7-(2-Carbamoy L-1-oxaspiro(2,x)alkane-carboxamido) penicillanic acids
United States Patent 1 1 Sellstedt et al.  
 [ Apr. 22, 1975 7-(2-CARBAMOY L-l-OXASPlRO( 2,X)ALKANE- CARBOXAMIDO) PENICILLANIC ACIDS [75] Inventors: John H. Sellstedt, Montgomery;  
 Daniel M. Teller. Chester. both of Pa.  
 [73] Assignee: American Home Products Corporation, New York. NY.  
 [22] Filed: Dec. 29, 1972 [2]] Appl. No.: 319.413  
 [52] US. Cl. 260/2391; 424/246; 424/271:  
  260/243 C [51] Int. Cl. C07d 99/16; C07d 99/24 [58] Field of Search 260/239.1  
 [56] References Cited UNITED STATES PATENTS 3.041.333 6/1962 Chow et al 260/239 Primary Iiruminer-Nicholas S. Rizzo Allurm), Agwz! or Firm-Stephen Venetianer [57] ABSTRACT 5 Claims, N0 Drawings O :1 and wherein:  
  R is selected from the class consisting of hydrogen and lower alkyl;  
  R is any non-toxic organic substituent that is considered suitable in the cephalosporin art for substitution at the 3-position on the cephalosporin nucleus by linkage through the methylene group:  
  R is either hydrogen, non-toxic cation or an organic radical which forms a non-toxic ester with the carboxylic acid group: and n is a whole number from I through 4.  
  The substituents represented by R are preferably selected from the class consisting of hydrogen, hydroxy. acyloxy derived from a hydrocarbon carboxylic acid having up to eight carbon atoms (e.g. acetoxy, propionoyloxy, butanolyloxy, pentanolyoxy, etc.) and a quaternary ammonium group (eg l-pyridinium, lquinolinium, picolinium etc.). Other organic groups may also be used which are defined by a hydroxy group which is esterified with a carboxylic acid and in which the ester oxygens may be replaced by sulfur atoms: a primary, secondary or tertiary amine [e.g. (lower) alkylamino, di(lower)alkylamino, phenyl(lower) alkyl amino, N-heterocyclic tertiary amines etc]: a guanylmercapto group; and a mercapto group which has been etherfied. Illustrative of specific groups defined by R are those described in US. Pat. Nos. 3,483,197; 3,516,997: 3,533.20 3.536.698; 3,627,760: 3.637.678; 3,641,02l; 3,644,347; Examples of such groups defined by R include 5-thiothiazolyl. 5- .thiothiadiazolyl, 5-thiotriazolyl, pivaloyloxy. benzoylmereapto, diethylamino, 3-pyrrolidino, etc.  
  0 s. --c --C--NH CONH i (CH CONH2 Illustrative of cation and organic groups represented by R are: (l) a metallic cation such as sodium, potassium, calcium, aluminum, etc.: (2) a non-metallic cation formed from a tri(lo\ver) alkylamine or a di(lo\ver)alkylamine (e&#39;.g. triethylamine, procaine, dibenzylamine, N.N&#39;- dibenzylethylene diamine. l-ephenamine); (3) N- (lo\ver)alkyl piperidines (eg. N-methylpiperidine): (4) a heterocyclic quaternary ammonium group of aro- 1 CH2 R (II) cs 3-OR2 40 of smooth reaction with the carboxylic acid group to form an ester and is stable during reaction of a compound of formulae I and II with a compound containing an active hydrogen and such organic groups being removable chemically or enzymatically under mild condi tions without destruction of the penicillin or cephalosporin nucleus.  
  Illustrative of such organic groups are aryl, aryl(- lower) alkylene, cycloalkyl, substituted aryl(lower- )alkylene, halo(lower) alkyl. C -C tert(lower)alkyl, ar-  
  oyl-CH substituted aroyl-CH diarylmethylene, substituted diarylmethylene, phthalimido(lower) alkylene, succinimido(lower)alkylene, C to C,- tert-alkenyl. C to C tert-alkynyl. tri(lower)alkyl silyl, di(lower)silene esters as described in U.S. Pat. No. 3,654,266. 1,3,2  
  dioxaphosphoranyl, etc. A more detailed list of R groups is found in US. Pat. Nos, 3,249,622; 3,284,451; 3,466,275; 3,483,188: 3,485,819: 3,553,203; 3,588,602; 3,574,799; 3,621,011;  
 3,635,953; 3,654,266; 3,655,658; 3.660395: the disclosures of which are incorporated herein by reference.  
  Preferably R is selected from the group defined supra by hydrogen, a metallic cation and a non-metallic cation formed from a trialkylamine or a dialkylamine.  
 The term (lower)alkyl means a straight or branched chain having one through six carbon atoms (cg.  
 methyl, ethyl, isopropyl, hexyl, etc.).  
  The novel cephalosporins and penicillins of the present invention may be prepared in accordance with the following reaction sequence drofuran 11!. 10 ml) is added all at once. The mixture 2 n CONH condensing agent (III) (IV) u C-C -HN-.--  
  ca conn wherein R may be either The starting materials defined by formula IV are described in the literature [.I. Org. Chem.. 28. 3088 (1963)] or can be prepared by conventional prior art techniques. The starting materials of formula III are either commercially available such as o-APA or 7-ACA or their preparation is described in the prior art. in preparing the compounds of this invention. a carboxylic acid of formula [V is reacted with a carboxyl group activating reagent in the presence of a tertiary amine (e.g. triethyl amine. N-ethylpiperidine. etc.) in an inert anhydrous organic solvent at a temperature below +20C. As solvents. toluene. tetrahydrofuran. dichloromethane. chloroform. ethylenedichloride. etc. may be employed. After formation of the activated ester of the carboxylic acid starting material of IV. a compound of formula lll is added in the form ofa solution containing a strong base and a water/organic solvent mixture. The reaction of a compound of formula III with the activated ester is carried out at a temperature in the range of l 5 to about 40C. Illustrative of suitable carboxyl group activating reagents are carbonyldiimidazole. dicyclohexyl carbodiimide. isobutyl chloroform-ate. N- hydroxy succinimide. ethylchloroformate. etc.  
  The following examples are illustrative of the preparation of the compounds of the present invention.  
 EXAMPLE l 7-( Z-Carbamoyll oxaspiro [2.5 ]octane-Z-carboxamido )cephalosporanic acid To a suspension of Z-carbamoyll oxaspirol2.5]octane2-carboxylic) acid (0.50 g. 0.0025 moles) in dry tetrahydrofuran (10 ml) containing triethylamine (0.35 ml) at -l0C under nitrogen is added all at once isobutyl chloroformate (0.35 ml, 0.0050 moles). The mixture is stirred at l0C for 10 minutes and a solution of 7-ACA (0.68 g. 0.0025 moles) and triethylamine (0.35 ml) in water/tetrahyis stirred at 5C for one hour and 25C for one hour. The tetrahydrofuran is evaporated in vacuo 40C and a solution of 60 ml of water and 20 ml of ethyl acetate is added. The mixture is shaken thoroughly and the organic layer discarded. The aqueous layer is cooled to 5C. 60 ml of ethyl acetate is added and the mixture acidified to pH 2.9 with 10 percent aqueous hydrochloric acid. The organic layer is separated and the aqueous layer is extracted with 40 ml of ethyl acetate. The combined extract and organic layer are washed with water. brine and dried over anhydrous sodium sulfate. Evaporation in vacuo 40C leaves a glass. mp. 98l00C )t,,,,,,&#34; 3.00, 5.61. 5.90; NMR has sharp singlet at 2.02 ppm.  
 EXAMPLE 2 6-(2-Carbamoyl-l-oxaspiro[2.5]octane-2-carboxamido)penicillanic acid potassium salt To a solution of 2-carbamoyl-l-oxaspiro 2.5 octane- Z-carboxylic acid (0.50 g. 0.0025 moles) in dry dimethylformamide (5.0 ml) at room temperature is added carbonyl diimidazole (0.4] g. 0.0025 moles) under nitrogen. Carbon dioxide evolution begins immediately. After 30 minutes at room temperature the residual carbon dioxide is removed under vacuum. the mixture cooled to l0C and a solution of 6-APA (0.54 g, 0.0095 moles) in dry methylene chloride (10 ml) containing triethylamine (l.04 ml) is added all at once. After stirring 2 hours at room temperature. the methylene chloride is removed in vacuo at 40C, n-butanol (2.5 ml) is added then potassium ethyl hexanoate l.25 ml of a 2 M solution in n-butanol). After stirring 10 minutes, ethyl ether 100 ml) is added. the product filtered and dried in vacuo at room temperature to yield a tan solid, mp. 2l0-2l5C(d); h 5.63. 5.90. 618a; NMR has 151 and 1.59 ppm peaks.  
  3,879,381 6 EXAMPLE 3 In accordance with the procedure ofExample l. the the appropriate compounds of formula III with the curfollowing cephalosporins can be obtained by reacting boxlic acid of formula IV.  
 O= COR 2i i a d -OC-OCH3 K 3 s crr H 4 -cH 2 S- J-CH3 s c CH3 CH 3 -s HN(CH3)3 2 o o c CH3 S.&#39;L(CH3)3 3 EXAMPLE 4 In accordance with the procedure of Example 2. the following penicillins can be obtained by reacting the appropriate compounds of formula lll with the carboxylic acid of formula IV.  
  5 I A cc---NH (CH2) n (JOHN centration expressed in ,ug/ml. defined as the least amount of material that completely inhibits the test organism.  
  When the non-toxic cephalosporins and penicillins are employed pharmaceutically. i.e. as antibacterial -ca o (b O ll ca 0-cc (CH 3 The cephalosporin and penicillin compounds of this invention exhibit antibacterial activity in in vitro tests against gram positive and gram-negative microorganisms. These compounds are tested in vitro by the agar 60 agerits. they may be administered to a host afflicted with a bacterial infection alone or in combination with pharmaceutically acceptable carriers. the proportion of which is determined by the solubility and chemical nature of the compound. chosen route of administration and standard pharmacological practice. For example. they may be administered orally in the form of tablets or capsules containing such excipients as starch. milk. sugar. and so forth. They may be administered orally in the form of solution or they may be injected parenter-- ally. e.g. intramuscularly. For parenteral administration. they may be used in the form of a sterile solution or suspensions containing other solutes. for example. enough saline or glucose to make the solution isotonic.  
  The dosage of the present pharmacologically active agents will vary with the form of administration and the particular compound Chosen. Furthermore. it will vary with the particular subject under treatment. Generally. treatment is initiated with small dosage substantially less than the optimum dose of the compound. Thereafter. the dosage is increased by small increments until the optimum effect under the circumstances is reached. It will generally be found that when the composition is administered orally. the larger quantities of the active agent will be required to produce the same effect as a smaller quantity given parenterally.  
 What is claimed is:  
  l. A compound represented by the following formula:  
  R is selected from the class consisting of hydrogen and (lower) alkyl; R is selected from the class consisting of hydrogen. a metallic cation. a non-metallic cation formed from a tri(lower) alltylamine or di(lower- )alkylamine. a heterocyclic quaternary ammonium group of aromatic character containing nitrogen as the only heterocyclic atom selected from the class consisting of pyridinium. quinolinium and picolinium. an N- (lower)alkyl pipcridine and n is a whole number from 1 through 4.  
  2. A compound according to claim 1 wherein R is hydrogen.  
  3. A compound according to claim 1 wherein the quaternary ammonium group is pyridinium.  
  4. A compound according to claim 1 which is: 6-( Z-carbamoyll -o. :aspiro [2,510ctane-2- carboxamido) penicillanic acid.  
  5. The compound of claim 4 in the form of a nontoxic salt.