GB2067551A - Phthalidyl eaters of the acetone adduct of epicillin - Google Patents
Phthalidyl eaters of the acetone adduct of epicillin Download PDFInfo
- Publication number
- GB2067551A GB2067551A GB8000970A GB8000970A GB2067551A GB 2067551 A GB2067551 A GB 2067551A GB 8000970 A GB8000970 A GB 8000970A GB 8000970 A GB8000970 A GB 8000970A GB 2067551 A GB2067551 A GB 2067551A
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- Prior art keywords
- methoxy
- hydrogen
- formula
- oxo
- compound
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- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 title description 12
- RPBAFSBGYDKNRG-NJBDSQKTSA-N epicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CCC=CC1 RPBAFSBGYDKNRG-NJBDSQKTSA-N 0.000 title description 11
- 229960002457 epicillin Drugs 0.000 title description 11
- 125000005633 phthalidyl group Chemical group 0.000 title description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims abstract description 23
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 14
- 239000001257 hydrogen Substances 0.000 claims abstract description 14
- 150000003839 salts Chemical class 0.000 claims abstract description 11
- 239000002253 acid Substances 0.000 claims abstract description 10
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 8
- 125000001246 bromo group Chemical group Br* 0.000 claims abstract description 6
- 125000001309 chloro group Chemical group Cl* 0.000 claims abstract description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 5
- 150000001875 compounds Chemical class 0.000 claims description 12
- -1 1 , 3-dihydro-3-oxo- 1 -isobenzofuranyl ester Chemical class 0.000 claims description 10
- 238000000034 method Methods 0.000 claims description 6
- 150000002431 hydrogen Chemical group 0.000 claims description 4
- 239000000203 mixture Substances 0.000 claims description 4
- NKBWMBRPILTCRD-UHFFFAOYSA-N 2-Methylheptanoic acid Chemical compound CCCCCC(C)C(O)=O NKBWMBRPILTCRD-UHFFFAOYSA-N 0.000 claims description 3
- 239000003242 anti bacterial agent Substances 0.000 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- 230000000844 anti-bacterial effect Effects 0.000 claims description 2
- 208000035143 Bacterial infection Diseases 0.000 claims 3
- 241000282414 Homo sapiens Species 0.000 claims 3
- 208000022362 bacterial infectious disease Diseases 0.000 claims 3
- 241000894007 species Species 0.000 claims 2
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 claims 1
- 239000003937 drug carrier Substances 0.000 claims 1
- 239000008194 pharmaceutical composition Substances 0.000 claims 1
- 150000002148 esters Chemical class 0.000 abstract description 13
- 238000010521 absorption reaction Methods 0.000 abstract description 2
- 210000004369 blood Anatomy 0.000 abstract description 2
- 239000008280 blood Substances 0.000 abstract description 2
- 210000001519 tissue Anatomy 0.000 abstract description 2
- 210000002700 urine Anatomy 0.000 abstract description 2
- 229930182555 Penicillin Natural products 0.000 abstract 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 abstract 1
- 229940049954 penicillin Drugs 0.000 abstract 1
- 150000002960 penicillins Chemical class 0.000 abstract 1
- 239000000047 product Substances 0.000 description 11
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- UXGVMFHEKMGWMA-UHFFFAOYSA-N 2-benzofuran Chemical compound C1=CC=CC2=COC=C21 UXGVMFHEKMGWMA-UHFFFAOYSA-N 0.000 description 3
- PBIUDEUWYGBHDW-UHFFFAOYSA-N 2-chloro-1-pyridin-3-ylethanone;hydrochloride Chemical compound Cl.ClCC(=O)C1=CC=CN=C1 PBIUDEUWYGBHDW-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 3
- 235000019439 ethyl acetate Nutrition 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- NGHVIOIJCVXTGV-ALEPSDHESA-N 6-aminopenicillanic acid Chemical compound [O-]C(=O)[C@H]1C(C)(C)S[C@@H]2[C@H]([NH3+])C(=O)N21 NGHVIOIJCVXTGV-ALEPSDHESA-N 0.000 description 2
- NGHVIOIJCVXTGV-UHFFFAOYSA-N 6beta-amino-penicillanic acid Natural products OC(=O)C1C(C)(C)SC2C(N)C(=O)N21 NGHVIOIJCVXTGV-UHFFFAOYSA-N 0.000 description 2
- 241000894006 Bacteria Species 0.000 description 2
- 206010012735 Diarrhoea Diseases 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 239000002808 molecular sieve Substances 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 2
- HFVMEOPYDLEHBR-UHFFFAOYSA-N (2-fluorophenyl)-phenylmethanol Chemical compound C=1C=CC=C(F)C=1C(O)C1=CC=CC=C1 HFVMEOPYDLEHBR-UHFFFAOYSA-N 0.000 description 1
- QXQAPNSHUJORMC-UHFFFAOYSA-N 1-chloro-4-propylbenzene Chemical compound CCCC1=CC=C(Cl)C=C1 QXQAPNSHUJORMC-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- CLMSHAWYULIVFQ-UHFFFAOYSA-N 3-bromo-3h-2-benzofuran-1-one Chemical compound C1=CC=C2C(Br)OC(=O)C2=C1 CLMSHAWYULIVFQ-UHFFFAOYSA-N 0.000 description 1
- WRFYIYOXJWKONR-UHFFFAOYSA-N 4-bromo-2-methoxyaniline Chemical compound COC1=CC(Br)=CC=C1N WRFYIYOXJWKONR-UHFFFAOYSA-N 0.000 description 1
- PXRKCOCTEMYUEG-UHFFFAOYSA-N 5-aminoisoindole-1,3-dione Chemical compound NC1=CC=C2C(=O)NC(=O)C2=C1 PXRKCOCTEMYUEG-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 1
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 1
- 241000194032 Enterococcus faecalis Species 0.000 description 1
- 241000588724 Escherichia coli Species 0.000 description 1
- 241000192125 Firmicutes Species 0.000 description 1
- 206010061182 Genitourinary tract infection Diseases 0.000 description 1
- 241000606768 Haemophilus influenzae Species 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 241000588652 Neisseria gonorrhoeae Species 0.000 description 1
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 206010035664 Pneumonia Diseases 0.000 description 1
- 241000588770 Proteus mirabilis Species 0.000 description 1
- 206010057190 Respiratory tract infections Diseases 0.000 description 1
- 241000531795 Salmonella enterica subsp. enterica serovar Paratyphi A Species 0.000 description 1
- 241000293871 Salmonella enterica subsp. enterica serovar Typhi Species 0.000 description 1
- 241000607768 Shigella Species 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 206010062255 Soft tissue infection Diseases 0.000 description 1
- 241000191963 Staphylococcus epidermidis Species 0.000 description 1
- 241001312524 Streptococcus viridans Species 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric Acid Chemical compound [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- WXBLLCUINBKULX-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1.OC(=O)C1=CC=CC=C1 WXBLLCUINBKULX-UHFFFAOYSA-N 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 239000013058 crude material Substances 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 230000009429 distress Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 206010040872 skin infection Diseases 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000001665 trituration Methods 0.000 description 1
- 208000019206 urinary tract infection Diseases 0.000 description 1
Classifications
-
- 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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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Penicillin esters and their acid addition salts of the formula <IMAGE> wherein X is hydrogen, methyl, methoxy, chloro, or bromo and n is an integer from 1 to 3 provided that n is 2 or 3 only when X is hydrogen or methoxy; are disclosed. Upon oral administration, these esters provide improved absorption and result in high concentrations of the antibacterially active parent penicillin in the blood, tissues and urine.
Description
SPECIFICATION
Phthalidyl esters of the acetone adduct of epicillin
This invention is directed to phthalidyl penicillin esters of the formula
and acid addition salts thereof wherein X is hydrogen, methyl, methoxy, chloro, or bromo and n is an integer from 1 to 3 provided that n is 2 or 3 only when X is hydrogen or methoxy.
The ester products of formula I can be prepared by several methods. For example, epicillin can be reacted with acetone in the presence of triethylamine to yield the intermediate of the formula
The intermediate of formula II can then be reacted with an isobenzofuran of the formula
wherein L is hydroxy or bromo to yield the ester product of formula I.
The ester products of formula- I can also be prepared by reacting epicillin with the isobenzofuran of formula Ill to yield the intermediate of the formula
The intermediate of formula IV is then treated with acetone to yield the ester product of formula 1.
The intermediate of formula IV can also be obtained by reacting the phthalidyl ester of 6aminopenicillanic acid (6-APA) with an a-(protected amino)-1 4-cyclohexadienyl acylating agent followed by removal of the a-amino protecting group.
The ester products of formula I are conveniently isolated in the form of their acid addition salt.
Acids useful for this purpose include inorganic acids such as hydrochloric, hydrobromic, sulfuric, nitric, and phosphoric acid, and organic acids such as maleic, furmaric, tartaric, citric, acetic, benzoic, 2-acetoxybenzoic, salicylic, succinic, nicotinic, methansulfonic, and cyclohexanesulfamic acid. These acid addition salts can be converted into the free form by reacting with a basic agent and, if desired, then converted to a different acid addition salt.
Preferred compounds of this invention are those of the formula
wherein X6 is hydrogen, methoxy, bromo, or chloro; X5 is hydrogen or methoxy provided that X5 is methoxy only when X6 is methoxy, and X4 is hydrogen or methoxy provided X4 is methoxy only when X6 and X5 are both methoxy.
Most preferred is the unsubstituted phthalidyl ester of formula V wherein X4, X5, and X6 are all hydrogen.
The esters of formula I upon administration act as prod rug of epicillin having the identical spectra of antibacterial activity. Thus, these esters are particularly useful in treating respiratory tract, gastrointestinal tract and genitourinary tract infections and skin and soft tissue infections due to susceptible strains of various gram-positive and gram-negative bacteria. Among the grampositive bacteria that can be treated are beta-hemolytic streptococci, Streptococcus viridans,
Streptococcus faecalis, Diplococcus pneumonia, Staphylococcus albus, and non-penicillanase producing strains of Straphylococcus aureus and among the gram-negative bacteria are
Escherichia coli, Proteus mirabilis, Hemophilus influenzae, Salmonella typhi, Salmonella paratyphi, Shigella and Neisseria gonorrhoeae.
The esters of formula I are particularly useful when administered orally due to their improved rate of absorption. These esters provide higher concentrations of epicillin in the blood, tissues and urine that can be achieved by the oral administration of epicillin itself and they also decrease the incidence of gastrointestinal distress such as diarrhea and loose stools. The esters of formula I can be administered to the infected mammal in amounts ranging from about 1 5 to about 50 mg./kg./day in one or more doses. The amount of compound administered will vary, of course, depending upon the severity and nature of the infection; i.e. a urinary tract infection will in general require a higher dose of antibacterial agent than a respiratory tract infection.
The esters of formula I and their acid addition salts are formulated for oral administration according to conventional pharmaceutical procedures. For example, the compounds can be encapsulated along with conventional excipients and preservatives, as may be necessary, so as to provide in a unitary dose the equivalent of 250 mg. or 500 mg. of epicillin. The compounds can also be formulated as a concentrate containing conventional excipients and flavoring agents which when reconstituted will provide a flavored suspension containing the equivalent of 1 25 mg. and 250 mg. of epicillin per 5 ml. teaspoonful. The compound can also be formulated as pediatric drops which provide after reconstitution a flavored suspension containing the equivalent of 100 mg. of epicillin per one ml.
Illustrative process details are provided in the examples for the various reactions. All temperatures are on the centigrade scale.
Example 1 6-[-4-(1, 4-Cyclohexadien- -yl)-2, 2-dimethyl-5-oxo- I 4midazolidinylj-3, 3-dimethyl- 7-oxo-4-thia
1 -azabicyclof3. 2. Ojheptane-2-carboxylic acid, 1, 3-dih ydro-3-oxo- 1 -isobenzofuranyl ester, hydrochloride (1:1) a) 6-[4-(1, 4-Cyclohexadien- 1 -yl)-2, 2-dim ethyl-5-oxo- 1 -imidazolidinyl]-3, 3-dimethyl- 7-oxo-4-thia
1 -azabicyclo[3. 2. Ojheptane-2-carboxylic acid
A suspension of 10 g of epicillin in 50 ml. of acetone (previously dried over Linde 4A molecular sieves) is stirred with 7 ml. of triethylamine for 24 hours at 25 and an additional 24 hours at 30'.The resulting solution is filtered and added dropwise to 50 ml. of water maintained at 0-10 and pH 2.5-3.0 by the simultaneous addition of cold 30% sulfuric acid solution. The resulting slurry is stirred for 2 hours at 0" and pH 2.55 and is then filtered. The crystalline product is washed with 20 ml. of cold water and dried at 40-50" over P205 in vacuo to yield 6.1 9 g. of 6-[4-( 1 ,4-cyclohexadien-1 -yl)-2,2-dimethyl-5-oxo- 1 -imidazolidinyl3, 3-dime- thyl-7-oxo-5-thia-1-azabicyclo[3.2.OJ heptane-2-carboxylic acid; m.p. 186 (dec., browns at 1 74').
Analysis Calculated for C19H2sSN304: C, 58.29; H, 6.44; N, 10.73; S, 8.19.
Found: C, 58.06; H, 6.52; N, 10.62; S 7.99.
b) 6-f4-( 1, 4-Cyclohexadien- 1 -yl)-2, 2-dimethyl-5-oxo- 1-imidazolidinyl]-3, 3dimethyl- 7-oxo-4-thia- 1-azabicyclof3. 2. O]heptane-2-carboxylic acid, 1, 3-dihydro-3-oxo- 1-isobenzofuranyl ester, hydrochloride (1:1) A mixture of 14.81 g. (0.0378) mole) of the acid product from part (a) and 5.3 ml. (0.0378 mole) of triethylamine in 265 ml. of acetone (previously dried over Linde 4A molecular sieves) is stirred at room temperature for 30 minutes. 3.78 g. of potassium bicarbonate and 8 g. of 3bromophthalide are added.After four hours, the resulting mixture is filtered and the filtrate is concentrated in vacuoto about 9.5 ml. 375 ml. of ethyl acetate is added and the resulting solution is washed with 2% sodium bicarbonate solution (2 x 40 ml.), water (2 X 40 ml.), dried, and concentrated to yield 19.89 9. of crude product. This crude material is passed through a column containing 800 g. of silica gel (sili CAR CC-7) and eluted with (1:1) EtOAc: benzene to give one fraction containing 3.55 g. of product and a second fraction containing 8.34 g. of purer product. The 8.34 9. purer fraction is dissolved in 140 ml. of (1:1) EtOAc: ethyl ether and 1.66 mmoles/ ml. of HCI solution in ethyl ether (as determined by trituration) is added. The HCI salt product is filtered immediately, washed with ether and dried overnight without heating to yield 8.33 g. of 6-E4-(1 ,4-cyclohexadien-l -yl)-2,2-dimethyl-5-oxo-l -imidazolidinyl]-3, 3-dimethyl- 7-oxo-4-thia- 1 -azabicyclo[3.2.0] heptane-2-carboxylic acid, 1 , 3-dihydro-3-oxo- 1 -isobenzofuranyl ester, hydrochloride (1:1); m.p. 160-162".
Analysis Calculated for C27H29N306S.HCI: C, 57.90; H, 5.40; S, 5.72; Cl,
6.33; N, 7.50
Found: C, 57.01; H, 5.78; S, 5.61; Cl,
5.93; N, 7.25.
Examples 2-10
Following the procedure of Example 1 but employing the substituted isobenzofuran shown in
Col. I one obtains the phthalidyl ester product shown in Col. II.
Col. I
Col. ll
Ex. X4 X5 X6 X7 2 H H CH3 H 3 H H OCH3 H 4 H H Br H 5 H H Cl H 6 H SOCH, OCH3 H 7 0CH3 OCH3 OCH3 H 8 Cl H H H 9 OCH3 H H H 10 CH3 H H H
Claims (9)
1. Compounds of the formula:
wherein X is hydrogen, methyl, methoxy, bromo, or chloro; n is an integer from 1 to 3 provided that n is 2 or 3 only when X is hydrogen or methoxy; and acid addition salts thereof.
2. A compound according to Claim 1 having the formula:
wherein X6 is hydrogen, methoxy, bromo, or chloro; X5 is hydrogen or methoxy provided that X5 is methoxy only if X6 is methoxy; X4 is hydrogen or methoxy provided that X4 is methoxy only if both X5 and X6 are methoxy; and acid addition salts thereof.
3. The compound of Claim 2 wherein X4, X5, and X6 are all hydrogen.
4. The hydrochloride salt of the compound of Claim 3.
5. An antibacterial pharmaceutical composition comprising a pharmaceutically acceptable carrier and, as the active antibacterial agent, one or more of the compounds or salts claimed in claim 1 or 2.
6. A composition according to Claim 5, wherein the antibacterial agent is 6-[4-(1,4cyclohexadien- 1 -yl)-2, 2-dimethyl-5-oxo- 1 -imiflazolidinyl]-3,3-dimethyl-7-oxo-4-th ia- 1 -azabicy cloL3.2 .0]heptane-2-carboxylic acid, 1 , 3-dihydro-3-oxo- 1 -isobenzofuranyl ester.
7. A method of treating a bacterial infection in a mammalian specie other than homo sapiens which comprises orally administering an effective amount of a compound or salt as claimed in any one of claims 1-4.
8. A method of treating a bacterial infection in a mammalian specie other than homo sapiens which comprises orally administering an effective amount of a composition according to claim 5 or 6.
9. A compound or salt according to any one of claims 1-4 for use in the treatment of bacterial infections in homo sapiens.
Priority Applications (6)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB8000970A GB2067551A (en) | 1980-01-11 | 1980-01-11 | Phthalidyl eaters of the acetone adduct of epicillin |
| DE19803001590 DE3001590A1 (en) | 1980-01-11 | 1980-01-17 | PHTHALIDYLESTER OF THE ACETONE ADDUCT OF EPICILLIN AND MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS |
| IE10580A IE800105L (en) | 1980-01-11 | 1980-01-18 | Phthalidyl esters of the acetone adduct of epicillin |
| FR8001202A FR2474033A1 (en) | 1980-01-11 | 1980-01-21 | Phthalide ester(s) of epicillin-acetone addn. cpd. - useful as antibacterials rapidly absorbed after oral admin. |
| BE0/199077A BE881304A (en) | 1980-01-11 | 1980-01-23 | PHTHALIDYL ESTERS OF THE ACETONIC ADDITION PRODUCT OF EPICILLIN, WITH ANTIBACTERIAL ACTION |
| NL8000512A NL8000512A (en) | 1980-01-11 | 1980-01-28 | PHTHALIDYL ESTERS OF AN ACETONE ADDUCT FROM EPICILLIN. |
Applications Claiming Priority (7)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB8000970A GB2067551A (en) | 1980-01-11 | 1980-01-11 | Phthalidyl eaters of the acetone adduct of epicillin |
| DE19803001590 DE3001590A1 (en) | 1980-01-11 | 1980-01-17 | PHTHALIDYLESTER OF THE ACETONE ADDUCT OF EPICILLIN AND MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS |
| IE10580A IE800105L (en) | 1980-01-11 | 1980-01-18 | Phthalidyl esters of the acetone adduct of epicillin |
| FR8001202A FR2474033A1 (en) | 1980-01-11 | 1980-01-21 | Phthalide ester(s) of epicillin-acetone addn. cpd. - useful as antibacterials rapidly absorbed after oral admin. |
| BE0/199077A BE881304A (en) | 1980-01-11 | 1980-01-23 | PHTHALIDYL ESTERS OF THE ACETONIC ADDITION PRODUCT OF EPICILLIN, WITH ANTIBACTERIAL ACTION |
| BE881304 | 1980-01-23 | ||
| NL8000512A NL8000512A (en) | 1980-01-11 | 1980-01-28 | PHTHALIDYL ESTERS OF AN ACETONE ADDUCT FROM EPICILLIN. |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| GB2067551A true GB2067551A (en) | 1981-07-30 |
Family
ID=27560762
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB8000970A Withdrawn GB2067551A (en) | 1980-01-11 | 1980-01-11 | Phthalidyl eaters of the acetone adduct of epicillin |
Country Status (1)
| Country | Link |
|---|---|
| GB (1) | GB2067551A (en) |
-
1980
- 1980-01-11 GB GB8000970A patent/GB2067551A/en not_active Withdrawn
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| WAP | Application withdrawn, taken to be withdrawn or refused ** after publication under section 16(1) |