JPS609515B2 - 3'-Noroxacephalosporins - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to 1-oxadethia 3-cephem compounds and derivatives thereof.

More specifically, it relates to 3-substituted or unsubstituted-7-acylamino-1-oxa-1-dethia-3-cephemu-4-carboxylic acid and derivatives thereof. The compound of the present invention can be represented by the following general formula. {During the ceremony,
× is a hydrogen atom or a methoxy group, Y is a hydrogen atom, a lower alkoxy group, a halogen atom, a lower alkylsulfonyloxy group, or a lower alkyltetrazolylthio group, Z is a group [where RI is a fenyl group or a chenyl group, R2 is hydrogen Atom, one OR3 group, one NHR3 group or -C
OOR3 group, R3 is a hydrogen atom, formyl group, lower alkoxycarbonyl group, (nitro or phenyl) penzyl group, lower alkyl group or lower alkyl diketopiverazinyl carboninole group] R is a hydrogen atom or (nitro or phenyl ) penzyl group, respectively} In the compound represented by the general formula (1), when R is a hydrogen atom, or when a free carboxyl group or amino group is present in the 7-position acylamino group,
Salts may be formed with pharmaceutically acceptable inorganic or organic acids or bases.

The compound of the present invention represented by general formula (1) has the corresponding 7
-Amino transfer derivative (produced by acylating the following general formula m).

The reaction process can be expressed as follows. Reaction process diagram 1 (However, in the formula, ×, Y, Z, and R have the same meanings as described above.

) The raw material compound represented by the general formula (b) is the raw material compound represented by the general formula (a).
} (Tokusekki Sho 51-41385)
Therefore, it can be produced by the method shown in reaction process diagram 2.

In Reaction Process Diagram 2, "The terminus represents an amino protecting group, L represents a halogen atom or a sulfonyloxy group, Y' represents a hydrogen atom, an arylthio group or a monocyclic heterocyclic thio group, and R' represents a lower alkyl group." .

The reaction to the raw material compounds 'ame) and 'b} is carried out using the 3-position hydroxyl group (
halogenation or sulfonylation of the phenolic hydroxyl group), and this reaction introduces a halogen atom or a sulfonyloxy group at the 3-position.

When the amino protecting group Z' is removed from the intermediate [b',
In the raw material compound (0) of the present invention, compounds where X=day and Y=halogen atom or sulfonyloxy group are obtained. On the other hand, if the intermediate {b} is subjected to a reduction reaction (preferably under zinc monoacetic acid conditions), the intermediate {ci(Y
=H) is obtained, and when subjected to a substitution reaction with an arylthiol or a monocyclic heterocyclic thiol, an intermediate {c-(Y=
an arylthio group or a monocyclic heterocyclic thio group).

When the amino-protecting group Z' is removed from these intermediates (c), compounds in which x=day and Y=arylthio group or monocyclic heterocyclic thio group are obtained in the starting material compound (b) of the present invention. When the raw material compound 'a- is subjected to an alkylation reaction (preferably a reaction using a diazoalkane), an intermediate compound (d- (R=lower alkyl group) in which Y corresponds to a lower alkoxy group) is obtained.

When the amino protecting group is removed in the same manner as described above, among the raw material compounds (0) of the present invention, compounds with x=day and Y=lower alkoxy group are obtained. When a methoxy group is introduced into these starting compounds (b) where X=day by a known method, starting compound (0) where X:OCH3 is obtained.

Known methods for introducing a methoxy group include, for example, the method described in Tokukan Sho 50-150394. The acylation reaction of the amino group at the 7-position shown in Reaction Process Diagram 2 may be carried out according to the acylation reaction method commonly used in the chemistry of penicillin and cephalosporin.

As an acylating agent, the desired acyl group Z (i.e. Z-CO
), or reactive derivatives thereof, such as acid halides, acid anhydrides (including mixed acid anhydrides), esters, azides, imidazolides,
Pyrazolides, triazolides, etc. may be used. Any of these acylating agents can be subjected to an acylation reaction according to a known method, but among them, free carboxylic acids and acid halides, which are particularly useful in the present invention, will be exemplified below. When free carboxylic acid Z'-COO is used as an acylating agent on the 7-amino group, D
It is preferable to carry out the reaction in the presence of a carbodiimide such as CC (N·N-dicyclohexylcarbodiimide).

In this case, methylene chloride, acetonitrile, dimethylformamide, pyridine, tetrahydrofuran, or the like can be used as a reaction solvent, and the reaction can be carried out at room temperature or a temperature lower than that. When using an acid halide, specifically acid chloride or acid bromide is used, and the reaction is usually preferably carried out in an inert solvent under low temperature cooling. As the inert solvent, aprotic solvents such as benzene, ether, methylene chloride, and chloroform are preferably used. In carrying out these reactions, R in the starting compound (D)
= day, or if there is a functional group that is easily acylated (amino group, hydroxyl group, etc.) in another position, or if the acylating agent contains an amino group, hydroxyl group, carboxyl group, etc. It goes without saying that the reaction should be carried out with appropriate protection depending on the situation.

Introduction and removal of the protecting group may be carried out according to conventional methods.
The present inventors have confirmed that the compound (1) of the present invention has significantly superior antibacterial activity compared to known cephalosporin antibiotics having a normal cephalosporin skeleton (i.e., 1-thia). It was done.

In particular, it exhibits a strong antibacterial effect against Gram enterobacteria and negative bacteria, and can be used for the prevention and treatment of infectious diseases caused by these bacteria. For example, for the prevention or treatment of infectious diseases in humans, the usual daily dose is 10 to 5 days administered intravenously;
Alternatively, administer by other appropriate methods (orally, externally, etc.). The following examples detail embodiments of the invention, but the invention is not limited to these examples.

In the Examples and Tables, PNB represents p-nitrobenzyl and BOC represents t-butyloxycarbonyl. Example 1 78-(2-thienyl)acetamide 1-oxer 1
-Dethia-3-cephem-4-carboxylic acid:
．． 25 mmole) is suspended in three volumes of acetonitrile, and to this is added 100 moles (1 equivalent) of bis(trimethylsilyl)acetamide.

Add 35 grams of triethylamine (1 equivalent) to the mixture under ice-cooling, and stir at room temperature for 1. Insect time flies worship. This mixture was heated to -20o
41 mmol of N-methylmorpholine (1.5 equivalents) and 60 mmol of chenylacetyl chloride (1.5 mmol.)
After adding the equivalent amount of 100ml, the mixture was heated to room temperature again and incubated for 1 hour. This was cooled on ice, poured into a 5% aqueous phosphoric acid solution, and extracted with ethyl acetate. After washing the extract with water and drying, the solvent is distilled off under reduced pressure. The resulting residual groove 116 was analyzed by column chromatography (silica gel 12) and ethyl acetate-acetic acid (100:1
-50:1) and washing the eluate with petroleum ether gives the title compound 7 (90%) as a powder.
IR: Rehoko acid so 31790, 1680, 1515 skin-1
0NMR: (CDC130CD30D):64.53(
s, bait), 5.09 (d, IH, J=4.0HZ), 5
．． 49 (d, IH, J = 4.0 days 2), 6.52 (m,
IH), 7.05-7.32 (m, pan) leg.

Table 1 lists compounds synthesized from the corresponding 7-amino forms in a similar manner.

Table I Ship Example 2 [1] 78-(2-Phenyl-2-benzohydryloxycarbonyl)acetamide 1-oxa-1-decithia-3-cephem-4-carboxylic acid p-nitrobenzyl ester (1:X=Y= H:Z=C6 days 5CH<≦sa.

CH (C6 day 5) 2:R=C ratio C6 day 4N02) 78-
Amino-1-oxa-1-dethia-3-cephem-4-carboxylic acid p-nitrobenzyl ester (D:R=C
Ratio・C6日4・N02-p:X=Y=H) 76 of 9(0
．． Dissolve 238 moles of N-methylmorpholine in 8 volumes of methylene chloride, cool the mixture to -2000, and add 39 moles of N-methylmorpholine (1.5 equivalents).

Furthermore, 9 of 2-phenylmalonic acid/diphenylmethyl ester 124 (1.5 equivalents), triethylamine 50
(1.5 equivalents) and a methylene chloride solution of the acid chloride prepared from Ogisalyl chloride 30A was added and the mixture was heated at -2000 for 30 minutes. The mixed solution is poured into ice water, methylene chloride is added, and after washing with water and drying, the solvent is distilled off under reduced pressure. The remaining 244 p is column chromatographed (silica gel 6 nights) and eluted with benzene-ethyl acetate (5:1) to give the title compound 116-9 (75.3%) as a foam. 21R:〃CmH salt X and 31800/1730/1680/1640/1610
・1520/1350 skin-10NMR: (CDC13)
:64.47 (m, ga), 4.77 (s, IH), 5.
03 (d, IH, J = 4.0 days 2), 5.39 (s, pan), 5.73 (dd, IH, J: 4.0:9.0HZ)
, 36.57 (m, IH), 6.94 (s, IH), 7
．． 64-8.27 (N B2q, 4th, J=9.0HZ)
side.

■ 78-(2-phenyl-2-penzohydryloxycarbonyl)acetamido-1-oxa-1-dethia 3-cefim-4-carboxylic acid (1:Z=C6day5CH
NOCO :R=\COOCH(C6 day 5) 2X=
Y=H) Product 109 of Example 2-m (0.168 skin mol
Dissolve e) in a mixture of 5 parts of methylene chloride and 5 parts of acetic acid, and add 9 parts of 100 parts of activated zinc powder under ice cooling.

Stir the mixture for 60 minutes, then add 50 parts of zinc powder. After 70 minutes, the passed liquid is filtered, methylene chloride is added to the furnace liquid, and after washing with water and drying, the solvent is distilled off under reduced pressure. The resulting residual liquid is chromatographed. Dissolve in form, remove insoluble materials, perform column chromatography (silica gel for 2.5 min), and elute with ethyl acetate-chloroform-acetic acid (50:5:1). When this eluate was washed with petroleum ether, the title compound 53 was obtained.
(61.6%) is obtained. IR: Le Kinhei 318ou1
-10NM of 730, 1680, 1640/1520C
R: (CDC130 CD30D): 64.29 (b, 2
H), 4.78 (s, IH), 5.07 (d, IH, J
= 4.0HZ), 5.68 (d, IH, J: 4.0HZ
), 6.51 (m, 1H), 6.95 (S, IH) skin.

Specific optical rotation; [Q] volume. 5-5.9±1.90 (c=0.
239CHC13).

The compounds listed in Tables 2 and 3 were synthesized in the same manner as described above.

Table 1 Example 3 '1' 3-Chlor-7Q-methoxy73-(2-phenyl-2-benzohydryloxycarbonyl)acetamido-1-oxa-1-dethia 3-cephemu 4-carboxylic acid p-nitrobetanyl ester 2
At 0q0, methylene chloride was dissolved in J. Ren 3 skin, N-methylmorpholine 15 (1.5 equivalents) and 2-phenyl-2-benzohydryloxycarbonylacetyl chloride (1.5 equivalents) were added, and at the same temperature. Worship the hawk for an hour.

The mixture was cooled on ice, poured into a 5% aqueous phosphoric acid solution, and extracted with J ethyl acetate. After washing the extract with water and drying, the solvent is distilled off under reduced pressure. The obtained residual liquid 9 of 93 was subjected to column chromatography (
Silica gel (10:1) and benzene-ethyl acetate (10:1)
) to give 54m9 (83.2%) of the title compound. 2TLC: Rf = 0.30 (benzene: ethyl acetate = 5:1) IR: Rf 81795
, 1740, 1730, 1695・1350ka-10N
MR: (CDC13): 63.40, 3.44 (1:1
, 2 general), 4.33 (bs, ga), 4.44 (s, IH
), 5.13 (s, IH), 5.43 (ABq, ga),
6.97 (s, IH), 7.68 (d, J=9HZ, ga), 8.29 (d, J=9HZ, 2H) legs.

(2'3-chloro-7Q-methoxy-78-(2-3 phenyl-2-benzohydryloxycarbonyl)acetamido 1-oxer 1-dethia-3-cephemu 4-carboxylic acid Example 3-Product of 1-53 9 was dissolved in a mixture of 2.5 parts of methylene chloride and 2.5 parts of acetic acid,
While cooling on ice, add 50 parts of activated zinc powder and stir for 5 minutes.

The mixed solution is filtered, methylene chloride is added to the solution, washed with water, dried, and the solvent is distilled off under reduced pressure. The resulting residue 50% was subjected to column chromatography (10% water-silica gel 2.5 times) and eluted with chloroform-methanol (95:5) to yield the title compound 35 (81.6%) as a powder. It will be done. TLC: Rf=0.32 (Ethyl acetate: Acetic acid: Water = 18:1:1) IR: Les bonito 1757, 1702 arc-10 NMR: (CDC13-C
D30D): 63.42 (s, thin), 5,09 (戊, I
H), 6,94 (s, IH), leg 3-Chloru 7Q-
Methoxy-78-(2-phenyl-2-carboxy)acetamido-1-oxa-1-dethia-3-cephemu-4-carboxylic acid Example 3 9 of product 33 of [2] was dissolved in 1.5 parts of methylene chloride and cooled on ice. Anisole 0. below.
Add 2 parts of [and 0.2 parts of trifluoroacetic acid, 30
Worship for a minute.

Add 5' of toluene to this mixture and concentrate under reduced pressure. The residue is then washed with petroleum ether to obtain the title compound 24 as onion powder. TLC: Rf=0.52 (ethyl acetate:acetic acid:water=5:1:1)

Claims (1)

[Claims] 1. A 3'-norcephalosporin derivative represented by the general formula ▲ Numerical formula, chemical formula, table, etc. ▼. {wherein, [Here, R^1 is a phenyl group or thienyl group, R^2 is a hydrogen atom, -OR^3 group, -NHR^3 group, or -COO
R^3 group, R^3 is a hydrogen atom, formyl group, lower alkoxycarbonyl group, (nitro or phenyl)benzyl group, lower alkyl group or lower alkyldiketopiperazinylcarbonyl group] R is a hydrogen atom or ( nitro or phenyl) benzyl group, respectively}.