JP2001288106A - Therapeutic agent for inflammatory disease - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a therapeutic agent for inflammatory diseases comprising a 4-hydroxyproline (4-Hyp) derivative or its salt effective in the prophylaxis and treatment of the inflammatory diseases as an active ingredient. SOLUTION: This therapeutic agent for the inflammatory diseases comprises the 4-Hyp derivative represented by the following general formula (1) or (2) (wherein, R1 and R2 are each same or different, and hydrogen atom or a protecting group of the hydroxyl group) or its salt as an active ingredient.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

[0001] The present invention relates to a therapeutic agent for inflammatory diseases. More specifically, the present invention relates to a therapeutic agent for an inflammatory disease containing a hydroxyproline derivative or a salt thereof as an active ingredient.

[0002]

2. Description of the Related Art It has been known that human placenta and its hydrolyzate contain various physiologically active substances. For example, the Filatov's method is a tissue treatment method using human placental hydrolyzate, which is said to cause the regeneration of elastic fibers and muscle fibers of the blood vessel wall, and is used for the treatment of chronic intractable diseases such as asthma, rheumatism and hepatitis. It is used for treatment or anti-aging.

[0003]

As described above, human placenta hydrolyzate is presumed to contain a physiologically active substance, but the nature of the substance is unknown. From such a problem, the present inventors separated and purified human placental hydrolyzate in order to identify a physiologically active substance in human placenta hydrolyzate, and found that hydroxyproline having a cell growth action, a cytoprotective action, etc. He found a derivative and filed a patent application (Japanese Unexamined Patent Publication No.
No. 21295, Japanese Patent Application No. 2000-21807). The present inventors have conducted research on the above-mentioned hydroxyproline derivative, and found that the hydroxyproline derivative is effective for prevention and treatment of inflammatory diseases, and completed the present invention. The present invention has been made based on such findings, and an object of the present invention is to provide a therapeutic agent for inflammatory diseases containing a 4-hydroxyproline (4-Hyp) derivative and a salt thereof as an active ingredient.

[0004]

The gist of the present invention made to solve the above-mentioned problems is represented by the following general formula (1) or (2):

Embedded image

Wherein R ₁ and R ₂ are the same or different and each is a hydroxyproline derivative represented by the formula (I) or a salt thereof, or a salt thereof as an active ingredient; _The therapeutic agent for an inflammatory disease according to the above, wherein ₁ and R ₂ are both a hydrogen atom or both an acetyl group; the therapeutic agent for an inflammatory disease, which is a therapeutic agent for rheumatoid arthritis; Or the therapeutic agent for an inflammatory disease described above.

[0006]

BEST MODE FOR CARRYING OUT THE INVENTION In the compounds represented by the above general formulas (1) and (2), R ₁ and R ₂ are the same or different and are a hydrogen atom or a hydroxyl-protecting group. Examples of the hydroxyl-protecting group include conventional hydroxyl-protecting groups,
Examples include acyl groups such as acetyl, propionyl, pivaloyl, chloroacetyl, bromoacetyl, benzoyl, and substituted benzoyl; aralkyl groups such as benzyl and p-chlorobenzyl; aryloxycarbonyl groups; and alkyloxycarbonyl groups. Particularly, an acetyl group and a benzyl group are preferable.

The salt of the compound represented by the general formula (1) is not particularly limited as long as it is pharmacologically acceptable and non-toxic. Examples of the acid addition salt include salts with inorganic acids. (Hydrochloride, hydrobromide, phosphate, sulfate, etc.) and salts with organic acids (acetate, succinate, maleate, fumarate, malate, tartrate, etc.) Examples of the base addition salt include salts with inorganic bases (eg, sodium salt, potassium salt, calcium salt, ammonium salt, etc.) and salts with organic bases (eg, triethylamine salt,
And salts with arginine). The compounds represented by the general formulas (1) and (2) have an asymmetric carbon and a ring structure in the molecule, and optical isomers, geometric isomers, and mixtures thereof based on the asymmetric carbon and the ring structure Are all intended to be encompassed by the compounds of the present invention.

In the therapeutic agent for an inflammatory disease of the present invention, the inflammatory disease includes a specific inflammatory disease and a non-specific inflammatory disease, for example, rheumatoid arthritis; ulcerative colitis,
Inflammatory bowel diseases such as Crohn's disease; allergic diseases;

The compounds represented by the general formulas (1) and (2), which are the active ingredients of the therapeutic agent for inflammatory diseases of the present invention, are generally prepared by a chemical synthesis method. The preparation method is not particularly limited. For example, Japanese Patent Application Laid-Open No.
No. 5, Japanese Patent Application No. 2000-21807, and the like. More specifically, the target compound can be obtained by a method represented by the following formula.

[0010]

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(In the above formula, R ₁ and R ₂ are the same as above, Y is a carboxyl-protecting group, and Z is an amino-protecting group.)

In the above reaction scheme, the general formula (5)
Can be obtained by condensing a 4-hydroxyproline derivative (3) in which an amino group is protected with a conventional protecting group and a serine derivative (4) in which a carboxyl group is protected with a conventional protecting group. it can. Such condensation is
It can be carried out according to a method using a condensing agent such as dicyclohexylcarbodiimide or a conventional amidation method such as an active esterification method. Compound (3) having a protecting group
And (4) can also be prepared according to a conventional method. In addition, as a protecting group of an amino group, a t-butoxycarbonyl group, a benzyloxycarbonyl group, etc. are exemplified, and as a protecting group of a carboxyl group, for example,
Examples thereof include an alkyl group which may have a substituent such as methyl, ethyl, propyl and phenacyl, and an aralkyl group such as benzyl and substituted benzyl.

The thus-obtained compound represented by the general formula (5) is subjected to an elimination reaction of protecting groups Z and Y according to a conventional method to give a compound of the present invention represented by the general formula (1) Is obtained. Further, by cyclizing the compound represented by the general formula (1) using the above-mentioned condensing agent, the compound represented by the general formula (2)
Can be obtained.

The compounds represented by the above-mentioned general formulas (1) and (2) have an anti-inflammatory action as shown in the following Examples, and are useful for treating inflammatory diseases. The therapeutic agent for inflammatory diseases of the present invention is based on the above-described actions and effects, and contains a compound represented by the general formula (1) and / or (2) or a salt thereof as an active ingredient. In particular, it is suitably used for the prevention and treatment of rheumatoid arthritis and inflammatory bowel disease. The therapeutic agent of the present invention comprises a compound represented by the general formula (1) and / or (2) or a salt thereof, which is added to an appropriate pharmaceutically acceptable additive (eg, a carrier, an excipient, a diluent) Powders, granules, tablets including enteric coated tablets, capsules, injections, external preparations including ointments, nasal drops, eye drops, suppositories, sublingual tablets, etc. It is prepared into a pharmaceutical preparation in the form of an oral preparation containing an orally disintegrating agent, and administered orally or parenterally. The preparation can be prepared according to a conventional method for preparation. The content of the compounds represented by the general formulas (1) and / or (2) or salts thereof can be appropriately changed depending on the form of the preparation, diseases, symptoms of patients, and the like. And / or an effective amount of the compound represented by (2) or a salt thereof is blended. Effective dosages and schedules for the formulations of the present invention can be determined empirically, and such determinations will be obvious to those skilled in the art. The route of administration of the preparation can be appropriately set depending on the form of the preparation. For example, an injection can be administered intravenously, intraarterially, subcutaneously, intramuscularly, intraarticularly, and the like. In addition, the dose is appropriately adjusted according to the administration route, symptoms, patient weight or age, etc.
~ 300 mg / kg body weight, with a preferred range of 0.
5 to 200 mg / kg body weight, which is administered once or several times a day.

[0015]

The compounds represented by the general formulas (1) and (2), which are the active ingredients of the therapeutic agent of the present invention, have an anti-inflammatory effect, and the therapeutic agent of the present invention has various inflammatory diseases. It can be used for prevention and treatment of

[0016]

EXAMPLES Hereinafter, the present invention will be described in more detail with reference to examples, but the present invention is not limited to these examples.

Embodiment 1Effects on inflammatory bowel disease  Literature (Eur. J. Pharmacol.309, 261, 1996)
In accordance with the law, hydroxyproline derivative inflammatory bowel disease
The effect on was examined. Specifically, weight 180 ± 2
0 g of male Wistar rats were used in a group of 7 rats. 100mg
/ Kg of test compound is orally administered for 7 consecutive days (once a day)
did. On the second day, rats 2 hours after the administration of the test compound,
DNBS (2,4-dinitorobenzene sulfo)
nic acid) 30mg (dissolved in 30% ethanol)
Was administered by infusion to induce colitis. Test compound
Twenty-four hours after the last dose, the rats are killed and the colon is weighed.
And the ratio of colon weight to body weight was used as an evaluation index. as a result
Is shown in FIG. The number of colon ulcers, large intestine and other organs
Observe adhesions to organs, and record diarrheal status every day during the test.
Recorded. Table 1 shows the results.

The following compounds were used as test compounds.
did. Test compound abbreviation JBP-2: 3'-hydroxymethyl-4-hydroxypyrrolide
[1,2-f] 2 ', 5'-piperazinedione (general formula
In the compound represented by (2), R₁And R ₂Is hydrogen
Atom compound) JBP-3: 4-hydroxyprolylserine (represented by the general formula (1))
In the compound₁And R₂Is a compound of a hydrogen atom
Product) JBP-6: 4-acetoxyprolyl- (3-acetyl) serine (one
In the compound represented by the general formula (1), R₁And R₂But
Acetyl group compound) Positive control: Sulfasalazine The test compounds JBP-2, 3, and 6 were obtained from the above-mentioned JP
11-21295 and Japanese Patent Application No. 2000-21807.
It can be prepared by a method or the like.

[0019]

[Table 1]

As shown in FIG. 1 and Table 1, JBP-2, 3, and 6, which are the active ingredients of the therapeutic agent for inflammatory diseases of the present invention, are effective for the treatment of inflammatory bowel disease and have few side effects. Became clear.

Embodiment 2Effects on collagen arthritis  Literature (Autoimmunitytwenty two, 137, 1995).
Of hydroxyproline derivatives against collagen arthritis
Effects were examined. Specifically, BALB / cBy at 6-8 weeks of age
J mice were used in 3 mice per group. 4mg / mouse for mouse
Anti-type II collagen monoclonal antibody (mA
b) was injected intravenously. On the fourth day after injection, 25 μg
/ Inject lipopolysaccharide intravenously at the dose of mice
From the same day, 25 mg / kg of JBP-2 was administered for 3 days (1
(Once a day) continuous oral administration. On the other hand, as a positive control, 3
mg / kg indomethacin was administered. mAb treatment
Thereafter, on days 5, 7, and 10, the hind limb of the mouse was placed on Plethysm
The swelling volume (Swollen volume) was determined by measuring with an ometer.
The result is shown in FIG. As shown in FIG.
-2 suppresses the formation of swelling and is associated with collagen arthritis.
It was found to be effective for treatment.

Formulation Example 1 JBP-2 was added to an enteric capsule in an amount of 250 m according to a conventional method.
g to prepare an enteric coated capsule formulation.

[Brief description of the drawings]

FIG. 1 shows the active ingredient of the therapeutic agent of the present invention, JBP-2,
It is a figure which shows the effect with respect to inflammatory bowel disease of 3 and 6.
Numerical values in the figure are mean ± standard error (*: p <0.0
5, **: p <0.01)

FIG. 2 is a graph showing the effect of JBP-2, which is an active ingredient of the therapeutic agent of the present invention, on collagen arthritis. Numerical values in the figure are mean ± standard error (*: p <0.05, *
*: P <0.01)

──────────────────────────────────────────────────の Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) // C07D 487/04 140 A61K 37/02 (72) Inventor Kiji Kakuda 5-30 Sengoku Higashicho, Kadoma City, Osaka Prefecture -2 F term (reference) 4C050 AA01 BB04 CC08 EE02 FF02 GG03 HH01 4C084 AA02 BA08 BA14 BA23 BA24 CA59 NA14 ZA661 ZA962 ZB111 ZB151 4C086 AA01 AA02 CB05 MA01 MA04 NA14 ZA68 ZA96 ZB11 ZB15

Claims (4)

[Claims] 1. A compound represented by the general formula (1) or (2): (In the formula, R ₁ and R ₂ are the same or different and each is a hydrogen atom or a protecting group for a hydroxyl group) A therapeutic agent for an inflammatory disease comprising a hydroxyproline derivative represented by the formula or a salt thereof as an active ingredient. 2. The therapeutic agent for an inflammatory disease according to claim 1, wherein both R ₁ and R ₂ are hydrogen atoms or both acetyl groups. 3. The method according to claim 1, which is a therapeutic agent for rheumatoid arthritis.
Or the therapeutic agent for inflammatory disease according to 2. 4. The therapeutic agent for an inflammatory disease according to claim 1, which is a therapeutic agent for an inflammatory bowel disease.