CN1346827A - 1,2,3-thiadiazole compounds, and their preparing process and bioactivity - Google Patents
1,2,3-thiadiazole compounds, and their preparing process and bioactivity Download PDFInfo
- Publication number
- CN1346827A CN1346827A CN 01136684 CN01136684A CN1346827A CN 1346827 A CN1346827 A CN 1346827A CN 01136684 CN01136684 CN 01136684 CN 01136684 A CN01136684 A CN 01136684A CN 1346827 A CN1346827 A CN 1346827A
- Authority
- CN
- China
- Prior art keywords
- compound
- substituted
- thiadiazole
- solvent
- alkyl
- 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.)
- Granted
Links
- UGUHFDPGDQDVGX-UHFFFAOYSA-N 1,2,3-thiadiazole Chemical class C1=CSN=N1 UGUHFDPGDQDVGX-UHFFFAOYSA-N 0.000 title claims abstract description 7
- 238000000034 method Methods 0.000 title claims description 11
- 241000700605 Viruses Species 0.000 claims abstract description 21
- 208000002672 hepatitis B Diseases 0.000 claims abstract description 7
- 238000004519 manufacturing process Methods 0.000 claims abstract description 6
- 150000001875 compounds Chemical class 0.000 claims description 66
- 239000007787 solid Substances 0.000 claims description 51
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 33
- -1 1, 2, 3-thiadiazole compound Chemical class 0.000 claims description 29
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 26
- 239000002904 solvent Substances 0.000 claims description 23
- 238000003756 stirring Methods 0.000 claims description 23
- 229910052717 sulfur Inorganic materials 0.000 claims description 19
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 18
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 18
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 18
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 18
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 16
- 241000196324 Embryophyta Species 0.000 claims description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 15
- 238000006243 chemical reaction Methods 0.000 claims description 15
- 229910052757 nitrogen Inorganic materials 0.000 claims description 15
- 125000000217 alkyl group Chemical group 0.000 claims description 14
- 229910052739 hydrogen Inorganic materials 0.000 claims description 13
- 239000001257 hydrogen Substances 0.000 claims description 13
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 12
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 12
- 125000003118 aryl group Chemical group 0.000 claims description 11
- 238000001704 evaporation Methods 0.000 claims description 11
- 238000000967 suction filtration Methods 0.000 claims description 11
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 9
- 125000003545 alkoxy group Chemical group 0.000 claims description 9
- 125000003282 alkyl amino group Chemical group 0.000 claims description 9
- 229910052760 oxygen Inorganic materials 0.000 claims description 9
- 238000011282 treatment Methods 0.000 claims description 9
- 125000004070 6 membered heterocyclic group Chemical group 0.000 claims description 8
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 8
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 8
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 8
- 125000003107 substituted aryl group Chemical group 0.000 claims description 8
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims description 7
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 7
- 125000004104 aryloxy group Chemical group 0.000 claims description 7
- 238000010438 heat treatment Methods 0.000 claims description 7
- 150000004982 aromatic amines Chemical class 0.000 claims description 6
- 239000003960 organic solvent Substances 0.000 claims description 6
- 238000002360 preparation method Methods 0.000 claims description 6
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical group [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 5
- 125000000623 heterocyclic group Chemical group 0.000 claims description 5
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 claims description 4
- 235000002637 Nicotiana tabacum Nutrition 0.000 claims description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 4
- POLCUAVZOMRGSN-UHFFFAOYSA-N dipropyl ether Chemical compound CCCOCCC POLCUAVZOMRGSN-UHFFFAOYSA-N 0.000 claims description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
- 238000002386 leaching Methods 0.000 claims description 4
- 239000000203 mixture Substances 0.000 claims description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 4
- 239000000741 silica gel Substances 0.000 claims description 4
- 229910002027 silica gel Inorganic materials 0.000 claims description 4
- 241000208125 Nicotiana Species 0.000 claims description 3
- 239000003513 alkali Substances 0.000 claims description 3
- 239000007864 aqueous solution Substances 0.000 claims description 3
- 239000002585 base Substances 0.000 claims description 3
- 239000007800 oxidant agent Substances 0.000 claims description 3
- UIIMBOGNXHQVGW-UHFFFAOYSA-M sodium bicarbonate Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 3
- RAHZWNYVWXNFOC-UHFFFAOYSA-N sulfur dioxide Inorganic materials O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 claims description 3
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical group NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims description 2
- 125000004414 alkyl thio group Chemical group 0.000 claims description 2
- 125000001769 aryl amino group Chemical group 0.000 claims description 2
- 125000005110 aryl thio group Chemical group 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 150000002367 halogens Chemical class 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- 239000007788 liquid Substances 0.000 claims description 2
- 230000001590 oxidative effect Effects 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- 238000001953 recrystallisation Methods 0.000 claims description 2
- FWMUJAIKEJWSSY-UHFFFAOYSA-N sulfur dichloride Chemical compound ClSCl FWMUJAIKEJWSSY-UHFFFAOYSA-N 0.000 claims description 2
- 125000003396 thiol group Chemical group [H]S* 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims 7
- ZMANZCXQSJIPKH-UHFFFAOYSA-N N,N-Diethylethanamine Substances CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims 2
- JVVRCYWZTJLJSG-UHFFFAOYSA-N 4-dimethylaminophenol Chemical compound CN(C)C1=CC=C(O)C=C1 JVVRCYWZTJLJSG-UHFFFAOYSA-N 0.000 claims 1
- 229960000549 4-dimethylaminophenol Drugs 0.000 claims 1
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-dimethylaminopyridine Substances CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims 1
- 239000007900 aqueous suspension Substances 0.000 claims 1
- 239000004495 emulsifiable concentrate Substances 0.000 claims 1
- 239000012046 mixed solvent Substances 0.000 claims 1
- 150000004965 peroxy acids Chemical class 0.000 claims 1
- 239000012286 potassium permanganate Substances 0.000 claims 1
- 239000000843 powder Substances 0.000 claims 1
- 238000011321 prophylaxis Methods 0.000 claims 1
- 239000000243 solution Substances 0.000 claims 1
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 claims 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 24
- OHLUUHNLEMFGTQ-UHFFFAOYSA-N N-methylacetamide Chemical compound CNC(C)=O OHLUUHNLEMFGTQ-UHFFFAOYSA-N 0.000 description 20
- 230000005764 inhibitory process Effects 0.000 description 16
- 230000015572 biosynthetic process Effects 0.000 description 15
- 238000003786 synthesis reaction Methods 0.000 description 15
- 230000000694 effects Effects 0.000 description 11
- 241000700721 Hepatitis B virus Species 0.000 description 10
- 150000003839 salts Chemical class 0.000 description 10
- 238000005406 washing Methods 0.000 description 10
- 241000723873 Tobacco mosaic virus Species 0.000 description 8
- 239000003444 phase transfer catalyst Substances 0.000 description 7
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 6
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 6
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 6
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
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- 230000002363 herbicidal effect Effects 0.000 description 5
- 230000002401 inhibitory effect Effects 0.000 description 5
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 241000192043 Echinochloa Species 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 4
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 4
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- 235000004977 Brassica sinapistrum Nutrition 0.000 description 3
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
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- FCEHBMOGCRZNNI-UHFFFAOYSA-N 1-benzothiophene Chemical compound C1=CC=C2SC=CC2=C1 FCEHBMOGCRZNNI-UHFFFAOYSA-N 0.000 description 2
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- HJKGBRPNSJADMB-UHFFFAOYSA-N 3-phenylpyridine Chemical compound C1=CC=CC=C1C1=CC=CN=C1 HJKGBRPNSJADMB-UHFFFAOYSA-N 0.000 description 2
- JVZRCNQLWOELDU-UHFFFAOYSA-N 4-Phenylpyridine Chemical compound C1=CC=CC=C1C1=CC=NC=C1 JVZRCNQLWOELDU-UHFFFAOYSA-N 0.000 description 2
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Landscapes
- Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The present invention relates to a process for preparing 1,2,3-thiadiazole compounds, which can be used to prevent and treat hepatitis B and plant viruses.
Description
Technical Field
The invention relates to preparation of thiadiazole compounds, which can be applied to treatment and/or prevention of hepatitis B and prevention and treatment of plant viruses in agriculture.
Background
Hepatitis B Virus (HBV) is a considerable public health problem because of its ability to cause both acute and chronic infections. Chronic HBV infection can lead to cirrhosis and primary hepatocellular carcinoma. Although hepatitis B virus vaccines have been known for many years, there is currently no successful effective therapeutic approach to control chronic HBV infection. There are still 3 billion people worldwide infected with HBV, with 75% of china, who cannot benefit from the commercial vaccines available. The existing HBV treatment means has insufficient efficacy or serious toxic and side effects, such as that the interferon with definite curative effect is only acknowledged to have the effective rate of 25 to 40 percent, and meanwhile, 10 to 40 percent of patients have serious side effects. Therefore, effective means for treating HBV is urgently needed.
Plant viruses are also a great hazard in agricultural production, almost all crops and economic crops are harmed by 2-3 viruses, and the plant viruses are called plant cancers, so that great loss is caused to agricultural production due to difficult control, for example, the agricultural loss caused by the plant viruses reaches 800 billion yen in 1983 Japan.
In order to control plant viruses, various researches have been carried out, since the 70 th 20 th century, Schuster found that triazine compounds (DHT) have better inhibiting effect on plant viruses, chemists have found that various compounds have better plant virus inhibiting activity so far, such as casticin, ribavirin, citrinin, purine and pyrimidine, plant hormone and some natural antiviral substances, but have different problems and limit the application of the compounds. If the chestnut blight bacteriocin has no systemic property, the chestnut blight bacteriocin can not be absorbed by tissues; ribavirin has the defects of short duration, serious phytotoxicity and high cost; pyrimidines and purines also present serious problems with phytotoxicity, and are sometimes completely ineffective; while the plant hormone medicine mainly stimulates the growth of crops and has no effect on the proliferation of viruses.
Disclosure of Invention
The object of the present invention is to provide 1, 2, 3-thiadiazole compounds which are useful against hepatitis B virus and against plant viruses.
The present invention is a compound of the following structural formula (I):wherein R is1Is hydrogen, halogen, alkyl, substituted aryl, alkoxy, substituted aryloxy, alkylthio, substituted arylthio, amino, alkylamino, arylamino, five-or six-membered heterocycle containing N, S elements; r2Is hydrogen, alkyl, substituted aryl, alkoxy, substituted aryloxy, amino, alkylamino, substituted arylamine, five-or six-membered heterocycle containing N, S elements; r3Is hydrogen, alkyl, substituted aryl, alkoxy, substituted aryloxy, alkylamino, substituted arylamine, substituted benzyl, substituted arylethyl, five-or six-membered heterocycle containing N, S elements or the likeHeterocyclic methyl, ethyl; x is O, S, CH2CHR ', NH, NR'; r' is hydrogen, alkyl or aryl; y is O, S, SO2NH, NR'; y may also be a five-or six-membered heterocyclic ring containing the element N, S.
A preferred group of the present invention are compounds of structure (II):
wherein
Y is oxygen, sulfur, NH, NR', SO or SO2(ii) a R' is hydrogen, alkyl or aryl
R3Is hydrogen, alkyl, substituted aryl, alkoxy, substituted aryloxy, alkylamino, substituted arylamine, substituted benzyl, substituted arylethyl, five-membered or six-membered heterocycle containing N, S elements or heterocyclic methyl and ethyl thereof;
some examples of compounds of structure (II) and their physico-chemical constants are shown in Table 1.
The term "aryl" as used herein refers to any compound comprising or consisting of one or more aromatic rings which may be carbocyclic, heterocyclic or pseudoaromatic and may be a mono-or polycyclic ring system and preferably contain from 3 to 20 carbon atoms. The aromatic ring may also contain one or more heteroatoms selected from N, S, O and P. Examples of suitable rings include, but are not limited to, benzene, biphenyl, terphenyl, quaterphenyl, naphthalene, tetralin, 1-benzylnaphthalene, anthracene, dihydroanthracene, benzanthracene, dibenzanthracene, phenanthrene, pyridine, 4-phenylpyridine, 3-phenylpyridine, thiophene, benzothiophene, benzopyran, pyrrole, imidazole, pyrazine, pyrimidine, pyridazine, triazine, indole, isoindole, purine, quinoline, isoquinoline, quinoxaline, pteridine, carbazole, phenanthridine, phenazine, furan, thiophene, pyrrole, isothiazole, isoxazole, triazole, thiadiazole, oxadiazole, and the like, and also include any two of the above aromatic rings connected directly or through an atom such as C, O, N, each of which is optionally substituted. The term "pseudo-aromatic" refers to a ring system that, although not strictly aromatic, is stabilized by delocalization of the electrons and behaves similarly to an aromatic ring. Examples of pseudoaromatic rings include, but are not limited to: furan, thiophene, pyrrole, and the like.
Alkyl refers to straight C1-30Alkyl or branched C1-30Alkyl and branched or unbranched C3-30Cycloalkyl groups, these groups may be saturated or unsaturated.
Alkoxy means straight C1-30Alkoxy or branched C1-30Alkoxy and branched or unbranched C3-30Cycloalkoxy groups, these groups may be saturated or unsaturated.
The basic preparation method of the invention is described as follows:
a. dissolving the alpha-chlorodicarbonyl compound (1) in a solvent of methanol, ethanol, acetonitrile, chloroform, dichloromethane, diethyl ether, dipropyl ether, DMF or DMSO, adding ethyl carbazate or p-toluenesulfonyl hydrazide at the temperature of between 0 and 80 ℃, continuously reacting for 0.5 to 20 hours at the temperature of between 0 and 80 ℃, removing part of the solvent in vacuum, and recrystallizing to obtain a viscous liquid or a solid target product (2).
b. Adding 1-20 times of thionyl chloride or sulfur dichloride into a reaction bottle at the temperature of-15-35 ℃, adding the product (2) into the reaction bottle in batches under stirring, raising the temperature to 0-120 ℃ after adding, reacting for 5-48 hours, and pouring alkali (such as KOH, NaOH and K)2CO3、Na2CO3、NaHCO3Etc.), a large amount of solid is precipitated in the aqueous solution, filtered, and recrystallized with an appropriate solvent to obtain the target product (3).
c. Dissolving compound containing hydroxyl, amino (amine) group and sulfhydryl in appropriate organic solvent (methanol, ethanol, acetonitrile, chloroform, dichloromethane, ethyl acetate, diethyl ether, dipropyl ether, acetone, butanone, DMF or DMSO), and adding 0.8-5 times of base (such as KOH, NaOH, K)2CO3、Na2CO3、NaHCO3And (3) adding 0.8-3 times of compound (3) at the temperature of 0-80 ℃, after the reaction is finished, evaporating the solvent in vacuum, and carrying out reduced pressure leaching on the residue on a silica gel column to obtain a solid target product (4). When Y is oxygen, sulfur, nitrogen, etc. at an atom or nitrogen of a five-or six-membered heterocyclic ring, it can be synthesized by a similar method.
d. When Y is S, the compound of the structural formula (4) is dissolved in a proper organic solvent (water, methanol, ethanol, acetonitrile, acetic acid, chloroform, dichloromethane, ethyl acetate, diethyl ether, dipropyl ether, acetone, butanone, DMF or DMSO), 0.9-5 times of oxidant is added, the reaction is carried out for 1-48 hours at the temperature of-15 ℃ to 60 ℃, after the solvent is removed, the compound of the structural formula (5) of which Y is SO is obtained by recrystallization with a proper solvent. Reacting at 5-100 deg.C for 0.5-24 hr to obtain Y as SO2The compound of formula (5).
The compound of the structural formula (I) is used for treating and/or preventing hepatitis B virus infection and preventing and treating plant viruses in agriculture. The salt of the compound with the structural formula (I) and the application of the pharmacologically allowable derivative thereof and the application in the aspect of preventing and treating agricultural viruses.
The compounds of formula (I) or formula (II) show a relatively high activity in an anti-hepatitis B assay. At the same time, the compounds show quite high activity in the anti-tobacco mosaic virus test.
The compounds of the invention are further useful for the manufacture of a medicament for the treatment or prevention of HBV. Thus, the present invention provides that the salts of the compounds of formula (I) or formula (II) are preferably pharmacologically acceptable, but it will be appreciated that non-pharmacologically acceptable salts thereof are also within the scope of the invention, as they are useful intermediates in the preparation of pharmacologically acceptable salts. Pharmacologically acceptable salts include: examples of acid addition salts include, but are not limited to, salts derived from pharmacologically acceptable cations such as acetic, propionic, citric, lactic, methanesulfonic, toluenesulfonic, benzenesulfonic, salicylic, ascorbic, hydrochloric, orthophosphoric, sulfuric, and hydrobromic acids, base salts include, but are not limited to, salts derived from pharmacologically acceptable cations such as sodium, potassium, lithium, calcium, magnesium, ammonia, and alkylamines. The compounds of formula (I) are prepared by treating them with the appropriate metal hydroxide, with reagents such as lower alkyl halides, e.g. chloro-, o-and iodo-substituted methanes, ethanes, propanes and butanes; dialkyl sulfates such as dimethyl sulfate and diethyl sulfate; and other basic nitrogen-containing groups may also be quaternized.
The compounds of the invention may be crystalline or solvated (e.g., hydrated), both states falling within the scope of the invention. Solvation methods are well known in the art.
The pharmaceutically acceptable derivatives may include any pharmaceutically acceptable salts or hydrates.
The compounds of formula (I) or (II) have asymmetric structures and thus may exist in more than one stereoisomer. Each form of these isomers and mixtures thereof, including racemates, are encompassed by the present invention. Isomers can generally be separated by chromatography or by use of resolving agents. Alternatively, the individual isomers may be prepared by asymmetric synthesis using chiral intermediates or enzymes.
The compounds of the formula (I) or (II) according to the invention can furthermore be used in formulations or mixtures for controlling plant viruses.
The compound of the structural formula (I) or the structural formula (II) not only has good tobacco mosaic virus resisting activity, but also simultaneously has plant growth regulating activity and plant safety characteristic, which cannot be simultaneously possessed by most other agricultural antiviral medicaments.
The 1, 2, 3-thiadiazole compound is easy to synthesize, low in cost, good in inhibition effect on animal viruses and plant viruses, novel in structure and free from reports of 1, 2, 3-thiadiazole ring in the currently known compounds with good inhibition effect on viruses. The invention meets the requirements of environment-friendly and green chemistry from design, production to application.
Detailed Description
For a further understanding of the invention, examples are provided. The particular materials and conditions used are intended to be illustrative of the invention and not limiting of its reasonable scope.
Reagents not mentioned were purchased from the market and used as such unless otherwise indicated.
All temperatures are degrees celsius.
The scheme is as follows:
example 1:
synthesis of alpha-chloroacetoacetylmethylamine-N-ethoxycarbonylhydrazone
Dissolving 21g (90%) (0.125mol) of alpha-chloroacetoacetamidone in 60mL of absolute ethanol, slowly and dropwise adding 12.9g (0.125mol) of ethyl carbazinate at room temperature, reacting at room temperature for 18h, removing part of solvent in vacuum, and recrystallizing to obtain 21g of white solid, wherein the yield is 71%, and the melting point is as follows: 120-121 ℃. Elemental analysis: found, C: 40.78, H: 5.51, N: 17.64 of; calculated values: c: 40.77, H: 5.99, N: 17.83.1H NMR(CDCl3)：1.30(t，J＝7.2，3H，CH3)，1.90(s，3H，CH3)，2.87(d，J＝4.6，3H，NCH3)，4.25(q，J＝7.0，2H，OCH2)，5.11(s，1H，CH)，6.76(br，1H，NH)，7.90(br，1H，NH)。
example 2:
synthesis of alpha-chloro-1, 2, 3-thiadiazole acetyl methylamine
Adding 25mL of thionyl chloride into a reaction bottle, cooling to 5 ℃, adding 21g of the product obtained in the previous step into the reaction bottle in batches under stirring, controlling the temperature to be not more than 10 ℃, heating to room temperature for reaction for 48 hours after the addition is finished, and pouring a saturated aqueous solution of sodium carbonateIn the process, a large amount of solid is separated out, filtered, recrystallized by ethanol to obtain 14.5g of a product, the yield is 85 percent, and the melting point is as follows: 144-145 ℃. Elemental analysis: found, C: 31.45, H: 2.89, N: 21.77, respectively; calculated values: c: 31.34, H: 3.16, N: 21.93.1HNMR(CDCl3)：2.93(d，J＝4.8，3H，NCH3)，5.91(s，1H，CH)，6.96(br，1H，NH)，8.67(s，1H，thiadiazole-H)。
example 3:
synthesis of alpha-substituted phenoxy-1, 2, 3-thiadiazole acetyl methylamine (II-3a)
Dissolving 0.87g (4mmol) of p-bromophenol in 10mL of methanol, adding 0.24g (5mmol) of sodium hydroxide, stirring for 10 minutes at room temperature, adding 0.77g (4mmol) of alpha-chloro-1, 2, 3-thiadiazole acetyl methylamine, stirring for 48 hours at room temperature, evaporating the solvent in vacuum, washing the solid with 10mL of water, carrying out suction filtration, and eluting the residue on a silica gel column by using an eluting agent ethyl acetate/petroleum ether (v: v ═ 1: 5) under reduced pressure to obtain 0.6g of a pure product.
Example 4:
synthesis of alpha- (beta-naphthoxy) -1, 2, 3-thiadiazole acetyl methylamine (II-4)
Dissolving 0.72g (5mmol) of beta-naphthol in 10mL of methanol, adding 0.24g (6mmol) of sodium hydroxide, stirring to dissolve, adding 0.77g (3mmol) of alpha-chloro-1, 2, 3-thiadiazole acetyl methylamine, stirring at room temperature for 48h, evaporating the solvent in vacuum, washing the solid with 10mL of water, filtering, and leaching the residue on a silica gel column by using a leaching agent ethyl acetate/petroleum ether (v: v ═ 1: 5) under reduced pressure to obtain 0.32g of a pure product.
Example 5:
synthesis of alpha-substituted thiophenyl-1, 2, 3-thiadiazole acetyl methylamine (II-5a)
Dissolving 1.53g (8mmol) of alpha-chloro-1, 2, 3-thiadiazole acetyl methylamine in 20mL of acetonitrile, adding 1.39g (10mmol) of anhydrous potassium carbonate and 0.01g of phase transfer catalyst, dropwise adding 1.4g (10mmol) of 2, 5-dimethylthiophenol under stirring at room temperature, stirring at room temperature for reacting for 6h, evaporating the solvent in vacuum, washing the solid with 10mL of water, carrying out suction filtration, and recrystallizing the residue with anhydrous ethanol to obtain 1.59g of a pure product.
Example 6:
synthesis of alpha- (4-chlorobenzylthio) -1, 2, 3-thiadiazole acetylmethylamine (II-6)
Dissolving 1.53g (8mmol) of alpha-chloro-1, 2, 3-thiadiazole acetyl methylamine in 20mL of acetonitrile, adding 1.4g (10mmol) of anhydrous potassium carbonate and 0.01g of phase transfer catalyst, dropwise adding 1.45g (8mmol) of p-chlorobenzyl mercaptan under stirring at room temperature, stirring at room temperature for reaction for 6h, evaporating the solvent in vacuum, washing the solid with 10mL of water, carrying out suction filtration, and recrystallizing the residue with anhydrous ethanol to obtain 1.6g of a pure product.
Example 7:
synthesis of alpha-substituted benzenesulfinyl-1, 2, 3-thiadiazole acetyl methylamine (II-7e)
Adding 0.53g (1.8mmol) of alpha-p-chlorobenzenethiol-1, 2, 3-thiadiazole acetyl methylamine into 10mL of acetic acid, heating to dissolve, cooling to 25-30 ℃, dropwise adding 3.5mmol of hydrogen peroxide (30%), shaking uniformly, standing for 2h, stirring at room temperature for 24h, adding 20mL of water, standing, performing suction filtration, and recrystallizing the obtained solid with absolute ethyl alcohol to obtain 0.30g of a pure product.
Example 8:
synthesis of alpha-substituted benzylsulfinyl-1, 2, 3-thiadiazole acetyl methylamine (II-8)
Adding 0.53g (1.7mmol) of alpha-p-chlorobenzylthio-1, 2, 3-thiadiazole acetyl methylamine into 10mL of acetic acid, heating to dissolve, cooling to 25-30 ℃, dropwise adding 3.5mmol of hydrogen peroxide (30%), shaking uniformly, standing for 2h, stirring at room temperature for 24h, adding 20mL of water, standing, performing suction filtration, and recrystallizing the obtained solid with absolute ethyl alcohol to obtain 0.30g of a pure product.
Example 9:
synthesis of alpha-substituted benzenesulfonyl-1, 2, 3-thiadiazole acetyl methylamine (II-9a)
Adding 0.50g (1.7mmol) of alpha-2, 5-dimethylphenylthio-1, 2, 3-thiadiazole acetyl methylamine into 10mL of acetic acid, dropwise adding 7mmol of hydrogen peroxide (30%), heating to 80 ℃, reacting for 6h, cooling to room temperature, adding 20mL of water, standing, performing suction filtration, and recrystallizing the obtained solid with absolute ethyl alcohol to obtain 0.35g of a pure product.
Example 10:
synthesis of alpha-substituted benzylsulfonyl-1, 2, 3-thiadiazole acetyl methylamine (II-10)
Adding 0.53g (1.7mmol) of alpha-p-chlorobenzylthio-1, 2, 3-thiadiazole acetyl methylamine into 10mL of acetic acid, dropwise adding 7mmol of hydrogen peroxide (30%), heating to 80 ℃, reacting for 6h, cooling to room temperature, adding 20mL of water, standing, performing suction filtration, and recrystallizing the obtained solid with absolute ethyl alcohol to obtain 0.39g of a pure product.
Example 11:
synthesis of alpha- [2- (1-methyl-3-ethylpyrazol-5-yl) -1, 3, 4-oxadiazole-5-mercapto ] -1, 2, 3-thiadiazole acetylmethylamine (II-11)
Dissolving 0.55g (2.9mmol) of alpha-chloro-1, 2, 3-thiadiazole acetyl methylamine in 10mL of acetonitrile, adding 0.42g (3mmol) of anhydrous potassium carbonate and 0.01g of phase transfer catalyst, stirring at room temperature, adding 0.66g (2.9mmol) of 2- (1-methyl-3-ethylpyrazol-5-yl) -5-mercapto-1, 3, 4-oxadiazole, stirring at room temperature for reaction for 6h, evaporating the solvent in vacuum, washing the solid with 10mL of water, filtering, and recrystallizing the residue with anhydrous ethanol to obtain 0.16g of a pure product.
Example 12:
synthesis of alpha- [2- (1-methyl-3-methyl-5-methylthiopyrazol-4-yl) -1, 3, 4-thiadiazole-5-mercapto ] -1, 2, 3-thiadiazole acexamine (II-12)
Dissolving 0.55g (2.6mmol) of alpha-chloro-1, 2, 3-thiadiazole acetyl methylamine in 10mL of acetonitrile, adding 0.38g (2.7mmol) of anhydrous potassium carbonate and 0.01g of phase transfer catalyst, stirring at room temperature, adding 0.70g (2.7mmol) of 2- (1-methyl-3-methyl-5-methylthio pyrazol-4-yl) -5-mercapto-1, 3, 4-thiadiazole, stirring at room temperature for reacting for 6h, evaporating the solvent in vacuum, washing the solid with 10mL of water, performing suction filtration, and recrystallizing the residue with anhydrous ethanol to obtain 0.43g of a pure product.
Example 13:
synthesis of alpha- [2- (1-methyl-3-methyl-5-methylthiopyrazol-4-yl) -1, 3, 4-oxadiazole-5-mercapto ] -1, 2, 3-thiadiazole acexamine (II-12)
Dissolving 0.50g (2.6mmol) of alpha-chloro-1, 2, 3-thiadiazole acetyl methylamine in 10mL of acetonitrile, adding 0.38g (2.7mmol) of anhydrous potassium carbonate and 0.01g of phase transfer catalyst, adding 0.63g (2.6mmol) of 2- (1-methyl-3-methyl-5-methylthio pyrazol-4-yl) -5-mercapto-1, 3, 4-oxadiazole under stirring at room temperature, reacting for 6h under stirring at room temperature, evaporating the solvent in vacuum, washing the solid with 10mL of water, performing suction filtration, and recrystallizing the residue with anhydrous ethanol to obtain 0.17g of pure alpha-chloro-1, 2, 3-thiadiazole acetyl methylamine.
Example 14:
synthesis of alpha- (5, 7-dimethyl-1, 2, 4-triazolo [1, 5-a ] pyrimidine-2-mercapto) -1, 2, 3-thiadiazole acetyl methylamine (II-13)
Dissolving 0.85g (4.4mmol) of alpha-chloro-1, 2, 3-thiadiazole acetyl methylamine in 10mL of acetonitrile, adding 0.69g (5mmol) of anhydrous potassium carbonate and 0.01g of phase transfer catalyst, adding 0.6g (5mmol) of 2-mercapto-5, 7-dimethyl-1, 2, 4-triazole [1, 5-a ] pyrimidine under stirring at room temperature, stirring at room temperature for reaction for 6h, evaporating the solvent in vacuum, washing the solid with 10mL of water, filtering, and recrystallizing the residue with anhydrous ethanol to obtain 0.64g of a pure product.
Example 15:
synthesis of alpha- (1, 2, 4-triazol-1-yl) -1, 2, 3-thiadiazole acetyl methylamine (II-14)
Dissolving 0.19g (1mmol) of alpha-chloro-1, 2, 3-thiadiazole acetyl methylamine in 10mL of acetonitrile, adding 0.2g (1.4mmol) of anhydrous potassium carbonate and 0.005g of phase transfer catalyst, adding 0.1g (1.4mmol) of 1, 2, 4-triazole under stirring at room temperature, stirring at room temperature for reaction for 48h, evaporating the solvent in vacuum, washing the solid with 10mL of water, carrying out suction filtration, and purifying the residue by ethyl acetate/petroleum ether (V: V is 1: 1) through reduced pressure column chromatography to obtain 0.08g of a pure product.
TABLE 1: physicochemical data for Compounds of formula (II)
| Compound (I) | Y | R3 | Traits | Melting Point C | Yield of |
| II-3a | O | p-Br-C6H4 | White solid | 140-142 | 46 |
| II-3b | O | 2-Cl-5-Me-C6H3 | White solid | 13II-135 | 27 |
| II-3c | O | p-I-C6H4 | White solid | 157-158 | 23 |
| II-3d | O | o-Br-C6H4 | White solid | 148-149 | 29 |
| II-3e | O | C6H5 | White solid | 140-141 | 29 |
| II-3f | O | p-Me-C6H4 | White solid | 130-132 | 15 |
| II-3g | O | m-Me-C6H4 | White solid | 127-128 | 38 |
| II-3h | O | 3-Me-3-Me-C6H3 | White solid | 116-117 | 63 |
| II-3i | O | m-Cl-C6H4 | White solid | 118-119 | 27 |
| II-4 | O | naphthoxy | White solid | 172-173 | 27 |
| II-5a | S | 2-Me-5-Me-C6H3 | White solid | 139-140 | 68 |
| II-5b | S | p-F-C6H4 | White solid | 126-127 | 62 |
| II-5c | S | p-Cl-C6H4 | White solid | 140-141 | 52 |
| II-5d | S | 2-Cl-5-Cl-C6H3 | White solid | 170-172 | 45 |
| II-5e | S | p-OMe-C6H4 | White solid | 110-111 | 74 |
| II-5f | S | o-F-C6H4 | White solid | 135-137 | 68 |
| II-5g | S | p-NH2-C6H4 | White solid | 139-141 | 77 |
| II-6 | S | p-Cl-C6H4CH2 | White solid | 143-143 | 64 |
| II-7a | SO | 2-Me-5-Me-C6H3 | White solid | 160-161.5 | 94 |
| II-7b | SO | p-F-C6H4 | White solid | 157.5-159 | 51 |
| II-7c | SO | p-Cl-C6H4 | White solid | 126-129 | 62 |
| II-7d | SO | 2-Cl-5-Cl-C6H3 | White solid | 170-172 | 57 |
| II-7e | SO | p-OMe-C6H4 | White solid | 163-165 | 38 |
| II-7f | SO | o-F-C6H4 | White solid | 170-172 | 72 |
| II-8 | SO | p-Cl-C6H4CH2 | White solid | 126-129 | 53 |
| II-9a | SO2 | 2-Me-5-Me-C6H3 | White solid | 176-178 | 63 |
| II-9b | SO2 | p-F-C6H4 | White solid | 156-158 | 92 |
| II-9c | SO2 | p-Cl-C6H4 | White solid | 196-198 | 87 |
| II-9d | SO2 | 2-Cl-5-Cl-C6H3 | White solid | 172-174 | 53 |
| II-9e | SO2 | p-OMe-C6H4 | White solid | 178-179.5 | 94 |
Table 2: elemental analysis data for the Compound of formula (II)
| Compound (I) | Elemental analysis | |||||
| Calculated value (%) | Measured value (%) | |||||
| C | H | N | C | H | N | |
| II-3a | 40.26 | 3.07 | 12.80 | 40.41 | 2.77 | 12.61 |
| II-3b | 48.40 | 4.06 | 14.11 | 48.54 | 3.91 | 13.90 |
| II-3c | 35.21 | 2.69 | 11.20 | 35.08 | 2.55 | 11.29 |
| II-3d | 40.26 | 3.07 | 12.08 | 40.29 | 3.08 | 12.90 |
| II-3e | 53.00 | 4.45 | 16.86 | 53.18 | 4.46 | 16.60 |
| II-3f | 54.74 | 4.98 | 15.96 | 54.46 | 4.97 | 15.97 |
| II-3g | 54.74 | 4.98 | 15.96 | 54.68 | 4.70 | 15.95 |
| II-3h | 56.30 | 5.45 | 15.15 | 56.20 | 5.54 | 15.06 |
| II-3i | 46.56 | 3.55 | 14.81 | 46.39 | 3.30 | 14.86 |
| II-4 | 60.18 | 4.38 | 14.04 | 60.07 | 4.31 | 13.86 |
| II-5a | 53.22 | 5.15 | 14.32 | 53.08 | 4.98 | 14.14 |
| II-5b | 46.63 | 3.56 | 14.83 | 46.77 | 3.54 | 14.81 |
| II-5c | 44.07 | 3.36 | 14.02 | 43.94 | 3.41 | 13.88 |
| II-5d | 39.53 | 2.71 | 12.57 | 39.26 | 2.93 | 12.78 |
| II-5e | 48.79 | 4.44 | 14.23 | 48.82 | 4.44 | 14.18 |
| II-5f | 46.63 | 3.56 | 14.83 | 46.56 | 3.55 | 14.68 |
| II-5g | 47.12 | 4.31 | 19.98 | 47.25 | 4.20 | 19.90 |
| II-6 | 45.93 | 3.85 | 13.39 | 45.71 | 3.63 | 13.36 |
| II-7a | 50.46 | 4.89 | 13.58 | 50.38 | 4.90 | 13.46 |
| II-7b | 44.14 | 3.37 | 14.04 | 44.16 | 3.17 | 13.85 |
| II-7c | 41.84 | 3.19 | 13.31 | 41.54 | 3.04 | 13.09 |
| II-7d | 37.72 | 2.59 | 12.00 | 37.52 | 2.81 | 12.29 |
| II-7e | 46.29 | 4.21 | 13.49 | 46.16 | 4.16 | 13.42 |
| II-7f | 44.14 | 3.37 | 14.04 | 44.00 | 3.38 | 13.85 |
| II-8 | 43.70 | 3.67 | 12.74 | 43.66 | 3.39 | 12.50 |
| II-9a | 47.98 | 4.65 | 12.91 | 47.74 | 4.40 | 12.91 |
| II-9b | 41.90 | 3.20 | 13.33 | 41.66 | 3.14 | 13.17 |
| II-9c | 39.82 | 3.04 | 12.66 | 39.63 | 3.10 | 12.44 |
| II-9d | 36.07 | 2.48 | 11.47 | 36.14 | 2.48 | 11.44 |
| II-9e | 44.02 | 4.00 | 12.84 | 44.04 | 3.91 | 12.86 |
| II-9f | 41.90 | 3.20 | 13.30 | 41.66 | 3.03 | 13.28 |
| II-10 | 41.68 | 3.50 | 12.15 | 41.40 | 3.75 | 12.39 |
| II-11 | 42.73 | 4.14 | 26.83 | 42.63 | 3.95 | 26.69 |
| II-12 | 37.75 | 3.66 | 23.71 | 37.89 | 3.12 | 23.81 |
| II-13 | 39.28 | 3.80 | 24.67 | 39.37 | 3.64 | 24.69 |
| II-14 | 42.97 | 3.91 | 29.23 | 42.83 | 3.70 | 29.54 |
| II-15 | 37.49 | 3.60 | 37.48 | 37.25 | 3.43 | 37.36 |
Table 3: process for preparing compounds of formula (II)1H NMR data
| Compound (I) | 1H NMR(CDCl3，ppm) |
| II-3a | 2.91(d，J＝4.8，3H，NCH3)，6.12(s，1H，CH)，6.94(br，1H，NH)，6.85-7.38(m，4H，Ph)，8.63(s，1H，thiadiazole-H) |
| II-3b | 2.29(s，3H，CH3)，2.91(d，J＝4.9，3H，NCH3)，6.11(s，1H，CH)，6.96(br，1H，NH)，6.68-7.24(m，3H，Ph)，8.62(s，1H，thiadiazole-H) |
| II-3c | 2.91(d，J＝4.8，3H，NCH3)，6.12(s，1H，CH)，6.92(br，1H，NH)，6.74-7.57(m，4H，Ph)，8.62(s，1H，thiadiazole-H) |
| II-3d | 2.95(d，J＝5.0，3H，NCH3)，6.24(s，1H，CH)，7.28(br，1H，NH)，6.91-7.58(m，4H，Ph)，8.66(s，1H，thiadiazole-H) |
| II-3e | 2.91(d，J＝5.0，3H，NCH3)，6.16(s，1H，CH)，6.95-7.30(m，5H，Ph)，8.62(s，1H，thiadiazole-H) |
| II-3f | 2.26(s，3H，CH3)，2.92(d，J＝5.0，3H，NCH3)，6.11(s，1H，CH)，7.02(br，1H，NH)，6.84-7.08(m，4H，Ph)，8.59(s，1H，thiadiazole-H) |
| II-3g | 2.29(s，3H，CH3)，2.91(d，J＝5.1，3H，NCH3)，6.15(s，1H，CH)，6.98(br，1H，NH)，6.80-7.14(m，4H，Ph)，8.61(s，1H，thiadiazole-H) |
| II-3h | 2.15(s，3H，CH3)，2.18(s，3H，CH3)，2.91(d，J＝4.6，3H，NCH3)，6.11(s，1H，CH)，6.71-7.02(m，4H，Ph+NH)，8.60(s，1H，thiadiazole-H) |
| II-3i | 2.89(d，J＝4.6，3H，NCH3)，6.16(s，1H，CH)，6.88-7.23(m，5H，Ph+NH)，8.66(s，1H，thiadiazole-H) |
| II-4 | 2.94(d，J＝4.8，3H，NCH3)，6.33(s，1H，CH)，7.04(br，1H，NH)，7.20-7.79(m，7H，naphthalene)，8.67(s，1H，thiadiazole-H) |
| II-5a | 2.24(s，3H，CH3)，2.27(s，3H，CH3)，2.84(d，J＝4.7，3H，NCH3)，5.34(s，1H，CH)，6.88(br，1H，NH)，6.92-7.15(m，3H，Ph)，8.46(s，1H，thiadiazole-H) |
| II-5b | 2.82(d，J＝5.0，3H，NCH3)，5.41(s，1H，CH)，6.90-7.34(m，5H，Ph+NH)，8.52(s，1H，thiadiazole-H) |
| II-5c | 2.84(d，J＝5.0，3H，NCH3)，5.42(s，1H，CH)，6.92(br，1H，NH)，7.22-7.40(m，4H，Ph)，8.53(s，1H，thiadiazole-H) |
| II-5d | 2.82(d，J＝4.4，3H，NCH3)，5.48(s，1H，CH)，7.04 (br，1H，NH)，7.14-7.32(m，3H，Ph)，8.58(s，1H，thiadiazole-H) |
| II-5e | 2.81(d，J＝4.5，3H，NCH3)，3.73(s，3H，CH3)，5.30(s，1H，CH)，6.84(br，1H，NH)，6.72-7.23 (m，4H，Ph)，8.40(s，1H，thiadiazole-H) |
| II-5g | 2.84(d，J＝4.2，3H，NCH3)，5.49(s，1H，CH)，6.96(br，1H，NH)，7.05-7.33(m，4H，Ph)，8.57(s，1H，thiadiazole-H) |
| II-5h | 2.88(d，J＝4.8，3H，NCH3)，2.76(br，2H，NH2)，5.30(s，1H，CH)，6.92 (br，1H，NH)，6.55-7.14(m，4H，Ph)，8.43(s，1H，thiadiazole-H) |
| II-6 | 2.80(d，J＝4.8，3H，NCH3)，3.75，3.79(q，AB，2H，CH2)，5.30(s，1H，CH)，6.84(br，1H，NH)，6.72-7.23(m，4H，Ph)，8.40(s，1H，thiadiazole-H) |
| II-7a | 2.24(s，3H，CH3)，2.27(s，3H，CH3)，2.84(d，J＝4.7，3H，NCH3)，5.34(s，1H，CH)，6.88 (br，1H，NH)，6.92-7.15(m，3H，Ph)，8.46(s，1H，thiadiazole-H) |
| II-7b | 2.86(d，3H，NCH3)，5.44(s，1H，CH)，6.96(br，1H，NH)，7.05-7.34(m，5H，Ph)，8.65(s，1H，thiadiazole-H) |
| II-7c* | 3.30(s，3H，NCH3)，5.69(s，1H，CH)，6.92(br，1H，NH)，7.3 1-7.52(m，4H，Ph)，9.15(s，1H，thiadiazole-H) |
| II-7d | 2.85(d，J＝4.6，3H，NCH3)，5.38(s，1H，CH)，6.95(br，1H，NH)，7.07-7.37(m，4H，Ph)，8.75(s，1H，thiadiazole-H) |
| II-7e | 2.90(s，3H，NCH3)，3.81(s，3H，CH3)，5.46(s，1H，CH)，6.84-7.21(m，5H，Ph+NH)，8.56(s，1H，thiadiazole-H) |
| II-7f | 2.94(d，J＝4.5，3H，NCH3)，5.62(s，1H，CH)，6.80(br，1H，NH)，7.07-7.44(m，4H，Ph)，8.69(s，1H，thiadiazole-H) |
| II-8 | 2.88(d，J＝4.2，3H，NCH3)，3.88，3.92(q，AB，2H，CH2)，5.23(s，1H，CH)，6.96(br，1H，NH)，7.15-7.36(m，4H，Ph)，8.79(s，1H，thiadiazole-H) |
| II-9a | 2.21(s，3H，CH3)，2.55(s，3H，CH3)，2.94(d，J＝4.7，3H，NCH3)，5.91(s，1H，CH)，7.12-7.29(m，4H，Ph+NH)，8.89(s，1H，thiadiazole-H) |
| II-9b | 2.91(d，J＝4.8，3H，NCH3)，5.99(s，1H，CH)，7.13-7.66(m，6H，Ph+NH)，8.92(s，1H，thiadiazole-H) |
| II-9c | 2.93(d，J＝4.8，3H，NCH3)，5.88(s，1H，CH)，7.07(br，1H，NH)，7.28-7.60(m，4H，Ph)，8.90(s，1H，thiadiazole-H) |
| II-9d | 2.95(d，J＝4.2，3H，NCH3)，6.42(s，1H，CH)，7.06(br，1H，NH)，7.10-7.62(m，4H，Ph)，9.07(s，1H，thiadiazole-H) |
| II-9e | 2.93(s，3H，NCH3)，3.83(s，3H，CH3)，5.94(s，1H，CH)，7.17(br，1H，NH)，6.86-7.51(m，4H，Ph)，8.90(s，1H，thiadiazole-H) |
| II-9f | 2.93(d，J＝4.4，3H，NCH3)，6.15(s，1H，CH)，7.11-7.63(m，5H，Ph+NH)，8.69(s，1H，thiadiazole-H) |
| II-10 | 2.87(d，J＝4.2，3H，NCH3)，4.28，4.40(q，AB，2H，CH2)，5.63(s，1H，CH)，7.12(br，1H，NH)，7.21-7.42(m，4H，Ph)，8.91(s，1H，thiadiazole-H) |
| II-11 | 1.23(t，J＝6.9，3H，CH3)，2.64(q，J＝7.2，2H，CH2)，2.89(d，3H，NCH3)，4.16(s，3H，pyrazole-CH3)，6.26(s，1H，CH)，6.57(s，1H，pyrazole-H)，7.14 (br，1H，NH)，8.96(s，1H，thiadiazole-H) |
| II-12* | 2.47(s，3H，SCH3)，2.59(s，3H，pyrazole-CH3)，3.31(s，3H，NCH3)，3.83(s，3H，pyrazole-CH3)，6.25(s，1H，CH)，9.16(s，1H，thiadiazole-H) |
| II-13* | 2.48(s，3H，SCH3)，2.62(s，3H，pyrazole-CH3)，3.33(s，3H，NCH3)，3.85(s，3H，pyrazole-CH3)，6.28(s，1H，CH)，9.16(s，1H，thiadiazole-H) |
| II-14* | 2.49(s，6H，2×CH3)，2.64(s，3H，NCH3)，6.31(s，1H，CH)，7.12(s，1H，pyrimidne-H)，8.64(br，1H，NH)，9.15(s，1H，thiadiazole-H) |
| II-15 | 2.90(d，J＝4.4，3H，NCH3)，6.77(s，1H，CH)，6.88(br，1H，NH)，8.06(s，1H，triazole-H)，8.42(s，1H，triazole-H)，8.74(s，1H，thiadiazole-H) |
*The solvent used was acetone-d 6.
Table 4: MS and IR data for the Compound of formula (II)
| Compound (I) | IR(cm-1) | MS(12eV) |
| II-3a | 3405，3145，1662，1580，1486，1443，1412，1297，1229 | 329(M+，81Br，13)，327(M+，81Br，13)，272(81Br，7)，270(81Br，8)，174(81Br，29)，172(81Br，31)，156(6)，128(100) |
| II-3b | 3393，3088，1668，1621，1559，1481，1409，1306，1235，1171 | 297(M+，34)，240(11)，156(4)，142(100)，128(82) |
| II-5a | 3382，3118，3000，1647，1546，1463，1383，1332，1237，1209，1188 | 293(M+，25)，232(25)，234(21)，203(22)，175(30)，138(63)，105(68)，58(100) |
| II-5b | 3389，3138，2990，1645，1617，1582，1484，1394，1289，1233，1190，1154 | 283(M+，27)，226(83)，193(22)，165(52)，128(77)，58(100) |
| II-7f* | 299(M+，0.35)，156(6.0)，144(57)，143(24)，128(67)，58(100) | |
| II-7c* | 3391，3163，2929，1689，1556，1472，1399，1279，1046 | |
| II-8* | 3301，3130，2961，1664，1559，1489，1406，1286，1231，1032 | |
| II-9b | 3384，3181，2931，1683，1585，1509，1410，1318，1233，1146 | 251(10)，194(11)，128(100)，58(83) |
| II-9c | 267(5.8)，210(8.4)，128(48)，58(100) |
| II-10 | 3352，3124，1664，1590，1527，1488，1420，1332，1131 |
*The electron bombardment source used for MS is 70eV
Example 15:
anti-Hepatitis B Virus (HBV) Effect of Compounds of structural formula (1)
The material and the method are as follows:
a. in vitro cell model: HepG22.2.1.5
b. MTT method for detecting toxicity of sample to cells
c. EIA method (Huamei bioengineering company HBsAg and HbeAg diagnostic kit)
d. Positive drug control: aziluowei (ACV)
Table 5: anti-hepatitis B virus effect of compound of structural formula (II)
| Compound (I) | Maximum nontoxic concentration TCD0(□mol/ml) | Inhibitory rate against HBsAg (%) | Inhibition ratio (%) for HBeAg |
| II-3d | 0.6 | ＞55 | 15.5 |
| II-5f | 0.6 | ＞55 | 16.2 |
| II-7c | 0.6 | 48.5 | 0 |
| II-9b | 0.6 | 46.8 | 1.3 |
| II-13 | 0.4 | ＞55 | 7.1 |
When ACV is 0.4 □ mol/ml, the inhibition ratio for HBsAg is 52.9%, and the inhibition ratio for HBeAg is 44.2%.
Example 16:
anti-tobacco mosaic virus activity of compound with structural formula (1)
Testing a toxic source: tobacco Mosaic Virus (TMV); the test plants: sansheng tobacco (Nicotiana Tabacum cv, "Samsum")
The test method comprises the following steps: the virus inoculation adopts a juice friction inoculation method: taking Sansheng tobacco leaves with typical TMV virus symptoms, adding phosphoric acid buffer solution (0.01mol/L, pH7.2), grinding in a mortar, dipping juice with a truncated writing brush boiled in boiling water, inoculating on leaf surfaces scattered with carborundum, rapidly washing with clear water, standing for a moment, and moving. Sample treatment: and after TMV inoculation is carried out for 1.5-2 h, cutting off inoculated leaves, cutting the inoculated leaves into two equal half leaves along the main pulse of the leaves, soaking half leaves in different compounds for treating, soaking the other half leaves in clear water for comparison, and investigating and counting half leaf dry spots after 72 h.
The survey statistical method comprises the following steps: the inhibition rate (%) of scorched spots was ═ number of half-leaf scorched spots of blank control-number of half-leaf scorched spots of drug-like treatment)/number of half-leaf scorched spots of blank control × 100%
The activity against tobacco mosaic virus of the compound of formula (II) at a concentration of 500ppm is shown in Table 6. Wherein the alpha-triazole substituted compound (II-15) has an inhibitory rate of 42% against tobacco mosaic virus at 250 ppm.
Table 6: inhibitory activity of compound with structural formula (II) on tobacco mosaic virus
| Ethers | Thioether | Sulfoxides | Sulfones | ||||
| Compound (I) | Inhibition ratio% | Compound (I) | Inhibition ratio% | Compound (I) | Inhibition ratio% | No. | Inhibition ratio% |
| II-3d | 44 | II-5a | 0 | II-7a | 0 | II-10 | 51 |
| II-3g | 5.5 | II-5b | 33 | II-8 | 20 | II-9f | 82 |
| II-3h | 3 | II-5d | 0 | II-7c | 31 | II-9a | 12 |
| II-3i | 53 | II-5g | 37 | II-7f* | 19 | II-9e | 0 |
| II-3b | 56 | II-5h | 15 | II-7b | 11 | II-9b | 19 |
| II-3a* | 64 | II-6 | 35 | ||||
| II-4* | 22 | II-5c | 42 | ||||
| II-12 | 35 | ||||||
| II-13 | 5 |
The control agent was virus A, used at a concentration of 100ppm, and had an inhibition rate of 71%.
*The control agent inhibition was 58%.
Example 17:
in vitro herbicidal activity of the compound of formula (1)
Most of the synthesized compounds were tested for herbicidal activity using the barnyard grass cupping and rape plate method.
Table 7: in vitro herbicidal activity of the compounds of formula (II)
| Concentration ppm of | Ethers | Thioether | Sulfoxides | Sulfones | ||||||||
| Compound (I) | Inhibition ratio% | Compound (I) | Inhibition ratio% | Compound (I) | Inhibition ratio% | Compound (I) | Inhibition ratio% | |||||
| Barnyard grass | Rape seed | Barnyard grass | Rape seed | Barnyard grass | Rape seed | Barnyard grass | Rape seed | |||||
| 100 | II-3d | 44 | 35 | II-5a | 21 | 39 | II-7f | 0 | 0 | II-10 | 23 | 89 |
| 10 | 0 | 0 | 0 | 6 | 0 | 0 | 0 | 25 | ||||
| 100 | II-3g | 22 | 20 | II-5b | 17 | 29 | II-7a | 13 | 0 | II-9f | 27 | 23 |
| 10 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | ||||
| 100 | II-3h | 35 | 30 | II-5d | 12 | 10 | II-8 | 35 | 0 | II-9a | 20 | 10 |
| 10 | 0 | 0 | 4 | 0 | 0 | 0 | 0 | 0 | ||||
| 100 | II-3i | 34 | 17 | II-5g | 14 | 0 | II-7d | 8 | 14 | II-9e | 0 | 0 |
| 10 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | ||||
| 100 | II-3c | 13 | 64 | II-5h | 19 | 4 | II-7c | 0 | 0 | II-9b | 24 | 0 |
| 10 | 0 | 9 | 0 | 0 | 0 | 0 | 0 | 0 | ||||
| 100 | II-6 | 12 | 6 | |||||||||
| 10 | 11 | 5 | ||||||||||
| 100 | II-12 | 20 | 41 | |||||||||
| 10 | 0 | 0 | ||||||||||
| 100 | II-13 | 0 | 11 | |||||||||
| 10 | 0 | 0 | ||||||||||
Example 17:
in vivo herbicidal activity of the compounds of formula (II)
Some compounds were subjected to a pot weeding test.
Table 8: in vivo herbicidal activity of the compounds of formula (II)
| Compound (I) | Soil treatment | Treatment of stems and leaves | ||||||||
| Barnyard grass | Tang style food | Amaranthus mangostanus L.var.amaranth | Rape seed | Alfalfa | Barnyard grass | Tang style food | Amaranthus mangostanus L.var.amaranth | Rape seed | Alfalfa | |
| II-3a | 0 | 0 | 21 | 0 | 17 | 0 | 62 | 0 | 0 | 20 |
| II-3b | 0 | 0 | 0 | 0 | 0 | 40 | 7 | 0 | 0 | |
Example 18:
plant growth regulating Activity of Compounds of formula (II)
We performed tests of plant growth regulating activity on partially differentiated compounds.
Table 9: growth regulating Activity of Compounds of formula (II)
| Test object | Concentration (ppm) | II-3a | II-3b | II-9f | II-7c | ||||
| Elongation of coleoptile of wheat | 10 | -1.9 | - | 10 | + | ||||
| Rooting of cucumber cotyledons | 10 | 107.5 | ++ | 69.2 | + | 15.4 | - | 61.5 | + |
| Expansion of cucumber cotyledon | 10 | -2.2 | - | 0 | - | ||||
| Rape hypocotyl | 10 | 6.5 | - | 10.1 | - | 10.2 | - | 18.1 | - |
Claims (9)
1. A1, 2, 3-thiadiazole compound characterized in that it is a compound of the structural formula (I):
wherein,
R1is hydrogen, halogen, alkyl, substituted aryl, alkoxy, substituted aryloxy, alkylthio, substituted arylthio, amino, alkylamino, arylamino, five-or six-membered heterocycle containing N, S elements;
R2is hydrogen, alkyl, substituted aryl, alkoxy, substitutedAryloxy, amino, alkylamino, substituted arylamine, five-or six-membered heterocycle containing N, S elements;
R3is hydrogen, alkyl, substituted aryl, alkoxy, substituted aryloxy, alkylamino, substituted arylamine, substituted benzyl, substituted arylethyl, five-membered or six-membered heterocycle containing N, S elements or heterocyclic methyl and ethyl thereof;
x is O, S, CH2CHR ', NH, NR ', R ' is hydrogen, alkyl or aryl;
y is O, S, SO2NH, NR ', R' is hydrogen, alkyl or aryl; y may also be a five-or six-membered heterocyclic ring containing the element N, S.
2. The 1, 2, 3-thiadiazole-based compound as defined in claim 1, which is a compound of the structural formula (II):
wherein,
R3is hydrogen, alkyl, substituted aryl, alkoxy, substituted aryloxy, alkylamino, substituted arylamine, alkylamino, substituted benzyl, substituted arylethyl, five-membered or six-membered heterocycle containing N, S elements or its heterocyclic methyl, ethyl;
y is O, S, SO2NH, NR ', R' is hydrogen, alkyl or aryl; y may also be a substituted five-or six-membered heterocyclic ring containing the element N, S.
3. A process for preparing a 1, 2, 3-thiadiazole compound as claimed in claim 1, which comprises the steps of:
(1) dissolving an alpha-chlorodicarbonyl compound (1) in an organic solvent, adding 0.8-10 times of hydrazide at the temperature of 0-80 ℃, continuously reacting for 0.5-20 hours, removing part of the solvent in vacuum, and recrystallizing to obtain a viscous liquid or solid target product (2);
(2) adding 1-20 times of thionyl chloride or sulfur dichloride into a reaction bottle, heating to-15-35 ℃, adding the compound (2) into the reaction bottle in batches under stirring, heating to 0-120 ℃ after adding, reacting for 5-48 hours, pouring into an alkali solution, separating out a large amount of solids, performing suction filtration, and recrystallizing with a solvent to obtain a target product (3);
(3) dissolving a compound containing hydroxyl, amino (amine) group and sulfhydryl in a proper organic solvent, adding 0.8-5 times of alkali, adding 0.8-3 times of compound (3) at the temperature of 0-80 ℃, after the reaction is finished, evaporating the solvent in vacuum, and leaching the residue on a silica gel column under reduced pressure to obtain a solid target product (4);
(4) when Y is S, the compound of the structural formula (4) is dissolved in a proper organic solvent, 0.9-5 times of oxidant is added, the reaction is carried out for 1-48 hours at the temperature of-15 ℃ to 60 ℃, after the solvent is removed, the solvent is used for recrystallization, and the compound of the structural formula (5) with Y being SO can be obtained. Reacting at 5-100 deg.C for 0.5-24 hr to obtain Y as SO2The structural formula (5).
4. A process for the preparation of 1, 2, 3-thiadiazoles according to claim 3, characterized in that said base is KOH, NaOH, K2CO3、Na2CO3、NaHCO3Triethylamine, tri-n-butylamine, pyridine or DMAP.
5. The process for producing 1, 2, 3-thiadiazole compound according to claim 3, wherein the organic solvent is a single solvent or a mixed solvent of water, methanol, ethanol, acetonitrile, acetic acid, ethyl acetate, diethyl ether, dipropyl ether, chloroform, dichloromethane, acetone, methyl ethyl ketone, DMF or DMSO.
6. A process for preparing a 1, 2, 3-thiadiazole compound according to claim 3, characterized in that said oxidizing agent is H2O2Potassium permanganate or peroxyacid.
7. The use of a 1, 2, 3-thiadiazole compound as claimed in claim 1, for the treatment or prophylaxis of hepatitis b virus infection.
8. The use of the 1, 2, 3-thiadiazole compound according to claim 1, which is characterized in that it is formulated into a mixture or a preparation including emulsifiable concentrate, powder, aqueous solution or suspension for controlling plant viruses in agriculture.
9. Use of 1, 2, 3-thiadiazoles according to claim 8, characterized in that it is used for the control of tobacco leaf virus.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101250168B (en) * | 2008-03-28 | 2011-12-14 | 南开大学 | Thiadiazoles imine derivative as well as synthesis and uses thereof |
| CN103214432A (en) * | 2013-05-02 | 2013-07-24 | 南开大学 | 5-methyl-1,2,3-thiadiazole based alpha-(substituted)oxyamide derivatives and preparation methods and application thereof |
| CN103214476A (en) * | 2013-05-02 | 2013-07-24 | 南开大学 | Formamidine derivatives containing 4-methyl-1,2,3-thiadiazole, and preparation methods and uses |
| CN103214475A (en) * | 2013-05-02 | 2013-07-24 | 南开大学 | Alpha-(substituted)oxyamide derivatives containing 4-methyl-1,2,3-thiadiazole and preparation methods and application thereof |
| CN103232448A (en) * | 2013-05-02 | 2013-08-07 | 南开大学 | 4, 5-dihydro thiazole alcoholic ester derivative containing 4-methyl-1, 2, 3-thiadiazole and preparation method and application thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101250168B (en) * | 2008-03-28 | 2011-12-14 | 南开大学 | Thiadiazoles imine derivative as well as synthesis and uses thereof |
| CN103214432A (en) * | 2013-05-02 | 2013-07-24 | 南开大学 | 5-methyl-1,2,3-thiadiazole based alpha-(substituted)oxyamide derivatives and preparation methods and application thereof |
| CN103214476A (en) * | 2013-05-02 | 2013-07-24 | 南开大学 | Formamidine derivatives containing 4-methyl-1,2,3-thiadiazole, and preparation methods and uses |
| CN103214475A (en) * | 2013-05-02 | 2013-07-24 | 南开大学 | Alpha-(substituted)oxyamide derivatives containing 4-methyl-1,2,3-thiadiazole and preparation methods and application thereof |
| CN103232448A (en) * | 2013-05-02 | 2013-08-07 | 南开大学 | 4, 5-dihydro thiazole alcoholic ester derivative containing 4-methyl-1, 2, 3-thiadiazole and preparation method and application thereof |
| CN103214432B (en) * | 2013-05-02 | 2015-08-26 | 南开大学 | Based on 5-methyl isophthalic acid, α-(replacement) hydroxyamide derivatives of 2,3-thiadiazoles and its production and use |
| CN103214475B (en) * | 2013-05-02 | 2016-01-20 | 南开大学 | One class contains 4-methyl isophthalic acid, α-(replacement) hydroxyamide derivatives of 2,3-thiadiazoles and its production and use |
| CN103232448B (en) * | 2013-05-02 | 2016-03-30 | 南开大学 | One class contains 4-methyl isophthalic acid, 4,5-thiazoline carboxylic ester derivatives of 2,3-thiadiazoles and its production and use |
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| CN1166650C (en) | 2004-09-15 |
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