GB2104505A - Thiazolyloxime carboxylic acids - Google Patents

Abstract

Compounds of the formula <IMAGE> wherein R<1> is amino or protected amino and R<2> is ar(lower)alkenyl, and salts thereof may be used as intermediates of antibacterial synthetic cephalosporin derivatives.

Description

SPECIFICATION Thiazolyloxime carboxylic acids The present invention relates to compounds of the formula

wherein R1 is amino or a protected amino and R2 is ar(lower)alkenyl, and salts thereof.

The compounds of the present invention are useful as intermediates in the preparation of 3,7disubstituted-3-cephem-4-carboxylic acid compounds having the formula:

wherein R1 is amino or protected amino; R2 is lower alkylthio(lower)alkyl, ar(lower)alkenyl, carboxy(lower)alkyl, protected carboxy(lower)alkyl, isoxazolyl(lower)alkyl or ar(lower)alkyl which may have halogen, hydroxy, amino(lower)allvl or acyiamino- (lower)alkyl; R3 is carboxy or a protected carboxy; and R4 is acetoxy, thiadiazolylthio, tetrazolylthio, which may have lower alkyl, or tetrazolopyridazinylthio, with the proviso that R2 is not carboxy(lower)alkyl, protected carboxy(lower)alkyl or benzyl when R4 is acetoxy or tetrazolylthio having a methyl, as substituent, and pharmaceutically-acceptable salts thereof.

These 3,7-disu bstituted-3-cephem-4-ca rboxylic acid compounds have antibacterial activity and form the subject of our copending Patent Application published under the No. 2031413 A.

The compounds of the invention can be prepared by the processes which are illustrated by the following scheme.

wherein R1 and R2 are each as defined above, R1a is a protected amino Z is a protected carboxy and Y is halogen.

It is to be understood that the compounds of the invention include tautomeric isomers relating to their thiazole group. That is, in case that the group represented by the formula:

(wherein R' is as defined above) in the formula of said object and starting compounds take the formula:

(R1 is as defined above), said group of the formula:

can also be alternatively represented by its tautomeric formula:

(wherein Rib is imino or a protected imino). That is, both of the said groups (A) and (B) are in the state of equilibrium as so-called tautomeric forms which can be represented by the following equilibrium:

(wherein R1 and Rib are each as defined above).

These types of tautomerism between 2-amino-thiazole compounds and 2-iminothiazoline compounds as stated above have been well known in the literature, and it is obvious to a person skilled in the art that both of the tautomeric isomers are equilibrated and easily convertible reciprocally, and accordingly it is to be understood that such isomers are included within the same category of the compound per se. Accordingly, both of the tautomericforms of the compounds of the invention are clearly included within the scope of the present invention. In the present specification and examples, the object compounds including the group of such tautomeric isomers are represented by using one of the expressions therefor, that is the formula:

only for the convenient sake.

Furthermore, it is to be understood that the object compounds include syn-isomer, anti-isomer and a mixture thereof. For example, regarding the object compound, said syn-isomer can be represented by the partial structure of the formula:

in its molecule, while the corresponding anti-isomer is represented by the partial structure of the formula:

in its molecule, and in case that it is convenient for the explanation of this invention to express both of the syn-isomer and anti-isomer by one general formula, it is represented by the partial structure of the formula:

In the above and subsequent descriptions of the present specification, suitable examples and illustrations of the various definitions which the present invention intend to include within the scope thereof are explained in details as follows.

The term "lower" is intended to mean 1 to 6 carbon atom(s), unless otherwise provided.

Suitable protected amino may include an acylamino and amino group substituted by a conventional protective group other than the acyl group such as ar(lower)alkyl (e.g. benzyl, trityl, etc.) or the like.

Suitable protected imino may include an acylimino and imino group substituted by a conventional protective group other than the acyl group such as ar(lower)alkyl (e.g. benzyl, trityl, etc.) and the like.

Suitable acyl moiety in the terms "acylamino" and "acylimino" may include carbamoyl, aliphatic acyl group and acyl group containing an aromatic or heterocyclic ring. And, suitable examples of the said acyl may be lower alkanoyl (e.g. formyl, acetyl, propionyl, butyryl, isobutyryl,, valeryl, isovaleryl, oxalyl, succinyl, pivaloyl and hexanoyl), preferably one having 1 to 4 carbon atom(s), more preferably one having 1 to 2 carbon atoms(s); lower alkoxycarbonyl having 2 to 7 carbon atoms (e.g. methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, 1 -cyclopropylethoxyca rbonyl, isopropoxycarbonyl, butoxycarbonyl, t-butoxycarbonyl, pentyloxycarbonyl, t-pentyloxycarbonyl and hexyloxycarbonyl); lower alkanesulfonyl (e.g. mesyl, ethanesulfonyl, propanesulfonyl, isopropanesulfonyl and butanesulfonyl); arenesulfonyl (e.g. benzenesulfonyl and tosyl); aroyl (e.g. benzoyl, toluoyl, naphthoyl, phthaloyl and indancarbonyl); ar(lower)alkanoyl (e.g.

phenylacetyl and phenylpropionyl);and ar(lower)alkoxycarbonyl (e.g. benzyloxycarbonyl and phenethyloxycarbonyl).

The acyl moiety as stated above may have 1 to 3 suitable substituent(s) such as halogen (e.g. chlorine, bromine, iodine or fluorine), hydroxy, cyano, nitro, lower alkoxy (e.g. methoxy, ethoxy, propoxy or isopropoxy), lower alkyl (e.g. methyl, ethyl, propyl,isopropyl or butyl), lower alkenyl (e.g. vinyl or allyl), or aryl (e.g. phenyl ortolyl).

Preferable example of acylamino may be loweralkanoylamino or mono-, di-ortrihalo(lower)alkanoylamino.

Suitable lower alkenyl is one having from 2 to 6 carbon atoms and may include, for example, vinyl, allyl, isopropenyl, 1-propenyl, 2-butenyl,3-pentyl and the like.

Suitable aryl moiety in the ar(lower)alkenyl group for R2 may include phenyl, tolyl, xylyl, mesityl, cumenyl, naphthyl and the like, wherein said aryl may have from 1 to 3 suitable substituents such as halogen (e.g.

chlorine, bromine, iodine or fluorine), hydroxy,amino(lower) alkyl (e.g. aminomethyl, aminoethyl, aminopropyl, and aminobutyl) or protected amino(lower)alkyl, wherein "protected amino" is as defined above, preferably lower alkoxycarbonylamino (lower alkyl) e.g. methoxycarbonylaminomethyl, ethoxycarbonylaminomethyl, t-butoxycarbonylaminomethyl etc.). A preferred ar(lower)alkenyl group for R2 is cinnamyl.

Suitable protected carboxy for the "Z" group above, may include esterified carboxy in which the ester moiety may be one such as lower alkyl ester (e.g. methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester, t-butyl ester, pentyl ester, t-pentyl ester, hexyl ester or 1-cyclopropylethyl ester), wherein lower alkyl moiety may preferably be one having 1 to 4 carbon atom(s); lower alkenyl ester (e.g.

vinyl ester or allyl ester); lower alkynyl ester (e.g. ethynyl ester or propynyl ester); mono-(or di-or tri-)-halo(lower)alkyl ester (e.g. 2-iodoethyl ester or 2,2,2,-trichloroethyl ester); lower alkanoyloxy(lower)alkyl ester (e.g. acetoxymethyl ester, propionyloxymethyl ester, butyryloxymethyl ester, valeryloxymethyl ester, pivaloyloxymethyl ester, hexanoyloxymethyl ester, 2-acetoxyethyl ester or 2-propionyloxyethyl ester); lower alkenesulfonyl(lower)alkyl ester (e.g. mesylmethyl ester or 2-mesylethyl ester, etc.); ar(lower)alkyl ester, for example, phenyl(lower)-alkyl ester which may have one or more suitable substituent(s) (e.g. benzyl ester, 4-methoxybenzyl ester, 4-nitrobenzyl ester, phenethyl ester, trityl ester, diphenylmethyl ester, bis(methoxyphenyl)-methyl ester, 3,4-dimethoxybenzyl ester, 4-hydroxy-3,5-ditertiarybutylbenzyl ester, etc); aryl ester which may have one or more suitable substituent(s) (e.g. phenyl ester, tolyl ester, tertiarybutylphenyl ester, xylyl ester, mesityl ester or cumenyl ester and the like.

Preferable example of protected carboxy may be lower alkoxycarbonyl (e.g. methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, t-butoxycarbonyl, t-pentyloxycarbonyl, hexyloxycarbonyl, etc.) having 2 to 7 carbon atoms, preferably one having 2 to 5 carbon atoms.

Suitable lower alkoxy may include one which may be branched, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxy and the like, and preferably one having 1 to 4 carbon atom(s), and more preferably one having 1 to 2 carbon atom(s). Preferable example of R2 may be phenyl(lower)alkenyl).

Suitable halogen may include chlorine, bromine fluorine and iodine.

Suitable salt of the compounds of the invention may include an acid addition salt such as an organic acid salt (e.g. acetate, maleate, tartrate, benzenesulfonate ortoluenesulfonate) or an inorganic acid salt (e.g.

hydrochloride, hydrobromide, sulfate or phosphate); a metal salt (e.g. sodium salt, potassium salt, calcium salt or magnesium salt); ammonium salt; and an organic amine salt (e.g. triethylamine salt or dicyclohexylamine salt).

Example 1 To a suspension of N-(cinnamyloxy)phthalimide (21.0 g) in ethanol (200 ml) was added hydrazine hydrate (8.3 g) at 60"C and the mixture was stirred for 1.5 hours at the same temperature. To the mixture were added conc. hydrochloric acid (22 ml) and water (220 ml) and the resulting mixture was filtered. The filtrate was concentrated to give precipitates, which were filtered off. The filtrate was adjusted to pH 7.0 and to the solution containing O-cinnamyl hydroxylamine were added ethanoi (300 ml) and 2-(2-formamidothiazol-4yl)glyoxylic acid (10.0 g). The mixture was stirred for 2 hours at pH 4.0 to 4.5.

The reaction mixture was concentrated and adjusted to pH 2.0 after addition of ethyl acetate. The organic layer was washed with an aqueous solution of sodium chloride, dried over magnesium sulfate and evaporated to give 2-cinnamyl-oxyimino-2-(2-formamidothiazol-4-yi)-acetic acid (syn isomer) (8.6 g).

I.R. (Nujol) (RTM) 3400-3100, 1700, 1550cm N.M.R. (DMSO-d6, ( 4.85 (2H,d, J J=5Hz), 6.2-6.93 (2H,m), 7.2-7.72 (5H,m), 7.6(1 H,s),8.57(1 H,s),1 2.7(1 H, broad s).

Claims (3)

1. Acompound oftheformula:

wherein R1 is amino or a protected amino and R2 is ar(lower)alkenyl, and a salt thereof.

2. Syn isomer of a compound of claim 1, wherein R2 is cinnamyl.

3. A process for preparing a compound of the formula:

wherein R' is amino or a protected amino and R2 is ar(lower)alkenyl, or a salt thereof, which comprises reacting a compound of the formula:

wherein R1 is as defined above, with a compound of the formula: R2-ONH2 wherein R2 is as defined above or a salt thereof.