CA1114808A - Derivatives of 7-¬substituted oxyiminoacetamido| cephalosporins - Google Patents
Derivatives of 7-¬substituted oxyiminoacetamido| cephalosporinsInfo
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- CA1114808A CA1114808A CA304,644A CA304644A CA1114808A CA 1114808 A CA1114808 A CA 1114808A CA 304644 A CA304644 A CA 304644A CA 1114808 A CA1114808 A CA 1114808A
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-
- 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
- C07D501/36—Methylene radicals, substituted by sulfur atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
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- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Communicable Diseases (AREA)
- Pharmacology & Pharmacy (AREA)
- Oncology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
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- Veterinary Medicine (AREA)
- Cephalosporin Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Saccharide Compounds (AREA)
Abstract
A b s t r a c t Acyl derivatives of the general formula (I) , wherein R represents furyl, thienyl or phenyl optionally substituted by halogen, hydroxy, lower alkoxy or lower alkyl, R1 represents lower alkyl or aminocarbonylmethyl and X represents a group of the formula , or (a) (b) (c) in which one of the two symbols R2 and R3 or R4 and R5 represents hydrogen and the other represents lower alkyl, carboxymethyl or sulphomethyl, as well as salts of said compounds and hydrates of said salts and process for their manufacture.
The products have antibiotic, especially bacteri-cidal, activity.
The products have antibiotic, especially bacteri-cidal, activity.
Description
~ RAN 4410/118 The present invention relates to acyl derivati~es. More particularly, the invention is concerned with acyl derivatives, a process for the manufacture thereof and pharmaceutical preparations containing same.
The acyl derivatives provided by the present invention are compounds of the general for.mula R H H
R lON=C--CONH~
o~N~CH2~S--X ( I ) COOH
, wherein R represents furyl, thienyl or phenyl optionally substituted by halogen, hydroxy, lower alkoxy or lower alkyl, Rl represents ~lkyl or aminocarbonylmethyl and X represents a group of the formula R2 R4 o N~ ~ ~S~N~I~O ~NH2 (a) (b~ (c) in which one of the two s~mbols R2 and R3 or ~ and R5 represents hydrogen and the Mn/20.4.1978 . . .
' other represents lower aLkyl, carboxymethyl or sulphomethyl, r~ac~c~ C~ ?Cc~
~JI as well as~salts of said compounds and hydrates of said salts.
Examples of salts of the compounds of formula I are alkali metal salts such as the sodium and potassium salt, the ammonium salt, alkaline earth metal salts such as the calcium salt, salts with organic bases such as salts with amines (e.g. salts with N-ethyl-piperidine, procaine, dibenzylamine, N,N'-dibenzylethyl-ethylenediamine, alkylamines or diaLkylamines) as well as salts with amino acids (e.g~ salts with arginine or lysine). The salts can be mono-salts or di-salts. The second salt formation occurs at the tautomeric enol form of the triazine group (b), said form being acidic.
..
The compounds of formula I also form acid addition salts with organic or inorganic acids. Examples of such salts are hydrohalides (e.g. hydrochlorides, hydrobromides and hydro--iodides) as well as other mineral acid salts (e.g. sulphates, nitrates, phosphates and the like), alkylsulphonates and mono-arylsulphonates (e.g. ethanesulphonates, toluenesulphonates, benzenesulphonates and the like) and other organic acid salts (e.g. acetates, tartrates, maleates, citrates, benzoates, salicylates, ascorbates and the like).
The salts of the compounds of formula I can be hydrated.
The hydration can be effected in the course of the manufacturing process or can occur gradually as a consequence of the hygro-scopic properties of an initially anhydrous salt of a compound of formula I.
4~n~
The aforementioned lower alkyl groups are either straight--chain or branched-chain and can contain up to 7 carbon atoms (e.g. methyl, ethyl, n-propyl, isopropyl, n-pentyl and n-heptyl).
The lower alkoxy groups have an anaLogous significance. The halogen atom is rluorine, chlorine, bromine or iodine with chlorine and bromine being preferred.
Preferred gxoups denoted by R are furyl, thienyl and phenyl, especially furyl. Rl preferably represents methyl.
X preferably represents the group of ~ormula (c) or a group of formula (a) or (b) in which one of the two symbols R2 and R3 or R4 and R5 represents hydrogen and the other represents methyl.
Especially preferred groups denoted by X are the 1,2,5,6--tetrahydro-2-methyl-5,6-dioxo-as-triazin-3-yl group and the 1,4,5,6-tetrahydro-4-methyl-S,6-dioxo-as-triazin-3 yl group.
Preferred acyl derivatives provided by the present invention are the compound (R)-7-~2-(2-furyl)~2-~methoxyimino)-acetamido]-3- r [(1,2,5,6-tetrahydro-2-methyl-5,6-dioxo-as--tria~in-3-yl)thio]methyl_/-3-cephem-4-carboxylic acid and salts thereof as well as the hydrates of said salts.
The compounds of formula I as well as their salts and hydrates of said salts can exist in the syn-isomeric form R C--C O N H--s N
or in the anti-isomeric form . ~ ' .
R--C~ C O N H - -;
N
or as mixtures of these two forms. The syn-isomeric form is preferred as are mixtures in which the syn-isomeric form predominates.
According to the process provided by the present invention, the acyl derivatives aforesaid (i.e. the compounds of formula I
~ I ,oh~r~ c ~ ~ * c ~ c c ~f~ ~/G
~31 as well as their~salts and hydrates of said salts) are manufactured by (a) reacting a compound of the general formula H H
H2N~/~
10~ N ~ CH2 - S ~ X (II) COOH
, wherein X has the significance given earlier and the carboxy group can be present in protected form, with an acid of the general formula 15RlON = C - COOH (III) , wherein R and Rl have the significance given earlier, or with a reactive functional deriv?tLve of this acid and, where required, cleaving off the protecting group, or (b) reacting a compound of the general formula R ON C CONH H H S ( IV) ~CH2 Y
COOH
, wherQin R and Rl have the significance given earlier and Y re-presents a leaving group, with a thiol of the general formula HS - X (V) , wherein X has the significance given earlier, in the presence of water and (c) if desired, converting the reaction product into a salt or a hydrate of such a salt.
The carboxy groups present in the starting material of formula II can be protected if desired; for example, by ester-ification to ~orm a readily cleavable ester such as a silyl ester (e.g. the trimethylsilyl ester). The carboxy group can also be protected by salt formation with an inorganic base or a tertiary organic base such as triethylamine.
~ ~ -6-~ 7 ~ '~
Examples of reactive functional derivatives of acids of formula III include halides (i.e. chlorides, bromides and fluorides), azides, anhydrides, especially mixed anhydrides with strong acids, reactive esters, (e.g. N-hydroxysuccinimide esters) and amides (e.g. imidazolides).
Examples of leaving groups denoted by Y in compounds of formula IV include halogen atoms (e.g. chlorine, bromine or iodine)~ acyloxy sroups (e.g. lower alkanoyl groups such as acetoxy), lower alkylsulphonyloxy or arylsulphonyloxy groups (e.g. mesyloxy or tosyloxy) and the azido group.
The reaction of a compound of formula II with an acid of formula III or a reactive derivative thereof can be caxried out in a manner known per se. Thus, for example, a free acid of formula III can be condensed with one of the arorementioned esters of a compound of formula II in the presence of a carbodi-imide (e.g. dicyclohexylcarbodiimide) in an inert solvent (e.g.
ethyl acetate, acetonitrile, dioxan, chloroform, methylene chloride, benzene or dimethylformamide~ and the ester group can subsequently be cleaved off. Oxazolium salts (e.g. N-ethyl-S--phenyl-isoxazolium-3l-sulphonate) can be used in the place of carbodiimidesO
According to another embodiment, a salt of an acid of formula II (e.g. a trialkylammonium salt) is reacted with a reactive functional derivative of an acid of formula III as mentioned earlier in an inert solvent (e.gO one of the solvents specified earlier).
According to a further embodiment, an acid halide, preferably the acid chloride, of an acid of formula III is reacted with an amine of formula II. The reaction is preferably carried out in the presence of an acid-binding agent; for example, in the presence of aqueous alkali, preferably sodium hydroxide, or in the presence of an alkali metal carbonate such as potassium car-bonate, or in the presence of a lower-alkylated amine such as trimethylamine. Water is preferably used as the solvent, although the reaction can also be carried out in an aprotic organic solvent such as, for example, dimethylformamide, dimethyl sulphoxide or hexamethylphosphoric acid triamide.
The reaction of a compound of formula II with a compound of formula III or a reactive functional derivative thereof can be carried out conveniently at a temperature between about -40C
and room temperature, for example at about 0-10C.
The reaction of a compound of formula IV with a thiol of formula V can be carried out in a mannerknown per se; for example, at a temperature between about 40C and 80C. conveniently at about 60C, in water or in a buffer solution having a pH of about 6 to 7, preferably 6.5.
After completion of the reaction of a compound of formula II with an acid of formula III or a reactive derivative thereof : ~ -8-any protecting group present is eleaved off. Where the protecting group is a silyl group (silyl ester), this group ean be eleaved ofE espeeially readily by treating the reaction produet with water.
Where the earboxyl group is protected by salt formation (e.g. with triethylamine), then the cleavage of this salt-forming protecting group can be earried out by treatment with acid. In this case there can be used as the aeid, for example, hydroehloric acid, sulphuric acid, phosphoric acid or citric aeid.
The starting materials of formula II hereinbefore can be prepared by reaeting a eompound of the general Eormula ~H H
H2N ~ - ~ ~ (VI) /~ N CH2 Y
O
COOH
,wherein Y has the signifieanee given earlier, with a thiol of formula V hereinbefore. The reaetion ean be earried out under the same eonditions as deseribed earlier in connection with the reaetion of a eompound of formula IV with a thiol of formula V.
A syn/anti mixture of a compound of formula I which may be obtained can be separated into the corresponding syn- and anti--forms in the usual manner; for example, by recrystallisation or by chromatographic methods using a suitable solvent or 5 solvent mixture.
The compounds of formula I, their salts and the h~ydrates of said salts have antlbiotic, especially bactericidal, activlty.
They have a wide spectrum of activity against gram-positive and gram-negative microorganisms, including ~lactamase forming Staphylococci and various ~-lactamase forming gram-negatlve bacteria such as, for example, Haemophilus influenzae, Escherichia coli, Proteus species and Klebsiella species.
The compounds of formula I as well as their pharmaceutically acceptable salts and hydrates of said salts can be used for the treatment and prophylaxis of infectious diseases. In the case of adults a daily dosage of about l g to about 4 g may be administered. Administration by the paxenteral route is especially preferred.
In order to demonstrate the antimicrobial activity of the compounds provided by the present invention, the following representative compounds were tested:
Compound A: (7R)-7-[2~(2-furyl)-2-(methoxyimino)acetamido]-3--~ [(l,2,5,6-tetrahydro-2-methyl-5,6-dioxo-as--1:riazin-3~yl)thio]methyl /-3-cephem-4-carboxylic acid.
,:
Compound B: (7R)-7-[2-(2-~uryl)-2-(methoxyimino)acetamidol-3--/ [(l-amino-1,2 dihydro-2-oxo~4-pyr~midinyl)thio]-methyl /-3-cephem-4-carboxylic acid.
Compound C: (7R)-7-[2-(phenyl)--2 (methoxyimino)acetamido]-3--/ [(1,2,5,6-tetrahydro-2-methyl-5,6-dioxo~as--triazin-3-yl)thio:lmethyl 7-3-cephem-4-carboxylic acid.
Compound D: (7R)-7-[2-(2-furyl)-2-(methoxyimino)acetamido]-3---/ [(1,4,5,6-tetrahydro-4-methyl-5,6-dioxo-as--triazin-3-yl)thio]methyl 7~3-cephem-4-carboxylic acid.
Compound E: (7R)-7-[2-(methoxyimino)~2-(2-thienyl)acetamido]--3-/ [(1,2,5,6-tetrahydro-2-methyl-5,6-dioxo-as--triazin-3-yl)thio]methyl /-3-cephem-4-carboxyllc acid.
Compound F: (7R)-3-/ [(1-ethyl 1,4,5,6-tetrahydro-5,6-dioxo--as-triazin-3-yl)thio]methyl_7-7-~2-(2-furyl)-2--(methoxyimino)acetamido]-3-cephem-4-carboxylic acid.
Compound G: (7R)-7-/ 2-[(carbamoylmethoxy)imino]-2-(2-furyl)-acetamido_/-3- r [(1,4,5,6-tetrahydro-4-methyl-5,6--dioxo as triazin-3-yl)thio]methyl /-3-cephem~-4--carboxylic acid.
..
: ' , ' ~ '~: .
. ~ , .
: ~ ' . ~ "
~ 12 ~
Activity in vitro: Minimum Inhlbitory Concentration (~g/ml) :
- E C D E F G
Haemophilus influenzae strain 1 1.2 2.5 2.5 2.5 2.5 ~.5 5.0 strain 2 0.16 0.63 0.16 0.31 0.16 0.31 0.63 strain 3 O.L6 0.63 0.16 0.31 0~16 1.2 0.31 strain 4 0.16 0.:31 0.16 0.31 0.16 0.16 0.63 strain 5 0.08 0.31 0.08 0.16 0.08 0.08 0.31 strain 6 0.16 0.31 0.08 0.16 0.08 0.08 0.63 strain 7 0.08 0.31 0~08 0.16 0~08 0.16 0.63 . , _ _ _ _ __ Klebsiella pneumoniae 10 20 20 5 40 40 2.5 Escherichia coli strain 1 0.63 2.5 1.2 0.16 2.5 1.2 0.31 ~ strain 2 40 20 10 5 20 80 _ 15 ~ Proteus mirabilis strain 1 2.5 10 10 10 10 20 5 strain 2 5 40 20 20 20 40 10 Proteus vulgaris 5 40 10 1.2 10 20 1.2 ._ _ , ,_ . . ~
Proteus rettgeri 0.63 2.5 0.63 0.63 2.5 10 0.63 Staphylococcus aureus ATCC 6538 2.5 0.16 2.5 0.63 2.5 5 1.2 Penicillin resistant strain ¦ 5 1.2 2.5 0.63 2.5 5 1.2 Activity _n vivo Groups of 10 mice are infected intraperitoneally with an aqueous suspension of Proteus mirabilis. One hour after the infection the test compound is administered subcutaneously.
The number o~ surviving mice is determined on the 4th day.
Various dosages of test compound are administered and the dosage ~ 13 ~ 3~r~
at which 50% of the mice survive (CD50, mg/kg) is determined by interpolation.
. _ . ., Test compound A B C D E F G
CD50, mg/kg 0.09 3.0 0 60 0~70 1.15 0.850.80 Toxicity (micP, 24 hour values) Test compound A B
.. .._ .
LD50, mg/kg i.v. 500- 1000- 1000-500- 2000- 1000-~4000 1000 2000 20001000 40~0 2000 s.c. ~4000 ~4000 p40~ . ~=
Pharmaceutical preparations, preferably dry ampoules, can contain the compounds of formula I, their pharmaceutically acceptable salts ox hydrates of said salts, optionally in admixture with another therapeutically valuable substance.
Such compounds, salts or hydrates are conveniently mixed with pharmaceutical inorganic or organic inert carrier material, especially one which is suitable for parenteral administration, such as, fox example, water or gum arabic. The pharmaceutical preparations are preferably made up in liqu~d form (e.g. as solutions, suspensions or emulsions). ~he pharmaceutical preparations may be sterilised and/or may contain adjuvants such as preserving agents, stabilising agents, wetting agents, emulsifying agents, salts for varying the osmotic pressure or buffers.
- 14 ~
The foLlowing Exarnples illustrate the process provided by the present invention:
.
Example 1 Pre~aration of the sodium salt o ~
S _ ~ tet=~bydro-2-methyl-5,6--dioxo-as-triazin-3-yl)thio]methyl 7-3-cephem-4-carboxylic acid 5.06 g of 2-meth~xyimino-2-furyl-acetic acid (syn/anti mixture 80:20) are dissolved in 150 mL of benzene and treated at 5-10C while gassing with nitrogen with 4.2 ml of triethyl-amine, 2.6 ml of oxalyl chloride and 6 drops o~ dlmethylformamide.The mixture is stirred while gassing with nitrogen at 5-10C
for 1 hour and at 25C for 0.5 hour and then evaporated at 40C
in vacuo. The residue is suspended in 150 ml of acetone and treated at 0C with a solution of 11.2 g of (7R)-7-amino-3--desacetoxy-3 ~ ,5,6-tetrahydro-2-methyl-5,6-dioxo-as--triazin-3-yl)thio]cephalosporanic acid in 15~ ml of water, which has previously been adjusted to pH 7.5 using 2-N aqueous sodium hydroxide. The mixture is stirred at 0-10C for 2.5 hours under nitrogen, the pH being held between 7.5 and 8.0 by the addition of 2-N aqueous sodium hydroxide. 500 ml of ethyl acetate are then added and the pH is adjusted to 1.5 with 2-N
aqueous hydrochloric acid. After separating the organic phase, the aqueous ph~se is extracted once with ethyl acetate. The combined organic phases are washed twice wlth saturated aqueous sodium chloride solution, dried over sodi~m sulphate and concentrated t:o a volume of ca lO0 ml. Insolubles are filtered off and the orange coloured filtrate obtained is diluted with 1000 ml of e-ther. 'rhe amorphous (7R)-7-[2-(2-furyl)-2--(methoxyimino)acetamido]-3- ~[(1,2,5,6-tetrahydro-2-methyl-5,6-dioxo-as-triazin-3-yl)thio]methyl7 -3-cephem-4-carboxylic acid which thereby precipitates is filtered off under suction and washed with ether and with low-boiling petroleum ether.
The beige coloured product obtained is dissolved in 250 ml of ethyl acetate and insolubles are f'iltered off. The orange coloured filtrate is treated with 10 ml of a 2-N solution of sodium 2-ethylcaproate in ethyl acetate, whereby the sodium salt of (7R)-7-[2-(2-furyl)-2-(methoxyimino)acetamido]-3- ~[(1,2,5,6-tetrahydro-2-methyl-5,6-dioxo-as-triazin-3-yl)thiolmethy,17 -3-cephem-4-carboxylic acid precipitates. This is filtered off under suction, washed with ethyl acetate and low-boiling petroleum ether and dried at 25C in vacuo for 2 days. The product obtained is a beige coloured powder (syn/anti mixture 80:20); [~]D = -108.6 (c = 0.5 in water); Rf value = 0.10 [thin-layer chromatography on Kieselgel*-F254-finished plates in butanol/glacial acetic acid/water (4:1:1), visualisation with ultraviolet light].
Example 2 Preparation of the sodium salt of (7R)-7-[2-(2-Euryl)-2--(meth_xyimino?acetamido]-3- ~ (1-amino-1,2-dihydro-2-oxo-4--pyrimidinyl)thio]metllyl ~-3-cephem-4-carboxylic acid This salt is prepared in a manner analogous to that described in Example 1 from 3.4 g of 2-methoxyimino-2-furyl-acetic acid and 7.11 g of (7R)-7-amino-3-desacetoxy-3-[(1-amino-1,2-dihydro-2-oxo-4-pyrimidinyl)thio]cephalosporanic *Kieselgel is a generic term meaning silicagel. - l-S~ -.
.:
.
- 16 ~ ~ 'rv"3 acid. The product is a beige powder (syn/anti mixture 70:30);
Rf value = 0.40 [thin-layer chromatography on Kieselgel F254--finished plates in butanol/glacial acetic acid/water (4:1:1), visualisation with ultraviolet light].
Example 3 ~ of ~7R?-7-~2-(phenyl)-2-(methoxy-imino)acetamido~-3-/ [(1,2,5,6-tetrahydro-2-methyl-5,6-dioxo--as-triazin-3-yl)thio]methyl 7-3-cephem-4-carbo~lic acid This salt is prepared in a manner analogous to that described in Example 1 from 1.8 g of 2-methoxyimino-phenyl-- --acetic acid (syn/anti mixture 90:10) and 3.75 g of (7R)-7--amino~3-desacetoxy-3-[(1,2,5,6-tetrahydro-2~methyl-5,6-dioxo--as-triazin-3-yl)thio]cephalosporanic acid. The product is a beige powder (syn/anti mixture 90:10); [a]20 = -135 (c = 0.5 in water); Rf value - 0.17 [thin-layer chromatography on Kieselgel-F254-finished plates in butanol/glacial acetic acid~
water (4:1:1), visualisation with ultraviolet light].
Example 4 Pre aration of the sodium salt of (7R)-7-[2-(2-furyl)-2-P _ , , ~
-5,6.-dioxo-as-triazin-3-yl)thio]methyl 7-3-cephem 4-carboxylic acid This salt is prepared in a manner analogous to that described in Example 1 from 3.4 g of 2-methoxyimino-2-furyl--acetic acid (syn/an=i mlxture 80:20) and 7.46 g oi ~7R~-7-, -amino-3-desacetoxy-3-~(1,4,5,6-tetrahydro-4-methyl-5,6-dioxo-as triazin-3-yl)thio]cephalosporanic acid. The product is a beige powder (syn/anti mixture B0:20); Ca]20 3 -44 (c = 0.5 in water); Rf value = 0.34 ~thin-layer chromato~raphy on Kieselgel--F254-finished plates in butanol/glacial acetic acid/water (4:1:1), visualisation with ultraviolet light].
Example 5 Preparation of the _ odium salt of (7R) -?- ~2-(methoxyimino)-2--(2-thienyl)acetamido]-3-/ ~(1,2,5,6-tetrah~dro-2-met~1-5,6--dioso-as-triazin-3-yl)thio]methyl 7-3-cephem-4-carboxylic ac d This salt is prepared in a manner analogous to that described in Example 1 from 1.85 g of 2-methoxyimino-2-thienyl--acetic acid (syn/anti mixture ca 70:30) and 3.71 g of (7R)-7--amino 3-desacetoxy-3-~(1,2,5,6-tetrahydro-2-methyl-5,6-dioxo--as-triazin-3-yl)thio]-cephalosporanic acid. The product is a beige powder (syn/anti mixture ca 70 30); [~20 = -128.2 (c = 0.5 in water); R~ value = 0.21 ~thin-layer chromatography on Kieselgel-F254-finished plates in butanol/glacial acetic acid/
water (4:1:1), visualisation with ultraviolet light].
Exam~le 6 Preparation of the disodium salt of (7R)-7-[2-(2-furyl)-2-.-(methoxyimino)acetamido]-3-/ ~(2~5-dihydro-2-methyl-5-oxo-6--hydroxy-as-triazin-3-yl)thio]methyl 7-3-cephem-~-carboxylic acid This salt is prepared in a manner analogous to that described in Example 1 from 10.12 g of 2-methoxyimino-2-furyl-- 18 ~
-acetic acid (syn isomer) and 18.7 g of (7R)-7~amino-3--desacetoxy-3-[(1,2,5,6 tetrahydro-2-methyl-5,6-dioxo-as--triazin-3-yl)thio]-cephalosporanic acid. ~or the salt--formation there are used 20 ml (2 equivalents) of a 2-N
S solution of sodium 2-ethylcaproate in ethyl acetate. The product is an almost colourless powder (sy~ isomer); [a]20 =
-141.6 (c ~ 0.5 in water); Rf value = 0.14 [thin~layer chromatography on Kieselgel-F254-finished plates in butanol/
glacial acetic acid/wa~er (4:~:1), visualisa~ion with ultraviolet light].
Example 7 Preparation of the sodium salt of (7R)-3~ ethyl-1,4,5,6-tetrahydro-5,6-dioxo-as-triazin-3-yl)thio]methyl 7-7-~2-(2--furyl)-2-(methoxyimino)acetamido]-3-cephem-4-carboxylic acid ... . __ . ~ _ . . . . _. ... . . _ . . .
This salt is prepared in a manner analogous to that described in Example 1 from 1.69 g of 2-methoxyimino-2-furyl--acetic acid (syn isomer) and 3.85 5 o (7R)-7-amino-3--desacetoxy-3-[(1-ethyl-1,4,5,6-tetrahydro-5,6 dioxo-as--triazin-3-yl)thio]-cephalosporanic acid. The product is a beige powder (syn/anti mixture ca. 70:30); [a]20 = -47.2 (c = 0.5 in water); Rf value = 0.47 [thin-layer chromato-graphy on Kieselgel-F254-finished plates in butanol/
~lacial acetic acid/water (4:1:1), visualisation with ultraviolet light].
-- 19 ~
Example 8 Pre~aration of the sodium salt of (7R)-7-/ 2-~(carbamoylmethoxy)-imino]-2-(2-furyl)acetamido 7-3-/ [(1,4 ! 5,6-tetrahydro-4-methyl-.
-5,6-dioxo-as-triazin-3-yl)thio]methyl 7-3-cephem-4-carboxylic a _ 9.76 g of r a ~(carbamoylmethoxy)imino]furfuryl 7cephalo-sporin sodium salt (syn/anti mixture ca 70:30) are suspended together with 4.77 g of 1,4,5,6-tetrahydro-4-methyl-5,6-dioxo--3-mercapto-as-triazine in 200 ml of phosphate buffer having a pH of 6.4. The pH is adjusted to 6.4 using l-N sodium hydroxide while gassing with nitrogen, whereby a dark solution is obtained.
This solution is stirred at pH 6.4-6.5 for 6 hours at 55-60C
while gassing with nitrogen, the p~ being held constant with the ~ aid of an autotitrator with the addition of l-N sodium hydroxide.
lS The solution is cooled to 0-5C and the pH is adjusted to 2 with 2-N hydrochloric acid, whereby the product separates out as the acid. This is filtered off under suction, washed with ice/water and dried at 40C overnight in vacuo. The product is obtained in the form of the crude acid. For purification, this crude acid is dissolved in 150 ml of methanol and the solution is boiled with active carbon for 2 minutes. The mixture is filtered through a ~luted filter and the orange coloured filtrate is concentrated in vacuo. The resin which thereby precipitates is separated and rejected. The concentrated methanolic solution is poured into ether. The acid which thereby precipitates is filtered off under suction and washed with ether and with low-boiling petroleum ether.
The product is obtained in the form of the pure acid which, for &
conversion into the sodium salt, is dis$;olved in 100 ml of methanol and treated with S ml o~ a 2-N solution of sodium
The acyl derivatives provided by the present invention are compounds of the general for.mula R H H
R lON=C--CONH~
o~N~CH2~S--X ( I ) COOH
, wherein R represents furyl, thienyl or phenyl optionally substituted by halogen, hydroxy, lower alkoxy or lower alkyl, Rl represents ~lkyl or aminocarbonylmethyl and X represents a group of the formula R2 R4 o N~ ~ ~S~N~I~O ~NH2 (a) (b~ (c) in which one of the two s~mbols R2 and R3 or ~ and R5 represents hydrogen and the Mn/20.4.1978 . . .
' other represents lower aLkyl, carboxymethyl or sulphomethyl, r~ac~c~ C~ ?Cc~
~JI as well as~salts of said compounds and hydrates of said salts.
Examples of salts of the compounds of formula I are alkali metal salts such as the sodium and potassium salt, the ammonium salt, alkaline earth metal salts such as the calcium salt, salts with organic bases such as salts with amines (e.g. salts with N-ethyl-piperidine, procaine, dibenzylamine, N,N'-dibenzylethyl-ethylenediamine, alkylamines or diaLkylamines) as well as salts with amino acids (e.g~ salts with arginine or lysine). The salts can be mono-salts or di-salts. The second salt formation occurs at the tautomeric enol form of the triazine group (b), said form being acidic.
..
The compounds of formula I also form acid addition salts with organic or inorganic acids. Examples of such salts are hydrohalides (e.g. hydrochlorides, hydrobromides and hydro--iodides) as well as other mineral acid salts (e.g. sulphates, nitrates, phosphates and the like), alkylsulphonates and mono-arylsulphonates (e.g. ethanesulphonates, toluenesulphonates, benzenesulphonates and the like) and other organic acid salts (e.g. acetates, tartrates, maleates, citrates, benzoates, salicylates, ascorbates and the like).
The salts of the compounds of formula I can be hydrated.
The hydration can be effected in the course of the manufacturing process or can occur gradually as a consequence of the hygro-scopic properties of an initially anhydrous salt of a compound of formula I.
4~n~
The aforementioned lower alkyl groups are either straight--chain or branched-chain and can contain up to 7 carbon atoms (e.g. methyl, ethyl, n-propyl, isopropyl, n-pentyl and n-heptyl).
The lower alkoxy groups have an anaLogous significance. The halogen atom is rluorine, chlorine, bromine or iodine with chlorine and bromine being preferred.
Preferred gxoups denoted by R are furyl, thienyl and phenyl, especially furyl. Rl preferably represents methyl.
X preferably represents the group of ~ormula (c) or a group of formula (a) or (b) in which one of the two symbols R2 and R3 or R4 and R5 represents hydrogen and the other represents methyl.
Especially preferred groups denoted by X are the 1,2,5,6--tetrahydro-2-methyl-5,6-dioxo-as-triazin-3-yl group and the 1,4,5,6-tetrahydro-4-methyl-S,6-dioxo-as-triazin-3 yl group.
Preferred acyl derivatives provided by the present invention are the compound (R)-7-~2-(2-furyl)~2-~methoxyimino)-acetamido]-3- r [(1,2,5,6-tetrahydro-2-methyl-5,6-dioxo-as--tria~in-3-yl)thio]methyl_/-3-cephem-4-carboxylic acid and salts thereof as well as the hydrates of said salts.
The compounds of formula I as well as their salts and hydrates of said salts can exist in the syn-isomeric form R C--C O N H--s N
or in the anti-isomeric form . ~ ' .
R--C~ C O N H - -;
N
or as mixtures of these two forms. The syn-isomeric form is preferred as are mixtures in which the syn-isomeric form predominates.
According to the process provided by the present invention, the acyl derivatives aforesaid (i.e. the compounds of formula I
~ I ,oh~r~ c ~ ~ * c ~ c c ~f~ ~/G
~31 as well as their~salts and hydrates of said salts) are manufactured by (a) reacting a compound of the general formula H H
H2N~/~
10~ N ~ CH2 - S ~ X (II) COOH
, wherein X has the significance given earlier and the carboxy group can be present in protected form, with an acid of the general formula 15RlON = C - COOH (III) , wherein R and Rl have the significance given earlier, or with a reactive functional deriv?tLve of this acid and, where required, cleaving off the protecting group, or (b) reacting a compound of the general formula R ON C CONH H H S ( IV) ~CH2 Y
COOH
, wherQin R and Rl have the significance given earlier and Y re-presents a leaving group, with a thiol of the general formula HS - X (V) , wherein X has the significance given earlier, in the presence of water and (c) if desired, converting the reaction product into a salt or a hydrate of such a salt.
The carboxy groups present in the starting material of formula II can be protected if desired; for example, by ester-ification to ~orm a readily cleavable ester such as a silyl ester (e.g. the trimethylsilyl ester). The carboxy group can also be protected by salt formation with an inorganic base or a tertiary organic base such as triethylamine.
~ ~ -6-~ 7 ~ '~
Examples of reactive functional derivatives of acids of formula III include halides (i.e. chlorides, bromides and fluorides), azides, anhydrides, especially mixed anhydrides with strong acids, reactive esters, (e.g. N-hydroxysuccinimide esters) and amides (e.g. imidazolides).
Examples of leaving groups denoted by Y in compounds of formula IV include halogen atoms (e.g. chlorine, bromine or iodine)~ acyloxy sroups (e.g. lower alkanoyl groups such as acetoxy), lower alkylsulphonyloxy or arylsulphonyloxy groups (e.g. mesyloxy or tosyloxy) and the azido group.
The reaction of a compound of formula II with an acid of formula III or a reactive derivative thereof can be caxried out in a manner known per se. Thus, for example, a free acid of formula III can be condensed with one of the arorementioned esters of a compound of formula II in the presence of a carbodi-imide (e.g. dicyclohexylcarbodiimide) in an inert solvent (e.g.
ethyl acetate, acetonitrile, dioxan, chloroform, methylene chloride, benzene or dimethylformamide~ and the ester group can subsequently be cleaved off. Oxazolium salts (e.g. N-ethyl-S--phenyl-isoxazolium-3l-sulphonate) can be used in the place of carbodiimidesO
According to another embodiment, a salt of an acid of formula II (e.g. a trialkylammonium salt) is reacted with a reactive functional derivative of an acid of formula III as mentioned earlier in an inert solvent (e.gO one of the solvents specified earlier).
According to a further embodiment, an acid halide, preferably the acid chloride, of an acid of formula III is reacted with an amine of formula II. The reaction is preferably carried out in the presence of an acid-binding agent; for example, in the presence of aqueous alkali, preferably sodium hydroxide, or in the presence of an alkali metal carbonate such as potassium car-bonate, or in the presence of a lower-alkylated amine such as trimethylamine. Water is preferably used as the solvent, although the reaction can also be carried out in an aprotic organic solvent such as, for example, dimethylformamide, dimethyl sulphoxide or hexamethylphosphoric acid triamide.
The reaction of a compound of formula II with a compound of formula III or a reactive functional derivative thereof can be carried out conveniently at a temperature between about -40C
and room temperature, for example at about 0-10C.
The reaction of a compound of formula IV with a thiol of formula V can be carried out in a mannerknown per se; for example, at a temperature between about 40C and 80C. conveniently at about 60C, in water or in a buffer solution having a pH of about 6 to 7, preferably 6.5.
After completion of the reaction of a compound of formula II with an acid of formula III or a reactive derivative thereof : ~ -8-any protecting group present is eleaved off. Where the protecting group is a silyl group (silyl ester), this group ean be eleaved ofE espeeially readily by treating the reaction produet with water.
Where the earboxyl group is protected by salt formation (e.g. with triethylamine), then the cleavage of this salt-forming protecting group can be earried out by treatment with acid. In this case there can be used as the aeid, for example, hydroehloric acid, sulphuric acid, phosphoric acid or citric aeid.
The starting materials of formula II hereinbefore can be prepared by reaeting a eompound of the general Eormula ~H H
H2N ~ - ~ ~ (VI) /~ N CH2 Y
O
COOH
,wherein Y has the signifieanee given earlier, with a thiol of formula V hereinbefore. The reaetion ean be earried out under the same eonditions as deseribed earlier in connection with the reaetion of a eompound of formula IV with a thiol of formula V.
A syn/anti mixture of a compound of formula I which may be obtained can be separated into the corresponding syn- and anti--forms in the usual manner; for example, by recrystallisation or by chromatographic methods using a suitable solvent or 5 solvent mixture.
The compounds of formula I, their salts and the h~ydrates of said salts have antlbiotic, especially bactericidal, activlty.
They have a wide spectrum of activity against gram-positive and gram-negative microorganisms, including ~lactamase forming Staphylococci and various ~-lactamase forming gram-negatlve bacteria such as, for example, Haemophilus influenzae, Escherichia coli, Proteus species and Klebsiella species.
The compounds of formula I as well as their pharmaceutically acceptable salts and hydrates of said salts can be used for the treatment and prophylaxis of infectious diseases. In the case of adults a daily dosage of about l g to about 4 g may be administered. Administration by the paxenteral route is especially preferred.
In order to demonstrate the antimicrobial activity of the compounds provided by the present invention, the following representative compounds were tested:
Compound A: (7R)-7-[2~(2-furyl)-2-(methoxyimino)acetamido]-3--~ [(l,2,5,6-tetrahydro-2-methyl-5,6-dioxo-as--1:riazin-3~yl)thio]methyl /-3-cephem-4-carboxylic acid.
,:
Compound B: (7R)-7-[2-(2-~uryl)-2-(methoxyimino)acetamidol-3--/ [(l-amino-1,2 dihydro-2-oxo~4-pyr~midinyl)thio]-methyl /-3-cephem-4-carboxylic acid.
Compound C: (7R)-7-[2-(phenyl)--2 (methoxyimino)acetamido]-3--/ [(1,2,5,6-tetrahydro-2-methyl-5,6-dioxo~as--triazin-3-yl)thio:lmethyl 7-3-cephem-4-carboxylic acid.
Compound D: (7R)-7-[2-(2-furyl)-2-(methoxyimino)acetamido]-3---/ [(1,4,5,6-tetrahydro-4-methyl-5,6-dioxo-as--triazin-3-yl)thio]methyl 7~3-cephem-4-carboxylic acid.
Compound E: (7R)-7-[2-(methoxyimino)~2-(2-thienyl)acetamido]--3-/ [(1,2,5,6-tetrahydro-2-methyl-5,6-dioxo-as--triazin-3-yl)thio]methyl /-3-cephem-4-carboxyllc acid.
Compound F: (7R)-3-/ [(1-ethyl 1,4,5,6-tetrahydro-5,6-dioxo--as-triazin-3-yl)thio]methyl_7-7-~2-(2-furyl)-2--(methoxyimino)acetamido]-3-cephem-4-carboxylic acid.
Compound G: (7R)-7-/ 2-[(carbamoylmethoxy)imino]-2-(2-furyl)-acetamido_/-3- r [(1,4,5,6-tetrahydro-4-methyl-5,6--dioxo as triazin-3-yl)thio]methyl /-3-cephem~-4--carboxylic acid.
..
: ' , ' ~ '~: .
. ~ , .
: ~ ' . ~ "
~ 12 ~
Activity in vitro: Minimum Inhlbitory Concentration (~g/ml) :
- E C D E F G
Haemophilus influenzae strain 1 1.2 2.5 2.5 2.5 2.5 ~.5 5.0 strain 2 0.16 0.63 0.16 0.31 0.16 0.31 0.63 strain 3 O.L6 0.63 0.16 0.31 0~16 1.2 0.31 strain 4 0.16 0.:31 0.16 0.31 0.16 0.16 0.63 strain 5 0.08 0.31 0.08 0.16 0.08 0.08 0.31 strain 6 0.16 0.31 0.08 0.16 0.08 0.08 0.63 strain 7 0.08 0.31 0~08 0.16 0~08 0.16 0.63 . , _ _ _ _ __ Klebsiella pneumoniae 10 20 20 5 40 40 2.5 Escherichia coli strain 1 0.63 2.5 1.2 0.16 2.5 1.2 0.31 ~ strain 2 40 20 10 5 20 80 _ 15 ~ Proteus mirabilis strain 1 2.5 10 10 10 10 20 5 strain 2 5 40 20 20 20 40 10 Proteus vulgaris 5 40 10 1.2 10 20 1.2 ._ _ , ,_ . . ~
Proteus rettgeri 0.63 2.5 0.63 0.63 2.5 10 0.63 Staphylococcus aureus ATCC 6538 2.5 0.16 2.5 0.63 2.5 5 1.2 Penicillin resistant strain ¦ 5 1.2 2.5 0.63 2.5 5 1.2 Activity _n vivo Groups of 10 mice are infected intraperitoneally with an aqueous suspension of Proteus mirabilis. One hour after the infection the test compound is administered subcutaneously.
The number o~ surviving mice is determined on the 4th day.
Various dosages of test compound are administered and the dosage ~ 13 ~ 3~r~
at which 50% of the mice survive (CD50, mg/kg) is determined by interpolation.
. _ . ., Test compound A B C D E F G
CD50, mg/kg 0.09 3.0 0 60 0~70 1.15 0.850.80 Toxicity (micP, 24 hour values) Test compound A B
.. .._ .
LD50, mg/kg i.v. 500- 1000- 1000-500- 2000- 1000-~4000 1000 2000 20001000 40~0 2000 s.c. ~4000 ~4000 p40~ . ~=
Pharmaceutical preparations, preferably dry ampoules, can contain the compounds of formula I, their pharmaceutically acceptable salts ox hydrates of said salts, optionally in admixture with another therapeutically valuable substance.
Such compounds, salts or hydrates are conveniently mixed with pharmaceutical inorganic or organic inert carrier material, especially one which is suitable for parenteral administration, such as, fox example, water or gum arabic. The pharmaceutical preparations are preferably made up in liqu~d form (e.g. as solutions, suspensions or emulsions). ~he pharmaceutical preparations may be sterilised and/or may contain adjuvants such as preserving agents, stabilising agents, wetting agents, emulsifying agents, salts for varying the osmotic pressure or buffers.
- 14 ~
The foLlowing Exarnples illustrate the process provided by the present invention:
.
Example 1 Pre~aration of the sodium salt o ~
S _ ~ tet=~bydro-2-methyl-5,6--dioxo-as-triazin-3-yl)thio]methyl 7-3-cephem-4-carboxylic acid 5.06 g of 2-meth~xyimino-2-furyl-acetic acid (syn/anti mixture 80:20) are dissolved in 150 mL of benzene and treated at 5-10C while gassing with nitrogen with 4.2 ml of triethyl-amine, 2.6 ml of oxalyl chloride and 6 drops o~ dlmethylformamide.The mixture is stirred while gassing with nitrogen at 5-10C
for 1 hour and at 25C for 0.5 hour and then evaporated at 40C
in vacuo. The residue is suspended in 150 ml of acetone and treated at 0C with a solution of 11.2 g of (7R)-7-amino-3--desacetoxy-3 ~ ,5,6-tetrahydro-2-methyl-5,6-dioxo-as--triazin-3-yl)thio]cephalosporanic acid in 15~ ml of water, which has previously been adjusted to pH 7.5 using 2-N aqueous sodium hydroxide. The mixture is stirred at 0-10C for 2.5 hours under nitrogen, the pH being held between 7.5 and 8.0 by the addition of 2-N aqueous sodium hydroxide. 500 ml of ethyl acetate are then added and the pH is adjusted to 1.5 with 2-N
aqueous hydrochloric acid. After separating the organic phase, the aqueous ph~se is extracted once with ethyl acetate. The combined organic phases are washed twice wlth saturated aqueous sodium chloride solution, dried over sodi~m sulphate and concentrated t:o a volume of ca lO0 ml. Insolubles are filtered off and the orange coloured filtrate obtained is diluted with 1000 ml of e-ther. 'rhe amorphous (7R)-7-[2-(2-furyl)-2--(methoxyimino)acetamido]-3- ~[(1,2,5,6-tetrahydro-2-methyl-5,6-dioxo-as-triazin-3-yl)thio]methyl7 -3-cephem-4-carboxylic acid which thereby precipitates is filtered off under suction and washed with ether and with low-boiling petroleum ether.
The beige coloured product obtained is dissolved in 250 ml of ethyl acetate and insolubles are f'iltered off. The orange coloured filtrate is treated with 10 ml of a 2-N solution of sodium 2-ethylcaproate in ethyl acetate, whereby the sodium salt of (7R)-7-[2-(2-furyl)-2-(methoxyimino)acetamido]-3- ~[(1,2,5,6-tetrahydro-2-methyl-5,6-dioxo-as-triazin-3-yl)thiolmethy,17 -3-cephem-4-carboxylic acid precipitates. This is filtered off under suction, washed with ethyl acetate and low-boiling petroleum ether and dried at 25C in vacuo for 2 days. The product obtained is a beige coloured powder (syn/anti mixture 80:20); [~]D = -108.6 (c = 0.5 in water); Rf value = 0.10 [thin-layer chromatography on Kieselgel*-F254-finished plates in butanol/glacial acetic acid/water (4:1:1), visualisation with ultraviolet light].
Example 2 Preparation of the sodium salt of (7R)-7-[2-(2-Euryl)-2--(meth_xyimino?acetamido]-3- ~ (1-amino-1,2-dihydro-2-oxo-4--pyrimidinyl)thio]metllyl ~-3-cephem-4-carboxylic acid This salt is prepared in a manner analogous to that described in Example 1 from 3.4 g of 2-methoxyimino-2-furyl-acetic acid and 7.11 g of (7R)-7-amino-3-desacetoxy-3-[(1-amino-1,2-dihydro-2-oxo-4-pyrimidinyl)thio]cephalosporanic *Kieselgel is a generic term meaning silicagel. - l-S~ -.
.:
.
- 16 ~ ~ 'rv"3 acid. The product is a beige powder (syn/anti mixture 70:30);
Rf value = 0.40 [thin-layer chromatography on Kieselgel F254--finished plates in butanol/glacial acetic acid/water (4:1:1), visualisation with ultraviolet light].
Example 3 ~ of ~7R?-7-~2-(phenyl)-2-(methoxy-imino)acetamido~-3-/ [(1,2,5,6-tetrahydro-2-methyl-5,6-dioxo--as-triazin-3-yl)thio]methyl 7-3-cephem-4-carbo~lic acid This salt is prepared in a manner analogous to that described in Example 1 from 1.8 g of 2-methoxyimino-phenyl-- --acetic acid (syn/anti mixture 90:10) and 3.75 g of (7R)-7--amino~3-desacetoxy-3-[(1,2,5,6-tetrahydro-2~methyl-5,6-dioxo--as-triazin-3-yl)thio]cephalosporanic acid. The product is a beige powder (syn/anti mixture 90:10); [a]20 = -135 (c = 0.5 in water); Rf value - 0.17 [thin-layer chromatography on Kieselgel-F254-finished plates in butanol/glacial acetic acid~
water (4:1:1), visualisation with ultraviolet light].
Example 4 Pre aration of the sodium salt of (7R)-7-[2-(2-furyl)-2-P _ , , ~
-5,6.-dioxo-as-triazin-3-yl)thio]methyl 7-3-cephem 4-carboxylic acid This salt is prepared in a manner analogous to that described in Example 1 from 3.4 g of 2-methoxyimino-2-furyl--acetic acid (syn/an=i mlxture 80:20) and 7.46 g oi ~7R~-7-, -amino-3-desacetoxy-3-~(1,4,5,6-tetrahydro-4-methyl-5,6-dioxo-as triazin-3-yl)thio]cephalosporanic acid. The product is a beige powder (syn/anti mixture B0:20); Ca]20 3 -44 (c = 0.5 in water); Rf value = 0.34 ~thin-layer chromato~raphy on Kieselgel--F254-finished plates in butanol/glacial acetic acid/water (4:1:1), visualisation with ultraviolet light].
Example 5 Preparation of the _ odium salt of (7R) -?- ~2-(methoxyimino)-2--(2-thienyl)acetamido]-3-/ ~(1,2,5,6-tetrah~dro-2-met~1-5,6--dioso-as-triazin-3-yl)thio]methyl 7-3-cephem-4-carboxylic ac d This salt is prepared in a manner analogous to that described in Example 1 from 1.85 g of 2-methoxyimino-2-thienyl--acetic acid (syn/anti mixture ca 70:30) and 3.71 g of (7R)-7--amino 3-desacetoxy-3-~(1,2,5,6-tetrahydro-2-methyl-5,6-dioxo--as-triazin-3-yl)thio]-cephalosporanic acid. The product is a beige powder (syn/anti mixture ca 70 30); [~20 = -128.2 (c = 0.5 in water); R~ value = 0.21 ~thin-layer chromatography on Kieselgel-F254-finished plates in butanol/glacial acetic acid/
water (4:1:1), visualisation with ultraviolet light].
Exam~le 6 Preparation of the disodium salt of (7R)-7-[2-(2-furyl)-2-.-(methoxyimino)acetamido]-3-/ ~(2~5-dihydro-2-methyl-5-oxo-6--hydroxy-as-triazin-3-yl)thio]methyl 7-3-cephem-~-carboxylic acid This salt is prepared in a manner analogous to that described in Example 1 from 10.12 g of 2-methoxyimino-2-furyl-- 18 ~
-acetic acid (syn isomer) and 18.7 g of (7R)-7~amino-3--desacetoxy-3-[(1,2,5,6 tetrahydro-2-methyl-5,6-dioxo-as--triazin-3-yl)thio]-cephalosporanic acid. ~or the salt--formation there are used 20 ml (2 equivalents) of a 2-N
S solution of sodium 2-ethylcaproate in ethyl acetate. The product is an almost colourless powder (sy~ isomer); [a]20 =
-141.6 (c ~ 0.5 in water); Rf value = 0.14 [thin~layer chromatography on Kieselgel-F254-finished plates in butanol/
glacial acetic acid/wa~er (4:~:1), visualisa~ion with ultraviolet light].
Example 7 Preparation of the sodium salt of (7R)-3~ ethyl-1,4,5,6-tetrahydro-5,6-dioxo-as-triazin-3-yl)thio]methyl 7-7-~2-(2--furyl)-2-(methoxyimino)acetamido]-3-cephem-4-carboxylic acid ... . __ . ~ _ . . . . _. ... . . _ . . .
This salt is prepared in a manner analogous to that described in Example 1 from 1.69 g of 2-methoxyimino-2-furyl--acetic acid (syn isomer) and 3.85 5 o (7R)-7-amino-3--desacetoxy-3-[(1-ethyl-1,4,5,6-tetrahydro-5,6 dioxo-as--triazin-3-yl)thio]-cephalosporanic acid. The product is a beige powder (syn/anti mixture ca. 70:30); [a]20 = -47.2 (c = 0.5 in water); Rf value = 0.47 [thin-layer chromato-graphy on Kieselgel-F254-finished plates in butanol/
~lacial acetic acid/water (4:1:1), visualisation with ultraviolet light].
-- 19 ~
Example 8 Pre~aration of the sodium salt of (7R)-7-/ 2-~(carbamoylmethoxy)-imino]-2-(2-furyl)acetamido 7-3-/ [(1,4 ! 5,6-tetrahydro-4-methyl-.
-5,6-dioxo-as-triazin-3-yl)thio]methyl 7-3-cephem-4-carboxylic a _ 9.76 g of r a ~(carbamoylmethoxy)imino]furfuryl 7cephalo-sporin sodium salt (syn/anti mixture ca 70:30) are suspended together with 4.77 g of 1,4,5,6-tetrahydro-4-methyl-5,6-dioxo--3-mercapto-as-triazine in 200 ml of phosphate buffer having a pH of 6.4. The pH is adjusted to 6.4 using l-N sodium hydroxide while gassing with nitrogen, whereby a dark solution is obtained.
This solution is stirred at pH 6.4-6.5 for 6 hours at 55-60C
while gassing with nitrogen, the p~ being held constant with the ~ aid of an autotitrator with the addition of l-N sodium hydroxide.
lS The solution is cooled to 0-5C and the pH is adjusted to 2 with 2-N hydrochloric acid, whereby the product separates out as the acid. This is filtered off under suction, washed with ice/water and dried at 40C overnight in vacuo. The product is obtained in the form of the crude acid. For purification, this crude acid is dissolved in 150 ml of methanol and the solution is boiled with active carbon for 2 minutes. The mixture is filtered through a ~luted filter and the orange coloured filtrate is concentrated in vacuo. The resin which thereby precipitates is separated and rejected. The concentrated methanolic solution is poured into ether. The acid which thereby precipitates is filtered off under suction and washed with ether and with low-boiling petroleum ether.
The product is obtained in the form of the pure acid which, for &
conversion into the sodium salt, is dis$;olved in 100 ml of methanol and treated with S ml o~ a 2-N solution of sodium
2-ethylcaproate in ethyl acetate. A small amount o~ insolubles is filtered off and the orange coloured filtrate is concentrated at 40C in vacuo. This concentrated solution is added to ethanoL, whereby the sodium salt precipitates. This salt is filtered off under suction, washed with ethanol and low-boiling petroleum ~ther and dried at 40C overnight in vacuo, There i5 obtained the sodium salt of (7R)-7-/ 2-~(carbamoylmethoxy)-imino]-2-(2-furyl)acetamido 7-3- r [(1,4,5,6-tetrahydro-4-methyl--5,6-dioxo-as-triazin-3--yl)thio]methyl 7-3-cephem-4-carboxylic acid in the fo~n of a beige powder (syn/anti mixture ca 70:30);
[a]20 = -30.1 (c = 1 in water)j Rf value = 0.29 [thin-layer chromatography on Kieselgel-F254-finished plates in butanol/
glacial acetic acid/water (4:1:1), visualisation with ultra~iolet lig,ht].
When the starting materials used in the preceding paragraph are replaced by equivalent amounts f r a-[(methoxy)-imino]furfuryl /cephalosporin and 1,2,5,6-tetrahydro-2-methyl--5,6-dioxo-3-mercapto-as-triazine, then there is obtained under otherwise similar conditions the sodium salt of (7R)-7-[2-(2--furyl)-2-(methoxyimino)acetamido]-3-/ [(1,2,5,6-tetrahydro-2--methyl 5,6-dLoxo-as-triazin-3-yl)thio]methyl /-3-cephem-4 -carboxylic acid. This salt is identical with the salt obtained according to Example 1.
The folLowing Example illustrates the preparation of a pharmaceutical preparation provided by the present invention:
Preparation of dry ampoules for intramuscular admin.istration A lyophiLisate of l g of the sodium salt of (7R)-7-[2-(2-furyl)-2-methoxyimino)acetamido]-3-/ [(1,2,5,6-tetrahydro-2-S -methyl-5,6-dioxo-as-triazin-3-yl)thlo]methyl 7-3-cephem--carboxylic acid is prepared in the usual manner and filled into an ampoule. Prior to the administration, the latter is treated with 2.5 ml of a 2% aqueous lidocaine hydrochloride solution.
[a]20 = -30.1 (c = 1 in water)j Rf value = 0.29 [thin-layer chromatography on Kieselgel-F254-finished plates in butanol/
glacial acetic acid/water (4:1:1), visualisation with ultra~iolet lig,ht].
When the starting materials used in the preceding paragraph are replaced by equivalent amounts f r a-[(methoxy)-imino]furfuryl /cephalosporin and 1,2,5,6-tetrahydro-2-methyl--5,6-dioxo-3-mercapto-as-triazine, then there is obtained under otherwise similar conditions the sodium salt of (7R)-7-[2-(2--furyl)-2-(methoxyimino)acetamido]-3-/ [(1,2,5,6-tetrahydro-2--methyl 5,6-dLoxo-as-triazin-3-yl)thio]methyl /-3-cephem-4 -carboxylic acid. This salt is identical with the salt obtained according to Example 1.
The folLowing Example illustrates the preparation of a pharmaceutical preparation provided by the present invention:
Preparation of dry ampoules for intramuscular admin.istration A lyophiLisate of l g of the sodium salt of (7R)-7-[2-(2-furyl)-2-methoxyimino)acetamido]-3-/ [(1,2,5,6-tetrahydro-2-S -methyl-5,6-dioxo-as-triazin-3-yl)thlo]methyl 7-3-cephem--carboxylic acid is prepared in the usual manner and filled into an ampoule. Prior to the administration, the latter is treated with 2.5 ml of a 2% aqueous lidocaine hydrochloride solution.
Claims (16)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. Process for the manufacture of acyl derivatives of the general formula (I) , wherein R represents furyl, thienyl or phenyl optionally substituted by halogen, hydroxy, lower alkoxy or lower alkyl, R1 represents lower alkyl or aminocarbonylmethyl and X represents a group of the formula or (a) (b) (c) (c) in which one of the two symbols R2 and R3 or R4 and R5 represents hydrogen and the other represents lower alkyl, carboxymethyl or sulphomethyl, as well as pharmaceutically acceptable salts of said compounds and hydrates of said salts, which process comprises (a) reacting a compound of the general formula (II) , wherein X has the significance given above and the carboxy group can be present in protected form, with an acid of the general formula (III) ,wherein R and R1 have the significance given above, or with a reactive functional derivative of this acid and, where required, cleaving off the protecting group, or (b) reacting a compound of the formula (IV) ,wherein R and R1 have the significance given above, Y represents a leaving group with a thiol of the general formula HS-X (V) ,wherein X has the significance given above, in the presence of water, and (e) if desired, converting the reaction product into a pharmaceutically acceptable salt or a hydrate of such a salt .
2. A process according to claim 1, wherein a compound of for-mula II is reacted with an acid of formula III or a reactive func-tional derivative thereof.
3. A process according to claim 2, wherein an acid chloride of an acid of formula III is reacted with a compound of formula II in aqueous alkali.
4. A process according to claim 1 inclusive, wherein there is manufactured a compound of formula I in which R represents furyl or a pharmaceutically acceptable salt thereof or a hydrate of such a salt, which comprises using a starting compound of formula III or IV in which R
represents furyl.
represents furyl.
5. A process according to claim 1 inclusive, wherein there is manufactured a compound of formula I in which R1 represents methyl or a pharmaceutically acceptable salt thereof or a hydrate of such a salt which comprises using a starting compound of formula III or IV in which R1 represents methyl.
6. A process according to claim 1 wherein there is manufactured a compound of formula I in which X represents the group of the formula (c) or a group of the formula (a) or (b) in which one of the two symbols R2 and R3 or R4 and R5 represents hydrogen and the other represents methyl or a pharmaceutically acceptable salt thereof or a hydrate of such a salt, which comprises using a starting material of formula II or V in which X has the said meaning.
7. A process according to claim 6, wherein there is manufactured a compound of formula I in which X represents the 1,2,5,6-tetrahydro-2-methyl-5, 6,dioxo-as-triazin-3-yl group or a pharmaceutically acceptable salt thereof or a hydrate of such a salt, which comprises using a starting material of formula II or V in which X represents the said group.
8. A process according to claim 6, wherein there is manufactured a compound of formula I in which X represents the 1,4,5,6-tetrahydro-4-methyl-5,6-dioxo-as-triazin-3-yl group or a pharmaceutically acceptable salt thereof or a hydrate of such a salt, which comprises using a starting material of formula II or V in which X represents the said group.
9. A process according to claim 7, wherein there is manufactured (7R)-7-[2-(2-furyl)-2-(methoxyimino)acetamido]-3-/ ?1,2,5,6-tetrahydro-2-methyl-5,6-dioxo-as-trlazin-3-yl)-thio] methyl/-3-cephem-4-carboxylic acid or a pharmaceutically acceptable salt thereof or a hydrate of such a salt, which comprises using a starting material of formula III or IV in which R is furyl, and R1 is methyl, and a starting material of formula II or V in which X is the 1,2,5,6-tetrahydro-2-methyl-5,6-dioxo-as-triazin 3-yl group.
10. Acyl derivatives of the general formula (I) wherein R represents furyl, thienyl or phenyl optionally substituted by halogen, hydroxy, lower alkoxy or lcwer alkyl, R1 represents lower alkyl or aminocarbonylmethyl and X represents a group of the formula or (a) (b) (c) in which one of the two symbols R2 and R3 or R4 and R5 represents hydrogen and the other represents lower alkyl, carboxymethyl or sulphomethyl, as well as pharmaceutically acceptable salts of said compounds and hydrates of said salts, whenever prepared according to the process claimed in claim 1 or by an obvious chemical equivalent thereof.
11. Acyl derivatives as set forth in claim 10, wherein R1 represents furyl, as well as pharmaceutically acceptable salts of said compounds and hydrates of said salts, whenever prepared according to the process claimed in claim 4 or by an obvious chemical equivalent thereof.
12. Acyl derivatives as set forth in claim 10, wherein R1 represents methyl, as well as pharmaceutically acceptable salts of said compounds and hydrates of said salts, whenever prepared according to the process in claim 5 or by an obvious chemical equivalent thereof.
13. Acyl derivatives as set forth in claim 10, wherein X represents the group of formula (c) or a group of formula (a) or (b) in which one of the two symbols R2 and R3 or R4 and R5 represents hydrogen and the other represents methyl, as well as pharmaceutically acceptable salts of said compounds and hydrates of said salts, whenever prepared according to the process claimed in claim 6 or by an obvious chemical equivalent thereof.
14. Acyl derivatives as set forth in claim 10, wherein X represents the1,2,5,6-tetrahydro-2-methyl-5,6-dioxo-as-triazin-3-yl group, as well as pharmaceutically acceptable salts of said compounds and hydrates of said salts whenever prepared according to the process claimed in claim 7 or by an obvious chemical equivalent thereof.
15. Acyl derivatives as set forth in claim 10, wherein X represents the 1,4,5,6-tetrahydro-4-methyl-dioxo-as-triazin-3-yl group, as well as pharmaceutically acceptable salts of said compounds and hydrates of said salts, whenever prepared according to the process claimed in claim 8 or by an obvious chernical eqlivalent thereof.
16. (7R)-7-[2-(2-Furyl)-2-(rnethoxyimino)acetamido]-3-/ [(1,2,5,6-tetrahydro-2-methyl-5,6-dioxo-as-triazin-3-yl)thio]methyl7-3-cephern-4-carboxylic acid as well as pharmaceutically acceptable salts of this corn-pound and hydrates of said salts, whenever prepared according to the process claimed in claim 9 or by an obvious chemical equivalent thereof.
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
LU77485 | 1977-06-03 | ||
LU77485 | 1977-06-03 | ||
CH314278 | 1978-03-22 | ||
CH3142/78 | 1978-03-22 |
Publications (1)
Publication Number | Publication Date |
---|---|
CA1114808A true CA1114808A (en) | 1981-12-22 |
Family
ID=25692293
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CA304,644A Expired CA1114808A (en) | 1977-06-03 | 1978-06-02 | Derivatives of 7-¬substituted oxyiminoacetamido| cephalosporins |
Country Status (26)
Country | Link |
---|---|
EP (1) | EP0000005B1 (en) |
JP (1) | JPS5412394A (en) |
AR (1) | AR225134A1 (en) |
AT (2) | AT362501B (en) |
AU (1) | AU518648B2 (en) |
BR (1) | BR7803565A (en) |
CA (1) | CA1114808A (en) |
CU (1) | CU21118A (en) |
DE (2) | DE2824065A1 (en) |
DK (1) | DK246878A (en) |
ES (2) | ES470442A1 (en) |
FI (1) | FI781754A (en) |
FR (1) | FR2393000A1 (en) |
GB (1) | GB1599232A (en) |
GR (1) | GR73554B (en) |
HU (1) | HU182498B (en) |
IE (1) | IE46903B1 (en) |
IL (1) | IL54803A (en) |
IT (1) | IT1098306B (en) |
MC (1) | MC1195A1 (en) |
NL (1) | NL7805715A (en) |
NO (1) | NO781934L (en) |
NZ (1) | NZ187392A (en) |
PH (1) | PH14653A (en) |
PT (1) | PT68134A (en) |
SE (1) | SE7806465L (en) |
Families Citing this family (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4200745A (en) * | 1977-12-20 | 1980-04-29 | Eli Lilly And Company | 7[2-(2-Aminothiazol-4-yl)-2-alkoxyimino]acetamido 3[4-alkyl-5-oxo-6-hydroxy-3,4 dihydro 1,2,4-triazin 3-yl]thio methyl cephalosporins |
FR2432521A1 (en) * | 1978-03-31 | 1980-02-29 | Roussel Uclaf | NOVEL O-SUBSTITUTED OXIMES DERIVED FROM 7-AMINO THIAZOLYL ACETAMIDO CEPHALOSPORANIC ACID, THEIR PREPARATION PROCESS AND THEIR USE AS MEDICAMENTS |
MC1259A1 (en) * | 1978-05-30 | 1980-01-14 | Hoffmann La Roche | ACYL DERIVATIVES |
FI782683A (en) * | 1978-07-19 | 1980-01-20 | Hoffmann La Roche | KEFALOSPORINESTRAR OCH -ESTRAR |
US4472574A (en) * | 1981-05-22 | 1984-09-18 | Hoffman-La Roche Inc. | Process for the manufacture of a cephem carboxylic acid derivative |
US4698338A (en) * | 1986-02-19 | 1987-10-06 | Eli Lilly And Company | 7[2-(2-aminothiazol-4-yl)-2-benzyloximino]acetamido-3[4-alkyl-5-oxo-6-hydroxy-3,4-dihydro-1,2,4-triazin-3-yl]thiomethyl cephalosporins |
Family Cites Families (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB1399086A (en) * | 1971-05-14 | 1975-06-25 | Glaxo Lab Ltd | Cephalosporin compounds |
CH609989A5 (en) * | 1974-06-21 | 1979-03-30 | Hoffmann La Roche | Process for the preparation of acyl derivatives |
CA1100129A (en) * | 1974-08-02 | 1981-04-28 | William H.W. Lunn | Cephalosporin compounds |
GB1555471A (en) * | 1975-06-19 | 1979-11-14 | Glaxo Lab Ltd | 7 carbamoylalkoxyimino acetamido 3 em 4 carboxylic acidsand derivatives thereof |
GB1576625A (en) * | 1976-04-12 | 1980-10-08 | Fujisawa Pharmaceutical Co | Syn isomer 3,7 disubstituted 3 cephem 4 carboxylic acid compounds and processes for the preparation thereof |
GB1596278A (en) * | 1976-11-30 | 1981-08-26 | Glaxo Operations Ltd | 7-(-oxyimino-acetamino)cephalosporin derivatives |
-
1978
- 1978-05-25 GB GB22499/78A patent/GB1599232A/en not_active Expired
- 1978-05-25 NL NL7805715A patent/NL7805715A/en not_active Application Discontinuation
- 1978-05-26 NZ NZ187392A patent/NZ187392A/en unknown
- 1978-05-26 MC MC781305A patent/MC1195A1/en unknown
- 1978-05-26 IE IE1056/78A patent/IE46903B1/en unknown
- 1978-05-29 AU AU36588/78A patent/AU518648B2/en not_active Expired
- 1978-05-29 IL IL54803A patent/IL54803A/en unknown
- 1978-05-31 HU HU78HO2077A patent/HU182498B/en unknown
- 1978-06-01 JP JP6501078A patent/JPS5412394A/en active Pending
- 1978-06-01 FI FI781754A patent/FI781754A/en not_active Application Discontinuation
- 1978-06-01 DE DE19782824065 patent/DE2824065A1/en not_active Withdrawn
- 1978-06-01 FR FR7816468A patent/FR2393000A1/en active Granted
- 1978-06-01 EP EP78100078A patent/EP0000005B1/en not_active Expired
- 1978-06-01 SE SE7806465A patent/SE7806465L/en unknown
- 1978-06-01 GR GR56409A patent/GR73554B/el unknown
- 1978-06-01 DE DE7878100078T patent/DE2860248D1/en not_active Expired
- 1978-06-02 NO NO781934A patent/NO781934L/en unknown
- 1978-06-02 AR AR272437A patent/AR225134A1/en active
- 1978-06-02 PH PH21225A patent/PH14653A/en unknown
- 1978-06-02 AT AT403578A patent/AT362501B/en not_active IP Right Cessation
- 1978-06-02 IT IT24165/78A patent/IT1098306B/en active
- 1978-06-02 PT PT68134A patent/PT68134A/en unknown
- 1978-06-02 BR BR787803565A patent/BR7803565A/en unknown
- 1978-06-02 ES ES470442A patent/ES470442A1/en not_active Expired
- 1978-06-02 CA CA304,644A patent/CA1114808A/en not_active Expired
- 1978-06-02 DK DK246878A patent/DK246878A/en not_active Application Discontinuation
- 1978-07-03 CU CU7834929A patent/CU21118A/en unknown
-
1979
- 1979-02-27 ES ES478115A patent/ES478115A1/en not_active Expired
-
1980
- 1980-07-02 AT AT0345980A patent/AT365197B/en not_active IP Right Cessation
Also Published As
Publication number | Publication date |
---|---|
AU3658878A (en) | 1979-12-06 |
AR225134A1 (en) | 1982-02-26 |
GB1599232A (en) | 1981-09-30 |
FI781754A (en) | 1978-12-04 |
BR7803565A (en) | 1979-02-20 |
DE2824065A1 (en) | 1978-12-14 |
GR73554B (en) | 1984-03-14 |
SE7806465L (en) | 1978-12-04 |
DK246878A (en) | 1978-12-04 |
IL54803A (en) | 1982-01-31 |
FR2393000B1 (en) | 1982-10-29 |
MC1195A1 (en) | 1979-02-23 |
AT362501B (en) | 1981-05-25 |
EP0000005A1 (en) | 1978-12-20 |
IL54803A0 (en) | 1978-07-31 |
DE2860248D1 (en) | 1981-01-29 |
AU518648B2 (en) | 1981-10-15 |
NL7805715A (en) | 1978-12-05 |
ATA403578A (en) | 1980-10-15 |
IE46903B1 (en) | 1983-11-02 |
PH14653A (en) | 1981-10-14 |
ES478115A1 (en) | 1979-06-01 |
ATA345980A (en) | 1981-05-15 |
AT365197B (en) | 1981-12-28 |
IT7824165A0 (en) | 1978-06-02 |
JPS5412394A (en) | 1979-01-30 |
HU182498B (en) | 1984-01-30 |
EP0000005B1 (en) | 1980-10-29 |
ES470442A1 (en) | 1979-10-01 |
IT1098306B (en) | 1985-09-07 |
FR2393000A1 (en) | 1978-12-29 |
PT68134A (en) | 1978-07-01 |
NZ187392A (en) | 1984-05-31 |
CU21118A (en) | 1983-04-06 |
NO781934L (en) | 1978-12-05 |
IE781056L (en) | 1978-12-03 |
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