CA1133471A - Cephapirin salts with amino acids - Google Patents
Cephapirin salts with amino acidsInfo
- Publication number
- CA1133471A CA1133471A CA374,263A CA374263A CA1133471A CA 1133471 A CA1133471 A CA 1133471A CA 374263 A CA374263 A CA 374263A CA 1133471 A CA1133471 A CA 1133471A
- Authority
- CA
- Canada
- Prior art keywords
- cephapirin
- arginine
- salt
- salts
- lysine
- 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
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/14—Compounds having a nitrogen atom directly attached in position 7
- C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
- C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
- C07D501/24—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with hydrocarbon radicals, substituted by hetero atoms or hetero rings, attached in position 3
- C07D501/26—Methylene radicals, substituted by oxygen atoms; Lactones thereof with the 2-carboxyl group
- C07D501/34—Methylene radicals, substituted by oxygen atoms; Lactones thereof with the 2-carboxyl group with the 7-amino radical acylated by carboxylic acids containing hetero rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Cephalosporin Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
ABSTRACT OF THE DISCLOSURE
The invention relates to salts of cephapirin with an amino acid selected from the group consisting of L - lysine, L - arginine and acetylcy-steine. Said salts are obtained reacting an aqueous solution of cephapirin with an aqueous solution of an amino acid or its derivative, selected from the group consisting of L - lysine, L - arginine and acetylcysteine. To isolate the salt, the aqueous solution is submitted to lyophilization. The salts of the invention can be injected without causing such as pain as when the sodium salt of cephapirin is injected.
The invention relates to salts of cephapirin with an amino acid selected from the group consisting of L - lysine, L - arginine and acetylcy-steine. Said salts are obtained reacting an aqueous solution of cephapirin with an aqueous solution of an amino acid or its derivative, selected from the group consisting of L - lysine, L - arginine and acetylcysteine. To isolate the salt, the aqueous solution is submitted to lyophilization. The salts of the invention can be injected without causing such as pain as when the sodium salt of cephapirin is injected.
Description
1133~-71 The present invention relates to novel cephapirin salts with amino acids, said salts having antibiotic activity.
Cephapirin is a well known antibiotic, which is described in United States Patent 3,422,100 and in Japanese Patent publication 44-26107.
Cephapirin is usually administered parenterally as its sodium salt.
It is well known that sodium salts of this kind of antibiotics, and in particular of cephapirin, are painful on administration by injection.
It is an object of the present invention to provide new salts of cephapirin, which are injectable without inducing painful reactions when administered.
It is another object of the present invention to provide new salts of cephapirin which increase the absorption of the antibiotic substance and which, when absorbed by organism, are able to give and to join with the antibiotic activity ~hich is peculiar to cephapirin their own specific activity, which may have some interest from the pharmacological point of view.
The present invention provides salts of cephapirin with an amino acid ; selected from the group consisting of L - lysine, L - arginine and acetylcy-steine.
The salts can be obtained by reacting cephapirin with the amino acid or a reactive derivative thereof in aqueous solution. The reaction can be carried out at room temperature or at 0C, with stirring. The preferred method of isolating the salt from the aqueous solution is lyophilization.
In order that this invention may be readily available to and under-stood by those skilled in the art, methods of preparing each of the three salts, ~hich are obiects of the present invention, are described in the following e~amples, which are given merely in illustration of the present invention.
113~
Cephapirin lysinate having formula N/~-S-CH2-CONH' ~ ~
COOH. H2N-~CH2)4 -c~l-cooH
~ idistilled ~ater ~500 ml) and cephapirin as acid ~42.3 g, 0.1 mole) ~ere charged at 0C in a reaction vessel; pH was measured and was 3.5. A 50%
L - lysine base aqueous solution, containing 14.6 g ~0.1 mole) of L - lysine base, ~as added; the mixture was kept under stirrlng for 1 hour at 0C. A
complete dissolution ~as obtained and the pH value raised up to 8. Decolorizing car~on ~1.5 g~ was added to the resultant solutlon, ~hich ~as filtered through filter plates and poured into a tray, till a 1 cm layer ~as obtained~ The solution was then freezed at -40C and lyophilized. After 24 hours the result-ing material was discharged and screened; cephapirin lysinate ~54 g) was obtain-ed.
K~ 1.5%
TLC slngle product ~]D ~c = 1 , H20) : ~ 127 Micr~biological titer = 730 mcg/mg as cephapirin as acid.
Cephapirin arginine salt having formula -S-CH2-CO-NH ~ ~ S
N ~ CH20C0C113 NH2 COOH. H2N
C-NH-~CH2)3-CH-COOH
NH
~13347'1 Bidistilled water (450 ml) and cephapirin as acid (42.3 g , 0.1 mole) were charged at 0C in a reaction vessel; pH was 3.5.
A 10% L - arginine aqueous solution ~210 ml), containing 21 g of L - arginine, was added at 0C.
The reaction mixture was kept at 0C or 30 minutes, the pH value raised up to 8.5. Decolorizing carbon (5 g) was added to the resultant solution which was filtered through filter plates and poured into a tray, till a 1 cm layer was obtained. After pre-freezing at -45C, lyophilization was started. Lyophilization ended after 24 hours, the resulting material was dis-charged and screened; cephapirin arginine salt (55 g) was obtained.
Kp 1.2%
TLC single product ~]D ~c = 1 , HzO~ : + 120 ~icrobiological titer - 687 mcg/g as cephapirin as acid.
Cephapirin acetylcysteinate having formula HS-CH2-CH-COOH.N, ~ -S-CH2-CO-NH ~ S ~
NH-COCH3 0 ~ N ~ CH20COCH3 COOH
; ~ater ~500 ml) and cephapirin as acid ~42. g, 0.1 mole~ were charged in a reaction vessel. After cooling at O C, an aqueous solution containing 16.3 g ~0.1. mole) of acetylc~steine was added. A complete dissolution was o~tained the resultant pH was 2.1. The mixture was allowed to react for 1 hour;
then carbon ~3 g) was added. The resultant solution was filtered through filter plates, poured into a tray till a 1 cm layer was obtained and subjected to prefreezing.
At -40C solution was completely frozen and was lyophilized. L~ophili-zation was finished in 36 hours.
__3__ 11334~71 The resultant material was screened and cephapirin acetylcysteinate ~55.6 g) was obtained.
KF 1%
TLC single product [~ p ~c = 1 , H20 : + 118 Microbiological titer = 707 mcg/mg as cephapirin as acid.
-4~
Cephapirin is a well known antibiotic, which is described in United States Patent 3,422,100 and in Japanese Patent publication 44-26107.
Cephapirin is usually administered parenterally as its sodium salt.
It is well known that sodium salts of this kind of antibiotics, and in particular of cephapirin, are painful on administration by injection.
It is an object of the present invention to provide new salts of cephapirin, which are injectable without inducing painful reactions when administered.
It is another object of the present invention to provide new salts of cephapirin which increase the absorption of the antibiotic substance and which, when absorbed by organism, are able to give and to join with the antibiotic activity ~hich is peculiar to cephapirin their own specific activity, which may have some interest from the pharmacological point of view.
The present invention provides salts of cephapirin with an amino acid ; selected from the group consisting of L - lysine, L - arginine and acetylcy-steine.
The salts can be obtained by reacting cephapirin with the amino acid or a reactive derivative thereof in aqueous solution. The reaction can be carried out at room temperature or at 0C, with stirring. The preferred method of isolating the salt from the aqueous solution is lyophilization.
In order that this invention may be readily available to and under-stood by those skilled in the art, methods of preparing each of the three salts, ~hich are obiects of the present invention, are described in the following e~amples, which are given merely in illustration of the present invention.
113~
Cephapirin lysinate having formula N/~-S-CH2-CONH' ~ ~
COOH. H2N-~CH2)4 -c~l-cooH
~ idistilled ~ater ~500 ml) and cephapirin as acid ~42.3 g, 0.1 mole) ~ere charged at 0C in a reaction vessel; pH was measured and was 3.5. A 50%
L - lysine base aqueous solution, containing 14.6 g ~0.1 mole) of L - lysine base, ~as added; the mixture was kept under stirrlng for 1 hour at 0C. A
complete dissolution ~as obtained and the pH value raised up to 8. Decolorizing car~on ~1.5 g~ was added to the resultant solutlon, ~hich ~as filtered through filter plates and poured into a tray, till a 1 cm layer ~as obtained~ The solution was then freezed at -40C and lyophilized. After 24 hours the result-ing material was discharged and screened; cephapirin lysinate ~54 g) was obtain-ed.
K~ 1.5%
TLC slngle product ~]D ~c = 1 , H20) : ~ 127 Micr~biological titer = 730 mcg/mg as cephapirin as acid.
Cephapirin arginine salt having formula -S-CH2-CO-NH ~ ~ S
N ~ CH20C0C113 NH2 COOH. H2N
C-NH-~CH2)3-CH-COOH
NH
~13347'1 Bidistilled water (450 ml) and cephapirin as acid (42.3 g , 0.1 mole) were charged at 0C in a reaction vessel; pH was 3.5.
A 10% L - arginine aqueous solution ~210 ml), containing 21 g of L - arginine, was added at 0C.
The reaction mixture was kept at 0C or 30 minutes, the pH value raised up to 8.5. Decolorizing carbon (5 g) was added to the resultant solution which was filtered through filter plates and poured into a tray, till a 1 cm layer was obtained. After pre-freezing at -45C, lyophilization was started. Lyophilization ended after 24 hours, the resulting material was dis-charged and screened; cephapirin arginine salt (55 g) was obtained.
Kp 1.2%
TLC single product ~]D ~c = 1 , HzO~ : + 120 ~icrobiological titer - 687 mcg/g as cephapirin as acid.
Cephapirin acetylcysteinate having formula HS-CH2-CH-COOH.N, ~ -S-CH2-CO-NH ~ S ~
NH-COCH3 0 ~ N ~ CH20COCH3 COOH
; ~ater ~500 ml) and cephapirin as acid ~42. g, 0.1 mole~ were charged in a reaction vessel. After cooling at O C, an aqueous solution containing 16.3 g ~0.1. mole) of acetylc~steine was added. A complete dissolution was o~tained the resultant pH was 2.1. The mixture was allowed to react for 1 hour;
then carbon ~3 g) was added. The resultant solution was filtered through filter plates, poured into a tray till a 1 cm layer was obtained and subjected to prefreezing.
At -40C solution was completely frozen and was lyophilized. L~ophili-zation was finished in 36 hours.
__3__ 11334~71 The resultant material was screened and cephapirin acetylcysteinate ~55.6 g) was obtained.
KF 1%
TLC single product [~ p ~c = 1 , H20 : + 118 Microbiological titer = 707 mcg/mg as cephapirin as acid.
-4~
Claims (9)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for preparing a salt of cephapirin with an amino acid selected from the group consisting of L - lysine, L - arginine and acetylcy-steine which comprises reacting cephapirin with respectively L - lysine, L - arginine or acetylcysteine or a reactive derivative thereof.
2. A process according to claim 1 wherein cephapirin is reacted with the amino acid or reactive derivative thereof in aqueous solution, and the cephapir-in salt is solated from the aqueous solution by lyophilization.
3. A salt of cephapirin and an amino acid selected from the group consisting of L - lysine, L - arginine and acetylcysteine, when prepared by a process according to claim 1 or 2 or an obvious chemical equivalent thereof.
4. A process for preparing cephapirin lysinate which comprises reacting cephapirin with L - lysine in solution in distilled water, followed by lyophili-zation to obtain the required salt.
5. Cephapirin lysinate when prepared by a process according to claim 4 or an obvious chemical equivalent thereof.
6. A process for preparing cephapirin arginine which comprises reacting cephapirin with arginine in solution in distilled water, followed by lyophili-zation to obtain the required salt.
7. Cephapirin arginine salt when prepared by a process according to claim 6 or an obvious chemical equivalent thereof.
8. A process for preparing cephapirin acetylcysteinate which comprises reacting cephapirin with acetylcysteine in solution in distilled water followed by lyophilization to obtain the required salt.
9. Cephapirin acetylcysteinate when prepared by a process according to claim 8 or an obvious chemical equivalent thereof.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IT21097A/80 | 1980-04-01 | ||
| IT21097/80A IT1141406B (en) | 1980-04-01 | 1980-04-01 | SALTS OF CEPHAPIRINE WITH AMINO ACIDS |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1133471A true CA1133471A (en) | 1982-10-12 |
Family
ID=11176688
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA374,263A Expired CA1133471A (en) | 1980-04-01 | 1981-03-31 | Cephapirin salts with amino acids |
Country Status (10)
| Country | Link |
|---|---|
| JP (1) | JPS56152490A (en) |
| CA (1) | CA1133471A (en) |
| CH (1) | CH651050A5 (en) |
| DE (1) | DE3110190A1 (en) |
| FR (1) | FR2479228A1 (en) |
| GB (1) | GB2072675B (en) |
| IL (1) | IL62254A (en) |
| IT (1) | IT1141406B (en) |
| NL (1) | NL8101274A (en) |
| YU (1) | YU82781A (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA1242699A (en) * | 1985-02-01 | 1988-10-04 | Bristol-Myers Company | Cefbuperazone and derivatives thereof |
| US6566401B2 (en) * | 2001-03-30 | 2003-05-20 | The Board Of Trustees Of The Leland Stanford Junior University | N-acetylcysteine compositions and methods for the treatment and prevention of drug toxicity |
| CN102351885B (en) * | 2011-08-19 | 2012-08-22 | 深圳立健药业有限公司 | Method for preparing cefuroxime-L-arginine hydrate |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IL29235A (en) * | 1967-01-05 | 1971-10-20 | Bristol Myers Co | 7-(pyridylthioacetamido)cephalosporanic acid derivatives and their preparation |
| ES412429A1 (en) * | 1973-03-08 | 1976-01-01 | Gallardo Antonio Sa | Soluble salt of a cephalosporin |
| JPS5089517A (en) * | 1973-12-18 | 1975-07-18 | ||
| JPS51125714A (en) * | 1975-02-19 | 1976-11-02 | Banyu Pharmaceut Co Ltd | A process for preparing salts of an antibacterial compound |
| JPS557434A (en) * | 1978-06-30 | 1980-01-19 | Matsushita Electric Works Ltd | Preparation of woody cement board |
-
1980
- 1980-04-01 IT IT21097/80A patent/IT1141406B/en active
-
1981
- 1981-03-02 IL IL62254A patent/IL62254A/en unknown
- 1981-03-09 CH CH1586/81A patent/CH651050A5/en not_active IP Right Cessation
- 1981-03-16 NL NL8101274A patent/NL8101274A/en not_active Application Discontinuation
- 1981-03-17 DE DE19813110190 patent/DE3110190A1/en not_active Withdrawn
- 1981-03-25 FR FR8106002A patent/FR2479228A1/en active Granted
- 1981-03-27 JP JP4421681A patent/JPS56152490A/en active Pending
- 1981-03-30 YU YU00827/81A patent/YU82781A/en unknown
- 1981-03-31 GB GB8109978A patent/GB2072675B/en not_active Expired
- 1981-03-31 CA CA374,263A patent/CA1133471A/en not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| JPS56152490A (en) | 1981-11-26 |
| IT1141406B (en) | 1986-10-01 |
| IT8021097A0 (en) | 1980-04-01 |
| GB2072675B (en) | 1983-12-07 |
| IL62254A0 (en) | 1981-05-20 |
| YU82781A (en) | 1983-09-30 |
| CH651050A5 (en) | 1985-08-30 |
| FR2479228B1 (en) | 1985-04-26 |
| IL62254A (en) | 1984-09-30 |
| DE3110190A1 (en) | 1982-02-18 |
| GB2072675A (en) | 1981-10-07 |
| NL8101274A (en) | 1981-11-02 |
| FR2479228A1 (en) | 1981-10-02 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MKEX | Expiry |