JP2002332279A - Benzothiazolylhydroxamic acid derivative and its use - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a benzothiazolylhydroxxamic acid derivative having a potent peptidedeformylase(PDF) inhibitory activity and antibacterial activity. SOLUTION: This PDF inhibitory agent and antibacterial agent contains a compound expressed by the formula (I) [wherein, (n) is 0, 1 or 2 integer; R is an alkyl] or its salt.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a novel benzothiazolylhydroxamic acid derivative having peptide deformylase inhibitory activity and antibacterial activity and a medicament containing the derivative as an active ingredient.

[0002]

2. Description of the Related Art In order to exert antibacterial activity against drug-resistant bacteria that appear one after another, compounds having a new mechanism of action have been demanded. Protein synthesis in prokaryotes begins with formylation of methionyl tRNA, where a polypeptide having a formyl group at the N-terminus is first synthesized (Meinnel, T., Mechulam, Y., Blanquet,
S., Biochimie, 75, 1161-75 (1993)). Peptide deformylase (hereinafter sometimes referred to as PDF)
Is an enzyme that cleaves the N-terminal formyl group from this polypeptide and is an enzyme that functions as a protein, and is an essential enzyme for the growth of prokaryotes (Adams,
JM, J. Mol. Biol., 33, 571-89 (1968), Livingsto
n, DM, Leder, P., Biochemistry, 8, 435-43 (196
8), Takeda, M., Webster, RE, Pro. Natl. Acad. Sc
i. USA, 60, 1487-94 (1968)). On the other hand, protein synthesis in eukaryotes such as humans involves formylation of peptides.
It does not have PDF because it does not require reformylation.
Thus, inhibition of PDF, which is only present in prokaryotes such as bacteria, is an attractive target for antimicrobial development. PDF
Is a metalloprotease having iron in the active site, and its instability makes purification difficult, and the activity cannot be measured to search for an inhibitor. However, due to recent advances in molecular biology, PDF has been isolated and purified, and the development of its inhibitors has begun (Rajagopalan, PTR, Yu, XC, Pei, D., J. et al.
Am. Chem. Soc., 119, 12418-9 (1997), Rajagopala
n, PTR, Datta, A., Pei, D., Biochemistry, 36, 1
3910-8 (1997), Becker, A., Schlichting, I., Kabsc
h, W., Shultz, S., Wagner, AFV, J. Biol. Che
m., 273, 11413-16 (1998), Meinnel, T., Blanquet,
S., Dardel, F., J. Mol. Biol., 262, 375-86 (199
6), Chan, MK, Gong, WM, Rajagopalan, PTR, H
ao, B., Tsai, CM, Pei, D., Biochemistry, 36, 139
04-9 (1997), Dardel, F., Ragusa, S., Lazennec,
C., Blanquet, S., Meinnel, T., J. Mol. Biol., 262,
375-86 (1996)).

[0003] The PDF inhibitors reported so far include natural products of actinonin (Chen, Dawn Z .;
Patel, Dinesh V .; Hackbarth, Corinne J .; Wang, We
n; Dreyer, Geoffrey; Young, Dennis C .; Margolis, P
eter S .; Wu, Charlotte; Ni, Zi-Jie; Trias, Joaqui
m; White, Richard J .; Yuan, Zhengyu, Biochemistr
y, 39, 1256-62 (2000)) and H-phospho.
nate derivative (Hu, Yun-Jin; Rajagopalan, PT Ra
vi; Pei, Dehua, Bioorg. Med. Chem. Lett., 8, 2479-
82, (1998)), peptide aldehyde derivatives (Durand, Da
niel J .; Gordon Green, Barbara; O'Connell, John
F .; Grant, Stephan K., Arch. Biochem. Biophys., 36
7, 297-302, (1999)), biphenyl acid derivatives (Green, B
arbara Gordon; Toney, Jeffrey H .; Kozarich, John
W .; Grant, Stephan K., Arch. Biochem. Biophys., 37.
5,355-8, (2000)), peptide thiol derivatives (Huntin
gton, Kristi M .; Yi, Tian; Wei, Yaoming; Pei, Dehu
a, Biochemistry, 39, 4543-51 (2000)), peptide hydroxamic acid derivatives (WO 99/57097), sulfonyl hydroxamic acid derivatives (Apfel, Christian; Banner, David)
W .; Bur, Daniel; Dietz, Michel; Hirata, Takahiro;
Hubschwerlen, Christian; Locher, Hans; Page, Malco
lm GP; Pirson, Wolfgang; Rosse, Gerard; Speckli
n, Jean-Luc, J. Med. Chem., 43, 2324-31 (2000)),
Hydroxyamine derivatives (WO 99/39704; Clements, Jo
hn M .; Beckett, R. Paul; Brown, Anthony; Catlin, G
raham; Lobell, Mario; Palan, Shilpa; Thomas, Wayn
e; Whittaker, Mark; Wood, Stephen; Salama, Sameeh;
Baker, Patrick J .; Rodgers, H. Fiona; Barynin, Vl
adimir; Rice, David W .; Hunter, Michael G., Antimic
rob. Agents Chemother., 45, 563-570 (2001)), but none has been used clinically yet.
It is the stage of research and development. Therefore, the inventors have conducted intensive studies in an attempt to develop a novel compound having a PDF inhibitory activity.

[0004]

SUMMARY OF THE INVENTION An object of the present invention is to provide a benzothiazolyl hydroxamic acid derivative having a strong PDF inhibitory action and an antibacterial action.

[0005]

Means for Solving the Problems The present inventors have made intensive studies to solve the above-mentioned problems, and as a result, have found a benzothiazolyl hydroxamic acid derivative and a salt thereof having strong PDF inhibitory activity and antibacterial activity. The present invention was completed by further research.

That is, the present invention provides: (1) The following general formula (I)

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[Wherein, n represents an integer of 0, 1 or 2, and R represents an alkyl group. (2) the compound or a salt thereof according to the above (1), wherein R is a linear lower alkyl group; (3) a medicament containing the compound or a salt thereof according to the above (1); (4) The above (3), which is a peptide deformylase inhibitor
And (5) an antibacterial agent.

BEST MODE FOR CARRYING OUT THE INVENTION

In the above formula (I), the alkyl group represented by R preferably has up to 12 carbon atoms, such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl and Linear alkyl groups such as dodecyl, and isopropyl, isobutyl, sec-butyl, tert-butyl, 2-methylpentyl, 3-methylpentyl, 4-isocapryl,
Examples include branched alkyl groups such as 4-ethylpentyl, 6-methyldecyl, 9-methyldecyl, 6-ethylnonyl and 5-propyloctyl. More preferably, a straight-chain lower alkyl group, specifically methyl having up to 5 carbon atoms,
Ethyl, propyl, butyl and pentyl are preferred, and a linear alkyl group having 3 to 5 carbon atoms (propyl, butyl and pentyl) is particularly preferred.

The salt of the compound represented by formula (I) in the present invention is preferably a physiologically acceptable salt.
Examples thereof include salts with inorganic bases, salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids, and the like. Preferred examples of the salt with an inorganic base include:
Examples thereof include alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as calcium salts and magnesium salts; aluminum salts and ammonium salts. Preferred examples of the salt with an organic base include, for example, salts with trimethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N, N-dibenzylethylenediamine and the like. Preferable examples of the salt with an inorganic acid include, for example, salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like. Suitable examples of salts with organic acids include, for example, formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p -Salts with toluenesulfonic acid and the like.
Preferable examples of the salt with a basic amino acid include, for example, salts with arginine, lysine, ornithine, and preferable examples of the salt with an acidic amino acid include, for example, salts with aspartic acid, glutamic acid, and the like. Can be

The compound of the present invention can be prepared, for example, by the following general reaction formula:

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[In the reaction scheme, n and R have the same meaning as defined in the above general formula (I). X represents a halogen atom, and R ¹ represents a lower alkyl group. ] Can be produced. In the following description, “lower alkyl” means an alkyl group having 1 to 5 carbon atoms, and “halogen” or “halo” means fluorine, chlorine, bromine, and iodine, unless otherwise specified.

Benzothiazole (II) is reacted with a halogen compound (III) to give a benzothiazolium salt derivative represented by the general formula (IV) [hereinafter sometimes referred to as compound (IV). ] Can be manufactured. As the halogen compound (III), an iodine compound and a bromine compound are preferable. Examples of the iodine compound include iodomethane, iodoethane, 1-iodopropane, 2-iodopropane, 1-iodobutane, 2-iodobutane, 1-iodopentane, 2-iodopentane, 1-iodohexane, 2-iodohexane, 1-iodopentane Iodoheptane, 2-iodoheptane, 1-iodooctane, 2-iodooctane, 1-iodononane, 1-iododecane, 1-iodoundecane, 1-iodododecane, 1-iodo-2-methylpropane, 2-iodo-2 -Methylpropane, 1-
Iodo-2,2-dimethylpropane, 2-ethyl-1-
Examples thereof include iodohexane and 1-iodo-3-methylbutane. Examples of the bromine compound include bromomethane and
Bromoethane, 1-bromopropane, 2-bromopropane, 1-bromobutane, 2-bromobutane, 1-bromopentane, 2-bromopentane, 3-bromopentane,
1-bromoheptane, 2-bromoheptane, 3-bromoheptane, 4-bromoheptane, 1-bromooctane,
2-bromooctane, 3-bromooctane, 4-bromooctane, 1-bromononane, 2-bromononane, 1-
Bromodecane, 2-bromodecane, 1-bromododecane, 2-bromododecane, 1-bromo-2-methylpropane, 1-bromo-2,2-dimethylpropane, 1-bromo-3-methylbutane, 2-bromo-2- Methyl propane, 2-bromo-2-methylbutane and the like are mentioned. Examples of the reaction solvent include conventional solvents that do not adversely influence the reaction, such as ethyl acetate, N, N-dimethylacetamide, N, N-dimethylformamide, and tetrahydrofuran, or a mixed solvent thereof. Preferably, it is N, N-dimethylformamide. The reaction temperature is usually in the range of room temperature to under heating, and preferably in the range of 50C to 150C.

Next, the compound (IV) is reacted with a compound represented by the general formula (V) under strongly basic conditions to obtain a compound of the general formula (VI)
[Hereinafter, it may be described as compound (VI). ] Can be manufactured. Examples of the lower alkyl group represented by R ¹ include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and t-butyl.
tert-butyl and the like. Preferably methyl,
Ethyl. Examples of the strong base include methyl lithium, butyl lithium, tert-butyl lithium, lithium diisopropylamide, lithium amide, sodium amide, sodium methoxide, sodium ethoxide, sodium hydride and the like. Preferably, it is lithium diisopropylamide. As the reaction solvent, for example, anhydrous tetrahydrofuran, benzene, toluene,
Examples of such solvents include ethylbenzene, cyclohexane, hexane, heptane, diethyl ether, and other conventional solvents which do not adversely affect the reaction, or mixed solvents thereof. Preferably, it is anhydrous tetrahydrofuran. It is preferable to carry out the reaction under cooling (−78 ° C. ± 10 ° C.) for 1 to 2 hours from the start of the reaction, and then to carry out the reaction at room temperature for 1 to 5 hours.

Subsequently, the compound (VI) is oxidized to give a compound represented by the general formula (VII) [hereinafter sometimes referred to as compound (VII). ] Can be manufactured. Examples of the oxidizing agent used include m-chloroperbenzoic acid, potassium permanganate, trifluoroperacetic acid, hydrogen peroxide, potassium peroxide and monopersulfate compounds (monopotassium monopersulfate.
A mixture of dipotassium sulfate and potassium hydrogen sulfate (hereinafter referred to as OX)
ONE (registered trademark; DuPont). ) Etc.]. Preferably, it is m-chloroperbenzoic acid. As a reaction solvent, for example, dichloromethane, chloroform, anhydrous tetrahydrofuran,
Examples of such solvents include benzene, toluene, ethylbenzene, cyclohexane, hexane, heptane, diethyl ether, and other conventional solvents which do not adversely affect the reaction, or mixed solvents thereof. Preferably, it is dichloromethane. The reaction temperature is usually in a range from cooling to heating, and preferably in a range of 0 ° C to 30 ° C.

When n is 1 or 2 in the general formula (I), the compound (VII) is further oxidized to give a compound represented by the general formula (VIII) [hereinafter sometimes referred to as compound (VIII). ] Can be manufactured. When n is 1, the oxidizing agent used includes hydrogen peroxide, potassium peroxide, m-chloroperbenzoic acid, trifluoroperacetic acid, and OX.
ONE and the like. Preferably, it is OXONE. Examples of the reaction solvent include water, alcohols (e.g., methanol and ethanol), ethers (e.g., tetrahydrofuran, 1,4-dioxane), and other conventional solvents that do not adversely affect the reaction, or a mixed solvent thereof. Preferably, it is a mixed solvent of water and methanol.
The reaction temperature is usually in a range from cooling to heating, and preferably in a range of 0 ° C to 30 ° C. When n is 2, examples of the oxidizing agent include hydrogen peroxide, potassium peroxide, m-chloroperbenzoic acid, trifluoroperacetic acid, and OXONE. Preferably, it is m-chloroperbenzoic acid. Examples of the reaction solvent include conventional solvents that do not adversely affect the reaction, such as dichloromethane, chloroform, anhydrous tetrahydrofuran, benzene, toluene, ethylbenzene, cyclohexane, hexane, heptane, and diethyl ether, or a mixed solvent thereof. Preferably, it is dichloromethane. The reaction temperature is usually in a range from cooling to heating, and preferably in a range of 0 ° C to 30 ° C.

Compound (VII) or compound (VIII) is hydrolyzed with an alkali or an acid by a conventional method to give a compound of the formula (I)
X) [The compound represented by the formula [IX] ] Can be manufactured.

Finally, the compound (IX) or a reactive derivative thereof at the carboxyl group or a salt thereof is condensed with hydroxylamine in an organic solvent to give a compound represented by the formula (I) [hereinafter referred to as a compound ( Sometimes described as I). ] Can be manufactured. Suitable reactive derivatives at the carboxyl group of compound (IX) include acid halides, acid anhydrides, activated amides, activated esters and the like. Acid halides include acid chlorides, and acid anhydrides include, for example, substituted phosphoric acid (di-lower alkyl phosphoric acid, phenyl phosphoric acid, diphenyl phosphoric acid, dibenzyl phosphoric acid, halogenated phosphoric acid, etc.), Di-lower alkyl phosphorous acid, sulfurous acid, thiosulfuric acid, sulfuric acid, sulfonic acid (such as methanesulfonic acid),
Aliphatic carboxylic acids (acetic acid, propionic acid, butyric acid, isobutyric acid, pivalic acid, pentanoic acid, isopentanoic acid, trichloroacetic acid, etc.) or aromatic carboxylic acids (benzoic acid, etc.)
And a mixed acid anhydride or a symmetric acid anhydride with an acid such as Suitable examples of the activated amide include, for example, imidazole, 4-substituted imidazole, dimethylpyrazole, triazole or tetrazole. Preferred examples of the activated ester include, for example, cyanomethyl ester, methoxymethyl ester, dimethyliminomethyl ester, vinyl ester, propargyl ester, p-nitrophenyl ester, trichlorophenyl ester, pentachlorophenyl ester, methylphenyl ester, phenylazo Phenyl ester, phenyl thioester, p-nitrophenyl thioester, p-cresyl thioester, carboxymethyl thioester, pyranyl ester, pyridyl ester, 8-
Quinolyl thioester, or ester with N-hydroxy compound such as N, N-dimethylhydroxyamine, 1-hydroxy-2- (1H) -pyridone, N-hydroxysuccinimide, N-hydroxyphthalimide, 1-hydroxybenzotriazole, etc. Is mentioned.
Suitable salts of compound (IX) and its reactive derivatives include, for example, alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as calcium salt and magnesium salt, and aluminum salt, ammonium salt,
For example, base salts such as organic base salts such as trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, diethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N, N-dibenzylethylenediamine salt and the like can be mentioned. Can be These reactive derivatives can be arbitrarily selected depending on the type of compound (IX) used. In this reaction, when the compound (IX) is used in a free form or a salt thereof, N, N'-dicyclohexylcarbodiimide, N-
Cyclohexyl-N'-morpholinoethylcarbodiimide, N-cyclohexyl-N '-(4-diethylaminocyclohexyl) carbodiimide, N, N'-diethylcarbodiimide, N, N'-diisopropylcarbodiimide, N-ethyl-N'-(3- Dimethylaminopropyl) carbodiimide, N, N'-carbonylbis (2-
Methylimidazole), pentamethyleneketene-N-cyclohexylimine, diphenylketene-N-cyclohexylimine, ethoxyacetylene, 1-alkoxy-
1-chloroethylene, trimethyl phosphite, ethyl polyphosphate, isopropyl polyphosphate, phosphorus oxychloride, diphenylphosphoryl azide, thionyl chloride, oxalyl chloride, for example, lower alkyl haloformate such as ethyl chloroformate and isopropyl chloroformate, triphenyl Phosphine, 2-ethyl-7-hydroxybenzisoxazolium salt, 2-ethyl-5- (m-sulfophenyl) isoxazolium hydroxide inner salt, N-hydroxybenzotriazole, 1- (p-chlorobenzene Sulfonyloxy) -6-chloro-1H-benzotriazole, a so-called Vilsmeier reagent prepared by the reaction of N, N-dimethylformamide with thionyl chloride, phosgene, trichloromethyl chloroformate, phosphorus oxychloride and the like. It is desirable to carry out the reaction in the presence of a condensing agent use. The condensation is carried out by using an inorganic base such as an alkali metal bicarbonate, or a tri-lower alkylamine, pyridine, N
-May be carried out in the presence of an organic base such as lower alkylmorpholine and 1-hydroxybenzyltriazole. 1-ethyl-3- (3-dimethylaminopropyl)
Combinations of carbodiimide hydrochloride and 1-hydroxybenzotriazole are preferred. Examples of the organic solvent include conventional solvents such as dichloromethane, chloroform, N, N-dimethylformamide and tetrahydrofuran, or a mixed solvent thereof. Preferably,
N, N-dimethylformamide. The reaction temperature is usually in a range from cooling to heating, preferably 20 ° C.
~ 50 ° C.

Further, among the compounds represented by the general formula (I), the compound in which n is 2 is a compound represented by the following reaction formula in which the compound in which n is 0 in the compound (I) obtained by the above general reaction formula.

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[In the reaction formula, R has the same meaning as defined in the above general formula (I). ] And can be produced by oxidation.

In this case, as the oxidizing agent, hydrogen peroxide,
Potassium peroxide, m-chloroperbenzoic acid, trifluoroperacetic acid, OXONE and the like are preferred. OXONE is particularly preferred. The reaction solvent may be a conventional solvent such as water, alcohols (eg, methanol, ethanol) and ethers (eg, tetrahydrofuran, 1,4-dioxane) which does not adversely affect the reaction, or a mixed solvent thereof. . Particularly, a mixed solvent of water and methanol is preferable. The reaction temperature is generally in a range from cooling to heating, and preferably in a range of 0 ° C to 30 ° C.

The compound of the present invention represented by the general formula (I) and a salt thereof (hereinafter sometimes abbreviated as the compound of the present invention) are novel compounds which have not been published in the literature, and are shown in Test Examples described later. Since they have excellent PDF inhibitory activity and antibacterial activity, they are useful as PDF inhibitors and antibacterial agents by combining them as active ingredients and, if necessary, combining carriers described below.

The medicament containing the compound of the present invention is administered systemically or locally to a warm-blooded animal (eg, human, rat, mouse, rabbit, cow, pig, dog, cat, etc.). In addition to systemic oral administration, intravenous injection, subcutaneous injection,
It is administered by parenteral methods such as intramuscular injection. It is topically administered to the skin, mucous membranes, intranasally, intraocularly, and the like. Formulations that are orally administered to humans include, for example, powders, granules, tablets,
Capsules, syrups, liquids and the like can be mentioned.
When the preparation is manufactured as a powder, granules, tablets, capsules and the like, any pharmaceutical carrier suitable for preparing solid preparations, such as excipients (starch, mannitol, glucose, fructose, sucrose, etc.), lubricating Agents (magnesium stearate, calcium stearate, etc.), disintegrants (starch, crystalline cellulose, etc.), binders (starch, gum arabic, etc.), etc., and are coated with a coating agent (gelatin, sucrose, etc.) Is also good. When the preparation is prepared as a syrup or liquid, for example, a stabilizer (eg, sodium edetate), a suspending agent (eg, gum arabic, carmellose), a flavoring agent (eg, simple syrup, dextrose), a fragrance, etc. You can choose to use. Parenteral preparations include injections, suppositories and the like. When the preparation is manufactured as an injection, for example, a solvent (such as distilled water for injection), a stabilizer (such as sodium edetate), an isotonic agent (such as sodium chloride, glycerin, and mannitol),
pH adjusters (hydrochloric acid, citric acid, sodium hydroxide, etc.) and suspending agents (methyl cellulose, etc.) can be used. When manufactured as suppositories, for example, suppository bases (cocoa butter, macrogol, etc.) And the like can be appropriately selected and used. Examples of external preparations include ointments, creams, lotions, nasal drops and eye drops. In these external preparations, in addition to the compound of the present invention, for example, ointment bases (such as petrolatum, beeswax, and lanolin), solvents (such as physiological saline and purified water), stabilizers (such as sodium edetate and citric acid), and wetting agents (Eg, glycerin), emulsifier (eg, polyvinylpyrrolidone), suspending agent (eg, hydroxypropylmethylcellulose, methylcellulose), surfactant (eg, polysorbate 80, polyoxyethylene hydrogenated castor oil), preservative (eg, benzalkonium chloride, paraben) , Chlorobutanol, etc.), buffers (boric acid, borax, sodium acetate, citrate buffer, phosphate buffer, etc.), isotonic agents (sodium chloride, glycerin, mannitol, etc.), pH adjusters (hydrochloric acid) , Sodium hydroxide, etc.)
Excipients, solvents and the like can be appropriately selected and used.

The dose of the compound of the present invention depends on the disease to be treated,
Although it varies depending on symptoms, administration subject, administration method, etc., when used for infectious diseases in adults, the dose per administration is usually 1 to 1000 mg, preferably 10 to 200 mg for oral administration.
mg 1 to 4 times a day. When applied topically to the skin, an ointment containing the compound of the present invention in an amount of 0.01 to 10% w / w%, preferably 0.1 to 5% w / w%, usually 1 to 10% / day is used.
It is preferable to apply five times. When used topically for adult eye infections, the compound of the present invention is usually 0.001 to 0.001.
1.0 w / v%, preferably 0.01 to 0.5 w / v%
The ophthalmic solution to be contained is preferably instilled 20 to 50 μl at a time, 1 to 6 times a day.

The preparation of the present invention may optionally contain other antibacterial components and / or other kinds of medicinal components as long as the object of the present invention is not violated.

[0025]

The present invention will be described in more detail with reference to the following Examples, Test Examples and Formulation Examples, but the present invention is not limited thereto.

Example 1 2- (3-butyl-3-hydrobenzothiazole-2-ylidene) ethanehydroxamic acid (compound 1) Step 1) Benzothiazole (10.00 g, 73.9)
7 mmol) and 1-iodobutane (81.67 g,
443.82 mmol) was dissolved in 20 mL of N, N-dimethylformamide and stirred at 100 ° C. for 2 hours. After completion of the reaction, 200 mL of diethyl ether was added to the reaction solution, and the mixture was poured into ice water to completely precipitate the product. The product was collected by filtration and washed with ether. The crude product was recrystallized from 5 mL of methanol to obtain 3-butylbenzothiazolium iodide (14.50 g, 61.4%) as colorless crystals. 113.7-113.9 ° C. ¹ H-NMR spectrum (300 MHz, DMSO-d ₆ ) δ: 0.91 (3H,
t, J = 7.2 Hz), 1.30-1.42 (2H, m), 1.86-1.96 (2
H, m), 4.84 (2H, t, J = 7.5 Hz), 7.82-7.96 (2H,
m), 8.41-8.54 (2H, m), 10.60 (1H, S).

Step 2) Ethyl acetate (5.27 g, 5
(2.63 mmol) in anhydrous tetrahydrofuran 10
0 mL of a 2M lithium diisopropylamide solution (solvent: tetrahydrofuran / heptane /
26.32 mL of ethylbenzene solution) was added. After stirring this solution for 1 hour, 3-butylbenzothiazolium iodide (14.00 g, 43.86 mmol) was added.
The mixture was stirred at -78 ° C for 1 hour and then at room temperature for 2 hours. The reaction solution was quenched with water, and tetrahydrofuran was distilled off under reduced pressure. 200 mL of diethyl ether was added to the residue, and the mixture was washed with a saturated saline solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to give ethyl 2- (3-butyl-
2,3-Dihydrobenzothiazol-2-yl) acetate (10.99 g, 89.7%) was obtained as a yellow oil. ¹ H-NMR spectrum (300 MHz, CDCl ₃ ) δ: 0.95 (3H, t,
J = 7.2Hz), 1.27 (3H, t, J = 7.2Hz), 1.16-1.43 (2
H, m), 1.57-1.67 (2H, m), 2.78 (1H, dd, J = 16.
2, 8.4Hz), 2.93 (1H, dd, J = 16.2, 4.8Hz), 3.06
(1H, ddd, J = 14.1, 9.0, 6.3Hz), 3.28 (1H, ddd, J
= 14.1, 9.0, 6.0 Hz), 4.17 (2H, q, J = 7.2 Hz), 5.4
1 (1H, dd, J = 8.4, 4.8 Hz), 6.46 (1H, m), 6.69 (1
H, m), 6.96 (1H, m), 7.04 (1H, m). ¹³ C-NMR spectrum (75 MHz, CDCl ₃ ) δ: 13.9, 14.2, 2
0.3, 29.5, 42.5, 49.1, 60.8, 87.6, 109.6 (2C), 11
9.6, 121.9 (2C), 125.3, 170.5.

Step 3) Ethyl 2- (3-butyl-
2,3-Dihydrobenzothiazol-2-yl) acetate (6.00 g, 21.48 mmol) was dissolved in 20 mL of dichloromethane, and m-chloroperbenzoic acid (4.45 g, 25.77 mmol) was gradually added under ice-cooling. Added.
The solution was stirred overnight at room temperature. After the completion of the reaction, the resultant was washed with a saturated aqueous solution of sodium hydrogencarbonate and a saturated saline solution, and then dried and dried over anhydrous sodium sulfate. After filtering off the inorganics,
The solvent was distilled off under reduced pressure to obtain a brown oil. The crude product was purified by flash column chromatography [Silica gel].
60N (40-50 mesh), a mixed solution of ethyl acetate and hexane (1:20 v / v)].
-(3-Butyl-3-hydrobenzothiazol-2-ylidene) acetate (5.10 g, 85.6%) was obtained as a yellow oil. ¹ H-NMR spectrum (300 MHz, CDCl ₃ ) δ: 0.98 (3H, t,
J = 7.2Hz), 1.28 (3H, t, J = 7.2Hz), 1.38−1.51 (2
H, m), 1.62-1.72 (2H, m), 3.38 (2H, t, J = 7.5H
z), 4.19 (2H, q, J = 7.2Hz), 6.48 (1H, m), 6.77
−6.79 (2H, m), 6.90 (1H, m), 7.07 (1H, s). ¹³ C-NMR spectrum (75 MHz, CDCl ₃ ) δ: 13.8, 14.4, 1
9.9, 29.5, 51.6, 60.7, 93.9, 112.9, 121.8, 124.7,
127.3, 127.6, 139.8, 143.8, 163.8.

Step 4) Ethyl 2- (3-butyl-3)
-Hydrobenzothiazole-2-ylidene) acetate (1.80 g, 6.14 mmol) in 40 m of ethanol
L, and 6N-potassium hydroxide (10 mL, 60 m
mol) aqueous solution. This solution was stirred under reflux for 5 hours. After completion of the reaction, the solvent was distilled off under reduced pressure.
And washed with diethyl ether. Water layer under ice cooling,
The pH was adjusted to 2 with 2N hydrochloric acid. The product was collected by filtration, washed with water and hexane, and washed with 2- (3-butyl-3-hydrobenzothiazol-2-ylidene) acetic acid (1.38 g,
90.1%) as brown crystals. Melting point: 119.8-120.1 ° C. ¹ H-NMR spectrum (300 MHz, DMSO-d ₆ ) δ: 0.90 (3H,
t, J = 7.2 Hz), 1.29-1.41 (2H, m), 1.46-1.56 (2
H, m), 3.44 (2H, t, J = 7.2Hz), 6.65 (1H, m), 6.
69−6.79 (2H, m), 6.92 (1H, m), 7.10 (1H, s), 1
2.18 (1H, br s). ¹³ C-NMR spectrum (75 MHz, DMSO-d ₆ ) δ: 13.6, 19.
2, 29.0, 50.3, 92.7, 113.7, 120.8, 124.6, 127.0, 1
27.6, 139.0, 143.8, 164.3. Anal. _{Calcd for C 13 H 15 NO 2} S: C, 62.63; H, 6.06; N,
5.62. Found: C, 62.45; H, 6.09; N, 5.53.

Step 5) 2- (3-butyl-3-hydrobenzothiazole-2-ylidene) acetic acid (0.72 g,
2.87 mmol) in N, N-dimethylformamide 1
Dissolved in 5 mL, 1-hydroxybenzotriazole (0.93 g, 6.88 mmol) and 1-ethyl-
3- (3-Dimethylaminopropyl) carbodiimide hydrochloride (1.54 g, 8.03 mmol) was added. After stirring at room temperature for 1 hour, hydroxylamine hydrochloride (1.59 g, 22.94 mmol) and triethylamine (2.90 g, 28.68 mmol) were added to the reaction solution, and the mixture was stirred at room temperature overnight. After the completion of the reaction, 100 mL of dichloromethane and water were added to the reaction solution and partitioned. The organic layer was successively washed with 1N hydrochloric acid and saturated saline, and then dried over anhydrous sodium sulfate and dried. After filtering off the inorganic substance, the solvent was distilled off under reduced pressure to obtain a brown solid. The crude crystals were washed several times with ethyl ether and purified to give 2- (3-butyl-3-hydrobenzothiazol-2-ylidene) ethanehydroxamic acid (0.54 g, 70.7%) as brown crystals. . Melting point: 126.5-126.9 ° C. ¹ H-NMR spectrum (300 MHz, DMSO-d ₆ ) δ: 0.91 (3H,
t, J = 7.2 Hz), 1.30-1.42 (2H, m), 1.49-1.59 (2
H, m), 3.40 (2H, t, J = 7.2 Hz), 6.68 (1H, m), 6.
76−6.79 (2H, m), 6.95−7.00 (2H, m), 8.70 (1H, m
s), 10.34 (1H, s). ¹³ C-NMR spectrum (75 MHz, DMSO-d ₆ ) δ: 13.6, 19.
2, 28.9, 50.0, 96.0, 113.0, 120.3, 123.9, 127.1, 1
27.7, 139.2, 141.0, 161.9. Anal. _{Calcd for C 13 H 16 N 2} O 2 S: C, 59.07; H, 6.10;
N, 10.60. Found: C, 58.96; H, 6.16; N, 10.63.

Example 2 2- (3-hydro-3-propylbenzothiazole-2-ylidene) ethanehydroxamic acid (compound 2) 1-iodopropane was used in place of 1-iodobutane in Step 1 of Example 1, The same operation as in Example 1 was performed, and 2-
(3-Hydroxy-3-propylbenzothiazole-2-ylidene) ethanehydroxamic acid was obtained as orange crystals. Melting point: 118.6-119.4 ° C. ¹ H-NMR spectrum (300 MHz, DMSO-d ₆ ) δ: 0.92 (3H,
t, J = 7.2 Hz), 1.52-1.64 (2H, m), 3.36 (2H, t, J
= 7.2Hz), 6.68 (1H, m), 6.77-6.79 (2H, m), 6.9
4-7.00 (2H, m), 8.69 (1H, s), 10.33 (1H, s). ¹³ C-NMR spectrum (75 MHz, CDCl ₃ ) δ: 12.3, 19.4, 2
8.7, 56.4, 73.5, 80.8, 84.4, 87.6, 88.2, 99.7, 10
1.5, 122.4.

Example 3 2- (3-hydro-3-pentylbenzothiazole-2-ylidene) ethane hydroxamic acid (compound 3) 1-iodopentane was used in place of 1-iodobutane in Step 1 of Example 1, The same operation as in Example 1 was performed, and 2-
(3-Hydro-3-pentylbenzothiazole-2-ylidene) ethanehydroxamic acid was obtained as a yellow oil. ¹ H-NMR spectrum (300 MHz, DMSO-d ₆ ) δ: 0.85-0.87
(3H, m), 1.29-1.32 (4H, m), 1.54-1.56 (2H,
m), 3.39 (2H, t, J = 6.9Hz), 6.67 (1H, m), 6.77
−6.78 (2H, m), 6.95−7.00 (2H, m), 8.69 (1H, m
s), 10.33 (1H, s).

Example 4 2- (3-hydro-3-ethylbenzothiazole-2-ylidene) ethane hydroxamic acid The same operation as in Example 1 except that iodoethane was used instead of 1-iodobutane in Step 1 of Example 1. And 2- (3-
Hydro-3-ethylbenzothiazole-2-ylidene)
Ethane hydroxamic acid was obtained as a yellow oil. ¹ H-NMR spectrum (300 MHz, DMSO-d ₆ ) δ: 1.18 (3H,
t, J = 7.2 Hz), 3.49 (2H, q, J = 7.2 Hz), 6.72 (1H,
m), 6.80-7.10 (4H, m), 8.70 (1H, s), 10.34 (1H,
s).

Example 5 2- (3-butyl-1-oxo-3-hydrobenzothiazol-2-ylidene) ethanehydroxamic acid Step 1) Ethyl 2-
(3-butyl-3-hydrobenzothiazole-2-ylidene) acetate (0.27 g, 0.97 mmol) was dissolved in 5 mL of methanol, and OXONE (0.66 g,
1.07 mmol) 5 mL of an aqueous solution was gradually added under ice-cooling, followed by stirring at room temperature for 1 hour. After completion of the reaction, water was added, and the mixture was extracted with 100 mL of ethyl acetate. The organic layer was washed with saturated saline and then dehydrated and dried with anhydrous sodium sulfate. After the inorganic substances were removed by filtration, the solvent was distilled off under reduced pressure, and ethyl 2- (3
-Butyl-1-oxo-3-hydrobenzothiazole-
2-ylidene) acetate (0.26 g, 90.3%)
Was obtained as a yellow oil. ¹ H-NMR spectrum (300 MHz, CDCl ₃ ) δ: 0.98 (3H, t,
J = 7.5Hz), 1.38-1.49 (5H, m), 1.81-1.91 (2H,
m), 4.01 (1H, m), 4.22 (1H, m), 4.34-4.45 (2
H, m), 7.41-7.46 (2H, m), 7.66 (1H, m), 8.02
(1H, m), 8.15 (1H, s).

Step 2) Ethyl 2 of Step 4 of Example 1
Instead of-(3-butyl-3-hydrobenzothiazol-2-ylidene) acetate, the ethyl 2- (3-butyl-1-oxo-3-hydrobenzothiazol-2-ylidene) acetate obtained above was replaced by And the same operation as in step 4 and step 5 of Example 1 was performed to obtain 2- (3-
Butyl-1-oxo-3-hydrobenzothiazole-2
-Ylidene) ethanehydroxamic acid was obtained as a yellow solid. ¹ H-NMR spectrum (300 MHz, DMSO-d ₆ ) δ: 0.86 (3H,
t, J = 7.5 Hz), 1.26-1.34 (2H, m), 1.48-1.52 (2
H, m), 3.97−4.07 (2H, m), 7.36 (1H, m), 7.57−
7.64 (2H, m), 7.73 (1H, m), 7.85 (1H, m).

Example 6 2- (3-butyl-1,1-dioxo-3-hydrobenzothiazol-2-ylidene)
Ethane hydroxamic acid (compound 4) Step 1) Ethyl 2- obtained in Step 3 of Example 1
(3-butyl-3-hydrobenzothiazole-2-ylidene) acetate (3.00 g, 10.82 mmol)
Was dissolved in 50 mL of dichloromethane, m-chloroperbenzoic acid (4.22 g, 24.44 mmol) was gradually added under ice-cooling, and the mixture was stirred at room temperature for 24 hours. After completion of the reaction, the resultant was washed with a saturated aqueous solution of sodium hydrogen carbonate and saturated saline,
It was dehydrated and dried with anhydrous sodium sulfate. After filtering off the inorganic substance, the solvent was distilled off under reduced pressure to obtain a brown oily substance. The crude product was purified by flash column chromatography [Silica
gel 60N (40-50 mesh), ethyl acetate-
Hexane mixture (1: 2 v / v)]
2- (3-butyl-1,1-dioxo-3-hydrobenzothiazole-2-ylidene) acetate (1.80
g, 53.8%) as a yellow oil. ¹ H-NMR spectrum (300 MHz, CDCl ₃ ) δ: 0.99 (3H, t,
J = 7.2Hz), 1.41 (3H, t, J = 7.2Hz), 1.38-1.47 (2
H, m), 1.74-1.87 (2H, m), 3.99 (2H, t, J = 7.5H
z), 4.41 (2H, q, J = 7.2Hz), 7.20 (1H, m), 7.42
(1H, m), 7.62 (1H, m), 7.91 (1H, s), 8.19 (1
H, m). ¹³ C-NMR spectrum (75 MHz, CDCl ₃ ) δ: 13.6, 14.3, 1
9.8, 30.2, 54.5, 61.9, 105.3, 115.5, 125.2, 125.
4, 129.8, 132.6, 135.4, 145.0, 162.7.

Step 2) Ethyl 2 of Step 4 of Example 1
Instead of-(3-butyl-3-hydrobenzothiazol-2-ylidene) acetate, the ethyl 2- (3-butyl-1,1-dioxo-3-hydrobenzothiazol-2-ylidene) obtained above was obtained. Using acetate,
By performing the same operation as in Steps 4 and 5 of Example 1, 2-
(3-Butyl-1,1-dioxo-3-hydrobenzothiazole-2-ylidene) ethanehydroxamic acid was obtained as colorless crystals. ¹ H-NMR spectrum (300 MHz, DMSO-d ₆ ) δ: 0.89 (3H,
t, J = 7.2Hz), 1.24-1.37 (2H, m), 1.60-1.70 (2
H, m), 4.14 (2H, t, J = 7.2 Hz), 7.45 (1H, m), 7.
60 (1H, m), 7.74 (1H, m), 7.96−7.99 (2H, m),
9.19 (1H, s), 10.20 (1H, s). ¹³ C-NMR spectrum (75 MHz, DMSO-d ₆ ) δ: 13.5, 19.
0, 29.8, 52.6, 105.4, 116.7, 123.0, 124.7, 126.8,
132.9, 135.9, 142.5, 159.0. Anal. _{Calcd for C 13 H 16 N 2} O 4 S: C, 52.69; H, 5.44;
N, 9.45. Found: C, 52.79; H, 5.51; N, 9.25.

Example 7 2- (3-butyl-1,1-dioxo-3-hydrobenzothiazol-2-ylidene)
Ethane hydroxamic acid (compound 4) Compound 1 obtained in Example 1 (0.20 g, 0.76 mmol)
l) was dissolved in 5 mL of methanol, and OXONE (0.5
5 g of an aqueous solution (1 g, 0.83 mmol) was gradually added under ice-cooling, and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, water was added, and the mixture was extracted with 100 mL of ethyl acetate. The organic layer was washed with saturated saline and then dehydrated and dried with anhydrous sodium sulfate. After the inorganic substances were removed by filtration, the solvent was distilled off under reduced pressure to give 2- (3
-Butyl-1,1-dioxo-3-hydrobenzothiazole-2-ylidene) ethanehydroxamic acid (0.21
g, 93.7%).

Test Example 1 Inhibition of E. coli-derived Ni-PDF enzyme in vitro was measured by the method of Lazennec et al. (Lazennec, C. an.
d Meinnel, T. Anal. Biochem., 244, 1997, 180-1
82.). The Ni-PDF was isolated and purified by the method of Chen et al. (Chen, Dawn Z .; Patel, Dinesh).
V .; Hackbarth, Corinne J .; Wang, Wen; Dreyer, Geo
ffrey; Young, Dennis C .; Margolis, Peter S .; Wu, C
harlotte; Ni, Zi-Jie; Trias, Joaquim; White, Richa
rd J .; Yuan, Zhengyu, Biochemistry, 39, 2000, 1256
-62. ). That is, 50 mM N- (2
-Hydroxyethyl) piperazine-N'-2-ethanesulfonic acid (HEPES, pH 7.2), 10 mM sodium chloride, 0.2 mg / mL bovine serum albumin (B
SA) (90 μL) in dimethylsulfoxide in a buffer solution (90 μL) and Ni-PDF (0.
021 U / mg, 10 μL) and incubated at room temperature for 10 minutes. There, 0.021 U / mg formate dehydrogenase (FDH), 1 mM oxidized beta nicotinamide adenine dinucleotide (β-N
A mixed solution (90 μL) of (AD ⁺ ) 0.6 mM and 0.1 mM formylmethionine alanine serine (fMAS) was added, and the mixture was reacted for 20 minutes. Then, the value (A) of decrease in absorbance at 340 nm was measured. The values of absorbance decrease (B, C) obtained by simultaneously measuring the reaction solution containing no test drug and the reaction solution containing no Ni-PDF under the same conditions were applied to the following formula, and the values of the test drug at various concentrations were determined. Inhibition rate (%)
Was calculated. Inhibition rate (%) = {1− (AC) / (BC)} × 10
0 A: 340 of the reaction solution containing Ni-PDF and the test drug
B: the value of the absorbance decrease at 340 nm of the reaction solution not containing the test drug C: the value of the absorbance decrease at 340 nm of the reaction solution not containing Ni-PDF The relationship with the concentration was plotted on a logarithmic graph to determine the amount required for 50% inhibition (IC ₅₀ ).

Test Results 1 The results are shown in Table 1.

[0041]

[Table 1]

Test Example 2 The antibacterial activity was measured by the method of measuring the minimum inhibitory concentration (MIC) of the Japanese Society of Chemotherapy (Chemotherapy 1981, 29 (1), 76-).
79.). That is, each test drug is
00, 50, 25, 12.5, 6.25, 3.13,
1.56, 0.78, 0.39, 0.2, 0.1,.
10 mL of Mueller-Hinton agar plate medium added to give a concentration of 0.05 and 0.0025 μg / mL were inoculated with the test bacterial solutions prepared at various concentrations, and then incubated at about 37 ° C. for 18 to 2 hours.
After culturing for 0 hours, observation was performed. In addition, dimethyl sulfoxide was used for dissolution of the test drug.

Test Results 2 The results are shown in Table 2.

[0044]

[Table 2]

Formulation Example 1 Tablets Compound 1 100 mg Lactose 80 mg Starch 17 mg Magnesium stearate 3 mg The above ingredients are uniformly mixed as a material for one tablet, and a tablet is formed by a conventional method. Sugar coating may be applied as necessary.

Formulation Example 2 Ointment Compound 2 1 g Purified lanolin 5 g Salami beeswax 5 g White petrolatum A total of 100 g The above components are mixed by a conventional method to prepare an ointment.

Formulation Example 3 Ophthalmic solution Compound 1 50 mg Boric acid 700 mg Borax proper amount Sodium chloride 500 mg Hydroxymethylcellulose 0.5 g Sodium edetate 0.05 mg Benzalkonium chloride 0.005 mg Mix to form eye drops.

Formulation Example 4 Capsule Compound 4 75 mg Mannitol 75 mg Starch 17 mg Calcium stearate 3 mg The above components are uniformly mixed as a material for one capsule, granulated by a conventional method, and filled into hard capsules.

[0049]

Industrial Applicability The compounds represented by the general formula (I) and salts thereof of the present invention have excellent PDF inhibitory and antibacterial activities, and thus can be used as PDF inhibitors and antibacterial agents.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI theme coat ゛ (reference) C12N 9/99 C12N 9/99 F term (reference) 4C086 AA01 AA02 AA03 BC84 MA01 MA04 NA14 ZA33 ZA90 ZB35 ZC20

Claims (5)

[Claims] 1. A compound of the general formula (I) [In the formula, n represents an integer of 0, 1, or 2, and R represents an alkyl group. Or a salt thereof. 2. The method according to claim 1, wherein R is a linear lower alkyl group.
Or a salt thereof. 3. A medicament comprising the compound according to claim 1 or a salt thereof. 4. The medicament according to claim 3, which is a peptide deformylase inhibitor. 5. The medicament according to claim 3, which is an antibacterial agent.