JPS5817476B2 - Thieno (2,3-B) Pyridine carbonate - Google Patents

Description

Detailed Description of the Invention The present invention relates to a compound represented by the general formula (n) [wherein R1 and R2 each represent a hydrogen atom, a lower alkyl group, a halogen atom or a nitro group, and R3 represents a lower alkyl group] or Reactive derivatives in the carboxyl group and general formula (II) [In the formula, X represents a hydroxyl group or a rogen atom, and A represents a lower alkylene group.

R4 and R5 each represent a lower alkyl group, R4
, R5 may be bonded together with adjacent nitrogen atoms to form a heterocyclic ring] [In the formula, R1 to R6 and A are The present invention relates to a method for producing a cheno[2<3-b]pyridinecarboxylic acid derivative which is useful as a pharmaceutical and has the same meaning as above].

The lower alkyl group represented by R1 to R5 in each of the above general formulas is preferably a lower alkyl group having 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, secondary butyl, tertiary Examples include butyl.

The halogen atoms represented by R1, R2 and X are fluorine,
chlorine.

It is a bromine or iodine atom.

When the lower alkyl groups represented by R4, R, bond to each other to form a heterocyclic ring with adjacent nitrogen atoms, the heterocyclic ring may further contain other heteroatoms (e.g., oxygen, nitrogen, sulfur atoms, etc.) The ring may contain one or two lower alkyl groups similar to those represented by R1-R5 on the ring as a substituent.

Examples of such heterocycles include pyrrolidine, piperidine, 2-methylpiperidine, 3-methylpiperidine, 4
-methylpiperidine, 2,6-dimethylpiperidine, morpholine, 2,6-dimethylmorpholine, N-monomethylpiperazine, and the like.

Note that the α-position of the thiophene ring [Compound (I). (■) No. 2
As the substituent at the β-position, a halogen atom, a nitro group, or a lower alkyl group is preferable compared to other cases, and the substituent at the β-position [3-position of compound (I), (n)] is a hydrogen atom ( That is, the case where there is no substituent at the β-position) is preferable compared to other cases.

Examples of the lower alkylene group represented by A include ethylene, propylene, trimethylene, and tetramethylene groups.

The method of the invention is carried out by reacting a compound of general formula (II) or a reactive derivative thereof at the carboxyl group with a compound of general formula (n).

Examples of reactive derivatives in the carboxyl group of compound (II) include lower alkyl esters in which the alkyl moiety has about 1 to 4 carbon atoms (e.g., methyl ester, ethyl ester,
propyl ester, butyl ester).

Active esters (e.g., 2,4-dinitrophenyl ester, pentachlorophenyl ester, N-hydroxysuccinimide ester, etc.), acid halides (e.g., acid chloride, acid bromide, etc.) or mixed acid anhydrides (e.g., monomethyl carbonate, etc.) or a mixed acid anhydride with monoethyl carbonate), but acid halides are particularly preferred in terms of reactivity.

The acid halide of compound (n) can be used to convert compound (Il) into a phosphorus halide, an oxyhalide (e.g., phosphorus trichloride,
(phosphorus tribromide, phosphorus pentachloride, phosphorus oxychloride, etc.) or thionyl chloride, etc., in an appropriate solvent (e.g., benzene, toluene, xylene, chloroform, dichloromethane, tetrahydrofuran, etc.) or itself as a solvent, under water cooling. It can be easily produced by reacting under heating up to or near the boiling point of the solvent used.

The acid halide of compound (II) produced as described above can be isolated and purified if necessary, but
The reaction solution containing the reactive derivative without isolation
iit or the residue obtained by simply distilling off the solvent may be used as it is in the reaction of the present invention with a compound vessel.

In the reaction of the present invention, compound (n) is used as one of the raw materials.
When using as a free carboxylic acid, a compound in which X is a halogen atom in a general weapon is used as the other raw material compound, and a reactive derivative in the carboxyl group of compound (I[), such as an acid halide, is used as one raw material. When used, as the other raw material compound, general formula GII
), the reaction is carried out using a compound in which X is a hydroxyl group.

These reactions are preferably carried out in an appropriate solvent in the presence of a deoxidizing agent.

The reaction solvent may be any solvent that is inert to the reaction.
For example, dimethylformamide, dimethylsulfoxide, tetrahydrofuran, chloroform, dichloromethane.

Examples include benzene and toluene.

When the reaction is carried out between compound (II) and a compound of the general formula @) in which X is a halogen atom, it is preferable to use anhydrous dimethylformamide or dimethyl sulfoxide as the solvent.

Examples of deoxidizers used in this reaction include alkali metal carbonates (eg, potassium carbonate, sodium carbonate).

Alkali metal hydroxides (e.g. potassium hydroxide.

Examples include sodium hydroxide) and tertiary amines (eg, triethylamine).

When using a deoxidizing agent, it is not necessary to coexist in the reaction system, and the starting compound (n) can be introduced into the corresponding salt with these bases in advance and this can be used as the starting material. ) in the case of a reaction between an acid halide and a compound in which X is a hydroxyl group in the general formula book, an excess amount of the compound @)
It can also serve as a deoxidizing agent.

In addition, when using a deoxidizing agent, the amount used is based on the compound (■
) It is usually about 1 to 10 mol per 1 mol.

In addition, the amount of the starting compound @) to be used in this reaction is as follows:
It is usually about 1 to 5 moles.

The reaction temperature can be selected as appropriate from the temperature range of 0° to 200°C.

Since the target compound (1) produced in this manner has a basic nitrogen atom in the molecule, an appropriate acid addition salt can be formed.

Such salts include, for example, hydrochloride, hydrobromide, sulfate, oxalate.

Examples include succinate, maleate, malate, tartrate, etc., and these salts have excellent water solubility.

The object compound (1) of the present invention - Matakeso salt is a new compound, and it
ccusaureus, Bacillus 5ubt
ilis) and Gram-negative bacteria (e.g. Escher
ichia coli, Klebsiella pne
urmnia.

It has a wide range of antibacterial effects against Proteus vulgaris) and is therefore useful as a medicine, such as a chemotherapeutic agent.

Compound (I) and its acid addition salts may be used as such or, if desired, together with an appropriate pharmacologically acceptable carrier, for example, in the form of tablets, powders, or granules.

It can be administered orally or parenterally in dosage forms such as injections, capsules, syrups, suppositories, and ointments.

When compound (I) or an acid addition salt thereof is used, for example, as a chemotherapeutic agent, the dosage can be appropriately selected from the range of about 0.2 to 10.9 doses per day for adults.

Among the raw material compounds (II) of the present invention, those in which R1 and R2 are hydrogen atoms, lower alkyl groups, or halogen atoms are produced, for example, by the steps shown in the following formula. [In the formula R'1. R', , are hydrogen atoms, R1,
R2 represents a lower alkyl group or a halogen atom, R6-R8 represents a lower alkyl group similar to R1-R6, and Y represents a hydrogen atom or a carboxyl group. After heating and ring-closing using poly-IJ-IJ acid ester, if necessary, dehalogenation by reduction reaction with zinc and acetic acid, and further hydrolysis known per se and N-alkylation corresponding to the lower alkyl group represented by R3. It can be easily synthesized by

Further, among the compounds (n), the compounds in which R1 and R2 are represented by nitro groups are R1. Compound (II) in which R2 is a hydrogen atom can be synthesized by nitration using, for example, a mixed acid of nitric acid and concentrated sulfuric acid by a method known per se.

For example, the following compounds can be produced by the method of the present invention.

02-dimethylaminoethyl 7-nityl-4゜7-sihydro-4-oxoceno(2,3-b)pyridine-5
-Carboxylate 02-dimethylaminoethyl 7-nityl-4゜7-sihydro-2-methyl-4-oxoceno(2,3-b)
Pyridine-5-carboxylate 02-cy:r-thylaminoethyl 7-nityl-4゜7-sihydro-2-methyl-4-oxoceno(2,3
-b) Pyridine-5-carboxylate 02-piperidinoethyl 7-ethyl-4,fusihydro 2-methyl-4-oxoceno(2,3-b) Pyridine-5-carboxylate 02-(4-methylpiperidino)ethyl 7-ethyl -4, Fushihydro 2-methyl-4-oxoceno(2,3-b)pyridine-5-
Carboxylate 02-morpholinoethyl 7-ethyl-4,fusihydro 2-methyl-4-oxocheno(2,3-b)pyridine-5-carboxylate 03-dimethylaminopropyl 7-nityl-4,7-sihydro 2-methyl- 4
-oxocheno(2,3-b)pyridine-5-carboxylate 02-piperidinoethyl 4,7-cyhydro-2-methyl-4-oxo-7-propylcheno(2,3-b)pyridine-5-carboxylate 02-( 4-Methylpiperazino)ethyl 7-butyl-4,7-sihydro-2-methyl-4-oxoceno(2
, 3-b) Pyridine-5-carboxylate 02-piperidinoethyl 2. 7-Dinityru 4.7
-Sihydro 4-oxocheno[2,3-b]pyridine-5-carboxylate 02-piperidinoethyl 7-nityl 4. 7-Sihydro2,3-dimethyl-4-oxoceno(2,3-
b) Pyridine-5-carboxylate 02-dimethylaminoethyl 2-promorph-ethyl-4, fushihydro 4-oxoceno(2,3-b)
Pyridine-5-carboxylate 02-diethylamine ethyl 2-promo 7-ethyl-4, fushihydro 4-oxothieno (2,3-b)
Pyridine-5-carboxylate 03-dimethylaminopropyl 2-bromo-7-ethyl-4,fusihydro 4-oxothieno(2,3-b
) Pyridine-5-carboxylate 02-pyrrolidinoethyl 2-7" rom-7-ethyl-4,7-sihydro-4-oxoceno(2,3-b) pyridine-5-carboxylate 02-piperidinoethyl 2-bromo-7- Ethyl-4,fusihydro-4-oxothieno(2,3-b)pyridine-5-carboxylate 02-(4-methylpiperidino)ethyl 2-promo7-ethyl-4,fusihydro-4-oxothieno(2,3-b)pyridine -5-carboxylate 02-morpholinoethyl 2-promo 7-ethyl-4
, Fushihydro 4-oxothieno(2,3-b)pyridine-5-carboxylate 02-(4-methylpiperazino)ethyl 2-bromo-7-ethyl-4, Fushihydro 4-oxothieno(2,3-b)pyridine-5 −
Carboxylate 02-(4-(2-hydroxyethyl)piperidinoethyl 2-bromo-7-nityl-4゜7-sihydro-4-
Oxocheno(2,3-b)pyridine-5-carboxylate 02-dimethylaminoethyl 2-bromo-7-ethyl-4, fusihydro 3-methyl-4-oxocheno(
2,3-b) Pyridine-5-carboxylate 02-piperidinoethyl 2-bromo-7-ethyl-4
, Fushihydro 3-methyl-4-oxocheno (2,
3-b) Pyridine-5-carboxylate○ 2-diethylamine ethyl 2-chloro-7-ethyl-4,fusihydro 4-oxothieno
) Pyridine-5-carboxylate 02-piperidinoethyl 2-chloro-7-ethyl-4
, Fushihydro 4-oxothieno(2,3-b)pyridine-5-carboxylate 02-(4-methylpiperidino)ethyl 2-chloro-7-ethyl-4, Fushihydro 4-oxothieno(2,3-b)pyridine-5 −
Carboxylate 02-morpholinoethyl 2-chloro-7-ethyl-4
, Fushihydro 4-oxothieno(2,3-b)pyridine-5-carboxylate 02-piperidinoethyl
7-ethyl-4,fusihydro 2-iodo-4-oxocheno(2,3-b)pyridine-5-carboxylate 02-morpholinoethyl 7-ethyl-4,fusihydro 2-nitro-4-oxocheno(2,3-b) b) Pyridine-5-carboxylate 02-piperidinoethyl 7-ethyl-4,fusihydro 3-methyl-2-nitro-4-oxoceno(2,'3-b,lPyridine-5-carboxylate Example 1 2-bromo- 7-ethyl-4,fusihydro-4-oxothieno(2,3-b)pyridine-5-carboxylic acid 0.
After stirring a mixture of 302 g of potassium carbonate, 0.83 g of fine powder of potassium carbonate, and 6 ml of dry dimethylformamide at 100°C for 1 hour, dimethylaminoethyl chloride hydrochloride 0.
．． Add 43g and stir at 100°C for another 4 hours.

Insoluble matter in the resulting reaction mixture was filtered off.

After the solution f was concentrated to dryness under reduced pressure, the residue was extracted with chloroform, and the insoluble matter was filtered off.

The chloroform was distilled off and the residue was recrystallized from benzene-ether to give 2-dimethylamine ethyl 2-7" lomo7-ethyl-4,7-sihydro-4-oxocheno(
2,3-b) Pyridine-5-carboxylate is obtained as colorless needles.

Melting point 128-129°C Elemental analysis value C14H1□Br
N203S calculated value C45, 04, H4, 59, H7,
51 Experimental Value C45,20, H4,62, H7,41 Example 2 7-Ethyl-4, Fushihydro 2-methyl-4-oxocheno(2,3-b)pyridine-5-carboxylic acid 0.
237@ and dimethylaminoethyl chloride hydrochloride 0.4
3. When reacted with p under the same reaction conditions as in Example 1, crude 2-dimethylamine ethyl 7-ethyl-4,fusihydro 2-methyl-4-oxoceno(2,3-b)pyridine-5-carboxylate was obtained. An oil is obtained.

When this is dissolved in acetone and an acetone solution of oxalic acid is added, the corresponding acidic oxalate is obtained as hygroscopic crystals.

Recrystallization from ethanol gives pale yellow platelets with a melting point of 187-189°C (decomposition).

Elemental analysis value C15H2ON203 S' C2H2
04"3/2H20 Calculated value C47,99, H5,92, H6,58 Experimental value C48,15, H5°94.H6,58; The reaction was carried out under the same reaction conditions as in Examples 1 and 2, and then The compound is obtained.

Example 10 2-bromo-7-ethyl-4,fusihydro-4-oxothieno(2,'3-b)pyridine-5-carboxylic acid 0
．． After stirring a mixture of 302g and 4rrLl of thionyl chloride at room temperature for 5 hours, the precipitated crystals (chloride) were collected by filtration, thoroughly washed with dichloromethane, and immediately poured into 4ml of dichloromethane.
to make a suspension.

Then, while stirring at room temperature, 0.51 rL of 2-dimethylaminoethanol was added, and the mixture was stirred for 1 hour.

Remove the precipitate and concentrate the filtrate to dryness. The residue was extracted with benzene, and the insoluble matter was filtered off, and the benzene solution was concentrated and ether was added to obtain 2-dimethylamine ethyl 2-bromo-7-ethyl-41fusihydro-4-oxinthieno(2,3-b)pyridine. -5-carboxylate is obtained as crystals.

Melting point 129-13 when recrystallized from benzene-ether
Gives needle-shaped crystals exhibiting 0°C.

Motoichi shows the same infrared absorption spectrum as that obtained in Example 1.

Claims (1)

[Scope of Claims] 1. A compound represented by the general formula [wherein R1 and R2 are a hydrogen atom, a lower alkyl group, a rogen atom, or a nitro group, respectively, and R3 is a lower alkyl group] or its carboxyl group Reactive derivatives and the general formula [wherein X is a hydroxyl group or)]/a rogene atom, and A represents a lower alkylene group. R4 and R5 each represent a lower alkyl group, R4
, R, may be bonded to each other with adjacent nitrogen atoms to form a heterocyclic ring] [wherein R1 to R5 and A are as defined above] A method for producing a cheno(2,3-b)pyridinecarboxylic acid derivative represented by the same meaning.