JPS6236383A - Pyridonecarboxylic acid derivative - Google Patents

Abstract

NEW MATERIAL:A compound shown by the formula I (X1 is halogen; X2 is H or halogen; Y is O or -CH2; R1 and R2 are H, lower alkyl or cycloalkyl; j is 0 or 1; k is 3 or 4 or 5; m and n are 0, 1 or 2; with the proviso that m and n are 1 or 2 when X1=0 and j is 1 when Y=0;), its ester and salt. EXAMPLE:10-(cis-3-Acetylamiomethyl-4-fluoro-1-pyrrolidinyl)-9-fluoro-2 ,3-dihydro-3- methyl-7-oxo-7H-pyrido[1,2,3-de][1-,4]b-en-zoxazine-6-carboxylic acid. USE:An antimicrobial also usable as a food preservative. PREPARATION:A carboxylic acid shown by the formula II(Z is functional group replaceable with cyclic amine derivative) or its ester (preferably lower lalkyl ester) is reacted with a cyclic amine derivative shown by the formula III to give a compound shown by the formula I.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel pyridonecarboxylic acid v4W, its ester and its salt, which exhibit extremely excellent antibacterial activity.

More specifically, the compound of the present invention has the following general formula (wherein X
I means a halogen atom, X2 means a hydrogen atom or a halogen atom, Y is an acid, ÷; F; 1 atom or -
C112-, R1 and R2 are the same or different and represent a hydrogen atom, a lower alkyl group or a chloroalkyl group, j represents an integer of 0 or 1, and k represents an integer of 3, 4 or 5. , m+n means an integer 0.1 or 2.

However, when %X2 is a hydrogen atom, m and n mean an integer 1 or 2, and Y is P! When it is an lI index atom, j means the integer 1. ) Pyridone carbon rtt derivative Jg derivative, its ester and its salt.

In this specification, halogen atom means fluorine.

chlorine, bromine or iodine, one lower alkyl means one alkyl having 1 to 5 charcoal particles, and cycloalkyl means a cycloalkyl group having 3 to 6 carbon atoms. do.

Salts of the compounds of the invention include acetic acid, lactic acid, and succinic acid.

Salts with organic acids such as methanesulfone WL, maleic acid, malon ff, curconic acid, or amino acids such as asparagus and glutamic acid, or hydrochloric acid.

These are salts with inorganic acids such as phosphoric acid, metal salts such as sodium, hlium, zinc, flJ, etc. of the compound of formula [I], or salts with a metal group.

The ester of the compound of the formula CI] refers to a lower alkyl ester such as methyl ester or ethyl ester of the compound [I], or a known compound that is easily eliminated by hydrolysis or in vivo to become the compound CI]. esters, such as acetoxymethyl ester, pivaloyloxymethyl ester, ethoxyloxymethyl ester,
Choline ester, dimethylaminoethyl ester and 1-
It means aminoethyl esters such as piperidinyl ethyl ester, 5-indanyl ester, phthalidyl ester, etc.

Compounds of the invention may also exist as hydrates. Therefore, such forms are naturally included in the compounds of the present invention.

Since the compound of the present invention has an asymmetric carbon atom in its 7-position substituent, it can exist as an optically active form. Therefore, these optically active substances are included in the compounds of the present invention.

Furthermore, since the compound of the present invention has two asymmetric carbon atoms in its 7-position substituent, it can exist as different stereoisomers (nce form, trans form).

These stereoisomers and mixtures thereof are also included in the compounds of the present invention.

The method for producing the compound of the present invention will be explained below.

The compound of the present invention is a carboxylic acid represented by the following general formula (wherein Z means a functional group that can be substituted with the cyclic amine derivative described below, and X+, Y and j are the same as above) or an ester thereof. (preferably lower alkyl ester) and the following general formula (wherein, X21
R11R2, k, m and n are the same as above. ) It can be produced by reacting a cyclic amine derivative represented by the formula (2) and cleaving the product using a conventional method.

The reactive functional group represented by 2 in formula [[i] includes halogen atom, arylsulfonyl, arylsulfinyl,
lower alkylsulfonyl, lower alkylsulfinyl,
Arylsulfonyloxy.

Examples include lower alkylsulfonyloxy.

This reaction consists of ethanol, acetonitrile, dioxa/,
10 to 180" C1, preferably 2
At 0 to 150°C, the dairy compound [11] or its ester and [Inl] are heated for 30 minutes to 15 hours, usually for 1 to 15 hours.
This can be carried out by mixing for 5 hours (q.
The amount used for [I] is a temporary measurement. Depending on the type of functional group Z in the raw material compound [II] or its ester, an acid such as hydrochloric acid may be produced as a by-product as a result of the reaction.In such cases, it is common to use an acid acceptor; nll may be used in excess to serve as an acid receptor.

Further, each family compound [I[13] used in this reaction may be used in a protected form with Anru W or the like, and the protecting group may be removed by a conventional method after the reaction is completed.

The starting compound [II] or its ester can be produced by the method described in the following literature or by the method learned therefrom.

1i:+11 Compound [I[1] can be produced by the method α described in Example 1 of the reference number, or a method similar thereto.

When the compound of the present invention obtained by the above method is an ester, it can be converted into a compound of formula [II] by hydrolyzing the ester moiety by a conventional method.

Furthermore, if necessary, the compound of formula [1] may be esterified by a conventional method to form an ester of the compound of formula [II].

The compound of the present invention produced in this way is prepared according to j7: method! +'-m, purified. Depending on the isolation and purification conditions, it can be obtained in the form of a salt, a free carboxylic acid, or a free amine, but these can be mutually converted depending on the purpose, and the compound of the present invention in the desired form can be obtained with i! ! will be built.

Stereoisomers (cis, trans) of the compounds of the invention can be separated from each other by conventional methods, such as fractional crystallization, chromatographic separation, and the like. Incidentally, the compound CI[1] having a cis or trans configuration
] The compounds of the present invention having cis and trans configurations can also be produced by the above method.

Optically active forms of the compounds of the present invention can be separated by applying known methods.

The thus obtained compound [II, its ester and its salt are all frJ3'! It is a compound. In particular, compound [1] and its salts exhibit extremely excellent antibacterial activity and are therefore valuable as antibacterial agents.

Compound [1] or a salt thereof can be used not only as a medicine for humans and animals, but also as a medicine for fish diseases, an agricultural chemical, a food preservative, and the like. In addition, the ester form of compound [II is of course valuable as a raw material for the synthesis of compound [II, but if this compound is easily converted into compound [■] in vivo, it may be equivalent to compound [II]. It is effective as an antibacterial agent.
It is a useful compound.

Next, data regarding the antibacterial activity of the compounds of the present invention are listed below.

1 Experimental conditions The minimum inhibitory concentration (MIC: μg/l) is Chamot
Harapy, 29(1), 7[1 (1981)], and the results are shown in the table above.

'When the compound of the present invention is used as an antibacterial agent in humans, the dosage varies depending on age, body weight, symptoms, route of administration, but it is 5 to 5 g per day, once or divided into several doses. It is recommended that the patient be administered at the same time.

Dan! ] The route may be either oral or parenteral.

Although the compound of the present invention may be administered as a bulk powder, it is usually administered in a prepared form together with a pharmaceutical carrier. the! Examples include tablets, capsules, and granules.

Examples include fine granules, powders, lozenges, and injections. These formulations are prepared according to conventional methods. Starch and mannitol are used as carriers for oral preparations.

Substances commonly used in the pharmaceutical field, such as crystalline cellulose and CMCNa, which do not react with the compound of the present invention are used. Examples of carriers for injection include carriers commonly used in the field of injection drugs, such as water, physiological saline, glucose solutions, and infusion preparations.

Next, the method for producing the compound of the present invention will be explained in more detail with reference to Examples and Reference Examples.

Reference Example 1 3-acetylamide/methyl-4-fluoro[J-pyrrolidine: (1) Known compound l-benzyl-3-hydroxy-4
-Human[''xymethylpyrrolidine[J, Org, Cha
m.

30, 740 (+905)] 1-be/gi-3-
81 g of hydroxy-4-methanesulfonyloxymethylpyrrolidine are obtained. IR spectrum (liquid film) c++-'
: 3370.1350. +170. Cis spectrum m/z: 285 (M”), 208.190
．． 91゜■ 50g of this compound and 22g of sodium azide
．． 8 g are reacted in dimethylformamide at 120-130 DEG C. to obtain 30 g of 3-azidomethyl-1-benzyl-4-hydroxypyrrolidine of 7III. ! R spectrum (liquid N) am-': 3350.2100
．． 1450.1205. Mass spectrum m/z: 2
32 (M+), 175.158.9+.

(3) To a solution of 32 g of this compound in chloroform is added 04 g of hexafluoropropene 7-diethylamine reagent to cause a reaction, and the crude product is purified in minutes by silica gel column chromatography to obtain the following product.

As the initial outflow? 3.5 g of trans-3-azidomethyl-1-be/giru-4-fluoropyrrolidine in d+ form
get. IR spectrum (liquid ff1) clI-': 21
00, 1450.1270. cis spectrum m/z
: 234 (M”), +77, 91. NMR spectrum (CDCl3) δ: 3.04 (2II,
s, ClI2pH), 4.5 and 5.2 (
IH, br, H-1-F), 7.30 (5H,
s, CoHs).

As the rear effluent, cis-3-azidomethyl-1 of Yufu
3.0 g of -benzyl-4-fluoropyrrolidine are obtained.

IR spectrum (liquid 112) cs-': 2+0
0°+450.1270. Mass spectrum m/z:
234 (M”).

177, 91. NMR spectrum (CDCl3) δ
: 3. C8(2II, s, Cl12f'h
), 4.75 and 5.45 (I II, b
r.

11-+-F), 7.30 (5II, s,
C11H5).

As intermediate effluent, 3-azidomethyl-1-benzyl-
7.3 g of a mixture of cis and trans forms of 4-fluoropyrrolidine is obtained.

(4) 2.9 g of the above compound (cis form) was reduced with sodium bis(2-methoxyethoxy)aluminum hydride and then acetylated to give Urafushi's cis-3-acetylaminomethyl-1-benzyl-4-fluoro 2.1 g of pyrrolidine are obtained. IR spectrum (liquid film)
cs-': 3270.1050.1550. Mass spectrum m/z: 250 (M”), +5
! l, 91. NMRy, Beck) k (CDC
l3) δ: 1.98 (311,s,
COCH3).

3.00 (21-1, s, C112pH), 4
．． 75 and 5.48 (III, br, 1l-1
-F), 7.31 (5H,s, Co11s).

■ Dissolve the above compound (cis form) in ethanol and
A Hydrolysis using palladium-carbon as a catalyst. The catalyst is filtered off to obtain an ethanol solution of cis-3-acetylaminomethyl-4-fluoropyrrolidine. This solution is used in the next substitution reaction.

Example 1 10-(cis-3-aminomethyl-4-fluoro1-
pyrrolidinyl)-〇-fluoro2,3-dihydro3
-Methyl-7-oxo-7■-pyrido[1,2,3-d
el [1,/1]benzoxazine-6-carboxylic hydrochloride: (1) 9.10-difluoro-2,3-dihydro-3
-/ Chill-7-, t Ki7-7 H-Hi') F [
1,2,3-del[1,4]benzooxidine-6-
Calbo/M1. Og, cis-3-acetylaminomethyl-4-fluoropyrrolidine 730 g, triethylamine 1.0 ml, dimethyl sulfoxide 10 x 1
The mixture is heated and stirred at 100 to 110°C for 3 hours. Add water and collect 4 precipitated crystals. Recrystallization from acetonitrile gave 10-(cis-3-acetylaminomethyl-4-fluoro-1-pyrrolidinyl)-9-fluoro-
1.13 g of 2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-del[1,4]benzoxazino-6-carvone Wa is obtained.

m, p, 201-262°C.

Claims (2)

[Claims] (1) General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, X_1 means a halogen atom, X_2 means a hydrogen atom or a halogen atom, Y means an oxygen atom or -CH_2-, R_1, R_
2 are the same or different and represent a hydrogen atom, a lower alkyl group, or a cycloalkyl group, j is an integer of 0 or 1, and k is an integer of 3, 4, or 5;
m and n are integers 0, 1 or 2. However, when X_2 is a hydrogen atom, m and n mean an integer 1 or 2, and when Y is an oxygen atom, j means an integer 1. ) Pyridonecarboxylic acid derivatives, esters thereof and salts thereof. (2) The pyridonecarboxylic acid derivative, its ester, and its salt according to claim 1, wherein X_1 is a fluorine atom and k is 4.