US3925370A - 2-Thiocyanatoalkyl and aralkylcarboxamido cephalosporanic and penicillanic acid derivatives - Google Patents
2-Thiocyanatoalkyl and aralkylcarboxamido cephalosporanic and penicillanic acid derivatives Download PDFInfo
- Publication number
- US3925370A US3925370A US452085A US45208574A US3925370A US 3925370 A US3925370 A US 3925370A US 452085 A US452085 A US 452085A US 45208574 A US45208574 A US 45208574A US 3925370 A US3925370 A US 3925370A
- Authority
- US
- United States
- Prior art keywords
- cephalosporanic
- group
- aralkylcarboxamido
- thiocyanatoalkyl
- member selected
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
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- YGBFLZPYDUKSPT-MRVPVSSYSA-N cephalosporanic acid Chemical compound S1CC(COC(=O)C)=C(C(O)=O)N2C(=O)C[C@H]21 YGBFLZPYDUKSPT-MRVPVSSYSA-N 0.000 title claims description 10
- RBKMMJSQKNKNEV-RITPCOANSA-N penicillanic acid Chemical class OC(=O)[C@H]1C(C)(C)S[C@@H]2CC(=O)N21 RBKMMJSQKNKNEV-RITPCOANSA-N 0.000 title description 7
- 150000001875 compounds Chemical class 0.000 claims description 14
- 125000004432 carbon atom Chemical group C* 0.000 abstract description 6
- 239000003242 anti bacterial agent Substances 0.000 abstract description 5
- 229910052783 alkali metal Inorganic materials 0.000 abstract description 4
- 150000001340 alkali metals Chemical class 0.000 abstract description 4
- 125000004423 acyloxy group Chemical group 0.000 abstract description 3
- 125000003118 aryl group Chemical group 0.000 abstract description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- 229910052739 hydrogen Inorganic materials 0.000 description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- 230000001580 bacterial effect Effects 0.000 description 5
- 239000001257 hydrogen Substances 0.000 description 5
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- ZNNZYHKDIALBAK-UHFFFAOYSA-M potassium thiocyanate Chemical compound [K+].[S-]C#N ZNNZYHKDIALBAK-UHFFFAOYSA-M 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 241000894006 Bacteria Species 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 3
- 229940116357 potassium thiocyanate Drugs 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 229930186147 Cephalosporin Natural products 0.000 description 2
- 206010061217 Infestation Diseases 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 2
- 125000003668 acetyloxy group Chemical group [H]C([H])([H])C(=O)O[*] 0.000 description 2
- 230000000844 anti-bacterial effect Effects 0.000 description 2
- 229940124587 cephalosporin Drugs 0.000 description 2
- 150000001780 cephalosporins Chemical class 0.000 description 2
- 238000000921 elemental analysis Methods 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 150000002960 penicillins Chemical class 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 229920001817 Agar Polymers 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 244000063299 Bacillus subtilis Species 0.000 description 1
- 235000014469 Bacillus subtilis Nutrition 0.000 description 1
- 208000035143 Bacterial infection Diseases 0.000 description 1
- 241000588779 Bordetella bronchiseptica Species 0.000 description 1
- 241000588724 Escherichia coli Species 0.000 description 1
- 241000588747 Klebsiella pneumoniae Species 0.000 description 1
- 241000588653 Neisseria Species 0.000 description 1
- 241000588767 Proteus vulgaris Species 0.000 description 1
- 241000589517 Pseudomonas aeruginosa Species 0.000 description 1
- 241000531795 Salmonella enterica subsp. enterica serovar Paratyphi A Species 0.000 description 1
- 241000191967 Staphylococcus aureus Species 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000003929 acidic solution Substances 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 208000022362 bacterial infectious disease Diseases 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 239000002024 ethyl acetate extract Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 229940007042 proteus vulgaris Drugs 0.000 description 1
- JUJWROOIHBZHMG-UHFFFAOYSA-O pyridinium Chemical compound C1=CC=[NH+]C=C1 JUJWROOIHBZHMG-UHFFFAOYSA-O 0.000 description 1
- 238000013207 serial dilution Methods 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- -1 thiocyanatoacetamido Chemical group 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
Definitions
- R is a member selected from the group consisting of -H and aryl of 6 to [0 carbon atoms; R is a member selected from the group consisting of H. an alkali metal and NH,,; n is one of the integers l), l and 2; Y is 11 member selected from the group consisting of or, when taken with the 3-curboxy group,
- antibacterial agents of the formula:
- R is a member selected from the group consisting of -H and aryl of 6 to 10 carbon atoms
- R is a member selected from the group consisting of H, and alkali metal and NH n is one of the integers 0, 1 and 2
- R is I-l, alkanoyloxy of 2 to 6 carbon atoms
- the compounds of this invention are prepared by reaction of potassium thiocyanate with a 2-haloalkyl or aralkylcarboxamido cephalosporanic or penicillanic acid derivative in an inert organic solvent at ambient temperature.
- the preferred compounds are those of the formula:
- R is a member selected from the group consisting -H and phenyl; and Y is a member selected from the group consisting of wherein R is -H or acetoxy.
- the compounds of this invention are antibacterial agents of relatively broad spectrum activity in that they are effective inhibitors of both gram-positive and gramnegative bacteria. Their activity was established via the well known and scientifically recognized agar serial dilution testing technique whereby the minimum inhibitory concentration (MIC) required to achieve percent inhibition of various specific bacterial strains was determined. Thus, the compounds of this invention are useful in the fields of comparative pharmacology and in microbiology for the control and analysis of bacterial infestations.
- the antibacterial agents of this invention are used, in the manner and by the same means as other antibacterial cephalosporin and penicillin derivatives, for the control of bacterial infections.
- KSCN (0.19 gram, 2 millimole) and 7-(2- Bromoacetamido) cephalosporanic acid (0.79 gram, 2 millimole) were dissolved in acetone and the solution was stirred at room temperature overnight. After filtration of the salts the filtrate was evaporated, and the residue was dissolved in ethyl acetate. The ethyl acetate solution was washed with water and dried over anhydrous magnesium sulfate. Evaporation of the solvent gave 0.35 gram of residual solid which was triturated with diethyl ether and collected.
- R is hydrogen, an alkali metal or the ammonium ion.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Cephalosporin Compounds (AREA)
Abstract
OR, WHEN TAKEN WITH THE 3-CARBOXY
wherein R2 is -H, alkanoyloxy of 2 to 6 carbon atoms,
IN WHICH R1 is a member selected from the group consisting of -H and aryl of 6 to 10 carbon atoms; R3 is a member selected from the group consisting of -H, an alkali metal and -NH4; n is one of the integers 0, 1 and 2; Y is a member selected from the group consisting of
The antibacterial agents of this invention present the following structural formula:
wherein R2 is -H, alkanoyloxy of 2 to 6 carbon atoms,
IN WHICH R1 is a member selected from the group consisting of -H and aryl of 6 to 10 carbon atoms; R3 is a member selected from the group consisting of -H, an alkali metal and -NH4; n is one of the integers 0, 1 and 2; Y is a member selected from the group consisting of
The antibacterial agents of this invention present the following structural formula:
Description
United States Patent [1 1 Wei et al.
l l Z-THIOCYANATOALKYL AND ARALKYLCARBOXAMIDO CEPHALOSPORANIC AND PENICILLANIC ACID DERIVATIVES [75] Inventors: Peter H. L. Wei, Springfield; Ronald J. McCaully, Malvern, both of Pa.
[73] Assignee: American Home Products Corporation, New York, NY.
221 Filed: Mar. 18, 1974 21 Apple N0,;4s2,0ss
[52] US. Cl .v 260/243 C; 260/239]; 424/246;
[Sl] Int. CI..,...CO7D 50l/28; CU7D 499/62; A6l K 3l/545', A6lK 31/43 [58] Field of Search 260/243 C [56] References Cited OTHER PUBLICATIONS Sassiver et al, Advances in Applied Microbiology, Vol. I], pp. l63-236, D. Perlmzm, ed. Academic Press, N.Y, (I970) pp, I63, 170, 177 relied on. Koninklijke Nederlandische Gisten Spiritusfuhriek N.\/., Chemical Abstracts, Vol. 75, 88.62% (197! Primary Exuminer-Donaltl (i. Dzlus Axsixlan! IixumincrDiunu (it Rivers Attorney, Agent, or FirmRichurd K. Jackson [57] ABSTRACT The antibacterial agents oi this invention present the following structural formula:
[ Dec. 9, 1975 SCN in which R is a member selected from the group consisting of -H and aryl of 6 to [0 carbon atoms; R is a member selected from the group consisting of H. an alkali metal and NH,,; n is one of the integers l), l and 2; Y is 11 member selected from the group consisting of or, when taken with the 3-curboxy group,
4 Claims, N0 Drawings Z-THIOCYANATOALKYL AND ARALKYLCARBOXAMIDO CEPI-IALOSPORANIC AND PENICILLANIC ACID DERIVATIVES In accordance with this invention there is provided antibacterial agents of the formula:
SCN l I i s R -(CH -CHOONH f in which R is a member selected from the group consisting of -H and aryl of 6 to 10 carbon atoms; R is a member selected from the group consisting of H, and alkali metal and NH n is one of the integers 0, 1 and 2; Y is a member selected from the group consisting of H3 CH,R= X and CH,
wherein R is I-l, alkanoyloxy of 2 to 6 carbon atoms,
N Iii '1' -s s cn f -s {N H or, when taken with the 3-carboxy group,
The compounds of this invention are prepared by reaction of potassium thiocyanate with a 2-haloalkyl or aralkylcarboxamido cephalosporanic or penicillanic acid derivative in an inert organic solvent at ambient temperature. The products, as recovered frequently contain a small amount of solvent which is readily removed, if desired, by additional vacuum stripping.
The preferred compounds are those of the formula:
l S R -CHCONH SCN 0 i y C0 in which R is a member selected from the group consisting -H and phenyl; and Y is a member selected from the group consisting of wherein R is -H or acetoxy.
The compounds of this invention are antibacterial agents of relatively broad spectrum activity in that they are effective inhibitors of both gram-positive and gramnegative bacteria. Their activity was established via the well known and scientifically recognized agar serial dilution testing technique whereby the minimum inhibitory concentration (MIC) required to achieve percent inhibition of various specific bacterial strains was determined. Thus, the compounds of this invention are useful in the fields of comparative pharmacology and in microbiology for the control and analysis of bacterial infestations. The antibacterial agents of this invention are used, in the manner and by the same means as other antibacterial cephalosporin and penicillin derivatives, for the control of bacterial infections.
The following examples illustrate the preparation of representative cephalosporin and penicillin derivatives. The activity of each product is presented for those 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 antibacterial 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 bacteria are named followed by the specific strain and the concentration in micrograms per milliliter at which 100 percent inhibition occurred. The abbreviation for each bacterium are:
BA SU Bacillus subtilis BO BR Bordetella bronchiseptica ES CO Escherichia coli HE SP Herellea species KL IN Klebsiella pneumoniae NE CA Neisseria catarrhalis PR VU Proteus vulgaris PS AE Pseudomonas aeruginosa SA PA Salmonella paratyphi ST AU Staphylococcus aureus EXAMPLE I 7-( 2-thiocyanatoacetamido )cephalosporanic acid. KSCN (0.19 gram, 2 millimole) and 7-(2- Bromoacetamido) cephalosporanic acid (0.79 gram, 2 millimole) were dissolved in acetone and the solution was stirred at room temperature overnight. After filtration of the salts the filtrate was evaporated, and the residue was dissolved in ethyl acetate. The ethyl acetate solution was washed with water and dried over anhydrous magnesium sulfate. Evaporation of the solvent gave 0.35 gram of residual solid which was triturated with diethyl ether and collected.
Elemental Analysis for c,,,H,,N .o,s 1/2(C I-1,) O: Calcd: C, 43.13; H, 4.01; N, 10.77. Found: C, 42.75; H, 3.87; N, 10.93.
BA SU 6633 .976 B0 BR 4617 250 ES CO 9637 250 volume of pentane to afford the product as an amorphous solid.
Elemental Analysis for CHHI3N304S2 H O: Calcd: C, 4l.60; H, 4.62; N. ll.80. Found: C. 5 4l.l8; H, 4.70; N, ll.07.
7-(2-phenyl-2-thiocyanatoacetamido)cephalosporanic 5 acid.
BA SU HE SP NE (A PR VU SA PA ST AU ST AU ST AU 6633 7.8l 9955 250 8193 I 6896 250 H737 62.5 6538i L95 SMITH L95 (HP 125 What is claimed is:
I. A compound of the formula:
7 2-Bromo-Z-phenylacetamido )cephalosporanic acid (US. Pat. No. 3,338,897) (0.47 gram, l millimole) and potassium thiocyanate were stirred in acetone at room temperature over a period of hours.
BA SU KL PN SA PA ST All ST AU S'l' AU ST AU 6633 l003| 1 I737 6538? SMITH SLIM) 6-( 2-Thiocyanatoacetamido )penicillanic acid.
EXAMPLE Ill 6-(Z-Bromoacetamido)penicillanic acid potassium salt (CA 70, 68389i) (3.0 gram, 5.7 millimole) and potassium thiocyanate (0.72 gram. 5.7 millimole) were dissolved in l5 milliliters dimethylformamide and the solution stirred at room temperature for 2 hours. The undissolved salt was filtered and the filtrate was evaporated. The residue was dissolved in water and the aqueous solution was acidified with acetic acid. The acidic solution was extracted with ethyl acetate. The ethyl acetate extracts were combined and dried over anhydrous magnesium sulfate. The residual solid that was obtained after evaporation of the solvent was dissolved in diethyl ether and precipitated by addition to a large SON n -cucorm 2 (II-[ R 3 CO R 25 in which R is hydrogen or phenyl; R is hydrogen, alkanoyloxy of 2 to 6 carbon atoms or, when taken with the 3-carboxy group, N- 30 pyridinium',
and
R is hydrogen, an alkali metal or the ammonium ion. 2. A compound of claim I of the formula:
C 1 S R -CHCONH in which and R is hydrogen or phenyl R is hydrogen or acetoxy. 3. The compound of claim 1 which is 7-(2-thiocyanatoacetamido)cephalosporanic acid.
4. The compound of claim I which is 7-(2-phenyl-2- 50 thiocyanatoacetamido)cephalosporanic acid.
* ll i I
Claims (4)
1. A COMPOUND OF THE FORMULA:
2. A compound of claim 1 of the formula:
3. The compound of claim 1 which is 7-(2-thiocyanatoacetamido)cephalosporanic acid.
4. The compound of claim 1 which is 7-(2-phenyl-2-thiocyanatoacetamido)cephalosporanic acid.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US452085A US3925370A (en) | 1974-03-18 | 1974-03-18 | 2-Thiocyanatoalkyl and aralkylcarboxamido cephalosporanic and penicillanic acid derivatives |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US452085A US3925370A (en) | 1974-03-18 | 1974-03-18 | 2-Thiocyanatoalkyl and aralkylcarboxamido cephalosporanic and penicillanic acid derivatives |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| US3925370A true US3925370A (en) | 1975-12-09 |
Family
ID=23794964
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| US452085A Expired - Lifetime US3925370A (en) | 1974-03-18 | 1974-03-18 | 2-Thiocyanatoalkyl and aralkylcarboxamido cephalosporanic and penicillanic acid derivatives |
Country Status (1)
| Country | Link |
|---|---|
| US (1) | US3925370A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4328225A (en) * | 1979-07-19 | 1982-05-04 | Roussel Uclaf | Novel 7-(2-amino-4-thiazolyl)-acetamido-cephalosporanic acids |
| US4465668A (en) * | 1981-02-27 | 1984-08-14 | Asahi Kasei Kogyo Kabushiki Kaisha | Method for improving intestinal absorption of cephalosporin derivatives |
-
1974
- 1974-03-18 US US452085A patent/US3925370A/en not_active Expired - Lifetime
Non-Patent Citations (2)
| Title |
|---|
| Koninklijke Nederlandische Gisten Spiritusfabriek N.V., Chemical Abstracts, Vol. 75, 88,627s (1971) * |
| Sassiver et al., Advances in Applied Microbiology, Vol. 13, pp. 163-236, D. Perlman, ed., Academic Press, N.Y. (1970) pp. 163, 170, 177 relied on * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4328225A (en) * | 1979-07-19 | 1982-05-04 | Roussel Uclaf | Novel 7-(2-amino-4-thiazolyl)-acetamido-cephalosporanic acids |
| US4465668A (en) * | 1981-02-27 | 1984-08-14 | Asahi Kasei Kogyo Kabushiki Kaisha | Method for improving intestinal absorption of cephalosporin derivatives |
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