TRICYCLIC(AZETO-ISOQUINOLINE)B-LACTAMES

Abstract: A new compound with a nucleus containing a benzo-fused carbocyclic ss-lactame system is disclosed. The compound has antibacterial activity against B. subtilis.

Description: TRICYCLIC (AZETO-ISOQUINOLINE) β-LACTAMS , Research in the β-lactam field has centered mainly on penicillins and cephalosporin compounds, both of which have the β-lactam fused in a bicyclic ring system. Recently, new β-lactam systems which maintain their antibiotic properties have been reported. Examples include nocardicin [J. Amer. Che . Soc, 98, 3023 (1976)], which contains a monocyclic β-lactam nucleus, clavulanic acid (Belgian Patent No. 827,926), which has an όxygen- containing bicyclic β-lactam nucleus, and bicyclic systems related to cephalosporins in which the sulfur atom has been moved to another position, [J. Amer. Chem. Soc. , 99, 2353 (1977)] or has been replaced by oxygen or a ethylene group [J. Med. Chem. , 20, 551 (1977)]. The carbocyclic cephalosporin system noted above is believed to be the closest prior art; however it is also believed not to be material to the patentability of the compounds of this invention. Other similar β-lactams systems have been reported; however, all these systems are also not believed material prior art to the present invention. I have now prepared a novel tricyclic β-lactam system--which-jcontains a fused benzo system; in particular, derivatives of the lα-amino-l,2-dihydro-2-oxo-9bβH-azeto- [2,1-a]isoquinoline-4-carboxylic acid nucleus. DESCRIPTION OF THE INVENTION The compounds of this invention have the following chemical formula wherein M is hydrogen, a carboxylic acid protective ester residue, or a pharmaceutically acceptable non-toxic cation. The term "a carboxylic acid protective ester group" is one which has a clear and definite meaning within the art. Many ester groups are known and used in the art to protect a carboxylic acid group from interfering with chemical reactions in undesired ways. At the appropriate time, the esters are cleaved by standard methods to give the desired free carboxylic acid moiety. Many examples of such ester groups are set forth in the chemical litera¬ ture, including review articles and books such as "Protective Groups in Organic Chemistry", McO ie ed., Plenum Press, New York, 1973. Examples of the most common esters include t-butyl, benzyl, nitrobenzyl, methoxybenzyl, benzhydryl, and trichloroethyl. The selection of which ester group to use depends on various factors, including subsequent reaction conditions and desired methods of removal. The selection of the proper ester group is within the ability of persons skilled in the art. Pharmaceutically acceptable non-toxic cations are also well-known in the art. In general, they include alkali metal cations, alkaline earth cations and organic or inorganic ammonium cations. The sodium and potassium salts are particularly advantageous. Again, the selection of useful and proper cations is within the ability of persons skilled in the art. 1 « v» The compounds of this invention are prepared by a totally synthetic route with the monocyclic β-lactam (1) as starting material. Compound 1 is prepared by the sequence of reactions set forth in Scheme I. Conversion of β-lactam 1 into the compounds of this invention is outlined in Scheme II, OMPI 7 -tyA - WIPO 2 3 DMB = 6 SCHEME I URE _ OMPI ^NAT COOCH 2 Ph COOCH 2 Ph SCHEME II Benzyl alcohol 2 [J. Chem. Soc. (C) , 1818 (1969)] is oxidized by standard oxidizing agents such as Crθ3 to benzaldehyde ^. Condensation of 3 ^ with 2,4-dimethoxy- benzylamine gives i ine 4, which is reacted directly with phthalimidoacetyl chloride to give monocyclic β- lactam wherein Ft is phthalimido. Treatment of 5 with methylhydrazine gives the amino-β-lactam derivative 6. Acylation of 6 with phenoxyacetyl chloride by standard methods followed by oxidative cleavage of the dimethoxy¬ benzyl group with K2S2O8 gives the monocyclic β-lactam 1. When β-lactam 1 is treated with an ester of glyoxylic acid (where the ester is selected from those protective esters known within the art) in the presence of triethylamine, compound 7 is obtained. The alcohol moiety of 7 is converted to the chloro derivative by treatment with thionyl chloride and pyridine. Reaction of the chloro derivative with triphenyl phosphine gives the ylide 8. Treatment of 8 with a mild acid such as p_-toluensulfonic acid yields the ester compounds of this invention. Cleavage of the ester group by standard methods gives the compounds of the invention where M is hydrogen. The free acids can be converted to the pharmaceutically acceptable salts by standard methods known in the art. The compounds of this invention where M is hydrogen or a cation have antibacterial activity against B. subtilis. They are useful for sterilization of laboratory glassware or for treating infections of B. subtilis in animals. The compounds of this invention where M is a protective ester group are useful as intermediates for the antibacterially active compounds. The following examples are presented to il¬ lustrate general methods of preparing the compounds of this invention to one skilled in the art and are not to be construed as limiting the scope thereof. All tempera¬ tures are given in degrees Centigrade. EXAMPLE 1 2-(2-Dioxolanyl)benzaldehyde A suspension of sodium acetate (6.56 g, 0.08 mol and pyridinium chlorochromate (17.2 g, 0.08 mol) in dry methylene chloride (200 ml) was cooled in an ice bath under a nitrogen atmosphere and treated with a solution of 2f-(2-dioxolanyl)benzyl alcohol (9.6 g, 0.053 mol) in methylene chloride (25 ml) over a 15 minute period. The reaction was stirred at room temperature for 2 hours and diluted with ether (200 ml) . The solid was collected and washed with ether, and the filtrate was washed with 5% aHC03 and brine and dried. The solution was evaporated to give the title aldehyde; 7.8 g (82%). EXAMPLE 2 cis-1-(2,4-Dimethoxybenzyl)-2-[2-(2-dioxolanyl)phenyl]-4- oxo-3-phthalimidoazetidine To an ice-cold solution of 2,4-dimethoxybenzyl- amine (3.6 g, 21.5 mmol) in methylene chloride (40 ml) was added a solution of aldehyde from Example 1 (5.0 g, 22.4 mmol) in methylene chloride (25 ml). The solution was stirred 10 minutes, 4A molecular sieves (9 g) were added, and the reaction was stirred at room temperature for 1.75 hours. IR analysis indicated no amine or ' aldehyde groups. The mixture was cooled in ice and triethyla ine (2.61 g, 25.8 mmol) was added, followed by the dropwise addition of phthalimidoacetyl chloride (5.54 g, 24.8 mmol) in methylene chloride (40 ml) over a 15 minute period. The reaction was stirred for 30 minutes and then filtered. The filtrate was washed with 5% NaHC0 3 and brine, and the organic phase was dried and evaporated to an oil, which on standing with ether and chloroform gave a solid product; 9.3 g. The solid was recrystallized from ethyl acetate; 7.1 g (64%), mp 170-172°. EXAMPLE 3 cis-3-Amino-l-(2,4-dimethoxybenzyl)-2-[2-(2-dioxolanyl)- phenyl]-4-oxoazetidini " The product from Example 2 (5.8 g) was dissolved in methylene chloride (40 ml) and filtered to remove a trace of insoluble solids (0.15 g) . The»filtrate was cooled with an ice bath and treated under a nitrogen 1 atmosphere with methylhydrazine (0.85 g, 18.7 mmol). The reaction was stirred 2 days under nitrogen at room temper ture and then filtered to remove a solid, which was washe with a small amount of methylene chloride. The filtrate 5 was evaporated in vacuo to give 4.65 g of the title pro¬ duct. EXAMPLE 4 cis-1-(2,4-Dimethoxybenzyl)-2-[2-(2-dioxolanyl)phenyl]-4- 10 oxo-3-phenoxyacetylaminoazetidine The amino compound from Example 3 (4.22 g, 11 mmol) was dissolved in ethyl acetate (60 ml) and cooled in an ice-alcohol bath. Triethylamine (1.67 g, 16.5 mmol) was added, followed by the dropwise addition 15 of phenoxyacetyl chloride (2.06 g, 12.1 mmol) over a period of 5 minutes. The reaction was stirred for 45 minutes with cooling and then filtered. The filtrate was washed- with 5% NaHCθ3 and brine. The dried filtrate was evaporated to give the title product; 2.0 g. The 20 product was recrystallized from ethyl acetate-ether; 1.02 g, mp 137-138°. The solid which was filtered from the reaction solution was stirred with hot ethyl acetate (100 ml) and filtered. The filtrate was treated with ether (200 ml) and cooled to give additional product; 253.91 g, mp 138-139°. EXAMPLE 5 cis-2-[2-(2-Dioxolanyl)phenyl]-4-oxo-3-phenoxyacetyl- aminoazetidine 0 The product of Example 4 (1.56 g, 3 mmol) was dissolved in a mixture of acetonitrile (120 ml) and dis¬ tilled water (30 ml) , degassed with argon for 30 minutes, and brought to reflux. A degassed solution of K 2 S2θs (5.67 g, 21 mmol) and Na 2 HP0 -7H 2 0 (2.81 g, 10.5 mmol) 5 in distilled water (120 ml) was added in 8 equal portions at 4 minute intervals to the refluxing solution, the reaction being kept at pH >6 by the addition of solid Na 2 HP0 4 *7H 2 0. The acetonitrile was evaporated and the residue was extracted with ethyl acetate. The extracts were washed with brine, dried, and evaporated to an oil, 2.07 g. The oil was extracted with petroleum ether to remove the dimethoxybenzaldehyde and then was triturated with ethyl acetate-ether. It was cooled in ice and the resulting solid product was collected; 0.54 g (49%), mp 137-138°dec. EXAMPLE 6 Benzyl α-Hydroxy-α-fcis-2-[2-(2-dioxolanyl)phenyl]-4-oxo- 3-phenoxyacetylamino-l-azetidinyl]acetate " Freshly distilled benzyl glyoxylate (312 mg, 1.9 mmol) and freshly distilled tetrahydrofuran (15 ml) were stirred with 4A molecular sieves for one hour and then cooled in ice. To this solution was added the solid product from Example 5 (437 mg, 1.19 mmol) followed by the dropwise addition of triethylamine (240 mg, 2.37 mmol). The ice bath was removed and the reaction was stirred for 1.5 hours. The solution was filtered and the filtrate was evaporated to dryne'ss. The residue was dissolved in chloroform and chromatographed on a silica gel column with a chloroform-ethyl acetate gradient as eluant to give the title product, 525 mg (83%) . EXAMPLE 7 Benzyl 1,2-dihydro-2-oxo-lα-(phenoxyacetylamino)-9bβH- azetό[2,1-ajisoquinoline-4-carboxylate ' The product of Example 6 (309 mg, 0.58 mmol) was dissolved in freshly distilled tetrahydrofuran (20 ml) and cooled to -6°. To the cold solution was added pyridine (68 μl, 0.847 mmol) and thionyl chloride (58 μl, 0.812 mmol), and the reaction was stirred for 2 hours at -6°.. The solid pyridine salt was collected and the filtrate was evaporated to dryness under high vacuum. The chloro product was dissolved in freshly dis¬ tilled tetrahydrofuran (15 ml) and was treated with pyridine (103 μl, 1.28 mmol) and triphenylphosphine (304 mg, 1.16 mmol). The reaction was refluxed 1.5 hours under an argon atmosphere, stirred overnight at room temperature, and then refluxed an additional 4.5 hours. The solution was decanted from a small amount of solid and evaporated to dryness. The oil was dissolved in chloroform:ethyl acetate (1:1) and chromatographed on silica gel (25 g) with chloroform:ethyl acetate (1:1) and then ethyl acetate as eluants to give the ylide product, 280 mg (62%) . The above product (277 mg, 0.357 mmol) was dissolved in 9:5 acetone:water (9 ml) which had been previously degassed with argon. The solution was cooled in an ice bath and treated with p_-toluenesulfonic acid (277 mg, 1.46 mmol). The reaction was stirred at room temperature for 1.75 hours during which time the product precipitated. The solution was cooled in an ice bath and the title product was collected and washed with additiona cold acetone-water solvent; 105 mg (65%-) , mp 136-8°. EXAMPLE 8 1,2-Dihydro-2-oxo-lα-(phenoxyacetylamino)-9bβH-azeto- [2,1-a]isoquinoline-4-carboxylic acid The product of Example 7 (55 mg, 0.12 mmol) was dissolved in freshly distilled tetrahydrofuran (24 ml) and hydrogenated at atmospheric pressure for 2 hours in the presence of 10% Pd on carbon (55 mg) . The catalyst was removed by filtration and the filtrate was evaporated to dryness. The product was triturated with ether and ethyl acetate; 25 mg, mp 167-168 dec.

Claims: I claim : 1. A compound of the formula: where M is hydrogen, a carboxylic ac d protective ester residue, or a pharmaceutically acceptable non-toxic cation. 2. A compound as claimed in claim 1 where M is hydrogen, t-butyl, benzyl, nitrobenzyl, methoxybenzyl, benzhydryl, trichloroethyl, sodium ion, or potassium ion, 3. A compound as claimed in claim 2 where M is hydrogen. 4. A compound as claimed in claim 2 where M is sodium ion. 5. A compound as claimed in claim 2 where M is potassium ion. 6. A compound of the formula: 7. Antibacterial compositions comprising a compound of claim 1 where M is hydrogen or a pharmaceuti¬ cally acceptable non-toxic cation. . . 1. A compound of the formula; where M is hydrogen, a carboxylic acid protective ester residue, or a pharmaceutically acceptable non-toxic cation. 2. A compound as claimed in claim 1 where M is hydrogen, t-butyl, benzyl, nitrobenzyl, methoxybenzyl, benzhydryl, trichloroethyl, sodium ion, or potassium ion. 3. A compound as claimed in claim 2 where M is hydrogen. 4. A compound as claimed in claim 2 where M is sodium ion. 5. A compound as claimed in claim 2 where M is potassium ion. 6 . Cancelled. 7. Antibacterial compositions comprising a compound of claim 1 where M is hydrogen or a pharmaceuti¬ cally acceptable non-toxic cation. IJUR O Λr- WI

Inventors: PERCHONOCK C
Applicants: SMITHKLINE CORP
Application year: 1979
Main classification: C07D451
IPC codes: C07D317, C07D463