JPH11292878A - Imidazonaphthylidine derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a new compound capable of effectively and selectively inhibiting IV-type phosphodiesterase, with slight side effects, and useful in the prevention/treatment of respiratory diseases such as bronchial asthma, chronic bronchitis and pneumonic disorders. SOLUTION: This new compound is shown by formula I [R<1> to R<3> are each H or the like; R<4> and R<5> are each H or the like; A is a (substituted) cycloalkyl or the like; X is N or the like; dotted line denotes a single bond or the like], e.g. 5-(3-bromophenyl)-2-methyl-8,9-dihydroimidazo[1,2-a]pyrido[3,2-e]pyrim idine. The compound of formula I is obtained, for example, by reaction between a compound of formula II [e.g. 3-(3-bromobenzoyl)-2-(imidazolidine-2-thion-1-yl)-6- methylpyridine] and an alkylating agent such as methyl iodide in an organic solvent such as acetone in the presence of a base such as anhydrous potassium carbonate under cooling to heating followed by further reaction with an aminating agent such as ammonium acetate in a solvent under cooling to heating.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a medicament, particularly a novel imidazonaphthyridine derivative or a salt thereof, and a type IV phosphodiesterase inhibitor containing them as an active ingredient.

[0002]

2. Description of the Related Art Asthma is a respiratory disease in which wheezing and seizures due to contraction of the airway are repeated. The number of patients has been steadily increasing, and is expected to increase in the future. Currently, xanthine derivatives such as aminophylline and theophylline and β-stimulants such as procaterol are mainly used as bronchodilators for the treatment of asthma.

The mechanism of action of these compounds is to activate adenylate cyclase, an enzyme that produces intracellular adenosine 3 ', 5'-cyclic monophosphate (cAMP), in airway smooth muscle, or to degrade cAMP. Inhibiting certain phosphodiesterases (PDEs) increases intracellular cAMP levels and relieves airway smooth muscle contraction. (Internal Medicine 69, 207-214 (1992)). Intracellular c
Elevated AMP levels are known to cause suppression of contraction in airway smooth muscle (Clin. Exp. Allergy, 22,
337-344 (1992), Drugs of the Future, 17, 799-807
(1992)), which is effective in improving asthma symptoms.

[0004] However, xanthine derivatives exhibit systemic side effects such as lowering blood pressure and inotropic effect (J. Cyc.
lic Nucleotide and Protein Phosphorylation Res., 1
0, 551-564 (1985), J. Pharmacol. Exp. Ther., 257,
741-747 (1991)), and β-stimulants are liable to cause desensitization, and it is known that an increased amount of use causes side effects such as finger tremor and palpitations. On the other hand, PDE is at least I
~ V type, and it has been elucidated that there are differences in distribution or function (Pharmaco
l. Ther., 51, 13-33 (1991)). In particular, type IV PDEs
Among nucleotides, it specifically degrades cAMP without acting on guanosine 3 ', 5'-cyclic monophosphate (cGMP), and its presence is recognized in both airway smooth muscle and infiltrating cells. I have.

A type IV PDE inhibitor has an inhibitory effect on eosinophil infiltration by antigen and platelet activating factor in guinea pigs (Eur. J. Pharmacol., 255, 253-2).
56 (1994)), impaired proteins from eosinophils (MBP, EC
P) release (Br. J. Pharmacol., 115, 39-4)
7 (1995)). In addition, it has an inhibitory effect on the contraction of airway smooth muscle by contractile substances (histamine, methacholine, LTD ₄ ) (Br. J. Pharmacol., 1).
13, 1423-1431 (1994)), inhibiting the production of IL-4, a cytokine that is said to be deeply involved in asthma (J. Invest. Dermatol., 100, 681-684 (1993)).
To exert an inhibitory effect on the enhancement of vascular permeability in the respiratory tract (Fundam. Clin. Pharmacol., 6, 247-249 (19
92)), showing an inhibitory effect on airway hyperresponsiveness (Eur.
J. Pharmacol., 275, 75-82 (1995)). Therefore, it is expected that a type IV PDE inhibitor can be a therapeutic agent for asthma with few side effects.

[0006] As naphthyridine derivatives having type IV PDE inhibitory activity, 1H, 5H- or 3H, 5H- represented by the following general formula:
Imidazo [4,5-c] [1,8] naphthyridin-4-one derivatives are described in J.
Med. Chem., 35, 4866-4878 (1992) and EP 459505.

[0007]

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(Where XYZ is -N (R ² ) -C (R ³ )
= N- or ^{-N = C (R 3) -N} (R 2) - a, R ¹ is illustrates lower alkyl or optionally substituted with aryl, respectively. (Refer to the gazette below.))

[0009]

SUMMARY OF THE INVENTION The present inventors have proposed an IV type P
Research aimed at providing novel compounds useful for the prevention and treatment of respiratory diseases such as bronchial asthma with good and selective inhibition of DE and few side effects, and also to provide pharmaceuticals containing these compounds. went.

[0010]

Means for Solving the Problems The present inventors have proposed an IV type PD.
As a result of intensive studies on compounds having an inhibitory activity on E, imidazonaphthyridine derivatives having a structure completely different from those of conventional type IV PDE inhibitors show good and selective IV type P
The present inventors have found that they have a DE inhibitory action, and have completed the present invention. That is, the present invention relates to a novel imidazonaphthyridine derivative represented by the following general formula (I) or a pharmaceutically acceptable salt thereof, and a medicament containing these as an active ingredient.

[0011]

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(The symbols in the formulas have the following meanings: R ¹ , R ² and R ^{3 are the} same or different and are —H, —halogen, —lower alkyl, —O-lower alkyl, —S-lower alkyl. , -CO- lower alkyl, -NO _2, -CN,
_{-OH, -SH, -CO 2 H,} -NR 6 R 7, -CO 2 - lower ^{alkyl, -CONR 6 R 7, -NR 6} CO- lower alkyl, - cycloalkyl or - aryl, A: substituted Optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl or optionally substituted heteroaryl, X: N or CR ⁸ , R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ : the same or different, and
Or -lower alkyl, dotted line: single bond or double bond. The same applies hereinafter. Also, according to the present invention, there is provided a medicine, particularly a type IV PDE inhibitor, comprising an imidazonaphthyridine derivative or a salt thereof.

[0013]

DESCRIPTION OF THE PREFERRED EMBODIMENTS The present invention will be described below in detail.
As used herein, the term "lower" means a straight or branched hydrocarbon chain having 1 to 6 carbon atoms. "Lower alkyl" is preferably alkyl having 1 to 3 carbon atoms, and particularly preferably methyl and ethyl. “Cycloalkyl” is preferably cycloalkyl having 3 to 8 carbon atoms. "Cycloalkenyl" is preferably cycloalkenyl having 5 to 8 carbon atoms. "Aryl"
Represents an aromatic hydrocarbon group having 6 to 14 carbon atoms, and is preferably phenyl. "Heteroaryl" is preferably a monocyclic 5- to 6-membered aromatic heterocyclic group having one or two heteroatoms consisting of an oxygen atom, a sulfur atom and a nitrogen atom, preferably pyridyl, pyrimidinyl, Thiazolyl and thienyl.

Specific substituents of "cycloalkyl", "cycloalkenyl", "aryl" or "heteroaryl" which may be substituted include -halogen,
- lower alkyl, -O- lower alkyl, -S- lower alkyl, -CO- lower alkyl, -NO _2, -CN, -O
_{H, -SH, -CO 2 H,} -NR a R b, -CO 2 - lower ^{alkyl, -CONR a R b, -NR a} CO -lower alkyl can be mentioned (R ^a and R ^b are the same or different -H or-
Lower alkyl), preferably -halogen, -lower alkyl. “Halogen” refers to F, Cl, Br and I.

The compound of the present invention is represented by the general formula (I):
When X = CR ⁸ , the imidazo [1,2-a] [1,8] naphthyridine skeleton is used. When X = N, the imidazo [1,2-a] pyrido [3,2-
e] each having a pyrimidine skeleton. In the present specification, the compound of the present invention having both of these skeletons,
It is described as "imidazonaphthyridine derivative".

The compound of the present invention may have a geometrical isomer or a tautomer depending on the kind of the substituent, and the present invention includes a separated form or a mixture of these isomers. Further, the compound of the present invention may have an asymmetric carbon atom, and (R) -form and (S) -form optical isomers based on this may exist. The present invention includes all the mixtures and isolated forms of these optical isomers.

The compound of the present invention may form an acid addition salt or a salt with a base depending on the kind of the substituent. Such salts are pharmaceutically acceptable salts, and specifically include inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, and propionic acid. , Oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid,
Acid addition salts with organic acids such as ethanesulfonic acid, aspartic acid and glutamic acid, inorganic bases such as sodium, potassium, magnesium, calcium and aluminum, and salts with organic bases such as methylamine, ethylamine, ethanolamine, lysine and ornithine And ammonium salts. Furthermore, the present invention also includes various hydrates, solvates, and polymorphs of the compound (I) of the present invention and salts thereof.

(Preparation Method) The compound of the present invention and its pharmaceutically acceptable salt can be prepared by applying various known synthetic methods by utilizing the characteristics based on the basic skeleton or the type of the substituent. Can be. At that time, depending on the type of the functional group, it is effective in the production technology to replace the functional group with an appropriate protecting group at the stage of the raw material or intermediate, that is, a group which can be easily converted to the functional group. There is. Thereafter, the desired compound can be obtained by removing the protecting group as necessary. Examples of such a functional group include a hydroxyl group and a carboxyl group, and examples of such a protective group include green (Greene) and Wut (Wut).
s), “Protective Groups in Organic Synthesis”
(2nd edition) ", and these may be appropriately used depending on the reaction conditions. First manufacturing method

[0019]

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(In the formula, L ¹ represents a leaving group.) In this production method, the pyridyl ketone derivative (II) is converted to a compound of the general formula (III)
And reacting the imidazole derivative represented by the formula (1) to obtain the compound (Ia) of the present invention. The leaving group represented by L ¹ includes:
Preferably, halogen, methanesulfonyloxy, p-
And organic sulfonic acid residues such as toluenesulfonyloxy. The reaction is carried out by halogenated hydrocarbons such as dichloromethane, dichloroethane and chloroform; aromatic hydrocarbons such as benzene, toluene, xylene and dichlorobenzene; ethers such as ether, tetrahydrofuran, dioxane and diphenyl ether; N, N-dimethylformamide ( DMF), N, N-dimethylacetamide (DM
The reaction is carried out in an organic solvent inert to the reaction such as A) and N-methylpyrrolidone or in the absence of a solvent at room temperature to under heating. In the reaction, the pyridyl ketone derivative (II) and the general formula (II
The imidazole derivative represented by I) can be used in an equivalent amount or an excess amount, and an organic base (preferably,
Triethylamine, pyridine, 4- (N, N-dimethylamino)
In some cases, the reaction in the presence of pyridine) is advantageous in that the reaction proceeds smoothly. Second manufacturing method

[0021]

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(Wherein, R ^X represents -alkyl having 1 to 5 carbon atoms; L ² represents a leaving group similar to L ¹ ) In the compound of the present invention, R ¹ is an alkyl group ( Ic) can also be produced by alkylating the compound of the present invention (Ib) wherein R ¹ is a methyl group. The reaction is carried out in an organic solvent inert to the reaction of aromatic hydrocarbons, ethers, alcohols (methanol, ethanol, etc.), DMF, dimethylsulfoxide, etc., in an equivalent amount or one of compound (Ib) and compound (IV). The reaction is carried out under cooling to heating in an excess amount in the presence of a metal salt base (sodium hydride, potassium tert-butoxide, butyllithium, lithium diisopropylamide, sodium amide, methylmagnesium bromide, etc.). Third manufacturing method

[0023]

Embedded image This production method is a method for obtaining the present compound (Ie) by dehydrogenating the present compound (Id). For the reaction, a conventional method of dehydrogenation can be used, and examples thereof include a method described in “Experimental Chemistry Course” edited by The Chemical Society of Japan (Maruzen) and the like.

Fourth manufacturing method

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(In the formula, R ^Y represents -lower alkyl.) This production method is a method for obtaining the compound (Id) of the present invention by alkylating the imidazolidinethione derivative (V) and then amination cyclization. The alkylation reaction is carried out in an organic solvent inert to a reaction such as halogenated hydrocarbons, aromatic hydrocarbons, ethers, ketones (acetone, 2-butanone, etc.), DMF, DMA and N-methylpyrrolidone.
Using the compound (V) and an alkylating agent in an equivalent amount or one of them in an excess amount, in the presence of the above-mentioned organic or metal salt base or inorganic base (preferably sodium hydroxide or potassium carbonate) under cooling to heating. Done in The alkylating agent is preferably methyl iodide or isopropyl iodide.

The amination cyclization reaction is carried out in a solvent inert to the reaction such as halogenated hydrocarbons, aromatic hydrocarbons, ethers, alcohols or water, or in a mixed solvent thereof.
The reaction is carried out at room temperature to under heating using an equivalent amount of the compound (VI) and the aminating agent or an excess amount of one of them. The aminating agent is preferably ammonia, ammonium formate, or ammonium acetate. The above-mentioned starting compound (V) can be easily synthesized by a production method represented by the following reaction formula or a method analogous thereto.

[0027]

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This reaction is a step in which an pyridine derivative (II) is reacted with an ethylenediamine derivative represented by the general formula (VII) to give a compound (VIII), which is subsequently cyclized to obtain an imidazolidinethione derivative (V). The substitution reaction is carried out in a solvent inert to the reaction, such as aromatic hydrocarbons, ethers, alcohols or water, or in a mixed solvent thereof by using an equivalent amount of compound (II) and compound (VII) or an excess amount of one. Perform at room temperature to under heating. At the time of the reaction, it is sometimes advantageous to carry out the reaction in the presence of the above-mentioned organic base in order to make the reaction proceed smoothly. The cyclization reaction is carried out in a solvent inert to the reaction such as halogenated hydrocarbons, aromatic hydrocarbons or ethers, using an equivalent amount of the compound (VIII) and the cyclizing agent or an excess amount of one, and under cooling to heating. Done in The cyclizing agent is preferably thiocarbonyldiimidazole or thiophosgene. At the time of the reaction, it is sometimes advantageous to carry out the reaction in the presence of the above-mentioned organic base in order to make the reaction proceed smoothly. Raw material compound (II)
Can be synthesized by the method described in WO97 / 19078, pages 19-21.

The reaction product obtained by each of the above production methods is isolated and purified as a free compound, salt or hydrate, and various solvates. The salt can be obtained by subjecting the salt to a usual salt formation treatment. Isolation and purification include extraction, concentration, solvent evaporation,
Normal chemical operations such as crystallization, filtration, recrystallization, and various types of chromatography can be appropriately applied. Various isomers can be isolated by a conventional method utilizing the physicochemical difference between the isomers. The optical isomers can be separated by a general optical resolution method, for example, fractional crystallization or chromatography. Alternatively, it can be produced from a suitable optically active raw material.

[0030]

EFFECT OF THE INVENTION The PDE inhibitory action has been
To V-types are known.
In particular, it has excellent inhibitory activity against type IV PDE and is associated with type IV PDE (eg, bronchial asthma (including atopic asthma), chronic bronchitis, pneumonia, adult respiratory distress syndrome (ARDS), etc.) It is useful as a prophylactic / therapeutic agent. In particular, it can be expected as a prophylactic / therapeutic agent for bronchial asthma.

Furthermore, the compounds of the present invention are involved in other diseases in which the involvement of type IV PDE is known, such as cytokines (IL-1, IL-4, IL-6 and TNF (tumor necrosis factor)). Diseases (eg, rheumatoid arthritis, ulcerative colitis, Crohn's disease, sepsis, septic shock, endotoxic shock, Gram-negative septicemia, toxic shock syndrome, nephritis, hepatitis, infection (bacteria and virus), circulation It is also useful as a prophylactic / therapeutic agent for insufficiency (heart failure, arteriosclerosis, myocardial infarction, stroke) and the like.

The selective type IV PDE inhibitory activity of the compound of the present invention was confirmed by the following test. (1) Type IV PDE inhibitory activity measurement test 1) Purification of type IV PDE 200 ml of dextran (3%) saline was added to 500 ml of heparin-treated peripheral blood of a healthy person, and incubated at 37 ° C. for 40 minutes. Red blood cells were sedimented. The supernatant after erythrocyte sedimentation was collected and centrifuged once, and the sediment was washed with buffer A (140 mM NaCl,
The cells were suspended in 5 mM KCl, 5 mM glucose, 10 mM hepes, pH = 7.4), layered on a density gradient centrifugation solution (Ficoll solution), and centrifuged at 450 G for 40 minutes at room temperature to obtain a mononuclear cell fraction and granulocytes. The fractions were separated. Granulocyte fraction was added to buffer B (140 mM NaCl,
After washing once with 5 mM KCl, 1 mM CaCl2, 1 mM MgCl2, 5 mM glucose, 10 mM hepes, pH = 7.4, various protease inhibitors (50 μM phenyl-methyl-sulfonyl-fluori
de, 5 μM pepstatin A, 40 μM leupeptin, 20 μM apr
Buffer C (20 mM Bis) containing otinin and 2 mM benzamidine
-Tris, 5 mM dithioerythritol, 2 mM EGTA, 50 mM
After suspending the cells in sodium acetate, pH = 6.5), disrupt the cells with a polytron and a sonicator, and ultracentrifuge (4 ° C, 100,000G, 6
(0 min) to obtain a soluble fraction.

The resulting soluble fraction was loaded on a 1.6 × 10 cm Q Sepharose column equilibrated with buffer C.
The column was then washed with 300 ml of buffer C to remove unbound protein. The PDE was eluted with 200 ml of buffer C containing a linear gradient of 0.05-1.25 M sodium acetate, 5.
Forty fractions of 0 ml were collected. Each fraction was cAMP and cGM
P metabolism was examined for PDE activity. CGMP in each fraction
Rather, the fractions having cAMP metabolic activity and having lost metabolic activity with 10 μM rolipram (rolipram: a type IV PDE selective inhibitor) were collected and used as a stock solution for testing type IV PDE inhibitory activity. used.

2) Method for measuring inhibitory activity The test compound was prepared at a desired concentration of 40 mM Tris-HCl (pH = 8.
0), 5 mM MgCl2, 4 mM 2-mercaptoethanol, 0.3
μM cilostamide (a type III PDE selective inhibitor), 1 μM cAMP, 10 nM ³ H-cAMP and type IV P
The reaction was carried out at 30 ° C. for 10 minutes in the reaction mixture containing the DE stock solution. The reaction solution was heated at 90 ° C. for 1 minute, cooled on ice, and further added with 1 unit of 5′-nucleotidase.
The reaction was performed at 10 ° C. for 10 minutes, and 1 ml of methanol was added to stop the reaction. The reaction solution was passed through a Dowex 1 × 8 column to adsorb undecomposed products, and then radioactivity was measured. IC50 is IV type PDE
Was calculated for each compound as the concentration of the test compound that inhibited the metabolic activity of the compound by 50%.

(2) Method for Measuring Inhibitory Activity against Various PDEs 1) In order to evaluate the selectivity of the compound of the present invention for type IV PDE, the compounds of type I and II were evaluated in the same manner as described on page 37 of WO 97/19078. Type III, Type III and Type V PDEs were purified. 2) The inhibitory activity was 0.3% of the type IV PDE inhibitory activity measurement method.
The same procedure was performed in place of 10 μM rolipram for μM cilostamide. However, in the case of V-type PDE, 1 μM cAMP,
10 nM ³ H-cAMP was added to 1 μM cGMP and 10 nM ³
This was performed in place of H-cGMP. As a result of the inhibitory activity measurement test, it was confirmed that the compound of the present invention had excellent selective type IV PDE inhibitory activity.

A preparation containing one or more of the compound of the present invention or a salt thereof as an active ingredient is prepared using carriers, excipients, and other additives usually used in the preparation of preparations. For oral administration, such as tablets, pills, capsules, granules, powders, and liquids, or injections such as intravenous and intramuscular injections,
It may be in any form of parenteral administration such as suppository, transdermal, nasal or inhalant. The dosage is appropriately determined depending on the individual case in consideration of the symptoms, age, sex, etc. of the administration subject.
It is about 0.001 mg / kg to 100 mg / kg.
Alternatively, it is administered in 2 to 4 divided doses. When given intravenously due to symptoms, it is usually 0.001 per adult
The dose is in the range of mg / kg to 10 mg / kg once to several times a day. In the case of inhalation, the dose is usually 0.1 per adult.
0001 mg / kg to 1 mg / kg, once or more times a day, in the case of application, 0.0001 mg / kg to 1 mg / kg, once or more times a day .

As the solid composition for oral administration according to the present invention, tablets, powders, granules and the like are used. In such a solid composition, the one or more active substances comprise at least one inert diluent, such as lactose,
It is mixed with mannitol, glucose, hydroxypropyl cellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, magnesium aluminate metasilicate and the like. The composition may contain, in a conventional manner, additives other than an inert diluent, for example, a lubricant such as magnesium stearate, a disintegrant such as calcium cellulose glycolate, a stabilizer such as lactose, glutamic acid or asparagine. A solubilizing agent such as an acid may be contained. If necessary, tablets or pills may be coated with a sugar coating such as sucrose, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, or a film of a gastric or enteric substance.

Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs and the like, and commonly used inert diluents, For example, it contains purified water and ethanol. The composition may contain, in addition to the inert diluent, adjuvants such as wetting agents and suspending agents, sweetening agents, flavoring agents, fragrances, and preservatives.

Injections for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, and emulsions. Aqueous solutions and suspensions include, for example, distilled water for injection and physiological saline. Examples of the non-aqueous solution and suspension include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol, and polysorbate 80 (trade name). Such compositions may also contain adjuvants such as preserving, wetting, emulsifying, dispersing, stabilizing (eg, lactose) and solubilizing agents (eg, glutamic acid, aspartic acid). These are sterilized by, for example, filtration through a bacteria retaining filter, blending of a bactericide or irradiation. In addition, these can be used by producing a sterile solid composition and dissolving it in sterile water or a sterile injection solvent before use.

[0040]

EXAMPLES The present invention will be described below in more detail with reference to examples, but these examples do not limit the scope of the present invention. The production methods of the starting compounds are shown in Reference Examples.

Reference Example 1 2-Chloropyridine was reacted with lithium diisopropylamide and 3-chlorobenzaldehyde, and then oxidized with manganese dioxide to obtain 2-chloro-3- (3-chlorobenzoyl) pyridine. Reference Example 2 2-chlorobenzonitrile was prepared in the presence of sodium hydride.
After reacting with acetonitrile, it is hydrolyzed with 3N aqueous hydrochloric acid,
3- (2-Chlorophenyl) -3-oxopropanenitrile was obtained and hydrolyzed with polyphosphoric acid to give 3- (2-chlorophenyl) -3-oxopropanamide. This is
After reacting with dimethoxy-3-butanone, it was reacted with phosphorus oxychloride to obtain 2-chloro-3- (2-chlorobenzoyl) -6-methylpyridine. Reference Example 3 2-Chloro-6-methylnicotinic acid was reacted with 4-chlorophenylmagnesium bromide to obtain 2-chloro-3- (4-chlorobenzoyl) -6-methylpyridine. Reference Example 4 Using 3-bromobenzonitrile, 3- (3
-Bromobenzoyl) -6-methyl-2-pyridone was reacted with p-toluenesulfonyl chloride to give 3- (3-
(Bromobenzoyl) -6-methyl-2- (p-toluenesulfonyloxy) pyridine was obtained. Reference Example 5 Methyl cyclohexanecarboxylate was reacted with acetonitrile in the presence of n-butyllithium. Thereafter, 3-cyclohexanecarbonyl-6-methyl-2- (p-toluenesulfonyloxy) was obtained in the same manner as in Reference Examples 3 and 4. ) Pyridine was obtained. Reference Example 6 The compound obtained in Reference Example 4 was reacted with ethylenediamine, and then treated with 1,1′-thiocarbonylbis-1H-imidazole to give 3- (3-bromobenzoyl) -2- (imidazolidin- 2-Thion-1-yl) -6-methylpyridine was obtained. In the same manner as in Reference Example 3, the compounds of Reference Examples 7 to 10 shown in Table 1 were prepared.
The compounds of Reference Examples 11 and 12 shown in Table 1 in the same manner as in Reference Example 4, and the compounds of Reference Example 13 shown in Table 2 in the same manner as in Reference Example 6
To 19 compounds were obtained. Other, WO97 / 19078 publication
The starting compounds described in Reference Examples 2, 4, 10, 21, 48 and 64 on pages 40 to 52 were used. Tables 1 and 2 show the structures and NMR data of the compounds of Reference Examples 1 to 19.

Example 1 3- (3-bromobenzoyl) -2- (imidazolidin-2-thione-
3.20 g of 1-yl) -6-methylpyridine, anhydrous potassium carbonate 1.
A mixture of 17 g, 1.05 ml of methyl iodide and 60 ml of acetone was heated under reflux for 3 hours. After concentrating the reaction solution, chloroform was added to the obtained residue, and the mixture was washed with water and saturated saline.
After drying the organic layer, the solvent was distilled off, and crude 3- (3-bromobenzoyl) -2- (4,5-dihydro-2-methylthio-1H-imidazol-1-yl) -6-methylpyridine 3.4 g were obtained. 3.28 g of ammonium acetate and 100 ml of ethanol were added to the compound, and the mixture was stirred at 60 ° C. for 17 hours. The reaction solution was concentrated, a 1 M aqueous sodium hydroxide solution was added to the obtained residue, and the mixture was extracted with chloroform. The organic layer was washed with saturated saline, dried, and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (chloroform-methanol-29% aqueous ammonia), and the obtained crystals were recrystallized from 2-propanol to give 5- (3-bromophenyl) -2-methyl-. 8,9-Dihydroimidazo [1,2-a] pyrido [3,2-e] pyrimidine376 mg
I got

Example 2 5- (3-bromophenyl) -2-methyl-8,9-dihydroimidazo
[1,2-a] pyrido [3,2-e] pyrimidine 796 mg, benzyltriethylammonium chloride 424 mg, water 5 ml and benzene 15
Add 295 ml of potassium permanganate to the mixture of
A solution of mg in 10 ml of water was added dropwise and stirred for 2 hours. The insoluble matter was removed by filtration and extracted with toluene. The organic layer was washed with saturated saline, dried, and the solvent was distilled off. The obtained residue is subjected to silica gel column chromatography (hexane-ethyl acetate).
And then recrystallized from ethyl acetate-isopropyl ether to give 5- (3-bromophenyl) -2-methylimidazo
[1,2-a] pyrido [3,2-e] pyrimidine (88 mg) was obtained.

Example 3 2-chloro-3- (3-chlorobenzoyl) -6-ethylpyridine 6.
4 g, 2-methylimidazole 6.0 g, potassium carbonate 10.0 g
And 50 ml of N-methylpyrrolidone were stirred at 160 ° C. for 2 days. After cooling to room temperature, a saturated aqueous solution of ammonium chloride and ethyl acetate were added. After filtering off unnecessary substances, the organic layer was washed with water and saturated saline. After drying the organic layer, the solvent was distilled off and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate), and then recrystallized from ethyl acetate-diisopropyl ether to give 2-ethyl-5- (3 791 mg of -chlorophenyl) imidazo [1,2-a] [1,8] naphthyridine was obtained.

Example 4 650 mg of diisopropylamine in 30 m of tetrahydrofuran
To the solution, 3.7 ml of a 1.6 M butyllithium hexane solution was added under cooling to −78 ° C., and the mixture was reacted for 30 minutes. After that, 5- (3-chlorophenyl) -2-methylimidazo [1,2-a] [1 , 8] Naphthyridine 1.00 g was added and stirred for 1 hour. Further, 3.00 g of propane iodide was added, and the mixture was stirred for 30 minutes, and then heated to room temperature and further stirred for 1 hour. Water was added to the reaction solution, extracted with ethyl acetate, and the organic layer was washed with saturated saline. After drying the organic layer, the solvent was distilled off, and the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate), and then recrystallized from diisopropyl ether to give 2-butyl-5.
460 mg of-(3-chlorophenyl) imidazo [1,2-a] [1,8] naphthyridine were obtained.

In the same manner as in Example 1, Examples 5 to 1 in Table 3 were used.
The compound of Example 1 was prepared in the same manner as in Example 2 except that the compound of Example 12 in Table 4 was used.
The compounds of Examples 19 to 30 in Table 5 were obtained in the same manner as in Example 3, and the compounds of Examples 31 and 32 in Table 5 were obtained in the same manner as Example 4. Tables 3 to 5 show the structures and NMR data of these Examples. In Example 17 the measurement solvent NMR is a DMSO-d _6, others were used CDCl _3. Tables 6 and 7 show the structures of other compounds of the present invention. These can be easily synthesized by using the above-mentioned production methods and the methods described in the Examples and methods obvious to those skilled in the art, or modified methods thereof. In the table, the following abbreviations are used. Rex: Reference example number, Ex: Example number, Co: Compound number, c
-Pen: cyclopentyl, c-Hex: cyclohexyl, c-He
p: cycloheptyl, Imt: imidazolidine-2-thione-1-
Il, OTs: p-toluenesulfonyloxy, Py: pyridyl, Pym: pyrimidinyl, ThN: thiazolyl, Th: thienyl.

[0047]

[Table 1]

[Table 2]

[0048]

[Table 3]

[0049]

[Table 4]

[Table 5]

[0050]

[Table 6]

[0051]

[Table 7]

 ──────────────────────────────────────────────────の Continued on front page (72) Inventor Masahiro Fukunaga 21 Miyukigaoka, Tsukuba, Ibaraki Pref. Yamanouchi Pharmaceutical Co., Ltd.

Claims (3)

[Claims] 1. A compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof. Embedded image (The symbols in the formula have the following meanings: R ¹ , R ² and R ^{3 are the} same or different and are —H, —halogen, —lower alkyl, —O-lower alkyl, —S-lower alkyl, —CO - lower alkyl, -NO _2, -CN,
_{-OH, -SH, -CO 2 H,} -NR 6 R 7, -CO 2 - lower ^{alkyl, -CONR 6 R 7, -NR 6} CO- lower alkyl, - cycloalkyl or - aryl, A: substituted Optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl or optionally substituted heteroaryl, X: N or CR ⁸ , R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ : the same or different, and
Or -lower alkyl, dotted line: single bond or double bond. ) 2. A medicament comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient. 3. A type IV phosphodiesterase inhibitor comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient.