JPH11322729A - Dithiocarbamic acid derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a new compound having excellent antimicrobial activities against various bacteria and fungi including multiple resistant microbe and atypical mycobacteria, and useful as an antibacterial or antifungal agent. SOLUTION: This new compound is the one of formula I [R<1> is a (substituted) alkyl, a (substituted)cycloalkyl, a (substituted)aryl or the like; A is a (substituted) phenyl], e.g. methyl (S)-N-[2-oxo-3-[4-(thiomorpholin-4-yl)phenyl] oxazolin-5- yl]methyldithiocarbamate. The compound is obtained, for example, by using a compound of formula II as a raw material, reacting the compound of formula II with carbon disulfide in the presence of a base such as triethylamine in the absence of a solvent or in the solvent such as diethyl ether to provide a compound of formula III, and reacting the compound of formula III with an alkylation agent of the formula X-R<1> in the presence or absence of a base in the absence of the solvent or in the solvent within the temperature range from an ice-cooled temperature to 200 deg.C.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a novel dithiocarbamic acid derivative or a salt thereof which is useful as a medicine, particularly as an antibacterial agent or an antifungal agent.

[0002]

BACKGROUND OF THE INVENTION Compounds having a 3-aryl-2-oxooxazolidine skeleton similar to the present invention are disclosed in JP-A-60-8277 and Journal of Medicinal Chemistr.
y), Vol. 39, p. 673 (1996).
[(3-aryl-2-oxooxazolidin-5-yl) methyl] acetamide derivatives are also available from Current Pharmaceutic Design.
al Design), Volume 2, p. 175 (1996) and Journal
of Medicinal Chemistry, 32, 1673 (198
9 years) and the like, 3-aryl-5-hydroxymethyl-2
-Oxooxazolidine derivatives, 3-aryl-5-halogenomethyl-2-oxooxazolidine derivatives and the like are disclosed, and JP-A-9-316073 and the like disclose N-
-(3-heteroaryl-2-oxooxazolidine-
5-yl) methylthioacetamide derivatives and N- (3-
Heteroaryl-2-oxooxazolidin-5-yl) methyl-N'-methylthiourea derivatives and the like are disclosed, all of which are described as having antibacterial activity against Gram-positive bacteria. Also, U.S. Pat. No. 4,128,654 describes that 3-aryl-5-halogenomethyl-2-oxooxazolidine derivatives are useful for the protection of plants from fungal and bacterial diseases. However,
The antibacterial activity of these compounds is not yet sufficient, and the development of better antibacterial or antifungal agents has been a challenge.

[0003]

[PROBLEMS TO BE SOLVED BY THE INVENTION] As a therapeutic agent for infectious diseases caused by various causative bacteria including gram-positive bacteria, gram-negative bacteria, anaerobic bacteria, fungi, etc., the mechanism of action of antibiotics and synthetic antibacterial agents is considered. A variety of different antimicrobial agents are in clinical practice. However, one of the factors that has made chemotherapy with these antibiotics more difficult in recent years is the methicillin-resistant Staphylococcus aureus (MRSA; Methicillin-resist
ant Staphylococcus aureus). On the other hand, opportunistic infections have been pointed out in so-called immunocompromised patients such as those who have already received chemotherapy with an underlying disease, patients who have received immunosuppressive drugs with organ transplantation, or AIDS patients. In particular, chemotherapy for atypical mycobacteriosis and mycosis, which lacks effective antibacterial agents, has become a problem. Among the atypical mycobacteriosis, Mycobacterium avium complex (Mycobacterium
ium avium, Mycobacterium intracellulare), and among mycosis, Candida,
Chemotherapy for deep mycosis caused by yeasts or filamentous fungi such as Cryptococcus and Aspergillus has become a particularly serious problem. An object of the present invention is to provide a compound having excellent antibacterial activity against various bacteria or fungi including multidrug-resistant bacteria and atypical mycobacteria.

[0004]

Means for Solving the Problems The inventors of the present invention have conducted intensive studies to solve the above-mentioned problems, and as a result, the novel dithiocarbamic acid derivative or a salt thereof according to the present invention was found to be resistant to multidrug-resistant bacteria and atypical acid-resistant bacteria. The present inventors have found that the compound has excellent antibacterial activity against various bacteria including fungi or fungi, and completed the present invention.

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

Embedded image (In the formula, R ¹ represents an optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted aryl group or an optionally substituted aralkyl group, and A represents a substituted A phenyl group which may be represented by the formula: or a salt thereof.

According to a preferred embodiment of the present invention, the following general formula (II)

Embedded image(Where R^Two, R^ThreeAnd R^FourIs independently a hydrogen atom,
Halogen atom, hydroxyl group, mercapto group, amino group, shea
No group, nitro group, formyl group, carboxyl group, carba
Moyl group, optionally substituted alkyl group, substituted
Optionally substituted cycloalkyl group, optionally substituted
Alkenyl group, alkynyl group which may be substituted,
Optionally substituted alkoxy group, optionally substituted
Alkylthio groups and optionally substituted alkoxyca
A rubonyl group, an optionally substituted alkylamino group,
An optionally substituted dialkylamino group, substituted
An optionally substituted alkylaminocarbonyl group, substituted
Dialkylaminocarbonyl group, which may be substituted
Optionally substituted alkanoyl groups, optionally substituted alkanoyl groups
Sulfonyl group, arylcarbo which may be substituted
Nyl group, optionally substituted aryl group, substituted
Aralkyl group which may be substituted, aryl which may be substituted
Substituted with a hetero atom as a ring-constituting atom
Optionally substituted cycloalkyloxy group, substituted
Optionally substituted heterocyclic group or optionally substituted aryl
Represents a condensed saturated heterocyclic group;^Two,
R^ThreeAnd R ^FourAny two of
Represents a silyl group or substituted with a benzene ring
May form a good hydrocarbon condensed ring;¹Is the same as above
Indicates significance. Novel dithiocarbamic acid derivative represented by
A conductor or a salt thereof is provided.

According to a further preferred aspect of the present invention,
The following general formula (III)

Embedded image (Wherein, R ⁵ , R ⁶ and R ⁷ are each independently a hydrogen atom,
Halogen atom, hydroxyl group, mercapto group, amino group, cyano group, nitro group, formyl group, carboxyl group, carbamoyl group, optionally substituted alkyl group, optionally substituted cycloalkyl group, optionally substituted R ¹ is the same as defined above for a good alkenyl group, an optionally substituted alkynyl group, an optionally substituted alkoxy group or an optionally substituted alkanoyl group. )
And a novel dithiocarbamic acid derivative represented by the formula: or a salt thereof.

[0008] In another aspect of the present invention, according to the present invention,
A medicament comprising the above dithiocarbamic acid derivative or a salt thereof as an active ingredient is provided. The medicament provided by the present invention can be suitably used, for example, as an antibacterial agent or an antifungal agent.

[0009]

BEST MODE FOR CARRYING OUT THE INVENTION The above general formulas (II) and (III), which are preferred embodiments of the dithiocarbamic acid derivative of the present invention,
The compound is specifically described. This compound
It is included in the dithiocarbamic acid derivative represented by the general formula (I) of the present invention, and has a specific substituted phenyl group or an unsubstituted phenyl group as the group represented by A in the general formula (I). It is characterized by: However, the scope of the present invention is not limited to the compounds of the general formulas (II) and (III), and any compound having a substituted phenyl group or an unsubstituted phenyl group as A is included in the scope of the present invention. Needless to say.

In the general formulas (II) and (III) of the present invention, the alkyl group represented by R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ has 1 to 1 carbon atoms. 6 linear or branched alkyl groups such as methyl, ethyl,
n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl,
Examples thereof include an isopentyl group, a neopentyl group, and an n-hexyl group.
There may be mentioned up to 6 cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like. (In this specification,
The term “cycloalkyl group” is used as a concept including an alkyl group containing a cycloalkyl moiety (eg, a cyclopropylmethyl group). )

In the general formula (II) of the present invention,
The aryl groups represented by R ¹ , R ² , R ³ and R ⁴ include:
Represents an aromatic ring composed of a single ring or two or more rings that may contain 1 to 4 heteroatoms as ring constituent atoms, for example,
Phenyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrazin-2-yl,
Pyrimidin-2-yl group, pyrimidin-4-yl group, pyrimidin-5-yl group, furan-2-yl group, furan-
3-yl group, thiophen-2-yl group, thiophen-3
-Yl group, pyrrol-1-yl group, pyrrol-2-yl group, pyrrol-3-yl group, pyrazol-1-yl group,
A pyrazol-3-yl group, a pyrazol-4-yl group, a pyrazol-5-yl group, an imidazol-1-yl group, an imidazol-2-yl group, an imidazol-4-yl group,
Imidazol-5-yl, 1H-1,2,3-triazol-1-yl, 1H-1,2,3-triazol-4-yl, 1H-1,2,3-triazol-5
Yl group, 1H-1,2,4-triazol-1-yl group, 1H-1,2,4-triazol-3-yl group, 1
H-1,2,4-triazol-5-yl group, tetrazol-1-yl group, tetrazol-5-yl group, oxazol-2-yl group, oxazol-4-yl group, oxazol-5-yl group, Thiazol-2-yl group, thiazol-4-yl group, thiazol-5-yl group, naphthalen-1-yl group, naphthalen-2-yl group, benzofuran-2-yl group, benzofuran-3-yl group, benzofuran -4-yl group, benzofuran-5-yl group, benzofuran-6-yl group, benzofuran-7-yl group, benzo [b] thiophen-2-yl group, benzo [b] thiophen-3-yl group, benzo [B] thiophen-4-yl group, benzo [b] thiophen-5-yl group, benzo [b] thiophen-6-yl group, benzo [b] thiophen-7-yl group, i Doll-1-yl group, indol-2-yl group, indol-3-yl group, indole -
4-yl group, indol-5-yl group, indole-6
-Yl group, indol-7-yl group, benzimidazol-1-yl group, benzimidazol-2-yl group, benzimidazol-4-yl group, benzimidazole-
5-yl group, benzimidazol-6-yl group, benzimidazol-7-yl group, benzotriazol-1-
Yl, benzotriazol-4-yl, benzotriazol-5-yl, benzotriazol-6-yl, benzotriazol-7-yl, benzoxazol-2-yl, benzoxazol-4-yl ,
Benzoxazol-5-yl group, benzoxazol-6-yl group, benzoxazol-7-yl group, benzothiazol-2-yl group, benzothiazol-4-yl group, benzothiazol-5-yl group, benzothiazole -6-yl group, benzothiazol-7-yl group and the like, and the aralkyl group represents an alkyl group having 1 to 4 carbon atoms in which the above-mentioned aryl group is substituted at an arbitrary position. Phenethyl group, phenylpropyl group, phenylbutyl group, (pyridin-2-yl) methyl group, (pyrazin-2-yl) methyl group, (pyrimidin-2-yl) methyl group, furfuryl group, thenyl group,
(Pyrrole-1-yl) methyl group, (pyrazole-1-
Yl) methyl group, (imidazol-1-yl) methyl group, (1H-1,2,3-triazol-1-yl) methyl group, (1H-1,2,4-triazol-1-yl) methyl group , (Tetrazol-5-yl) methyl group,
(Oxazol-2-yl) methyl group, (thiazole-
2-yl) methyl group, (naphthalen-1-yl) methyl group, (benzofuran-2-yl) methyl group, (benzo [b] thiophen-2-yl) methyl group, (indol-1-yl) methyl group , (Benzimidazol-1-yl) methyl group, (benzotriazol-1-yl) methyl group, (benzoxazol-2-yl) methyl group,
And a (benzothiazol-2-yl) methyl group.

In the general formulas (II) and (III) of the present invention, the halogen atom represented by R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ is a fluorine atom, a chlorine atom, a bromine Atom or iodine atom has 2 to 2 carbon atoms as an alkenyl group.
Examples thereof include four alkenyl groups such as a vinyl group, a propenyl group, a butenyl group, and a butadienyl group. Examples of the alkynyl group include an alkynyl group having 2 to 4 carbon atoms, such as an ethynyl group, a propynyl group, and a butynyl group. And the like. Examples of the alkoxy group include an alkoxy group containing a linear or branched alkyl group having 1 to 6 carbon atoms, such as a methoxy group, an ethoxy group, and the like.
n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-
Examples thereof include a pentyloxy group, an isopentyloxy group, a neopentyloxy group, an n-hexyloxy group, and the like. Examples of the alkanoyl group include an acetyl group, a propionyl group, a butyryl group, an isobutyryl group, a valeryl group, and an isovaleryl group. , Hexanoyl group, heptanoyl group, etc.

In the general formula (II) of the present invention,
The alkylthio groups represented by R ² , R ³ and R ⁴ include:
An alkylthio group containing a linear or branched alkyl group having 1 to 6 carbon atoms, such as methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, sec-butylthio group, te
Examples thereof include an rt-butylthio group, an n-pentylthio group, an isopentylthio group, a neopentylthio group, and an n-hexylthio group. Examples of the alkoxycarbonyl group include a linear or branched alkoxy group having 1 to 6 carbon atoms. Alkoxycarbonyl groups containing linear alkyl groups, such as methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, Examples thereof include a tert-butoxycarbonyl group, an n-pentyloxycarbonyl group, an isopentyloxycarbonyl group, a neopentyloxycarbonyl group, and an n-hexyloxycarbonyl group.

In the general formula (II) of the present invention,
The alkylamino group or dialkylamino group represented by R ² , R ³ and R ⁴ is a linear or branched alkyl group having 1 to 6 carbon atoms, or a cycloalkyl group having 3 to 6 carbon atoms. Represents an amino group substituted with, for example, a methylamino group, an ethylamino group, an n-propylamino group, an isopropylamino group, an n-butylamino group, an isobutylamino group, a sec-butylamino group, a tert-butylamino group , N-pentylamino group, isopentylamino group, neopentylamino group, n-hexylamino group, dimethylamino group, diethylamino group, N-ethyl-N-methylamino group, N
-Methyl-NN-propylamino group, N-isopropyl-N-methylamino group, Nn-butyl-N-methylamino group, N-isobutyl-N-methylamino group, N-sec-
Butyl-N-methylamino group, N-tert-butyl-N-
Methylamino group, N-methyl-NN-pentylamino group, N-isopentyl-N-methylamino group, N-methyl-N-neopentylamino group, Nn-hexyl-N-
Methylamino group, cyclopropylamino group, cyclobutylamino group, cyclopentylamino group, cyclohexylamino group, N-cyclopropyl-N-methylamino group,
Examples thereof include an N-cyclobutyl-N-methylamino group, an N-cyclopentyl-N-methylamino group, and an N-cyclohexylmethyl-N-methylamino group.

In the general formula (II) of the present invention,
The alkylaminocarbonyl group or dialkylaminocarbonyl group represented by R ² , R ³ and R ⁴ has 1 to 6 carbon atoms.
Represents a straight-chain or branched-chain alkyl group or an aminocarbonyl group substituted by a cycloalkyl group having 3 to 6 carbon atoms, such as methylaminocarbonyl group, ethylaminocarbonyl group, n-propyl Aminocarbonyl group, isopropylaminocarbonyl group, n-butylaminocarbonyl group, isobutylaminocarbonyl group, sec-butylaminocarbonyl group, tert-butylaminocarbonyl group, n-pentylaminocarbonyl group, isopentylaminocarbonyl group, neopentyl Aminocarbonyl group,
n-hexylaminocarbonyl group, dimethylaminocarbonyl group, diethylaminocarbonyl group, N-ethyl-N
-Methylaminocarbonyl group, N-methyl-NN-propylaminocarbonyl group, N-isopropyl-N-methylaminocarbonyl group, Nn-butyl-N-methylaminocarbonyl group, N-isobutyl-N-methyl Aminocarbonyl group, N-sec-butyl-N-methylaminocarbonyl group, N-tert-butyl-N-methylaminocarbonyl group, N-methyl-NN-pentylaminocarbonyl group, N-isopentyl-N-methyl Aminocarbonyl group, N-methyl-N-neopentylaminocarbonyl group, Nn-hexyl-N-methylaminocarbonyl group,
Cyclopropylaminocarbonyl group, cyclobutylaminocarbonyl group, cyclopentylaminocarbonyl group,
Cyclohexylaminocarbonyl group, N-cyclopropyl-N-methylaminocarbonyl group, N-cyclobutyl-N-methylaminocarbonyl group, N-cyclopentyl-N-methylaminocarbonyl group, N-cyclohexylmethyl-N-methylaminocarbonyl group And the like.

In the general formula (II) of the present invention,
The alkane sulfonyl group represented by R ² , R ³ and R ⁴ is
Represents a sulfonyl group substituted by a linear or branched alkyl group having 1 to 6 carbon atoms, for example, a methanesulfonyl group, an ethanesulfonyl group, an n-propanesulfonyl group,
Isopropanesulfonyl group, n-butanesulfonyl group, n-
Hexanesulfonyl and the like can be mentioned. The arylcarbonyl group represents a group in which the above-mentioned aryl group is substituted with a carbonyl group, for example, a benzoyl group, a (pyridin-2-yl) carbonyl group, a (pyrazin-2-yl)
Carbonyl group, (pyrimidin-2-yl) carbonyl group, (furan-2-yl) carbonyl group, thenoyl group,
(Pyrrole-1-yl) carbonyl group, (pyrazole-
1-yl) carbonyl group, (imidazol-1-yl)
Carbonyl group, (1H-1,2,3-triazole-1
-Yl) carbonyl group, (1H-1,2,4-triazol-1-yl) carbonyl group, (tetrazol-5-
Yl) carbonyl group, (oxazol-2-yl) carbonyl group, (thiazol-2-yl) carbonyl group,
(Naphthalen-1-yl) carbonyl group, (benzofuran-2-yl) carbonyl group, (benzo [b] thiophen-2-yl) carbonyl group, (indol-1-yl) carbonyl group, (benzimidazole-1- Ill)
Examples thereof include a carbonyl group, a (benzotriazol-1-yl) carbonyl group, a (benzoxazol-2-yl) carbonyl group, and a (benzothiazol-2-yl) carbonyl group. Examples of the aryloxy group include: Phenoxy group, (pyridin-2-yl) oxy group,
(Pyrazin-2-yl) oxy group, (pyrimidin-2-
Yl) oxy, (furan-2-yl) oxy, (thiophen-2-yl) oxy, (pyrrole-2-yl) oxy, (pyrazol-5-yl) oxy,
An (imidazol-5-yl) oxy group, (1H-1,
2,3-triazol-5-yl) oxy group, (1H-
1,2,4-triazol-5-yl) oxy group, (tetrazol-5-yl) oxy group, (oxazole-2
-Yl) oxy group, (thiazol-2-yl) oxy group, (naphthalen-1-yl) oxy group, (benzofuran-2-yl) oxy group, (benzo [b] thiophene-
2-yl) oxy group, (indol-4-yl) oxy group, (benzimidazol-4-yl) oxy group, (benzotriazol-4-yl) oxy group, (benzoxazol-2-yl) oxy group, (Benzothiazole-
2-yl) oxy group and the like.

In the general formula (II) of the present invention,
Examples of the cycloalkyloxy group containing a hetero atom as a ring-constituting atom represented by R ² , R ³ and R ⁴ include, for example, azetidinyloxy group, pyrrolidinyloxy group, piperidyloxy group, homopiperidyloxy group, oxetanyl An oxy group, a tetrahydrofuranyloxy group, a tetrahydropyranyloxy group, a thietanyloxy group, a tetrahydrothiophenyloxy group, a tetrahydrothiopyranyloxy group, an oxazolidinyloxy group, a thiazolidinyloxy group, a piperazinyloxy group, Morpholinyloxy group,
Thiomorpholinyloxy group, 1-oxidethiomorpholinyloxy group, 1,1-dioxidethiomorpholinyloxy group, homopiperazinyloxy group, 3-azabicyclo [3.3.0] octanyloxy And a 3,7-diazabicyclo [3.3.0] octanyloxy group. Examples of the saturated heterocyclic group include an azetidinyl group, a pyrrolidinyl group, an oxazolidinyl group, a thiazolidinyl group, a piperidyl group, and a piperazinyl group. Group, oxetanyl group, tetrahydrofuranyl group, tetrahydropyranyl group, thietanyl group, tetrahydrothiophenyl group, tetrahydrothiopyranyl group, morpholinyl group, thiomorpholinyl group, 1-oxidethiomorpholinyl group, 1,1-
Dioxidethiomorpholinyl group, homopiperidyl group, homopiperazinyl group, 3-azabicyclo [3.3.0] octanyl group, 3,7-diazabicyclo [3.3.0] octanyl group, and the like. Examples of the saturated heterocyclic group obtained by condensing an aryl group include, for example, indolinyl group, isoindolinyl group, 1,2,3,4-tetrahydroisoquinolyl group, 2,3-dihydro-1H-pyrrolo [3,4-b And a 2,3-dihydro-1H-pyrrolo [3,4-c] pyridin-2-yl group.

In the general formula (II) of the present invention,
When any two of R ² , R ³ and R ⁴ are taken together to form a hydrocarbon condensed ring with a benzene ring, examples of the condensed ring group include an indan-5-yl group, 1-indanone-5- Yl group, inden-5-yl group, inden-6
Yl group, 1-indanone-6-yl group, 2-indanone-5-yl group, 1,3-indandione-5-yl group,
Naphthalen-2-yl group, 1 (2H) -naphthalenone-
6-yl group, 1 (2H) -naphthalenone-7-yl group,
1,2,3,4-tetrahydronaphthalen-6-yl group, 1,2,3,4-tetrahydro-1-naphthalen-6-yl group, 1,2,3,4-tetrahydro-1-naphthalenone-7 -Yl group, 1,2,3,4-tetrahydro-2-naphthalen-6-yl group, 1,2,3,4-
Tetrahydro-2-naphthalenone-7-yl group, 1,2
-Naphthoquinone-6-yl group, 1,2-naphthoquinone-
7-yl group, 1,4-naphthoquinone-6-yl group, fluoren-2-yl group, fluoren-3-yl group, fluorenone-2-yl group, fluorenone-3-yl group, anthracen-1-yl group , Anthracen-2-yl group and the like.

In the general formula (II) of the present invention, when a functional group is "optionally substituted", the number and type of the substituent are not particularly limited, and two or more substituents may be used. When they are present, they may be the same or different. Examples of such a substituent include an alkyl group, a cycloalkyl group, a hydroxyl group, a mercapto group, an alkoxy group, an alkylthio group, a halogen atom,
Amino group, alkylamino group, dialkylamino group, cyano group, nitro group, formyl group, alkoxycarbonyl group, alkoxyalkyl group, alkoxycarbonylalkyl group, carboxyalkyl group, hydroxyalkanoyl group, alkoxyalkoxy group, alkoxyalkanoyl group, benzyl Oxycarbonyl group, benzyloxyalkanoyl group, alkylaminoalkoxy group, dialkylaminoalkylthio group, dialkylaminoalkoxy group, alkylaminoalkyl group, dialkylaminoalkyl group, halogenoalkyl group, oxo group, hydroxyimino group, alkoxyimino group, aryl Oxyimino group, carboxyl group, alkanoyl group, alkanoylalkyl group, carbamoyl group, aryl group, aralkyl group, alkoxycarbo Le aminoalkyl group, alkylaminocarbonyl group, can be exemplified alkane sulfonylamino group or the like.

In the general formula (III) of the present invention, when a certain functional group is "optionally substituted", the number and type of the substituent are not particularly limited, and may be 2
If more than one substituent is present, they may be the same or different. Examples of such a substituent include an alkyl group, a cycloalkyl group, a hydroxyl group, a mercapto group, an alkoxy group, an alkylthio group, a halogen atom,
Amino group, alkylamino group, dialkylamino group, cyano group, nitro group, formyl group, oxo group, hydroxyimino group, alkoxyimino group, aryloxyimino group, carboxyl group, alkanoyl group, carbamoyl group, etc. .

The dithiocarbamic acid derivative of the present invention has one asymmetric carbon in the oxazolidine ring, and may further have one or more asymmetric carbons depending on the type of the substituent. The asymmetric carbons present in the compounds of the present invention can each independently have the (R) or (S) configuration, and can be stereoisomers such as optical isomers and diastereoisomers based on one or more asymmetric carbons. May be present. Pure stereoisomers, any mixtures of stereoisomers, racemates and the like are all included in the scope of the present invention.

The dithiocarbamic acid derivative of the present invention can be converted into a salt, preferably a pharmacologically acceptable salt, if desired, and the resulting salt can be converted into a compound in a free form. Salts of the compounds of the present invention include acid addition salts and alkali addition salts. Examples of acid addition salts include hydrochloride, hydrobromide, nitrate, sulfate, hydroiodide and phosphate. Or mineral salts such as acetate, maleate, fumarate, citrate,
Oxalate, malate, methanesulfonate, p-toluenesulfonate, mandelicate, 10-camphorsulfonate, tartrate, lactate, 5-oxotetrahydrofuran-2-carboxylate or 2- An organic acid salt such as hydroxyglutarate can be used. Examples of the alkali addition salt include an inorganic alkali salt such as a sodium salt, a potassium salt, a calcium salt, a magnesium salt or an ammonium salt, or an ethanolamine salt, an N, N-dialkylethanolamine salt, a triethanolamine salt, or the like. Salts of organic bases such as piperidine salt, piperazine salt, morpholine salt or thiomorpholine salt can be used.

The dithiocarbamic acid derivative or a salt thereof of the present invention can exist as an arbitrary crystal form or as an arbitrary hydrate or solvate depending on production conditions. Crystal forms, hydrates and solvates and mixtures thereof are also included in the scope of the present invention.

Preferred compounds of the present invention include the following compounds, but the present invention is not limited to these examples. The abbreviations in the table have the following meanings. Me: methyl group, Et: ethyl group, n-Pr: n-propyl group, i-Pr: isopropyl group, n-Bu: n-butyl group, iB
u: isobutyl group, tert-Bu: tert-butyl group, n-Pent: n
-Pentyl group, n-Hex: n-hexyl group, Ph: phenyl group,
Bn: benzyl group.

[0025]

[Table 1]

[0026]

[Table 2]

[0027]

[Table 3]

[0028]

[Table 4]

[0029]

[Table 5]

[0030]

[Table 6]

[0031]

[Table 7]

[0032]

[Table 8]

[0033]

[Table 9]

[0034]

[Table 10]

[0035]

[Table 11]

The dithiocarbamic acid derivative represented by the general formula (I) of the present invention can be produced, for example, by the methods described below, but the production method of the compound is not limited to these methods. is not. In the following production methods, the compounds represented by the general formula (I) will be specifically described. However, the compounds represented by the general formulas (II) and (III) are included in these production methods. It is self-evident. Further, the examples herein include:
Specific and detailed production methods for representative compounds of the dithiocarbamic acid derivative of the present invention are described.
Therefore, by referring to the following general description and the specific description of the examples, by appropriately selecting the starting compounds, reaction reagents, reaction conditions, and the like, by appropriately modifying or modifying these methods as necessary. A person skilled in the art can easily produce any of the compounds of the present invention included in the general formula (I).

The compound of the present invention can be produced, for example, by the following method.

Embedded image (Wherein, R ¹ and A have the same meanings as described above, and X represents a halogen atom, a methanesulfonyloxy group or a p-toluenesulfonyloxy group.) That is, as a method for producing the compound of the present invention, a compound represented by the general formula (IV) The compound of formula (V) is reacted with carbon disulfide in the absence of a solvent or in a solvent in the presence of a base to give the compound of formula (V). It can be produced by reacting the indicated alkylating agent in the presence or absence of a base in the absence or presence of a solvent.

As the base used in the present production method, for example, triethylamine, N, N-diisopropylethylamine, 4-dimethylaminopyridine, 1,8
-Diazabicyclo [5.4.0] -7-undecene,
Organic bases such as 1,2,2,6,6-pentamethylpiperidine and inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium hydride and the like. Can be The solvent used may be any solvent as long as it is inert in the reaction itself and does not inhibit the reaction. Examples thereof include ether solvents such as diethyl ether, diisopropyl ether and tetrahydrofuran, acetone, acetonitrile, N 2 , N-dimethylformamide, N-methyl-2-pyrrolidone, dimethylsulfoxide, tetramethylenesulfone, tetramethylenesulfoxide, hexamethylphosphoric triamide, etc., aprotic polar solvents, ester solvents such as methyl acetate, ethyl acetate, etc. Benzene, toluene and other aromatic hydrocarbon solvents, pyridine, picoline, lutidine, collidine and other organic base solvents; dichloromethane, 1,2-dichloroethane, chloroform and other halogenated hydrocarbon solvents;
Alternatively, a mixed solvent thereof and the like can be mentioned, and all reactions are performed in a range from ice-cooling to 200 ° C.

In the process for producing the compound of the present invention, a part of the compound represented by the general formula (IV) as a raw material is
-73455 and Journal of Medicinal Chemistr
y, Vol. 39, p. 673 and p. 680 (1996), etc., are known compounds whose production methods and the like have already been disclosed.
In addition, a partially novel compound can be produced, for example, by the following method, and details of the production method are described in Reference Examples.

Embedded image (In the formula, A represents the same meaning as described above, Boc represents a tert-butoxycarbonyl group, Z represents a benzyloxycarbonyl group, Ms represents a methanesulfonyl group, and Ph represents a phenyl group.)

In the step 1, the compound of the formula (VII) is reduced by an appropriate reduction method, for example, a hydrogenation reduction method using a catalyst such as platinum oxide, Raney nickel or palladium carbon, or iron powder and hydrochloric acid, acetic acid or the like. The nitro group can be reduced by a conventional method such as a reduction method to obtain a compound of the general formula (VIII).

In step 2, the compound of the formula (VIII) is urethanized with di-tert-butyl dicarbonate using a suitable organic solvent such as methanol or tetrahydrofuran, or water or acetone, methanol, tetrahydrofuran or the like. After urethanization using benzyloxycarbonyl chloride in the presence of a base such as triethylamine, potassium carbonate, sodium carbonate or sodium hydrogencarbonate using an organic solvent or a mixed solvent thereof, tetrahydrofuran, N, N-dimethylformamide or the like is used. Treatment with a base such as n-butyllithium in a suitable aprotic organic solvent at a temperature ranging from −78 ° C. to the reflux temperature of the solvent, followed by reaction with glycidyl butyrate, gives a compound of the general formula (IX) A compound can be obtained.

In the step 3, the compound of the formula (IX) is prepared by using methanesulfonyl chloride in an organic solvent such as dichloromethane or tetrahydrofuran in the presence of a base such as triethylamine under ice-cooling to the reflux temperature of the solvent. By reacting within the range, the compound of the general formula (X) can be obtained.

In step 4, the compound of the general formula (X) is converted to tetrahydrofuran,
The compound of the general formula (XI) can be obtained by reacting in an organic solvent such as N, N-dimethylformamide in a range from ice-cooling to the reflux temperature of the solvent.

In the compound of the general formula (X), the substitution of the substituent in the compound of the general formula (XI) is also possible depending on the type of the functional group to be substituted for the optionally substituted phenyl group A. . As an example of the substituent conversion in the general formula (XI), for example, when A is a substituted phenyl group substituted with a protected nitrogen atom, after the azidation reaction in Step 4 is performed, A deprotection reaction of the nitrogen atom is performed, and then an appropriate alkylation reaction, acylation reaction, urethanation reaction, or the like can be performed on the deprotected amino group. The deprotection reaction can be performed by various methods depending on the type of the protecting group for the nitrogen atom. For example, when the protecting group is an amide-type protecting group such as an acyl group, it can be produced by deprotecting by a hydrolysis reaction using an acid or a base. The hydrolysis reaction of the amide is a method known per se, and an acid such as hydrochloric acid, sulfuric acid or trifluoroacetic acid can be used for the acidic hydrolysis, and a base such as sodium hydroxide or potassium hydroxide can be used for the basic hydrolysis. Can be used. These acids or bases can be used as an aqueous solution, but alcoholic solvents such as methanol, ethanol, n-butanol, sec-butanol and tert-butanol, ether solvents such as diethyl ether, diisopropyl ether and tetrahydrofuran, methyl acetate It can also be carried out in an organic solvent such as an ester solvent such as ethyl acetate and ethyl acetate, or in a water-containing organic solvent. Further, when the protecting group for the nitrogen atom is a urethane-type protecting group such as a lower alkoxycarbonyl group,
Deprotection by treatment with an acid such as hydrochloric acid, sulfuric acid, hydrobromic acid, trifluoroacetic acid or the like without solvent or in acetic acid, ethyl acetate, 1,4-dioxane, water, methanol, ethanol or a mixed solvent thereof. , Can be manufactured.

The alkylation reaction of the deprotected amino group is carried out in the presence or absence of a base in the presence of a suitable reagent such as an alkylation reaction with an alkyl halide or an alkane sulfonate, or a Michael addition with an acrylate ester. It is performed by a reaction or the like. In addition, a compound of the general formula (XI) can be obtained by performing an acylation reaction with an acyl halide or the like, or a urethanation reaction with an alkyl chlorocarbonate or the like in the presence of a base.

In the step 5, the compound of the formula (XI) is reduced by an appropriate reduction method, for example, a hydrogenation reduction method using a catalyst such as platinum oxide or palladium carbon, or a method using triphenylphosphine and water. Reducing the azide group,
The compound represented by the general formula (IV) can be obtained.

The medicament of the present invention is characterized by containing a dithiocarbamic acid derivative represented by the above general formula (I) or a salt thereof as an active ingredient. As the active ingredient of the medicament of the present invention, a substance selected from the group consisting of the above-mentioned compound in free form and a physiologically acceptable salt, and a solvate or hydrate thereof can be used. More than one substance may be used in combination. As the medicament of the present invention, the above-mentioned substance itself may be used as it is, but it is usually provided as a form of a pharmaceutical composition containing the above-mentioned substance which is an active ingredient and one or more kinds of pharmaceutical additives. It is desirable to be done.

Although the form of the pharmaceutical composition is not particularly limited,
For example, oral preparations such as capsules, tablets, fine granules, granules, powders, syrups, or injections, suppositories, eye drops, eye ointments, ear drops, transdermal mucosal absorbents, inhalants Alternatively, it can be prepared as a parenteral administration agent such as a dermatological agent. These preparations can be manufactured by a conventional method by adding pharmacologically and pharmaceutically acceptable additives.
That is, in the case of oral preparations and suppositories, excipients (lactose, D
-Mannitol, corn starch, crystalline cellulose, etc., disintegrants (carboxymethylcellulose, carboxymethylcellulose calcium, etc.), binders (hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, etc.), lubricants (magnesium stearate, talc, etc.) Pharmaceutical ingredients such as coating agents (hydroxypropylmethylcellulose, sucrose, titanium oxide, etc.), plasticizers (polyethylene glycol, etc.) and bases (polyethylene glycol, hard fat, etc.) are used in injections, eye drops, and ear drops. There are solubilizers or solubilizers (distilled water for injection, physiological saline, propylene glycol, etc.) that can constitute aqueous or ready-to-use dosage forms, pH regulators (inorganic or organic acids or bases),
Pharmaceutical ingredients such as tonicity agents (salts, glucose, glycerin, etc.) and stabilizers, and ophthalmic ointments and dermatological preparations, suitable for ointments, creams, and patches Ingredients (white petrolatum, macrogol, glycerin, liquid paraffin, cotton cloth, etc.) are used.

The medicament of the present invention can be administered, for example, as an antibacterial or antifungal agent for treating or preventing infectious diseases in mammals including humans. The dose of the medicament of the present invention is not particularly limited, and it is possible to select an appropriate dose according to the type of pathogenic bacteria, the age and weight of the patient, the severity of the disease, and the like. Usually, in the case of an adult, the daily dose is about 10 to 2000 mg by oral administration and 1 to 1000 mg by parenteral administration.
The dose can be administered once or several times a day. However, it is desirable to appropriately increase or decrease according to the purpose of treatment or prevention, the site of infection or the type of pathogenic bacteria, the age and symptoms of the patient, and the like.

[0050]

EXAMPLES Hereinafter, the present invention will be described with reference examples and examples, but the scope of the present invention is not limited to these examples. The abbreviations in the table have the following meanings. Me: methyl group, Et: ethyl group, n-Pr: n-propyl group, n-Bu: n-butyl group, Boc: tert-butoxycarbonyl group, Z: benzyloxycarbonyl group, Ms: methanesulfonyl group, Bn :
Benzyl group.

Reference Example 1 N-tert-butoxycarbonyl-4-piperidinol To a suspension of 50.0 g of 4-piperidinol in 250 ml of anhydrous tetrahydrofuran was added 125 ml of di-tert-butyl dicarbonate under ice-cooling and stirring, followed by stirring for 30 minutes. The solvent was distilled off under reduced pressure to obtain 120.5 g of a pale yellow liquid. NMR spectrum (CDCl ₃ ) δppm: 1.46 (9H, s), 1.47-1.5
0 (2H, m), 1.81-1.87 (2H, m), 3.01-3.10 (2H, m), 3.73-3.87
(3H, m) IR spectrum ν (liq.) Cm ^-1 : 1698,3684 Mass spectrum (m / z): 201 (M ⁺ )

The compound of Reference Example 2 was obtained in the same manner as in Reference Example 1.

Reference Example 2 N-tert-butoxycarbonyl-3-azetidinol Property: Yellow liquid NMR spectrum (DMSO-d ₆ ) δ ppm: 1.37 (9H, s), 3.55-
3.60 (2H, m), 3.95-4.00 (2H, m), 4.30-4.40 (1H, m), 5.50 (1
(H, d, J = 6Hz) IR spectrum ν (liq.) Cm ^-1 : 1678,3416

Reference Example 3 N-tert-butoxycarbonyl-4-methoxypiperidine A suspension of 8.77 g of 60% sodium hydride in 300 ml of anhydrous N, N-dimethylformamide was stirred at room temperature with N-te
rt-butoxycarbonyl-4-piperidinol 49.0
g of 190 g of anhydrous N, N-dimethylformamide was added, and 30.4 ml of methyl iodide was added dropwise and stirred for 5 hours. The reaction solution was added to ice water and extracted with ethyl acetate. The extract was washed with brine and dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to column chromatography (silica gel,
Purification with ethyl acetate: n-heptane = 1: 2 → 1: 1)
44.1 g of a colorless liquid were obtained. NMR spectrum (CDCl ₃ ) δ ppm: 1.45-1.55 (2H, m), 1.4
6 (9H, s), 1.80-1.90 (2H, m), 3.05-3.15 (2H, m), 3.30-3.40
(1H, m), 3.35 (3H, s), 3.70-3.80 (2H, m) IR spectrum ν (liq.) Cm ^-1 : 1698 Mass spectrum (m / z): 215 (M ⁺ )

Reference Example 4 N-tert-butoxycarbonyl-3- (2-methoxyethoxy) azetidine N-tert-butane was added to a suspension of 0.25 g of 60% sodium hydride in 5 ml of anhydrous N, N-dimethylformamide at room temperature with stirring. -
After adding a solution of 1.00 g of butoxycarbonyl-3-azetidinol in 3 ml of anhydrous N, N-dimethylformamide, 0.98 g of 2-methoxyethyl methanesulfonate was added.
Of anhydrous N, N-dimethylformamide was added dropwise and stirred for 4 hours. The reaction solution was added to ice water and extracted with ethyl acetate. The extract was washed successively with water and saturated saline, dried over sodium sulfate, and the solvent was distilled off under reduced pressure. Column chromatography of the residue (silica gel, ethyl acetate: n-heptane = 1: 3)
And 0.67 g of a colorless liquid was obtained. NMR spectrum (DMSO-d ₆ ) δ ppm: 1.37 (9H, s), 3.25 (3
H, s), 3.41-3.45 (2H, m), 3.46-3.49 (2H, m), 3.64 (2H, dd, J =
9,4Hz), 3.98 (2H, dd, J = 9,6.5Hz), 4.21-4.26 (1H, m) IR spectrum ν (liq.) Cm ^-1 : 1706

Reference Example 5 A solution of 43.9 g of N-tert-butoxycarbonyl-4-methoxypiperidine in 220 ml of ethyl acetate was added to 220 ml of a 9% solution of 4-methoxypiperidine hydrochloride hydrochloride under ice-cooling with stirring. And stirred for 2.5 hours. The precipitated crystals were collected by filtration to obtain 29.1 g of colorless crystals. NMR spectrum (CDCl ₃ ) δ ppm: 1.95-2.05 (2H, m), 2.10
-2.20 (2H, m), 3.15-3.30 (4H, m), 3.33 (3H, s), 3.50-3.60 (1
H, m) IR spectrum ν (liq.) Cm ^-1 : 3448 Mass spectrum (m / z): 115 (M ⁺ )

The compound of Reference Example 6 was obtained in the same manner as in Reference Example 5.

Reference Example 6 3- (2-methoxyethoxy) azetidine / hydrochloride Property: pale yellow liquid NMR spectrum (DMSO-d ₆ ) δ ppm: 3.26 (3H, s), 3.43 (2
(H, t, J = 4.5Hz), 3.54 (2H, t, J = 4.5Hz), 3.75--3.80 (2H, m), 4.
05-4.10 (2H, m), 4.35-4.40 (1H, m) IR spectrum ν (liq.) Cm ^-1 : 3436 Mass spectrum (m / z): 131 (M ⁺ )

Reference Example 7 3-Fluoro-4- (4-methoxypiperidin-1-yl) nitrobenzene 15.0 g of 3,4-difluoronitrobenzene and N, N
-4-methoxypiperidine hydrochloride 1 in a solution of 41 ml of diisopropylethylamine in 150 ml of anhydrous acetonitrile
5.8 g was added and the mixture was heated under reflux for 5 hours. After evaporating the solvent under reduced pressure, the residue was basified by adding water and a 10% aqueous sodium hydroxide solution, and extracted with ethyl acetate. The extract was washed with saturated saline and dried over sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 24.1 g of a tan liquid. NMR spectrum (DMSO-d ₆ ) δ ppm: 1.54-1.62 (2H, m),
1.92-2.00 (2H, m), 3.08-3.16 (2H, m), 3.28 (3H, s), 3.38-3.
46 (1H, m), 3.49-3.57 (2H, m), 7.16 (1H, t, J = 8.5Hz), 7.95 (1
H, dd, J = 14,3Hz), 7.97 (1H, dd, J = 8.5,3Hz) IR spectrum ν (liq.) Cm ^-1 : 1336,1518 Mass spectrum (m / z): 254 (M ⁺ )

The compounds of Reference Examples 8 to 20 were obtained in the same manner as in Reference Example 7.

[0061]

[Table 12]

[0062]

[Table 13]

Reference Example 21 4- (2-Dimethylaminoethoxy) -3-fluoronitrobenzene To a suspension of 1.38 g of 60% sodium hydride in 1.38 g of anhydrous tetrahydrofuran was added 3.50 ml of 2-dimethylaminoethanol under ice-cooling and stirring. Of anhydrous tetrahydrofuran 10
ml solution was added dropwise. After stirring at the same temperature for 30 minutes,
A solution of 5.00 g of difluoronitrobenzene in 30 ml of anhydrous tetrahydrofuran was added dropwise, and the mixture was stirred at room temperature for 30 minutes. After the reaction solution was added to ice water, the aqueous layer was extracted with ethyl acetate. The extract was washed successively with water and saturated saline, dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to column chromatography (silica gel, dichloromethane: methanol = 1)
0: 1) to give 7.60 g of a tan liquid. NMR spectrum (CDCl ₃ ) δ ppm; 2.36 (6H, s), 2.82 (2H,
(t, J = 5.5Hz), 4.24 (2H, t, J = 5.5Hz), 7.05 (1H, t, J = 9Hz), 8.0
0 (1H, dd, J = 10.5,2.5Hz), 8.05 (1H, dd, J = 9,2.5Hz) IR spectrum ν (liq.) Cm ^-1 : 1348,1526 Mass spectrum (m / z): 228 (M ⁺ )

Reference Examples 22 to 2 were made in the same manner as Reference Example 21.
9 compounds were obtained.

[0065]

[Table 14]

[0066]

[Table 15]

Reference Example 30 3- (2-methoxyethoxy) -4- (morpholine-4
To a suspension of 4.80 g of 60% sodium hydride in 180 ml of anhydrous N, N-dimethylformamide was added dropwise 6.90 ml of 2-methoxyethanol at room temperature.
4- (morpholin-4-yl) nitrobenzene 18.0
g was added and stirred at room temperature for 2 hours. The reaction solution was added to ice water, and the precipitated crystals were collected by filtration to obtain 19.7 g of yellow-brown crystals. Recrystallization from isopropanol gave a melting point of 109-1.
10 ° C. yellow needles were obtained. Elemental analysis C ₁₃ H ₁₈ N ₂ O ₅ theory C, 55.31; H, 6.43; N, 9.92 Found C, 55.23; H, 6.29; N, 9.98

The compound of Reference Example 31 was obtained in the same manner as in Reference Example 30.

Reference Example 31 4- (morpholin-4-yl) -3-n-propoxynitrobenzene Property Yellow prismatic crystal (recrystallization solvent: Et ₂ O) Melting point 110-111 ° C. Elemental analysis value C ₁₃ H ₁₈ N ₂ O ₄ theoretical value C, 58.63; H, 6.81; N, 10.52 Found C, 58.62; H, 6.90; N, 10.53

Reference Example 32 4- (2-Dimethylaminoethoxy) -3-fluoroaniline A methanol suspension of 2.00 g of 4- (2-dimethylaminoethoxy) -3-fluoronitrobenzene and 0.02 g of platinum oxide was prepared. The catalytic reduction was carried out at room temperature under a hydrogen pressure of 2 kg / cm ^{2 for} 1.5 hours. After removing the catalyst by filtration, the filtrate was concentrated under reduced pressure to obtain 1.78 g of a tan liquid. NMR spectrum (DMSO-d ₆ ) δ ppm; 2.20 (6H, s), 2.56 (2
H, t, J = 6Hz), 3.93 (2H, t, J = 6Hz), 4.82 (2H, br-s), 6.28 (1H,
dd, J = 9,2.5Hz), 6.41 (1H, dd, J = 13.5,2.5Hz), 6.82 (1H, t, J
= 9Hz) IR spectrum ν (liq.) Cm ^-1 : 3352 Mass spectrum (m / z): 198 (M ⁺ )

Reference Examples 33 to 5 were made in the same manner as Reference Example 32.
Compound 6 was obtained.

[0072]

[Table 16]

[0073]

[Table 17]

[0074]

[Table 18]

[0075]

[Table 19]

[0076]

[Table 20]

Reference Example 57 N-benzyloxycarbonyl-4- (thiomorpholin-4-yl) aniline A mixture of 19.0 g of 4- (thiomorpholin-4-yl) aniline in 190 ml of a 10% aqueous sodium carbonate solution and 190 ml of acetone. Under ice cooling and stirring, 21.0 ml of benzyloxycarbonyl chloride was added dropwise.
After stirring at room temperature for 30 minutes, the precipitated crystals were collected by filtration and washed with diisopropyl ether to obtain 25.5 g of pale brown crystals. Recrystallization from a mixed solution of ethyl acetate-diisopropyl ether gave colorless needles having a melting point of 145 to 146.5 ° C. Elemental analysis C ₁₈ H ₂₀ N ₂ O ₂ S Theoretical C, 65.83; H, 6.14; N, 8.53 Experimental C, 65.69; H, 6.12; N, 8.38

In the same manner as in Reference Example 57, Reference Examples 58 to 8
Compound 8 was obtained.

[0079]

[Table 21]

[0080]

[Table 22]

[0081]

[Table 23]

[0082]

[Table 24]

[0083]

[Table 25]

Reference Example 89 N, N'-di-tert-butoxycarbonyl-3-fluoro-4- (piperazin-1-yl) aniline 5.56 g of di-tert-butyl dicarbonate in 10 ml of methanol
The solution was stirred at room temperature with 3-fluoro-4- (piperazine-
A solution of 2.00 g of 1-yl) aniline in 10 ml of methanol was added dropwise and stirred at room temperature overnight. The precipitated crystals were collected by filtration and washed with ethanol to obtain 3.12 g of yellow crystals.
Recrystallization from ethyl acetate gave pale yellow crystals having a melting point of 194-195 ° C. Elemental analysis C ₂₀ H ₃₀ FN ₃ O ₄ Theoretical value C, 60.74; H, 7.65; N, 10.63 Found C, 60.47; H, 7.93; N, 10.53

In the same manner as in Reference Example 89, Reference Examples 90 to 9
Compound 2 was obtained.

[0086]

[Table 26]

Reference Example 93 (R) -5-hydroxymethyl-2-oxo-3- [4
-(Thiomorpholin-4-yl) phenyl] oxazolidine A solution of 25.0 g of N-benzyloxycarbonyl-4- (thiomorpholin-4-yl) aniline in 250 ml of anhydrous tetrahydrofuran was heated at 1.63 mol / L n- in a stream of nitrogen. 50 ml of a butyllithium n-hexane solution was added dropwise with stirring at -78 ° C. After the addition, the mixture was stirred at the same temperature for 1 hour. To this mixture, 11.5 ml of (R)-(-)-glycidyl butyrate was added dropwise, and after the addition, the mixture was stirred at the same temperature for 1 hour and then at room temperature for 23 hours. A 10% aqueous ammonium chloride solution 2 was added to the reaction solution.
50 ml was added and extracted with ethyl acetate. The extract was washed sequentially with water and saturated saline, dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was washed with diisopropyl ether to obtain 18.8 g of grey-brown crystals. Recrystallized from ethyl acetate, melting point 1
Colorless crystals of 26.5-127.5 ° C were obtained. Elemental analysis value C ₁₄ H ₁₈ N ₂ O ₃ S Theoretical value C, 57.12; H, 6.16; N, 9.52 Experimental value C, 56.85; H, 6.13; N, 9.25 Specific rotation [α] _D ²⁰ −40.9 ° ( c = 0.1, DMSO)

In the same manner as in Reference Example 93,
30 compounds were obtained.

[0089]

[Table 27]

[0090]

[Table 28]

[0091]

[Table 29]

[0092]

[Table 30]

[0093]

[Table 31]

[0094]

[Table 32]

[0095]

[Table 33]

[0096]

[Table 34]

Reference Example 131 (R) -5-Methanesulfonyloxymethyl-2-oxo-3- [4- (thiomorpholin-4-yl) phenyl] oxazolidine (R) -5-hydroxymethyl-2-oxo- 3- [4
To a solution of 10.0 g of-(thiomorpholin-4-yl) phenyl] oxazolidine and 10.5 ml of triethylamine in 200 ml of dichloromethane was added dropwise 3.20 ml of methanesulfonyl chloride under ice-cooling, followed by stirring at room temperature for 2 hours. 200 ml of water was added to the reaction solution, and extracted with dichloromethane. The extract was washed sequentially with water and saturated saline, dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was washed with diisopropyl ether to obtain 11.5 g of grayish brown crystals. Recrystallization from ethyl acetate gave colorless prisms with a melting point of 174.5-175.5 ° C. Elemental analysis C ₁₅ H ₂₀ N ₂ O ₅ S ₂ Theoretical C, 48.37; H, 5.41; N, 7.52 Experimental C, 48.41; H, 5.33; N, 7.36 Specific rotation [α] _D ²⁰ −54.2 − (C = 0.1, DMSO)

The compounds of Reference Examples 132 to 170 were obtained in the same manner as in Reference Example 131.

[0099]

[Table 35]

[0100]

[Table 36]

[0101]

[Table 37]

[0102]

[Table 38]

[0103]

[Table 39]

[0104]

[Table 40]

[0105]

[Table 41]

[0106]

[Table 42]

Reference Example 171 (R) -5-azidomethyl-2-oxo-3- [4-
(Thiomorpholin-4-yl) phenyl] oxazolidine 11.5 g of (R) -5-methanesulfonyloxymethyl-2-oxo-3- [4- (thiomorpholin-4-yl) phenyl] oxazolidine and sodium azide 8 .
35 g of anhydrous N, N-dimethylformamide 110 ml suspension was heated and stirred at 65 ° C. for 5 hours. After cooling, 200 ml of water was added to the reaction solution, and the mixture was extracted with ethyl acetate. Extract water with water,
The extract was successively washed with saturated saline, dried over sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was washed with diisopropyl ether to obtain 8.85 g of grayish brown crystals. Recrystallization from ethyl acetate gave colorless crystals having a melting point of 110 to 111 ° C. Elemental analysis value C ₁₄ H ₁₇ N ₅ O ₂ S Theoretical value C, 52.65; H, 5.37; N, 21.93 Experimental value C, 52.47; H, 5.35; N, 21.65 Specific rotation [α] _D ²⁰ −124.4 ゜ ( c = 0.1, DMSO)

In the same manner as in Reference Example 171, the compounds of Reference Examples 172 to 212 were obtained.

[0109]

[Table 43]

[0110]

[Table 44]

[0111]

[Table 45]

[0112]

[Table 46]

[0113]

[Table 47]

[0114]

[Table 48]

[0115]

[Table 49]

[0116]

[Table 50]

[0117]

[Table 51]

Reference Example 213 (R) -5-azidomethyl-3- [3-fluoro-4-
(Piperazin-1-yl) phenyl] -2-oxooxazolidine (R) -5-azidomethyl-3- [4- (4-tert-butoxycarbonylpiperazin-1-yl) -3-fluorophenyl] -2-oxo Oxazolidine 1.00 g
Then, 20 ml of a 16% ethyl acetate solution of hydrogen chloride was added, and the mixture was stirred at room temperature for 30 minutes, and the precipitated crystals were collected by filtration. The crystals were made alkaline by adding water and a 10% aqueous sodium hydroxide solution, and then extracted with ethyl acetate. The extract was washed with saturated saline and dried over sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 0.72 g of pale brown crystals. Recrystallization from isopropanol gave colorless crystals having a melting point of 114 to 115 ° C. Elemental analysis value C ₁₄ H ₁₇ FN ₆ O ₂ Theoretical value C, 52.49; H, 5.35; N, 26.24 Experimental value C, 52.24; H, 5.21; N, 26.15 Specific rotation [α] _D ²⁰ −127.3 ゜ (c = 0.1, DMSO)

In the same manner as in Reference Example 213, the compounds of Reference Examples 214 to 215 were obtained.

[0120]

[Table 52]

Reference Example 216 (R) -5-azidomethyl-3- [4- (4-ethylpiperazin-1-yl) -3-fluorophenyl] -2-
Oxooxazolidine (R) -5-azidomethyl-3- [3-fluoro-4-
To a solution of (piperazin-1-yl) phenyl] -2-oxooxazolidine (5.00 g) and potassium carbonate (2.16 g) in anhydrous N, N-dimethylformamide, 1.40 ml of ethyl iodide was added dropwise at room temperature, and the mixture was stirred at room temperature for 3 hours. . Water was added to the reaction solution, which was extracted with ethyl acetate. The extract was washed with saturated saline, dried over sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 4.53 g of pale brown crystals. Recrystallization from a mixed solution of ethyl acetate-n-heptane gave colorless crystals having a melting point of 90 to 91 ° C. Elemental analysis value C ₁₆ H ₂₁ FN ₆ O ₂ Theoretical value C, 55.16; H, 6.08; N, 24.12 Experimental value C, 55.22; H, 6.20; N, 24.03 Specific rotation [α] _D ²⁰ −120.9 ° (c = 0.1, DMSO)

In the same manner as in Reference Example 216, the compounds of Reference Examples 217 to 220 were obtained.

[0123]

[Table 53]

Reference Example 221 Ethyl (R)-(R) -3- [4- [4- (5-azidomethyl-2-oxooxazolidin-3-yl) -2-fluorophenyl] piperazin-1-yl] propionate 5-azidomethyl-3- [3-fluoro-4-
(Piperazin-1-yl) phenyl] -2-oxooxazolidine (7.00 g) and ethyl acrylate (3.56 ml) in ethanol (70 ml) were refluxed for 1 hour. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (silica gel, diethyl ether) to obtain 7.50 g of colorless crystals. Recrystallized from isopropanol, melting point 82-83 ° C
To obtain colorless crystals. Elemental analysis C ₁₉ H ₂₅ FN ₆ O ₄ Theoretical C, 54.28; H, 5.99; N, 19.99 Experimental C, 53.99; H, 5.88; N, 19.97 Specific rotation [α] _D ²⁰ −95.0 − (c = 0.1, DMSO)

Reference Example 222 (R) -5-azidomethyl-3- [3-fluoro-4-
[4- (3-methoxypropionyl) piperazine-1-
Yl] phenyl] -2-oxooxazolidine (R) -5-azidomethyl-3- [3-fluoro-4-
To a solution of 5.00 g of (piperazin-1-yl) phenyl] -2-oxooxazolidine and 3.26 ml of triethylamine in 50 ml of tetrahydrofuran was added dropwise a solution of 2.30 g of 3-methoxypropionyl chloride in 10 ml of tetrahydrofuran under ice-cooling and stirring. The mixture was stirred on ice for hours. Water was added to the reaction solution, which was extracted with ethyl acetate. The extract was washed successively with diluted hydrochloric acid, a saturated aqueous solution of sodium hydrogen carbonate and saturated saline, dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was crystallized from a mixed solution of isopropanol-diisopropyl ether to obtain 4.35 g of pale yellow crystals. Recrystallization from ethanol gave pale yellow prisms with a melting point of 99-101 ° C. Elemental analysis C ₁₈ H ₂₃ FN ₆ O ₄ Theoretical C, 53.20; H, 5.70; N, 20.68 Experimental C, 53.07; H, 5.68; N, 20.75 Specific rotation [α] _D ²⁰ −106.9 ° (c = 0.1, DMSO)

Compounds of Reference Examples 223 to 226 were obtained in the same manner as in Reference Example 222.

[0127]

[Table 54]

Reference Example 227 (S) -5-Aminomethyl-2-oxo-3- [4-
(Thiomorpholin-4-yl) phenyl] oxazolidine (R) -5-azidomethyl-2-oxo-3- [4-
A solution of 8.50 g of (thiomorpholin-4-yl) phenyl] oxazolidine and 7.68 g of triphenylphosphine in 130 ml of anhydrous tetrahydrofuran was stirred at room temperature for 15 hours. To this mixture was added 4.8 ml of water, and the mixture was added at 40 ° C for 14 hours.
The mixture was heated and stirred for hours. After cooling, 100 ml of water was added to the reaction solution, and 1
After acidifying with 0% hydrochloric acid, the mixture was washed with diethyl ether. The aqueous layer was made alkaline with potassium carbonate, and then extracted with a mixed solution of dichloromethane-methanol (30: 1).
The extract was washed with saturated saline and dried over sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 6.88 g of colorless crystals. Recrystallization from ethyl acetate gave colorless crystals having a melting point of 119.5 to 121 ° C. Elemental analysis C ₁₄ H ₁₉ N ₃ O ₂ S Theoretical C, 57.31; H, 6.53; N, 14.32 Experimental C, 57.36; H, 6.45; N, 14.06 Specific rotation [α] _D ²⁰ −35.9 ° ( c = 0.1, DMSO)

In the same manner as in Reference Example 227, the compounds of Reference Examples 228 to 278 were obtained.

[0130]

[Table 55]

[0131]

[Table 56]

[0132]

[Table 57]

[0133]

[Table 58]

[0134]

[Table 59]

[0135]

[Table 60]

[0136]

[Table 61]

[0137]

[Table 62]

[0138]

[Table 63]

[0139]

[Table 64]

[0140]

[Table 65]

[0141]

[Table 66]

Example 1 (S) -N- [2-oxo-3- [4- (thiomorpholin-4-yl) phenyl] oxazolidin-5-yl]
Methyl methyldithiocarbamate (S) -5-aminomethyl-2-oxo-3- [4-
(Thiomorpholin-4-yl) phenyl] oxazolidine (1.00 g) and triethylamine (0.48 ml) in dichloromethane (10 ml) were stirred under ice-cooling with carbon disulfide (0.40 ml).
, And stirred at the same temperature for 4 hours. 0.22 ml of methyl iodide was added to the mixture, and the mixture was stirred under ice cooling for 30 minutes. Water was added to the reaction solution, which was extracted with dichloromethane. The extract was washed with saturated saline and dried over sodium sulfate, and the solvent was distilled off under reduced pressure to obtain pale brown crystals. The crystals were recrystallized from ethyl acetate to obtain 0.80 g of pale brown crystals having a melting point of 157.5 to 158.5 ° C. Elemental analysis C ₁₆ H ₂₁ N ₃ O ₂ S ₃ Theoretical C, 50.10; H, 5.52; N, 10.96 Experimental C, 50.16; H, 5.55; N, 10.77 Specific rotation [α] _D ²⁰ −27.8 ° (C = 0.1, DMSO)

In the same manner as in Example 1, the compounds of Examples 2 to 56 were obtained.

[0144]

[Table 67]

[0145]

[Table 68]

[0146]

[Table 69]

[0147]

[Table 70]

[0148]

[Table 71]

[0149]

[Table 72]

[0150]

[Table 73]

[0151]

[Table 74]

[0152]

[Table 75]

[0153]

[Table 76]

[0154]

[Table 77]

[0155]

[Table 78]

[0156]

[Table 79]

Hereinafter, in order to confirm the excellent effect of the dithiocarbamic acid derivative of the present invention, an antibacterial test against bacteria and fungi was conducted. Table 80 shows the results of the antibacterial test on bacteria.
Table 81 shows the results of the antibacterial test against fungi. In addition, Linezolid [Journal of Medicinal Ch.
emistry, vol. 39, p. 673 (1996)], and fluconazole [The Merck Index, 12th edition, 4th edition] as a control compound B.
158] was used.

Embedded image

1. Antibacterial Spectrum against Bacteria The antibacterial activity (minimum inhibitory concentration) was measured by the standard method of the Japanese Chemotherapy Society [Journal of the Japan Chemotherapy Society, Vol. 29, p.
1981)], using standard bacteria and strains isolated from patients with infectious diseases (including clinical isolates and atypical mycobacteria)
The number of viable bacteria was 10 ⁶ / ml. The results are shown in Table 80. The compound of the present invention showed the same level of antibacterial activity in the standard bacterium as compared to the control compound A, and also showed better antibacterial activity against clinically isolated strains. The names of the bacteria in the table are as follows. Staphylococcus aureus (S. aureus) Bacillus subtilis (B. subtilis) Clinical isolate Methicillin-resistant Staphylococcus aureus (MRSA) Staphylococcus epidermidis (S.epidermidis) Enterococcus faecalis (E.faecalis) Enterococcus faecium (E.faecium) Mycobacterium avium (M.avium) Mycobacterium intracellulare (M. intracellulare)

[0159]

[Table 80]

2. Antibacterial spectrum against fungi The antibacterial activity (80% inhibitory concentration) was measured according to the method described in the Standard Committee of the Japanese Society for Medical Mycology [Journal of the Japanese Society for Medical Mycology, Vol. 36, p. 61 (1995)]. Accordingly, using clinical isolates,
The test was performed at a viable cell count of 10 ³ cells / ml. The results are shown in Table 81. The compound of the present invention showed extremely excellent antibacterial activity against clinically isolated strains as compared with control compound A and control compound B. The names of the bacteria in the table are as follows. Clinical isolate Aspergillus fumigatus (A. fumigatus) Candida albicans (C. albican
s)

[0161]

[Table 81]

[0162]

The dithiocarbamic acid derivative or its salt according to the present invention has excellent antibacterial activity against various bacteria and fungi including not only standard bacteria but also multidrug-resistant bacteria and atypical mycobacteria. It is extremely useful as an antibacterial or antifungal agent.

────────────────────────────────────────────────── ─── Continued on the front page (51) Int.Cl. ⁶ Identification code FI A61K 31/42 602 A61K 31/42 602 31/44 609 31/44 609 613 613 313 31/445 614 31/445 614 31/495 601 31/495 601 31/535 606 31/535 606 31/54 601 31/54 601 C07M 7:00

Claims (6)

[Claims] (1) The following general formula: (In the formula, R ¹ represents an optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted aryl group or an optionally substituted aralkyl group, and A represents a substituted A dithiocarbamic acid derivative or a salt thereof. 2. The following general formula: (Wherein, R ¹ represents an optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted aryl group or an optionally substituted aralkyl group, R ^2, R ³ and R ⁴ are each independently a hydrogen atom,
Halogen atom, hydroxyl group, mercapto group, amino group, cyano group, nitro group, formyl group, carboxyl group, carbamoyl group, optionally substituted alkyl group, optionally substituted cycloalkyl group, optionally substituted Good alkenyl group, optionally substituted alkynyl group, optionally substituted alkoxy group, optionally substituted alkylthio group, optionally substituted alkoxycarbonyl group, optionally substituted alkylamino group ,
An optionally substituted dialkylamino group, an optionally substituted alkylaminocarbonyl group, an optionally substituted dialkylaminocarbonyl group, an optionally substituted alkanoyl group, an optionally substituted alkanesulfonyl group , An optionally substituted arylcarbonyl group, an optionally substituted aryl group, an optionally substituted aralkyl group, an optionally substituted aryloxy group, and a substituted ring atom containing a heteroatom. Represents an optionally substituted cycloalkyloxy group, an optionally substituted saturated heterocyclic group, or an optionally substituted saturated heterocyclic group, or R ² ,
Any two of R ³ and R ⁴ may together represent an ethylenedioxy group, or form an optionally substituted hydrocarbon condensed ring with a benzene ring. ) Or a salt thereof. 3. The following general formula: (Wherein, R ¹ represents an optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted aryl group or an optionally substituted aralkyl group, R ^5, R ⁶ and R ⁷ are each independently a hydrogen atom,
Halogen atom, hydroxyl group, mercapto group, amino group, cyano group, nitro group, formyl group, carboxyl group, carbamoyl group, optionally substituted alkyl group, optionally substituted cycloalkyl group, optionally substituted It represents a good alkenyl group, an optionally substituted alkynyl group, an optionally substituted alkoxy group or an optionally substituted alkanoyl group. ) Or a salt thereof. 4. A medicament comprising the compound according to any one of claims 1 to 3 or a salt thereof as an active ingredient. 5. The method according to claim 1, which is an antibacterial agent.
The medicament according to item. 6. The medicament according to any one of claims 1 to 3, which is an antifungal agent.