CN102040595B - 1,3,4-hiadiazine derivatives as well as preparation method and application thereof - Google Patents
1,3,4-hiadiazine derivatives as well as preparation method and application thereof Download PDFInfo
- Publication number
- CN102040595B CN102040595B CN 200910235377 CN200910235377A CN102040595B CN 102040595 B CN102040595 B CN 102040595B CN 200910235377 CN200910235377 CN 200910235377 CN 200910235377 A CN200910235377 A CN 200910235377A CN 102040595 B CN102040595 B CN 102040595B
- Authority
- CN
- China
- Prior art keywords
- thiadiazine
- phthalimide
- structural formula
- chemical structural
- ethyl
- 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.)
- Active
Links
- 0 CC(C(*)C(C1*)[C@@]2C1C(O1)=O)[C@@](C)(*)C2C1=O Chemical compound CC(C(*)C(C1*)[C@@]2C1C(O1)=O)[C@@](C)(*)C2C1=O 0.000 description 7
- IFJOKHVJBYSWMM-UHFFFAOYSA-N CC(C1=NN=C(N(C)C)SC1)N(C(c1c2cccc1)=O)C2=O Chemical compound CC(C1=NN=C(N(C)C)SC1)N(C(c1c2cccc1)=O)C2=O IFJOKHVJBYSWMM-UHFFFAOYSA-N 0.000 description 1
- ZJLZXUYLSUCDSE-UHFFFAOYSA-N CC(C1=NN=C(Nc(cc2)ccc2Cl)SC1)N(C(c1ccccc11)=O)C1=O Chemical compound CC(C1=NN=C(Nc(cc2)ccc2Cl)SC1)N(C(c1ccccc11)=O)C1=O ZJLZXUYLSUCDSE-UHFFFAOYSA-N 0.000 description 1
- SHWFVDZOGSEYLC-UHFFFAOYSA-N CC(C1=NN=C(Nc(cc2)ccc2[N+]([O-])=O)SC1)N(C(c1c2cccc1)=O)C2=O Chemical compound CC(C1=NN=C(Nc(cc2)ccc2[N+]([O-])=O)SC1)N(C(c1c2cccc1)=O)C2=O SHWFVDZOGSEYLC-UHFFFAOYSA-N 0.000 description 1
- IWNAGUJELPBFNB-UHFFFAOYSA-N CC(C1=NN=C(Nc2ccccc2)SC1)N(C(c1ccccc11)=O)C1=O Chemical compound CC(C1=NN=C(Nc2ccccc2)SC1)N(C(c1ccccc11)=O)C1=O IWNAGUJELPBFNB-UHFFFAOYSA-N 0.000 description 1
- WOVVIMYGCAFKAW-UHFFFAOYSA-N CCOC(CN(c1ccccc1)C(SC1)=NN=C1C(C)N(C(c1c2cccc1)=O)C2=O)O Chemical compound CCOC(CN(c1ccccc1)C(SC1)=NN=C1C(C)N(C(c1c2cccc1)=O)C2=O)O WOVVIMYGCAFKAW-UHFFFAOYSA-N 0.000 description 1
- NMZUVAQWDKHIOQ-UHFFFAOYSA-N O=C(c1c2cccc1)N(C(Cc1ccccc1)C1=NN=C(Nc3ccccc3)SC1)C2=O Chemical compound O=C(c1c2cccc1)N(C(Cc1ccccc1)C1=NN=C(Nc3ccccc3)SC1)C2=O NMZUVAQWDKHIOQ-UHFFFAOYSA-N 0.000 description 1
- VIBWOQDEYFTVMN-UHFFFAOYSA-N O=C(c1ccccc11)N(CCC2=NN=C(Nc3ccccc3)SC2)C1=O Chemical compound O=C(c1ccccc11)N(CCC2=NN=C(Nc3ccccc3)SC2)C1=O VIBWOQDEYFTVMN-UHFFFAOYSA-N 0.000 description 1
- JLFTXGUKRRJEKT-UHFFFAOYSA-N O=C(c1ccccc11)N(CCCC2=NN=C(Nc3ccccc3)SC2)C1=O Chemical compound O=C(c1ccccc11)N(CCCC2=NN=C(Nc3ccccc3)SC2)C1=O JLFTXGUKRRJEKT-UHFFFAOYSA-N 0.000 description 1
Abstract
The invention discloses a kind of novel medicament compositions for treating virus infection as well as a preparation method and application thereof. The medicament compositions comprise compounds of formula (I) shown as the specification or pharmaceutical salts or esters thereof as active components, in the formula, R1, R2, R3, R4, R5, R6 and R7 are defined as in the specification.
Description
Invention field
The present invention relates to new 1,3,4-thiadiazine derivatives and can do medicinal salt or ester, its preparation method contains their pharmaceutical composition, and as medicine, especially as the purposes of antiviral.
Background technology
The nerpes vinrus hominis is divided into 8 types, mainly through contact transmission, invades the tissue (comprising skin, mucous membrane and nervous tissue) in ectoderm source.Herpes simplex virus type 1 (herpes simplex virus-1 wherein; HSV-1), herpes simplex virus type 2 (HSV-2), varicella zoster virus (varicella-zoster virus; VZV), cytomegalovirus (cytomegalovirus, CMV), Epstein-Barr virus (Epstein-Barr virus, EBV), human herpes virus type 8 (human herpes virus-8; HHV-8) all skin mucosa be can cause, oral cavity and phallic sick the damage comprised.
1,3, the 4-thiadiazine is a 6-membered heterocyclic compound, has multiple physiologically active and pharmacological actions such as anti-inflammatory, pain relieving, antimicrobial, antibiotic, Ivy extract, relaxed muscle.As one type of important physical active substance, its synthetic people's attention that always receives.But Shang Weijian is about synthesizing 1,3, and the 4-thiadiazine derivatives is to obtain the bibliographical information of stronger antiviral activity.
The present invention is in order to strengthen its activity; Introduce different substituted radicals, obtained one type novel 1,3; 4-thiadiazine derivatives and can do medicinal salt or ester; Tested its antiviral activity, can be developed further into antiviral such as relevant with it treatment bleb, trachoma, to satisfy the needs of clinical application.
Summary of the invention
The object of the present invention is to provide new 1,3,4-thiadiazine derivatives and can do medicinal salt or ester;
Another object of the present invention is to provide new 1,3,4-thiadiazine derivatives and can be the preparation method of medicinal salt or ester;
Another object of the present invention is to provide new 1,3,4-thiadiazine derivatives and can do medicinal salt or ester, its compsn is as the application of medicine.
One aspect of the present invention relates to pharmaceutical composition, and it comprises carrier commonly used in the compound shown in the general formula (I) as active ingredient and optical isomer and the pharmacy field.
Further aspect of the present invention relates to is compound shown in the general formula (I) and can does medicinal salt or ester or contain the anti-viral uses of their pharmaceutical composition.
The present invention has synthesized has 1,3 shown in the following general formula (I), 4-thiadiazine derivatives and at pharmaceutically acceptable salt and ester:
In the general formula (I): the A ring can be preferably phenyl ring for phenyl ring, cyclohexene ring, cyclohexane ring;
R
1, R
2, R
3, R
4Can be identical or different, R
1, R
2, R
3, R
4, be independently selected from Wasserstoffatoms, halogen, nitro, amino, hydroxyl, C
1-
18Alkyl, C
1-
18Alkoxyl group, C
1-
18Alkylamino, C
1-
18Alkoxy acyl, nitro, C
1-
18Replacement of alkyl list or bis substituted amine base, C
2-
18Naphthenic base, C
2-
18Thiazolinyl, C
2-
18The substituted aryl of alkynyl, aryl, electron-donating group or electron-withdrawing group, heterocycle, the substituted naphthenic base of heteroatoms, fatty acyl group, aromaticacyl radical;
Preferred R
1, R
2, R
3, R
4Be selected from Wasserstoffatoms, fluorine atom, chlorine atom, bromine atoms, hydroxyl, amino, C
1-4Alkyl, C
1-4Alkoxyl group, C
1-4Alkoxy acyl, C
1-4Replacement of alkyl list or bis substituted amine base, C
2-4Thiazolinyl, C
2-4Alkynyl, C
3-6Naphthenic base;
Preferred R
1, R
2, R
3, R
4Be Wasserstoffatoms, bromine atoms, nitro, hydroxyl, methyl, ethyl, propyl group, sec.-propyl, normal-butyl;
R
5, represent Wasserstoffatoms, halogen, nitro, amino, hydroxyl, C
1-18Alkyl, C
1-18Alkoxyl group, C
1-18Replacement of alkyl list or bis substituted amine base, C
2-18Naphthenic base, C
2-18Thiazolinyl, C
2-18The substituted aryl of alkynyl, aryl, electron-donating group or electron-withdrawing group, aralkyl;
Preferred R
5Be Wasserstoffatoms, C
1-6Alkyl, C
1-6Aralkyl, C
1-6Alkoxyl group, aryl, substituted aryl;
R
6, R
7Can be identical or different, R
6, R
7Be independently selected from Wasserstoffatoms, C
1-18Alkyl, naphthenic base, C
2-18Thiazolinyl, C
1-18Alkoxyl group, C
1-18Alkylamino, fatty acyl group, aryl, heterocycle, aromaticacyl radical, aralkyl;
Preferred R
6, R
7Be Wasserstoffatoms, C
1-4Alkyl, hexanaphthene, C
1-4Alkoxyl group, allyl amido, nitro, ethanoyl, benzoyl-, benzyl, ethoxycarbonylmethyl group;
N is 0-10, is preferably 0-2.
Of the present invention 1,3, the 4-thiadiazine derivatives can prepare through following method:
Reaction formula (I)
Compound 1 obtains compound 2 under the effect of catalyzer and solvent, temperature of reaction is 50～150 ℃, and the reaction times is 1～24 hour; Said solvent is Glacial acetic acid min. 99.5, ethanol, methyl alcohol, and said catalyzer comprises NaHCO
3, Na
2CO
3, K
2CO
3, triethylamine or pyridine etc.;
Compound 2 obtains compound 3 under the effect of catalyzer and solvent, temperature of reaction is-15～100 ℃, and the reaction times is 1～24 hour; Said solvent is methylene dichloride, chloroform, DMF, and said catalyzer comprises SOCl
2, (COCl)
2Deng;
Compound 3 obtains compound 4 under the effect of catalyzer and solvent, temperature of reaction is-15～50 ℃, and the reaction times is 1～24 hour; Said solvent is ether, toluene, DMF, and said catalyzer is a diazomethane;
Compound 4 obtains compound 5 under the effect of catalyzer and solvent, temperature of reaction is-15～50 ℃, and the reaction times is 1～24 hour; Said solvent is Glacial acetic acid min. 99.5, THF, DMF, and said catalyzer is Hydrogen bromide, spirit of salt, hydroiodic acid HI etc.;
Compound 5 obtains target compound 6 under the effect of catalyzer and solvent, temperature of reaction is 20～150 ℃, and the reaction times is 1～24 hour; Said solvent is ethanol, methyl alcohol, toluene, acetonitrile, DMF, and said catalyzer comprises NaHCO
3, Na
2CO
3, K
2CO
3, triethylamine or pyridine etc.;
Contain basic group in the compound molecule of the present invention, thereby can form acid salt.The example of this type acid salt comprises: with mineral acid, and haloid acid (like hydrofluoric acid, spirit of salt, Hydrogen bromide or hydroiodic acid HI) especially, nitric acid, carbonic acid, the salt that sulfuric acid or phosphoric acid became; With low alkyl group sulfonic acid, like methylsulfonic acid, the salt that trifluoromethanesulfonic acid or ethyl sulfonic acid became; With aryl sulfonic acid, like the salt that Phenylsulfonic acid or tosic acid became; With organic carboxyl acid, like acetate, fumaric acid, tartrate, oxalic acid, toxilic acid, oxysuccinic acid, the salt that succsinic acid or Hydrocerol A became; With amino acid, like the salt that L-glutamic acid or aspartic acid became.The compounds of this invention can through common means, like s.t., change into pharmacy acceptable salt as this specialty is generally acknowledged.
The compounds of this invention is capsule for example, tablet, and pulvis, granule, syrup or similar dosage form oral administration, or through injection, ointment, suppository or the administration of similar formulation parenteral.These pharmaceutical prepns can be through the auxiliary of knowing with general specialty, like tackiness agent, and vehicle, stablizer; Disintegrating agent, correctives, lubricant or the like generates with usual way, though dosage is with symptom and patient's age; The approach of the character of disease or imbalance and seriousness and administration and mode and become, but concerning adult patient's case of oral administration, the normal administration of The compounds of this invention are total dose 1 to 1000mg every day; Being preferably 5 to 500mg, thinking single dose, perhaps is the divided dose form; For example every day secondary or three times; For intravenous situation, can divide every day and give for one to three time with 0.1 to 100mg, be preferably 0.5 to 50mg dosage.
The compounds of this invention shows the predominant suppressing effect to dna virus especially simplexvirus, thereby is used to treat dna virus infection property disease especially skin, reproductive system disease of viral infection, and is very useful as the antiviral therapy medicine.
The BA of The compounds of this invention and toxicity are through measuring the IC that it suppresses dna virus infection VERO cell
50And TD
50, TD
0Test is accomplished.
Embodiment
Below further set forth the present invention through embodiment, but do not limit the present invention in any way.
Embodiment 12-anilino-5-(1-phthalimide ethyl)-6H-1,3, the preparation of 4-thiadiazine (T1)
1-a:2-phthalimide propionic acid is Tetra hydro Phthalic anhydride 5.00g (33.8mmol), L-Ala 3.60g (40.4mmol), Glacial acetic acid min. 99.5 20mL; Place the 50mL reaction flask, be back to no raw material residue, put cold; Pour in the 50mL cold water, separate out white solid, filter; Washing, dry white solid 6.50g, the productive rate 87.8% of getting.
1HNMR(300M，DMSO-d
6)：δ1.54(d，3H)，4.86(q，1H)，7.84-7.91(m，4H)，13.11(s，1H).
1-b:1-bromo-3-phthalimide-2-butanone is with 2-phthalimide propionic acid 2.19g (10.0mmol), and thionyl chloride 10mL places the 50mL reaction flask, is back to no raw material residue, and decompression is revolved dried, gets a brown oil, and is subsequent use.The 15mL 50%KOH aqueous solution is joined in the 40mL ether, place under the ice bath, slowly add 6.00g (33.8mmol) nitrous methyl urea in batches, finish, ether layer is told in jolting 10 minutes, with sheet KOH dry 2 hours.The above-mentioned diethyl ether solution that contains diazomethane is put into the 100mL reaction flask, place under the ice bath, slowly drip the toluene solution (2mL) of above-mentioned oily matter, finish, to reacting completely, filter, with the ether flushing, dry gained solid is subsequent use.Solid is dissolved in the 20mL THF, drips 2mL 40%HBr, to reacting completely, decompression is revolved dried.Add 100mL ETHYLE ACETATE, place separating funnel, use saturated NaHCO respectively
3, water, saturated NaCl solution washes anhydrous Mg
2SO
4Dry.Decompression is revolved dried, through 95% ethyl alcohol recrystallization, obtains white solid 1.90g, yield 64.2%.
1HNMR(300M，CDCl
3)：δ1.67(d，3H)，3.99(dd，2H)，5.22(q，1H)，7.76-7.80(m，2H)，7.87-7.90(m，2H).
1-c:2-anilino-5-(1-phthalimide ethyl)-6H-1,3, the 4-thiadiazine is 1-bromo-3-phthalimide-2-butanone 0.296g (1.00mmol), 4-phenyl-3-thiosemicarbazide 0.167g (1.00mmol), NaHCO
30.084g (1.00mmol), ethanol 15mL places the 50mL reaction flask, is back to no raw material residue, puts coldly, pours in the 15mL cold water, filters washing, drying.The gained solid gets white solid 0.175g, productive rate 48.1% through 95% ethanol/DMF recrystallization.
1HNMR(300M，DMSO-d
6)：δ1.66(d，3H)，3.43(s，2H)，5.14(q，1H)，6.96-7.01(m，3H)，7.22-7.27(m，2H)，7.83-7.90(m，4H)；ESI-MS：[M+H]
+365.1089，[M+Na]
+387.0906.
Embodiment 22-(4-fluoro-anilino)-5-(1-phthalimide ethyl)-6H-1,3, the preparation of 4-thiadiazine (T2)
With 1-bromo-3-phthalimide-2-butanone 0.296g (1.00mmol), 4-(4-fluoro-phenyl)-3-thiosemicarbazide 0.185g (1.00mmol), NaHCO
30.084g (1.00mmol), ethanol 15mL places the 50mL reaction flask, is back to no raw material residue, puts coldly, pours in the 15mL cold water, filters washing, drying.The gained solid gets white solid 0.170g, productive rate 44.5% through 95% ethanol/DMF recrystallization.
1HNMR(300M，DMSO-d
6)：δ1.65(d，3H)，3.45(s，2H)，5.13(q，1H)，6.79(s，1H)，7.08(dd，2H)，7.83-7.90(m，4H)，10.98(s，1H).
Embodiment 32-(4-chloro-anilino)-5-(1-phthalimide ethyl)-6H-1,3, the preparation of 4-thiadiazine (T3)
With 1-bromo-3-phthalimide-2-butanone 0.296g (1.00mmol), 4-(4-fluoro-phenyl)-3-thiosemicarbazide 0.201g (1.00mmol), NaHCO
30.084g (1.00mmol), ethanol 15mL places the 50mL reaction flask, is back to no raw material residue, puts coldly, pours in the 15mL cold water, filters washing, drying.The gained solid gets white solid 0.300g, productive rate 65.3% through 95% ethanol/DMF recrystallization.
1HNMR(300M，DMSO-d
6)：δ1.66(d，3H)，3.47(s，2H)，5.14(q，1H)，6.79(s，1H)，7.29(d，2H)，7.83-7.90(m，4H)，11.05(s，1H).
Embodiment 42-benzamido group-5-(1-phthalimide ethyl)-6H-1,3, the preparation of 4-thiadiazine (T4)
With 1-bromo-3-phthalimide-2-butanone 0.296g (1.00mmol), 4-benzyl-3-thiosemicarbazide 0.181g (1.00mmol), NaHCO
30.084g (1.00mmol), ethanol 15mL places the 50mL reaction flask, is back to no raw material residue, puts coldly, pours in the 50mL cold water, with 50mL ethyl acetate extraction three times.ETHYLE ACETATE merges mutually, concentrates, and silicagel column separates, and through petrol ether/ethyl acetate different ratios wash-out, gets yellow oil 0.240g, productive rate 63.4%.
1HNMR(300M，DMSO-d
6)：δ1.67(d，3H)，3.27(s，2H)，4.46(s，2H)，5.12(q，1H)，6.79-7.33(m，5H)，7.82-7.89(m，4H).
Embodiment 52-hexanaphthene amido-5-(1-phthalimide ethyl)-6H-1,3, the preparation of 4-thiadiazine (T5)
With 1-bromo-3-phthalimide-2-butanone 0.296g (1.00mmol), 4-cyclohexyl-3-thiosemicarbazide 0.173g (1.00mmol), NaHCO
30.084g (1.00mmol), ethanol 15mL places the 50mL reaction flask, is back to no raw material residue, puts coldly, pours in the 50mL cold water, with 50mL ethyl acetate extraction three times.ETHYLE ACETATE merges mutually, concentrates, and silicagel column separates, and through petrol ether/ethyl acetate different ratios wash-out, gets yellow solid 0.192g, productive rate 51.8%.
1HNMR(300M，CDCl
3)：δ1.11-1.42(m，6H)，1.59-1.73(m，4H)，1.80(d，3H)，3.15(dd，2H)，5.29(q，1H)，7.71-7.86(m，4H).
Embodiment 62-dimethylin-5-(1-phthalimide ethyl)-6H-1,3, the preparation of 4-thiadiazine (T6)
With 1-bromo-3-phthalimide-2-butanone 0.296g (1.00mmol), 4,4-dimethyl--3-thiosemicarbazide 0.119g (1.00mmol), NaHCO
30.084g (1.00mmol), ethanol 15mL places the 50mL reaction flask, is back to no raw material residue, puts coldly, pours in the 50mL cold water, with 50mL ethyl acetate extraction three times.ETHYLE ACETATE merges mutually, concentrates, and silicagel column separates, and through petrol ether/ethyl acetate different ratios wash-out, gets yellow oil 0.170g, productive rate 57.7%.
1HNMR(300M，CDCl
3)：δ1.78(d，3H)，2.15(s，3H)，3.12-3.17(m，5H)，5.28(q，1H)，7.69-7.83(m，4H).
Embodiment 72-allyl amido-5-(1-phthalimide ethyl)-6H-1,3, the preparation of 4-thiadiazine (T7)
With 1-bromo-3-phthalimide-2-butanone 0.296g (1.00mmol), 4-allyl group-3-thiosemicarbazide 0.131g (1.00mmol), NaHCO
30.084g (1.00mmol), ethanol 15mL places the 50mL reaction flask, is back to no raw material residue, puts coldly, pours in the 50mL cold water, with 50mL ethyl acetate extraction three times.ETHYLE ACETATE merges mutually, concentrates, and silicagel column separates, and through petrol ether/ethyl acetate different ratios wash-out, gets yellow solid 0.264g, productive rate 80.4%.
1HNMR(300M，CDCl
3)：δ1.76(d，3H)，3.13(dd，2H)，4.04(d，2H)，5.09-5.29(m，2H)，5.85-5.94(m，1H)，7.67-7.82(m，4H).
Embodiment 82-(4-nitro-anilino)-5-(1-phthalimide ethyl)-6H-1,3, the preparation of 4-thiadiazine (T8)
With 1-bromo-3-phthalimide-2-butanone 0.296g (1.00mmol), 4-(4-nitro-phenyl)-3-thiosemicarbazide 0.212g (1.00mmol), NaHCO
30.084g (1.00mmol), ethanol 15mL places the 50mL reaction flask, is back to no raw material residue, puts coldly, pours in the 15mL cold water, filters washing, drying.The gained solid gets white solid 0.240g, productive rate 58.6% through 95% ethanol/DMF recrystallization.
1HNMR(300M，CD
3COCD
3)：δ1.77(d，3H)，3.59(s，2H)，5.27(q，1H)，7.09(s，1H)，7.87(s，4H)，8.17(d，2H).
Embodiment 92-(4-methoxyl group-anilino)-5-(1-phthalimide ethyl)-6H-1,3, the preparation of 4-thiadiazine (T9)
With 1-bromo-3-phthalimide-2-butanone 0.296g (1.00mmol), 4-(4-methoxyl group-phenyl)-3-thiosemicarbazide 0.197g (1.00mmol), NaHCO
30.084g (1.00mmol), ethanol 15mL places the 50mL reaction flask, is back to no raw material residue, puts coldly, pours in the 50mL cold water, with 50mL ethyl acetate extraction three times.ETHYLE ACETATE merges mutually, concentrates, and silicagel column separates, and through petrol ether/ethyl acetate different ratios wash-out, gets yellow solid 0.130g, productive rate 33.0%.
1HNMR(300M，CD
3COCD
3)：δ1.75(d，3H)，3.48(dd，2H)，3.74(s，2H)，5.23(q，1H)，6.81-6.89(m，4H)，7.83-7.86(m，4H).
Embodiment 102-(4-methyl-anilino)-5-(1-phthalimide ethyl)-6H-1,3, the preparation of 4-thiadiazine (T10)
With 1-bromo-3-phthalimide-2-butanone 0.296g (1.00mmol), 4-(4-methyl-phenyl)-3-thiosemicarbazide 0.181g (1.00mmol), NaHCO
30.084g (1.00mmol), ethanol 15mL places the 50mL reaction flask, is back to no raw material residue, puts coldly, pours in the 15mL cold water, filters washing, drying.The gained solid gets white solid 0.200g, productive rate 52.8% through 95% ethanol/DMF recrystallization.
1HNMR(300M，CD
3COCD
3)：δ1.75(d，3H)，2.25(s，3H)，3.48(dd，2H)，5.23(q，1H)，6.88(d，2H)，7.05(d，2H)，7.83-7.86(m，4H).
Embodiment 112-(2-fluoro-anilino)-5-(1-phthalimide ethyl)-6H-1,3, the preparation of 4-thiadiazine (T11)
With 1-bromo-3-phthalimide-2-butanone 0.296g (1.00mmol), 4-(4-fluoro-phenyl)-3-thiosemicarbazide 0.185g (1.00mmol), NaHCO
30.084g (1.00mmol), ethanol 15mL places the 50mL reaction flask, is back to no raw material residue, puts coldly, pours in the 50mL cold water, with 50mL ethyl acetate extraction three times.ETHYLE ACETATE merges mutually, concentrates, and silicagel column separates, and through petrol ether/ethyl acetate different ratios wash-out, gets yellow solid 0.240g, productive rate 62.8%.
1HNMR(300M，CD
3COCD
3)：δ1.74(d，3H)，3.56(dd，2H)，5.27(q，1H)，6.95-6.7.11(m，4H)，7.83-7.86(m，4H).
Embodiment 122-(4-chloro-benzamido group)-5-(1-phthalimide ethyl)-6H-1,3, the preparation of 4-thiadiazine (T12)
With 1-bromo-3-phthalimide-2-butanone 0.296g (1.00mmol), 4-(4-chloro-benzyl)-3-thiosemicarbazide 0.216g (1.00mmol), NaHCO
30.084g (1.00mmol), ethanol 15mL places the 50mL reaction flask, is back to no raw material residue, puts coldly, pours in the 50mL cold water, with 50mL ethyl acetate extraction three times.ETHYLE ACETATE merges mutually, concentrates, and silicagel column separates, and through petrol ether/ethyl acetate different ratios wash-out, gets yellow oil 0.145g, productive rate 35.1%.
1HNMR(300M，DMSO-d
6)：δ1.67(d，3H)，3.28(s，2H)，3.43(dd，2H)，5.12(q，1H)，7.29-7.37(m，4H)，7.82-7.86(m，4H).
Embodiment 132-(3-pyridine amido)-5-(1-phthalimide ethyl)-6H-1,3, the preparation of 4-thiadiazine (T13)
With 1-bromo-3-phthalimide-2-butanone 0.296g (1.00mmol), 4-(3-pyridyl)-3-thiosemicarbazide 0.168g (1.00mmol), NaHCO
30.084g (1.00mmol), ethanol 15mL places the 50mL reaction flask, is back to no raw material residue, puts coldly, pours in the 50mL cold water, with 50mL ethyl acetate extraction three times.ETHYLE ACETATE merges mutually, concentrates, and silicagel column separates, and through petrol ether/ethyl acetate different ratios wash-out, gets yellow solid 0.180g, productive rate 49.3%.
1HNMR(300M，DMSO-d
6)：δ1.65(d，3H)，3.50(dd，2H)，5.13(q，1H)，7.20(s，1H)，7.26-7.30(m，1H)，7.83-7.90(m，4H)，8.07(s，1H)，8.20(s，1H)，11.19(s，1H).
Embodiment 142-(2-pyridine amido)-5-(1-phthalimide ethyl)-6H-1,3, the preparation of 4-thiadiazine (T14)
With 1-bromo-3-phthalimide-2-butanone 0.296g (1.00mmol), 4-(2-pyridyl)-3-thiosemicarbazide 0.168g (1.00mmol), NaHCO
30.084g (1.00mmol), ethanol 15mL places the 50mL reaction flask, is back to no raw material residue, puts coldly, pours in the 50mL cold water, with 50mL ethyl acetate extraction three times.ETHYLE ACETATE merges mutually, concentrates, and silicagel column separates, and through petrol ether/ethyl acetate different ratios wash-out, gets yellow solid 0.150g, productive rate 41.1%.
1HNMR(300M，DMSO-d
6)：δ1.67(d，3H)，3.28(dd，2H)，5.16(q，1H)，6.94-6.98(m，1H)，7.03-7.06(m，1H)，7.63-7.69(m，1H)，7.84-7.91(m，4H)，8.29-8.30(m，1H)，11.27(s，1H).
Embodiment 152-anilino-5-(1-(4-bromo-phthalimide) ethyl)-6H-1,3, the preparation of 4-thiadiazine (T15)
15-a:2-(4-bromo-phthalimide) propionic acid is with 3.00g (13.2mmol) 4-phthalate bromine acid anhydride, L-Ala 1.20g (13.5mmol), Glacial acetic acid min. 99.5 20mL; Place the 50mL reaction flask, be back to no raw material residue, put cold; Pour in the 50mL cold water, separate out white solid, filter; Washing, dry white solid 2.89g, the productive rate 73.4% of getting.
1HNMR(300M，CD
3COCD
3)：δ1.67(d，3H)，4.98(q，1H)，7.81(d，1H)，8.01-8.08(m，2H).
15-b:1-bromo-3-(4-bromo-phthalimide)-2-butanone is with 2-(4-bromo-phthalimide) propionic acid 2.50g (8.39mmol), and thionyl chloride 10mL places the 50mL reaction flask, is back to no raw material residue, and decompression is revolved dried, gets a brown oil, and is subsequent use.The 15mL 50%KOH aqueous solution is joined in the 40mL ether, place under the ice bath, slowly add 6.00g (33.8mmol) nitrous methyl urea in batches, finish, ether layer is told in jolting 10 minutes, with sheet KOH dry 2 hours.The above-mentioned diethyl ether solution that contains diazomethane is put into the 100mL reaction flask, place under the ice bath, slowly drip the toluene solution (2mL) of above-mentioned oily matter, finish, to reacting completely, filter, with the ether flushing, dry gained solid is subsequent use.Solid is dissolved in the 20mL THF, drips 2mL 40%HBr, to reacting completely, decompression is revolved dried.Add 100mL ETHYLE ACETATE, place separating funnel, use saturated NaHCO respectively
3, water, saturated NaCl solution washes anhydrous Mg
2SO
4Dry.Decompression is revolved dried, through 95% ethyl alcohol recrystallization, obtains white solid 2.50g, yield 79.5%.
1HNMR(300M，CDCl
3)：δ1.68(d，3H)，3.98(s，2H)，5.22(q，1H)，7.77(dd，1H)，7.91(dd，1H)，8.01(dd，1H).
15-c:2-anilino-5-(1-(4-bromo-phthalimide) ethyl)-6H-1,3, the 4-thiadiazine is with 1-bromo-3-(4-bromo-phthalimide)-2-butanone 0.200g (0.533mmol), 4-phenyl-3-thiosemicarbazide 0.090g (0.539mmol), NaHCO
30.050g (0.595mmol), ethanol 15mL places the 50mL reaction flask, is back to no raw material residue, puts coldly, pours in the 15mL cold water, filters washing, drying.The gained solid gets white solid 0.059g, productive rate 25.0% through 95% ethanol/DMF recrystallization.
1HNMR(300M，DMSO-d
6)：δ1.65(d，3H)，3.42(s，2H)，5.12(q，1H)，6.79(s，1H)，6.96-7.01(m，1H)，7.22-7.27(m，2H)，7.81(d，1H)，8.04-8.09(m，2H)，10.97(s，1H).
Embodiment 162-anilino-5-(1-(3-nitro-phthalimide) ethyl)-6H-1,3, the preparation of 4-thiadiazine (T16)
16-a:2-(3-nitro-phthalimide) propionic acid is with 3.90g (20.2mmol) 3-nitrophthalic acid acid anhydride, L-Ala 2.20g (24.7mmol), Glacial acetic acid min. 99.5 20mL; Place the 50mL reaction flask, be back to no raw material residue, put cold; Pour in the 50mL cold water, separate out white solid, filter; Washing, dry white solid 4.57g, the productive rate 85.7% of getting.
1HNMR(300M，DMSO-d
6)：δ1.53(d，3H)，4.89(q，1H)，8.09(dd，1H)，8.21(dd，1H)，8.31(dd，1H)，13.21(s，1H).
16-b:1-bromo-3-(3-nitro-phthalimide)-2-butanone is with 2-(3-nitro-phthalimide) propionic acid 2.64g (10.0mmol), and thionyl chloride 10mL places the 50mL reaction flask, is back to no raw material residue, and decompression is revolved dried, gets a brown oil, and is subsequent use.The 15mL 50%KOH aqueous solution is joined in the 40mL ether, place under the ice bath, slowly add 6.00g (33.8mmol) nitrous methyl urea in batches, finish, ether layer is told in jolting 10 minutes, with sheet KOH dry 2 hours.The above-mentioned diethyl ether solution that contains diazomethane is put into the 100mL reaction flask, place under the ice bath, slowly drip the toluene solution (2mL) of above-mentioned oily matter, finish, to reacting completely, filter, with the ether flushing, dry gained solid is subsequent use.Solid is dissolved in the 20mL THF, drips 2mL 40%HBr, to reacting completely, decompression is revolved dried.Add 100mL ETHYLE ACETATE, place separating funnel, use saturated NaHCO respectively
3, water, saturated NaCl solution washes anhydrous Mg
2SO
4Dry.Decompression is revolved dried, through column chromatography for separation, obtains brown oil 2.10g, yield 61.8%.
1HNMR(300M，DMSO-d
6)：δ1.67(d，3H)，4.43(dd，2H)，5.24(q，1H)，8.12-8.29(m，3H).
16-c:2-anilino-5-(1-(3-nitro-phthalimide) ethyl)-6H-1,3, the 4-thiadiazine is 1-bromo-3-(3-nitro-phthalimide)-2-butanone 0.200g (0.53mmol), 4-phenyl-3-thiosemicarbazide 0.090g (0.54mmol), NaHCO
30.050g (0.60mmol), ethanol 15mL places the 50mL reaction flask, is back to no raw material residue, puts coldly, pours in the 15mL cold water, filters washing, drying.The gained solid gets white solid 0.095g, productive rate 40.2% through 95% ethanol/DMF recrystallization.
1HNMR(300M，CDCl
3)：δ1.76(d，3H)，3.33(dd，2H)，5.24(q，1H)，6.91-6.93(m，1H)，6.99-7.08(m，1H)，7.22-7.27(m，2H)，7.89-7.94(m，1H)，8.04-8.12(m，2H).
Embodiment 172-anilino-5-(phthalimide methyl)-6H-1,3, the preparation of 4-thiadiazine (T17)
17-a:2-phthalimide acetate is with 14.8g (100mmol) Tetra hydro Phthalic anhydride, Padil 7.50g (100mmol), Glacial acetic acid min. 99.5 30mL; Place the 100mL reaction flask, be back to no raw material residue, put cold; Pour in the 50mL cold water, separate out white solid, filter; Washing, dry white solid 18.0g, the productive rate 90.0% of getting.
1HNMR(300M，CDCl
3)：δ4.50(s，2H)，7.74-7.76(m，2H)，7.89-7.91(m，2H).
17-b:1-bromo-3-phthalimide acetone is with 2-phthalimide acetate 2.05g (10.0mmol), and thionyl chloride 10mL places the 50mL reaction flask, is back to no raw material residue, and decompression is revolved dried, gets a brown oil, and is subsequent use.The 15mL 50%KOH aqueous solution is joined in the 40mL ether, place under the ice bath, slowly add 6.00g (33.8mmol) nitrous methyl urea in batches, finish, ether layer is told in jolting 10 minutes, with sheet KOH dry 2 hours.The above-mentioned diethyl ether solution that contains diazomethane is put into the 100mL reaction flask, place under the ice bath, slowly drip the toluene solution (2mL) of above-mentioned oily matter, finish, to reacting completely, filter, with the ether flushing, dry gained solid is subsequent use.Solid is dissolved in the 20mL THF, drips 2mL 40%HBr, to reacting completely, decompression is revolved dried.Add 100mL ETHYLE ACETATE, place separating funnel, use saturated NaHCO respectively
3, water, saturated NaC1 solution washes anhydrous Mg
2SO
4Dry.Decompression is revolved dried, through 95% ethyl alcohol recrystallization, obtains white solid 1.24g, yield 44.0%.
1HNMR(300M，CDCl
3)：δ4.01(s，2H)，4.78(dd，2H)，7.75-7.77(m，2H)，7.88-7.90(m，2H).
17-c:2-anilino-5-(phthalimide methyl)-6H-1,3, the 4-thiadiazine is 1-bromo-3-phthalimide acetone 0.200g (0.709mmol), 4-phenyl-3-thiosemicarbazide 0.120g (0.719mmol), NaHCO
30.060g (0.714mmol), ethanol 15mL places the 50mL reaction flask, is back to no raw material residue, puts coldly, pours in the 15mL cold water, filters washing, drying.The gained solid gets white solid 0.163g, productive rate 65.7% through 95% ethanol/DMF recrystallization.
1HNMR(300M，DMSO-d
6)：δ3.46(s，2H)，4.59(s，2H)，6.79(s，1H)，6.98(s，1H)，7.21-7.26(m，2H)，7.85-7.94(m，4H)，10.85(s，1H).
Embodiment 182-anilino-5-(2-phthalimide ethyl)-6H-1,3, the preparation of 4-thiadiazine (T18)
18-a:3-phthalimide propionic acid is with 3.00g (20.3mmol) Tetra hydro Phthalic anhydride, 3-alanine 2.70g (30.3mmol), Glacial acetic acid min. 99.5 30mL; Place the 100mL reaction flask, be back to no raw material residue, put cold; Pour in the 50mL cold water, separate out white solid, filter; Washing, dry white solid 3.60g, the productive rate 81.8% of getting.
1HNMR(300M，DMSO-d
6)：δ2.59(t，2H)，3.38(t，2H)，7.80-7.87(m，4H)，12.36(s，1H).
18-b:1-bromo-4-phthalimide-2-butanone is with 3-phthalimide propionic acid 2.19g (10.0mmol), and thionyl chloride 10mL places the 50mL reaction flask, is back to no raw material residue, and decompression is revolved dried, gets a brown oil, and is subsequent use.The 15mL 50%KOH aqueous solution is joined in the 40mL ether, place under the ice bath, slowly add 6.00g (33.8mmol) nitrous methyl urea in batches, finish, ether layer is told in jolting 10 minutes, with sheet KOH dry 2 hours.The above-mentioned diethyl ether solution that contains diazomethane is put into the 100mL reaction flask, place under the ice bath, slowly drip the toluene solution (2mL) of above-mentioned oily matter, finish, to reacting completely, filter, with the ether flushing, dry gained solid is subsequent use.Solid is dissolved in the 20mL THF, drips 2mL 40%HBr, to reacting completely, decompression is revolved dried.Add 100mL ETHYLE ACETATE, place separating funnel, use saturated NaHCO respectively
3, water, saturated NaCl solution washes anhydrous Mg
2SO
4Dry.Decompression is revolved dried, through 95% ethyl alcohol recrystallization, obtains white solid 2.60g, yield 87.5%.
1HNMR(300M，DMSO-d
6)：δ2.98(t，2H)，3.79(t，2H)，4.36(s，2H)，7.80-7.87(m，4H).
18-c:2-anilino-5-(2-phthalimide ethyl)-6H-1,3, the 4-thiadiazine is 1-bromo-4-phthalimide-2-butanone 0.200g (0.676mmol), 4-phenyl-3-thiosemicarbazide 0.113g (0.676mmol), NaHCO
30.060g (0.714mmol), ethanol 15mL places the 50mL reaction flask, is back to no raw material residue, puts coldly, pours in the 15mL cold water, filters washing, drying.The gained solid gets white solid 0.103g, productive rate 41.9% through 95% ethanol/DMF recrystallization.
1HNMR(300M，DMSO-d
6)：δ2.72(s，2H)，3.41(s，2H)，3.82(s，2H)，6.74(s，1H)，6.98(s，1H)，7.22-7.27(m，2H)，7.82-7.89(m，4H)，10.77(s，1H).
Embodiment 192-anilino-5-(3-phthalimide propyl group)-6H-1,3, the preparation of 4-thiadiazine (T19)
19-a:4-phthalimide butyric acid is with 3.00g (20.3mmol) Tetra hydro Phthalic anhydride, 4-propalanine 2.50g (24.2mmol), Glacial acetic acid min. 99.5 30mL; Place the 100mL reaction flask, be back to no raw material residue, put cold; Pour in the 50mL cold water, separate out white solid, filter; Washing, dry white solid 3.60g, the productive rate 76.2% of getting.
1HNMR(300M，DMSO-d
6)：δ1.78-1.85(m，2H)，2.26(t，2H)，3.59(t，2H)，7.80-7.87(m，4H)，12.05(s，1H).
19-b:1-bromo-5-phthalimide-2 pentanone is with 4-phthalimide butyric acid 2.40g (10.3mmol), and thionyl chloride 10mL places the 50mL reaction flask, is back to no raw material residue, and decompression is revolved dried, gets a brown oil, and is subsequent use.The 15mL 50%KOH aqueous solution is joined in the 40mL ether, place under the ice bath, slowly add 6.00g (33.8mmol) nitrous methyl urea in batches, finish, ether layer is told in jolting 10 minutes, with sheet KOH dry 2 hours.The above-mentioned diethyl ether solution that contains diazomethane is put into the 100mL reaction flask, place under the ice bath, slowly drip the toluene solution (2mL) of above-mentioned oily matter, finish, to reacting completely, filter, with the ether flushing, dry gained solid is subsequent use.Solid is dissolved in the 20mL THF, drips 2mL 40%HBr, to reacting completely, decompression is revolved dried.Add 100mL ETHYLE ACETATE, place separating funnel, use saturated NaHCO respectively
3, water, saturated NaCl solution washes anhydrous Mg
2SO
4Dry.Decompression is revolved dried, through 95% ethyl alcohol recrystallization, obtains white solid 2.40g, yield 75.2%.
1HNMR(300M，DMSO-d
6)：δ2.00-2.04(m，2H)，2.72(t，2H)，3.73(t，2H)，3.92(s，2H)，7.71-7.74(m，2H)，7.83-7.86(m，2H).
19-c:2-anilino-5-(3-phthalimide propyl group)-6H-1,3, the 4-thiadiazine is 1-bromo-5-phthalimide-2 pentanone 0.400g (1.29mmol), 4-phenyl-3-thiosemicarbazide 0.220g (1.32mmol), NaHCO
30.120g (1.43mmol), ethanol 15mL places the 50mL reaction flask, is back to no raw material residue, puts coldly, pours in the 15mL cold water, filters washing, drying.The gained solid gets white solid 0.196g, productive rate 40.1% through 95% ethanol/DMF recrystallization.
1HNMR(300M，DMSO-d
6)：δ2.90-2.95(m，2H)，2.49-2.54(m，4H)，3.65(dd，2H)，6.74(s，1H)，6.93-6.98(m，2H)，7.22-7.31(m，2H)，7.82-7.94(m，4H)，10.75(s，1H).
Embodiment 202-anilino-5-(1-phthalimide styroyl)-6H-1,3, the preparation of 4-thiadiazine (T20)
20-a:2-phthalimide phenylpropionic acid is with 5.00g (33.8mmol) Tetra hydro Phthalic anhydride, phenylalanine(Phe) 6.70g (40.6mmol), Glacial acetic acid min. 99.5 30mL; Place the 100mL reaction flask, be back to no raw material residue, put cold; Pour in the 50mL cold water, separate out white solid, filter; Washing, dry white solid 9.30g, the productive rate 93.4% of getting.
1HNMR(300M，DMSO-d
6)：δ3.32(dd，1H)，3.47(dd，1H)，5.11(dd，1H)，7.09-7.16(m，5H)，7.83(s，4H).
20-b:1-bromo-3-phthalimide-4-phenyl-2-butanone is with 2-phthalimide phenylpropionic acid 2.95g (10.0mmol), and thionyl chloride 10mL places the 50mL reaction flask, is back to no raw material residue, and decompression is revolved dried, gets a brown oil, and is subsequent use.The 15mL 50%KOH aqueous solution is joined in the 40mL ether, place under the ice bath, slowly add 6.00g (33.8mmol) nitrous methyl urea in batches, finish, ether layer is told in jolting 10 minutes, with sheet KOH dry 2 hours.The above-mentioned diethyl ether solution that contains diazomethane is put into the 100mL reaction flask, place under the ice bath, slowly drip the toluene solution (2mL) of above-mentioned oily matter, finish, to reacting completely, filter, with the ether flushing, dry gained solid is subsequent use.Solid is dissolved in the 20mL THF, drips 2mL 40%HBr, to reacting completely, decompression is revolved dried.Add 100mL ETHYLE ACETATE, place separating funnel, use saturated NaHCO respectively
3, water, saturated NaCl solution washes anhydrous Mg
2SO
4Dry.Decompression is revolved dried, through 95% ethyl alcohol recrystallization, obtains white solid 1.80g, yield 48.4%.
1HNMR(300M，CD
3COCD
3)：δ3.39(dd，1H)，3.63(dd，1H)，4.48(dd，2H)，5.44(dd，1H)，7.06-7.19(m，5H)，7.79-7.89(m，4H).
20-c:2-anilino-5-(1-phthalimide styroyl)-6H-1,3, the 4-thiadiazine is 1-bromo-3-phthalimide-4-phenyl-2-butanone 0.186g (0.452mmol), 4-phenyl-3-thiosemicarbazide 0.085g (0.509mmol), NaHCO
30.045g (0.536mmol), ethanol 15mL places the 50mL reaction flask, is back to no raw material residue, puts coldly, pours in the 50mL cold water, with 50mL ethyl acetate extraction three times.ETHYLE ACETATE merges mutually, concentrates, and silicagel column separates, and through petrol ether/ethyl acetate different ratios wash-out, gets yellow solid 0.150g, productive rate 68.2%.
1HNMR(300M，DMSO-d
6)：δ3.50-3.54(m，4H)，5.33(m，1H)，6.79(s，1H)，6.95-7.32(m，9H)，7.80(s，4H)，10.05(s，1H).
Embodiment 212-anilino-5-(1-phthalimide-3-methylbutyl)-6H-1,3, the preparation of 4-thiadiazine (T21)
21-a:2-phthalimide-4-methylvaleric acid is with 2.00g (13.5mmol) Tetra hydro Phthalic anhydride, leucine 2.13g (16.2mmol), Glacial acetic acid min. 99.5 15mL; Place the 50mL reaction flask, be back to no raw material residue, put cold; Pour in the 50mL cold water, separate out white solid, filter; Washing, dry white solid 2.20g, the productive rate 63.0% of getting.
1HNMR(300M，CD
3COCD
3)：δ0.92-0.97(m，6H)，1.54-1.56(m，1H)，1.92-1.98(m，1H)，2.30-2.40(m，1H)，4.95(dd，1H)，7.90-7.91(m，4H).
21-b:1-bromo-3-phthalimide-5 methy 12 hexanone is with 2-phthalimide-4-methylvaleric acid 2.60g (10.0mmol), and thionyl chloride 10mL places the 50mL reaction flask, is back to no raw material residue, and decompression is revolved dried, gets a brown oil, and is subsequent use.The 15mL 50%KOH aqueous solution is joined in the 40mL ether, place under the ice bath, slowly add 6.00g (33.8mmol) nitrous methyl urea in batches, finish, ether layer is told in jolting 10 minutes, with sheet KOH dry 2 hours.The above-mentioned diethyl ether solution that contains diazomethane is put into the 100mL reaction flask, place under the ice bath, slowly drip the toluene solution (2mL) of above-mentioned oily matter, finish, to reacting completely, filter, with the ether flushing, dry gained solid is subsequent use.Solid is dissolved in the 20mL THF, drips 2mL 40%HBr, to reacting completely, decompression is revolved dried.Add 100mL ETHYLE ACETATE, place separating funnel, use saturated NaHCO respectively
3, water, saturated NaCl solution washes anhydrous Mg
2SO
4Dry.Decompression is revolved dried, through 95% ethyl alcohol recrystallization, obtains white solid 3.00g, yield 88.7%.
1HNMR(300M，CD
3COCD
3)：δ0.90-0.96(m，6H)，1.47-1.56(m，1H)，1.93-2.02(m，1H)，2.06-2.28(m，1H)，4.62(dd，2H)，5.20(dd，1H)，7.87-7.91(m，4H).
21-c:2-anilino-5-(1-phthalimide-2-methylbutyl)-6H-1,3, the 4-thiadiazine is 1-bromo-3-phthalimide-5 methy 12 hexanone 0.200g (0.592mmol), 4-phenyl-3-thiosemicarbazide 0.100g (0.599mmol), NaHCO
30.050g (0.595mmol), ethanol 15mL places the 50mL reaction flask, is back to no raw material residue, puts coldly, pours in the 15mL cold water, filters washing, drying.The gained solid gets white solid 0.080g, productive rate 33.3% through 95% ethanol/DMF recrystallization.
1HNMR(300M，DMSO-d
6)：δ0.87-0.91(m，6H)，1.48-1.52(m，1H)，1.86-1.96(m，1H)，2.24-2.34(m，1H)，3.47(dd，2H)，5.07-5.12(m，1H)，6.96-7.01(m，3H)，7.22-7.27(m，2H)，7.85-7.92(m，4H).
Embodiment 222-(N-phenyl-N-ethanoyl)-5-(1-phthalimide ethyl)-6H-1,3, the preparation of 4-thiadiazine (T22)
With 2-anilino-5-(1-phthalimide ethyl)-6H-1,3,4-thiadiazine 0.100g (0.275mmol), Acetyl Chloride 98Min. 0.040g (0.327mmol), triethylamine 0.5mL, methylene dichloride 5mL places the 25mL reaction flask, to reacting completely.Add the 50mL methylene dichloride, place separating funnel, use saturated NaHCO respectively
3, water, saturated NaCl solution washes anhydrous Mg
2SO
4Dry.Decompression is revolved dried, through 95% ethyl alcohol recrystallization, obtains white solid 0.074g, yield 66.3%.
1HNMR(300M，DMSO-d
6)：δ1.68(d，3H)，1.91(s，3H)，3.15(dd，2H)，5.19(q，1H)，7.35-7.49(m，5H)，7.85(s，4H).
Embodiment 232-(N-phenyl-N-benzoyl-)-5-(1-phthalimide ethyl)-6H-1,3, the preparation of 4-thiadiazine (T23)
With 2-anilino-5-(1-phthalimide ethyl)-6H-1,3,4-thiadiazine 0.100g (0.275mmol), Benzoyl chloride 99min. 0.046g (0.513mmol), triethylamine 0.5mL, methylene dichloride 5mL places the 25mL reaction flask, to reacting completely.Add the 50mL methylene dichloride, place separating funnel, use saturated NaHCO respectively
3, water, saturated NaCl solution washes anhydrous Mg
2SO
4Dry.Decompression is revolved dried, through column chromatography for separation, obtains colorless oil 0.075g, yield 58.3%.
1HNMR(300M，CDCl
3)：δ1.79(d，3H)，3.01(dd，2H)，5.31(q，1H)，7.01-7.49(m，10H)，7.71-7.87(m，4H).
Embodiment 242-(N-phenyl-N-benzyl)-5-(1-phthalimide ethyl)-6H-1,3, the preparation of 4-thiadiazine (T24)
With 2-anilino-5-(1-phthalimide ethyl)-6H-1,3,4-thiadiazine 0.100g (0.275mmol), cylite 0.070g (0.409mmol), salt of wormwood 0.060g (0.435mmol), DMF 5mL places the 25mL reaction flask, to reacting completely.Add 50mL ETHYLE ACETATE, place separating funnel, water, saturated NaCl solution are washed anhydrous Mg respectively
2SO
4Dry.Decompression is revolved dried, through the preparation Thin-layer separation, obtains yellow solid 0.100g, yield 82.5%.
1HNMR(300M，CDCl
3)：δ1.71(d，3H)，3.25(dd，2H)，5.16(q，1H)，5.22(s，2H)，6.77-6.79(m，2H)，7.01-7.06(m，1H)，7.21-7.28(m，4H)，7.33-7.37(m，3H)，7.70-7.73(m，2H)，7.81-7.84(m，2H).
Embodiment 252-(N-phenyl-N-methyl)-5-(1-phthalimide ethyl)-6H-1,3, the preparation of 4-thiadiazine (T25)
With 2-anilino-5-(1-phthalimide ethyl)-6H-1,3,4-thiadiazine 0.080g (0.220mmol), methyl iodide 0.041g (0.289mmol), salt of wormwood 0.040g (0.290mmol), DMF 5mL places the 25mL reaction flask, to reacting completely.Add 50mL ETHYLE ACETATE, place separating funnel, water, saturated NaCl solution are washed anhydrous Mg respectively
2SO
4Dry.Decompression is revolved dried, through the preparation Thin-layer separation, obtains yellow oil 0.050g, yield 60.2%.
1HNMR(300M，CDCl
3)：δ1.74(d，3H)，3.29(dd，2H)，3.55(s，3H)，5.21(q，1H)，6.83-6.85(m，2H)，7.03-7.08(m，1H)，7.25-7.30(m，2H)，7.73-7.77(m，2H)，7.85-7.88(m，2H).
Embodiment 262-(N-phenyl-N-ethoxycarbonylmethyl group)-5-(1-phthalimide ethyl)-6H-1,3, the preparation of 4-thiadiazine (T26)
With 2-anilino-5-(1-phthalimide ethyl)-6H-1,3,4-thiadiazine 0.054g (0.148mmol), METHYL BROMOACETATE 0.032g (0.192mmol), salt of wormwood 0.030g (0.217mmol), DMF 5mL places the 25mL reaction flask, to reacting completely.Add 50mL ETHYLE ACETATE, place separating funnel, water, saturated NaCl solution are washed anhydrous Mg respectively
2SO
4Dry.Decompression is revolved dried, through the preparation Thin-layer separation, obtains yellow solid 0.040g, yield 59.9%.
1HNMR(300M，CDCl
3)：δ1.26(t，3H)，1.72(d，3H)，3.45(s，2H)，4.20(q，2H)，4.74(dd，2H)，5.22(q，1H)，6.78-6.81(m，2H)，7.03-7.08(m，1H)，7.23-7.29(m，2H)，7.73-7.77(m，2H)，7.83-7.87(m，2H).
Embodiment 272-(N-phenyl-N-allyl group)-5-(1-phthalimide ethyl)-6H-1,3, the preparation of 4-thiadiazine (T27)
With 2-anilino-5-(1-phthalimide ethyl)-6H-1,3,4-thiadiazine 0.075g (0.206mmol), bromopropylene 0.035g (0.289mmol), salt of wormwood 0.060g (0.435mmol), DMF 5mL places the 25mL reaction flask, to reacting completely.Add 50mL ETHYLE ACETATE, place separating funnel, water, saturated NaCl solution are washed anhydrous Mg respectively
2SO
4Dry.Decompression is revolved dried, through the preparation Thin-layer separation, obtains yellow liquid 0.048g, yield 57.7%.
1HNMR(300M，CDCl
3)：δ1.74(d，3H)，3.28(s，2H)，4.63(d，2H)，5.10-5.22(m，3H)，5.95-6.10(m，1H)，6.80-6.83(m，2H)，7.03-7.08(m，1H)，7.25-7.30(m，2H)，7.73-7.76(m，2H)，7.85-7.87(m，2H).
The experiment of embodiment 28 in-vitro screenings
Material and method
1. cell: Vero cell (African green monkey kidney) cultivation of going down to posterity voluntarily.
2. viral: HSV-1 (VR733), HSV-2 (SAV)
3. reagent, experimental article and instrument
3.1 reagent: Eagles MEM dry powder, U.S. GIBCO Company products; NBCS, river, Tianjin page or leaf biochemical product ltd product;
Sodium hydrogencarbonate, people pharmaceutical factory of Tianjin amino acid company produces; Penicillium mould, Streptomycin sulphate and kantlex are North China Pharmaceutical Factory's product.
3.2 experimental article and instrument: culturing bottle, Jiangyin City, Jiangsu science and technology glassware factory produces; Culture plate 96 orifice plates, U.S. Costa Company products;
The carbonic acid gas incubator, U.S. MALLINCKRODT Company products.
3.3 cell culture fluid and reagent preparation MEM nutrient solution 100mL: contain NBCS 10%, Stimulina, penicillium mould, each 100U/mL of Streptomycin sulphate and kantlex, NaHCO
35%; Cell dissociation buffer: 0.25% pancreatin, with the preparation of Hanks liquid, 0.02%EDTA.
4 experimental techniques
In covering with the culturing bottle of cell, add 0.25% pancreatin 0.2mL, 0.02%EDTA 4mL, 37 ℃ digested 20～25 minutes, discarded Digestive system; Add nutrient solution piping and druming, go down to posterity at 1: 3, covered with in 3 days, be mixed with every milliliter 20～300,000 cells; Inoculate 96 porocyte culture plates, every hole 0.1mL, 37 ℃, 5%CO
2Cultivated 24 hours, cell experimentizes after growing up to individual layer.Cover with the cell of individual layer, abandon nutrient solution, add an amount of virus, adsorb after 1-1.5 hour, abandon viral liquid, add the nutrient solution that contains different concns doubling dilution medicine, establish the virus control group simultaneously, put 37 ℃, 5%CO
2Incubator is cultivated, when treating that the virus control group reaches 4 plus siges, and the observation of cell pathology, cell control well 3 holes are all set in each experiment, and the result calculates medium effective concentration IC with the Reed-Muench method
50
A=log＞50% drug level B=log＜50% drug level C=log extension rate
Table 1, table 2 have been enumerated the TD of each compound among the embodiment
50, TD
0, IC
50
Table 11,3, the external anti-HSV-1 of 4-thiadiazine derivatives is active
| Compound embodiment number | TD 50(μg/mL) | TD 0(μg/mL) | IC 50(μg/mL) | SI a |
| T1 | 1000 | 333.33 | 77.04 | 12.9 |
| T2 | 64.15 | 37.03 | ＞37.03 | |
| T3 | 64.15 | 37.03 | ＞37.03 | |
| T4 | 192.45 | 111.11 | 77.04 | 2.5 |
| T5 | 192.45 | 111.11 | ＞111.11 | |
| T7 | 557.35 | 333.33 | 77.04 | 7.23 |
| T8 | 192.45 | 111.11 | ＞111.11 | |
| T9 | 192.45 | 111.11 | 64.15 | 3.0 |
| T10 | 192.45 | 111.11 | ＞111.11 | |
| T11 | 21.38 | 12.34 | ＞12.34 | |
| T13 | 557.35 | 333.33 | ＞333.33 | |
| T14 | 333.33 | 111.11 | 333.33 | 1 |
| T15 | 192.45 | 111.11 | ＞111.11 | |
| T16 | 480.75 | 111.11 | 111.11 | 4.32 |
| T17 | 192.45 | 111.11 | ＞111.11 | |
| T18 | 192.45 | 111.11 | ＞111.11 | |
| T19 | 192.45 | 111.11 | 25.68 | 7.49 |
| T20 | 53.41 | 12.34 | 12.34 | 4.32 |
| T21 | 192.45 | 111.11 | ＞111.11 | |
| T22 | 192.45 | 111.11 | 111.11 | 1.73 |
| T23 | 111.11 | 37.04 | ＞37.04 | |
| T24 | 192.45 | 111.11 | ＞111.11 | |
| T25 | 192.45 | 111.11 | 47.72 | 4.0 |
| TDA b | 353.55 | 250 | 106.52 | 3.3 |
| ACV c | 4.4 |
A SI: SI, SI=TD
50/ IC
50B TDA: Ftibamzone; C ACV: acyclovir.
Table 21,3, the external anti-HSV-2 of 4-thiadiazine derivatives is active
| compound | TD 50(μg/mL) | TD 0(μg/mL) | IC 50(μg/mL) | SI a |
| T1 | 1000 | 333.33 | 30.0 | 33.3 |
| T7 | 557.35 | 333.33 | ＞333.33 | |
| T19 | 192.45 | 111.11 | ＞111.11 | |
| TDA b | 353.55 | 250 | 73.05 | 4.8 |
| ACV c | 8.4 |
A SI: SI, SI=TD
50/ IC
50B TDA: Ftibamzone; C ACV: acyclovir.
The shortenings note:
THF: THF
DMF:N, the N-dimethylformamide
DMSO: DMSO 99.8MIN.
Claims (4)
1. one type has 1,3 shown in the following general formula (I), and 4-thiadiazine derivatives or its can be done medicinal salt:
In the general formula (I): the A ring is phenyl ring;
R
1, R
2, R
3, R
4Can be identical or different, R
1, R
2, R
3, R
4, be independently selected from Wasserstoffatoms, halogen, nitro, amino, hydroxyl;
R
5Represent Wasserstoffatoms, halogen, nitro, amino, hydroxyl, C
1-18Alkyl;
R
6, R
7Can be identical or different, R
6, R
7Be independently selected from Wasserstoffatoms, C
1-18Alkyl, cyclohexyl, C
2-18Thiazolinyl, ethanoyl, benzoyl-, benzyl are got rid of compound 2-amido-5-(2-phthalimide ethyl)-6H-1, and 3,4-thiadiazine and 2-ethanoyl-5-(2-phthalimide ethyl)-6H-1,3,4-thiadiazine;
N is 0-10.
2. compound is selected from:
2-anilino-5-(1-phthalimide ethyl)-6H-1,3, the 4-thiadiazine, its chemical structural formula is:
2-(4-fluoro-anilino)-5-(1-phthalimide ethyl)-6H-1,3, the 4-thiadiazine, its chemical structural formula is:
2-(4-chloro-anilino)-5-(1-phthalimide ethyl)-6H-1,3, the 4-thiadiazine, its chemical structural formula is:
2-benzamido group-5-(1-phthalimide ethyl)-6H-1,3, the 4-thiadiazine, its chemical structural formula is:
2-(4-nitro-anilino)-5-(1-phthalimide ethyl)-6H-1,3, the 4-thiadiazine, its chemical structural formula is:
2-(4-methoxyl group-anilino)-5-(1-phthalimide ethyl)-6H-1,3, the 4-thiadiazine, its chemical structural formula is:
2-(4-methyl-anilino)-5-(1-phthalimide ethyl)-6H-1,3, the 4-thiadiazine, its chemical structural formula is:
2-(2-fluoro-anilino)-5-(1-phthalimide ethyl)-6H-1,3, the 4-thiadiazine, its chemical structural formula is:
2-(4-chloro-benzamido group)-5-(1-phthalimide ethyl)-6H-1,3, the 4-thiadiazine, its chemical structural formula is:
2-(3-pyridine amido)-5-(1-phthalimide ethyl)-6H-1,3, the 4-thiadiazine, its chemical structural formula is:
2-(2-pyridine amido)-5-(1-phthalimide ethyl)-6H-1,3, the 4-thiadiazine, its chemical structural formula is:
2-anilino-5-(1-(4-bromo-phthalimide) ethyl)-6H-1,3, the 4-thiadiazine, its chemical structural formula is:
2-anilino-5-(1-(3-nitro-phthalimide) ethyl)-6H-1,3, the 4-thiadiazine, its chemical structural formula is:
2-anilino-5-(phthalimide methyl)-6H-1,3, the 4-thiadiazine, its chemical structural formula is:
2-anilino-5-(2-phthalimide ethyl)-6H-1,3, the 4-thiadiazine, its chemical structural formula is:
2-anilino-5-(3-phthalimide propyl group)-6H-1,3, the 4-thiadiazine, its chemical structural formula is:
2-anilino-5-(1-phthalimide styroyl)-6H-1,3, the 4-thiadiazine, its chemical structural formula is:
2-anilino-5-(1-phthalimide-3-methylbutyl)-6H-1,3, the 4-thiadiazine, its chemical structural formula is:
2-(N-phenyl-N-ethanoyl-amido)-5-(1-phthalimide ethyl)-6H-1,3, the 4-thiadiazine, its chemical structural formula is:
2-(N-phenyl-N-benzoyl--amido)-5-(1-phthalimide ethyl)-6H-1,3, the 4-thiadiazine, its chemical structural formula is:
2-(N-phenyl-N-benzyl-amido)-5-(1-phthalimide ethyl)-6H-1,3, the 4-thiadiazine, its chemical structural formula is:
2-(N-phenyl-N-methyl-amido)-5-(1-phthalimide ethyl)-6H-1,3, the 4-thiadiazine, its chemical structural formula is:
2-(N-phenyl-N-ethoxycarbonylmethyl group-amido)-5-(1-phthalimide ethyl)-6H-1,3, the 4-thiadiazine, its chemical structural formula is:
2-(N-phenyl-N-allyl group-amido)-5-(1-phthalimide ethyl)-6H-1,3, the 4-thiadiazine, its chemical structural formula is:
3. claim 1 is described 1,3, and 4-thiadiazine derivatives or its can be made the preparation method of medicinal salt, it is characterized in that the preparation of compound comprises the steps:
Reaction formula (I)
Compound 1 obtains compound 2 under the effect of catalyzer and solvent, temperature of reaction is 50～150 ℃, and the reaction times is 1～24 hour; Said solvent is Glacial acetic acid min. 99.5, ethanol, methyl alcohol, and said catalyzer is selected from NaHCO
3, Na
2CO
3, K
2CO
3, triethylamine or pyridine;
Compound 2 obtains compound 3 under the effect of catalyzer and solvent, temperature of reaction is-15～100 ℃, and the reaction times is 1～24 hour; Said solvent is methylene dichloride, chloroform, DMF, and said catalyzer is selected from SOCl
2, (COCl)
2
Compound 3 obtains compound 4 under the effect of catalyzer and solvent, temperature of reaction is-15～50 ℃, and the reaction times is 1～24 hour; Said solvent is ether, toluene, DMF, and said catalyzer is a diazomethane;
Compound 4 obtains compound 5 under the effect of catalyzer and solvent, temperature of reaction is-15～50 ℃, and the reaction times is 1～24 hour; Said solvent is Glacial acetic acid min. 99.5, THF, DMF, and said catalyzer is Hydrogen bromide, spirit of salt, hydroiodic acid HI;
Compound 5 obtains target compound 6 under the effect of catalyzer and solvent, temperature of reaction is 20～150 ℃, and the reaction times is 1～24 hour; Said solvent is ethanol, methyl alcohol, toluene, acetonitrile, DMF, and said catalyzer is selected from NaHCO
3, Na
2CO
3, K
2CO
3, triethylamine or pyridine.
4. claim 1 is described 1,3, and 4-thiadiazine derivatives or its can be done medicinal salt, or contain their pharmaceutical composition, the application in the preparation antiviral.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200910235377 CN102040595B (en) | 2009-10-22 | 2009-10-22 | 1,3,4-hiadiazine derivatives as well as preparation method and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200910235377 CN102040595B (en) | 2009-10-22 | 2009-10-22 | 1,3,4-hiadiazine derivatives as well as preparation method and application thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN102040595A CN102040595A (en) | 2011-05-04 |
| CN102040595B true CN102040595B (en) | 2012-12-12 |
Family
ID=43907161
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 200910235377 Active CN102040595B (en) | 2009-10-22 | 2009-10-22 | 1,3,4-hiadiazine derivatives as well as preparation method and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN102040595B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104844538B (en) * | 2015-04-08 | 2017-04-12 | 浙江大学 | Polysubstituted 1,3,4-thiadiazine compound and preparation method thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006093801A1 (en) * | 2005-02-25 | 2006-09-08 | Abbott Laboratories | Thiadiazine derivatives useful as anti-infective agents |
| WO2009032125A1 (en) * | 2007-08-29 | 2009-03-12 | Schering Corporation | 2,3-substituted azaindole derivatives for treating viral infections |
-
2009
- 2009-10-22 CN CN 200910235377 patent/CN102040595B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006093801A1 (en) * | 2005-02-25 | 2006-09-08 | Abbott Laboratories | Thiadiazine derivatives useful as anti-infective agents |
| WO2009032125A1 (en) * | 2007-08-29 | 2009-03-12 | Schering Corporation | 2,3-substituted azaindole derivatives for treating viral infections |
Non-Patent Citations (2)
| Title |
|---|
| Hadacek J.等.The preparation and transformation of 2-amino-5-(b-phthalimidoethyl)-1 |
| Hadacek, J.等.The preparation and transformation of 2-amino-5-(b-phthalimidoethyl)-1,3,4-thiadiazine.《Spisy prirodovedecke fak. univ. Brne》.1961,第22卷(第409期),39-44. * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN102040595A (en) | 2011-05-04 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| AU2008315651B2 (en) | Histone deacetylase inhibitors | |
| FI95033C (en) | Process for the preparation of pharmacologically active 8-substituted xanthine derivatives | |
| CN106083847B (en) | A kind of imidazopyridine mercapto phenylacetic acid derivative and the preparation method and application thereof | |
| AU2009203124B2 (en) | Quinazolines and related heterocyclic compounds, and their therapeutic use | |
| CN102036956A (en) | Substituted pyrrolidine and piperidine compounds, derivatives thereof, and methods for treating pain | |
| WO2014145512A2 (en) | Potent small molecule inhibitors of autophagy, and methods of use thereof | |
| CN1990470B (en) | Phthiobuzonum derivative, its manufacturing process, pharmaceutical combination and uses thereof | |
| ES2355421T3 (en) | PREVENTIVE OR THERAPEUTIC AGENT FOR DISEASES ASSOCIATED WITH HERPES VIRUS. | |
| CN102040595B (en) | 1,3,4-hiadiazine derivatives as well as preparation method and application thereof | |
| CN108191770B (en) | 2, 3-phthalazinone or 2, 3-naphthyridine derivatives and uses thereof | |
| CA2179314A1 (en) | Esters and amides of 9(z)-retinoic acid | |
| CA3135921C (en) | Quinolyl-containing compound and pharmaceutical composition, and use thereof | |
| CN103965182A (en) | Medicament of 1,3,4-oxadiazole containing pyrazole compound prepared for treating tumor | |
| JP6279145B2 (en) | 2,2'-bisthiazole-based compound, its production method and use | |
| DE10109856A1 (en) | Use of N-phenyl arylamide for treating or preventing chronic or acute hepatitis B viral infections in humans or animals, including co-infections with hepatitis D virus | |
| EP1020451B1 (en) | Anilide compounds and drugs containing the same | |
| CN113735927A (en) | Nucleotide analogue and preparation method and application thereof | |
| SU1493106A3 (en) | Method of producing isoxasol derivatives | |
| NIŢULESCU et al. | Synthesis and pharmacological evaluation of some new pyrazole derivatives | |
| EP0197386B1 (en) | 2-(substituted sulfamyl) derivatives of 6-nitrobenzoic acid, process for their preparation and pharmaceutical compositions containing them | |
| EP1844775B1 (en) | Therapeutic agent for the treatment of herpes progenitalis after development of lesions | |
| US4647588A (en) | 2-(substituted sulfamyl)-6-nitrobenzoic acid amides and pharmaceutical compositions | |
| US4654369A (en) | Esters of 2-(substituted sulfamyl)-6-nitro-benzoic acid and pharmaceutical compositions | |
| JP2022527279A (en) | Quinoline derivatives and their use for the treatment of cancer | |
| JP2003526639A (en) | Drugs for viral diseases |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| CP03 | Change of name, title or address |
Address after: 102600 building 7, 37 Yongwang Road, Daxing biomedical industrial base, Zhongguancun Science and Technology Park, Daxing District, Beijing Patentee after: Beijing Xiehe Pharmaceutical Co.,Ltd. Patentee after: INSTITUTE OF MATARIA MEDICA, CHINESE ACADEMY OF MEDICAL SCIENCES Address before: 100260 Xingye North Road, Huangcun Town, Daxing District, Beijing Patentee before: Beijing Union Pharmaceutical Factory Patentee before: INSTITUTE OF MATARIA MEDICA, CHINESE ACADEMY OF MEDICAL SCIENCES |
|
| CP03 | Change of name, title or address |