JP2003119180A - Naphthalene compound - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a new naphthalene compound having excellent inhibitory actions on phosphodiesterase 4 (PDE4) and useful as a prophylactic or a therapeutic agent for asthma, etc. SOLUTION: This naphthalene compound is represented by the general formula [I] (wherein, R<1> and R<2> are each the same or different and denote each hydroxy group or a lower alkoxy group; R<3> and R<4> are each the same or different and denote each hydrogen atom or an acyl group; and n denotes an integer of 1-6) or its pharmaceutically acceptable salt.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel naphthalene compound having an excellent PDE4 inhibitory action.

[0002]

2. Description of the Related Art c is an intracellular second messenger
AMP and cGMP are phosphodiesterases (PDE)
Is decomposed and inactivated by. Inhibiting PDE increases the intracellular cAMP and cGMP concentrations. PDEs are classified into several isozymes, and substrates (cAMP, c
GMP) specificity, biodistribution, etc. differ from isozyme to isozyme, and 4 types of PDE isozymes (PDE) (PDE
4) is known to specifically decompose cAMP.

Inhibition of PDE4 activity can also inhibit the release of inflammatory mediators [Journal of Molecular and Cellular Cardiology (J. Mol. Cell. Card.
iol. ) 12 (Suppl.II), S61 (198
9)], a PDE4 inhibitor is a cytokine T that is released by mononuclear phagocytes in response to immune stimulation.
It is known that it suppresses the production of NF-α and is useful for the treatment of various inflammatory diseases in which TNF-α is involved [Table 2000-503678, Table 2000-50272].
No. 4, Special Table 2000-510105, Special Table 2000-
No. 514804, Tokuyo 2000-502350, Tokuyo 2000-501741].

Theophylline, which is a typical PDE inhibitor, has been conventionally used for the treatment of asthma.
Since the E inhibitory action is non-specific, it has a cardiotonic action and a central action in addition to the bronchial smooth muscle relaxing action, and therefore side effects must always be noted. Therefore, among various PDE isozymes, there is a demand for the development of a new drug having a specific inhibitory action against PDE4, which is present in many bronchial smooth muscles and inflammatory cells. It is considered that such drugs can be excellent prophylactic / therapeutic agents for asthma (or prophylactic / therapeutic agents for inflammatory diseases, etc.).

On the other hand, regarding a naphthalene compound having a structure similar to that of the object compound of the present invention, JP-A-9-59255 describes a compound having a structure in which a nitrogen atom is further bonded to the pyridine ring on the 1-position of the naphthalene skeleton. . However, the naphthalene skeleton 1 such as the target compound of the present invention
A compound having a structure in which a carbon atom is directly bonded to the pyridine ring at position
Not disclosed.

[0006]

The present invention provides novel naphthalene compounds useful as PDE4 inhibitors.

[0007]

The present invention has the general formula [I]:

[0008]

[Chemical 2]

(Wherein R ¹ and R ² are the same or different and are a hydroxyl group or a lower alkoxy group, R ³ and R ⁴ are the same or different and are a hydrogen atom or an acyl group, and n is 1 to 1).
Represents an integer of 6. ), A naphthalene compound or a pharmacologically acceptable salt thereof.

[0010]

BEST MODE FOR CARRYING OUT THE INVENTION In the object compound [I] of the present invention, examples of the acyl group in R ³ and R ⁴ include a lower alkanoyl group, of which the acetyl group is preferable. n is an integer of 1 to 6, but is preferably 2 to 4, and especially 3. As the lower alkoxy group for R ¹ and R ² , a methoxy group or an ethoxy group is particularly preferable.

Of the object compounds [I] of the present invention, preferred
As a compound, R¹And R^TwoAre the same or different
Lower alkoxy group, R^ThreeAnd R^FourIs an acetyl group
Is a hydrogen atom or a compound in which n is 3. further
Preferred compounds include R ¹And R^TwoAre the same or
Differently lower alkoxy group, R^ThreeAnd R^FourIs hydrogen
And a compound in which n is 3. Of this, the wrinkle
As a preferable compound, 6,7-dimethoxy-1-
[2- (1,3-dioxocyclohexan-2-yl)
Pyridin-4-yl] -2,3-bis (hydroxymethyl)
Le) naphthalene.

The object compound [I] of the present invention or a pharmacologically acceptable salt thereof has an excellent inhibitory effect on PDE4, and is useful for preventing various diseases associated with PDE4.
Useful for treatment. Examples of such diseases include various inflammatory diseases and allergic diseases, and more specifically, for example, asthma, chronic obstructive pulmonary disease (COPD), chronic bronchitis, atopic dermatitis, urticaria, allergic diseases. Rhinitis,
Allergic conjunctivitis, spring catarrh, eosinophilia, psoriasis, rheumatoid arthritis, septic shock, ulcerative colitis, Crohn's disease, reperfusion injury, chronic glomerulonephritis, endotoxin shock, adult respiratory distress syndrome, bone Examples include arthritis.

The object compound [I] of the present invention or a pharmacologically acceptable salt thereof is useful as a bronchoconstrictor suppressor because it has an excellent bronchoconstrictor suppressive action.

The present applicant has found that a compound having a PDE4 inhibitory action is also useful for promoting fracture healing and repairing and treating cartilage disease (eg osteoarthritis), and separately filed a patent application (patent application). 2001-154064 and Japanese Patent Application No. 2001-154048). Based on this finding, the object compound [I] of the present invention or a pharmacologically acceptable salt thereof is effective in promoting fracture healing and cartilage disease (eg osteoarthritis).
It is also useful for repair treatment of.

Further, since the object compound of the present invention selectively inhibits PDE4, it has few side effects. further,
The object compound [I] of the present invention has low toxicity and is also highly safe as a medicine.

The object compound [I] of the present invention can be used for medicinal use either in a free form or in the form of a pharmaceutically acceptable salt thereof. Examples of the pharmaceutically acceptable salt include inorganic acid salts such as hydrochlorides, sulfates, phosphates or hydrobromides, organic acids such as methanesulfonate, benzenesulfonate or tosylate. Salt etc. are mentioned.

The object compound [I] or a salt thereof of the present invention includes any of its inner salt, adduct, solvate or hydrate thereof.

The object compound [I] of the present invention or a pharmacologically acceptable salt thereof can be administered orally or parenterally, and also tablets, granules, capsules, powders and injections. , Can be used as a conventional pharmaceutical preparation such as an inhalant.

The dose of the object compound [I] of the present invention or a pharmacologically acceptable salt thereof is determined by the method of administration, the age of the patient,
Although it depends on the body weight and condition, an injection is usually about 0.01 to 10 mg / kg, especially about 0.03 to 3 mg / kg per day, and an oral preparation is usually
About 0.1 to 30 mg / kg per day, especially about 0.3
It is preferably about 10 mg / kg.

<Method for Producing Naphthalene Compound> According to the present invention, the naphthalene compound [I] which is the object compound of the present invention.
Can be manufactured by the following methods, but is not limited thereto.

[0021]

[Chemical 3]

(In the formula, R ³¹ and R ⁴² are the same or different and each represents an acyl group, and other symbols have the same meanings as described above.) Of the object compounds of the present invention, R ³ and R ⁴ in the formula [I] are represented.
Is an acyl group (ie, compound [Ia])
Can be produced by reacting the starting compound [II] with the starting compound [III]. This reaction is
Dehydrating agent (eg acetic anhydride, trifluoroacetic anhydride, etc.)
In the presence of, it can be carried out under heating to heating.

Further, among the target compounds of the present application, the compound of the formula [I] in which R ³ and R ⁴ are hydrogen atoms (that is, the compound [Ib]) is obtained by subjecting the compound [Ia] to a usual deacylation reaction. It can be manufactured by attaching to. For example, the deacylation reaction can be carried out in the presence of a suitable nucleophile (eg, sodium methoxide, sodium ethoxide, sodium hydroxide, lithium hydroxide, etc.). The amount of the nucleophile to be used can be 1 equivalent to 4 equivalents, preferably 1.2 equivalents to 2 equivalents, relative to compound [Ia]. This reaction can be carried out under ice cooling to room temperature, and particularly preferably proceeds at 5 ° C to 20 ° C.

The desired compound [I] of the present invention obtained by the above-mentioned production method can be converted into a pharmacologically acceptable salt, if desired. Conversion to a pharmacologically acceptable salt may be performed according to a method known to those skilled in the art.

The starting compound [I
[I] can be produced according to the method described in JP-A-5-229987.

In the present specification, the "acyl group" includes a lower alkanoyl group, and the lower alkanoyl group includes a straight or branched one having 1 to 6 carbon atoms, especially 2 to 4 carbon atoms. . Examples of the "lower alkoxy group" include linear or branched ones having 1 to 6 carbon atoms, especially 1 to 4 carbon atoms.

[0027]

[Examples] Specific examples (Examples) of the target compound [I] of the present invention synthesized by the above-mentioned methods are shown below, but the present invention is not limited thereto.

Example 1 6,7-Dimethoxy-1- (1-oxypyridine-4-
(2.23 g) of (yl) -2,3-bis (acetoxymethyl) naphthalene was suspended in 5 ml of acetic anhydride, and 1,3 under ice cooling.
-0.71 g of cyclohexanedione is added, and the mixture is stirred at room temperature overnight, and then reacted at 90 ° C for 6 hours. The brown reaction solution is returned to room temperature and concentrated under reduced pressure. Aqueous sodium hydrogen carbonate solution is added to the residue, and the mixture is extracted with ethyl acetate. The organic layer is washed with brine, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (developing solvent; chloroform: acetone = 10: 1) to give crude product 1.
Get 0 g. Further, it was purified with chromatolone (developing solvent; chloroform: acetone = 10: 1) and crystallized with diethyl ether to give 6,7-dimethoxy-1.
580 mg of-[2- (1,3-dioxocyclohexan-2-yl) pyridin-4-yl] -2,3-bis (acetoxymethyl) naphthalene are obtained. Melting point: 210-
213 ° C.

Example 2 440 mg of the compound obtained in Example 1 was added to 3 m of methanol.
It is suspended in 1 and 0.495 ml of sodium methoxide (28% methanol solution) is added under ice cooling. After stirring at room temperature for 30 minutes (a crystal once deposited after becoming a solution),
The reaction mixture is ice-cooled and 1M hydrochloric acid is added to adjust the pH to 4. The precipitated crystals were collected by filtration and washed with water to give 6,7-dimethoxy-1- [2- (1,3-dioxocyclohexan-2-yl) pyridin-4-yl] -2,3-bis (. 320 mg of hydroxymethyl) naphthalene are obtained. Melting point:> 220 ° C.

   ─────────────────────────────────────────────────── ─── Continued front page    F-term (reference) 4C055 AA01 BA02 BA07 BA42 CA01                       DA06 DA08 DA16 DA42 DB01                       DB02                 4C086 AA03 BC17 MA01 MA04 ZC20

Claims (4)

[Claims] 1. A compound represented by the general formula [I]: (In the formula, R ¹ and R ² are the same or different and are a hydroxyl group or a lower alkoxy group, R ³ and R ⁴ are the same or different and are a hydrogen atom or an acyl group, and n is an integer of 1 to 6). A naphthalene compound or a pharmacologically acceptable salt thereof. 2. R¹And R^TwoAre the same or different and low
Primary alkoxy group, R ^ThreeAnd R^FourIs a hydrogen atom or ace
The compound according to claim 1, wherein the tyl group and n are 3. 3. The compound according to claim 2, wherein R ³ and R ⁴ are hydrogen atoms. 4. 6,7-Dimethoxy-1- [2- (1,
3-dioxocyclohexane-2-yl) pyridine-4
-Yl] -2,3-bis (hydroxymethyl) naphthalene or a pharmaceutically acceptable salt thereof.