JPS59231086A - 4-methoxyethyl-2-azetidinone-1-sulfonic acid derivative - Google Patents

Abstract

NEW MATERIAL:The compound of formula I (R<1> is H or protecting group; R<2> is lower alkyl; R<3> is H or methoxy) or its salt. EXAMPLE:[3S(Z), 4R]-3-[2-(2-Amino-4-thiazolyl)-2-methoxyiminoacetyl-amino]-4-(2- methoxyethyl)-2-oxo-1-azetidinesulfonic acid sodium salt. USE:Useful for the remedy of bacteriosis, e.g. respiratory and urethral infecftious diseases, etc. It has especially excellent antibacterial activity against Gram-negative bacteria, and has beta-lactamase inhibiting action. PREPARATION:The compound of formula I can be prepared by reacting the compound of formula II or its salt with a sulfonation agent such as SO3 in an inert organic solvent such as DMF at -20-+80 deg.C.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel goumethoxyshetyl-coazetidinone-/-sulfonic acid derivatives.

As a result of repeated research on coazetidinone-/-sulfonic acid derivatives, the present inventors found a compound in which the y-position is substituted with a methoxyethyl group, that is, the following formula (summer): In the formula, R is a hydrogen atom or a protective group. , 2 R1 represents a lower alkyl group, and represents a hydrogen atom or a methoxy group. The methoxyethyl-coazetidinone-/-sulfonic acid derivative of and also has a β-lactamase inhibitory effect, leading to the completion of the present invention. Common amino protecting groups that can be easily removed without affecting the moiety are preferred, such as chloroacetyl, benzyloxycarbonyl,
Examples include p-nitrobenzyloxycarbonyl, 2,2.2-trichloroethoxycarbonyl, and t-butyldimethylsilyl. The "lower alkyl group" represented by R includes alkyl groups having up to 6 carbon atoms such as methyl, ethyl, and inglovir groups, with methyl being particularly preferred.

According to the present invention, salts of the compounds of formula (1) above are also provided. Examples of such salts include salts with alkaline earth metals such as Na) IJ, potassium and calcium, and salts with organic bases such as triethylamine, pyridine and dimethylaniline.

According to the present invention, the compound of formula (1) or a salt thereof is obtained by sulfonating the compound of (a) where R', R1 and R3 have the above meanings, or (b)
A compound of the formula or a salt thereof, in which R has the meaning given above, is reacted with a compound of the formula or a reactive derivative thereof, in which R and R2 have the meaning given above, and (C) the necessary (d) if necessary, converting the obtained compound of formula (1) into its salt, or It can be produced by a method consisting of converting the salt of the compound of formula (1) into another salt or the free form of the compound of formula (1).

According to the above reaction (a), the metal compound of the above formula (...) or a salt thereof is sulfonated.

The reaction is generally carried out in an inert organic solvent, for example, with halogenated hydrocarbons such as methylene chloride and chloroform; amides such as dimethylformamide and dimethylacetamide; ethers such as dioxane, tetrahydrofuran, and ethyl ether; and esters such as ethyl acetate. sulfonating agents such as sulfur trioxide or adducts of sulfur trioxide and pyridine, dimethylacetamide, dioxane, picoline, chlorosulfonic acid, etc., or in mixtures of two or more of these. can be done.

The reaction temperature is usually −0 to 0° C1, preferably 00 to
Temperatures within the range gθ°C are suitable.

- In the above reaction, the amount of the sulfonating agent to be used with respect to the compound of formula (1) or its salt is not particularly limited, but generally the amount of the sulfonating agent is 7 to 7 per mole of the compound of formula (II) or its salt. It is advantageous to use a proportion of the order of 70 mol, preferably co-j mol.

As a result, the target compound of formula (1) or its salt is produced, and the target compound can be separated and purified from the reaction mixture by extraction, filtration, recrystallization, chromatography, etc. according to conventional methods. can.

Note that the compound of formula (It) used as a starting material in the above reaction is a novel compound that has not been described in conventional literature, and can be synthesized by the method described below.

According to the above method (b), the compound of the formula (1) or a salt thereof is diacylated with the compound of the formula (IV) or a reactive derivative thereof.

Acylation is generally carried out in an inert organic solvent, such as with halogenated hydrocarbons such as methylene chloride and chloroform; ethers such as dioxane and tetrahydrofuran; amides such as dimethylformamide and dimethylacetamide; A compound of formula (1) or a salt thereof in ethyl acetate or the like is combined with a compound of formula (IV) and a condensing agent (for example, N,N'-dicyclohexylcarbodiimide, N-ethyl-R'-jethylaminobromine). or reactive derivatives of the compound of formula (IV) (e.g., acid halides such as acid chlorides, mixed acid anhydrides such as isopropyl carbonate anhydride, activated amides such as imidazolides, This can be carried out by reacting with active esters such as esters of N-hydroxysuccinimide, etc.). Although the reaction temperature is not particularly limited, a temperature between cooling and room temperature is generally suitable.

In the above reaction, the amount of the compound of formula (■) or its reactive derivative to be used relative to the compound of formula (1) or its salt is:
Generally, formula <W) per mole of the compound of formula (1) or its salt
or its reactive derivatives in a proportion of at least 1 mol, preferably from 7 to 2 mol.

As a result, the desired compound of formula (1) or a salt thereof is obtained.

Incidentally, the compound of the above formula (seal), which is a starting material in this reaction, is also a new compound, and can be synthesized by the method described below.

The compound of formula (1) or a salt thereof produced by the method described above is converted into a compound of formula (1) in which R represents a hydrogen atom by removing a protecting group as necessary. be able to.

Removal of the protecting group can be easily achieved by methods known per se, such as acid or base hydrolysis, hydrogenolysis, etc., which are appropriately selected depending on the type of the protecting group.

Moreover, the conversion of the compound of formula (1) into a salt can be carried out according to a conventional method,
For example, this can be carried out by treatment with a base.

Furthermore, when converting the salt of the compound of formula (1) into another salt, according to a conventional method, for example, by treatment with an ion exchange resin, on the other hand, when converting to the compound of formula (I) in free form, This can be easily achieved by a conventional method, for example, by treatment with an acid.

The compound of formula (It) or its salt, which is the starting material in the method (a), can be prepared, for example, by the method described in the reaction formula below,
Alternatively, it can be manufactured by a method similar thereto.

(n) In each of the above formulas, R, R and R have the above meanings, and R'l
and R' each independently represent an amino protecting group.

Furthermore, the starting material in the method (b) is represented by formula (I)
The compound or a salt thereof can be produced, for example, by the method described in the reaction formula below or a method analogous thereto.

(厘) In each of the above formulas, R2, R'' and R' have the above meanings.

The above-described compound of formula (1) of the present invention or a salt thereof exhibits particularly excellent antibacterial activity against Durham-negative bacteria, and is useful for the treatment of bacterial infections, such as respiratory infections, urinary tract infections, and purulent infections. It is an extremely useful compound for the treatment of sexual diseases, etc.

vf of the compound of formula (1) of the present invention, [an example of the action is shown below. The test method was based on the MIC agar diffusion method.

Thus, the compound of formula (r) or a salt thereof of the present invention can be administered orally or parenterally (for example, intramuscularly,
(intravenous injection, rectal administration, etc.).

When used as a drug, the compound of the present invention may be prepared in accordance with conventional methods using non-toxic excipients, binders, lubricants, disintegrants, preservatives, tonicity agents, and stabilizers commonly used in such drugs. , a buffering agent, and the like. The dosage of the compound of the present invention depends on the type of human or other mammal to be treated,
It can vary widely depending on the route of administration, severity of symptoms, doctor's diagnosis, etc., but in general, it is 7 days per day! ~20θq/Kq
.

It can be suitably set to /θ~/θθMf//Kg.

The present invention will be further explained below with reference to Examples.

Example/゛(a) (4tR) -/ -t-Butyldimethylsilyl-4l-(2-hydroxyethyl)-,2-7zetidynoy //71q/ (0,!/ mmol) under ice cooling , approx./, FN diazomethane/ether solution 311
(10.2 mmol), and 2 j μl of boron trifluoride Nieteller) was added dropwise under stirring while cooling with water. At this time, nitrogen gas is violently generated. After the dropwise addition, /M phosphate buffer (pH 7,0) was added, and the mixture was extracted with ethyl ether. The solvent was distilled off under reduced pressure, the residue was subjected to silica gel column chromatography, and methylene chloride/ethyl ether (!:/
), (GR)-/-t-butyldimethylsilyl-(2-methoxyethyl)-coazetidinone! and got a cape. In addition, raw material 37119 was recovered.

[α]ゎ -Evening! , 30 (C= /, 0 evening, CHCl,
) [R(CHCI,) 2 /72! an-'NM
R (CDC: 1.) a: 0, 2'1 (6H,
s), 0.91s(riH, F3), /, 6.2
(/H, m), 2. /? (/H.

m), 2. Otsu (/H, ad, , T:J'H2
, /J-Hz), 3. /g(/H,da ,,T=6j
Hz, /j Hz), 3.22 (3H, θ)
, 3. 'Iθ(,2H,t, J=6;Hz), 3.4
j (/H, In) (b) Dissolve 0 μl of Shiitsubu pyramine/Otsu in 2xl of anhydrous tetrahydrofuran under an argon atmosphere, -
While stirring at 70°C, 173 µl of n-butyllithium/hexane solution of 1 mol/liter was added dropwise, and the mixture was stirred at -7°C for 1/2 minute. Then, (47R)-/- is converted into -butyldimethylsilyl-gu(2-methoxyethyl)
-λ-Azetidino:y/4tOqt (OJ7 m
A solution obtained by dissolving mol) in anhydrous tetrahydrofuran was slowly added dropwise, and the mixture was further stirred for 20 minutes. Further, 3 µl of isoamyl nitrite was added at once, and the temperature was brought to O''C for about 7 hours while stirring, then cooled again to -7θ°C, and the reaction was terminated with acetic acid/θθ µl. Ethyl acetate. was added, washed with saturated brine, dried, and concentrated under reduced pressure.The obtained oily residue was purified by thin layer chromatography (methylene chloride/ethyl ether =, 3-:/) to obtain (GR)-/-t-butyl Dimethylsilyl-3-hydroxyimino-\-(,2-methoxyethyl)-2-azetidinone/θoq was obtained as an oil.

IR (CHCl, 7): 3 evening 30,. 32jθ, /
7g, ftx-'(C)(GR)-/-t-butyldimethylsilyl-3-hydroxyimino-'1-(2-methoxyethyl)-coazetidinone/otq(o,t♂
7 mmol) in 2 ml of ethyl acetate, platinum oxide!
01q was added and the mixture was vigorously stirred for 7 hours under a hydrogen atmosphere.

After the reaction was completed, the catalyst was removed by filtration through Celite, and the r liquid was concentrated under reduced pressure. The obtained oily residue was washed with Rover Color b (Lic
It was purified with hroprepoSi(θ) (ethyl, v ether/methanol = coθ2/), and (3B.

￥R)-3-amino-/-1-butyldimethylsilyl-
¥-(2-methoxyethyl)-coazetidinone 791
19 was obtained as an oil.

[α] -zat,,! ? o (c = θ,!♂, CHC
l,)1) IR(CHCI,): /72jCIl-'NMR(
CDCl,)δ:O,mu2(3H,s),0.2g(3
H, s), 0.9 g (H, a), /, 92 (2H.

m), 3.32 (3H,e), 3. ¥r (,2
H,t, J=6Hz), 3.7.2(/H,m),
g, 3θ (/H0a, J=jjH2) (d) Dimethylformamide 3! μl and methylene chloride/go solution under stirring at -70°C, phosgene die-r-/
J”pl (θ, /J m mol) was added dropwise at room temperature.
Stirred for 0 minutes. At this time, a white precipitate was deposited. This material was cooled to -7g°C, and (Z)-2-chloroacetylamino-α-methoxyimino-guthiazoleacetic acid r3MI
f (0.3 mmol), Trini F-/l/
A methylene chloride solution/ml of 42 μl (0.1 mmol) of 7 min.

It was cooled again to -7θ°C, and (38,4tR)-3-amino-/-1-butyldimethylsilyl-Q-(,2-methoxyethyl)-coazetidinone (about θ, 2F
m mol), triethylamine 39 μl (0,
, 2rm mol) of methylene chloride solution was added dropwise, and the mixture was stirred until the temperature naturally reached 0°C. Saturated sodium bicarbonate solution was added and extracted with methylene chloride.

The organic layer was dried and concentrated under reduced pressure, and the resulting oily residue was subjected to silica gel column chromatography and eluted with methylene chloride/methanol (-20:/). The eluate was concentrated and treated with ether/hexane to give an amorphous powder (J'8(Z),
GR) --? -(co(2-chloroacetylamino-guthiazolyl)-λ-nodoxyiminoacetylamino)
-/-1-Butyldimethylsilyl-'1-(2-methoxyethyl)-noazetidinone Pufferfish 3119 was obtained.

m, p, and 5-9/°C (α)) 1-J7. θo (C-/, θ0, CHC
l, ) fR (KBr): 32 θ, 3/za θ, /
22θ, /17j an-'NMR (CDC1,?)
a: 0.2 yen (3H, B), 0.30 (3H, Sun), 0.9 Otsu (9H, 8), /, 5+ Otsu (,2
H.

m), , 3.30 (3H, S), 3.3
0-3. evening. (,2H.

” ), 3.9o -g, 7θ (/H, m), 3.
97 (3H.

S), ¥,,22(/H,s),g,23(/H,
s).

3 澾'l (/H, da, J=j0.3-Hz,
/Hz).

7.0za(/H,e),,,23(/H,d,
J-ZHz) (e) (3S (Z), e R) -3-(,
2-(2-chloroacetylamino-couthiazolyl)-
1-methoxyiminoacetylamine)-/-1-butyldimethylsilyl-￥-(,2-methoxyethyl)-2-
Azetidinone/30 ~ (θ, 2 mmol) in methanol 3. After dissolving the mixture in θml and adding /N hydrochloric acid θ and Mt dropwise under ice-cooling, the mixture was stirred at room temperature for an hour. The precipitated crystals were filtered, washed with methanol and ether, and dried (3S(
Z), ￥R]-3-(-,2-(2-chloroacetylamino-Z-thiazolyl),2-methoxyiminoacetylamine)-&-(J-methoxyethyl)-identified azetidinone tazari was obtained .

m, p, 2/0°C (decomposition) [α) D-7,060 (C-/, θri, DMF) I
R (KBr): 3.270, /7￥3, /Otsu? ,
3-, #; Otsu θ pieces-'NMR ((C horse), so)
δ: /, 7θ (2H, m), 3.22 (3H, 8),
3. J'7 (3H, s), g, 3J (certified H.

s ), L/J' (/H, ad, J=JHz, 9Hz
).

7 Shio 2 (/H, s), J", 32 (/H, s), ?,
3θ (/H, d, J=-5'H2).

(f) Under argon atmosphere (3s(z),!R)-3-[
2-(2-chloroacetylamino-Z-thiazolyl)-
comethoxyiminoacetylamino]-\-(,2-methoxyethyl)-coazetidinone Z7~ at 2.0.
l of dimethylformamide/methylene chloride (/ : /
Vv), sulfur trioxide-pyridine complex? The mixture was stirred at 30°C for 7.5 hours. The reaction solution was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography using chloroform/methanol/water (/θ0:30:
It was eluted with water. [3S
(Z), 'l R) -3-(2-(2-rio
o 7cetylaminoguthiazolyl)-λ-methoxyiminoacetylamino)-4-(J-methoxyethyl)-11okine-/-sodium azetidinesulfonate OJ-my was obtained as a freeze-dried powder.

[α), -2,2,10(C=/,θor HJ
O) Engineering R (KBr): 3 Otsu 00-3.200, /7
Otsu J,/neto.

/-2za0-8Uθ, /θ30tytt-'NMR(D
, O) δ:2. /θ(,2H,m), 3.3(3H,
B), 3.10 (2H, t, J=7Hz).

g, θ2(3H,e), 41.32-￥j2(/H,m
).

A and 4. 2 (2H, Sun), 1. <Do/(
/H,d,;J=3,6Hz),7. Guza(/H,s
) Example (3S(Z), 4tR)-3-(-2-(2,-chloroacetylamino-guthiazolyl)-11methoxyiminoacetylamine)-4-(2-methoxyethyl)-cooxo/- Dissolve sodium azetidine sulfonate in water and θtttl, add sodium monomethyldithiocarbamate/ottq while stirring under water cooling,
After stirring at room temperature for 7 hours, 3~ of sodium monomethyldithiocarbamate was added, and the mixture was further stirred at room temperature for 3θ minutes.

The deposited precipitate was filtered, the P solution was washed with ether, the aqueous layer was subjected to HP, 20 column chromatography, and after purification, it was lyophilized to obtain (J'E'(Z), GR>3- C-co(,2
Two volumes of sodium -amino-guthiazolyl)-comethoxyiminoacetylamino)-4-(,2-methoxyethyl)-cooxo/-azetidinesulfonate were obtained as a freeze-dried powder.

Ding R (KBr): 300θ-320θ, /7
Otsu θ, / Koot θ.

/2? θ-8220, 10g! α-′NMR (D, 0
)δ: 2,0(!?(2H,m), 3.33
(3H,e), 3.31? (2H,t,,T-7
Hz), 3.9J" (3H,s), <do, 4do0 (/H
, m), 3.3f (/H.

a, J=jJHz), ly, 9
6 (/H, El) Patent applicant Teikoku Zoki Seiyaku Co., Ltd. Procedural amendment (voluntary) Showa! July 2, 1996 Kazuo Wakasugi, Commissioner of the Japan Patent Office, Mr. Z Indication of the case Showa Go and 2013 Patent Application No. 1 Theta Yuotori No. 6 3 Name of the invention Go methoxyethyl-noazetidinone-/-sulfonic acid derivative 3 Make amendment Relationship with the patent case Patent applicant's residence 2-chome Akasaka, Minato-ku, Tokyo 702! Number/None 3- Target of correction

Claims (1)

[Scope of Claims] A compound or a salt thereof, wherein R' represents a hydrogen atom or a protecting group, R4 represents a lower alkyl group, and RJ represents a hydrogen atom or a methoxy group.