JP2002293745A - Rheumatoid arthritis treatment - Google Patents

Abstract

(57) [Summary] PROBLEM TO BE SOLVED: To provide a chronic joint resection having an effect of inhibiting synovial cell proliferation.
A therapeutic agent for rheumatism and a synovial cell growth inhibitor are provided. SOLUTION: The compound represented by the following general formula (I) is provided.
An agent for treating rheumatoid arthritis, which is contained as an active ingredient. Embedded image Where R¹, R², R³And R⁴Is the same
May be different, each of which is hydrogen, halogen,
Loxyl group, nitro group, (substituted) alkyl group or
R) represents an alkoxyl group,¹And R², R²And R
³And R³And R ⁴Are connected to each other,
It may form a dioxy group. R⁵Is hydrogen or
(Substituted) represents an alkyl group. R⁶Is hydrogen or (substituted)
Represents an alkyl group.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a therapeutic agent for rheumatoid arthritis and a synovial cell proliferation inhibitor having an inhibitory effect on synovial cell proliferation.

[0002]

BACKGROUND OF THE INVENTION Rheumatoid arthritis is a chronic inflammatory disease of which the main symptom is polyarthritis, the cause of which has not yet been identified. Rheumatoid arthritis is accompanied by inflammatory infiltration of the synovium, proliferation of synovial cells, stratification and angiogenesis, and the disease state progresses. In particular, abnormal proliferation and activation of synovial cells
It is considered one of the main lesions of rheumatism (Harri
set al. , 1990, N.M. Eng. J. Med.
322, 1277-1289), examination of the joints of rheumatic patients reveals that the synovial villi are multiplied and that the synovial tissue cells are multi-layered, and that synovial cells are abnormally proliferating. However, the cause of such over-function of synovial cells, which plays an important role in the pathogenesis of rheumatoid arthritis, has not yet been fully elucidated. It is clear that it is extremely important in the treatment of rheumatism.

[0003] In recent years, the activation of synovial cells has been studied by various approaches, but the activation mechanism is still largely unknown. Cell fate is regulated as a process leading to proliferation, differentiation and cell death. However, why the differentiated synovial cells forming the joints are proliferated and activated again remains a question. In many cases, interactions and cytokine stimulation by autoreactive T cells alone cannot sufficiently explain. Rather, it is considered that synovial cells may have abnormal homeostasis.

[0004]

SUMMARY OF THE INVENTION The present invention has been made in view of the above circumstances and aims to provide a therapeutic agent for rheumatoid arthritis and a synovial cell proliferation inhibitor having an effect of inhibiting synovial cell proliferation. It is.

[0005]

Means for Solving the Problems The present inventors have paid attention to quinolone derivatives and have intensively studied their new pharmacological action. It has been found that it has an effect, and further, an effect of treating rheumatism.

[0006]

BEST MODE FOR CARRYING OUT THE INVENTION The present invention relates to a therapeutic agent for rheumatoid arthritis and a synovial cell growth inhibitor comprising a compound represented by the following general formula (I) (hereinafter also referred to as compound (I)) as an active ingredient. Things.

[0007]

Embedded image

Wherein R ¹ , R ² , R ³ and R ⁴ may be the same or different and are each hydrogen, halogen, hydroxyl, nitro, (substituted) alkyl or (substituted) ) Represents an alkoxyl group, R ¹ and R ² , R
^2, and ^{R 3} and ^{R 3} and ^{R 4} are respectively connected,
An alkylenedioxy group may be formed. R ⁵ is
Represents hydrogen or a (substituted) alkyl group. R ⁶ represents hydrogen or a (substituted) alkyl group. The groups defined above will be described in more detail. Halogen refers to fluorine, chlorine, bromine and iodine. The alkyl group is a straight-chain or branched alkyl group having 1 to 6 carbon atoms such as a methyl group, an ethyl group, a propyl group, a butyl group, a hexyl group, an isopropyl group, an isobutyl group, and a tert-butyl group. Show. The alkoxyl group is a linear or branched alkoxyl group having 1 to 6 carbon atoms such as a methoxyl group, an ethoxyl group, a propoxyl group, a butoxyl group, a hexyloxyl group, an isopropoxyl group and a tert-butoxyl group. Is shown. An alkylenedioxy group refers to a group having 1 to 6 carbon atoms between two oxygen atoms such as a methylenedioxy group, an ethylenedioxy group, a (dimethyl) methylenedioxy group, and a (diethyl) methylenedioxy group. It represents an alkylenedioxy group having a linear or branched alkylene.

(Substituted) alkyl groups include halogen, hydroxyl group, alkoxyl group, alkylenedioxy group,
It represents an alkyl group which may be substituted with a nitro group, an amino group or a phenyl group, and the phenyl group may be substituted with a halogen, a hydroxyl group, an alkoxyl group or an alkylenedioxy group. The (substituted) alkoxyl group is an alkoxyl group which may be substituted with a halogen, a hydroxyl group, an alkoxyl group, an alkylenedioxy group, a nitro group, an amino group or a phenyl group, wherein the phenyl group is a halogen, hydroxyl group , An alkoxyl group or an alkylenedioxy group.

A preferred compound in the present invention is
In the general formula (I), R¹, R², R ³And R⁴From
At least one substituent selected from the group
Is a compound. Specific examples of preferred compounds of the present invention
Are represented by the following structural formulas, Compounds A to H, etc.
And particularly preferred compounds.
3- (5,8-difluoro-4-quinolone) carbo
Acid ethyl ester (Compound E) and 3- (5,7-di
Chloro-4-quinolone) carboxylic acid ethyl ester
Compound G) can be mentioned.

[0011]

Embedded image

Compounds A to H represented by the structural formulas
Is available as a commercial product, and a commercial product was provided for the synovial cell proliferation inhibition test derived from a rheumatoid arthritis patient shown in the Examples section.

As a method for producing the above compound (I), known methods can be used. Med. Cem. ,
11 , 160-163 (1968); Med. Ce
m. , 22 , 816-823 (1979); Me
d. Cem. , 28 , 298-302 (1985); M
agn. Reson. Chem. , 34 , 972-97
8 (1996).

Until now, several compounds having a therapeutic effect on rheumatism and arthritis have been found. Among them, quinolone carboxylic acid derivatives are disclosed in JP-A-6-3 / 1994.
JP-A-16521, JP-A-8-73453, JP-A-10-130240, JP-A-10-31657
No. 00, Japanese Patent Publication No. 11-513021, WO9
8/23608, JP-A-2-134321 and JP-A-62-207269 are known.

On the other hand, the above-mentioned various compounds exemplified as the compound (I) are all conventionally known compounds, and are used, for example, as synthetic intermediates of other quinolone derivatives. However, it has never been known that these compounds (I) have an inhibitory effect on synovial cell proliferation and further have a therapeutic effect on rheumatism, and these were first discovered by the present inventors. It is knowledge.

Examination of the structures of quinolone carboxylic acid derivatives which are conventionally known to have a therapeutic effect on rheumatism and arthritis revealed that these compounds have the following common features. . (1) When the carboxylic acid moiety is a carboxylic acid or a carboxylic acid ester, a nitrogen-containing hetero ring such as a piperazine ring or a diazepan ring is always introduced as a substituent at the 7-position. (2) When the range of substituents introduced at the 1-position and the 5- to 8-positions is wide, the carboxylic acid moiety is always an amide.

Accordingly, quinolone carboxylic acid derivatives which are conventionally known to have a therapeutic effect on rheumatism and arthritis have a structure distinctly different from the above-mentioned compound (I). Obviously, it is extremely difficult to come to compound (I) from the derivative. In addition, none of the quinolone carboxylic acid derivatives conventionally known to have a therapeutic effect on rheumatism and arthritis has been reported to have an inhibitory effect on synovial cell proliferation.

The therapeutic agent for rheumatoid arthritis and the synovial cell proliferation inhibitor of the present invention may contain a pharmacologically acceptable carrier. Further, a means for transporting the active ingredient represented by the above general formula (I) to a desired tissue, and a means for facilitating transfer into a target cell, for example,
It may include the use of liposomes with pharmacologically acceptable cationic lipids and the like.

The method for administering the therapeutic agent for rheumatoid arthritis and the synovial cell proliferation inhibitor of the present invention is not particularly limited, and may be oral or parenteral. Examples of the dosage form of the therapeutic agent for rheumatoid arthritis and the synovial cell proliferation inhibitor of the present invention include tablets, capsules, granules, powders, injections, and the like. Can be For example, if the therapeutic agent for rheumatoid arthritis and the synovial cell growth inhibitor of the present invention are oral preparations such as tablets, capsules, granules and powders, lactose, crystalline cellulose, bulking agents such as starch, magnesium stearate, etc. Lubricant such as talc, binder such as hydroxypropylcellulose polyvinylpyrrolidone, disintegrant such as calcium carboxymethylcellulose, low-substituted hydroxypropylmethylcellulose, coating agent such as hydroxypropylmethylcellulose, macrogol, silicone resin, etc. as required And add it.

The dose of the compound (I) can be appropriately selected depending on the condition, age, dosage form and the like. In the case of an oral preparation, it is generally 0.01 to 6000 mg per day, preferably 1 to 6000 mg per day.
600 mg may be administered once or in several divided doses.

[0021]

The present invention will be described in more detail with reference to the following Examples and Preparation Examples, which are only for the purpose of understanding the present invention, and the present invention is not limited thereto. Absent.

(Example) Synovial cell proliferation inhibition test derived from rheumatoid arthritis patients As synovial cells, blood cell cells were obtained from synovial tissue obtained with the consent of knee joint surgery in rheumatoid arthritis patients. After the exclusion, the synovial cells were collected on a plastic plate, and collected in RPMI1640 (manufactured by Japan Immunological Research Institute) (containing 10% FCS containing penicillin and streptomycin).
What had been cultured for 5 passages was used.

Synovial cells were placed in a 96-well plate at 1 × 10 ⁴ /
well sowed and 10% FCS-containing RPM
The cells were cultured overnight in an I1640 medium. The medium was replaced with fresh 0.5% FCS-containing RPMI 1640 medium,
The cells were cultured for 4 hours. After that, the medium is replaced with fresh 0.5%
RPMI1640 medium containing FCS 150 μl / well
Changed to The test compound was dissolved in DMSO, and 20 μl of this was added to the medium.

On the other hand, the negative control group and the control group contained 1% DMSO-0.5% FCS-RPM.
I1640 medium was added. In addition, 5 ng / ml of TNF-α was added to a group other than the negative control group for 20 μL.
0.5% FC for the negative control group.
S-RPMI 1640 medium was added. In ^{length, [3} H]
Deoxyuridine (1 μCi / well) was added and 4
The cells were cultured for 8 hours. After the culture, the cells were collected, and the incorporation of [ ³ H] deoxyuridine was measured by TOP COUNT (Pack).
ard, CA, USA).

As test compounds, eight commercially available compounds A to H were used, each having a concentration in the culture broth of 0.
Tests at 01, 0.1, 1 and 10 μM were performed. Table 1
The IC _{50 of} each compound calculated from the results at each concentration
Indicates a value.

[0026]

[Table 1]

As shown in Table 1, it was revealed that compound (I) can significantly suppress TNF-α-induced synovial cell proliferation at a low concentration.

Formulation Examples The following are examples of oral preparations and injections containing compound (I).
The following is a general formulation example. 1)tablet  Prescription 1 Compound (I) in 100 mg 1 mg Lactose 66.4 mg Corn starch 20 mg Carboxymethylcellulose Calcium 6 mg Hydroxypropylcellulose 4 mg Magnesium stearate 0.6 mg Coating agent (for example, hydroxy
Cypropyl methylcellulose, macrogol, silicon
Coating using 2mg of ordinary coating agent such as resin)
To obtain the target tablet (the tablets of the following formulation are also
J).

Formulation 2 Compound (I) 5 mg Lactose 62.4 mg Corn starch 20 mg Carboxymethylcellulose Calcium 6 mg Hydroxypropylcellulose 4 mg Magnesium stearate 0.6 mg Coating agent 2 mg in 100 mg

Formulation 3 Compound (I) 20 mg Lactose 51 mg Maize starch 15 mg Carboxymethyl cellulose calcium 5 mg Hydroxypropyl cellulose 5 mg Magnesium stearate 1 mg Talc 1 mg Coating agent 2 mg in 100 mg

Formulation 4 Compound (I) 40 mg Lactose 34 mg Maize starch 10 mg Carboxymethyl cellulose calcium 5 mg Hydroxypropyl cellulose 5 mg Magnesium stearate 2 mg Talc 2 mg Coating agent 2 mg in 100 mg

Formulation 5 Compound (I) 100 mg Lactose 67 mg Maize starch 20 mg Carboxymethyl cellulose calcium 10 mg Hydroxypropyl cellulose 10 mg Magnesium stearate 4 mg Talc 4 mg Coating agent 5 mg in 220 mg

2)Capsule  Prescription 1 Compound (I) 5 mg Lactose 145 mg in 150 mg By changing the mixing ratio of compound (I) and lactose,
The ingredient amount of the product (I) is 10 mg / capsule, 30 mg / capsule
Puser, 50mg / capsule, 100mg / capsule
Capsules were also prepared.

3)Granules  Prescription 1 Compound (I) 30 mg Mannitol 46.5 mg Polyvinylpyrrolidone K-30 7 mg Eudragit RL 15 mg Triacetin 1.5 mg in 100 mg

Formulation 2 Compound (I) 50 mg Lactose 55 mg Potato starch 20 mg Hydroxypropyl cellulose 4 mg Talc in 130 mg

4)Injection  Prescription 1 10 ml Compound (I) 10-100 mg sodium chloride 90 mg sodium hydroxide qs sterile purified water qs

[0037]

EFFECTS OF THE INVENTION Since the present invention has the above-mentioned constitution, it can effectively suppress the proliferation of synovial cells, and has a therapeutic effect on rheumatoid arthritis and synovial cell proliferation inhibition. An agent can be provided.

 ──────────────────────────────────────────────────続 き Continued on the front page (72) Inventor Ryoji Fujii 1-111-35, Yoshiyuki Fujisawa-shi, Kanagawa (72) Inventor Kusuki Nishioka 4-1-5-802 Hiroo, Shibuya-ku, Tokyo (72) Inventor Hiroyuki Aono 3-9-19 Shimoshinjo, Higashiyodogawa-ku, Osaka-shi, Osaka Santan Pharmaceutical Co., Ltd. (72) Inventor Miwa Takai 3-9-19 Shimoshinjo, Higashiyodogawa-ku, Osaka-shi, Osaka F-term (reference) 4C031 EA18 4C086 AA01 BC28 MA04 NA14 ZA96 ZB15

Claims (4)

[Claims] 1. A compound having the following general formula (I):
Rheumatoid arthritis characterized by containing as an active ingredient
H therapeutic agent. Embedded imageWhere R¹, R², R³And R⁴Is the same
May be different, each of which is hydrogen, halogen,
Loxyl group, nitro group, (substituted) alkyl group or
R) represents an alkoxyl group,¹And R², R²And R
³And R³And R ⁴Are connected to each other,
It may form a dioxy group. R⁵Is hydrogen or
(Substituted) represents an alkyl group. R⁶Is hydrogen or (substituted)
Represents an alkyl group. 2. The therapeutic agent for rheumatoid arthritis according to claim 1, wherein at least one substituent selected from the group consisting of R ¹ , R ² , R ³ and R ⁴ is halogen. 3. A compound having the following general formula (I):
Synovial cell growth inhibition characterized by containing as an active ingredient
Agents. Embedded imageWhere R¹, R², R³And R⁴Is the same
May be different, each of which is hydrogen, halogen,
Loxyl group, nitro group, (substituted) alkyl group or
R) represents an alkoxyl group,¹And R², R²And R
³And R³And R ⁴Are connected to each other,
It may form a dioxy group. R⁵Is hydrogen or
(Substituted) represents an alkyl group. R⁶Is hydrogen or (substituted)
Represents an alkyl group. 4. The synovial cell proliferation inhibitor according to claim 3, wherein at least one substituent selected from the group consisting of R ¹ , R ² , R ³ and R ⁴ is halogen.