CN101684101B - Piperazinone substituted tetracycline derivatives - Google Patents
Piperazinone substituted tetracycline derivatives Download PDFInfo
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Abstract
The invention belongs to the technical field of medicament, and particularly relates to piperazinone substituted tetracycline derivatives shown in a general formula (I), and pharmaceutically acceptable salts or isomers thereof, wherein R<1a>, R<1b>, R<2>, R<3a>, R<3b>, R<4>, R<5a>, R<5b>, R<6>, R<7>, R<8>, R<9>, R<10>, R<11>, R<12>, R<13>, X and Y are defined in the specification. The invention also relates to a method for preparing the compounds, medicinal composition containing the compounds, as well as application of the compounds in the preparation of medicaments for treating and/or preventing tetracycline sensitive diseases, particularly in the preparation of medicaments for treating infectious diseases.
Description
1, technical field
The invention belongs to medical technical field, be specifically related to tetracycline derivant, its pharmacy acceptable salt or its isomer that piperazine ketone replaces, the preparation method of these compounds, the pharmaceutical composition that contains these compounds, and these compounds treat and/or prevent purposes, the especially purposes in the medicine of preparation treatment infectious diseases in the medicine of tetracyclines sensitive disease in preparation.
2, background technology
Tetracycline antibiotics is oral Broad spectrum antibiotics of a class and the semisynthetic derivative that is produced by the fermentation of actinomycetes streptomyces, and Rickettsiae, many gram-positive microorganisms and Gram-negative bacteria, lymphogranuloma venereum pathogenic agent, inclusion conjunctivitis pathogenic agent and psittacosis pathogenic agent are had good pharmacological effect.
First tetracycline antibiotics is to separate the duomycin that obtains from golden Streptothrix in 1948, has developed terramycin, tsiklomitsin subsequently in succession and Ledermycins, and all belongs to natural product, has height resistance and multiple side effect.Afterwards, the chemical structure of these compounds is studied, synthesized no methyl tetracycline antibiotics, MINOCYCLINE HCL class microbiotic.Yet, cause bacterium to these antibiotic resistances owing to be extensive use of tsiklomitsin, and resistance is more and more serious, make tetracycline antibiotics in use reduce comprehensively.
Early 1990s has been researched and developed the new class tetracycline medication, develops glycylcycline class medicine (glycyclines), represent medicine be Minocycline HCl the derivative Tigecycline (tigecylcine, GAR-936).The Tigecycline has a broad antifungal spectrum not only has the anti-microbial activity of early stage tetracyclines, and to because of the mechanism of effluxing and rrna protection mechanism the drug-fast pathogenic bacteria of tetracyclines also being had an anti-microbial activity, still active not ideal for the part Gram-negative bacteria.And Tigecycline can only intravenous drip, needs medication twice in one day, and the medication inconvenience is brought misery to the patient.Its structural formula is as follows:
Therefore, research and development new have good anti-microbial activity and medication easily tetracycline antibiotics be clinical required.
3, summary of the invention
Technical scheme of the present invention is as follows:
The invention provides the compound shown in the general formula (I):
Wherein, R
1a, R
1b, R
2, R
8, R
9And R
10Independently be respectively: hydrogen or prodrug part;
R
6For: hydrogen, halogen, hydroxyl, cyano group or NR
6aR
6b
R
3a, R
3b, R
6aAnd R
6bIndependently be respectively: hydrogen, C
1～6Alkyl, halo C
1～6Alkyl, C
2～6Thiazolinyl, C
2～6Alkynyl, C
1～6Alkoxyl group, hydroxyl C
1～6Alkyl, carboxyl C
1～6Alkyl, amino C
1～6Alkyl, C
1～6Alkyl-carbonyl, C
1～6Alkoxy carbonyl, C
1～6Alkyl sulphinyl, sulfonic group C
1～6Alkyl, C
1～6Alkyl amine group alkylsulfonyl, formamyl, C
6～14Aryl or C
6～14Aryl C
1～6Alkyl;
R
4, R
7, R
5aAnd R
5bIndependently be respectively: hydrogen, halogen, hydroxyl, amino, C
1～6Alkyl, halo C
1～6Alkyl, C
1～6Alkoxyl group, C
1～6Alkyl amine group, hydroxyl C
1～6Alkyl, C
1～6Alkyl-carbonyl, C
1～6Alkyl carbonyl oxy, C
1～6Alkoxy carbonyl, sulfonic acid amido, C
1～6Alkylsulfonamido, amino-sulfonyl, C
1～6Alkyl amine group alkylsulfonyl or formamyl C
1～6Alkyl;
X, Y independently are respectively: methylene radical or carbonyl;
R
11For: hydrogen, C
1～6Alkyl, halo C
1～6Alkyl, C
1～6Alkoxyl group, hydroxyl C
1～6Alkyl, carboxyl C
1～6Alkyl, amino C
1～6Alkyl, C
1～6Alkyl-carbonyl, C
1～6Alkoxy carbonyl, C
1～6Alkyl sulphinyl, C
1～6Alkyl sulphonyl, sulfonic acid amido C
1～6Alkyl, amino-sulfonyl C
1～6Alkyl, C
1～6Alkyl amine group alkylsulfonyl, C
1～6Alkyl amine group formyl radical, formamyl C
1～6Alkyl, C
6～14Aryl, C
6～14Aryl C
1～6Alkyl, C
6～14Aryl-acyl, C
6～14Aryl acyloxy, C
6～14Aryl sulfonyl, C
6～14Aryl C
1～6Alkyl acyl, 3-14 unit heterocyclic radical, the heterocyclic radical C of 3-14 unit
1～6Alkyl, bridged ring base or bridged ring base alkyl;
R
12, R
13Independently be respectively: hydrogen, halogen, hydroxyl, amino, carboxyl, C
1～6Alkyl, halo C
1～6Alkyl, C
1～6Alkoxyl group, C
1～6Alkyl amine group, two (C
1～6Alkyl) amido, hydroxyl C
1～6Alkyl, amino C
1～6Alkyl, C
1～6Alkyl-carbonyl, C
1～6Alkyl carbonyl oxy, C
1～6Alkoxy carbonyl, C
1～6Alkyl sulphinyl, C
1～6Alkyl sulphonyl, sulfonic group C
1～6Alkyl, sulfonic acid amido, sulfonic acid amido C
1～6Alkyl, amino-sulfonyl, C
1～6Alkyl amine group alkylsulfonyl, two (C
1～6Alkyl) amido alkylsulfonyl, C
1～6Alkylamidoalkyl, two (C
1～6Alkyl) amido formyl radical, formamyl, C
6～14Aryl or R
12With R
11Or R
13With R
11Be interconnected to 3-14 unit's heterocyclic radical or bridged ring group;
Above-mentioned R
11, R
12, R
13In C
6～14Aryl, 3-14 unit heterocyclic radical, bridged ring base can further be replaced by one or more substituting groups, and substituting group is selected from C
1～6Alkyl, halo C
1～6Alkyl, C
1～6Alkoxyl group, hydroxyl, carboxyl, amino, hydroxyl C
1～6Alkyl, carboxyl C
1～6Alkyl, amino C
1～6Alkyl, sulfonic group, C
1～6Alkyl acyl, C
1～6Alkoxy carbonyl, sulfonic acid amido, sulfonic acid amido C
1～6Alkyl, amino-sulfonyl, amino-sulfonyl C
1～6Alkyl or formamyl.
Preferred compound is:
Wherein, R
1a, R
1b, R
2, R
4, R
7, R
5a, R
5b, R
8, R
9And R
10Independently be respectively: hydrogen;
R
6For: NR
6aR
6b
R
3a, R
3b, R
6aAnd R
6bIndependently be respectively: methyl;
X, Y independently are respectively: methylene radical or carbonyl;
R
11For: hydrogen, C
1～6Alkyl, halo C
1～4Alkyl, C
1～4Alkoxyl group, hydroxyl C
1～4Alkyl, carboxyl C
1～4Alkyl, amino C
1～4Alkyl, C
1～4Alkyl-carbonyl, C
1～4Alkoxy carbonyl, C
1～4Alkyl sulphinyl, C
1～4Alkyl sulphonyl, sulfonic acid amido C
1～4Alkyl, amino-sulfonyl C
1～4Alkyl, C
1～4Alkyl amine group alkylsulfonyl, C
1～4Alkyl amine group formyl radical, formamyl C
1～4Alkyl, C
6～10Aryl, C
6～10Aryl C
1～4Alkyl, C
6～10Aryl-acyl, C
6～10Aryl acyloxy, C
6～10Aryl sulfonyl, C
6～10Aryl C
1～4Alkyl acyl, 4-10 unit heterocyclic radical, the heterocyclic radical C of 4-10 unit
1～4Alkyl, bridged ring base or bridged ring base alkyl;
R
12, R
13Independently be respectively: hydrogen, halogen, hydroxyl, amino, carboxyl, C
1～4Alkyl, halo C
1～4Alkyl, C
1～4Alkoxyl group, C
1～4Alkyl amine group, two (C
1～4Alkyl) amido, hydroxyl C
1～4Alkyl, amino C
1～4Alkyl, C
1～4Alkyl-carbonyl, C
1～4Alkyl carbonyl oxy, C
1～4Alkoxy carbonyl, C
1～4Alkyl sulphinyl, C
1～4Alkyl sulphonyl, sulfonic acid amido, amino-sulfonyl, C
1～4Alkyl amine group alkylsulfonyl, C
1～4Alkylamidoalkyl, formamyl, C
6～10Aryl or R
12With R
11Or R
13With R
11Be interconnected to 4-10 unit's heterocyclic radical or bridged ring group;
Above-mentioned R
11, R
12, R
13In C
6～10Aryl, 4-10 unit heterocyclic radical, bridged ring base can further be replaced by one or more substituting groups, and substituting group is selected from C
1～4Alkyl, halo C
1～4Alkyl, C
1～4Alkoxyl group, hydroxyl, carboxyl, amino, hydroxyl C
1～4Alkyl, carboxyl C
1～4Alkyl, amino C
1～4Alkyl, sulfonic group, C
1～4Alkyl acyl, C
1～4Alkoxy carbonyl, sulfonic acid amido, sulfonic acid amido C
1～4Alkyl, amino-sulfonyl, amino-sulfonyl C
1～4Alkyl or formamyl.
Further preferred compound is:
Wherein, R
1a, R
1b, R
2, R
4, R
7, R
5a, R
5b, R
8, R
9And R
10Independently be respectively: hydrogen;
R
6For: NR
6aR
6b
R
3a, R
3b, R
6aAnd R
6bIndependently be respectively: methyl;
X, Y independently are respectively: methylene radical or carbonyl;
R
11For: hydrogen, C
1～6Alkyl, fluoro C
1～4Alkyl, chloro C
1～4Alkyl, bromo C
1～4Alkyl, C
1～4Alkoxyl group, hydroxyl C
1～4Alkyl, carboxyl C
1～4Alkyl, amino C
1～4Alkyl, C
1～4Alkyl-carbonyl, C
1～4Alkoxy carbonyl, C
1～4Alkyl sulphinyl, C
1～4Alkyl sulphonyl, sulfonic acid amido C
1～4Alkyl, amino-sulfonyl C
1～4Alkyl, C
1～4Alkyl amine group alkylsulfonyl, C
1～4Alkyl amine group formyl radical, formamyl C
1～4Alkyl, phenyl, phenyl C
1～4Alkyl, phenyl acyl group, phenyl acyloxy, phenyl sulfonyl, phenyl C
1～4Alkyl acyl, 4～6 yuan of single heterocyclic radicals, 4～6 yuan of single heterocyclic radical C
1～4Alkyl or bridged ring base;
R
12, R
13Independently be respectively: hydrogen, halogen, hydroxyl, amino, carboxyl, C
1～4Alkyl, halo C
1～4Alkyl, C
1～4Alkoxyl group, C
1～4Alkyl amine group, two (C
1～4Alkyl) amido, hydroxyl C
1～4Alkyl, amino C
1～4Alkyl, C
1～4Alkyl-carbonyl, C
1～4Alkyl carbonyl oxy, C
1～4Alkoxy carbonyl, C
1～4Alkyl sulphinyl, C
1～4Alkyl sulphonyl, sulfonic acid amido, amino-sulfonyl, C
1～4Alkyl amine group alkylsulfonyl, C
1～4Alkylamidoalkyl, formamyl, phenyl or R
12With R
11Or R
13With R
11Be interconnected to 4～6 yuan of single heterocyclic radicals or bridged ring group;
Above-mentioned R
11, R
12, R
13Phenyl in the substituting group, 4～6 yuan of single heterocyclic radicals, bridged ring bases can further be replaced by one or more substituting groups, and substituting group is selected from C
1～4Alkyl, halo C
1～4Alkyl, C
1～4Alkoxyl group, hydroxyl, carboxyl, amino, hydroxyl C
1～4Alkyl, carboxyl C
1～4Alkyl, amino C
1～4Alkyl, sulfonic group, C
1～4Alkyl acyl, C
1～4Alkoxy carbonyl, sulfonic acid amido, sulfonic acid amido C
1～4Alkyl, amino-sulfonyl, amino-sulfonyl C
1～4Alkyl or formamyl.
Further preferred compound is:
Wherein, R
1a, R
1b, R
2, R
4, R
7, R
5a, R
5b, R
8, R
9And R
10Independently be respectively: hydrogen;
R
6For: NR
6aR
6b
R
3a, R
3b, R
6aAnd R
6bIndependently be respectively: methyl;
X, Y independently are respectively: methylene radical or carbonyl;
R
11For: hydrogen, C
1～6Alkyl, fluoro C
1～4Alkyl, chloro C
1～4Alkyl, bromo C
1～4Alkyl, hydroxyl C
1～4Alkyl, carboxyl C
1～4Alkyl, amino C
1～4Alkyl, C
1～4Alkyl-carbonyl, C
1～4Alkyl sulphinyl, C
1～4Alkyl sulphonyl, sulfonic acid amido C
1～4Alkyl, amino-sulfonyl C
1～4Alkyl, C
1～4Alkyl amine group formyl radical, formamyl C
1～4Alkyl, phenyl, phenyl C
1～4Alkyl, phenyl acyl group, phenyl acyloxy, phenyl sulfonyl, phenyl C
1～4Alkyl acyl, 4～6 yuan of single heterocyclic radicals, 4～6 yuan of single heterocyclic radical C
1～4Alkyl or adamantyl;
R
12, R
13Independently be respectively: hydrogen, hydroxyl, amino, carboxyl, C
1～4Alkyl, fluoro C
1～4Alkyl, chloro C
1～4Alkyl, bromo C
1～4Alkyl, C
1～4Alkoxyl group, C
1～4Alkyl amine group, two (C
1～4Alkyl) amido, hydroxyl C
1～4Alkyl, amino C
1～4Alkyl, C
1～4Alkyl-carbonyl, C
1～4Alkoxy carbonyl, C
1～4Alkyl amine group alkylsulfonyl, C
1～4Alkylamidoalkyl, phenyl or R
12With R
11Or R
13With R
11Be interconnected to 4～6 yuan of single heterocycles.
Further preferred compound is:
Wherein, R
1a, R
1b, R
2, R
4, R
7, R
5a, R
5b, R
8, R
9And R
10Independently be respectively: hydrogen;
R
6For: NR
6aR
6b
R
3a, R
3b, R
6aAnd R
6bIndependently be respectively: methyl;
X and Y independently are respectively: carbonyl or methylene radical;
R
11For: hydrogen, methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl, the Skellysolve A base, the isoamyl alkyl, neopentyl, hexyl, the 2-methylpentane, the 3-methylpentane, 2, the 3-dimethylbutane, 2, the 2-dimethylbutane, 2-ethyl butane, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, one methyl fluoride, difluoromethyl, trifluoromethyl, the 1-fluoro ethyl, the 2-fluoro ethyl, 1,1-two fluoro ethyls, 1,2-two fluoro ethyls, 2,2-two fluoro ethyls, 1,1, the 1-trifluoroethyl, 1,2, the 2-trifluoroethyl, 2,2, the 2-trifluoroethyl, methylol, the 1-hydroxyethyl, the 2-hydroxyethyl, 1, the 1-dihydroxy ethyl, 1, the 2-dihydroxy ethyl, 2, the 2-dihydroxy ethyl, 1,1, the 1-trihydroxyethyl, 1,2, the 2-trihydroxyethyl, 2,2, the 2-trihydroxyethyl, amino methyl, the 1-amino-ethyl, the 2-amino-ethyl, 1, the 1-diamino ethyl, 1, the 2-diamino ethyl, 2, the 2-diamino ethyl, 1,1,1-triamino ethyl, 1,2,2-triamino ethyl, 2,2,2-triamino ethyl, the carboxyl methyl, the 1-carboxy ethyl, the 2-carboxy ethyl, 1,1-dicarboxyl ethyl, 1,2-dicarboxyl ethyl, 2,2-dicarboxyl ethyl, 1,1,1-three carboxyl ethyls, 1,2,2-three carboxyl ethyls, 2,2,2-three carboxyl ethyls, the carbamyl ethyl, phenyl, azetidinyl, pyrryl, furyl, thienyl oxazole, thiazole, imidazoles, pyridine, pyridazine, pyrazine, piperazine or adamantyl;
R
12, R
13Independently be respectively: hydrogen or R
12With R
11Or R
13With R
11Be interconnected to azetidine, tetramethyleneimine or piperidine.
Further preferred again compound is:
Wherein, R
1a, R
1b, R
2, R
4, R
7, R
5a, R
5b, R
8, R
9And R
10Independently be respectively: hydrogen;
R
6For: NR
6aR
6b
R
3a, R
3b, R
6aAnd R
6bIndependently be respectively: methyl;
X is: carbonyl;
Y is: carbonyl or methylene radical;
R
11For: hydrogen, methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, a methyl fluoride, difluoromethyl, trifluoromethyl, methylol, 2-hydroxyethyl, amino methyl, 2-amino-ethyl, carbamyl ethyl, phenyl or adamantyl;
R
12, R
13Independently be respectively: hydrogen or R
12With R
11Or R
13With R
11Be interconnected to azetidine, tetramethyleneimine or piperidine.
Particularly preferred compound is as follows:
Term " C
1-6Alkyl " be meant the straight chained alkyl of 6 following carbon atoms, the branched-chain alkyl of 3-6 carbon atom and cycloalkyl, methyl for example, ethyl, n-propyl; sec.-propyl, normal-butyl, isobutyl-, sec-butyl; the tertiary butyl, Skellysolve A base, isoamyl alkyl, neopentyl; 2-methylpentane, the 3-methylpentane, 2,3-dimethylbutane; 2, the 2-dimethylbutane, 2-ethyl butane, cyclopropyl; cyclobutyl, cyclopentyl, cyclohexyl etc. can further preferred 4 following carbon atoms.
Term " C
1-6Alkoxyl group " be meant C
1-6Alkyl-alkyl is connected to Sauerstoffatom with covalent linkage, C
1-6Alkyl as mentioned above.
Term " C
1-6Alkylthio " be meant C
1-6Alkyl is connected to sulphur atom with covalent linkage, C
1-6Alkyl as mentioned above.
Term " C
2-6Thiazolinyl " be meant length and above-mentioned C
2-6Alkyls seemingly, but comprise the unsaturated aliphatic group of two keys at least, comprise straight alkenyl (as vinyl, propenyl, butenyl, pentenyl, hexenyl etc.), branched alkenyl, cycloalkenyl group (as cyclopropenyl radical, cyclopentenyl, cyclohexenyl).The one or more carbon that also comprise the alkene main chain are by oxygen, nitrogen, sulphur or phosphorus atom alternate alkenyl.In embodiments, the main chain of straight or branched alkenyl can have 6 following carbon atoms, and preferred 4 following carbon atoms are (as C
2-4Straight alkenyl, C
3-4Branched alkenyl), cycloalkenyl group can have 3-6 carbon atom.
Term " C
2-6Alkynyl " be meant length and above-mentioned C
2-6Alkyls seemingly but comprises a triple-linked unsaturated aliphatic group at least.Comprise straight-chain alkynyl groups (as ethynyl, proyl, butynyl, pentynyl, hexin base etc.), side chain alkynyl group.The one or more carbon that also comprise the alkynes main chain are by oxygen, nitrogen, sulphur or phosphorus atom alternate alkynyl group.In embodiments, straight or branched alkynyl group main chain can have 6 following carbon atoms, preferred 4 following carbon atoms.
Term " C
6-14Aryl " be meant monocycle or condensed aromatic group, as phenyl, naphthyl, phenanthryl etc.
Term " 3-14 unit heterocyclic radical " is meant and contains heteroatomic cyclic group, comprises " the saturated or unsaturated 1-4 of containing the first heteromonocyclic group of heteroatomic 3-8 " and " the saturated or unsaturated 1-4 of containing the assorted many cyclic groups of heteroatomic 8-14 unit "; Term " heteroatoms " comprises any element atom beyond carbon or the hydrogen, preferred nitrogen, oxygen, sulphur, phosphorus.
" the saturated or unsaturated 1-4 of containing the first heteromonocyclic group of heteroatomic 3-8 " comprising: the assorted monocycle of saturated or undersaturated 3-8 unit that contains 1-4 nitrogen-atoms in (1) ring, as ethylenimine, the 2H-ethylenimine, diazacyclo propane, 3H-diazacyclo propylene, azetidine, 1, the 2-diazetidine, azete, 1, the 2-diazetine, the pyrroles, pyrrolin, tetramethyleneimine, imidazoles, 4, the 5-glyoxalidine, imidazolidine, pyrazoles, 4, the 5-pyrazoline, pyrazolidine, 1,2,3-triazoles, 1,2, the 4-triazole, tetrazolium, pyridine, the 2-pyridone, the 4-pyridone, piperidines, pyridazine, pyrimidine, pyrazine, piperazine, 1,2, the 3-triazine, 1,2, the 4-triazine, 1,3,5-triazines, 1,2,4, the 5-tetrazine, the nitrogen heterocyclic heptantriene, 1,2-diazacyclo heptantriene, 1,3-diazacyclo heptantriene, 1,4-diazacyclo heptantriene, the nitrogen heterocyclic octatetraene, 1,4-dihydro-1,4-diazacyclo sarohornene etc.; (2) contain the assorted monocycle of the saturated or undersaturated 3-8 of 1-2 Sauerstoffatom or sulphur atom unit in the ring, as oxyethane, dioxirane, thiirane, trimethylene oxide, 1, the 2-dioxetane, Thietane, 1,2-dithia cyclobutene, furans, tetrahydrofuran (THF), thiophene, 2, the 5-dihydro-thiophene, tetramethylene sulfide, 1, the 3-dioxolane, 1,2-dithia cyclopentenes, 1, the 3-dithiolane, the 2H-pyrans, the 2H-pyran-2-one, 3,4-dihydro 2H-pyrans, the 4H-pyrans, tetrahydropyrans, 4H-pyrans-4-ketone, 1, the 4-Dioxin, 1,4-dithia cyclohexadiene, 1, the 4-oxathiin, 1, the 4-dioxane, 1, the 3-dioxane, 1, the 3-oxathiane, oxepin, the thia cycloheptatriene, 1,4-dioxane sarohornene etc.; (3) contain 1-2 Sauerstoffatom or sulphur atom and 1-3 the assorted monocycle of the saturated or undersaturated 3-8 of nitrogen-atoms unit in the ring, as oxaza propane oxazole, 4,5-dihydro-oxazole isoxazole, 4, the 5-dihydro-isoxazole, 2, the 3-dihydro-isoxazole, 1,2, the 3-oxadiazole, 1,2, the 5-oxadiazole, thiazole, 4, the 5-thiazoline, isothiazole, 1,2, the 3-thiadiazoles, 1,2, the 4-thiadiazoles, 1,3, the 4-thiadiazoles, 2H-1, the 2-oxazine, 4H-1, the 2-oxazine, 6H-1, the 2-oxazine, 2H-1, the 3-oxazine, 4H-1, the 3-oxazine, 5,6-dihydro-4H-1, the 3-oxazine, 6H-1, the 3-oxazine, 2H-1, the 4-oxazine, 4H-1, the 4-oxazine, 2H-1, the 3-thiazine, 4H-1, the 3-thiazine, 5,6-dihydro-4H-1, the 3-thiazine, 6H-1, the 3-thiazine, 2H-1, the 4-thiazine, 4H-1, the 4-thiazine, morpholine etc.
" the saturated or unsaturated assorted many cyclic groups of the individual heteroatomic 8-14 unit of 1-4 that contain ", comprise: the assorted many rings of saturated or undersaturated 8-14 unit that contain 1-5 nitrogen-atoms in (1) ring, as indoles, isoindole, carbazole, benzoglyoxaline, indazole, benzotriazole, imidazolidine also [4,5-c] pyridine, quinoline, isoquinoline 99.9, the 2-quinolinone, the 4-quinolinone, the 1-isoquinolines, acridine, phenanthridines, cinnolines, phthalazines, quinazoline, 3, the 4-dihydroquinazoline, quinoxaline, 1, the 2-dihydro-quinoxaline, 1, the 8-naphthyridines, 1, the 7-naphthyridines, 1, the 6-naphthyridines, 1, the 5-naphthyridines, 2, the 7-naphthyridines, 2, the 6-naphthyridines, purine, pteridine, azophenlyene etc.; (2) first the mixing of saturated or undersaturated 8-14 of containing 1-2 Sauerstoffatom or sulphur atom in the ring encircled more, as benzo [b] furans, different benzo [b] furans, dibenzo [b] furans, benzo [b] thiophene, benzo [c] thiophene, 2H-chromogen alkene, 2H-chromogen alkene-2-ketone, 4H-chromene, 4H-chromene-4-ketone, chroman etc.; (3) first the mixing of saturated or undersaturated 8-14 of containing 1-2 Sauerstoffatom or sulphur atom and 1-3 nitrogen-atoms in the ring encircled more, as benzoxazole, benzothiazole, 4H-1,3-benzoxazine, azophenlyene, thiodiphenylamine, 4,6-dihydro-1H-furo [3,4-d] imidazoles, 4,6-dihydro-1H-thieno-[3,4-d] imidazoles, 4,6-dihydro-1H-pyrrolo-[3,4-d] imidazoles, 4,5,6,7-tetrahydrochysene-1H-benzo [d] imidazoles, 3a, 4,6,6a-tetrahydrochysene-1H-furo [3,4-d] imidazoles, 3a, 5,6,7,7a-six hydrogen-1H-benzo [d] imidazoles etc.
Term " bridged ring base " is meant that it is not the ring that connects by adjacent carbons that interannular connects, as: azabicyclic [3.1.0] hexane, two ring [3.2.1] octanes, 1,4-diazabicylo [2.2.2] octane, 7H-7-azabicyclic [2.2.1]-2,5-heptadiene, diamantane etc.
Term " halogen " comprises fluorine, bromine, chlorine, iodine etc.
Term " halo C
1～6Alkyl ", " halo C
1～6Alkoxyl group " in " halo " be meant that one or more hydrogen atom on the carbon atom in the alkyl is replaced by halogen atom.
Term " prodrug part " comprises in vivo and can metabolism be the part of hydroxyl and advantageously keep the part of esterification in vivo.The preferred precursor drug moiety by esterase or other mechanism in vivo metabolism be hydroxyl or other useful group.Prodrug example and purposes are that this area is well-known.Prodrug can separate or prepare in position during the purification compound final, or by make pure compound with its free acid form or OH-form respectively with suitable esterifying agent prepared in reaction.Hydroxyl can change into ester by handling with carboxylic acid.The example of prodrug part comprises and replaces and do not replace; straight or branched alkyl carboxylic acid ester moiety (as propionic ester); rudimentary chain acid ester; dialkyl-7-amino-low alkyl group acid esters (as the dimethylamino acetic ester); acylaminoalkyl acid esters (as the kharophen manthanoate); acyloxy alkyl acid esters (as pivalyl oxygen manthanoate); aryl acid esters (phenyl acid esters); aryl-alkyl acid esters (as benzoic ether); replace (as methyl; halogen or methoxyl group substituting group) phenyl acid esters and aryl-alkyl acid esters, acyl group; alkyl acyl; dialkyl amide ethyl hydroxyl acyl group.Be preferably alkyl carboxylic acid ester, acyloxy alkyl acid esters and acyl group.
The present invention also provides the preparation method of above-claimed cpd, but is not limited only to following method, and reaction equation is as follows:
Reactions steps:
The preparation of step 1 intermediate 1
Throw raw material 1 in reaction flask, the vitriol oil stirs ice bath cooling down, adds SODIUMNITRATE then, and mixture stirs in ice bath.Reaction is finished, and this mixture is dropped in the ether, separates out solid, with a small amount of ether washing after drying.This solid is added in the ethanol, add the palladium charcoal then, stirring at room under the 2MPa hydrogen pressure.Filter, concentrating under reduced pressure, residuum add 1 ether under vigorous stirring.Filter, drying, compd A
The preparation of step 2 The compounds of this invention
Add toluene in the exsiccant reaction flask, compd B stirs and heats up, and slowly adds compd A in batches, refluxes and stirs.Reaction is finished, cooling.In the impouring trash ice, separate out solid under the vigorous stirring.Filter, the filter cake ethyl alcohol recrystallization gets The compounds of this invention.
R
1a, R
1b, R
2, R
3a, R
3b, R
4, R
5a, R
5b, R
6, R
7, R
8, R
9, R
10, R
11, R
12, R
13, the group represented of X, Y as mentioned before.
The tetracycline derivant that alkaline piperazine ketone of the present invention replaces can form various salt with different nontoxic inorganic or organic acids, described salt comprises pharmaceutically acceptable anionic salt, for example hydrochloride, hydrobromate, hydriodate, nitrate, vitriol, hydrosulfate, phosphoric acid salt, acid phosphate, the isonicotine hydrochlorate, acetate, lactic acid salt, salicylate, Citrate trianion, the acid Citrate trianion, fumarate, tartrate, pantothenate, bitartrate, ascorbate salt, succinate, maleate, gentisate, fumarate, gluconate, glucarate, saccharate, formate, benzoate, glutaminate, mesylate, esilate, benzene sulfonate, tosilate, palmitate etc.Although it must be pharmaceutically acceptable during Mammals for example that described salt gives the patient, but the pharmaceutically unacceptable salt that usually needs at first from reaction mixture, to isolate tetracycline compound of the present invention in the practice, handle the latter with alkaline reagents then and be translated into free basic cpd simply, then back one free alkali is converted into pharmaceutically-acceptable acid addition.
The tetracycline derivant that acid piperazine ketone of the present invention replaces can form various salt with different nontoxic inorganic or organic basess, and described salt includes but not limited to for example other alkali salt of alkali metal cation (for example potassium and sodium) and alkaline earth metal cation (for example calcium, magnesium and zinc), ammonium or water-soluble amine additive salt (for example N-methylglucosamine (meglumine) and low-grade alkane alcohol ammonium) the pharmaceutically acceptable organic amine of ethyl of salt that described pharmaceutically acceptable positively charged ion produces.This pharmaceutically acceptable base addition salt as tart tetracycline compound of the present invention can form with ordinary method and pharmaceutically acceptable positively charged ion.
The structure of tetracyclines derivative of the present invention comprises asymmetric c atom.Therefore, unless stated otherwise, otherwise the isomer (as all enantiomers and diastereomer) that is produced by described asymmetry all is included in the protection domain of the present invention.Described isomer can be by standard isolation technique and the abundant purity isomer of the synthetic acquisition of stereochemistry control.
The pharmaceutical composition of tetracycline derivant, its pharmacy acceptable salt or its isomer and other active pharmaceutical ingredients that the further claimed piperazine ketone of the present invention replaces, described other active pharmaceutical ingredients comprises trimethoprim.
The present invention is the claimed pharmaceutical composition that comprises arbitrary compound recited above, its pharmacy acceptable salt or its steric isomer and one or more pharmaceutical carriers and/or thinner further; for clinically or pharmaceutically acceptable arbitrary formulation, be preferably oral preparations, injection or external preparation.Wherein contain the compound shown in the general formula (I) of physiology significant quantity.
Compound shown in the general formula (I) of physiology significant quantity mentioned above is to treat and/or prevent the necessary amount of a kind of tetracyclines sensitive disease or enough amounts.Described significant quantity can change according to the bodily form and body weight, the type of disease or the concrete factors such as tetracycline derivant of the present invention as the patient.Those of ordinary skill in the art can study the significant quantity of aforementioned factor and definite tetracycline derivant of the present invention and test improperly
Usually, the The compounds of this invention that is used for the treatment of can give the patient according to the dosage that other tsiklomitsin treatment is in the past used, for example can give the patient according to the dosage that the MINOCYCLINE HCL treatment is used, the suitable effective dosage ranges of one or more compounds of the present invention is from 0.01-100mg/kg weight in patients/sky, preferred 0.1-50mg/kg weight in patients/sky.The dosage that requires can be suitably gives by divided dose once a day or several times, 2-5 divided dose for example, and every day is with appropriate intervals or other suitable progress administration.
The compounds of this invention or derivatives thereof and the composition that comprises the The compounds of this invention or derivatives thereof can take any form of medication of prior art to be used for the patient, can make the disclosed various formulations of prior art, described prior art is published referring to " pharmaceutics " version Chinese Medicine science and technology in 2002 press, but is not limited only to " pharmaceutics " version Chinese Medicine science and technology in 2002 press.
The invention still further relates to and contain tetracycline derivant that piperazine ketone replaces and treat and/or prevent application in the tetracyclines sensitive diseases medicine in preparation.The tetracyclines sensitive disease comprises infection (comprising that other tetracycline compound resistance infects), cancer, diabetes and has been found that tetracycline compound is to other effective other disease.Described tetracycline compound comprises many compounds with tsiklomitsin ring structure, the example of tetracycline compound comprises: duomycin, terramycin, Demethylchlortetracycline, metacycline, Sancycline, Rolitetracycline, guamecycline, Minocycline HCl, Vibravenos, chelocardin, other contains in the derivative of similar Fourth Ring structure and analogue be also included within.
The tetracycline compound has a broad antifungal spectrum that contains the replacement of piperazine ketone of the present invention, the anti-microbial activity height common comprises that Grain-negative or positive bacteria such as MSSA (MSSA), methicillin-resistant staphylococcus aureus (MRSA), enterococcus faecalis, faecium, intestinal bacteria, hemophilus influenzae etc. all show outstanding anti-microbial activity to most of.Described " tetracyclines sensitive disease " comprises and gives the disease that tetracycline compound that the present invention contains formohydrazide group can treat, prevents or improve.
The tetracycline derivant that piperazine ketone of the present invention replaces can be used for preparing the medicine that treats and/or prevents infectation of bacteria, wherein infectation of bacteria may be caused by various different gram-positives and gram-negative bacteria, the for example infection of Klebsiella Pneumoniae acinetobacter calcoaceticus, hemophilus influenzae, intestinal bacteria, Pseudomonas aeruginosa, faecium, streptococcus aureus or enterococcus faecalis etc., The compounds of this invention is also effective to the microbial infection of other tetracycline compound resistance.
Piperazine ketone substituted tetracycline derivative of the present invention also can be used for preparing the medicine of the tetracyclines susceptibility infection for the treatment of other, other tetracyclines susceptibility infects and comprises rickettsial infection, and lymphogranuloma venereum, inclusion conjunctivitis and psittacosis pathogenic infection etc.
The tetracycline derivant that piperazine ketone of the present invention replaces is compared with immediate prior art, has the following advantages:
(1) The compounds of this invention has good anti-microbial activity, and side effect is little, and shows hypotoxicity, can being used for the treatment of and/or preventing various Mammalss (comprising the mankind) by the caused various diseases of sensitive organism by safety;
(2) the present invention has carried out the in-vitro antibacterial test, show the The compounds of this invention has a broad antifungal spectrum, the anti-microbial activity height, infection to most of common bacterial isolate bacterium that comprise resistant organism all has better curative effect, comprises that Grain-negative or positive bacteria, aerobic and anerobe and methicillin-resistant gold Portugal bacterium (MRSA), enterococcus faecalis and faecium resistant organism show outstanding anti-microbial activity;
(3) The compounds of this invention and other tetracycline compound do not have cross resistance;
(4) The compounds of this invention has pharmacokinetic property preferably, and is easy to use;
(5) the The compounds of this invention production technique is fairly simple, no severe condition, and medicine purity height, yield height, steady quality are easy to carry out large-scale commercial production.
Below further set forth the beneficial effect of tetracycline derivant of the present invention by in-vitro antibacterial experiment, but this should be interpreted as that tetracycline derivant of the present invention only has following beneficial effect.
The antimicrobial spectrum of experimental example The compounds of this invention and antibacterial activity in vitro
For trying bacterial classification: following bacterial strain is all bought in public institution
The clinical isolates strain
Gram positive organism: MSSA (MSSA), methicillin-resistant staphylococcus aureus (MRSA), enterococcus faecalis, faecium;
Gram-negative bacteria: intestinal bacteria, hemophilus influenzae.
Trial-product: compound 1～16, its chemical name and structural formula are seen the preparation embodiment of each compound.
Tigecycline, linwzolid: commercial;
Experimental technique: agar dilution, with reference to " pharmacological testing methodology " P1659-1660, People's Health Publisher, chief editor: Xu Shuyun etc., release: the 1st edition the 3rd edition the 5th printing January in 2002 in August nineteen eighty-two.
Experimental result and conclusion:
Table 1 The compounds of this invention is to the anti-microbial activity of clinical isolates strain
By table 1 experimental result as seen, The compounds of this invention all has the excellent antibiotic activity to above clinical Gram-positive and negative representative strain, and is stronger or suitable than the anti-microbial activity of Tigecycline.
Above-mentioned experimental result shows that The compounds of this invention is compared with immediate prior art, and effect is more excellent, has has a broad antifungal spectrum, advantage that anti-microbial activity is high, for having the new compound of good clinical application potential.
4, embodiment
The embodiment of form is described in further detail foregoing of the present invention by the following examples.But this should be interpreted as that the scope of the above-mentioned theme of the present invention only limits to following examples.
Embodiment 1 [S-(4 α, 12a α)]-9-amino-4, two (dimethylin)-1,4 of 7-, 4a, 5,5a, 6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1, the preparation of 11-dioxo-2-tetracene methane amide
In reaction flask, throw 22.8g (50mmol) [S-(4 α, 12a α)]-4, two (dimethylin)-1 of 7-, 4,4a, 5,5a, 6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-tetracene methane amide dihydrochloride is dissolved in the vitriol oil of 150ml, stir ice bath cooling down, add the 6.8g SODIUMNITRATE then, mixture stirs 1h in ice bath.Reaction is finished, and this mixture is dropped in the 2000ml ether, separates out solid, with a small amount of ether washing after drying.This solid is added in the 100ml ethanol, add the palladium charcoal of 2g 10% then, stirring at room 1.5h under the 2MPa hydrogen pressure.Filter, concentrating under reduced pressure, residuum add the 800ml ether under vigorous stirring.Filter, drying gets solid chemical compound 19.2g, yield: 81.2%.
Embodiment 2 4-tertiary butyl morpholine-2s, the preparation of 6-diketone
The preparation of 1,2,2 '-[(tertiary butyl) amino] oxalic acid
In reaction flask, add Mono Chloro Acetic Acid 4.7g (50mmol), 40ml water, KOH5.6g (100mmol), tert-butylamine 1.8g (25mmol), heating in water bath to 70 ℃, reaction 4h postcooling are to room temperature, with the neutralization of 7N aqueous hydrochloric acid, underpressure distillation, filter, the filtrate pH value transfers to about 3, cooling, get product 3.5g, yield: 75.0%.
2,4-tertiary butyl morpholine-2, the preparation of 6-diketone
In reaction flask, add 2,2 '-[(tertiary butyl) amino] oxalic acid 9.5g (50mmol), diacetyl oxide 20ml, heating in water bath to 70 ℃, underpressure distillation gets product 5.3g, yield behind the reaction 24h: 62%.
Embodiment 3 [S-(4 α, 12a α)]-9-[N-4-tertiary butyl piperazine-2,6-diketone-1-yl]-4, two (dimethylin)-1,4 of 7-, 4a, 5,5a, 6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1, the preparation of 11-dioxo-2-tetracene methane amide (compound 9)
In the exsiccant reaction flask, add toluene 100ml, 4-tertiary butyl morpholine-2,6-diketone 8.9g (52mmol), stirring is warming up to more than 80 ℃, slowly add [S-(4 α, 12a α)]-9-amino-4, two (dimethylin)-1 of 7-in batches, 4,4a, 5,5a, 6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-tetracene methane amide 14.2g (30mmol) refluxes and stirs 4h.Reaction is finished, and is chilled to 60 ℃.In the impouring trash ice, separate out solid under the vigorous stirring.Filter, the filter cake ethyl alcohol recrystallization gets target compound 12.7g, yield: 67.8%.
Molecular formula: C
31H
39N
5O
9Molecular weight: 625.67 mass spectrums: (m/e): 626 (M+1)
Ultimate analysis: theoretical value: C, 59.51%; H, 6.28%; N, 11.19% measured value: C, 59.42%; H, 6.37%; N, 11.10%
1H-NMR(600MHz，CDCl
3)：δ1.12(s，9H)，1.43(t，1H)，1.76(t，1H)，2.26(s，1H)，2.45(s，6H)，2.31(t，1H)，2.32(m，1H)，2.42(d，1H)，2.68(d，1H)，2.83(s，6H)，3.16(d，1H)，3.31(s，4H)，5.45(s，1H)，6.09(s，2H)，7.15(s，1H)，11.17(s，1H)，12.46(s，1H)
Embodiment 4 4-methylmorpholines-2, the preparation of 6-diketone
With reference to embodiment 2, throw methylamine 0.8g (25mmol), Mono Chloro Acetic Acid 4.7g (50mmol), 2,2 '-(methylamino-) oxalic acid 7.4g (50mmol), diacetyl oxide 20ml gets compound 4.5g, yield: 70.0%.
Embodiment 5 [S-(4 α, 12a α)]-9-[N-4-methylpiperazine-2,6-diketone-1-yl]-4, two (dimethylin)-1,4 of 7-, 4a, 5,5a, 6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1, the preparation of 11-dioxo-2-tetracene methane amide (compound 10)
With reference to embodiment 3, throw 4-methylmorpholine-2,6-diketone 6.7g (52mmol), [S-(4 α, 12a α)]-and 9-amino-4, two (dimethylin)-1,4 of 7-, 4a, 5,5a, 6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-tetracene methane amide 14.2g (30mmol) gets target compound 11.9g, yield: 68.2%.
Molecular formula: C
28H
33N
5O
9Molecular weight: 583.59 mass spectrums: (m/e): 584 (M+1)
Ultimate analysis: theoretical value: C, 57.63%; H, 5.70%; N, 12.00% measured value: C, 57.52%; H, 5.81%; N, 11.92%
1H-NMR(600MHz，CDCl
3)：δ1.43(t，1H)，1.76(t，1H)，2.25(s，3H)，2.26(s，1H)，2.31(t，1H)，2.32(m，1H)，2.42(d，1H)，2.43(s，6H)，2.69(d，1H)，2.86(s，6H)，3.16(d，1H)，3.32(s，4H)，5.45(s，1H)，6.07(s，2H)，7.05(s，1H)，11.15(s，1H)，12.49(s，1H)
Embodiment 6 4-cyclopropyl morpholine-2s, the preparation of 6-diketone
With reference to embodiment 2, the propylamine 1.4g (25mmol) that commits suicide by hanging, Mono Chloro Acetic Acid 4.7g (50mmol), 2,2 '-[(cyclopropyl) amino] oxalic acid 8.6g (50mmol), diacetyl oxide 20ml gets compound 5.4g, yield: 69.8%.
Embodiment 7 [S-(4 α, 12a α)]-9-[N-4-cyclopropyl piperazine-2,6-diketone-1-yl]-4, two (dimethylin)-1,4 of 7-, 4a, 5,5a, 6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1, the preparation of 11-dioxo-2-tetracene methane amide (compound 11)
With reference to embodiment 3, throw 4-cyclopropyl morpholine-2,6-diketone 8.1g (52mmol), [S-(4 α, 12a α)]-and 9-amino-4, two (dimethylin)-1,4 of 7-, 4a, 5,5a, 6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-tetracene methane amide 14.2g (30mmol) gets target compound 12.1g, yield: 66.2%.
Molecular formula: C
30H
35N
5O
9Molecular weight: 609.63 mass spectrums: (m/e): 610 (M+1)
Ultimate analysis: theoretical value: C, 59.11%; H, 5.79%; N, 11.49% measured value: C, 59.02%; H, 5.86%; N, 11.39%
1H-NMR(600MHz，CDCl
3)：δ0.18(q，2H)，0.43(q，2H)，1.32(m，1H)，1.41(t，1H)，1.74(t，1H)，2.26(s，1H)，2.31(t，1H)，2.32(m，1H)，2.41(d，1H)，2.42(s，6H)，2.68(d，1H)，2.86(s，6H)，3.14(d，1H)，3.32(s，4H)，5.45(s，1H)，6.05(s，2H)，7.02(s，1H)，11.13(s，1H)，12.48(s，1H)
Embodiment 8 4-cyclobutyl morpholine-2s, the preparation of 6-diketone
With reference to embodiment 2, the butylamine 1.8g (25mmol) that commits suicide by hanging, Mono Chloro Acetic Acid 4.7g (50mmol), 2,2 '-[(cyclobutyl) amino] oxalic acid 9.4g (50mmol), diacetyl oxide 20ml gets compound 6.1g, yield: 72.4%.
Embodiment 9 [S-(4 α, 12a α)]-9-[N-4-cyclobutyl piperazine-2,6-diketone-1-yl]-4, two (dimethylin)-1,4 of 7-, 4a, 5,5a, 6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1, the preparation of 11-dioxo-2-tetracene methane amide (compound 12)
With reference to embodiment 3, throw 4-cyclobutyl morpholine-2,6-diketone 8.8g (52mmol), [S-(4 α, 12a α)]-and 9-amino-4, two (dimethylin)-1,4 of 7-, 4a, 5,5a, 6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-tetracene methane amide 14.2g (30mmol) gets target compound 12.6g, yield: 67.5%.
Molecular formula: C
31H
37N
5O
9Molecular weight: 623.65 mass spectrums: (m/e): 624 (M+1)
Ultimate analysis: theoretical value: C, 59.70%; H, 5.98%; N, 11.23% measured value: C, 59.60%; H, 6.08%; N, 11.16%
1H-NMR(600MHz，CDCl
3)：δ1.43(t，1H)，1.78(t，1H)，1.88(q，2H)，1.90(m，1H)，2.00(m，1H)，2.13(q，2H)，2.28(s，1H)，2.32(m，1H)，2.36(t，1H)，2.43(s，6H)，2.44(d，1H)，2.69(d，1H)，2.87(s，6H)，3.11(m，1H)，3.16(d，1H)，3.31(s，4H)，5.45(s，1H)，6.07(s，2H)，7.06(s，1H)，11.17(s，1H)，12.47(s，1H)
Embodiment 10 4-cyclopentyl morpholine-2s, the preparation of 6-diketone
With reference to embodiment 2, the amylamine 2.1g (25mmol) that commits suicide by hanging, Mono Chloro Acetic Acid 4.7g (50mmol), 2,2 '-[(cyclopentyl) amino] oxalic acid 10.1g (50mmol), diacetyl oxide 20ml gets compound 6.8g, yield: 74.2%.
Embodiment 11 [S-(4 α, 12a α)]-9-[N-4-cyclopentyl-based piperazine-2,6-diketone-1-yl]-4, two (dimethylin)-1,4 of 7-, 4a, 5,5a, 6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1, the preparation of 11-dioxo-2-tetracene methane amide (compound 13)
With reference to embodiment 3, throw 4-cyclopentyl morpholine-2,6-diketone 9.5g (52mmol), [S-(4 α, 12a α)]-and 9-amino-4, two (dimethylin)-1,4 of 7-, 4a, 5,5a, 6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-tetracene methane amide 14.2g (30mmol) gets target compound 13.2g, yield: 68.9%.
Molecular formula: C
32H
39N
5O
9Molecular weight: 637.68 mass spectrums: (m/e): 638 (M+1)
Ultimate analysis: theoretical value: C, 60.27%; H, 6.16%; N, 10.98% measured value: C, 60.16%; H, 6.26%; N, 10.89%
1H-NMR(600MHz，CDCl
3)：δ1.44(m，2H)，1.45(m，2H)，1.46(t，1H)，1.55(m，2H)，1.69(m，2H)，1.78(t，1H)，2.28(s，1H)，2.32(m，1H)，2.36(t，1H)，2.42(s，6H)，2.45(d，1H)，2.62(m，1H)，2.69(d，1H)，2.87(s，6H)，3.15(d，1H)，3.31(s，4H)，5.46(s，1H)，6.06(s，2H)，7.08(s，1H)，11.18(s，1H)，12.46(s，1H)
Embodiment 12 1, and 3-dioxo-tetrahydro-1 H-pyrrolo is [2,1-c] [preparation of 1,4] oxazine also
1, the preparation of 1-(tertbutyloxycarbonyl) pyrryl-2-carboxyl-2 '-sym-dichloroacetic anhydride
In reaction flask, add 1-(tertbutyloxycarbonyl) pyrryl-2-carboxylic acid 10.7g (50mmol), chloroacetyl chloride 11.3g (100mmol), Mono Chloro Acetic Acid 9g, after being heated to back flow reaction 4h, partial solvent is removed in distillation, is chilled to about 0 ℃ with ice bath then, adds saturated sodium bicarbonate solution and transfers to neutrality, get product 10.5g, yield: 72%.
2,2-Mono Chloro Acetic Acid pyrryl-2-acid anhydrides is synthetic
In reaction flask, add 1-(tertbutyloxycarbonyl) pyrryl-2-carboxyl-2 '-sym-dichloroacetic anhydride 14.6g (50mmol), AlCl
313.3g (100mmol), 1,2-ethylene dichloride 30ml behind the reflux 2h, with cryosel bath cooling, adds 50ml water, and with 50ml ethyl acetate extraction twice, organic layer concentrates, and gets product 8.1g, yield: 85%.
3,1,3-dioxo-tetrahydro-1 H-pyrrolo is [2,1-c] [preparation of 1,4] oxazine also
In reaction flask, add 2-Mono Chloro Acetic Acid pyrryl-2-acid anhydrides 9.6g (50mmol), 40mlCH
2Cl
2, Et
3N10.1g (100mmol), heating in water bath is to refluxing, and reaction 4h postcooling is to room temperature, and with the neutralization of 7N aqueous hydrochloric acid, underpressure distillation gets product 5.6g, yield: 72.5%.
Embodiment 13[S-(4 α, 12a α)]-9-[1,3-dioxo hexahydropyrrolo is [1,2-a] piperazine-2 (1H)-yl also]-4, two (dimethylin)-1,4 of 7-, 4a, 5,5a, 6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1, the preparation of 11-dioxo 2-tetracene methane amide (compound 14)
With reference to embodiment 3, throw 1,3-dioxo-tetrahydro-1 H-pyrrolo is [2,1-c] [1 also, 4] oxazine 8.1g (52mmol), [S-(4 α, 12a α)]-9-amino-4, two (dimethylin)-1 of 7-, 4,4a, 5,5a, 6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-tetracene methane amide 14.2g (30mmol) gets target compound 11.0g, yield: 60.5%.
Molecular formula: C
30H
35N
5O
9Molecular weight: 609.63 mass spectrums: (m/e): 610 (M+1)
Ultimate analysis: theoretical value: C, 59.11%; H, 5.79%; N, 11.49% measured value: C, 59.02%; H, 5.88%; N, 11.38%
1H-NMR(600MHz，CDCl
3)：δ1.46(t，1H)，1.55(m，1H)，1.65(m，1H)，1.78(t，1H)，1.81(m，1H)，2.04(m，1H)，2.21(t，1H)，2.28(s，1H)，2.31(t，1H)，2.32(m，1H)，2.36(t，1H)，2.43(s，6H)，2.45(d，1H)，2.69(d，1H)，2.87(s，6H)，3.15(d，1H)，3.18(t，1H)，3.24(s，1H)，3.36(s，1H)，5.46(s，1H)，6.06(s，2H)，7.08(s，1H)，11.18(s，1H)，12.46(s，1H)
Embodiment 14 1,3-dioxo-tetrahydrochysene-(4H, 6H) pyrido [2,1-c] [preparation of 1,4] oxazine
With reference to embodiment 12, throw 1-(tertbutyloxycarbonyl) piperidyl-2-carboxylic acid 11.5g (50mmol), chloroacetyl chloride 11.3g (100mmol), 1-(tertbutyloxycarbonyl) piperidyl-2-carboxyl-2 '-sym-dichloroacetic anhydride 15.3 (50mmol), AlCl
313.3g (100mmol), 2-Mono Chloro Acetic Acid piperidines-2-acid anhydrides 10.3g (50mmol) gets target compound 6.2g, yield: 73.2%.
Embodiment 15[S-(4 α, 12a α)]-9-[1,3-dioxo dihydro-1H-piperidines is [1,2-a] piperazine-2 (6H also, 7H, 8H, 9H, 9aH)-and yl]-4, two (dimethylin)-1,4 of 7-, 4a, 5,5a, 6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1, the preparation of 11-dioxo-2-tetracene methane amide (compound 15)
With reference to embodiment 3, throw 1,3-dioxo-tetrahydrochysene-(4H, 6H) pyrido [2,1-c] [1,4] oxazine 8.8g (52mmol), [S-(4 α, 12a α)]-9-amino-4, two (dimethylin)-1,4 of 7-, 4a, 5,5a, 6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-tetracene methane amide 14.2g (30mmol) gets target compound 11.7g, yield: 62.4%.
Molecular formula: C
31H
37N
5O
9Molecular weight: 623.26 mass spectrums: (m/e): 624 (M+1)
Ultimate analysis: theoretical value: C, 59.7%; H, 5.98%; N, 11.23% measured value: C, 59.6%; H, 6.07%; N, 11.15%
1H-NMR(600MHz，CDCl
3)：δ1.46(m，1H)，1.48(t，1H)，1.49(m，1H)，1.51(m，1H)，1.55(m，1H)，1.71(m，1H)，1.76(t，1H)，1.96(m，1H)，2.21(t，1H)，2.28(s，1H)，2.31(t，1H)，2.34(m，1H)，2.36(t，1H)，2.41(d，1H)，2.43(s，6H)，2.66(t，1H)，2.68(d，1H)，2.86(s，6H)，3.16(d，1H)，3.24(s，1H)，3.37(s，1H)，5.42(s，1H)，6.07(s，2H)，7.06(s，1H)，11.15(s，1H)，12.48(s，1H)
Embodiment 16 4-(1-adamantyl) morpholine-2, the preparation of 6-diketone
With reference to embodiment 2, throw amantadine 3.8g (25mmol), Mono Chloro Acetic Acid 4.7g (50mmol), 2,2 '-[(adamantyl) amino] oxalic acid 13.4g (50mmol), diacetyl oxide 20ml gets compound 8.8g, yield: 70.3%.
Embodiment 17 [S-(4 α, 12a α)]-9-[N-4-(1-adamantyl) piperazine-2,6-diketone-1-yl]-4, two (dimethylin)-1,4 of 7-, 4a, 5,5a, 6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1, the preparation of 11-dioxo-2-tetracene methane amide (compound 16)
With reference to embodiment 3, throw 4-(1-adamantyl) morpholine-2,6-diketone 12.9g (52mmol), [S-(4 α, 12a α)]-and 9-amino-4, two (dimethylin)-1,4 of 7-, 4a, 5,5a, 6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-tetracene methane amide 14.2g (30mmol) gets target compound 14.0g, yield: 66.5%.
Molecular formula: C
38H
46N
4O
9Molecular weight: 702.79 mass spectrums: (m/e): 703 (M+1)
Ultimate analysis: theoretical value: C, 64.94%; H, 6.60%; N, 7.97% measured value: C, 64.86%; H, 6.70%; N, 7.89%
1H-NMR(600MHz，CDCl
3)：δ1.14(d，1H)，1.18(t，4H)，1.24(d，1H)，1.40(m，1H)，1.41(m，3H)，1.43(t，1H)，1.49(d，1H)，1.52(d，1H)，1.56(t，4H)，1.74(t，1H)，2.29(s，1H)，2.32(m，1H)，2.40(t，1H)，2.42(s，6H)，2.43(d，1H)，2.68(d，1H)，2.82(s，6H)，3.19(d，1H)，3.31(s，4H)，5.41(s，1H)，6.09(s，2H)，6.17(s，1H)，11.15(s，1H)，12.43(s，1H)
Embodiment 18 [S-(4 α, 12a α)]-9-[N-4-tertiary butyl piperazine-2-ketone-1-yl]-4, two (dimethylin)-1,4 of 7-, 4a, 5,5a, 6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1, the preparation of 11-dioxo-2-tetracene methane amide (compound 1)
In the exsiccant reaction flask, add [S-(4 α, 12a α)]-9-[N-4-tertiary butyl piperazine-2,6-diketone-1-yl]-4, two (dimethylin)-1,4 of 7-, 4a, 5,5a, 6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-tetracene methane amide 6.3g (10mmol) and methyl alcohol 50ml, stirring down, gradation adds 0.76g (20mmol) sodium borohydride, heated and stirred back flow reaction 2h.Reaction is finished, decompression and solvent recovery.Residuum adds entry, ether 100ml respectively, divides water-yielding stratum, the organic layer anhydrous sodium sulfate drying.Organic layer is the agitation and dropping cyclohexane solution under ice bath, and crystallization filters and drying, gets target compound 5.1g, yield: 83.8%.
Molecular formula: C
31H
41N
5O
8Molecular weight: 611.69 mass spectrums: (m/e): 612 (M+1)
Ultimate analysis: theoretical value: C, 60.87%; H, 6.76%; N, 11.45% measured value: C, 60.80%; H, 6.85%; N, 11.36%
1H-NMR(600MHz，CDCl
3)：δ1.12(s，9H)，1.42(t，1H)，1.73(t，1H)，2.26(s，1H)，2.31(t，1H)，2.32(m，1H)，2.41(d，1H)，2.43(s，6H)，2.52(t，2H)，2.66(d，1H)，2.83(s，6H)，3.16(d，1H)，3.31(s，2H)，3.45(t，2H)，5.41(s，1H)，6.09(s，2H)，6.15(s，1H)，11.15(s，1H)，12.46(s，1H)
Embodiment 19 [S-(4 α, 12a α)]-9-[N-4-methylpiperazine-2-ketone-1-yl]-4, two (dimethylin)-1,4 of 7-, 4a, 5,5a, 6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1, the preparation of 11-dioxo-2-tetracene methane amide (compound 2)
With reference to embodiment 18, throw [S-(4 α, 12a α)]-9-[N-4-methylpiperazine-2,6-diketone-1-yl]-4, two (dimethylin)-1,4 of 7-, 4a, 5,5a, 6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-tetracene methane amide 5.8g (10mmol), sodium borohydride 0.76g (20mmol) gets target compound 4.8g, yield: 84.8%.
Molecular formula: C
28H
35N
5O
8Molecular weight: 569.61 mass spectrums: (m/e): 570 (M+1)
Ultimate analysis: theoretical value: C, 59.04%; H, 6.19%; N, 12.30% measured value: C, 58.96%; H, 6.30%; N, 12.21%
1H-NMR(600MHz，CDCl
3)：δ1.43(t，1H)，1.72(t，1H)，2.21(s，1H)，2.25(s，3H)，2.31(m，1H)，2.34(t，1H)，2.38(s，6H)，2.41(d，1H)，2.52(t，2H)，2.68(d，1H)，2.82(s，6H)，3.17(d，1H)，3.31(s，2H)，3.47(t，2H)，5.40(s，1H)，6.11(s，2H)，6.18(s，1H)，11.19(s，1H)，12.46(s，1H)
Embodiment 20 [S-(4 α, 12a α)]-9-[N-4-cyclopropyl piperazine-2-ketone-1-yl]-4, two (dimethylin)-1,4 of 7-, 4a, 5,5a, 6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1, the preparation of 11-dioxo-2-tetracene methane amide (compound 3)
With reference to embodiment 18, throw [S-(4 α, 12a α)]-9-[N-4-cyclopropyl piperazine-2,6-diketone-1-yl]-4, two (dimethylin)-1,4 of 7-, 4a, 5,5a, 6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-tetracene methane amide 6.1g (10mmol), sodium borohydride 0.76g (20mmol) gets target compound 4.9g, yield: 82.8%.
Molecular formula: C
30H
37N
5O
8Molecular weight: 595.64 mass spectrums: (m/e): 596 (M+1)
Ultimate analysis: theoretical value: C, 60.49%; H, 6.26%; N, 11.76% measured value: C, 60.38%; H, 6.35%; N, 11.67%
1H-NMR(600MHz，CDCl
3)：δ0.17(q，2H)，0.40(q，2H)，1.36(m，1H)，1.48(t，1H)，1.76(t，1H)，2.26(s，1H)，2.31(t，1H)，2.32(m，1H)，2.41(d，1H)，2.43(s，6H)，2.50(t，2H)，2.65(d，1H)，2.82(s，6H)，3.17(d，1H)，3.31(s，2H)，3.47(t，2H)，5.42(s，1H)，6.12(s，2H)，6.16(s，1H)，11.16(s，1H)，12.49(s，1H)
Embodiment 21 [S-(4 α, 12a α)]-9-[N-4-cyclobutyl piperazine-2-ketone-1-yl]-4, two (dimethylin)-1,4 of 7-, 4a, 5,5a, 6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1, the preparation of 11-dioxo-2-tetracene methane amide (compound 4)
With reference to embodiment 18, throw [S-(4 α, 12a α)]-9-[N-4-cyclobutyl piperazine-2,6-diketone-1-yl]-4, two (dimethylin)-1,4 of 7-, 4a, 5,5a, 6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-tetracene methane amide 6.2g (10mmol), sodium borohydride 0.76g (20mmol) gets target compound 5.2g, yield: 85.1%.
Molecular formula: C
31H
39N
5O
8Molecular weight: 609.607 mass spectrums: (m/e): 610 (M+1)
Ultimate analysis: theoretical value: C, 61.07%; H, 6.45%; N, 11.49% measured value: C, 61.00%; H, 6.54%; N, 11.38%
1H-NMR(600MHz，CDCl
3)：δ1.45(t，1H)，1.73(t，1H)，1.90(q，2H)，1.91(m，1H)，2.00(m，1H)，2.15(q，2H)，2.26(s，1H)，2.31(t，1H)，2.35(m，1H)，2.41(d，1H)，2.45(s，6H)，2.53(t，2H)，2.66(d，1H)，2.83(s，6H)，3.10(m，1H)，3.15(d，1H)，3.32(s，2H)，3.49(t，2H)，5.41(s，1H)，6.09(s，2H)，6.12(s，?1H)，11.16(s，1H)，12.43(s，1H)
Embodiment 22[S-(4 α, 12a α)]-9-[N-4-cyclopentyl-based piperazine-2-ketone-1-yl]-4, two (dimethylin)-1,4 of 7-, 4a, 5,5a, 6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1, the preparation of 11-dioxo 2-tetracene methane amide (compound 5)
With reference to embodiment 18, throw [S-(4 α, 12a α)]-9-[N-4-cyclopentyl-based piperazine-2,6-diketone-1-yl]-4, two (dimethylin)-1,4 of 7-, 4a, 5,5a, 6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-tetracene methane amide 6.4g (10mmol), sodium borohydride 0.76g (20mmol) gets target compound 5.3g, yield: 84.8%.
Molecular formula: C
32H
41N
5O
8Molecular weight: 623.70 mass spectrums: (m/e): 624 (M+1)
Ultimate analysis: theoretical value: C, 61.62%; H, 6.63%; N, 11.23% measured value: C, 61.53%; H, 6.73%; N, 11.14%
1H-NMR(600MHz，CDCl
3)：δ1.44(q，2H)，1.45(m，2H)，1.55(m，2H)，1.67(t，2H)，1.69(q，2H)，2.24(s，1H)，2.30(t，1H)，2.33(m，1H)，2.45(s，6H)，2.50(t，2H)，2.51(d，2H)，2.63(m，1H)，2.82(s，6H)，3.17(d，1H)，3.31(s，2H)，3.47(t，2H)，5.39(s，1H)6.08(s，2H)，6.18(s，1H)，11.12(s，1H)，12.49(s，1H)
Embodiment 23[S-(4 α, 12a α)]-9-[1-oxo hexahydropyrrolo [1,2-a] piperazine-2 (1H)-yl also]-4, two (dimethylin)-1,4 of 7-, 4a, 5,5a, 6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1, the preparation of 11-dioxo 2-tetracene methane amide (compound 6)
With reference to embodiment 18, throw [S-(4 α, 12a α)]-9-[1,3-dioxo hexahydropyrrolo also [1,2-a] piperazine-2 (1H)-yl]-4, two (dimethylin)-1,4 of 7-, 4a, 5,5a, 6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-tetracene methane amide 6.4g (10mmol), sodium borohydride 0.76g (20mmol) gets target compound 4.9g, yield: 82.5%.
Molecular formula: C
30H
37N
5O
8Molecular weight: 595.64 mass spectrums: (m/e): 596 (M+1)
Ultimate analysis: theoretical value: C, 60.49%; H, 6.26%; N, 11.76% measured value: C, 60.40%; H, 6.36%; N, 11.68%
1H-NMR(600MHz，CDCl
3)：δ1.43(t，1H)，1.55(m，1H)，1.65(m，1H)，1.71(t，1H)，1.81(q，1H)，2.06(q，1H)，2.21(t，1H)，2.24(s，1H)，2.31(t，1H)，2.32(t，1H)，2.33(m，1H)，2.41(s，6H)，2.43(d，1H)，2.47(t，1H)，2.57(t，1H)，2.68(d，1H)，2.83(s，6H)，3.17(d，1H)，3.20(t，1H)，3.47(t，1H)，3.51(t，1H)，5.39(s，1H)，6.08(s，2H)，6.18(s，1H)，11.12(s，1H)，12.47(s，1H)
Embodiment 24[S-(4 α, 12a α)] 9-[1-oxo-dihydro-1H-piperidines [1,2-a] piperazine-2 (6H, 7H also, 8H, 9H, 9aH)-and yl]-4, two (dimethylin)-1,4 of 7-, 4a, 5,5a, 6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1, the preparation of 11-dioxo-2-tetracene methane amide (compound 7)
With reference to embodiment 18, throw [S-(4 α, 12a α)]-9-[1,3-dioxo dihydro-1H-
PiperidinesAnd [1,2-a] piperazine-2 (6H, 7H, 8H, 9H, 9aH)-yl]-4, two (dimethylin)-1,4 of 7-, 4a, 5,5a, 6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-tetracene methane amide 6.2g (10mmol), sodium borohydride 0.76g (20mmol) gets target compound 5.1g, yield: 83.2%.
Molecular formula: C
31H
39N
5O
8Molecular weight: 609.67 mass spectrums: (m/e): 610 (M+1)
Ultimate analysis: theoretical value: C, 61.07%; H, 6.45%; N, 11.49% measured value: C, 60.40%; H, 6.36%; N, 11.68%
1H-NMR(600MHz，CDCl
3)：δ1.43(t，1H)，1.44(m，1H)，1.48(m，1H)，1.50(m，1H)，1.54(m，1H)，1.71(m，1H)，1.74(t，1H)，1.96(m，1H)，2.20(t，1H)，2.25(s，1H)，2.28(t，1H)，2.32(m，1H)，2.36(t，1H)，2.42(s，6H)，2.43(d，1H)，2.47(t，1H)，2.57(t，1H)，2.67(t，1H)，2.68(d，1H)，2.82(s，6H)，3.19(d，1H)，3.46(t，1H)，3.49(t，1H)，5.41(s，1H)，6.09(s，2H)，6.17(s，1H)，11.15(s，1H)，12.49(s，1H)
Embodiment 25 [S-(4 α, 12a α)]-9-[N-4-(1-adamantyl) piperazine-2-ketone-1-yl]-4, two (dimethylin)-1,4 of 7-, 4a, 5,5a, 6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1, the preparation of 11-dioxo-2-tetracene methane amide (compound 8)
With reference to embodiment 18, throw [S-(4 α, 12a α)]-9-[N-4-(1-adamantyl) piperazine-2,6-diketone-1-yl]-4, two (dimethylin)-1,4 of 7-, 4a, 5,5a, 6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-tetracene methane amide 7.0g (10mmol), sodium borohydride 0.76g (20mmol) gets target compound 5.1g, yield: 80.2%.
Molecular formula: C
38H
48N
4O
8Molecular weight: 688.81 mass spectrums: (m/e): 689 (M+1)
Ultimate analysis: theoretical value: C, 66.26%; H, 7.02%; N, 8.13% measured value: C, 66.18%; H, 7.13%; N, 8.05%
1H-NMR(600MHz，CDCl
3)：δ1.14(d，1H)，1.18(t，4H)，1.24(d，1H)，1.40(m，1H)，1.41(m，3H)，1.43(t，1H)，1.49(d，1H)，1.52(d，1H)，1.56(t，4H)，1.74(t，1H)，2.29(s，1H)，2.32(m，1H)，2.40(t，1H)，2.42(s，6H)，2.43(d，1H)，2.51(t，2H)，2.68(d，1H)，2.82(s，6H)，3.19(d，1H)，3.31(s，2H)，3.47(t，2H)，5.41(s，1H)，6.09(s，2H)，6.17(s，1H)，11.15(s，1H)，12.43(s，1H)
According to above-mentioned preparation method, the present invention has also prepared following compound:
The preparation technology of embodiment 26 The compounds of this invention freeze-dried powders
1, prescription:
Prescription 1 prescription 2
Compound 1 50g compound 9 100g
N.F,USP MANNITOL 300g dextran 500g
It is an amount of to prepare 1000 waters for injection altogether
Water for injection prepares 1000 in right amount altogether
2, preparation technology: take by weighing raw material and auxiliary material according to prescription, N.F,USP MANNITOL is added about 80% water for injection stirring and dissolving (dextran boils dissolving to be put cold), add the raw material stirring dissolving again, regulate the appropriate pH value, benefit adds to the full amount of water for injection, add dosing amount 0.05% needle-use activated carbon absorption 15 minutes, filtering decarbonization, smart filter, work in-process chemical examination, can, lid is rolled in freeze-drying, tamponade.Step of freeze drying is :-40 ℃ of pre-freezes 3 hours, with on average per hour 2 ℃ heat up, be warming up to 0 ℃ and carry out low-temperature vacuum drying, the 33 ℃ of high-temperature vacuum dryings that are rapidly heated, vacuum degree control is below the 0.1mm mercury column.
The preparation of embodiment 27 The compounds of this invention aseptic powder injections
1, prescription:
Prescription 1
Compound 2 10g
Arginine 990g
Prepare 1000 altogether
Prescription 2
Compound 8 100g
Prepare 1000 altogether
2, preparation technology: will prepare used antibiotic glass bottle, plug etc. and carry out aseptically process; Take by weighing raw material and auxiliary material by prescription, pulverize mixing, place the portioning machine packing, detect loading amount at any time; Jump a queue, gland, finished product is examined entirely, the packing warehouse-in.
The preparation of embodiment 28 The compounds of this invention tablets
1, prescription:
Prescription 1
Compound 5 25g
Starch 50g
Hydroxypropylcellulose 40g
Microcrystalline Cellulose 40g
The 50% aqueous ethanolic solution 20g of 1%HPMC
Micropowder silica gel 2.0g
Magnesium Stearate 2.0g
Prepare 1000 altogether
Prescription 2
Compound 10 50g
Starch 30g
Hydroxypropylcellulose 15g
Microcrystalline Cellulose 40g
2%PVP-K30 aqueous solution 25g
Micropowder silica gel 1.0g
Magnesium Stearate 1.5g
Prepare 1000 altogether
2, preparation technology: preparation technology: take by weighing raw material and auxiliary material according to prescription, raw material pulverizing is crossed 100 mesh sieves, all the other auxiliary materials are crossed 100 mesh sieves respectively; Raw material, starch, hydroxypropylcellulose and Microcrystalline Cellulose are mixed, add mixer-granulator, 50% aqueous ethanolic solution (or 2%PVP-K30 aqueous solution) that adds 1%HPMC is an amount of, stirs 15 minutes, makes particle; Particle is dried being lower than under 60 ℃ the condition; Dry good particle adds micropowder silica gel and Magnesium Stearate, and whole grain mixes; Sampling, the work in-process chemical examination; According to the definite sheet weight sheet of chemical examination; Finished product is examined entirely, the packing warehouse-in.
The preparation of embodiment 29 The compounds of this invention gelifying agents
1, prescription
Prescription 1 prescription 2
Compound 5 12g compounds 11 15g
Carbopol 940 5g carbopols 940 9g
Ethanol 50g ethanol 50g
Glycerine 50g glycerine 50g
Tween 80 2g tween 80 2g
Ethyl p-hydroxybenzoate 0.5g ethyl p-hydroxybenzoate 0.5g
Distilled water to 1000g distilled water to 1000g
Prepare 100 altogether and prepare 100 altogether
2, preparation technology: under agitation, Xiang Shuizhong stirs and adds carbopol 940, adds compound 5 or compound 11 in glycerine and tween 80, and stirring and dissolving adds in the above-mentioned dispersion system; With the ethyl p-hydroxybenzoate dissolve with ethanol, add in the above-mentioned solution, stir evenly, the gelifying agent of water-soluble base.
Those skilled in the art will know or only use routine test just can determine many embodiments that are equal to of concrete grammar described herein.The embodiment that is equal to is like this considered within the scope of the present invention, and is included in claims scope.
Claims (9)
1. the compound shown in the general formula (I) or its pharmacy acceptable salt:
Wherein, R
1a, R
1b, R
2, R
8, R
9And R
10Independently be respectively: hydrogen;
R
6For: NR
6aR
6b
R
3a, R
3b, R
6aAnd R
6bIndependently be respectively: hydrogen or C
1～6Alkyl;
R
4, R
7, R
5aAnd R
5bIndependently be respectively: hydrogen;
X is: carbonyl;
Y is: carbonyl or methylene radical;
R
11For: hydrogen, C
1～6Alkyl or adamantyl;
R
12, R
13Independently be respectively: hydrogen or C
1～6Alkyl, perhaps R
12With R
11Or R
13With R
11Be interconnected to 3-10 unit heterocyclic radical;
Above-mentioned R
12With R
11Or R
13With R
11The 3-10 unit heterocyclic radical that is interconnected to can further be replaced by one or more substituting groups, and substituting group is selected from C
1～6Alkyl, halo C
1～6Alkyl or C
1～6Alkoxyl group;
Above-mentioned C
1-6Alkyl is meant the straight chained alkyl of 6 following carbon atoms, the branched-chain alkyl of 3-6 carbon atom and cycloalkyl, and wherein the cycloalkyl of 3-6 carbon atom is meant cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.
2. compound as claimed in claim 1 or its pharmacy acceptable salt:
Wherein, R
1a, R
1b, R
2, R
4, R
7, R
5a, R
5b, R
8, R
9And R
10Independently be respectively: hydrogen;
R
6For: NR
6aR
6b
R
3a, R
3b, R
6aAnd R
6bIndependently be respectively: methyl;
X is: carbonyl;
Y is: carbonyl or methylene radical;
R
11For: hydrogen, C
1～6Alkyl or adamantyl;
R
12, R
13Independently be respectively: hydrogen or C
1～4Alkyl, perhaps R
12With R
11Or R
13With R
11Be interconnected to 4～6 yuan of single heterocyclic radicals;
Above-mentioned R
12With R
11Or R
13With R
114～6 yuan of single heterocyclic radicals that are interconnected to can further be replaced by one or more substituting groups, and substituting group is selected from C
1～4Alkyl, halo C
1～4Alkyl or C
1～4Alkoxyl group;
Above-mentioned C
1-6Alkyl is meant the straight chained alkyl of 6 following carbon atoms, the branched-chain alkyl of 3-6 carbon atom and cycloalkyl, and wherein the cycloalkyl of 3-6 carbon atom is meant cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.
3. compound as claimed in claim 2 or its pharmacy acceptable salt:
Wherein, R
1a, R
1b, R
2, R
4, R
7, R
5a, R
5b, R
8, R
9And R
10Independently be respectively: hydrogen;
R
6For: NR
6aR
6b
R
3a, R
3b, R
6aAnd R
6bIndependently be respectively: methyl;
X is: carbonyl;
Y is: carbonyl or methylene radical;
R
11For: hydrogen, C
1～6Alkyl or adamantyl;
R
12, R
13Independently be respectively: hydrogen or C
1～4Alkyl, perhaps R
12With R
11Or R
13With R
11Be interconnected to 4～6 yuan of single heterocyclic radicals;
Above-mentioned C
1-6Alkyl is meant the straight chained alkyl of 6 following carbon atoms, the branched-chain alkyl of 3-6 carbon atom and cycloalkyl, and wherein the cycloalkyl of 3-6 carbon atom is meant cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.
4. compound as claimed in claim 3 or its pharmacy acceptable salt:
Wherein, R
1a, R
1b, R
2, R
4, R
7, R
5a, R
5b, R
8, R
9And R
10Independently be respectively: hydrogen;
R
6For: NR
6aR
6b
R
3a, R
3b, R
6aAnd R
6bIndependently be respectively: methyl;
X is: carbonyl;
Y is: carbonyl or methylene radical;
R
11For: hydrogen, methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl, Skellysolve A base, isoamyl alkyl, neopentyl, hexyl, 2-methyl amyl, 3-methyl amyl, 2,3-dimethylbutyl, 2,2-dimethylbutyl, 2-ethyl-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or adamantyl;
R
12, R
13Independently be respectively: hydrogen, perhaps R
12With R
11Or R
13With R
11Be interconnected to azetidine, tetramethyleneimine or piperidine.
5. compound as claimed in claim 4 or its pharmacy acceptable salt:
Wherein, R
1a, R
1b, R
2, R
4, R
7, R
5a, R
5b, R
8, R
9And R
10Independently be respectively: hydrogen;
R
6For: NR
6aR
6b
R
3a, R
3b, R
6aAnd R
6bIndependently be respectively: methyl;
X is: carbonyl;
Y is: carbonyl or methylene radical;
R
11For: hydrogen, methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or adamantyl;
R
12, R
13Independently be respectively: hydrogen, perhaps R
12With R
11Or R
13With R
11Be interconnected to azetidine, tetramethyleneimine or piperidine.
6. compound as claimed in claim 5 or its pharmacy acceptable salt, described compound is selected from:
[S-(4 α, 12a α)]-9-[N-4-tertiary butyl piperazine-2-ketone-1-yl]-4, two (dimethylin)-1,4 of 7-, 4a, 5,5a, 6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-tetracene methane amide,
[S-(4 α, 12a α)]-9-[N-4-methylpiperazine-2-ketone-1-yl]-4, two (dimethylin)-1,4 of 7-, 4a, 5,5a, 6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-tetracene methane amide,
[S-(4 α, 12a α)]-9-[N-4-cyclopropyl piperazine-2-ketone-1-yl]-4, two (dimethylin)-1,4 of 7-, 4a, 5,5a, 6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-tetracene methane amide,
[S-(4 α, 12a α)]-9-[N-4-cyclobutyl piperazine-2-ketone-1-yl]-4, two (dimethylin)-1,4 of 7-, 4a, 5,5a, 6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-tetracene methane amide,
[S-(4 α, 12a α)]-9-[N-4-cyclopentyl-based piperazine-2-ketone-1-yl]-4, two (dimethylin)-1,4 of 7-, 4a, 5,5a, 6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-tetracene methane amide,
[S-(4 α, 12a α)]-9-[1-oxo hexahydropyrrolo [1,2-a] piperazine-2 (1H)-yl]-4, two (dimethylin)-1,4 of 7-, 4a, 5,5a, 6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-tetracene methane amide,
[S-(4 α, 12a α)]-9-[1-oxo-dihydro-1H-piperidines also [1,2-a] piperazine-2 (6H, 7H, 8H, 9H, 9aH)-yl]-4, two (dimethylin)-1,4 of 7-, 4a, 5,5a, 6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-tetracene methane amide
[S-(4 α, 12a α)]-9-[N-4-(1-adamantyl) piperazine-2-ketone-1-yl]-4, two (dimethylin)-1,4 of 7-, 4a, 5,5a, 6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-tetracene methane amide,
[S-(4 α, 12a α)]-9-[N-4-tertiary butyl piperazine-2,6-diketone-1-yl]-4, two (dimethylin)-1,4 of 7-, 4a, 5,5a, 6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-tetracene methane amide,
[S-(4 α, 12a α)]-9-[N-4-methylpiperazine-2,6-diketone-1-yl]-4, two (dimethylin)-1,4 of 7-, 4a, 5,5a, 6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-tetracene methane amide,
[S-(4 α, 12a α)]-9-[N-4-cyclopropyl piperazine-2,6-diketone-1-yl]-4, two (dimethylin)-1,4 of 7-, 4a, 5,5a, 6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-tetracene methane amide,
[S-(4 α, 12a α)]-9-[N-4-cyclobutyl piperazine-2,6-diketone-1-yl]-4, two (dimethylin)-1,4 of 7-, 4a, 5,5a, 6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-tetracene methane amide,
[S-(4 α, 12a α)]-9-[N-4-cyclopentyl-based piperazine-2,6-diketone-1-yl]-4, two (dimethylin)-1,4 of 7-, 4a, 5,5a, 6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-tetracene methane amide,
[S-(4 α, 12a α)]-9-[1,3-dioxo hexahydropyrrolo [1,2-a] piperazine-2 (1H)-yl]-4, two (dimethylin)-1,4 of 7-, 4a, 5,5a, 6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-tetracene methane amide,
[S-(4 α, 12a α)]-9-[1,3-dioxo dihydro-1H-piperidines is [1,2-a] piperazine-2 (6H, 7H, 8H, 9H also, 9aH)-and yl]-4, two (dimethylin)-1,4 of 7-, 4a, 5,5a, 6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-tetracene methane amide and
[S-(4 α, 12a α)]-9-[N-4-(1-adamantyl) piperazine-2,6-diketone-1-yl]-4, two (dimethylin)-1,4 of 7-, 4a, 5,5a, 6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-tetracene methane amide.
7. the pharmaceutical composition that comprises each described compound of claim 1～6 and other active pharmaceutical ingredients.
8. as the pharmaceutical composition of the described compound of the arbitrary claim of claim 1～6 and one or more pharmaceutical carriers and/or thinner, be the arbitrary formulation of acceptable pharmaceutically.
9. be used for preparing the application that treats and/or prevents tetracyclines sensitive diseases medicine as the described compound of the arbitrary claim of claim 1～6.
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|---|---|---|---|
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|---|---|---|---|
| CN200810139459.4 | 2008-09-16 | ||
| CN200810139459 | 2008-09-16 | ||
| CN2009101742900A CN101684101B (en) | 2008-09-16 | 2009-09-16 | Piperazinone substituted tetracycline derivatives |
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| US8486921B2 (en) | 2006-04-07 | 2013-07-16 | President And Fellows Of Harvard College | Synthesis of tetracyclines and analogues thereof |
| EP3056487B1 (en) | 2006-10-11 | 2018-02-21 | President and Fellows of Harvard College | Synthesis of enone intermediate |
| WO2010126607A2 (en) | 2009-04-30 | 2010-11-04 | President And Fellows Of Harvard College | Synthesis of tetracyclines and intermediates thereto |
| WO2012047907A1 (en) * | 2010-10-04 | 2012-04-12 | President And Fellows Of Harvard College | Synthesis of c5-substituted tetracyclines, uses thereof, and intermediates thereto |
| CN109912538B (en) * | 2019-01-22 | 2021-03-12 | 安徽赛乐普制药有限公司 | Preparation method of antidepressant vortioxetine |
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|---|---|---|---|---|
| CN1653037A (en) * | 2002-03-21 | 2005-08-10 | 帕拉特克药品公司 | Substituted tetracycline compounds |
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Effective date of registration: 20190701 Address after: 578101 Yangpu Economic Development Zone, Hainan Province, 1201 Building K2, Huating Coastal Road, Gangbei Road Patentee after: Hainan Sihuan Pharmaceutical Co.,Ltd Address before: 250101 No. 2518 Tianchen Street, Jinan High-tech Development Zone, Shandong Province Patentee before: Shandong Xuanzhu Medical Technology Co., Ltd. |
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Application publication date: 20100331 Assignee: Beijing Tianxinyuan Pharmaceutical Science and Technology Development Co., Ltd. Assignor: Hainan Sihuan Pharmaceutical Co.,Ltd Contract record no.: X2019980000727 Denomination of invention: Piperazinone substituted tetracycline derivatives Granted publication date: 20111109 License type: Common License Record date: 20191126 |