Method of obtaining derivatives of phenem or their pharmaceutically acceptable salts

专利摘要:
There are provided compounds of formula I : wherein R' is hydrogen or a C1-C4 alkyl group either unsubstituted or substituted by one or more substituents chosen from a free or protected hydroxy or halogen atom; R2 is a free or esterified carboxy group or carboxylate anion; R3 and R4 are each independently hydrogen or organic group, X is ,-S-, Q is either (a") free or protected hydroxy, or (b") a C1-C4 acyloxy, or (c") carbamoyloxy OCONH2, or (d") an optionally substituted heterocyclylthio group, or (e") an optionally substituted imido group, or (f") an optionally substituted quaternary ammonium group or (g") a halogen atom, and the pharmaceutically or veterinarily acceptable salts thereof. There are provided also methods for preparing compounds of formula 1. The compounds of formula I are useful as antibacterial agents.
公开号:SU1579461A3
申请号:SU874202195
申请日:1987-03-05
公开日:1990-07-15
发明作者:Перроне Этторе；Алпеджани Марко；Бедески Анджело；Зарини Франко；Делла Бруна Константино；Франчески Джованни
申请人:Фармиталиа Карло Эрба С.П.А. (Фирма)；
IPC主号:

专利说明:

tetrabutylammonium fluoride in CCH STSOOH with separation of the compound, where R is an allyloxyxycarbonyl group. Allal protecting groups are removed with triphenylphosphine and tetrakis (triphenylfoss
15794614
fin palladium. The desired product is isolated in the form of an acid or its salt. New compounds are low-toxic and active against intestinal gram-positive and gram-negative bacteria, - 1 tab.
1C The invention relates to a method
obtaining new antibiotics of the pemene series or their pharmaceutically acceptable salts, which have anti-bacterial properties, and can be used in medicine or in veterinary medicine.
The aim of the invention is the creation of new penem antibiotics with improved antibacterial properties.
Example 1, Preparation of (5R, 6S) - -6- Ј (1R) -oxyethylP-2-JJ4- (1-pyridinio) methylphenylP-oxymethylpenem-3-carboxylate (compound 4) .25
Stage A.
BUT- (o) -CH7OH - BUT- (o) -pHg08 Pb gVa-1
In a stirred solution of 4-hydroxymethylphenol (6.2 g) in anhydrous dimethylformamide (100 ml), imidazole (9.5 g) and tert butyldiphenylsilyl chloride (12.8 ml) are added successively at room temperature. The resulting solution is stirred for 2 hours at room temperature, then poured into diisopropyl ether and washed twice with water. The organic layer is dried over sodium sulfate and the solvent is distilled off in vacuum. After purification on a column of silica gel (230-400 mesh, eluent mixture of n-hexane with ethyl acetate), 4-tert-butyldiphenylsilyloxymethylphenol is obtained in the form of an oil (12.0 d)
NMR (60 MHz, CDC1,)), MNND: 1.13 (9H, s); 4.72 (2H, s); 5.53 (1H, shir, s); 6.73 (2H, d, 0 Hz); 7.17 (2H, d, J 9.0 Hz); 7.3-7.7 (UN, m).
Stage B.
OSiMe Bu-t „S, OH
OSiMeBu-t
: OGNGCH-CH BUT - @ - CH7OSsPh 78u -t
CO CH-jCV CH
d
five
0
five
0
five
0
five
A solution of diethyl azodicarboxylate (4 mM) and triphenylphosphine (4 mM) in tetrahydrofuran (10 ml) was stirred at 0 ° C for 1 hour. This mixture was added to the solution of allyl (5R, 6S) -6- Ј (1R) tert-butyldimethylsilyloxyethyl-2-hydroxymethylene-3-carboxylate (1.0 g) and 4-tert-butyldiphenylsilyloxymethylphenol (1.0 g) in anhydrous tetrahydrofuran (20 ml) at 0 ° C. The solution obtained stirred for 30 minutes at room temperature, then concentrated in vacuo and purified by flash chromatography on silica gel, resulting in an al yl (5R, 6S) -6- (1 0-t-Bu-tildimetilsililoksi etshG -2- (4-tert -butildifenilsililoksimetilfenil) Oak simetilpenem-3-carboxylate as a pale yellow syrup (600 mg)
A solution of this product in tetrahydrofuran (20 ml) is stirred for 8 hours at room temperature in the presence of acetic acid (0.40 ml) and tetrabutylammonium fluoride trihydrate (0.40 g). The solvent is distilled off in vacuo and the residue is fractionated on a silica gel column (Merck 60 HP 230-400 Mesh, eluent is a mixture of n-hexane and ethyl acetate), resulting in allyl (5R, 6S) -6-p1R) tert-butyldimethylsilyloxy - (4-hydroxymethylphenyl) oxymethylpenem-3-carboxylate (370 mg).
IR (SNSC)) fM01KC: 1787, 1702, 1605, 1580.
NMR (200 MHz, CDC13) Ј, ppm: 0.06 (6H, s); 0.86 (9H, s); 1.21 (3N, d, J 6.4 Hz); 3.70 (W, dd, J 1.7 and 4.6 Hz); 4.22 (1H, dk, J 4.6 and 6.4 Hz); 4.62 (2H, s); 4.7 (2H, m); 5.26 (1H, d, J 10.3 Hz); 5.13 and 5.39 (2H, ABc, J 15.6 Hz); 5.41 (1H, d, J 17 Hz); 5.58 (1H, D, J 1.7 Hz); 5.9t (1H, m); 6.91 and 7.29 (each 2H, d, J 8.7 Hz).
Stage C.
OSiMejBu-l
i
: N-x P so7sn7sn sn7
The appropriate fractions are combined, purified by freezing, and 30 mg of the white powder indicated in the title are obtained. .UV (H20) AMak, c: 258 and 307 nm. (
IR (KBr) 3Maxc: 1765, 1600 cm. Solution allyl (5R, 6S) -6-plR) - ЖР (200 MHz,) & ppm: 1.22
tert-butyldimethylsilyloxymethyl -2-yN d J 63 Hz. 372 (-1N dd J
- (4-hydroxymethylphenyl) hydroxymethylpenem-3-10 H5 and r "J5 (1H dk J
carboxylate (200 mg) in anhydrous and 63 502 and 2N each
   Dj d, J 14.4 Hz); 5.43 (1H, d, J
ethanol-free dichloromethane, ,, „. , q / ic l., 1 "5 Hz): 5j7U t / H, L.Yu. and b, jy.
(15 ml) is cooled in nitrogen atmosphere, „/}„ t Q П1 / ou
up to - 70 ° С and then successively to –C – 2H kaadi, D, J - 8.6 Hz); 8.01 (2H,
Bavle with stirring (pyridine t5VD1, 6 7.0 Hz); 8.50 (1H, t J-
, (0.23 ml) and trifluoromethanesulland- 7} ° Hz); (D) J, 6 Hz) REED (0.22 ml). The reaction temperature is PREMIER2. In the same way
the mixture is allowed to rise to -5 ° C and for-° C ° ° C 1 ° but replacing
the reaction was quenched with the aid of 0.1 M of water -., PyrIDIN "and N-methylpyrrolidine of the obtained HC1 solution. The organic layer is (5R b8) -6- (1U-hydroxyethyl -2-4g (1-.
separated, washed with brine, dried - methyl-pyrrolidinio) methylphenyl, evaporated and evaporated to give a resin-3-carboxylate-3-carboxylate (combined residue)
 NMR (200 MHz, BrO) D ppm: 1.27
 25 (3N, d, J - 6.3 Hz); 2.22 (4H, m);
The product is dissolved in tetrahydrofu-2 93 (3N, s); 3.30-3.65 (4H, m): 3.84
wound (8 ml) and treated with a sequence- (1H, d, J 6.0 Hz); 4.23 (1H, m);
acetic acid (0.55 ml) (2H s). 5J9 and (2H two
tetrabutylammonium fluoride; ZN40j 14 Hz). (1H s); 6.95-7.55
(0.5 g). The clear solution is left 39 (4n m)
at room temperature for 20 h, UV (H20) max: 308 nm. after which it is concentrated and skipping (KBG) kc. 1760, 1605,
cabin through a column of silica gel (230-1580
400 mesh, diameter 2 cm, height 8 cm).
Example 3: Sodium (5R, 6S) -6P Figure 3: Sodium (5R, 6S) -6. Elution is first carried out clean - (1K) -0xyethyl -2- (4 -oxymethylphenokPU .HPPtlil PU PT I CV PM W4-J
CH2C12, then with a mixture of CH2C1Z / CH3CN (70:30, then 50:50), then with pure acetonitrile, after which the final rinsing was carried out with a mixture (1: 2). The latter fractions are added, l NaCl, extracted, then concentrated in vacuo to give the crude allylic ester of the title product as a foam.
This compound is placed in a mixture of “j 5 ml of CH2Cl2 and 0.1 ml of acetic acid and stirred with triphenylphosphine (0.025 g) and tetrakis (triphenylphosphine) Pd (0) (0.025 g) for 30 minutes, methyl) -3- carboxylate. (compound 2)
OSiMe, Bu-t
HE
,,
C07CHNCHN CH7C07NQ
sh
Allyl solution (5R, 6S) -6-Ј- (1R) -t-butyldimethylsilyloxyethyl -2- (4-oxymethylphenoxy) methylpenem-3-carboxylate (0., 5 g) in tetrahydrofuran (7 ml) process
For the completion of the reaction (another .50 acetic acid (0.25 ml) and tert-15 min), PPHE (0.02 g) and Ph butylammonium fluoride with trihydrate (PPh) 4 (0.02 g) are added. (0 44g) This mixture is stirred into a reaction mixture and is concentrated for 15 minutes, then it is incubated and the residue is mixed with ethyl acetate. At room temperature for 6 hours, the resulting substance is dissolved in demineralized solvent. The solvent is removed in vacuo, the residual water and the current is chromatographed and purified by chromatography on a Lichroprep RP-18 column, eluted on silica gel and get allyl first. water, and then 10% solution of the ester of the named rum CH-jCN in water compound (0.35 g). This substance
.157946 T6
The appropriate fractions are combined, purified by freezing, and 30 mg of the white powder indicated in the title are obtained. .UV (H20) AMak, c: 258 and 307 nm. (
IR (KBr) 3Maxc: 1765, 1600 cm. LR (200 MHz) & ppm: 1.22
Example 3. Sodium (5R, 6S) -61K) -0xyethyl -2- (4-hydroxymethylphenok- (1K) -0xyxyethyl -2- (4-hydroxymethylphenok W4-J
her) methylpenem-3-carboxylate. (compound 2)
OSiMe, Bu-t
HE
,,
C07CHNCHN CH7C07NQ
Allyl solution (5R, 6S) -6-Ј- (1R) -t-butyldimethylsilyloxyethyl -2- (4-oxymethylphenoxy) methylpenem-3-carboxylate (0., 5 g) in tetrahydrofuran (7 ml) process
(0.28 g) in a mixture of tetrahydrofuran (5 ml) and dichloromethane (4 mt) are treated with stirring toiphenylphosphine (25 ml) and tetrakis (gripenylphosphine) palladium (0.25 mg), and then sodium 2-ethylhexanoate ( 0.11 g). After stirring for 30 minutes, ethyl ether is added and the precipitate is separated by centrifugation. The resulting solid is dissolved in a small amount of water and passed through a reversed phase column (Merck Lichroprep C-18), distilled water. Freeze-drying gave the title compound as a white powder (0.15 g).
IR (CIHD) schs: 1770, 1600 cm.
PRI me R 4-. Sodium (5R, 6S) -6- - (1R) -oxyethyl -2- (4-carbamoyloxymethylphenoxy) methylpenem-3-carboxylate (compound 1). Stage A „
HE
Oconh7
AtA
g
0С01СН7СН СН2
Trichloroacetyl isocyanate (0.15 ml) is added dropwise to a solution of allyl (5R, b8) -6-Ј (1K) -t-butyldimethylsilyloxymethylG-2- (4-hydroxymethylphenoxy) methylpenem-3-carboxylate, - radiated, as described in example 1, stage B, (0.3 g) in cold (-40 ° C) dichloromethane. The mixture was allowed to warm to room temperature and then concentrated in vacuo. The residue is dissolved in THF (8 ml) and treated with acetic acid (0.6 ml) and tetrabutyl ammonium fluoride trihydrate (0.75 g). After 20 hours at room temperature, the solvent is removed, the residue is purified by flash chromatography on silica gel, and allyl (5R, 6S) -6- (1R) -oxyethyl -2- (4-carbamoyl-oxymethylphenoxy) methylpenem-3-carboxylate is obtained (0.25 g) as an amorphous solid.
Stage B.
The above substance, CO, 2 g) is diallylated with triphenylphosphine and tetrakis (triphenylphosphine) palladium (0) in the presence of sodium ethyl hexanoate, as described in Example 3.
Using reverse phase chromatography, the title compound (0.13 g) is obtained.
IR (KBG) a) with: 1760, 1715, 1605 cm4.
NMR (200 MHz, DZ0): 1.26 (3N, d, J 6.3 Hz); 3.79 (1H, dv, d, J 1.6, 5.8 Hz); 4.19 (1H, dv, q. J 5.8, 6.3 Hz); 4.98 (2H, s); 5.44 and 5.12 (2H, AB squ., J 14-, 6 Hz); 5.52 (W, d, J 1.6 Hz) -; 6.97 (2H, d, J 8.5 Hz); 7.31 (2H, d, J 8.5 Hz).
Example 5 Sodium (5R, 6S) -6-, - (1R) -oxyetuite -2- ft- (1-methyl-1,2, 3,4-tetrazol-5-yl) thiomethylphenoxy-methylpenem-3 -carboxylate (compound 3).
Stage A.
OSiMeBu-t 1n s
С02СН7СН СНг
gsiMegu-tN N

СН3 СОГСН7СН- СН7
0
to
five
five
50
A mixture of triphenylphosphine (700 mg) and diethyl azodicarboxylate (0.42 g) in dry THF (15 ml) was pre-mixed at 0 ° C for 30 minutes and then allyl (5R, 6S) -6- Ј (W tert-butyldimethylsilyloxyethyl -2- (4-oximeSh1phenoxy) methylpenem-3-carboxylate (400 mg) and 1-methyl-5-mercapto-1,2,3,4-tetrazole (100 mg) including the same solvent (30 ml), keeping the temperature below 10 ° C. After 15 minutes, the solvent was removed in vacuo, the residue was purified by chromatography on silica gel (cyclohexane-ethyl acetate) to obtain allyl (5R, 6S) -6- (III) -t-butyldimethylsilyloxy-ethyl (1-methyl-1 , 2,3,4-β-tetrazol-5-yl) thiomethylphenoxy methyl penem-3-carboxylate as a foam (405 hmg).
IR (1790, 1705.
Stage B.
From the above substance (0.4 g) / by successive desililation and deallyllation according to the procedure described in Example 3, the title compound (0.12 g) is obtained as an amorphous solid after freeze-drying.
IR (KBr) Smsp (C: 1765, 1605. Example 6. (5R, 6S) -6- (1R) - -Oxyethyl - 4- (1-pyridinomethyl) -benzoyloxy methylpenem-3-carboxylate ( compound 6).
OSiMeiBu-t
OSiMe-jBa-t
 re.ЈU |
FROM IT-TH
...
OSiPhjBu-t
C07CH2CH CHjСОгСНгСН СН7
IR (CHCl 2), 3MAC: 1790, 1720 cm4 NMR (60 MHz, CDCl 3), ppm 0.05 (6H, s); 0.9 (9H, s); 1.2 (3N, d, J = 6 Hz); 2.35 (1H, broad s.); 3.65 (1H, dd J 2 and 5 Hz); 4.2 (1H, m); 4.65 (4H, m); 5.1-5.5 (2H, m); 5.45, (2H, AB, ap., J 15 Hz); 5.55 (1H, I, J 2 Hz); 5.9 (1H, m); 7.2-8.1 (4H, m).
i Stage C.
OSiMeiBu-t lH x
HE
©
° Y @ "L JbSWoY © n®
sogsnsnn7
Diisopropyl azodicarboxylate (0.2 ml) is added to a cold (0 ° C) solution of allyl (5R, 6S) -6- Ј (1R) -TpeT-butyldimethylsilyloxyethyl-2-hydroxy, 5 methylpene-3-carboxylate (0, 21 g), triphenylphosphine (0.25 g) and 4- (tert-β-butyl-dimethylsilyloxymethyl) benzoic acid (0.2 g) in dry tetrahydrofuran (10 ml). After stirring for 15 minutes, the reaction mixture is diluted ethyl acetate, washed with ethyl acetate (1 ml) in water (50 ml). The organic layer is further washed with brine, 25-tert-butyldimethylsilyloxyethyl-2- is dried with MgSO4 and the solvent is evaporated. (hydroxymethyl) benzoyloxymethyl- using chromatography on silica gel-3-carboxylate (250 mg) in dry form gives allyl (5R, 6S) -6- (1R) - without ethanol dichloromethane (10 ml) after-tert- The dimethylsilyloxyethyl -2- is subsequently treated at -40 ° C with 4- (t-butyldiphenylsilyloxymethyl) zo under nitrogen with pyridine (0.25 ml) and trop-benzoyl-methylmethyne-3-carboxyfluoromethanesulfonic anhydride (0.125 ml).
со®
Allyl (5R, 6S) -6- (1R) lat solution (approximately 400 mg).
IR (CH313Mast: 1790, 1720 cm.
NMR (60 MHz, CO1g), ppm: 0.1 (6H, s); 0.9 (9H, s); 1.12 (9H, s); 1.20 (3N, d, J Hz); 3.70 (1H, dd.d. 2 and 4.5 Hz); 4.2 (1H, m); 4.6-4.8 (AH, m); 5.1-5.6 (2H, m); 5.55 (2H, AB squ.); 4.65 (1H, d, J 2 Hz); 5.9 (1H, m), 7.8-8.2 (14H, m).
Stage B.
35
The treatment of the reaction mixture and the subsequent desilylation and deallylation are carried out as described in Example 1, and the title compound (60 mg) is obtained,
40
236 and 307 nm. 1765, 1720,
UV (
IR (KBG) max 1600.
NMR (200 MHz, 020), ppm: 1.27 (G, d, J 6.3 Hz); 3.79 (W, dv, d, J 1.5 and 5.9 Hz); 4.21 (1H, m); 5.07 and 5.74 (2H, each, d, J 14.8); 5.51 (1H, d, J 1.5 Hz); 5.92 (2H, s); 7.50 and 7.94 (4H, each d, J 8.4 Hz); 8.14 (1H, dv, d. J 6.5 and and 7.7 Hz); 8.63 (1H, t, J 7.7 Hz); 8.99 (1H, d, J 6.5 Hz).
SiMejBu-l U OSitle2Bu-t
1H S cKJOJOSiPh u-l H S n. lOJOH
f °
 СОгСНгСН СН2 С07СНгСН СНг
A solution of the substance from stage A (400 mg) in tetrahydrofuran (10 ml) is treated with acetic acid (0.1 ml) and tetrabutylammonium fluoride with trihydrate (225 mg). After stirring for 2 hours, the solvent is removed in vacuo, the residue is purified by flash chromatography to give allyl (5R, 6S) -6- (1K) -t-butyldimethylsilyloxyethyl -2-4- (ok
simethyl) benzoyloxy methylpenem-3-carboxylate as a light yellow oil (250 mg).
IR (СНС1г), 3МакС: 1790, 1720 sm4. NMR (60 MHz, CDCl), ppm 0.05 (6H, s); 0.9 (9H, s); 1.2 (3N, d, J = 6 Hz); 2.35 (1H, broad s.); 3.65 (1H, dd J 2 and 5 Hz); 4.2 (1H, m); 4.65 (4H, m); 5.1-5.5 (2H, m); 5.45, (2H, AB, ap., J 15 Hz); 5.55 (1H, I, J 2 Hz); 5.9 (1H, m); 7.2-8.1 (4H, m).
i Stage C.
tert-butyldimethylsilyloxyethylL-2- (hydroxymethyl) benzoyloxy methylpene-3-carboxylate (250 mg) in dichloromethane (10 ml), dry without ethanol, is successively treated at -40 ° C under nitrogen with pyridine (0.25 ml) and trn-fluoromethanesulfanhydride (0.125 ml).
OSiMeiBu-t lH x
HE
©
° Y @ "L JbSWoY © n®
sogsnsnn7
et-butyldimethylsilyloxyethyl-2- (hydroxymethyl) benzoyloxy methyl-3-carboxylate (250 mg) in dry ethanol with dichloromethane (10 ml) is orally treated at -40 ° with pyridine nitrogen (0.25 ml) and t-methanesulfonic anhydride (0.125 ml
со®
et-butyldimethylsilyloxyethyl-2- - (hydroxymethyl) benzoyloxy methyl-β-3-carboxylate (250 mg) in dry ethanol, dichloromethane (10 ml) is ovally treated at -40 ° C with nitrogen, pyridine (0.25 ml) and methylene sulfide anhydride (0.125) ml)
Allyl (5R, 6S) -6- (1R) solution
The treatment of the reaction mixture and the subsequent desilylation and deallylation are carried out as described in Example 1, and the title compound (60 mg) is obtained,
0
236 and 307 nm. 1765, 1720,
five
0
UV (
IR (KBG) max 1600.
NMR (200 MHz, 020), ppm: 1.27 (G, d, J 6.3 Hz); 3.79 (W, dv, d, J 1.5 and 5.9 Hz); 4.21 (1H, m); 5.07 and 5.74 (2H, each, d, J 14.8); 5.51 (1H, d, J 1.5 Hz); 5.92 (2H, s); 7.50 and 7.94 (4H, each d, J 8.4 Hz); 8.14 (1H, dv, d. J 6.5 and and 7.7 Hz); 8.63 (1H, t, J 7.7 Hz); 8.99 (1H, d, J 6.5 Hz).
Example. (5R, 6S) -6- (1R) - -oxyethyl -2-Gk-4 ((1-pyridinio) methyl phenylT-carbamoyloxymethylpenem-3-carboxylate (compound 7).
Stage A.
noos
; - oXcH2os1Ph2Ba-t-NV (SrOSiPh2Bu 1
To a solution of 4 (tert-butyldiphenylsilyloxy) -methylbenzoic acid (2 g) in anhydrous dichloromethane (25 ml) are added thionyl chloride (1j1 ml) and anhydrous dimethylforma g (3 drops). After stirring for 2 hours at room temperature under vacuum, the remaining volatile components are removed. The crude chloride-anhydride thus obtained is dissolved in acetone (25 ml) and, with stirring, at 0 ° C, mixed with a solution of sodium azide (0.97 g) in water (4 ml). After a few minutes, most of the acetone is removed in vacuo, and the reaction mixture is extracted with benzene. The organic extracts are washed with brine, dried and evaporated to low volume, leaving a concentrated solution of 4- (tert-butyl-diphenylsilyloxy) methyl-benzoyl azide, which is used as such in the next step.
IR (film): 2155, 1705 cm.
Stage B.
iiPhjBu-t -) -CH7.0SiPh2Bu-t
The benzene solution of the acylazide obtained in step A is heated at the reflux temperature for 4 hours. The solvent is distilled off in vacuo, thus obtaining crude 4- (tert-butyl diphenylsilyloxymethyl) phenyl isocyanate. (
IR (film) m "kc: 2190 cm
Stage C.
"not.-. o ChoU051 8 1-4 A OH + OSiMeBu-t JtSTbsiPthBu-t
Zh-AjKONH
Soggsnsn CIS & & & -%
SOgSNGSN SNG
A solution of crude 4- (tert-butyldiphenylsilyloxymethyl) phenyl isocyanate obtained in Step C (2 g) in chloroform (80 ml), free from ethanol, is successively treated with allyl- (5R, 6S) -6-Ј (1R) - tert-butyldimethylsilyloxyethyl 3-oxymethylpenem-3 car boxylate (2 g) and 4-dimethylaminopi-pyridine (0.06 g). The solution is heated at reflux for 2 hours, then washed with dilute hydrochloric acid and water. After removal of the solvent and chromatography allyl (5R, 6S) -b- (1U-tert-butyldimethylsilyloxyethyl -2- | 11- (tert-butyldiphenylsilyloxymethyl) bamoyloxymethylpenem-3-carboxylate is obtained
(1.9 g).
Stage D.
/ -OOSiPh-jBu-t O
J-iL N-OCONHs
(
COGCH7CH CH7



A solution of the bis-silylated product from step C (1.6 g) in tetrahydrofuran (50 ml) is stirred with tetrabutylammonium fluoride trihydrate (0.95 g) and acetic acid (0.35 ml), until thin layer chromatography (Si02 ethyl acetate - cyclohexane 1: 2) will not show the complete disappearance of the starting compound. According to the evaporative chromatography, allyl (5R, 6S) -6-. (1К.) -T-butyldimethylsilyloxymethyl-| -2-2-H-G4- (oxymethyl) fenshG {carbamoyloxymethylphene-3-carboxylate (0.6 d).
Stage E.
he / §По)
DU., 5 OCONH
Sallyl (5R, B5) -6-C () - tert-butyl-dimethylsilyloxyethyl) 2-M-Ј4 (hydroxymethyl) phenst carbamoyloxymethyl-penem-3-carboxylate (0.1 g) in anhydrous (10 ml) is sequentially treated pyridine (0.1 ml) and trifluoromethanesulfoanhydride (0.05 ml) at –40 ° C. under argon atmosphere. The reaction mixture is successively washed with dilute hydrochloric acid and brine, and the solvent is distilled off in vacuo. The residue was diluted with diethyl ether and the resulting intermediate pyridine salt (70 mg) was dissolved in tetrahydrofuran (5 ml) and acetic acid (0.06 ml) and stirred for 30 hours with tetrabutylammonium fluoride trihydrate ( 95 mg). After removal of the solvent, the product is purified on a SiOa column, followed by using as eluent
1315
a mixture of CKaCl and MeCN, then pure MeCN, then a mixture of MeCN and H20. The desilylated intermediate product is extracted from the last fractions, washed with brine and the organic layer is evaporated. This compound (50 mg) dissolved in a mixture of THF and (1 ml each), is treated with acetic acid (0.1 ml), triphenylphosphine (50 mg) and tetrakis (triphenylphosphine) Pd (50 mg). After 15 minutes, ethyl ether is added, the precipitate is collected, dissolved in water and passed through a Lichroprep RP-18 column using water as eluant and then a mixture of MeCN and water. After drying by freezing the appropriate fractions, the title compound (25 mg) is obtained.
NMR (200 MHz,), ppm: 1.24 (ZN, d, J 6.4 Hz); 3.82 (1H, dd, J 1.6 and 5.8 Hz); 4.18 (1H, dk, J 5.8 and 6.4 Hz); 5.05 and 5.42 (2H AVk, -J 14.6 Hz); 5.55 (1H, fl, J 1.6 Hz); 5.75 (2H, m); 7.43 (4H, m); 8.05 (2H, m); 8.53 (1H, m); 8.89 (2H, m).
Example (5R, 6S) -6- (1R) -OK seethyl -2-4- (3,5-dimethyl-1-pyridinio) methylphenyl oxymethylpenem-3-carboxylate (compound 11).
A solution of allyl (5R, 6S) -6- (1K) -trimethylsilyloxyeth-2-4- (bromomethyl) phenyl oxymethylpenem-3-carboxylate (O, 1 g) in anhydrous dimethylformamide (2 ml) is stirred overnight with 3.5 -dimethylpyridine (0.15 ml). The solution was removed in vacuo and the residue was diluted with diethyl ether to give a yellowish solid (0.1 g), which was stirred for 30 minutes in THF - water - acetic acid (6: 2: 1, 9 ml). The mixture was evaporated to give the crude allyl ester of the title product, which was then obtained by delylation in the presence of a Pd catalyst, as described in Example 1.
IR (KBG) ZmaX: 1765, 1605 cm.
UV (CgO) ma (s: 308 nm.
Sample According to the procedure described in Example 8, replacing 3,5-dimethylpyridine with 3-hydroxypyridine and sodium 4-pyridine ethanesulfonate, the following products are obtained.
(5R, 6S) -6- (1R) -Oxyethyl 2- b- (3- 1-hydroxy-1-pyridinio) -methylphenyl methyl-3-carboxylate (compound 12).


one
14
IR (KBr)} Walcc. : 1763, 1600. UV (H80) s 256 and 307 nm. (5R, B8) -6-GOC-hydroxyethyl -2-4- (4- -suphoethyl-1-pyridinio) methylphenyl hydroxymethyl-3-carboxylate (compound 13).
IR (KBr)) MOIKC: 1765 cm. UV (HjO) max: 308 nm. Example 10. (5R, B5) -6- (1U- -Oxyethyl -2-4- (1-pyridinio) methylphenoxycarbonyloxymethyl-3-carboxylate (compound 8).
To a solution of allyl (5R, 6S) -5- (1-R) -t-butyldimethylsilyloxyethyl3-2-hydroxymethylpenem-3-carboxylate (400 mg) in anhydrous dichloromethane (20 ml) is added at -10 ° C to under a nitrogen atmosphere, 4- (tert-butyldiphenylsilyloxymethyl) - phenyl chlorocarbonate (500 mg) and triethylamine (0.2 ml). The reaction mixture is heated to room temperature, washed with an aqueous solution of NaHCOj, dried and evaporated. After chromatography on silica gel, allyl (5R, B5) -5-C (1) tert-butyldimethylsilyloxyethyl-D-2- 4- (tert-butyldnphenylsilyloxy) methylphenoxycarbonyloxymethylpenem-3-carboxylate (0.6 g) is obtained. A solution of this product in THF (20 ml) is stirred for 8 hours in the presence of acetic acid (0.4 ml) and tetrabutyl ammonium trihydrate (0.4 g). The solvent is removed in vacuo, the residue is fractionated on a silica gel column (n-hexane-ethyl acetate) to obtain allyl (5R, 6S) -6- (j (tR) -TpeT-butyldimethylsilyloxyethyl2 2- (4-hydroxymethylphenoxy) carbonyloxymethylpenem-3carboxylate (0.35 g). This compound is sequentially reacted with pyridine / trifluoromethanesulfonic anhydride, desilylated and deallylated according to the procedure described in example 1, step C, and the title compound is obtained as an amorphous solid substances (75 mg).
IR (KBr) 3MC, KC: 1765, 1750, 1600.
UV aizO) MOMЈ0: 307 nm. Example 11. (5R, 6S) -6-j (1R) - -Oxyetshu-2-4- (1-pyridinio) methylphenyl thiomethylpenem-3-carboxylate (compound 9).
Sodium borohydride (3.8 g) is added at 0 ° C to a solution of 4-methylthiobenzaldehyde (15.2 g) in methanol (200 ml). After neutralizing the HC1, the reaction mixture is concentrated and separated between 10
do EtOAc and brine. After removal of the solvent, 4-methylthio benzyl alcohol is obtained. This compound (13.3 g) is treated with CPPC (15.5 g) in CHC1E 300 ml at 0 ° C. After 30 minutes, the solution is washed with an aqueous solution of NaHCO $ and evaporated, resulting in 4-methylsulfonylbenyl sulphate. This compound (7.9 g) in anhydrous dichloromethane (100 ml) is treated with trifluoromethane sulfoanhydride (19.5 ml) and heated at reflux for 30 minutes. The reaction mixture is poured into a solution of NaOH in ethanol and a crude 4-mercaptobenzyl alcohol is obtained, the solution of which in chloroform is immediately oxidized with an aqueous solution of KI (added dropwise until a stable color appears). After washing with NaHCO 3 and brine and removing the solvent, 4-hydroxymethylphenyl disulfide is obtained. This compound (3 g) is treated with tert-butyldiphenylsilyl chloride (6.5 ml) and imidazole (5 g) in anhydrous dimethylformamide. After 2 hours of stirring at room temperature and chromatography, 4-tert-butyldiphenylsilyloxymethylphenyl disulfide (5.5 g) is obtained in
Lyloxyethyl -2-chloromethylpenem-3-carboxylate. The reaction mixture was partitioned between water and ethyl acetate, the residue from the dry organic layer was purified by chromatography on silica gel, and allyl (5R, 6S) -6- Ј (1R) -t-butyldimethylsilyloxyethyl-2- (4-hydroxymethylphenyl) sulfonylmethyl was obtained - Penem-3-carboxylate. This substance is treated with pyridine / trifluoromethanesulfonic anhydride, then desilylated and de-ethylated according to the procedure described in example 1, and the title compound is obtained.
Icomax: 1765, 1605,
Example 13. (5R, 6S) -6- (lR) -Oxyethye | -2-Ј4- (4-carboxy-1-pyridinio) -methylphenyl hydroxypropyl-3-cartoxylate (compound 14).
Stage A. Protection of the carboxyl function represented in this reaction.
Triethylamine (8.4 ml) was added to a suspension of isonicotinic acid (6.15 g) in dry DMF (100 ml) and the resulting solution was stirred overnight in the presence of allyl bromide
 five
35
form of syrup. Immediately before use (5.1 ml). The reaction mixture is separated.
between water and ethyl acetate and the organic layer is separated with brine, dried over,), evaporated in vacuo to give 4-allyloxycaronylpyridine (3.1 g) as a colorless oil.
NMR (90 MHz, SOSTS), ppm: 4.77 (2H, m); 5.24 (1H, d, J 10 Hz); 5.37 (1H, d, J 12 Hz); 5.94 (1H, m); 7.80 (2H, m); 8, / O (2H, m).
Step B. Condensation with allyl (5R, 6S) -6-H 1R) -oxyethyl-2- (4-bromomethyl-phenyl) hydroxymethyl-3-carboxylate.
The intermediate product mentioned in the title, containing the bromomethylphenyl substituent (LOO mg), is stirred overnight with 4-allyloxycarbonyl pyridine (800 mg) in dry DMF. After removal of the solvent under high vacuum, the residue is taken up in dichloromethane and poured into a simple ethyl ester dropwise, the precipitate is collected (500 mg) and used for the next step.
Stage C. Removal of protective groups.
Crude allyl (5R, 6S) -6- (W) -Oxy-3THLnJ-2- j4- (4-allylcarbonyl-1-pyridinio) methylbenzene oxymethten-3-carboxylate (bromide) obtained in the previous step, mixed in the course of using the above disulfide (1 g) is reduced to 4- (tert-butyldiphenylsilyloxy-ethyl) thiophenol by brief treatment with zinc powder (1 g) in a mixture of acetic acid and dichloromethane (20 ml). The crude mercaptan thus obtained is combined with allyl- (5R, 6S) -5- (1R) -tr-butyldimethylsilyloxyethyl -2-hydroxymethyl-3-carboxylate under conditions described in example 1, step B. The allyl (5R, 6S) -6-f (1R) -tert-butyldimethylsilyloxy-2-th (2- (4-hydroxymethylphenyl) thiomethylpenem-3-carboxylate) obtained is treated with a mixture of pyridine and trifluoromethanesulfonic anhydride, desilylated and decomposed according to the procedure of the procedure, followed by the procedure and using a procedure and procedure, followed by procedure, and the procedure is followed. as a result, the title compound is obtained.
IR (KBr) 3Mcm: 3300, 1765.1600 gML50 Example 12. (5R, 6S) -6 - ((1R) - -Yuxie-2-Ј4- (1-pyridinio) -methyl-phenyl sulfonylmethyl-pen-3-carboxy- lat (compound 10).
A solution of sodium 4- (hydroxymethyl) phenylsulfinate in dry THF is stirred overnight with 1 M equivalent of allyl (, 6S) -b (III) -t-butyldimethyl)
five
Lyloxyethyl -2-chloromethylpenem-3-carboxylate. The reaction mixture was partitioned between water and ethyl acetate, the residue from the dry organic layer was purified by chromatography on silica gel, and allyl (5R, 6S) -6- Ј (1R) -t-butyldimethylsilyloxyethyl-2- (4-hydroxymethylphenyl) sulfonylmethyl was obtained - Penem-3-carboxylate. This substance is treated with pyridine / trifluoromethanesulfonic anhydride, then desilylated and de-ethylated according to the procedure described in example 1, and the title compound is obtained.
Icomax: 1765, 1605,
Example 13. (5R, 6S) -6- (lR) -Oxyethye | -2-Ј4- (4-carboxy-1-pyridinio) -methylphenyl hydroxypropyl-3-cartoxylate (compound 14).
Stage A. Protection of the carboxyl function represented in this reaction.
Triethylamine (8.4 ml) was added to a suspension of isonicotinic acid (6.15 g) in dry DMF (100 ml) and the resulting solution was stirred overnight in the presence of allyl bromide
five
30 min with triphenylphosphine (250 mg and Pd (PhjP) (250 mg), acetonitrile (50 mg) and acetic acid (5 ml). Then add additional PPh and Pd () H (each 250 mg) and the mixture stirred for 30 minutes, then diluted with ethyl ether (190 ml). The precipitated solid is collected by filtration, washed with diethyl ether, dissolved in aqueous NaHCO and subjected to chromatography on Lichrop-rep RP-18, eluted first with water and then with a mixture of acetone - water.
The corresponding portions were combined, freeze dried, and 240 mg of the title compound was obtained as a white powder.
NMR (200 MHz, UZ0) $, ppm: 1.31 (ZN, d, J 6.6 Hz); 3.98, d, J = 1.6 and 6.0 Hz); 4.26 (1H, dd, J 6.0 and 6.6 Hz); 5.26 (2H, ABsq); 5.77 (1H, d, J 1.6 Hz); 5.84 (2H s); 7.46 (4H, m); 8.25 (2H, m); 8.95 (2H, m).
Y
IR (KVG) at MO (KS
Example 14
-OxyeticsH | -2-P4- (4-dimethylamino-1-pyridinio) -methyl phenyl-Oxymethyl-penem-3-carboxylate (compound 15).
A solution of 4-dimethylaminopyridine (1 g) and allyl (5R, 6S) -6- (1K) -oxy- (4-bromomethylphenyl) oxymethyl-enem-3-carboxylate (500 mg) in dry DMF (5 ml) is stirred at 12 hours at room temperature. The solvent is distilled off under high vacuum and the residue is triturated with ethyl ether to give a resinous precipitate of the allyl ester (bromide) indicated in the title compound. Without further purification, this substance is dissolved in 50 ml of dichloromethane and acetic acid (1 ml), triphenylphosphine (0.25 g) and tetrakis (triphenylphosphine) Pd (0) (0.25 g) are added in the indicated order. After stirring for 30 minutes, the reaction mixture is concentrated and the residue is triturated with ethyl acetate and subjected to chromatography on Lichroprep RP-18, eluting first with water and then with 10% CH4 CN in water. Freeze-drying of the appropriate fractions afforded the title compound (270 mg) as a white powder.
308 nm.
1765, 1630. (5R, 6S) -6- (1R)
0
Q
UV (NgOPma) m ;: 307 nm.
IR (KBG) max: 1760, 1600 cm.
Example 15. (5R, 6S) -5- (1R) - -oxyethyl -2- 4- (1-methylpiperazinio) -methyl phenyl hydroxymethyl-3-carboxylate (compound 16).
Stage A. Protection of the N-functional group present in the reagent.
A solution of allyl chloroformate (15 ml) in dry dichloromethane is added at -20 ° C with stirring to a solution of N-methyl piperazine (10 g) in the same solvent. After 30 minutes, the temperature was raised to 15 ° C and the reaction mixture was poured into water. The organic layer is poured, 1N is added to pH 7, NaOH and the mixture is extracted with dichloromethane. Extracts SNGS12 dehydrate (MgSOjj.), Evaporated, the resulting oil | distilled at 118 ° (at 18 mm Hg) and 4-allyloxycarbonyl-1-methyl-piperazine (15.3 g) is obtained.
Step B. Condensation with allyl (5R, 5 6S) -6-G (III) -oxyethyl-2- (bromomethylphenyl) hydroxymethyl-3-carboxylate.
Condensation of the title compound with 4-allyloxycarbonate-1-methylpiperazine is carried out as described in Example 13, Step B,
Stage C. Removal of protective groups.
The crude allyl (5R, B5) - (t) hydroxyethols 2- –P4-allyloxycarbonyl-2-methylpiperazinio) -methylphenshyl hydroxymethyl-3-carboxylate obtained at the previous stage is treated with PPhj Pd (PPh) jHOAc under the conditions described in Princer 13, Stage C. Wire cleaning using reverse phase chromatography (Lichroprep RP-fB) and freeze-drying, the title compound is obtained.
No. Br) JMaVC
% opma (ss
1765, 1600 308 nm.
cm
Example 16. According to the procedure of Example 13 (steps B and C), replacing 4-allyloxycarbonylpyridine with 4-sulfoethane-pyridine, 3-allyloxycarbonyl-etheneshiryridine, 3-allyloxycarbonylmethyl-pyridine and 4-allyloxycarbonylaminomethylpyridine-to-pyridine-dimethylpyridine. :
a) (5R, 65) -6-Ј (1Я) -hydroxyethyl - -2-H- (4-sulfonatoethane-pyridinio) methylphenoxymethyl-Penem-3-carboxylic acid
nineteen
he
Well
COiH
UV (H50) iMOUO: 258, 308 nm; IR (KVG) Ac: 1760, 1570 - 1610
V.
c) (5R, 6S) -6-Ј (1К) -hydroxyethyl - -2-4- (3-carboxylate-phenyl) -pipyridinium methylphenyl hydroxymethyl-3-carboxylic acid
T S SNg (H1
-Vf T o-1
uCOjH
.СН7ч®
4J / -V
Kf0
sn sn-coz
UV (H10) MO | VC: 306 nm;
c) (5R, b8) -6- (1К) -hydroxyethyl - -2-4- (3-carboxylate methyl) -pyridinium methylphenyl 1-oxymethyl-penem-3-carboxylic acid
2Q
CH7cof
UV (N SMiaks: 303 nm 4225;
IR - (KBr) 3 1610 cm 1;
Max
1665, 1580 d) (5R, 6S) -6-Г (Ш-hydroxymethyl -2-4- (4-allyloxycarbonylaminomethyl) pyridinimethylphenylJoxymethylpene-3-carboxylate
©
CIS-o-sng-t "-sn7 tso2 cn sr-si i
with
UV (HgO) 1 mv1se: 307 nm; IR (KBr) 1765, 1705, 1750 - 1610 cm-;
In in vivo tests after intravenous administration, the compounds of the formula I showed very high therapeutic activity in the treatment of infections caused by both gram-positive and gram-negative bacteria, and their toxicity is negligible.
The table shows the data on the study of the minimum inhibitory con45
e) (5R, 6S) -6- (1K) -hydroxymethyl centrations of penem compounds. -2- {H- (4-aminomethyl) -pyridinomethylene-Compound, obtained by predaphenyl} oxymethylpenem-3-carboxylate, Q hydrochloride
they have anti-bacterial activity and therefore can be used in the treatment of respiratory tract infections, such as bronchitis, bronchopneumonia, levritis, hepatobiliary and abdominal infections, such as septicemia, urinary tract infections, such as pyelonephritis, cystitis, obstetric and gynecological infections, cer-
s
.1Х, sn7-о- (о -сн1-н @) - sn% 3a g
from:
UV (): 257 nm, 308 nm; IR (KBG) mox: 1/65, 1560 - 1U10 cm-.
ten

579461 2 °
The compounds of the formula I obtained by the proposed method are strong broad spectrum antibacterial preparations.
In in vivo tests, they showed very interesting pharmacokinetic properties and high therapeutic efficacy in the treatment of infections caused by gram-positive and gram-negative bacteria. In addition, the compounds of formula I have shown high efficacy when administered orally.
The compounds of formula I are effective and in vitro at the following dosages: against Coeci (including penicillin-forming) 0.001-1 μg / ml, against intestinal bacteria (including | 3-lactam-2Q-forming) 0.5-50 μg / ml. Test data for (5R, 6S) -6- (III) -hydroxy-ethyl 1-2-4- (1-pyridinio) methylphenyl hydroxymethylene 3-carboxylate (Example 1, compound 4) in vivo:
t µg / ml.min
15
1/2 r.
Absorption
% 100
-
35
Mice 3361 27 Rats 6150 28 3Q Effect on experimentally induced mice (intraperitoneally administered 3 x DTsr-for control of infection, treatment 30.90 and 360 minutes after infection, 3JL mg / kg, total dose:
Staphilococcus aureus Smith 4.0,032 Escherichia coli Gil1,55
In in vivo tests, after intravenous administration, the compounds of formula I showed very high therapeutic activity in the treatment of infections caused by both gram-positive and gram-negative bacteria, and their toxicity is negligible.
The table shows the data on the study of the minimum inhibitory con40
45
centrations of penem compounds. Compounds prepared according to the invention.
antibiotic activity and therefore can be used in the treatment of respiratory tract infections, such as bronchitis, bronchopneumonia, levrit, hepatobiliary and abdominal infections, such as septicemia, urinary tract infections, such as pyelonephritis, cystitis, obstetric and gynecological infections, for example cer-
vicites, endometritis, infections of the ear, throat, nose, such as otitis, sinusitis, mumps.
These compounds can be administered to animals as well as humans in various forms, for example, orally in the form of tablets, capsules, drops or syrups, rectally in the form of candles, parenterally, for example intravenously or intramuscularly (as solutions or suspensions). ), and in emergency situations, solutions are preferred, by inhalation in the form of aerosols or solutions for intravaginally in the form of pes- / sariums, or topically in the form of ointments, creams. Pharmaceutical or veterinary compositions containing compounds of the formula I can be obtained using conventional carriers or diluents, for example, used for cephalosporins.
Common solvents or diluents are water, gelatin, lactose, starches, magnesium stearate, talc, vegetable mills, cellulose, and t. P. The daily dose is 0.5-100 mg / kg body weight, and for different patients the specific dose depends on the age, weight and condition and on method 3 of administration.
Preferred for administration of the compounds of formula I is the parenteral method. In these cases, compounds for adult patients can be administered at a dose of 200-500 mg per dose, preferably 400 mg per dose, 1-4 times a day, dissolved in a suitable solvent, such as sterile. water or lidocaine hydrochloride solution 4 for intramuscular injections, sterile water, saline, dextrose solution or conventional intravenous fluids or electrolytes for intramuscular injections. 4 In addition, the compounds of the formula I can be used as antibacterial preparations for prophylactic purposes, for example, in cleaning or washing or disinfecting surface compositions, for example, in a concentration of 0.2-1% by weight in a mixture with suspended or dissolved inert dry or aqueous carriers for washing or spraying.
i
These compounds can also be used as useful food additives in animal feed.

权利要求:
Claims (1)
[1]
Invention Formula
The method of obtaining derivatives of the penim of the general formula I
 9H; / -h
, A - gsng-x- -sn2a
where R is a free carboxy group, allyloxycarbonyl. group and carboxyatanion;
X is oxygen or sulfur, an oxycarbonyl group, an oxycarbonyl amino group, an oxycarbonyloxy group, or a sulfonyl group;
Q - hydroxy, carbamoyloxy, 1-methyl tetrazol-5-ylthio, pyridinio, N-methylpyrrolidino, 3,5-dimethylpyridinio, 3-hydroxypyridinio, 4-sulfo-ethylpyridinio, 4-carboxyl, sipyridinio, 4-di - methylaminopyridine, N-Me- tilpitserazinio, 4-sulfona- toetanpiridinio, 3-carboxy silatetenilpiridinno, karboksilatmetilpiri- dinio-3, 4-aminometilpiri- dinio or 4-alliloksikar- bonilaminometilpiridinio, or pharmaceutically acceptable salts thereof, wherein the compound is General formula II
OSi (CH3)
 VCHjL
 COOCH2CH CH2
where L is a hydroxy group or chlorine, is reacted with a compound of the general formula III
A- -CH2Qi
where QJ is a halogen or a group of the formula
-OSi (CgH5-) 2C (} H9-t;
A - hydroxyl, mercapto, carboxyl, chlorocarbonyl isocyanato, chlorocarbonyloxy group or sulfino group, in tetrahydrofuran, chloroform or dichloromethane medium at a temperature of (-10) to (+65) ° C followed by, if necessary, removing it with a third bu23
a tyldiphenyl protecting group with tetrabutylammonium fluoride in acetic acid and the resulting compound of general formula IV
osKow Hg-t
VCH x 0-CHrQ
.-T-X
about
СООСН2СН СН2
15
where X has the indicated meanings;
Qj-halogen or hydroxy-group, is reacted with trichloro-acetyl-isocyanate, 1-methyl-5-mercapto -1,2,3-4-tetra-el, pyridine, N-methylpyrrolidine, 3,5-dimethylpyridine, 3-hydroxypyridine , sodium pyridine-4-ethanesulfonate, 4-allyloxycarbonylpyridine, 4-dimethylaminopyridine, 4-allyloxycarbonyl-1-methylpiperazine, pyridine-4-ethanesulfonic
ten
5794612
acid, 3-allyloxycarbonylethenyl-pyridine, 3-allyloxycarbonylmethylpyridine or 4-allyloxycarbonylamino-methylpyridine in dimethylformamide, dichloromethane or tetrahydrofuran at (-70) to (+25) ° C and forming a compound. IV, in which Q.2 is a hydroxy group, remove the tert-butyl dimethyl protective group with tetrabutylammonium fluoride in acetic acid and select the target product, where R is the allyloxycarbonyl group, or the allyl protective group is removed or the lilnye protecting groups by treatment with triphenyl phosphine and tetrakis (triphenylphosphine) palladium with desired product isolated as a free acid or in the form of inner salt or in form farsoli.
15
20
perfectly acceptable
g

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同族专利:

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公开号 | 公开日

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DK115087D0|1987-03-05|

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ZA871640B|1988-05-25|

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AU625735B2|1992-07-16|

---

IL81733D0|1987-10-20|

---

DK115087A|1987-09-07|

---

NZ219478A|1989-06-28|

---

JPS62270588A|1987-11-24|

---

FI87650C|1993-02-10|

---

IE870562L|1987-09-06|

---

HUT43612A|1987-11-30|

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DE3750233D1|1994-08-25|

---

JPH0784473B2|1995-09-13|

---

EP0236880A2|1987-09-16|

---

HU198498B|1989-10-30|

---

KR870008893A|1987-10-22|

---

DE3750233T2|1994-10-27|

---

ES2061444T3|1994-12-16|

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FI870934A|1987-09-07|

---

PT84419A|1987-04-01|

---

FI87650B|1992-10-30|

---

GB8605549D0|1986-04-09|

---

FI870934A0|1987-03-03|

---

IL81733A|1992-03-29|

---

PT84419B|1989-10-04|

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EP0236880B1|1994-07-20|

---

AT108796T|1994-08-15|

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US4886793A|1989-12-12|

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EP0236880A3|1988-04-06|

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AU6963187A|1987-09-10|

引用文献:

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US4272437A|1978-12-18|1981-06-09|Bristol-Myers Company|Antibacterial agents, and 4-thio azetidinone intermediates|

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US4482565B1|1980-02-22|1987-11-03|

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US4558042A|1981-05-06|1985-12-10|Farmitalia Carlo Erba S.P.A.|β-Lactam-containing antibacterial agents and β-lactamase inhibitors|

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ES8305366A1|1981-07-08|1983-04-01|Hoechst Uk Ltd|Antibacterial penem derivatives.|

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US4742052A|1981-07-15|1988-05-03|Sumitomo Pharmaceuticals Company, Limited|Antibacterial β-lactam compounds|

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NO831160L|1982-04-08|1983-10-10|Erba Farmitalia|PREPARATION OF SUBSTITUTED PENEM DERIVATIVES|

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GB8416652D0|1984-06-29|1984-08-01|Erba Farmitalia|Penem derivatives|

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GB8416651D0|1984-06-29|1984-08-01|Erba Farmitalia|Penem derivatives|

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GB8509180D0|1985-04-10|1985-05-15|Erba Farmitalia|Penem derivatives|

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GB2187448B|1986-03-06|1990-10-24|Erba Farmitalia|Penem derivatives|

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GB8605549D0|1986-03-06|1986-04-09|Erba Farmitalia|Penem derivatives|

---

DE3882730D1|1987-02-11|1993-09-09|Ciba Geigy Ag|BICYCLIC BETA LACTAM CARBON ACIDS.|GB8605549D0|1986-03-06|1986-04-09|Erba Farmitalia|Penem derivatives|

---

DE3882730D1|1987-02-11|1993-09-09|Ciba Geigy Ag|BICYCLIC BETA LACTAM CARBON ACIDS.|

---

EP0597401A3|1992-11-11|1995-07-26|Takeda Chemical Industries Ltd|Production of penem.|

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CN100417654C|2004-01-09|2008-09-10|中国医学科学院医药生物技术研究所|2-benzene carboxylate penicillen compounds and its preparation method and application|

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CN1305875C|2005-04-25|2007-03-21|中国医学科学院医药生物技术研究所|Substituted 2-benzoyl piperazine methyl penem compound, and its preparing method and use|

法律状态:

优先权:

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申请号 | 申请日 | 专利标题

---

GB868605549A|GB8605549D0|1986-03-06|1986-03-06|Penem derivatives|

---