JP3005273B2 - Thiazolylacetamide-3-cephem derivatives - Google Patents

Description

Description: TECHNICAL FIELD The present invention relates to a novel thiazolylacetamide-3-cephem derivative having excellent action as a medicine.

[Problems to be solved by conventional technology and invention]

European Patent Application No. 30630 describes the formula (Where R is a lower alkyl group, a lower alkenyl group, a lower alkynyl group or a carboxy lower alkyl group.) 7-acylamino-3-
Vinyl cephalosporanic acid derivatives are disclosed.

JP-A-59-89089 discloses a 7-substituted-3-vinyl-3-cephem compound represented by the general formula: (Wherein, R ¹ represents an amino group or an amino group protected with a protecting group, and R ² represents a carboxyl group or a carboxyl group protected with a protecting group, respectively).

On the other hand, JP-A-62-491 discloses a compound represented by the following general formula.

(Wherein R ³ is a hydrogen atom or a normal amino protecting group,
R ⁴ is a hydrogen atom, a linear or branched alkyl group having 1 to 4 carbon atoms, an alkenyl or alkynyl group having 2 to 4 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms A cycloalkylalkyl group having a 3-6 membered ring and 4-10 carbon atoms, or 2-4
R ⁵ is a hydrogen atom, a lower alkyl group having 1 to 3 carbon atoms, 1
Lower alkoxy groups having from 2 to 3 carbon atoms, lower alkanoyloxy groups having from 2 to 3 carbon atoms,
R ⁶ is a hydrogen atom or a physiologically hydrolyzable ester group,
For example, acetoxymethyl, 1-acetoxyethyl, pivaloyloxymethyl, 5-methyl-2-oxo-1,3-
Dioxolen-4-ylmethyl, 1- (ethoxycarbonyloxy) ethyl, or 4-glycyloxybenzoyloxymethyl group).

However, none of them has sufficient antibacterial activity.

[Means for Solving the Problems] The present inventors have found that a novel thiazolylacetamide cephem derivative having a cyclopropylvinyl group at the 3-position has excellent antibacterial activity, and have already filed a patent application.

Furthermore, as a result of the study, it was found that a compound having excellent antibacterial activity can be obtained by introducing a vinyl group having a specific substituent different from the above at the 3-position of the thiazolylacetamide cephem derivative. The present inventors have found that a thiazolylacetamide-3-cephem derivative is useful as an antibacterial agent having high activity against various pathogenic bacteria, particularly useful as an antibacterial agent for oral administration, and completed the present invention.

That is, the present invention provides a thiazolylacetamide-3-cephem derivative represented by the following general formula (1), a pharmaceutically acceptable salt thereof, a production method thereof, and an antibacterial agent comprising the same.

(In the formula, R ¹ represents a hydroxyl group or a lower alkoxy group. R ² represents a carboxyl group or a carboxyl group protected by a protecting group. R ³ represents a lower halogenated alkyl group or a lower alkenyl group.) Wherein the lower alkoxy group represented by R ¹ includes
Examples thereof include alkoxy groups having 1 to 4 carbon atoms such as methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, sec-butoxy, and t-butoxy. Examples of the lower alkyl group represented by R ³ include methyl, ethyl, n-propyl, i-propyl, n-butyl, sec-butyl, and t.
And an alkyl group having 1 to 4 carbon atoms such as -butyl. Examples of the protecting group for the carboxyl group of R ² include lower alkyl groups such as methyl, ethyl and t-butyl; substitution with p-methoxybenzyl, p-nitrobenzyl, 3,4-dimethoxybenzyl, diphenylmethyl, trityl, phenethyl and the like. A lower alkyl group substituted by a phenyl group which may have a group; a halogenated lower alkyl group such as 2,2,2-trichloroethyl or 2-iodoethyl; pivaloyloxymethyl, acetoxymethyl, propionyloxymethyl ,
Lower alkanoyloxy lower alkyl groups such as butyryloxymethyl, valeryloxymethyl, 1-acetoxyethyl, 2-acetoxyethyl, 1-pivaloyloxyethyl and 2-pivaloyloxyethyl; palmitoyloxyethyl, heptapeca Higher alkanoyloxy lower alkyl groups such as noyloxymethyl and 1-palmitoyloxyethyl; methoxycarbonyloxymethyl, 1-
Lower alkoxycarbonyloxy lower alkyl groups such as butoxycarbonyloxyethyl, 1-t-butoxycarbonyloxyethyl, 1-ethoxycarbonyloxyethyl and 1- (isopropoxycarbonyloxy) ethyl; carboxy such as carboxymethyl and 2-carboxyethyl; Lower alkyl group; heterocyclic group such as 3-phthalidyl; 4-glycyloxybenzoyloxymethyl, 4-
A benzoyloxy lower alkyl group which may have a substituent such as [N- (t-butoxycarbonyl) glycyloxy] benzoyloxymethyl; (5-methyl-2-
(Substituted dioxolen) lower alkyl groups such as oxo-1,3-dioxolen-4-yl) methyl; cycloalkyl-substituted lower alkanoyloxy lower alkyl groups such as 1-cyclohexylacetyloxyethyl; 1-cyclohexyloxycarbonyloxyethyl; And a cycloalkyloxycarbonyloxy lower alkyl group.

Pharmaceutically acceptable salts include, for example, alkali metal salts such as sodium salt and potassium salt; ammonium salt; quaternary ammonium salts such as tetraethylammonium salt and betaine salt; alkaline earth metals such as calcium salt and magnesium salt Salts; inorganic salts such as hydrochloride, hydrobromide, hydroiodide, sulfate, carbonate, bicarbonate; organic carboxylic acids such as acetate, maleate, lactate, tartrate; Organic sulfonates such as methanesulfonate, hydroxymethanesulfonate, hydroxyethanesulfonate, taurine, benzenesulfonate and toluenesulfonate; arginine, lysine, serine, aspartate, glutamic acid Salts, amino acids such as glycine; trimethylamine, triethylamine, pyridine, Rockine salt, picoline salt, dicyclohexylamine salt, N, N'-dibenzylethylenediamine salt, N-methylglucamine salt, diethanolamine salt, triethanolamine salt, tris (hydroxymethylamino) methane salt, phenethylbenzylamine salt, etc. Amine salts and the like.

The compound of the present invention can be produced by the following method.

Manufacturing method General formula (II) (Wherein, R ² represents a carboxyl group or a carboxyl group protected with a protecting group. R ⁴ represents an amino group or an amino group protected with a protecting group. R ⁵ is a hydroxyl group or a hydroxyl group protected with a protecting group. Or a lower alkoxy group) or a salt thereof, and a compound represented by the formula R ³ —N ＝ C ＝ O (wherein
R ³ represents a lower halogenated alkyl group or a lower alkenyl group. ), And if necessary, the protecting group for an amino group, a hydroxyl group or a carboxyl group is eliminated to obtain a compound of the formula (I) (Wherein, R ¹ , R ² and R ³ have the same meanings as described above) and a pharmaceutically acceptable salt thereof.

The above reaction is carried out in an inert solvent such as dichloromethane, chloroform, tetrahydrofuran, acetone, ethyl acetate, methanol, ethanol, dimethylsulfoxide, benzene, toluene, hexane, etc., at a reaction temperature of −10 ° C. to 50 ° C.
Can be done with The elimination of the protecting group can be performed by a conventional method according to the type of the protecting group used.

Examples of the protecting group for the amino group of R ⁴ include a formyl group,
Acetyl group, chloroacetyl group, dichloroacetyl group,
Phenylacetyl group, thienylacetyl group, t-butoxycarbonyl group, benzyloxycarbonyl group, trityl group, p-methoxybenzyl group, diphenylmethyl group,
Examples include a benzylidene group, a p-nitrobenzylidene group, an m-nitrobenzylidene group, a 3,4-methylenedioxybenzylidene group, and an m-chlorobenzylidene group.

As the lower alkoxy group for R ^5, the same groups as those for R ¹ can be mentioned. Examples of the hydroxyl-protecting group for R ⁵ include a trityl group and a tetrahydropyranyl group.

The compound of the present invention obtained by the above method has excellent antibacterial activity, and is particularly useful as an oral antibacterial agent.

Acute toxicity value of the compound of the present invention [LD ₅₀ (mouse, oral)]
Was 2 g / kg or more.

When the compound of the present invention is used as an antibacterial agent,
It can be administered orally or parenterally in 100 mg to 5 g per day in 1 to 4 divided doses. The dose may be increased or decreased depending on age and symptoms.

Formulations include tablets, granules, powders, capsules, syrups, liquids and the like. These can be manufactured by a conventional method by adding a known pharmaceutical carrier.

Next, the present invention will be described in more detail with reference to Examples,
The present invention is not limited to these examples.

In addition, the synthesis example of the compound used as the raw material of the compound of the present invention is shown as a production example. In the formula, Trt means a trityl group.

Production Example 1 7-[(Z) -2- (2-tritylaminothiazole-
4-yl) -2-trityloxyiminoacetamide]
-3-[(Z) -3-tert-butyldimethylsilyloxy-1-propenyl] -3-cephem-4-carboxylate 4-methoxyphenylmethyl 7-[(Z) -2- (2-tritylaminothiazol-4-yl) -2-trityloxyiminoacetamido] -3- (triphenylphosphoranylidene) methyl-
A solution of 9.07 g (7.27 mmol) of 4-methoxyphenylmethyl 3-cephem-4-carboxylate and 1.8 g (10.34 mmol) of t-butyldimethylsilyloxyacetaldehyde in 100 ml of dichloromethane was stirred at room temperature for 16 hours. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 2.5: 1) to obtain 4.99 g (4.36 mmol, 60.0%) of the desired compound.

NMR (CDCl ₃ ) δ: 0.20 (6H, bs, CH ₃ × 2), 1.04 (9H, bs, C (CH ₃ ) ₃ ),
_{3.40~3.60 (2H, m, CH 2} ), 3.88 (3H, s, OCH 3), 4.20~4.4
_{0 (2H, m, -CH 2} OSi), 5.00~5.20 (1H, m, CH), 5.28 (2H,
_{s, CO 2 CH 2),} 5.60~6.40 (3H, m, CH, -CH = CH -), 6.56
(1H, s, thiazole H), 6.90-7.80 (34H, m) Production Example 2 7-[(Z) -2- (2-tritylaminothiazole-
4-yl) -2-trityloxyiminoacetamide]
-3-[(Z) -3-hydroxy-1-propenyl]-
4-methoxyphenylmethyl 3-cephem-4-carboxylate To a solution of 4.99 g (4.36 mmol) of the compound obtained in Production Example 1 in 50 ml of acetone was added 10 ml of 1N hydrochloric acid, and the mixture was stirred at room temperature for 2 hours. After acetone was distilled off under reduced pressure, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with water, washed with saturated saline, and dried by adding magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (n-hexane:
The product was purified with ethyl acetate = 1: 1) to obtain 2.2 g (2.14 m) of the desired compound.
mol, 49.0%).

NMR (CDCl ₃ ) δ: 3.24 (2H, ABq, J = 18.0 Hz, CH ₂ ), 3.80 (3H, s, OCH ₃ ),
_{3.90~4.10 (2H, m, -CH 2} O -), 5.02 (1H, d, J = 4.8Hz, C
H), 5.16 (2H, s, CO ₂ CH ₂ −), 5.60 to 6.00 (2H, m, CH, = CH
−), 6.14 (1H, d, J = 12.5 Hz, −CH =), 6.42 (1H, s, thiazole H), 6.80 to 7.70 (34H) p Mass (m / z): 1029 (M ⁺ ), 1030 (M ⁺⁺ 1) Production Example 3 7-[(Z) -2- (2-tritylaminothiazole-
4-yl) -2-trityloxyiminoacetamide]
-3-[(Z) -3- (N- (2-chloroethyl) carbamoyloxy) -1-propenyl] -3-cephem-
4-methoxyphenylmethyl 4-carboxylate 1.6 g (15.2 mmol) of 2-chloroethyl isocyanate and a catalytic amount of triethylamine were added to a solution of 2 g (1.944 mmol) of the compound obtained in Production Example 2 in 40 ml of dry tetrahydrofuran, and the mixture was heated at 60 ° C. for 4 hours. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (dichloromethane: acetone = 95: 5) to obtain 0.6 g of the desired compound.
(0.53 mmol, 27%).

_{NMR (CDCl 3) δ: 3.2~3.7} (6H, m, CH 2 CH 2 Cl, CH 2), 3.78 (3H, s, OCH 3),
_{4.3~4.6 (2H, m, CH 2} ), 5.05 (1H, d, J = 5Hz, CH), 5.15
(2H, s, CO ₂ CH ₂ ), 5.55-6.00 (2H, m, CH, CH =), 6.22 (1
H, d, J = 12Hz, CH =), 6.38 (1H, s, thiazole H), 6.70
-7.50 (34H, m) Production Example 4 7-[(Z) -2- (2-tritylaminothiazole-
4-yl) -2-trityloxyiminoacetamide]
-3-[(Z) -3- (N- (2-allylcarbamoyloxy) -1-propenyl] -3-cephem-4-carboxylic acid 4-methoxyphenylmethyl 1.3 g of allyl isocyanate was added to a solution of 2 g (1.944 mmol) of the compound obtained in Production Example 2 in 40 ml of dry tetrahydrofuran.
(15.6 mmol) and a catalytic amount of triethylamine, and
For 4 hours. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (dichloromethane: acetone = 95: 5) to obtain 1 g (0.90 mmol, 46
%)Obtained.

Example 1 7-[(Z) -2- (2-aminothiazol-4-yl) -2-hydroxyiminoacetamide] -3-
[(Z) -3- (N- (2-chloroethyl) carbamoyloxy) -1-propenyl] -3-cephem-4-carboxylic acid sodium salt To a solution of 0.6 mg (0.53 mmol) of the compound obtained in Production Example 3 in 3 ml of anisole was added dropwise 3 ml of trifluoroacetic acid under ice-cooling.
Thereafter, the mixture was stirred at room temperature for 2 hours. After concentration under reduced pressure, the concentrated solution was added dropwise to a mixed solution of 20 ml of isopropyl ether and 80 ml of n-hexane, and the precipitated crystals were collected by filtration. 90% formic acid 10 crystals
Then, the mixture was stirred at room temperature for 3 hours. After evaporating the solvent under reduced pressure,
The residue was triturated with isopropyl ether, and the crystals were collected by filtration. Dissolve the crystals in 20 ml of methanol and add sodium acetate 30
0 mg (5 mmol) was added and the solvent was distilled off under reduced pressure. 2 crude products
-Trituration with propanol and filtration of the crude crystals. OD crude crystals
The product was purified by S column chromatography (7% aqueous methanol), and the eluate was concentrated under reduced pressure and freeze-dried to obtain 140 mg (0.25 mmol, 48%) of the target compound.

_{NMR (DMSO-d 6) δ} : 3.38 (6H, m, NHCH 2), 3.59 (2H, t, J = 6.8Hz, CH 2 Cl),
3.53 (2H, ABq, J = 16.5Hz, CH 2), 4.60 (2H, d, ABq, J = 7H
z, 13.9Hz, CH ₂ ), 5.03 (1H, d, J = 4.8Hz, CH), 5.03 (1H,
m, −CH =), 5.58 (1H, dd, J = 4.8Hz, 8.4Hz, −CH), 6.64
(1H, d, J = 12.8Hz , -CH =), 6.65 (1H, s, thiazole H), 7.09 (2H, s , NH 2) Example 2 7 - [(Z) -2- (2- Amino Thiazol-4-yl) -2-hydroxyiminoacetamide] -3-
[(Z) -3- (N- (2-chloroethyl) carbamoyloxy) -1-propenyl] -3-cephem-4-carboxylate pivaloyloxymethyl To a solution of 80 mg (0.14 mmol) of the compound obtained in Example 1 in 3 ml of dry dimethylformamide was added 37 mg (0.16 mmol) of iodomethyl pivalate in 0.3 ml of dry dimethylformamide under ice cooling.
A 5 ml solution was added dropwise and stirred for 30 minutes. Ethyl acetate was added to the reaction solution, and the mixture was washed with water and saturated brine, dried over magnesium sulfate. The mixture was concentrated under reduced pressure, and the concentrated solution was added dropwise to 50 ml of n-hexane. The precipitated crystals were filtered and dried to give 63 mg (0.1 mmol, 70%) of the target compound.

_{NMR (DMSO-d 6) δ} : 1.15 (9H, s, C (CH 3) 3), 3.29 (2H, dt, J = 5.9Hz, 12.
1 Hz, NHCH ₂ ), 3.58 (2H, t, J = 12.1 Hz, CH ₂ Cl, 3.5 to 3.9 (2
_{H, m, CH 2),} 4.3~4.6 (2H, m, CH 2), 5.28 (1H, d, J = 4.7H
z, CH), 5.5-5.65 (1H, m, = CH-), 5.77 (1H, dd, J = 4.7
Hz, 7.8Hz, CH), 5.84 (2H, ABq, J = 3.3Hz, CH 2 O), 6.29 (1
H, d, J = 11.7Hz, -CH =), 6.83 (1H, s, thiazole H),
7.45 (1H, t, J = 5.9 Hz, NH), 9.68 (1H, d, J = 7.8 Hz, NH) Example 3 7-[(Z) -2- (2-aminothiazol-4-yl)- 2-hydroxyiminoacetamide] -3-
[(Z) -3- (N-allylcarbamoyloxy) -1
-Propenyl] -3-cephem-4-carboxylic acid sodium salt To a solution of 1 mg (0.9 mmol) of the compound obtained in Production Example 4 in 3 ml of anisole was added dropwise 3 ml of trifluoroacetic acid under ice-cooling, followed by stirring at room temperature for 2 hours. After concentration under reduced pressure, the concentrated solution was added dropwise to a mixed solution of 20 ml of isopropyl ether and 80 ml of n-hexane, and the precipitated crystals were collected by filtration. Crystals 90% formic acid 10ml
And stirred at room temperature for 3 hours. After evaporating the solvent under reduced pressure, the residue was triturated with isopropyl ether and the crystals were collected by filtration.
Dissolve the crystals in methanol 20ml, sodium acetate 300mg
(5 mmol) was added and the solvent was distilled off under reduced pressure. 2 crude products
-Trituration with propanol and filtration of the crude crystals. OD crude crystals
Purification was performed by S column chromatography (10% aqueous methanol), and the eluate was concentrated under reduced pressure and lyophilized to obtain 80 mg (0.15 mmol, 17%) of the target compound.

_{NMR (D 2 O-d 6} ) δ: 3.62 (2H, ABq, J = 17Hz, CH 2), 3.84 (2H, dJ = 4.8Hz, N
_{HCH 2), 4.55~4.85 (2H,} m, CH 2), 4.87 (2H, ABq, J = 17.1
Hz, CH ₂ ), 5.25 (1H, dd, J = 1.5 Hz, 10.3 Hz, = CH ₂ ), 5.30
(1H, dd, J = 1.5Hz , 17.2Hz, = CH 2), 5.42 (1H, d, J = 4.7H
z, CH), 5.78-5.87 (1H, m, = CH-), 5.92-6.03 (1H, m,
−CH =), 5.97 (1H, d, J = 4.7 Hz, CH), 6.32 (1H, d, J = 1)
1.8 Hz, -CH =), 7.12 (1H, s, thiazole H) Example 4 7-[(Z) -2- (2-aminothiazol-4-yl) -2-hydroxyiminoacetamido] -3-
[(Z) -3- (N-2-allylcarbamoyloxy)
-1-propenyl] -3-cephem-4-carboxylic acid
Pivaloyloxymethyl To a solution of 50 mg (0.09 mmol) of the compound obtained in Example 3 in 3 ml of dry dimethylformamide was added 24 mg (0.1 mmol) of iodomethyl pivalate in 0.5 ml of dry dimethylformamide under ice cooling.
The ml solution was added dropwise and stirred for 30 minutes. Ethyl acetate was added to the reaction solution, and the mixture was washed with water and saturated brine, dried over magnesium sulfate. Concentrate under reduced pressure, and concentrate the concentrated solution with n-hexane.
It was added dropwise to 50 ml. The precipitated crystals were filtered and dried to give 35 mg (0.06 mmol, 61%) of the target compound.

_{NMR (DMSO-d 6) δ} : 1.15 (9H, s, C (CH 3) 3), 3.55~3.77 (4H, m, CH 2, C
_{H 2), 4.35~4.65 (2H,} m, CH 2), 5.04 (1H, dd, J = 1.4Hz, 1
0.2Hz, = CH ₂ ), 5.10 (1H, dd, J = 1.4Hz, 17.2Hz, = CH ₂ ),
5.25 (1H, d, J = 5.1Hz, CH), 5.60-5.70 (1H, m, -CH
=), 5.70~5.90 (4H, m , -CH =, OCH 2, CH), 6.27 (1H, d,
J = 11.7Hz, -CH =), 6.67 (1H, s, thiazole H)

────────────────────────────────────────────────── ─── Continuation of the front page Examiner Junko Uchida (56) References JP-A-55-154981 (JP, A) JP-A-3-128381 (JP, A) US Patent 4094978 (US, A) (58) Search Field (Int.Cl. ⁷ , DB name) C07D 501/00-501/62 A61K 31/00-31/80 CA (STN) REGISTRY (STN)

Claims (3)

(57) [Claims] (1) Expression (In the formula, R ¹ represents a hydroxyl group or a lower alkoxy group. R ² represents a carboxy group or a carboxyl group protected by a protecting group. R ³ represents a lower halogenated alkyl group or a lower alkenyl group.) The represented thiazolylacetamide-3-cephem derivative or a pharmaceutically acceptable salt thereof. (2) (Wherein, R ² represents a carboxyl group or a carboxyl group protected with a protecting group. R ⁴ represents an amino group or an amino group protected with a protecting group. R ⁵ is a hydroxyl group or a hydroxyl group protected with a protecting group. Or a salt thereof, or a salt thereof, and a formula R ³ —N ＝ C ＝ O (where R ³ represents a lower halogenated alkyl group or a lower alkenyl group). A formula characterized by reacting with an isocyanate and, if necessary, removing a protecting group for an amino group, a hydroxyl group or a carboxyl group. (In the formula, R ¹ represents a hydroxyl group or a lower alkoxy group. R ² represents a carboxy group or a carboxyl group protected by a protecting group. R ³ represents a lower halogenated alkyl group or a lower alkenyl group.) A method for producing the represented thiazolylacetamide-3-cephem derivative or a pharmaceutically acceptable salt thereof. 3. The formula: (In the formula, R ¹ represents a hydroxyl group or a lower alkoxy group. R ² represents a carboxy group or a carboxyl group protected by a protecting group. R ³ represents a lower halogenated alkyl group or a lower alkenyl group.) An antibacterial agent comprising the represented thiazolylacetamide-3-cephem derivative or a pharmaceutically acceptable salt thereof.