GB1564537A

GB1564537A - Carbon analogues of y7aminocephalosporanic acid

Info

Publication number: GB1564537A
Application number: GB3980276A
Authority: GB
Original assignee: Massachusetts Institute of Technology
Current assignee: Massachusetts Institute of Technology
Priority date: 1975-09-26
Filing date: 1976-09-24
Publication date: 1980-04-10
Also published as: DE2643085A1; FR2325380A1; FR2378036A1; JPS5262293A; CA1102308A; FR2325380B1; FR2378036B1; GB1564538A

Description

(54) CARBON ANALOGS OF 7-AMINOCEPHALOSPORANIC ACID (71) We, MASSACHUSETTS INSTI TUTE OF TECHNOLOGY, a corporation organised and existing under the laws of the State of Massachusetts, United States of America, of 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States of America, do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement: This invention relates to carbon analogs of 7 - aminocephalosporanic acrid.

Following the discovery of the penicillins and their synthesis, perhaps one of the most important advances in medical research was the discovery of the cephalosporin antibiotics and their use in clinical medicine. The cephalosporin antibiotics, though not penicillins, have a structure quite similar to penicillins and the two can be co-produced in the fermentation of a cephalospaoium organism.

Additionally, the similarity between cephalosporins and penicillins has suggested that interconversions between the two series of antibiotics are feasible. Such conversions are described by R B. Morin et al, "Chemistry of Cephalosporin Antibiotics XV. Transformation of Penicilin Sulfoxide", J. Amer. Chem. Soc.

91, 1401 (1969). An illustrative transformation between the two antibiotic families is the heating of Penicillin V sulfoxide methyl ester with a trace of acid to afford a desacetoxy cephalosporin.

Because of such similarity in both structure and chemical reactivity, considerable research has been devoted to the derivatization of cephalosporins, employing chemical reactions analogous to those finding utility in penicillin moditication. For example, 7 - aminocephalosporanic acid (7-ACA) may be obtained by mild acid hydrolysis of Cephalosporin C. This acid may then be readily transformed into myriad derivatives of varied chemical properties and biological activity. For example, acylation of 7-ACA with phenylacetyl chloride affords an ester having an antibacterial activity about 100 times that of Cephalosporin C.

Numerous other reactions of 7-ACA are likewise well-known and reported in the literature.

Thus, acyl groups, isocyanates isothiocyanates, halogen compounds, methylisoureas, ethylene oxides, ethylene imines and the like have been introduced into 7-ACA.

In addition to the above derivatives, reactions modifying both the ss-lactam and the dihydrothiazine ring systems of cephalosporins are well-known. For example, epimerization at C-7 may be effected with triethylamine in refluxing chloroform. Analogously, reactivity through the C-3 substituents, the carboxyl group and the C,4 double bond affords a vast number of possible derivatives.

Reactions of the cephalosporins, as illustrated above, are reported in part by R. B. Morin and B. G. Jackson, "Chemistry of Cephalosporin Antibiotics," Progress in the Chemistry of Organic Natural Products XXVIII, Wein, Springer-Verlag (1970).

A new series of derivatives of cephalosporins has recently been described in British Patent No. 1,521,763. This series was based upon the discovery of certain esters of 7 - oxocephalosporanic acid and methods for their formation.

These esters were employed as intermediates in the formation of the biologically active oxygen analog (7,,B - hydroxycephalosporanic acid) of 7-ACA. Such an analog serves as the starting material for a wide variety of biologically active derivatives analogous to the derivatives of 7-ACA, described above.

For brevity, the commonly accepted abbreviations of "7-ACA" for 7 - aminocephalosporanic acid and "iAPA" for 6 - amino penicillanic acid will be used throughout this specification.

The present invention provides a novel class of derivatives of 7-ACA, the 7 - carbon analogs thereof. These carbon analogs of 7-ACA are analogous to and prepared from the carbon analogs of 6APA, disclosed in German Patent Application No. P 24 16 492.9, which was laid open on October 31st 1974.

The synthetic approach to this cephalosporin series involves the oxidation of 6 - carbon analogs of SAPA and the rearrangement of the resulting sulfoxide to the respective carbon analog of 7-ACA, as described more fully in our co-pending Application No.

10238/79, Serial No. 1,564,538.

The present invention provides a carbon analog of 7 - aminocephalosporanic acid having the formula:

where R is hydrogen or a pharmaceutically acceptable group, R' is hydrogen or an organic acid radical, R" is hydrogen or an organic nucleophile and X is hydrogen or an organic nucleophile.

Groups represented by R include hydrogen or substituted or unsubstituted (1) aliphatic, alicyclic or aromatic, e.g. alkyl! preferably methyl, ethyl or propyl, alkenyl, preferably ethenyl, propenyl, and butenyl; aryl; alkaryl; alkynyl, preferably ethynyl, propynyl and butynyl; cycloalkyl or cycloalkenyl, such as cyclohexyl; aralkyl such as benzyl and phenylethyl; and ss,,ss,ss - trichloroethyl; (2) acyl compounds, including acylalkyl, preferably acetylmethyl, acetylethyl, acetylpropyl; acylamino, preferably acetylamino, propionylamino, and butyrylamino; acyl amino alkyl, preferably acetylaminomethyl, acetylaminoethyl, imino (see U.S. Patent No. 3,876,630), and arylacyls such as phenylacyl and its derivatives (e.g. p methoxyphenacyl, m-chlorophenacyl, and 2,5dimethyloxyphenacyl); (3) salt formers, e.g.

alkali metal ions such as sodium or potassium ions, or organic groups such as tri (alkyl)ammonium (preferably triethylammonium) or piperidino or N - alkyl piperidino, e.g. N ethylpiperidino, or benzylammonium or dicyclohexylamino; and (4) organo silyl groups such as trimethyl silyl. While it should be understood that some of the aforesaid groups may be more difficult to remove than others, most are groups heretofore used as protective groups in analogous reactions of penicillins and cephalosporins. Removal of such blocking groups is effected pursuant to recognized and well-known procedures, dependent upon the identity of the protective group.

R' represents an organic electrophilic moiety.

A wide variety of substituents are suitable, including substituted or unsubstituted aliphatic, e.g. akyl, preferably methyl, ethyl, propyl, hexyl, etc.; alicyclic, e.g. cycloalkyl, such as cyclopentyl, cyclohexyl, methylcyclohexyl; aromatic, e.g. phenyl, benzyl, tolyl; acyl, e.g.

benzoyl, phenoxyacetyl, chloroacetyl and beomoacetyl; carboxylic; carbonic; sulfonic; and amide radicals. Preferably R' may be selected from the group of (1) organic acyl radicals such as phenylacetyl, phenoxyacetyl, 2,6 flirnethylbenzoyla a - carboxyphenylacetyl, and a - aminophenylacetyl; (2) organic carbonic acid radicals such as carbethoxy, carbobenzyl oxy, and ,ss,ss, - trichlorocarbethoxy; (3) organic sulfonic acid radicals such as methylsulfonyl; and (4) amide radicals such as carbamyl, phenylcarbamyl, and methyl carbamyl. Most preferred are those R' groups which are bound to the oxygen by a carbonyl group.Suitable R' substituents include hydrogen, formyl, acetyl, phenyl, phenylacetyl, phenoxyacetyl, p - aminophenylacetyl, a - carboxyphenylacetyl, benzyl, benzoyl, 2 - thienylacetyl, aminocarbamyl, phenylglycyl, methyl sulfonyl, benzyl suffonyl, o - aminophenylsulfonyl, p aminobenzylsulfonyl, carbobenzoxy, a - carbonaphthoxy, carbo(2 - thienylmethoxy), and (1 phenyl - 2 - formylamino)ethoxycarbonyl.

X represents hydrogen or an organic nucleophile. Substituents employed in this manner include inter alia cyano, alkoxy, aryloxy, alkylamino, arylamino, halogen, hydroxy, carboalkoxy, acyloxy, carboxyl, carbonyl, sulfonyl, carbamyl, thiocarboxyl, and analogous func tionalities.

R" is hydrogen or an organic nucleophile, preferably hydrogen or acyl oxy, e.g. formyl oxy, acetoxy, phenylacetoxy, benzoyloxy, but a wide variety of substituents can be placed there (e.g. halogen, hydroxy, alkoxy, aryloxy, alkylamino, arylamino, carboxyl, carbonyl, sulfonyl, carboxyl, thio carboxyl, and other analogous functionalities).

Specific examples of R' and R" are set forth below:

R' cont.

R" -H, 41, -Br, OH, OCH, -OCH2CH3, -OC6H5

Reference is drawn to our copending application No. 10238/79, serial No. 1,564,538, referred to above, which describes and claims a process for the formation of analogs of 7 aminocephalosporanic acid and to sulfoxide intermediates useful for the formation of analogs of 7 - aminocephalosporanic acid.

The invention will be further described with reference to the following illustrative examples.

Example 1 ss,ss,ss - Trichloroethyl 6ss - Carbobenzyloxy- methylpenicillanate ss,ss,ss - Trichloroethyl 6ss - carbobenzyloxy methylpenicillanate was prepared in accord ance with the procedures of German Patent Application No. P2416492.9, It displayed the following characteristics: nmr (CDCl3, ppm): 1.60 (s, 3H); 1.70 (s, 3H); 2.8-3.1 (m, 2H); 3.8-4.3 (m, 1H); 4.50 (s, 1H); 4.73 (s, 2K); 5.10 (s, 2H); 5.57 (d, 1H, J=4.5 Hz); 727 (s, 5H); IR (CHCl Cm-'): 1780, 1740 (sh), mp 4250 .

Anal: Calc.

C, 47.46; H, 4.19; N, 2.91; Cl, 22.12 Found: C, 47.68; H, 4.20; N, 3.09; Cl, 22.25 Example 2 ss,ss,ss - Trichioroethyl 6ss - Carbobenzyloxy- methylpenicillanate - 1 - sulfoxide A solution of ss,ss,ss - trichloroethyl 6ss carbobenzyloxymethylpenicillanate (493.0 mg, 1.02 mmol) in 30 ml of chloroform was cooled in ice. m - Chloroperbenzoic acid (181.9 mg, 1.05 m mol) in 20 ml of chloroform was added dropwise to this chilled solution over about 30 min. The resulting solution was stirred at 0 for 1 hour and at ambient temperature for one hour. The reaction mixture was washed with sodium bicarbonate solution and the organic layer dried over magnesium sulfate and evacuated to remove the solvent Addition of ether to the residual oil afforded crystalliza tion.Recrystallization of the crude product from methylene chloride-pet ether yielded the pure sulfoxide as white needles: mp 153 1560; IR (CHCl3, Cm-1): 1800, 1780 (sh), 1730 and 1185; nmr (CDCl3, ppm): 1.37 (s, 3H); 1.83 (s, 3H); 2.6-4.4 (m, 3H); 4.73 (s, 3H); 4.8-5.0 (m, 3H); 5.17 (s, 3H)i 7.33 (s, 5H).

Example 3 ss,* trichloroethyl 7ss - Carbobenzyloxy- methyl - 3 - desacetoxycephalosporanate A mixture of the sulfoxides (105.0 mg, 2.09x10-4 mol; mixture of tz and ss isomers), 8 ml of benzene, 6 ml of DMA and 2 drops of methane-sulfonic acid were refluxed under a Dean-Stark trap for 17 hours. The benzene was removed under reduced pressure and the DMA by a short path high vacuum distillation (water bath 500; 2 mm). The residual oil was purified by silica gel chromatography (20 X 20 plate, 2 mm) using a 2% methanol-chloro form eluent. Isolation of the major fraction afforded the cephalosporanate as a yellow oil (72.6 mg, 72%).This product exhibited the following properties: nmr (CDCl3, ppm): 2.20 (s, 3H); 2.83 (s, 1H); 2.91 (s, 1H); 3.33 (d, 2H; J=4.0 Hz); 3.90-4.40 (m, 1H); 4.90 (d, 2H: J=3.0 Hz); 5.00 (d, 1H; J=4.5 Hz); 5.33 (s, 2H); 6.8e 7.50 (m, 3H); IR (CHCl3, Cm-1): 1770, 1730, 1385, 1300.

Example 4 - - Carbobenzyloxymethyl - 3 - desacetoxy - cephalosporanic acid ss,ss,ss - trichloroethyl 7!S - carbobenzyloxy- methyl - 3 - desacetoxy cephalosporanate (75.5 mg, i.58x10-4 mol) was dissolved in 90% acetic acid (2 ml). The solution was cooled to 0 via an ice bath and zinc dust (124.1 mg) was added. The resulting heterogeneous mixture was stirred for 3.5 hours. The zinc was removed by filtration ("Celite") and washed with methylene chloride (50 ml), the filtrate being combined with an ice water mixture "Celite" is a Registered Trade Mark.

The organic layer was separated and washed with ice and water. The aqueous phase was extracted with methylene chloride (2 x 50 ml).

The combined organic fractions were dried over magnesium sulfate and the solvent removed in vacuo in the absence of external heating. The last traces of acetic acid were removed at reduced pressure.

The residue, an oil, was dissolved in methylene chloride (20 ml) and extracted with 5% sodium bicarbonate solution (10 ml). The organic layer was separated and the aqueous layer after cooling in ice was acidified with 10 hydrochloric acid (10 ml). This acidified aqueous fraction was extracted with methylene chloride (.sox10 ml). The combined organic extracts were dried over magnesium sulfate and the solvent removed in vacuo in the absence of external heating. The cephalosporanic acid remained as a clear oil: nmr (CDCl3, ppm): 2.23 (s, 3H); 2.93 (d, 2H; J=7.0 Hz); 3.33 (d, 2H, J=5.0 Hz); 3.8-4.4 (m, lH); 4.97 (d, 1H, J=5.0 Hz); 5.10 (s, 2H); 7.27 (s, 5H); 8.10 (m, 1H).

Bioassay results (minimum inhibitory concentration in mg/ml): S. Aureus (200), S fecalis ( > 400), E Coli ( > 400), A. aerogenes ( > 400), S. pullorum ( > 400), P.. mirabilis ( > 400), P. Vulgaris ( > 400), S marcescens ( > 400), K. pneumonia ( > 400), and B. Subtilis ( > 400).

WHAT WE CLAIM IS:- 1. A carbon analog of 7 - aminocephalosporanic acid having the formula:

where R is hydrogen or a pharmaceutically acceptable group, R' is hydrogen or an organic acid radical, R" is hydrogen or an organic nucleophile, and X is hydrogen or an organic nucleophile.

2. A compound as claimed in claim 1 wherein R" is selected from hydrogen, halogen, hydroxy, alkoxy, aryloxy, alkylamino, arylamino, carboxyl, carbamyl, and sulfonyl.

3. A compound as claimed in claim 2 wherein R" is acetoxy.

4. A compound as claimed in claim 2 wherein R" is a pyridinium salt.

5. A compound as claimed in claim 2 wherein R" is carbamyloxy.

6. A compound as claimed in any of claims 1 to 5 wherein R' is a carboxylic acid radical or a methylsulfonyl radical.

7. A compound as claimed in claim 6 wherein R' is selected from formyl, phenylacetyl, phenoxyacetyl, 2,6 - dimethylbenzoyl, acetyl, carbamyl, phenylcarbamyl, and methyl carbamyl.

8. A compound as claimed in any of claims 1 to 7 wherein R is selected from alkyl, cycloalkyl, aryl, alkaryl, aralkyl, phenacyl, cations and organo silyl groups.

9. A compound as claimed in claim 8 where in R is methyl.

10. A compound as claimed in claim 8 wherein R is benzyl.

11. A compound as claimed in claim 8 wherein R is benzhydryl.

12. A compound as claimed in claim 8 wherein R is B > PP - trichloroethyl.

13. A compound as claimed in claim 8 wherein R is p - nitrobenzyl.

14. A compound as claimed in claim 8 wherein R is pmethoxybenzyl.

15. A compound as claimed in any of claims 1 to 14 wherein X is selected from hydrogen, cyano, hydroxy, alkoxy, aryloxy, halogen, carboalkoxy, and carboaryloxy.

16. A compound as claimed in claim 15 wherein X is methoxy.

17. A compound as claimed in claim 15 wherein X is chloro.

18. A compound as claimed in claim 15 wherein X is carbethoxy.

**WARNING** end of DESC field may overlap start of CLMS **.

Claims

**WARNING** start of CLMS field may overlap end of DESC **. methyl - 3 - desacetoxy cephalosporanate (75.5 mg, i.58x10-4 mol) was dissolved in 90% acetic acid (2 ml). The solution was cooled to 0 via an ice bath and zinc dust (124.1 mg) was added. The resulting heterogeneous mixture was stirred for 3.5 hours. The zinc was removed by filtration ("Celite") and washed with methylene chloride (50 ml), the filtrate being combined with an ice water mixture "Celite" is a Registered Trade Mark. The organic layer was separated and washed with ice and water. The aqueous phase was extracted with methylene chloride (2 x 50 ml). The combined organic fractions were dried over magnesium sulfate and the solvent removed in vacuo in the absence of external heating. The last traces of acetic acid were removed at reduced pressure. The residue, an oil, was dissolved in methylene chloride (20 ml) and extracted with 5% sodium bicarbonate solution (10 ml). The organic layer was separated and the aqueous layer after cooling in ice was acidified with 10 hydrochloric acid (10 ml). This acidified aqueous fraction was extracted with methylene chloride (.sox10 ml). The combined organic extracts were dried over magnesium sulfate and the solvent removed in vacuo in the absence of external heating. The cephalosporanic acid remained as a clear oil: nmr (CDCl3, ppm): 2.23 (s, 3H); 2.93 (d, 2H; J=7.0 Hz); 3.33 (d, 2H, J=5.0 Hz); 3.8-4.4 (m, lH); 4.97 (d, 1H, J=5.0 Hz); 5.10 (s, 2H); 7.27 (s, 5H); 8.10 (m, 1H). Bioassay results (minimum inhibitory concentration in mg/ml): S. Aureus (200), S fecalis ( > 400), E Coli ( > 400), A. aerogenes ( > 400), S. pullorum ( > 400), P.. mirabilis ( > 400), P. Vulgaris ( > 400), S marcescens ( > 400), K. pneumonia ( > 400), and B. Subtilis ( > 400). WHAT WE CLAIM IS:-

1. A carbon analog of 7 - aminocephalosporanic acid having the formula: