CN101759604A - Guanidyl substitutional tetracycline derivative - Google Patents
Guanidyl substitutional tetracycline derivative Download PDFInfo
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- CN101759604A CN101759604A CN 200910173214 CN200910173214A CN101759604A CN 101759604 A CN101759604 A CN 101759604A CN 200910173214 CN200910173214 CN 200910173214 CN 200910173214 A CN200910173214 A CN 200910173214A CN 101759604 A CN101759604 A CN 101759604A
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Abstract
The invention belongs to the field of medical technology, in particular to a guanidyl substitutional tetracycline derivative shown by a general formula (I), wherein R2, R2', R3, R4, R4', R5, R6, R6', R7, R8, R9, r9', R10, R11 and R12 are defined in an instruction book; the invention further relates to a preparation method of compounds, and medicine composites containing the compounds and the application of the compounds to treating and/or preventing tetracyclines sensitive diseases, particular for the application of anti-infective drugs.
Description
1, technical field
The invention belongs to medical technical field, be specifically related to tetracycline derivant, its pharmacy acceptable salt and isomer thereof that guanidine radicals replaces, the preparation method of these compounds, and these compounds treat and/or prevent the especially purposes of anti-infectives of tetracyclines sensitive diseases being used for preparing.
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 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
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
8Independently be hydrogen separately, 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, aryl, aryl C
1-6Alkyl, aroyl, aryl acyloxy, C
1-6The alkane aroyl, heteromonocyclic group or heteromonocyclic group C
1-6Alkyl;
R
7Be hydrogen, hydroxyl, nitro, cyano group, halogen, amido or-NR
7' R
7";
R
4, R
4', R
7' and R
7" independently be hydrogen separately, 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, aryl, aryl C
1-6Alkyl, heteromonocyclic group, heteromonocyclic group C
1-6Alkyl or prodrug part;
R
9And R
9' independently be hydrogen separately, C
1-6Alkyl, C
1-6Alkoxyl group, C
1-6Alkylthio, amino, C
1-6Alkyl amine group, C
1-6Alkoxy amino, C
1-6Alkylthio amino, C
1-6Alkyl-carbonyl, C
1-6Alkoxy carbonyl, sulfonic group, C
1-6Alkyl sulphonyl, C
1-6Alkyl sulphinyl, C
1-6The alkyl amine group alkylsulfonyl, amido C
1-6Alkyl, amino C
1-6Alkyl acyl, two (C
1-6Alkyl) amido acyl group, second sulfinyl, C
1-6Alkyl sulfonyl amino, two (C
1-6Alkyl) amido alkylsulfonyl, C
1-6Alkyl acyl, C
1-6The alkyl amine group alkylsulfonyl, C
2-6Thiazolinyl, C
2-6Alkynyl, C
3-8Cycloalkyl, phenyl, aryl C
1-4Alkyl, C
4-6Heteromonocyclic group, C
4-6Heteromonocyclic group C
1-4Alkyl, bridged ring base or R
9And R
9' coupled nitrogen-atoms formation heteromonocyclic group,
Described C
1-6Alkyl can further be replaced, and described substituting group is selected from: hydroxyl, carboxyl, amino, halogen, amino C
1-6Alkyl acyl, C
1-6Alkyl amine group, alkylsulfonyl or amino-sulfonyl,
Described C
1-6Alkyl acyl can further be replaced, and described substituting group is selected from: amino or C
1-6Alkyl amine group, two (C
1-6Alkyl) amido or amino C
1-6Alkyl acyl,
Described amino or C
1-6Alkyl amine group can further be substituted, and described substituting group is selected from: hydroxyl, carboxyl, C
1-6Alkyl sulphonyl, C
1-6Alkoxyl group, C
1-6Alkylthio or halogen,
Described aryl, aryl C
1-6Alkyl, C
3-8Cycloalkyl, heteromonocyclic group, heteromonocyclic group C
1-6Alkyl, the coupled nitrogen-atoms of bridged ring base or R9 and R9 ' forms heteromonocyclic group can further be substituted the base replacement, 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, C
1-4Alkyl acyl, 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
1-6Alkyl sulfonyl amino, amino-sulfonyl, C
1-6Alkyl amine group alkylsulfonyl, two (C
1-6Alkyl) amido alkylsulfonyl, amino-sulfonyl C
1-6Alkyl, C
1-6Alkyl amido, C
1-6Alkyl amine group C
1-6Alkyl acyl, two (C
1-6Alkyl) amido C
1-6Alkyl acyl, amino C
1-6Alkyl acyl, amino C
1-6Alkyl acyl C
1-6Alkyl or the C that is replaced by hydroxyl, amino, carboxyl, halogen
1-6Alkyl or C
1-6Alkoxyl group.
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
8Independently be hydrogen separately, hydroxyl or C
1-6Alkyl;
R
7Be hydrogen, halogen or-NR
7' R
7";
R
4, R
4', R
7' and R
7" independently be hydrogen separately, C
1-6Alkyl or C
1-4Alkyl-carbonyl;
R
9And R
9' independently be hydrogen separately, C
1-6Alkyl, amino, C
1-4Alkyl amine group, C
1-4Alkoxy amino, C
1-4Alkylthio amino, C
1-4Alkyl-carbonyl, C
1-4Alkoxy carbonyl, sulfonic group, C
1-4Alkyl sulphonyl, amido C
1-4Alkyl, amino C
1-4Alkyl acyl, two (C
1-4Alkyl) amido C
1-4Alkyl acyl, second sulfinyl, C
1-4Alkyl sulfonyl amino, two (C
1-4Alkyl) amido alkylsulfonyl, C
1-4Alkyl acyl, C
1-4The alkyl amine group alkylsulfonyl, C
2-4Thiazolinyl, C
2-4Alkynyl, C
3-8Cycloalkyl, phenyl, aryl C
1-4Alkyl, C
4-6Heteromonocyclic group, C
4-6Heteromonocyclic group C
1-4Alkyl, bridged ring base or R
9And R
9' coupled nitrogen-atoms formation C
4-6Heteromonocyclic group,
Described C
1-6Alkyl can further be replaced, and described substituting group is selected from: hydroxyl, carboxyl, amino, halogen, amino C
1-4Alkyl acyl, C
1-4Alkyl amine group, alkylsulfonyl or amino-sulfonyl,
Described C
1-4Alkyl acyl can further be replaced, and described substituting group is selected from: amino, C
1-4Alkyl amine group or two (C
1-4Alkyl) amido,
Described amino or C
1-4Alkyl amine group can further be substituted, and described substituting group is selected from: hydroxyl, carboxyl, C
1-4Alkyl sulphonyl, C
1-4Alkoxyl group, C
1-4Alkylthio or halogen,
Described aryl, aryl C
1-4Alkyl, C
3-8Cycloalkyl, C
4-6Heteromonocyclic group, C
4-6Heteromonocyclic group C
1-4Alkyl, bridged ring base or R
9And R
9' coupled nitrogen-atoms formation C
4-6Heteromonocyclic group can further be substituted base and replace, and described substituting group is selected from: hydroxyl, amino, carboxyl, halogen, C
1-6Alkyl, C
1-4Alkyl amine group, C
1-4Alkoxyl group, C
1-4Alkyl acyl, 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
1-4Alkyl sulfonyl amino, amino-sulfonyl, C
1-4Alkyl amine group alkylsulfonyl, amino-sulfonyl C
1-4Alkyl, C
1-4Alkyl amido, C
1-4Alkyl amine group C
1-4Alkyl acyl, two (C
1-4Alkyl) amido C
1-4Alkyl acyl, amino C
1-4Alkyl acyl, amino C
1-4Alkyl acyl C
1-4Alkyl or the C that is replaced by hydroxyl, amino, carboxyl, halogen
1-6Alkyl or C
1-4Alkoxyl group.
More preferably:
Wherein, R
2, R
2', R
3, R
5, R
6, R
6', R
8, 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" independently be hydrogen or C separately
1-4Alkyl;
R
9And R
9' independently be hydrogen separately, C
1-6Alkyl, amino, C
1-4Alkyl amine group, C
1-4Alkoxy amino, C
1-4Alkylthio amino, C
1-4Alkyl-carbonyl, sulfonic group, C
1-4Alkyl sulphonyl, C
1-4Alkyl acyl, C
1-4The alkyl amine group alkylsulfonyl, amido C
1-4Alkyl, amino C
1-4Alkyl acyl, two (C
1-4Alkyl) amido C
1-4Alkyl acyl, second sulfinyl, C
1-4Alkyl sulfonyl amino, two (C
1-4Alkyl) amido alkylsulfonyl, C
2-4Thiazolinyl, C
2-4Alkynyl, C
3-6Cycloalkyl, phenyl, aryl C
1-4Alkyl, C
4-6Heteromonocyclic group, C
4-6Heteromonocyclic group C
1-4Alkyl, bridged ring base or R
9And R
9' coupled nitrogen-atoms formation C
4-6Heteromonocyclic group,
Described C
1-6Alkyl can further be replaced, and described substituting group is selected from: formamyl, C
1-4Alkyl amine group, alkylsulfonyl or amino-sulfonyl,
Described C
1-4Alkyl acyl can further be replaced, and described substituting group is selected from: amino C
1-4Alkyl amine group or two (C
1-4Alkyl) amido
Described amino or C
1-4Alkyl amine group can further be substituted, and described substituting group is selected from: hydroxyl, carboxyl,
1-4Alkyl sulphonyl, C
1-4Alkoxyl group, C
1-4Alkylthio or halogen,
Described aryl, aryl C
1-4Alkyl, C
3-6Cycloalkyl, C
4-6Heteromonocyclic group, C
4-6Heteromonocyclic group C
1-4Alkyl, bridged ring base or R
9And R
9' coupled nitrogen-atoms formation C
4-6Heteromonocyclic group can further be substituted base and replace, and described substituting group is selected from: C
1-4Alkyl, C
1-4Alkoxyl group, halogen, amino, amino C
1-4Alkyl, carboxyl, C
1-4Alkyl amine group, C
1-4Alkyl acyl, C
1-4Alkyl carbonyl oxy, C
1-4Carbalkoxy, amino-sulfonyl or the C that is replaced by hydroxyl, amino, carboxyl, halogen
1-4Alkyl or C
1-4Alkoxyl group.
More preferably:
Wherein, R
2, R
2', R
3, R
5, R
6, R
6', R
8, 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" methyl of respectively doing for oneself;
R
9And R
9' independently be hydrogen separately, methyl, ethyl, propyl group; sec.-propyl, the tertiary butyl, amido methyl, formamyl; the methylamino-methyl, dimethylamino formyl radical, ethanoyl, ethylamino alkylsulfonyl; the dimethylamino alkylsulfonyl, aminosulfonyl methyl, sulfonyloxy methyl amino, sulfonic acid methyl; sulfonic group, third alkylsulfonyl, second sulfinyl, isopropyl carbonyl; the difluoro methylamino-, carboxyl methylamino-, hydroxyl third amino, oxyethyl group amino; methylthio group amino, allyl group, propargyl, cyclopropyl; cyclobutyl, cyclopentyl, cyclohexyl, phenyl; benzyl, furyl, thienyl, thiazolyl; isothiazolyl, pyridyl, picolyl, pyrimidyl oxazinyl, dioxane base, dioxolanyl ， oxazolyl isoxazolyl, isothiazolyl, tetrahydrofuran base, tetrahydro-thienyl; imidazolyl, 1H-imidazolyl, pyrazolyl, 1H-pyrazolyl; the imidazolidine base, Pyrrolidine base, adamantyl or R
9And R
9' coupled nitrogen-atoms formation azetidinyl, pyrrolidyl, piperidyl, morpholinyl, oxazinyl or piperazinyl,
Described 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 and can further be substituted base and replace, described substituting group is selected from: methyl, ethyl, methoxyl group, trifluoromethyl, trifluoromethoxy, aminomethyl, methylol, chlorine atom, amino, methylamino, aminomethyl, carboxyl, ethanoyl, carboxymethyl, methoxycarbonyl or amino-sulfonyl.
More preferably:
Wherein, R
2, R
2', R
3, R
5, R
6, R
6', R
8, 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" methyl of respectively doing for oneself;
R
9And R
9' independently be hydrogen separately, methyl, ethyl, propyl group, sec.-propyl; the tertiary butyl, amido methyl, formamyl, N, N dimethylamine base formyl radical; N-ethyl amido alkylsulfonyl, N, N dimethylamine alkylsulfonyl, aminosulfonyl methyl, sulfonyloxy methyl amino; sulfonic acid methyl, sulfonic group, third alkylsulfonyl, second sulfinyl, isopropyl carbonyl; the difluoro methylamino-, carboxyl methylamino-, hydroxyl third amino, oxyethyl group amino, methylthio group amino; allyl group, propargyl, cyclopropyl, cyclobutyl, cyclopentyl; cyclohexyl, phenyl, phenmethyl, furyl; thienyl, thiazolyl, pyridyl, picolyl; pyrimidyl ， oxazinyl, 1,3-dioxane base; 1,3-dioxolanyl ， oxazolyl ， isoxazolyl; isothiazolyl, tetrahydrofuran base, tetrahydro-thienyl, 1H-imidazolyl; the 1H-pyrazolyl, imidazolidine base, Pyrrolidine base, adamantyl or R
9And R
9' coupled nitrogen-atoms formation azetidinyl, pyrrolidyl, piperidyl, morpholinyl, oxazinyl or piperazinyl,
Described cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, furyl, thienyl, thiazolyl, pyridyl, picolyl, adamantyl or R
9And R
9' coupled nitrogen-atoms formation azetidinyl, pyrrolidyl, piperidyl, oxazinyl, 3; 4; 5; 6-tetrahydrochysene-2H-1; 2-oxazine or piperazinyl can further be substituted base and replace, and described substituting group is selected from: methyl, ethyl, methoxyl group, trifluoromethyl, trifluoromethoxy, aminomethyl, methylol, chlorine atom, amino, methylamino, aminomethyl, carboxyl, ethanoyl, carboxymethyl, methoxycarbonyl or amino-sulfonyl.
Further be preferably:
Wherein, R
2, R
2', R
3, R
5, R
6, R
6', R
8, 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" methyl of respectively doing for oneself;
R
9And R
9' independently be hydrogen separately, methyl, ethyl, the tertiary butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, furyl, thienyl, thiazolyl, pyridyl, picolyl, adamantyl or R
9And R
9' coupled nitrogen-atoms formation azetidinyl, pyrrolidyl, piperidyl, 3,4,5,6-tetrahydrochysene-2H-1,2-oxazinyl or piperazinyl,
Described cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, furyl, thienyl, thiazolyl, pyridyl, picolyl, adamantyl or R
9And R
9' coupled nitrogen-atoms formation azetidinyl, pyrrolidyl, piperidyl, 3,4,5,6-tetrahydrochysene-2H-1,2-oxazinyl or piperazinyl can further be substituted base and replace, and described substituting group is selected from methyl, trifluoromethyl or trifluoromethoxy.
Be preferably especially:
Term " C
1-6Alkyl " hydrocarbon that refers to contain 1～6 carbon atom partly removes the alkyl of a hydrogen atom deutero-straight or branched; as methyl; ethyl; n-propyl; sec.-propyl; normal-butyl, isobutyl-, sec-butyl, the tertiary butyl, n-pentyl, isopentyl, the 2-methyl butyl, neo-pentyl, the 1-ethyl propyl, n-hexyl, isohexyl, the 4-methyl amyl, the 3-methyl amyl, the 2-methyl amyl, the 1-methyl amyl, 3, the 3-dimethylbutyl, 2, the 2-dimethylbutyl, 1, the 1-dimethylbutyl, 1, the 2-dimethylbutyl, 1, the 3-dimethylbutyl, 2, the 3-dimethylbutyl, the 2-ethyl-butyl, 1-methyl-2-methyl-propyl etc.Term " C
1-4Alkyl " refer to the specific examples that contains 1～4 carbon atom in the above-mentioned example.
Term " C
3-8Cycloalkyl " refer to contain the cyclic alkyl of 3～8 carbon atoms, as cyclopropyl, cyclobutyl, 1-methyl cyclobutyl, cyclopentyl, cyclohexyl etc.Term " C
3-6Cycloalkyl " refer to the specific examples that contains 3～6 carbon atoms in the above-mentioned example.
Term " C
1-6Alkoxyl group " refer to term " C
1-6Alkyl " group that is connected with other structures by Sauerstoffatom, as term " C
1-6Alkyl " the specific examples that is connected with other structures with Sauerstoffatom of specific examples.
Term " C
1-6Alkylthio " be meant the group that the carbon atom on the moieties is replaced by sulphur atom, described example is meant term " C
1-6Alkyl " specific examples in the group that replace to be formed by sulphur atom of carbon atom.
Term " C
2-6Thiazolinyl " be meant that length and abovementioned alkyl are similar; 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.Term " C
2-4Thiazolinyl " refer to the specific examples that contains 2～4 carbon atoms in the above-mentioned example.
Term " C
2-6Alkynyl " be meant that length and abovementioned alkyl are similar, but comprise 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.Term " C
2-4Alkynyl " refer to the specific examples that contains 2～4 carbon atoms in the above-mentioned example.
Term " aryl " is meant monocycle or condensed aromatic group, as phenyl, naphthyl, phenanthryl etc.
Term " heteromonocyclic group " is meant and contains 1 heteroatomic 3～8 yuan of cyclic group at least, comprise: 3～8 yuan of saturated or undersaturated assorted monocycles that contain 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, the 3-triazole, 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, the 5-triazine, 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 3～8 yuan of saturated or undersaturated assorted monocycles of 1-2 Sauerstoffatom or sulphur atom 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 3～8 yuan of saturated or undersaturated assorted monocycles of 1-2 Sauerstoffatom or sulphur atom and 1-3 nitrogen-atoms 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.Term " 4～6 yuan of saturated or undersaturated heteromonocyclic groups ", " saturated or undersaturated 5～6 yuan of heteromonocyclic groups " refer to the specific examples that contains 4～6 carbon atoms, 5～6 carbon atoms in the above-mentioned example.
Term " heteroatoms " comprises any element atom beyond carbon or the hydrogen, preferred nitrogen, oxygen, sulphur, phosphorus.
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 " in " halo " be meant C
1-6One or more hydrogen atom on the carbon atom in the alkyl is replaced by halogen atom.
The present invention also provides the preparation method of above-claimed cpd, reaction equation:
Reactions steps:
The preparation of step 1 formula II compound
In reaction flask, drop into raw material 1, trifluoroacetic acid, add methylol-benzyl carbamate (HMBC) after the stirring and dissolving, stirring reaction under the room temperature, reaction is finished, filter reaction mixture, filtrate decompression concentrates to remove trifluoroacetic acid, after residuum is dissolved in an amount of ethanol, splash in the ether, separate out solid after the stirring, gained solid purifying gets formula II compound.
The preparation of step 2 formula I compound
In reaction flask, add HCl-ethanol, raw material 3, in stirring at room, add dissolve with ethanol again after removing solvent under reduced pressure, slowly add formula II compound then in batches, reflux to stir and spend the night, reaction solution removes most of solvent under reduced pressure, drips ether down in ice bath then, separates 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
10, R
11And R
12The group such as the preamble of representative define.
The claimed pharmaceutical composition that comprises arbitrary compound recited above and one or more pharmaceutical carriers and/or thinner of the present invention is for clinically or pharmaceutically acceptable arbitrary formulation.Be applied to the patient who needs this treatment with oral, parenteral, rectum, through modes such as lung or topical administrations.When being used for oral administration, can be made into conventional solid preparation, as tablet, capsule, pill, granule etc.; Also can be made into oral liquid, as oral solution, oral suspensions, syrup etc.When making oral preparations, can add suitable weighting agent, tackiness agent, disintegrating agent, lubricant etc.When being used for administered parenterally, can be made into injection, comprise injection liquid, injectable sterile powder and concentrated solution for injection.When making injection, can adopt the ordinary method production in the existing pharmacy field, during the preparation injection, can not add additives, also can add suitable additives according to the character of medicine.When being used for rectal administration, can be made into suppository etc.Be used for when the lung administration, can be made into inhalation or sprays etc.During topical administration, can also make external solid, semi-solid preparations such as ointment, ointment, gelifying agent, powder, rubber-emplastrum, cataplasma, patch.
The tetracycline derivant that the further claimed guanidine radicals of the present invention replaces and the pharmaceutical composition of other active pharmaceutical ingredients, described other active pharmaceutical ingredients comprises trimethoprim.
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 invention still further relates to and have tetracycline derivant that guanidine radicals replaces and treat and/or prevent the especially application in the anti-infectives of tetracyclines sensitive diseases in preparation.Tetracycline derivant has a broad antifungal spectrum with guanidine radicals replacement 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 that giving the present invention has the disease that tetracycline compound that guanidine radicals replaces can treat, prevents or improve.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.
Tetracycline derivant with guanidine radicals replacement 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.
Of the present invention to have a tetracycline derivant side effect that guanidine radicals replaces 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 that guanidine radicals of the present invention replaces by in-vitro antibacterial experiment, but this should be interpreted as that the tetracycline derivant that guanidine radicals of the present invention replaces 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, vancomycin: 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-[N '-tertiary butyl guanidine radicals] methyl-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)
Step 1 [S-(4 α, 12a α)]-9-amino methyl-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, drop into [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 4.6g (10mmol) adds trifluoroacetic acid 100ml, and stirring and dissolving adds 3.6g (20mmol) methylol-benzyl carbamate (HMBC) then, stirring reaction 2d under the room temperature, reaction is finished, filter reaction mixture, and filtrate decompression concentrates to remove trifluoroacetic acid, after residuum is dissolved in an amount of ethanol, splash in the 1L ether, separate out solid behind the stirring 2h, the gained solid can be with preparing the HPLC purifying.Get solid chemical compound 2.0g, yield: 41%.
The preparation of step 2 compound 1
The HCl-ethanol 50ml of adding 10% in reaction flask, tertiary butyl cyanamide 4.9g (50mmol) is in stirring at room 2h, add the 100ml dissolve with ethanol again after removing solvent under reduced pressure, slowly add [S-(4 α, 12a α)]-9-amino methyl-4 then in batches, 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 12.2g (25mmol) refluxes to stir and spends the night, reaction solution removes most of solvent under reduced pressure, under ice bath, in the ether of Dropwise 5 00ml, separate out solid then, filter and drying, get target compound 7.4g, yield: 50.8%.
Molecular formula: C
29H
40N
6O
7Molecular weight: 584.66 mass spectrums (m/e): 585 (M+1)
Ultimate analysis: theoretical value: C, 59.57%; H, 6.90%; N, 14.37%
Measured value: C, 59.45%; H, 7.01%; N, 14.30%
1H-NMR(600MHz，CDCl
3)：δ1.12(s，9H)，1.44(t，1H)，1.75(t，1H)，2.11(s，1H)，2.16(s，1H)，2.23(s，1H)，2.32(t，1H)，2.34(m，1H)，2.43(s，6H)，2.44(d，1H)，2.65(d，1H)，2.83(s，6H)，3.19(d，1H)，3.92(s，2H)，5.14(s，1H)，5.41(s，1H)，6.05(s，2H)，6.39(s，1H)，11.18(s，1H)，12.45(s，1H)
Embodiment 2 [S-(4 α, 12a α)]-9-[N '-(N, N-dimethyl) guanidine radicals] methyl-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 (compound 2) preparation
With reference to embodiment 1 step 2, throw [S-(4 α, 12a α)]-9-amino methyl-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 12.2g (25mmol), N, N-N-Cyanodimethylamine 3.5g (50mmol).Get target compound 6.9g, yield: 50.0%.
Molecular formula: C
27H
36N
6O
7Molecular weight: 556.61 mass spectrums (m/e): 557 (M+1)
Ultimate analysis: theoretical value: C, 58.26%; H, 6.52%; N, 15.10%
Measured value: C, 58.15%; H, 6.65%; N, 15.01%
1H-NMR(600MHz，CDCl
3)：δ1.45(t，1H)，1.77(t，1H)，2.12(s，1H)，2.28(s，1H)，2.32(t，1H)，2.34(s，6H)，2.38(m，1H)，2.45(s，6H)，2.48(d，1H)，2.71(d，1H)，2.83(s，6H)，3.27(d，1H)，4.03(s，2H)，5.14(s，1H)，5.43(s，1H)，6.05(s，2H)，6.42(s，1H)，11.17(s，1H)，12.51(s，1H)
Embodiment 3 [S-(4 α, 12a α)]-9-[N '-(N, N-diethyl) guanidine radicals] methyl-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 (compound 3) preparation
With reference to embodiment 1 step 2, throw [S-(4 α, 12a α)]-9-amino methyl-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 12.2g (25mmol), N, N-diethyl cyanamide 4.9g (50mmol).Get target compound 7.4g, yield: 50.5%.
Molecular formula: C
29H
40N
6O
7Molecular weight: 584.66 mass spectrums (m/e): 585 (M+1)
Ultimate analysis: theoretical value: C, 59.57%; H, 6.90%; N, 14.37%
Measured value: C, 59.47%; H, 7.00%; N, 14.25%
1H-NMR(600MHz，CDCl
3)：δ1.03(t，6H)，1.46(t，1H)，1.75(t，1H)，2.08(s，1H)，2.26(s，1H)，2.29(s，6H)，2.31(t，1H)，2.36(m，1H)，2.46(d，1H)，2.57(q，4H)，2.70(d，1H)，2.83(s，6H)，3.25(d，1H)，4.02(s，2H)，5.14(s，1H)，5.41(s，1H)，6.07(s，2H)，6.52(s，1H)，11.17(s，1H)，12.46(s，1H)
Embodiment 4 [S-(4 α, 12a α)]-9-[N '-(furans-2-yl) guanidine radicals] methyl-4, two (dimethylin)-1,4 of 7-, 4a, 5,5a, 6,11,12a-eight
Hydrogen-3,10,12,12a-tetrahydroxy-1, the preparation of 11-dioxo 2-tetracene methane amide (compound 4)
The preparation of step 1 2-(cyano group) amido furans
Throw 2-amino furans 4.2g (50mmol) in reaction flask, add acetonitrile 100ml, triethylamine 14ml (100mmol) stirs after 5 minutes and adds 5.3g (50mmol) cyanogen bromide, stirring reaction 2d under the room temperature, and adding NaHCO is finished in reaction
3Saturated solution is to neutral, and with 100ml ethyl acetate extraction twice, ethyl acetate layer concentrated solution upper prop, getting product is 4.4g, yield: 82%.
The preparation of step 2 compound 4
With reference to embodiment 1 step 2, throw [S-(4 α, 12a α)]-9-amino methyl-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 12.2g (25mmol), 2-(cyano group) amido furans 5.4g (50mmol).Get target compound 7.4g, yield: 50.0%.
Molecular formula: C
29H
34N
6O
8Molecular weight: 594.62 mass spectrums (m/e): 595 (M+1)
Ultimate analysis: theoretical value: C, 58.58%; H, 5.76%; N, 14.13%
Measured value: C, 58.49%; H, 5.86%; N, 14.03%
1H-NMR(600MHz，CDCl
3)：δ1.45(t，1H)，1.74(t，1H)，2.08(s，1H)，2.26(s，1H)，2.29(s，6H)，2.31(t，1H)，2.36(m，1H)，2.44(d，1H)，2.71(d，1H)，2.86(s，6H)，3.25(d，1H)，3.93(s，2H)，4.02(s，1H)，5.14(s，1H)，5.41(s，1H)，6.07(s，2H)，6.38(d，1H)，6.41(t，1H)，6.52(s，1H)，7.42(d，1H)，11.17(s，1H)，12.46(s，1H)
Embodiment 5 [S-(4 α, 12a α)]-9-[N '-(thiophene 2-yl) guanidine radicals] methyl-4, two (dimethylin)-1,4 of 7-, 4a, 5,5a, 6,11,12a-eight
Hydrogen-3,10,12,12a-tetrahydroxy-1, the preparation of 11-dioxo-2-tetracene methane amide (compound 5)
The preparation of step 1 2-(cyano group) amido thiophene
With reference to embodiment 4 steps 1, throw 2-aminothiophene 4.9g (50mmol), cyanogen bromide 5.3g (50mmol), getting product is 4.6g, yield: 74.2%.
The preparation of step 2 compound 5
With reference to embodiment 1 step 2, throw [S-(4 α, 12a α)]-9-amino methyl-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 12.2g (25mmol), 2-(cyano group) amido thiophene 6.2g (50mmol).Get target compound 7.6g, yield: 49.8%.
Molecular formula: C
29H
34N
6O
7S molecular weight: 610.68 mass spectrums (m/e): 611 (M+1)
Ultimate analysis: theoretical value: C, 57.04%; H, 5.61%; N, 13.76%
Measured value: C, 56.95%; H, 5.75%; N, 13.67%
1H-NMR(600MHz，CDCl
3)：δ1.44(t，1H)，1.75(t，1H)，2.06(s，1H)，2.20(s，1H)，2.25(s，6H)，2.29(t，1H)，2.35(m，1H)，2.46(d，1H)，2.73(d，1H)，2.87(s，6H)，3.27(d，1H)，3.92(s，2H)，4.03(s，1H)，5.15(s，1H)，5.40(s，1H)，6.03(d，1H)，6.06(s，2H)，6.37(d，1H)，6.48(s，1H)，6.52(t，1H)，11.15(s，1H)，12.49(s，1H)
Embodiment 6 [S-(4 α, 12a α)]-9-[N '-(thiazole 2-yl) guanidine radicals] methyl-4, two (dimethylin)-1,4 of 7-, 4a, 5,5a, 6,11,12a-eight
Hydrogen-3,10,12,12a-tetrahydroxy-1, the preparation of 11-dioxo-2-tetracene methane amide (compound 6)
The preparation of step 1 2-(cyano group) amido thiazole
With reference to embodiment 4 steps 1, throw thiazolamine 5.0g (50mmol), cyanogen bromide 5.3g (50mmol), getting target product is 4.6g, yield: 73.8%.
The preparation of step 2 compound 6
With reference to embodiment 1 step 2, throw [S-(4 α, 12a α)]-9-amino methyl-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 12.2g (25mmol), 2-(cyano group) amido thiazole 6.3g (50mmol).Get target compound 7.6g, yield: 49.5%.
Molecular formula: C
28H
33N
7O
7S molecular weight: 611.67 mass spectrums (m/e): 612 (M+1)
Ultimate analysis: theoretical value: C, 54.98%; H, 5.44%; N, 16.03%
Measured value: C, 54.89%; H, 5.56%; N, 15.95%
1H-NMR(600MHz，CDCl
3)：δ1.46(t，1H)，1.75(t，1H)，2.05(s，1H)，2.20(s，1H)，2.28(s，6H)，2.29(t，1H)，2.37(m，1H)，2.46(d，1H)，2.71(d，1H)，2.86(s，6H)，3.25(d，1H)，3.92(s，2H)，4.03(s，1H)，5.16(s，1H)，5.38(s，1H)，6.05(s，2H)，6.48(s，1H)，6.57(d，1H)，7.55(d，1H)，11.17(s，1H)，12.50(s，1H)
Embodiment 7 [S-(4 α, 12a α)]-9-[N '-(4-trifluoromethyl) guanidine radicals] methyl-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) system
Be equipped with
The preparation of step 1 4-Trifluoromethyl-1-(cyano group) amido benzene
With reference to embodiment 4 steps 1, throw 4-5-trifluoromethylaniline 8.0g (50mmol), cyanogen bromide 5.3g (50mmol), getting product is 6.9g, yield: 74.5%.
The preparation of step 2 compound 7
With reference to embodiment 1 step 2, throw [S-(4 α, 12a α)]-9-amino methyl-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 12.2g (25mmol), 4-Trifluoromethyl-1-(cyano group) amido benzene 9.3g (50mmol).Get target compound 8.3g, yield: 49.6%.
Molecular formula: C
32H
35F
3N
6O
7Molecular weight: 672.65 mass spectrums (m/e): 673 (M+1)
Ultimate analysis: theoretical value: C, 57.14%; H, 5.24%; N, 12.49%; F, 8.47%
Measured value: C, 57.05%; H, 5.35%; N, 12.39%; F, 8.38%
1H-NMR(600MHz，CDCl
3)：δ1.46(t，1H)，1.76(t，1H)，2.03(s，1H)，2.21(s，1H)，2.29(s，6H)，2.31(t，1H)，2.38(m，1H)，2.46(d，1H)，2.70(d，1H)，2.86(s，6H)，3.31(d，1H)，3.91(s，2H)，4.05(s，1H)，5.18(s，1H)，5.36(s，1H)，6.08(s，2H)，6.37(d，2H)，6.47(s，1H)，7.25(d，2H)，11.19(s，1H)，12.49(s，1H)
Embodiment 8 [S-(4 α, 12a α)]-9-[N '-(4-trifluoromethoxy benzaldehyde base) guanidine radicals] methyl-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 4-trifluoromethoxy-1-(cyano group) amido benzene
With reference to embodiment 4 steps 1, throw 4-trifluoro-methoxyaniline 8.8g (50mmol), cyanogen bromide 5.3g (50mmol), getting product is 7.6g, yield: 75.8%.
The preparation of step 2 compound 8
With reference to embodiment 1 step 2, throw [S-(4 α, 12a α)]-9-amino methyl-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 12.2g (25mmol), 4-trifluoromethoxy-1-(cyano group) amido benzene 10.1g (50mmol).Get target compound 8.6g, yield: 50.0%.
Molecular formula: C
32H
35F
3N
6O
8Molecular weight: 688.65 mass spectrums (m/e): 689 (M+1)
Ultimate analysis: theoretical value: C, 55.81%; H, 5.12%; N, 12.20%; F, 8.28%
Measured value: C, 55.73%; H, 5.25%; N, 12.12%; F, 8.19%
1H-NMR(600MHz，CDCl
3)：δ1.46(t，1H)，1.73(t，1H)，2.01(s，1H)，2.25(s，1H)，2.27(s，6H)，2.29(t，1H)，2.36(m，1H)，2.46(d，1H)，2.67(d，1H)，2.85(s，6H)，3.35(d，1H)，3.93(s，2H)，4.07(s，1H)，5.15(s，1H)，5.34(s，1H)，6.09(s，2H)，6.38(d，2H)，6.45(s，1H)，6.55(d，2H)，11.17(s，1H)，12.47(s，1H)
Embodiment 9 [S-(4 α, 12a α)]-9-[N '-(pyridin-3-yl) guanidine radicals] methyl-4, two (dimethylin)-1,4 of 7-, 4a, 5,5a, 6,11,12a-eight
Hydrogen-3,10,12,12a-tetrahydroxy-1, the preparation of 11-dioxo-2-tetracene methane amide (compound 9)
The preparation of step 1 3-(cyano group) amido pyridine
With reference to embodiment 4 steps 1, throw 3-pyridine amine 4.7g (50mmol), cyanogen bromide 5.3g (50mmol), getting product is 4.4g, yield: 73.6%.
The preparation of step 2 compound 9
With reference to embodiment 1 step 2, throw [S-(4 α, 12a α)]-9-amino methyl-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 12.2g (25mmol), 3-(cyano group) amido pyridine 5.9g (50mmol).Get target compound 7.5g, yield: 49.8%.
Molecular formula: C
30H
35N
7O
7Molecular weight: 605.64 mass spectrums (m/e): 606 (M+1)
Ultimate analysis: theoretical value: C, 59.49%; H, 5.82%; N, 16.19%
Measured value: C, 59.40%; H, 5.93%; N, 16.09%
1H-NMR(600MHz，CDCl
3)：δ1.46(t，1H)，1.72(t，1H)，2.01(s，1H)，2.26(s，1H)，2.28(t，1H)，2.29(s，6H)，2.37(m，1H)，2.47(d，1H)，2.66(d，1H)，2.83(s，6H)，3.36(d，1H)，3.91(s，2H)，4.07(s，1H)，5.15(s，1H)，5.37(s，1H)，6.05(s，2H)，6.46(s，1H)，7.25(d，1H)，7.41(t，1H)，8.25(d，1H)，8.55(s，1H)，11.15(s，1H)，12.48(s，1H)
Embodiment 10 [S-(4 α, 12a α)]-9-[N '-[(pyridin-3-yl) methyl] guanidine radicals] methyl-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 10) preparation
The preparation of step 1 3-(cyano group) aminomethyl pyridine
With reference to embodiment 4 steps 1, throw 3-aminomethyl-pyridine 5.4g (50mmol), cyanogen bromide 5.3g (50mmol), getting product is 4.9g, yield: 74.2%.
The preparation of step 2 compound 10
With reference to embodiment 1 step 2, throw [S-(4 α, 12a α)]-9-amino methyl-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 12.2g (25mmol), 3-(cyano group) aminomethyl pyridine 6.6g (50mmol).Get target compound 7.5g, yield: 48.8%.
Molecular formula: C
31H
37N
7O
7Molecular weight: 619.67 mass spectrums (m/e): 620 (M+1)
Ultimate analysis: theoretical value: C, 60.09%; H, 6.02%; N, 15.82%
Measured value: C, 60.00%; H, 6.13%; N, 15.74%
1H-NMR(600MHz，CDCl
3)：δ1.46(t，1H)，1.76(t，1H)，2.01(s，1H)，2.05(s，1H)，2.25(s，1H)，2.27(t，1H)，2.29(s，6H)，2.37(m，1H)，2.46(d，1H)，2.69(d，1H)，2.84(s，6H)，3.39(d，1H)，3.92(s，2H)，3.95(s，2H)，5.15(s，1H)，5.36(s，1H)，6.07(s，2H)，6.47(s，1H)，7.41(t，1H)，7.85(d，1H)，8.55(d，1H)，8.78(s，1H)，11.15(s，1H)，12.48(s，1H)
Embodiment 11 [S-(4 α, 12a α)]-9-[N '-(cyclopropyl-1-yl) guanidine radicals] methyl-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 (compound 11) preparation
The preparation of step 1 1-(cyano group) amido cyclopropane
With reference to embodiment 4 steps 1, the propylamine 2.8g (50mmol) that commits suicide by hanging, cyanogen bromide 5.3g (50mmol), getting product is 2.9g, yield: 70%.
The preparation of step 2 compound 11
With reference to embodiment 1 step 2, throw [S-(4 α, 12a α)]-9-amino methyl-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 12.2g (25mmol), 1-(cyano group) amido cyclopropane 4.1g (50mmol).Get target compound 7.0g, yield: 49.3%.
Molecular formula: C
28H
36N
6O
7Molecular weight: 568.62 mass spectrums (m/e): 569 (M+1)
Ultimate analysis: theoretical value: C, 59.14%; H, 6.38%; N, 14.78% measured value: C, 59.05%; H, 6.49%; N, 14.65%
1H-NMR(600MHz，CDCl
3)：δ0.45(d，4H)，1.37(m，1H)，1.46(t，1H)，1.71(t，1H)，2.03(s，1H)，2.05(s，1H)，2.23(s，1H)，2.26(s，6H)，2.27(t，1H)，2.37(m，1H)，2.46(d，1H)，2.68(d，1H)，2.86(s，6H)，3.37(d，1H)，3.93(s，2H)，5.17(s，1H)，5.38(s，1H)，6.08(s，2H)，6.47(s，1H)，11.19(s，1H)，12.46(s，1H)
Embodiment 12 [S-(4 α, 12a α)]-9-[N '-(cyclobutyl-1-yl) guanidine radicals] methyl-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) system
Be equipped with
The preparation of step 1 1-(cyano group) amido tetramethylene
With reference to embodiment 4 steps 1, the butylamine 3.5g (50mmol) that commits suicide by hanging, cyanogen bromide 5.3g (50mmol), getting product is 3.5g, yield: 72.6%.
The preparation of step 2 compound 12
With reference to embodiment 1 step 2, throw [S-(4 α, 12a α)]-9-amino methyl-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 12.2g (25mmol), 1-(cyano group) amido tetramethylene 4.8g (50mmol).Get target compound 7.2g, yield: 49.5%.
Molecular formula: C
29H
38N
6O
7Molecular weight: 582.65 mass spectrums (m/e): 583 (M+1)
Ultimate analysis: theoretical value: C, 59.78%; H, 6.57%; N, 14.42%
Measured value: C, 59.65%; H, 6.68%; N, 14.31%
1H-NMR(600MHz，CDCl
3)：δ1.46(t，1H)，1.73(t，1H)，1.95(m，2H)，2.02(s，1H)，2.06(s，1H)，2.18(q，4H)，2.26(t，1H)，2.28(s，6H)，2.29(s，1H)，2.39(m，1H)，2.46(d，1H)，2.75(d，1H)，2.87(s，6H)，3.03(m，1H)，3.31(d，1H)，3.95(s，2H)，5.13(s，1H)，5.42(s，1H)，6.05(s，2H)，6.46(s，1H)，11.28(s，1H)，12.42(s，1H)
Embodiment 13 [S-(4 α, 12a α)]-9-[N '-cyclopentyl guanidine radicals] methyl-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)
The preparation of step 1 1-(cyano group) amido pentamethylene
With reference to embodiment 4 steps 1, the amylamine 4.3g (50mmol) that commits suicide by hanging, cyanogen bromide 5.3g (50mmol), getting product is 4.1g, yield: 74.5%.
The preparation of step 2 compound 13
With reference to embodiment 1 step 2, throw [S-(4 α, 12a α)]-9-amino methyl-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 12.2g (25mmol), 1-(cyano group) amido pentamethylene 5.5g (50mmol).Get target compound 7.3g, yield: 49.0%.
Molecular formula: C
30H
40N
6O
7Molecular weight: 596.67 mass spectrums (m/e): 597 (M+1)
Ultimate analysis: theoretical value: C, 60.39%; H, 6.76%; N, 14.08%
Measured value: C, 60.30%; H, 6.86%; N, 14.01%
1H-NMR(600MHz，CDCl
3)：δ1.46(t，1H)，1.50(m，4H)，1.73(q，4H)，1.77(t，1H)，2.03(s，1H)，2.06(s，1H)，2.26(s，1H)，2.28(s，6H)，2.30(t，1H)，2.37(m，1H)，2.46(d，1H)，2.67(m，1H)，2.72(d，1H)，2.83(s，6H)，3.28(d，1H)，3.93(s，2H)，5.21(s，1H)，5.41(s，1H)，6.07(s，2H)，6.42(s，1H)，11.14(s，1H)，12.47(s，1H)
Embodiment 14 [S-(4 α, 12a α)]-9-[N '-(cyclohexyl) guanidine radicals] methyl-4, two (dimethylin)-1,4 of 7-, 4a, 5,5a, 6,11,12a-eight
Hydrogen-3,10,12,12a-tetrahydroxy-1, the preparation of 11-dioxo-2-tetracene methane amide (compound 14)
The preparation of step 1 1-(cyano group) amido hexanaphthene
With reference to embodiment 4 steps 1, the hexylamine 4.9g (50mmol) that commits suicide by hanging, cyanogen bromide 5.3g (50mmol), getting product is 4.7g, yield: 76.2%.
The preparation of step 2 compound 14
With reference to embodiment 1 step 2, throw [S-(4 α, 12a α)]-9-amino methyl-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 12.2g (25mmol), 1-(cyano group) amido hexanaphthene 6.2g (50mmol).Get target compound 7.5g, yield: 49.0%.
Molecular formula: C
31H
42N
6O
7Molecular weight: 610.70 mass spectrums (m/e): 611 (M+1)
Ultimate analysis: theoretical value: C, 60.97%; H, 6.93%; N, 13.76%
Measured value: C, 60.86%; H, 7.08%; N, 13.68%
1H-NMR(600MHz，CDCl
3)：δ1.43(m，2H)，1.45(m，4H)，1.46(t，1H)，1.66(m，4H)，1.76(t，1H)2.06(s，1H)，2.08(s，1H)，2.28(s，6H)，2.31(s，1H)，2.35(t，1H)，2.37(m，1H)，2.46(d，1H)，2.55(m，1H)，2.71(d，1H)，2.86(s，6H)，3.27d，1H)，3.95(s，2H)，5.19(s，1H)，5.38(s，1H)，6.10(s，2H)，6.43(s，1H)，11.18(s，1H)，12.45(s，1H)
Embodiment 15 [S-(4 α, 12a α)]-9-[N '-(azetidine-1-yl) amidino groups] methyl-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 1-cyano group-azetidine
With reference to embodiment 4 steps 1, throw azetidine 2.8g (50mmol), cyanogen bromide 5.3g (50mmol), getting product is 2.9g, yield: 71.5%.
The preparation of step 2 compound 15
With reference to embodiment 1 step 2, throw [S-(4 α, 12a α)]-9-amino methyl-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 12.2g (25mmol), 1-cyano group-azetidine 4.1g (50mmol).Get target compound 7.0g, yield: 49.5%.
Molecular formula: C
28H
36N
6O
7Molecular weight: 568.62 mass spectrums (m/e): 569 (M+1)
Ultimate analysis: theoretical value: C, 59.14%; H, 6.38%; N, 14.78%
Measured value: C, 59.04%; H, 6.45%; N, 14.68%
1H-NMR(600MHz，CDCl
3)：δ1.43(t，1H)，1.71(t，1H)，2.08(s，1H)，2.25(m，2H)，2.29(s，6H)，2.33(s，1H)，2.35(m，1H)，2.36(t，1H)，2.45(d，1H)，2.67(d，1H)，2.88(s，6H)，3.28(d，1H)，3.56(t，2H)，3.59(t，2H)，3.95(s，2H)，5.18(s，1H)，5.36(s，1H)，6.11(s，2H)，6.47(s，1H)，11.17(s，1H)，12.48(s，1H)
Embodiment 16 [S-(4 α, 12a α)]-9-[N '-(aza-cyclopentane-1-yl) amidino groups] methyl-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 16) preparation
The preparation of step 1 1-cyano group-aza-cyclopentane
With reference to embodiment 4 steps 1, throw aza-cyclopentane 3.5g (50mmol), cyanogen bromide 5.3g (50mmol), getting product is 3.5g, yield: 73.5%.
The preparation of step 2 compound 16
With reference to embodiment 1 step 2, throw [S-(4 α, 12a α)]-9-amino methyl-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 12.2g (25mmol), 1-cyano group-aza-cyclopentane 4.8g (50mmol).Get target compound 7.3g, yield: 49.9%.
Molecular formula: C
29H
38N
6O
7Molecular weight: 582.65 mass spectrums (m/e): 583 (M+1)
Ultimate analysis: theoretical value: C, 59.78%; H, 6.57%; N, 14.42%
Measured value: C, 59.70%; H, 6.68%; N, 14.31%
1H-NMR(600MHz，CDCl
3)：δ1.43(t，1H)，1.58(m，4H)，1.75(t，1H)，2.07(s，1H)，2.26(s，6H)，2.31(t，1H)，2.33(m，1H)，2.34(s，1H)，2.45(d，1H)，2.71(d，1H)，2.86(t，4H)，2.88(s，6H)，3.27(d，1H)，3.93(s，2H)，5.19(s，1H)，5.34(s，1H)，6.08(s，2H)，6.49(s，1H)，11.12(s，1H)，12.51(s，1H)
Embodiment 17[S-(4 α, 12a α)]-9-[N '-(piperidyl-1-yl) amidino groups] methyl-4,7-is two
(dimethylamine
Base)-1,4,4a, 5,5a, 6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-tetracene methane amide (compound 17) preparation
The preparation of step 1 1-cyano group-piperidine
With reference to embodiment 4 steps 1, throw piperidine 4.2g (50mmol), cyanogen bromide 5.3g (50mmol), getting product is 4.1g, yield: 74.5%.
The preparation of step 2 compound 17
With reference to embodiment 1 step 2, throw [4S-(4 α, 12a α)]-9-amino methyl-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 12.2g (25mmol), 1-cyano group-piperidine 5.5g (50mmol).Get target compound 7.6g, yield: 50.8%.
Molecular formula: C
30H
40N
6O
7Molecular weight: 596.67 mass spectrums (m/e): 597 (M+1)
Ultimate analysis: theoretical value: C, 60.39%; H, 6.76%; N, 14.08%
Measured value: C, 60.30%; H, 6.86%; N, 14.00%
1H-NMR(600MHz，CDCl
3)：δ1.46(t，1H)，1.51(m，2H)，1.56(m，4H)，1.75(t，1H)，2.07(s，1H)，2.25(s，6H)，2.31(s，1H)，2.36(t，1H)，2.39(m，1H)，2.44(d，1H)，2.68(d，1H)，2.79(t，4H)，2.87(s，6H)，3.26(d，1H)，3.95(s，2H)，5.20(s，1H)，5.36(s，1H)，6.03(s，2H)，6.43(s，1H)，11.18(s，1H)，12.45(s，1H)
Embodiment 18 [S-(4 α, 12a α)]-9-[N '-(3,4,5,6-tetrahydrochysene-2H-1,2-oxazine-2-yl) amidino groups] methyl-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 18) preparation
Step 1 2-cyano group-3,4,5,6-tetrahydrochysene-2H-1, the preparation of 2-oxazine
With reference to embodiment 4 steps 1, throw 3,4,5,6-tetrahydrochysene-2H-1,2-oxazine 4.3g (50mmol), cyanogen bromide 5.3g (50mmol), getting product is 4.0g, yield: 72.5%.
The preparation of step 2 compound 18
With reference to embodiment 1 step 2, throw [S-(4 α, 12a α)]-9-amino methyl-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 12.2g (25mmol), 3,4,5,6-tetrahydrochysene-2H-2-cyano group-1,2-oxazine 5.6g (50mmol).Get target compound 7.2g, yield: 48.2%.
Molecular formula: C
29H
38N
6O
8Molecular weight: 598.65 mass spectrums (m/e): 599 (M+1)
Ultimate analysis: theoretical value: C, 58.18%; H, 6.40%; N, 14.04%
Measured value: C, 58.09%; H, 6.49%; N, 13.95%
1H-NMR(600MHz，CDCl
3)：δ1.46(t，1H)，1.48(m，2H)，1.56(m，2H)，1.72(t，1H)，2.07(s，1H)，2.28(s，6H)，2.30(s，1H)，2.32(t，1H)，2.37(m，1H)，2.48(d，1H)，2.69(t，2H)，2.70(d，1H)，2.87(s，6H)，3.26(d，1H)，3.56(t，2H)，3.93(s，2H)，5.18(s，1H)，5.38(s，1H)，6.09(s，2H)，6.42(s，1H)，11.36(s，1H)，12.37(s，1H)
Embodiment 19 [S-(4 α, 12a α)]-9-[N '-(4-methyl-piperazine-1-yl) amidino groups] methyl-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 19) preparation
The preparation of step 1 4-methyl isophthalic acid-cyano group-piperazine
With reference to embodiment 4 steps 1,1-methylpiperazine 5.0g (50mmol), cyanogen bromide 5.3g (50mmol), getting product is 4.6g, yield: 73.6%.
The preparation of step 2 compound 19
With reference to embodiment 1 step 2, throw [S-(4 α, 12a α)]-9-amino methyl-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 12.2g (25mmol), 4-methyl isophthalic acid-cyano group-piperazine 6.2g (50mmol).Get target compound 7.3g, yield: 48.0%.
Molecular formula: C
30H
41N
7O
7Molecular weight: 611.69 mass spectrums (m/e): 612 (M+1)
Ultimate analysis: theoretical value: C, 58.91%; H, 6.76%; N, 16.03%
Measured value: C, 58.80%; H, 6.85%; N, 15.95%
1H-NMR(600MHz，CDCl
3)：δ1.48(t，1H)，1.76(t，1H)，2.07(s，1H)，2.26(s，3H)，2.29(s，6H)，2.31(s，1H)，2.35(t，1H)，2.38(m，1H)，2.47(d，1H)，2.49(t，4H)，2.69(t，4H)，2.71(d，1H)，2.88(s，6H)，3.28(d，1H)，3.94(s，2H)，5.17(s，1H)，5.36(s，1H)，6.11(s，2H)，6.43(s，1H)，11.18(s，1H)，12.43(s，1H)
Embodiment 20 [S-(4 α, 12a α)]-9-[N '-(diamantane-1-yl) guanidine radicals] methyl-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 (compound 20) preparation
The preparation of step 1 1-(cyano group) amido diamantane
With reference to embodiment 4 steps 1,1-amantadine 7.5g (50mmol), cyanogen bromide 5.3g (50mmol), getting product is 6.4g, yield: 72.5%.
The preparation of step 2 compound 20
With reference to embodiment 1 step 2, throw [S-(4 α, 12a α)]-9-amino methyl-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 12.2g (25mmol), 1-(cyano group) amido diamantane 8.8g (50mmol).Get target compound 7.8g, yield: 47.0%.
Molecular formula: C
35H
46N
6O
7Molecular weight: 662.78 mass spectrums (m/e): 663 (M+1)
Ultimate analysis: theoretical value: C, 63.43%; H, 7.00%; N, 12.68%
Measured value: C, 63.32%; H, 7.08%; N, 12.59%
1H-NMR(600MHz，CDCl
3)：δ1.16(t，4H)，1.35(d，1H)，1.40(m，3H)，1.45(d，1H)，1.47(t，1H)，1.55(t，4H)，1.70(d，1H)，1.73(d，1H)，1.76(t，1H)，2.06(s，1H)，2.08(s，1H)，2.28(s，6H)，2.33(s，1H)，2.37(t，1H)，2.39(m，1H)，2.46(d，1H)，2.72(d，1H)，2.87(s，6H)，3.29(d，1H)，3.92(s，2H)，5.15(s，1H)，5.38(s，1H)，6.12(s，2H)，6.45(s，1H)，11.15(s，1H)，12.41(s，1H)
With reference to above preparation method, also can prepare following compound.
The preparation of embodiment 21 freeze-dried powders
Prescription 1 prescription 2
Compound 1 50g compound 19 100g
The intoxicated 500g of N.F,USP MANNITOL 300g dextrose
An amount of water for injection of water for injection is an amount of
Prepare 1000 altogether and prepare 1000 altogether
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 (dextrose intoxicated boil dissolving 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 4 hours, with on average per hour 1.5 ℃ heat up, be warming up to 0 ℃ and carry out low-temperature vacuum drying, the 35 ℃ 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
Prescription 1 prescription 2
Compound 9 10g compounds 15 100g
Arginine 990g prepares 1000 altogether
Prepare 1000 altogether
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
Prescription 1
Compound 5 25g
Starch 50g
Hydroxypropylcellulose 40g
Microcrystalline Cellulose 40g
The aqueous solution 40g of 1%HPMC
Micropowder silica gel 4.0g
Magnesium Stearate 4.0g
Prepare 1000 altogether
Prescription 2
Compound 13 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: 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, the aqueous 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.
Claims (10)
1. the compound shown in the general formula (I):
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
8Independently be hydrogen separately, 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, aryl, aryl C
1-6Alkyl, aroyl, aryl acyloxy, C
1-6The alkane aroyl, heteromonocyclic group or heteromonocyclic group C
1-6Alkyl;
R
7Be hydrogen, hydroxyl, nitro, cyano group, halogen, amido or-NR
7' R
7";
R
4, R
4', R
7' and R
7" independently be hydrogen separately, 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, aryl, aryl C
1-6Alkyl, heteromonocyclic group, heteromonocyclic group C
1-6Alkyl or prodrug part;
R
9And R
9' independently be hydrogen separately, C
1-6Alkyl, C
1-6Alkoxyl group, C
1-6Alkylthio, amino, C
1-6Alkyl amine group, C
1-6Alkoxy amino, C
1-6Alkylthio amino, C
1-6Alkyl-carbonyl, C
1-6Alkoxy carbonyl, sulfonic group, C
1-6Alkyl sulphonyl, C
1-6Alkyl sulphinyl, C
1-6The alkyl amine group alkylsulfonyl, amido C
1-6Alkyl, amino C
1-6Alkyl acyl, two (C
1-6Alkyl) amido acyl group, second sulfinyl, C
1-6Alkyl sulfonyl amino, two (C
1-6Alkyl) amido alkylsulfonyl, C
1-6Alkyl acyl, C
1-6The alkyl amine group alkylsulfonyl, C
2-6Thiazolinyl, C
2-6Alkynyl, C
3-8Cycloalkyl, phenyl, aryl C
1-4Alkyl, C
4-6Heteromonocyclic group, C
4-6Heteromonocyclic group C
1-4Alkyl, bridged ring base or R
9And R
9' coupled nitrogen-atoms formation heteromonocyclic group,
Described C
1-6Alkyl can further be replaced, and described substituting group is selected from: hydroxyl, carboxyl, amino, halogen, amino C
1-6Alkyl acyl, C
1-6Alkyl amine group, alkylsulfonyl or amino-sulfonyl,
Described C
1-6Alkyl acyl can further be replaced, and described substituting group is selected from: amino or C
1-6Alkyl amine group, two (C
1-6Alkyl) amido or amino C
1-6Alkyl acyl,
Described amino or C
1-6Alkyl amine group can further be substituted, and described substituting group is selected from: hydroxyl, carboxyl, C
1-6Alkyl sulphonyl, C
1-6Alkoxyl group, C
1-6Alkylthio or halogen,
Described aryl, aryl C
1-6Alkyl, C
3-8Cycloalkyl, heteromonocyclic group, heteromonocyclic group C
1-6Alkyl, the coupled nitrogen-atoms of bridged ring base or R9 and R9 ' forms heteromonocyclic group can further be substituted the base replacement, 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, C
1-4Alkyl acyl, 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
1-6Alkyl sulfonyl amino, amino-sulfonyl, C
1-6Alkyl amine group alkylsulfonyl, two (C
1-6Alkyl) amido alkylsulfonyl, amino-sulfonyl C
1-6Alkyl, C
1-6Alkyl amido, C
1-6Alkyl amine group C
1-6Alkyl acyl, two (C
1-6Alkyl) amido C
1-6Alkyl acyl, amino C
1-6Alkyl acyl, amino C
1-6Alkyl acyl C
1-6Alkyl or the C that is replaced by hydroxyl, amino, carboxyl, halogen
1-6Alkyl or C
1-6Alkoxyl group.
2. compound as claimed in claim 1:
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
8Independently be hydrogen separately, hydroxyl or C
1-6Alkyl;
R
7Be hydrogen, halogen or-NR
7' R
7";
R
4, R
4', R
7' and R
7" independently be hydrogen separately, C
1-6Alkyl or C
1-4Alkyl-carbonyl;
R
9And R
9' independently be hydrogen separately, C
1-6Alkyl, amino, C
1-4Alkyl amine group, C
1-4Alkoxy amino, C
1-4Alkylthio amino, C
1-4Alkyl-carbonyl, C
1-4Alkoxy carbonyl, sulfonic group, C
1-4Alkyl sulphonyl, amido C
1-4Alkyl, amino C
1-4Alkyl acyl, two (C
1-4Alkyl) amido C
1-4Alkyl acyl, second sulfinyl, C
1-4Alkyl sulfonyl amino, two (C
1-4Alkyl) amido alkylsulfonyl, C
1-4Alkyl acyl, C
1-4The alkyl amine group alkylsulfonyl, C
2-4Thiazolinyl, C
2-4Alkynyl, C
3-8Cycloalkyl, phenyl, aryl C
1-4Alkyl, C
4-6Heteromonocyclic group, C
4-6Heteromonocyclic group C
1-4Alkyl, bridged ring base or R
9And R
9' coupled nitrogen-atoms formation C
4-6Heteromonocyclic group,
Described C
1-6Alkyl can further be replaced, and described substituting group is selected from: hydroxyl, carboxyl, amino, halogen, amino C
1-4Alkyl acyl, C
1-4Alkyl amine group, alkylsulfonyl or amino-sulfonyl,
Described C
1-4Alkyl acyl can further be replaced, and described substituting group is selected from: amino, C
1-4Alkyl amine group or two (C
1-4Alkyl) amido,
Described amino or C
1-4Alkyl amine group can further be substituted, and described substituting group is selected from: hydroxyl, carboxyl, C
1-4Alkyl sulphonyl, C
1-4Alkoxyl group, C
1-4Alkylthio or halogen,
Described aryl, aryl C
1-4Alkyl, C
3-8Cycloalkyl, C
4-6Heteromonocyclic group, C
4-6Heteromonocyclic group C
1-4Alkyl, bridged ring base or R
9And R
9' coupled nitrogen-atoms formation C
4-6Heteromonocyclic group can further be substituted base and replace, and described substituting group is selected from: hydroxyl, amino, carboxyl, halogen, C
1-6Alkyl, C
1-4Alkyl amine group, C
1-4Alkoxyl group, C
1-4Alkyl acyl, 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
1-4Alkyl sulfonyl amino, amino-sulfonyl, C
1-4Alkyl amine group alkylsulfonyl, amino-sulfonyl C
1-4Alkyl, C
1-4Alkyl amido, C
1-4Alkyl amine group C
1-4Alkyl acyl, two (C
1-4Alkyl) amido C
1-4Alkyl acyl, amino C
1-4Alkyl acyl, amino C
1-4Alkyl acyl C
1-4Alkyl or the C that is replaced by hydroxyl, amino, carboxyl, halogen
1-6Alkyl or C
1-4Alkoxyl group.
3. compound as claimed in claim 2:
Wherein, R
2, R
2', R
3, R
5, R
6, R
6', R
8, 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" independently be hydrogen or C separately
1-4Alkyl;
R
9And R
9' independently be hydrogen separately, C
1-6Alkyl, amino, C
1-4Alkyl amine group, C
1-4Alkoxy amino, C
1-4Alkylthio amino, C
1-4Alkyl-carbonyl, sulfonic group, C
1-4Alkyl sulphonyl, C
1-4Alkyl acyl, C
1-4The alkyl amine group alkylsulfonyl, amido C
1-4Alkyl, amino C
1-4Alkyl acyl, two (C
1-4Alkyl) amido C
1-4Alkyl acyl, second sulfinyl, C
1-4Alkyl sulfonyl amino, two (C
1-4Alkyl) amido alkylsulfonyl, C
2-4Thiazolinyl, C
2-4Alkynyl, C
3-6Cycloalkyl, phenyl, aryl C
1-4Alkyl, C
4-6Heteromonocyclic group, C
4-6Heteromonocyclic group C
1-4Alkyl, bridged ring base or R
9And R
9' coupled nitrogen-atoms formation C
4-6Heteromonocyclic group,
Described C
1-6Alkyl can further be replaced, and described substituting group is selected from: formamyl, C
1-4Alkyl amine group, alkylsulfonyl or amino-sulfonyl,
Described C
1-4Alkyl acyl can further be replaced, and described substituting group is selected from: amino C
1-4Alkyl amine group or two (C
1-4Alkyl) amido
Described amino or C
1-4Alkyl amine group can further be substituted, and described substituting group is selected from: hydroxyl, carboxyl,
1-4Alkyl sulphonyl, C
1-4Alkoxyl group, C
1-4Alkylthio or halogen,
Described aryl, aryl C
1-4Alkyl, C
3-6Cycloalkyl, C
4-6Heteromonocyclic group, C
4-6Heteromonocyclic group C
1-4Alkyl, bridged ring base or R
9And R
9' coupled nitrogen-atoms formation C
4-6Heteromonocyclic group can further be substituted base and replace, and described substituting group is selected from: C
1-4Alkyl, C
1-4Alkoxyl group, halogen, amino, amino C
1-4Alkyl, carboxyl, C
1-4Alkyl amine group, C
1-4Alkyl acyl, C
1-4Alkyl carbonyl oxy, C
1-4Carbalkoxy, amino-sulfonyl or the C that is replaced by hydroxyl, amino, carboxyl, halogen
1-4Alkyl or C
1-4Alkoxyl group.
4. compound as claimed in claim 3:
Wherein, R
2, R
2', R
3, R
5, R
6, R
6', R
8, 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" methyl of respectively doing for oneself;
R
9And R
9' independently be hydrogen separately, methyl, ethyl, propyl group; sec.-propyl, the tertiary butyl, amido methyl, formamyl; the methylamino-methyl, dimethylamino formyl radical, ethanoyl, ethylamino alkylsulfonyl; the dimethylamino alkylsulfonyl, aminosulfonyl methyl, sulfonyloxy methyl amino, sulfonic acid methyl; sulfonic group, third alkylsulfonyl, second sulfinyl, isopropyl carbonyl; the difluoro methylamino-, carboxyl methylamino-, hydroxyl third amino, oxyethyl group amino; methylthio group amino, allyl group, propargyl, cyclopropyl; cyclobutyl, cyclopentyl, cyclohexyl, phenyl; benzyl, furyl, thienyl, thiazolyl; isothiazolyl, pyridyl, picolyl, pyrimidyl oxazinyl, dioxane base, dioxolanyl ， oxazolyl isoxazolyl, isothiazolyl, tetrahydrofuran base, tetrahydro-thienyl; imidazolyl, 1H-imidazolyl, pyrazolyl, 1H-pyrazolyl; the imidazolidine base, Pyrrolidine base, adamantyl or R
9And R
9' coupled nitrogen-atoms formation azetidinyl, pyrrolidyl, piperidyl, morpholinyl, oxazinyl or piperazinyl,
Described 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 and can further be substituted base and replace, described substituting group is selected from: methyl, ethyl, methoxyl group, trifluoromethyl, trifluoromethoxy, aminomethyl, methylol, chlorine atom, amino, methylamino, aminomethyl, carboxyl, ethanoyl, carboxymethyl, methoxycarbonyl or amino-sulfonyl.
5. compound as claimed in claim 4:
Wherein, R
2, R
2', R
3, R
5, R
6, R
6', R
8, 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" methyl of respectively doing for oneself;
R
9And R
9' independently be hydrogen separately, methyl, ethyl, propyl group, sec.-propyl; the tertiary butyl, amido methyl, formamyl, N, N dimethylamine base formyl radical; N-ethyl amido alkylsulfonyl, N, N dimethylamine alkylsulfonyl, aminosulfonyl methyl, sulfonyloxy methyl amino; sulfonic acid methyl, sulfonic group, third alkylsulfonyl, second sulfinyl, isopropyl carbonyl; the difluoro methylamino-, carboxyl methylamino-, hydroxyl third amino, oxyethyl group amino, methylthio group amino; allyl group, propargyl, cyclopropyl, cyclobutyl, cyclopentyl; cyclohexyl, phenyl, phenmethyl, furyl; thienyl, thiazolyl, pyridyl, picolyl; pyrimidyl ， oxazinyl, 1,3-dioxane base; 1,3-dioxolanyl ， oxazolyl ， isoxazolyl; isothiazolyl, tetrahydrofuran base, tetrahydro-thienyl, 1H-imidazolyl; the 1H-pyrazolyl, imidazolidine base, Pyrrolidine base, adamantyl or R
9And R
9' coupled nitrogen-atoms formation azetidinyl, pyrrolidyl, piperidyl, morpholinyl, oxazinyl or piperazinyl,
Described cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, furyl, thienyl, thiazolyl, pyridyl, picolyl, adamantyl or R
9And R
9' coupled nitrogen-atoms formation azetidinyl, pyrrolidyl, piperidyl, oxazinyl, 3; 4; 5; 6-tetrahydrochysene-2H-1; 2-oxazine or piperazinyl can further be substituted base and replace, and described substituting group is selected from: methyl, ethyl, methoxyl group, trifluoromethyl, trifluoromethoxy, aminomethyl, methylol, chlorine atom, amino, methylamino, aminomethyl, carboxyl, ethanoyl, carboxymethyl, methoxycarbonyl or amino-sulfonyl.
6. compound as claimed in claim 5:
Wherein, R
2, R
2', R
3, R
5, R
6, R
6', R
8, 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" methyl of respectively doing for oneself;
R
9And R
9' independently be hydrogen separately, methyl, ethyl, the tertiary butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, furyl, thienyl, thiazolyl, pyridyl, picolyl, adamantyl or R
9And R
9' coupled nitrogen-atoms formation azetidinyl, pyrrolidyl, piperidyl, 3,4,5,6-tetrahydrochysene-2H-1,2-oxazinyl or piperazinyl,
Described cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, furyl, thienyl, thiazolyl, pyridyl, picolyl, adamantyl or R
9And R
9' coupled nitrogen-atoms formation azetidinyl, pyrrolidyl, piperidyl, 3,4,5,6-tetrahydrochysene-2H-1,2-oxazinyl or piperazinyl can further be substituted base and replace, and described substituting group is selected from methyl, trifluoromethyl or trifluoromethoxy.
7. the described compound of compound as claimed in claim 6 is:
[S-(4 α, 12a α)]-9-[N '-tertiary butyl guanidine radicals] methyl-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 '-(N, N-dimethyl) guanidine radicals] methyl-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 '-(N, N-diethyl) guanidine radicals] methyl-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 '-(furans-2-yl) guanidine radicals] methyl-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 '-(thiophene-2-yl) guanidine radicals] methyl-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 '-(thiazol-2-yl) guanidine radicals] methyl-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-trifluoromethyl) guanidine radicals] methyl-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-trifluoromethoxy benzaldehyde base) guanidine radicals] methyl-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 '-(pyridin-3-yl) guanidine radicals] methyl-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 '-[(pyridin-3-yl) methyl] guanidine radicals] methyl-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 '-(cyclopropyl-1-yl) guanidine radicals] methyl-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 '-(cyclobutyl-1-yl) guanidine radicals] methyl-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 '-cyclopentyl guanidine radicals] methyl-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 '-(cyclohexyl) guanidine radicals] methyl-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 '-(azetidine-1-yl) amidino groups] methyl-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 '-(aza-cyclopentane-1-yl) amidino groups] methyl-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 '-(piperidyl-1-yl) amidino groups] methyl-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 '-(3,4,5,6-tetrahydrochysene-2H-1,2-oxazine-2-yl) amidino groups] methyl-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-methyl-piperazine-1-yl) amidino groups] methyl-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 '-(diamantane-1-yl) guanidine radicals] methyl-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.
8. the pharmaceutical composition that comprises the described compound of each claim of claim 1～7 and other active pharmaceutical ingredients.
9. the pharmaceutical composition that comprises the described compound of each claim of claim 1～7 and one or more pharmaceutical carriers and/or thinner is pharmaceutically acceptable arbitrary formulation.
10. treat and/or prevent application in the tetracyclines sensitive diseases medicine as the described compound of each claim of claim 1～7 in preparation.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200910173214 CN101759604A (en) | 2008-09-12 | 2009-09-12 | Guanidyl substitutional tetracycline derivative |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200810140009.7 | 2008-09-12 | ||
| CN 200910173214 CN101759604A (en) | 2008-09-12 | 2009-09-12 | Guanidyl substitutional tetracycline derivative |
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| Publication Number | Publication Date |
|---|---|
| CN101759604A true CN101759604A (en) | 2010-06-30 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 200910173214 Pending CN101759604A (en) | 2008-09-12 | 2009-09-12 | Guanidyl substitutional tetracycline derivative |
Country Status (1)
| Country | Link |
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| CN (1) | CN101759604A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103717571A (en) * | 2011-07-26 | 2014-04-09 | 山东亨利医药科技有限责任公司 | 9-aminomethyl substituted tetracycline compound |
-
2009
- 2009-09-12 CN CN 200910173214 patent/CN101759604A/en active Pending
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103717571A (en) * | 2011-07-26 | 2014-04-09 | 山东亨利医药科技有限责任公司 | 9-aminomethyl substituted tetracycline compound |
| CN103717571B (en) * | 2011-07-26 | 2016-01-13 | 山东亨利医药科技有限责任公司 | The tetracycline compound that 9-amino methyl replaces |
| US9365499B2 (en) | 2011-07-26 | 2016-06-14 | Kbp Biosciences Co., Ltd. | 9-aminomethyl substituted tetracycline compounds |
| CN103717571B8 (en) * | 2011-07-26 | 2017-05-17 | 山东亨利医药科技有限责任公司 | 9-aminomethyl substituted tetracycline compound |
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Open date: 20100630 |