CN1188417C - 3,6-disubstituted penam sulfone derivatives as antibacteriuls - Google Patents
3,6-disubstituted penam sulfone derivatives as antibacteriuls Download PDFInfo
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- CN1188417C CN1188417C CNB008030766A CN00803076A CN1188417C CN 1188417 C CN1188417 C CN 1188417C CN B008030766 A CNB008030766 A CN B008030766A CN 00803076 A CN00803076 A CN 00803076A CN 1188417 C CN1188417 C CN 1188417C
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
Abstract
Compounds are provided having formulae (I) and (II) wherein n is 0 or 1 and when n=1, R is a 5 or 6 membered heterocyclic ring, hydroxy, halogen, oxo, carbamoyl, alkoxy, or disubstituted amino, when n=0, R is an ester, cyano or amide group; X is CH or NH; R3 is cyano, methoxy, or acetamido; R1 is hydrogen, alkyl, a negative charge, a cation selected from the group consisting of sodium, potassium and tetraalkylammonium and acyloxyalkyl, or alkoxycarbonyloxyalkyl; and R2 is hydrogen, acyl, trisubstituted silyl carbamoyl or an amino acid residue; or pharmaceutically acceptable salts thereof.
Description
Technical field
The present invention relates to the beta-lactamase inhibitor that share with beta-lactam antibiotics.More particularly, the present invention relates to prove 3 of the active novelty of potential beta-lactamase inhibitor, 6-two replaces the mould sulfone derivatives.
Background technology
Penicillins and cephalosporins are the most frequently used and the most widely used beta-lactam antibioticss.But bacterium is kept effective treatment to infectation of bacteria to impairing of these antibiotic resistances.
It is to produce category-A and C class Serine β-Nei Xiananmei that bacterium produces the most significant chemical sproof mechanisms known to beta-lactam antibiotics.These β-Nei Xiananmei degradation beta-lactam antibioticss cause the forfeiture of anti-microbial activity.The known molecular amount is the main hydrolyzing penicillin class of category-A Serine β-Nei Xiananmei of 29kDa, and molecular weight is the main hydrolysis cephalosporins of C class Serine β-Nei Xiananmei of 39kDa.Beta-lactam antibiotics share the compound that suppresses these enzymes can significantly reduce bacterium to these antibiotic resistances.
Known in the state of the art have a lot of beta-lactamase inhibitors.For example, U.S. Patent No. 4,234,579 disclose and have been used to strengthen the active penicillanic acid 1 of some beta-lactam antibioticss, 1-dioxide (being Sulbactam); U.S. Patent No. 4,562,073 discloses the penicillin derivative (Tazobactam) as beta-lactamase inhibitor.Equally, United States Patent (USP) NO.4,287,181 and 5,637,579 disclose the penicillanic acid derivative that is used to strengthen the beta-lactam antibiotics effect.But, in these patents disclosed compound only at category-A Serine β-Nei Xiananmei, and proof active very poor to c class β-Nei Xiananmei.
There are two positions to be modified on the mould sulfone skeleton: i.e. 3 Beta-methyls and 6-position.In the compound of Tao Luning, 3 or 6 are had only a place to be modified in the above.So far, finally the single modification of mould sulfone structure is not produced the activity of desired anti-category-A and C class Serine β-Nei Xiananmei.Therefore, as seen have required to compound with double activity.
Summary of the invention
The invention provides all has β-Nei Xiananmei to suppress active compound or its pharmacy acceptable salt to category-A and C class Serine β-Nei Xiananmei, and these compounds have following general formula (A):
Wherein Y is
Or
Be that A has as shown in the formula one of I and II:
Wherein, n is 0 or 1,
When n=1, R is five yuan or hexa-member heterocycle, hydroxyl, halogen, oxo, formamyl, alkoxyl group or substituted-amino,
When n=0, R is ester group, cyano group or amido;
X is CH or NH;
R
3Be cyano group, methoxyl group or kharophen;
R
1For hydrogen, alkyl, negative charge, be selected from the positively charged ion of sodium, potassium and tetra-allkylammonium and acyloxy alkyl or alkoxy carbonyl oxyalkyl;
R
2For hydrogen, acyl group, three replace silyl, formamyl, two-(C
1-4Alkyl) aminocarboxyl or amino-acid residue.
Detailed Description Of The Invention
The heterocycle of R can be aromatics or non-aromatic heterocyclic, has 1-3 the identical or different heteroatoms that is selected from oxygen, nitrogen and sulphur.Its example comprises 1,2,3-triazoles, isoxazole, imidazoles or pyridine.
Example when R is disubstituted amido has two-(C
1-4Alkyl) amino, wherein alkyl is identical or different.Example when R is ester group has alkyl ester, and wherein alkyl has 1-4 carbon atom.Example when R is amido has CONH
2Or single or two-(C
1-4Alkyl) amido, wherein alkyl is identical or different.
R
2Example when being three replacement silyls has three-(C
1-4Alkyl) silyl, wherein alkyl is identical or different.R
2Example during for acyl group has (C
1-4Alkyl) carbonyl.R
2Example during for amino-acid residue has glycyl, alanyl, leucyl, isoleucyl and valyl.
Compound of the present invention is preferably has following substituent compound or its pharmacy acceptable salt: n is 1 in the above-mentioned general formula; R is 1,2,3-triazoles base, isoxazolyl, imidazolyl or pyridyl; R
1Be sodium; R
2Be hydrogen.
Preferable asymmetric center has 2S, 3S, 5R, 6R configuration.
Best The compounds of this invention is:
(2S, 3S, 5R, 6R)-and 6-hydroxymethyl-3-methyl-4,4,7-trioxy--3-[1,2,3] triazol-1-yl methyl-4-λ (6)-thia-1 azabicyclic (3.2.0) heptane-2-formic acid;
(2S, 3R, 5R, 6R)-and 6-hydroxymethyl-3-(methoxyimino methyl)-3-methyl-4,4,7-trioxy---4-λ (6)-thia-1-azabicyclic (3.2.0) heptane-2-formic acid;
(Z)-(2S, 3S, 5R, 6R)-and 6-hydroxymethyl-3-methyl-3-(3-nitrilo propenyl)-4,4,7-trioxy--4-λ (6)-thia-1-azabicyclic (3.2.0) heptane-2-formic acid; Or
(E)-(2S, 3S, 5R, 6R)-and 6-hydroxymethyl-3-methyl-3-(3-nitrilo propenyl)-4,4,7-trioxy--4-λ (6)-thia-1-azabicyclic (3.2.0) heptane-2-formic acid.
The straight or branched carbochain of term used herein " alkyl " and 1-6 carbon atom of " alkoxyl group " expression.Term " halogen " expression chlorine, bromine, fluorine and iodine.
Compound of the present invention comprises unsymmetrical carbon, therefore has optical isomer and diastereomer.Do not consider stereochemistry, the present invention includes such optical isomer and diastereomer; The R and the S steric isomer of the racemic and enantiomer-pure that splits; Other mixtures of R and S steric isomer; And their pharmacy acceptable salt.People recognize that an optical isomer (comprising diastereomer and enantiomorph) or comparable another of steric isomer have favorable properties.Therefore, open and claimed when of the present invention, when disclosing a kind of racemic mixture, mean that obviously the steric isomer of two kinds of optical isomers (comprising diastereomer and enantiomorph) or essentially no another isomer is revealed and claimed.
Compound of the present invention also can be used for forming the pharmaceutically-acceptable acid addition with free alkali effectiveness.These salt made from the prior art currently known methods can form with following mineral acid or organic acid: fumaric acid, phenylformic acid, toxilic acid, xitix, pamoic acid, succsinic acid, the dimethylene Whitfield's ointment, methylsulfonic acid, ethyl sulfonic acid, acetate, oxalic acid, propionic acid, tartrate, Whitfield's ointment, citric acid, glyconic acid, lactic acid, oxysuccinic acid, amygdalic acid, annamic acid, citraconic acid, aspartic acid, stearic acid, palmitinic acid, methylene-succinic acid, glycolic acid, para-amino benzoic acid, L-glutamic acid, Phenylsulfonic acid, hydrochloric acid, Hydrogen bromide, sulfuric acid, cyclohexylsulfamic acid, phosphoric acid and nitric acid.
The present invention also comprises the method for preparation formula A compound, comprises following method:
A) the formula III compound is gone protection, obtain corresponding formula A compound
Wherein Y, R
2, Z and n definition as above, Q is suitable protecting group, as diphenyl-methyl; Or
B) mixture (as racemic modification) of split-type A compound optically active isomer separates a kind of enantiomorph or diastereomer, wherein is substantially free of another kind of enantiomorph or diastereomer; Or
C) with pharmaceutically acceptable acid with the acidifying of formula A basic cpd, obtain pharmacy acceptable salt.
As method a) as described in the removal protecting group can carry out with the currently known methods of prior art, so that formula A to be provided compound.
About method b), can use the standard isolation technique to separate specific enantiomorph or diastereomer.For example, racemic mixture can be converted into the optical activity diastereomer by a kind of enantiomorph reaction (for example form diastereomeric salt or form covalent linkage) with " resolving agent ".The optical activity non-enantiomer mixture available standards technology (as crystallization process or chromatography) of gained is separated, and handles each optical activity diastereomer then removing resolving agent, thereby obtains the single enantiomer of mixture of the present invention.Chiral chromatography (with chiral support, eluent or ion-pairing agent) also can be used for direct separation of racemic mixture.
Use such as above-mentioned acid and handle, formula A compound separation can be become the salt of pharmaceutically acceptable acid (as organic acid or mineral acid).
Compound of the present invention can be prepared with any proper method well known by persons skilled in the art.But, can more advantageously prepare The compounds of this invention by following flow process.
Flow process 1
Flow process 2
BH: diphenyl-methyl
The BT:2-benzothiazolyl
Flow process 3
Intermediate 1
Preparation (2S, 5R)-6,6-two bromo-3,3-dimethyl-4,7-dioxo-4-thia-1-azabicyclic (3.2.0) heptane-2-formic acid benzhydryl ester (2.42g, 4.47mmol; Press
Heterocycles, 32:1505 (1991) makes) and solution in acetonitrile (20ml).Adding the TMS-triazole (presses
Chem.Pharm.Bull., 45 (7): 1140 (1997) make), with 110 ℃ of heating of reaction mixture 4 hours.Then, be cooled to room temperature, dilute with methylene dichloride.Organic solution is washed with water, and dried over mgso is evaporated to driedly, after flash chromatography separates (30% ethyl acetate/hexane), obtains 0.63g (13.8%) intermediate 1.
NMR(CDCl
3)δ：7.86(1H，s)，7.75(1H，s)，6.90(1H，s)，5.92(1H，s)，5.01(1H，s)，
4.86 (1H, d; J=14.4Hz), 4.42 (1H, d; J=14.4Hz), 1.17 (3H, s) .FAB high separations
M+H＝590.9694(Δm＝0.7mDa)
Intermediate 2
Preparation intermediate 1 (1.0g, 1.6883mmol) solution in methylene dichloride (12ml) and acetate (2.4ml).(640mg 4.05mmol), heats reaction mixture 3.5 hours for 38 ℃ to add potassium permanganate.Be cooled to the ice bath temperature then, with methylene dichloride (12ml) and water (6ml) dilution.Destroy superfluous potassium permanganate with metabisulfite solution.Separate organic phase, water, saturated sodium bicarbonate washing, dried over mgso is evaporated to driedly, obtains 935g (89%) intermediate 2.
NMR(CDCl
3)δ：7.74(1H，d；J＝0.9Hz)，7.72(1H，d；J＝0.9Hz)，7.3(10H，m)，
6.99(1H，s)，5.09(1H，d；J＝4.8Hz)，5.03(1H，s)，4.79(1H，s)，1.08(3H，s).
Intermediate 3
Under room temperature, (624.3mg 1mmol) is dissolved in anhydrous tetrahydro furan (2ml) with intermediate 2.Solution is cooled to-78 ℃ in nitrogen.Be maintained at and dripping chlorination tertiary butyl magnesium under-78 ℃ the temperature at ether (550 μ l, 1.1mmol) the 2M solution in.This yellow solution in-78 ℃ of stirrings 45 minutes, is added cold anhydrous formaldehyde THF solution (excessive), and temperature maintenance is in below 66 ℃.Continue to stir 30 minutes in-78 ℃, use THF (0.5ml) solution of HOAc (57 μ l) will react quencher.Make reaction mixture be warming up to room temperature,, and filter then with the ethyl acetate dilution.Filtrate is evaporated to dried, after flash chromatography separates (50% ethyl acetate/hexane), obtains 165mg (28.7%) intermediate 3.
NMR(CDCl
3)δ：7.73(1H，s)，7.70(1H，s)，7.38(10H，m)，6.99(1H，s)，5.13(2H，q)，
4.84(1H，s)，4.81(1H，s)，4.18(1H，m)，4.71(1H，m)，2.52(1H，q，OH)，1.08(3H，s).
FAB high separation M+H=575.0609 (Δ m=-0.9mDa).
Intermediate 4
(513mg 0.892mmol) is dissolved in methylene dichloride (5ml) with intermediate 3.Add 1,1 '-azepine two (cyclohexane nitrile) (5mg) and tributyltin hydride (240 μ l 0.892mmol), with reaction mixture refluxed 30 minutes, are evaporated to driedly then, obtain 344mg (78%) intermediate 4 after the flash chromatography separation.
NMR(CDCl
3)δ：7.71(2H，d；J＝3.18Hz)，7.38(10H，m)，6.98(1H，s)，5.12(2H，q)，4.71(1H，s)，4.70(1H，d；J＝4.6Hz)，4.25(3H，m)，2.10(1H，OH)，1.06(3H，s).
ESI?MS：497.3(M+H).
Embodiment 1
(2S, 3S, 5R, 6R)-and 6-hydroxymethyl-3-methyl-4,4,7-trioxy--3-[1,2,3] triazol-1-yl methyl-4-λ (6)-thia-1-azabicyclic (3.2.0) heptane-2-formic acid
Preparation intermediate 4 (298.5mg, the 0.6mmol) solution in meta-cresol (1.8ml), and in 47 ℃ of heating 3.5 hours.Be cooled to room temperature then,, filter, wash with ether with the ether dilution.Solid matter is dissolved in the water (5ml) that contains sodium bicarbonate (50.4mg), filters.Filtrate is washed with ether, and lyophilize obtains 109mg (51.5%) product, is a white solid.
NMR(D
2O)δ：8.12(1H，s)，7.85(1H，s)，5.37(1H，d；J＝15.4Hz)，5.16(1H，d；J＝15.4Hz)，5.08(1H，d；J＝4.6Hz)，4.57(1H，s)，4.38-4.31(1H，m)，4.28-3.98(2H，m)，1.41(3H，s).
Intermediate 5
At nitrogen and cooling off under-77 ℃, and preparation (2S, 5R)-6,6-two bromo-3,3-dimethyl-7-oxo-4-thia-1-azabicyclic (3.2.0) heptane-2-formic acid benzhydryl ester (10.0g, 0.019mol; Press
J.Org. Chem., 52:3659 (1987) makes) and solution in anhydrous THF (60ml).Under abundant stirring, (11ml, 0.0209mol), its speed is maintained at below-65 ℃ for temperature in making to add 2M chlorination tertiary butyl magnesium diethyl ether solution in this cold soln.This cold reaction mixture was stirred 45 minutes.Add anhydrous THF (100ml) solution of cold dried monomer formaldehyde through syringe in this solution, temperature maintenance is in below-65 ℃.Monomer formaldehyde/THF formulations prepared from solutions is as follows: (30g, 1.0mol) (4.9g 15mmol) places three-necked flask, adds tetrahydrofuran (THF) (1.0L) with the tosic acid acid anhydride with paraformaldehyde.With mixture heating up, continue slow solvent distillation.Under weak nitrogen gas stream, the THF solution of no aqueous monomer paraformaldehyde is collected in the dry combustion method bottle that is maintained at-78 ℃.Solution is stored in-78 ℃.Reaction mixture is at last in-77 ℃ of stirrings 30 minutes, with THF (10ml) the solution quencher reaction of Glacial acetic acid (1.2ml).
Make reaction mixture be warming up to room temperature, with ethyl acetate (100ml) and water (50ml) dilution.Take out organic phase, wash with water, dried over sodium sulfate is evaporated to driedly, after flash chromatography separates (30% ethyl acetate/hexane), obtains 3.2g (36%) intermediate 5, is α, beta isomer alcohol (75% β and 25% α).
β-alcohol: NMR (CDCl
3) δ: 7.31 (10H, m), 6.93 (1H, s), 5.56 (1H, s), 4.61 (1H, s), 4.23-4.06 (2H, m), 2.25 (1H, t, OH), 1.58 (3H, s), 1.26 (3H, s).
α-alcohol: NMR (CDClCl
3) δ: 7.33 (10H, m), 6.98 (1H, s), 5.66 (1H, s), 4.56 (1H, s), 4.27-4.06 (2H, m), 2.24 (1H, t, OH), 1.58 (3H, s), 1.29 (3H, s). high separation MS: calculated value M+H=476.0531, measured value=476.0351 (Δ m=0.0mDa).
Intermediate 6
Under nitrogen, (12.7g adds tributyltin hydride (7.16ml in anhydrous methylene chloride 26.65mmol) (160ml) solution to intermediate 5,26.65mmol) and 1,1 '-azepine two (cyclohexane nitrile) (159mg) refluxes the solution of gained 2 hours, is evaporated to dried then.The oily residue is handled with 50% ethyl acetate/hexane, and the crystallization of filtering separation obtains 9.8g (92.9%) intermediate 6.
NMR (CDCl
3) δ: 7.35 (10H, m), 6.92 (1H, s), 5.5 (1H, d; J=4.3Hz) the .EI high separation 397.1341
Intermediate 7
(11.5g, 28.9mmol) solution in anhydrous methylene chloride (290ml) is cooled to-20 ℃ in nitrogen with intermediate 6.Add Hunig ' s alkali (7.2ml, 41.3mmol), add then trifluoromethanesulfonic acid tertiary butyl dimethylsilane ester (8.6ml, 37.5mmol).The yellow solution of gained stirred 30 minutes in-20 ℃.Wash twice then with water, each 75ml uses dried over mgso, is evaporated to driedly, obtains the intermediate 7 of (30% ethyl acetate/hexane) of 13.5g (91.3%) chromatographic separation.
NMR (CDCl
3) δ: 7.3 (10H, m), 6.93 (1H, s), 5.44 (1H, d; J=4.2Hz), 4.44 (1H, s), 4.09-3.81 (3H, m), 1.63 (3H, s), 1.25 (3H, s), 0.88 (9H, s) .CI high separation (M+H) 512.2249.
Intermediate 8
(1.26g 2.246mmol) is dissolved in methylene dichloride (7ml) with intermediate 7.Adding formic acid (88%, 0.36ml), add 35% hydrogen peroxide (0.43ml) then.The reaction solution of gained was in 35 ℃ of heating 30 minutes.Add water (1.8ml), with solution restir 15 minutes.Take out organic phase, water, saturated sodium bicarbonate, water washing are evaporated to driedly, obtain 908mg (70%) intermediate 8 (α, β-mixture of isomers) after flash chromatography separates (20% ethyl acetate/hexane).
NMR (CDCl
3) δ:
Alpha-isomer:7.3 (10H, m), 6.99 (1H, s), 4.69 (1H, s), 4.67 (1H, d; J=3.9Hz), 4.4 (1H, t; J=7.2Hz), 4.02 (1H, m), 3.91 (1H, dd; J=5.4Hz).
β-isomer:7.35 (10H, m), 6.97 (1H, s), 4.62 (1H, d; J=3.6Hz), 4.39 (1H, s), 4.08 (2H, d; J=4.5Hz), 3.95 (1H, m), 1.4 (3H, s), 1.1 (3h, s), 0.91 (9H, s).
Intermediate 9
With Dean and Stark apparatus with intermediate 8 (9.65g, 18.28mmol) and 2-mercaptobenzothiazole (3.12g, 18.28mmol) vlil in dry toluene (64ml) is 1.5 hours.Remove thermal source then.Reaction mixture is cooled to room temperature, is evaporated to driedly, obtain 12.37g intermediate 9, be directly used in next step.
NMR (CDCl
3) δ: 7.86-7.20 (14H-m), 6.99 (1H, s), 5.52 (1H, d; J=5.4Hz), 5.1 (2H, d; J=14.1), 4.86 (1H, s), 4.14 (2H, m), 3.78 (1H, m), 1.96 (3H, s), 0.94 (9H, and s) 0.08 (6H, d). high separation MS: calculated value M+H=677.1998, measured value: 677.2016 (Δ m=1.8mDa).
Intermediate 10
(6.1g, (3.05g 18.17mmol), adds Mono Chloro Acetic Acid (36.6g, anhydrous methylene chloride 388mmol) (94ml) solution through addition funnel then to add Silver monoacetate in anhydrous methylene chloride 9.02mmol) (40ml) solution to intermediate 9.With reaction mixture stirring at room 48 hours, filter through celite then.Filtrate is evaporated to dried, with flash chromatography the crude product residue is purified, and obtains 1.5g (27.7%) intermediate 10.
NMR(CDCl
3)δ：7.26(10H，m)，6.86(1H，s)，5.48(1H，d；J＝4.1?Hz)，4.71(1H，s)，4.25-
3.75(7H，m)，1.2(3H，s)，0.81(9H，s)，0.015(6H，s).
High separation MS: calculated value M+H=604.1956, measured value=604.1907 (Δ m=4.9mDa).
Intermediate 11
Preparation intermediate 10 (1.5g, 2.48mmol) solution in methylene dichloride (12.5ml).In this solution, add acetate (3.7ml) and potassium permanganate (1.05g, 6.65mmol).With reaction mixture stirring at room 3 hours.Then mixture is cooled off in ice bath, destroy superfluous potassium permanganate with metabisulfite solution.The separate dichloromethane phase, through washing, dried over mgso is evaporated to dried.Crude product is purified (20% ethyl acetate/hexane) with flash chromatography, obtains 1.38g (88%) intermediate 11.
NMR(CDCl
3)δ：7.28(10H，m)，6.89(1H，s)，4.67(2H，dd；J＝12.0?&?17.4Hz)，
4.54(2H，d；J＝12.6Hz)，4.33(1H，t；J＝9.9Hz)，4.09(1H，m)，4.0(2H，d；J＝0.6Hz)，
3.89(1H，dd；J＝6.9?&?7.1Hz)，1.01(3H，s)，0.81(9H，s)，0.08(6H，s).
High separation MS: calculated value M+H=636.1854, measured value=636.1847 (Δ m=0.7mDa).
Intermediate 12
Preparation intermediate 11 (636.24mg, 1mmol) and thiocarbamide (229mg, the 3mmo1) solution in dried DMF (1.2ml) and anhydrous pyridine (480 μ l), stirring at room 3 hours.The suspension of gained is diluted with ethyl acetate, filter, wash with ethyl acetate.Combined ethyl acetate solution is evaporated to dried.Residue is dissolved in methylene dichloride, washes with water.The organic phase dried over mgso is evaporated to driedly, obtains 542mg, and 97% intermediate 12 is a white solid.
NMR(CDCl
3)δ：7.27(10H，m)，6.9(1H，s)，5.18(1H，s)，4.48(1H，d；J＝4.8Hz)，
4.32(1H，t；J＝10.02&?9.93Hz)，4.09(1H，m)，4.01?&3.97(1H，dd；J＝3.6?&?3.54Hz)，
3.87(1H，dd；J＝7.2?Hz)，3.69(1H，dd；J＝10.7Hz)，2.62(1H，dd；J＝3.7Hz)，0.91(3H，
s)，0.81(9H，s).
Intermediate 13
With pyridinium chlorochromate (1.07g, 4.8mmol) and silica gel (1.5g) in anhydrous methylene chloride (12m), make slurry.Under fully stirring, in this mixture, add intermediate 12 (559.7mg, anhydrous methylene chloride 1mmol) (4ml) solution.The reaction mixture stirring at room of gained 16 hours.With the methylene dichloride dilution, filter then, use washed with dichloromethane.Filtrate is used dried over mgso with the 30-50ml water washing several times, is evaporated to driedly, obtains intermediate aldehydes 13 (382mg, 68.4%).
NMR(CDCl
3)δ：9.61(1H，s)，7.25(10H，m)，6.92(1H，s)，5.41(1H，s)，4.58(1H，d；
J＝4.8Hz)，4.29(1H，t；J＝9.9Hz)，4.15(1H，m)，3.88(1H，dd；J＝7.2Hz)，1.2(3H，s)，
0.81(9H，s).
Intermediate 14
In-20 ℃, (387.2mg, 1.286mmol press with cyano group methylene tri phenyl phosphorane
Chem.Ber., 94:578 (1961) preparation) and lithium perchlorate (137.6mg 1.29mmol) makes slurry in anhydrous methylene chloride (3.2m).(640mg, 1.147ml), temperature maintenance is in-20 ℃ to drip intermediate 13 in this cold suspension.Then, remove cryostat, with reaction mixture stirring at room 5 hours.The green solution of gained is evaporated to dried, separates two kinds of isomer with flash chromatography, obtains intermediate 14 (cis) 302.2mg; 45.4% and (trans) 158mg, 27.2%.
NMR (CDCl
3) δ:
Cis-isomeride: 7.36 (10H, m), 6.96 (1H, s), 6.44 (1H, d; J=123Hz,
5.88(1H，d；J＝12.2Hz)，4.9(1H，s)4.71(1H，d；J＝4.9Hz)，4.39(1H，t，J＝9.96Hz)，
4.2(1H，m)，3.96(1H，dd；J＝7.26Hz)，1.66(3H，s)，0.89(9H，s)，0.07(6H，s).
Trans-isomer(ide): 7.23 (10H, m), 6.98 (1H, s), 6.77 (1H, d; J=16.5Hz), 5.28 (1H, d; J=16.5
Hz)，4.75(1H，s)，4.6(1H，d；J＝4.9Hz)，4.39(1H，t；J＝6.9?&?9.99)，4.2(1H，m)，
3.95(1H，dd；J＝7.29Hz)，1.22(3H，s)，0.88(9H，s)，0.07(6H，s).
Intermediate 15
(106mg, (135mg 0.2324mmol) is dissolved in the solution of exsiccant DMF (0.888ml) and N-N-methyl-2-2-pyrrolidone N-(0.325ml) 1.86mmol) to be added to intermediate 15 (cis-isomeride) with bifluoride hydrogen ammonium.The limpid faint yellow of gained was dissolved in stirring at room 5 hours, filtered.Filtrate is evaporated to dried, obtains intermediate 15 (cis-isomeride) (95mg, 88%) through chromatographic separation.
NMR(CDCl
3)δ：736(10H，m)，6.97(1H，s)，6.5(1H，D；J＝12.3Hz)，5.9(1H，D；
J＝12.3Hz)，4.95(1H，s)，4.78(1H，d；J＝4.59Hz)，4.3-4.1(3H，m)，1.6(3H，s).
High separation MS: calculated value M+H=467.1277, measured value: 467.1260 (Δ m=1.7mDa).
Prepare trans-isomer(ide) by same condition.
NMR(CDCl
3)δ：7.3(10H，m)，6.98(1H，s)，6.84(1H，d；J＝16.5Hz，5.374.84(1H，s)，
(1H，d；J＝16.5Hz)，4.74(1H，d；J＝4.56Hz)，4.3-4.1(3H，m)，1.2(3H，s).
Embodiment 2
(Z)-(2S, 3S, 5R, 6R)-6-hydroxymethyl-3-methyl-3-(3-nitrilo propenyl)-4,4,7-trioxy--4-λ (6)-thia-1-azabicyclic (3.2.0) heptane-2-formic acid and
(E)-(2S, 3S, 5R, 6R)-and 6-hydroxymethyl-3-methyl-3-(3-nitrilo propenyl)-4,4,7-trioxy--4-λ (6)-thia-1-azabicyclic (3.2.0) heptane-2-formic acid
(226mg, 0.4845mmol) solution in meta-cresol (1.5ml) is cooled to room temperature then in 47 ℃ of heating 4 hours with intermediate 15 (cis-isomeride).With the ether dilution, and the adding sodium hydrogen carbonate solution (40.7mg, 0.4845mmol).Water phase separated with ether washing, lyophilize, obtains the mixture (123.5mg, 79%) of title cis-isomeride.
NMR(D
2O)δ：6.68(1H，d；J＝12.4Hz)，6.16(1H，d；J＝12.4Hz)，5.25(1H，d；J＝4.7
Hz)，4.36(1H，m)，4.22(1H，dd；J-8.73Hz)，4.08(1H，dd；8.16Hz)，1.94(3H，s).
High separation MS: calculated value M-H=299.0338, measured value=299.0343 (Δ m=-0.5mDa).
Prepare trans-isomer(ide) by same condition.
NMR(D
2O)δ：7.08(1H，d；J＝16.5Hz)，6.07(1H，d；J＝16.5Hz)，5.2(1H，s)，
4.36(1H，m)，4.21(1H，dd；J＝8.10Hz)，4.07(1H，dd；J＝8.10Hz)，1.64(3H，s).
Intermediate 16
With intermediate 13 (381.5mg, 0.684mmol) and methoxamine hydrochloride (58.3mg is 0.684mmol) in anhydrous methylene chloride (1.5ml) and anhydrous pyridine (83 μ l, the solution stirring at room that forms in 1.026mmol) 7.5 hours.Then reaction mixture is diluted with methylene dichloride, solution with water is given a baby a bath on the third day after its birth inferior (each 40ml).The organic phase dried over mgso obtains 192mg intermediate 16, yield 47% behind rapid column chromatography (20% ethyl acetate/hexane).
NMR(CDCl
3)δ：7.5(1H，s)，6.96(1H，s)，5.08(1H，s)，4.67(1H,d；J＝4.5Hz).4.4(1H，
t)，4.1(1H，m)，3.97(3H，s)，3.9(1H，dd)，1.33(3H，s)，0.8(6H，d).
High separation MS:M+H=587.2226 (Δ m=2.1mDa).
Intermediate 17
(185mg, 0.3153mmol) (72mg, 1.26mmol) the solution stirring at room in doing (molecular sieve) DMF (1.2ml) and 1-Methyl-2-Pyrrolidone (0.49ml) is 24 hours with two ammonium hydrogen difluorides with intermediate 16.Reaction mixture is filtered, be evaporated to driedly, behind rapid column chromatography (20-50% ethyl acetate/hexane), obtain 114.5mg intermediate 17, yield 76.5%.
NMR(CDCl
3)δ：7.48(1H，s)，6.96(1H，s)，5.2(1H，s)，4.7((1H，d；J＝4.5Hz)，4.3(1H，
m)，4.15(2H，m)，3.98(3H，s)，1.33(3H，s).
High separation MS:M+H=473.1393 (Δ m=-1.1mDa).
Embodiment 3
(2S, 3S, 5R, 6R)-and 6-hydroxymethyl-3-(methoxyl group amino methyl)-3-methyl-4,4,7-trioxy---4-λ (6)-thia-1-azabicyclic (3.2.0) heptane-2-formic acid
(107.5mg, 0.2275mmol) solution in meta-cresol (0.7ml) was in 47 ℃ of heating 4 hours with intermediate 17.Then solution is cooled to room temperature, dilutes with ether.Adding contains sodium bicarbonate, and (19.1mg, water 0.2275mmol) (10ml) solution branch goes organic phase.Water washs with ether, and lyophilize obtains 47.8mg product (yield 64%).
NMR(D
2O)δ：7.68(1H，s)5.18(1H，d；J＝4.5Hz)，4.88(1H，s)，4.35(1H，m)，4.2(1H，
t)，4.08(1H，dd)，3.97(3H，s)，1.66(3H，s).
High separation MS:M-H=305.0443 (Δ m=-1mDa)
Activity with following pharmacological experimental method proof The compounds of this invention.
Representative compounds of the present invention and Penicillin antibiotics piperacillin are tested in microbiological test together.Collaborative enhancing anti-microbial activity is represented the β-Nei Xiananmei inhibition activity of The compounds of this invention.In these trials, with the minimum inhibition activity (MIC) of some 2 times of diluent determinings in broth culture, the ratio of piperacillin and inhibitor is 1: 1 (N.A.Kuck, N.V.Jacobus, P.J.Peterson, W.J.Weiss ﹠amp; R.T.Testa,
Antibiotic Agents and Chemotherapy, 33:1964-1969 (1989)).The results are shown in Table 1.
Also with representative compounds of the present invention with respect to commercially available inhibitor tazobactam, measure the restraining effect of AmpC and TEM-1 β-Nei Xiananmei.Before adding Nitrocefin azoles is as substrate, enzyme and inhibitor one are arised from 25 ℃ of pre-cultivations 10 minutes, use spectrophotometry IC
50Value.The result sees Table 1 equally.
Table 1
IC
50(nM) MIC(μg/ml；1∶1
d)
Compound
TEM-1 AmpC E.coli a?
S.marcescens b
Embodiment 16 360 2
c16
e
Embodiment 2 (cis) 19 270 48
Embodiment 2 (trans) 74 280 16 4
Embodiment 3 64 280 8 16
Tazobactam 60 47,700 2 32
Piperacillin＞64 32
aGC6265, TEM-1 (category-A);
bGC4132, AmpC (C class);
cGC2847, TEM-1 (category-A);
dPiperacillin: inhibitor ratio;
eGC2894; AmpC (C class).
When The compounds of this invention is used for above-mentioned practical aspect, they can share with one or more pharmaceutically acceptable carriers (as solvent, thinner etc.), and can sterile solution for injection or the form parenteral admin of suspension, suspension is contained in etc. and oozes about 0.05% in the medium to about 5% suspension agent.Such medicament can contain has an appointment 0.05% to about 90% activeconstituents, and contains about 5% to 60 weight % carrier usually.
The effective dose of used activeconstituents can change according to the severity of used specific compound, administering mode and the disease of being treated.But, in general, when compound of the present invention dosage every day is about 2-100mg/kg (be preferably and divide 2-4 administration every day), obtain satisfied result.One day total dose is generally about 100-750mg, is preferably about 100-500mg.Be applicable to that formulation for oral administration comprises and the mixed uniformly active substance 100-750mg of pharmaceutically acceptable liquid vehicle.This dosage can adjust, so that the suitableeest therapeutic response to be provided.For example, can give the dosage that separates several times in one day, or reduce dosage in proportion by the treatment situation.The advantage of a reality is that The compounds of this invention can be through vein, muscle or subcutaneous route administration.Liquid vehicle comprises sterilized water, polyoxyethylene glycol, nonionic surface active agent and suitable edible oil (as Semen Maydis oil, peanut oil and sesame oil).The adjuvant of using always in the time of can using useful in preparing drug formulations, for example, vitamin-E, xitix, BHT and BHA.
But The compounds of this invention parenteral or intraperitoneal administration.The solution of these active compounds or suspension can be used and prepare such as the suitable blended water of tensio-active agents such as hydroxypropylcellulose.Available glycerine, liquid macrogol and the mixture in oil thereof prepare dispersion liquid.Under common storage and working conditions, these preparations comprise sanitas, to prevent microbial growth.
The medicament forms that is suitable for injection comprises the sterile powder that sterile water solution and preparation sterile solution for injection or dispersion liquid are used.In all cases, medicament forms must be sterilization and must be liquid, thereby easily injection.Must stablize under preparation and condition of storage, it must antimicrobial contamination and anticorrosion.Carrier can be solvent or contain for example dispersion medium of water, ethanol, polyvalent alcohol (as glycerine, propylene glycol and liquid macrogol) and vegetables oil.
The present invention can show as other particular forms and not deviate from its spirit and basic contribution, therefore, when indicating scope of the present invention, should be referring to appending claims, rather than referring to the specification sheets of front.
Claims (10)
1. the compound or its pharmacy acceptable salt that have following general formula (A):
Wherein Y is
Or
Be that A has as shown in the formula one of I and II:
Wherein, n is 1,
R is five yuan or hexa-atomic aromatics or non-aromatic heterocyclic, has 1-3 the identical or different heteroatoms that is selected from oxygen, nitrogen and sulphur;
X is CH or NH;
R
3Be cyano group, methoxyl group or kharophen;
R
1Be hydrogen, C
1-6Alkyl or alkoxy carbonyl oxyalkyl;
R
2Be hydrogen, C
1-4Alkyl-carbonyl, three-(C
1-4Alkyl) silyl, formamyl, two-(C
1-4Alkyl) aminocarboxyl or amino-acid residue.
2. compound as claimed in claim 1 or its pharmacy acceptable salt, wherein R is 1,2,3-triazoles, isoxazole, imidazoles or piperidines.
3. compound as claimed in claim 1 or its pharmacy acceptable salt, wherein n is 1; R is a 1,2,3-triazoles; R
1Be sodium; R
2Be hydrogen.
4. compound as claimed in claim 1, described compound be (2S, 3S, 5R, 6R)-6-hydroxymethyl-3-methyl-4,4,7-trioxy--3-[1,2,3] triazol-1-yl methyl-4-λ (6)-thia-1-azabicyclic (3.2.0) heptane-2-formic acid.
5. compound as claimed in claim 1, described compound be (2S, 3S, 5R, 6R)-6-hydroxymethyl-3-(methoxyimino methyl)-3-methyl-4,4,7-trioxy--4-λ (6)-thia-1-azabicyclic (3.2.0) heptane-2-formic acid.
6. compound as claimed in claim 1, described compound be (Z)-(2S, 3S, 5R, 6R)-6-hydroxymethyl-3-methyl-3-(3-nitrilo propenyl)-4,4,7-trioxy--4-λ (6)-thia-1-azabicyclic (3.2.0) heptane-2-formic acid.
7. compound as claimed in claim 1, described compound be (E)-(2S, 3S, 5R, 6R)-6-hydroxymethyl-3-methyl-3-(3-nitrilo propenyl)-4,4,7-trioxy--4-λ (6)-thia-1-azabicyclic (3.2.0) heptane-2-formic acid.
8. the pharmaceutical composition that contains formula I and formula II compound or its pharmacy acceptable salt:
Wherein, n is 1,
R is five yuan or hexa-atomic aromatics or non-aromatic heterocyclic, has 1-3 the identical or different heteroatoms that is selected from oxygen, nitrogen and sulphur;
X is CH or NH;
R
3Be cyano group, methoxyl group or kharophen;
R
1Be hydrogen, C
1-6Alkyl or alkoxy carbonyl oxyalkyl;
R
2Be hydrogen, C
1-4Alkyl-carbonyl, three-(C
1-4Alkyl) silyl, formamyl or amino-acid residue.
9. the method for preparing the described formula A compound of claim 1 is characterized in that comprising one of following method:
A) the formula III compound is gone protection, obtain corresponding formula A compound
Wherein Y is
Wherein, n is 1,
R is five yuan or hexa-atomic aromatics or non-aromatic heterocyclic, has 1-3 the identical or different heteroatoms that is selected from oxygen, nitrogen and sulphur;
X is CH or NH;
R
3Be cyano group, methoxyl group or kharophen;
R
2Be hydrogen, C
1-4Alkyl-carbonyl, three-(C
1-4Alkyl) silyl, formamyl, two-(C
1-4Alkyl) aminocarboxyl or amino-acid residue;
Q is a protecting group; Or
B) mixture of split-type A compound optically active isomer separates a kind of enantiomorph or diastereomer, wherein is substantially free of another kind of enantiomorph or diastereomer; Or
C) with pharmaceutically acceptable acid with the acidifying of formula A basic cpd, obtain pharmacy acceptable salt.
10. method as claimed in claim 9 is characterized in that described Q is a diphenyl-methyl.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US23772699A | 1999-01-26 | 1999-01-26 | |
| US09/237,726 | 1999-01-26 |
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| Publication Number | Publication Date |
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| CN1337965A CN1337965A (en) | 2002-02-27 |
| CN1188417C true CN1188417C (en) | 2005-02-09 |
Family
ID=22894903
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|---|---|
| EP (1) | EP1144418A1 (en) |
| JP (1) | JP2002535335A (en) |
| KR (1) | KR20010101649A (en) |
| CN (1) | CN1188417C (en) |
| AU (1) | AU2624600A (en) |
| BG (1) | BG105737A (en) |
| BR (1) | BR0007729A (en) |
| CA (1) | CA2355738A1 (en) |
| CZ (1) | CZ20012691A3 (en) |
| EA (1) | EA200100813A1 (en) |
| HK (1) | HK1038747A1 (en) |
| HU (1) | HUP0200013A3 (en) |
| ID (1) | ID29400A (en) |
| IL (1) | IL144116A0 (en) |
| NO (1) | NO20013640D0 (en) |
| PL (1) | PL349874A1 (en) |
| SK (1) | SK10142001A3 (en) |
| TR (1) | TR200102133T2 (en) |
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| KR20110125651A (en) * | 2009-03-10 | 2011-11-21 | 레르 리키드 쏘시에떼 아노님 뿌르 레드 에렉스뿔라따시옹 데 프로세데 조르즈 클로드 | Cyclic amino compounds for low-k silylation |
| CN109422765B (en) * | 2017-09-05 | 2020-08-28 | 香港理工大学深圳研究院 | C-class beta-lactamase inhibitor and preparation method and application thereof |
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| GB2076812A (en) * | 1980-05-22 | 1981-12-09 | Ciba Geigy Ag | Penam-dioxide compounds, processes for their manufacture, and their use |
| GR77151B (en) * | 1982-01-11 | 1984-09-07 | Prizer | |
| US4562073A (en) * | 1982-12-24 | 1985-12-31 | Taiho Pharmaceutical Company Limited | Penicillin derivatives |
| US4503040A (en) * | 1984-02-27 | 1985-03-05 | Pfizer Inc. | 6-(Aminoacyloxymethyl)penicillanic acid 1,1-dioxides as beta-lactamase inhibitors |
| US4591459A (en) * | 1984-12-03 | 1986-05-27 | Pfizer Inc. | Intermediates for 6-(aminoacyloxymethyl) penicillanic acid 1,1-dioxides |
| TW383308B (en) * | 1993-08-24 | 2000-03-01 | Hoffmann La Roche | 2-beta-alkenyl penam sulfones as beta-lactamase inhibitors |
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2000
- 2000-01-26 CN CNB008030766A patent/CN1188417C/en not_active Expired - Fee Related
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2001
- 2001-05-25 ZA ZA200104323A patent/ZA200104323B/en unknown
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| EP1144418A1 (en) | 2001-10-17 |
| HK1038747A1 (en) | 2002-03-28 |
| HUP0200013A3 (en) | 2002-10-28 |
| HUP0200013A2 (en) | 2002-05-29 |
| ID29400A (en) | 2001-08-30 |
| SK10142001A3 (en) | 2002-07-02 |
| ZA200104323B (en) | 2002-08-26 |
| WO2000043399A1 (en) | 2000-07-27 |
| EA200100813A1 (en) | 2003-02-27 |
| JP2002535335A (en) | 2002-10-22 |
| PL349874A1 (en) | 2002-09-23 |
| IL144116A0 (en) | 2002-05-23 |
| CA2355738A1 (en) | 2000-07-27 |
| NO20013640L (en) | 2001-07-24 |
| CN1337965A (en) | 2002-02-27 |
| TR200102133T2 (en) | 2001-12-21 |
| BG105737A (en) | 2002-05-31 |
| KR20010101649A (en) | 2001-11-14 |
| CZ20012691A3 (en) | 2002-06-12 |
| NO20013640D0 (en) | 2001-07-24 |
| BR0007729A (en) | 2001-10-30 |
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