JPS58206589A - 2-azetidinone derivative - Google Patents

Abstract

NEW MATERIAL:A compound of formula I {R1 is H or lower alkyl; M is H or cation; X is -(CH2)n- (n is an integer 1-4) or >C=N-O-R2 [R2 is lower alkyl or formula II (R3 and R4 are H or lower alkyl)]}. EXAMPLE:Potassium 3(S)-3-( 2-amino-4-thiazolylacetamido )-2-zetidinone-1-oxysulfonate of formula III. USE:An excellent antimicrobial agent effective against Gram-positive and Gram- negative bacteria, particularly the Gram-negative bacteria. PROCESS:A compound of formula IV, e.g. (3S)-3-amino-2-azetidinone-1-oxysulfonic acid, is reacted with a compound of formula V (or a reactive derivative), e.g. 2-amino-4-thiazolyacetic acid, preferably in an organic solvent, e.g. dimethylformamide (DMF), at room temperature in the presence of a base, e.g. triethylamine.

Description

[Detailed description of the invention] The present invention is.

General formula (in the formula + R1 is a hydrogen atom or a lower alkyl group with 1M
is a hydrogen atom or a cation, X is -(CH2)n
(n is an integer of 1 to 4) or >C=N-3 o R2CR2 is a lower alkyl group or -C-COO
M Table 4 (R3 and R1 are the same or different and represent a hydrogen atom or a lower alkyl group, and 2M has the same meaning as above.

). ] represents.

Same below) The present invention relates to a 2-azetidinone derivative represented by

The lower alkyl group in the above definitions of R2 to R4 means a branched or linear group having 1 to 6 carbon atoms, such as a methyl group, ethyl group, brobyl group, isopropyl group, butyl group, tert -butyl group, pentyl group, hexyl group, etc. Also, as a cation in the definition of M.

Examples include alkali metal ions such as sodium and potassium; alkaline earth metal ions such as calcium and magnesium; alkylammonium ions such as triethylammonium ions; pyridinium ions and dicyclohexylammonium ions.

The compound (1) of the present invention has excellent antibacterial activity against Durham-positive bacteria and -negative bacteria, especially against Durham-negative bacteria, and is a useful compound as an antibacterial agent.

Point tC has chemical structural characteristics with 10508M group at the 1st position of azetidine.

Conventionally, compounds having a 1807M'') group at the 1-position of azetidine have been known as 2-azetidine derivatives having antibacterial activity (Japanese Unexamined Patent Publication No. 125362/1989, etc.).
2 This is the result of intensive research by the inventors.

-OS 03'' at the 1st position of azetidine -8OpM'' group
It was discovered that the antibacterial activity was dramatically increased by Qζ by converting it into an M'' group, and the present invention was completed.

The compound (1) of the present invention can be produced by various methods, for example.

Reacting a compound represented by the general formula with a compound represented by the general formula or a reactive derivative thereof9
Then, if desired, it can be produced by converting it into an oxysulfonate.

Examples of the reactive derivatives of the compound (1) include acid halides such as acid bromide and acid chloride; acid anhydrides; mixed acid anhydrides with alkyl carbonates, etc.; N-hydroxybenzotriazole, N-hydroxysuccinimide, 4- Active esters with nitrophenol, 2,4-dinitrophenol, etc.;
Examples include activated amides with pyrazole, imidazole, etc.

The reaction between compound (■) and compound (gate) is carried out in an organic solvent at room temperature, preferably in the presence of a base.

Any organic solvent may be used as long as it does not participate in the reaction.

For example, acetate/tetrahydrofuraf, acetonitrile, methylene chloride, chloroform.

Dimethylformamide, dimethyl sulfoxide, etc. can be used alone or in an appropriate mixture. Also, triethylamine is used as a base.

Pyridine and the like are preferred.

When compound (1) is used as it is in the free acid state, N,N'-dicyclohexylcarbodiimide)',
The reaction can be easily progressed by using a condensing agent such as N,N'-carbonylimidazole.

In addition, in compound (1).

In the case of + R2, the carboxylic acid in R2 is protected with a tert-butyl group, hensyl group, p-methoxybenzyl group, p/zhydryl group, trityl group, etc., and then subjected to reaction with compound (II) and protected after the reaction. The desired product is preferably obtained by removing the group by a conventional chemical operation such as using an acid such as hydrochloric acid, sulfuric acid, or trifluoroacetic acid or by catalytic reduction using a catalyst.

Compound (1) of the present invention A compound in which KO(・teM is a cation, that is, an oxysulfonate is a compound (It)
It can be obtained by common salt-forming means after the reaction of compound (II) with compound (It) and compound (seal).
The oxysulfonate can be formed simultaneously with the reaction of , and the reaction product thus obtained as the oxysulfonate can be further converted into another oxysulfonate.

Compound (1) obtained by the above method.

1. Filtration, recrystallization, extraction, column chromatography
It can be isolated and purified by normal operations such as -.

Note that the lower alkyl group at the 3-position side chain and R of the compound (1) of the present invention can have either an α-1 or β-configuration.

Compound (II) used in this method was published in the Journal American Chemical Society (J, Am.

Chem, Sac, ) Volume 102 (423) 702
It can be produced by the method of pages 6 to 7032 (1980) or by hydrolyzing the compound obtained according to the method and then sulfonating the compound.

The compound (1) of the present invention can be prepared as a powder, granule, capsule, or pill using conventional pharmaceutical additives.

It is possible to prepare preparations such as injections and suppositories and administer them orally or parenterally.

Next, the present invention will be explained in detail by way of examples.

Example 1 106,111 g of (3S)-3-amino-2-azetidinone-1-oxysulfonic acid was mixed with 2.1 g of dimethylformamide.
Dissolve in 5 ml of 2-amino-4-thiazolyl acetic acid 53
rOg.

Add 451Qg of 1-hydroxybenzotriazole, 47μt of rietheramine and 69111g of synchhexylcarbodiimide and stir at room temperature for 10 hours.

The precipitate was removed, dimethylformamide was distilled off, 30 ml of ether was added to the residue, and ether insoluble matter was obtained by decantation. Add 30m of chloroform to this
1 is added and treated to solidify. One portion of this was taken and subjected to column chromatography (25 g of silica gel, chloroform-
Purified with methanol, 10:1 → 1:1),
(38), 17.81 TIg of -3-(2-amino-4-naazolyl acetamide)-2-azetidinone-1-oxysulfonic acid triethylamine salt is obtained.

Dissolve this in 1 ml of methanol and add 15.6 rQg of perfluorobutanesulfonic acid potassium salt in acetone 3.
Add rnl solution, dilute with 5 ml of acetone, further dilute with 20 mA of ether, centrifuge the precipitate, and obtain a brown powder of 3(S)-3-(2-amino-4-thiazolyl acetamide)-2. -Azetidinone-1-oxysulfonic acid potassium salt 15.9 rllg are obtained.

1) Infrared absorption spectrum (KBr) 1765Crn'' (β-lactam C-0) 11) Nuclear magnetic resonance spectrum (DMSO-d6) ppm3.2
6 (2H, s, -CH,,C0-)4.68-4
．． 86 (IH, m, C3-H) 624 (IH1s 1 mouth H) 6.87 (2H, 'broad s, -NH2) 8 near 0 (IH, d, J=9Hz) Example 2゜(38)-3 -Amino-2-azetidinone-1-oxysulfonic acid (191 μm) was dissolved in dimethylformamide (2.5 m).
Dissolved in Z, 83 μt of triethylamine, (Z)
-α-(2-amino-4-thiazolyl)-α-methoxyiminoacetic acid (120.6 μg), 8 HQg of l-hydroxybenzotriazole and 124,111 g of synchlohexylcarbodiimide were added, and the mixture was stirred at room temperature for 35 hours. The precipitate was removed and dimethylformamide was distilled off.

The residue was treated with ether 50[11Z and decanted to obtain an ether insoluble material. When this is treated with 30 mt of chloroform, it solidifies. A lot of this was collected and purified by column chromatography (20 g of silica gel, chloroform-methanol 10:1 → 1:1), and (3S)-3-Cα-(2-amino-4-thiazolyl)-α-methoxyimino Acetamide]-2-azetidinone-1-oxysulfonic acid triethylamine salt 67.
Get 4 ■.

52.4 rllg of this product was dissolved in 2rnl of methanol.

Perfluorobutanesulfonic acid potassium salt 42.6 r
Add a solution of 1g of l' in 3ml of acetone, and add 7mt of acetone.
, diluted with 30 mt of ether and collected the precipitate to obtain a white powder of (3S)-3-1:α-(2-amino-4-thiazolyl)-α-methoxyiminoacetamide]-2- Zetin 7'-1-oxysulfonic acid potassium salt 394■
get.

(1) Infrared absorption spectrum (KBr): 1755cm
-' (β-lactam C=O')3.83 (3H
, s, -0CHs) 3.98 (1B, t, J=6
Hz) 4.78-4.98 (IH, m, C, -H) 6.74
(IH, s, chapter □).

7.20 (2H, broads, -NH2)9
．． 34 (IH, d, J=9Hz, -CONH-) (38
)-3-Amino-2-azetidinone-1-oxysulfonic acid 318ff1g was dissolved in dimethylbormamide 5rnl, triethylamine 0.14mZ, (Z)-
to α(2-amino-4-thiazolyl')-α-(1-diphenylmethoxycarbonyl-1-methylethoxyimino) Acetic acid 219■, 1-hydroxybenzotriazole 67IT! g and dicyclohexylcarbodiimide 11031r1 were added, and the mixture was stirred at room temperature for 20 hours.

The precipitate was removed, 50 mZ of ether was added, and the ether solution was removed by decantation. The ether solution was purified by column chromatography (30 g of silica gel + chloroform-methanoal 20:1 → 5:1) to obtain (Z)-1"3S)-3-[α-(2-amino-4-
thiazolyl)-α-(1-diphenylmethoxycarbonyl-1-methylethoxyimino)acetamide]-2-azetidinone-1-oxysulfonic acid triethylamine salt 44 is obtained.

0.14 rnl of anisole was added to 44 mg of the above product, and after cooling to about -10C, 0.7 rnl of trifluoroacetic acid was added.
Add 8 ml dropwise at =10 to -5C. After stirring at the same temperature for 10 minutes, 2 mZ of ether and 1 rnl of hexane are added while maintaining the temperature. The temperature is returned to room temperature while stirring, and the precipitate is separated by centrifugation, washed twice with ether, and then dried. This solid was suspended in 10ml of cold water.

Adjust the pH to 6 with cold 0.4N aqueous potassium hydroxide solution.

This solution was subjected to column chromatography () (P2O,6
The eluate was concentrated and lyophilized to give (Z)-(38)-3-[α-(
25 µ of dipotassium salt of 2-amino-4-thiazolyl)-α-(1-carboxy-1-methylethoxyimino)-2-azethipannon-1-oxysulfonic acid is obtained.

(1) Infrared absorption spectrum (KBr): 1770
礪-1 (β-lactam c=o) (11) Nuclear magnetic resonance spectrum CDMSO-d6) ppm3.5-3.6
2 (IH, m, C3-=H) 3.94-4.06 (IH
, m, C4-H) 4.80-5.00 (1)1. m,
C4-H) 6.75 (IH ・ ° ・ 7.15 (2H, broad s , -N) (2)
11.6 (IH, m, -CONH-) Example 4 223 mg of (3S, 48)-3-amino/-4-methyl-2-azetidinone-1-oxysulfonic acid was dissolved in 5 mt of dimethylformamide, and triethylamine l) ,1
4rn1. 2-amino-4-thiazolyl acetic acid 176■
, 1-hydroxybenzotriazole 135. rQg and dicyclohexylcarbodiimide 206rl'1g
processed.

Stir at room temperature for 15 hours. The precipitate was removed, dimethylformamide was distilled off under reduced W, and the mixture was treated with 50 rnl of ether.The ether solution was removed by decantation, and 30n+Z of chloroform was added and treated to form a powder. This was collected and subjected to column chromatography (30 g of silica gel, 20 g of chloroform-methanol:
1→1:1) and purified (3S,4S3-3-(2-
Amino-4-thiazolyl acetamide)-4-methyl-2
142 mg of -azetidinone-1-oxysulfonic acid triethylamine salt is obtained. Add this to 0.5 ml of methanol
Add a solution of 118 μl of potassium salt of fluorobutanesulfonic acid in 3 ml of acetone, and add 10 ml of acetone solution.
Dilute in ml. Take 1 precipitate and add 2 to 17rl1g.
Furthermore, 30 ml of ether was added to the mother liquor, the precipitate was collected, and 92 mg of brown powder (38,48)-3-(2-
Amino-4-thiazolyl acetamide)-4-methyl-2
, -azetidinone-1-oxysulfonic acid potassium salt is obtained.

(1) Infrared absorption spectrum (KBr): 1765儂-
1 (β-lactam-C20) (11) Nuclear magnetic resonance spectrum (DMSO-d6) ppm 1.34 (3H, d
, J=7Hz, C4-Me)3.85 (IH, dq
, J=7, 2Hz, C4-H)4.30 (I
H, dd, J=8, 2Hz, C3-H)6.
23 (IH, s, 卆) 6.90 (2H, broad s, -NH2) 9.8
2 (IH, d, J=8 Hz, -CONH-) Example 5 (3S, 4S)-3-amino-4-methyl-2=azetidinone-1-oxysulfonic acid 236rI1gtDissolved in 5mZ of dimethylformamide, triethylamine 0.
14 ml, (Z)-α-(2-amino-4-thiazolyl)-α-methoxyimino, acetic acid 201ff1g
, 137111 g of 1-hydroxybenzotriazole and 210 tllg of synchhexylcarbodiimide
and stirred at room temperature for 17 hours. The precipitate was subjected to the f method, dimethylbormamide was distilled off under reduced pressure, 100 rnl of ether was added to the residue, and the insoluble matter was obtained by decantation.

This was subjected to column chromatography (20 g of silica gel,
Methylene chloride-methanol, 10:1→1:
233rQg of brown solid (Z
)-(3S.

48)-3-(α-(2-amino-4-thiazolyl)-
[alpha]-methoxyiminoacetamide]-4-methyl-2-azetidinone-1-oxysulfonic acid triethylamine salt is obtained. This was dissolved in 1 mZ of methanol, a 3 ml solution of perfluorobutanesulfonic acid potassium salt 183 [Qg in acetone and 30 fflt of ether were added, and the precipitated white solid was collected.

(3S, 48)-3-(α-(2-amino-4-thiazolyl)-α-methoxyiminoacetamide]-4-methyl-2-azetidinone-1-oxysulfonic acid potassium acid 113 fftg is obtained. .

(1) Infrared absorption spectrum (KBr): 1770
cm-' (β-lactam C-0) (11) Nuclear magnetic resonance spectrum (DMSO-d, )
ppm1.39 (3H, d, J=7Hz, C,
-CR2)3.84 (3H,s, -0CH3)3.
95 (IH, dq, J near, 2Hz, C, -
H) 4.43 (IH, dd, J=8.2Hz, C
3-H) 6.72 (t H+ s+ J7H) 7,
I B (2H, broads, -NH2)9.
46 (IH, d, J-=8Hz, -CONH-
) Example 6 co, -C-CH.

0OK 1), (38,4S) -3-amino-4-methyl-2
-Azetidinone-1-oxysulfonic acid (445 mg) was dissolved in dimethylformamide lomZ, triethylamine (0.28 mt), Z-α-(2-amino-1-thiazolyl)-α-(1-methyl-1-diphenylmethoxycarbonylethoxy) imino)acetic acid 878111g,
Add 2701Qg of 1-hydroxybenzotriazole and 412rr@ of dicyclohexylcarbodiimide,
Stir at room temperature for 13 hours. The precipitate was removed and dimethylformamide was distilled off under reduced pressure.

After treatment by adding 50 ml of ether, the ether solution was removed by decantation, and the residue was purified by column chromatography (20 g of silica gel, chloroform-methanol 20:1).

(Z)-(38,4S)-3-(CL-(2-'7minor-4-thiazolyl)-α-(1-methyl-1-diphenylmethoxycarbonylethoxyimino)-acetamido-4-methyl-2- 1 g of azetidinone-1-oxysulfonic acid triethylamine salt (528 ff) was obtained. This was dissolved in 1 ml of methanol.

Addition of a solution of potassium perfluorobutanesulfonate [249 ml in 5 rnl of acetone and 50 mZ of ether liberates an oil. The supernatant was removed by decantation and solidified by treatment with 501 nl of ether. Take 1 part of this and make white powder (Z)-(38,4S)-3
-Ca-(2-amino-4-thiazolyl)-α-(1-
Methyl-1-diphenylmethoxycarbonylethoxyimino)acetamide]-4-methyl-2-azetidino/-
1-oxysulfonic acid potassium salt 278 nl! get g.

1 (1) Infrared absorption spectrum, KBr: 177
0cm (β-lactam C-0) (11) Nuclear magnetic resonance spectrum (DMSOda) p
pm1.39 (3H, d, J = 7 Hz,
C4-CH3) 3.97 (IH, dq, J=7.
2Hz, C, -H) 4.48 (IH, dd, J
=8.2Hz, C3-H)6.67(IH,!+,
-CH(-0)2)6.7 g (IH9s+
XV H)7.2-7.5 (IOH,m, -CH(-
Q) 2) 9.29 (I H, d, J=8Hz,
-CONH-)2) Add 05rr1g of anisole to 140ff1g of the above product.

Cool to -20℃, add 2.5 ml of trifluoroacetic acid dropwise, and stir at -10''C for 10 minutes. Centrifuge the precipitate and wash it twice with ether to obtain a white powder.
ml, adjusted to pH 5.8 with cold 0.4N aqueous potassium hydroxide solution, and subjected to column chromatography (HP
-20, eluted with water). The fraction containing the ``1'' bent product was freeze-dried to obtain a white powder of (Z)-(3S, 48
)-3-(α-(2-amino-4-thiazolyl)-α-
89.9 mg of (l-methyl-1-carboxyethoxyimino)acetamide]-4-methyl-2-azetidinone-1-oxysulfonic acid dipotassium salt is obtained.

(i) Infrared absorption spectrum (KBr): 1770
cm-' (β-lactam C=O) (11) Nuclear magnetic resonance spectrum (DMS 0-da)
ppm1.36-1.42 (9H, m, C, -CH3
, -o-c<Ten: )4.03 (IH, dq,
J=7.2Hz, C4-4()4.47 (IH,
dd, J=8.2Hz, C3-H)6.76
(IHt SI N)I, m-)7.14 (2
H, broad s, -Nl2) 12.0
(I H, d, J=8Hz, -CONH-) Example 7 CHCH,CH.

Dissolve 154 fQg of (38,48)-3-amino-4-methyl-2-azetidinone]-oxysulfonic acid in 2 ml of dimethylformamide, and dissolve 70 fQg of triethylamine.
Add μl. In this solution, l (Z)-2-) IJ
Thylamino-α-(] -]1-phytok7carbonylpropoxyimino-4-thiazolyl acetic acid 286 ff1
g of dimethylformamide 1 ml and medile chloride 1 ml
5mt solution was added, and 67.5+11g of l-hydroquine benzotriazole and 1ci3rr of N,N'-dicyclohexylcarbodiimide were added, and the
Stir for an hour. Insoluble urea was filtered off, and the P solution was concentrated under reduced pressure.

The residue was subjected to column chromatography using 50 g of silica gel. Chloroform-methanol (11,5:, 1)
When the solvent was distilled off, a pale brown powder (Z)-(
38,48)-3-((χ-(2-tritylamino-・
1-thiazolyl)-α-(1-t-butoxycarbonylpropoxyimino)]]]acetamide 4-methyl-1-
Oxysulfonic acid triethylamine salt 23OrlI is obtained.

203 mg of this triethylamine salt was added to anisole 05
React with mZ and trifluoroacetic acid S in mZ for 1 hour at 15°C. The reaction solution was cooled to -10°C, 3 mZ of water was added dropwise, and the reaction was further allowed to react at 10-15°C for 45 minutes. Filter the insoluble matter once and concentrate under reduced pressure. The residue is treated with ethanol to remove insoluble materials. Concentrate solution e under reduced pressure.

Tritify the residue with ether. After quickly removing the hygroscopic solid and dissolving it in cold water, add hydrogen carbonate)
Adjust the pH to 7 with an aqueous IJ solution. Subjected to solution column chromatography (Diaion HP-20), 1
The 0% methanol solution was collected and dried under reduced pressure to obtain (Z)-(38,48)-3-(α-(2-amino-
4-thiazolyl)-α-(1-carboxypropoxyimino)acetamide]-4-methyl-2-azetidinone-
15 mg of 1-oxysulfonic acid disodium salt is obtained.

(1) Infrared absorption spectrum/L/ (KBr) cm-
': 176L 1650+1590, 1285
．． 1255. 1057(11) Nuclear magnetic resonance spectrum (DC30D) ppm 1.04 (3H, t, J=
81 (z, -CH2CH,) ( 1,55 (3H, d, J=7Hz, C, -CH
5) 1.90 (2-H, m, cn2CH3)4
．． 30 (IH, dq+ J= 8.2Hz, C4-
H) 4.40 (IH, d, J= 2Hz, C3-
H; 4.57 (I H, t, J==6.5Hz,
-CdanEt) Agent Akira Sasaki - Applicant Yamanouchi Pharmaceutical Co., Ltd.

Claims (1)

[Claims] General formula (in the formula + R1 represents a hydrogen atom or a lower argyl atom, 1M
is a hydrogen atom or a cation, X is -(CH2)
(n is an integer of 1 to 4) or) C-N-3 O-R2 [R2 is a lower alkyl group or -C-COOM
(R3 and R1 are the same or different and represent a hydrogen atom or a lower alkyl group, and 1M has the same meaning as above). ] represents. ) A 2-azetidinone derivative represented by