Patent Publication Number: US-3879385-A

Title: 3-(Alpha-trifluoromethylarylacetamido)-1,4-cyclo(1,-carboxyl)alkylenethio)-azetidin-2-one derivatives

Description:
United States Patent 1 Teller et al.  
 [ S-(ALPHA- TRIFLUOROMETHYLARYLACETAMIDO l,4-CYCLO( l,-CARBOXYL)ALKYLENETHI- O)-AZETlDlN-2-ONE DERIVATIVES [75] lnventors: Daniel M, Teller, Devon; John H.  
 Sellstedt; Charles J. Gainosso, both of King of Prussia. all of Pa.  
 [73} Assignee: American Home Products Corporation, New York. NY.  
 [22] Filed: May 16, 1973 [21] Appl. No: 360,857  
 [52] U.S. Cl 260/243 C; 424/246; 260/239];  
  424/271 [5 l] Int. Cl. C07d 99/24; C07d 99/16 [58] Field of Search 260/243 C [451 Apr. 22, 1975 [56] References Cited UNITED STATES PATENTS 3.64l.02l 2/l972 Ryan 260/243 C Primary E.\&#39;mninerNich0las S. Rizzo Almrney, Agent. or FirmRichard K. Jackson [57] AISTRACT 3-( a-Trifluoromethylarylacetamido )-l ,4-[cyclo-( l carboxy)alkylenethioIazetidin-Z-one derivatives possessing antibacterial activity are produced by the reaction of 3.3,3-trifluoro-Z-phenylpropanoic acid or 3.3.- 3-trifluoro-2-p-hydroxyphenylpropanoic acid and a 3- amino- 1 ,4-[cyclo( l &#39;-carboxy)alkylenethio1-azetidin- 2-one derivative in the presence of a condensing agent or by conversion of the propanoic acid derivative to an acid halide.  
 3 Claims, No Drawings S-(ALPHA- TRIFLUOROMETHYLARYLACETAMIDO)-l,4- CYCLO(1,-CARBOXYL)ALKYLENETHIO)- AZETIDIN-Z-ONE DERIVATIVES BACKGROUND OF THE INVENTION Acylated 7aminocephalosporanic acid derivatives containing a chloroalkyl group in Z-position of the moiety are disclosed by Kujoshi Hattori in Japanese Pat. No. 29,258/69 (Derwent Report No. 41452).  
 DESCRIPTION OF THE INVENTION In accordance with this invention there is provided a group of azetidin-2-one derivatives which are active antibacterials. More specifically. the compounds ofthis invention may be generically termed 3-[a-trifluoromethylphenyl and p-hydroxyphenyl)acetamido1-l.4- [cyclo( l -carboxyl)alkylenethioll-azetidin-Z-one derivatives which present the structural formula:  
 COR  
 wherein R is a member selected from the group consisting of H and OI-I.  
 R is a member selected from the group consisting of -H and an alkali metal cation. and  
 Y is a member selected from the group consisting of CH (311 a C and CH C= CH in which R;, is --H. (lower)alkanoyloxy.  
  N-&#39;-N II II N-pyridim&#39;nm, SC C--CH and N N a: ll  
  The expression l.4-[cyclo( l &#39;-carboxy )alkylenethio. used in the generic name for the compounds of this invention. is intended to embrace the I-CZlI&#39;bOX) bridge member equation F3CCHC02H H NR condensing} F.3CCHCONHR1 agent in which R is H or Oh and the condensing agent is such as carbonyldiimidazole. dicyclohexylcarbodiimide. dicyclohexylcarbodiimide in the presence of N-hydroxysuccinimide or 1- hydroxybenzotriazole. isobutylchloroformate, and the like. These and similar condensing agents which are operable in the preparation of the antibacterial agents of this invention are presented in Spencer et. al.. J. Med. Chem. 15. pp 333-335 (1972); Klausner et.al.. Synthesis. pp 453-463 (197.2) and US. Pat. No. 3.338.896.  
  Alternatively, the a-trifluoromethylarylacetic acid precursor may be converted by known methods to an acid halide which is then used in aqueous medium to acylate the free amino group of either a tertiary amine salt or an alkali metal salt of the 3-amino azetidinone derivative. In addition. the oz-trifluoromethylarylacetic acid halide precursor may be used to react in organic.  
 solution with either a tertiary amine salt or a silylated. phosphorylated or saccharinated derivative of the 3- aminoazetidinone reactant. In each case. the protecting groups are readily removed by hydrolysis at the conclusion of the reaction.  
  The 3.3.3-trifluoro-2-phenyl (and phydroxyphenyl)propanoic acid reactants are prepared by the technique of Aaron et.al., J. Org. Chem. 32, pp. 27972803 (1967).  
  The compounds of this invention are antibacterial agents effective against gram-positive and gramnegative test organisms as well as penicillin resistant staphylococcus at an inhibitory concentration at or below 250 micrograms per milliliter using the well known and scientifically accepted agar serial dilution technique. Thus. the compounds of this invention are useful in the fields of comparative pharmacology and microbiology and may be used as growth promoters in animals and for the treatment of infections amenable to treatment with penicillins and cephalosporins.  
  The following examples are presented for purposes of illustrating the invention and are not to be construed as limitations upon the true scope of the contribution. The biological activity data presented at the conclusion of each example illustrate the compounds activity against specific bacteria of the designated strain in terms of the minimum inhibitory concentration of the compound in micrograms per milliliter to completely inhibit the test organism. The abbreviations for each bacteria are ST AL&#39; Staphylococcus aureus BA SL Bacillus suhtilis NE CA Neisseria catarrhalis HE SP Hcrellea species ES CO Escherichia coli PR \L&#39; Proteus vulgaris SA PA Salmonella paratyphi BO BR Bordetella hrochiseptica EN AE Enterohacter aerogenes ES lN Escherichia intermedia Kl. PN Klehsiella pneumoniae In the working examples. the expression ACA refers to aminocephalosporanic acid. ADCA refers to aminodesacetoxy-cephalosporanic acid. acid. and APA refers to aminopenicillanic acid.  
 EXAMPLE 1 7-(3.3.3-Trifluoro-Z-phenylpropionamido)cephalosporanic acid.  
  To a solution of 3.3.3-trifluoro-2-phenylpropanoic acid (0.5] g, 0.0025 moles) in dry dimethylformamide (3.0 ml) at room temperature is added carbonyl diimidazole (0.41 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 is cooled to lC. and a solution of 7-ACA (0.68 g. 0.00095 moles) in dry methylene chloride (l0 ml.) containing triethyl amine l .04 ml.) is added all at once. After stirring 2 hours at room temperature. the mixture was concentrated at below 40C. n-Butanol (2.5 ml.) is added. then potassium ethyl hexanoate (1.25 ml. of 2M solution in n-butanol). After stirring minutes. diethyl ether 100 ml.) is added. the product filtered and dried in vacuo at room temperature to yield a tan solid, mp. l50200C. (decomp.); x,,,,,,&#39;&#34;&#34; 5.52. 5.73. 6.20 a; NMR has 187 and 2.02 ppm methyl peaks.  
 3-Methyl-8-oxo-7-( 3,3 .3-trifluoro-2- 2.55 ppm peaks.  
 BA so 6633 7.81  
 ST AU 6538P 15.6  
 ST AU SMITH 15.6  
 ST AU 53-l80 62.5  
 ST AU CHP 125 x1. PN 10031 250 EXAMPLE 3 6-( 3.3 .3-Trifluoro-2-phenylpropionamido )penicillanic acid.  
  Using the procedure described in Example 1 but substituting .6-APA (0.54 g, 0.0025 moles) for 7-ACA gives the title compound. mp. l45160C. (decomp.); A,,,,,,&#39; 5.54. 6.20 (shoulder). 6.40-6.95 11.; NMR has 1.48 ppm and 1.52 ppm peaks.  
 ST AU 6538P .976 ST AU SMITH L BA SL&#39; 6633 l5.6 NE CA 8I93 15.6 HE SP 9955 31.3 ES CO 9637 I25 PR VU 6896 SA PA I I737 I25 ST AU CHP 125 ST AU 53-l80 I25 B0 BR 46l7 251) EN AE 130411 250 ES lN 65-l 250 KL PN 10031 250 What is claimed is: l. A compound of the formula:  
 F CCHCONHI/ S 3 0 N CH R 2 CO R in which R is H or -OH;  
 R&#39;- is H or an alkali metal cation; and  
 R&#34; is H. (lower)alkanoyloxy or N-pyridinium.  
  2. The compound of claim 1 which is 7-(3,3.3- trifluoro-2-phenylpropionamido)cephalosporanic acid and the alkali metal salts thereof.  
  3. The compound of claim 1 which is 3-methyl-8- oxo7-( 3 .3 .3-trifluoro-2-phenylpropionamido )-5-thia- 1-azabicyclo-[4.2.0]-oct-2-ene-2-carboxylic acid and the alkali metal salts thereof. 1