CN101684083B - Guanidinoalkanoylamino substituted tetracycline derivatives - Google Patents
Guanidinoalkanoylamino substituted tetracycline derivatives Download PDFInfo
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Abstract
The present invention belongs to the technical field of medicament, in particular, relating to guanidinoalkanoylamino substituted tetracycline derivatives shown in a general formula (I), and pharmaceutically acceptable salts or isomers thereof, wherein R<2>, R<2'>, R<3>, R<4>, R<4'>, R<5>, R<6>, R<6'>, R<7>, R<8>, R<9>, R<9'>, R<9''> and n are defined in the specification. The present 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 and the isomer thereof of Guanidinoalkanoylamisubstituted replacement, the preparation method of these compounds, and these compounds treat and/or prevent the especially application in the medicine of infectious diseases of tetracyclines sensitive diseases 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 the duomycin that obtains from golden Streptothrix separation in 1948, has developed terramycin, tsiklomitsin and Demethylchlortetracycline subsequently in succession, 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 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), its pharmacy acceptable salt and isomer thereof:
Wherein, R
2, R
2 ', R
3, R
10, R
11And R
12Respectively do for oneself hydrogen or prodrug part;
R
5, R
6, R
6 'And R
8The hydrogen of respectively doing for oneself, sulfydryl, halogen, hydroxyl, amino, carboxyl, C
1-6Alkyl, halo C
1-6Alkyl, C
2-6Thiazolinyl, C
2-6Alkynyl, C
1-6Alkoxyl group, C
1-6Alkylthio, C
1-6Alkyl amine group, two (C
1-6Alkyl) amido, hydroxyl C
1-6Alkyl, amino C
1-6Alkyl, C
1-6Alkyl amine group C
1-6Alkyl, carboxyl 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, alkylsulfonyl C
1-6Alkyl, sulfoamido, sulfoamido C
1-6Alkyl, C
1-6Alkylsulfonamido, amino-sulfonyl, C
1-6The alkyl amine group alkylsulfonyl, two (C
1-6Alkyl) amido alkylsulfonyl, amino-sulfonyl C
1-6Alkyl, C
1-6Alkylamidoalkyl, C
1-6The alkyl amine group formyl radical, two (C
1-6Alkyl) amido formyl radical, formamyl, formamyl C
1-6Alkyl, C
6-14Aryl, C
6-14Aryl C
1-6Alkyl, C
6-14Aroyl, C
6-14Aryl acyloxy, C
1-6Alkyl C
6-14Aryl-acyl, 3-14 unit's heterocyclic radical or the heterocyclic radical C of 3-14 unit
1-6Alkyl;
R
7Be hydrogen, hydroxyl, nitro, cyano group, halogen, amide group or-NR
7 'R
7 "
R
4, R
4 ', R
7 'And R
7 "The hydrogen of respectively doing for oneself, C
1-6Alkyl, C
2-6Thiazolinyl, C
2-6Alkynyl, C
1-6Alkoxyl group, C
1-6Alkylthio, hydroxyl C
1-6Alkyl, carboxyl C
1-6Alkyl, amino C
1-6Alkyl, halo C
1-6Alkyl, C
1-6Alkyl amine group C
1-6Alkyl, C
1-6Alkyl-carbonyl, C
1-6Alkoxy carbonyl, C
1-6Alkyl sulphinyl, C
1-6Alkyl sulphonyl, sulfonic group, alkylsulfonyl C
1-6Alkyl, sulfoamido C
1-6Alkyl, amino-sulfonyl, amino-sulfonyl C
1-6Alkyl, C
1-6The alkyl amine group alkylsulfonyl, two (C
1-6Alkyl) amido alkylsulfonyl, formamyl, C
1-6The alkyl amine group formyl radical, two (C
1-6Alkyl) amido formyl radical, formamyl C
1-6Alkyl, C
6-14Aryl, C
6-14Aryl C
1-6Alkyl, 3-14 unit heterocyclic radical, the heterocyclic radical C of 3-14 unit
1-6Alkyl or prodrug part;
R
9And R
9 'The hydrogen of respectively doing for oneself, C
1-6Alkyl, C
2-6Thiazolinyl, C
2-6Alkynyl, C
1-6Alkoxyl group, C
1-6Alkylthio, hydroxyl C
1-6Alkyl, carboxyl C
1-6Alkyl, amino C
1-6Alkyl, halo C
1-6Alkyl, C
1-6Alkyl amine group C
1-6Alkyl, C
1-6Alkyl-carbonyl, C
1-6Alkoxy carbonyl, C
1-6Alkyl sulphinyl, C
1-6Alkyl sulphonyl, sulfonic group, alkylsulfonyl C
1-6Alkyl, sulfoamido C
1-6Alkyl, amino-sulfonyl, amino-sulfonyl C
1-6Alkyl, C
1-6The alkyl amine group alkylsulfonyl, two (C
1-6Alkyl) amido alkylsulfonyl, formamyl, C
1-6The alkyl amine group formyl radical, two (C
1-6Alkyl) amido formyl radical, formamyl C
1-6Alkyl, C
6-14Aryl, C
6-14Aryl C
1-6Alkyl, 3-14 unit heterocyclic radical, the heterocyclic radical C of 3-14 unit
1-6Alkyl, bridged ring base or R
9And R
9 'Coupled nitrogen-atoms forms the 4-6 unit heterocyclic radical that contains a nitrogen-atoms at least,
Described C
6-14Aryl, 3-14 unit heterocyclic radical, bridged ring base and 4-6 unit heterocyclic radical can further be substituted base and replace, and described substituting group is selected from hydroxyl, amino, carboxyl, halogen, sulfydryl, C
1-6Alkyl, C
1-6Alkoxyl group, C
1-6Alkylthio, C
1-6Alkyl amine group, two (C
1-6Alkyl) amido, C
1-6Alkyl amine group C
1-6Alkyl, C
1-6Alkyl-carbonyl, C
1-6Alkyl carbonyl oxy, C
1-6Alkoxy carbonyl, C
1-6Alkylsulfonamido, amino-sulfonyl, C
1-6Alkyl amine group alkylsulfonyl, two (C
1-6Alkyl) amido alkylsulfonyl, amino-sulfonyl C
1-6Alkyl, C
1-6Alkylamidoalkyl, C
1-6Alkyl amine group formyl radical, two (C
1-6Alkyl) amido formyl radical, formamyl, formamyl C
1-6Alkyl or the C that is replaced by hydroxyl, amino, carboxyl, halogen
1-6Alkyl or C
1-6Alkoxyl group;
R
9 "Be hydrogen or C
1-6Alkyl;
N is the integer of 0-3.
Be preferably:
Wherein, R
2, R
2 ', R
3, R
10, R
11And R
12The hydrogen of respectively doing for oneself;
R
5, R
6, R
6 'And R
8The hydrogen of respectively doing for oneself, hydroxyl or C
1-6Alkyl;
R
7Be hydrogen, halogen or-NR
7 'R
7 "
R
4, R
4 ', R
7 'And R
7 "The hydrogen of respectively doing for oneself, C
1-6Alkyl or C
1-4Alkyl-carbonyl;
R
9And R
9 'The hydrogen of respectively doing for oneself, C
1-6Alkyl, hydroxyl C
1-4Alkyl, carboxyl C
1-4Alkyl, amino C
1-4Alkyl, halo C
1-4Alkyl, C
1-4Alkyl amine group C
1-4Alkyl, C
1-4Alkyl-carbonyl, C
1-4Alkoxy carbonyl, C
6-10Aryl, C
6-10Aryl C
1-4Alkyl, 4-6 unit heteromonocyclic group, the assorted many cyclic groups of 8-14 unit, the heteromonocyclic group C of 4-6 unit
1-4Alkyl, the assorted many cyclic groups C of 8-14 unit
1-4Alkyl, bridged ring base or R
9And R
9 'Coupled nitrogen-atoms forms C
4-6Heteromonocyclic group,
Described C
6-10Aryl, 4-6 unit heteromonocyclic group, the assorted many cyclic groups of 8-14 unit, the bridged ring base can further be substituted base and replace, and described substituting group is selected from hydroxyl, amino, carboxyl, halogen, C
1-6Alkyl, C
1-4Alkoxyl group, C
1-4Alkyl amine group, two (C
1-4Alkyl) amido, C
1-4Alkyl amine group C
1-4Alkyl, C
1-4Alkyl-carbonyl, C
1-4Alkyl carbonyl oxy, C
1-4Alkoxy carbonyl, C
1-4Alkylsulfonamido, amino-sulfonyl, C
1-4Alkyl amine group alkylsulfonyl, two (C
1-4Alkyl) amido alkylsulfonyl, amino-sulfonyl C
1-4Alkyl, C
1-4Alkylamidoalkyl, C
1-4Alkyl amine group formyl radical, two (C
1-4Alkyl) amido formyl radical, formamyl, formamyl C
1-4Alkyl or the C that is replaced by hydroxyl, amino, carboxyl, halogen
1-4Alkyl or C
1-4Alkoxyl group;
R
9 "Be hydrogen or methyl;
N is 0 or 1.
More preferably:
Wherein, R
2, R
2 ', R
3, R
5, R
6, R
6 ', R
8, R
9 ", R
10, R
11And R
12The hydrogen of respectively doing for oneself;
R
7For hydrogen or-NR
7 'R
7 "
R
4, R
4 ', R
7 'And R
7 "Hydrogen or C respectively do for oneself
1-6Alkyl;
R
9And R
9 'The hydrogen of respectively doing for oneself, C
1-6Alkyl, hydroxyl C
1-4Alkyl, amino C
1-4Alkyl, fluoro C
1-4Alkyl, chloro C
1-4Alkyl, bromo C
1-4Alkyl, C
1-4Alkyl amine group C
1-4Alkyl, C
1-4Alkyl-carbonyl, phenyl, phenyl C
1-4Alkyl, 4-6 unit heteromonocyclic group, the heteromonocyclic group C of 4-6 unit
1-4Alkyl, bridged ring base or R
9And R
9 'Coupled nitrogen-atoms forms 4-6 unit heteromonocyclic group,
Described phenyl, phenyl C
1-4Alkyl, 4-6 unit heteromonocyclic group, the heteromonocyclic group C of 4-6 unit
1-4Alkyl, bridged ring base or R
9And R
9 'Coupled nitrogen-atoms forms 4-6 unit heteromonocyclic group can further be substituted the base replacement, and described substituting group is selected from hydroxyl, amino, carboxyl, fluorine atom, chlorine atom, bromine atoms, C
1-4Alkyl, C
1-4Alkoxyl group, C
1-4Alkyl amine group, two (C
1-4Alkyl) amido, C
1-4Alkyl amine group C
1-4Alkyl, C
1-4Alkyl-carbonyl, C
1-4Alkyl carbonyl oxy, C
1-4Alkoxy carbonyl or the C that is replaced by hydroxyl, amino, carboxyl, fluorine
1-4Alkyl or C
1-4Alkoxyl group;
N is 0.
More preferably:
Wherein, R
2, R
2 ', R
3, R
5, R
6, R
6 ', R
8, R
9 ", R
10, R
11And R
12The hydrogen of respectively doing for oneself;
R
7For hydrogen or-NR
7 'R
7 "
R
4, R
4 ', R
7 'And R
7 "The methyl of respectively doing for oneself;
R
9And R
9 'The hydrogen of respectively doing for oneself, methyl, ethyl, n-propyl, sec.-propyl; normal-butyl, isobutyl-, sec-butyl, the tertiary butyl, Skellysolve A base; the isoamyl alkyl, neopentyl, 2-methylpentane, 3-methylpentane, 2; the 3-dimethylbutane, 2,2-dimethylbutane, 2-ethyl butane; cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; methylol, aminomethyl, trifluoromethyl, methylamino methyl; ethanoyl, tetrahydrofuran base, tetrahydro-thienyl, phenyl; benzyl, furyl, thienyl, thiazolyl; isothiazolyl ， oxazolyl ， isoxazolyl, imidazolyl; pyrazolyl, pyridyl, picolyl, adamantyl or R
9And R
9 'Coupled nitrogen-atoms forms azetidinyl, pyrrolidyl, piperidyl, oxazinyl, morpholinyl or piperazinyl,
Described tetrahydrofuran base, tetrahydro-thienyl, phenyl, benzyl, furyl, thienyl, thiazolyl, isothiazolyl ， oxazolyl ， isoxazolyl, imidazolyl, pyrazolyl, pyridyl, picolyl, adamantyl or R
9And R
9 'Coupled nitrogen-atoms forms azetidinyl, pyrrolidyl, piperidyl, oxazinyl, morpholinyl or piperazinyl, can further be substituted base and replace, described substituting group be selected from methyl, ethyl, methoxyl group, trifluoromethyl, trifluoromethoxy, aminomethyl, hydroxyl, methylol, fluorine atom, chlorine atom, amino, methyl amido, ethanoyl, methoxycarbonyl or methyl carbonyl oxygen base;
N is 0.
More preferably:
Wherein, R
2, R
2 ', R
3, R
5, R
6, R
6 ', R
8, R
9 ", R
10, R
11And R
12The hydrogen of respectively doing for oneself;
R
7For-NR
7 'R
7 "
R
4, R
4 ', R
7 'And R
7 "The methyl of respectively doing for oneself;
R
9And R
9 'The hydrogen of respectively doing for oneself, methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl, Skellysolve A base, the isoamyl alkyl, neopentyl, 2-methylpentane, 3-methylpentane, 2, the 3-dimethylbutane, 2,2-dimethylbutane, 2-ethyl butane, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, furyl, thienyl, thiazolyl, pyridyl, picolyl, adamantyl or R
9And R
9 'Coupled nitrogen-atoms forms azetidinyl, pyrrolidyl, piperidyl, oxazinyl or piperazinyl,
Described phenyl, furyl, thienyl, thiazolyl, pyridyl, picolyl, adamantyl or R
9And R
9 'Coupled nitrogen-atoms forms azetidinyl, pyrrolidyl, piperidyl, oxazinyl or piperazinyl and can further be substituted base and replace, described substituting group be selected from methyl, ethyl, methoxyl group, trifluoromethyl, trifluoromethoxy, aminomethyl, methylol, fluorine atom, chlorine atom, amino or methyl amido;
N is 0.
More preferably:
Wherein, R
2, R
2 ', R
3, R
5, R
6, R
6 ', R
8, R
9 ", R
10, R
11And R
12The hydrogen of respectively doing for oneself;
R
7For-NR
7 'R
7 "
R
4, R
4 ', R
7 'And R
7 "The methyl of respectively doing for oneself;
R
9And R
9 'The methyl of respectively doing for oneself, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, 2-trifluoromethyl, the 3-trifluoromethyl, 4-trifluoromethyl, 2-Trifluoromethoxyphen-l, the 3-Trifluoromethoxyphen-l, 4-Trifluoromethoxyphen-l, 2,3-two (trifluoromethoxy) phenyl, 2,4-two (trifluoromethoxy) phenyl, 3,4-two (trifluoromethoxy) phenyl, furyl, thienyl, thiazolyl, pyridyl, picolyl, adamantyl, adamantyl methyl or R
9And R
9 'Coupled nitrogen-atoms forms azetidine, tetramethyleneimine, methyl piperidine, piperidines, 3,4,5,6-tetrahydrochysene-2H-1,2-oxazine, piperazine or methylpiperazine;
N is 0.
Be preferably especially:
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.
" halo " in the term " haloalkyl " is 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, reaction equation:
Reactions steps:
The preparation of step 1 formula III compound
In reaction flask, throw the dihydrochloride of raw material 1, be dissolved in the vitriol oil, stir ice bath cooling down, add SODIUMNITRATE then, mixture stirs in ice bath, and reaction is finished, this mixture is dropped in the ether, separate 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 hydrogen pressure, filter, concentrating under reduced pressure, residuum adds ether under vigorous stirring, filter, drying gets the formula III compound.
The preparation of step 2 formula II compound
Low temperature adds the formula III compound in the mixing solutions of N,N-DIMETHYLACETAMIDE and acetonitrile, add powdery yellow soda ash then, after mixing, slowly be added dropwise to raw material 2/ dichloromethane solution, stirring reaction, filter, under the vigorous stirring filtrate is dropped in the ether of hydrochloric acid, collect gained solid and the dry formula II compound that gets.
The preparation of step 3 formula I compound
Under room temperature, the nitrogen protection; in the exsiccant reaction flask, add intermediate dihydrochloride and N,N-DIMETHYLACETAMIDE, stir adding raw material 3 hydrochlorides down, stirring reaction; reaction is finished; add ethanol, filter, add ether again; ice bath drips down and contains in the ether of triethylamine; separate out solid, filter and drying, get formula I compound.
R in the above reaction equation
2, R
2 ', R
3, R
4, R
4 ', R
5, R
6, R
6 ', R
7, R
8, R
9, R
9 ', R
9 ", R
10, R
11, R
12, n as mentioned before.
The tetracycline derivant of the Guanidinoalkanoylamisubstituted replacement of alkalescence of the present invention 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 the tetracycline derivant of the Guanidinoalkanoylamisubstituted replacement 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 of the Guanidinoalkanoylamisubstituted replacement of acidity of the present invention 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 the tetracycline derivant of the Guanidinoalkanoylamisubstituted replacement of tart the present invention can form with ordinary method and pharmaceutically acceptable positively charged ion.
The tetracycline derivant structure of Guanidinoalkanoylamisubstituted replacement 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 present invention is the pharmaceutical composition of tetracycline derivant, its pharmacy acceptable salt or its isomer and other active pharmaceutical ingredients of claimed Guanidinoalkanoylamisubstituted replacement further, and described other active pharmaceutical ingredients comprises trimethoprim.
The present invention is the claimed pharmaceutical composition that comprises compound recited above, its pharmacy acceptable salt or its isomer and one or more pharmaceutical carriers and/or thinner further, is pharmaceutically acceptable arbitrary formulation.Comprise oral administered dosage form, injecting medicine-feeding form, respiratory tract administration formulation, percutaneous drug delivery formulation, mucosa delivery formulation or cavity/canal drug administration formulation.
Above-mentioned preparation single-dose amount contains the compound 0.002～100mg/kg weight in patients shown in the general formula (I), and preferred 0.02～50mg/kg weight in patients is for treating and/or preventing the necessary amount of a kind of tetracyclines sensitive disease or enough amounts.This dosage 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 aforementioned factor and determine the significant quantity of The compounds of this invention.Usually, in clinical The compounds of this invention can according to before the dosage of the clinical use of other tetracycline medication give the patient, for example can give the patient according to the dosage of the clinical use of MINOCYCLINE HCL, the dosage that requires can be suitably by giving once a day, or several times divided dose for example 2-5 dosage every day with the appropriate intervals administration or with other suitable progress administrations.
It is also understood that and consider to give usually the conventional known precaution of tsiklomitsin to guarantee its effect under regular service condition.Especially when being used for the treatment of humans and animals interior therapeutic, the attending doctor should consider that all common-sense precaution are to avoid conventional known taboo and toxic action.Therefore, the usually side effect of generally acknowledging: gastrointestinal discomfort and inflammation, renal toxicity, anaphylaxis, blood picture change and aluminium, calcium and magnesium ion malabsorption, should routine with due regard to.
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 referring to the 2nd printing January in 2006 of " pharmaceutics " Chinese Medicine science and technology release of press in August, 2002 first version, but is not limited only to the 2nd printing January in 2006 of " pharmaceutics " Chinese Medicine science and technology release of press in August, 2002 first version.
The invention still further relates to the tetracycline compound that contains formohydrazide group 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 formohydrazide group 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 The compounds of this invention side effect is little, and toxicity is low, does not have cross resistance with other tetracycline compound; Has good pharmacokinetic property.
Below further set forth the beneficial effect of the tetracycline derivant of the Guanidinoalkanoylamisubstituted replacement of the present invention by in-vitro antibacterial experiment, but this should be interpreted as that the tetracycline derivant of the Guanidinoalkanoylamisubstituted replacement 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: the clinical isolates strain that following bacterial strain is all bought in public institution
Gram positive organism: MSSA (MSSA), methicillin-resistant staphylococcus aureus (MRSA), enterococcus faecalis, faecium; Gram-negative bacteria: intestinal bacteria, hemophilus influenzae.
Trial-product: compound 1～20, its chemical name and the structural formula literary composition that sees before; Tigecycline: 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 1-20 has the excellent antibiotic activity to supplying examination Gram-positive and negative representative strain, and is stronger or suitable than the anti-microbial activity of Tigecycline.Show that The compounds of this invention is compared with immediate prior art, has a broad antifungal spectrum, anti-microbial activity height have the 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-[2-[(N '-tertiary butyl) guanidine radicals] acetamido]-4, the two (dimethylamine of 7-
Base)-1,4,4a, 5,5a, 6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-tetracene methane amide (compound 1) preparation
Step 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-four
Hydroxyl-1, the preparation of 11-dioxo-2-tetracene methane amide
In reaction flask, throw 11.4g (25mmol) [S-(4 α, 12a α)]-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 dihydrochloride is dissolved in the vitriol oil of 80ml, stirs ice bath cooling down, add the 3.4g SODIUMNITRATE then, mixture stirs 1h in ice bath, and reaction is finished, this mixture is dropped in the 1000ml ether, separate out solid, with a small amount of ether washing after drying.This solid is added in the 50ml ethanol, add the palladium charcoal of 1g 10% then, stirring at room 1.5h under the 2MPa hydrogen pressure filters, and concentrating under reduced pressure, residuum add the 400ml ether under vigorous stirring.Filter, drying gets solid chemical compound 9.1g, yield: 76.8%.
Step 2 [S-(4 α, 12a α)]-9-[(chloracetyl) amido]-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 dihydrochloride
Under 0 ℃ with 6.7g (10mmol) [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 dihydrochloride add in the mixing solutions of N,N-DIMETHYLACETAMIDE 60ml and 10ml acetonitrile, add 6.4g powdery yellow soda ash then, after mixing, slowly be added dropwise to 1.4g chloroacetyl chloride/10ml dichloromethane solution, stirring reaction 120min, filter, under the vigorous stirring filtrate is dropped to 200ml and contain in the ether of 5ml 1M hydrochloric acid, collect gained solid and the dry 5.8g of getting, yield: 93.3%.
The preparation of step 3 compound 1
Room temperature; under the nitrogen protection, in the exsiccant reaction flask, add [S-(4 α, 12a α)]-9-[(chloracetyl) amido]-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 dihydrochloride 3.1g (5mmol) and N,N-DIMETHYLACETAMIDE 50ml; stir adding 1.7g (15mmol) tertiary butyl guanidinesalt hydrochlorate down, stirring reaction 2h, reaction is finished; the ethanol that adds 50ml; remove by filter the excessive tertiary butyl guanidinesalt hydrochlorate of separating out, add the ether of 100ml again, ice bath drips 100ml down and contains in the ether of 6ml triethylamine; separate out solid; filter and drying, get target compound 2.5g, yield: 79.6%.
Molecular formula: C
30H
41N
7O
8Molecular weight: 627.69 mass spectrums (m/e): 629 (M+1)
Ultimate analysis: measured value: C, 57.12%; H, 6.85%; N, 15.33%
Theoretical value: C, 57.40%; H, 6.58%; N, 15.62%
1H-NMR(600MHz，CDCl
3)：δ1.11(s，9H)，1.45(t，1H)，1.76(t，1H)，2.28(s，1H)，2.31(s，1H)，2.32(m，1H)，2.35(t，2H)，2.36(t，1H)，2.45(d，1H)，2.46(s，6H)，2.69(d，1H)，2.86(s，6H)，3.17(d，1H)，3.58(t，2H)，5.16(s，1H)，5.41(s，1H)，6.07(s，2H)，7.01(s，1H)，11.17(s，1H)，12.48(s，1H)
Embodiment 2 [S-(4 α, 12a α)]-9-[2-[(N ', N '-dimethyl) guanidine radicals] acetamido]-4, the two (dimethylamine of 7-
Base)-1,4,4a, 5,5a, 6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-tetracene methane amide (compound 2) preparation
The preparation method drops into [S-(4 α, 12a α)]-9-[(chloracetyl with reference to embodiment 1 step 3) amido]-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 dihydrochloride 3.1g (5mmol) and 2.3g (15mmol) N '; N '-dimethylguanidine hydrochloride, react target compound 2.4g, yield: 81.5%.
Molecular formula: C
28H
37N
7O
8Molecular weight: 599.64 mass spectrums (m/e): 601 (M+1)
Ultimate analysis: measured value: C, 55.84%; H, 6.48%; N, 16.11%;
Theoretical value: C, 56.08%; H, 6.22%; N, 16.35%;
1H-NMR(600MHz，CDCl
3)：δ1.43(t，1H)，1.75(t，1H)，2.27(s，1H)，2.31(s，1H)，2.32(m，1H)，2.35(t，1H)，2.43(d，1H)，2.44(s，6H)，2.45(s，6H)，2.66(d，1H)，2.83(s，6H)，3.16(d，1H)，3.58(s，2H)，5.16(s，1H)，5.41(s，1H)，6.05(s，2H)，7.05(s，1H)，8.58(s，1H)，11.16(s，1H)，12.46(s，1H)
Embodiment 3[S-(4 α, 12a α)]-9-[2-[(N ', N '-diethyl) guanidine radicals] acetamido]-4, the two (dimethylamine of 7-
Base)-1,4,4a, 5,5a, 6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-and four
Benzamide (compound 3) preparation
The preparation method drops into [S-(4 α, 12a α)]-9-[(chloracetyl with reference to embodiment 1 step 3) amido]-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 dihydrochloride 3.1g (5mmol) and 2.3g (15mmol) N '; N '-diethyl guanidinesalt hydrochlorate, react target compound 2.4g, yield: 76.3%.
Molecular formula: C
30H
41N
7O
8Molecular weight: 627.69 mass spectrums (m/e): 629 (M+1)
Ultimate analysis: measured value: C, 57.12%; H, 6.85%; N, 15.87%;
Theoretical value: C, 57.40%; H, 6.58%; N, 15.62%;
1H-NMR(600MHz，CDCl
3)：δ1.02(t，6H)，1.44(t，1H)，1.76(t，1H)，2.28(s，1H)，2.31(s，1H)，2.34(m，1H)，2.36(t，1H)，2.45(d，1H)，2.46(s，6H)，2.60(q，4H)，2.68(d，1H)，2.87(s，6H)，3.15(d，1H)，3.58(s，2H)，5.16(s，1H)，5.41(s，1H)，6.07(s，2H)，7.06(s，1H)，8.55(s，1H)，11.17(s，1H)，12.47(s，1H)
Embodiment 4 [S-(4 α, 12a α)]-9-[2-(N '-the cyclopropyl guanidine radicals) acetamido]-4, the two (dimethylamine of 7-
Base)-1,4,4a, 5,5a, 6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-tetracene methane amide (compound 4) preparation
The preparation method drops into [S-(4 α, 12a α)]-9-[(chloracetyl with reference to embodiment 1 step 3) amido]-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 dihydrochloride 3.1g (5mmol) and 2.0g (15mmol) 1-cyclopropane base guanidinesalt hydrochlorate; react target compound 2.2g, yield: 71.5%.
Molecular formula: C
29H
37N
7O
8Molecular weight: 611.65 mass spectrums (m/e): 613 (M+1)
Ultimate analysis: measured value: C, 56.74%; H, 6.35%; N, 15.87%;
Theoretical value: C, 56.95%; H, 6.10%; N, 16.03%;
1H-NMR(600MHz，CDCl
3)：δ0.32(q，2H)，0.57(q，2H)，1.36(m，1H)，1.45(t，1H)，1.77(t，1H)，2.25(s，1H)，2.26(s，1H)，2.31(s，1H)，2.35(t，1H)，2.36(m，1H)，2.43(d，1H)，2.44(s，6H)，2.69(d，1H)，2.86(s，6H)，3.16(d，1H)，3.57(s，2H)，5.16(s，1H)，5.39(s，1H)，6.09(s，2H)，7.05(s，1H)，8.51(s，1H)，11.15(s，1H)，12.48(s，1H)
Embodiment 5[S-(4 α, 12a α)]-9-[2-(N '-the cyclobutyl guanidine radicals) acetamido]-4, the two (dimethylamine of 7-
Base)-1,4,4a, 5,5a, 6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-tetracene methane amide (compound 5) preparation
The preparation of step 1 1-tetramethylene base guanidine sulfate
In reaction flask, add 1-ammonia tetramethylene 1.5g (24mmol); water 12ml; 0.1mol/L sulfuric acid 48.0ml; cyanamide 3.0g (72.0mmol) is under nitrogen protection; behind 85 ℃ of stirring 48h; add cyanamide 0.6g (12.0mmol) again, continue insulation reaction 24h, filter; filtrate decompression is concentrated into dried; separate out solid, in solid, add methyl alcohol 120ml, after heated and stirred refluxes; add dehydrated alcohol 450ml; (whole process keeps 2～3h), adds dehydrated alcohol-Virahol (3: 1) mixed solution 760ml again, is evaporated to 110ml to steam solvent simultaneously; in room temperature 7～8h; separate out crystallization, filter drying; obtain target product 3.6g, yield: 72.6%.
The preparation of step 2 compound 5
The preparation method drops into [S-(4 α, 12a α)]-9-[(chloracetyl with reference to embodiment 1 step 3) amido]-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 dihydrochloride 3.1g (5mmol) and 3.2g (15mmol) 1-tetramethylene base guanidine sulfate; react target compound 2.4g, yield: 76.8%.
Molecular formula: C
30H
39N
7O
8Molecular weight: 625.67 mass spectrums (m/e): 627 (M+1)
Ultimate analysis: measured value: C, 57.32%; H, 6.45%; N, 15.41%;
Theoretical value: C, 57.59%; H, 6.28%; N, 15.67%;
1H-NMR(600MHz，CDCl
3)：δ1.46(t，1H)，1.78(t，1H)，1.91(m，1H)，2.01(m，1H)，2.06(m，2H)，2.23(s，1H)，2.26(s，1H)，2.31(s，1H)，2.33(m，2H)，2.36(m，1H)，2.37(t，1H)，2.43(s，6H)，2.44(d，1H)，2.71(d，1H)，2.83(s，6H)，3.08(m，1H)，3.17(d，1H)，3.57(s，2H)，5.16(s，1H)，5.37(s，1H)，6.08(s，2H)，7.06(s，1H)，8.48(s，1H)，11.16(s，1H)，12.46(s，1H)
Embodiment 6 [S-(4 α, 12a α)]-9-[2-(N '-the cyclopentyl guanidine radicals) acetamido]-4, the two (dimethylamine of 7-
Base)-1,4,4a, 5,5a, 6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-tetracene methane amide (compound 6) preparation
The preparation method drops into [S-(4 α, 12a α)]-9-[(chloracetyl with reference to embodiment 1 step 3) amido]-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 dihydrochloride 3.1g (5mmol) and 2.4g (15mmol) 1-cyclopentyl guanidinesalt hydrochlorate; react target compound 2.4g, yield: 74.1%.
Molecular formula: C
31H
41N
7O
8Molecular weight: 639.70 mass spectrums (m/e): 641 (M+1)
Ultimate analysis: measured value: C, 57.94%; H, 6.72%; N, 15.12%;
Theoretical value: C, 58.20%; H, 6.46%; N, 15.33%;
1H-NMR(600MHz，CDCl
3)：1.45(m，2H)，1.46(t，1H)，1.55(m，2H)，1.60(m，2H)，1.78(t，1H)，1.85(m，2H)，2.25(s，1H)，2.26(s，1H)，2.33(s，1H)，2.36(m，1H)，2.37(t，1H)，2.43(s，6H)，2.44(d，1H)，2.68(m，1H)，2.71(d，1H)，2.83(s，6H)，3.17(d，1H)，3.57(s，2H)，5.17(s，1H)，5.37(s，1H)，6.08(s，2H)，7.06(s，1H)，8.48(s，1H)，11.16(s，1H)，12.46(s，1H)
Embodiment 7 [S-(4 α, 12a α)]-9-[2-(N '-the cyclohexyl guanidine radicals) acetamido]-4, the two (dimethylamine of 7-
Base)-1,4,4a, 5,5a, 6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-tetracene methane amide (compound 7) preparation
The preparation method drops into [S-(4 α, 12a α)]-9-[(chloracetyl with reference to embodiment 1 step 3) amido]-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 dihydrochloride 3.1g (5mmol) and 2.7g (15mmol) 1-cyclohexyl guanidinesalt hydrochlorate; react target compound 2.3g, yield: 69.1%.
Molecular formula: C
32H
43N
7O
8Molecular weight: 653.73 mass spectrums (m/e): 655 (M+1)
Ultimate analysis: measured value: C, 58.68%; H, 6.81%; N, 14.82%;
Theoretical value: C, 58.79%; H, 6.63%; N, 15.00%;
1H-NMR(600MHz，CDCl
3)：δ1.38(m，2H)，1.43(m，1H)，1.45(m，1H)，1.48(t，1H)，1.49(m，2H)，1.52(m，2H)，1.76(t，1H)，1.77(m，2H)，2.28(s，1H)，2.29(s，1H)，2.35(s，1H)，2.38(t，1H)，2.39(m，1H)，2.41(d，1H)，2.45(s，6H)，2.56(m，1H)，2.70(d，1H)，2.86(s，6H)，3.16(d，1H)，3.60(s，2H)，5.16(s，1H)，5.39(s，1H)，6.07(s，2H)，7.05(s，1H)，8.46(s，1H)，11.19(s，1H)，12.48(s，1H)
Embodiment 8 [S-(4 α, 12a α)]-9-[2-(N '-furans-2-base guanidine radicals) acetamido]-4, the two (dimethylamine of 7-
Base)-1,4,4a, 5,5a, 6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-tetracene methane amide (compound 8) preparation
The preparation of step 1 2-furyl guanidine sulfate
With reference to embodiment 5 steps 1, drop into the amino furans 2.1g (24mmol) of 2-, cyanamide 2.6g (84.0mmol), 0.1mol/L sulfuric acid 48.0ml, react target compound 3.6g, yield: 68.5%.
The preparation of step 2 compound 8
The preparation method drops into [S-(4 α, 12a α)]-9-[(chloracetyl with reference to embodiment 1 step 3) amido]-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 dihydrochloride 3.1g (5mmol) and 3.3g (15mmol) 2-furyl guanidine sulfate; react target compound 2.3g, yield: 69.1%.
Molecular formula: C
30H
35N
7O
9Molecular weight: 637.64 mass spectrums (m/e): 639 (M+1)
Ultimate analysis: measured value: C, 56.30%; H, 5.84%; N, 15.12%;
Theoretical value: C, 56.51%; H, 5.53%; N, 15.38%;
1H-NMR(600MHz，CDCl
3)：δ1.49(t，1H)，1.78(t，1H)，2.32(s，1H)，2.35(s，1H)，2.38(t，1H)，2.39(m，1H)，2.43(d，1H)，2.46(s，6H)，2.71(d，1H)，2.87(s，6H)，3.22(d，1H)，3.61(s，2H)，4.28(s，1H)，5.17(s，1H)，5.39(s，1H)，6.09(s，2H)，6.35(d，1H)，6.39(t，1H)，7.06(s，1H)，7.35(d，1H)，8.49(s，1H)，11.19(s，1H)，12.48(s，1H)
Embodiment 9 [S-(4 α, 12a α)]-9-[2-(N '-thiophene-2-base guanidine radicals) acetamido]-4, the two (dimethylamine of 7-
Base)-1,4,4a, 5,5a, 6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-tetracene methane amide (compound 9) preparation
The preparation of step 1 2-thienyl guanidine sulfate
With reference to embodiment 5 steps 1, drop into 2-aminothiophene 2.1g (24mmol), cyanamide 2.6g (84.0mmol), 0.1mol/L sulfuric acid 48.0ml, react target compound 4.0g, yield: 70.3%.
The preparation of step 2 compound 9
The preparation method drops into [S-(4 α, 12a α)]-9-[(chloracetyl with reference to embodiment 1 step 3) amido]-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 dihydrochloride 3.1g (5mmol) and 3.6g (15mmol) 2-thienyl guanidine sulfate; react target compound 2.0g, yield: 62.5%.
Molecular formula: C
30H
35N
7O
8S molecular weight: 653.71 mass spectrums (m/e): 655 (M+1)
Ultimate analysis: measured value: C, 54.87%; H, 5.64%; N, 14.78%; S, 4.70%
Theoretical value: C, 55.12%; H, 5.40%; N, 15.00%; S, 4.91%
1H-NMR(600MHz，CDCl
3)：δ1.46(t，1H)，1.77(t，1H)，2.31(s，1H)，2.37(t，1H)，2.38(s，1H)，2.42(m，1H)，2.43(s，6H)，2.45(d，1H)，2.69(d，1H)，2.83(s，6H)，3.21(d，1H)，3.62(s，2H)，4.27(s，1H)，5.19(s，1H)，5.41(s，1H)，6.02(d，1H)，6.08(s，2H)，6.34(d，1H)，6.50(t，1H)，7.05(s，1H)，8.47(s，1H)，11.18(s，1H)，12.49(s，1H)
Embodiment 10 [S-(4 α, 12a α)]-9-[2-(N '-the thiazol-2-yl guanidine radicals) acetamido]-4, the two (dimethylamine of 7-
Base)-1,4,4a, 5,5a, 6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-and four
Benzamide (compound 10) preparation
The preparation of step 1 2-thiazolyl guanidine sulfate
With reference to embodiment 5 steps 1, drop into thiazolamine 2.4g (24mmol), cyanamide 2.6g (84.0mmol), 0.1mol/L sulfuric acid 48.0ml, react target compound 3.7g, yield: 65.1%.
The preparation of step 2 compound 10
The preparation method drops into [S-(4 α, 12a α)]-9-[(chloracetyl with reference to embodiment 1 step 3) amido]-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 dihydrochloride 3.1g (5mmol) and 3.6g (15mmol) thiazol-2-yl guanidine sulfate; react target compound 2.5g, yield: 75.8%.
Molecular formula: C
29H
34N
8O
8S molecular weight: 654.69 mass spectrums (m/e): 656 (M+1)
Ultimate analysis: measured value: C, 52.95%; H, 5.44%; N, 15.92%; S, 5.14%
Theoretical value: C, 53.20%; H, 5.23%; N, 17.12%; S, 4.90%
1H-NMR(600MHz，CDCl
3)：δ1.46(t，1H)，1.77(t，1H)，2.31(s，1H)，2.37(t，1H)，2.38(s，1H)，2.40(s，6H)，2.41(d，1H)，2.42(m，1H)，2.66(d，1H)，2.83(s，6H)，3.22(d，1H)，3.61(s，2H)，4.25(s，1H)，5.19(s，1H)，5.41(s，1H)，6.09(s，2H)，6.52(d，1H)，7.02(s，1H)，7.51(d，1H)，8.47(s，1H)，11.18(s，1H)，12.47(s，1H)
Embodiment 11 [S-(4 α, 12a α)]-9-[2-[N '-(4-trifluoromethyl) guanidine radicals] acetamido]-4, the two (dimethylamine of 7-
Base)-1,4,4a, 5,5a, 6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-tetracene methane amide (compound 11) preparation
The preparation of step 1 4-fluoroform phenyl guanidine sulfate
With reference to embodiment 5 steps 1, drop into 4-trifluro toluidine 3.9g (24mmol), cyanamide 2.6g (84.0mmol), 0.1mol/L sulfuric acid 48.0ml, react target compound 5.4g, yield: 74.3%.
The preparation of step 2 compound 11
The preparation method drops into [S-(4 α, 12a α)]-9-[(chloracetyl with reference to embodiment 1 step 3) amido]-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 dihydrochloride 3.1g (5mmol) and 4.5g (15mmol) 4-fluoroform phenyl guanidine sulfate; react target compound 2.5g, yield: 70.2%.
Molecular formula: C
33H
36F
3N
7O
8Molecular weight: 715.68 mass spectrums (m/e): 717 (M+1)
Ultimate analysis: measured value: C, 55.15%; H, 5.34%; N, 13.42%; F, 8.12%
Theoretical value: C, 55.38%; H, 5.07%; N, 13.70%; F, 7.96%
1H-NMR(600MHz，CDCl
3)：δ1.46(t，1H)，1.77(t，1H)，2.31(s，1H)，2.37(t，1H)，2.39(s，1H)，2.41(d，1H)，2.42(m，1H)，2.44(s，6H)，2.66(d，1H)，2.82(s，6H)，3.20(d，1H)，3.61(s，2H)，4.23(s，1H)，5.19(s，1H)，5.41(s，1H)，6.07(s，2H)，6.40(d，2H)，7.01(s，1H)，7.21(d，2H)，8.46(s，1H)，11.17(s，1H)，12.48(s，1H)
Embodiment 12 [S-(4 α, 12a α)]-9-[2-[N '-(4-Trifluoromethoxyphen-l) guanidine radicals] acetamido]-4, the two (dimethylamine of 7-
Base)-1,4,4a, 5,5a, 6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-tetracene methane amide (compound 12) preparation
The preparation of step 1 4-trifluoromethoxy benzaldehyde base guanidine sulfate
With reference to embodiment 5 steps 1, drop into 4-trifluoromethoxy benzaldehyde amine 4.2g (24.0mmol), cyanamide 2.6g (84.0mmol), 0.1mol/L sulfuric acid 48.0ml, react target compound 5.8g, yield: 76.7%.
The preparation of step 2 compound 12
The preparation method drops into [S-(4 α, 12a α)]-9-[(chloracetyl with reference to embodiment 1 step 3) amido]-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 dihydrochloride 3.1g (5mmol) and 4.8g (15mmol) 4-trifluoromethoxy benzaldehyde base guanidine sulfate; react target compound 2.7g, yield: 73.1%.
Molecular formula: C
33H
36F
3N
7O
9Molecular weight: 731.68 mass spectrums (m/e): 733 (M+1)
Ultimate analysis: measured value: C, 53.89%; H, 5.24%; N, 13.12%; F, 7.54%
Theoretical value: C, 54.17%; H, 4.96%; N, 13.40%; F, 7.79%
1H-NMR(600MHz，CDCl
3)：δ1.46(t，1H)，1.77(t，1H)，2.31(s，1H)，2.37(t，1H)，2.38(m，1H)，2.39(s，1H)，2.40(d，1H)，2.44(s，6H)，2.65(d，1H)，2.83(s，6H)，3.18(d，1H)，3.62(s，2H)，4.21(s，1H)，5.18(s，1H)，5.41(s，1H)，6.06(s，2H)，6.33(d，2H)，6.50(d，2H)，7.04(s，1H)，8.48(s，1H)，11.17(s，1H)，12.47(s，1H)
Embodiment 13 [S-(4 α, 12a α)]-9-[2-[N '-(pyridin-3-yl) guanidine radicals] acetamido]-4, the two (dimethylamine of 7-
Base)-1,4,4a, 5,5a, 6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-tetracene methane amide (compound 13) preparation
The preparation method drops into [S-(4 α, 12a α)]-9-[(chloracetyl with reference to embodiment 1 step 3) amido]-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 dihydrochloride 3.1g (5mmol) and 2.6g (15mmol) pyridin-3-yl guanidinesalt hydrochlorate; react target compound 2.4g, yield: 75.1%.
Molecular formula: C
31H
36N
8O
8Molecular weight: 648.67 mass spectrums (m/e): 650 (M+1)
Ultimate analysis: measured value: C, 57.20%; H, 5.85%; N, 17.02%;
Theoretical value: C, 57.40%; H, 5.59%; N, 17.27%;
1H-NMR(600MHz，CDCl
3)：δ1.45(t，1H)，1.78(t，1H)，2.31(s，1H)，2.35(t，1H)，2.38(s，1H)，2.39(m，1H)，2.41(d，1H)，2.45(s，6H)，2.66(d，1H)，2.82(s，6H)，3.17(d，1H)，3.60(s，2H)，4.20(s，1H)，5.16(s，1H)，5.41(s，1H)，6.07(s，2H)，7.25(d，1H)，7.41(t，1H)，8.24(d，1H)，8.46(s，1H)，8.51(s，1H)，7.03(s，1H)，11.19(s，1H)，12.49(s，1H)
Embodiment 14 [S-(4 α, 12a α)]-9-[2-[N '-(pyridine-3-methyl) guanidine radicals] acetamido]-4, the two (dimethylamine of 7-
Base)-1,4,4a, 5,5a, 6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-tetracene methane amide (compound 14) preparation
The preparation method drops into [S-(4 α, 12a α)]-9-[(chloracetyl with reference to embodiment 1 step 3) amido]-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 dihydrochloride 3.1g (5mmol) and 2.8g (15mmol) pyridine-3-methylguanidine hydrochloride; react target compound 2.3g, yield: 69.7%.
Molecular formula: C
32H
38N
8O
8Molecular weight: 662.69 mass spectrums (m/e): 664 (M+1)
Ultimate analysis: measured value: C, 57.78%; H, 6.02%; N, 16.72%;
Theoretical value: C, 58.00%; H, 5.78%; N, 16.91%;
1H-NMR(600MHz，CDCl
3)：δ1.43(t，1H)，1.78(t，1H)，2.31(s，1H)，2.34(s，1H)，2.35(t，1H)，2.36(s，1H)，2.38(m，1H)，2.43(d，1H)，2.46(s，6H)，2.68(d，1H)，2.83(s，6H)，3.16(d，1H)，3.60(s，2H)，3.93(s，2H)，5.14(s，1H)，5.42(s，1H)，6.05(s，2H)，7.06(s，1H)，7.41(t，1H)，7.85(d，1H)，8.42(s，1H)，8.57(d，1H)，8.73(s，1H)，11.17(s，1H)，12.48(s，1H)
Embodiment 15 [S-(4 α, 12a α)]-9-[2-(azetidine-1-base amidino groups) acetamido]-4, the two (dimethylamine of 7-
Base)-1,4,4a, 5,5a, 6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-tetracene methane amide (compound 15) preparation
The preparation of step 1 azetidine-1-amidine vitriol
With reference to embodiment 5 steps 1, drop into ring butylamine 1.4g (24mmol), cyanamide 2.6g (84.0mmol), 0.1mol/L sulfuric acid 48.0ml, reaction makes target compound 3.1g, yield: 65.2%.
The preparation of step 2 compound 15
The preparation method drops into [S-(4 α, 12a α)]-9-[(chloracetyl with reference to embodiment 1 step 3) amido]-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 dihydrochloride 3.1g (5mmol) and 3.0g (15mmol) azetidine-1-base amidine vitriol; react target compound 2.0g, yield: 65.2%.
Molecular formula: C
29H
37N
7O
8Molecular weight: 611.65 mass spectrums (m/e): 613 (M+1)
Ultimate analysis: measured value: C, 56.71%; H, 6.29%; N, 15.81%;
Theoretical value: C, 56.95%; H, 6.10%; N, 16.03%;
1H-NMR(600MHz，CDCl
3)：δ1.43(t，1H)，1.78(t，1H)，2.25(m，2H)，2.31(s，1H)，2.35(t，1H)，2.36(s，1H)，2.38(m，1H)，2.41(s，6H)，2.45(d，1H)，2.69(d，1H)，2.82(s，6H)，3.16(d，1H)，3.53(t，2H)，3.56(t，2H)，3.60(s，2H)，5.16(s，1H)，5.42(s，1H)，6.07(s，2H)，7.06(s，1H)，8.41(s，1H)，11.18(s，1H)，12.49(s，1H)
Embodiment 16 [S-(4 α, 12a α)]-9-[2-(tetramethyleneimine-1-base amidino groups) acetamido]-4, the two (dimethylamine of 7-
Base)-1,4,4a, 5,5a, 6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1, the preparation of 11-dioxo-2-tetracene methane amide
The preparation method drops into [S-(4 α, 12a α)]-9-[(chloracetyl with reference to embodiment 1 step 3) amido]-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 dihydrochloride 3.1g (5mmol) and 2.2g (15mmol) tetramethyleneimine-1-base amidine hydrochloride; react target compound 2.1g, yield: 68.1%.
Molecular formula: C
30H
39N
7O
8Molecular weight: 625.67 mass spectrums (m/e): 627 (M+1)
Ultimate analysis: measured value: C, 57.31%; H, 6.40%; N, 15.52%;
Theoretical value: C, 57.59%; H, 6.28%; N, 15.67%;
1H-NMR(600MHz，CDCl
3)：δ1.43(t，1H)，1.60(m，4H)，1.78(t，1H)，2.31(s，1H)，2.35(t，1H)，2.36(s，1H)，2.38(m，1H)，2.41(s，6H)，2.45(d，1H)，2.69(d，1H)，2.83(t，4H)，2.86(s，6H)，3.17(d，1H)，3.61(s，2H)，5.15(s，1H)，5.42(s，1H)，6.09(s，2H)，7.05(s，1H)，8.43(s，1H)，11.17(s，1H)，12.47(s，1H)
Embodiment 17[S-(4 α, 12a α)]-9-[2-(piperidine-1-base amidino groups) acetamido]-4, the two (dimethylamine of 7-
Base)-1,4,4a, 5,5a, 6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1, the preparation of 11-dioxo 2-tetracene methane amide
The preparation method drops into [S-(4 α, 12a α)]-9-[(chloracetyl with reference to embodiment 1 step 3) amido]-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 dihydrochloride 3.1g (5mmol) and 2.4g (15mmol) piperidine-1-base amidine hydrochloride; react target compound 2.3g, yield: 72.5%.
Molecular formula: C
31H
41N
7O
8Molecular weight: 639.70 mass spectrums (m/e): 641 (M+1) ultimate analysis: measured value: C, 58.00%; H, 6.69%; N, 15.12%;
Theoretical value: C, 58.20%; H, 6.46%; N, 15.33%;
1H-NMR(600MHz，CDCl
3)：δ1.43(t，1H)，1.52(m，2H)，1.56(m，4H)，1.78(t，1H)，2.31(s，1H)，2.35(t，1H)，2.36(s，1H)，2.38(m，1H)，2.41(d，1H)，2.42(s，6H)，2.66(d，1H)，2.75(t，4H)，2.86(s，6H)，3.18(d，1H)，3.61(s，2H)，5.16(s，1H)，5.41(s，1H)，6.07(s，2H)，7.05(s，1H)，8.43(s，1H)，11.16(s，1H)，12.48(s，1H)
Embodiment 18[S-(4 α, 12a α)]-9-[[(3,4,5,6-tetrahydrochysene-2H-1,2-oxazine-2-yl) amidino groups] acetamido]-4, the two (diformazans of 7-
Amido)-1,4,4a, 5,5a, 6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo 2-tetracene methane amide (compound 18) system
Be equipped with
Step 13,4,5,6-tetrahydrochysene-2H-1, the preparation of 2-oxazine-2-amidine vitriol
With reference to embodiment 5 steps 1, drop into 3,4,5,6-tetrahydrochysene-2H-1,2-oxazine 2.1g (24mmol), cyanamide 2.6g (84.0mmol), 0.1mol/L sulfuric acid 48.0ml, reaction makes target compound 3.4g, yield: 62.8%.
The preparation of step 2 compound 18
The preparation method drops into [S-(4 α, 12a α)]-9-[(chloracetyl with reference to embodiment 1 step 3) amido]-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 3.1g (5mmol) and 3.4g (15mmol) 3; 4,5,6-tetrahydrochysene-2H-1; 2-oxazine-2-base amidine vitriol, react target compound 2.1g, yield: 65.6%.
Molecular formula: C
30H
39N
7O
9Molecular weight: 641.67 mass spectrums (m/e): 643 (M+1)
Ultimate analysis: measured value: C, 55.87%; H, 6.39%; N, 15.02%;
Theoretical value: C, 56.15%; H, 6.13%; N, 15.28%;
1H-NMR(600MHz，CDCl
3)：δ1.43(t，1H)，1.46(m，2H)，1.56(m，2H)，1.78(t，1H)，2.31(s，1H)，2.35(t，1H)，2.37(s，1H)，2.38(m，1H)，2.41(d，1H)，2.42(s，6H)，2.63(t，2H)，2.66(d，1H)，2.83(s，6H)，3.16(d，1H)，3.53(t，2H)，3.62(s，2H)，5.18(s，1H)，5.41(s，1H)，6.08(s，2H)，7.06(s，1H)，8.41(s，1H)，11.17(s，1H)，12.47(s，1H)
Embodiment 19 [S-(4 α, 12a α)]-9-[2-(4-methylpiperazine-1-base amidino groups) acetamido]-4, the two (dimethylamine of 7-
Base)-1,4,4a, 5,5a, 6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1, the preparation of 11-dioxo-2-tetracene methane amide
The preparation method drops into [S-(4 α, 12a α)]-9-[(chloracetyl with reference to embodiment 1 step 3) amido]-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 dihydrochloride 3.1g (5mmol) and 2.7g (15mmol) 4-methylpiperazine-1-base amidine hydrochloride; react target compound 2.2g, yield: 68.1%.
Molecular formula: C
31H
42N
8O
8Molecular weight: 654.71 mass spectrums (m/e): 656 (M+1)
Ultimate analysis: measured value: C, 56.62%; H, 6.79%; N, 16.85%;
Theoretical value: C, 56.87%; H, 6.47%; N, 17.11%;
1H-NMR(600MHz，CDCl
3)：δ1.45(t，1H)，1.76(t，1H)，2.26(s，3H)，2.31(s，1H)，2.35(t，1H)，2.36(s，1H)，2.37(m，1H)，2.40(d，1H)，2.43(s，6H)，2.46(t，4H)，2.63(t，4H)，2.65(d，1H)，2.87(s，6H)，3.17(d，1H)，3.60(s，2H)，5.16(s，1H)，5.41(s，1H)，6.05(s，2H)，7.06(s，1H)，8.41(s，1H)，11.19(s，1H)，12.46(s，1H)
Embodiment 20 [S-(4 α, 12a α)]-9-[2-[N '-(diamantane-1-yl) guanidine radicals] acetamido]-4, the two (dimethylamine of 7-
Base)-1,4,4a, 5,5a, 6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1, the preparation of 11-dioxo-2-tetracene methane amide
The preparation method drops into [S-(4 α, 12a α)]-9-[(chloracetyl with reference to embodiment 1 step 3) amido]-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 dihydrochloride 3.1g (5mmol) and 3.5g (15mmol) diamantane-1-base guanidinesalt hydrochlorate; react target compound 2.2g, yield: 63.7%.
Molecular formula: C
36H
47N
7O
8Molecular weight: 705.80 mass spectrums (m/e): 707 (M+1)
Ultimate analysis: measured value: C, 61.03%; H, 6.98%; N, 13.62%;
Theoretical value: C, 61.26%; H, 6.71%; N, 13.89%;
1H-NMR(600MHz，CDCl
3)：δ1.18(t，4H)，1.37(d，1H)，1.41(m，3H)，1.44(t，1H)，1.45(d，1H)，1.56(t，4H)，1.70(d，1H)，1.72(d，1H)，1.75(t，1H)，2.28(s，1H)，2.29(s，1H)，2.32(s，1H)，2.33(m，1H)，2.36(t，1H)，2.42(s，6H)，2.45(d，1H)，2.69(d，1H)，2.83(s，6H)，3.17(d，1H)，3.58(s，2H)，5.13(s，1H)，5.41(s，1H)，6.08(s，2H)，7.01(s，1H)，8.42(s，1H)，11.17(s，1H)，12.46(s，1H)
With reference to above preparation method, also can prepare following compound.
The preparation of embodiment 21 freeze-dried powders
1, prescription:
Prescription 1 prescription 2
Compound 250g compound 14 100g
N.F,USP MANNITOL 300g dextran 500g
An amount of water for injection of water for injection is an amount of
Prepare 1000 altogether and prepare 1000 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 30 ℃ of high-temperature vacuum dryings that are rapidly heated, vacuum degree control is below the 0.1mm mercury column.
The preparation of embodiment 22 aseptic powder injections
1, prescription:
Prescription 1 prescription 2
Compound 9 10g compounds 10 100g
Arginine 990g prepares 1000 altogether
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 23 tablets
1, prescription:
Prescription 1 prescription 2
Compound 625g compound 8 50g
Starch 50g starch 30g
Hydroxypropylcellulose 40g hydroxypropylcellulose 15g
Microcrystalline Cellulose 40g Microcrystalline Cellulose 40g
The 50% aqueous ethanolic solution 40g 2%PVP-K30 aqueous solution 25g of 1%HPMC
Micropowder silica gel 4.0g micropowder silica gel 1.0g
Magnesium Stearate 4.0g Magnesium Stearate 1.5g
Prepare 1000 altogether and prepare 1000 altogether
2, preparation technology: take by weighing raw material and auxiliary material according to prescription, with raw material powder
Broken mistake 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 24 The compounds of this invention gelifying agents
1, prescription
Prescription 1: prescription 2:
Compound 3 10g compounds 13 30g
Carbopol 940 1g carbopols 940 1g
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 3 or compound 13 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.
Claims (6)
1. the compound shown in the general formula (I) or its pharmacy acceptable salt:
Wherein, R
2, R
2', R
3, R
5, R
6, R
6', R
8, R
9", R
10, R
11And R
12The hydrogen of respectively doing for oneself;
R
4, R
4' methyl of respectively doing for oneself;
R
7For-N (CH
3)
2
R
9Be hydrogen or C
1-6The straight or branched alkyl;
R
9' be hydrogen, C
1-6The straight or branched alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, 4-6 unit heteromonocyclic group, the heteromonocyclic group C of 4-6 unit
1-4The straight or branched alkyl, adamantyl or R
9And R
9' coupled nitrogen-atoms formation 4-6 unit heteromonocyclic group,
Described phenyl, 4-6 unit heteromonocyclic group, the heteromonocyclic group C of 4-6 unit
1-4The straight or branched alkyl, adamantyl or R
9And R
9' coupled nitrogen-atoms forms the optional base that further is substituted of 4-6 unit heteromonocyclic group and replace, described substituting group is selected from C
1-4Straight or branched alkyl, C
1-4Straight or branched alkoxyl group or the C that is replaced by fluorine
1-4Straight or branched alkyl or C
1-4The straight or branched alkoxyl group;
N is 0.
2. compound as claimed in claim 1 or its pharmacy acceptable salt:
R
9' be hydrogen, methyl, ethyl, the tertiary butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, furyl, thienyl, thiazolyl, pyridyl, picolyl or adamantyl, described phenyl, furyl, thienyl, thiazolyl, pyridyl, the optional base that further is substituted of picolyl or adamantyl replaces, and substituting group is selected from methyl, trifluoromethyl or trifluoromethoxy;
Or R
9And R
9' coupled nitrogen-atoms formation azetidinyl, pyrrolidyl, piperidyl, oxazinyl or piperazinyl,
The optional base that further is substituted of described azetidinyl, pyrrolidyl, piperidyl, oxazinyl or piperazinyl replaces, and described substituting group is selected from methyl;
N is 0.
3. compound as described below or its pharmacy acceptable salt, described compound is:
[S-(4 α, 12a α)]-9-[2-[(N '-tertiary butyl) guanidine radicals] acetamido]-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-[2-[(N ', N '-dimethyl) guanidine radicals] acetamido]-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-[2-[(N ', N '-diethyl) guanidine radicals] acetamido]-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-[2-(N '-the cyclopropyl guanidine radicals) acetamido]-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-[2-(N '-the cyclobutyl guanidine radicals) acetamido]-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-[2-(N '-the cyclopentyl guanidine radicals) acetamido]-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-[2-(N '-the cyclohexyl guanidine radicals) acetamido]-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-[2-(N '-furans-2-base guanidine radicals) acetamido]-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-[2-(N '-thiophene-2-base guanidine radicals) acetamido]-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-[2-(N '-thiazole-2-guanidine radicals) acetamido]-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-[2-[N '-(4-trifluoromethyl) guanidine radicals] acetamido]-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-[2-[N '-(4-Trifluoromethoxyphen-l) guanidine radicals] acetamido]-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-[2-[N '-(pyridin-3-yl) guanidine radicals] acetamido]-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-[2-[N '-(pyridine-3-methyl) guanidine radicals] acetamido]-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-[2-(azetidine-1-base amidino groups) acetamido]-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-[2-(tetramethyleneimine-1-base amidino groups) acetamido]-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-[2-(piperidine-1-base amidino groups) acetamido]-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-[[(3,4,5,6-tetrahydrochysene-2H-1,2-oxazine-2-yl) amidino groups] acetamido]-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-[2-(4-methylpiperazine-1-base amidino groups) acetamido]-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-[2-[N '-(diamantane-1-yl) guanidine radicals] acetamido]-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.
4. the pharmaceutical composition that comprises each described compound of claim 1～3 or its pharmacy acceptable salt and other active pharmaceutical ingredients.
5. the pharmaceutical composition that comprises each described compound of claim 1～3 or its pharmacy acceptable salt and one or more pharmaceutical carriers and/or thinner is pharmaceutically acceptable arbitrary formulation.
6. treat and/or prevent application in the tetracyclines sensitive diseases medicine as each described compound of claim 1～3 or its pharmacy acceptable salt in preparation.
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| CN1430600A (en) * | 2000-03-31 | 2003-07-16 | 塔夫茨大学信托人 | 7-and 9-carbamate, urea, thiourea, thiocarbamate and heteroaryl-amino substituted tetracycline compounds |
| CN1471509A (en) * | 2000-07-07 | 2004-01-28 | ���Ĵ���ѧ | 9-substituted minocycline compounds |
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|---|---|---|---|---|
| CN1430600A (en) * | 2000-03-31 | 2003-07-16 | 塔夫茨大学信托人 | 7-and 9-carbamate, urea, thiourea, thiocarbamate and heteroaryl-amino substituted tetracycline compounds |
| CN1471509A (en) * | 2000-07-07 | 2004-01-28 | ���Ĵ���ѧ | 9-substituted minocycline compounds |
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Effective date of registration: 20190704 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 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: Guanidinoalkanoylamino substituted tetracycline derivatives Granted publication date: 20111005 License type: Common License Record date: 20191126 |
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