JPS61106582A - Cephem derivative - Google Patents

Abstract

NEW MATERIAL:A compound shown by the formula I (R<1> is H, or methyl; R<2> is group shown by the formula II; n is 0 or 1). EXAMPLE:7-[(Z-2-Methoxyimino-2-(thiazol-4-yl)acetamido]-3-(3-methyl-1, 2,4-thia diazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid(5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl ester. USE:An antibacterial agent. A preventive and remedy for microbism for oral administration. PREPARATION:A compound shown by the formula III (R<3> is as shown for R<2>, or carboxyl, etc.) is reacted with a compound shown by the formula IV in an inert solvent at <=50 deg.C, and, if necessary, a protective group is removed, and esterified further to give a compound shown by the formula I.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel cephem derivative, and more particularly, it has the general formula (r) (wherein R1 is a hydrogen atom or a methyl group, generally a group represented by the formula, and n is 0 or 1).

The 7-position side chain portion of the general formula (I) has geometric isomers such as syn isomer and anti isomer, but the preferred compound is the syn isomer.

In recent years, the development of cephem antibiotics as therapeutic agents for infectious diseases has been remarkable, and compounds with antibacterial activity and a broad antibacterial spectrum are now commercially available. However, all of these compounds are poorly absorbed when administered orally, and are only effective when injected.

1 Orally administered cephem antibiotics and compounds such as cefatridine and cefaclor are used for treatment, but these have somewhat weak antibacterial activity, have a somewhat narrow antibacterial spectrum, and are resistant to beta-lactamase production. Since it is ineffective against bacteria, it is desired to develop a compound that is further improved against these bacteria.

On the other hand, among penicillin compounds, compounds whose carboxylic acids are esterified to increase oral absorption as so-called prodrugs are in clinical use. It is thought that it is hydrolyzed by enzymes present in body tissues, becoming the parent compound of the original carboxylic acid and exerting its effects. Similar attempts have been made with cephalosporin compounds, but so far no compound has been found that has sufficient oral absorption to be used clinically.

That is, a certain heel ester group that is effective in increasing the oral absorption of penicillin compounds may not be equally effective in cephalosporin compounds.

The present inventors have repeatedly conducted research on improving oral absorption using prodrugs of cephalosporin compounds, but oral absorption was completely unpredictable and greatly depended on the structure and properties of the selected parent compound. I found out that it depends.

The present invention was completed based on this knowledge, and among the compounds of the present invention represented by the general formula (I), the compound in which n is O has a high It is a compound with excellent properties such as oral absorption and rapid decomposition by esterase. Furthermore, the sulfoxide compound where n is 1 is useful as an intermediate in producing the above-mentioned compound of the present invention where n is 0, as described below.

The compound of the present invention in which n is 0 has excellent oral absorption, and after absorption becomes the parent compound represented by the general formula (xI) (xI) (wherein R1 is as described above). It is effective.

One of the characteristics of this parent compound is that it is highly excreted into urine.

Therefore, the above-mentioned ester compound of the present invention is an extremely valuable compound or product as an orally administered drug for preventing or treating bacterial infections.

The parent compound represented by the general formula (XI) has strong anti-aging activity against Durum-positive bacteria and Durum-negative bacteria, and also has strong antibacterial activity against beta-lactamase-producing resistant bacteria. Next, a method for producing the cephem compound of the present invention, which is a useful compound in itself, will be explained.

The compound of the present invention can be produced according to a known method. For example, the following ta) * (b)
, I tc).

(a) General formula (m) R3 (In the formula, n and R1 are the same as above. Bll has the same meaning as above or represents a carboxyl group or a protected carboxyl group.) 7 -amino-8-(1,2,4-thiadiazol-5-yl)thiomethyl-8-cephem-4-carboxylic acid derivative (i, acyl In the case where R3 is a protected carboxyl group, the protecting group is removed and the carboxyl group is further converted into nisteryl.

(b) General formula (IT) R device (in the formula, R3 and = are the same as above.
a or a halogen atom. ) A method of esterifying the 8-position X of a compound represented by 3-(substituted or unsubstituted)-1,2,4-thiadiazole.

(0) A method for deriving the 7-position acyl group of the compound (I) of the present invention from another acyl group.

Below, the above methods (a), (b) and (C) will be explained in further detail.

(1 &) By reacting the carboxylic acid represented by the general formula (I[) or its reactive derivative with the compound represented by the general formula (m) or its salt, the general formula (■
') (where n, Bl and R8 are the same as above) or a salt thereof can be obtained. Furthermore, L
When the group represented by is a carboxyl group or a salt thereof, the compound of the present invention represented by the general formula (I) can be obtained by esterifying the compound.

Further, when the group represented by R8 is a protected carboxyl group, the protecting group of the compound is removed and then esterified.

A reactive derivative of a compound or product represented by the general formula (II) means a reactive derivative of a carboxyl group that can form an amide bond with a compound represented by the general formula (01), such as an acid Examples include acid anhydrides, acid azolides, active esters, and acid azides. More specifically, dialkyl phosphoric acid, phenyl phosphoric acid, diphenyl phosphoric acid,
Dibenzyl phosphoric acid, dialkyl phosphorous acid, methanesulfonic acid, toluenesulfonic acid, naphthalenesulfonic acid,
Alkyl carbonates, aliphatic carboxylic acids (e.g. pivalic acid, pentanoic acid, isopentanoic acid, 2-ethylbutanoic acid)
, mixed or symmetrical acid anhydrides with acids such as aromatic carboxylic acids; acid azolides with imidazole, substituted imidazole, dimethylpyrazole, triazole, tetrazole, etc.; cyanomethyl ester, methoxymethyl ester, p-nitrophenyl Esters, 2,4-dinitrophenyl ester, trichlorophenyl ester, pentachlorphenyl ester, methanesulfonylphenyl ester, phenylthiophenyl ester, P-nitrophenyl thioester, baracryl thioester 1
．． Carboxymethyl thioester, pyranyl ester,
Pyridyl ester, piperidyl ester, 8-quinolylthioester, or N,N'-dimethylhydroxylamine, 1-hydroxyni2(IH)-pyridone, N-
Examples include active esters such as esters with hydroxyphthalimide, N-hydroxyphthalimide, or hydroxybenttriazole.

Furthermore, when the compound represented by the general formula (n) is used in the form of a free acid (or a salt thereof), the amidation reaction can be carried out in the presence of a binder. As a binder,
For example, N.

N'-dicyclohexylcarbodiimide, N-cyclohexyl-N'-morpholinoethylcarbodiimide, N-
Cyclohexyl-N'-(4-diethylaminocyclohexyl)carbosiba)1 imide, N, N
'-diethylcarbodiimide, N,N'-diisopropylcarbodiimide, N-,ethyl-N'-(3-dimethylaminopropyl)carbodiimide, N,N'
-Carbonylbis(2-methylimidazole), pentamethyleneketene-N-cyclohexylimine, diphenylketene-N-cyclohexylimine, alkoxyacetylene, 1-alkoxy-1-chloroethylene, phosphorous acid trialkyl ester, polyphosphoric acid ethyl ester ,
Polyphosphoric acid isopropyl ester, phosphorus oxychloride, phosphorus trichloride, thionyl chloride, oxalyl chloride, triphenylphosphine, 2-ethyl-7-hydroxybenzisoxazolium salt, 2-ethyl-5-(m-sulfonyl)iso Vilsmeier reagents such as compounds produced from xazolium hydroxide inner salt, (chloromethylene)dimethylammonium chloride, phosphorous oxychloride and dimethylformamide, and the like can be mentioned.

Thus, amidation methods commonly used in peptide chemistry, penicillin-cephalosporin chemistry, or other fields are employed in the present invention.

As the salt of the compound of general formula (IIL), general formula (m)
Salts of compounds represented by with organic bases such as sodium, calimine, triethylamine, quinoline salts, and collidine salts; organic sulfonates such as toluenesulfonic acid, naphthalenesulfonic acid, and tetralinsulfonic acid; hydrochlorides;
Examples include inorganic salts such as sulfates and nitrates.

The protected carboxyl group represented by the general formula (A) includes, for example, a carboxyl group protected by esterification or amidation. After the acylation reaction, the protected carboxyl group is Groups that readily decompose to give the free carboxylic acid by hydrolysis or alcoholysis, hydrogenolysis, reduction, oxidation, nucleophilic substitution, photoreaction, or enzymatic reaction in the medium are desirable. Such protection Examples of the carboxyl group derivatives include silyl ester, organotin ester, toluenesulfonyl ester, baranitrobenzyl ester, diphenylmethyl ester, trityl ester, trichloroethyl ester, phthalimidomethyl ester, 2-nitrobenzyl ester, 2.
Examples include known carboxylic acid protecting groups such as 2-dinitrobenzyl ester. Furthermore, in the case of a silyl ester, a site that can be silylated, ie, an amino group, may be silylated.

More specifically, the inert solvent used in the reaction between the compound represented by the general formula (n) and the compound represented by the general formula (III) includes dichloromethane, chloroform,
Polar solvents such as acetone, tetrahydrofuran, dioxane, acetonitrile, methyl isobutyl ketone, dimethylformamide, dimethylacetamide, dimethyl sulfoxide, hexamethylphosphoric triamide, sulfolane; or nonpolar solvents such as benzene, toluene, petroleum ether, n-hexane; Mixed solvents thereof are used. Depending on the case, a water-containing mixed solvent thereof may also be used.

A carboxylic acid represented by general formula (II) or a reactive derivative thereof and a compound represented by general formula (m) or a salt thereof,
The reaction temperature with the compound or its derivative can be set to any desired temperature, but is usually 50°C or less.

The compound represented by the general formula (I') can be produced in the manner described above. Here, the group represented by 8 is
When the compound is a carboxyl group or a salt thereof, the compound of the present invention represented by the general formula (I) can be produced by esterifying the compound.

The esterification reaction can be carried out by a method known per se. For example, a compound in which the group represented by 8 in general formula (■')/1' is an alkali metal salt of a carboxyl group, and a halogen compound (preferably iodine, bromine or chloride compound) corresponding to the alcohol moiety forming an ester. ) in an inert solvent to produce an ester compound. At this time, known methods such as a method of carrying out esterification in the presence of a crown ether or in the presence of a phase transfer catalyst can be used. Further, it is advantageous to carry out this esterification reaction in the presence of a base, and as the base, an organic base such as triethylamine or an inorganic base such as sodium carbonate or potassium carbonate is advantageously used. .

When alcohol is used as an esterification agent,
The reaction is preferably carried out in the presence of a condensing agent. Examples of such condensing agents include, for example, N,N'-dicyclohexylcarbodiimide, N,N'-□diethylcarbodiimide, N-cyclohexyl-N'-(4-
carbodiimide compounds such as diethylaminocyclohexyl)carbodiimide, sulfonic acid esters of N-hydroxybenzotriazole derivatives such as 1-(4-chlorobenzenesulfonyloxy)-6-chloroIH-benzotriazole, benzenesulfonic acid chloride, dimethylformamide and Examples include so-called Vilsmeier reagents produced by reactions with halogen compounds such as thionyl chloride and phosphorus oxychloride.

Although the reaction temperature is not particularly limited, it is usually carried out at 50°C or less. As the inert solvent used for esterification, the same inert solvent used for the above-mentioned amidation reaction is used.

When the product obtained by the above-mentioned esterification reaction is a sulfide compound where n is 0, 2-
May contain cephem bodies. In this case, the 2-cephem compound can be removed by subjecting the product to operations such as recrystallization and reprecipitation, column purification, etc. Alternatively, a product containing 2-cephems is oxidized with metachloroperbenzoic acid, peracetic acid, periodic acid, etc.
By reducing the cephem-1-oxide form with, for example, a combination of phosphorus trichloride, stannous chloride and 7-cetyl chloride, substantially pure 8-8-
The ester form of cephem can be obtained. Oxidation of the sulfur atom of the cephem ring can be carried out according to conventional methods. Depending on the oxidizing agent used at that time, 8- and 3-oxides are produced, both of which are included in the present invention. Oxidation of the sulfur atom of the cephem ring and its reduction are described, for example, in Vcaphalospori, edited by E. Flynn.
ns and penicillins.

Chemistry and BiologyJ (
Mu academic press.

(1972) Chapter 4, pages 18-5.

The raw material compound represented by general formula (II) is produced, for example, by the method described in JP-A-54-154785 and JP-A-55-138885.

Further, the raw material compound represented by the general formula (m) is, for example, 7
A known method for reacting aminocephalosporanic acid with 8-(substituted or unsubstituted)-1,2,4-thiadiazole-5-thiol (for example, U.S. Pat. No. 8.97
9.888 specification, JP-A-58-98987, 55
-9048, 55-049888, 57-8289
(described in Japanese Patent No. 2').

Direction General formula <rv> a (In the formula, B1.n and X are the same as above.) The 3-position X of the compound represented by
After nucleophilic substitution with 1,2,4-thiadiazole-5-thiol, the protecting group is removed and the carboxyl group is esterified as necessary to obtain the general formula (I).
The compound of the present invention represented by can be obtained. A known method can be applied to the nucleophilic substitution method itself. 〔for example,
F4 Flynn lI “0ephalosporins
and penicillins -Ohami
Try and Biology J (Aca
demicpress, 1972) Chapter 4, Chapter 15
8 pages, JP-A-58-180689, J Elk
s Edit 1 macent Advances in th
e Chemistry of 7-Lactam An
tibiotics, Cambridge.

England, 2g-gQ June,
1976 J(The Chemical 8
ociety, Burlington E[ous
e, London WLV OBN) page 109.

Tezrahedron Letters 22
, 8915 (1981). ] The compound of the general formula (rV) is obtained by combining the carboxylic acid of the general formula (I[) and the compound represented by the general formula (V) (wherein, It can be produced by reacting in the same manner as the method for obtaining the compound represented by (I').

Further, among the compounds represented by the general formula (rV), compounds in which X is a halogen atom are described, for example, by J Elks, i
Collection ``Racant Advances in th''
e Chemistry ofp-Laotam An
tibiotics Cambridge.

England, 28-80 June, 19
75 J (theChsimicaL8ociat
y, Burlington House.

London WIV OBN’) page 106.

Tetrabsdron Letters 22
, 8915 (1981).

The halogen atom refers to an iodine atom, a bromine atom, and a chlorine atom.

(C) Examples of methods for chemically deriving the 7-position acyl group of the compound represented by formula (f) from other acyl groups include the following method.

A carboxylic acid represented by the general formula <VX> or a reactive derivative thereof is reacted with a compound represented by the general formula (m) or a salt thereof or a derivative thereof to form a compound represented by the general formula (VU) (where n, R', R'' is the same as above.) is obtained, and then reacted with methoxyamine, followed by removal of the protecting group and esterification of the carboxyl group as necessary to obtain the compound represented by the general formula (I). Method of obtaining invention compounds.

Alternatively, the general formula (■) R8 (in the formula, BJI, 7. and n are the same as the above l)
The 8th position of the compound represented by
After the reaction with methoxyamine in step t), the protecting group is removed and the carboxyl group is esterified as necessary to obtain the compound of the present invention represented by the general formula (I). How to get.

Or general formula (X) (In the formula, Bl, Bl and n are the same as above.

After reacting the compound represented by (X' represents a chlorine atom or a bromine atom) with thioformamide, the protecting group is removed and the carboxyl group is esterified as necessary to obtain the compound represented by the general formula (I). The carboxylic acid represented by the general formula (Vt) is a known compound and is described, for example, in JP-A-54-154785.

A compound represented by the general formula (VI) and a compound represented by the general formula <m> are reacted to form the general formula (■
) The method for obtaining the compound represented by the above-mentioned general formula (I
It can be produced in the same manner as the method for producing the compound represented by general formula (I) by reacting the compound represented by [) with the compound represented by general formula (m).

The reaction between the compound represented by the general formula (■) and methoxyamine can be carried out according to known methods (for example, JP-A-54-52096).

The compound represented by general formula (X) can also be produced according to known methods. (For example, JP-A-58-18
5996) A method for obtaining a compound represented by general formula (I) by reacting a compound represented by general formula (X) with thioformamide can also be carried out according to known reaction conditions.

As mentioned above, the sulfide compound of the present invention in which n is 0 has excellent oral absorbability and is therefore useful as an orally administrable antibacterial agent.

When administering the compound of the present invention orally, capsules, powders, granules, tablets, etc. can be prepared and administered according to conventional formulations for oral administration. and the usual excipients, binders, etc.

It can contain lubricants, fire agents, disintegrants, etc.

The compounds of the present invention represented by general formula (r) can also be formulated as rectal compositions (eg, suppositories or retention enemas) or as injections.

The dosage varies depending on age, body weight, symptoms, etc., but it can usually be administered to adults at 0.2f to 21f/day in one or several divided doses.

Next, in order to clarify the excellent properties of the compound of the present invention,
Oral absorption test results and antibacterial test results are shown.

Next, the method for producing the compound of the present invention will be specifically explained with reference to Examples, but the present invention is not limited thereto.

(a) Dissolve 18.6jF of (Z)-2-methoxyimino-2-(thiazol-4-yl)acetic acid in dimethylformamide 100-, and add 1-hydroxybenzotriazole 18.5F and dimethylformamide 100-
A solution consisting of was added. Then, the mixture was stirred at 30° C. for 2 hours using a dicyclohexyl carboxylic acid tF22.7N4 tube.

The generated urea compound was removed, and the R solution was added dropwise into 1250ml of cold water. After stirring for 1 hour under water cooling, the precipitate was removed.
After washing with water and drying under reduced pressure, active ester compound 29.81 was obtained.

IR(nujol)1820. 1725 cIR-1
"H-NMR (DMSO-cl g > δ value; 4.00
(S, lH), 7.6 ~ 8.4 (m, 4H)
.

8J8 (d, In), 9.17 (d, ll1)
(b) 7-Amino-8-(8-methyl-1,2゜4-thiadiazol-5-yl)thiomethyl-8-cephem-
4-carboxylic acid L72f with dimethylformamide 8-,
Triethylamine 1. In addition to the solution of OlN, the active ester compound 1.82F was added while cooling with water, and the mixture was stirred for 4 hours. The reaction solution was poured into 100 ml of water, and the pH was adjusted to 2.0 with 2N HCl while cooling with water. The precipitated crystals were collected, washed with water, and dried under reduced pressure over phosphorus pentoxide to obtain the title compound 1.651.
I got it. This product was subjected to reverse phase liquid chromatography [Column: Li chloroprep ■IILP-gKeys B
(810X-25 size), manufactured by Merck; Mobile phase: 0.01
M phosphorus-buffer-acetonitrile (88-22, v/v
)'), take the necessary fractions and concentrate under reduced pressure.
A purified product of the title compound was obtained by acid precipitation.

IHNMR (DM80-d6) δ value; 2.52 (8,8H,OHa), 3.55.8.
76(AB(1.

2JJ=1gH2,02-n2).

8.91(s, IH, OCE[a), 4.24.4.6
8 (ABq.

2H, J = 18H2, Ca -01112).

5.16 (d, IJJ=5Hz, C5-H).

5.88 (dd, LH, J=8.5Hz', Cy-H
).

7.98 (d, IH, J=2Hz, thiazole 5th H)
.

9.15 (d, LH, J=2Hz, thiazole 2-position H)
.

9.68 (d, IE, J=gHz, -〇〇NM-
) Bonic acid 7-amino-8-(1,2,4-thiadiazole-; LI-
Add 8.81f of 5-yl)thiomethyl-8-cephem-4-levonic acid to a solution of 15-dimethylformamide and 2.02jF of triethylamine to obtain the active ester compound 8.68f described in Reference Example 1(a). Add and cool on ice, 5
Stir for hours. The reaction solution was poured into 300ml of diethyl ether with stirring. After standing still, the upper diethyl ether layer was removed, and the lower oil layer was dried under reduced pressure to obtain a calomel-like substance containing the title compound. Dissolve this in sodium bicarbonate water to create a reverse phase liquid. v8 Guu, E [Kau A: Lichro
prep■RF-8; Size CX 2 pieces (manufactured by Merck);
Mobile phase: 0.01M phosphate buffer-acetonitrile (8
6-14, V/v)], take the necessary fractions, concentrate under reduced pressure, acid precipitate with 6N-HCt, and dry under reduced pressure over phosphorus pentoxide to obtain a purified product of the title compound (0.79 g).
I got f. Furthermore, the t solution was extracted with ethyl acetate, dried with magnesium sulfate, and concentrated to dryness.11:
The title compound was obtained with a concentration of 0.281.

IHNMR (DMSO-d6) δ value; 8.58,
8.77CABq, gH, J=1gHz, C2=H2
').

3.91 (11, BIl, CH8).

4.82, 4.60 (ABq, 2J J=13
fIz, 0s-(H2).

5.17 (d, LH, J-5fiz, 0s-H).

5.84 (dd, IH, J=8.5Hz, 07-II)
.

7.94 (d, tH, J=2Hz, H at 5-position of thiazole)
.

8.72 (8, IH/thiadiazole 8th H).

9.15 (d, IH, J = 2Hz, thiazole 2-position H).

9.58(d, IH, J=glllz, -CON
H-) 0.791 of the title compound was dissolved in 10 m of water and 0.18 m of baking soda.
The sodium salt of the title compound was obtained by dissolving in an aqueous solution consisting of 5f and freeze-drying.

2-methoxyimino-2-(thiazole-
4-yl)acetamido)-3-(3-methyl-1,2
,4-thiadiazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid sodium 586q to N,N-
After dissolving in dimethylformamide 5- and cooling to -5°C, 4-bromomethyl-5-methyl-1,8-dioxolen-2-one 886-f was added and stirred at the same temperature for 1.3 hours. This reaction solution was poured into a stirred mixture of ethyl acetate 180.r+j and water (adjusted to pH 8 with dilute hydrochloric acid) and 80-.The ethyl acetate layer was separated and separated, and water (adjusted to pTIB with dilute hydrochloric acid) was poured into the mixture. After washing sequentially with 80 d of water, 30 d of 10% dipotassium phosphate aqueous solution, and 20 d of saturated saline,
It was dried with magnesium sulfate. The ethyl acetate layer was concentrated under reduced pressure, and the residue was diluted with 40% ether. d, petroleum ether 40-
The precipitated crystals were collected and washed with petroleum ether. Drying under reduced pressure gave the title compound 890q.

'HNMfL (DM80-da) a value (PPm);
2.50-2.52 (thiadiazole 8th position (H8).

overlaps with the measurement solvent DM80).

8.59.8.79 (ABq, 2H, J=18] 111
Z, C2-H2).

8.90 (8, 8H, -〇(Ha)).

4.22, 4.57 (MuBq, 2H, J=18.5
Hz, Ca-CH2).

5.87 (dd, III, C7-H).

'7.98 (d, LH, J-2Hz, thiazole 5-position H).

9.15 (d, LH, J=2Hz, thiazole 2nd position I
I).

9.67 (d, tH, J=gHz, -CONH-)7-
[(Homogenous 2-methoxyimino-2-(thiazole-4-
yl)acetamido)-8-(1,2,4-thiadiazol-5-yl)thiomethyl-3-ceph,em-4-carboxylic acid sodium 522wIf was dissolved in N,N-dimethylformamide 5d and heated to -5°C. It was cooled to

, 4-bromomethyl-5-methyl-IJ8-dioi-solen-2-one 8'86 was added and stirred at the same temperature for 1.8 hours. Example 1 and the parent species ":" were treated to yield the title compound 190.

IHNMR (DM80-da) a value (ppm); stone 8.61, 8.80 (MuBq, 2H, J = 18Hz
, C2-H2).

8.90 (s, 8H9OCHs).

4.24, 4.64 (MuBq, 2H, J-14Hz
, On -CH2).

δ 5J6 (dd, LH, Cy-II).

7.91 (d, IH, J-2Hz, thiazole 5th H)
68.69 (s, III, thiadiazole 8th H) s9
．． 16 (d, 2 Hz in IL, thiazole 2-position H).

Claims (2)

[Claims] (1) General formula▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R^1 is a hydrogen atom or a methyl group, and R^2 is a group represented by the formula▲There are mathematical formulas, chemical formulas, tables, etc.▼ , n represents 0 or 1). (2) The cephem derivative according to claim 1, wherein the side chain moiety at position 7 is an isomer with syn coordination, represented by the formula ▲ Numerical formula, chemical formula, table, etc. ▼.