CN1865274A - Macrolide medicine double-side-chain erythromycin A derivative, synthesis method and application - Google Patents
Macrolide medicine double-side-chain erythromycin A derivative, synthesis method and application Download PDFInfo
- Publication number
- CN1865274A CN1865274A CNA2006100277556A CN200610027755A CN1865274A CN 1865274 A CN1865274 A CN 1865274A CN A2006100277556 A CNA2006100277556 A CN A2006100277556A CN 200610027755 A CN200610027755 A CN 200610027755A CN 1865274 A CN1865274 A CN 1865274A
- Authority
- CN
- China
- Prior art keywords
- oxygen carbonyl
- imino
- butyl
- erythromycin
- imidazoles
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- ULGZDMOVFRHVEP-RWJQBGPGSA-N Erythromycin Chemical class O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 ULGZDMOVFRHVEP-RWJQBGPGSA-N 0.000 title claims abstract description 165
- 239000003814 drug Substances 0.000 title claims abstract description 13
- 239000003120 macrolide antibiotic agent Substances 0.000 title description 7
- 238000001308 synthesis method Methods 0.000 title 1
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- 230000000840 anti-viral effect Effects 0.000 claims abstract description 4
- 229910052760 oxygen Inorganic materials 0.000 claims description 159
- 239000001301 oxygen Substances 0.000 claims description 159
- -1 nitro, carboxyl Chemical group 0.000 claims description 112
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 claims description 96
- 229960003276 erythromycin Drugs 0.000 claims description 84
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 81
- 239000000047 product Substances 0.000 claims description 66
- QQVIHTHCMHWDBS-UHFFFAOYSA-N perisophthalic acid Natural products OC(=O)C1=CC=CC(C(O)=O)=C1 QQVIHTHCMHWDBS-UHFFFAOYSA-N 0.000 claims description 51
- 238000006243 chemical reaction Methods 0.000 claims description 50
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 48
- 238000000034 method Methods 0.000 claims description 34
- 125000000217 alkyl group Chemical group 0.000 claims description 25
- 150000001875 compounds Chemical class 0.000 claims description 25
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 24
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 23
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 22
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- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 206010057190 Respiratory tract infections Diseases 0.000 description 1
- 241000191963 Staphylococcus epidermidis Species 0.000 description 1
- 239000004098 Tetracycline Substances 0.000 description 1
- 108010059993 Vancomycin Proteins 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 230000001046 anti-mould Effects 0.000 description 1
- 239000002546 antimould Substances 0.000 description 1
- 229960004099 azithromycin Drugs 0.000 description 1
- MQTOSJVFKKJCRP-BICOPXKESA-N azithromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)N(C)C[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 MQTOSJVFKKJCRP-BICOPXKESA-N 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 1
- 239000004327 boric acid Substances 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
- WIIZWVCIJKGZOK-RKDXNWHRSA-N chloramphenicol Chemical compound ClC(Cl)C(=O)N[C@H](CO)[C@H](O)C1=CC=C([N+]([O-])=O)C=C1 WIIZWVCIJKGZOK-RKDXNWHRSA-N 0.000 description 1
- AJSDVNKVGFVAQU-BIIVOSGPSA-N cladinose Chemical compound O=CC[C@@](C)(OC)[C@@H](O)[C@H](C)O AJSDVNKVGFVAQU-BIIVOSGPSA-N 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 238000013461 design Methods 0.000 description 1
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- 229920000159 gelatin Polymers 0.000 description 1
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- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 229920000591 gum Polymers 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 239000003835 ketolide antibiotic agent Substances 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 208000015688 methicillin-resistant staphylococcus aureus infectious disease Diseases 0.000 description 1
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 210000004400 mucous membrane Anatomy 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 229940049547 paraxin Drugs 0.000 description 1
- 239000006072 paste Substances 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 239000002831 pharmacologic agent Substances 0.000 description 1
- 229960003562 phentermine Drugs 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 description 1
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
- 229960003415 propylparaben Drugs 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 238000001243 protein synthesis Methods 0.000 description 1
- 210000000664 rectum Anatomy 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 1
- 239000004299 sodium benzoate Substances 0.000 description 1
- 235000010234 sodium benzoate Nutrition 0.000 description 1
- 235000002639 sodium chloride Nutrition 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000012177 spermaceti Substances 0.000 description 1
- 229940084106 spermaceti Drugs 0.000 description 1
- 229960005404 sulfamethoxazole Drugs 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000019364 tetracycline Nutrition 0.000 description 1
- 150000003522 tetracyclines Chemical class 0.000 description 1
- 229940040944 tetracyclines Drugs 0.000 description 1
- 238000013519 translation Methods 0.000 description 1
- 201000008827 tuberculosis Diseases 0.000 description 1
- 229960003165 vancomycin Drugs 0.000 description 1
- MYPYJXKWCTUITO-UHFFFAOYSA-N vancomycin Natural products O1C(C(=C2)Cl)=CC=C2C(O)C(C(NC(C2=CC(O)=CC(O)=C2C=2C(O)=CC=C3C=2)C(O)=O)=O)NC(=O)C3NC(=O)C2NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(CC(C)C)NC)C(O)C(C=C3Cl)=CC=C3OC3=CC2=CC1=C3OC1OC(CO)C(O)C(O)C1OC1CC(C)(N)C(O)C(C)O1 MYPYJXKWCTUITO-UHFFFAOYSA-N 0.000 description 1
- MYPYJXKWCTUITO-LYRMYLQWSA-O vancomycin(1+) Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=C2C=C3C=C1OC1=CC=C(C=C1Cl)[C@@H](O)[C@H](C(N[C@@H](CC(N)=O)C(=O)N[C@H]3C(=O)N[C@H]1C(=O)N[C@H](C(N[C@@H](C3=CC(O)=CC(O)=C3C=3C(O)=CC=C1C=3)C([O-])=O)=O)[C@H](O)C1=CC=C(C(=C1)Cl)O2)=O)NC(=O)[C@@H](CC(C)C)[NH2+]C)[C@H]1C[C@](C)([NH3+])[C@H](O)[C@H](C)O1 MYPYJXKWCTUITO-LYRMYLQWSA-O 0.000 description 1
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Landscapes
- Saccharide Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to a bilateral chain erythromycin A derivative, a preparation method thereof, a preparation method of a pharmaceutical composition and application thereof in preparing potential antibacterial and antiviral medicaments, and the bilateral chain erythromycin A derivative is shown in a structural general formula.
Description
Technical field
The present invention relates to a kind of bilateral chain Erythromycin A analog derivative and synthetic method thereof and this compounds as purposes antibiotic, antiviral.
Background technology
Microbiotic and antiseptic-germicide resistant organism are increasing rapidly, methicillin-resistant staphylococcus aureus, the methicillin-resistant staphylococcus epidermidis, anti-mould parapneumonia suis, the appearance of the faecalis of vancomycin resistance etc., the chemical sproof quick growth of streptococcus pneumoniae, the appearance of multidrug resistant problem, penicillin, Macrolide, Trimethyl phosphate-sulfamethoxazole, tetracyclines, resistance such as fluoroquinolone and paraxin and the acquired respiratory tract infection of multidrug resistant streptococcus pneumoniae community are in rising trend year by year, multidrug resistant mycobacterium tuberculosis infection (L.Katz and G.W.Ashley Translation and Protein Synthesis:MacrolidesChem.Rev.2005 (105) p499-527 that is on the rise; G.G.Zhanel, M.Walter, A.Noreddin et al TheKetolides Drug 2,002 62 (12) p1771-1804).Many microbiotic significantly subtract effect because of resistance.Therefore be necessary to accelerate new antibiotic research, the compound that design and screening have new chemical structure, raising suppresses active to the Macrolide resistant organism, reduce and avoid the inducible resistance of medicine bacterial strain, solve the multidrug resistant problem, clinical safe and effective medicine (the S.Pal A Journey Across the SequentialDevelopment of Macrolides and Ketolides Related to Erythromycin Tetrahedron 20051-31 more that provides is provided; W.A.Craig Overview of Newer Antimicrobial Formulations for OvercomingPneumococcal Resistance The Amer.J.Med.2004 117 (3A) 16-24).
Summary of the invention
The object of the invention provides a kind of bilateral chain Erythromycin A analog derivative.
Purpose of the present invention also provides a kind of synthetic method of above-mentioned bilateral chain Erythromycin A analog derivative, so that safer, convenient, synthetic and suitability for industrialized production efficiently.
Another object of the present invention provides a kind of purposes of above-mentioned bilateral chain Erythromycin A analog derivative, purposes antibiotic, antiviral that this analog derivative can be used as.
Bilateral chain Erythromycin A analog derivative of the present invention is the macrolides compound with following structural formula 1:
Structural formula 1,
Wherein, described R
1Be expressed as-R
4-R
5
R
2Be expressed as H ,-CONR
6-R
7, aminoacyl (OCNH
2), ethanoyl, benzoyl, by R
12The ethanoyl that replaces and by R
12The benzoyl that replaces;
R
3Be expressed as H or-CONR
8-R
9, aminoacyl (OCNH
2), ethanoyl, benzoyl, by R
12The ethanoyl that replaces and by R
12The benzoyl that replaces; R
12Be hydroxyl, halogen atom, nitro, carboxyl, C (O) H, (O), HS, (S), CF
3, OH, NH
2, cyano group, contain 1 to 4 carbon atom the chain alkyl, contain oxyalkyl, sulfur-bearing alkyl, sulfur-bearing alkynyl or sulfur-bearing thiazolinyl, contain azanyl or contain 2 to 4 carbon atoms chain thiazolinyl, chain alkynyl, contain the oxycetylene base or contain oxy alkylene, nitrogenous alkynyl or nitrogenous thiazolinyl;
R
4, R
6, R
8The representative contain the alkyl of 1～30 carbon atom, by R
10The alkyl that replaces is perhaps by an alkyl of blocking to five heteroatomss; 1～30 above-mentioned carbon atom alkyl is the cycloalkyl of the alkyl of 1～30 carbon atom, 3～30 carbon atoms, 3～30 alkenyl or alkynyls, and fragrant substituted alkyl or virtue are for alkynyl; Described R
10Be selected from hydroxyl, halogen atom, nitro, carboxyl, C (O) H, (O), HS, (S), CF3, OH, NH2, cyano group, contain 1 to 4 carbon atom the chain alkyl, contain oxyalkyl, sulfur-bearing alkyl, sulfur-bearing alkynyl or sulfur-bearing thiazolinyl, contain azanyl or contain 2 to 4 carbon atoms chain thiazolinyl, chain alkynyl, contain the oxycetylene base or contain oxy alkylene, nitrogenous alkynyl or nitrogenous thiazolinyl;
R
5, R
7, R
9Represent an aryl that contains 6～12 carbon atoms, aromatic heterocyclic, by R
11The aryl that replaces and by R
11The aromatic heterocyclic that replaces; Represented aryl is phenyl, naphthyl or contains 1～5 heteroatomic ternary to ten yuan fragrant heterocycle, these aromatic heterocyclics be sulfur-bearing, nitrogenous, contain oxygen or a fragrant heterocycle contains a kind of aromatic heterocyclic to five kinds of above-mentioned three kinds of different elemental nitrogen, oxygen, sulphur; R
11Be hydroxyl, halogen atom, nitro, carboxyl, C (O) H, (O), HS, (S), CF
3, OH, NH
2, cyano group, contain 1 to 4 carbon atom the chain alkyl, contain oxyalkyl, sulfur-bearing alkyl, sulfur-bearing alkynyl or sulfur-bearing thiazolinyl, contain azanyl or contain 2 to 4 carbon atoms chain thiazolinyl, chain alkynyl, contain the oxycetylene base or contain oxy alkylene, nitrogenous alkynyl or nitrogenous thiazolinyl.
Above-mentioned " several " are recommended as 1～5 except that other explanation, further be recommended as 1～3.
Recommend: R
1=
Recommend: R
2Or R
3=
R in the formula
2Or R
3Be recommended as hydrogen or aminoacyl (OCNH
2).
The preferred compound of the present invention is specifically listed as follows:
(1) 11,12-dideoxy-5-(2-oxygen carbonyl (4-phenyl) butyl) imino-) dimethylamine sugar-6-O-methyl isophthalic acid 2,11-oxygen carbonyl ((4-(phenyl) butyl) imino-) erythromycin;
(2) 1,12-dideoxy-5-(2-oxygen carbonyl amino) dimethylamine sugar-6-O-methyl isophthalic acid 2,11-oxygen carbonyl ((4-(benzene butyl) imino-) erythromycin;
(3) 11,12-dideoxy-6-O-methyl-3-O-((4-oxygen carbonyl phenyl butyl) amino) cladinose-12,11-(oxygen carbonyl (4-(phenyl butyl) imino-)) erythromycin;
(4) 11,12-dideoxy-5-(2-oxygen carbonyl (4-(3H-imidazo (4,5b)-pyridine-3-) butyl) imino-) dimethylamine sugar-6-O-methyl isophthalic acid 2,11-oxygen carbonyl ((4-(the 3H-imidazo (4,5b)-pyridine-3) butyl) imino-) erythromycin;
(5) 11,12-dideoxy-5-(2-oxygen carbonyl amino) dimethylamine sugar-6-O-methyl isophthalic acid 2,11-oxygen carbonyl ((4-(the 3H-imidazo (4,5b)-pyridine-3) butyl) imino-) erythromycin;
(6) 11,12-dideoxy-6-O-methyl-3-O-(4-oxygen carbonyl (4-(the 3H-imidazo (4,5b)-pyridine-3) butyl amino) cladinose-12,11-oxygen carbonyl ((4-(the 3H-imidazo (4,5b)-pyridine-3) butyl) imino-) erythromycin;
(7) 11,12-dideoxy-5-(2-oxygen carbonyl (4-(the 1H-imidazo (4,5b)-pyridine-1) butyl) imino-) dimethylamine sugar-6-O-methyl isophthalic acid 2,11-oxygen carbonyl ((4-(the 1H-imidazo (4,5b)-pyridine-1) butyl) imino-) erythromycin;
(8) 11,12-dideoxy-5-(2-oxygen carbonyl amino) dimethylamine sugar-6-O-methyl isophthalic acid 2,11-oxygen carbonyl ((4-(the 1H-imidazo (4,5b)-pyridine-1) butyl) imino-) erythromycin;
(9) 11,12-dideoxy-6-O-methyl-3-O-(4-oxygen carbonyl-(4-(the 1H-imidazo (4,5b)-pyridine-1) butyl) amino) cladinose-12,11-oxygen carbonyl ((4-(the 1H-imidazo (4,5b)-pyridine-1) butyl) imino-) erythromycin;
(10) 11,12-dideoxy-5-(2-oxygen carbonyl (4-((3-pyridyl)-1H-imidazoles-1) butyl) imino-) dimethylamine sugar-6-O-methyl isophthalic acid 2,11-oxygen carbonyl (4-((3-pyridyl)-1H-imidazoles-1) butyl) imino-erythromycin;
(11) 11,12-dideoxy-5-(2-oxygen carbonyl amino) dimethylamine sugar-6-O-methyl isophthalic acid 2,11-oxygen carbonyl ((4-((3-pyridyl)-1H-imidazoles-1) butyl) imino-) erythromycin;
(12) 11,12-dideoxy-6-O-methyl-3-O-(4-oxygen carbonyl-(4-((3-pyridyl)-1H-imidazoles-1) butyl amino) cladinose-12,11-oxygen carbonyl ((4-((3-pyridyl)-1H-imidazoles-1) butyl) imino-) erythromycin;
(13) 11,12-dideoxy-5-(2-oxygen carbonyl (4-((4-pyridyl)-1H-imidazoles-1) butyl) imino-) dimethylamine sugar-6-O-methyl isophthalic acid 2,11-oxygen carbonyl ((4-((4-pyridyl)-1H-imidazoles-1) butyl) imino-) erythromycin;
(14) 11,12-dideoxy-5-(2-oxygen carbonyl amino) dimethylamine sugar-6-O-methyl isophthalic acid 2,11-oxygen carbonyl ((4-((4-pyridyl)-1H-imidazoles-1) butyl) imino-) erythromycin;
(15) 11,12-dideoxy-6-O-methyl-3-O-(4-oxygen carbonyl (4-((4-pyridyl)-1H-imidazoles-1) butyl) amino) cladinose-12,11-oxygen carbonyl ((4-((4-pyridyl)-1H-imidazoles-1) butyl) imino-) erythromycin;
(16) 11,12-dideoxy-5-(2-oxygen carbonyl (4-(phenyl-1H-imidazoles-1) butyl) imino-) dimethylamine sugar-6-O-methyl isophthalic acid 2,11-(oxygen carbonyl (4-(phenyl-1H-imidazoles-1) butyl) imino-) erythromycin;
(17) 11,12-dideoxy-5-(2-oxygen carbonyl amino) dimethylamine sugar-6-O-methyl isophthalic acid 2,11-(oxygen carbonyl (4-(phenyl-1H-imidazoles-1) butyl) imino-) erythromycin;
(18) 11,12-dideoxy-6-O-methyl-3-O-(4-oxygen carbonyl (4-(phenyl-1H-imidazoles-1) butyl amino)) cladinose-12,11-oxygen carbonyl ((4-(phenyl-1H-imidazoles-1) butyl) imino-) erythromycin;
(19) 11,12-dideoxy-5-(2-oxygen carbonyl (3-(5-methoxyl group-1H-imidazoles (4,5b) pyridine-2-sulfydryl replaces) propyl group) imino-) dimethylamine sugar-6-O-methyl isophthalic acid 2,11-oxygen carbonyl ((3-((5-methoxyl group-1H-imidazoles (4,5b) pyridine-2-sulfydryl replaces) propyl group) imino-) erythromycin;
(20) 11,12-dideoxy-5-(2-oxygen carbonyl amino) dimethylamine sugar-6-O-methyl isophthalic acid 2,11-oxygen carbonyl ((3-(5-methoxyl group-1H-imidazoles (4,5b) pyridine-2-sulfydryl replaces) propyl group) imino-) erythromycin;
(21) 11,12-dideoxy-6-O-methyl-3-O-4-oxygen carbonyl (3-(5-methoxyl group-1H-imidazoles (4,5b) pyridine-2-sulfydryl replaces) propyl group amino) cladinose-12,11-oxygen carbonyl ((3-(5-methoxyl group-1H-imidazoles (4,5b) pyridine-2-sulfydryl replaces) propyl group) imino-) erythromycin;
(22) 11,12-dideoxy-5-(2-oxygen carbonyl (3-(3-pyridyl)-1H-imidazoles-2-sulfydryl replaces-2)-propyl group) imino-) dimethylamine sugar-6-O-methyl isophthalic acid 2,11-oxygen carbonyl ((3-(3-pyridyl)-1H-imidazoles-2-sulfydryl replacement-2-propyl group) imino-) erythromycin;
(23) 11,12-dideoxy-5-(2-oxygen carbonyl amino) dimethylamine sugar-6-O-methyl isophthalic acid 2,11-oxygen carbonyl ((3-((3-pyridyl)-1H-imidazoles-2-sulfydryl replace-2-) propyl group) imino-) erythromycin;
(24) 11,12-dideoxy-6-O-methyl-3-O-4-oxygen carbonyl ((3-((3-pyridyl)-1H-imidazoles-2-sulfydryl replace-2-) propyl group amino) cladinose-12,11-oxygen carbonyl ((3-((3-pyridyl)-1H-imidazoles-2-sulfydryl replace-2-) propyl group) imino-) erythromycin.
Another theme of the present invention is the preparation method with compound of structural formula 1.
The method for preparing structural formula 1 described compound of the present invention comprises erythromycin derivatives raw material and R with due care
2NH
2Or R
3NH
2The linked reaction of side chain, the deacetylate alkali of products therefrom is separated reaction.Comprise and making with the following method:
(A) select suitable erythromycin derivatives and R for use
6R
7-NH
2Side chain carries out coupling at different positions simultaneously, obtains bilateral chain product;
(B) to the cladinose 4 of gained bilateral chain product " a position hydroxyl carries out the selectivity deprotection, obtains having the compound of following array structure:
Structural formula 1.
Specifically, novel macrolides compound of the present invention adopts known feasible reaction method on known bibliographical information or the synthetic chemistry promptly from clarithromycin, obtains suitable derivatives as raw material of the present invention.As compound 1, can adopt document J.Med.Chem, 41,4080-4100, the preparation of 1998 reported method; Compound 3 can adopt document " Protective Groups in Organic Synthesis " Third Edition.Theodora W.Greene, the preparation of Peter G.M.Wuts reported method.Concrete operations are as follows:
(1) preparation of raw material 1: can adopt document J.Med.Chem, 41,4080-4100, the preparation of 1998 report methods.Getting the exsiccant clarithromycin is dissolved in the exsiccant methylene dichloride.Add the pyridine of dimethylamino arsenic, drip aceticanhydride.Stirring at room three hours.Add the 2N NaOH aqueous solution to pH=8. through water, after the saturated common salt water washing, Na
2SO
4Dry.Obtain thick product after concentrating.Silica gel column chromatography obtains 2 ', 4 "-two-ethanoyl-6-O-erythromycin (2 ', 4 "-two-ethanoyl clarithromycin).Clarithromycin, the pyridine of dimethylamino arsenic, vinegar cash mol ratio is 1: 0.4～1: 5～8.
Get aforementioned product thorough drying, be dissolved in the tetrahydrofuran (THF).At-40 ℃, the N gas shiled adds bis-tetramethyl silicon sodium hydrogen down, stirs 2 hours under this temperature, slowly drips the N of carbonyl dimidazoles, N-dimethylformamide solution.Stirring at room 20 hours.Add 5%KH
2PO
4The aqueous solution, dichloromethane extraction.After organic phase is used the saturated common salt water washing, Na
2SO
4Dry.Concentrate the back and use purification by silica gel column chromatography, must be scheduled to intermediate product.Reaction raw materials: bis-tetramethyl silicon sodium hydrogen: the carbonyl dimidazoles mol ratio is 1: 1.2～2.4: 4～8.
Get aforementioned intermediate product and be dissolved in acetonitrile/water (10: the 1) mixed solvent, add aryl and replace butylamine.60 ℃ were stirred 4 hours, added 5%KH
2PO
4The aqueous solution.Dichloromethane extraction.Merge organic phase.Water successively, after the saturated common salt water washing, Na
2SO
4Dry.Use purification by silica gel column chromatography, products obtained therefrom to be dissolved in the methyl alcohol after concentrating and refluxed 4 hours, obtain raw material 1.Reaction raw materials wherein: it is 1: 4～6 that aryl replaces the butylamine mol ratio.
(2) preparation of raw material 3: get the exsiccant clarithromycin and be dissolved in the exsiccant methylene dichloride.Add the pyridine of dimethylamino arsenic, drip aceticanhydride.Stirring at room three hours.Add the 2N NaOH aqueous solution to pH=8 through water, after the saturated common salt water washing, Na
2SO
4Dry.Obtain thick product after concentrating.Silica gel column chromatography obtains 2 ', 4 "-two-ethanoyl-6-O-erythromycin (2 ', 4 "-two-ethanoyl clarithromycin).Clarithromycin wherein, the pyridine of dimethylamino arsenic, vinegar cash mol ratio is 1: 0.4～1: 5～8.
2 ', 4 "-two-ethanoyl-6-O-erythromycin is dissolved in the methyl alcohol, add mol ratio and be 0.1～2 salt of wormwood reaction got final product in 1～24 hour starting compound 3.
The preparation method of compound described in present method comprises the steps:
CDI described in the reaction formula is a carbonyl dimidazoles, and DMF is N, and N dimethyl formamide, Ac are ethanoyl, and DBU is 1.8-diazabicylo [5.4.0] hendecene-7, R wherein
1, R
2, R
3, R
8, R
9As previously mentioned.
Method of the present invention further describes as (1) or (2) two kinds of methods:
(1) by the method for starting compound 1 synthetic compound 2
Under-10 ℃～10 ℃ temperature of organic solvent neutralization, raw material 1, carbonyl dimidazoles and sodium hydride reacted 1～24 hour; Products therefrom is in organic solvent, and R
1NH
2And 1,8-diazacyclo hendecene reaction 1～24 hour; Products therefrom is dissolved in the methyl alcohol again, room temperature～80 ℃ reaction 1～24 hour or add mol ratio be 0.1～2 salt of wormwood reaction got final product in 1～24 hour compound 2.Described raw material 1, carbonyl dimidazoles, sodium hydride, R
1NH
2, 1, the mol ratio of 8-diazacyclo hendecene and salt of wormwood is 1: 1～5: 1～3: 1～2: 1～2: 0.1～2.The recommendation response temperature is 0 ℃.
(2) by the method for starting compound 3 synthetic compounds 6
In organic solvent, go back under-10 ℃～0 ℃ temperature, 2 '-O-ethanoyl-clarithromycin, carbonyl dimidazoles and sodium hydride were reacted 1～24 hour; Products therefrom under-10 ℃～room temperature of organic solvent neutralization with R
1NH
2With 1,8-diazacyclo hendecene reaction 1～24 hour; Products therefrom is at C
1～4Alcohol in reacted 1～24 hour, react usually and promptly got compound 6 in 2～5 hours.Described 2 '-O-ethanoyl-clarithromycin, carbonyl dimidazoles, sodium hydride, R
1NH
2With 1, the mol ratio of 8-diazacyclo hendecene is 1: 2～5: 1～3: 2～5: 2～5.
Compound of the present invention is simple synthetic method not only, is fit to suitability for industrialized production, and this compound is to gram positive bacterium, and as staphylococcus, suis, streptococcus pneumoniae etc. all have outstanding anti-microbial activity and antimicrobial agent activity, can be used for preparing antibacterials.
Compound of the present invention and they and mineral acid, the organic acid additive salt can be used as medicinal.As the bacterial infection of pharmacological agent, particularly treat gram positive bacterium, as staphylococcus, the infection that suis, streptococcus pneumoniae etc. cause.The compounds of this invention has activity to following bacterial infection simultaneously: rickettsia Salmonella, mycoplasma pneumoniae, chlamydozoan, the Rome pathogenic agent, hematuria slurry, toxoplasma, mycobacterium, monocytosis Li Site Salmonella, the disease that meningococcus etc. cause.
The compounds of this invention can comprise the medicine that the contains at least a above-mentioned definition structure pharmaceutical composition as active ingredient simultaneously.With this compound and pharmaceutical excipient such as vehicle, thinner, stablizers etc. are mixed and made into tablet, capsule, granule, powder, syrup etc. with gastrointestinal administration or with formulations such as injections with administered in parenteral form.These compositions can be by oral, rectum, parenterai administration mode or by on coating and the skin or the partial mode drug treatment of mucous membrane.But preferred mode is oral.The antimicrobial compound (medicinal preparations) that it is effective constituent that the present invention also provides with above-mentioned structural formula 1 derivative; With this compound and pharmaceutical excipient such as vehicle, thinner, stablizers etc. are mixed and made into tablet, capsule, granule, powder, syrup etc. with gastrointestinal administration or with formulations such as injections with administered in parenteral form.The said medicine preparation can prepare by ordinary method.Described auxiliary material can comprise vehicle, as carbohydrate (lactose, glucose, mannitol, Sorbitol Powder, W-Gum, potato starch, dextrin, carboxymethyl cellulose etc.Tackiness agent such as gelatin, polyvinylpyrrolidone, polyoxyethylene glycol; Disintegrating agent such as carboxymethyl cellulose, polyvinylpyrrolidone; Lubricant such as talcum, calcium stearate, Magnesium Stearate, spermaceti, boric acid, Sodium Benzoate etc.; Stablizer such as methyl p-hydroxybenzoate, propylparaben etc.; Correctives, thinner etc.
These compositions can be solid or liquid, are the usual way of people's medication, such as: tablet, single agent, sugar-coat agent, capsule, granule, suppository, injection, paste, emulsion, gelifying agent.Their preparation method is ordinary method.
Embodiment
Below with reference to embodiment invention is described further, but does not limit the scope of the invention.The determining instrument that uses among the embodiment: NMR (Nuclear Magnetic Resonance) spectrum is used Mercury-400 type nuclear magnetic resonance analyser, and mass spectrograph uses VGZAB-2F type mass spectrograph.
Embodiment 1
(1) 11,12-dideoxy-5-(2-oxygen carbonyl (4-phenyl) butyl) imino-) dimethylamine sugar-6-O-methyl isophthalic acid 2,11-oxygen carbonyl ((4-(phenyl) butyl) imino-) erythromycin
Getting exsiccant clamycin 2 0g is dissolved in the 90ml exsiccant methylene dichloride.Add the pyridine of 1.3g dimethylamino arsenic, drip 13ml vinegar cash.Stirring at room three hours.Add the 2N NaOH aqueous solution to pH=8. through water, after the saturated common salt water washing, the Na2SO4 drying.Obtain thick product after concentrating.Silica gel column chromatography obtains 7.5g2 ', and 4 "-two-ethanoyl-6-O-erythromycin (2 ', 4 "-two-ethanoyl clarithromycin).Get 5g product thorough drying, be dissolved in the 50ml tetrahydrofuran (THF).-40C, the N gas shiled adds NaH (TMS) 20.5ml down, stirs 2 hours under this temperature, slowly drips carbonyl dimidazoles (500mg) N, N-dimethylformamide solution 6ml.Stirring at room 20 hours.Add the 5%KH2PO4 aqueous solution, dichloromethane extraction.After organic phase is used the saturated common salt water washing, the Na2SO4 drying.Concentrate the back and use purification by silica gel column chromatography, obtain the predetermined intermediate product of 5.2g.Get the aforementioned product of 2g and be dissolved in 50ml CH3CN/H2O (10: the 1) mixed solvent, add the 1.8g PHENTERMINE.60 degree stirred 4 hours, added the 5%KH2PO4 aqueous solution.Dichloromethane extraction.Merge organic phase.Water successively, after the saturated common salt water washing, the Na2SO4 drying.Use purification by silica gel column chromatography, products obtained therefrom to be dissolved in the methyl alcohol after concentrating and refluxed 4 hours, obtain 900mg 4 "-O-ethanoyl-11,12-dideoxy-12,11-(oxygen carbonyl-(N-(4-(4-phenyl) butyl) imino-))-clarithromycin.
Get 880mg 4 "-O-ethanoyl-11,12-dideoxy-12,11-(oxygen carbonyl-(N-(4-(4-phenyl) butyl) imino-))-clarithromycin; methylbenzene azeotropic band water three times; be dissolved in 8ml exsiccant N in 0 ℃ in the N-dimethylformamide, feed exsiccant nitrogen.Add 8ml 1, the N of 1 '-carbonyl dimidazoles (603mg), N-dimethylformamide solution in 0 ℃.Subsequently 52mg sodium hydride (60%) powder is added reactor at twice, it is muddy that reaction solution becomes.In 0 ℃ of stirring reaction 5 hours.Add the 30ml frozen water,, merge organic phase with dichloromethane extraction (40ml * 3 time), water and saturated sodium-chloride water solution washing respectively, the anhydrous sodium sulphate powder for drying concentrates.Get white foam shape solid 920mg.Methylbenzene azeotropic band water is dissolved in 8ml exsiccant N, and the N-dimethylformamide feeds drying nitrogen.Add 0.28ml 4-phenyl fourth ammonia and 1.57ml 1 successively in room temperature, 8-diazacyclo hendecene, the little yellow clarification of reaction solution, stirring at room reaction 12 hours.Add saturated sodium bicarbonate solution cancellation reaction, dichloromethane extraction (20ml * 3 time) merges organic phase, water and saturated sodium-chloride water solution washing respectively, and the anhydrous sodium sulphate powder for drying concentrates.Get thick product 950mg; the normal pressure silica gel column chromatography; get product 420mg 11; 12-dideoxy-5-(2-oxygen carbonyl-(4-phenyl) butyl imino-)-dimethylamine sugar)-3-takes off ((2; 6-dideoxy-3-(methyl-3-O-methyl-α-L-pyrans nuclear hexose)-6-O-methyl-4 "-ethanoyl-12,11-(oxygen carbonyl (4-(phenyl) butyl) imino-) erythromycin.
Get the above-mentioned product of 68mg and be dissolved in the 2ml methyl alcohol, add 16.8mg salt of wormwood powder, 60 ℃ of oil baths reactions 20 hours add the 10ml methylene dichloride, water successively, the saturated sodium-chloride water solution washing, anhydrous sodium sulfate drying concentrates, the 50mg predetermined prod.
13C-NMR (100MHz) δ: 216.0 (C-9); 176.0 (C-1); 157.3 (12-O-C=O); 155.4 (2 '-O-C=OO); (142.5 phenyl ring-1 C); (141.9 phenyl ring-1 C); (128.4 phenyl ring-2,6 C); (128.3 phenyl ring-2,6 C); (128.3 phenyl ring-3,5 C); (128.1 phenyl ring-3,5 C); (125.8 phenyl ring-4 C); (125.5 phenyl ring-4 C); 100.8 (C-1 '); 95.6 (C-1 "); 82.4; 79.6; 78.8; 77.7; 76.2; 72.7; 68.1; 65.8; 63.4; 60.1; 50.2 (3 "-OCH
3); 49.4 (6-O-CH
3); 45.3; 45.2; 43.2; 40.8; 40.5; 38.9; 38.4; 35.5; 35.5; 35.3; 34.8; 30.8; 29.8; 29.6; 29.0; 28.6; 28.4; 26.9; 22.0; 21.4; 21.2; 20.1; 18.7; 15.9; 15.4; 14.3; 14.1; 10.3; 8.6;
1H-NMR (400MHz) δ: 7.30-7.11 (m, phenyl ring 10H), 4.97 (dd, 1H), 4.91 (d, 1H), 4.64 (t, 2H), 4.49 (d, 1H), 3.97 (m, 1H), 3.69 (t, 2H), 3.61 (t, 3H), 3.48 (m, 1H), 3.32 (s, 3H), and 3.26-3.13 (m, 3H), 3.04 (m, 2H), 2.92 (s, 3H, 6-O-CH
3), 2.83 (m, 1H), 2.63 (m, 6H), 2.32 (s, 6H, 3 '-NMe
2), 1.85 (m, 2H), 1.35 (s, 6H), 1.25 (m, 6H), 1.21 (m, 6H), 1.12 (m, 6H), 0.99 (d, 3H), 0.91 (d, 3H), 0.83 (t, 3H);
ESI/MS：m/z?1080.8[M+H]
+。
Embodiment 2
(2) 11,12-dideoxy-5-(2-oxygen carbonyl amino) dimethylamine sugar-6-O-methyl isophthalic acid 2,11-oxygen carbonyl ((4-(benzene butyl) imino-) erythromycin
With 70mg exsiccant 6-O-methyl-4 "-ethanoyl-11; 12-dideoxy-12; 11-(oxygen carbonyl-(N-(4-(4-phenyl) butyl) imino-)) erythromycin is dissolved in 1ml exsiccant N; in the N-dimethylformamide; reduce to 0 ℃; add 1 subsequently, 1 '-carbonyl dimidazoles 48mg and sodium hydride (60%) 4.2mg, the yellow clarification of reaction solution.0 ℃ of stirring reaction 3 hours adds frozen water 5ml, and dichloromethane extraction (10ml * 3 time) merges organic phase, the saturated nacl aqueous solution washing, anhydrous sodium sulfate drying concentrates, thick product 75mg.The normal pressure silica gel column chromatographic separation gets product 33mg.Above-mentioned products obtained therefrom is dissolved in the 1ml methyl alcohol, adds salt of wormwood 8mg, in 45 ℃ of oil baths reactions 12 hours,, dichloromethane extraction (15ml * 3 time) merges organic phase, the saturated nacl aqueous solution washing, anhydrous sodium sulfate drying concentrates, thick product 19mg.The normal pressure silica gel column chromatography purification gets product 14mg.
13C-NMR (100MHz) δ: 215.8 (C-9); 175.9 (C-1); 170.3 (2 '-O-C=O); 157.3 (12-O-C=O); 155.2 (2 '-O-C=O); (142.5 phenyl ring-1 C); (128.4 phenyl ring-2,6 C); (128.1 phenyl ring-3,5 C); (125.5 phenyl ring-4 C); 99.8 (C-1 '); 95.8 (C-1 "); 82.4; 79.5; 78.6; 78.5; 77.2; 76.1; 72.6; 67.3; 63.1; 62.9; 60.2; 54.5; 50.2 (3 "-OCH
3); 49.4 (6-O-CH
3); 45.4; 44.9; 43.3; 40.7; 38.9; 38.4; 38.4; 35.5; 35.1; 29.0; 26.9; 22.0; 21.4; 21.0; 20.8; 20.0; 18.7; 18.3; 15.8; 14.3; 14.1; 10.3; 8.5.
Embodiment 3
(3) 11,12-dideoxy-6-O-methyl-3-O-((4-oxygen carbonyl phenyl butyl) amino) cladinose-12,11-(oxygen carbonyl (4-(phenyl butyl) imino-)) erythromycin
Get 2.0g 2 '-O-ethanoyl-clarithromycin, methylbenzene azeotropic band water three times is dissolved in 20ml exsiccant N in 0 ℃, in the N-dimethylformamide, feeds exsiccant nitrogen.Add 44ml 1, the N of 1 '-carbonyl dimidazoles (3.3g), N-dimethylformamide solution in 0 ℃.Subsequently 148mg sodium hydride (60%) powder is divided three times and add reactor, it is muddy that reaction solution becomes.In 0 ℃ of stirring reaction 5 hours.Add the 150ml frozen water,, merge organic phase with dichloromethane extraction (60ml * 3 time), water and saturated sodium-chloride water solution washing respectively, the anhydrous sodium sulphate powder for drying concentrates.Get white foam shape solid 2.5g.Methylbenzene azeotropic band water is dissolved in 80ml exsiccant N, and the N-dimethylformamide feeds drying nitrogen.Add 0.9ml 4-phenyl fourth ammonia and 4.7ml 1 successively in room temperature, 8-diazacyclo hendecene, the little yellow clarification of reaction solution, stirring at room reaction 12 hours.Add saturated sodium bicarbonate solution 180ml cancellation reaction, dichloromethane extraction (60ml * 3 time) merges organic phase, water and saturated sodium-chloride water solution washing respectively, and the anhydrous sodium sulphate powder for drying concentrates.Get thick product 2.7g; the normal pressure silica gel column chromatography; get 820mg 4 "-O-(N-(4-(4-phenyl) butyl) amino) formyl radical-2 '-O-ethanoyl-10-methyl isophthalic acid 0; 11-dehydration-clarithromycin and 850mg 4 "-O-(N-(4-(4-phenyl) butyl) amino) formyl radical-6-O-methyl-2 '-O-ethanoyl-11; 12-dideoxy-12,11-(oxygen carbonyl-(N-(4-(4-phenyl) butyl) imino-)) erythromycin.Get 150mg the said products and be dissolved in the 5ml methyl alcohol, 80 ℃ of oil baths were reacted 20 hours, concentrated, and got thick product 144mg, and the normal pressure silica gel column chromatography gets product 96mg.
13C-NMR (100MHz) δ; 216.0 (C-9); 176.1 (C-1); 157.4 (12-O-C=O); 156.2 (4 "-O-C=O); (142.6 phenyl ring-1 C); (141.9 phenyl ring-1 C); (128.4 phenyl ring-2,6 C); (128.3 phenyl ring-2,6 C and phenyl ring-3,5 C); (128.1 phenyl ring-3,5 C); (125.8 phenyl ring-4 C); (125.5 phenyl ring-4 C); 102.4 (C-1 '); 96.3 (C-1 "); 82.5; 79.7; 78.9; 78.7; 78.0; 76.2; 72.9; 71.0; 68.1; 65.1; 63.4; 60.1; 50.5 (3 "-OCH
3); 49.6 (6-O-CH
3); 45.4; 45.1; 43.3; 40.9; 40.2; 39.0 (3 '-NMe
2); 35.6; 35.4; 35.2; 29.5; 29.1; 28.4; 26.9; 22.0; 21.6; 20.8; 20.1; 18.8; 18.2; 15.9; 14.2; 14.1; 10.3; 9.0;
ESI/MS：m/z?1079[M+H]
+。
Embodiment 4
(4) 11,12-dideoxy-5-(2-oxygen carbonyl (4-(3H-imidazo (4,5b)-pyridine-3-) butyl) imino-) dimethylamine sugar-6-O-methyl isophthalic acid 2,11-oxygen carbonyl ((4-(the 3H-imidazo (4,5b)-pyridine-3) butyl) imino-) erythromycin
Get 80mg according to case study on implementation 1 method prepare 11; 12-dideoxy-5-(2-oxygen carbonyl (4-(3H-imidazo (4; 5b)-and the butyl of pyridine-3-)) imino--dimethylamine sugar)-6-O-methyl-4 "-ethanoyl-12; 11-(4-(3H-imidazo (4; 5b)-pyridine-3-) butyl) imino-erythromycin; be dissolved in the 4ml methyl alcohol; add 18mg salt of wormwood powder; 60 ℃ of oil baths reactions 24 hours add the 10ml methylene dichloride, successively water; the saturated sodium-chloride water solution washing; anhydrous sodium sulfate drying concentrates, and gets the 45mg product.
1H-NMR(400MHz)δ：8.38(m，2H)，8.15(s，2H)，8.02(m，2H)，7.23(m，2H)，5.03(dd，1H)，4.97(d，1H)，4.62(t，2H)，4.54(d，1H)，3.94(m，1H)，3.71(t，2H)，3.60(t，3H)，3.48(m，1H)，.35(s，3H)，3.30-3.15(m，3H)，3.11(m，2H)，2.95(s，3H，6-O-CH
3)，2.83(m，1H)，2.67(m，6H)，2.32(s，6H，3’-NMe
2)，ESI/MS：m/z?1161。
Embodiment 5
(5) 11,12-dideoxy-5-(2-oxygen carbonyl amino) dimethylamine sugar-6-O-methyl isophthalic acid 2,11-oxygen carbonyl ((4-(the 3H-imidazo (4,5b)-pyridine-3) butyl) imino-) erythromycin
With the exsiccant 6-O-methyl isophthalic acid 1 of 90mg by similar case study on implementation 2 methods preparation; 12-dideoxy-4-O-ethanoyl-12; 11-(oxygen carbonyl-(N-(4-(3H-imidazo (4; 5b)-and pyridine-3) butyl) imino-)) erythromycin is dissolved in 1ml exsiccant N; in the N-dimethylformamide, reduce to 0 ℃, add 1 subsequently; 1 '-carbonyl dimidazoles 50mg and sodium hydride (60%) 5mg, the yellow clarification of reaction solution.0 ℃ of stirring reaction 5 hours adds frozen water 5ml, and dichloromethane extraction (10ml * 3 time) merges organic phase, the saturated nacl aqueous solution washing, anhydrous sodium sulfate drying concentrates, thick product 63mg.The normal pressure silica gel column chromatographic separation gets product 43mg.Above-mentioned products obtained therefrom is dissolved in the 1ml methyl alcohol, adds salt of wormwood 4mg, in 45 ℃ of oil baths reactions 10 hours,, dichloromethane extraction (10ml * 3 time) merges organic phase, the saturated nacl aqueous solution washing, anhydrous sodium sulfate drying concentrates, thick product 39mg.The normal pressure silica gel column chromatography purification gets product 24mg.
13C-NMR(100MHz)δ：215.0(C-9)；173.7(C-1)；170.9(2’-O-C＝O)；158(12-O-C＝O)；155.6(2’-O-C＝O)；99.4(C-1’)；93.8(C-1”)。
Embodiment 6
(6) 11,12-dideoxy-6-O-methyl-3-O-(4-oxygen carbonyl (the 3H-imidazo (4,5b)-pyridine-3) butyl amino) cladinose-12,11-oxygen carbonyl ((4-((the 3H-imidazo (4,5b)-pyridine-3) butyl) imino-) erythromycin
Get 2.0g 2 '-O-ethanoyl-clarithromycin, methylbenzene azeotropic band water three times is dissolved in 20ml exsiccant N in 0 ℃, in the N-dimethylformamide, feeds exsiccant nitrogen.Add 44ml 1, the N of 1 '-carbonyl dimidazoles (3.3g), N-dimethylformamide solution in 0 ℃.Subsequently 148mg sodium hydride powder is divided three times and add reactor, it is muddy that reaction solution becomes.In 0 ℃ of stirring reaction 5 hours.Add the 150ml frozen water,, merge organic phase with dichloromethane extraction (60ml * 3 time), water and saturated sodium-chloride water solution washing respectively, the anhydrous sodium sulphate powder for drying concentrates.Get white foam shape solid 2.5g.Get this spumescence solid of 200mg, methylbenzene azeotropic band water is dissolved in 5ml exsiccant N, and the N-dimethylformamide feeds drying nitrogen.Add 90mg 4-(3H-imidazoles [4,5-b] pyridin-3-yl)-1-butylamine and 0.4ml 1 successively in room temperature, 8-diazacyclo hendecene, the little yellow clarification of reaction solution, stirring at room reaction 12 hours.Add saturated sodium bicarbonate solution 8ml cancellation reaction, ethyl acetate extraction (5ml * 3 time) merges organic phase, and toluene concentrates.Get thick product 187mg; the normal pressure silica gel column chromatography; obtain 85mg4 "-O-(N-(4-(3-3H-imidazoles [4; 5-b]-pyridyl) butyl) amino) formyl radical-2 '-O-ethanoyl-11; 12-dideoxy-12; 11-(oxygen carbonyl-(N-(4-(3-3H-imidazoles [4,5-b]-pyridyl) butyl) imino-))-6-O-methyl-erythromycin.Get 40mg the said products and be dissolved in the 2ml methyl alcohol, 80 ℃ of oil baths were reacted 20 hours, concentrated, and got thick product 32mg, and the normal pressure silica gel column chromatography gets product 25mg.
13C-NMR (100MHz) δ: 216.1 (C-9); 176.2 (C-1); 157.3 (12-O-C=O); 156.4 (4 "-O-C=O); (146.9 2 heterocycle-4 C); (144.1 heterocycle-2 C); (144.1 heterocycle-2 C); (144.0 heterocycle-8 C); (143.9 heterocycle-8 C); (135.3 2 heterocycle-5 C); (127.8 heterocycle-6 C); (127.6 heterocycle-6 C); (118.1 heterocycle-7 C); (117.9 heterocycle-7 C); 102.1 (C-1 '); 96.3 (C-1 "); 82.6; 80.2; 78.7; 76.1; 73.0; 70.7; 67.5; 65.1; 63.3; 63.3; 59.8; 52.9; 50.3 (3 "-O-CH
3); 49.3 (6-O-CH
3); 45.3; 45.0; 43.4; 43.1; 42.6; 40.2 (3 '-NMe
2); 40.0; 38.9; 38.8; 35.1; 29.5; 27.4; 27.0; 26.9; 24.4; 21.8; 21.2; 20.8; 20.1; 18.7; 18.1; 16.0; 14.1; 14.0; 10.3; 9.2;
1H-NMR (400MHz) δ: 8.34 (m, 2H, 2 heterocycle-8 H), 8.11 (s, 1H, heterocycle-2 H), 8.07 (s, 1H, heterocycle-2 H), 8.00 (m, 2H, 2 heterocycle-8 H), 7.18 (m, 2H, heterocycle-7 H), 4.90 (m, 2H), 4.50 (d, 2H), 4.31 (t, 3H), 4.21 (m, 1H) 3.56 (m), 3.26 (s, 3H, 6-O-CH
3), 3.04 (m, 2H), 2.83 (s, 3H), 2.51 (s, 6H, 3 '-NMe
2), 1.94 (m, 3H), 1.83 (m, 1H), 1.66 (m, 2H), 1.42 (t, 12H), 1.34 (d, 6H), 0.94 (d, 3H), 1.10 (m, 15H), 0.78 (t, 3H);
ESI/MS：m/z?1162.8[M+H]
+。
Embodiment 7
(7) 11,12-dideoxy-5-(2-oxygen carbonyl (4-(the 1H-imidazo (4,5b)-pyridine-1) butyl) imino-) dimethylamine sugar-6-O-methyl isophthalic acid 2,11-oxygen carbonyl ((4-(the 1H-imidazo (4,5b)-pyridine-1) butyl) imino-) erythromycin
Get the intermediate 11 that 46mg prepares according to similar case study on implementation 1 method; 12-dideoxy-5-(2-oxygen carbonyl (4-(1H-imidazo (4; 5b)-and pyridine-1) butyl) imino--dimethylamine sugar)-6-O-methyl-4 "-ethanoyl-12; and 11-(4-(the 1H-imidazo (4; 5b)-pyridine-1) butyl) imino-erythromycin; be dissolved in the 2ml methyl alcohol; add the 10.4mg potassium carbonate powder; 60 ℃ of oil baths were reacted 20 hours, added the 10ml methylene dichloride, successively water; the saturated sodium-chloride water solution washing; anhydrous sodium sulfate drying concentrates, and gets the 28mg title product.
1H-NMR(400MHz)8.60(2H)，8.10(2H)，8.09(2H)，7.74(2H)，7.20(2H)，4.74，2.74，2.50，2.00，1.90，1.53；
ESI/MS：m/z?1161。
Embodiment 8
(8) 11,12-dideoxy-5-(2-oxygen carbonyl amino) dimethylamine sugar-6-O-methyl isophthalic acid 2,11-oxygen carbonyl ((4-(the 1H-imidazo (4,5b)-pyridine-1) butyl) imino-) erythromycin
With the exsiccant 6-O-methyl isophthalic acid 1 of 40mg by similar case study on implementation 2 methods preparation; 12-dideoxy-4-O-ethanoyl-12; 11-(oxygen carbonyl-(N-(4-(3H-imidazo (4; 5b)-and pyridine-3) butyl) imino-)) erythromycin is dissolved in 1ml exsiccant N; in the N-dimethylformamide, reduce to 0 ℃, add 1 subsequently; 1 '-carbonyl dimidazoles 30mg and sodium hydride (60%) 4mg, the yellow clarification of reaction solution.0 ℃ of stirring reaction 4 hours adds frozen water 5ml, and dichloromethane extraction (10ml * 3 time) merges organic phase, the saturated nacl aqueous solution washing, anhydrous sodium sulfate drying concentrates, thick product 33mg.Above-mentioned thick product is dissolved in the 1ml methyl alcohol, adds salt of wormwood 3mg, in 45 ℃ of oil baths reactions 12 hours,, dichloromethane extraction (10ml * 3 time) merges organic phase, the saturated nacl aqueous solution washing, anhydrous sodium sulfate drying concentrates, thick product 29mg.The normal pressure silica gel column chromatography purification gets product 20mg.
13C-NMR(100MHz)δ：215.7(C-9)；175.7(C-1)；172.2(4”-O-C＝O)；153.6(12-O-C＝O)；155.3(2’-O-C＝O)；97.9(C-1’)；935.1(C-1”)。
Embodiment 9
(9) 11,12-dideoxy-6-O-methyl-3-O-(4-oxygen carbonyl-(4-(the 1H-imidazo (4,5b)-pyridine-1) butyl) amino) cladinose-12,11-oxygen carbonyl ((4-(the 1H-imidazo (4,5b)-pyridine-1) butyl) imino-) erythromycin
Get 2.0g 2 '-O-ethanoyl-clarithromycin, methylbenzene azeotropic band water three times is dissolved in 20ml exsiccant N in 0 ℃, in the N-dimethylformamide, feeds exsiccant nitrogen.Add 44ml 1, the N of 1 '-carbonyl dimidazoles (3.3g), N-dimethylformamide solution in 0 ℃.Subsequently 148mg sodium hydride powder is divided three times and add reactor, it is muddy that reaction solution becomes.In 0 ℃ of stirring reaction 5 hours.Add the 150ml frozen water,, merge organic phase with dichloromethane extraction (60ml * 3 time), water and saturated sodium-chloride water solution washing respectively, the anhydrous sodium sulphate powder for drying concentrates.Get white foam shape solid 2.5g.Get this spumescence solid of 200mg, methylbenzene azeotropic band water is dissolved in 5ml exsiccant N, and the N-dimethylformamide feeds drying nitrogen.Add 109mg 4-(1H-imidazoles [4,5-b] pyridine-1-yl)-1-butylamine and 0.4ml 1 successively in room temperature, 8-diazacyclo hendecene, the little yellow clarification of reaction solution, stirring at room reaction 12 hours.Add saturated sodium bicarbonate solution 8ml cancellation reaction, ethyl acetate extraction (5ml * 3 time) merges organic phase, and toluene concentrates.Get thick product 200mg.Above-mentioned products obtained therefrom is dissolved in the 10ml methyl alcohol, adds salt of wormwood 40mg, in 45 ℃ of oil baths reactions 10 hours,, dichloromethane extraction (10ml * 3 time) merges organic phase, the saturated nacl aqueous solution washing, anhydrous sodium sulfate drying concentrates, thick product 139mg.The normal pressure silica gel column chromatography purification gets product 86mg.
The normal pressure silica gel column chromatography gets the 66mg title compound.
1H-NMR(400MHz)：8.59(2H)，8.10(2H)，8.07(2H)，7.30-7.10，4.87，4.65，2.60，2.32；
ESI/MS：m/z?1161。
Embodiment 10
(10) 11,12-dideoxy-5-(2-oxygen carbonyl (4-(3-pyridyl)-1H-imidazoles-1) butyl) imino-) dimethylamine sugar-6-O-methyl isophthalic acid 2,11-oxygen carbonyl ((4-((3-pyridyl)-1H-imidazoles-1) butyl) imino-) erythromycin
Carry out according to embodiment 1 method, difference is to use (4-(3-pyridyl)-1H-imidazoles-1) butyl amino to obtain title product as substituting group.
1H-NMR(400MHz)：8.87(2H)，8.62(2H)，8.07(2H)，7.40-7.55，7.30(2H)，4.90，4.87，4.60，4.51，4.01，3.72，3.62，3.48，3.32，3.26-3.13，3.05，2.97，2.84，2.32。
Embodiment 11
(11) 11,12-dideoxy-5-(2-oxygen carbonyl amino) dimethylamine sugar-6-O-methyl isophthalic acid 2,11-oxygen carbonyl ((4-((3-pyridyl)-1H-imidazoles-1) butyl) imino-) erythromycin
Carry out according to embodiment 2 methods, difference is to use (4-(3-pyridyl)-1H-imidazoles-1) butyl amino to obtain title product as substituting group.
Embodiment 12
(12) 11,12-dideoxy-6-O-methyl-3-O-(4-oxygen carbonyl-(4-((3-pyridyl)-1H-imidazoles-1) butyl amino) cladinose-12,11-oxygen carbonyl ((4-((3-pyridyl)-1H-imidazoles-1) butyl) imino-) erythromycin
Carry out according to embodiment 3 methods, difference is to use (4-(3-pyridyl)-1H-imidazoles-1) butyl amino to obtain title product as substituting group.
1H-NMR(400MHz)：8.91(2H)，8.64(2H)，8.10(2H)，7.40-7.55(m)，7.33，4.67，3.67，3.07，2.32。
Embodiment 13
(13) 11,12-dideoxy-5-(2-oxygen carbonyl (4-((4-pyridyl)-1H-imidazoles-1) butyl) imino-) dimethylamine sugar-6-O-methyl isophthalic acid 2,11-oxygen carbonyl ((4-((4-pyridyl)-1H-imidazoles-1) butyl) imino-) erythromycin
Carry out according to embodiment 1 method, difference is to use (4-(4-pyridyl)-1H-imidazoles-1) butyl amino to obtain title product as substituting group.
1H-NMR(400MHz)：8.55(2H)，7.60-7.75(m)，7.20(2H)，6.09，4.90，4.67，4.53，4.05，3.77，3.67，3.58，3.32，3.27-3.20，3.05，3.06，2.80，2.32。
Embodiment 14
(14) 11,12-dideoxy-5-(2-oxygen carbonyl amino) dimethylamine sugar-6-O-methyl isophthalic acid 2,11-oxygen carbonyl ((4-((4-pyridyl)-1H-imidazoles-1) butyl) imino-) erythromycin
Carry out according to embodiment 2 methods, difference is to use (4-(4-pyridyl)-1H-imidazoles-1) butyl amino to obtain title product as substituting group.
Embodiment 15
(15) 11,12-dideoxy-6-O-methyl-3-O-(4-oxygen carbonyl (4-((4-pyridyl)-1H-imidazoles-1) butyl) amino) cladinose-12,11-oxygen carbonyl ((4-((4-pyridyl)-1H-imidazoles-1) butyl) imino-) erythromycin
Carry out according to embodiment 3 methods, difference is to use (4-(4-pyridyl)-1H-imidazoles-1) butyl amino to obtain title product as substituting group.
1H-NMR(400MHz)：8.56(4H)，7.37-7.60(m)，7.27，4.79，3.66，3.07，2.35。
Embodiment 16
(16) 11,12-dideoxy-5-(2-oxygen carbonyl (4-(phenyl-1H-imidazoles-1) butyl) imino-) dimethylamine sugar-6-O-methyl isophthalic acid 2,11-oxygen carbonyl ((4-((phenyl-1H-imidazoles-1) butyl) imino-) erythromycin
Carry out according to embodiment 1 method, difference is to use (4-(phenyl)-1H-imidazoles-1) butyl amino to obtain title product as substituting group.
1H-NMR(400MHz)：8.00(2H)，7.97(2H)，7.49(2H)，7.20-7.35(m)，4.93，4.77，4.65，4.54，4.00，3.85，3.65，3.58，3.36，3.36-3.23，3.05，2.91，2.80，2.32。
Embodiment 17
(17) 11,12-dideoxy-5-(2-oxygen carbonyl amino) dimethylamine sugar-6-O-methyl isophthalic acid 2,11-oxygen carbonyl ((4-((phenyl-1H-imidazoles-1) butyl) imino-) erythromycin
Carry out according to embodiment 2 methods, difference is to use (4-(phenyl)-1H-imidazoles-1) butyl amino to obtain title product as substituting group.
Embodiment 18
(18) 11,12-dideoxy-6-O-methyl-3-O-(4-oxygen carbonyl ((phenyl-1H-imidazoles-1) butyl amino) cladinose-12,11-oxygen carbonyl ((4-(((phenyl-1H-imidazoles-1) butyl) imino-) erythromycin
Carry out according to embodiment 3 methods, difference is to use (4-(phenyl)-1H-imidazoles-1) butyl amino to obtain title product as substituting group.
1H-NMR(400MHz)：7.99(2H)，7.87(2H)，7.59(2H)，7.20-7.35(m)，4.93(m，2H)，4.57(d，2H)，4.39(t，3H)，4.25(m，1H)，3.50(m)，3.23(s，3H，6-O-CH
3)，3.04(m，2H)，2.86(s，3H)，2.57(s，6H，3’-NMe
2)，1.93(m，3H)，1.82(m，1H)，1.67(m，2H)，1.40(t，12H)，1.35(d，6H)，0.99(d，3H)，1.13(m，15H)，0.78(t，3H)。
Embodiment 19
(19) 11,12-dideoxy-5-(2-oxygen carbonyl (3-(5-methoxyl group-1H-imidazoles (4,5b) pyridine-2-sulfydryl replaces) propyl group) imino-) dimethylamine sugar-6-O-methyl isophthalic acid 2,11-oxygen carbonyl ((3-((5-methoxyl group-1H-imidazoles (4,5b) pyridine-2-sulfydryl replaces) propyl group) imino-) erythromycin
Get the corresponding intermediate of 35mg, be dissolved in the 1ml methyl alcohol, add the 7.8mg potassium carbonate powder, 60 ℃ of oil baths reactions 20 hours add the 10ml methylene dichloride, water successively, the saturated sodium-chloride water solution washing, anhydrous sodium sulfate drying concentrates, the 22mg title product.
1H-NMR(400MHz)：7.72(2H)，6.68(2H)，4.98(dd，1H)，4.94(d，1H)，4.53(d，1H)，4.07(25’-OCH
3)，3.95(m，1H)，3.76(2CH
2)，3.62(t，3H)，3.47(m，1H)，3.40(2CH
2)，3.31(s，3H)，3.27-3.15(m，3H)，2.92(s，3H，6-O-CH
3)，2.85(m，1H)，2.60(m，6H)，2.32(s，6H，3’-NMe
2)，1.89(4CH
2)，ESI/MS：m/z?1197。
Embodiment 20
(20) 11,12-dideoxy-5-(2-oxygen carbonyl amino) dimethylamine sugar-6-O-methyl isophthalic acid 2,11-oxygen carbonyl ((3-(5-methoxyl group-1H-imidazoles (4,5b) pyridine-2-sulfydryl replaces) propyl group) imino-) erythromycin
Carry out according to embodiment 2 methods, obtain title product.
Embodiment 21
(21) 11,12-dideoxy-6-O-methyl-3-O-(4-oxygen carbonyl (3-(5-methoxyl group-1H-imidazoles (4,5b) pyridine-2-sulfydryl replaces) propyl group amino) cladinose-12,11-oxygen carbonyl ((3-(5-methoxyl group-1H-imidazoles (4,5b) pyridine-2-sulfydryl replaces) propyl group) imino-) erythromycin
Carry out according to embodiment 3 methods, different are to use, and (3-(5-methoxyl group-1H-imidazoles (4,5b) pyridine-2-sulfydryl replaces) propyl group) imino-obtains title product as substituting group.
1H-NMR(400MHz)：δ：7.73(2H)，6.65(2H)，4.90(m，2H)，4.50(d，2H)，4.04(25’-OCH
3)，4.31(t，3H)，4.21(m，1H)，3.76(2CH
2)，3.56(m)，3.40(2CH
2)，3.26(s，3H，6-O-CH
3)，3.04(m，2H)，2.83(s，3H)，2.51(s，6H，3’-NMe
2)，1.89(4CH
2)，1.83(m，1H)。
Embodiment 22
(22) 11,12-dideoxy-5-(2-oxygen carbonyl (3-(3-pyridyl)-1H-imidazoles-2-sulfydryl replaces-2)-propyl group) imino-) dimethylamine sugar-6-O-methyl isophthalic acid 2,11-oxygen carbonyl ((3-(3-pyridyl)-1H-imidazoles-2-sulfydryl replacement-2-propyl group) imino-) erythromycin
Get the corresponding intermediate of 58mg, be dissolved in the 2.0ml methyl alcohol, add salt of wormwood 8mg, in 45 ℃ of oil bath reactions 10 hours,, dichloromethane extraction (10ml * 3 time) merges organic phase, the saturated nacl aqueous solution washing, anhydrous sodium sulfate drying concentrates, and gets thick product 139mg.The normal pressure silica gel column chromatography purification gets product 55mg.
1H-NMR(400MHz)：9.03(2H)，8.67(2H)，8.44(2H)，7.82(2H)，7.75(2H)，4.95(dd，1H)，4.92(d，1H)，4.63(t，2H)，4.56(d，1H)，3.96(m，1H)，3.67(t，2H)，3.68(t，3H)，3.49(m，1H)，3.31(s，3H)，3.25-3.19(m，3H)，3.09(m，2H)，2.95(s，3H，6-O-CH
3)，2.88(m，1H)，2.69(m，6H)，2.35(s，6H，3’-NMe
2)，1.87(m，2H)，
ESI/MS：m/z?1197。
Embodiment 23
(23) 11,12-dideoxy-5-(2-oxygen carbonyl amino) dimethylamine sugar-6-O-methyl isophthalic acid 2,11-oxygen carbonyl ((3-((3-pyridyl)-1H-imidazoles-2-sulfydryl replace-2-) propyl group) imino-) erythromycin
Carry out according to embodiment 2 methods, obtain title product.
Embodiment 24
(24) 11,12-dideoxy-6-O-methyl-3-O-4-oxygen carbonyl ((3-((3-pyridyl)-1H-imidazoles-2-sulfydryl replace-2-) propyl group amino) cladinose-12,11-oxygen carbonyl ((3-((3-pyridyl)-1H-imidazoles-2-sulfydryl replace-2-) propyl group) imino-) erythromycin
Carry out according to embodiment 3 methods, different are to use, and (3-((3-pyridyl)-1H-imidazoles-2-sulfydryl replace-2-) propyl group) imino-obtains title product as substituting group.
1H-NMR(400MHz)：9.02(2H)，8.762(2H)，8.54(2H)，7.73(2H)，7.70(2H)，4.91(m，2H)，4.54(d，2H)，4.32(t，3H)，4.23(m，1H)，3.59(m)，3.27(s，3H，6-O-CH
3)，3.05(m，2H)，2.85(s，3H)，2.50(s，6H，3’-NMe
2)，1.97(m，3H)。
Embodiment 25
Provide the purposes of above-claimed cpd with following antibacterial activity in vitro experiment at antibiosis.
(1) experimental technique: the standard agar plate doubling dilution that adopts NCCL to propose carries out minimum antibacterial (MIC) to compound and measures.With MIC value judgement sample anti-microbial activity and anti-microbial effect power.
(2) contrast medicine: azithromycin, clarithromycin
(3) measure bacterium:
MRSA described in the form is a methicillin-resistant staphylococcus aureus, and MSSA is a MSSA.
The compound that experiment showed, the structural formula of the present invention 1 of method for preparing has antibiotic and the antimicrobial agent activity, can be used for preparing antibacterials.
Claims (10)
1. Erythromycin A analog derivative, its structural formula is as follows:
Wherein, described R
1Be expressed as-R
4-R
5
R
2Be expressed as H ,-CONR
6-R
7, aminoacyl, ethanoyl, benzoyl, by R
12The ethanoyl that replaces and by R
12The benzoyl that replaces;
R
3Be expressed as H or-CONR
8-R
9, aminoacyl, ethanoyl, benzoyl, by R
12The ethanoyl that replaces and by R
12The benzoyl that replaces; R
12Be hydroxyl, halogen atom, nitro, carboxyl, C (O) H, (O), HS, (S), CF
3, OH, NH
2, cyano group, contain 1 to 4 carbon atom the chain alkyl, contain oxyalkyl, sulfur-bearing alkyl, sulfur-bearing alkynyl or sulfur-bearing thiazolinyl, contain azanyl or contain 2 to 4 carbon atoms chain thiazolinyl, chain alkynyl, contain the oxycetylene base or contain oxy alkylene, nitrogenous alkynyl or nitrogenous thiazolinyl;
R
4, R
6, R
8The representative contain the alkyl of 1～30 carbon atom, by R
10The alkyl that replaces is perhaps by an alkyl of blocking to five heteroatomss; 1～30 above-mentioned carbon atom alkyl is the cycloalkyl of the alkyl of 1～30 carbon atom, 3～30 carbon atoms, 3～30 alkenyl or alkynyls, and fragrant substituted alkyl or virtue are for alkynyl; Described R
10Be selected from hydroxyl, halogen atom, nitro, carboxyl, C (O) H, (O), HS, (S), CF
3, OH, NH
2, cyano group, contain 1 to 4 carbon atom the chain alkyl, contain oxyalkyl, sulfur-bearing alkyl, sulfur-bearing alkynyl or sulfur-bearing thiazolinyl, contain azanyl or contain 2 to 4 carbon atoms chain thiazolinyl, chain alkynyl, contain the oxycetylene base or contain oxy alkylene, nitrogenous alkynyl or nitrogenous thiazolinyl;
R
5, R
7, R
9Represent an aryl that contains 6～12 carbon atoms, aromatic heterocyclic, by R
11The aryl that replaces and by R
11The aromatic heterocyclic that replaces; Represented aryl is phenyl, naphthyl or contains 1～5 heteroatomic ternary to ten yuan fragrant heterocycle, these aromatic heterocyclics be sulfur-bearing, nitrogenous, contain oxygen or a fragrant heterocycle contains a kind of aromatic heterocyclic to five kinds of above-mentioned three kinds of different elemental nitrogen, oxygen, sulphur; R
11Be hydroxyl, halogen atom, nitro, carboxyl, C (O) H, (O), HS, (S), CF
3, OH, NH
2, cyano group, contain 1 to 4 carbon atom the chain alkyl, contain oxyalkyl, sulfur-bearing alkyl, sulfur-bearing alkynyl or sulfur-bearing thiazolinyl, contain azanyl or contain 2 to 4 carbon atoms chain thiazolinyl, chain alkynyl, contain the oxycetylene base or contain oxy alkylene, nitrogenous alkynyl or nitrogenous thiazolinyl.
2. derivative as claimed in claim 1 is characterized in that described alkyl, alkenyl or alkynyl are methyl, ethyl, propyl group, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, decyl, dodecyl, triacontyl, vinyl allyl group ethynyl, proyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;
Described aryl is a phenyl or naphthyl.
3. derivative as claimed in claim 1 is characterized in that described aromatic heterocyclic is thienyl, furyl, pyrryl, thiazolyl, oxazolyl, triazol radical, tetrazole base, imidazolyl, thiadiazolyl group, pyrazoles or imidazole base, pyridyl, pyrimidyl, reaches piperazine, pyrazinyl, indyl, benzofuryl, benzothiazolyl or quinolyl.
4. derivative as claimed in claim 1, described R during its feature
1For-R
4R
5, described R
2For-CONR
6R
7, described R
3For-CONR
8R
9, wherein said R
4, R
6Or R
8Be the alkyl that contains 1～8 carbon atom or the alkyl that contains 1～5 nitrogen, phosphorus, sulphur or oxygen heteroatom, R
10The alkyl that replaces; Described R
10Substituting group is selected from halogen, C (O) H, (O), HS, CF3, the alkyl of OH, C1～C4, halogen, NH
2
5. require described derivative as right 1, it is characterized in that R
1Be one of following group:
6. derivative as claimed in claim 1 is characterized in that described R
2Or R
3Be one of following group:
Or
7. derivative as claimed in claim 1 is characterized in that this compound is following compound:
(1) 11,12-dideoxy-5-(2-oxygen carbonyl (4-phenyl) butyl) imino-) dimethylamine sugar-6-O-methyl isophthalic acid 2,11-oxygen carbonyl ((4-(phenyl) butyl) imino-) erythromycin;
(2) 1,12-dideoxy-5-(2-oxygen carbonyl amino) dimethylamine sugar-6-O-methyl isophthalic acid 2,11-oxygen carbonyl ((4-(benzene butyl) imino-) erythromycin;
(3) 11,12-dideoxy-6-O-methyl-3-O-((4-oxygen carbonyl phenyl butyl) amino) cladinose-12,11-(oxygen carbonyl (4-(phenyl butyl) imino-)) erythromycin;
(4) 11,12-dideoxy-5-(2-oxygen carbonyl (4-(3H-imidazo (4,5b)-pyridine-3-) butyl) imino-) dimethylamine sugar-6-O-methyl isophthalic acid 2,11-oxygen carbonyl ((4-(the 3H-imidazo (4,5b)-pyridine-3) butyl) imino-) erythromycin;
(5) 11,12-dideoxy-5-(2-oxygen carbonyl amino) dimethylamine sugar-6-O-methyl isophthalic acid 2,11-oxygen carbonyl ((4-(the 3H-imidazo (4,5b)-pyridine-3) butyl) imino-) erythromycin;
(6) 11,12-dideoxy-6-O-methyl-3-O-(4-oxygen carbonyl (4-(the 3H-imidazo (4,5b)-pyridine-3) butyl amino) cladinose-12,11-oxygen carbonyl ((4-(the 3H-imidazo (4,5b)-pyridine-3) butyl) imino-) erythromycin;
(7) 11,12-dideoxy-5-(2-oxygen carbonyl (4-(the 1H-imidazo (4,5b)-pyridine-1) butyl) imino-) dimethylamine sugar-6-O-methyl isophthalic acid 2,11-oxygen carbonyl ((4-(the 1H-imidazo (4,5b)-pyridine-1) butyl) imino-) erythromycin;
(8) 11,12-dideoxy-5-(2-oxygen carbonyl amino) dimethylamine sugar-6-O-methyl isophthalic acid 2,11-oxygen carbonyl ((4-(the 1H-imidazo (4,5b)-pyridine-1) butyl) imino-) erythromycin;
(9) 11,12-dideoxy-6-O-methyl-3-O-(4-oxygen carbonyl-(4-(the 1H-imidazo (4,5b)-pyridine-1) butyl) amino) cladinose-12,11-oxygen carbonyl ((4-(the 1H-imidazo (4,5b)-pyridine-1) butyl) imino-) erythromycin;
(10) 11,12-dideoxy-5-(2-oxygen carbonyl (4-((3-pyridyl)-1H-imidazoles-1) butyl) imino-) dimethylamine sugar-6-O-methyl isophthalic acid 2,11-oxygen carbonyl (4-((3-pyridyl)-1H-imidazoles-1) butyl) imino-erythromycin;
(11) 11,12-dideoxy-5-(2-oxygen carbonyl amino) dimethylamine sugar-6-O-methyl isophthalic acid 2,11-oxygen carbonyl ((4-((3-pyridyl)-1H-imidazoles-1) butyl) imino-) erythromycin;
(12) 11,12-dideoxy-6-O-methyl-3-O-(4-oxygen carbonyl-(4-((3-pyridyl)-1H-imidazoles-1) butyl amino) cladinose-12,11-oxygen carbonyl ((4-((3-pyridyl)-1H-imidazoles-1) butyl) imino-) erythromycin;
(13) 11,12-dideoxy-5-(2-oxygen carbonyl (4-((4-pyridyl)-1H-imidazoles-1) butyl) imino-) dimethylamine sugar-6-O-methyl isophthalic acid 2,11-oxygen carbonyl ((4-((4-pyridyl)-1H-imidazoles-1) butyl) imino-) erythromycin;
(14) 11,12-dideoxy-5-(2-oxygen carbonyl amino) dimethylamine sugar-6-O-methyl isophthalic acid 2,11-oxygen carbonyl ((4-((4-pyridyl)-1H-imidazoles-1) butyl) imino-) erythromycin;
(15) 11,12-dideoxy-6-O-methyl-3-O-(4-oxygen carbonyl (4-((4-pyridyl)-1H-imidazoles-1) butyl) amino) cladinose-12,11-oxygen carbonyl ((4-((4-pyridyl)-1H-imidazoles-1) butyl) imino-) erythromycin;
(16) 11,12-dideoxy-5-(2-oxygen carbonyl (4-(phenyl-1H-imidazoles-1) butyl) imino-) dimethylamine sugar-6-O-methyl isophthalic acid 2,11-(oxygen carbonyl (4-(phenyl-1H-imidazoles-1) butyl) imino-) erythromycin;
(17) 11,12-dideoxy-5-(2-oxygen carbonyl amino) dimethylamine sugar-6-O-methyl isophthalic acid 2,11-(oxygen carbonyl (4-(phenyl-1H-imidazoles-1) butyl) imino-) erythromycin;
(18) 11,12-dideoxy-6-O-methyl-3-O-(4-oxygen carbonyl (4-(phenyl-1H-imidazoles-1) butyl amino)) cladinose-12,11-oxygen carbonyl ((4-(phenyl-1H-imidazoles-1) butyl) imino-) erythromycin;
(19) 11,12-dideoxy-5-(2-oxygen carbonyl (3-(5-methoxyl group-1H-imidazoles (4,5b) pyridine-2-sulfydryl replaces) propyl group) imino-) dimethylamine sugar-6-O-methyl isophthalic acid 2,11-oxygen carbonyl ((3-((5-methoxyl group-1H-imidazoles (4,5b) pyridine-2-sulfydryl replaces) propyl group) imino-) erythromycin;
(20) 11,12-dideoxy-5-(2-oxygen carbonyl amino) dimethylamine sugar-6-O-methyl isophthalic acid 2,11-oxygen carbonyl ((3-(5-methoxyl group-1H-imidazoles (4,5b) pyridine-2-sulfydryl replaces) propyl group) imino-) erythromycin;
(21) 11,12-dideoxy-6-O-methyl-3-O-4-oxygen carbonyl (3-(5-methoxyl group-1H-imidazoles (4,5b) pyridine-2-sulfydryl replaces) propyl group amino) cladinose-12,11-oxygen carbonyl ((3-(5-methoxyl group-1H-imidazoles (4,5b) pyridine-2-sulfydryl replaces) propyl group) imino-) erythromycin;
(22) 11,12-dideoxy-5-(2-oxygen carbonyl (3-(3-pyridyl)-1H-imidazoles-2-sulfydryl replaces-2)-propyl group) imino-) dimethylamine sugar-6-O-methyl isophthalic acid 2,11-oxygen carbonyl ((3-(3-pyridyl)-1H-imidazoles-2-sulfydryl replacement-2-propyl group) imino-) erythromycin;
(23) 11,12-dideoxy-5-(2-oxygen carbonyl amino) dimethylamine sugar-6-O-methyl isophthalic acid 2,11-oxygen carbonyl ((3-((3-pyridine base)-1H-imidazoles-2-sulfydryl replace-2-) propyl group) imino-) erythromycin or
(24) 11,12-dideoxy-6-O-methyl-3-O-4-oxygen carbonyl ((3-((3-pyridyl)-1H-imidazoles-2-sulfydryl replace-2-) propyl group amino) cladinose-12,11-oxygen carbonyl ((3-((3-pyridyl)-1H-imidazoles-2-sulfydryl replace-2-) propyl group) imino-) erythromycin.
8. the preparation method of an Erythromycin A analog derivative as claimed in claim 1 is characterized in that as (1) or (2) two kinds of methods:
(1) by the method for starting compound 1 synthetic compound 2
Under-10 ℃～0 ℃ temperature of organic solvent neutralization, raw material 1, carbonyl dimidazoles and sodium hydride reacted 1～24 hour; Products therefrom is in organic solvent, and R
1NH
2And 1,8-diazacyclo hendecene reaction 1～24 hour; Products therefrom is dissolved in the methyl alcohol again, room temperature～80 ℃ reaction 1～24 hour or add mol ratio be 0.1～2 salt of wormwood reaction got final product in 1～24 hour compound 2; Described raw material 1, carbonyl dimidazoles, sodium hydride, R
1NH
2, 1, the mol ratio of 8-diazacyclo hendecene and salt of wormwood is 1: 1～5: 1～3: 1～2: 1～2: 0.1～2.
(2) by the method for starting compound 3 synthetic compounds 6
Under-10 ℃～0 ℃ temperature of organic solvent neutralization, with 2 '-O-ethanoyl-clarithromycin, carbonyl dimidazoles and sodium hydride reaction 1～24 hour; Products therefrom under-10 ℃～room temperature of organic solvent neutralization with R
1NH
2With 1,8-diazacyclo hendecene reaction 1～24 hour; Products therefrom reacted in the alcohol of C1～4 1～24 hour, reacted usually promptly to get compound 6 in 2～5 hours; Described 2 '-O-ethanoyl-clarithromycin, carbonyl dimidazoles, sodium hydride, R
1NH
2With 1, the mol ratio of 8-diazacyclo hendecene is 1: 2～5: 1～3: 2～5: 2～5;
The structural formula of described raw material 1 and compound 3 is as follows:
Raw material 1, raw material 3;
R in the formula
1, R
2, R
3And R ', R " definition according to claim 1.
9. the purposes of a derivative as claimed in claim 1 is characterized in that being used to prepare antibiotic, antiviral.
10. the purposes of a derivative as claimed in claim 9 is characterized in that described medicine is the medicine of the following disease of treatment: SARS courses of infection disease; Staphylococcal infections disease, the infection of the evil staphylococcal infections of face or skin, suppurative dermatitis, wound or suppuration, furuncle, carbuncle, cellular tissue's inflammation, courage poison and acne, the acute pharyngolaryngitis of initial stage infection, postgrippal pharyngitis, bronchopneumonia, lung's suppuration, the disease of streptococcal infection, pneumonia, the diphtheria that streptococcus pneumoniae causes; Hemophilus influenzae genus, rickettsia, Rome pathogenic agent, mycoplasma pneumoniae, chlamydozoan, hematuria slurry, toxoplasma, mycobacterium, monocytosis Li Site Salmonella, meningococcal infection.
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| CN102417530A (en) * | 2010-09-26 | 2012-04-18 | 中国医学科学院药物研究所 | Synthesis method of broad spectrum antibiotics erythromycin A macrocyclic ketolide derivatives and application |
| CN107129514A (en) * | 2016-03-02 | 2017-09-05 | 中国医学科学院药物研究所 | Erythromycin A ketolide antibiotics derivative, its preparation method and application |
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|---|---|---|---|---|
| CZ180799A3 (en) * | 1996-11-27 | 1999-09-15 | Taisho Pharmaceutical Co., Ltd. | Erythromycin a derivatives |
| JP2002542197A (en) * | 1999-04-16 | 2002-12-10 | オーソ−マクニール・フアーマシユーチカル・インコーポレーテツド | Ketolide antibacterial agent |
| US6437106B1 (en) * | 1999-06-24 | 2002-08-20 | Abbott Laboratories | Process for preparing 6-o-substituted erythromycin derivatives |
| TWI225067B (en) * | 2000-08-14 | 2004-12-11 | Taisho Pharmaceutical Co Ltd | Processes for preparing erythromycin derivatives |
| CN1318441C (en) * | 2005-04-25 | 2007-05-30 | 中国医学科学院医药生物技术研究所 | Macrilides ketolide compound, and its preparing method and use |
-
2006
- 2006-06-19 CN CN200610027755A patent/CN100577678C/en not_active Expired - Fee Related
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102417530A (en) * | 2010-09-26 | 2012-04-18 | 中国医学科学院药物研究所 | Synthesis method of broad spectrum antibiotics erythromycin A macrocyclic ketolide derivatives and application |
| CN107129514A (en) * | 2016-03-02 | 2017-09-05 | 中国医学科学院药物研究所 | Erythromycin A ketolide antibiotics derivative, its preparation method and application |
| CN107129514B (en) * | 2016-03-02 | 2019-12-13 | 中国医学科学院药物研究所 | erythromycin A ketolide antibiotic derivative, and preparation method and application thereof |
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| Publication number | Publication date |
|---|---|
| CN100577678C (en) | 2010-01-06 |
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