JPH0920792A - Nucleotide dimer - Google Patents
Nucleotide dimerInfo
- Publication number
- JPH0920792A JPH0920792A JP7197113A JP19711395A JPH0920792A JP H0920792 A JPH0920792 A JP H0920792A JP 7197113 A JP7197113 A JP 7197113A JP 19711395 A JP19711395 A JP 19711395A JP H0920792 A JPH0920792 A JP H0920792A
- Authority
- JP
- Japan
- Prior art keywords
- azt
- formula
- compound
- hiv
- nucleotide dimer
- 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
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
- A61K47/55—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug, i.e. a dimer, oligomer or polymer of pharmacologically or therapeutically active compounds
Landscapes
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Epidemiology (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Saccharide Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
【０００１】[0001]
【産業上の利用分野】本発明は、抗ＨＩＶ活性を有する
新規なヌクレオチドダイマー及びその用途に関するもの
である。FIELD OF THE INVENTION The present invention relates to a novel nucleotide dimer having anti-HIV activity and its use.
【０００２】[0002]
【従来の技術】３’−アジド−３’−デオキシチミジン
（ＡＺＴ）は優れた抗ＨＩＶ活性を有し、エイズ治療剤
として広く使用されている。しかし、ＡＺＴは、治療有
効量と毒性発生量との差が少なく、重篤な副作用を有す
るという欠点があった。かかる観点から、ＡＺＴに代わ
りうる抗レトロウイルス剤の開発が活発に行なわれた結
果、ＡＺＴ−Ｐ−ＤＤＩが優れた抗ＨＩＶ作用を有し、
かつ安全性も高いことからエイズ治療剤として有用であ
ることが報告されている（特公平５−４６３５８号公
報、米国特許第５１８７１６３号、AIDS RESEARCH AND
HUMAN RETROVIRUSES,4(6),449-455(1988)、ANTIMICROBIA
L AGENTS AND CHEMOTHERAPY,34(6),1061-1067(199
0)）。2. Description of the Related Art 3'-Azido-3'-deoxythymidine (AZT) has excellent anti-HIV activity and is widely used as a therapeutic agent for AIDS. However, AZT has a drawback in that there is a small difference between the therapeutically effective dose and the toxicity-causing dose, and that it has serious side effects. From this point of view, as a result of active development of antiretroviral agents that can replace AZT, AZT-P-DDI has an excellent anti-HIV action,
It is also reported to be useful as a therapeutic agent for AIDS due to its high safety (Japanese Patent Publication No. 5-46358, US Pat. No. 5,187,163, AIDS RESEARCH AND
HUMAN RETROVIRUSES, 4 (6), 449-455 (1988), ANTIMICROBIA
L AGENTS AND CHEMOTHERAPY, 34 (6), 1061-1067 (199
0)).
【０００３】[0003]
【発明が解決しようとする課題】しかしながら、後述の
試験例でも明らかなようにＡＺＴ−Ｐ−ＤＤＩはＡＺＴ
耐性株に対して必ずしも満足できる抗ＨＩＶ活性を示さ
ないということが本発明者らの試験により明らかにされ
た。したがって、本発明は、この新しい知見に基づき、
ＡＺＴ野生株はもとよりＡＺＴ耐性株さらには非核酸系
逆転写酵素阻害剤耐性株に対しても優れた抗ＨＩＶ活性
を有する物質を得るという新規な課題を解決することを
主たる目的とするものである。However, as will be apparent from the test examples described later, AZT-P-DDI is not suitable for AZT.
Our tests revealed that they do not always show satisfactory anti-HIV activity against resistant strains. Therefore, the present invention is based on this new finding,
The main object is to solve the novel problem of obtaining a substance having an excellent anti-HIV activity not only for AZT wild-type strains but also for AZT-resistant strains as well as non-nucleic acid reverse transcriptase inhibitor-resistant strains. .
【０００４】[0004]
【発明の開示】本発明者らは、上記目的を達成するため
鋭意検討を重ねた結果、下記式（Ｉ）で表される新規な
ヌクレオチドダイマーが、野生株はもとよりＡＺＴ耐性
株さらには非核酸系逆転写酵素阻害剤耐性株に対しても
優れた抗ＨＩＶ活性を有することを見いだし、本発明を
完成させた。すなわち、本発明は、下記式（Ｉ）で表さ
れるヌクレオチドダイマーに関するものである。また、
本発明は、該ヌクレオチドダイマー（以下、本発明化合
物と称する。）を有効成分として含有する医薬組成物に
関するものである。DISCLOSURE OF THE INVENTION As a result of intensive studies to achieve the above object, the present inventors have found that a novel nucleotide dimer represented by the following formula (I) is found to be a wild strain, an AZT resistant strain, and a non-nucleic acid. The present invention was completed by discovering that it also has excellent anti-HIV activity against strains resistant to reverse transcriptase inhibitors. That is, the present invention relates to a nucleotide dimer represented by the following formula (I). Also,
The present invention relates to a pharmaceutical composition containing the nucleotide dimer (hereinafter referred to as the compound of the present invention) as an active ingredient.
【０００５】[0005]
【化２】 （式中、Ｒ1〜Ｒ3は水素または低級アルキルを示す。）Embedded image (In the formula, R 1 to R 3 represent hydrogen or lower alkyl.)
【０００６】以下、本発明を詳細に説明する。 （１）化合物 本発明化合物は上記式（Ｉ）で表されるものである。式
中、Ｒ1〜Ｒ3で表される低級アルキルとしては炭素数１
〜５程度のものを意味し、具体的にはメチル、エチル、
プロピルなどが例示される。また、Ｒ2およびＲ3の置換
位置は特に制限されるものではないが、活性の点からは
メタの位置が好ましい。このような本発明化合物の中で
好ましい化合物としては、例えば後述の実施例で合成さ
れた化合物などを例示することができる。また、本発明
化合物は塩の形態であってもよく、たとえば、ナトリウ
ム、カリウムなどアルカリ金属塩、カルシウム、マグネ
シウムなどのアルカリ土類金属塩などの各種金属塩を例
示することができる。Hereinafter, the present invention will be described in detail. (1) Compound The compound of the present invention is represented by the above formula (I). In the formula, the lower alkyl represented by R 1 to R 3 has 1 carbon atom.
~ 5, specifically, methyl, ethyl,
Examples include propyl and the like. The substitution position of R 2 and R 3 is not particularly limited, but the meta position is preferable from the viewpoint of activity. Examples of preferable compounds among the compounds of the present invention include compounds synthesized in Examples described later. Further, the compound of the present invention may be in the form of a salt, and examples thereof include various metal salts such as alkali metal salts such as sodium and potassium, alkaline earth metal salts such as calcium and magnesium.
【０００７】（２）製造法 本発明化合物の反応経路をフローチャートで示せば、次
のとおりである。(2) Production Method The reaction route of the compound of the present invention is shown by a flow chart as follows.
【０００８】[0008]
【化３】 Embedded image
【０００９】最初の工程は、ＡＺＴ−ＣＥＰ・ＴＥＡと
下記式（ＩＩ）で表されるＨＥＰＴ誘導体（ＨＥＰＴ）
とを縮合剤を用いて反応させてＡＺＴ−ＣＥＰ−ＨＥＰ
Ｔを調製する工程である。なお、反応に使用するＡＺＴ
−ＣＥＰ・ＴＥＡおよびＨＥＰＴは公知化合物であり、
常法により調製することができる（AIDS Research and
Human Retroviruses, 1988, 4, 449-455、 J.Med.Chem.,
1981,24,1177-1181、J.Med.Chem., 1981,24,1078-1083、
J.Med.Chem., 1991,34,349-357、J.Med.Chem.,1992,35,3
37-345、特公平７−５１５６７号公報）。The first step is AZT-CEP.TEA and a HEPT derivative (HEPT) represented by the following formula (II).
Are reacted with a condensing agent to produce AZT-CEP-HEP
This is a step of preparing T. The AZT used in the reaction
-CEP-TEA and HEPT are known compounds,
It can be prepared by a conventional method (AIDS Research and
Human Retroviruses, 1988, 4, 449-455, J.Med.Chem.,
1981,24,1177-1181, J.Med.Chem., 1981,24,1078-1083,
J.Med.Chem., 1991,34,349-357, J.Med.Chem., 1992,35,3
37-345, Japanese Patent Publication No. 7-51567).
【００１０】[0010]
【化４】 （式中、Ｒ1〜Ｒ3は水素または低級アルキルを示す。）Embedded image (In the formula, R 1 to R 3 represent hydrogen or lower alkyl.)
【００１１】反応に使用する縮合剤としては、メシチル
スルホニルクロライド、トリイソプロピルベンゼンスル
ホニルクロライドなどの酸性触媒を例示することができ
る。縮合反応は、ピリジン、トリエチルアミンなどの塩
基性溶媒中、ＡＺＴ−ＣＥＰ・ＴＥＡ １モルに対し１
〜３倍モルのＨＥＰＴ及び０．５〜２倍モルの縮合剤を
用い、１０〜３０℃で１０〜５０時間程度撹拌混合させ
ることにより実施することができる。また、反応液中に
１−メチルイミダゾールなどの酸受容体を添加すること
により、縮合反応を効率的に進行させることができる。
得られた反応液の溶媒を留去し、さらに必要により上記
と同様の吸着樹脂を用いたカラムクロマトグラフィ−処
理に付してＡＺＴ−ＣＥＰ−ＨＥＰＴを精製し、次の工
程に供する。Examples of the condensing agent used in the reaction include acidic catalysts such as mesityl sulfonyl chloride and triisopropylbenzene sulfonyl chloride. The condensation reaction is carried out in a basic solvent such as pyridine or triethylamine with 1 mol per 1 mol of AZT-CEP.TEA.
It can be carried out by using 3 to 3 times mol of HEPT and 0.5 to 2 times mol of the condensing agent and stirring and mixing at 10 to 30 ° C. for about 10 to 50 hours. Moreover, the condensation reaction can be efficiently progressed by adding an acid acceptor such as 1-methylimidazole to the reaction solution.
The solvent of the obtained reaction solution is distilled off, and if necessary, the same AZT-CEP-HEPT is purified by subjecting it to column chromatography using the same adsorption resin as described above, and then used in the next step.
【００１２】次の工程は、ＡＺＴ−ＣＥＰ−ＨＥＰＴと
アルカリとを反応させてシアノエチル基を除去し、本発
明化合物のＡＺＴ−Ｐ−ＨＥＰＴを調製する工程であ
る。反応に使用するアルカリとしては、アンモニア、水
酸化ナトリウム、水酸化カリウム、水酸化カルシウムな
ど通常の塩基性触媒を使用することができる。反応は、
たとえばアルカリとして水酸化ナトリウムを使用する場
合には、水酸化ナトリウム水溶液に上記ＡＺＴ−ＣＥＰ
−ＨＥＰＴを加え、２０〜５０℃で１〜２０時間程度反
応させることによりＡＺＴ−Ｐ−ＨＥＰＴのナトリウム
塩を得ることができる。The next step is a step of reacting AZT-CEP-HEPT with an alkali to remove the cyanoethyl group to prepare AZT-P-HEPT of the compound of the present invention. As the alkali used in the reaction, a usual basic catalyst such as ammonia, sodium hydroxide, potassium hydroxide or calcium hydroxide can be used. The reaction is
For example, when sodium hydroxide is used as the alkali, the above AZT-CEP is added to the sodium hydroxide aqueous solution.
The sodium salt of AZT-P-HEPT can be obtained by adding -HEPT and reacting at 20 to 50 ° C for about 1 to 20 hours.
【００１３】かくして得られた本発明化合物は、後述の
試験例でも示されているように、野生株はもとよりＡＺ
Ｔ耐性株および非核酸系逆転写酵素阻害剤耐性株に対し
ても抗ＨＩＶ活性を有し、医薬品として優れた特性を有
するものである。従って、本発明化合物を有効成分とし
て含有する医薬組成物は、ＲＮＡウイルス、特にＨＩＶ
などのレトロウイルスの感染の予防または治療に有用で
あり、ヒトのウイルスの感染の予防または治療のために
（特にエイズの治療のために）使用されうる。本発明化
合物の投与方法は経口、経腸、非経口、局所投与などの
いずれの投与経路であってもよく、投与量は、患者の年
齢、病態、体重などに応じ適宜決定されるが、通常は１
日当たり０．０１〜１０００ｍｇ／ｋｇ体重、好ましく
は１〜１００ｍｇ／ｋｇ体重の範囲内から選ばれ、一回
または複数回に分けて投与される。The compound of the present invention thus obtained can be used not only in the wild strain but also in AZ, as shown in the test examples described below.
It also has anti-HIV activity against T-resistant strains and non-nucleic acid reverse transcriptase inhibitor-resistant strains, and has excellent properties as a drug. Therefore, a pharmaceutical composition containing the compound of the present invention as an active ingredient is an RNA virus, particularly HIV.
It is useful for the prevention or treatment of retroviral infections such as and may be used for the prevention or treatment of human viral infections, especially for the treatment of AIDS. The administration method of the compound of the present invention may be any of the administration routes such as oral, enteral, parenteral, and topical administration, and the dose is appropriately determined according to the age, pathological condition, body weight, etc. of the patient. Is 1
It is selected from the range of 0.01 to 1000 mg / kg body weight, preferably 1 to 100 mg / kg body weight per day, and is administered in one or multiple doses.
【００１４】本発明の医薬組成物は、通常医薬に使用さ
れる賦形剤、その他の添加剤を含む組成物として使用す
るのが普通である。これらの例として、固体状のものと
しては、乳糖、カオリン、ショ糖、結晶セルロース、コ
ーンスターチ、タルク、寒天、ペクチン、ステアリン
酸、ステアリン酸マグネシウム、レシチン、塩化ナトリ
ウムなどが挙げられ、液体状のものとしてはグリセリ
ン、落花生油、ポリビニルピロリドン、オリーブ油、エ
タノール、ベンジルアルコール、プロピレングリコー
ル、水などが挙げられる。組成物の剤形としては任意の
形態を採ることができ、例えば錠剤、散剤、顆粒剤、カ
プセル化剤、坐剤、トローチ剤などの固形製剤、シロッ
プ、乳液、軟ゼラチンカプセル、クリーム、ゲル、ペー
スト、スプレー、注射などの液状製剤が挙げられる。The pharmaceutical composition of the present invention is usually used as a composition containing excipients and other additives usually used in medicine. As examples of these, solid ones include lactose, kaolin, sucrose, crystalline cellulose, corn starch, talc, agar, pectin, stearic acid, magnesium stearate, lecithin, sodium chloride, etc., and liquid ones. Examples thereof include glycerin, peanut oil, polyvinylpyrrolidone, olive oil, ethanol, benzyl alcohol, propylene glycol, water and the like. The composition may take any form, for example, tablets, powders, granules, capsules, suppositories, solid preparations such as troches, syrups, emulsions, soft gelatin capsules, creams, gels, Liquid preparations such as pastes, sprays and injections can be mentioned.
【００１５】[0015]
【発明の効果】本発明化合物は、野生株はもとよりＡＺ
Ｔ耐性株および非核酸系逆転写酵素阻害耐性株に対して
優れた抗ＨＩＶ活性を有し、抗ＨＩＶ剤等の医薬品とし
て有用である。なお、本発明化合物は、耐性株の出現率
が現在の医薬品より低いと考えられる。INDUSTRIAL APPLICABILITY The compound of the present invention is used in AZ
It has excellent anti-HIV activity against T-resistant strains and non-nucleic acid reverse transcriptase inhibition resistant strains, and is useful as a drug such as an anti-HIV agent. The compound of the present invention is considered to have a lower incidence of resistant strains than the current pharmaceutical products.
【００１６】[0016]
【実施例】次に実施例を挙げて本発明を詳細に説明する
が、本発明にはこれに何ら限定されるものではない。 合成例：ＡＺＴ−Ｐ−（Ｅ−ＨＥＰＵ−ｄＭ）ナトリウ
ム塩〔式（Ｉ）；Ｒ1＝エチル、Ｒ2（３位）＝メチル、
Ｒ3（５位）＝メチル〕の調製EXAMPLES The present invention will now be described in detail with reference to examples, but the present invention is not limited thereto. Synthesis example: AZT-P- (E-HEPU-dM) sodium salt [Formula (I); R 1 = ethyl, R 2 (3-position) = methyl,
Preparation of R 3 (5-position) = methyl]
【００１７】ＡＺＴ−ＣＥＰ・ＴＥＡ０．５ｇのピリジ
ン溶液（１０ｍｌ）にトリイソプロピルベンゼンスルホ
ニルクロライド６０５ｍｇを加え、室温で３０分間撹拌
し、１−メチルイミダゾール０．３５ｍｌを加え、室温
で３０分間撹拌した後、Ｅ−ＨＥＰＵ−ｄＭ〔式（Ｉ
Ｉ）；Ｒ1＝エチル、Ｒ2（３位）＝メチル、Ｒ3（５
位）＝メチル〕３５０ｍｇを加え、室温で１時間撹拌し
てＡＺＴ−ＣＥＰ−（Ｅ−ＨＥＰＵ−ｄＭ）を合成し
た。反応液を水（５０ｍｌ）及び酢酸エチル（５０ｍ
ｌ）を用いて分配し、有機層を飽和食塩水（５０ｍｌｘ
２）で洗浄後、有機層を無水硫酸ナトリウムを用いて脱
水し、溶媒を乾固した。得られた残渣をシリカゲルカラ
ムクロマトグラフィー（溶出溶媒：クロロホルム）で精
製後、１Ｎ水酸化ナトリウム溶液（１．３ｍｌ）を加
え、４０℃で２時間加熱反応させた。反応後、イソプロ
パノールを用いて結晶化した後、エタノールにより再結
晶化してＡＺＴ−Ｐ−（Ｅ−ＨＥＰＵ−ｄＭ）ナトリウ
ム塩（３６２ｍｇ，５３．３％）を得た。After adding 605 mg of triisopropylbenzenesulfonyl chloride to a pyridine solution (10 ml) of 0.5 g of AZT-CEP.TEA and stirring at room temperature for 30 minutes, 0.35 ml of 1-methylimidazole was added and after stirring at room temperature for 30 minutes. , E-HEPU-dM [Formula (I
I); R 1 = ethyl, R 2 (3-position) = methyl, R 3 (5
Position) = methyl] 350 mg, and the mixture was stirred at room temperature for 1 hour to synthesize AZT-CEP- (E-HEPU-dM). The reaction solution was mixed with water (50 ml) and ethyl acetate (50 m).
l), and the organic layer was saturated brine (50 ml x
After washing in 2), the organic layer was dehydrated with anhydrous sodium sulfate and the solvent was evaporated to dryness. The obtained residue was purified by silica gel column chromatography (eluting solvent: chloroform), 1N sodium hydroxide solution (1.3 ml) was added, and the mixture was heated at 40 ° C. for 2 hr. After the reaction, the product was crystallized with isopropanol and then recrystallized with ethanol to obtain AZT-P- (E-HEPU-dM) sodium salt (362 mg, 53.3%).
【００１８】ＮＭＲ（ＤＭＳＯ−ｄ6）：８．３０
（ｓ，１Ｈ，ＮＨ），７．７６（ｓ，１Ｈ，６Ｈ），
６．８１（ｓ，１Ｈ，フェニル−４），６．７６（ｓ，
２Ｈ，フェニル−２，６），６．１４（ｔ，１Ｈ，１’
−Ｈ），５．２７（ｓ，２Ｈ，ＮＣＨ2Ｏ４），４．４
７（ｍ，１Ｈ，３’−Ｈ），３．９１（ｍ，１Ｈ，４’
−Ｈ），３．８０（ｍ，２Ｈ，５’−Ｈ），３．７８〜
３．５２（ｍ，４Ｈ，ＯＣＨ2ＣＨ2０），２．４３
（ｍ，３Ｈ，２’−Ｈ及び−ＣＨ2−），２．３５
（ｍ，１Ｈ，２’−Ｈ），２．２０（ｓ，６Ｈ，−ＣＨ
3×２），１．８０（ｓ，３Ｈ，−ＣＨ3），０．８５
（ｔ，３Ｈ，−ＣＨ3）NMR (DMSO-d 6 ): 8.30
(S, 1H, NH), 7.76 (s, 1H, 6H),
6.81 (s, 1H, phenyl-4), 6.76 (s,
2H, phenyl-2,6), 6.14 (t, 1H, 1 '
-H), 5.27 (s, 2H , NCH 2 O4), 4.4
7 (m, 1H, 3'-H), 3.91 (m, 1H, 4 '
-H), 3.80 (m, 2H, 5'-H), 3.78-.
3.52 (m, 4H, OCH 2 CH 2 0), 2.43
(M, 3H, 2'-H and -CH 2 -), 2.35
(M, 1H, 2'-H), 2.20 (s, 6H, -CH
3 × 2), 1.80 (s , 3H, -CH 3), 0.85
(T, 3H, -CH 3)
【００１９】試験例：ＨＩＶ感染の防止効果 １０％牛胎児血清、１００ＵのペニシリンＧおよび１０
０μｇ／ｍｌのストレプトマイシンを含むＲＰＭＩ １
６４０培地中でＭＴ−４細胞（ＨＩＶの感染を受けると
死滅する）１×１０4個に、細胞１個当り０．０２個の
ＨＩＶを感染させ、直ちに本発明化合物を含む検体を所
定量添加し、３７℃で培養した。培養後５日後に生存細
胞数をＭＴＴ法により測定し、ＭＴ−４細胞の細胞死を
５０％防ぐのに要する化合物濃度（ＥＣ50）を求めた。
また、ＨＩＶを感染させずに上記と同様に培養し、ＭＴ
−４細胞の５０％が死滅する化合物濃度（ＣＣ50）を求
めた。Test Example: Preventive effect against HIV infection 10% fetal bovine serum, 100 U penicillin G and 10
RPMI 1 containing 0 μg / ml streptomycin
1 × 10 4 MT-4 cells (which die when infected with HIV) in 640 medium are infected with 0.02 HIV per cell, and a predetermined amount of a sample containing the compound of the present invention is immediately added. And cultured at 37 ° C. After 5 days of culture, the number of surviving cells was measured by the MTT method to determine the compound concentration (EC 50 ) required to prevent 50% cell death of MT-4 cells.
In addition, the same culture as above was carried out without infection with HIV, and MT
The compound concentration at which 50% of -4 cells were killed (CC 50 ) was determined.
【００２０】[0020]
【表１】表１ ＨＴＬＶ−ＩＩＩBは、野性型ＨＩＶ−１を、ＨＴＬＶ
−ＩＩＩB/AZT及びＨＴＬＶ−ＩＩＩB-Rは夫々ＡＺＴ耐
性突然変異体及び非核酸系逆転写酵素阻害剤耐性突然変
異体を表わす。[Table 1] Table 1 HTLV-III B converts wild type HIV-1 into HTLV
-III B / AZT and HTLV-III BR represent AZT resistant mutants and non-nucleic acid reverse transcriptase inhibitor resistant mutants, respectively.
───────────────────────────────────────────────────── フロントページの続き (72)発明者 馬 場 昌 範 鹿児島県鹿児島市西陵７−10−16 (72)発明者 藤 原 将 寿 福島県福島市蓬莱町３−４−16 (72)発明者 横 田 智 之 福島県福島市飯坂町平野字北下里20−１ ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Masanori Baba 7-10-16 Nishiryo, Kagoshima City, Kagoshima Prefecture (72) Inventor Masatoshi Fujiwara 3-4-16 Horai Town, Fukushima City, Fukushima Prefecture (72) Invention Tomoyuki Yokota 20-1 Kitashitasato, Hirano, Iizaka-cho, Fukushima-shi, Fukushima Prefecture
Claims (6)
マー。 【化１】 （式中、Ｒ1〜Ｒ3は水素または低級アルキルを示す。）1. A nucleotide dimer represented by the formula (I). Embedded image (In the formula, R 1 to R 3 represent hydrogen or lower alkyl.)
ある、請求項１記載のヌクレオチドダイマー。2. The nucleotide dimer according to claim 1, wherein R 1 is ethyl and R 2 and R 3 are methyl.
オチドダイマー。3. The nucleotide dimer according to claim 1, which is in the form of a salt.
を有効成分として含有する医薬組成物。4. A pharmaceutical composition containing the nucleotide dimer according to claim 1 as an active ingredient.
組成物。5. The pharmaceutical composition according to claim 4, which is an anti-HIV agent.
薬組成物。6. The pharmaceutical composition according to claim 4, which is an oral dosage form.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP7197113A JPH0920792A (en) | 1995-07-11 | 1995-07-11 | Nucleotide dimer |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP7197113A JPH0920792A (en) | 1995-07-11 | 1995-07-11 | Nucleotide dimer |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH0920792A true JPH0920792A (en) | 1997-01-21 |
Family
ID=16368953
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP7197113A Pending JPH0920792A (en) | 1995-07-11 | 1995-07-11 | Nucleotide dimer |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH0920792A (en) |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004112838A3 (en) * | 2003-05-21 | 2005-04-07 | Control Delivery Sys Inc | Codrugs of diclofenac |
| WO2006013203A2 (en) * | 2004-08-03 | 2006-02-09 | Protera S.R.L. | Prodrugs activated by rna-dependent dna-polymerases |
| US8119800B2 (en) | 2007-12-21 | 2012-02-21 | Korea Research Institute Of Chemical Technology | Processes for preparing HIV reverse transcriptase inhibitors |
| US8334295B2 (en) | 2007-06-29 | 2012-12-18 | Korea Research Institute Of Chemical Technology | Pyrimidine derivatives as HIV reverse transcriptase inhibitors |
| US8354421B2 (en) | 2007-06-29 | 2013-01-15 | Korea Research Insitute Of Chemical Technology | HIV reverse transcriptase inhibitors |
-
1995
- 1995-07-11 JP JP7197113A patent/JPH0920792A/en active Pending
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004112838A3 (en) * | 2003-05-21 | 2005-04-07 | Control Delivery Sys Inc | Codrugs of diclofenac |
| WO2006013203A2 (en) * | 2004-08-03 | 2006-02-09 | Protera S.R.L. | Prodrugs activated by rna-dependent dna-polymerases |
| WO2006013203A3 (en) * | 2004-08-03 | 2006-07-27 | Protera S R L | Prodrugs activated by rna-dependent dna-polymerases |
| JP2008509110A (en) * | 2004-08-03 | 2008-03-27 | プロテラ ソシエタ ア レスポンサビリタ リミタータ | Prodrug activated by RNA-dependent DNA polymerase |
| US8334295B2 (en) | 2007-06-29 | 2012-12-18 | Korea Research Institute Of Chemical Technology | Pyrimidine derivatives as HIV reverse transcriptase inhibitors |
| US8354421B2 (en) | 2007-06-29 | 2013-01-15 | Korea Research Insitute Of Chemical Technology | HIV reverse transcriptase inhibitors |
| US8119800B2 (en) | 2007-12-21 | 2012-02-21 | Korea Research Institute Of Chemical Technology | Processes for preparing HIV reverse transcriptase inhibitors |
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