GB2103212A - 4-Substituted derivatives of 2-oxo-1-azatidinesulfonic acid salts - Google Patents
4-Substituted derivatives of 2-oxo-1-azatidinesulfonic acid salts Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- 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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
- C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
- C07D205/06—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D205/08—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams
- C07D205/09—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams with a sulfur atom directly attached in position 4
- C07D205/095—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams with a sulfur atom directly attached in position 4 and with a nitrogen atom directly attached in position 3
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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Abstract
Antibacterial activity is exhibited by beta -lactams having the formula <IMAGE> wherein R is hydrogen or methoxy; R1 is acyl; R2 is alkyl, haloalkyl, aryl or arylalkyl; and M<(+)> is hydrogen or a cation.
Description
SPECIFICATION 4-Substituted derivatives of 2-oxo-1 -azetidinesulfonic acid salts
Antibacterial activity is exhibited by p-lactams having the formula
In formula I, and throughout the specification the symbols are as defined below.
R is hydrogen or methoxy; Rr is acyl;
R2 is alkyl, haloalkyl, aryl or arylalkyl; and Mao is hydrogen or a cation
Listed below are definitions of various terms used to describe the p-lactams of this invention.
These definitions apply to the terms as they are used throughout the specification (unless they are otherwise limited in specific instances) either individually or as part of a larger group.
The terms "alkyl", and "alkoxy" refer to both straight and branched chain groups. Those groups having 1 to 10 carbon atoms are preferred.
The terms "alkanoyl" and "alkenyl" refer to both straight and branched chain groups. Those groups having 1 to 10 carbon atoms are preferred.
The terms "cycloalkyl" and "cycloalkenyl" refer to groups having 3, 4, 5, 6 or 7 carbon atoms.
The terms "halo" and "halogen" refer to fluorine, chlorine, bromine and iodine.
The term "aryl" refers to phenyl and phenyl substituted with 1,2 or 3 amino (-NH2), halogen, hydroxyl, trifluoromethyl, alkyl (of 1 to 4 carbon atoms), or alkoxy (of 1 to 4 carbon atoms) groups.
The term "acyl" includes all organic radicals derived from an organic acid (i.e., a carboxylic acid) by removal of the hydroxyl group. Certain acyl groups are, or course, preferred but this preference should not be viewed as a limitation of the scope of this invention. Exemplary acyl groups are those acyl groups which have been used in the past to acylate p-lactam antibiotics including 6aminopenicilianic acid and derivatives and 7-aminocephalosporanic acid and derivatives; see, for example, Cephalosporins and Penicillins, edited by Flynn, Academic Press (1972), German
Offenlegungsschrift 2,716,677, published October 10, 1 978, Belgian patent 867,994, published
December 11, 1978, United States patent 4,152,432, issued May 1, 1979, United States patent 3,971,778, issued July 1976, United States patent 4,172,199, issued October 1979, and
British patent 1,348,894, published March 27, 1 974. The portions of these references describing various acyl groups are incorporated herein by reference. The following list of acyl groups is presented to further exemplify the term "acyl" it should not be regarded as limiting that term.Exemplary acyl groups are:
(a) Aliphatic groups having the formula
wherein Ra is alkyl; cycloalkyl; alkoxy; alkenyl; cycloalkenyl; cyclohexadienyl; or alkyl or alkenyl substituted with one or more halogen, cyano, nitro, amino, mercapto, alkylthio, or cyanomethylthio groups.
(b) Carbocyclic aromatic groups having the formula
wherein n is 0, 1,2 or 3; Rb, Rc, and Rd each is independently hydrogen, halogen, hydroxyl, nitro, amino, cyano, trifluoromethyl, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms or aminomethyl; and
Re is amino, hydroxyl, a carboxyl salt, protected carboxyl, formyloxy, a sulfo salt, a sulfoamino salt, azido, halogen, hydrazino, alkylhydrazino, phenylhydrazino, or [(alkylthio)thioxomethyl]thio.
Preferred carbocyclic aromatic acyl groups include those having the formula
(Re is preferably a carboxyl salt or sulfo salt) and
(Re is preferably a carboxyl salt or sulfo salt).
(c) Heteroaromatic groups having the formula
wherein n is 0, 1,2 or 3; Re is as defined above; and Rf is a substituted or unsubstituted 5-, or 7membered heterocyclic ring containing 1, 2, 3 or 4 (preferably 1 or 2) nitrogen, oxygen and sulfur atoms. Exemplary heterocyclic rings are thienyl, furyl, pyrrolyl, pyridinyl, pyrazolyl, pyrazinyl, thiazolyl, pyrimidinyl and tetrazolyl.Exemplary substituents are halogen, hydroxyl, nitro, amino, cyano, trifluoromethyl, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, or
Preferred heteroaromatic acyl groups include those groups of the above formulas wherein Rf is 2 amino-4-thiazolyl, 2-amino-5-halo-4-thiazolyl, 4-aminopyrimidin-2-yl, 5-amino-1 ,2,4-thiadiazol-3-yI, 2-thienyl, 2-furanyl, or 6-aminopyridin-2-yl.
(d) [[(4-Substituted-2,3-dioxo- 1 -piperazinyl)carbonyl]amino]arylacetyl groups having the formula
wherein Ra is an aromatic group (including carbocyclic aromatics such as those of the formx
and heteroaromatics as included within the definition of Ref); and Rh is alkyl, substituted alkyl (wherein the alkyl group is substituted with one or more halogen, cyano, nitro, amino or mercapto groups), arylmethyleneamino (i.e., N=CHRg wherein R g is as defined above), arylcarbonylamino (i.e.,
wherein R, is as defined above) or alkylcarbonylamino.
Preferred [[(4-substituted-2,3-dioxo- 1 -piperazinyl)carbonyl]a mino] arylacetyl groups include those wherein Rh is ethyl, phenylmethyleneamino or 2-furylmethyleneamino.
(e) (Substituted oxyimino)arylacetyl groups having the formula
wherein Rg is as defined above and R, is hydrogen, alkyl, cycloalkyl, alkylaminocarbonyl, arylaminocarbonyl (i.e.,
wherein R, is as defined above) or substituted alkyl (wherein the alkyl group is substituted with 1 or more halogen, cyano, nitro, amino, mercapto, alkylthio, aromatic group (as defined by Rg), carboxyl (including salts thereof), amido, alkoxycarbonyl, phenylmethoxycarbonyl, diphenylmethoxycarbonyl, hydroxyalkoxyphosphinyl, dihydroxyphosphinyl, hydroxy(phenylmethoxy)phosphinyl, or dialkoxyphosphinyl substituents).
Preferred (substituted oxyimino)arylacetyl groups include those wherein Rg is 2-amino-4thiazolyl. Also preferred are those groups wherein R; is methyl, ethyl, carboxymethyl, 1 -carboxy-1 methylethyl or 2,2,2-trifluoroethyl.
(f) (Acylamino)arylacetyl groups having the formula
wherein Rg is as defined above and Ri is
amino, alkylamino, (cyanoalkyl)amino, amido, aikylamido, (cyanoalkyl)amido,
Preferred (acylamino)arylacetyl groups of the above formula include those groups wherein R. is amino or amido. Also preferred are those groups wherein Rg is phenyl or 2-thienyl.
(9) [[(3-Substituted-2-oxo- 1 -imidazolidinyl]carbonyl]amino]arylacetyl groups having the formula
wherein Rg is as defined above and Rk is hydrogen, alkylsulfonyl, arylmethyleneamino (i.e., -N=CH- Rg wherein Rg is as defined above),
(wherein Rm is hydrogen, alkyl or halogen substituted alkyl), aromatic group (as defined by Rg above), alkyl or substituted alkyl (wherein the alkyl group is substituted with one or more halogen, cyano, nitro, amino or mercapto groups).
Preferred [[(3-substituted-2-oxo- 1 -i midazolidinyl]carbonyl]amino]arylacetyl groups of the above formula include those wherein Rg is phenyl or 2-thienyl. Also preferred are those groups wherein Rk is hydrogen, methylsuifonyl, phenylmethyleneamino or 2-furylmethyleneamino.
The term "cation", as used throughout the specification, refers to any positively charged atom or group of atoms. The "--SOO,MO" substituent on the nitrogen atom of the p-lactams of this invention encompasses all sulfonic acid salts. Pharmaceutically acceptable salts are, of course, preferred, although other salts are also useful in purifying the products of this invention or as intermediates for the preparation of pharmaceutically acceptable salts. The cationic portion of the sulfonic acid salts of this invention can be obtained from either organic or inorganic bases.Such cationic portion includes, but is not limited to, the following ions: ammonium; substituted ammonium, such as alkylammonium (e.g., tetra-n-butylammonium, referred to hereinafter as tetrabutylammonium); alkali metal, such as lithium, sodium and potassium; alkaline earth metal, such as calcium and magnesium; pyridinium; dicyclohexylammonium; hydrabaminium; benzathinium; N-methyl-D-glucaminium.
As set forth in formula I, and in the definitions following formula I, Ms can be hydrogen. Such compounds are often referred to in the art as "inner salts" by virtue of a positive and negative charge in the molecule.
This invention is directed to those p-lactams which have been described above, wherein the stereochemisty at the chiral center in the 3-position of the p-lactam nucleus is the same as the configuration at the carbon atom in the 6-position of naturally occurring penicillins (e.g., penicillin G) and as the configuration at the carbon atom in the 7-position of naturally occurring cephamycins (e.g., cephamycin C).
The p-lactams of formula I have activity against a range of gram-negative and gram-positive organisms. The compounds of this invention can be used as agents to combat bacterial infections (including urinary tract infections and respiratory infections) in mammalian species, such as domesticated animals (e.g., dogs, cats, cows, horses, and the like) and humans.
For combating bacterial infections in mammals a compound of this invention can be administered to a mammal in need thereof in an amount of about 1.4 mg/kg/day to about 350 mg/kg/day, preferably about 14 mg/kg/day to about 100 mg/kg/day. All modes of administration which have been used in the past to deliver penicillins and cephalosporins to the site of the infection are also contempiated for use with the novel p-lactams of this invention. Such methods of administration include oral, intravenous, intramuscular, and as a suppository.
The compound of formula I can be prepared from an azetidine having the formula
Introduction of a sulfo (SO033) group to the 1-position of a compound of formula II yields the corresponding compound having the formula
The conversion can be accomplished by reacting a compound of formula Il with a complex of pyridine and sulfur trioxide. The reaction can be run in an organic solvent or in a mixture of organic solvents, preferably a mixture of a polar solvent such as dimethylformamide and a halogenated hydrocarbon such as dichloromethane. This reaction yields a compound of formula Ill wherein Ms is pyridinium ion.
Instead of using a pre-formed complex of pyridine and sulfur trioxide, the complex can be formed in situ, e.g., using chlorosulfonyltrimethylsilyl ester and pyridine as reagents. Alternatively, a complex of dimethylformamide-sulfur trioxide, 2-picolinesulfur trioxide or 2,6-lutidine-sulfur trioxide can be used.
Using conventional techniques (e.g., ion-exchange resins, crystallization, or ion-pair extraction) the pyridinium salt formed by the above procedure can be converted to other salts. These techniques can also be used to convert the products of formula I, or any of the intermediates described herein, to other salts.
A second method for introducing the sulfo group to the 1 -position of an azetidine of formula II comprises first silylating the compound and then subjecting the silated compound to a silyl interchange reaction. Exemplary silylating agents are monosilyltrifluoroacetamide, trimethylsilylchloride/triethylamine, and bis-trimethylsilyltrifluoroacetamide, and an exemplary reagent useful for the silyl interchange reaction is trimethylsilyl chlorosulfonate.
Deprotection of an azetidine of formula Ill yields a zwitterion having the formula
The deprotection techniques used are conventional, and will depend on the particular protecting group (A1) present. Treatment with acid (e.g., formic acid or trifluoroacetic acid) cleaves a triphenylmethyl or a t-butoxycarbonyl protecting group. A benzyloxycarbonylamino protecting group can be cleaved by treatment with trimethylsilyl iodide or by catalytic hydrogenation. Treatment with phosgene or phosphorous pentachloride cleaves an amide protecting group. The zwitterions of formula IV are novel intermediates, and as such, constitute an integral part of this invention.
Conventional acylation techniques can be used to prepare the products of formula I (wherein R is hydrogen) from a zwitterion of formula IV. Exemplary acylation techniques include reaction with a carboxylic acid halide or carboxylic acid anhydride. The reaction with a carboxylic acid proceeds most readily in the presence of a carbodiimide and a substance capable of forming an active ester in situ such as N-hydroxybenzotriazole. In those instances wherein the acyl group (R,) contains reactive functionality (such as amino or carboxyl groups) it may be necessary to first protect those functional groups, then carry out the acylation reaction, and finally deprotect the resulting product.
The oB-lactams of formula I wherein R is methoxy can be prepared from the corresponding compound of formula I wherein R is hydrogen. Halogenation of the amide nitrogen of anon- methoxylated compound of formula I yields, in situ, an intermediate having the formula
Reaction of an intermediate of formula V with a methoxylating agent, e.g., an alkali metal methoxide yields a product of formula I wherein R is methoxy. The reaction can be run in an organic solvent, e.g., a polar organic solvent such as dimethylformamide, at a reduced temperature.
An alternative synthesis for preparing the compounds of formula I wherein R is methoxy comprises first alkoxylating a compound of formula II wherein A1NH is a carbamate (e.g., A1 is benzyloxycarbonyl) and then introducing a sulfo group in the 1-position of the resulting compound.
Deprotection and acylation, using the procedures described above, yields the products of formula I wherein R is methoxy.
Azetidinones of formula II can be synthesized using various procedures. Secopenicillins having the formula
wherein R3 is alkyl, halogenated alkyl, aryl or arylalkyl, can be oxidized and treated with an acid to yield the corresponding azetidinone of formula II.
Alternatively, a cis azetidinone of formula II can be treated with a thiolate salt having the formula R2Sç3X@, VII wherein Xs is a cation (preferably an alkali metal), to yield a mixture of diastereomers having the formulas
Separation of the above compounds can be accomplished using conventional chromatographic or fractional crystallization techniques. Oxidation of a compound of formula VIII or IX yields the corresponding azetidinone of formula II. Exemplary oxidizing agents are potassium permanganate, ozone, hydrogen peroxide and metachloroperbenzoic acid.
Still another procedure for preparing azetidinones of formula II utilizes 2-azetidinone-4-disulfides having the formula
Treatment of an azetidinone of formula X with triphenylphosphine or trimethoxyphosphine yields the corresponding azetidinone having the formula VI, which can be oxidized and treated with an acid to yield the corresponding azetidinone of formula II. Alternatively, a compound of formula VI can be treated to remove the protecting group (A1) and then reprotected with a different group before proceeding with the oxidation.
Still another procedure for preparing azetidinones of formula II utilizes bicyclic thiazoline azetidinones having the formula
wherein R4 is acyl. Reaction of a compound of formula Xl with a compound having the formula
XII R2-Y, wherein Y is a leaving group such as halogen, yields the corresponding compound having the formula
Depending on the particular R4 group, it may be necessary to deacylate a compound of formula XIII (yielding the corresponding 3-amino-2-azetidinone) and then reprotect the amino group prior to oxidation of the compound.
Still another procedure for preparing azetidinones of formula II comprises reacting an azetidinone having the formula
with a thiolate salt of formula VII to yield the corresponding mixture of diastereomers VIII and IX. This mixture can be converted to the desired azetidinone of formula II using the procedures described above.
Still another procedure for preparing azetidinones of formula II comprises reacting an azetidinone of formula XIV with a salt having the formula
XV R2SOe2Xo+ to yield the corresponding mixture of diastereomers
Separation of the above compounds can be accomplished using conventional chromatographic or fractional crystallization techniques.
Still another procedure for preparing azetidinones of formula II comprises reacting an azetidinone of formula XVII wherein R2 is methyl with a salt of formula XV to yield the corresponding mixture of diastereomers of formulas XVI and XVII, which can be separated as described above.
The following examples are specific embodiments of this invention.
Example 1 (3S-cis)-3-Amino-4-(methylsulfonyl)-2-oxo-1 -azetidinesulfonic acid, inner salt
A) (3R-cis)-4-(Methylsulfonyl)-2-oxo-3-[(triphenylmethyl)aminoi-1 -azetidinesulfonic acid, tetrabutylammonium salt (cis)-[2-Oxo-3-[(triphenylmethyi)amino]-4-azetidinyl]methyl sulfone (2.01 g) and 3.2 gof a pyridine-sulfur trioxide are stirred in 20 ml of absolute dimethylformamide at 700C for 24 hours.
Dimethylformamide is distilled off in vacuo. The remaining oil is dissolved in 50 ml of dichloromethane.
This solution is poured into 100 ml of ice-water containing 1.7 g of tetrabutylammonium hydrogen sulfate. The pH is adjusted to 5.3 with 1 N potassium hydroxide. The separated organic phase is dried over sodium sulfate and the solvent is distilled off yielding 3.6 g of the title compound as an oil.
B) (3S-cis)-3-Amino-4-(methylsulfonyl)-2-oxo-1 -azetidinesulfonic acid, inner salt (3R-cis)-4-(Methylsulfonyl)-2-oxo-3-[(triphenylmethyl)amino]-1 -azetidinesulfonic acid, tetrabutylammonium salt (3.4 g) is dissolved in 15 ml of formic acid/dichloromethane (3:2) and stirred at -50C for 40 minutes. The solution is then poured into 200 ml of ether. The title compound is collected and dried, yielding 0.9 g, melting point 11 00C, dec.
Example 2 [3R-[3a,4(Z)]]-3-[[(2-Amino-4-thiazoIyI)-(methoxyimino)acetyljamino]-4-(methyIsulfonyI)-2- oxo-1-azetidinesulfonic acid, potassium salt (3S-cis)-3-Amino-4-(methylsulfonyl)-2-oxo-1 -azetidinesulfonic acid, inner salt (0.344 g; see example 1), 0.202 g of (Z)-2-amino-a-(methoxyimino)-4-thiazoleacetic acid and 0.175 g of Nhydroxybenzotriazole are dissolved in 10 ml of absolute dimethylformamide. The solution is cooled to Ooh and 0.101 g of triethylamine is added, followed buy a solution of 0.202 g of dicyclohexylcarbodiimide in 5 ml of tetrahydrofuran; stirring is continued for 4 hours.
Dimethylformamide is distilled off in vacuo and the residue is dissolved in 20 ml of acetone.
Dicyclohexylurea is separated by filtration. After adding 0.34 g of potassium perfluorobutanesulfonate to the filtrate, the title compound precipitates. Using water and water/acetone (9:1) as eluents, the title compound is purified by column chromatography on HP20 resin; fractions containing the title compound are freeze-dried. The product has a melting point of 21 80C, dec.
Example 3 (3R-trans)-3-Amino-4-( methylsulfonyl)-2-oxo-1 -azetidinesulfonic, inner salt
Following the procedure of example 1, but substituting (trans)-[2-oxo-3 [(triphenylmethyl)amino]-4-azetidinyljmethyl sulfone for the corresponding cis isomer, yields the title compound, melting point 1270C, dec.
Example 4 [3 R-[3a,4a( R)]]-3-[[[(4-Ethyl-2,3-dioxo-1 -piperazinyl)carbonyl]a mino]phenylacetyl]-4- (methylsulfonyl)-2-oxo-1 -azetidinesulfonic acid, potassium salt
Following the procedure of example 2, but substituting (R-a-[[(4-ethyl-2,3-dioxo-1 - piperazi nyl)carbonyl]a mino] phenylacetic acid for (Z)-2-amino-a-(methoxyimino)-4-thiazoleacetic acid, yields the title compound, melting point 149-1 530C, dec.
Examples 5-8
Following the procedures of examples 1 and 2, but substituting the compound listed in column I for (cis)-[2-oxo-3-[(triphenylmethyl)-amino]-4-azetidinyl]methyl sulfone and the acid listed in column II for (Z)-2-amino-a-(methoxyimino)-4-thiazoleacetic acid, yields the product listed in column III.
Examples 6 and 7 require a deprotection step at the end of the reaction sequence. Deprotection is accomplished in example 6 by treatment of the protected compound with trifluoroacetic acid and anisole at --150C. Deprotection is accomplished in example 7 by catalytic (10% palladium on charcoal) hydrogenation of the protected compound.
Column I Column 11 Column Ill o o 5) fi- CNHS025) Y C-OH NEC-CHZ-S-CHZ-C-NH u 0NII N-SO KW 0 0 CII (Z) 0 0 CII 6) (, so -CII Ci II 1 3 II 1 (Z) 2 C--O-N=C-C-OH II0-C-C-0-N=C-C-NII /SOZ-CHZC1 I CII CII 3 -so x 0NH 3II2? II2N 0 3 0 cQ,, 4"'- 0 0 0 II II C-0-C-CII-C-OII 7) 3CNII ( O )3 N2 II II i3C-O-C 6 -C-OR so 1 I5 (Z) 0 8) o CNN S02-CII2 (Z) ?l CN30N=CCNNII S02-CN2 8) (O) CNH S02CH2 NH NS03OX(D 3 ..P B 1"''
Claims (12)
1. A compound having the formula
wherein R is hydrogen or methoxy; R1 is acyl; R2 is alkyl, haloalkyl, aryl or arylalkyl; and Ms is hydrogen or a cation.
2. A compound in accordance with claim 1 wherein R is hydrogen.
3. A compound in accordance with claim 1 wherein R2 is alkyl or haloalkyl.
4. A compound in accordance with claim 1 wherein R2 is aryl.
5. A compound in accordance with claim 1 wherein R2 is arylalkyl.
6. The compound in accordance with claim 1 [3R-[3a,4cr(Z)]]-3-[[(2-amino-4-thiazolyl)- (methoxyimino)acetyl]amino]-4-(methylsulfonyl)-2-oxo- 1 -azetidinesulfonic acid, potassium salt.
7. The compound in accordance with claim 1 [3R-[3a,4a(R)]]-3-[[[(4-ethyl-2,3-dioxo-1- piperazinyl)carbonyl]am ino]phenylacetyl]-4-(methylsuifonyl)-2-oxo- 1 -azetidinesulfonic acid, potassium salt.
8. A compound having the formula
wherein R2 is alkyl, haloalkyl, aryl or arylalkyl.
9. The compound in accordance with claim 8, (3S-cis)-3-amino-4-(methylsulfonyl)-2-oxo-1- azetidinesulfonic acid, inner salt.
10. The compound in accordance with claim 8 (3R-trans)-3-amino-4-(methylsulfonyl)-2-oxo-1 azetidinesulfonic, inner salt.
11. A process for preparing a compound of the formula
characterized by acylating a compound of the formula
12. A process for preparing a compound of the formula
characterized by introducing a sulfo group (S03-) to the 1-position of a compound of the formula
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US28372081A | 1981-07-16 | 1981-07-16 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| GB2103212A true GB2103212A (en) | 1983-02-16 |
| GB2103212B GB2103212B (en) | 1985-05-01 |
Family
ID=23087268
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB08220058A Expired GB2103212B (en) | 1981-07-16 | 1982-07-09 | 4-substituted derivatives of 2-oxo-1-azetidinesulfonic acid salts |
Country Status (5)
| Country | Link |
|---|---|
| JP (1) | JPS5823662A (en) |
| DE (1) | DE3225619A1 (en) |
| FR (2) | FR2509726B1 (en) |
| GB (1) | GB2103212B (en) |
| IT (1) | IT1157292B (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0109816A1 (en) * | 1982-11-16 | 1984-05-30 | Eli Lilly And Company | N-substituted-2-(R)-(sulfinic acid)-3-(S)-(acylamido)-4-oxo-azetidines and process |
| EP0499232A2 (en) * | 1991-02-12 | 1992-08-19 | PLIVA Handels GmbH | 4-Oxo-azetidine-2-sulfonic acids and their salts, processes for the preparation thereof and their use |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| MX7096E (en) * | 1980-12-05 | 1987-06-19 | Takeda Chemical Industries Ltd | METHOD FOR PREPARATION OF 2-OXOAZETIDINE DERIVATIVES |
| JPS58210060A (en) * | 1982-05-31 | 1983-12-07 | Takeda Chem Ind Ltd | 2-oxoazetidine derivative, its preparation and use |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0021678B1 (en) * | 1979-06-08 | 1984-11-07 | Takeda Chemical Industries, Ltd. | 1-sulpho-2-oxoazetidine derivatives, their production and pharmaceutical compositions thereof |
| WO1982003858A1 (en) * | 1981-04-30 | 1982-11-11 | Takeda Chemical Industries Ltd | Acetidine derivatives and process for their preparation |
| MX7096E (en) * | 1980-12-05 | 1987-06-19 | Takeda Chemical Industries Ltd | METHOD FOR PREPARATION OF 2-OXOAZETIDINE DERIVATIVES |
| WO1982001872A1 (en) * | 1980-12-05 | 1982-06-10 | Takeda Chemical Industries Ltd | Azetidine derivatives and process for their preparation |
-
1982
- 1982-07-07 FR FR8211927A patent/FR2509726B1/fr not_active Expired
- 1982-07-07 IT IT22279/82A patent/IT1157292B/en active
- 1982-07-08 DE DE19823225619 patent/DE3225619A1/en not_active Ceased
- 1982-07-09 GB GB08220058A patent/GB2103212B/en not_active Expired
- 1982-07-16 JP JP57124980A patent/JPS5823662A/en active Pending
- 1982-12-02 FR FR8220208A patent/FR2515178A1/en active Pending
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0109816A1 (en) * | 1982-11-16 | 1984-05-30 | Eli Lilly And Company | N-substituted-2-(R)-(sulfinic acid)-3-(S)-(acylamido)-4-oxo-azetidines and process |
| EP0499232A2 (en) * | 1991-02-12 | 1992-08-19 | PLIVA Handels GmbH | 4-Oxo-azetidine-2-sulfonic acids and their salts, processes for the preparation thereof and their use |
| EP0499232A3 (en) * | 1991-02-12 | 1992-12-02 | Pliva Handels Gmbh | 4-oxo-azetidine-2-sulfonic acids and their salts, processes for the preparation thereof and their use |
Also Published As
| Publication number | Publication date |
|---|---|
| FR2509726A1 (en) | 1983-01-21 |
| FR2509726B1 (en) | 1984-04-27 |
| JPS5823662A (en) | 1983-02-12 |
| FR2515178A1 (en) | 1983-04-29 |
| DE3225619A1 (en) | 1983-02-10 |
| IT8222279A0 (en) | 1982-07-07 |
| IT1157292B (en) | 1987-02-11 |
| GB2103212B (en) | 1985-05-01 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PCNP | Patent ceased through non-payment of renewal fee |