alkylamide group and an antiviral agent containing a sulfonate thereof as an active ingredient.
【０００２】[0002]
【従来の技術及び発明が解決しようとする課題】近年、
新たなウイルスによる疾病が出現あるいは発見されてき
ており、ウイルス病の予防や治療が益々必要になってき
ている。そのうち、特にＨＩＶ（HumanImmunodeficienc
y Virus）はヒトのレトロウイルスでヒトのヘルパーＴ
細胞に特異的に感染し免疫阻害を引き起こすことが知ら
れている。この感染によって、後天性免疫不全症候群
（acquired immune deficiency syndrome ）に陥りその
結果、いろいろな外部からの感染に対する抵抗力がなく
なることで致死を招く。2. Description of the Related Art In recent years,
With the emergence or discovery of new viral diseases, prevention and treatment of viral diseases are becoming more and more necessary. Among them, especially HIV (Human Immunodeficienc
y Virus) is a human retrovirus and a human helper T
It is known to specifically infect cells and cause immunosuppression. This infection causes the acquired immune deficiency syndrome, which results in death by losing resistance to various external infections.
【０００３】現在、抗エイズウイルス剤として種々の化
合物が提案され、医薬品として開発されている。その中
で臨床的に効果があるとされ、実際に市販されているも
のとしては、唯一、逆転写酵素の阻害作用を有するアジ
ドチミジン（ＡＺＴ）があるが骨髄細胞の増殖抑制等の
副作用があり、またＡＩＤＳの症状の進行において重要
な役割を演じている免疫Ｔ細胞の破壊の原因となってい
る感染細胞と非感染細胞の融合（巨細胞形成）の抑制活
性は無い。さらに現在類似の逆転写酵素阻害剤としてＤ
ＤＩ，ＤＤＧ等の核酸誘導体の抗ＨＩＶ剤について検討
されているが非核酸系の逆転写酵素阻害剤については余
り有効なものは見い出されていない。At present, various compounds have been proposed as anti-AIDS virus agents and are being developed as pharmaceuticals. Of these, azidothymidine (AZT), which has a reverse transcriptase inhibitory effect, is the only drug that is clinically effective and is actually commercially available, but it has side effects such as suppression of bone marrow cell proliferation. In addition, there is no inhibitory activity on the fusion (giant cell formation) of infected cells and non-infected cells, which causes the destruction of immune T cells, which plays an important role in the progression of AIDS symptoms. Furthermore, as a similar reverse transcriptase inhibitor, D
Nucleic acid derivative anti-HIV agents such as DI and DDG have been investigated, but none have been found to be effective as non-nucleic acid reverse transcriptase inhibitors.
【０００４】感染阻害活性のある薬剤としてはデキスト
ラン硫酸などの多糖のスルホン化物が知られている（特
開平2-7577号公報）が、実用化には至っていない。これ
らはスルホン基が糖の水酸基とエステル結合をしている
ため、血中ではスルファターゼの作用を受けすぐに脱ス
ルホン化するので効果を発揮しないといわれている。Sulfonates of polysaccharides such as dextran sulfate are known as drugs having an infection inhibitory activity (Japanese Patent Application Laid-Open No. 2-7577), but they have not been put to practical use. Since these sulfone groups form an ester bond with the hydroxyl group of sugar, they are said to be ineffective because they are immediately desulfonated by the action of sulfatase in blood.
【０００５】また、炭素原子に直接スルホン基が結合し
た高分子スルホン化物としては、リグニンスルホン酸が
ある（特開平3-120223号公報）が、これはフェニルプロ
パノールがランダムに重合したポリマーであり、その構
造やスルホン基の導入されている位置がはっきりしない
といった欠点がある。Further, as a polymer sulfonate in which a sulfone group is directly bonded to a carbon atom, there is lignin sulfonic acid (JP-A-3-120223), which is a polymer in which phenyl propanol is randomly polymerized, There is a drawback that the structure and the position where the sulfone group is introduced are not clear.
【０００６】[0006]
【課題を解決するための手段】そこで本発明者らは上記
課題を解決すべく鋭意検討した結果、アルキルアミド基
を有するナフタレンジスルホン酸化合物およびその塩が
優れた抗ウイルス作用、特に抗ＨＩＶ活性を有すること
を見いだし、本発明を完成した。ナフタレンジスルホン
酸のアルキルアミド基はｎ＝１〜20のものが活性が高く
なると考えられる。Therefore, as a result of intensive studies to solve the above problems, the present inventors have found that naphthalene disulfonic acid compounds having an alkylamide group and salts thereof have excellent antiviral activity, particularly anti-HIV activity. The present invention has been completed and the present invention has been completed. It is considered that the activity of the alkylamide group of naphthalenedisulfonic acid is higher when n = 1 to 20.
【０００７】[0007]
【作用】本発明のスルホン化物は従来知られているスル
ホン化多糖と異なり炭素原子に直接スルホン基が結合し
た物である。従来知られているスルホン化多糖は炭素原
子とスルホン基がエステル結合しているため、血中では
スルファターゼの作用を受けすぐに脱スルホン化し活性
がなくなってしまうが、本発明品は直接炭素原子をスル
ホン化しているためスルファターゼの作用を受けず安定
性が高くなっている事が予想される。さらに本発明は巨
細胞形成の抑制能や逆転写酵素の阻害活性も有しており
極めて有効な抗ウイルス剤と考えられる。The sulfonated product of the present invention is a product in which a sulfo group is directly bonded to a carbon atom, unlike the conventionally known sulfonated polysaccharides. Since the conventionally known sulfonated polysaccharide has a carbon atom and a sulfone group ester-bonded to each other, in blood, it is immediately desulfonated by the action of sulfatase and loses its activity. Since it is sulfonated, it is expected that stability will be high without being affected by sulfatase. Furthermore, the present invention has an ability to suppress giant cell formation and an activity to inhibit reverse transcriptase, and is considered to be an extremely effective antiviral agent.
【０００８】[0008]
【実施例】以下に実施例をもって本発明の詳細な説明を
行うが、本発明はこれに限定されるものではない。The present invention will be described in detail below with reference to examples, but the present invention is not limited thereto.
【０００９】（実施例１）下記の式（II）で表される４
−（アセチルアミノ）−５−ヒドロキシ−２，７−ナフ
タレンジスルホン酸について以下に示すような方法で抗
ＨＩＶ活性を測定した。抗ＨＩＶ活性としてはＨＩＶに
よる細胞破壊の抑制、逆転写酵素の阻害活性、巨細胞形
成抑制活性について試験した。 (Example 1) 4 represented by the following formula (II)
The anti-HIV activity of-(acetylamino) -5-hydroxy-2,7-naphthalenedisulfonic acid was measured by the following method. As the anti-HIV activity, inhibition of cell destruction by HIV, inhibitory activity of reverse transcriptase, and giant cell formation inhibitory activity were tested.
【００１０】抗ＨＩＶ活性の測定方法 （１）ＨＩＶによるＴ細胞破壊の抑制効果 ＭＴ−４細胞を１×１０5 個／ml懸濁させた培地に種々
の濃度の４−（アセチルアミノ）−５−ヒドロキシ−
２，７−ナフタレンジスルホン酸を加えた。これにＨＴ
ＬＶ− IIIB あるいはＨＩＶ−１HEを感染させた。感染
価は、ＭＯＩ＝0.02で感染させた。その後、37℃で４日
間培養した後生存している細胞をＭＴＴ色素で染める事
により生存している細胞数を定量した。また、同時に非
感染細胞についてもＭＴＴ色素で染める事により試料の
細胞に対する毒性も算出した。Method for measuring anti-HIV activity (1) Inhibitory effect of T cell destruction by HIV MT-4 cells were suspended at 1 × 10 5 cells / ml in various concentrations of 4- (acetylamino) -5. -Hydroxy-
2,7-Naphthalenedisulfonic acid was added. HT
The LV- III B or HIV-1 HE were infected. The infection titer was MOI = 0.02. Then, after culturing at 37 ° C. for 4 days, the number of surviving cells was quantified by staining the surviving cells with MTT dye. At the same time, non-infected cells were also stained with MTT dye to calculate the toxicity of the sample to the cells.
【００１１】上記のようにして活性を測定した結果、４
−（アセチルアミノ）−５−ヒドロキシ−２，７−ナフ
タレンジスルホン酸は各系において表１に示した様な50
％細胞破壊阻止濃度（ＥＣ50）、50％細胞毒性濃度（Ｃ
Ｃ50）、選択毒性（Ｔ．Ｉ．＝ＥＣ50／ＣＣ50）を示し
た。As a result of measuring the activity as described above, 4
In each system,-(acetylamino) -5-hydroxy-2,7-naphthalenedisulfonic acid is used as shown in Table 1.
% Cytocidal inhibitory concentration (EC 50 ), 50% cytotoxicity concentration (C
C 50 ), selective toxicity (T.I. = EC 50 / CC 50 ).
【００１２】（２）逆転写酵素阻害活性 50mMのトリス塩酸（pH8.4 ）、２mMのジチオスレイトー
ル、 100mMの塩化カリウム、10mM塩化マグネシウム、
0.1％のTriton X-100、１μＣｉのメチル− 3ＨｄＴＴ
Ｐ、0.01Ａ260 単位のpoly(A). oligo(dT)、４−アセチ
ル−５ヒドロキシ−２，７−ナフタレンジスルホン酸そ
して0.05Ｕの酵素を加えた反応混合物を37℃で30分間反
応させた後、５％のトリクロロ酢酸を加え生成した沈澱
中の放射活性を測定した。(2) Reverse transcriptase inhibitory activity 50 mM Tris-HCl (pH 8.4), 2 mM dithiothreitol, 100 mM potassium chloride, 10 mM magnesium chloride,
0.1% Triton X-100, 1 μCi Methyl- 3 HdTT
P, 0.01 A 260 units of poly (A). Oligo (dT), 4-acetyl-5-hydroxy-2,7-naphthalenedisulfonic acid and 0.05 U of enzyme were added and the reaction mixture was reacted at 37 ° C. for 30 minutes. Then, 5% trichloroacetic acid was added and the radioactivity in the formed precipitate was measured.
【００１３】上記のようにして逆転写酵素阻害活性を測
定した結果、４−アセチル−５−ヒドロキシ−２，７−
ナフタレンジスルホン酸の50％酵素阻害活性濃度（ＩＣ
50）は33.0μＭであった。As a result of measuring the reverse transcriptase inhibitory activity as described above, 4-acetyl-5-hydroxy-2,7-
Naphthalene disulfonic acid 50% enzyme inhibitory activity concentration (IC
50 ) was 33.0 μM.
【００１４】（３）巨細胞形成抑制 ４−（アセチルアミノ）−５−ヒドロキシ−２，７−ナ
フタレンジスルホン酸を加えた培地でＨＴＬＶ− IIIB
に感染したＭＯＬＴ−４細胞と非感染のＭＯＬＴ−４細
胞を同数個（５×１０4 ）ずつ培養し、培養24時間後に
顕微鏡下で生成した巨細胞数を数えた。[0014] (3) giant cell formation inhibition 4- in medium supplemented with (acetylamino) -5-hydroxy-2,7-naphthalene disulfonic acid HTLV III B
The same number (5 × 10 4 ) of MOLT-4 cells infected with and the uninfected MOLT-4 cells were cultured, and after 24 hours of culture, the number of giant cells generated under the microscope was counted.
【００１５】その結果、巨細胞形成抑制活性が認められ
た。As a result, giant cell formation inhibitory activity was recognized.
【００１６】[0016]
【表１】 ａ） ＥＣ50＝50％細胞破壊阻止濃度（μｇ／ｍｌ） ｂ） ＣＣ50＝50％細胞毒性濃度（μｇ／ｍｌ） ｃ） Ｔ．Ｉ．＝選択毒性（ＣＣ50／ＥＣ50）[Table 1] a) EC 50 = 50% cytocidal concentration (μg / ml) b) CC 50 = 50% cytotoxic concentration (μg / ml) c) T.I. I. = Selective toxicity (CC 50 / EC 50)
─────────────────────────────────────────────────────
─────────────────────────────────────────────────── ───
【手続補正書】[Procedure amendment]
【提出日】平成４年２月６日[Submission date] February 6, 1992
【手続補正２】[Procedure Amendment 2]
【補正対象書類名】明細書[Document name to be amended] Statement
【補正対象項目名】発明の名称[Name of item to be amended] Title of invention
【補正方法】変更[Correction method] Change
【補正内容】[Correction content]
【発明の名称】 抗ウイルス剤Title of the invention Antiviral agent
【手続補正３】[Procedure 3]
【補正対象書類名】明細書[Document name to be amended] Statement
【補正対象項目名】０００７[Correction target item name] 0007
【補正方法】変更[Correction method] Change
【補正内容】[Correction content]
【０００７】[0007]
【作用】本発明のスルホン化物は従来知られているスル
ホン化多糖と異なり炭素原子に直接スルホン基が結合し
た物である。従来知られているスルホン化多糖は水酸基
とスルホン基がエステル結合しているため、血中ではス
ルファターゼの作用を受けすぐに脱スルホン化し活性が
なくなってしまうが、本発明品は直接炭素原子をスルホ
ン化しているためスルファターゼの作用を受けず安定性
が高くなっている事が予想される。さらに本発明は巨細
胞形成の抑制能や逆転写酵素の阻害活性も有しており極
めて有効な抗ウイルス剤と考えられる。The sulfonated product of the present invention is a product in which a sulfo group is directly bonded to a carbon atom, unlike the conventionally known sulfonated polysaccharides. In the conventionally known sulfonated polysaccharide, the hydroxyl group and the sulfone group are ester-bonded, and therefore, in the blood, they are immediately desulfonated due to the action of sulfatase and lose their activity. It is expected that the stability will be high without being affected by sulfatase because it has changed. Furthermore, the present invention has the ability to suppress giant cell formation and the activity to inhibit reverse transcriptase, and is considered to be an extremely effective antiviral agent.
【手続補正４】[Procedure amendment 4]
【補正対象書類名】明細書[Document name to be amended] Statement
【補正対象項目名】００１１[Correction target item name] 0011
【補正方法】変更[Correction method] Change
【補正内容】[Correction content]
【００１１】上記のようにして活性を測定した結果、４
−（アセチルアミノ）−５−ヒドロキシ−２，７−ナフ
タレンジスルホン酸は各系において表１に示した様な５
０％細胞破壊阻止濃度（ＥＣ５０）、５０％細胞毒性濃
度（ＣＣ５０）、選択毒性（Ｔ．Ｉ．＝ＣＣ５０／ＥＣ
５０）を示した。As a result of measuring the activity as described above, 4
In each system, 5- (acetylamino) -5-hydroxy-2,7-naphthalenedisulfonic acid was used as shown in Table 1.
0% cytotoxicity inhibitory concentration (EC 50 ), 50% cytotoxicity concentration (CC 50 ), selective toxicity (T.I. = CC 50 / EC)
50 ).
Claims (4)
ド基を有するナフタレンジスルホン酸化合物およびその
生理学的に使用可能な塩である抗ウイルス剤。 1. An antiviral agent which is a naphthalenedisulfonic acid compound having an alkylamide group as represented by formula (I) and a physiologically usable salt thereof.
化合物のうちｎ＝１〜20である抗ウイルス剤。2. The antiviral agent of the naphthalenedisulfonic acid compound according to claim 1, wherein n = 1 to 20.
化合物が４−（アセチルアミノ）−５−ヒドロキシ−
２，７−ナフタレンジスルホン酸（式（II））である抗
ウイルス剤。 3. The naphthalene disulfonic acid compound according to claim 1 is 4- (acetylamino) -5-hydroxy-
An antiviral agent which is 2,7-naphthalenedisulfonic acid (formula (II)).
は３記載の抗ウイルス剤。4. The antiviral agent according to claim 1, wherein the virus is HIV.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP29624391A JPH05105626A (en) | 1991-10-16 | 1991-10-16 | Anti-viral agent |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP29624391A JPH05105626A (en) | 1991-10-16 | 1991-10-16 | Anti-viral agent |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH05105626A true JPH05105626A (en) | 1993-04-27 |
Family
ID=17831043
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP29624391A Pending JPH05105626A (en) | 1991-10-16 | 1991-10-16 | Anti-viral agent |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH05105626A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2006522073A (en) * | 2003-03-07 | 2006-09-28 | イタルファルマコ，ソシエダ アノニマ | Pharmaceutical composition comprising a sulfonic acid derivative |
-
1991
- 1991-10-16 JP JP29624391A patent/JPH05105626A/en active Pending
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2006522073A (en) * | 2003-03-07 | 2006-09-28 | イタルファルマコ，ソシエダ アノニマ | Pharmaceutical composition comprising a sulfonic acid derivative |
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