US3890311A - 7-(2-(1-(phenylsulfonyl)-2-pyrrolidinylthio)acetamino)cephalosporanic acids - Google Patents

7-(2-(1-(phenylsulfonyl)-2-pyrrolidinylthio)acetamino)cephalosporanic acids Download PDF

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US3890311A
US3890311A US452011A US45201174A US3890311A US 3890311 A US3890311 A US 3890311A US 452011 A US452011 A US 452011A US 45201174 A US45201174 A US 45201174A US 3890311 A US3890311 A US 3890311A
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pyrrolidinylthio
phenylsulfonyl
group
acid
acetamino
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US452011A
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Peter H L Wei
Carl Gochman
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Wyeth LLC
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American Home Products Corp
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/12—Oxygen or sulfur atoms

Definitions

  • YRR LID R is a member selected from the group consisting of PORANIC ACIDS -H, alkyl of l to 3 carbon atoms, halo, nitro, al- 5 kanoylamido of 2 to 6 carbon atoms and trifluorometh l.
  • the intermediate carboxylic acid is coupled with the R is a member selected from the group consisting of 7-amino cephalosporanic acid derivative by either the alkyl 0f 1 t0 3 Carbon atoms, halo, Him), dehydrative coupling or mixed anhydride technique kanoylamido of 2 to 6 carbon atoms, and trifluorocommonly employed in the production of amide linkmethyl; ages as in the field of polypeptide production.
  • the free R is a member selected from the group consisting of carboxyl group of the 7-amino cephalosporanic acid H and alkyl of l to 3 carbon atoms; derivative may be converted to a salt (e.g. alkali metal, is 11 member Selected mm the group ccmsisting of ammonium or trialkylamine) before or after the coulk n yl xy 0f 2 t0 6 carbon atOmS, pling reaction by techniques well known in the art.
  • a salt e.g. alkali metal, is 11 member Selected mm the group ccmsisting of ammonium or trialkylamine
  • M is a member selected from the group consisting of
  • the preferred anti-bacterial agents of this invention an alk "16ml 11nd from the standpoint of production economies are those
  • this invention provides intermediate of the formula: compounds for the production of the cephalosporin derivatives described in the foregoing paragraph.
  • the intermediate [l-(ph'enyl and substituted phenyl- R 2 sulfonyl)Lpyrrolidinylthiolacctic acids present the structural formula scacdiiii 8 t l r R (C 2 s l I y I 002'.”
  • R is a member selected from the group consisting of Cl, Br and NO- R is a member selected from the group consisting of -H and acetoxy; and M is a member selected from the group consisting of H, sodium and potassium.
  • cephalosporin derivatives of this invention have been found to be active anti-bacterial agents effective against gram-positive and gram-negative test organisms as well as penicillin resistant staphlococcus, in the well known and scientifically accepted agar serial dilution testing procedure.
  • the cephalosporin derivatives of this invention are useful in the fields of comparative pharmacology and in microbiology and for the treatment of bacterial infections amenable to treatment with penicillin and cephalosporin derivatives.
  • the intermediate carboxylic acids of this invention are useful for the preparation of the disclosed anti-bacterial ceph- 2O alosporin derivatives.
  • the following examples illustrate the preparation of representative intermediate carboxylic acids and representative cephalosporanic acid derivatives of those carboxylie acid reactants.
  • the cephalosporanic acid alkali metal salts were recovered in each instance, the free carboxylic acids being readily produced by known methods.
  • the small amount of residual solvent present in some of the products exemplified is readily removed, if desired by vacuum stripping.
  • the activity of each of the cephalosporin derivatives is provided for the specific bacterial strains against which the compound exemplified was active at or below 250 micrograms per milliliter.
  • the representative nature of the bacterial strains employed to demonstrate anti-bacterial activity are indicative of the broader applicability of the compounds of this invention in the control of bacterial infestations other than those specifically referred to in each of the following examples:
  • the title compound (m.p. l-l38C. from benzene) was prepared by a similar procedure to that described in Example I except that p-nitro-N-(4,4-die thoxybutyl)benzenc sulfonamide was utilized at room temperature.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Cephalosporin Compounds (AREA)

Abstract

The invention relates to 7-(2-(1-(phenyl or substituted phenylsulfonyl)-2-pyrrolidinylthio)-acetamido)cephalosporanic acids as anti-bacterial agents and the intermediate (1-(phenyl- or substituted phenyl-sulfonyl)-2-pyrrolidinylthio)acetic acids employed in their production.

Description

United States Patent 11 1 Wei et al.
[ 7-(2-[l-(PHENYLSULFONYLl-Z- PYRROLIDINYLTHIOlACETAMlNO)CEPH- ALOSPORANIC ACIDS [75] Inventors: Peter H. L. Wei, Springfield; Carl Gochman, Philadelphia. both of Pa.
[73] Assignee: American Home Products Corporation, New York, NY.
221 Filed: Mar. 18, 1974 1211 Appl. N0.: 452,011
[52] US. Cl 260/243 C; 260/239.6; 260/239.7;
260/326.42; 260/326.47; 424/246 [51] Int. Cl C07d 99/24 [58] Field of Search 260/243 C [56] References Cited UNITED STATES PATENTS 3.658.799 4/1972 Eardley et al 260/243 C June 17, 1975 Primary ExaminerDonald G. Daus Assistant Examiner-Anne Marie T. Tighe Attorney, Agent, or Firm-Richard K. Jackson; Vito Victor Bellino 5 7 ABSTRACT 3 Claims, No Drawings 7-(2-[1-(PHENYLSULFONYL)-2- in which YRR LID R is a member selected from the group consisting of PORANIC ACIDS -H, alkyl of l to 3 carbon atoms, halo, nitro, al- 5 kanoylamido of 2 to 6 carbon atoms and trifluorometh l.
DESCRIPTION OF THE lNVhNTlON The inl ermediate carboxylic acids are prepared by In accordance with this invention there is provided a reacting a thioglycolic acid with an appropriately subgroup of 7-(2-[ l-(phenyland substituted phenylsulfostituted N-(4,4-diethoxybutyl)benzene sulfonamide in nyl)-2-pyrrolidinylthiolacetamido)cephalosporanic the presence of a catalytic amount of a mineral acid,
acids and salts of the formula 10 thusly 0C .,ll R
R so,
sem'oui L, :r\ .I :1 v a "J T g l v f\.
. r -scHc0 ch 5: l (l N H l CO H in which The intermediate carboxylic acid is coupled with the R is a member selected from the group consisting of 7-amino cephalosporanic acid derivative by either the alkyl 0f 1 t0 3 Carbon atoms, halo, Him), dehydrative coupling or mixed anhydride technique kanoylamido of 2 to 6 carbon atoms, and trifluorocommonly employed in the production of amide linkmethyl; ages as in the field of polypeptide production. The free R is a member selected from the group consisting of carboxyl group of the 7-amino cephalosporanic acid H and alkyl of l to 3 carbon atoms; derivative may be converted to a salt (e.g. alkali metal, is 11 member Selected mm the group ccmsisting of ammonium or trialkylamine) before or after the coulk n yl xy 0f 2 t0 6 carbon atOmS, pling reaction by techniques well known in the art.
x,\ l i t l t h'- CH f'h or when I v taken M1 th the q-wm'bom group.
M is a member selected from the group consisting of The preferred anti-bacterial agents of this invention an alk "16ml 11nd from the standpoint of production economies are those In addition, this invention provides intermediate of the formula: compounds for the production of the cephalosporin derivatives described in the foregoing paragraph. The intermediate [l-(ph'enyl and substituted phenyl- R 2 sulfonyl)Lpyrrolidinylthiolacctic acids present the structural formula scacdiiii 8 t l r R (C 2 s l I y I 002'."
in wh ch R is a member selected from the group consisting of Cl, Br and NO- R is a member selected from the group consisting of -H and acetoxy; and M is a member selected from the group consisting of H, sodium and potassium.
The cephalosporin derivatives of this invention have been found to be active anti-bacterial agents effective against gram-positive and gram-negative test organisms as well as penicillin resistant staphlococcus, in the well known and scientifically accepted agar serial dilution testing procedure. Thus. the cephalosporin derivatives of this invention are useful in the fields of comparative pharmacology and in microbiology and for the treatment of bacterial infections amenable to treatment with penicillin and cephalosporin derivatives. The intermediate carboxylic acids of this invention are useful for the preparation of the disclosed anti-bacterial ceph- 2O alosporin derivatives.
The following examples illustrate the preparation of representative intermediate carboxylic acids and representative cephalosporanic acid derivatives of those carboxylie acid reactants. The cephalosporanic acid alkali metal salts were recovered in each instance, the free carboxylic acids being readily produced by known methods. The small amount of residual solvent present in some of the products exemplified is readily removed, if desired by vacuum stripping. The activity of each of the cephalosporin derivatives is provided for the specific bacterial strains against which the compound exemplified was active at or below 250 micrograms per milliliter. The representative nature of the bacterial strains employed to demonstrate anti-bacterial activity are indicative of the broader applicability of the compounds of this invention in the control of bacterial infestations other than those specifically referred to in each of the following examples:
NE CA Nt'isxcria calurrlialix BA SU Bacillus .rubtilis BO BR Bordelellu bmm'hisuplicu ES C O Escherichia 0011' SA PA Salmonella paralyplii KL PN Klelzriella pneunmniae ST AU Sluphyloc'm'cux aureus EXAMPLE l l-( p-Bromophenylsulfonyl)-2-pyrrolidinylthio]acetic Acid p-Bromo-N-(4,4-diethoxybutyl)benzene sulfonamide (3.8 grams, 0.01 milliliter) and thioglycolic acid (1.0 gram) were dissolved in dimethoxyethane and the solution was heated on a steam bath, in the presence of a few drops of 6N HCl solution for 3 hours. After removal of the solvent, the residue was dissolved in henzene. The benzene solution was extracted with a dilute NaHCO- solution and extracted several times with benzene. The benzene extracts were dried over anhydrous MgSO After the benzene was removed, the residue was recrystallized from a mixture of diethyl ether and pentane to afford the title compound, m.p. 8689C.
Elemental Analysis for H,,BrNo.s.
Calc'd: C. 37.89; H, 3.7]; N, 3118. Found: C, 38.05; H. 3. 2; N. 3.74.
EXAMPLE ll l-(p-Acetamidophenylsulfonyl)-2-pyrrolidinylthio]acetic Acid.
5 The title compound (m.p. l47l49C. from CH CN) was prepared by a similar procedure to that described in Example I except that p-acetamido-N- (4,4-diethoxybutyl)benzene sulfonamide was utilized at room temperature.
Elemental Analysis for C H,,.N ();,S
(alcdz C, 46.9]; H. 5.061N. 7.8 Found: C, 46.94; H. 5.09; 8 3
EXAMPLE 1]] l-(p-Nitrophenylsulfonyl)2-pyrrolidinylthio]acetic Acid.
The title compound (m.p. l-l38C. from benzene) was prepared by a similar procedure to that described in Example I except that p-nitro-N-(4,4-die thoxybutyl)benzenc sulfonamide was utilized at room temperature.
Elemental Analysis for C H N O S lIIZC H Calcd: C. 42.54: H. 3.l4: N, 7.94.
30 Found: C. 42.94; H, 4.26; N, 8.05.
EXAMPLE lV 7-(2-[1-(p-Bromophenylsulfonyl)-2- pyrroidinylthio]acetamido)cephalosporanic Acid.
To l-(p-bromophenylsulfonyl )-2-pyrrolidinylthio]acetic acid (0.76 gram, 2 millimole) in 4 milliliter dimethylformamide was added carbonyl diimidazole (0.32 gram, 2 millimole) in one portion. The mixture was stirred under nitrogen atmosphere for /2 hour and under vacuum for /2 hour. To the above solution in an ice bath was added a cold solution of 7-aminocephalos- 5 poranic acid (0.56 gram, 2 millimole) and triethylamine (020 gram) in methlene chloride. The solution was stirred in an ice bath for 1 hour and at room temperature for l hour. Some insoluble material was filtered off. The filtrate was evaporated under reduced pressure at approximately 30C. To the residue dissolved in methylene chloride was added one milliliter of a 2M potassium Z-ethyl hexanoate. Addition of anhydrous diethyl ether caused precipitation of a salt, which was collected, washed with diethyl ether and dried.
Elemental Analysis for C H .BrN .,o.s ,K:
7-(2-l l-(p-Nitrophenylsulfonyl )-2- pyrrolidinylthiolacetamido)cephalosporanic Acid.
The title compound was prepared by a procedure in which similar to that described in Example IV except that [1- I (p-nitrophenylsulfonyl)-2-pyrrolidinylthio]acetic acid R 15 a member Elected from the group conslstlng of was utilized. H, Cl, Br and NO 5 R is a member selected from the group consisting of l-l and acetoxy; and
El tlAl"fCHNOK.
men a 82 5 2 Z% r 5& '3??? M 15 a member selected from the group consisting of Found: c, 40.12; H. 3,67; N, 8.25 H, sodium and potassium. BA SU 6633 .244 B0 BR 4617 250 is (2 1?I 138;? 2235 2. The compound of claim 1 which is 7-(2-[1-(p- SA PA 1 1737 bromophenylsulfonyD-Z sT AU 6538p 244 pyrrolldmylthio]acetamido)cephalosporamc acid. ST AU SMITH .244 ST AU CHP .976 ST AU 53480 3. The compound of claim 1 which is 7-(2-[l-(p- I nitrophenylsulfonyl)-2- what clalmed pyrrolidinylthio]acetamido)cephalosporanic acid.
1. A compound of the formula:

Claims (3)

1. A COMPOUND OF THE FORMULA
2. The compound of claim 1 which is 7-(2-(1-(p-bromophenylsulfonyl)-2-pyrrolidinylthio)acetamido)cephalosporanic acid.
3. The compound of claim 1 which is 7-(2-(1-(p-nitrophenylsulfonyl)-2-pyrrolidinylthio)acetamido)cephalosporanic acid.
US452011A 1974-03-18 1974-03-18 7-(2-(1-(phenylsulfonyl)-2-pyrrolidinylthio)acetamino)cephalosporanic acids Expired - Lifetime US3890311A (en)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7078424B2 (en) 1998-06-03 2006-07-18 Gpi Nil Holdings, Inc. N-linked sulfonamides of N-heterocyclic carboxylic acids or carboxylic acid isosteres
US20110200695A1 (en) * 1999-06-11 2011-08-18 Annette Bianchi Gel composition for filling a breast milk duct prior to surgical excision of the duct or other breast tissue
US8182842B1 (en) 2010-11-10 2012-05-22 The United States Of America As Represented By The Administrator Of The National Aeronautics And Space Administration Physico-chemical-managed killing of penicillin-resistant static and growing gram-positive and gram-negative vegetative bacteria

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3658799A (en) * 1967-08-21 1972-04-25 Glaxo Lab Ltd Cephalosporin compounds

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3658799A (en) * 1967-08-21 1972-04-25 Glaxo Lab Ltd Cephalosporin compounds

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7078424B2 (en) 1998-06-03 2006-07-18 Gpi Nil Holdings, Inc. N-linked sulfonamides of N-heterocyclic carboxylic acids or carboxylic acid isosteres
US7459473B2 (en) 1998-06-03 2008-12-02 Glia Med, Inc. N-linked sulfonamides of N-heterocyclic carboxylic acids or carboxylic acid isosteres
US20110200695A1 (en) * 1999-06-11 2011-08-18 Annette Bianchi Gel composition for filling a breast milk duct prior to surgical excision of the duct or other breast tissue
US8182842B1 (en) 2010-11-10 2012-05-22 The United States Of America As Represented By The Administrator Of The National Aeronautics And Space Administration Physico-chemical-managed killing of penicillin-resistant static and growing gram-positive and gram-negative vegetative bacteria

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