JPS58213786A - Novel cephalosporin derivative - Google Patents

Abstract

MEW MATERIAL:The compound of formula I [B is acetoxy or heterocyclic-thio of formula -S-R<1> (R<1> is thiazolyl or tetrazolyl which may be substituted with lower alkyl)] or its salt. EXAMPLE:7-(6-Hydroxy-3-pyridyl)thioacetamidocephalosporanic acid. USE:Antibacterial agent active to Gram-positive bacteria and Gram-negative bacteria. PROCESS:The compound of formula I can be prepared, e.g. by reacting the compound of formula II (X is halogen) [e.g. 7-bromoacetamidocephalosporanic acid] with the compound of formula III (A is H or group of formula IV)[e.g. bis(6- hydroxy-3-pyridyl)disulfide] in the presence of a base under ice cooling.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a compound of the general formula (1) [wherein B is an acetoxy group or a formula-8-R' (wherein R1 is a thiadiazolyl group or a tetrazolyl group which may be substituted with a lower alkyl group] means a heterocycle thio group represented by The same applies hereinafter] The present invention relates to a novel CefaOsporin derivative, a salt thereof, and a method for producing the same.

In the above-mentioned compound (1) of the present invention, each of the thiadiazolyl group or tetrazolyl group represented by B has a lower alkyl group which may include a methyl group, an ethyl group, a globyl group, Inglovir group, etc.

Furthermore, examples of non-toxic salts of the compound (1) of the present invention include alkali metal salts, ammonium salts, and salts with bases such as triethylamine and dicyclohexylamine.

Examples of the novel Cefa-Osporin derivatives of the present invention include the following.

fl+7-(6-hydroxy-3-pyridyl)thioacetamidocepha0 sporanic acid+217-(2-hydroxy-4-pyridyl)thioacetamidocepha0 sporanic acid f317-(6-hydroxy-3-pyridyl)thioacetamide-3- (1-methyltetrazole-5-(ru)
Thiomethyl-Δ3-cephem-4-carboxylic acid (417-(2-hydroxy-4-pyridyl)thioacetamide-3-(1-methyltetrazo-5-(l)thiomethyl-Δ3-cephem-4-carboxylic acid (1) To obtain the compound represented by the general formula ([1) [in the formula, X means a halogen atom and B is the same as above, the same applies hereinafter] and the compound represented by the general formula (1) in the presence of a base. (hereinafter abbreviated as the first method) and the compound (1) of the present invention has the general formula (
1) In the case of a novel cephalosporin derivative represented by '0OH (in the formula, R1 is the same as above).

A Cephalosborane hanging derivative represented by the general formula (B) and a general formula (V)
MS-R' (V) [In the formula, M means a hydrogen atom or an alkali metal, and R1 is the same as above. The same applies hereinafter] There is a method (hereinafter abbreviated as the second method) in which a compound represented by the following is reacted.

To carry out the first method of the present invention, the following steps are carried out.

That is, compound (11) and compound (1) were combined in the presence of a base at 9
It does not usually participate in the reaction under cooling or at room temperature (・The reaction is carried out in an organic solvent, water, or a mixture thereof. The base used is an aliphatic, aromatic, or heterocyclic ♀ base (・ is a carbonate or alkali metal bicarbonate salts, such as triethylamine, N,N-dimethylaniline, N-ethylmorpholine, pyridine, collidine, 2,6-lutidine, sodium carbonate, potassium carbonate, potassium bicarbonate and carbonate. Sodium hydrogen etc. are used. Examples of the halogen atom of X in compound (11) include a chlorine atom, a bromine atom, and a 77 element atom.

The amount of compound (lit) to be used is equimolar to excess molar relative to compound ([1) K, but preferably about 1 to 2 times the molar amount. Specific examples of organic solvents that do not participate in the reaction include methanol, chloroform, methylene chloride, ethylene chloride, acetone, tetrahydrofuran, and dimethylformamide.

The second method of the present invention is carried out as follows.

That is, compound (IV) and compound (V) are reacted.

This reaction is preferably carried out near neutrality.

Equimolar to excess molar amount of compound (IV) to compound (IV)
V) to react. Examples of the alkali metal for M in compound (V) include sodium and potassium. In addition, when using a compound in which M is a hydrogen atom in compound (V) K, alkali metal hydroxide, alkali metal carbonate,
Alkali metal bicarbonates and trialkylamines, pyridine.

It is preferable to carry out the reaction in the presence of a base such as dimethylaniline. The reaction usually involves acetone, dimethylformamide,
It is carried out in an organic solvent, water, or a mixture thereof, or in a phosphate buffer solution, which does not involve the reaction of methanol, ethanol, etc., at room temperature or under heating.

The compound (1) of the present invention has the general formula (Vl) (In the formula, R2 means a protecting group for a carboxy group.

B is the same as above. The same applies below) and the formula (Vil)HO-C)-8-CH,C0OH(Vl
The compound represented by l) or its reactive derivative with a carboxyl group is reacted with equimolar to an excess molar amount, preferably twice the molar amount, in an organic solvent that does not participate in the reaction, preferably in the presence of a base, to form a product. When has a protecting group R2, it can also be obtained by removing it.

The compound of the present invention thus obtained can be converted into a pharmaceutically acceptable non-toxic salt. To form a salt, follow the commonly used method (1. For example, add a n-butanol solution of alkali metal 2-ethylhexanoate; 1. By adding an alkali metal salt of the target compound (1), an equal amount to a slight excess of an organic base such as dicyclohexylamine, triethylamine, cyclohexylamine, trimethylamine, etc. is added and reacted to form a salt of the compound of the present invention with an organic base.

Further, by adding aqueous ammonia, an ammonium salt of the compound of the present invention can be obtained.

The compound (I) of the present invention or its salt may be isolated and purified by conventional methods.

The compound (1) of the present invention produced in this manner is an antibiotic having excellent antibacterial activity against both Gram-positive and virulent bacteria and is useful as a medicine.

The antibacterial activity of the compound (1) of the present invention (minimum effective 1 (-
concentration) of the known 7-[α-(IH-tetrazole-1-
yl)acetamide]-3-'(5-methyl-1,3,
4-thiadiazol-2-yl)-thiomethyl-Δ3~
A comparison with cephemu-4-carboxylic acid (generic name: cefazolin) is shown.

Therefore, the compound of the present invention (1) can be used as a therapeutic agent for combination infections in humans and animals caused by these bacteria and other bacteria for which the compound of the present invention is effective, and can be administered orally or as an injection (1 tablet), It is administered in a number of dosage forms such as TI preparations and external preparations. These preparations can be manufactured by conventional methods.

Example 1 Bis(6-hydroxy-3-pyridyl) disulfide 1
70,111 g, 1.2 ml of 1N sodium hydroxide, and 5 ml of water were mixed, and while stirring while cooling with water, 60,111 g of sodium borohydride was added.
Shuffle the time. This bath solution was added to a bath solution containing 450 ff 1 g of 7-bromoacetamidocephalosporanic acid, 9011 g of sodium bicarbonate; and 10 ml of water while stirring under water cooling, and then a 0.1 N phosphoric acid aqueous solution was immediately added dropwise. Adjust the pH to 7.5. After stirring this solution at room temperature for 15 hours, the pH was adjusted to 2.0 by adding a 0.1N phosphoric acid water bath and extracted three times with 50 mt each of a mixture of n-butanol and ethyl acetate (volume ratio 1:1).

The extracts were combined, washed twice with water, then twice with a saturated aqueous sodium chloride solution, dried over anhydrous #L magnesium acid, and the solvent was distilled off under reduced pressure to give 7-(6-hytroquine:u-pyridyl). Thioacetamidocephalosporanic acid 36
Get 0 ■.

Nuclear magnetic resonance spectrum (D, -DMSO) δ(p,p
, m, ): 2.02 (s, 3H), 3.20-3.70 (m, 4H
).

4.72-5.20 (m, 3H), 5.50 (q, IH
).

6.30 (d, IH), 7.48 (m, 2H) Example 2 7-(6-hydroxy-3-pyridyl)thioacetamidocephalosporanic acid 3301Qg, 5-mercapto-
115,111 g of 1-methyltetrazole, 145 H1 g of sodium hydrogen carbonate, and 15 mt of pH 6,8,6 phosphoric acid sanitation solution were mixed, stirred at 60°C for 12 hours, and then filtered. The f' solution was made acidic with 3 ml of 35% hydrochloric acid,
The precipitate was removed, and the solution was extracted with 50 ml of n-butanol-ethyl acetate (volume ratio 1:1) and then 40 ml. The extracts were combined and washed twice with water.

Wash twice with an aqueous solution of IJ (saturated sodium chloride), dry over anhydrous magnesium sulfate, and remove the solvent under reduced pressure.

The obtained residue was subjected to gel column chromatography and developed using a solution of chloroform-isopropanol-formic acid (volume ratio 90:10:3) to which methanol was successively added as an eluent. Fractions containing the target compound were collected and the solvent was distilled off to obtain 90ff1g of 7-(6-hydroxy-3-pyridyl)thioacetamido-3-(1-methyltetrazol-5-yl)thiomethyl-Δ3-cephemu-4-carboxylic acid. get.

Nuclear magnetic resonance spectrum (D6-DMSO) δ(p, p,
m, ); 3.44 (s, 2H), 3.68 (q, 2H)
, 3.94 (s, 3H).

4, :32(m, 2H), 5.08(d, IH)
, 5.64 (q, IH).

6.30 (d, IH), 7.50 (m, 2H) Example 3゜7-bromoacetamidocephalosporanic acid 16 (ll
l1g, 2-hydroxy-4-mercaptopyridine l
OQmg, pH 6,86 phosphate buffer 5ml, sodium bicarbonate 105rl@ and methanol 15m
Mix 1 and stir at room temperature for 5 hours. Methanol was distilled off from the reaction solution, and then sodium hydrogen carbonate was added to adjust the pH to 9.
Wait 1 hour after adjusting. Add 1.5% hydrochloric acid to solution f to make it acidic, and extract twice with 25 ml of a mixture of n-butanol and ethyl acetate (volume ratio 1:1). The combined extracts were washed twice with water, once and twice with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting powdery residue was tecanted with ethyl acetate and then ether to yield 78ff of 7-(2-hydroxy-4-pyridyl)thioacetamidocephalosporanic acid! glGru.

Nuclear magnetic resonance spectrum (D6-DMSO) δ(P, P
,”, ); 2.02 (a, 3H), 3.52 (q, 2H),
3.80(s, 21().

4.62-5.1'4 (m, 3H), 5.66 (q
, IH'), 6.08(d, IH).

6.12 (m, 2H), 6.20 (s, jH),
7.22 (d, IH) Example 4゜113fl1g of 7-promoacetamido-3-(1-methyltetrazol-5-yl)thiomethyl-Δ3-cephemu-4-carboxylic acid, 40ff1g of 2-hydroxy-4-mercaptopyridine, Sodium hydrogen carbonate 46ff
! g, 10mt methanol and 5ITlt water are mixed and stirred at room temperature for 4 hours. After distilling off methanol, the pH was adjusted to 9 by adding sodium bicarbonate, filtered, and
The second solution was made acidic with 15% hydrochloric acid, and n-butanol-
Extract with 60 ml of a mixture of ethyl acetate (volume ratio 1:l). The extracts were combined, washed with a saturated sodium chloride aqueous solution, water, and a saturated sodium chloride aqueous solution in this order, dried over anhydrous magnesium sulfate, and the solvent was distilled off to give 7-(2-hydroxy-
4-pyridyl)thioacetamido-3-(l-methyltetrazol-5-yl)thiomethyl-Δtwocephem-
110011t of 4-carboxylic acid is obtained.

Nuclear magnetic resonance spectrum (D6-IDMsO) δ(P, P
,”, ) ; 3.68 (Q, 2H), 3.80 (s, 2H),
3.92 (s, 3H).

4.28 (q, 2H), 5.04 (d, IH), 5.6
6 (q, IH) + 6.04 (d, IH), 6.14
(s, IH), 7.20 (d, IH) Example 5゜7-promoacetamido 3-(5-methyl-1,3,
1.63 g of 4-thiadiazol-2-yl)thiomethyl-Δtucephem-4-carboxylic acid, 2-hydroxy-
0.45 g of 4-mercaptopyridine.

Mix 50 ml of water and 100 mt of methanol, stir on a water bath, add 0.59 g of sodium bicarbonate, and stir at room temperature for 2 hours. Methanol was distilled off under reduced pressure, and after filtration and acidification with dilute hydrochloric acid, 200 ml of a mixture of n-butanol and ethyl acetate (volume ratio l:t) was added.
Extract with. The extract is washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then the solvent is distilled off.

One precipitated crystal was taken, washed with ethyl acetate, and dried to give 7-(
2-hydroxy-4-pyridyl)thioacetamide-3
-(5-Methyl-1,3,4-thiadiazol-2-yl)thiomethyl-Δ3-cephemu-4-carboxylic acid 1.
Obtain 23g.

Nuclear magnetic resonance spectrum (D, -DMSO) δ (p, p,
m, ); 2.68 (s, 3H), 3.66 (q, 2H).

3.84 (s, 2H), 4.36. (q, 2H)
.

5.08 (d, IH), 5.62 (Q, LH).

6.14 (d, LH), 6.24 (s, IH).

7.28 (d, IH)

Claims (1)

[Claims] [In the formula, B is an acetoxy group or a formula-8-R' (formula 1:11
R1 means a thiadiazolyl group or a tetrazolyl group which may be substituted with a lower alkyl group. ) means a heterocycle thio group. ] The compound according to claim f11, which is a novel cephalosporin derivative or a salt thereof (z+ BfJ: t-methyltetrazol-5-yl group).