CN1763018B - Oxazolidinone analog compound - Google Patents
Oxazolidinone analog compound Download PDFInfo
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- CN1763018B CN1763018B CN 200510015288 CN200510015288A CN1763018B CN 1763018 B CN1763018 B CN 1763018B CN 200510015288 CN200510015288 CN 200510015288 CN 200510015288 A CN200510015288 A CN 200510015288A CN 1763018 B CN1763018 B CN 1763018B
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- methyl
- phenyl
- fluoro
- oxazolidinyl
- oxo
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Abstract
The present invention is oxazolidone compound in the structure as shown or its pharmaceutically acceptable salt, and their use as medicine, especially as antibacterial medicine.
Description
Technical field
The invention belongs to medical technical field, or rather, relate to one type of compound with anti-microbial effect and as the purposes of antibacterials.
Background technology
In recent years; The resistant organism development of all kinds of microbiotic and antiseptic-germicide is rapid, for example: the appearance of methicillin-resistant staphylococcus aureus (MRSA), methicillin-resistant staphylococcus epidermidis (MRSE), penicillin resistant streptococcus pneumoniae (PRSP), multi-drug resistant tubercule bacillus, especially vancomycin-resistant enterococcus (VRE); Cause difficulty to clinical treatment; After the bacterium contact antibacterials, morph, obtain resistance through plasmid or karyomit(e) mediation.At present, consistent think mainly contain four kinds of mechanism of action, be respectively: produce antibiotic enzyme, deactivation microbiotic; Antibacterials are not replied in the target site variation; Change the outer permeability of film, blocking drugs gets into; Enhancing effluxes, and quickens to pump the intravital medicine of entering.Because these drug-fast bacteria infections of the still difficult effectively control of existing medicine impel Pharmaceutical Chemist to make great efforts development novel anti drug tolerant bacteria medicine, design and screening have the new antimicrobial drug of new chemical structure, new role mechanism or new role target position.
Oxazolidine ketone antiseptic-germicide is the complete synthesis antiseptic-germicide of chemistry, and the gram-positive microorganism and the mycobacterium tuberculosis infection that are used to treat anti-multiple medicine demonstrate fabulous prospect, have become one type of antibacterial agent at present.
The oxazolidone compounds has been shown in following document:
EP311090 discloses the N-Fang oxazolidinone compounds with anti-microbial effect; EP609905 discloses 3-(nitrogen is substituted) phenyl-5-β-amido Jia Ji oxazolidine-2-ketone compounds; CN1121919A discloses Wu unit heteroaryl-oxazolidinones; WO93/23384 discloses and has contained substituted diazine (piperazine) Bu Fen De oxazolidone and they purposes as biocide.WO93/09103 discloses substituted aryl and heteroaryl-phenyl-oxazolidones as biocide.WO90/02744 disclose as 5 of biocide '-indolinyl-5 β-amido methyl oxazolidinone, 3-(condensed ring is substituted) phenyl-5 β-amido methyl oxazolidinone, and 3-(nitrogen is substituted)-phenyl-5 β-amido methyl oxazolidinone.EP352781 discloses phenyl and the substituted phenyl oxazolidinones of pyridyl.EP316594 discloses the substituted Ben Yi of 3-Xi oxazolidinone.EP312000 discloses the substituted phenyl oxazolidinones of phenyl methyl.
Other reference discloses Ge kind various kinds De oxazolidone compounds, comprising: J.Med.Chem., 32,1673-81 (198); J.Med.Chem., 33,2569-78 (1990); Tetrahedron, 45,1323-26 (1989); J.Med.Chem., 35,1156 (1992); US4,801,600; US4,128,654; US4,250,318; US5,164,510; US5,523,403; US5,736,545; US5,981,528; US6,239,152B1; EP0657440; EP0694544; EP0738726; WO94/01110; WO95/07271; WO97/14690; WO97/37980; WO98/01447.
Summary of the invention
The invention discloses novel oxazolidinone derivatives and pharmacy acceptable salt thereof, and they are as the application of medicine, particularly as the application of antibacterials.
The present invention relates to the compound and the pharmacy acceptable salt thereof of general formula (I) structure.
R
1：
(a) amino (when X is NH);
(b)-NH-R
5；
R wherein
5Be C
1-C
8Alkyl, this alkyl can at random be replaced by following one or more group: fluorine, chlorine, hydroxyl, itrile group, carboxyl, amino, nitro, C
1-C
8Alkoxyl group, C
1-C
8Acyl group, phenyl, substituted-phenyl is by sulphur, oxygen, substituted five yuan of nitrogen heteroatom, hexa-member heterocycle;-CO-R
6Or-SO
2-R
7, R wherein
6, R
7Be C
1-C
8Alkyl or by fluorine, chlorine, hydroxyl, the substituted C of itrile group
1-C
8Alkyl; By chlorine, fluorine, C
1-C
6Alkyl, C
1-C
8Alkoxyl group, hydroxyl, itrile group, carboxyl, amino, the single, double or polysubstituted aryl of nitro.
R wherein
8, R
9Be hydrogen at the same time or separately, C
1-C
8Alkyl, this alkyl can be replaced by following one or more groups arbitrarily: fluorine, chlorine, hydroxyl, C
1-C
8Alkoxyl group, amino, C
1-C
8Alkylamino, C
1-C
8Dialkyl amido.Work as R
9Be H, then R
8During for aryl, this aryl can be replaced by following one or more group: C
1-C
6Alkyl, C
1-C
6Alkoxyl group, fluorine, chlorine, itrile group, carboxyl, amino, hydroxyl; If heterocyclic aryl can be five rings, the six ring heterocyclic aryls of sulfur-bearing, oxygen, nitrogen.
(d)-N＝R
10；
R wherein
10Be C
3-C
6Naphthenic base or by C
1-C
3Alkyl is by hydroxyl, fluorine, the substituted C of chlorine
3-C
6Naphthenic base contains by sulphur, oxygen, the substituted triatomic ring of nitrogen heteroatom, tetra-atomic ring, five-ring, six-ring, and this ring texture can be replaced by following one or more groups: hydroxyl, fluorine, chlorine, C
1-C
4Alkyl, C
1-C
4Alkoxyl group and by fluorine, the substituted C of chlorine
1-C
4Alkyl and C
1-C
4Alkoxyl group, phenyl, fluorine, chlorine, methyl, fluoro methyl, methoxyl group, single or disubstituted phenyl.
R
2, R
3: be hydrogen at the same time or separately, fluorine, chlorine, nitro, C
1-C
8The straight or branched alkyl, this alkyl can at random be replaced by following one or more group: fluorine, chlorine, hydroxyl, methylol, itrile group, C
1-C
6Alkoxyl group.
R
4: can be C
1-C
8Alkyl, this alkyl can at random be replaced by following one or more group: fluorine, chlorine, hydroxyl, itrile group, carboxyl, amino, nitro, C
1-C
8Alkoxyl group, C
1-C
8Acyl group, phenyl, substituted-phenyl is by sulphur, oxygen, substituted five yuan of nitrogen heteroatom, hexa-member heterocycle;-CO-R
11Or-SO
2-R
12, R wherein
11, R
12Be C
1-C
8Alkyl or by fluorine, chlorine, hydroxyl, the substituted C of itrile group
1-C
8Alkyl; By chlorine, fluorine, C
1-C
6Alkyl, C
1-C
8Alkoxyl group, hydroxyl, itrile group, carboxyl, amino, the single, double or polysubstituted aryl of nitro.
X：NH，S。
Y：CH，N。
Z:CH, N, O, S, wherein Z is O, during S, R
4Do not exist.
m，n：1～3。
C of the present invention
1-C
8The straight or branched alkyl comprises methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, amyl group, isopentyl or the like.
Described C
1-C
3Alkyl or chlorine, fluorine replace C
1-C
3Alkyl can be methyl, ethyl, propyl group, chloroethyl, fluoro ethyl; C
1-C
3Alkoxyl group or chlorine, fluorine list or disubstituted C
1-C
3Alkoxyl group; C
1-C
8Alkoxyl group can be methoxyl group, oxyethyl group, propoxy-, butoxy, isobutoxy, chloroethoxy, chlorine propoxy-, 1,1-dichloro propoxy-, 1-fluoro-2-chlorine propoxy-or the like.
Described C
1-C
8Alkylamino, C
1-C
8Replace alkylamino, C
1-C
8Dialkyl amido, C
1-C
8Replacing dialkyl amido can be ethylamino, third amino, hydroxyethylamino, two hydroxyethylaminos or the like.
Described C
2-C
8Alkyloyl such as ethanoyl, propionyl group, butyryl radicals, isobutyryl or the like.
Described C
3-C
6Naphthenic base can be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or the like.
Said substituted heteroatomic triatomic ring, tetra-atomic ring, five-ring, six-ring; Heteroatoms is selected from O, S, N; Can be N-methyl piperidine-4-base, N-ethylpiperidine-4-base, N-sec.-propyl piperidin-4-yl, 2; 2,6,6-tetramethyl piperidine-4-base, THTP-3-base, THF-4-base, tetrahydric thiapyran-4-group or the like.
More desirable compound and code thereof are:
L1: (S)-N-[[3-[3-fluoro-4-morpholinyl] phenyl]-2-oxo-5-oxazolidinyl] methyl-N '-HYDRAZINE CARBOXIMIDAMIDE hydriodate
L2: (S)-N-[[3-[3-fluoro-4-morpholinyl] phenyl]-2-oxo-5-oxazolidinyl] methyl-N '-cyclohexylidene base HYDRAZINE CARBOXIMIDAMIDE
L3: (S)-N-[[3-[3-fluoro-4-morpholinyl] phenyl]-2-oxo-5-oxazolidinyl] methyl-N '-[(4-sec.-propyl) benzene methene] HYDRAZINE CARBOXIMIDAMIDE
L4: (S)-N-[[3-[3-fluoro-4-morpholinyl] phenyl]-2-oxo-5-oxazolidinyl] methyl-N '-[(2-methyl-2-phenyl) ethylidene] HYDRAZINE CARBOXIMIDAMIDE
L5: (S)-N-[[3-[3-fluoro-4-morpholinyl] phenyl]-2-oxo-5-oxazolidinyl] methyl-N '-[2-benzo cyclohexylidene] HYDRAZINE CARBOXIMIDAMIDE
L6: (S)-N-[[3-[3-fluoro-4-morpholinyl] phenyl]-2-oxo-5-oxazolidinyl] methyl-N '-[(5-methyl) thenylidene] HYDRAZINE CARBOXIMIDAMIDE
L7: (S)-N-[[3-[3-fluoro-4-morpholinyl] phenyl]-2-oxo-5-oxazolidinyl] methyl-N '-[(4-hydroxyl) benzene methene] HYDRAZINE CARBOXIMIDAMIDE
L8: (S)-N-[[3-[3-fluoro-4-morpholinyl] phenyl]-2-oxo-5-oxazolidinyl] methyl-N '-[4-chlorobenzene methene] HYDRAZINE CARBOXIMIDAMIDE
L9: (S)-N-[[3-[3-fluoro-4-morpholinyl] phenyl]-2-oxo-5-oxazolidinyl] methyl-N '-[2-benzo cyclohexylidene] thiosemicarbazide
L10: (S)-N-[[3-[3-fluoro-4-piperidyl] phenyl]-2-oxo-5-oxazolidinyl] methyl-N '-cyclohexylidene base HYDRAZINE CARBOXIMIDAMIDE
L11: (S)-N-[[3-[3-fluoro-4-piperidyl] phenyl]-2-oxo-5-oxazolidinyl] methyl-N '-[2-benzo cyclohexylidene] HYDRAZINE CARBOXIMIDAMIDE
L12: (S)-N-[[3-[3-fluoro-4-piperidyl] phenyl]-2-oxo-5-oxazolidinyl] methyl-N '-[(5-methyl) thenylidene] HYDRAZINE CARBOXIMIDAMIDE
L13: (S)-N-[[3-[3-fluoro-4-piperidyl] phenyl]-2-oxo-5-oxazolidinyl] methyl-N '-[(4-hydroxyl) benzene methene] HYDRAZINE CARBOXIMIDAMIDE
L14: embodiment 14 (S)-N-[[3-[3-fluoro-4-piperidyl] phenyl]-2-oxo-5-oxazolidinyl] methyl)-N '-[furfurylidene] HYDRAZINE CARBOXIMIDAMIDE
Compound or its pharmacy acceptable salt with formula I structure of the present invention means: The compounds of this invention and mineral acid, organic acid salify, preferred especially salt is: hydrochloride, hydrobromate, hydriodate, vitriol, hydrosulfate, phosphoric acid salt, acetate, propionic salt, butyrates, lactic acid salt, mesylate, tosilate, PHENRAMINE MALEATE, benzoate, SUMATRIPTAN SUCCINATE, tartrate, Citrate trianion, fumarate, taurate or the like.As described salt, they can also be the salt that forms with conventional alkali, for example an alkali metal salt.
The preparation of pharmaceutical compositions of The compounds of this invention is following: use standard and conventional technology; Acceptable solid or liquid vehicle are combined, and make it at random with technology of pharmaceutics on acceptable auxiliary and vehicle combine to be prepared into particulate or microballoon.Solid dosage comprises tablet, discrete particles, capsule, slow releasing tablet, sustained release pellet or the like.Solid carrier can be at least a material, and it can serve as thinner, flavouring agent, solubilizing agent, lubricant, suspension agent, tackiness agent, disintegrating agent and coating agent.Inert solid carrier comprises trimagnesium phosphate, Magnesium Stearate, smoothers sugar, lactose, pectin, Ucar 35, Polysorbate 80, dextrin, starch, gelatin, cellulose substances for example methylcellulose gum, Microcrystalline Cellulose, low melt point paraffin, polyoxyethylene glycol, N.F,USP MANNITOL, theobroma oil etc.Liquid dosage form comprises solvent, suspension-s for example injection, pulvis or the like.
The amount of the active ingredient that contains in pharmaceutical composition and the unit dosage form (The compounds of this invention) can be according to patient's the state of an illness, specific being applied of situation of diagnosis; The amount of used compound or concentration are regulated in the scope of a broad; Usually, the weight range of active compound is 0.5%～90% (weight) of compsn.Another preferred range is 0.5%-70%.
Further specify the restraining effect of The compounds of this invention through bacteriostatic experiment below to bacterium.
1, experiment material
(1) substratum: microorganism identification substratum PH7.9 ± 0.1 Beijing, three medicine scientific and technological development company lot numbers: 020425
(2) bacterial classification: bacillus pumilus CMCC 63202; Staphylococcus epidermidis CMCC26069, blue pus organism CMCC10211, klebsiella pneumoniae CMCC 46117; ETEC CMCC 44113, above bacterial classification is all purchased in Nat'l Pharmaceutical & Biological Products Control Institute.
2, experimental technique
(1) sample and code:
Sample: L1, L2, L3, L4, L5, L6, L7, L8, L9, L10, L11, L12, L13, L14.
Compound method: take by weighing above-mentioned each sample of about 2mg respectively, in the 50ml volumetric flask, after a spot of DMF dissolving, add to scale with zero(ppm) water, concentration is 10 μ mol/L, and filtration sterilization is with the centrifuge tube packing of 2ml.
(2) preparation of culture dish:
Microorganism identification substratum I after a certain amount of sterilization (making substratum thickness is 3mm); Be chilled to 48-50 ℃, add an amount of bacterium liquid (bacteria concentration is 0.1%) respectively, pour in the culture dish of the level of mixing up; Carefully drive bubble away; After the culture medium solidifying,, subsequent use in the graze cattle position marked of Tianjin cup of needs.
(3) mensuration of sample
At interval 2.5-3cm places the Oxford cup on culture dish, notes correspondingly with mark position, gets each sample 50 μ l application of sample with micro sample adding appliance, is that 2-3 is individual to manage again, carries out the application of sample record, is placed on 37 ℃ of CO
2After cultivating 16-18h in the incubator, use the vernier caliper measurement antibacterial circle diameter.
3, experimental result:
The result shows that compound has bacteriostatic action to staphylococcus epidermidis, streptococcus aureus, streptococcus pneumoniae etc., and intestinal bacteria, Pseudomonas aeruginosa etc. are not seen bacteriostatic action, points out the compound of this class formation to have anti-G
+The effect of bacterium.
| ? | Staphylococcus epidermidis | Streptococcus aureus | Streptococcus pneumoniae | Intestinal bacteria | Pseudomonas aeruginosa |
| L1： | - | - | - | - | - |
| L2： | + | + | - | - | - |
| L3： | + | + | + | - | - |
| L4： | + | + | + | - | - |
| L5： | + | + | + | - | - |
| L6： | + | + | + | - | - |
| L7： | - | - | - | - | - |
| L8： | + | + | + | - | - |
| L9： | + | + | + | - | - |
| L10 | + | + | - | - | - |
| L11 | + | + | - | - | - |
| L12 | + | + | + | - | - |
| L13 | + | + | + | - | - |
| L14 | - | - | - | - | - |
+: bacteriostatic action is arranged;-: not seeing has bacteriostatic action
Embodiment:
Below in conjunction with embodiment the present invention is done further explanation; It is indicative that embodiment is merely; Mean that never it limits scope of the present invention by any way, the compound of invention is through performance liquid chromatography (HPLC), thin-layer chromatography (TLC); Fusing point (m.p.) detects, can adopt subsequently nucleus magnetic resonance (
1HNMR/
13CNMR) etc. further prove conclusively its structure.
Needed midbody in the experiment:
Amino substance 1 amino substance 2
Midbody 1 midbody 2
Midbody 3 midbodys 4
?
Midbody 5 midbodys 6
?
Midbody 7 midbodys 8
Midbody 9
The method that the preparation of amino substance 1 provides with reference to Journal of Medicinal Chemistry. 1996.39 (3): 673～378., amino substance 2 also can prepare as stated above, and this is to be familiar with this professional personage to understand.
Amino substance 1:R
f=0.38 (developping agent: absolute ethyl alcohol: triethylamine=30: 1); HPLC99.5%;
1HNMR (CDCl
3, 400Hz): δ 7.468 (dd, 1H, Ar-H), 7.147 (m, 1H, Ar-H), 6.924 (t, 1H, Ar-H), 4.655 (m, 1H, O-CH), 4.003 (t, 1H), 3.853 (m, 4H, CH
2OCH
2), 3.814 (t, 1H), 3.120 (dd, 1H), 3.047 (t, 4H, CH
2NCH
2), 2.981 (dd, 1H), 2.210 (s, 2H, NH
2).
Amino substance 2:R
f=0.23 (developping agent: absolute ethyl alcohol: triethylamine=30: 1); HPLC 99.2%;
1HNMR (DMSO, 400Hz): δ 7.173 (dd, 1H, Ar-H), 7.173 (dd, 1H, Ar-H), 7.028 (t, 1H, Ar-H), 4.573 (m, 1H, O-CH), 4.003 (t, 1H, CH-N), 3.806 (t, 1H, CH-N), 2.899 (m, 4H, CH
2O-CH
2), 2.841 (m, 2H, N-CH
2), 2.746 (m, 2H, NH
2), 1.631 (m, 4H ,-CH
2CH
2-), 1.513 (m, 2H ,-CH
2-).
Midbody 1～7 prepares by following logical method:
With methyl iodide back flow reaction 4 hours in anhydrous methanol, reaction is finished Deng the mole Urea,amino-, cooling.Separate out white solid, filter, anhydrous methanol is washed, and gets S-methylamino isothiourea.m.p.133.5～134.4℃。
S-methylamino isothiourea in methyl alcohol with equimolar pimelinketone, 4-isopropyl benzene formaldehyde, 2-methyl phenylacetaldehyde, 2-benzo pimelinketone, 5-thiotolene formaldehyde, PARA HYDROXY BENZALDEHYDE, furtural reaction, make corresponding midbody 1, midbody 2, midbody 3, midbody 4, midbody 5, midbody 6, midbody 7.
Midbody 8, midbody 9 can prepare by following method:
Equimolar Hydrazine Hydrate 80 (80%), dithiocarbonic anhydride, Pottasium Hydroxide (being dissolved in the water of 4 times of amounts) added in the Virahol, in 5～10 ℃ of reactions 4 hours.Drip equimolar methyl iodide then, added in about 30 minutes, continue insulation reaction and placed 4 hours after 3 hours.Filter and promptly get diazanyl dithio methyl-formiate.m.p.82.0～82.4℃。
Above-mentioned diazanyl dithio methyl-formiate in absolute ethyl alcohol 40～50 ℃ respectively with equimolar 4-chloro-benzaldehyde, α-benzo pimelinketone reaction, make corresponding midbody 8, midbody 9.
Embodiment 1
(S)-N-[[3-[3-fluoro-4-morpholinyl] phenyl]-2-oxo-5-oxazolidinyl] methyl-N '-HYDRAZINE CARBOXIMIDAMIDE hydriodate (L1)
1g (S)-N-[[3-[3-fluoro-4-morpholinyl] phenyl]-2-oxo-5-oxazolidinyl] methylamine (amino substance 1) and 0.8gS-methylamino isothiourea hydriodate put in the 10ml absolute ethyl alcohol behind 40 ℃ of reaction 5～6h, be warming up to backflow; Insulation reaction 2～3h; Filtered while hot; Drying, white solid, m.p.208.2～209.4 ℃.
Embodiment 2
(S)-N-[[3-[3-fluoro-4-morpholinyl] phenyl]-2-oxo-5-oxazolidinyl] methyl-N '-cyclohexylidene base HYDRAZINE CARBOXIMIDAMIDE (L2)
5g midbody 1 and 2.5g amino substance 1 are put in the 50ml absolute ethyl alcohol, and nitrogen protection is warming up to back flow reaction 3h; Add other 2.5g amino substance, back flow reaction 21h, solvent is to the greatest extent steamed in decompression; Silica gel column chromatography (moving phase: absolute ethyl alcohol: triethylamine=30: 1), get solid, drying; M.p.144.4～145.7 ℃, and the TLC chromatography (developping agent: absolute ethyl alcohol: triethylamine=30: 1), product point R
fValue 0.38.
Become Citrate trianion: get above-mentioned product 1.5g, be dissolved in the 45ml absolute ethyl alcohol, be heated to backflow, add and wait mole Hydrocerol A, insulation reaction 30min.Reduce to room temperature, placed 12 hours.Separate out white solid, filter.The gained solid is through being drying to obtain its Citrate trianion, m.p.206～207.6 ℃.
Embodiment 3
(S)-N-[[3-[3-fluoro-4-morpholinyl] phenyl]-2-oxo-5-oxazolidinyl] methyl-N '-[(4-sec.-propyl) benzene methene] HYDRAZINE CARBOXIMIDAMIDE (L3)
1.2g midbody 2 and 0.5g amino substance 1 are put in the 10ml absolute ethyl alcohol, and nitrogen protection is warming up to back flow reaction 3h; Add other 0.5g amino substance, back flow reaction 2～3h, solvent is to the greatest extent steamed in decompression; Silica gel column chromatography (moving phase: absolute ethyl alcohol: triethylamine=30: 1), get small amount of solid, drying; M.p.119.0～120.0 ℃, and the TLC chromatography (developping agent: absolute ethyl alcohol: triethylamine=30: 1), product point R
fValue 0.48.
Embodiment 4
(S)-N-[[3-[3-fluoro-4-morpholinyl] phenyl]-2-oxo-5-oxazolidinyl] methyl-N '-[(2-methyl-2-phenyl) ethylidene] HYDRAZINE CARBOXIMIDAMIDE (L4)
1.0g midbody 3 and 0.5g amino substance 1 are put in the 10ml absolute ethyl alcohol, and nitrogen protection is warming up to back flow reaction 3h; Add other 0.4g amino substance, back flow reaction 12h, solvent is to the greatest extent steamed in decompression; Silica gel column chromatography (moving phase: absolute ethyl alcohol: triethylamine=30: 1), get solid, drying; M.p.65～85 ℃, and the TLC chromatography (developping agent: absolute ethyl alcohol: triethylamine=30: 1), product point R
fValue 0.48.
Embodiment 5
(S)-N-[[3-[3-fluoro-4-morpholinyl] phenyl]-2-oxo-5-oxazolidinyl] methyl-N '-[2-benzo cyclohexylidene] HYDRAZINE CARBOXIMIDAMIDE (L5)
1.2g midbody 4 and 1.0g amino substance 1 are put in the 50ml absolute ethyl alcohol nitrogen protection, back flow reaction 12h; Solvent is to the greatest extent steamed in decompression, silica gel column chromatography (moving phase: absolute ethyl alcohol: triethylamine=30: 1), get solid; Dry; M.p.182.0～182.5 ℃, and the TLC chromatography (developping agent: absolute ethyl alcohol: triethylamine=30: 1), product point R
fValue 0.44.
Embodiment 6
(S)-N-[[3-[3-fluoro-4-morpholinyl] phenyl]-2-oxo-5-oxazolidinyl] methyl-N '-[(5-methyl) thenylidene] HYDRAZINE CARBOXIMIDAMIDE (L6)
1.2g midbody 5 and 1.1g amino substance 1 are put in the 50ml absolute ethyl alcohol nitrogen protection, back flow reaction 17h; Solvent is to the greatest extent steamed in decompression, silica gel column chromatography (moving phase: absolute ethyl alcohol: triethylamine=30: 1), get solid; Dry; M.p.161.3～161.7 ℃, and the TLC chromatography (developping agent: absolute ethyl alcohol: triethylamine=30: 1), product point R
fValue 0.51.
Embodiment 7
(S)-N-[[3-[3-fluoro-4-morpholinyl] phenyl]-2-oxo-5-oxazolidinyl] methyl-N '-[(4-hydroxyl) benzene methene] HYDRAZINE CARBOXIMIDAMIDE (L7)
4g midbody 6 and 5g amino substance 1 are put in the 50ml absolute ethyl alcohol nitrogen protection, back flow reaction 17h; Solvent is to the greatest extent steamed in decompression, silica gel column chromatography (moving phase: absolute ethyl alcohol: triethylamine=30: 1), get solid; Dry; M.p.182.4～182.9 ℃, and the TLC chromatography (developping agent: absolute ethyl alcohol: triethylamine=30: 1), product point R
fValue 0.30.
Become sodium salt: get above-mentioned product 2g, be dissolved in the 60ml methyl alcohol, frozen water is cooled to 10～15 ℃, stirs the aqueous sodium hydroxide solution of dropping 30% down; To the most solvent of PH10 decompression steaming, and adding 35ml absolute ethyl alcohol/water (6/4, V/V) mixing solutions; Be heated to backflow, filtered while hot is placed in the filtrate chamber.Filter, white solid, be drying to obtain its sodium salt, m.p.＞230 ℃.
Embodiment 8
(S)-N-[[3-[3-fluoro-4-morpholinyl] phenyl]-2-oxo-5-oxazolidinyl] methyl-N '-[4-chlorobenzene methene] HYDRAZINE CARBOXIMIDAMIDE (L8)
1g midbody 8 and 1.3g amino substance 1 are put in the 20ml absolute ethyl alcohol nitrogen protection, back flow reaction 17h; Solvent is to the greatest extent steamed in decompression, silica gel column chromatography (moving phase: ETHYLE ACETATE: sherwood oil: triethylamine=1: 1: 0.05), get solid; Dry; M.p.187.3～188.2 ℃, and the TCL chromatography (developping agent: ETHYLE ACETATE: sherwood oil: triethylamine=1: 1: 0.05), product point R
fValue 0.76.
Embodiment 9
(S)-N-[[3-[3-fluoro-4-morpholinyl] phenyl]-2-oxo-5-oxazolidinyl] methyl-N '-[2-benzo cyclohexylidene] thiosemicarbazide (L9)
1.5g midbody 9 and 1.0g amino substance 1 are put in the 25ml absolute ethyl alcohol nitrogen protection, back flow reaction 17h; Solvent is to the greatest extent steamed in decompression, silica gel column chromatography (moving phase: ETHYLE ACETATE: sherwood oil: triethylamine=4: 3: 0.05), get solid; Dry; M.p.153.3～154.8 ℃, and the TLC chromatography (developping agent: ETHYLE ACETATE: sherwood oil: triethylamine 1: 1: 0.05), product point R
fValue 0.80.
Embodiment 10
(S)-N-[[3-[3-fluoro-4-piperidyl] phenyl]-2-oxo-5-oxazolidinyl] methyl-N '-cyclohexylidene base HYDRAZINE CARBOXIMIDAMIDE (L10)
1g midbody 1 and 2.8g (S)-N-[[3-[3-fluoro-4-piperidyl] phenyl]-2-oxo-5-oxazolidinyl] methylamine (amino substance 2) put in the 150ml absolute ethyl alcohol behind 50 ℃ of reaction 5h, be warming up to back flow reaction 3h, TLC chromatography (developping agent: absolute ethyl alcohol: product point R triethylamine=30: 1)
fValue 0.65, column chromatography are collected Rf value 0.65 product point liquid, after liquid is dissolved among the DMF, add entry and generate to there being solid, filter, drying gets white solid, m.p.77.4～78.7 ℃.
Embodiment 11
(S)-N-[[3-[3-fluoro-4-piperidyl] phenyl]-2-oxo-5-oxazolidinyl] methyl-N '-[2-benzo cyclohexylidene] HYDRAZINE CARBOXIMIDAMIDE (L11)
1.5g midbody 4 and 1.5g amino substance 2 put in the 150ml absolute ethyl alcohol behind 50 ℃ of reaction 5h, be warming up to back flow reaction 3h, TLC chromatography (developping agent: absolute ethyl alcohol: product point R triethylamine=30: 1)
fValue 0.60, column chromatography are collected Rf value 0.60 product point liquid, after liquid is dissolved among the DMF, add entry and generate to there being solid, filter, drying gets white solid.
Embodiment 12
(S)-N-[[3-[3-fluoro-4-piperidyl] phenyl]-2-oxo-5-oxazolidinyl] methyl-N '-[(5-methyl) thenylidene] HYDRAZINE CARBOXIMIDAMIDE (L12)
1.5g midbody 5 and 2g amino substance 2 put in the 150ml absolute ethyl alcohol behind 50 ℃ of reaction 5h, be warming up to back flow reaction 3h, TLC chromatography (developping agent: absolute ethyl alcohol: product point R triethylamine=30: 1)
fValue 0.55, column chromatography are collected Rf value 0.55 product point liquid, after liquid is dissolved among the DMF, add entry and generate to there being solid, filter, drying gets white solid
Embodiment 13
(S)-N-[[3-[3-fluoro-4-piperidyl] phenyl]-2-oxo-5-oxazolidinyl] methyl-N '-[(4-hydroxyl) benzene methene] HYDRAZINE CARBOXIMIDAMIDE (L13)
2g midbody 6 and 2.5g amino substance 2 put in the 150ml absolute ethyl alcohol behind 50 ℃ of reaction 5h, be warming up to back flow reaction 3h, TLC chromatography (developping agent: absolute ethyl alcohol: product point R triethylamine=30: 1)
fValue 0.60, column chromatography are collected Rf value 0.60 product point liquid, after liquid is dissolved among the DMF, add entry and generate to there being solid, filter, drying gets white solid.
Become sylvite: get above-mentioned product 1g, be dissolved in the 87ml anhydrous methanol, frozen water is cooled to 10～15 ℃, stirs the potassium hydroxide aqueous solution of dropping 25% down, to PH11.Solvent is to the greatest extent steamed in decompression, add 26ml absolute ethyl alcohol/water (6/4, V/V) mixing solutions is heated to backflow, be incubated ten minutes, filtered while hot, white solid is separated out in placement filtrate chamber in, filtration is drying to obtain its sylvite, m.p.＞235 ℃.
Embodiment 14
(S)-N-[[3-[3-fluoro-4-piperidyl] phenyl]-2-oxo-5-oxazolidinyl] methyl)-N '-[furfurylidene] HYDRAZINE CARBOXIMIDAMIDE (L14)
1.7g midbody 7 and 1.0g amino substance 2 put in the 150ml absolute ethyl alcohol behind 50 ℃ of reaction 5h, be warming up to back flow reaction 3h, TLC chromatography (developping agent: absolute ethyl alcohol: product point R triethylamine=30: 1)
fValue 0.60, column chromatography are collected Rf value 0.60 product point liquid, after liquid is dissolved among the DMF, add entry and generate to there being solid, filter, drying gets white solid.
In order to explain enforcement of the present invention more fully, following FORMULATION EXAMPLE is provided.These embodiment explain rather than limit scope of the present invention.Preparation can adopt any compound among the present invention as activeconstituents.
Embodiment 1
Every tablet prepn that contains the 100mg activeconstituents:
The mg/ sheet
L-3 100
Lactose 50
Microcrystalline Cellulose 80
Starch 50
Hydroxyl methylcellulose 40
Magnesium Stearate 5
With activeconstituents; Lactose, starch, Microcrystalline Cellulose are crossed 100 mesh sieves; And abundant mixing, the 2% hydroxyl methylcellulose aqueous solution joined in the above-mentioned mixed powder mix, cross 20 mesh sieve system softwoods; Make wet granular in 45-55 ℃ of drying, carboxymethylstach sodium, Magnesium Stearate are joined compressing tablet in the above-mentioned dried particles.
Embodiment 2
It is following that every capsule contains the capsular preparation of 100mg activeconstituents:
Consumption/capsule weight concentration (%)
L-4 100mg 30.0
T 46155 dehydration sorb 0.05mg 0.02
The sugar alcohol monoleate
Starch 250mg 69.98
Amount to 350.05mg 100.00
Claims (6)
1. following compound or its pharmacy acceptable salt:
L2: (S)-N-[[3-[3-fluoro-4-morpholinyl] phenyl]-2-oxo-5-oxazolidinyl] methyl-N '-cyclohexylidene base HYDRAZINE CARBOXIMIDAMIDE;
L3: (S)-N-[[3-[3-fluoro-4-morpholinyl] phenyl]-2-oxo-5-oxazolidinyl] methyl-N '-[(4-sec.-propyl) benzene methene] HYDRAZINE CARBOXIMIDAMIDE;
L4: (S)-N-[[3-[3-fluoro-4-morpholinyl] phenyl]-2-oxo-5-oxazolidinyl] methyl-N '-[(2-methyl-2-phenyl) ethylidene] HYDRAZINE CARBOXIMIDAMIDE;
L5: (S)-N-[[3-[3-fluoro-4-morpholinyl] phenyl]-2-oxo-5-oxazolidinyl] methyl-N '-[2-benzo cyclohexylidene] HYDRAZINE CARBOXIMIDAMIDE;
L6: (S)-N-[[3-[3-fluoro-4-morpholinyl] phenyl]-2-oxo-5-oxazolidinyl] methyl-N '-[(5-methyl) thenylidene] HYDRAZINE CARBOXIMIDAMIDE;
L8: (S)-N-[[3-[3-fluoro-4-morpholinyl] phenyl]-2-oxo-5-oxazolidinyl] methyl-N '-[4-chlorobenzene methene] HYDRAZINE CARBOXIMIDAMIDE;
L9: (S)-N-[[3-[3-fluoro-4-morpholinyl] phenyl]-2-oxo-5-oxazolidinyl] methyl-N '-[2-benzo cyclohexylidene] thiosemicarbazide;
L10: (S)-N-[[3-[3-fluoro-4-piperidyl] phenyl]-2-oxo-5-oxazolidinyl] methyl-N '-cyclohexylidene base HYDRAZINE CARBOXIMIDAMIDE;
L11: (S)-N-[[3-[3-fluoro-4-piperidyl] phenyl]-2-oxo-5-oxazolidinyl] methyl-N '-[2-benzo cyclohexylidene] HYDRAZINE CARBOXIMIDAMIDE;
L12: (S)-N-[[3-[3-fluoro-4-piperidyl] phenyl]-2-oxo-5-oxazolidinyl] methyl-N '-[(5-methyl) thenylidene] HYDRAZINE CARBOXIMIDAMIDE;
L13: (S)-N-[[3-[3-fluoro-4-piperidyl] phenyl]-2-oxo-5-oxazolidinyl] methyl-N '-[(4-hydroxyl) benzene methene] HYDRAZINE CARBOXIMIDAMIDE.
2. compound according to claim 1, wherein said compound is following compound:
L3: (S)-N-[[3-[3-fluoro-4-morpholinyl] phenyl]-2-oxo-5-oxazolidinyl] methyl-N '-[(4-sec.-propyl) benzene methene] HYDRAZINE CARBOXIMIDAMIDE;
L4: (S)-N-[[3-[3-fluoro-4-morpholinyl] phenyl]-2-oxo-5-oxazolidinyl] methyl-N '-[(2-methyl-2-phenyl) ethylidene] HYDRAZINE CARBOXIMIDAMIDE;
L5: (S)-N-[[3-[3-fluoro-4-morpholinyl] phenyl]-2-oxo-5-oxazolidinyl] methyl-N '-[2-benzo cyclohexylidene] HYDRAZINE CARBOXIMIDAMIDE;
L6: (S)-N-[[3-[3-fluoro-4-morpholinyl] phenyl]-2-oxo-5-oxazolidinyl] methyl-N '-[(5-methyl) thenylidene] HYDRAZINE CARBOXIMIDAMIDE;
L8: (S)-N-[[3-[3-fluoro-4-morpholinyl] phenyl]-2-oxo-5-oxazolidinyl] methyl-N '-[4-chlorobenzene methene] HYDRAZINE CARBOXIMIDAMIDE;
L9: (S)-N-[[3-[3-fluoro-4-morpholinyl] phenyl]-2-oxo-5-oxazolidinyl] methyl-N '-[2-benzo cyclohexylidene] thiosemicarbazide;
L12: (S)-N-[[3-[3-fluoro-4-piperidyl] phenyl]-2-oxo-5-oxazolidinyl] methyl-N '-[(5-methyl) thenylidene] HYDRAZINE CARBOXIMIDAMIDE;
L13: (S)-N-[[3-[3-fluoro-4-piperidyl] phenyl]-2-oxo-5-oxazolidinyl] methyl-N '-[(4-hydroxyl) benzene methene] HYDRAZINE CARBOXIMIDAMIDE.
3. according to claim 1 or claim 2 compound, wherein pharmacy acceptable salt means said compound and sour salify, comprises mineral acid and organic acid; With the alkali salify, alkali is alkali-metal oxyhydroxide.
4. pharmaceutical composition, it contains each described compound and pharmaceutically acceptable one or more vehicle among the claim 1-3.
5. each described compound is used to treat G in preparation among the claim 1-3
+The application of the medicine aspect of bacterium infected patient, wherein said G
+Bacterium is staphylococcus epidermidis and streptococcus aureus.
6. the described compound of claim 2 is used to treat G in preparation
+The application of the medicine aspect of bacterium infected patient, wherein said G
+Bacterium is staphylococcus epidermidis, streptococcus aureus and streptococcus pneumoniae.
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| CN101220002B (en) * | 2007-12-28 | 2011-07-13 | 天津药物研究院 | Oxazolidinone compound as antimicrobial |
| AU2009302007B2 (en) * | 2008-10-10 | 2015-01-15 | Actelion Pharmaceuticals Ltd | Oxazolidinyl antibiotics |
| CN103232446B (en) * | 2013-05-17 | 2015-09-23 | 天津药物研究院 | Yi Zhong oxazolidinone derivative crystal form II and its production and use |
| CN103467358B (en) * | 2013-08-15 | 2015-09-02 | 蚌埠丰原医药科技发展有限公司 | The preparation method of Zelnorm |
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Non-Patent Citations (6)
| Title |
|---|
| .Structure-activity relationship (SAR) studies on oxazolidinone.antibacterial agents. 1. Conversion of 5-substituent onoxazolidinone.Chem. Pharm. Bull.，2001，49（4），347－35249 4.2001,49(4),347-352. |
| Suzuki, Tomio |
| Takahashi, Yoshiei |
| Tokuyama, Ryukou |
| Tokuyama, Ryukou;Takahashi, Yoshiei;Tomita, Yayoi;Suzuki, Tomio;.Structure-activity relationship (SAR) studies on oxazolidinone.antibacterial agents. 1. Conversion of 5-substituent onoxazolidinone.Chem. Pharm. Bull.,2001,49(4),347-35249 4.2001,49(4),347-352. * |
| Tomita, Yayoi |
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