JPH03503635A - Coumarins inhibit reverse transcriptase in humans - Google Patents
Coumarins inhibit reverse transcriptase in humansInfo
- Publication number
- JPH03503635A JPH03503635A JP1503059A JP50305989A JPH03503635A JP H03503635 A JPH03503635 A JP H03503635A JP 1503059 A JP1503059 A JP 1503059A JP 50305989 A JP50305989 A JP 50305989A JP H03503635 A JPH03503635 A JP H03503635A
- Authority
- JP
- Japan
- Prior art keywords
- compound
- coumarin
- carbamoyl
- bromo
- hydroxy
- 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
- 102100034343 Integrase Human genes 0.000 title description 8
- 108010092799 RNA-directed DNA polymerase Proteins 0.000 title description 8
- ZYGHJZDHTFUPRJ-UHFFFAOYSA-N benzo-alpha-pyrone Natural products C1=CC=C2OC(=O)C=CC2=C1 ZYGHJZDHTFUPRJ-UHFFFAOYSA-N 0.000 title description 5
- 235000001671 coumarin Nutrition 0.000 title description 4
- 150000004775 coumarins Chemical class 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims description 42
- 238000000034 method Methods 0.000 claims description 24
- BJGMDTFHOFUMBB-UHFFFAOYSA-N 3,4,5,6,7,8-hexachlorochromen-2-one Chemical compound ClC1=C(Cl)C(=O)OC2=C(Cl)C(Cl)=C(Cl)C(Cl)=C21 BJGMDTFHOFUMBB-UHFFFAOYSA-N 0.000 claims description 12
- 241000725303 Human immunodeficiency virus Species 0.000 claims description 10
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 8
- -1 2,5-dichlorophenyl Chemical group 0.000 claims description 7
- NRCQJAMRNSNGRE-ZHACJKMWSA-N 4-hydroxy-3-[(e)-3-phenylprop-2-enoyl]chromen-2-one Chemical compound O=C1OC=2C=CC=CC=2C(O)=C1C(=O)\C=C\C1=CC=CC=C1 NRCQJAMRNSNGRE-ZHACJKMWSA-N 0.000 claims description 5
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- LDECUSDQMXVUMP-UHFFFAOYSA-N benzyl 3-[6-[[2-(butylamino)-1-[3-methoxycarbonyl-4-(2-methoxy-2-oxoethoxy)phenyl]-2-oxoethyl]-hexylamino]-6-oxohexyl]-4-methyl-2-oxo-6-(4-phenylphenyl)-1,6-dihydropyrimidine-5-carboxylate Chemical compound O=C1NC(C=2C=CC(=CC=2)C=2C=CC=CC=2)C(C(=O)OCC=2C=CC=CC=2)=C(C)N1CCCCCC(=O)N(CCCCCC)C(C(=O)NCCCC)C1=CC=C(OCC(=O)OC)C(C(=O)OC)=C1 LDECUSDQMXVUMP-UHFFFAOYSA-N 0.000 claims description 3
- 229960000956 coumarin Drugs 0.000 claims description 3
- 125000000219 ethylidene group Chemical group [H]C(=[*])C([H])([H])[H] 0.000 claims description 3
- RNVWRDUQXNCMBP-UHFFFAOYSA-N 6-bromo-n-(2,5-dichlorophenyl)-2-oxochromene-3-carboxamide Chemical compound ClC1=CC=C(Cl)C(NC(=O)C=2C(OC3=CC=C(Br)C=C3C=2)=O)=C1 RNVWRDUQXNCMBP-UHFFFAOYSA-N 0.000 claims 1
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- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
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- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 2
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
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- 230000029812 viral genome replication Effects 0.000 description 2
- ZSLUVFAKFWKJRC-IGMARMGPSA-N 232Th Chemical compound [232Th] ZSLUVFAKFWKJRC-IGMARMGPSA-N 0.000 description 1
- GOLORTLGFDVFDW-UHFFFAOYSA-N 3-(1h-benzimidazol-2-yl)-7-(diethylamino)chromen-2-one Chemical compound C1=CC=C2NC(C3=CC4=CC=C(C=C4OC3=O)N(CC)CC)=NC2=C1 GOLORTLGFDVFDW-UHFFFAOYSA-N 0.000 description 1
- CSPIFKKOBWYOEX-UHFFFAOYSA-N 3-acetylcoumarin Chemical compound C1=CC=C2OC(=O)C(C(=O)C)=CC2=C1 CSPIFKKOBWYOEX-UHFFFAOYSA-N 0.000 description 1
- MJKVTPMWOKAVMS-UHFFFAOYSA-N 3-hydroxy-1-benzopyran-2-one Chemical class C1=CC=C2OC(=O)C(O)=CC2=C1 MJKVTPMWOKAVMS-UHFFFAOYSA-N 0.000 description 1
- MBVFRSJFKMJRHA-UHFFFAOYSA-N 4-fluoro-1-benzofuran-7-carbaldehyde Chemical compound FC1=CC=C(C=O)C2=C1C=CO2 MBVFRSJFKMJRHA-UHFFFAOYSA-N 0.000 description 1
- VXIXUWQIVKSKSA-UHFFFAOYSA-N 4-hydroxycoumarin Chemical class C1=CC=CC2=C1OC(=O)C=C2O VXIXUWQIVKSKSA-UHFFFAOYSA-N 0.000 description 1
- 241000220479 Acacia Species 0.000 description 1
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- 241000222122 Candida albicans Species 0.000 description 1
- 206010007134 Candida infections Diseases 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 241001247414 Couma Species 0.000 description 1
- 108020001019 DNA Primers Proteins 0.000 description 1
- 239000003155 DNA primer Substances 0.000 description 1
- 235000019739 Dicalciumphosphate Nutrition 0.000 description 1
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 208000031886 HIV Infections Diseases 0.000 description 1
- 108010078851 HIV Reverse Transcriptase Proteins 0.000 description 1
- 208000017604 Hodgkin disease Diseases 0.000 description 1
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 1
- 239000004264 Petrolatum Substances 0.000 description 1
- 241000233870 Pneumocystis Species 0.000 description 1
- 208000005384 Pneumocystis Pneumonia Diseases 0.000 description 1
- 206010073755 Pneumocystis jirovecii pneumonia Diseases 0.000 description 1
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- 229920001615 Tragacanth Polymers 0.000 description 1
- VVCFHDUWPMTSGI-UHFFFAOYSA-N [Fe]C1=CC=CC=C1 Chemical compound [Fe]C1=CC=CC=C1 VVCFHDUWPMTSGI-UHFFFAOYSA-N 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- SNAAJJQQZSMGQD-UHFFFAOYSA-N aluminum magnesium Chemical compound [Mg].[Al] SNAAJJQQZSMGQD-UHFFFAOYSA-N 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 239000000427 antigen Substances 0.000 description 1
- 102000036639 antigens Human genes 0.000 description 1
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- 239000000571 coke Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- NEFBYIFKOOEVPA-UHFFFAOYSA-K dicalcium phosphate Chemical compound [Ca+2].[Ca+2].[O-]P([O-])([O-])=O NEFBYIFKOOEVPA-UHFFFAOYSA-K 0.000 description 1
- 229940038472 dicalcium phosphate Drugs 0.000 description 1
- 229910000390 dicalcium phosphate Inorganic materials 0.000 description 1
- 229960003887 dichlorophen Drugs 0.000 description 1
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- VHJLVAABSRFDPM-QWWZWVQMSA-N dithiothreitol Chemical compound SC[C@@H](O)[C@H](O)CS VHJLVAABSRFDPM-QWWZWVQMSA-N 0.000 description 1
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- OWIUPIRUAQMTTK-UHFFFAOYSA-M n-aminocarbamate Chemical compound NNC([O-])=O OWIUPIRUAQMTTK-UHFFFAOYSA-M 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
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- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
- 229940081974 saccharin Drugs 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/365—Lactones
- A61K31/366—Lactones having six-membered rings, e.g. delta-lactones
- A61K31/37—Coumarins, e.g. psoralen
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Virology (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyrane Compounds (AREA)
Abstract
(57)【要約】本公報は電子出願前の出願データであるため要約のデータは記録されません。 (57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.
Description
【発明の詳細な説明】 ヒトにおいて逆転写酵素を抑制するクマリン類／発明の分野 本発明は、ヒト免疫不全ウィルスに感染した患者の新規治療である。[Detailed description of the invention] Coumarins inhibit reverse transcriptase in humans/Field of invention The present invention is a novel treatment for patients infected with human immunodeficiency virus.
類は公知である；しかしながら、該化合物のいずれもヒト免疫不全ウィルスまた はその株類に感染したヒトを治療するのに有用であることが知られていない。However, none of the compounds are known to be effective against human immunodeficiency virus or is not known to be useful in treating humans infected with that strain.
米国において１００万ないし１５０万人と見積もられる人々がヒト・レトロウィ ルス、後天性免疫不全症候群の病因たるヒト免疫不全ウィルス１梨、ＨＩＶ−１ に感染している［「エイズ緊急Ｓ２−ピリオンプログラム（Ｓ２−Ｂｉｌｌｉｏ ｎ Ｐｒｏｇｒａｍ Ｕｒｇｅｄ ｆｏｒ ＡＩＤＳ）Ｊ 、ノルマン・シイ（ ！ｌｏｒｍａｎ、 Ｃ，）、サイエンス（Ｓｃｉｅｎｃｅ）、 ２３４巻。An estimated 1 million to 1.5 million people in the United States have human retroviruses. Rus, human immunodeficiency virus 1, the cause of acquired immunodeficiency syndrome, HIV-1 [``AIDS Emergency S2-Pillion Program (S2-Billio n Program Urged for AIDS) J, Norman Sy ( ! Lorman, C.), Science, vol. 234.
６６１−６６２頁（１９８６）］。感染した者のうち、２５万人と見積もられる 人々はこれから先５年以内にエイズに進展するであろう［「エイズの疫学：現況 および将来予測（Ｔｈｅ Ｅｐｉｄｅｍｉｏｌｏｇｙ ｏｆＡＩＤＳ ： Ｃｕ ｒｒｅｎｔ ５ｔａｔｕｓ ａｎｄ Ｆｕｔｕｒｅ Ｐｒｏｓｐｅｃｔｓ） Ｊ −カラン°ジェイ。661-662 (1986)]. It is estimated that 250,000 people have been infected. People will develop AIDS within the next five years [“AIDS Epidemiology: Current Status”] and future predictions (The Epidemiology of AIDS: Cu rrent 5tatus and Future Prospects) J −Karan ° Jay.
ダブリニーら（Ｃｕｒｒａｎ、Ｊ、Ｌ、ｅｔ ａｌ） ＋ サイエンス（Ｓｃｉ ｅｎｃｅ）。D'Abriny et al. (Curran, J, L, et al) + Science (Sci ence).
２２９巻、４７２０号、１３５２−１３５７頁（１９８５）コ。229, No. 4720, pp. 1352-1357 (1985).
１９８７年３月２０日、ＦＤＡは、最近最初のエピソードとなった二ニーモジス テイス・カリニイ・ニューモニア（Ｐｎｅｕｍｏｃｙｓｔｉｓｃａｒｉｎｆｉ ｐｎｅｕｓｏｎｉａ）でのエイズ患者、二ニーモジステイス・カリニイ弓１−モ ニア（Ｐｎｅｕｍｏｃｙｓｔｉｓ ｃａｒｉｎｉｉ ｐｎｅｕｍｏｎｉａ）以外 の疾患でのエイズ患者、または末梢血液中、２００／ａｍ’未満の絶対ＣＤ４リ ンパ球数を持つウィルス感染患者を治療するための化合物シトプシン（ＡＺＴ） の使用を認可した。ＡＺＴはウィルス逆転写酵素、ヒト免疫不全ウィルス複製に 必要な酵素の公知抑制剤である。On March 20, 1987, the FDA announced that the first episode of Theis carinii pneumonia AIDS patients with pneusonia) Other than Pneumocystis carinii pneumonia AIDS patients with diseases such as The compound cytopsin (AZT) to treat virally infected patients with lymphocyte counts approved for use. AZT is a viral reverse transcriptase, involved in human immunodeficiency virus replication. It is a known inhibitor of necessary enzymes.
ある種の抗生物質類およびポリアニオン性染料類がレトロウィルス逆転写酵素を 抑制することが当該分野で知られている。本発明で特許請求する化合物はいずれ もヒト免疫不全ウィルス逆転写酵素を特別に抑制することは知られていなかった 。Certain antibiotics and polyanionic dyes can inhibit retroviral reverse transcriptase. It is known in the art to inhibit Which compounds are claimed in this invention? was not known to specifically inhibit human immunodeficiency virus reverse transcriptase. .
及咀９！わ 本発明は、６−ブロモ−３−［（ｍ−クロロフェニル）カルバモイルコークマリ ン、６−ブロモ−３−［（α、α、α−トリフルオローｍ−）ルイル）カルバモ イルコークマリン、６−ブロモ−３−［（２，５−ジクロロフェニル）カルバ、 モイルコークマリン、［［ビス（４−ヒドロキシ−２−オキソ−２Ｈ−１−ベン ゾビラン−３−イル）−メチル］シクロベンタジエニルコシクロベンタジエニル ー鉄、３−シンナモイル−４−ヒドロキシ−クマリン、ヘキサクロロクマリン、 ７−アセトキシクマリンまたは［１−（２−オ牛ソー２Ｈ−１−ベンゾピラン− ３−イル）エチリデン］−ヒドラジンカルボン酸フェニルメチルエステルまたは その医薬上許容される塩よりなる群から選択される化合物の有効量をヒト免疫不 全ウィルスの１または１を越える株に感染したヒトに投与することを特徴とする 該患者を治療する方法である。9! circle The present invention provides 6-bromo-3-[(m-chlorophenyl)carbamoyl 6-bromo-3-[(α,α,α-trifluoro-m-)ruyl)carbamo ylcocoumarin, 6-bromo-3-[(2,5-dichlorophenyl)carba, Moyl coumarin, [[bis(4-hydroxy-2-oxo-2H-1-ben zobilan-3-yl)-methyl]cyclobentadienylcocyclobentadienyl -Iron, 3-cinnamoyl-4-hydroxy-coumarin, hexachlorocoumarin, 7-acetoxycoumarin or [1-(2-Ogyuso2H-1-benzopyran- 3-yl)ethylidene]-hydrazinecarboxylic acid phenylmethyl ester or administering an effective amount of a compound selected from the group consisting of pharmaceutically acceptable salts thereof to a human immune system. characterized by administration to a human infected with one or more than one strain of all viruses A method of treating the patient.
発明の詳細な記載 本出願において、ヒト免疫不全ウィルスなる語は、当業者に明らかなごとく、ヒ ト免疫不全ウィルス夏型、ヒト免疫不全ウィルス■型、またはその株類を意味し 、これらは同一のウィルス科に属し、ヒト免疫不全ウィルスｌまたは■型として ヒトにおいて同様の生理学的影響を生じる。Detailed description of the invention In this application, the term human immunodeficiency virus refers to human immunodeficiency virus, as is clear to those skilled in the art. human immunodeficiency virus summer type, human immunodeficiency virus type ■, or its strains. , these belong to the same virus family and are known as human immunodeficiency virus type I or type II. Produces similar physiological effects in humans.
本発明で特許請求する方法を実施するのに用いる各化合物の構造式は、知られて いれば、構造チャートに示す。以下の化合物二６−ブロモ−３−［（ｍ−クロロ フェニル）カルバモイルコークマリン、６−ブロモ−３−［（α、α、α−トリ フルオローｍ−）ルイル）カルバモイルコークマリンおよび６−ブロモ−３−［ （２，５−ジクロロフェニル）カルバモイルコークマリンは商業的に入手した。The structural formula of each compound used in carrying out the method claimed in this invention is If so, show it in the structure chart. The following compound 26-bromo-3-[(m-chloro phenyl)carbamoyl coumarin, 6-bromo-3-[(α,α,α-tri Fluoro(m-)ruyl)carbamoylcoumarin and 6-bromo-3-[ (2,5-dichlorophenyl)carbamoyl coumarin was obtained commercially.
化合物３−シンナモイル−４−ヒドロキシ−クマリンの調製は「ツル・ヘミ−・ デス・４−ヒドロキシクマリン類（Ｚｕｒ Ｃｈｅｍｉｅ ｄｅｓ４−Ｈｙｄｏ ｘｙ−ｃｕｍａｒｉｎｓ） Ｊ 、モナートシエフテ拳フル・ヘミ−（Ｍｏｎａ ｔｓｈｅｆｔｅ ｆｕｒ ｃｈｅｍｉ）、 ８７巻、４３９−４４６頁（１９５ ６）に記載されている。化合物７−アセト牛シクマリンはヘミシェ・ベリヒテ（ Ｃｈｅｗ、 Ｂｅｒ−）＋ １２巻、９９３−９９９ （１８７９）に記載さ れている。化合物へキサクロロクマリンは、光の存在下で、クマリンのエタノー ル溶液に塩素を通気すると調製される。溶液にもはや検出可能な出発物質が存在 しなくなると、溶媒を除去し、ポリ塩素化生成物の混合物をクロマトグラフィー によって分離する。化金物［［ビス−（４−ヒドロキシ−２−オキソ−２Ｈ−１ −ベンゾピラン−３−イル）−メチルコシクロペンタジェニルコシクロペンタジ ェニル−鉄は、スリパンら（Ｓｕｌｌｊｖａｎ、 ａｔ ａｌ）、ＪＡＣ３゜６ ５巻、７−１２月、２２８８−２２９１頁（１９４３）、「４−ヒドロキシクマ リン類の研究■ アルデヒド類のヒドロキシクマリン類との縮合（Ｓｔｕｄｉｅ ｓ ｏｎ ４−ｈｙｄｒｏｘｙｃｏｕｍａｒｉｎｓ ＩＩ Ｔｈｅ Ｃｏｎｄｅ ｎ−ｓａｔｉｏｎ ｏｒ Ａｌｄｅｈｙｄｅｓ ｗｉｔｈ Ｈｙｄｒｏｘｙｃｏ ｕｍａｒｉｎｓ）Ｊに記載されている ′一般的な手法により、商業的 に入手可能な４−ヒドロ牛シクマリン２．０当量と商業的に入手可能なフェロセ ンカルボキシアルデヒド１．５当量とをエタノール中で縮合させることによって 調製される。The preparation of the compound 3-cinnamoyl-4-hydroxy-coumarin is Des4-Hydocoumarins (Zur Chemie des4-Hydo xy-cumarins) J, Monato Siefte Fist Full Hemi-(Mona tshefte fur chemistry), volume 87, pages 439-446 (195 6). Compound 7-acetobovine cycoumarin is Hemische Berichte ( Chew, Ber-) + Volume 12, 993-999 (1879). It is. The compound hexachlorocoumarin is an ethanolic compound of coumarin in the presence of light. It is prepared by bubbling chlorine through the solution. No more detectable starting material in solution Once the solvent is removed, the polychlorinated product mixture is chromatographed. Separate by. Metal compound [[bis-(4-hydroxy-2-oxo-2H-1 -benzopyran-3-yl)-methylcocyclopentadienylcocyclopentadi phenyl-iron, as described by Sulljvan et al., JAC3゜6 5, July-December, pp. 2288-2291 (1943), “4-Hydroxycouma Research on phosphorus ■ Condensation of aldehydes with hydroxycoumarins (Studie s on 4-hydroxycoumarins II The Conde n-sation or Aldehydes with Hydroxyco commercially by the general method described in J. 2.0 equivalents of 4-hydro-bovine cycoumarin available in by condensation with 1.5 equivalents of carboxaldehyde in ethanol. prepared.
化合物Ｅｌ−（２−オキソ−２Ｈ−１−ベンゾピラン−３−イル）エチリデンコ ーヒドラジンカルボン酸フェニルメチルエステルは、無水メタノール中の氷酢酸 の存在下で、商業的に入手可能な３−アセチルクマリンを商業的に入手可能なベ ンジルカルバザードと縮合させることによって調製される。試薬を還流し、水で 希釈し、冷却し、濾過して結晶性化合物を得る。Compound El-(2-oxo-2H-1-benzopyran-3-yl)ethylidene -Hydrazinecarboxylic acid phenylmethyl ester is dissolved in glacial acetic acid in anhydrous methanol. commercially available 3-acetylcoumarin in the presence of commercially available base It is prepared by condensation with carbazate. Reflux the reagents and add water to Dilute, cool and filter to obtain crystalline compound.
これらの化合物類またはその医薬上許容される塩は本発明で特許請求する方法を 実施するにおいて、使用し、投与することができる。These compounds or their pharmaceutically acceptable salts can be used in the method claimed in the present invention. can be used and administered in the practice.
医薬上許容される塩とは、処方、安定性、患者許容性および生物利用性のごとき 特性において親化合物と同等であることが製剤化学者に明らかである本発明で特 許請求する化合物の塩をいう。Pharmaceutically acceptable salts are defined by factors such as formulation, stability, patient tolerability and bioavailability. It is clear to the formulation chemist that the properties are equivalent to the parent compound. Refers to the salt of the compound for which permission is requested.
当業者ならば、本発明で特許請求する方法を実施するのに用いる化合物を適当な 医薬投与形に処方する方法は分かるであろう。投与形の例は錠剤またはカプセル 剤のごとき経口処方、あるいは滅菌液剤のごとき非経口処方を包含する。Those skilled in the art will be able to identify suitable compounds for use in carrying out the method claimed in this invention. One will know how to formulate it into a pharmaceutical dosage form. Examples of dosage forms are tablets or capsules This includes oral formulations such as pharmaceutical preparations, and parenteral formulations such as sterile liquid preparations.
本発明で特許請求する方法を実施するのに用いる化合物を経口投与する場合、有 効量は１日につき１ｋｇ当たり約１ないし１００ｍｇである。７０ｋｇのヒトに ついての典型的な単位用量は１日当たり工ないし４回摂取で約２００ｍｇないし １０００ｍｇとなろう。固体または液体投与形いずれも経口投与に調製できる。When the compounds used in carrying out the claimed method of this invention are administered orally, Effective doses are about 1 to 100 mg per kg per day. for a 70 kg human A typical unit dose is approximately 200 mg or 4 times per day. It will be 1000mg. Either solid or liquid dosage forms can be prepared for oral administration.
固体組成物は本発明で特許請求する方法を実施するのに用いる化合物を、タルク 、ステアリン酸マグネシウム、リン酸二カルシウム、ケイ酸アルミニウムマグネ シウム、硫酸カルシウム、スターチ、ラクトース、アカ、シア、メチルセルロー ス、または機能的に同様の医薬賦形剤および担体と混合することによって調製さ れる。カプセル剤は、本発明で特許請求する方法を実施するのに用いる化合物を 不活性な医薬賦形剤と混合し、該混合物を適当なサイズのハードゼラチンカプセ ルに入れることによって調製される。ソフトゼラチンカプセル剤は、本発、明で 特許請求する方法を実施するのに用いる化合物と植物油または軽質液状ベテロラ タムのごとき適当な不活性油とのスラリーを機械カプセル化することによって調 製される。シロ・ノブ剤は、本発明で特許請求する方法を実施するのに用いる化 合物を適当な水性ピヒクルに溶解し、糖、芳香フレーバー剤および保存剤を添加 することによって調製される。エリキシル剤は、エタノールのごときヒドロアル コール性ビヒクル、砂糖またはサッカリンのごとき適当な甘味剤および芳香フレ ーバー剤を用いて調製される。懸濁剤は水性ビヒクルとアカシア、トラガカント 、またはメチルセルロースのごとき懸濁化剤とで調製される。The solid composition contains the compounds used in carrying out the method claimed in this invention, including talc. , Magnesium Stearate, Dicalcium Phosphate, Magnesium Aluminum Silicate Shea, calcium sulfate, starch, lactose, aca, shea, methylcellulose prepared by mixing with pharmaceutical excipients and carriers, or functionally similar pharmaceutical excipients and carriers. It will be done. Capsules contain the compounds used to carry out the claimed method of the invention. Mix with an inert pharmaceutical excipient and pour the mixture into hard gelatin capsules of suitable size. It is prepared by placing it in a bottle. The soft gelatin capsules according to the present invention are Compounds used in carrying out the claimed method and vegetable oils or light liquid Betelola prepared by mechanical encapsulation of a slurry with a suitable inert oil such as Manufactured. Shiro Nobu agent is a compound used in carrying out the method claimed in this invention. Dissolve the compound in a suitable aqueous vehicle and add sugar, aromatic flavoring agents and preservatives. It is prepared by Elixirs are made from hydroalcohols such as ethanol. A alcoholic vehicle, a suitable sweetener such as sugar or saccharin, and an aromatic flavoring agent. It is prepared using a sorbent agent. The suspending agent is an aqueous vehicle and acacia, tragacanth. , or with a suspending agent such as methylcellulose.
本発明で特許請求する方法を実施するのに用いる化合物を非経口投与する場合、 注射または静脈注入によって投与できる。有効量は１日につき１ｋｇ当たり約１ ないし１００ｍｇである。非経口液剤は、本発明で特許請求する方法を実施する のに用いる化合物を水に溶解し、溶液を濾過滅菌し、しかる後に適当な密封可能 なバイアルまたはアンプルに入れることによって調製される。非経口懸濁剤は、 滅菌懸濁ビヒクルを用い、本発明で特許請求する方法を実施するのに用いる化合 物をエチレンオキシドまたは適当なガスで滅菌し、しかる後にビヒクル中に懸濁 させる以外は実質的に同様に調製される。When administering the compounds used in carrying out the claimed method parenterally, It can be administered by injection or intravenous infusion. Effective dose is approximately 1 kg per day to 100 mg. Parenteral solutions carry out the method claimed in this invention. The compound to be used for It is prepared by placing it in a vial or ampoule. Parenteral suspensions are Compounds used in carrying out the claimed methods of this invention using sterile suspension vehicles Sterilize the material with ethylene oxide or a suitable gas and then suspend it in the vehicle. It is prepared in substantially the same manner except for the following steps.
正確な投与経路、用量、または投与の頻度は当業者ならば容易に決定できるであ ろうし、それは、年令、一般的な身体状態、または治療されるべき患者に特別の 他の臨床的兆候に依存する。The precise route of administration, dose, or frequency of administration can be readily determined by one of ordinary skill in the art. wax, which depends on the age, general physical condition, or special condition of the patient to be treated. Depends on other clinical signs.
治療されるべき患者は＝１）測定可能なウィルス抗体または抗原いずれかが血清 中に存在することによって判断して１または１を越える株のヒト免疫不全ウィル スに感染した者、および２）ｉ）播種性ヒストブラスマ症、１１）インボリアシ ス（ｉｓｏｐｏｒｉａｓｉｇ）、１１１）二ニーモジステイス・二ニーモニア（ ｐｎｅｕｍｏｃｙｓｔｉｓ ｐｎｅｕａ＋ｏｎｉａ）を包含する気管支および肺 カンジダ症、１１・）非ホジキン（Ｈｏｄｇｋｉｎ）リンパ樺またはＶ）カボー ジ肉騰のごときはっきりした兆候いずれかのエイズ感染を有し、６０才未満の者 ；または抹消血液中、２００／ａｍ’未満の絶対ＣＤリンパ球数を有する者であ ろう。治療は、患者において、終始、本明細書中に開示する化合物の抑制レベル を維持することよりなり、第２のエイズ決定感染の兆候が生じて別の治療が要求 されるまで継続する。Patients to be treated = 1) measurable viral antibodies or antigens in the serum one or more strains of human immunodeficiency virus as determined by the presence in 2) i) disseminated histoblasmosis, 11) inboliosis isoporiasig, 111) Dinimodystis bimnemonia ( bronchi and lungs, including pneumocystis pneua+onia) Candidiasis, 11.) Non-Hodgkin's lymph birch or V) Cabo Persons under the age of 60 who have any of the clear signs of AIDS infection, such as AIDS infection. ; or have an absolute CD lymphocyte count of less than 200/am' in peripheral blood. Dew. Treatment continues to achieve suppressed levels of the compounds disclosed herein in the patient. If signs of a second AIDS-defining infection occur and another treatment is required. Continue until
当業者ならばミさらに技巧を凝らすことなく、本発明を最大限に実施できる。以 下の実施例は、１または１を越える株のヒト免疫不全ウィルスに感染したヒトを 治療するための、本発明で特許請求する化合物の使用方法をさらに詳しく記載す る。これらの実施例は例示に過ぎず、これまでの開示を限定するものではない。Without further elaboration, one skilled in the art can carry out the present invention to its fullest extent. Below The examples below demonstrate how humans infected with one or more strains of human immunodeficiency virus are The following describes in more detail the methods of using the compounds claimed in this invention for treatment. Ru. These examples are illustrative only and are not intended to limit the previous disclosure.
当業者ならば、実施例から適当な変法を直ちに理解するであろう。各実施例にお いて、本発明で特許請求するいずれの化合物も特定の実施例で用いる化合物と置 き換えることができる。Those skilled in the art will readily recognize suitable variations from the examples. For each example However, any compounds claimed in this invention may be replaced with the compounds used in the specific examples. It can be replaced.
ヘキサクロロクマリン ５０ｇｍラクトース １００ｇｍコーンスターチ ２０ｇｍタルク ２０ｇｍステアリン酸マグネシウム ２ｇｍより、各カプセ ルかへキサクロロクマリン５０ｍｇを含有する経口用ツーピース・ハードゼラチ ンカプセル１０００個を調製する。Hexachlorocoumarin 50gm lactose 100gm cornstarch 20gm talc 20gm Magnesium Stearate Each capsule from 2gm Two-piece hard gelatin for oral use containing 50 mg of chlorocoumarin Prepare 1000 capsules.
該ヘキサクロロクマリンを他の成分に添加し、混合し、常法によりカプセル化す る。The hexachlorocoumarin is added to other ingredients, mixed, and encapsulated using a conventional method. Ru.
ヘキサクロロクマリン ５０ｇｍラクトース ７５ｇｍコーンスターチ ５０ｇｍステアリン酸ヤグネシウ ム ４ｇｍ軽質液体ペテロラタム ５ｇｍ ″より、 各々がヘキサクロロクマリン５０ｍｇを含有する錠剤１０００個を調製する。Hexachlorocoumarin 50gm lactose 75gm cornstarch 50gm stearate From 4gm light liquid petrolatum 5gm 1000 tablets each containing 50 mg of hexachlorocoumarin are prepared.
該へキサクロロクマリンを他の成分に添加し、混合し、スラップ化する。力をか けて該スラップを１６番のスクリーンを通し、該スラツジを粉砕する。次いで、 得られた顆粒を圧縮して錠剤とする。Add the hexachlorocoumarin to the other ingredients, mix and slurp. Give me power Then pass the slurp through a No. 16 screen to crush the sludge. Then, The resulting granules are compressed into tablets.
亥施月１ 非経口液剤 溶液１リツトル中にヘキサクロロクマリン１５０ｍｇを含有する非経口静脈注射 用滅菌水性溶液を以下の：ヘキサクロロクマリン １５０ｇｍ注射用水 、適量 １０００ｇｍより調製する。Ishigetsu 1 Parenteral liquid preparation Parenteral intravenous injection containing 150 mg of hexachlorocoumarin in 1 liter of solution Sterile aqueous solution for: Hexachlorocoumarin 150gm water for injection , an appropriate amount of 1000 gm.
該へ牛すクロロクマリンを滅菌し、滅菌水に添加し、滅菌容器に充填し、密封す る。Sterilize the bovine chlorocoumarin, add it to sterile water, fill it into a sterile container, and seal it. Ru.
本発明の有用性は、本発明において特許請求する方法を実施するのに使用する化 合物がウィルス逆転写酵素、ヒト免疫不全ウィルス複製について必須の酵素を抑 制する能力によって証明される。この酵素は、それを他の公知細胞ポリメラーゼ と区別する特徴を有し、それは未感染細胞では見い出されないユニークな酵素で ある。ウィルス逆転写酵素は、ボッ・ニス・ビイら（Ｇｏｆｆ、 Ｓ、 Ｐ、、 ｅｔ ａｌ）、ジャーナル・オブ管バイｏａジー（Ｊｏｕｒｎａｌ ｏｆ Ｖ ｉｒｏｌｏｇｙ）、 ５９巻。The utility of the present invention lies in the fact that the invention can be used to carry out the claimed method. The compound inhibits viral reverse transcriptase, an enzyme essential for human immunodeficiency virus replication. evidenced by the ability to control. This enzyme combines it with other known cellular polymerases. It is a unique enzyme that is not found in uninfected cells. be. Viral reverse transcriptase was developed by Bott, Nis, B et al. (Goff, S., P., et al), Journal of V. irology), Volume 59.
３号、７４３−７４５頁（１９８６）、「エシェリヒア・コリにおけるヒトＴ− りンホトロピック・ウィルス■型（ＨＴＬＶ−［［／ＬＡＶ）の逆転写酵素の活 性の発現（Ｅｘｐｒｅｓｓｉｏｎ ｏｆ ＲｅｖｅｒｓｅＴｒａｎｓｃｒｉｐｔ ａｓｅ Ａｃｔｉｖｉｔｙ ｏｆ Ｈｕｍａｎ Ｔ−１ｙｓｐｈｏｔｒ ｏｐｉｃ Ｖｉｒｕｓ Ｔｙｐｅ@ １ ｉｎ Ｅｓｈｅｒｉｃｈａ ｃｏｌｉ） Ｊによって記載されている方法に従っ て調製した細菌クローンからの抽出物に見い出される。この酵素の抑制は、ＤＮ Ａに取り込まれた放射能活性プレカーサーのレベルを測定する細胞フリーアッセ イで決定される。クライト・ディ・シイら（Ｋｌｅｉｄ、 Ｄ、Ｇ、、ｅｔ ａ ｌ）、サイエンス（Ｓｃｉｅｎｃｅ）、 ２１４巻、４５２５号、１１２５− １１２９頁（１９８１）、「足および口の病気用のクローン化ビルラ蛋白ワクチ ン：ウシおよびブタにおける応答（Ｃ１ｏｎｅｄ Ｖｆｒｌａ Ｐｒｏｔｅｉｎ Ｖａｃｃｉｎｅ ｆｏｒ Ｆｏｏｔ−ａｎｄ−Ｍｏｕｔｈ Ｄｉｓｅａｓｅ ：Ｒｅ５ｐｏｎｓｅｓ ｉｎ Ｃａｔｔｌｅ ａｎｄ ５ｗ１ｎｅ）Ｊの手法に 従って調製した抽出物ヲ抑制剤、２０ｍＭジチオスレイトール、６０ｍＭ塩化ナ トリウム、０．０５％ＮＰ−４０，１０ｍＭ塩化マグネシウム、５０ｍＭｌ−１ ７２ｐＨ８，３，１０μＭ［”Ｓ］−標識ｆｔキシヌ’１Ｌｙｔ’／Ｖ−５’− トリホスフェート、ｉｏμｇ／ｍ２ＲＮＡ鋳型（ポ’）ｒｃ＊たはポリｒＡ）お よび５ｕｇ／ｍＱＤＮＡプライマー（オリゴｄＧまたはオリゴｄＴ）の混合物中 、３７℃で３０分間インキニベートする。3, pp. 743-745 (1986), “Human T- Reverse transcriptase activity of lymphotropic virus type ■ (HTLV-[[/LAV)] Expression of Reverse Transcript ase Activity of Human T-1yphotor opic Virus Type@1 According to the method described in Eschericha coli) J. found in extracts from bacterial clones prepared by Inhibition of this enzyme is DN Cell-free assay to measure the level of radioactive precursor incorporated into A. Determined by Kleid, D, G, et a l), Science, Volume 214, No. 4525, 1125- 1129 (1981), “Cloned Birla Protein Vaccine for Foot and Mouth Diseases” Response in cows and pigs (C1oned Vfrla Protein Vaccine for Foot-and-Mouth Disease :Re5ponses in Cattle and 5w1ne) J's method Therefore, the extract was prepared with inhibitors, 20mM dithiothreitol, 60mM sodium chloride. Thorium, 0.05% NP-40, 10mM magnesium chloride, 50mMl-1 72pH8, 3, 10 μM [”S]-labeled ft xinu '1Lyt'/V-5'- triphosphate, ioμg/m2 RNA template (po’)rc* or polyrA) or and 5ug/mQ DNA primer (oligo-dG or oligo-dT) in a mixture of , incubate for 30 minutes at 37°C.
放射性標識プレカーサーの取り込みは、反応混合物をＤＥ８１ベーパー上にスポ ットし、該ペーパーを洗浄して取り込まれなかったプレカーサーを除去し、乾燥 し、カウントすることによって決定される。第１表は本発明で特許請求する方法 を実施するのに用いる化合物についてのアッセイの結果を含む。Incorporation of the radiolabeled precursor is achieved by sprinkling the reaction mixture onto DE81 vapor. Wash the paper to remove unincorporated precursors, and dry. determined by counting. Table 1 shows how to claim a patent based on the present invention Contains the results of assays for compounds used to perform.
第１表 化合物（０，１ｍＭ） ％抑制６−ブロモー３ −［（ｍ−クロロフェニル）−２８カルバモイルコークマリン、 ６−ブロモ−３−［（α、α、α−３１トリフルオロ−ｍ−トルイル）− カルバモイルコークマリン、 ６−ブロモ−３−［（２，５−ジクロロフェニル）−４２カルバモイル］−クマ リン、 ［［ｔ’ス（４−ヒｔ’ａ牟シー２−ｔ＋ｖ−２８−６０１−ベンゾピラン−３ −イル）−メチル−］−シシクロペンタジェニルジシクロペンタジェニル鉄、３ −シンナモイル−４−ヒドロキシ−クマリン、３５ヘキサクロロクマリン、 ３４［：１−（２−オ牛ソー２Ｈ−１−ベンゾビ ラン−３１３−イル）エチリデンコーヒドラジンヵルボン酸−フェニルメチルエ ステル、 ７−アセトキシクマリン ２３構造チヤート ６−ブ。！−３−［（ｍ−クロロフェニル）−３−シンナモイル−４−ヒドロキ シ−クマリンカルバモイルコークマリン ６−ブロモ−３−［α、α、α−トリフルオロ−ヘキサク。、：１り、リン−ト ルイル）カルバモイルニークマリン６−ブロモ−３−［（２，５−ジクロロフェ ニル）−［１−（２−オキソ−２Ｈ−１−ベンゾビラン−カルバモイルコークマ リン ３−イル）エチリデン〕−ヒドラジンカルボン酸 −フェニルメチルエステル 暴内Ｍ＋ｅａａ番＾−＃ｊａ勧。＊に＊、ｐ（−コｒ／ＵＳ！１９１００４！１ ０Table 1 Compound (0,1mM) % Inhibition 6-Bromo 3 -[(m-chlorophenyl)-28 carbamoyl coumarin, 6-bromo-3-[(α,α,α-31 trifluoro-m-tolyl)- carbamoyl coke marine, 6-bromo-3-[(2,5-dichlorophenyl)-42carbamoyl]-bear Rin, [[t'su(4-human t'amus 2-t+v-28-601-benzopyran-3 -yl)-methyl-]-cyclopentadienyl dicyclopentadienyl iron, 3 -cinnamoyl-4-hydroxy-coumarin, 35 hexachlorocoumarin, 34 Ran-313-yl)ethylidenecohydrazinecarboxylic acid-phenylmethylether Stell, 7-acetoxycoumarin 23 structure chart 6-B. ! -3-[(m-chlorophenyl)-3-cinnamoyl-4-hydroxy Seekumarin carbamoyl cokemarine 6-bromo-3-[α,α,α-trifluoro-hexac. , :1ri, lint carbamoyl nicoumarin 6-bromo-3-[(2,5-dichlorophene) Nyl)-[1-(2-oxo-2H-1-benzobilane-carbamoyl couma Phosphorus 3-yl)ethylidene-hydrazinecarboxylic acid -phenyl methyl ester Inauchi M+eaa number ^-#ja recommendation. *ni*, p(-ko r/US!191004!1 0
Claims (1)
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US16255388A | 1988-03-01 | 1988-03-01 | |
| US162,553 | 1988-03-01 | ||
| US19003888A | 1988-05-04 | 1988-05-04 | |
| US190,038 | 1988-05-04 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH03503635A true JPH03503635A (en) | 1991-08-15 |
Family
ID=26858857
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP1503059A Pending JPH03503635A (en) | 1988-03-01 | 1989-02-08 | Coumarins inhibit reverse transcriptase in humans |
Country Status (5)
| Country | Link |
|---|---|
| EP (1) | EP0403535A1 (en) |
| JP (1) | JPH03503635A (en) |
| AU (1) | AU4074789A (en) |
| DK (1) | DK195690D0 (en) |
| WO (1) | WO1989007939A2 (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1997035565A1 (en) * | 1996-03-27 | 1997-10-02 | Toray Industries, Inc. | Ketone derivatives and medicinal use thereof |
| WO2005028441A1 (en) * | 2003-09-17 | 2005-03-31 | Sumitomo Chemical Company, Limited | Cinnamoyl derivatives and use thereof |
Families Citing this family (28)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1991004663A1 (en) * | 1989-09-26 | 1991-04-18 | The Regents Of The University Of California | 6-amino-1,2-benzopyrones useful for treatment of viral diseases |
| IL99731A0 (en) * | 1990-10-18 | 1992-08-18 | Merck & Co Inc | Hydroxylated pyridine derivatives,their preparation and pharmaceutical compositions containing them |
| US5484951A (en) * | 1990-10-19 | 1996-01-16 | Octamer, Incorporated | 5-iodo-6-amino-6-nitroso-1,2-benzopyrones useful as cytostatic and antiviral agents |
| WO1992018123A2 (en) * | 1991-04-10 | 1992-10-29 | Octamer, Inc. | A method for inhibition of retroviral replication |
| US5516941A (en) * | 1991-10-22 | 1996-05-14 | Octamer, Inc. | Specific inactivators of "retroviral" (asymmetric) zinc fingers |
| US5482975A (en) * | 1991-10-22 | 1996-01-09 | Octamer, Inc. | Adenosine diphosphoribose polymerase binding nitroso aromatic compounds useful as retroviral inactivating agents, anti-retroviral agents and anti-tumor agents |
| US5877185A (en) * | 1991-10-22 | 1999-03-02 | Octamer, Inc. | Synergistic compositions useful as anti-tumor agents |
| US5753674A (en) * | 1991-10-22 | 1998-05-19 | Octamer, Inc. | Adenosine diphosphoribose polymerase binding nitroso aromatic compounds useful as retroviral inactivating agents, anti-retroviral agents, anti-retroviral agents and anti-tumor agents |
| DE4136900C1 (en) * | 1991-11-09 | 1993-07-29 | Schaper & Bruemmer Gmbh & Co Kg, 3320 Salzgitter, De | |
| US5262564A (en) * | 1992-10-30 | 1993-11-16 | Octamer, Inc. | Sulfinic acid adducts of organo nitroso compounds useful as retroviral inactivating agents anti-retroviral agents and anti-tumor agents |
| ZA938019B (en) * | 1992-11-13 | 1995-04-28 | Upjohn Co | Pyran-2-ones and 5,6-dihydropyran-2-ones useful for treating HIV and other retroviruses |
| IL108459A0 (en) * | 1993-02-05 | 1994-04-12 | Opjohn Company | 4-Hydroxy-benzopyran-2-ones and 4-hydroxy-cycloalkyl [B] pyran-2-ones useful for treating infections due to hiv and other retroviruses |
| US5783599A (en) * | 1993-02-24 | 1998-07-21 | Octamer Inc | Methods of treating cancer and viral infections with 5-iodo-6-amino-and 5-iodo-6-nitroso-1 2-benzopyrones |
| US5637589A (en) * | 1993-10-29 | 1997-06-10 | University Of North Carolina At Chapel Hill | Suksdorfin, analogs, compositions thereof, and methods for making and using thereof |
| FI962021A7 (en) * | 1993-11-19 | 1996-07-12 | Parke Davis & Co | 5,6-dihydropyrone derivatives as protease inhibitors and antiviral agents |
| US5504104A (en) * | 1993-11-19 | 1996-04-02 | Warner-Lambert Company | Tricyclic pyrone derivatives as protease inhibitors and antiviral agents |
| US5840751A (en) * | 1993-11-19 | 1998-11-24 | Warner-Lambert Company | 5,6-dihydropyrone derivatives as protease inhibitors and antiviral agents |
| US6005103A (en) * | 1993-11-19 | 1999-12-21 | Warner-Lambert Company | Pyrone derivatives as protease inhibitors and antiviral agents |
| US5510375A (en) * | 1993-11-19 | 1996-04-23 | Warner-Lambert Company | Coumarin derivatives as protease inhibitors and antiviral agents |
| US6319929B1 (en) | 1994-04-29 | 2001-11-20 | The University Of North Carolina At Chapel Hill | Suksdorfin analogs, compositions thereof, and methods for making and using thereof |
| IL129871A (en) * | 1994-05-06 | 2003-11-23 | Pharmacia & Upjohn Inc | Process for preparing 4-phenyl-substituted octanoyl-oxazolidin-2-one intermediates that are useful for preparing pyran-2-ones useful for treating retroviral infections |
| US5455110A (en) * | 1994-06-29 | 1995-10-03 | Kimberly-Clark Corporation | Nonwoven laminated fabrics |
| CN1506359A (en) * | 2002-12-05 | 2004-06-23 | �й�ҽѧ��ѧԺҩ���о��� | Novel coumarin amide derivatives and its preparation method, its pharmaceutical composition and application |
| WO2006037468A1 (en) * | 2004-09-30 | 2006-04-13 | Istituto Di Ricerche Di Biologia Molecolare P Angeletti Spa | Hiv reverse transcriptase inhibitors |
| WO2007124617A1 (en) * | 2006-04-28 | 2007-11-08 | Institute Of Mataria Medica, Chinese Academy Of Medical Sciences | Coumarin derivatives, their preparation methods and their pharmaceutic compositions and uses |
| ATE541841T1 (en) | 2007-11-15 | 2012-02-15 | Boehringer Ingelheim Int | INHIBITORS OF REPLICATION OF THE HUMAN IMMUNODEFICIENCY VIRUS |
| EA019259B1 (en) | 2007-11-16 | 2014-02-28 | Джилид Сайенсиз, Инк. | Inhibitors of human immunodeficiency virus replication |
| CN113402491A (en) * | 2021-06-15 | 2021-09-17 | 山东大学苏州研究院 | Coumarin amide compound and preparation method and application thereof |
-
1989
- 1989-02-08 JP JP1503059A patent/JPH03503635A/en active Pending
- 1989-02-08 EP EP89903438A patent/EP0403535A1/en not_active Withdrawn
- 1989-02-08 WO PCT/US1989/000450 patent/WO1989007939A2/en not_active Ceased
- 1989-02-08 AU AU40747/89A patent/AU4074789A/en not_active Abandoned
-
1990
- 1990-08-16 DK DK195690A patent/DK195690D0/en not_active Application Discontinuation
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1997035565A1 (en) * | 1996-03-27 | 1997-10-02 | Toray Industries, Inc. | Ketone derivatives and medicinal use thereof |
| WO2005028441A1 (en) * | 2003-09-17 | 2005-03-31 | Sumitomo Chemical Company, Limited | Cinnamoyl derivatives and use thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| WO1989007939A3 (en) | 1989-10-19 |
| DK195690A (en) | 1990-08-16 |
| DK195690D0 (en) | 1990-08-16 |
| WO1989007939A2 (en) | 1989-09-08 |
| EP0403535A1 (en) | 1990-12-27 |
| AU4074789A (en) | 1989-09-22 |
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