WO1999035142A1 - 4-(3-indolyl)imidazole derivatives - Google Patents

Abstract

4-(3-Indolyl)imidazole derivatives represented by general formula (1) or salts thereof wherein R1 represents a group represented by general formula (a) or (b); R2 represents lower alkoxy; R3 represents lower alkyl, nitro, thienyl, alkoxycarbonyl, or halogeno; R4 represents lower alkyl, phenyl, hydroxy, phenoxy, cyano, alkoxycarbonyl, acylamino, alkylthio, carboxy, NR6R7, O(CF¿2)mR?8, or O(CH¿2?)nR?9; R5¿ represents hydrogen, lower alkyl, lower alkoxy, or halogeno; R?6 and R7¿ are the same or different and each represents lower alkyl or R?6 and R7¿ in combination form a polymethylene group; R8 represents hydrogen or halogeno; R9 represents phenyl or naphthyl; and m and n each is an integer of 1 to 4.

Description

 Specification -

— 4 I (3-indole) imidazole derivatives Technical field

 The present invention relates to a 4— (3-indolinyl) imidazole derivative and a salt thereof, which have a Ca—calmodulin-dependent phosphodiesterase (PDEI) inhibitory action. Background art

 Conventionally, it selectively inhibits C a -calmodulin-dependent phosphodiesterase (PDEI), increases intracellular cAMP and cGMP levels, and enhances cerebral vasodilation and central nervous system activity. Known compounds having a function-improving action include vinpocetine, 8—methoxymethyl—IBMX, KS—505, etc. (Physiol. Rev., 1995, 75 (4) , 725.). However, the compound having a 41- (3-indyl) imidazole skeleton shown in the present invention may have a Ca-calmodulin-dependent phosphodiesterase (PDEI) inhibitory action. There are no reports.

 On the other hand, Japanese Patent Application Laid-Open No. 188585/1992 discloses a 4- (3-indolinyl) imidazole derivative in which an aryl group such as a 3-fluorophenyl group is imidazole. A compound having a ring at the 2-position is disclosed, but the compound described in the present invention has not been reported. Disclosure of the invention

The present inventors have conducted intensive studies on compounds having a Ca—calmodulin-dependent phosphodiesterase (PDEI) inhibitory action, and as a result, have found that a certain 41- (3-indryl) imidazole skeleton has been developed. Possession The inventors have found that the compound satisfies the above purpose, and have further completed the present invention based on the knowledge.

 That is, the present invention provides the following formula (1)

Where R ¹ is the formula

で表される基を示 し、 R ²は低級アルコキシ基を示す。 R ³は低級 アルキル基、 ニ ト ロ基、 チェニル基、 アルコ キシカルボニル基 またはハロゲン原子を示 し、 R ⁴は低級アルキル基、 フ ヱニル基、 ヒ ドロキシ基、 フ エ ノ キシ基、 シァ ノ 基、 ァノレコ キシカノレポ二 ル基、 ァ シルァ ミ ノ 基、 アルキルチオ基、 カルボキシ基、 N R ⁶ R ⁷基、 0 ( C F ₂) _mR ⁸基ま たは 0 ( C H ₂) „R ⁹基を示 し、 R ⁵ は水素原子、 低級アルキル基、 低級アルコ キシ基ま たはハ ロ ゲ ン原子を示す。 R ^βおよび R ⁷はそれぞれ同一ま たは異な った低級 アルキル基を示すか、 または R 0と R ⁷が一緒にな つてポ リ メ チ レ ン基を形成する。 R ⁸は水素原子またはハロゲン原子を示 し、 R ⁹ はフ ヱニル基ま たはナフ チル基を示す。 m、 n はそれぞれ 1 か ら 4 の整数を示す。 ]で表わされる 4 一 （ 3 — イ ン ド リ ル） イ ミ ダゾール誘導体またはその塩である。 発明の実施の形態 ； 本発明 において低級アルキル基とは炭素数 1 〜 6 の直鎖ま た は分枝状のアルキル基を意味 し、 例えばメ チル基、 ェチル基、 プロ ピル基、 イ ソ プロ ピル基、 ブチル基、 イ ソ ブチル基、 sec - ブチル基、 tert-ブチル基、 ペンチル基、 イ ソペンチル基、 へキ 'シル基、 イ ソへキシル基等が挙げられる。

And R ² represents a lower alkoxy group. R ³ represents a lower alkyl group, a nitro group, a chenyl group, an alkoxycarbonyl group or a halogen atom, and R ⁴ represents a lower alkyl group, a phenyl group, a hydroxy group, a phenoxy group, a cyano group. , Anoreko Kishikanorepo two group, § Shirua Mi amino group, an alkylthio group, a carboxy group, NR ⁶ R ⁷ _{group, 0 (CF 2) m R} 8 Motoma others 0 (CH ₂₎ "shows the R ⁹ groups, R ⁵ represents a hydrogen atom, a lower alkyl group, a lower alkoxy group or a halogen atom R ^β and R ⁷ each represent the same or different lower alkyl group, or R ⁷ together form a polymethylene group, R ⁸ represents a hydrogen atom or a halogen atom, R ⁹ represents a phenyl group or a naphthyl group, m and n each represent Shows an integer from 1 to 4.] 4 (3—indrill) An imidazole derivative or a salt thereof. BEST MODE FOR CARRYING OUT THE INVENTION In the present invention, a lower alkyl group means a straight-chain or branched alkyl group having 1 to 6 carbon atoms, for example, a methyl group, an ethyl group, a propyl group, an isopropyl group. Examples include a pill group, a butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, a pentyl group, an isopentyl group, a hexyl group, and an isohexyl group.

 Alkoxycarbonyl group means a linear or branched alkoxycarbonyl group having 2 to 7 carbon atoms, such as a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group. , Isopropoxycarbonyl, butoxycanolebonyl, isobutoxycanolebonyl, sec-butoxycanolebonyl, tert-butoxycanoleboninole, pentinoleoxycanoleboninole, hexyloxycarbo And a benzyl group.

 The acylamino group means an aromatic acylamino group or an aliphatic acylamino group having 1 to 6 carbon atoms, such as a benzoylamino group, a naphthoinoinorea group, or an amino group. Examples thereof include a cetamide group, a propionylamino group, a petrylulamino group, and a valerylamino group.

 The alkylthio group means a linear or branched alkylthio group having 1 to 6 carbon atoms, such as methylthio, ethylthio, propylthio, isopropylthio, butylthio, and iso. Butylthio, sec-butylthio, tert-butylthio, pentynolethio, hexylthio and the like.

The lower alkoxy group means a linear or branched alkoxy group having 1 to 6 carbon atoms, such as a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, Butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, isopene Tiloxy group, hexyloxy group and the like.

 A halogen atom means a fluorine atom, a chlorine atom, a bromine atom or a iodine atom.

The Po Li main switch LES down harbor R ⁶ and R ⁷ are together a connexion forming means Po Li main Chi Le emissions group having 2-6, dimethyl Chi Le emissions group, Application Benefits main switch les down Group, tetramethylene group, pentamethylene group, hexamethylene group and the like.

 In addition, the salts may be those that are pharmaceutically enjoyable, for example, inorganic salts such as hydrochloride, hydrobromide, and sulfate, methansulfonate, p-toluene, and the like. Sulfonates such as sulfonates can be used.

 The imidazole compound of the formula (1) has the following tautomers in the imidazole portion thereof, and these tautomers are also present in the present invention. included in the range of j.

式 （ 1 ) の化合物は、 例えば下記に示す製造スキー ム に よ り 製造する こ とができ る。

The compound of the formula (1) can be produced, for example, by the following production scheme.

 (1)

(Wherein, R ¹ and R ² are as defined above.)

 That is, indole 3 — glyoxyl chloride and the formula

The compound represented by the formula (3) is condensed in the presence of Lewis acid to obtain the compound represented by the formula (3).

 Here, aluminum chloride, anhydrous stannic chloride, zinc bromide, anhydrous titanium tetrachloride, etc. can be used as the Lewis acid, and methyl chloride is used as the reaction solvent. Solvents can be used, such as benzene, black-mouthed form, 1,2-dichloroethane, carbon tetrachloride, carbon disulfide, nitroethane, and nitrobenzene. The reaction temperature is from 0 ° C to the reflux temperature.

Next, the compound of the present invention (1) is reacted by reacting the compound of the formula (3) with the compound of the formula (4) in the presence of excess ammonia or ammonium salt. Obtainable. Here, ammonium acetate, ammonium oxalate, ammonium carbonate, or the like can be used as the ammonium salt, and the reaction solvent such as acetic acid, propionic acid, or the like can be used. Fatty acids, methanol, Ananol such as ethanol, dioxane, ethers such as tetrahydrofuran and the like can be used. The reaction temperature ranges from room temperature to reflux temperature.

 The compound of the present invention can be converted into an appropriate pharmaceutical composition (tablets, pills, capsules, granules, dry mouth, injections, etc.) using known carriers, diluents and the like. It can be used orally or parenterally with adjustment. .

 Solid additives are manufactured using various additives such as excipients, disintegrants, binders, lubricants, and coating bases, using agitation granulation, fluidized bed granulation, and crushing. It can be manufactured by the granulation method.

 In addition, if necessary, an antioxidant, a coating agent, a coloring agent, a flavoring agent, a surfactant, a plasticizer, and the like can be added.

 The dosage of the active ingredient of the medicament of the present invention varies depending on the age, body weight, administration form and the like, but it is usually 0.1 to 100 mgz / day for an adult, which may be taken once a day or once a day. Administer several divided doses. Industrial availability

The compound of the present invention has a Ca—calmodulin-dependent phosphodiesterase (PDEI) inhibitory effect, and by increasing the concentration of cAMP and cGMP in cells, Exhibits pharmacological action. PDEI is abundant in vascular smooth muscle and brain, and PDEI inhibitors have cerebral vasodilatory and central nervous system improving functions, so central dysfunction after cerebral vascular occlusion, cerebrovascular dementia, senile dementia It is useful for improving cerebral circulation or central function for diseases such as dysfunction, memory and learning dysfunction. Best mode for applying the invention Hereinafter, the present invention will be described in more detail with reference to Examples and Test Examples.

Table ¹ shows the structural formulas of the compounds produced according to Examples 1 to 38. Here, the compound number indicates the example number. table 1

 H

 Structural formula

 l 'a coming p 4 6 2

 K R

 1 1 H n

2 4-CHMe H OCHq

 4 3-OH H OCH3

 5 4-OH 3-OCH3 OCH3

 6 3-OH 4-OCH3 OCH3

7 3-OCH ₂ Ph 4-OCH3 OCH3

8 3-OCH ₂ CH ₂ Ph 4-OCH3 OCH3

9 4-C0 ₂ e H OCH3

 10 4-Ph H OCH3

 11 4-NHAc H OCH3

 12 3-OPh H OCH3

13 4-SCH ₃ H OCH3

 14 4-CH3 H OCH3

15 3-CH3 4-CH ₃ OCH3

1 (continued)

Example 1

 4 — (3 — Indole) 1 5 — (4 — Methoxyphenyl) 1 2 — (3 — Methylphenyl) imidazole

(1) A solution of anisol (21.6 g, 0.20 mol) and a commercially available indole 3 — glyoxylyl-open mouth (20.8 g, 0.1 mol) in methylene chloride (200 ml) was added to ice. Under cooling, anhydrous aluminum chloride (40.0 g, 0.30 mol) was added little by little, and the mixture was stirred at room temperature overnight. The reaction solution was poured into ice water, and methylene chloride was distilled off under reduced pressure. The precipitated insoluble matter was collected by filtration, washed with water, and dissolved in acetone. After drying, the solvent is distilled off under reduced pressure. 1- (4-Methoxyoxydenyloxyl) indole (21.57 g) was obtained. This was used for the next reaction without further purification.

 (2) 3 — (4-Methoxy phenylenyloxyl) Indo J (0.56 g, 2. Ommo 1) and m ^ ^ / aredehyde (0.24 g, 2. Ommo 1) Ammonia acetate (1.56 g, 20.3 mmol) was added to the acetic acid (12 ml) solution, and the mixture was refluxed for 5 hours. After the reaction solution was cooled to room temperature, it was poured into water and neutralized with a saturated aqueous solution of sodium carbonate. The mixture was extracted with methylene chloride, dried, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography [eluent: chloroform] to obtain the title compound (0.60 g).

 m p. 204.5 ~ 206 ° C

 Ή-NMR (200MHz, DMS0-da) δ (ppm); 2.38 (s, 3H), 3.71 (s, 3Η), 6.73-7.62 (m, 11H), 7.86 (d, J = 8Hz, 1H), 7.92 (s, 1H), 11.42 (bs, 1H), 12.40 (s, 1H)

MASS (m / e); 379 (M ⁺ ) In the same manner as in Example 1, the following compounds of Examples 2 to 31 were obtained. Example 2

 4 — (3 —indryl) 1 2 — (4 —isopropylphenyl)-5-(4 -methoxyphenyl) imidazole

Ή-NMR (200 MHz, DMSO- d ₆ ) δ (ppm); 1.23 (d, J = 7 Hz, 6H), 2.93 (sept, J = 7 Hz, 1H), 3.72 (s, 3H), 6.82 (d, J) = 9Hz, 2H), 6.95 (t, J = 8Hz, 1H), 7.13 (t, J = 8Hz, 1H), 7.33 (d, J = 9Hz, 3H), 7.45 (d, J = 8Hz, 1H) ), 7.50 (s, 1H), 7.53 (d, J = 9Hz, 2H), 8.00 (d, J = 9Hz, 2H), 11.35 (bs, 1H), 1 2.40 (bs, 1H) \ Jifl

 Yo

A ^ ^ 7) 4 input ί ^ <^ 11- I: 7 input K 3 />- 2 — (3 — Hydroxy 1-4-methoxy ethoxy) 1-41 (3-Indolin) 1 5 — (4-methoxy fuino) imidazole H-NMR (200MHz, D S0-d _e ) δ (ppm); 3.71 (s, 3H), 3.82 (s, 3H),

6.81 (d, J = 8Hz, 2H), 6.90- 7.03 (m, 2H), 7.12 (t, J-8Hz, IH), 7.41-7.59 (m, 6H), 7.50 (s, IH), 9.10 (s, IH), 11.34 (s, IH), 12.41 (s, lH) o

MASS (m / e); 412 (M + + 1) Example 7

 2-[3-(Benjirokushi) 1 4-Metokishinori] 1 4 1 (3-Indolinore) 1 5-(4-Metokishino 2) ) Lee Mi Dazo

Ή - NMR (200MHz, DMS0- d e) δ (ppm); 3.72 (s, 3H), 3.82 (s, 3H), 5.15 (s, 2H), 6.82 (d, J = 8Hz, 2H), 6.95 ( t, J = 7Hz, IH), 7.09 (d, J = 8Hz, IH), 7.13 (t, J; 7Hz, IH), 7.31-7.55 (m, 10H), 7.68 (dd, J: 2, 8Hz, IH),

7.81 (d, J = 2Hz, IH), 11.37 (s, IH), 12.42 (s, IH)

MASS (m / e); 502 (M + + 1) Example 8

 4 1 (3 — Indolinole) 1 5 — (4 — Methoxy 2) 1 2-[4-Methoxy 3 — (2 — Vinyl ethoxy)ニ ル nil]

 Ή-NMR (200MHz, DMSO-d.) Δ (ppm); 3.10 (t, J = 7Hz, 2H), 3.70 (s, 3H), 3.81 (s, 3H), 4.23 (t, J = 7Hz, 2H ), 6.80 (d, J = 9Hz, 2H), 6.94 (t, J-7Hz, IH), 7.03-7.16 (m, 2H), 7.18-7.43 (m, 7H), 7.47 ~ 7.53 (m, 3H) , 7.63-7.68 (ra, 2H), 11.36 (s, IH), 12.39 (s, IH)

MA SS (m / e); 516 ( ⁺ + 1) Example 9

 4 — (3 — Indole) 1 2 — [4-1 (Methoxycarboxylic) boninole] 1 5 — (4-Indonex)

 m p. 261 ~ 262 ° C

 Ή-N MR (200MHz, DMSO d.) Δ (ppm); 3.72 (s, 3H), 3.87 (s, 3H),

6.74- 6.90 (m, 2H), 6.95 (t, J = 8Hz, IH), 7.06-7.21 (m, 2H), 7.42-7.6 6 (m, 4H), 8.05 (d, J = 9Hz, 2H), 8.-22 (d, J = 9Hz, 2H), 11.47 (s, IH), 12.74 (s, IH)

実施例 1 0

Example 10

 2 — (Bi-Finnori 4 — yl) 1 4 1 (3 — Indolino) 1 5 — (4 ト キ 二 二) Imidazol

 mp.264 ~ 265.5 ° C

Ή-NMR (200 MHz, DMS0-d ₆ ) δ (ppm); 3.72 (s, 3H), 6.77 6.88 (m, 2H), 6.96 (t, J = 7 Hz, IH), 7.13 (t, J = 7 Hz, IH), 7.33- 7.58 (m, 6H),

7.76 (d, J = 7Hz, 2H), 7.79 (d, J = 8Hz, 2H), 8.18 (d, J = 8Hz, 2H), 11.38 (s, IH), 12.55 (s, IH)

MASS (m / e); 442 (M + + 1) Example 1 1

 2 — [4 — (Acetamido) bininole] — 4 1 (3 — indole) 1 5 — (4 — methoxyphenyl) imidazole

Ή-NMR (200MHz, DMSO- d ₆ ) δ (ppm); 2.07 (s, 3H), 3.71 (s, 3H), 6.81 (d, J = 8Hz, 2H), 6.94 (t, J = 7Hz, IH ), 7.12 (t, J: 7Hz, IH), 7.24 (s, IH), 7.42-7.56 (m, 4H), 7.67 (d, J = 8Hz, 2H), 7.98 (d, J = 8Hz, 2H) , 10.05 (s, IH), 11.35 (s, IH), 12.45 (s, IH) SSV

CM

cm

2 () 0SW00s P2 H pd-. S086S or d.13dsc / 660

9 '4m, 9978 H (.,. / Z oS

/ a Y ($ m, 1 H

Example 2 1-2- (4—Hydroxy—3—Methylphenyl) _4—1 (3—Indril) -1 5— (4—Methoxyphenyl) Imidazole

 Ή-N MR (200MHz, DMSO-da) δ (ppm); 2.19 (s, 3H), 3.71 (s, 3H),

6.80 (d, J = 9Hz, 2H), 6.84 (d, J = 8Hz, 1H), 6.93 (t, J = 8Hz, 1H), 7.1 (t, J-8Hz, 1H), 7.25 ( d, J = 8Hz, 1H), 7.45 (d, J = 8Hz, 1H), 7.49 (s, 1H), 7.51 (d, J = 9Hz, 2H), 7.71 (d, J = 8Hz, 1H) , 7.81 (s, 1H), 9.52 (s, 1H), 11.32 (s, 1H), 12.15 (bs, 1H)

 4 1 (3—Indrill) 1 5— (4—Methoxy phenyl) 1 2— [3— (1,1,2,2—tetrafluoroethoxy) phenyl] Midazole

Ή-NMR (200MHz, CDCl ₃ ) δ (pm); 3.76 (s, 3H), 5.91 (tt, J-4, 53Hz, 1H), 6.77 (d, J = 9Hz, 2H), 7.08 (t, J = 8Hz, 1H), 7.15-7.26 (m, 3H),

7.35-7.57 (m, 5H), 7.76 (s, 1H), 7.78 (d, J = 8Hz, 1H), 8.44 (s, 1H)

4 - (3 _ i down drill relay) Single 5 - (4 - Main Toki Schiff et two le) one 2 -. [2 - (g Li Furuorome butoxy) phenyl] Lee Mi Dazo Ichiru mp 154~ 154.5 ⁰ C

 Ή-NMR (200MHz, CDC) δ (ppm); 378 (s, 3H), 6.82 (d, J = 9Hz, 2H), 7.07-7.44 (m, 8H), 7.54-7.65 (m, 3H), 8.48-8.55 (m, 2H) Example 2 4

2-(5-Chloro 2-Hydroxyphenyl) 1-4 (3-Indrill)-1 5-(4-Methoxyphenyl) Imidazole _{Ή - NMR (200MHz, CDC1 3} ) δ (ppm); 3.79 (s, 3H), 6.82 (d, J-9Hz, 2H), 7.00-7.57 (m, 10H), 8.34 (s, IH) Example 2 Five

 2-[41- (3-phenylene) phenyl]-4-(3-indolinole) 1-5-(4-methoxybenzene) imidazole

 m p. 249 ~ 249.5 ° C

Ή - NMR (200MHz, DMSO- d B) δ (ppm); 3.71 (s, 3H), 6.77 6.88 (m, 2H), 6.95 (t, J = 7Hz, IH), 7.12 (t, J = 7Hz, IH), 7.28 (d, J = 9 Hz, 2H), 7.30 (t, J = 9 Hz, 2H), 7.46 (t.J = 70 Hz, IH), 7.46 (d, J = 7 Hz, 2H), 7.52 (d , J = 9Hz, 2H), 8.12 (d, J = 9Hz, 2H), 11.39 (s, IH), 12.51 (s, IH)

MASS (m / e); 431 (M ⁺ )

 4 — (3 — Indole) 1 5 — (4-Infinity) 1 2-[3-(Trifluorometh) Ind.] Imidazo One liter

_{Ή - NMR (200MHz, CDC1 3} ) δ (ppm); 3.76 (s, 3H), 6.78 (d, J = 8Hz, 2H), 7.07 (. T J = 7Hz, IH), 7.15-7.23 (m, IH ), 7.24-7.27 (m, IH), 7.39 (d, J = 8Hz, IH), 7.45 (t, J = 8Hz, IH), 7.55 (d, J = 8Hz, 2H), 7.74- 7.82 (m, 2H), 8.40 (s, IH)

MASS (m / e); 449 (M ⁺ )

2-(2-Hydroxy 3-Methoxy Fir)-4-1 (3-1 Fri) 1 5-(4-Methoxy F2) Midazole mp. 136-139 ⁰ C

Ή-NMR (200MHz, DMSO-do) 5 (ppm); 3.71 (s, 3H), 3.82 (s, 3H), 6.78-7.02 (m, 5H), 7.08-7.20 (m, IH), 7.43- 7.69 (m, 5H), 11.53 (s, 1; H), 12.81 (s, IH), 13.33 (s, IH)

MASS (m / e); 411 (M ⁺ )

 2 — (2 — Hydroxyphenyl) 1-41 (3 — Indrill) — 5 — (4 -Methoxyphenyl)

 m p. 188.5-190.5 ° C

_{Ή - NMR (200MHz, CDC1 3} ) δ (ppm); 3.79 (s, 3H), 6.78- 6.94 (ra, 3H), 7.12 (t, J = 7Hz, 2H), 7.27 (t, J = 7Hz, IH ), 7.35-7.62 (m, 6H), 8.3 4 (s, IH)

MASS (m / e); 381 (M ⁺ )

 2 — (5 — Bromo 2 — Hydroxyphenyl) 1-41 (3 — Indril) 1 5 — (4 — Methoxyphenyl) imidazole

_{Ή - NMR (200MHz, CDC1 3} ) δ (ppm); 3.75 (s, 3H), 6.77 (d, J = 8Hz, 2H), 6.93 (d, J = 9Hz, IH), 7.07 (t, J = 7Hz , IH), 7.18-7.32 (ra, 3H), 7.3 7 7.58 (m, 5H), 8.32 (s, IH)

MASS (m / e); 459 (M +), 461 (M + + 2) Example 3 0

 2-(4-canopoxyphenyl) 1-4 (3-indolinole)-5-(4-methoxyphenyl) imidazole

 m p. 211.5 ° C (decomposition)

Ή-NMR (200MHz, DMSO- d ₆ ) δ (ppm); 3.72 (s, 3H), 6.83 (d, J = 8 Hz, 2H), 6.95 (t, J = 7Hz, IH), 7.13 (t, J = 7Hz, IH), 7.28 (s, IH), 7.46 (d, J = 8 Hz, 2H), 7.55 (d, J: 8 Hz, 2H), 8.03 (d, J = 7 Hz, 2H), 8.20 (d, J = 7 Hz, 2H), 11.40 (s, IH) , 12.75 (s, IH), 12.89 (s, IH)

MASS (m / e); 410 (M + + 1) Example 3 1

 2 — (4 — Cyanophenyl) 1 4-1 (3 — Indrill) 1 5-1 (4-Methoxyxinole) Imidazole

 m p. 22 g 223 ° C

¹ H-NMR (200 MHz, DMSO-d ₆ ) δ (ppm); 3.71 (s, 3H), 6.73 6.84 (m, IH), 6.92 to 7.00 (ra, 2H), 7.06-7.20 (m, 2H), 7.42-7.66 (m, 4H), 7.92 (d, J = 8 Hz, 2H), 8.24 (d, J = 8 Hz, 2H), 11.49 (s, IH), 12.80 (s, IH)

MASS (m / e); 390 (M ⁺ ) Example 3 2

 4 1 (3 — Indolinole) 1 5 — (4 — Methoxyfino) 1 2 1 (5 — Methyl 2 — Chenyl) imidazole hydrochloride

 (1) Anisole (21.6 g, 0.20 mol) and commercially available indole—3—glyoxyl chloride (20.8 g, 0.1 mol) in methylene chloride (200 ml) Under ice-cooling, anhydrous aluminum chloride (40.0 g, 0.30 nul) was added little by little to the solution, and the mixture was stirred at room temperature overnight. The reaction solution was poured into ice water, and methylene chloride was distilled off under reduced pressure. The precipitated insoluble matter was collected by filtration, washed with water, and dissolved in acetone. After drying, the solvent was distilled off under reduced pressure to obtain 3- (4-methoxyphenylglyoxyl) indole (21.57 g). This was used for the next reaction without further purification.

(2) 3 — (4-methoxyethoxyloxyl) indole (0.56 g, 2. Ommol) i: 5-methylthiophene 2 — carboxal To a solution of the aldehyde (0.25 g, 2.0 mol) in acetic acid (12 ml) was added ammonium acetate (1:56 g, 20.3πιπΐϋ1), and the mixture was refluxed for 2 hours. The reaction solution was cooled to room temperature, poured into water, and neutralized with a saturated aqueous solution of sodium carbonate. The mixture was extracted with methylene chloride, dried, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography chromatography [eluting solvent: black form], and then purified by 4- (3-indolino) -5— (4—methoxy). (Phenyl) -1- (5-methyl-2-ethyl-2-imidazole) imidazole (0.71 g) was obtained.

 (3) 4 — (3 — indole) 1 5 — (4 — methoxyphenyl) — 2 — (5 — methinolate 2 — chenyl) imidazole (0.71 g, 1.8m mo 1) 4) Hydrogen chloride monoethyl acetate solution (4 ml) was added to a solution of the above) in ethyl acetate (20 ml), and the mixture was stirred at room temperature for 30 minutes. The precipitated crystals were collected by filtration and dried to give the title compound (0.58 g).

 m p. 204.5 ~ 205 ° C

Ή-NMR (200 MHz, MS0-d ₆ ) δ (ppm); 2.58 (s, 3H), 3.63 (br, 2H), 3.75 (s, 3H), 6.90-7.18 (i, 6H), 7.45 to 7.57 ( m, 3H), 7.81 (d, J = 4Hz, 1H), 8.08 (d, J = 4Hz, IH), 11.80 (s, IH)

MASS (m / e); 385 (M ⁺ ) In the same manner as in Example 32, the following compounds of Examples 33 to 38 were obtained. Example 3 3

 4-(3-Indole) 1 5-(4-Metxifle) 1 2-(5-2 Troll 3-Chenore) Imidazo

mp. 157〜159 ⁰ C

_{Ή - NMR (200MHz, CDC1 3} ) δ (ppm); 3.73 (s, 3H), 6.86 (d, J = 9Hz, Sma i6d6 alse / 06-

υ

CO

 L

^>: R I H.

H (¾HW «SZ I- 2H), 6.89-6.98 (m, 2H), 7.02-7.13 (m, 3H), 7.15-7.22 (m, IH), 7.35 (d, J = 9Hz, 2H), 8.54 (s, IH)

MASS (m / e); 449 (M +), 451 (+ + 2) Example 3 7

 2 — (5 — Chlorine 2 — CH 2 Sole) 1 4 1 (3 — Indrill) 1 5 — (4 Methoxyphenyl) Imidazole

 m p109.5 ° C

 'H-NMR (200MHz, DMSO-da) δ (ppm); 3.71 (s, 3H), 6.74 6.87 (m, 2H), 6.94 (t, J = 7Hz, IH), 7.07-7.18 (m, 3H) , 7.39-7.60 (m, 5H), 1 1.42 (s, IH), 12.68 (s, IH)

MASS (m / e); 405 (M +), 407 (M + + 2) Example 3 8

 4 1 (3 — Indolinore) 1 2 — [5-(Mexican olive Boninole) — 2 — Cheninore] 1 5 — (4 — Metoxifonore) Imidazo Le

 m p. 123 ° C

Ή - NMR (200MHz, DMSO- d e) δ (ppm); 3.70 (s, 3H), 3.85 (s, 3H), 6.79 (d, J: 9Hz, 2H), 6.92-7.01 Cm, 2H), 7.09 -7.19 (m, IH), 7.44-7.5 4 (m, 3H), 7.61-7.72 (m, 2H), 7.81 (d, J = 4Hz, IH), 11.50 (s, IH), 12.87 (s, IH)

MASS (m / e); 429 (M ⁺ ) Test example 1

 P D E I inhibitory action

PDEI was prepared from bovine cerebrum and used in a two-step method (Bioche m. Biophys. Res. Commun., 169, 315-322).

To a reaction mixture of 50 mM Tris-HC1 (pH 8.0), 5 mM magnesium chloride, 0.1 mg / ml bovine serum albumin, 0.2 mM calcium chloride, ΙΟΟϋ / ml calmodurin The test compound dissolved in the PDEI solution and DMS 0 was added to the test tube, and the ratio was set to 0: [. 5 M as a substrate in a test tube ^{[8 - 3 H] c AMP} (50/1, 23.125Kbq / ml) was added (final concentration 1 // M, 4.625KBq / ml) final volume 250; / 1 and Then, the mixture was reacted in a water bath at 30 ° C. for 15 minutes. In this case, the concentration of each substance in the reaction mixture was adjusted to a final concentration of 2501, and the final concentration of DMS0 was adjusted to 1%. The reaction was stopped by transferring the test tube into a boiling water bath and heating for 5 minutes, then transferred into ice water and cooled.

Next, lmg / ml snake venom (501) was added, and reacted at 30 ° C for 10 minutes. Water (2ml) was added, and a cation exchange resin column [Bio-Rad Co., Ltd.] was added. , AG50W-X4 (resin capacity; 0.2 ml)]. After thoroughly washing the unreacted substances with water, the radioactive adenosine adsorbed on the resin is eluted with 1N-ammonia water (1 ml), placed in a vial for radioactivity measurement, and subjected to liquid scintillation. (7 ml) was added and stirred. The DPM value of [ ³ H] adenosine was measured with a liquid scintillation counter, and the value was defined as the enzyme activity.

The inhibitory activity of the test compound on PDEI was evaluated by comparing with the vehicle-treated group. Table 2 shows the results. Two

PDEI blocking activity

V / ο οτ ιηπΐυΐιιοπ ノ Compound number 10 μ

 1 64

 4 76

 17 65

 21 81

 28 76

 32 70

 36 53

 37 62

 38 51

Claims

The scope of the claims  1. Equation (1)

[Where R 'is the expression

And R ² represents a lower alkoxy group. R ′ represents a lower alkyl group, a nitro group, a phenyl group, a carbonyl group or a halogen atom; R ′ represents a lower alkyl group, a phenyl group, a hydroxy group, a phenoxy group, a cyano group, Arco key Shikarubo two group, Ashirua Mi amino group, an alkylthio group, a carboxy group, NR ^fi R ⁷ group, O ^"8 group or 0 (CH _2)" R ^a groups was shown, is a hydrogen atom, a lower alkyl group, Shows a lower alkoxy group or a halogen atom. R and R ⁷ each represent the same or different lower alkyl group, or R ⁶ and R ⁷ together form a polymethylene group. R "represents a hydrogen atom or a halogen atom, represents a phenyl group or a naphthyl group. M and n each represent an integer of 1 to 4.] An imidazole derivative or a salt thereof. 2-In equation (1), R '

(Wherein, R ³ has the same meaning as described above). 41- (3-indyl) imidazole derivative or a derivative thereof according to claim 1, which is a group represented by the following formula: salt. 3. In equation (1), R '

(Wherein, R ⁴ and R ⁵ have the same meanings as described above). 41- (3-indyl) imidazole according to claim 1 Derivatives or salts thereof.  4. A pharmaceutical composition comprising, as an active ingredient, the 4- (3-indolin) imidazole derivative or a salt thereof according to any one of claims 1 to 3.  5. The 4- (3-indolin) imidazole derivative or a salt thereof according to any one of claims 1 to 3 for use as a pharmaceutically active ingredient.  6. A PDEI inhibitor comprising, as an active ingredient, a 4 — (3 — indolyl) imidazole derivative or a salt thereof according to any one of claims 1 to 3.