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WO2009003307A1 - Dérivés de phtiobuzonum et préparation, composition pharmaceutique et utilisation de ceux-ci - Google Patents

Dérivés de phtiobuzonum et préparation, composition pharmaceutique et utilisation de ceux-ci Download PDF

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Publication number
WO2009003307A1
WO2009003307A1 PCT/CN2007/002034 CN2007002034W WO2009003307A1 WO 2009003307 A1 WO2009003307 A1 WO 2009003307A1 CN 2007002034 W CN2007002034 W CN 2007002034W WO 2009003307 A1 WO2009003307 A1 WO 2009003307A1
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WIPO (PCT)
Prior art keywords
chlorophenyl
fluorophenyl
group
phthalimide
oxo
Prior art date
Application number
PCT/CN2007/002034
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English (en)
Chinese (zh)
Inventor
Xiandao Pan
Jinghua Zhao
Yajun Yang
Original Assignee
Beijing Union Pharmaceutical Factory
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Beijing Union Pharmaceutical Factory filed Critical Beijing Union Pharmaceutical Factory
Priority to PCT/CN2007/002034 priority Critical patent/WO2009003307A1/fr
Publication of WO2009003307A1 publication Critical patent/WO2009003307A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C337/00—Derivatives of thiocarbonic acids containing functional groups covered by groups C07C333/00 or C07C335/00 in which at least one nitrogen atom of these functional groups is further bound to another nitrogen atom not being part of a nitro or nitroso group
    • C07C337/06—Compounds containing any of the groups, e.g. thiosemicarbazides
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
    • C07D209/48—Iso-indoles; Hydrogenated iso-indoles with oxygen atoms in positions 1 and 3, e.g. phthalimide
    • 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 a novel class of agmatine derivatives, a process for their preparation, pharmaceutical compositions containing them, and their use as medicaments, especially as antiviral drugs. Background technique
  • TDA is a bis-thiosemicarbazone compound
  • chemical name is 3-phthalimide -2-oxo-n-butyraldehyde bis-semicarbazone, and its structure is shown in Figure 1.
  • ⁇ has a significant inhibitory effect on the replication of herpes simplex virus type I (HSV-1) and type II (HSV-2) in tissue culture cells, and local administration of ⁇ preparation can prevent guinea pig HSV- I cell lesions.
  • Clinical trials have shown that ⁇ has a good effect on the skin diseases of herpes simplex and herpes zoster virus and the virulence-transmitted disease caused by human papillomavirus-condyloma acuminata (genital warts). In October 1984, it was the first antiviral chemotherapeutic drug created in China. Later, in order to solve the problem of water solubility and improve the curative effect of ⁇ , further structural modification was carried out, and various ⁇ derivatives were synthesized. Summary of the invention
  • Another object of the present invention is to provide a process for preparing a novel agmatine derivative
  • Another object of the present invention is to provide a novel butyl butyl derivative and a composition thereof as a pharmaceutical application; one aspect of the present invention relates to a pharmaceutical composition comprising the general formula (I), ( ⁇ ), ⁇ as an active ingredient , (iv), (V) (VI), and optical isomers thereof, and carriers commonly used in the pharmaceutical field.
  • the present invention relates to a compound of the formula (I)
  • Preferred halogens are selected from the group consisting of fluorine, chlorine, and bromine;
  • Preferred aryl groups are selected from phenyl
  • Preferred substituents on the phenyl group are: .5 fluorenyl, fluoro, chloro, bromo, trifluoromethyl, amino;
  • d- 5 alkyl allyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 5-fluorophenyl, 6-fluorophenyl, 3, 4-difluorophenyl, 3,5-difluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 5-chlorophenyl, 6-chlorophenyl, 3,4- Dichlorophenyl, 3,5-dichlorophenyl, 2-fluoro-4-chlorophenyl, 3-fluoro-4-chlorophenyl,
  • the most preferred compound of (I) is selected from:
  • Preferred halogens are selected from the group consisting of fluorine, chlorine, and bromine;
  • Preferred aryl groups are selected from phenyl
  • Preferred substituents on the phenyl group are: C 1-5 fluorenyl, fluoro, chloro, bromo, trifluoromethyl, amino;
  • R 2 independently selected from C 1-5 alkyl, allyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 5-fluorophenyl, 6-fluoro Phenyl, 3,4-difluorophenyl, 3,5-difluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 5-chlorophenyl, 6-chlorophenyl , 3,4-dichlorophenyl, 3,5-dichlorophenyl, 2-fluoro-4-chlorophenyl, 3-fluoro-4-chlorophenyl,
  • the most preferred ( ⁇ ) compound is selected from:
  • R 3 is selected from the group consisting of: hydrogen, halogen, -5 fluorenyl, Q.5 decyloxy, halo d. 5 alkyl, hydroxy, d- 5 fluorenyl C00, cyano, aldehyde, nitro, amino, carboxy, Acylhydrazino, C 1:5 alkyl alkoxycarbonyl, d- 5 decyloxycarbonylamino, d. 5 alkylalkylaminomethyl.
  • R 3 is selected from the group consisting of: C M decyl, C M alkoxy, fluorine, chlorine, bromine.
  • R 3 is selected from the group consisting of: C w thiol, fluorine, chlorine, bromine.
  • the most preferred compound (III) is selected from
  • C M alkyl More preferably selected from the group consisting of: C M alkyl, C 14 alkoxy, fluorine, chlorine, bromine. More preferably selected from the group consisting of: C M alkyl, fluorine, chlorine, .3,5-bistrifluoromethyl.
  • the most preferred compound (IV) is selected from:
  • R5 is selected from the group consisting of hydroxy, -8 alkyl, haloQ-8 fluorenyl, aryl substituted -8 alkyl, allyl, Q- 8 alkyl substituted aryl, monohalogenated or polyhalogenated aryl, halogenated -8 alkyl substituted aryl, amino substituted aryl, ammonia. ⁇ alkyl substituted aryl;
  • Preferred R5 is selected from the group consisting of hydroxyl, decyl, allyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 5-fluorophenyl, 6-fluorophenyl, 3,4-difluoro Phenyl, 3,5-difluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 5-chlorophenyl, 6-chlorophenyl, 3,4-dichlorophenyl , 3,5-dichlorophenyl, 2-fluoro-4-chlorophenyl, 3-fluoro-4-chlorophenyl, 4-fluoro-4-chlorophenyl, 5-fluoro-4-chlorophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 5-bromophenyl, 6-bromophenyl, 3,4-dibromophenyl
  • the most preferred compound (V) is selected from:
  • d- 8 fluorenyl halogenated C r8 alkyl, aryl substituted alkyl, allyl, d- 8 alkyl substituted aryl, monohalogenated or polyhalogenated aromatic a halogenated d- 8 alkyl substituted aryl group, an amino substituted aryl group, an amino Cr8 alkyl substituted aryl group;
  • Preferred halogens are selected from the group consisting of fluorine, chlorine, and bromine;
  • Preferred aryl groups are selected from phenyl
  • Preferred substituents on the phenyl group are: Cw alkyl, fluoro, chloro, bromo, trifluoromethyl, amino;
  • Re is selected from the group consisting of hydrogen, halogen, lower alkyl, lower alkoxy, halogenated lower alkyl, hydroxy, RCOO, cyano, aldehyde, nitro, amino, carboxy, hydrazide, lower methoxycarbonyl, lower alkane Oxycarbonylamino, lower alkylaminomethyl.
  • the invention also provides methods of preparing the compounds of the invention.
  • Methyl ketone (compound 0-1) and bromoketone (compound 0-2) are intermediates of acetonide, which are intermediates obtained in the synthesis of butyl butyl hydride. Their preparation can be synthesized by reference to literature methods.
  • Anthracene intermediate (compound 0-1 or 0-2) is oxidized with dimethyl sulfoxide (DMSO) or selenium dioxide (Se(3 ⁇ 4) to give an oxidation product (1,2-dicarbonyl compound, compound 0-1) ).
  • DMSO dimethyl sulfoxide
  • Se(3 ⁇ 4) selenium dioxide
  • the oxidation product of the butyl butyl intermediate (compound 0-3) is prepared by condensation of the corresponding substituted thiosemicarbazide.
  • Solvent ⁇ R ⁇ -Rr-thiosemicarbazide is dissolved in water, ethanol, ethanol and water, and can be heated to facilitate dissolution;
  • Reaction temperature may be a temperature from room temperature to reflux of the solvent, preferably a temperature at which the solvent is refluxed;
  • Reaction time 0.5-8 hours, preferably 1-4 hours, most preferably 2 hours, gradually forming a precipitate during the reaction;
  • Post-treatment After the reaction is completed, the reflux is stopped, and the mixture is cooled. Optionally, an appropriate amount of water can be added, and the mixture is filtered to obtain a crude product.
  • the refining of the crude product can be carried out by a conventional method. For example, washing with a solvent to remove impurities, preferably washing and dissolving
  • the agent is selected from the group consisting of chloroform, absolute ethanol, water, dichloromethane, chloroform, and methanol.
  • the crude product is dissolved in a small amount of chloroform, and subjected to silica gel column chromatography, eluting with different gradients of chloroform and ethyl acetate, petroleum ether and ethyl acetate.
  • the main spot is collected, concentrated, and dried to obtain the desired product. .
  • It can also be refined by recrystallization, for example, the crude product is recrystallized from 95% ethanol.
  • the oxidation product of the butyl butyl intermediate (compound 0-3) and the corresponding substituted thiosemicarbazide are prepared by condensation.
  • Solvent 4- -4-,-thiosemicarbazide is dissolved in water, ethanol, ethanol and water, and can be heated to facilitate dissolution;
  • Reaction temperature It may be a temperature from room temperature to reflux of the solvent, preferably a temperature at which the solvent is refluxed.
  • Reaction time 0.5-8 hours, preferably 1-4 hours, most preferably 2 hours, gradually forming a precipitate during the reaction;
  • Post-treatment After the reaction is completed, the reflux is stopped, and the mixture is cooled. Optionally, an appropriate amount of water can be added and filtered to obtain a crude product.
  • the refining of the crude product can be carried out by a conventional method.
  • the impurities are washed with a solvent, and the preferred lacquer solvent is selected from the group consisting of chloroform, absolute ethanol, water, dichloromethane, chloroform, and methanol.
  • use column chromatography The crude product is dissolved in a small amount of chloroform, and subjected to silica gel column chromatography, eluting with a gradient of chloroform and ethyl acetate, petroleum ether and ethyl acetate. The main spot is collected, concentrated, and dried to give the desired product. It can also be refined by recrystallization, for example, the crude product is recrystallized from 95% ethanol.
  • the bromoketone (compound 0-2) and the substituted amine are obtained by thiolation.
  • the reaction is preferably carried out under basic conditions, preferably Providing alkaline conditions with NaHC0 3 ;
  • Solvent The preferred solvent is ethanol;
  • Reaction temperature may be a temperature from room temperature to reflux of the solvent, preferably a temperature at which the solvent is refluxed;
  • the reaction time is 2 to 24 hours, preferably 4 to 8 hours, and most preferably 6 hours, and a precipitate is gradually formed during the reaction. After stopping heating, stir overnight;
  • Post-treatment The crude product was dissolved in a small amount of acetone, and subjected to silica gel column chromatography, eluting with a gradient of petroleum ether and acetone, petroleum ether and ethyl acetate. The main spot was collected, concentrated, and dried to give the desired product.
  • the bromoketone (compound 0-2) and the substituted amine are obtained by thiolation.
  • the reaction is preferably carried out under basic conditions, preferably basic conditions to provide with NaHC0 3; preferably carried out in the presence of KI;
  • the preferred solvent is acetonitrile
  • Reaction temperature may be room temperature to the reflux temperature of the solvent, and the preferred temperature is room temperature
  • Reaction time 1-4 hours, preferably 2-3 hours;
  • the cyclization reaction was carried out using ⁇ as a raw material.
  • the reaction is preferably carried out under basic conditions, preferably with NaOAc to provide basic conditions;
  • Solvent The preferred solvent is ethanol;
  • Reaction temperature may be room temperature to the reflux temperature of the solvent, the preferred temperature is the temperature at which the solvent is refluxed; reaction time: 5-12 hours, preferably 7-9 hours;
  • Compound 19' is an enol form and its stable structure is a compound 19.
  • the compound or the compound (1) is opened under the condition of hydrazine hydrate, and the substituent is obtained.
  • the preferred solvent is methanol
  • Reaction temperature may be room temperature to the reflux temperature of the solvent, and the preferred temperature is room temperature
  • Reaction time 0.5-4 hours, preferably 1-2 hours;
  • the crude product can be refined using conventional methods.
  • the impurities are washed away with a solvent, and the preferred washing solvent is selected from the group consisting of chloroform, absolute ethanol, water, dichloromethane, chloroform, and methanol.
  • the invention therefore also relates to a pharmaceutical composition comprising the compound of the invention as an active ingredient.
  • the pharmaceutical composition can be prepared according to methods well known in the art. Any dosage form suitable for human or animal use can be prepared by combining a compound of the invention with one or more pharmaceutically acceptable solid or liquid excipients and/or adjuvants.
  • the content of the compound of the present invention in its pharmaceutical composition is usually from 0,1 to 95% by weight.
  • the compound of the present invention or a pharmaceutical composition containing the same may be administered in a unit dosage form, which may be enterally or parenterally, such as oral, intravenous, intramuscular, subcutaneous, nasal, oral mucosa, eye, 'lung And the respiratory tract, skin, vagina, rectum, etc.
  • the dosage form can be a liquid dosage form, a solid dosage form or a semi-solid dosage form.
  • Liquid dosage forms can be solutions (including true and colloidal solutions), emulsions (including o/w type, w/o type and double emulsion), suspensions, injections (including water injections, powder injections and infusions), eye drops Agents, nasal drops, lotions, tinctures, etc.; solid dosage forms may be tablets (including plain tablets, enteric tablets, tablets, dispersible tablets, chewable tablets, effervescent tablets, orally disintegrating tablets), capsules ( Including hard capsules, soft capsules, enteric capsules), granules, powders, pellets, dropping pills, suppositories, films, patches, gas (powder) sprays, sprays, etc.; semi-solid dosage forms can be ointments, Gel, paste, etc.
  • the compounds of the present invention can be formulated into common preparations, as sustained release preparations, controlled release preparations, targeted preparations, and various microparticle delivery systems.
  • the diluent may be starch, dextrin, sucrose, glucose, lactose, mannitol, sorbitol, xylitol, microcrystalline cellulose, calcium sulfate, calcium hydrogen phosphate, calcium carbonate, etc.
  • the humectant may be water, ethanol, or different Propyl alcohol, etc.
  • the binder may be starch pulp, dextrin, sugarwood, honey, glucose solution, microcrystalline cellulose, gum arabic, gelatin, sodium carboxymethylcellulose, methylcellulose, hydroxypropyl Methyl cellulose, ethyl cellulose, acrylic resin, carbomer, polyvinylpyrrolidone, polyethylene glycol, etc.
  • disintegrant can be dry starch, microcrystalline cellulose
  • Tablets may also be further formulated into coated tablets, such as sugar coated tablets, film coated tablets, enteric coated tablets, or bilayer tablets and multilayer tablets.
  • the active ingredient compound of the present invention may be mixed with a diluent, a glidant, and the mixture may be directly placed in a hard capsule or a soft capsule.
  • the active ingredient can also be formulated into a granule or pellet with a diluent, a binder, a disintegrant, and then placed in a hard or soft capsule.
  • a variety of diluents, binders, wetting agents, disintegrants, glidants useful in the preparation of tablets of the compounds of the invention are also useful in the preparation of capsules of the compounds of the invention.
  • water, ethanol, isopropanol, propylene glycol or a mixture thereof may be used as a solvent, and an appropriate amount of a solubilizing agent, a solubilizing agent, a pH adjusting agent, and an osmotic pressure adjusting agent which are commonly used in the art may be added.
  • the solubilizer or co-solvent may be poloxamer, lecithin, hydroxypropyl- ⁇ -cyclodextrin, etc.; the pH adjusting agent may be phosphate, acetate, hydrochloric acid, sodium hydroxide, etc.; osmotic pressure regulator may It is sodium chloride, mannitol, glucose, phosphate, acetate, and the like.
  • mannitol, glucose or the like may also be added as a proppant.
  • coloring agents may also be added to the pharmaceutical preparations as needed.
  • the pharmaceutical or pharmaceutical composition of the present invention can be administered by any known administration method for the purpose of administration and enhancing the therapeutic effect.
  • the pharmaceutical composition of the present invention can be administered in a wide range of dosages depending on the nature and severity of the disease to be prevented or treated, the individual condition of the patient or animal, the route of administration and the dosage form, and the like.
  • a suitable daily dose of the compound of the present invention is from 0.001 to 150 mg/kg body weight, preferably from 0.1 to 100 mg/kg body weight, more preferably from ⁇ -100 mg/kg body weight.
  • the above dosages may be administered in one dosage unit or in divided dose units depending on the clinical experience of the physician and the dosage regimen including the use of other therapeutic means.
  • the compounds or compositions of the invention may be administered alone or in combination with other therapeutic or symptomatic agents.
  • the compound of the present invention synergizes with other therapeutic agents, its dosage should be adjusted according to the actual situation.
  • the compounds of the invention are treated by a suitable method of administration such as oral, parenteral administration such as IP, IV or topical treatment of the virus.
  • Viral infections include herpes simplex viruses type I and type II, herpes zoster virus, trachoma virus, condyloma acuminata, flat warts and other viral diseases.
  • 0.296 g (1.0 mmol) of 3-phthalimide-1-bromobutanone was dissolved in 1.5 mL of DMSO and allowed to stand at 30 ° C for 2 days, and the reaction solution gradually turned yellow.
  • 0.266 g (2.0 mmol) of 4-isopropyl-3-aminothiourea is dissolved in 1.5 mL of 80 ° C hot water, added to the solution A. After heating under reflux for 1 hour, a precipitate gradually formed. The reflux was quenched, cooled, and 25 mL of water was added and filtered.
  • Vero cells African green monkey kidney This room is subcultured by itself.
  • HSV-1 VR733
  • HSV-2 SAV
  • the virus solution After adsorption for 1-1.5 hours, the virus solution is discarded, and the culture solution containing the diluted drug at different concentrations is added, and the virus control group is set at 37 ° C, The cells were cultured in a 5% C0 2 incubator. When the virus control group reached 4 plus signs, the cell lesions were observed. Three wells of the cell control wells were set in each experiment. The results were calculated using the Reed-Muench method to calculate the half effective concentration IC 5 o.
  • Formulation amount 0.1g10g, 0.05g/10g, 0.025g/10gc
  • Formulation amount 0.1 g/10 g.
  • Formulation amount 0.1 g/10 g. .
  • Type 3.2.1 Vero cell line.
  • HSV-1 type quality control strain Sm44 strain.
  • Type 2.1 In vivo test.
  • Concentration group Set 3 concentration groups, namely O.lg/lOg (large concentration) group, 0.05g/10g (medium concentration) group-,: 0.025g/10g (small concentration) group.
  • test was set up as a matrix control group, and the application method was the same as that of the test drug group.
  • Concentration group Test setting One concentration group was used as a control, both of which were 0.1g/10g group.
  • Vero cells were used for routine culture in vitro, and obtained after 23 hours of exposure.
  • the TCID50 was measured to be 6.02.
  • the cream matrix group and the virus model control group, the 4-F-TDA cream large, medium and small concentration groups and the matrix group, respectively, were determined by Ridit analysis.
  • An ointment group and virus model control group, acyclovir gel and virus model control group, 4-F-TDA cream large, medium and small concentration group and Qidingan ointment group were compared.
  • control drug Ding'an ointment group did not show protective effect on skin lesions caused by HSV-1, and there was no significant difference (>ftO?) compared with the virus model control group.
  • the inhibitory effect of the acyclovir gel group was significantly different from that of the virus model (control group) (P ⁇ 0.01).
  • the concentration of the 4-C1-TDA cream group was significantly different from that of the Dingding ointment group ( ⁇ ( ⁇ ? and ? ⁇ 0.05), while the concentration was small. There is no difference in the group.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Communicable Diseases (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Virology (AREA)
  • Oncology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Indole Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne de nouveaux dérivés de phtiobuzonum, leur préparation, une composition pharmaceutique les comprenant et leur utilisation comme médicaments, en particulier comme médicaments antiviraux.
PCT/CN2007/002034 2007-06-29 2007-06-29 Dérivés de phtiobuzonum et préparation, composition pharmaceutique et utilisation de ceux-ci WO2009003307A1 (fr)

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PCT/CN2007/002034 WO2009003307A1 (fr) 2007-06-29 2007-06-29 Dérivés de phtiobuzonum et préparation, composition pharmaceutique et utilisation de ceux-ci

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102786464A (zh) * 2011-05-20 2012-11-21 北京协和药厂 酞丁安衍生物及其制备方法和用途
CN104557666A (zh) * 2015-01-16 2015-04-29 烟台贝森医药科技有限公司 一种合成3-酞酰亚胺-2-氧代丁醛-1,2-双缩氨基硫脲的新方法

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1990470A (zh) * 2005-12-30 2007-07-04 北京协和药厂 酞丁安衍生物及其制法和其药物组合物与用途

Patent Citations (1)

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Publication number Priority date Publication date Assignee Title
CN1990470A (zh) * 2005-12-30 2007-07-04 北京协和药厂 酞丁安衍生物及其制法和其药物组合物与用途

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HADACEK J. AND SLOUKA J.: "The applicability of the Wolff-lindenhayn method in the chemistry of asymmetric triazines", SPISY PRIRODOVEDECKE FAK. UNIV. BRNE, 1959, pages 15 - 22 *
WANG L., YANG H.M., ZHAO Z.Z.: "Studies on Antiviral Agents: Synthesis of TAI-DING-AN Analogs", ACTA PHARMACEUTICA SINICA, vol. 29, no. 6, 1994, pages 427 - 432, XP000566899 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102786464A (zh) * 2011-05-20 2012-11-21 北京协和药厂 酞丁安衍生物及其制备方法和用途
CN102786464B (zh) * 2011-05-20 2016-05-11 北京协和药厂 酞丁安衍生物及其制备方法和用途
CN104557666A (zh) * 2015-01-16 2015-04-29 烟台贝森医药科技有限公司 一种合成3-酞酰亚胺-2-氧代丁醛-1,2-双缩氨基硫脲的新方法

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