JP2003300884A - TNF-alpha PRODUCTION INHIBITOR - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To obtain a TNF-α production inhibitor. <P>SOLUTION: The TNF-α production inhibitor comprises a 6- phenyltetrahydro-1,3-oxazin-2-one derivative of formula (I), an optical isomer thereof, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof. Therapeutic or prophylactic medicaments containing this inhibitor for allergy, bronchial asthma, septicemia, arthritis (e.g. articular rheumatism/ arthrosis deformans) diabetes, psoriasis, Crohn's disease and ulcerous colitis, are also provided. <P>COPYRIGHT: (C)2004,JPO

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to diseases thought to involve TNF-α (eg, allergy, bronchial asthma, sepsis, arthritis (rheumatoid arthritis / osteoarthritis, etc.), diabetes, psoriasis, Crohn's disease, ulcer. TNF-α production inhibitor effective for prevention and treatment of inflammatory bowel disease and the like).

More specifically, 6-phenyltetrahydro-1,3-oxazine-2 described in WO98 / 04534.
The present invention relates to a TNF-α production inhibitor containing a -one derivative, an optical isomer thereof, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof.

[0003]

2. Description of the Related Art TNF-α is a type of cytokine produced by cells such as macrophages and it has become clear that it acts on various cells. For example, there are antitumor activity due to mitotic arrest / inhibition of tumor cells, interleukin-1 production of fibroblasts or macrophages, inhibition of cartilage proteoglycan synthesis and absorption, activation of neutrophils and generation of superoxide. Further, it is conceivable that disruption of TNF-α production regulation mechanism, for example, sustained and excessive production may be a cause of various diseases such as tissue damage or a factor of exacerbation. Therefore, preventing or inhibiting the overproduction or action of TNF-α may be a useful therapeutic agent for many inflammatory, infectious, immune-mediated diseases or malignant diseases.

[0004]

SUMMARY OF THE INVENTION The object of the present invention is to provide TNF.
-Disorders that are considered to be involved in TNF-α by inhibiting α production, such as allergy, bronchial asthma, sepsis, arthritis (rheumatoid arthritis / osteoarthritis, etc.), diabetes, psoriasis, Crohn's disease, ulcerative large intestine It is to provide a therapeutic or preventive drug for inflammation and the like.

[0005]

The present inventors have found that a 6-phenyltetrahydro-1,3-oxazin-2-one derivative has an excellent TNF-α production inhibitory action, and completed the present invention. Came to.

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

[0007]

[Chemical 2]

6-phenyltetrahydro represented by
Production of TNF-α, which comprises a 1,3-oxazin-2-one derivative, an optical isomer thereof, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof. Exists as an inhibitor.

[0009]

BEST MODE FOR CARRYING OUT THE INVENTION The present invention is described in detail below.

The compound represented by the above general formula (I) is T
It is useful for the prevention and / or treatment of inflammatory diseases involving NF (tumor necrosis factor) -α.

The compound represented by the general formula (I) is T
NF-α production inhibitory action, based on this, as a therapeutic or preventive drug for allergy, bronchial asthma, sepsis, arthritis (rheumatoid arthritis, osteoarthritis, etc.), diabetes, psoriasis, Crohn's disease, ulcerative colitis, etc. It is useful.

The TNF-α production inhibitor of the present invention is 6-phenyltetrahydro-1, represented by the above general formula (I).
A 3-oxazin-2-one derivative, an optical isomer thereof, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof is contained.

R ₁ of the compound represented by the general formula (I) is a C ₁ -C ₈ linear or branched alkyl group (methyl group, ethyl group, propyl group, isopropyl group, n-butyl group, isobutyl group). , Sec-butyl group, t-butyl group, n-pentyl group, 1,1-dimethylpropyl group, n
-Hexyl group, 1-methylpentyl group, 1,1-dimethylbutyl group, 2-ethylbutyl group, n-heptyl group, n
-Octyl group, etc., and these include substituents (halogen atom; hydroxyl group; nitro group; cyano group; amino group; carboxyl group; aryl groups such as phenyl group, tolyl group, naphthyl group; pyridyl group, thiazolyl group, A thienyl group,
An aromatic heterocycle such as a furyl group or a quinolyl group; a cycloalkyl group such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group or a cyclohexyl group; a haloalkyl group; a carbamoyl group; an alkoxy group; an alkylcarbonyl group or the like) Good.

The C ₁ -C ₈ alkyl group having a substituent is, for example, a cyclopropylmethyl group, a cyclobutylmethyl group, a cyclopentylmethyl group, a cyclohexylmethyl group, a 1-methylcyclopropylmethyl group or a 1-phenylcyclopropyl group. Methyl group, benzyl group, phenethyl group, 4-fluorophenethyl group, 3-phenylpropyl group, 4-phenylbutyl group, 5-phenylpentyl group,
2- (1-naphthyl) ethyl group, 2- (2-pyridyl)
Ethyl group, 2- (4-methyl-5-thiazolyl) ethyl group, 2- (benzyloxy) ethyl group, 2- (phenethyloxy) ethyl group, 2- (methoxy) ethyl group, 3-
(Methoxy) propyl group, 4- (methoxy) butyl group,
2- (ethoxy) ethyl group, 3- (ethoxy) propyl group, 2- (butoxy) ethyl group, 2- (cyclopropylmethyloxy) ethyl group, 2- (cyclopentyloxy) ethyl group, 2- (4-methyl) -1-Piperazinyl)
Examples thereof include an ethyl group and a 3- (4-benzyl-1-piperazinyl) propyl group.

R ₁ is a C ₃ -C ₇ cycloalkyl group (cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group, etc.)
And substituents (alkyl group; halogen atom; hydroxyl group; nitro group; cyano group; amino group; carboxyl group; aryl group such as phenyl group, tolyl group, naphthyl group, etc .; pyridyl group, thiazolyl group, thienyl group An aromatic heterocycle such as a furyl group or a quinolyl group; a cyclopropyl group,
A cycloalkyl group such as a cyclobutyl group, a cyclopentyl group and a cyclohexyl group; a haloalkyl group; a carbamoyl group; an alkoxy group; an alkylcarbonyl group and the like). Examples of the C ₃ -C ₇ cycloalkyl group having a substituent include a 4-phenylcyclohexyl group and 1
Examples include -methylcyclopentyl group and 3-methylcyclopentyl group.

Examples of R ₁ include heterocyclic groups (pyridyl group, thiazolyl group, furyl group, thienyl group, tetrahydrofuryl group, piperidinyl group, etc.), which are substituents (alkyl group; halogen atom; hydroxyl group). Nitro group; cyano group; amino group; carboxyl group; aryl group such as phenyl group, tolyl group, naphthyl group; aromatic heterocyclic group such as pyridyl group, thiazolyl group, thienyl group, furyl group, quinolyl group; benzyl group , Phenethyl group, 1-
Arylalkyl group such as naphthylmethyl group; Pyridylalkyl group; Cycloalkyl group such as cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group;
Haloalkyl group; carbamoyl group; alkoxy group; alkylcarbonyl group, etc.), and examples of the heterocyclic group having a substituent include, for example, 1-benzyl-4-piperidinyl group, 2-nitropyridyl group, 3- A tetrahydrofuryl group is mentioned. Further, R ₁ may be an indanyl group.

R ₁ is preferably a C ₁ -C ₆ alkyl group, a C ₄ -C ₆ cycloalkyl group or an indanyl group, more preferably a methyl group, a cyclopentyl group or a 2-indanyl group. To be

R ₂ of the compound represented by the general formula (I) is a C ₁ -C ₄ linear or branched alkyl group (methyl group, ethyl group, n-propyl group, isopropyl group, n-
Butyl group, sec-butyl group, t-butyl group and the like), preferably a methyl group or an ethyl group, and more preferably a methyl group.

R ₃ of the compound of the above formula (I) is a hydrogen atom, a C ₁ -C ₅ linear or branched alkyl group (methyl group, ethyl group, n-propyl group, isopropyl group, n- Butyl group, sec-butyl group, t-butyl group,
n-pentyl group). The C _{1 to} C ₅ linear or branched alkyl group may have a substituent,
As the substituent, an aryl group which may have a halogen atom as a substituent (phenyl group, tolyl group, naphthyl group, etc.); which may have a halogen atom as a substituent, oxygen atom, nitrogen atom, sulfur Aromatic heterocyclic group containing one or more heteroatoms selected from atoms (pyridyl group,
Thiazolyl group, furyl group, thienyl group, indolyl group, etc.); or an alkoxycarbonyl group.

Examples of the C ₁ -C ₅ alkyl group having a substituent of R ₃ include ethoxycarbonylmethyl group, benzyl group, 4-bromobenzyl group, phenethyl group, 3-phenylpropyl group, 4-phenylbutyl group. , 5-phenylpentyl group, pyridylmethyl group, furylmethyl group, thiazolylmethyl group, 2-quinolylmethyl group, 1-naphthylmethyl group, 2-indolylmethyl group and the like.

R ₃ is a C ₃ -C ₇ cycloalkyl group (cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group, etc.)
And these may have a substituent. Examples of R ₃ include aryl groups (phenyl group, tolyl group, naphthyl group), which may have a substituent. R ₃ is an aromatic heterocyclic group (pyridyl group, thiazolyl group, containing one or more heteroatoms selected from oxygen atom, nitrogen atom, and sulfur atom).
(Furyl group, thienyl group, quinolyl group, etc.), which may have a substituent. Furthermore, as R ₃ ,
Acyl group (formyl group, acetyl group, propionyl group,
Benzoyl group, 2-naphthoyl group, 3-furoyl group, 2
-Thenoyl group, nicotinoyl group, isonicotinoyl group and the like).

R ₃ is preferably a hydrogen atom, C _1-
Examples thereof include a C ₃ alkyl group or a C ₁ -C ₂ alkyl group having an aromatic heterocyclic group containing one or more heteroatoms selected from oxygen atom, nitrogen atom and sulfur atom as a substituent. And more preferably a hydrogen atom, a methyl group or a pyridylmethyl group.

R _{4 in} the compound of the general formula (I) is a hydrogen atom; a C _{1 to} C ₆ linear or branched alkyl group (methyl group, ethyl group, propyl group, isopropyl group,
Butyl group, sec-butyl group, t-butyl group, pentyl group, hexyl group, etc.), which may have a substituent. Examples of R ₄ include an aryl group which may have a substituent (phenyl group, tolyl group, naphthyl group, 4-methylphenyl group, 4-chlorophenyl group). Further, as R ₄ , oxygen atom, nitrogen atom,
Aromatic heterocyclic groups containing one or more heteroatoms selected from sulfur atoms (pyridyl group, thiazolyl group, thienyl group, furyl group, etc.) are mentioned, and these may have a substituent. good.

R ₄ is preferably a hydrogen atom, a methyl group, an ethyl group, or an aromatic heterocyclic group containing at least one hetero atom selected from an oxygen atom, a nitrogen atom and a sulfur atom. More preferably, a hydrogen atom, a methyl group and a pyridyl group are mentioned.

R ₅ and R ₆ of the compound of the above general formula (I)
Are each independently a hydrogen atom; a C _{1 to} C ₆ linear or branched alkyl group (methyl group, ethyl group, propyl group, isopropyl group, butyl group, sec-butyl group,
t-butyl group, pentyl group, hexyl group, etc.), aryl group (phenyl group, naphthyl group, etc.) or an aromatic complex containing one or more heteroatoms selected from oxygen atom, nitrogen atom and sulfur atom. Examples thereof include cyclic groups (pyridyl group, thiazolyl group, thienyl group, furyl group, etc.).

Further, the C ₁ -C ₆ alkyl groups of R ₅ and R ₆ are each independently a substituent (halogen atom; hydroxyl group;
Cyano group; amino group; carboxyl group; cycloalkyl group; haloalkyl group; carbamoyl group; alkoxy group;
Alkylcarbonyl group; aryl group such as phenyl group, tolyl group, naphthyl group, 4-methylphenyl group, 4-chlorophenyl group; containing one or more heteroatoms selected from oxygen atom, nitrogen atom and sulfur atom Aromatic heterocyclic group (pyridyl group, thiazolyl group, thienyl group, furyl group, etc.) and the like.

Further, the aryl group and aromatic heterocyclic group of R ₅ and R ₆ are each independently a substituent (halogen atom;
A hydroxyl group; a cyano group; an amino group; a carboxyl group; an alkyl group; a cycloalkyl group; a haloalkyl group; a carbamoyl group; an alkoxy group; an alkylcarbonyl group).

Preferred as R ₅ and R ₆ are hydrogen atoms.

Specific examples of the compound represented by the above general formula (I) include 6- (3,4-dimethoxyphenyl) -3,
4,5,6-Tetrahydro-2H-1,3-oxazin-2-one, 6- (3,4-dimethoxyphenyl)-
3-Methyl-3,4,5,6-tetrahydro-2H-
1,3-oxazin-2-one, 3-benzyl-6-
(3,4-dimethoxyphenyl) -3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one,
6- (3,4-dimethoxyphenyl) -6-methyl-
3,4,5,6-Tetrahydro-2H-1,3-oxazin-2-one, 6- (3,4-dimethoxyphenyl)
-6- (2-thiazolyl) -3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one, 6-
(3-Butoxy-4-methoxyphenyl) -3,4
5,6-Tetrahydro-2H-1,3-oxazine-2
-One, 6- (3-cyclopropylmethyloxy-4
-Methoxyphenyl) -3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one, 6- (3-
Cyclopentyloxy-4-methoxyphenyl) -3,
4,5,6-Tetrahydro-2H-1,3-oxazin-2-one, 6- (3-cyclopentyloxy-4-
Methoxyphenyl) -6-methyl-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one,
6- (3-Cyclopentyloxy-4-methoxyphenyl) -6-phenyl-3,4,5,6-tetrahydro-
2H-1,3-oxazin-2-one,

6- (3-cyclopentyloxy-4-methoxyphenyl) -3-methyl-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one, 3
-(4-Bromobenzyl) -6- (3-cyclopentyloxy-4-methoxyphenyl) -3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one, 6
-(3-Cyclopentyloxy-4-methoxyphenyl) -3- (2-quinolylmethyl) -3,4,5,6-
Tetrahydro-2H-1,3-oxazin-2-one,
6- (3-Cyclopentyloxy-4-methoxyphenyl) -3- (1-naphthylmethyl) -3,4,5,6
-Tetrahydro-2H-1,3-oxazin-2-one, 6- (3-cyclopentyloxy-4-methoxyphenyl) -3-[(4-pyridyl) methyl] -3,
4,5,6-Tetrahydro-2H-1,3-oxazin-2-one, 6- (3-cyclopentyloxy-4-
Methoxyphenyl) -3- (2-naphthylmethyl)-
3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one, 6- (3-cyclopentyloxy-
4-methoxyphenyl) -3- (2-pyridylmethyl)
-2H-1,3-oxazin-2-one, 3-butyl-6- (3-cyclopentyloxy-4-methoxyphenyl) -3,4,5,6-tetrahydro-2H-1,3
-Oxazin-2-one, 3-benzoyl-6- (3
-Cyclopentyloxy-4-methoxyphenyl)-
3,4,5,6-Tetrahydro-2H-1,3-oxazin-2-one, 6- (3-cyclopentyloxy-4
-Methoxyphenyl) -3- (ethoxycarbonylmethyl) -3,4,5,6-tetrahydro-2H-1,3-
Oxazin-2-one,

6- (3-cyclopentyloxy-4-methoxyphenyl) -3- (3-pyridylmethyl) -3,
4,5,6-Tetrahydro-2H-1,3-oxazin-2-one, 6- (3-cyclopentyloxy-4-
Methoxyphenyl) -3,6-dimethyl-3,4,5,5
6-tetrahydro-2H-1,3-oxazin-2-one, 6- (3-cyclopentyloxy-4-methoxyphenyl) -6-methyl-3- (4-pyridylmethyl)
-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one, 6- (3-cyclopentyloxy-4-methoxyphenyl) -6-ethyl-3,4,5,5
6-tetrahydro-2H-1,3-oxazin-2-one, 6- (3-cyclopentyloxy-4-methoxyphenyl) -3-ethyl-3,4,5,6-tetrahydro-2H-1,3- Oxazin-2-one, 6- (3
-Cyclopentyloxy-4-methoxyphenyl) -6
-(2-thienyl) -3,4,5,6-tetrahydro-
2H-1,3-oxazin-2-one, 6-butyl-
6- (3-Cyclopentyloxy-4-methoxyphenyl) -3,4,5,6-tetrahydro-2H-1,3-
Oxazin-2-one, 6- (3-cyclopentyloxy-4-methoxyphenyl) -6- (2-thiazolyl) -3,4,5,6-tetrahydro-2H-1,3-
Oxazin-2-one, 6- (3-cyclopentyloxy-4-methoxyphenyl) -3- [2- (1-piperidyl) ethyl] -3,4,5,6-tetrahydro-2
H-1,3-oxazin-2-one, 6- (3-cyclopentyloxy-4-methoxyphenyl) -3- [2
-(4-morpholino) ethyl] -3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one,

3- (1-Acetyl-3-methyl-2-indolylmethyl) -6- (3-cyclopentyloxy-
4-methoxyphenyl) -3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one, 6- (3
-Cyclopentyloxy-4-methoxyphenyl) -3
-(2-furylmethyl) -3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one, 6- (3
-Cyclopentyloxy-4-methoxyphenyl) -6
-(3-Pyridyl) -3,4,5,6-tetrahydro-
2H-1,3-oxazin-2-one, 6- (3-cyclopentyloxy-4-methoxyphenyl) -3-
(2-Pyrazinylmethyl) -3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one, 6-
(3-Cyclopentyloxy-4-methoxyphenyl)
-3- (2-thienylmethyl) -3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one, 6
-(3-Cyclopentyloxy-4-methoxyphenyl) -6- (2-pyridyl) -3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one, 6-
(4-Methoxy-3-phenethyloxyphenyl)-
3,4,5,6-Tetrahydro-2H-1,3-oxazin-2-one, 6- (4-methoxy-3-phenethyloxyphenyl) -3-methyl-3,4,5,6-tetrahydro- 2H-1,3-oxazin-2-one,
6- [4-methoxy-3- (5-phenylpentyloxy) phenyl] -6-methyl-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one, 6-
(4-Methoxy-3-phenethyloxyphenyl) -6
-Methyl-3,4,5,6-tetrahydro-2H-1,
3-oxazin-2-one,

3,6-Dimethyl-6- [4-methoxy-
3- (5-phenylpentyloxy) phenyl] -3,
4,5,6-Tetrahydro-2H-1,3-oxazin-2-one, 3,6-dimethyl-6- (4-methoxy-3-phenethyloxyphenyl) -3,4,5,6-
Tetrahydro-2H-1,3-oxazin-2-one,
6- [3- (2-Indanyloxy) -4-methoxyphenyl] -3,4,5,6-tetrahydro-2H-1,
3-oxazin-2-one, 6- [3- (2-indanyloxy) -4-methoxyphenyl] -3-methyl-
3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one, 6- [3- (2-indanyloxy) -4-methoxyphenyl] -6-methyl-3,4.
5,6-Tetrahydro-2H-1,3-oxazine-2
-One, 6- [4-methoxy-3- (5-phenylpentyloxy) phenyl] -3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one, 6-
[4-methoxy-3- (5-phenylpentyloxy)
Phenyl] -3-methyl-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one, 3,6-
Dimethyl-6- [3- (2-indanyloxy) -4-
Methoxyphenyl] -3,4,5,6-tetrahydro-
2H-1,3-oxazin-2-one, 6- (3-cyclopropylmethyloxy-4-methoxyphenyl)-
3-Methyl-3,4,5,6-tetrahydro-2H-
1,3-oxazin-2-one, 6- (3-cyclopropylmethyloxy-4-methoxyphenyl) -6-methyl-3,4,5,6-tetrahydro-2H-1,3-
Oxazin-2-one,

6- (3-cyclopropylmethyloxy-
4-methoxyphenyl) -3,6-dimethyl-3,4,
5,6-Tetrahydro-2H-1,3-oxazine-2
-One, 6- (3-butoxy-4-methoxyphenyl) -6-methyl-3,4,5,6-tetrahydro-2
H-1,3-oxazin-2-one, 6- (3-butoxy-4-methoxyphenyl) -3-methyl-3,4
5,6-Tetrahydro-2H-1,3-oxazine-2
-One, 6- (3-butoxy-4-methoxyphenyl) -3,6-dimethyl-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one, 6- [4
-Methoxy-3- [2- (2-pyridyl) ethoxy] phenyl] -3,4,5,6-tetrahydro-2H-1,
3-oxazin-2-one, 6- [4-methoxy-3
-[(1-phenylcyclopropyl) methyloxy] phenyl] -3,4,5,6-tetrahydro-2H-1,
3-oxazin-2-one, 6- [4-methoxy-3
-[(1-phenylcyclopropyl) methyloxy] phenyl] -3-methyl-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one, 6- [3-
(10,11-Dihydro-5H-dibenzo [a, d] cyclohepten-5-yloxy) -4-methoxyphenyl] -3,4,5,6-tetrahydro-2H-1,3-
Oxazin-2-one, 6- [3- (10,11-dihydro-5H-dibenzo [a, d] cycloheptene-5
-Yloxy) -4-methoxyphenyl] -3-methyl-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one, 6- [3- [3- (4-benzyl-1) -Piperazinyl) propoxy] -4-methoxyphenyl] -3,4,5,6-tetrahydro-2H-1,3
-Oxazin-2-one,

6- (3-cyclobutylmethyloxy-4
-Methoxyphenyl) -3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one, 6- (3-
Cyclobutylmethyloxy-4-methoxyphenyl)-
3-Methyl-3,4,5,6-tetrahydro-2H-
1,3-oxazin-2-one, 6- [4-methoxy-3-[(1-methylcyclopropyl) methyloxy]
Phenyl] -3,4,5,6-tetrahydro-2H-
1,3-oxazin-2-one, 6- [4-methoxy-3-[(1-methylcyclopropyl) methyloxy]
Phenyl] -3-methyl-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one, 6- [4-
Methoxy-3- (2-methylpropoxy) phenyl]-
3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one, 6- [4-methoxy-3- (2-methylpropoxy) phenyl] -3-methyl-3,4
5,6-Tetrahydro-2H-1,3-oxazine-2
-One, 6- [4-methoxy-3- [2- (1-naphthyl) ethoxy] phenyl] -3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one, 6-
[4-Methoxy-3- [2- (1-naphthyl) ethoxy] phenyl] -3-methyl-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one, 6-
[3- (2-Ethylbutoxy) -4-methoxyphenyl] -3,4,5,6-tetrahydro-2H-1,3-
Oxazin-2-one, 6- [3- (2-ethylbutoxy) -4-methoxyphenyl] -3-methyl-3,
4,5,6-tetrahydro-2H-1,3-oxazin-2-one,

3-Ethyl-6- [3- (2-indanyloxy) -4-methoxyphenyl] -3,4,5,6-
Tetrahydro-2H-1,3-oxazin-2-one,
6- [4-methoxy-3- [2- (4-methyl-5-
Thiazolyl) ethoxy] phenyl] -3,4,5,6-
Tetrahydro-2H-1,3-oxazin-2-one,
6- [4-methoxy-3- [2- (4-methyl-5-thiazolyl) ethoxy] phenyl] -3-methyl-3,
4,5,6-Tetrahydro-2H-1,3-oxazin-2-one, 6- [3- [2- (4-fluorophenyl) ethoxy] -4-methoxyphenyl] -3,4
5,6-Tetrahydro-2H-1,3-oxazine-2
-One, 6- [3- [2- (4-fluorophenyl)
Ethoxy] -4-methoxyphenyl] -3-methyl-
3,4,5,6-Tetrahydro-2H-1,3-oxazin-2-one, 6- (3-cyclopentylmethyloxy-4-methoxyphenyl) -3,4,5,6-tetrahydro-2H-1 , 3-oxazin-2-one, 6
-(3-Cyclopentylmethyloxy-4-methoxyphenyl) -3-methyl-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one, 6- [4-
Methoxy-3- (cis-4-phenylcyclohexyloxy) phenyl] -3,4,5,6-tetrahydro-
2H-1,3-oxazin-2-one, 6- [4-methoxy-3- (trans-4-phenylcyclohexyloxy) phenyl] -3,4,5,6-tetrahydro-2H-1,3-oxazine -2-one, 6- [4-
Methoxy-3- (trans-4-phenylcyclohexyloxy) phenyl] -3-methyl-3,4,5,6
-Tetrahydro-2H-1,3-oxazin-2-one,

6- [4-methoxy-3- (1-methylcyclopentyloxy) phenyl] -3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one,
6- [4-methoxy-3- (2-methylpropoxy) phenyl] -6-methyl-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one, 3,6-dimethyl- 6- [4-methoxy-3- (2-methylpropoxy) phenyl] -3,4,5,6-tetrahydro-2
H-1,3-oxazin-2-one, 6- [3- (2
-Benzyloxyethoxy) -4-methoxyphenyl]
-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one, 6- [3- (2-benzyloxyethoxy) -4-methoxyphenyl] -3-methyl-
3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one, 6- (3-cyclopentyloxy-
4-methoxyphenyl) -5,5-dimethyl-3,4
5,6-Tetrahydro-2H-1,3-oxazine-2
-One, 6- (3-cyclopentyloxy-4-methoxyphenyl) -3,5,5-trimethyl-3,4
5,6-Tetrahydro-2H-1,3-oxazine-2
-One, 5,5-dimethyl-6- [3- (2-indanyloxy) -4-methoxyphenyl] -3,4,5,
6-tetrahydro-2H-1,3-oxazin-2-one, (−)-6- [3- (2-indanyloxy) -4
-Methoxyphenyl] -6-methyl-3,4,5,6-
Tetrahydro-2H-1,3-oxazin-2-one,
6- [3- (2-Indanyloxy) -4-methoxyphenyl] -3,5,5-trimethyl-3,4,5,6
-Tetrahydro-2H-1,3-oxazin-2-one, 6- [3- (1-benzyl-4-piperidyloxy) -4-methoxyphenyl] -3,4,5,6-tetrahydro-2H-1 , 3-oxazin-2-one,

6- [3- [2- (cyclopropylmethyloxy) ethoxy] -4-methoxyphenyl] -3,
4,5,6-Tetrahydro-2H-1,3-oxazin-2-one, (+)-6- [3- (2-indanyloxy) -4-methoxyphenyl] -6-methyl-3,4 ，
5,6-Tetrahydro-2H-1,3-oxazine-2
-One, (5RS, 6SR) -6- (3-cyclopentyloxy-4-methoxyphenyl) -5-phenyl-
3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one, (5RS, 6RS) -6- (3-cyclopentyloxy-4-methoxyphenyl) -5-phenyl-3,4. 5,6-Tetrahydro-2H-1,3
-Oxazin-2-one, 6- [3- (3-tetrahydrofuryloxy) -4-methoxyphenyl] -3,
Examples include 4,5,6-tetrahydro-2H-1,3-oxazin-2-one.

The compound represented by the above general formula (I) is WO
It is manufactured by the method described in Japanese Patent Publication No. 98/04534.

Further, the compound represented by the above general formula (I) has an asymmetric carbon atom and has optical isomers.
These optically active pure compounds can be obtained by resolving the racemate produced by the method described in the above publication into two kinds of optically active substances by using high performance liquid chromatography (HPLC). Further, by recrystallizing the obtained optically active substance with various solvents, if necessary, it is possible to obtain an optically active substance with higher purity. These optical isomers are also included in the content of the TNF-α production inhibitor in the present invention.

The compound of the general formula (I) and salts of its stereoisomers or optical isomers are also included in the inclusion of the TNF-α production inhibitor in the present invention. Acceptable salts are preferred, for example inorganic acid salts such as hydrochlorides, hydrobromides, hydroiodides, phosphates and oxalates, maleates, fumarates,
Lactate, malate, citrate, tartrate, benzoate, methanesulfonate, p-toluenesulfonate, and other organic acid salts can be mentioned.

Further, the components contained in the TNF-α production inhibitor in the present invention include 6-type compounds represented by the above general formula (I).
Also included are phenyltetrahydro-1,3-oxazin-2-one derivatives, optical isomers thereof, or pharmaceutically acceptable salts thereof, or hydrates or solvates thereof, and as a solvent of the solvate , Methanol, ethanol, isopropanol, butanol, acetone, ethyl acetate, chloroform and the like.

The TNF-α production inhibitor of the present invention is 6-phenyltetrahydro-1, represented by the above general formula (I).
A 3-oxazin-2-one derivative, an optical isomer thereof, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, alone or mixed with a pharmaceutically acceptable carrier, It can be manufactured by preparing various dosage unit forms. Its composition is determined by the solubility, chemical properties, administration route, administration schedule, etc. of the compound.

Examples of dosage forms include granules, powders, tablets, pills, hard capsules, soft capsules, syrups,
It may be orally administered in the form of emulsion, suspension, liquid or the like, or injection (intravenous, intramuscular, subcutaneous), eye drop,
Parenteral administration such as eye ointment, ointment, suppository, aerosol and inhalant may be carried out. Alternatively, it may be made into powder for injection and prepared at the time of use. Pharmaceutical organic or inorganic solid or liquid carriers or diluents suitable for oral, enteral, parenteral or topical administration can be used with the compounds of this invention. For topical administration, eye drops, eye ointment,
Ointments, inhalants, tablets for systemic administration,
Examples thereof include granules, powders, capsules, solutions, injections and the like.

The TNF-α production inhibitor of the present invention is 6-phenyltetrahydro-1, represented by the above general formula (I).
Using a 3-oxazin-2-one derivative, an optical isomer thereof, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof and a pharmaceutically acceptable carrier, It is manufactured by a method known to those skilled in the art.

Further, if desired or necessary, suitable binders, lubricants, disintegrants, preservatives, buffers, thickeners, solubilizers, chelating agents, stabilizers, pH adjusters, isotonic agents, etc. Various additives usually used in formulation such as an agent may be added.

For example, in the case of oral preparations, excipients such as lactose, glucose, corn starch, sucrose, sorbitol, mannitol and erythritol, disintegrating agents such as calcium carboxymethyl cellulose and hydroxypropyl cellulose, calcium stearate, magnesium stearate, Lubricants such as talc, polyethylene glycol and hardened oil, wetting agents such as hydroxypropyl cellulose, hydroxypropylmethyl cellulose, carboxymethyl cellulose, polyvinyl alcohol, gelatin, gum arabic, etc. Can be prepared into a desired dosage form.

In the case of a parenteral preparation, a diluent such as water, ethanol, glycerin, propylene glycol, polyethylene glycol, agar, tragacanth gum, etc. may be used, if necessary, and a solubilizing agent (polyvinylpyrrolidone,
Polyoxyethylene hydrogenated castor oil, polyethylene glycol, polysorbate 80, polyoxyethylene monostearate, etc.), preservatives (chlorobutanol, sodium dehydroacetate, benzalkonium chloride, cetylpyridinium chloride, phenethyl alcohol, paraoxybenzoic acid esters, Bezethonium chloride, etc.), buffer (borate buffer, phosphate buffer, carbonate buffer, acetate buffer,
Citrate buffer, etc.), stabilizer (sodium edetate,
Sodium bisulfite, etc., pH adjuster (sodium hydroxide, potassium hydroxide, sodium carbonate, sodium hydrogen carbonate, acetic acid, citric acid, phosphoric acid, etc.), tonicity agent (sodium chloride, potassium chloride, glycerin, polyvalent) Alcohol, sorbitol, mannitol, glucose, etc.), soothing agents and the like can be used.

In the case of an ophthalmic ointment, a commonly used base (white ophthalmic petrolatum, plastibase, propet, etc.) can be used, and examples of additives include liquid paraffin.

When the dosage form of the compound of the above-mentioned general formula (I) used in the present invention is a preparation for systemic administration, when it is orally administered to an adult, the compound of the above-mentioned general formula (I) and (II) is used. As a compound, the daily dose is generally 0.01 to 1000 mg,
It is preferably 0.01 to 100 mg, but the age, medical condition, symptoms,
It is more preferable to appropriately increase or decrease depending on the presence or absence of simultaneous administration. For inhalants, the daily dose for adults is usually 0.001 to 300
mg, preferably 0.001 to 30 mg. In the case of eye drops, the compound concentration is usually 0.01 to 3 as the final concentration.
It is 0w / v%. The concentration in the case of eye ointment is usually 0.01 to 10.0 w / v% as the final concentration. The above-mentioned daily dose of the drug (the compound of the present invention) may be administered once a day, or twice or three times a day at appropriate intervals, or may be administered intermittently. When used as an injection, the compound of the present invention is administered to an adult in a single dose of 0.00
It is preferable to administer 1 to 100 mg continuously or intermittently.

Although the dosage and administration of the TNF-α production inhibitor of the present invention varies depending on age, medical condition, symptom, etc., in the case of eye drops, it is usually 1 to 6 times a day, or 1 to 2 times a day. Instill the drops. In the case of an eye ointment, an appropriate amount is usually applied to the conjunctival sac once or twice a day. In the case of oral administration, it should be taken once or several times a day. In the case of an injection, it is administered once or several times a day.

[0052]

EXAMPLES The present invention will now be described in detail with reference to reference examples, examples and test examples, but the present invention is not limited to the following examples and test examples as long as the gist thereof is not exceeded.

<Reference Example 1> Method for producing optical isomers Racemic (±) -6- [3- (2-indanyloxy) produced by the method described in WO98 / 04534.
-4-Methoxyphenyl] -6-methyl-3,4,5,
After dissolving 70 g of 6-tetrahydro-2H-1,3-oxazin-2-one in 7.0 L of denatured ethanol, about 3.0 g of the sample solution was injected into the column, and HPLC was performed under the following conditions. Column: CHIRALPAK AS (10 cm φ x 50 cm) Solvent: Denatured ethanol Flow rate: 100 mL / min Fractions of the first and second peaks were concentrated under reduced pressure, and ethanol and n-hexane were added to the resulting oily residue. Then, the mixture was concentrated under reduced pressure again to obtain a powdery optically active substance. By repeating the above operations, two types of optically active substances from (±) -body 70 g, (−)-body 31.5 g,
29.6 g of (+)-form was obtained. The structure was confirmed by comparison with ¹ H-NMR of the racemate before optical resolution.

(−)-Body: retention time 50 to 62 minutes, column temperature 40 ° C. [α] ²⁰ _D 68 ° (c = 1.00, MeOH) ¹ H-NMR (CDCl ₃ ) δ (ppm): 1.68 (3H , s),
2.14 (1H, ddd, J = 14.0, 10.6, 5.6 Hz), 2.30 (1H, d
dd, J = 14.0, 3.9, 3.9 Hz), 3.06 (1H, ddd, J = 10.6, 1
0.6, 4.8 Hz), 3.20 (1H, dd, J = 16.7, 3.9 Hz), 3.2
2 (1H, dd, J = 16.7, 3.9 Hz), 3.25-3.30 (1H, m),
3.36 (1H, dd, J = 16.7, 6.6 Hz), 3.37 (1H, dd, J = 1
6.7, 6.6 Hz), 3.81 (3H, s), 5.21 (1H, dddd, J = 6.
6, 6.6, 3.9, 3.9Hz), 6.13 (1H, broad), 6.86 (1H,
d, J = 8.3Hz), 6.90 (1H, dd, J = 8.3, 2.2Hz), 6.95
(1H, d, J = 2.2Hz), 7.15-7.19 (2H, m), 7.21-7.23
(2H, m) (+)-body: retention time 69 to 88 minutes, column temperature 40 ° C. [α] ²⁰ _D + 68 ° (c = 1.00, MeOH)

¹ H-NMR (CDCl ₃ ) δ (pp
m): 1.66 (3H, s), 2.11 (1H, ddd, J = 13.9, 10.3,
5.4Hz), 2.27 (1H, ddd, J = 13.9, 4.2, 4.2Hz), 3.00
-3.07 (1H, m), 3.20 (1H, dd, J = 16.6, 3.7Hz), 3.2
2 (1H, dd, J = 16.6, 3.7Hz), 3.22-3.29 (1H, m), 3.
36 (2H, dd, J = 16.6, 6.6Hz), 3.80 (3H, s), 5.21 (1
H, dddd, J = 6.6, 6.6, 3.7, 3.7Hz), 6.13 (1H, broa
d), 6.86 (1H, d, J = 8.3Hz), 6.90 (1H, dd, J = 8.3,
2.2Hz), 6.95 (1H, d, J = 2.2Hz), 7.14-7.18 (2H,
m), 7.19-7.23 (2H, m)

Example 1 Preparation of tablets 30 g of (−)-6- [3- (2-indanyloxy)
-4-Methoxyphenyl] -6-methyl-3,4,5,
6-Tetrahydro-2H-1,3-oxazin-2-one, 253 g of lactose, 63 g of corn starch, 40 g of low-substituted hydroxypropyl cellulose, 4 g of calcium stearate are mixed and compressed by a usual method to give each tablet 10 mg of the compound. To include.

Example 2 Preparation of Capsules 30 g of (-)-6- [3- (2-indanyloxy)
-4-Methoxyphenyl] -6-methyl-3,4,5,
6-Tetrahydro-2H-1,3-oxazin-2-one, 260 g of lactose, 66 g of corn starch and 4 g of calcium stearate were mixed and then filled in a gelatin capsule by a usual method, and each capsule was filled with the compound 10 described above.
Make sure to include mg.

Example 3 Production of Inhalant (-)-6- [3- (2-Indanyloxy) -4-methoxyphenyl] -6-methyl-3,4,5,6-tetrahydro-2H 0.15 g of -1,3-oxazin-2-one well pulverized to have a particle size of 1 to 5 μm and lactose (325 mesh, D.M.V.) 60
Mix g. Fill the capsules in the usual way, each capsule containing 50 μg of the compound. Inhalation is performed by loading a capsule into a powder inhalation container.

<Test Example 1> TNF-α production inhibitory effect Blood was collected from a test tube treated with heparin under anesthesia with pentobarbital. The same amount of RPM as the collected blood
I-1640 was added, the mixture was dispensed in a 24 well plate, a solvent (DMSO) or a test drug dissolved in the solvent was added, and preincubation was performed at 37 ° C. and 5% CO ₂ for 30 minutes. The reaction was started by adding LPS (lipopolysaccharide), and the reaction was continued for 4 hours at 37 ° C and 5% CO.
Incubation was performed at ₂ , and the reaction was stopped in an ice bath. After stopping the reaction, the mixture was centrifuged at 3000 rpm, 4 ° C. for 15 minutes, and TNF-α in the supernatant was measured by an ELISA method. The activity of the test drug was evaluated by determining the production suppression rate with respect to the solvent control group, and determining the concentration of the test drug that suppresses TNF-α production by 50%.

In Table 1, as a test substance, 6- [3,4-dimethoxyphenyl] -6-methyl-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one (Compound 1) , 6- [3-Cyclopentyloxy-4-methoxyphenyl] -3-methyl-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one (Compound 2), 6- [3- (2-Indanyloxy) -4-methoxyphenyl] -6-methyl-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one (compound 3), 6- [3-cyclopentyl Oxy-4-methoxyphenyl] -6-methyl-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one (Compound 4), (−)-6- [3- (2- Indanyloxy)-
4-Methoxyphenyl] -6-methyl-3,4,5,6
-Tetrahydro-2H-1,3-oxazin-2-one (Compound 5), 6- [3-Cyclopentyloxy-4-
Methoxyphenyl] -3-[(4-pyridyl) methyl]
-3,4,5,6-Tetrahydro-2H-1,3-oxazin-2-one (Compound 6), 6- [3- (2-Indanyloxy) -4-methoxyphenyl] -3-methyl- 3,4,5,6-Tetrahydro-2H-1,3-oxazin-2-one (Compound 7), (+)-6- [3-
(2-Indanyloxy) -4-methoxyphenyl]-
6-methyl-3,4,5,6-tetrahydro-2H-
1,3-oxazin-2-one (Compound 8), 6- [3
-Cyclopentyloxy-4-methoxyphenyl] -6
-(3-Pyridyl) -3,4,5,6-tetrahydro-
The result when 2H-1,3-oxazin-2-one (Compound 9) is used is shown.

[0061]

[Table 1] TNF-α production inhibitory action

[0062]

The TNF-α production inhibitor of the present invention is effective for allergy, bronchial asthma, sepsis, arthritis (rheumatoid arthritis
It is useful for treating or preventing osteoarthritis, etc.), diabetes, psoriasis, Crohn's disease, ulcerative colitis and the like.

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁷ Identification code FI theme code (reference) A61P 17/06 A61P 17/06 19/02 19/02 31/04 31/04 37/08 37/08 / / C07D 265/10 C07D 265/10 413/04 413/04 413/06 413/06 (72) Inventor Shinji Ina 1-346 Kitabukurocho, Saitama City, Saitama Niken Chemical Co., Ltd. F-term (Reference) ) 4C056 AA02 AB01 AC02 AD01 AE02 DB04 4C063 AA01 BB01 BB03 CC54 DD12 EE01 4C086 AA01 AA02 BC72 GA08 GA09 MA01 MA04 NA14 ZA59 ZA66 ZA89 ZA96 ZB13 ZB35 ZC35

Claims (4)

[Claims] 1. The following general formula (I): [In the above formula, R ₁ is a C ₁ -C which may have a substituent.
₈ alkyl group; C ₃ -C ₇ which may have a substituent
A cycloalkyl group represented by R ₂ which represents a heterocyclic group optionally having a substituent and containing at least one hetero atom selected from an oxygen atom, a nitrogen atom and a sulfur atom; or an indanyl group, R ₂ Represents a C ₁ -C ₄ alkyl group, R ₃ represents a hydrogen atom; a C ₁ -C ₅ alkyl group which may have a substituent, and a C ₃ -C ₇ which may have a substituent. A cycloalkyl group; optionally substituted aryl group; optionally substituted one or more heteroatoms selected from oxygen atom, nitrogen atom and sulfur atom An aromatic heterocyclic group; or an acyl group, R ₄ is a hydrogen atom, a C ₁ -C ₆ alkyl group which may have a substituent, an aryl group which may have a substituent, or a substituent Among the oxygen atom, nitrogen atom and sulfur atom which may have a group It represents an aromatic heterocyclic group containing one or more heteroatoms selected, R ₅ and R ₆ are each independently a hydrogen atom; an optionally substituted C ₁ -C ₅ alkyl group A C ₃ -C ₇ cycloalkyl group which may have a substituent; an aryl group which may have a substituent;
Alternatively, it represents an aromatic heterocyclic group which may have a substituent and which contains one or more heteroatoms selected from oxygen atom, nitrogen atom and sulfur atom. A 6-phenyltetrahydro-1,3-oxazin-2-one derivative represented by the following, an optical isomer thereof, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, A TNF-α production inhibitor comprising 2. R ₁ is a C _{1 to} C ₆ alkyl group, C ₄ to
A C ₆ cycloalkyl group or an indanyl group, R ₂
Is a methyl group or an ethyl group, R ₃ is a hydrogen atom, C ₁
To C ₃ alkyl group, or a C _{1 to} C ₂ alkyl group having an aromatic heterocyclic group containing one or more heteroatoms selected from oxygen atom, nitrogen atom and sulfur atom as a substituent. R ₄ is a hydrogen atom, a methyl group, an ethyl group,
Or 1 selected from oxygen atom, nitrogen atom, and sulfur atom
An aromatic heterocyclic group containing at least one heteroatom,
R ₅ and R ₆ are hydrogen atoms, and the 6-phenyltetrahydro-1,3-oxazin-2-one derivative according to claim 1, its optical isomer, or a pharmaceutically acceptable thereof. A TNF-α production inhibitor comprising a salt, or a hydrate or solvate thereof. 3. 6- [3,4-dimethoxyphenyl]-
6-methyl-3,4,5,6-tetrahydro-2H-
1,3-oxazin-2-one, 6- [3-cyclopentyloxy-4-methoxyphenyl] -3-methyl-
3,4,5,6-Tetrahydro-2H-1,3-oxazin-2-one, 6- [3- (2-indanyloxy)
-4-Methoxyphenyl] -6-methyl-3,4,5,
6-Tetrahydro-2H-1,3-oxazin-2-one, 6- [3-Cyclopentyloxy-4-methoxyphenyl] -6-methyl-3,4,5,6-tetrahydro-2H-1,3- Oxazin-2-one, (-)-6-
[3- (2-Indanyloxy) -4-methoxyphenyl] -6-methyl-3,4,5,6-tetrahydro-2
H-1,3-oxazin-2-one, 6- [3-cyclopentyloxy-4-methoxyphenyl] -3-[(4
-Pyridyl) methyl] -3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one, 6- [3-
(2-Indanyloxy) -4-methoxyphenyl]-
3-Methyl-3,4,5,6-tetrahydro-2H-
1,3-oxazin-2-one, (+)-6- [3-
(2-Indanyloxy) -4-methoxyphenyl]-
6-methyl-3,4,5,6-tetrahydro-2H-
1,3-oxazin-2-one, 6- [3-cyclopentyloxy-4-methoxyphenyl] -6- (3-pyridyl) -3,4,5,6-tetrahydro-2H-1,3
-A TNF-α production inhibitor comprising oxazin-2-one or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof. 4. The TNF- according to any one of claims 1 to 3.
A therapeutic or preventive agent for allergy, bronchial asthma, sepsis, arthritis (rheumatoid arthritis / osteoarthritis, etc.), diabetes, psoriasis, Crohn's disease, ulcerative colitis, which is based on the inhibitory action of an α production inhibitor.