WO2009094845A1 - Composés de 5-(3-phényl substitué par un cycle hétéroaromatique)tétrazole et leurs utilisations contre le vih/sida - Google Patents

Composés de 5-(3-phényl substitué par un cycle hétéroaromatique)tétrazole et leurs utilisations contre le vih/sida Download PDF

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WO2009094845A1
WO2009094845A1 PCT/CN2008/002105 CN2008002105W WO2009094845A1 WO 2009094845 A1 WO2009094845 A1 WO 2009094845A1 CN 2008002105 W CN2008002105 W CN 2008002105W WO 2009094845 A1 WO2009094845 A1 WO 2009094845A1
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phenyl
compound
halogen
alkoxy
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Lan Xie
Kun Liu
Ling HOU
Shibo Jiang
Hong Lu
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Institute Of Pharmacology And Toxicology Academy Of Military Medical Sciences P.L.A.
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
    • C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D257/04—Five-membered rings
    • 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
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/10—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • the present invention relates to 5-(3-aromatic heterocyclic phenyl)-tetrazole compounds, a process for the preparation thereof, pharmaceutical compositions containing same and their preparation for the treatment or prevention of diseases or conditions associated with HIV infection Application in medicine. Background technique
  • HIV is an RNA retrovirus that selectively infects cells with CD4 receptors on the surface of the body's immune system, such as lymphocytes, monocyte macrophages, and dendritic cells.
  • the surface of the virus is a double lipid membrane with two important glycoproteins: gpl20 and gp41, pl20 is on the outside of the membrane to identify the CD4 receptor on the cell surface; gp41 spans the viral membrane, and the main function is to fuse the virus.
  • the membrane and cell membrane which in turn release the core internal material of the virus into the host cytoplasm.
  • the viral membrane contains two single-stranded RNAs and some important enzymes (such as reverse transcriptase, proteolytic enzyme, integrase) and structural proteins (p24, pl7, p7, etc.). HIV cannot be propagated in vitro and must be reproduced by means of human cells.
  • the replication process is roughly divided into seven steps: virus binding, fusing, reverse transcript ion, integration (integration) ), transcr ipt ion, trans lat ion, and assembly & budding cells.
  • HIV is continuously replicated in such a cyclical process, infecting human immune cells, destroying the body's immune system, and ultimately leading to the complete loss of the body's immune function, causing patients to be in danger of various infections without resilience, thus causing more Infectious diseases and tumors eventually lead to death.
  • drugs can inhibit the virus and treat diseases as long as they block any part of the virus replication process. of.
  • HI V invading cells There are three main steps in the process of HI V invading cells: adhesion, binding to co-receptors, Membrane fusion.
  • the viral envelope glycoprotein gpl20 first binds to the CD4 molecule on the cell surface (Gallaher WR, Ball JM, Garry RF, et al. A general model for the surface glycoproteins of HIV and other retroviruses. AIDS Res Hum Retrovir, 1995, 11: 191 -202), the conformation changes and then binds to a co-receptor (chemokine such as CXCR4 or CCR5) (Dragic T, Litwin V, All away GP, et al.
  • chemokine such as CXCR4 or CCR5
  • HIV-1 entry into CD4+ cells is mediated by The cheraokine receptor CC-CKR-5. Na ture, 1996, 381: 667 73 ); Subsequently, gp41 was inserted into the cell membrane to form a 6-helix, and the viral membrane was brought close to the cell membrane to fuse it. In this process, gpl20 and gp41, CD4 receptors, and co-receptors are all considered potential drug targets. Among them, gp41 plays a vital role in the whole process of fusion.
  • the amino acid sequence of Gp41 has four functional regions.
  • the transmembrane domain (TM) at the C-terminus immobilizes gp41 on the viral membrane; the C-terminal heptad repeat (CHR) and NHI3 ⁇ 4 (N-terminal heptad repeat, NHR) are functional parts of the gp41 structure; Fus ion pept ide (FP) is a highly hydrophobic sequence at the N-terminus that is inserted into the host cell membrane (Mel iky an GB, Markosyan RM, Hemmati H, et al. Evidence that the transition of HIV-1 Gp41 into a six-helix bundle, not the bundle configuration, induces membrane fusion.
  • gpl20 on the surface of the virus binds to the CD4 receptor and co-receptor on the cell surface, and its conformation changes.
  • the NHR helix of gp41 extends from the center, and the N-terminal melt peptide is inserted into the cell membrane (Coleman CI, Musial BL and Ross J. Enfuvirtide: The first fusion inhibitor for the treatment of patients with HIV-1 infection. Formulary, 2003, 38: 204 222). Subsequently, NHR and CHR close together, re-forming a parallel six-element spiral beam.
  • This conformational change provides the energy needed to bring the viral envelope closer to the hydration surface of the host cell membrane, thereby bringing the viral membrane closer to the cell membrane and promoting fusion.
  • the two functional regions of gp41, NHR and CHR can be targets of HIV fusion inhibitors.
  • the first fusion inhibitor drug, T-20 (Fuzeon), approved by the US FDA, is a 36 amino acid peptide that mimics the CHR helical structural sequence.
  • T20 is a peptide drug, there are insufficient oral bioavailability and high production cost, so it is necessary to find a high-efficiency, low-toxic non-peptide small molecule HIV fusion inhibitor lead.
  • T20 is a peptide drug, there are insufficient oral bioavailability and high production cost, so it is necessary to find a high-efficiency, low-toxic non-peptide small molecule HIV fusion inhibitor lead.
  • Two aryl carboxylic acid-substituted azole-based small molecule compounds NB-2 and NB-64 (Jiang) through targeted activity screening of structurally diverse small molecule compound libraries Sh-B, Lu H, Liu Sh- , et al. N-Substituted Pyrrole Derivatives as Novel Human Immunodeficiency Virus Type 1 Entry Inhibitors That Interfere with the gp41 Six-Helix Bundle Formation and Block Virus Fusion.
  • the present invention relates to a compound of the formula I having a 5-substituted phenyl-tetrazole skeleton structure which is effective for inhibiting the formation of the HIV-1 surface glycoprotein gp41 hexamer, thereby inhibiting HIV replication.
  • An in-depth study of this class of compounds will likely lead to the discovery of novel non-peptide small molecule HIV fusion inhibitors that will become new anti-AIDS drugs.
  • One aspect of the invention relates to a tetrazolium aryl heterocyclic compound of formula I or a pharmaceutically acceptable salt thereof: among them,
  • R 2 - H, halogen, -N0 2 , —NH 2 , —leg, —N (R, ) 2 , —CN, —OH, d- 6 alkyl, d- 6 alkoxy, —CF 3 , -C00H, - S0 3 H, - C0NH 2 , -C0NHR' or -C00R';
  • Ar is a five-membered heteroaryl ring containing 1-3 hetero atoms selected from N, 0, S, selected from:
  • R 3 - CH0, COR', C00R, C00H, CF 3 , CH 2 R,, , halogen, 6 hydrocarbyl, 6 alkoxy, -NH 2 , -OH, -N0 2 , -CN, -HOCH- CN, - CH CH 2 ,
  • X and ⁇ are each independently selected from C, 0, S and ⁇ ;
  • R 4 -H, -CH 2 C00H, -CH 2 CH 2 C00H, -CH-CH- C00H, -CH 2 C00R' , - CH 2 CH 2 C00R, , -CH-CH- C00R, , d- 6 Hydrocarbyl group, phenyl group;
  • R 5 - H, halogen, -N0 2 , -NH 2 , - leg, - N (R, ) 2 , - CN, - 0H, hydrocarbyl, alkoxy, -CF 3 , CH0, - C00H, - S0 3 H, -C0NH 2 , -CONHR' or - C00R, ;
  • the above five-membered heteroaryl ring is optionally available at a ring position selected from the group consisting of an aldehyde group, a ketone group, an ester group, a carboxyl group, a cyano group, an ⁇ , an unsaturated ketone, an alkene, an alkyne, a d- 6 fluorenyl group, a substituent of alkoxy, halo, -NH 2 , -0H, -N0 2 and -CF 3 ;
  • R" is halogen, 0H or ( ⁇ alkoxy.
  • hydrocarbyl as used in the present invention includes alkyl, alkenyl and alkynyl groups.
  • the "lower heterocyclic group” referred to in the description of the substituent R 3 of the present invention includes, but is not limited to, 2,4-thiazolidinedione, 2-thio- 2,4-thiazolidinedione (circular tannin), Rhodanine ), succinimide, 2, 4 -imidazolidinone (hydantoin, hydantoin), 2-tuodihydantoin, pseudo-capinehydantoin (Pseudothiohydantoin) ) Wait.
  • a second aspect of the invention relates to a process for the preparation of a compound of formula I or a pharmaceutically acceptable salt thereof.
  • a third aspect of the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising at least one compound of formula I or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients.
  • Ar is a substituted pyrrole, as shown in formula II:
  • R 2 - H, halogen, -N0 2 , -NH 2 , - NHR, - N (R, ) 2 , - CN, -OH, d- 6 alkyl, alkoxy, -CF 3 , -C00H , -SO3H, -C0NH 2 , -C0NHR' or -C00R';
  • X and Y are each independently selected from C, 0, S and NH;
  • R 4 -H - CH 2 C00H, - CH 2 CH 2 COOH, - CH-CH-C00H, -CH 2 C00R' , - CH 2 CH 2 COOR, , - CH-CH- C00R, , Hydrocarbyl, Phenyl ;
  • R 5 - H, halogen, -N0 2 , - 2 , - leg, - N (R, ) 2 , - CN, -0H, d- 6 hydrocarbon, d- 6 alkoxy, -CF 3 , CH0, -C00H, -S0 3 H, -C0NH 2 , -CO wake up, or - C00R, ;
  • R 6 H, CH 3 , CF 3 , halogen or C 2 - 4 hydrocarbyl
  • R" is halogen, OH or ⁇ alkoxy.
  • Ar is 1,2,4-oxadiazole, as shown in the following formula III:
  • R 2 - H, halogen, -N0 2 , -NH 2 , - awake, -N (R, ) 2 , -CN, - 0H, d- 6 alkyl, d- 6 alkoxy, -CF 3 - C00H, - S0 3 H, - C0NH 2 , -CO leg, or -C00R';
  • X and Y are each independently selected from C, 0, S and NH;
  • R 5 HH, halogen, -N0 2 , -NH 2 , -NHR' , —N (R, ) 2 , —CN, —OH , d- 6 hydrocarbon, d— ⁇ alkoxy, —CF 3 , CH0 , ⁇ C00H, - S0 3 H, -C0NH 2 , -CONHR' or a C00R, ;
  • R' d- 6 hydrocarbyl
  • R" is halogen, OH or ( ⁇ 6 alkoxy.
  • Ar is a 5-substituted furan, as shown in the following formula IV:
  • X and Y are each independently selected from C, 0, S and NH;
  • R" is halogen, OH or 6 alkoxy.
  • the following compounds are more preferred in the present invention:
  • Route D For compounds in which Formula Ar is a five-membered heterocyclic ring (eg, pyrrole, furan, etc.) aldehyde:
  • Reaction conditions (vi) Suzuki coupling reaction, organoboric acid reagent, palladium catalyst; (vi i) condensation reaction (with ketone reagents shown or related in the figure), basic conditions: organic amine, strong inorganic base or weak acid Alkaline salt, methanol, ethanol, acetic acid, DMF or a mixed solvent of DMF and water, room temperature - 160 o C, 1-44 hours.
  • Ar, R!-R 4 , R 6 and X, Y in the above reaction scheme are as defined in the above formula I, and U, V and W each independently represent a hetero atom selected from N, 0, S or carbon. atom. Specifically,
  • Synthetic Route A The tetracycline ring can be synthesized by the action of the substituted phenyl cyanide compound (A) and sodium azide to obtain the target compound 1-1.
  • the nitrogen atom at the nitrogen position on the tetrazole ring reacts with the halogenated hydrocarbon.
  • Compound 1-2 can be obtained.
  • Scheme B Substituted 5-(3-amino)phenyl-tetrazolium (B) with 2, 5- Dimethoxytetrahydrofuran or ⁇ -substituted 1,4-butanone can be subjected to a 3 ⁇ 4orr reaction to obtain an arylpyrrole compound ( ⁇ -1), which is then reacted with a halogenated hydrocarbon to form a 1-substituted ⁇ tetrazole- Arylpyrroles ( ⁇ -2).
  • Synthetic route C using substituted 5-(3-cyano)phenyl-tetrazole (C) as a raw material, reacting with a few amines of hydrochloric acid to form an aminoguanidine intermediate (D), and then reacting with an acylating reagent to obtain 3 - aryl-1,2,4-oxadiazole compound ( ⁇ ⁇ -1 ), followed by halogenation of nitrogen to obtain the target compound 111-2.
  • non-peptide small molecule fusion inhibitors They act on HIV-1 gp41 and are expected to develop into a new class of anti-HIV drugs with specific targets: non-peptide small molecule fusion inhibitors.
  • the inhibitory activity of wild type HIV in the test was EC 5. The value was 7.70 ⁇ (SI>32), and it inhibited the replication of clinically isolated multiple types of HIV virus forests.
  • Known active compound NB-64 See the activity data of some related compounds. 1-2.
  • a compound represented by Il-la is a novel anti-HIV active compound having a broad antiviral spectrum which acts on the HIV-1 gp41 target, and can be developed into a non-peptide small molecule anti-peptide.
  • Inhibitors of HIV Fusion The compounds of the invention may be used either as such or in the form of pharmaceutically acceptable salts or solvates thereof.
  • the pharmaceutically acceptable salts of the compounds of formula I include pharmaceutically acceptable mineral acids Or an organic acid, or an inorganic base or a conventional salt formed by organic reduction.
  • suitable acid addition salts include with hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, perchloric acid, fumaric acid, acetic acid, propionic acid, succinic acid, glycolic acid, citric acid, lactic acid, maleic acid, Tartaric acid, citric acid, citric acid, malonic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, naphthalene-2-sulfonic acid, a salt formed from benzenesulfonic acid, hydroxynaphthoic acid, hydroiodic acid, malic acid, citric acid or the like.
  • Suitable base addition salts include sodium, lithium, potassium, magnesium, aluminum, calcium, zinc, N,N,-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, B. a salt formed by a diamine, N-methylglucamine, and procaine.
  • the compound of the formula I of the present invention can be combined with a conventional pharmaceutical carrier or excipient to constitute a pharmaceutical composition.
  • the pharmaceutical composition can be administered orally or parenterally.
  • the pharmaceutical composition of the present invention can be prepared into various dosage forms including, but not limited to, tablets, capsules, solutions, suspensions, granules or injections, by a conventional method in the art, orally or parenterally.
  • the dosage and method of use of the compounds of the invention depend on a number of factors, including the age, weight, sex, natural health, nutritional status of the compound, the strength of the compound, the time of administration, the rate of metabolism, the severity of the condition, and the diagnosis and treatment. Subjective judgment of the physician.
  • the preferred dosage is between 0.01 and 100 mg/kg body weight per day. . detailed description
  • Example 7 1-Ethoxycarbonylmethyl-5-(3-(3-ethoxycarbonyl-2,5-dimethyl- 1 ⁇ pyrrole-1-yl)phenyl)-1 ⁇ tetrazole (II- 2c) (Synthesis Route A or B) Add sodium ethoxide (61 mg, 0.9 mmol) and methyl bromoacetate (0.06 mL, 0.6 mmol) to a solution of II-Id (93 mg, 0.3 mmol) in ethanol (5 mL) The reaction was refluxed for 4 hours.
  • Trifluoroacetic anhydride (0.21 mL, 1.5 mmol) was added to EtOAc (3 mL)EtOAc.
  • III-lb (76 mg, 0.29 mmol) was reacted in a 10% aqueous NaOH solution (2 mL) at room temperature for 1.5 hr.
  • the ELISA plate was coated with HIVIG (2 g/mL), blocked with 1% fat-free milk, added to the virus lysate, and incubated for 60 minutes at 37 °C. After extensive washing, anti-p24 monoclonal antibody-183-12H-5C, biotinylated goat anti-mouse antibody and avidin-labeled horseradish peroxidase were added. The color density was then measured at 450 nm using TMB color development. Calculated with CalcuSyn software compound virus half inhibition concentration (EC 50). Table 1. Inhibition of HIV replication and target molecule a
  • the compound of the formula I of the present invention is a non-peptide small molecule inhibitor having a novel skeleton structure and acting on HIV-1 gp41. They can effectively inhibit the formation of HIV-1 gp41 six-helix bundle (6-HB), thereby inhibiting HIV replication. These compounds also have inhibitory activity against clinically isolated multi-type HIV strains and have a broad spectrum of antiviral.
  • the compounds of the present invention are expected to develop into a new class of anti-HIV drugs: non-peptide small molecule HIV-1 fusion inhibitors targeting gp41.

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Abstract

La présente invention concerne des composés de 5-(3-phényl substitué par un cycle hétéroaromatique) tétrazole de formule (I), leurs sels pharmaceutiquement acceptables, où les substituants sont tels que définis dans les revendications. L'invention a également pour objet leurs procédés de préparation, des compositions pharmaceutiques les renfermant et leurs utilisations médicales dans la fabrication d'un médicament en vue d'une utilisation dans le traitement ou la prophylaxie d'une maladie ou d'un trouble concernant une infection à VIH.
PCT/CN2008/002105 2007-12-28 2008-12-29 Composés de 5-(3-phényl substitué par un cycle hétéroaromatique)tétrazole et leurs utilisations contre le vih/sida WO2009094845A1 (fr)

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CN101775011B (zh) * 2009-01-13 2013-07-31 中国人民解放军军事医学科学院毒物药物研究所 N-取代苯基-3-甲烯杂环芳烃-2,5-二甲基吡咯类化合物及其抗hiv/aids的应用
WO2017076740A1 (fr) 2015-11-04 2017-05-11 Basf Se Utilisation d'oxadiazoles substitués pour lutter contre les champignons phytopathogènes
BR112018009539B1 (pt) 2015-11-13 2022-05-24 Basf Se Uso de compostos da fórmula i, compostos, mistura, composição agroquímica, uso dos compostos e método para combater fungos nocivos fitopatogênicos
AR106679A1 (es) 2015-11-13 2018-02-07 Basf Se Oxadiazoles sustituidos para combatir hongos fitopatógenos
BR112018008449B1 (pt) 2015-11-19 2021-07-06 Basf Se Compostos de fórmula i, mistura, composição agroquímica e método para combater fungos nocivos fitopatogênicos
AU2017250397A1 (en) 2016-04-11 2018-10-11 Basf Se Substituted oxadiazoles for combating phytopathogenic fungi

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CN1764659A (zh) * 2003-03-26 2006-04-26 麦克弗罗斯特加拿大有限公司 作为ep4受体拮抗剂的前列腺素类似物
JP2005225819A (ja) * 2004-02-13 2005-08-25 Orient Chem Ind Ltd ピロール環を有するアゾール化合物およびその製造方法
WO2005118575A1 (fr) * 2004-06-01 2005-12-15 Boehringer Ingelheim International Gmbh Inhibiteurs non nucléosidiques de la transcriptase inverse

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