CN101386620B - Thiazole derivative and preparation method and application thereof - Google Patents
Thiazole derivative and preparation method and application thereof Download PDFInfo
- Publication number
- CN101386620B CN101386620B CN2008101525374A CN200810152537A CN101386620B CN 101386620 B CN101386620 B CN 101386620B CN 2008101525374 A CN2008101525374 A CN 2008101525374A CN 200810152537 A CN200810152537 A CN 200810152537A CN 101386620 B CN101386620 B CN 101386620B
- Authority
- CN
- China
- Prior art keywords
- compound
- thiazole
- ethyl acetate
- oxo
- thiocarbamoyl imidazole
- 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.)
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- 238000002360 preparation method Methods 0.000 title claims description 19
- 150000007979 thiazole derivatives Chemical class 0.000 title abstract description 5
- 239000003814 drug Substances 0.000 claims abstract description 9
- 238000000034 method Methods 0.000 claims abstract description 4
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- -1 sec.-propyl Chemical group 0.000 claims description 69
- 150000001875 compounds Chemical class 0.000 claims description 56
- 238000006243 chemical reaction Methods 0.000 claims description 53
- 239000007787 solid Substances 0.000 claims description 27
- 239000003795 chemical substances by application Substances 0.000 claims description 17
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 14
- 150000003839 salts Chemical class 0.000 claims description 13
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 12
- 239000007788 liquid Substances 0.000 claims description 10
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 9
- 125000002252 acyl group Chemical group 0.000 claims description 8
- 239000003153 chemical reaction reagent Substances 0.000 claims description 8
- 239000007924 injection Substances 0.000 claims description 8
- 238000002347 injection Methods 0.000 claims description 8
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims description 6
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 5
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 5
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 5
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 5
- 229910052794 bromium Inorganic materials 0.000 claims description 5
- 239000000460 chlorine Substances 0.000 claims description 5
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- MVEAAGBEUOMFRX-UHFFFAOYSA-N ethyl acetate;hydrochloride Chemical compound Cl.CCOC(C)=O MVEAAGBEUOMFRX-UHFFFAOYSA-N 0.000 claims description 5
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- 239000011737 fluorine Substances 0.000 claims description 5
- 230000006103 sulfonylation Effects 0.000 claims description 5
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- 125000003368 amide group Chemical group 0.000 claims description 4
- VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical compound ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 0.000 claims description 3
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- GDEJFZHOQVIHRN-UHFFFAOYSA-N 1,2-oxazole 1,3-oxazole pyridine Chemical compound N1=CC=CC=C1.O1N=CC=C1.O1C=NC=C1 GDEJFZHOQVIHRN-UHFFFAOYSA-N 0.000 description 7
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- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- 235000005979 Citrus limon Nutrition 0.000 description 1
- 244000131522 Citrus pyriformis Species 0.000 description 1
- 229920002785 Croscarmellose sodium Polymers 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- BUDQDWGNQVEFAC-UHFFFAOYSA-N Dihydropyran Chemical class C1COC=CC1 BUDQDWGNQVEFAC-UHFFFAOYSA-N 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- DCXXMTOCNZCJGO-UHFFFAOYSA-N Glycerol trioctadecanoate Natural products CCCCCCCCCCCCCCCCCC(=O)OCC(OC(=O)CCCCCCCCCCCCCCCCC)COC(=O)CCCCCCCCCCCCCCCCC DCXXMTOCNZCJGO-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-PICCSMPSSA-N Maltose Natural products O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@@H](CO)OC(O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-PICCSMPSSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- SQVRNKJHWKZAKO-PFQGKNLYSA-N N-acetyl-beta-neuraminic acid Chemical compound CC(=O)N[C@@H]1[C@@H](O)C[C@@](O)(C(O)=O)O[C@H]1[C@H](O)[C@H](O)CO SQVRNKJHWKZAKO-PFQGKNLYSA-N 0.000 description 1
- SQVRNKJHWKZAKO-LUWBGTNYSA-N N-acetylneuraminic acid Chemical compound CC(=O)N[C@@H]1[C@@H](O)CC(O)(C(O)=O)O[C@H]1[C@H](O)[C@H](O)CO SQVRNKJHWKZAKO-LUWBGTNYSA-N 0.000 description 1
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 1
- 102000005348 Neuraminidase Human genes 0.000 description 1
- 108010006232 Neuraminidase Proteins 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
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- 206010034133 Pathogen resistance Diseases 0.000 description 1
- 206010035664 Pneumonia Diseases 0.000 description 1
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 1
- WINXNKPZLFISPD-UHFFFAOYSA-M Saccharin sodium Chemical compound [Na+].C1=CC=C2C(=O)[N-]S(=O)(=O)C2=C1 WINXNKPZLFISPD-UHFFFAOYSA-M 0.000 description 1
- 241000191967 Staphylococcus aureus Species 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- UEDUENGHJMELGK-HYDKPPNVSA-N Stevioside Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1O[C@]12C(=C)C[C@@]3(C1)CC[C@@H]1[C@@](C)(CCC[C@]1([C@@H]3CC2)C)C(=O)O[C@H]1[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O1)O)[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O UEDUENGHJMELGK-HYDKPPNVSA-N 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 150000001263 acyl chlorides Chemical class 0.000 description 1
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- 230000000996 additive effect Effects 0.000 description 1
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- 230000000181 anti-adherent effect Effects 0.000 description 1
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- 229910052728 basic metal Inorganic materials 0.000 description 1
- 150000003818 basic metals Chemical class 0.000 description 1
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- SQVRNKJHWKZAKO-UHFFFAOYSA-N beta-N-Acetyl-D-neuraminic acid Natural products CC(=O)NC1C(O)CC(O)(C(O)=O)OC1C(O)C(O)CO SQVRNKJHWKZAKO-UHFFFAOYSA-N 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 1
- 239000000920 calcium hydroxide Substances 0.000 description 1
- 229910001861 calcium hydroxide Inorganic materials 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
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- 238000001816 cooling Methods 0.000 description 1
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- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 1
- HGCIXCUEYOPUTN-UHFFFAOYSA-N cyclohexene Chemical class C1CCC=CC1 HGCIXCUEYOPUTN-UHFFFAOYSA-N 0.000 description 1
- 125000001511 cyclopentyl group Chemical class [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
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- SRCZQMGIVIYBBJ-UHFFFAOYSA-N ethoxyethane;ethyl acetate Chemical compound CCOCC.CCOC(C)=O SRCZQMGIVIYBBJ-UHFFFAOYSA-N 0.000 description 1
- 238000003810 ethyl acetate extraction Methods 0.000 description 1
- NUVBSKCKDOMJSU-UHFFFAOYSA-N ethylparaben Chemical compound CCOC(=O)C1=CC=C(O)C=C1 NUVBSKCKDOMJSU-UHFFFAOYSA-N 0.000 description 1
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- 239000012362 glacial acetic acid Substances 0.000 description 1
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 1
- 239000010931 gold Substances 0.000 description 1
- 229910052737 gold Inorganic materials 0.000 description 1
- 229920000591 gum Polymers 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
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- 238000005984 hydrogenation reaction Methods 0.000 description 1
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- 239000003112 inhibitor Substances 0.000 description 1
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- PGZUMBJQJWIWGJ-ONAKXNSWSA-N oseltamivir phosphate Chemical compound OP(O)(O)=O.CCOC(=O)C1=C[C@@H](OC(CC)CC)[C@H](NC(C)=O)[C@@H](N)C1 PGZUMBJQJWIWGJ-ONAKXNSWSA-N 0.000 description 1
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- 235000017550 sodium carbonate Nutrition 0.000 description 1
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- 239000008354 sodium chloride injection Substances 0.000 description 1
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Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to a thiazole derivative with the structure of formula I, a method for preparing the same, a drug composite containing the same, and application of the thiazole derivative as a drug, in particular as an anti-virus and anti-bacterial drug, wherein the definition of each group is as described in the specification.
Description
Technical field
The present invention relates to infect relevant pharmaceutical field, or rather, relate to a class and have thiazole derivative of antiviral, anti-microbial effect and preparation method thereof, and the pharmaceutical composition that contains them.
Background technology
In many microbies, all there are some enzymes can from other sugar, decomposite N-ethanoyl-neuraminic acid (NANA), also are sialic acid.Proved that neuraminidase inhibitor can prevent or treat by the virus or the bacterial disease of carrying neuraminidase.Many documents and patent report multiple structure neuraminidase inhibitor, as benzoic acids [US6509359]; Dihydropyrane class [WO9636628]; Tetrahydrobenzene class [Kim CU.et al, (1998) J.Med.Chem.41 (14), 2451-2460.]; Cyclopentanes [Chand P.et al, (2001) J.Med.Chem.44 (25), 4379-4392.]; Pyrrolidines [Wang GT.et al, (2001) J.Med.Chem.44 (8), 1192-1201; Hanessian S.et al, (2002) J.Am.Chem.Soc.124 (17), 4716-4721] or the like.At present, neuraminidase inhibitor is the new focus of the research of resisiting influenza virus.
The neuraminidase inhibitor class Tamiflu of having gone on the market at present has the zanamivir (zanamivir) of Ge Lansu company and the Ao Simiwei (oseltamivir) of Roche Holding Ag, on the one hand, the curative effect of two kinds of clinical drug application can not be satisfactory, long-term prescription causes viral resistance easily on the other hand, and this just presses for continuous searching novel structure, eutherapeutic medicine.
Infectation of bacteria is another serious infection problems that the mankind face always, and in recent years, because antibiotic being extensive use of, resistant organism rolls up and spreads, and presses for the new antibacterials of research.
Summary of the invention
An object of the present invention is at the deficiencies in the prior art, seek the antiviral or the antibacterials of new texture, compound or its steric isomer, tautomer, pharmacy acceptable salt or solvate with general formula I structure are provided.
Another object of the present invention provides the compound with general formula I structure or the preparation method of its steric isomer, tautomer, pharmacy acceptable salt or solvate.
A further object of the present invention provides and contains compound of Formula I or its steric isomer, tautomer, pharmacy acceptable salt or solvate as effective constituent, and the medicinal compositions of one or more pharmaceutically acceptable carriers, vehicle or thinner, and in preparation prevention with treat application in responsive virus, the bacterial infection medicine.
The compound that the present invention relates to general formula (I) has following array structure:
Wherein:
R
1: H, C
1-C
8Alkyl, and by halogen, hydroxyl, itrile group, carboxyl, amino, nitro, C
1-C
5Alkyl, C
3-C
8Cycloalkyl, C
1-C
5Alkoxyl group, C
1-C
5Group lists such as acyl group, phenyl, substituted-phenyl, five yuan, hexa-member heterocycle replace or polysubstituted C
1-C
8Alkyl;
R
2：
Wherein,
X＝O、S、N-R
5
R
4, R
5The time or be respectively H, R
6,
Wherein,
R
6Be C
1-C
8Alkyl, C
3-C
8Cycloalkyl, aryl, five yuan, hexa-member heterocycle, and by halogen, hydroxyl, itrile group, carboxyl, amino, nitro, C
1-C
5Alkyl, C
3-C
8Cycloalkyl, C
1-C
5Alkoxyl group, C
1-C
5Group lists such as acyl group, phenyl, substituted-phenyl, five yuan, hexa-member heterocycle replace or polysubstituted C
1-C
8Alkyl, C
3-C
8Cycloalkyl, aryl, five yuan, hexa-member heterocycle.
R
3：
Wherein:
Y＝O、S；
The time:
R
7For
R
7Be R
6,
X, R
4, R
5, R
6Same as above.
The compound that the present invention relates to general formula (I) structure optimization comprises:
R
1: H, C
1-C
5Alkyl, and by halogen, hydroxyl, itrile group, carboxyl, amino, nitro, C
1-C
5Alkyl, C
5-C
6Cycloalkyl, C
1-C
5Alkoxyl group, C
1-C
5Group lists such as acyl group, phenyl, substituted-phenyl, five yuan, hexa-member heterocycle replace or polysubstituted C
1-C
5Alkyl;
R
2：
Wherein,
X＝O、S、N-R
5
R
4, R
5The time or be respectively H, R
6,
Wherein,
R
6Be C
1-C
5Alkyl, C
5-C
6Cycloalkyl, phenyl, five yuan, hexa-member heterocycle, and by halogen, hydroxyl, itrile group, carboxyl, amino, nitro, C
1-C
5Alkyl, C
5-C
6Cycloalkyl, C
1-C
5Alkoxyl group, C
1-C
5Group lists such as acyl group, phenyl, substituted-phenyl, five yuan, hexa-member heterocycle replace or polysubstituted C
1-C
5Alkyl, C
5-C
6Cycloalkyl, phenyl, five yuan, hexa-member heterocycle;
R
3：
Wherein:
Y＝O、S；
R
2For
The time: R
7For
R
2For
The time: R
7Be R
6,
X, R
4, R
5, R
6Same as above.
The present invention relates to that preferred compound comprises in general formula (I) structure:
R
1: H, methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, amyl group, isopentyl, they are welcome to be replaced by following one to three group: fluorine, chlorine, bromine, hydroxyl, itrile group, carboxyl, amino, nitro, methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, amyl group, isopentyl, the pentamethylene base, cyclohexyl, methoxyl group, oxyethyl group, propoxy-, butoxy, isobutoxy, formyl radical, ethanoyl, propionyl, phenyl, imidazoles, pyridine oxazole isoxazole, furans, thiazole, pyrazoles, thiophene, the pyrroles, pyridazine, pyrimidine, pyrazine, piperidines, tetramethylene sulfide, tetrahydrofuran (THF), tetrahydric thiapyran, morpholine, piperazine, and by fluorine, chlorine, bromine, hydroxyl, itrile group, carboxyl, amino, nitro, methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, amyl group, isopentyl, the pentamethylene base, cyclohexyl, methoxyl group, oxyethyl group, propoxy-, butoxy, isobutoxy, formyl radical, ethanoyl, propionyl, phenyl, imidazoles, pyridine oxazole isoxazole, furans, thiazole, pyrazoles, thiophene, the pyrroles, pyridazine, pyrimidine, pyrazine, piperidines, tetramethylene sulfide, tetrahydrofuran (THF), tetrahydric thiapyran, morpholine, the benzene that piperazine or the like replaced, imidazoles, pyridine oxazole isoxazole, furans, thiazole, pyrazoles, thiophene, the pyrroles, pyridazine, pyrimidine, pyrazine, piperidines, tetramethylene sulfide, tetrahydrofuran (THF), tetrahydric thiapyran, morpholine, piperazine;
R
2：
Wherein,
X＝O、S、N-R
5
R
4, R
5The time or be respectively H, R
6,
Wherein,
R
6Be methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, amyl group, isopentyl, the pentamethylene base, cyclohexyl, phenyl, imidazoles, pyridine oxazole isoxazole, furans, thiazole, pyrazoles, thiophene, the pyrroles, pyridazine, pyrimidine, pyrazine, piperidines, tetramethylene sulfide, tetrahydrofuran (THF), tetrahydric thiapyran, morpholine, piperazine, they are welcome to be replaced by following one to three group: fluorine, chlorine, bromine, hydroxyl, itrile group, carboxyl, amino, nitro, methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, amyl group, isopentyl, the pentamethylene base, cyclohexyl, methoxyl group, oxyethyl group, propoxy-, butoxy, isobutoxy, formyl radical, ethanoyl, propionyl, phenyl, imidazoles, pyridine oxazole isoxazole, furans, thiazole, pyrazoles, thiophene, the pyrroles, pyridazine, pyrimidine, pyrazine, piperidines, tetramethylene sulfide, tetrahydrofuran (THF), tetrahydric thiapyran, morpholine, piperazine, and by fluorine, chlorine, bromine, hydroxyl, itrile group, carboxyl, amino, nitro, methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, amyl group, isopentyl, the pentamethylene base, cyclohexyl, methoxyl group, oxyethyl group, propoxy-, butoxy, isobutoxy, formyl radical, ethanoyl, propionyl, phenyl, imidazoles, pyridine oxazole isoxazole, furans, thiazole, pyrazoles, thiophene, the pyrroles, pyridazine, pyrimidine, pyrazine, piperidines, tetramethylene sulfide, tetrahydrofuran (THF), tetrahydric thiapyran, morpholine, the benzene that piperazine or the like replaced, imidazoles, pyridine oxazole isoxazole, furans, thiazole, pyrazoles, thiophene, the pyrroles, pyridazine, pyrimidine, pyrazine, piperidines, tetramethylene sulfide, tetrahydrofuran (THF), tetrahydric thiapyran, morpholine, piperazine;
R
3：
Wherein:
Y＝O、S；
R
2For
The time: R
7For
R
2For
The time: R
7Be R
6,
X, R
4, R
5, R
6Same as above.
The present invention relates in general formula (I) structure preferred compound and be numbered:
L1:2-(tertbutyloxycarbonyl amido)-2-(2-(5-oxo-2-thiocarbamoyl imidazole alkyl) thiazole-4-yl) ethyl acetate
L2:2-amino-2-(2-(5-oxo-2-thiocarbamoyl imidazole alkyl) thiazole-4-yl) ethyl acetate hydrochloride
L3:2-acetamido-2-(2-(5-oxo-2-thiocarbamoyl imidazole alkyl) thiazole-4-yl) ethyl acetate
L4:2-benzoylamino-2-(2-(5-oxo-2-thiocarbamoyl imidazole alkyl) thiazole-4-yl) ethyl acetate
L5:2-(furans-2-formamido-)-2-(2-(5-oxo-2-thiocarbamoyl imidazole alkyl) thiazole-4-yl) ethyl acetate
L6:2-(sulfonyl methane amido)-2-(2-(5-oxo-2-thiocarbamoyl imidazole alkyl) thiazole-4-yl) ethyl acetate
L7:2-(4-Methyl benzenesulfonyl amido)-2-(2-(5-oxo-2-thiocarbamoyl imidazole alkyl) thiazole-4-yl) ethyl acetate
L8:2-(tertbutyloxycarbonyl (methyl) amido)-2-(2-(5-oxo-2-thiocarbamoyl imidazole alkyl) thiazole-4-yl) ethyl acetate
L9:2-(methylamino)-2-(2-(5-oxo-2-thiocarbamoyl imidazole alkyl) thiazole-4-yl) ethyl acetate
L10:2-(2,3-two tertbutyloxycarbonyl guanidine radicals)-2-(2-(5-oxo-2-thiocarbamoyl imidazole alkyl) thiazole-4-yl) ethyl acetate
L11:2-guanidine radicals-2-(2-(5-oxo-2-thiocarbamoyl imidazole alkyl) thiazole-4-yl) ethyl acetate hydrochloride
L12:2-(tertbutyloxycarbonyl amido)-2-(2-(3-ethoxycarbonyl thioureido) thiazole-4-yl) ethyl acetate
L13:2-(2-(3-benzoylthioureas base) thiazole-4-yl)-2-(tertbutyloxycarbonyl amido) ethyl acetate
L14:2-(tertbutyloxycarbonyl amido)-2-(2-(3-(furans-2-formyl radical) thioureido) thiazole-4-yl) ethyl acetate
L15:2-(tertbutyloxycarbonyl amido)-2-(2-(3-(furans-2-formyl radical) urea groups) thiazole-4-yl) ethyl acetate
L16:2-(2-acetamido thiazole-4-yl)-2-(2,3-two tertbutyloxycarbonyl guanidine radicals) ethyl acetate
L17:2-(2,3-two tertbutyloxycarbonyl guanidine radicals)-2-(2-(2-chloracetyl amido) thiazole-4-yl) ethyl acetate
L18:2-(2-acetamido thiazole-4-yl)-2-guanidoacetic acid ethyl ester
L19:2-acetamido-2-(2-(5-oxo-2-thiocarbamoyl imidazole alkyl) thiazole-4-yl) acetate
L20:2-amino-2-(2-(5-oxo-2-thiocarbamoyl imidazole alkyl) thiazole-4-yl) acetic acid hydrochloride
L21:2-amino-2-(2-(3-ethoxycarbonyl thioureido) thiazole-4-yl) ethyl acetate hydrochloride
Compound of Formula I of the present invention is synthetic by following steps:
By II reduction preparation III, III is with tert-Butyl dicarbonate prepared in reaction IV, and IV is with chloroacetyl chloride prepared in reaction V, and V prepares Ia with rhodanide reaction, and Ia removes protection preparation Ib, the same again alkylating reagent of Ib, acylting agent or sulfonylation agent prepared in reaction Ic; But Ib also homophase answers reagent prepared in reaction Id;
The same acylting agent of IV, sulfonylation agent, acyl group lsothiocyanates or acyl isocyanate prepared in reaction Ie, Ie remove protection preparation If, the same again alkylating reagent of If, acylting agent or sulfonylation agent prepared in reaction Ig; But If also homophase answers reagent prepared in reaction Ih;
Ia, Ib, Ic, Id, Ie, If, Ig, Ih also can hydrolysis under the alkaline condition again acidifying become carboxylic acid, or further with the alkaline matter salify.
Amido in Ia, Ib, Ic, Id, Ie, If, Ig, the Ih compound also can be with various mineral acids or organic acid salify.
Wherein: R is H, alkyl.
X, Y, R
4, R
5Definition with above described.
The pharmacy acceptable salt of formula I compound of the present invention, can contain carboxyl or amido according to different derivatives, carboxyl can react with alkaline matter (as oxyhydroxide, carbonate and the supercarbonate of basic metal or alkaline-earth metal), they include, but are not limited to: sodium hydroxide, potassium hydroxide, calcium hydroxide, yellow soda ash etc. form pharmacy acceptable salt, as corresponding sodium salts, and sylvite or calcium salt or the like.Also can adopt nontoxic organic bases such as methylamine, triethylamine, meglumine etc. to generate salt; Amido can generate salt with various mineral acids (example hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid etc., but be not limited only to this) or organic acid (as formic acid, acetate, citric acid, oxalic acid, fumaric acid, toxilic acid, amino acid or the like, but being not limited only to this).
Formula I compound of the present invention or its steric isomer, tautomer, pharmacy acceptable salt or solvate can be made pharmaceutical composition jointly with one or more pharmaceutically acceptable carriers, vehicle or thinner.This pharmaceutical composition can be made formulations such as solid orally ingestible, liquid oral medicine, injection.
Described solid and liquid oral medicine comprise: tablet, dispersible tablet, enteric coated tablet, chewable tablet, orally disintegrating tablet, capsule, syrup, granule, oral solution.
Adopt lactose or starch thinner as described solid orally ingestible; Use gelatin, methylcellulose gum, hypromellose, polyvinylpyrrolidone, starch slurry etc. are as tackiness agent; Use starch, Xylo-Mucine, carboxymethylstach sodium, low-substituted hydroxypropyl methylcellulose, polyvinylpolypyrrolidone, Microcrystalline Cellulose as disintegrating agent; Use talcum powder, little part of silica gel, stearin, calcium stearate or magnesium etc. are as antiadhesives and lubricant.
The preparation method of described solid orally ingestible may further comprise the steps: with activeconstituents and carrier and optionally with a disintegration additive composition mixture, make the aqueous solution of this mixture and tackiness agent then, alcohol or aqueous alcohol solution carry out wet method or dry granulation in suitable device, dried particles, the disintegrating agent, lubricant and the antisticking agent that add other are subsequently made appropriate formulations.
Series compound of the present invention can also pass through non-enteron aisle form administration.Preferred parenterai administration form is the injection administration, comprises the injection liquid drugs injection, injection powder pin and primary infusion.
The actual dosage of taking compound of series compound of the present invention should be decided according to relevant situation by the doctor, these situations comprise by curer's physical state, patient's route of administration, age, body weight, to the individual reaction of medicine and severity of symptom or the like.
The biological activity of compound of Formula I of the present invention is measured in the following manner:
1, antivirus test
Get different titers experiment virus and plant stoste, aseptic subpackaged freezing preservation.Choose 20 of ICR kind mouse, be divided into 4 groups at random, 5 every group.With mouse with etherization after, respectively collunarium infects the virus stock solution used of different titers, every mouse 20ul.The time of symptoms of pneumonia and the fate of infection back dead mouse appear in the record mouse infection time, select to cause that mouse about 90% dead viral liquid are used for official test and infect.
Get ICR kind mouse, about body weight 15g, the male and female dual-purpose is respectively organized mouse with the titre collunarium infection that above-mentioned screening is good.Press the weight average grouping in 24 hours in virus inoculation, be respectively negative control group, different treatment group, dosage 50mg/kg.Route of administration is the filling stomach, once a day, and successive administration ten days.Observe mouse invasion rate and survival state in 14 days, with mortality ratio and survival time of animal be evaluation index.
2, bacteriostatic test:
Bacterial classification: standard bacillus canalis capsulatus CMCC 46117, standard gold staphylococcus aureus CMCC26003 purchase in Nat'l Pharmaceutical ﹠ Biological Products Control Institute.
Sample is prepared: accurate each sample 3.2mg of weighing, and after a small amount of DMSO dissolving, stroke-physiological saline solution is diluted to 5ml (concentration is 640 μ g/ml); Getting 1ml, to be diluted to concentration be 128 μ g/ml, uses behind the filtering with microporous membrane of diameter 0.22 μ m standby again.
The mensuration of MIC: the compound liquid for preparing with broth culture carries out doubling dilution, makes final concentration be respectively 128,64,32,16,8,4,2,1,0.5,0.25 μ g/ml.Add the contrast of 200 μ l bacterium liquid and broth culture respectively in 1 hole, 12 holes of 96 orifice plates; Add different concns soup 100 μ l afterwards from the 2-11 hole successively from high to low, add the bacterium liquid of 100 μ l afterwards again, the evenly rearmounted 37 ℃ of constant incubators of concussion were cultivated 16-18 hour, observed the Cmin (MIC) that does not have bacterial growth.
Embodiment:
The present invention is described further below in conjunction with embodiment, embodiment only is indicative, mean that never it limits the scope of the invention by any way, the invention compound detect through high performance liquid chromatography (HPLC), thin-layer chromatography (TLC) and fusing point (m.p.), adopt subsequently nucleus magnetic resonance (
1H-NMR) further prove conclusively its structure.
Embodiment 1
Add 30gII in the reaction flask, the 250ml dehydrated alcohol, the 50ml glacial acetic acid stirs the water-reducible 40ml concentrated hydrochloric acid of adding 500ml down, 4g10% palladium charcoal, normal pressure hydrogenation.React completely in conjunction with TLC control with hydrogen, filter, filter cake washes (50ml * 2) with water, merging filtrate, concentrating under reduced pressure, remaining about 150～200ml solution.
Get above-mentioned solution, ice bath, potassium carbonate powder regulator solution pH value to 8～9, engender insolubles, add the 100mlTHF solution of 30.0g tert-Butyl dicarbonate, add the back ice bath and stir 1h, a large amount of solids occur, rise to 25 ℃ of reactions, TLC control reacts completely, in the impouring 1000ml water, stir, filter, filter cake washes (200ml * 2) with water, and dehydrated alcohol is washed (100ml * 2), and sherwood oil is washed (100ml * 2), drying gets near-white solid IV30.0g.m.p.144.4～145.0℃，
1HNMR(DMSO，400MHz)，δ：1.145(t，3H，CH
3)，1.374(s，9H，N-Boc)，4.085(m，2H，OCH
2)，4.994(d，1H，CH-C＝O)，6.482(s，1H，Thiazole-H)，6.975(s，2H，Thiazole-NH
2)，7.111(d，1H，NH-Boc)。
Add 28.6gIV in the 250ml reaction flask, 100mlDMF, stirring and dissolving, ice bath adds 15～20g triethylamine down, and 0～10 ℃ drips 11.8g chloroacetyl chloride (about 30min adds), ice bath reaction 2h, remove ice bath, rise to 25 ℃ of reactions, TLC control reacts completely, in the impouring 800ml water, solid appears in stirring, filters, and filter cake washes (100ml * 3) with water, drying gets solid V33g.m.p.175.8～176.5℃，
1HNMR(DMSO，400MHz)，δ：1.150(t，3H，CH
3)，1.383(s，9H，N-Boc)，4.090(m，2H，OCH
2)，4.350(s，2H，ClCH
2C＝O)，5.240(d，1H，CH-C＝O)，7.210(s，1H，Thiazole-H)，7.500(d，1H，NH-Boc)，12.587(s，1H，Thiazole-NH)。
Add 33gV in the reaction flask, the 300ml acetonitrile stirs and heats up 50 ℃, not molten clear, add the 8.0g tetra-n-butyl ammonium bromide, the 10.0g potassiumiodide stirs 15min, add the 7.1g Sodium Thiocyanate 99,50 ℃ of stirring reaction 3h add the 1g Sodium Thiocyanate 99, and 60 ℃ of stirring reaction 2h heat up, the 70 ℃ of stirring reaction 1～2h that heat up, TLC control reacts completely.Cooling adds 100ml water, and reaction solution is molten clear, and acetonitrile is to the greatest extent steamed in decompression, on oily matter bubbles through the water column, the 250ml ethyl acetate extraction, organic phase is washed (20ml * 3) with the saturated NaCl aqueous solution, anhydrous sodium sulfate drying, evaporated under reduced pressure gets 22g light yellow solid L1.
Embodiment 2
Add 4gL1 in the reaction flask, the 10ml methylene dichloride, the 10ml trifluoroacetic acid, 30 ℃ of stirring reactions, the control of some plate reacts completely.Solvent is to the greatest extent steamed in decompression, gets oily matter, and adding 10ml trichloromethane, ice bath stir and add excessive hydrochloric acid ethanol down, solid occurs, filtration, and sherwood oil is washed (10ml * 2), and drying gets 1.4g off-white color solid L2.
Embodiment 3
Add 4gL1 in the reaction flask, the 10ml methylene dichloride, the 10ml trifluoroacetic acid, 30 ℃ of stirring reactions, the control of some plate reacts completely.Solvent is to the greatest extent steamed in decompression, gets oily matter.Add the 10ml tetrahydrofuran (THF), ice bath drips the 2.0g triethylamine down, stirs 10min, drip the 0.6g Acetyl Chloride 98Min., 25 ℃ of reactions, TLC control reacts completely, and adds 150ml ethyl acetate and 100ml water, phase-splitting, the organic phase anhydrous sodium sulfate drying, evaporated under reduced pressure gets oily matter, petroleum ether-ethyl acetate is refining, gets 2.5g light yellow solid L3.
Embodiment 4～7
With reference to the operation of embodiment 3,, obtain following compounds with the acyl chlorides of different structure or the excess acetyl chloride of SULPHURYL CHLORIDE alternate embodiment 3 in the table.
Embodiment 8
Add 1.6gL1 in the reaction flask, the 30ml tetrahydrofuran (THF), stirring and dissolving, ice bath adds 0.32g sodium hydroxide down, 1.1g salt of wormwood and 0.6g methyl iodide, the ice bath reaction, the control of some plate reacts completely.Add 100ml ethyl acetate and 20ml water, phase-splitting, the organic phase anhydrous sodium sulfate drying, evaporated under reduced pressure gets oily matter, silica gel column chromatography (sherwood oil: ethyl acetate=2: 1), get 0.8g light yellow solid L8.
Embodiment 9
Add 0.4gL8 in the reaction flask, the 6ml methylene dichloride, the 6ml trifluoroacetic acid, 30 ℃ of stirring reactions, the control of some plate reacts completely.Solvent is to the greatest extent steamed in decompression, gets oily matter.Adding 10ml water, ice bath drips triethylamine down and regulates pH to 9, solid occurs, filters, and filter cake washes with water, and sherwood oil is washed, and drying gets 0.14g light yellow solid L9.
Embodiment 10
Add 3gL1 in the reaction flask, the 10ml methylene dichloride, the 10ml trifluoroacetic acid, 30 ℃ of stirring reactions, the control of some plate reacts completely.Solvent is to the greatest extent steamed in decompression, gets oily matter.Add the 30ml tetrahydrofuran (THF), ice bath drips triethylamine down and regulates pH to 9, adds 2.3gN, N '-two tert-butoxycarbonyls-1H-pyrazoles-1-carbonamidine, 25 ℃ of reactions, TLC control reacts completely, add 150ml ethyl acetate and 100ml water, phase-splitting, organic phase is washed (10ml * 3), anhydrous sodium sulfate drying with saturated sodium-chloride water solution, evaporated under reduced pressure, get oily matter, silica gel column chromatography (sherwood oil: ethyl acetate=1: 1), get 1.0g light yellow oil L10.
Embodiment 11
Add 1.0gL10 in the reaction flask, the 10ml methylene dichloride, the 10ml trifluoroacetic acid, 30 ℃ of stirring reactions, the control of some plate reacts completely.Solvent is to the greatest extent steamed in decompression, gets oily matter, and adding 10ml trichloromethane, ice bath stir and add excessive hydrochloric acid ethanol down, solid occurs, filtration, and sherwood oil is washed (10ml * 2), and drying gets 0.56g off-white color solid L11.
Embodiment 12
The 0.52g Sodium Thiocyanate 99 is joined in the ethyl acetate of 30ml, stir and add the 0.70g Vinyl chloroformate, 60 ℃ of stirring reaction 1～3h add 1.6gIV, temperature rising reflux, the control of some plate reacts completely, filter, solvent is to the greatest extent steamed in decompression, gets oily matter, silica gel column chromatography (sherwood oil: ethyl acetate=2: 1), get 1.2g white solid L12.
Embodiment 13～15
With reference to the operation of embodiment 12, with in the acyl group lsothiocyanates of different structure or the acyl isocyanate alternate embodiment 12 in the table by the ethoxy acyl group lsothiocyanates reaction of Vinyl chloroformate and Sodium Thiocyanate 99 prepared in reaction, obtain following compounds.
Embodiment 16
Add 5gIV in the reaction flask, 20ml tetrahydrofuran (THF), ice bath stir and drip the 1.5g Acetyl Chloride 98Min. down, and ice bath reaction 2h removes ice bath, rise to 25 ℃ of reactions, TLC control reacts completely, and in the impouring 100ml water, solid appears in stirring, filter, filter cake washes (100ml * 3) with water, and drying gets the 3.5g solid.
Above-mentioned solid is joined in the 20ml methylene dichloride, add the 10ml trifluoroacetic acid, 30 ℃ of stirring reactions, the control of some plate reacts completely.Solvent is to the greatest extent steamed in decompression, gets oily matter.Add the 30ml acetonitrile, ice bath drips triethylamine down and regulates pH to 9, adds 2.3gN, N '-two tert-butoxycarbonyls-1H-pyrazoles-1-carbonamidine, 25 ℃ of reactions, TLC control reacts completely, add 150ml ethyl acetate and 100ml water, phase-splitting, organic phase is washed (10ml * 3), anhydrous sodium sulfate drying with saturated sodium-chloride water solution, evaporated under reduced pressure, get oily matter, silica gel column chromatography (sherwood oil: ethyl acetate=3: 1), get the shallow white solid L16 of 0.8g.
Embodiment 17
With reference to the operation of embodiment 16, make compound L 17 by compound V.
Embodiment 18
Add 0.4gL16 in the reaction flask, the 5ml methylene dichloride, the 5ml trifluoroacetic acid, 30 ℃ of stirring reactions,
The control of some plate reacts completely.Solvent is to the greatest extent steamed in decompression, gets oily matter, adding 5ml water, and ice bath drips triethylamine down and regulates pH to 9, solid occurs, filtration, filter cake washes with water, and sherwood oil is washed, and drying gets 0.20g light yellow solid L18.
Embodiment 19
Add 0.84gL3 in the reaction flask, the 20ml aqueous solution of 0.6g salt of wormwood, stirring and dissolving.Room temperature reaction, the control of some plate reacts completely, and solid appears in dilute hydrochloric acid adjusting pH to 3～4 under the ice bath, filter, a small amount of washing of filter cake, ethanol is washed (5ml * 2), and sherwood oil is washed (5ml * 3), and drying gets 0.3g yellow solid L19.
Embodiment 20
Operation with reference to embodiment 16 and embodiment 11 makes compound L 20 by compound L 1.
Embodiment 21
Operation with reference to real embodiment 11 makes compound L 21 by compound L 12.
The L1-L21 fusing point and
1H-NMR is as follows:
In order to explain enforcement of the present invention more fully, provide following example of formulations.These embodiment explain rather than limit the scope of the invention.Preparation can adopt any one compound among the present invention as activeconstituents.
Embodiment 22
Method for preparing tablet thereof is as follows:
1000 consumptions of writing out a prescription
L1-L3 80g
Microcrystalline Cellulose 30g
Pregelatinized Starch 40g
Lactose 120g
Hypromellose 8g
Sodium starch glycolate 12g
Magnesium Stearate qs
Silicon-dioxide qs
Technology: the activeconstituents auxiliary material is crossed 100 mesh sieves respectively; take by weighing the main ingredient and auxiliary material (half sodium starch glycolate) thorough mixing of recipe quantity; add the hypromellose aqueous solution and make softwood in right amount; cross 24 mesh sieves, make wet granular in 50-60 ℃ of baking oven dry about 2-3 hour, will remain sodium starch glycolate; Magnesium Stearate and silicon-dioxide and particle mix; whole grain is measured intermediate content, uses special-shaped stamping.
Embodiment 23
Capsular being prepared as follows:
The 1000 capsules consumptions of writing out a prescription
L6-L8 100g
Microcrystalline Cellulose 20g
Lactose 120g
Low-substituted hydroxypropyl cellulose 6g
10% starch slurry qs
Magnesium Stearate qs
Technology: the activeconstituents auxiliary material is crossed 100 mesh sieves respectively; take by weighing the main ingredient and the auxiliary material thorough mixing of recipe quantity; add the polyvidone aqueous solution and make softwood in right amount; cross 20 mesh sieves; make wet granular in 50-60 ℃ of baking oven dry about 2-3 hour, Magnesium Stearate and particle are mixed whole; measure intermediate content, with No. 2 capsule cans.
Embodiment 24
The preparation of oral solution (per 1000 bottles of amounts)
L11，L20 200g
N.F,USP MANNITOL 100g
Citric acid 20g
Orange flavor essence 10g
Aspartame 10g
Tegosept E qs
Distilled water 50000ml
Technology: get distilled water 10ml, the citric acid, N.F,USP MANNITOL, orange flavor essence, aspartame, the sample that take by weighing recipe quantity stir and make dissolving, and after the adding sanitas, can is in bottle.
Embodiment 25 (dispersible tablet) (per 1000 amounts)
L4-L5 50g
Lactose 120g
Microcrystalline Cellulose 40g
Crosslinked gathering for adding 10g in the ketone adds 10g
Aspartame 5g
Orange essence 5g
2% hypromellose qs
Silicon-dioxide qs
Magnesium Stearate qs
Technology: main ingredient and auxiliary material are crossed 100 mesh sieves respectively, and thorough mixing takes by weighing recipe quantity auxiliary material and main ingredient thorough mixing then.Add tackiness agent system softwood again, 20 mesh sieves are granulated, 55 ℃ of dryings, the whole grain of 18 mesh sieves.Add lubricant at last and remainingly crosslinkedly poly-mix compressing tablet for ketone.
Embodiment 26 (orally disintegrating tablet) (per 1000 amounts)
L13-L19 70g
N.F,USP MANNITOL 100g
Microcrystalline Cellulose 40g
Croscarmellose sodium, 20g
Magnesium Stearate qs
Silicon-dioxide qs
Technology: main ingredient and auxiliary material are crossed 100 mesh sieves respectively, and thorough mixing adopts the roll squeezer cake of press, crosses the whole grain of 18 mesh sieves with whole granula again, adds the even compressing tablet of mix lubricant at last.
Embodiment 27 (effervescent tablet) (per 1000 amounts)
L8-L9 50g
Tartrate 100g
Sodium bicarbonate 80g
Methylcellulose gum 10g
Maltose alcohol 10g
Lemon flavour 5g
Magnesium Stearate qs
Preparation technology is with embodiment 22.
Embodiment 28 (chewable tablet) (per 1000 amounts)
L10-L11 200g
N.F,USP MANNITOL 80g
Sorbyl alcohol 30g
Stevioside 5g
Pericarpium Citri junoris tincture 5g
5% polyvidone aqueous solution qs
Stearic acid qs
Preparation technology is with embodiment 22.
Embodiment 29 (per 1000 bags of granule)
L2-L4 300g
Lactose 600g
N.F,USP MANNITOL 180g
Soluble saccharin 5g
Essence 5g
2% hypromellose (water) qs
Technology: main ingredient and auxiliary material are crossed 100 mesh sieves respectively, and thorough mixing takes by weighing recipe quantity auxiliary material and main ingredient thorough mixing then.Add tackiness agent system softwood again, 14 mesh sieves are granulated, 55 ℃ of dryings, and the whole grain of 16 mesh sieves is measured heavily packing of bag.
Embodiment 30 (enteric coated tablet) (1000 amounts)
Plain tablet recipe
L5-L7 75g
Lactose 180g
Pregelatinized Starch 60g
Xylo-Mucine 10g
Sodium starch glycolate 10g
10% polyvidone aqueous solution qs
Magnesium Stearate qs
Preparation technology is with embodiment 22.
The dressing prescription:
Plain sheet 80g
Acrylic resin L100-55 8.0g
Talcum powder 2.0g
Titanium dioxide 1.6g
Triethyl citrate qs
95% alcohol adds to 145ml
Art for coating:
A, acrylic resin L100-55, titanium dioxide, talcum powder, the triethyl citrate of recipe quantity be dissolved in 95% the ethanol, fully mixing.
B, the plain sheet of recipe quantity is placed coating pan, start air blast, making the sheet temperature is about 40 ℃, sprays into enteric coating with spray gun, and spray speed is 5ml/ minute, sprayed to enteric coating, and dry 1h, packing gets final product.
Embodiment 31
The preparation of injection liquid (1000 component)
L19，L21 2.0g
SODIUM PHOSPHATE, MONOBASIC 1.0g
Citric acid 0.5g
Sodium-chlor 18g
Water for injection 2000ml
Technology: get water for injection 1000ml, the citric acid, SODIUM PHOSPHATE, MONOBASIC, the sodium-chlor that take by weighing recipe quantity stir and make dissolving, adding the sample stirring and dissolving, is 4.0-7.0 with hydrochloric acid or the sodium hydroxide adjust pH of 0.1mol/L, the charcoal absorption of adding 0.1% 20 minutes.Filter with 045 μ m filter membrane earlier, mend and add water to full dose, again with the smart filter of 022 μ m.Cut open 2 milliliters of cans by every peace, 105 ℃ of high-temperature sterilizations promptly got injection liquid in 30 minutes.
Embodiment 32
The preparation of freeze-dried powder (1000 component)
L19，L20 4.0g
N.F,USP MANNITOL 150g
Sodium-chlor 18g
Water for injection 2000ml
Technology: get water for injection 1000ml, the N.F,USP MANNITOL, sodium-chlor that take by weighing recipe quantity stir and make dissolving, add the sample stirring and dissolving, are 3.0-6.0 with hydrochloric acid or the sodium hydroxide adjust pH of 0.1mol/L, the charcoal absorption of adding 0.15% 20 minutes.Filter with 045 μ m filter membrane earlier, mend and add water to full dose, again with the smart filter of 022 μ m.Cut open 2 milliliters of cans by every peace, pre-freeze is after 2 hours, freezing drying under reduced pressure down 15 hours, to sample temperature after room temperature, dry 5 hours again, make the white loose block, seal and promptly get freeze-dried powder.
Embodiment 33
The preparation of primary infusion (100 component)
L2 5g
SODIUM PHOSPHATE, MONOBASIC 15g
Sodium-chlor 90g
Water for injection 10000ml
Technology: get water for injection 2000ml, the SODIUM PHOSPHATE, MONOBASIC, sodium-chlor that take by weighing recipe quantity stir and make dissolving, add the sample stirring and dissolving, are 4.0-6.0 with hydrochloric acid or the sodium hydroxide adjust pH of 0.1mol/L, the charcoal absorption of adding 0.10% 20 minutes.Filter with 045 μ m filter membrane earlier, moisturizing is to 10000ml, again with the smart filter of 022 μ m.Cut open every bottle of 100ml of embedding by every peace, sterilization promptly gets sodium chloride injection.
The present invention relates to the biological activity determination result of general formula (I) compound:
Annotate: 1, in the influence test to the mouse infection influenza virus, mouse death rate＜50% is+;
2, in the extracorporeal bacteria inhibitor test, MIC (μ g/ml)＜64 is+.
Claims (6)
1. the compound or pharmaceutically acceptable salt thereof of general formula (I) structure
Wherein:
R
1Be selected from H, methyl, ethyl, propyl group or sec.-propyl;
R
2Be selected from
Wherein,
X is NH;
R
4Be H;
R
5Be selected from H, R
6,
Wherein,
R
6Be selected from methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, phenyl, furyl or thienyl, it can be chosen wantonly and is selected from following group list replacement: fluorine, chlorine, bromine, methyl or ethyl;
R
3Be selected from
Wherein,
Y is selected from 0 or S;
R
7For
R
6Implication is the same.
2. the compound or pharmaceutically acceptable salt thereof of claimed formula (I) structure of claim 1 is selected from:
2-(tertbutyloxycarbonyl amido)-2-(2-(5-oxo-2-thiocarbamoyl imidazole alkyl) thiazole-4-yl) ethyl acetate;
2-amino-2-(2-(5-oxo-2-thiocarbamoyl imidazole alkyl) thiazole-4-yl) ethyl acetate hydrochloride;
2-acetamido-2-(2-(5-oxo-2-thiocarbamoyl imidazole alkyl) thiazole-4-yl) ethyl acetate;
2-benzamide base-2-(2-(5-oxo-2-thiocarbamoyl imidazole alkyl) thiazole-4-yl) ethyl acetate;
2-(furans-2-formamido-)-2-(2-(5-oxo-2-thiocarbamoyl imidazole alkyl) thiazole-4-yl) ethyl acetate;
2-(sulfonyl methane amido)-2-(2-(5-oxo-2-thiocarbamoyl imidazole alkyl) thiazole-4-yl) ethyl acetate;
2-(4-Methyl benzenesulfonyl amido)-2-(2-(5-oxo-2-thiocarbamoyl imidazole alkyl) thiazole-4-yl) ethyl acetate;
2-(methylamino)-2-(2-(5-oxo-2-thiocarbamoyl imidazole alkyl) thiazole-4-yl) ethyl acetate;
2-guanidine radicals-2-(2-(5-oxo-2-thiocarbamoyl imidazole alkyl) thiazole-4-yl) ethyl acetate hydrochloride;
2-(2-(3-benzoylthioureas base) thiazole-4-yl)-2-(tertbutyloxycarbonyl amido) ethyl acetate;
2-(tertbutyloxycarbonyl amido)-2-(2-(3-(furans-2-formyl radical) thioureido) thiazole-4-yl) ethyl acetate;
2-(tertbutyloxycarbonyl amido)-2-(2-(3-(furans-2-formyl radical) urea groups) thiazole-4-yl) ethyl acetate;
2-acetamido-2-(2-(5-oxo-2-thiocarbamoyl imidazole alkyl) thiazole-4-yl) acetate;
2-amino-2-(2-(5-oxo-2-thiocarbamoyl imidazole alkyl) thiazole-4-yl) acetic acid hydrochloride.
3. prepare the method for the compound or pharmaceutically acceptable salt thereof of claimed formula (I) structure of claim 1, may further comprise the steps:
Wherein: R is H or alkyl; Y, R
1, R
4, R
5, R
7Has the implication that provides in the claim 1;
By compound (II) reduction preparation compound (III), compound (III) and tert-Butyl dicarbonate prepared in reaction compound (IV), compound (IV) and chloroacetyl chloride prepared in reaction compound (V), compound (V) prepares compound (Ia) with rhodanide reaction, compound (Ia) removes protection preparation compound (Ib), compound (Ib) and alkylating reagent, acylting agent, sulfonylation agent prepared in reaction compound (Ic); Compound (Ib) but also homophase answer reagent prepared in reaction compound (Id); Compound (IV) and acyl group lsothiocyanates or acyl isocyanate prepared in reaction compound (Ie), compound (Ie) removes protection preparation compound (If), the same alkylating reagent of compound (If), acylting agent, sulfonylation agent prepared in reaction compound (Ig); Compound (If) but also homophase answer reagent prepared in reaction compound (Ih);
If necessary, compound (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih) also can hydrolysis under the alkaline condition again acidifying become carboxylic acid, or further with the alkaline matter salify;
If necessary, the amido among compound (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih) also can be with various mineral acids or organic acid salify.
4. the compound or pharmaceutically acceptable salt thereof of claim 1 or 2 each claimed formula (I) structures is used to prepare the purposes of antiviral/antibacterials.
5. pharmaceutical composition, the compound or pharmaceutically acceptable salt thereof that wherein contains at least a claim 1 or 2 each claimed formula (I) structures be as effective constituent, and contain one or more pharmaceutically acceptable carrier.
6. pharmaceutical composition according to claim 5, its described pharmaceutical composition is solid orally ingestible, liquid oral medicine or injection.
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| 黄长江等.吡唑类化合物的合成与药理活性研究.中国新药杂志.2007,16(24), * |
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