GB2100734A - New organic compounds processes for their production and their use - Google Patents
New organic compounds processes for their production and their use Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
- C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D257/04—Five-membered rings
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
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Abstract
Compounds of formula I <IMAGE> wherein, R1 represents 2-aminothiazol-4-yl or 1H-pyrazol-3-yl, R2 represents hydrogen, alkyl, carboxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, cyanoalkyl or carbamoylalkyl, R3 represents hydrogen, pivaloyloxymethyl, an easily removable ester group or a cation, and R4 represents optionally substituted aminotetrazolyl and salts thereof. These compounds can be used as chemotherapeuticals, particularly as anti-bacterially active antibiotics.
Description
SPECIFICATION
New organic compounds, processes for their production and their use
The present invention concerns noval derivatives of cephalosporanic acid, processes for their production and their use as pharmaceuticals.
A wide range of oximinoacetylaminocephalosporanic acid derivatives is known generally as is the antimicrobial activity thereof.
The present invention provides a novel group of cephalosporanic acid derivatives and salts thereof not previously disclosed as such. The compounds of the invention exhibit particularly advantageous anti-microbial properties.
More particularly the invention provides compounds of formula I
wherein
R, represents 2-aminothiazol-4-yl or 1 H-pyrazol-3-yl,
R2 represents hydrogen, alkyl, carboxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, cyanoalkyl or carbamoylalkyl,
R3 represents hydrogen, pivaloyloxymethyl, an easily removable ester group or a cation, and
R4 represents optionally substituted aminotetrazolyl and salts thereof, processes for their production and their use as pharmaceuticals.
According to the invention these compounds can be prepared
a) when R2 is other than alkoxycarbonylalkyl and R3 represents hydrogen or a cation, reacting a compound of formula II
wherein
R, R2 and R3 are as defined for formula I, with a compound of formula Ill HS-R4 Ill wherein
R4 is as defined above, and in which any free amino group may, if required, be protected and if required removing any protecting group in the product thus obtained or
b) when R2 represents carboxyalkyl, hydrolysing the corresponding compound of formula I wherein R2 represents alkoxycarbonylalkyl or carbamoylalkyl or
c) when R2 is other than carboxyalkyl, reacting a compound of formula IV
wherein
R3 and R4 are as defined above and R5 represents hydrogen or an amino protecting group, with a compound of formula V
wherein
R1 is as defined above and B2, has the same meaning as R2 with the exception of carboxyalkyl, or a reactive derivative thereof; and if desired converting a compound of formula I thus obtained wherein
R3 represents hydrogen and/or R2 represents carboxyalkyl into an ester, or salt thereof, or if desired removing an ester group if present as R3 or on R2; and recovering the compounds of the formula I thus obtained in free form or in the form of a salt as required.
Process a) can be carried in conventional manner such as described in "Cephalosporins and
Penicillins", Edwin H. Flynn, Acad. Press 1972, page 676. Conventional amino protecting groups may be employed. These can be removed conventionally e.g. by hydrolysis.
The reaction is such that while starting materials may contain esterified carboxy groups as COOR3 (R3+H) or R2 these will be split off during the reaction itself.
Process b) can be carried out in conventional manner for example by dissolving a starting material containing carbamoyl alkyl in a mixture of acetic acid and dilute sulphuric acid and adding at reduced temperature (e.g. ca. 0 C) an aqueous solution of an alkali metal nitrite. In cases where the starting material contains an alkoxycarbonylalkyl group as R2, hydrolysis can for example be carried out using aqueous NaOH.
Suitable reactive derivatives of the acid of formula V include acid halides or acid anhydrides, for example with pivalic acid or carbonic acid half-esters, activated complexes with dimethyl formamide/phosphorous oxychloride, acid azides or activated esters, for example derived from phenols, cyclic N-hydroximides or heterocyclic thiols, e.g. 2-pyridinethiol, 2,2'-dithiopyridine or particular 2benzthiazolthiol. The process is suitably effected by dissolving or suspending the compound of formula
V or derivative thereof in an inert solvent, such as chlorinated hydrocarbon, e.g. dichloromethane, or an acid ester, e.g. ethyl acetate. This solution or suspension is then suitably added to a solution or suspension of the compound of formula IV in an inert solvent, e.g. an acid ester, such as ethyl acetate, or an aromatic hydrocarbon, e.g. toluene.The process is conveniently effected at a temperature of, e.g.
-200C to room temperature. When the compound of formula V is used in free acid form, a condensation agent, such as dicyclohexyl carbodiimide or carboxydiimidazole is suitably added.
Where a compound of formula I is desired, in which the COOH group of the cephalosporanic acid is in free form, it is convenient to protect the carboxylic acid function in the starting material of formula
IV prior to reaction with the compound of formula V or derivative thereof. Conventional methods of protection may be employed. Examples of such protecting groups are tert.butyl, benzhydryl, ethyl, acetoxymethyl, pivaloyloxymethyl or trimethylsilyl.
These can be introduced by esterification e.g. in the case of trimethylsilyl by reaction with N,O- bis-trimethylsilylacetamide.
Removal of protecting groups can be carried out conventionally e.g. by hydrolysis.
In process a) and c) substantially neutral conditions are preferred.
The resulting compounds of formula I may be isolated and purified using conventional techniques. Where required, free acids (e.g. R3=H or R2=carboxyalkyl) may be converted into salt forms, e.g. alkali metal, alkaline earth metal and ammonium salt forms in conventional manner, and vice versa. Such salt forms are to be understood to include solvate forms obtained e.g. after recrystallisation from, for example, water or ethanol.
It will also be appreciated that various compounds of formula I may be inter-converted. For example, free acids (e.g. R3=H or R2=carboxyaíkyl) may be esterified in conventional manner to obtain compounds in which R3 is pivalcyloxymethyl or the residue of an easily splittable ester grouping or R2 is alkoxycarbonylalkyl or carbamoylalkyl). The latter may themselves be split in conventional manner to obtain free acids.
When R, represents a 1 H-pyrazol-3-yl nucleus this may exist in its other tautomeric form:
(lH-pyrazol-5-yl) (lH-pyrazol-3-yl) The position of the tautomeric equilibrium will, of course, depend on known factors such as temperature, aggregation condition, solvent and pH. Naturally, the invention is not limited to any particular tautomeric form.
The group OR2 in the compounds of the invention may be in the syn or anti-configuration to the carbonamido group. It is to be understood that the invention includes both isomeric forms as well as mixtures thereof. The syn isomers or isomeric mixtures in which the syn isomer predominates, e.g. to the extent of at least 75%, more particularly at least 90%, are however preferred.
If starting materials are employed in the form of syn isomers, then the product may be a syn
isomer or a mixture of the syn and an anti-isomer, depending on type of substitution and reaction conditions. Individual isomers may be isolated from mixtures by e.g. chromatographic methods.
The starting materials of formula II are either known or where novel can be produced analogously
to known methods such as
a)i) when in formula II R2 is other than carboxyalkyl reacting a compound of formula IVa
wherein
R3' represents hydrogen, pivaloyloxymethyl or a carboxyl protecting group with a compound of formula V as defined above or a reactive derivative thereof,
b)i) when in formula II R2 represents hydrogen, hydrogenating a compound of formula Ila
wherein R, and R3 are as defined above,
c)i) when in formula II R2 represents carboxyalkyl hydrolysing a corresponding compound of formula II wherein R2 represents carbamoylalkyl or alkoxycarbonylalkyl, and, if desired, converting a compound of formula II thus obtained wherein R3 represents hydrogen and/or R2 represents carboxyalkyl into an ester, or salt thereof, or if desired, removing an ester group if present as
R3 or on R2; and recovering the compounds of the formula II thus obtained in free form or in the form of a salt as required.
Process a)i) can be carried out analogously to c) above.
Hydrogenation according to b)i) can be carried out in conventional manner. for example the starting material (ill) can be dissolved or suspended in a solvent inert under the reaction conditions (e.g. water) and hydrogenated with hydrogen in the presence of a catalyst e.g. Pd/active charcoal.
Process c)i) can also be curried out in conventional manner. For example the starting material can be dissolved in a mixture of acetic and sulphuric acids and a solution of an alkali metal nitrite added at low temperature (e.g. OOC).
The compounds of formula Ill are new and thus also form part of the invention. They can be prepared, for example, as illustrated in the following reaction schemes. (Re and R8=independently H, lower acyl, lower alkyl or any of the other of the amino substituents listed hereinafter)
Process b) which also forms part of the invention can be carried qut in an inert solvent such as an alcohol (e.g. methanol or ethanol), an aliphatic ketone and aliphatic or aromatic ether or hydrocarbon or an aprotic dipolar solvent such as dimethylformamide, dimethylacetamide.or one or two phase mixtures of these with water and at temperatures of from -200C to 2000C (preferably 20.to 1 000C).
Examples of azides as MN3 are alkalimetal azides e.g. sodium-, potassium- or lithium azide or ammonium azide. Quaternary ammonium azides can also be employed.
Examples of B5-Y leaving groups are those wherein Y represents oxygen or sulphur and R5 represents C15 alkyl, e.g. methyl, aralkyl, e.g. benzyl, aryl e.g. phenyl, tolyl. Examples of such groups are methylthio and preferably tolyloxy or phenoxy.
The process can also be carried out under conventional phase transfer conditions.
The starting materials can be prepared in conventional manner (cf. K. A. Jensen et.al. Acta. Chem.
Scand. 23, 1916-1934 [1969]).
The compounds of formula IV are also new and form part of the invention. They can be prepared analogously to process a) above by reacting a compound of formula IVb
with a compound of formula Ill, or where esterified carboxy groups are required by esterifying the corresponding free carboxy compounds in conventional manner.
The compounds of formula I possess chemotherapeutic, in particular anti-microbial activity as indicated by their inhibiting effect against various bacteria, e.g. Staphylococcus aureus, Streptococcus pyogenes, Streptococcus faecalis, Escherichia coli, Proteus vulgaris, Proteus mirabilis, Proteus morganii, Klebsiella aerogenes, Klebsiella pneumoniae, Serratia marcescens, Salmonella Heidelberg,
Salmonella typhimurium, Salmonella enteritidis, and Neisseria gonorrhoeae, in vitro in the series dilution test at concentrations of, for example, 0.01 to 50 ,ug/ml, and in vivo in the mouse at dosages of, for example, about 0.1 to 100 mg/kg of animal body weight. The compounds are thus indicated for use as chemotherapeutics, e.g. as antibacterially active antibiotics.
An indicated suitable daily dosage for use as antibacterially active antibiotics is from about 60 to 3000 mg, 1000 to 3000 mg or 60 to 2000 mg.
The compounds of formula I may be employed in free acid form or in the form of a chemotherapeutically acceptable salt thereof, with a base or in the form of a chemotherapeutically acceptable solvate thereof, which forms have the same order of activity as the free acid. Suitable salt forms include alkali and alkaline earth metal and ammonium or amino acid salt forms which can also be in solvate form, for example, as hydrates and ethanolates.
The compounds may be admixed with conventional chemotherapeutically acceptable diluents and carriers, and administered in such forms as tablets or capsules or, particularly, parenterally. Such compositions also form part of the invention.
The'invention therefore also concerns a method of combatting bacteria comprising administering to a subject in need of such treatment an effective amount of a compound of formula I or a chemotherapeutically acceptable salt thereof and such compounds for use as chemotherapeutic agents, in particular anti-bacterially active antibiotics.
Alkyl groups appearing as substituents preferably have 1 to 4 especially 1 or 2 carbon atoms.
Bridging alkyl groups can be straight or branch-chained and include e.g. methylene and dimethylmethylene. R2 preferably represents alkyl, alkoxycarbonylalkyl or carbamoylalkyl. When R3 represents an easily removable ester group this can be e.g. 1 -ethoxycarbonyloxyethyl or 5-indanyl or especially hexanoyloxymethyl, phthalidyl, ethoxycarbonylmethoxymethyl or 3-ethoxycarbonyl-1 - acetonyl. The amino group on the tetrazole radical R4 can be unsubstituted or substituted by alkyl (mono- or di-), alkylidene, aryl (mono- or di-) or arylidene which in turn can themselves optionally be substituted by amino, hydroxy, C14aIkoxy, a carboxylic- or suiphonic acid residue, carbamido or C14aIkylthio. Aryl can include heterocycles such as furyl.
A particular group of aminotetrazole substituents R4 includes those wherein the amino group is optionally substituted by Alkyl (mono- or di-), lower acyl (mono- or di-), benzylidene, dimethylaminomethylidene. Particularly preferred are amino monoalkylamino- and benzylideneaminotetrazole. Compounds wherein the OR2 group is in syn transfiguration are also preferred.
A particularly preferred single compound is 7-[(methoximino)-2-aminothiazol-4-yl-acetyljamino- 3-desacetoxy-3-( -amino-l H-tetrazol-5-yl-thio)cephalosporanic acid and salts thereof e.g. the sodium salt.
The following examples illustrate the invention. All temperatures are in degrees centigrade.
Example 1 7-[(Methoxi mino)-2-aminothiazol-4-yl-acetyl]amino-3-desacetoxy-3-( 1 -benzylidenamino-1 Htetrazol-5-yl-thio)cephalosporanic acid sodium salt (syn isomer, cmpd. no. 1) (process a)
The pH value of a mixture of 477 mg syn-7-[(methoximino)-2-aminothiazol-4-ylacetyl]aminocephalosporanic acid and 205 mg of 1 -benzylidenamino-5-mercapto-1 H-tetrazole in 30 ml of water at 60O is held constant at 7.0 by the addition of 1 N NaOH. After 63 hours the pH of the reaction mixture is adjusted to 4.0 with 1 N HCI and the title compound extracted using ethylacetate.
The product can be purified, if required by chromatography on RP-18 silica gel.
Example 2 7-[(Methoximino)-2-aminothiazol-4-yl-acetyl]amino-3-desacetoxy-3-( 1-amino-I H-tetrazol-5-ylthio)cephalosporanic acid sodium salt (syn isomer, cmpd. no. 2) (process c)
780 mg of 7-amino-3-desacetoxy-3-( l-amino-l H-tetrazol-5-yl-thio)cephalosporanic acid sodium salt are suspended in a mixture of 5 ml of water, 2.5 ml of acetone and 6.2 ml of ethanol and adjusted to pH 7.0 using 1 N NaOH. Following the addition of 996 mg of syn-[(methoximino)-2aminothiazol-4-yl]acetic acid mercaptobenzthiazol ester the suspension is stirred for 3 hours at 400 and 36 hours at 500 while maintaining the pH value at 7.0. After cooling to 200 any solid residue is
removed by filtration and the filtrate concentrated.The resulting precipitate is filtered and the filtrate
(pH 7) extracted three times with ethyl acetate. The aqueous phase is acidified to pH 2.5 and the
resulting precipitate filtered. Extraction of the filtrate (Sxwith ethylacetate/n-butanol=2/1), drying of the extracts with Mg SO4, concentration on a rotary evaporator and trituration of the residue with diisopropylether yields the title compound. After dissolving this raw product in water/NaHCO3 and
reverse phase chromatography (RP-18, elution with water) the pure substance is obtained.
To prepare the free acid 100 mg of the sodium salt are dissolved in 4 ml of water and acidified to
pH 2.5 using 1 N HCI. The resulting free acid is filtered off washed with water and dried for 5 hours at
20 dgrs under high vacuum. A white powder is obtained.
The compound of this example can also be prepared analogously to example 1.
Example 3 7-[(Methoxycarbonyl methoximino)-2-aminothiazol-4-yl-acetyljamino-3-desacetoxy-3-( amino 1 H-tetrazol-5-yl thio)cephalosporanic acid sodium salt (syn isomer, cmpd. no. 3) (process c)
1.92 g of syn-[(methoxycarbonylmethoximino)-2-aminothiazol-4-yI]acetic acid and 2.37 g of triphenylphosphine are suspended in 40 ml of dichloromethane and at 40 3g of mercaptobenzthiazole disulphide added. This suspension is stirred for 1 + hours at 40, 5 hours at 200 and a further 1 6 hours at 40 and then concentrated to an oily residue.To this is added a solution prepared from 7-amino-3 desacetoxy-3-(1 -amino-l H-tetrazol-5-yl-thio)cephalosporanic acid sodium salt, 10 ml of water, 5 ml of acetone and 1 2 ml of ethanol. The reaction mixture is stirred for 3 hours at 400 and 1 hour at 450 while maintaining the pH value at 7.0. After concentration on a rotary evaporator the aqueous residue is diiuted with a little water and extracted at pH 7.0 with ethyl acetate. Acidification of the aqueous phase to pH 3 yields a raw product which after reverse phase chromatography (RP-18, elution with
H20/CH3CN=95/5) results in the title product.
Analogously to examples 1 to 3 or as otherwise hereinbefore described the following compounds of formula 1 may be prepared
Cmpd. No. R1 R2 R3 X configuration 4 2-aminothiazoi-4-yl CH3 Na -N=CH-N(CH3)2 syn 5 2-aminothiazol-4-yl CH3 Na -N(CH3)2 syn 6 2-aminothiazol-4-yl CH2COONa Na -NH2 syn 7 1 H-pyrazol-3-yl CH3 Na -N=CH-C6H5 syn 8 1 H-pyrazol-3-yl CH3 Na -NH2 syn 9 1 H-pyrazol-3-yl CH2COONa Na -NH2 syn 10 2-aminothiazol-4-yl CH3 Na -NH.CO.CH3 syn CH3 11 2-aminothiazol-4-yl -OCOOCH3 Na -NH2 syn CH3 CH3 12 2-aminothiazol-4-yl -CCOOC2H5 Na -NH2 syn I CH3
Example 4 7-[(Carboxymethoximino)-2-aminothiazol-4-yl-acetyl]am ino-3-desacetoxy-3-( 1-amino-1 Htetrazol-5-yl-thio)cephosporanic acid disodium salt (syn isomer, compound no. 6) (process b)
500 mg of syn-7-[(methoxycarbonylmethoximino-2-aminothiazol-4-ylacetyl]amino-3- desacetoxy-3-(1-amino-1 H-tetrazol-5-yl-thio)cephalosporanic acid sodium salt are dissolved in 25 ml of water and adjusted at 40 to pH 12 using 1 N NaOH. After la hour at 40 no starting material remains and reverse phase chromatography of the resulting solution (RP 1 8 elution with water yields pure title product.
Proceeding analogously 7-[[(1-carboxy-1-methyl)ethoximino]-2-aminothiazol-4-yl-acetyl]amino- 3-desacetoxy-3-( -amino- 1H-tetrazol-5-yl-thio)cephalosporanic acid disodium salt (syn isomer, compound no. 13) may be obtained.
Example 5 7-[(methoxim ino)-2-aminothiazol-4-yl-acetyl]amino-3-desacetoxy-3-( 1-amino-1 H-tetrazol-5-ylthio)-cephalosporanic acid pivaloyloxymethyl ester (syn isomer, compound no. 14) 5.7 g of syn-7-[(methoximino)-2-aminothiazol-4-yl-acetyl]-amino-3-desacetoxy-3-(1-amino-1H- tetrazol-5-yl-thio)cephalosporanic acid sodium salt are dissolved in 130 ml of dimethylformamide and reacted dropwise at - 10 with a solution of methyliodide pivalate in 40 ml of dimethylformamide.
After 30 minutes at - 10 the reaction mixture is poured into ice/water and the resulting precipitate filtered and washed with water. After drying at 15.6 mbar and 450 the title compound is obtained as a raw product. Further raw product can be obtained by extraction of the filtrate with ethyl acetate.
Chromatography of the combined raw portions on silica gel (elution with dichloromethane/methanol=95/5) pure (HPLC 91 %) product is obtained.
Example 6 7-[[(1 -Carboxy-1 -methyl)ethoximino]-1 H-pyrnzcl-3-yl acetyl]amino-3-desacetoxy-3-(1 amino 1 H-tetrazol-5-yl-thio)cephalosporanic acid disodium salt (syn isomer. compound no. 15) 5 g of syn-7-[(l -tert.butoxy-l -methyl)ethoximino]- 1 H-pyrazol-3-yl-acetyl]aminocephalosporanic acid sodium salt and 1.02 of 1 -amino-5-mercapto-1 H-tetrazole are dissolved in 50 ml of water and solid NaHCO3 added to a pH of 7.0. The solution is stirred for 16 hours at 600 while maintaining the pH of 7.0.Chromatography of the reaction mixture (RP 18: elution with water and water/methanol=9/1) yields the title compound together with 7-[(tert.butoxycarbonyl-1 -methyl)ethoximino]-1 H-pyrazol-3-ylacetyl]amino-3-desacetoxy-3-(1-amino-1 H-tetrazol-5-yl-thio)-cephalosporanic acid sodium salt (syn isomer, compound no. 18).
NMR Spectra
(D2O, ppm, RT):
Cmpd. Spectrum
1 3,55 (q, 2H); 4.44 (q, 2H); 5.05 (d, 1 H); 5.68 (dd, 1 H); 6.74
(DMSO) (s,1 H); 7,08 (sb, 2H); 7.62 (m, 4H); 8.00 (m, 2H); 9.37 (s, 1 H).
2 3.65 (q, 2H); 4.00 (s, 3H); 4.23 (q, 2H); 5.20 (d. 1 H); 5.78
(sodium salt) (d, 2H); 7.03 (s, 1 H).
2 3,83 (s); 4.33 (AB-quartet, J#13); 5.13 (d, J--5); 5.79 (dxd,
(free acid) J1 8, J2#5); 6.75 (s); 6.94 (br, s); 7.24 (br, s); 9.62 (d, J8).
(DMSO)
3 3.65 (AB-quartet, J#18 superimposed with 3.82 (s), together with
5H; 4.26 (AB-quartet, J#14, 2H); 4.89 (s, 2H); 5.24 (d, J#5, 1H); 5.85 (d, J#5, 1H); 7.14(s, 1H).
4 3.13 (d, 6H); 3.67 (q, 2H); 4.00 3H); 4.22 (q, 2H); 5.20 (d. 1 H); 5.80 (d, 1 H); 7.06 (s, 1 H); 8.32 (s, 1 H).
5 2.98 (s, 6H); 3.63 (q, 2H); 4.00 (s, 3H); 4.25 (q, 2H); 5.22 (d, 1 H);
5.80 (d, 1 H); 7.04 (s, 1 H).
6 3.65 (q, 2H); 4.25 (q, 2H); 4.60 (s, 2H); 5.22 (d, 1 H); 5.85 (d, 1H);7.10(s, 1H).
7 3.65 (q, 2H); 3.95 (s, 3H); 4.20 (q, 2H); 5.08 (d, 1H); 5.72 (q, 1 H); 6.68 (d, 1 H); 7.40--7.70 (m, 6H); 9.00 (d, 1 H).
Cmpd. Spectrum 8 3.62 (q, 2H); 4.02(s, 3H); 4.22 (q, ZH); 5.20 (d, 1 H); 5.82
(d, 1 H); 6.73 (d, H); 7.81 (d, 1 H).
9 3.65 (q, 2H); 4.25 (q, 2H); 4.61(s, 2H); 5.22 (d, 1 H); 5.87
(d, 1 H); 6.75 (d 1 H); 7.80 (d, 1 H).
10 2.18 (s, 3H); 3.64 (AB-quartet, J#18, 2H); 4.21 (AB-quartet, J#14), superimposed with 4.00 (s),together 5H; 5.19 (d, J-5, 1 H);
5.78 (d,J#5,1H);7.03 (s, 1H).
11 1.60 (s); 3.65 (AB-quartet,J18),superimposed with 3.80 (s), together 5H; 4.25 (AB-quartet, J#13,2H); 5.21 (d, J-5, lah); 5.82
(d,J#5,1H);7.05 (5, lH).
12 1.27 (t, J#7, 3H); 1.60 (s, 6H); 3.65 (AB-quartet, J#18, 2H); 4.00- .50 (q, J7, superimposed with AB-quartet, J#13, together 4H);
5.23 (d, J#5, 1 H); 5.84 (d, J--5, 1H); 7.07 (s, 1 H)
13 1.53 (s, 6H); 3.68 (AB-quartet, 5-18, 2H); 4.28 (AB-quartet, J#14, 2H); 5.23 (d, J-5, 1 H); 5.84 (d, J-5, 1 H); 7.03 (s, 1 H).
14 1.17 (s); 3.72 (AB-quartet, JN17) superimposed with 3.83 (s),
(DMSO) together 5H; 4.32 (AB-quartet, J#11,2H); 5.17 (d, J#5,1 H); 5.70-6.00 (AB-quartet, J#6, superimposed with dxd, J15, J 2""'8, together 3H); 6.74 (s); 6.91 (br, s); 7.13 (br, s); 9.54 (d, J8).
15 1.51(s, 6H); 3.65 (AB-quartet, J#18,2H); 4.23 (AB-quartet, J""14, 2H); 5.22 (d, J#5, 1 ); 5.84 (d, J#5, 1H); 6.75
(d, J~3,1 H); 7.78 (d, J~3,1 H).
The required starting materials of formula Ill can be prepared as follows:
A) 1 -Benzylideneamino-5-mercapto-1 H-tetrazole (for compounds 1 and 7)
21 ml of aqueous sodium hydrogensulphide are added dropwise at 600 with stirring to a solution of 10 g of 1 -benzylidene-amino-5-chloro-1 H-tetrazole. After 25 minutes at this temperature the reaction mixture is adjusted to pH 3.0 with 2N HCI and evaporated under vacuum. The residue is
dissolved in ca 300 ml of water, adjusted to pH 7.3 with sodium hydrogencarbonate, mixed with active
charcoal and filtered. The filtrate is adjusted to pH 2.0 with 6N HCI while maintaining the temperature
at 1012 with ice cooling.
The precipitating crystals are collected on a glass frit and washed free of HCI with water, m.p..
131135 NMR (CDCl3+DMSO):7.45 (m,3H);7.90 (m,2H);9.31 (s, 1H).
B) 1-Amino-1 H-tetrazole-5-thiol (for compounds 2,6, 8,9. 11, 12 and 15) a) Hydrazinedithiocarbonic acid ammonium salt
1 kg of hydrazinehydrate is added with stirring at 0 to a solution of 800 g of ammonia in 7 litre of ethanol. This is followed by the addition over 1 hour at -5 to -10 of 1.5 kg of carbon disulphide.
The resulting precipitate is filtered and dried under vacuum at room temperature.
b) Hydrazinedithiocarbonic acid methyl ester
2.3 kg of hydrazinedithiocarbonic acid ammonium salt are dissolved in 4 litre of water at 500 and mixed with 2 litre of ethanol. 1 litre of methyliodide is added dropwise with stirring over 3 hours at 10" and the mixture stirred for a further 2 hours at . Filtration of the precipitate yields the desired ester
m.p. 80-82 .
c) 1 -Amino-1 H-tetrazole-5-thiol 650 g of lithiumchloride are added in portions with stirring at 450 to a suspension of 1 kg of sodiumazide in 13 litres of methanol and the mixture is then refluxed for 8 hours. The reaction mixture is filtered, the filtrate mixed with 780 g hydrazinedithiocarbonic acid methyl ester, refluxed for 30 hours and the solvent then removed to yield a viscous oil. This is diluted with 0.5 litre of 1 N NaOH and the solution continuously extracted with ether for 6 hours; under constant passage of air acidification to pH 0 with 1.4 litre of conc. HCI is carried out over 11/2 hours. Perforation of this solution for 8 hours with
ether and concentration of the ether phase yields the title compound which, after recrystallisation from
isopropanol melts at 1700.
C) 1-Dimethylamino-1 H-tetrazole-5-thiol (for compound 5) a) N,N-Dimethyldithiocarbazinic acid ammonium salt
120 g of ammonia are condensed into a solution of 270-9 N,N-dimethylhydrazine in 2 litres of ethanol at 0 . To this are added, at the same temperature, and with stirring, 48 g of carbon disulphide.
After a reaction time of 4 hours the precipitated crystals are separated off and the filtrate mixed under stirring with ca 10 litres of diethylether. The desired ammonium salt is separated on a glass frit. m.p.
112--120".
b) 1,1 Dimethyldithiocarbazine acid methylester m.p. 8690 ; and c) 1-Dimethylamino-1 H-tetrazole-5-thiol m.p. 137-1 380 NMR (CDCI3: 3.04(s).
are then prepared analogously to examples B)b) and B)c).
D) 1 -Dimethylaminomethylidenamino-1 H-tetrazole-5-thiol (for compound 4) a) 1 -Dimethylaminomethylidenamino-1 H-tetrazole
A mixture of 32 g of 1amino1 H-tetrazole and 300 ml dimethylformamidedimethylacetal are allowed to stand for 3 hours at room temperature. The precipitated crystals are repeatedly washed with diisopropyletheron a glass frit and dried under vacuum m.p. 8890 . NMR (CDCl3):3.0 and 3.12 (2s, 6H); 8.32 (s, 1 H); 8.40 (s, 1 H).
b) 1 -Dimethylaminomethylidenamino-1 H-tetrazole-5-thiol At --600, 26 ml of a solution of n-butyllithium in hexane are added, dropwise to a solution of 5 g of 1 -dimethylaminomethylidenamino-1 H-tetrazol in 60 ml of abs. tetrahydrofuran. After 1 5 minutes 1.14 g of sulphur are added.
The reaction mixture is allowed to warm up over 45 minutes to 400 and then poured into 600 ml of diethylether. After stirring for 30 minutes the residue is separated on a glass frit, washed twice with ethylacetate and dissolved in 100 ml of water. This solution is extracted repeatedly with ethyl acetate and the aqueous phase adjusted to pH 2 using 1 N HCI. This mixture is repeatedly extracted with ethyl acetate and dried over Na2SO4 to yield the title compound m.p. 109-1 100 NMR (CDCl3): 3.12 Is, 6H); 8.20 (s, 1 H); 13.0 (s, 1 H).
E) 7-Amino-3-desacetoxy-3-( 1 -amino-1 H-tetrazol-5-yl-thio)-cephalosporanic acid sodium salt (for compounds 2, 3, 6, 8, 9, 11 and 12
23.24 g of 7-ACA and 10 g of 1-amino-5-mercapto-1 H-tetrazole are dissolved in 700 ml of H2O by adjusting the pH value to 7. The solution is stirred for 6 hours at 600, whereby the pH value is continually held at 7.0 using 2N NaOH. After cooling, the mixture is extracted three times at pH 7 with ethylacetate and the aqueous phase then acidified to pH 2.7 using 6N HCI. On extraction (4xwith ethyl acetate and 4xwith ethylacetate/n-butanol=3/1) unused 1 -amino-5-mercapto-1 H-tetrazol, only, passes into the organic phase.
After removal of the tetrazole the acidic water is evaporated under rotation at 1 6 mbar and the raw acid digested with methanol. Both filtrate and residue contain end product and they are dissolved together in H2O/NaHCO3 and twice chromatographed (reverse phase RP 18, elution with H2O). The title product is obtained after lyophilisation. 1 H-NMR-Spectrum (D2O): 3.63 (AB-quartet, J--1 8, 2H); 4.25 (AB-quartet, J--1 3, 2H); 4.75 (d, J~4, 1 H); 5.05 (d, J~4, 1 H).
F) 7-Amino-3-desacetoxy-3-( 1 -aceta m ido-1 H-tetrazol-5-yl-thio)cephalosporanic acid Na salt (for compound 10)
20 ml of borontrifluoride etherate is added dropwise over 30 minutes to a suspension of 2.7 g 7
ACA and 1.4 g of 1 -amino-1 H-tetrazol-5-thiol in 30 ml of glacial acetic acid. The mixture is stirred for 5 hours at 450, poured onto 60 ml of ice/water and with cooling adjusted to pH 3.5 by the addition of methanolic ammonia. The precipitate is filtered, washed with water and methanol and dissolved in 5% sodium bicarbonate.Chromatography on silica gel RP 18 (elution with water) and freeze drying of the appropriate fractions yields the title compound IR(KBr): 3421, 3375, 1753, 1643, 1596, 1407, 1355, 1289, 1238, 1200, 1 101 cm-' NMR (D2O): 5.05 (d, 5Hz, 1 H); 4.78 (d, 5Hz, 1 H); 4.38 (d, 14Hz, 1 H); 4.08 (d, 14Hz, 1 H); 3.78 (d, 18Hz, 1 H); 3.42 (d, 18Hz, 1 H); 2.2 (s, 3H).
G)1-Amino-l H-tetrazole-5-thiol
5.47 g of thiocarbazinic acid-O-4-tolyl ester, 75 ml of methanol and 2.15 g of sodium azide are refluxed for 2 hours with stirring. The reaction mixture is then concentrated, rinsed with 50 ml of water and then extracted three times with ether. The aqueous phase is concentrated and the solid but not completely dry residue taken up in ethanol with stirring at 800. The resulting suspension is cooled, stirred and filtered. After washing with ethanol and drying the title compound is obtained in the form of its sodium salt. m.p. 220--2250.
Claims (11)
1. Compounds of formula I
wherein
R, represents 2-aminothiazol-4-yl or 1 H-pyrazol-3-yl,
R2 represents hydrogen, alkyl, carboxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, cyanoalkyl or carbamoylalkyl,
R3 represents hydrogen, pivaloyloxymethyl, an easily removable ester group or a cation, and
R4 represents optionally substituted aminotetrazolyl and salts thereof.
2. 7-[( Methoximino)-2-am inothiazol-4-yl-acetyl]a m ino-3-desacetoxy-3-( 1 -a m ino-l H-tetrazol-5- yl-thio)cephalosporanic acid or a salt thereof.
3. A compound as claimed in Claim 1 or Claim 2 in syn isomeric form.
4. A process for preparing a compound as claimed in any one of Claims 1 to 3 which comprises
a) when R2 is other than alkoxycarbonylalkyl and R3 represents hydrogen or a cation, reacting a compound of formula II
wherein
R, R2 and R3 are as defined for formula I, with a compound of formula Ill HS-B4 Ill wherein
R4 is as defined above, and in which any free amino group may, if required, be protected and if required removing any protecting group in the product thus obtained or
b) when R2 represents carboxyalkyl hydrolysing the corresponding compound of formula I wherein R2 represents alkoxycarbonylalkyl or carbamoylalkyl or
c) when R2 is other than carboxyalkyl reacting a compound of formula IV
wherein
R3 and R4 are as defined above and R5 represents hydrogen or an amino protecting group, with a compound of formula V
wherein B1 is as defined above and B2, has the same meaning as R2 with the exception of carboxyalkyl, or a reactive derivative thereof; and if desired converting a compound of formula I thus obtained wherein R3 represents hydrogen and/or R2 represents carboxyalkyl into an ester, or salt thereof, or if desired removing an ester group if present as R3 or on R2; and recovering the compounds of the formula I thus obtained in free form or in the form of a salt as required.
5. A pharmaceutical composition comprising a compound of formula I as claimed in Claim 1 or a chemotherapeutically acceptable salt thereof together with a chemotherapeutically acceptable diluent or carrier.
6. A method of combatting bacteria comprising administering to a subject in need of such treatment an effective amount of a compound of formula I or a chemotherapeutically acceptable salt thereof.
7. A compound of formula I as claimed in Claim 1 or a chemotherapeutically acceptable salt thereof for use as a pharmaceutical.
8. A compound of formula I as claimed in Claim 1 or a chemotherapeutically acceptable salt thereof for use as an antibacterially active antibiotic.
9. The steps, features, compositions and compounds referred to or indicated in the specification and/or claims of this application, individually or collectively, and any and all combinations or any two or more of said steps or features.
10. A compound of the formula Ill or IV as hereinbefore defined.
11. A process for preparing a compound of formula Ill as hereinbefore defined which comprises reacting a compound of formula
as hereinbefore defined, with a metal azide.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH427481 | 1981-06-29 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| GB2100734A true GB2100734A (en) | 1983-01-06 |
Family
ID=4273043
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB08218422A Withdrawn GB2100734A (en) | 1981-06-29 | 1982-06-25 | New organic compounds processes for their production and their use |
Country Status (15)
| Country | Link |
|---|---|
| JP (1) | JPS5815983A (en) |
| AU (1) | AU8539182A (en) |
| BE (1) | BE893576A (en) |
| DE (1) | DE3223019A1 (en) |
| DK (1) | DK290882A (en) |
| ES (1) | ES513539A0 (en) |
| FI (1) | FI822244L (en) |
| FR (3) | FR2508458A1 (en) |
| GB (1) | GB2100734A (en) |
| IL (1) | IL66148A0 (en) |
| IT (1) | IT1186693B (en) |
| NL (1) | NL8202580A (en) |
| PT (1) | PT75139B (en) |
| SE (1) | SE8203988L (en) |
| ZA (1) | ZA824647B (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0117109A2 (en) * | 1983-02-22 | 1984-08-29 | Tanabe Seiyaku Co., Ltd. | Novel cephalosporin compound and a process for preparing same |
| EP0308559A2 (en) * | 1987-09-24 | 1989-03-29 | Beecham Group Plc | Cephalosporins, process for their preparation, pharmaceutical compositions containing them and intermediates |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB567353A (en) * | 1943-08-27 | 1945-02-09 | John David Kendall | Improvements in the manufacture of tetrazole compounds |
| GR63088B (en) * | 1976-04-14 | 1979-08-09 | Takeda Chemical Industries Ltd | Preparation process of novel cephalosporins |
| JPS6011713B2 (en) * | 1976-09-08 | 1985-03-27 | 武田薬品工業株式会社 | Cephalosporin derivatives and their production method |
| DE2714880A1 (en) * | 1977-04-02 | 1978-10-26 | Hoechst Ag | CEPHEMDER DERIVATIVES AND PROCESS FOR THEIR PRODUCTION |
-
1982
- 1982-06-18 FR FR8210845A patent/FR2508458A1/en not_active Withdrawn
- 1982-06-19 DE DE19823223019 patent/DE3223019A1/en not_active Withdrawn
- 1982-06-21 BE BE1/10536A patent/BE893576A/en not_active IP Right Cessation
- 1982-06-22 FI FI822244A patent/FI822244L/en not_active Application Discontinuation
- 1982-06-25 GB GB08218422A patent/GB2100734A/en not_active Withdrawn
- 1982-06-25 IT IT48704/82A patent/IT1186693B/en active
- 1982-06-25 NL NL8202580A patent/NL8202580A/en unknown
- 1982-06-28 JP JP57112439A patent/JPS5815983A/en active Pending
- 1982-06-28 ES ES513539A patent/ES513539A0/en active Granted
- 1982-06-28 PT PT75139A patent/PT75139B/en unknown
- 1982-06-28 SE SE8203988A patent/SE8203988L/en not_active Application Discontinuation
- 1982-06-28 DK DK290882A patent/DK290882A/en not_active Application Discontinuation
- 1982-06-28 IL IL66148A patent/IL66148A0/en unknown
- 1982-06-28 AU AU85391/82A patent/AU8539182A/en not_active Abandoned
- 1982-06-29 ZA ZA824647A patent/ZA824647B/en unknown
- 1982-09-27 FR FR8216349A patent/FR2511002A1/fr not_active Withdrawn
- 1982-09-27 FR FR8216348A patent/FR2510999A1/en not_active Withdrawn
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0117109A2 (en) * | 1983-02-22 | 1984-08-29 | Tanabe Seiyaku Co., Ltd. | Novel cephalosporin compound and a process for preparing same |
| EP0117109A3 (en) * | 1983-02-22 | 1985-08-28 | Tanabe Seiyaku Co., Ltd. | Novel cephalosporin compound and a process for preparing same |
| US4547494A (en) * | 1983-02-22 | 1985-10-15 | Tanabe Seiyaku Co., Ltd. | Pyrrolidomoxine cephalosporins |
| EP0308559A2 (en) * | 1987-09-24 | 1989-03-29 | Beecham Group Plc | Cephalosporins, process for their preparation, pharmaceutical compositions containing them and intermediates |
| EP0308559A3 (en) * | 1987-09-24 | 1989-08-30 | Beecham Group Plc | Cephalosporins, process for their preparation, pharmaceutical compositions containing them and intermediates |
Also Published As
| Publication number | Publication date |
|---|---|
| FR2508458A1 (en) | 1982-12-31 |
| IT1186693B (en) | 1987-12-04 |
| FR2510999A1 (en) | 1983-02-11 |
| DE3223019A1 (en) | 1983-01-05 |
| IL66148A0 (en) | 1982-09-30 |
| AU8539182A (en) | 1983-01-06 |
| BE893576A (en) | 1982-12-21 |
| IT8248704A0 (en) | 1982-06-25 |
| SE8203988D0 (en) | 1982-06-28 |
| SE8203988L (en) | 1982-12-30 |
| FI822244A0 (en) | 1982-06-22 |
| ES8401083A1 (en) | 1983-12-01 |
| PT75139B (en) | 1985-01-07 |
| PT75139A (en) | 1982-07-01 |
| ZA824647B (en) | 1984-02-29 |
| NL8202580A (en) | 1983-01-17 |
| ES513539A0 (en) | 1983-12-01 |
| DK290882A (en) | 1982-12-30 |
| FR2511002A1 (en) | 1983-02-11 |
| FI822244L (en) | 1982-12-30 |
| JPS5815983A (en) | 1983-01-29 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| WAP | Application withdrawn, taken to be withdrawn or refused ** after publication under section 16(1) |