Method of obtaining carbacephalosporin compounds

专利摘要:
7 beta -Acylamino-3-alkoxycarbonyl-(and 3-keto)-1-carba (1-dethia)-3-cephem-carboxylic acids and derivatives and related 3-substituted compounds are provided as antibiotics useful for treating infections in man and other animals. Pharmaceutical formulations comprising the antibiotics, intermediates, and a process for their preparation are also provided.
公开号:SU1575940A3
申请号:SU864028724
申请日:1986-12-29
公开日:1990-06-30
发明作者:Эдвин Манрой Джон
申请人:Эли Лилли Энд Компани (Фирма)；
IPC主号:

专利说明:

The mixture is transferred to a test tube and 20 (71.43%) unprotected t-product is placed in a centrifuge. The upper liquid layer of butyl-7-amino-3-methoxycarbonyl-1- is decanted, fresh diethyl ether is added, the mixture is sonicated, and again centrifuged. The ether is decanted, solid 7/3-amino-3-me
Carba-3-cephem-4-carboxylate as an oil.
To a mixture of 7 / l-amino-forming (80 mg; 25 0.27 mmol), 2-phenyl-2-tert-butyloxy (71.43%) unprotected product tert-butyl-7-amino-3-methoxycarbonl-1-
Carba-3-cephem-4-carboxylate as an oil.
To a mixture of 7 / l-amino-forming (80 mg; 0.27 mmol), 2-phenyl-2-tert-butyloxy
toxycarbonyl-1-carba-3-cephem-4-carboxylic acid is dissolved in a mixture of 1 ml of acetonitrile, 2.5 ml of tetrahydrofuran and silylated with BSTFA (337 mg; 1.31 mmol, 53 μl). are cooled, the solution is cooled to 0 ° C. Pyridine (52 mg; 0.6548 mmol, 41 µl) is added to the cooled solution, after which 2-thiopheneacetyl chloride (53 mg) is added. The mixture is stirred in the cold and poured into a mixture of 40 ml of diethyl ether and 20 ml of water. The mixture is first extracted twice with 40 ml of diethyl ether. Then the product is extracted from a mixture of 15% isopropanol in chloroform. The chloroform extract is dried over magnesium sulfate, filtered and evaporated under vacuum to give the product as a solid. The product is triturated with diethyl ether / hexane and dried to give 45 mg of the title compound.
Calculated,%: C, 52.74; H N 7.69; S 8.80,
Found,%: C 52.53; H 4.50; N 7.49; S 8.62.
PRI me R 3. Tertbutyl-7- (2-phenyl-2-tert-butyloxycarbonylaminoacetylamino) -3-methoxycarbonyl-1-carba-3-cephem-4-carboxylate.
To a solution of tert-butyl 3/3-tert-butyloxycarbonylamino-3-methoxycarbonyl-1-carba-3-cephem-4-carboxylate
five
carbonylaminoacetic acid (72 mg; 0.2835 mmol) and pyridine (0.036 ml; 0.447 mmol), cooled to 0 ° C, phosphorus oxychloride (0.028 ml;
0 0.298 mmol). The mixture is stirred for 40 minutes, then poured into 60 ml of ethyl acetate. The solution is washed twice with 30 ml portions of a saturated aqueous solution of sodium bicarbonate and once with 30 mp of brine, dried over magnesium sulfate, filtered and evaporated under reduced pressure to give the desired compound as a white solid.
0 EXAMPLE 4. Ashtil 7d- (2-phenyl-2-allyloxycarbonylaminoacetshtamino) -3-methoxy-carbonyl-1-carba-3-cephem-4-carboxylate.
Allyl Sp-tert-butyloxycarbonyl5 but-3-methoxycarbonyl-1-carb-3-cephem-4-carbsilicate (433 mg; 1.1383 mmol), prepared as described in Example 1, is dissolved in 8 ml of isoprolyl alcohol. Para-toluenesulfonic acid monohydrate (233 mg; 1.1724 mmol) was added to the solution. The mixture is agitated until dissolved and then concentrated by evaporation on a rotary evaporator at 45 ° C. The residue is again dissolved in iso5 propyl alcohol and evaporated at 45 ° C. The process of evaporation and re-dissolution is repeated five times to obtain the 7th-amino-allyl ester formation as a solid.
substances. The product is dissolved with 1C ml of chloroform, the solution is poured into 40 ml of a saturated aqueous solution of sodium bicarbonate in 80 ml of chloroform. The layers are separated, the aqueous layer is extracted twice with 50 ml portions of chloroform. The extracts are combined with the organic layer, dried over magnesium sulphate, filtered and evaporated under vacuum to obtain 300 mg of aloe ester as a yellow oil. Thin layer chromatography of the ester formation shows one spot.
The ester formation is dissolved in 2-3 ml of chloroform, 2 phenyl-2 - allyloxycarbonylaminoacetic acid (2.81 mg | 191952 mol) and pyridine (158845 mmol | 0.153 ml) are added. The mixture is cooled to 0 ° Ca. Then added phosphorus oxychloride (1S26 mmolts 0.117 ml). The mixture is stirred at room temperature for 3040 minutes and dug in 100 ml of ethyl acetate, 25 then shh over magnesium sulfate, filter
The solution is washed each time with 45 ml portions of 1N. hydrochloric acid, twice in portions of 45 ml each of saturated sodium bicarbonate solution and 50 ml of brine. Then the solution of zy shat over magnesium sulfate is filtered and evaporated under reduced pressure to give the product as a white solid. A thin layer chromatogram of the solid shows one basic FHTHO and a smaller spot. With a reduced RЈ value. The solid is chromatographed over 10 g of silica gel. using 45% ethyl acetate / hexane for elution. Many fractions are pooled. Fractions containing the desired product (as indicated by thin layer chromatography) are evaporated under reduced pressure to give 266 mg of the target compound (yield 47%) as a white solid.
EXAMPLE 5 Allyl 7th- (2 Phenyl-2-allsuxycarbonylaminoacetylamino) -3-ethoxycarbonyl-1-carba 3-cephem-4 carboxylate,
T-butyloxycarboni-protected Allyl ester-formation, prepared as described in Example 3 (272 mg | 056897 mmol) s, is treated to remove protecting cadavers in ethyl alcohol at 45 ° C with para-toluenesulfonic acid monohydrate, in a radiation of 7 / b Amino-3 ethoxycarbonyl 1
0
carba-3-cephem-4-carboxylate (203 mg). The ester formation of the acylirhumum is as follows: The ester formation (203 mg | 0.6897 mmol) is dissolved in 2-3 ml of methylene chloride, the solution is cooled to OeCj, N-allyloxycarbonylphenylglycine (O, 7242 mmol), pyridine (1.142 mmol5) is added to the cold solution. 0.092 ml) and phosphorus oxychloride (0S7587 mmol | 0} 071 ml), the solution is stirred in the cold for 30-40 minutes. Thin-layer chromatography of the mixture shows one main product spot and one small spot. Then the mixture is poured into a mixture of 80 ml of ethyl acetate and 40 ml of 1N hydrochloric acid. The layers are separated and the organic layer is washed once with 40 ml of 1 He hydrochloric acid twice - in portions of 40 ml of a saturated aqueous solution of sodium bicarbonate and once with 40 ml of brine. The organic layer containing the product is
5 then over magnesium sulfate, filtered;
P -
It is evaporated and evaporated under vacuum to give 300 mg of product as an oily solid. The product is chromatographed on 25 g of silica gel using 40% amylacetate / hexane for elution. The fractions containing the product are combined and evaporated under vacuum to give 211 mg (yield 60%) of the desired product as a white solid.
EXAMPLE 6 6 (2-Aminothiazol-4 yl) -2-methoxyimino acetamido J-3 acetyl ™ 1-carba (t; etthia) -3 cephem-4-cara lateral acid
To a solution of 60 mg (0 ,, 1647 mmol) allyl 7d- (tertbut loxcarbonylamino) -3-acetyl 1-kaoba (children) g-3-cephem 4 carboxylate in 5 ml of ethyl alcohol is added 32 mg (0SI679 mmol) paratoluene monohydrate acid; The mixture is evaporated at 45 ° C on a rotary evaporator. When thin-layer chromium - tography shows only one new spot (10% methyl alcohol - ethyl acetate), the residue is twice treated with 6 NOT toluene and evaporated after each treatment. The product is allyl 7 / e amino 3-acetyl-1 -carba (child) -3-cephem 4-carboxylate of tolylsulfonyl salt - triturated with 3 ml of diethgol5
ether and dried under vacuum. 71-1 mg of product are obtained.
Solution 78E2 mg (09274 mmol) 2- (2 allyloxy-carboni, p: aminothiazole 149 yl) -2-methoxyiminoacetic acid
in 2 ml of methylene chloride is cooled to 0 ° C and 48.1 mg is added.
(0S274 mmol) 2 chloro-436-dimethoxy-1,3, 5-triazine and N-methylmorpholine (0.274 mmol). The mixture is stirred for 1 hour. An additional equivalent of N-methylmorpholine (0.274 mmol) is added to the mixture, after which a solution of allyl 7/3-amino-3-acetyl-1 carba (child) -3-cephem-4-carboxylate is added tolylsulfonyl salt (prepared as described above) in 1 ml of chloride
l
methylene. The mixture is stirred for 15 (0.002 mmol) Pd (-OCCH3) g. The resulting
the solution is treated with 5.4 mg (0.038 mmol) of p-nitrophenol and 13 ml (05046 mmol) (CHjCHgCHjCH jSnH. After stirring for 7 minutes, another (CH3CEЈH2CHg) 38 pN is added, and the mixture is cooled to 0 ° C and treated with 9 (l l (0.0691 mmol) thienylacetyl chloride, 11 (Lf l. (0.124 mmol) pyridine and 0.5 mg dpmia
over magnesium sulphate, filter and vytylaminopyridine. After stirring, evaporate to an oily solid for another 10 minutes. Add another 9 (1 liter of residue to the residue (150 mg) to chromatograph on 10 g of silica gel using a mixture of 60:40 by volume ethyl acetate-hexane. Fractions containing the product (thin layer) chromatography)
20 hours, warm to room temperature. The reaction mixture is poured into a mixture of 75 ml of ethyl acetate and 40 ml of 1N. hydrochloric acid, the organic layer is separated, washed successively with 40 ml of 1N. hydrochloric acid, twice in portions of 35 ml of water, twice in portions of 35 ml of saturated sodium bicarbonate aqueous solution, dried
thienylacetyl chloride and 11 pl of pyridine. The mixture obtained is diluted with ethyl acetate and poured into a saturated NaHCOg solution. The organic phase is separated and extracted with 20 ml of saturated
Combine and evaporate to dryness. 70 mg of the product of N-acid precipitation — allyl- (2-allyloxycarbonylamino solution of NaHCO) are obtained, and twice - in portions of 20 ml of 1N HCl solution. Then the organic phase is dried over anhydrous
thiazol-4-yl) -2 methoxyiminoacetamido s5 MgSO4, filtered, and concentrated to po3-acetyl-1-carba (children) -3-cephem-4-carboxylate.
To a solution of 51 mg (0.096 mmol of the above diblocked 3-acetyl-1-carba-3-cephem in 1 ml of methylene chloride and 1 ml of diethyl ether, 9995 mg (0.38 mmol) of triphenylphosphine and 1.18 mg (0.005 mmol a) palladium di-acetate. The mixture is stirred.
emitting 60 mg of brown oil. The crude product is purified by chromatography on 5 g of silica gel using a solution consisting of ethyl acetate and hexane (40/60) as eluent to give 6 mg of the benzhydryl ester of the target compound.
B) To 7 mg of the compound obtained
within 15-20 minutes, cooled to 0 ° C 45 in part A, 0.5 ml of dry is added and CHaCli hydride is added with a syringe under a dry nitrogen atmosphere. Rub (n butyl) tin (0E1968 mmol). After the mixture warms to room temperature, it is stirred for 45 minutes. Concentrated hydrochloric acid (16S4 Mien) is added by means of a syringe. A fine precipitate is formed. To the acidified mixture is added the diethyl-irradiated solution is treated with 2.6 / ml of trimethylsilyl iodide. After 7 minutes, the reaction mixture was diluted with 20 ml of SO and extracted with 5 ml of a saturated solution of NaHCO3. The aqueous phase is transferred to a flask containing a mixture of
10% isopropanol and 90% CHC1E. The mixture is then acidified with 12N. HC1 solution to pH 2. The two phases are separated and the aqueous phase is extracted with 25 ml of a mixture consisting of 10% isopropanol and 90% CHCl3. CHC13 portions dried over
Lovy ether (8 ml), the solid is transferred to a 15 ml centrifuge tube and centrifuged with the upper liquid layer is decanted and 8 ml of fresh diethyl ether is added
YU
The solid is centrifuged again. The process is repeated three times. The solid is dried under vacuum to give 35 mg of the title compound with a purity greater than 95% (HPLC).
Example. 7/3-Thienylacetylamino-7a methoxy-3-ethyl-1-carba-3-cephem-3-carboxylate-4-carboxylic acid.
A) To 20.5 mg (0.0384 mmol) of the compound obtained in Example 6, add 1 ml, 2.5 mg {0.0096 mmol) triphenylphosphine and 0.5 mg
ABOUT
l
(0.002 mmol) Pd (-OCCH3) g. Received
tilaminopyridine. After stirring for 10 minutes, add another 9 (l
thienylacetyl chloride and 11 pL of pyridine. The mixture obtained is diluted with ethyl acetate and poured into a saturated solution of NaHCOg. The organic phase is separated and extracted with 20 ml of saturated
NaHCO solution, and twice in portions of 20 ml of 1N. HCl solution. The organic phase is then dried over anhydrous.
MgSO, filtered and concentrated with p
emitting 60 mg of brown oil. The crude product is purified by chromatography on 5 g of silica gel using a solution consisting of ethyl acetate and hexane (40/60) as eluent to give 6 mg of the benzhydryl ester of the target compound.
B) To 7 mg of the compound obtained
in Part A, 0.5 ml of dry CHaCli is added under a dry nitrogen atmosphere. The resulting solution is treated with 2.6 / ml of trimethylsilyl iodide. After 7 minutes, the reaction mixture was diluted with 20 ml and extracted with 5 ml of a saturated solution of NaHCO3. The aqueous phase is transferred to a flask containing a mixture of
in Part A, 0.5 ml of dry CHaCli is added under a dry nitrogen atmosphere. 10% of isolropanol and 90% of CHC1E. The mixture is then acidified with 12N. HCl solution to pH 2. The two phases are separated and the aqueous phase is extracted with 25 ml of a mixture consisting of 10% isolropanol and 90% CHCl3. CHC13 portions dried over
to
anhydrous., filtered and concentrated under reduced pressure to form 3.8 g of the target product, The crude product is purified by chromatography on t, 5 g of silica gel, using a solution consisting of 1% acetic acid and 99% ethyl acetate as eluent , with the formation of 2.5 mg of the target compound.
The following compounds are prepared analogously:
1- (iso-propyloxycarbonyloxy) ethyl 7 / h-2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamide-3-ethoxycarbonyl-1-carba- (1-children-) - 3 cefem-4- carboxrlate: Scheduled; And ethoxy and R2 1- (isopropoxycarbonyloxy) -ethyl |
7th Ј-2- (2-aminothiazole 4-yl) 2- (3,4-dihydroxybenzamido) acetamido-3-20 methoxycarbonyl-1 carba (1-child) -3-cephem-4-carboxylic acid; R p 2-am notiazol-4-yl; , 4-dihydroxybenzene; And methoxy,
1- (pivaloyloxy) ethyl (2-ami 25 othiazol-4-yl) -2-ethoxy-iminoacetamido-} -3-methoxycarbonyl-1 -carb (1-child) -3-cephem-4-carboxylate;
7 / 3- Ј2- (2-aminothiazole 4-yl) -2-memes, which are pathogenic and are commonly used to evaluate the anti-bacterial properties of d-lactam antibiotics.
As the tested compounds used:
 $ 2 Y
B
-CN-OCHNZO

A °
t 1 and
I
15
x
-sie
- WITH "
cis
-S-sn2-
-OCH3
™ CHEAS
carboxylic acid.
The resulting 1-carbacephalosporic inhibited the growth of microorganisms. These
test compound 1 2 3 4
 Test compounds 2 and 4 are compounds according to the invention, compounds 1 and 3 are known cephalosporin compounds
As can be seen from the table. 2, the minimum inhibitory concentrations (MIC) for compound 2 are usually lower than the inhibitory concentrations for the corresponding compound 1 (cephalosporin),
toKCHHMHHoa4eTaMHAO -3- (2-methoxycarzo This °, especially vr-o for gramotomitel- bonil) -1-carba (1-child) -3-cephem-4-b ™ - organisms in the test with organisms, starting from E0coli and continuing down through the entire list. “A similar pattern is established for compound 4
the substances are antibiotic compared with the corresponding broad-spectrum compounds and precipitation of 3 cephalosporins. The compounds are benno-effective against gram-like ™ that are the subject of the present inorganic bacteria. In tab. 1 shows Reteni, have a higher stability inhibiting concentration in solution than the MIC of the preferred compounds of the invention in relation to representatives of infectious bacteria. The values of inhibitory concentrations were obtained in standard tests outside the body, which were carried out by the method of D dilution with agar.
Comparative data for two pairs of compounds according to the invention and known compounds which are the most active preferred compounds are given below. The numerical values given in table. 2, correspond to the minimum inhibitory concentrations in micrograms per ml 4 (µg / ml) obtained for the test compounds using standard in vitro dilution test with agar. Standard microorganisms were used as microorganisms: a cephalosporin compound in which the sulfur atom is in the 1-position.

权利要求:
Claims (2)
[1]
1.Digits and letters correspond to the strain designations.
[2]
2. Test compound 1 7 /} - (B-phenylglcycylamino) -3-methoxycarbonyl-3-cephem-1carba (1-child) -4-carboxylic acid
2 (B-phenylglycylamino) -3-benzyloxycarbonyl-3-cefech1-carba- (1-children) -4-carboxylic acid
3 (B-phenylglycylamino) -3-n-butyloxycarbon-3-cephem-1-carba (1-unit) -A-carboxylic acid
4 7p- (0-benzotien-3-Јlglncylamino) -3-methoxycarbovil-3cepham-1-carba (1-child) -4-carboxylic acid
5 7Ј- (0-fenclglycylacino) -3-ethoxycarbonyl-3-cephem-1carba (1.-partyl) -4-carboxylic acid
6 (2- (2-aminothiazol-4-yl) snn-2-methoxynnmnoacetamido) 3-methoxycarbonyl-3-cephemN-carba (1-children) -4-carboxylic acid
R
one
hydrogen or methoxy;
R is hydrogen or carboxylic acid
Group;
A is a C 1 -C 4 alkyl, C C. Alkoxy, allyloxy or benzyloxy group;
differing in the fact that the unity of the general formula
ten
n2: m o
RI n
-t
N
ABOUT
II
SA
COOR2
where R, A have the indicated meanings,
acidified by the general formula
RCOOH
where R has the indicated meanings, or its reactive derivative.
Table 1
Note. Letters and numbers are the designations of the strains.
Table 2

类似技术:

---

公开号 | 公开日 | 专利标题

---

SU1303029A3|1987-04-07|Method for producing derivatives of cephalosporin

---

SK61684A3|1998-03-04|D-2-aminoacyl-3-|-propenyl cephalosporine derivatives, a method of preparation and pharmaceutical compositions containing the same

---

EP0236231B1|1994-05-04|Novel cephem compounds

---

SU1575940A3|1990-06-30|Method of obtaining carbacephalosporin compounds

---

US5461044A|1995-10-24|Cephalosporin derivatives

---

EP0264091B1|1992-02-05|3-propenylcephem derivative, preparation thereof, chemical intermediates therein, pharmaceutical composition and use

---

US5607927A|1997-03-04|Cephalosporin derivative

---

KR930007416B1|1993-08-10|Process for preparing 3-| propenylaminothiazolyl cephalosporanic acids

---

CA1059989A|1979-08-07|Cephamycins

---

US4103008A|1978-07-25|7[2|substituted 2 phenylacetamido]-3-2'-thiadiazolyl cephalosporanic acid derivatives

---

US4325951A|1982-04-20|1-Oxadethiacephalosporin derivatives and antibacterial use thereof

---

FI75165B|1988-01-29|FOERBAETTRAT FOERFARANDE FOER FRAMSTAELLNING AV PENICILLANSYRAKLORMETYLESTRAR.

---

RU2091384C1|1997-09-27|Cephalosporin derivatives and pharmacologically acceptable non-toxic salts, physiologically hydrolysable esters, syn-isomers and optical isomers, and method of preparation thereof

---

US5332731A|1994-07-26|Cephalosporin derivatives

---

US5464829A|1995-11-07|Cephalosporin derivatives

---

WO1992003445A1|1992-03-05|Novel cephalosporin compounds and processes for preparation thereof

---

SU1087076A3|1984-04-15|Process for preparing derivatives of cephalosporin

---

US4179502A|1979-12-18|7[2-Hydroxyiminoacetamido]cephalosporins

---

US4560749A|1985-12-24|Cephem-3-imidates and 3-amidines

---

US4137406A|1979-01-30|Cephalosporins having a sulfur containing functional group in the 7-position side chain

---

GB2102423A|1983-02-02|Cephalosporin derivatives

---

EP0076066A1|1983-04-06|Penicillin derivatives

---

US4465831A|1984-08-14|Ketoiminocephalosporin derivatives

---

EP0188781B1|1990-10-24|1-oxa-1-dethia-cephalosporin compounds and antibacterial agent comprising the same

---

SU1326195A3|1987-07-23|Method of producing 7-/2-|-/z/-2-|acetamido/-3-/|methyl/-3-cephem-4-carboxylate

同族专利:

---

公开号 | 公开日

---

JPH0791291B2|1995-10-04|

---

IL81115A|1992-05-25|

---

CA1274519A|1990-09-25|

---

KR900000267B1|1990-01-24|

---

DK631386D0|1986-12-29|

---

EP0232623B1|1993-03-17|

---

EP0232623A1|1987-08-19|

---

FI83959C|1991-09-25|

---

ES2053452T3|1994-08-01|

---

JP2634386B2|1997-07-23|

---

ZA869747B|1988-08-31|

---

IL81115D0|1987-03-31|

---

JPH0873457A|1996-03-19|

---

US4791106A|1988-12-13|

---

CN1020340C|1993-04-21|

---

FI865317A0|1986-12-29|

---

FI83959B|1991-06-14|

---

AU598504B2|1990-06-28|

---

PT84031A|1987-01-01|

---

DE3688066T2|1993-07-22|

---

HU204269B|1991-12-30|

---

JPS62158282A|1987-07-14|

---

EG18119A|1993-06-30|

---

IE863407L|1987-06-30|

---

AT86992T|1993-04-15|

---

DE3688066D1|1993-04-22|

---

DK631386A|1987-08-20|

---

HUT43851A|1987-12-28|

---

CN86108961A|1987-08-05|

---

US4892942A|1990-01-09|

---

PH25644A|1991-08-21|

---

AR245126A1|1993-12-30|

---

KR870006049A|1987-07-08|

---

PT84031B|1989-07-31|

---

AU6705586A|1987-07-02|

---

FI865317A|1987-07-01|

---

IE59727B1|1994-03-23|

---

SU1683499A3|1991-10-07|

引用文献:

---

公开号 | 申请日 | 公开日 | 申请人 | 专利标题

---

---

US4226866A|1972-11-06|1980-10-07|Merck & Co., Inc.|Novel antibiotic analogues of cephalosporins|

---

SE401549B|1977-01-18|1978-05-16|Skf Ab|SLIDING DEVICE FOR SLIDING BEARINGS|

---

NO790956L|1978-03-25|1979-09-26|Kyowa Hakko Kogyo Kk|ANALOGICAL PROCEDURES FOR THE PREPARATION OF CEPHALOSPORINE ANALOG OR PHARMACEUTICAL ACCEPTABLE SALTS THEREOF|

---

US4275207A|1978-08-14|1981-06-23|Merck & Co., Inc.|Process for preparing 7--3--1-carbadethiaceph-3-em-3-carboxylic acid and intermediate therefor|

---

NO155548C|1979-02-10|1987-04-15|Kyowa Hakko Kogyo Kk|PROCEDURE FOR THE PREPARATION OF OPTICALLY ACTIVE CEPHALOSPORIN ANALOGS.|

---

EP0112481A1|1982-11-12|1984-07-04|Kyowa Hakko Kogyo Co., Ltd|Beta-lactam compound|

---

JPH0564151B2|1984-02-21|1993-09-14|Kyowa Hakko Kogyo Kk|

---

JPH0791291B2|1985-12-30|1995-10-04|イ−ライ・リリ−・アンド・カンパニ−|1-carbacef allosporin antibiotic|US4673737A|1985-08-02|1987-06-16|Harvard University|7-acylamino--3-trifluoromethylsulfonyloxy-1-carba-3-cephem-4-carboxylic acids and esters thereof|

---

JPH0791291B2|1985-12-30|1995-10-04|イ−ライ・リリ−・アンド・カンパニ−|1-carbacef allosporin antibiotic|

---

EP0525057B1|1990-04-18|2000-06-14|Procter & Gamble Pharmaceuticals, Inc.|Antimicrobial quinolonyl lactams|

---

JPH069649A|1992-04-24|1994-01-18|Eli Lilly & Co|Improved production of cephalosporin|

---

US5750681A|1995-06-19|1998-05-12|University Of Notre Dame Du Lac|Bicyclic beta-lactams and process therefor|

法律状态:

优先权:

---

申请号 | 申请日 | 专利标题

---

US81494385A| true| 1985-12-30|1985-12-30|

---