JPH1017567A - New imidazopyrroloquinoline compound - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject new compound represented by a specific formula, excellent in physiological activities and expected to be useful for medicines, etc. SOLUTION: A compound of the formula (R is H, carbamoyl, phenyl, 4- methylphenyl, a 1-4C alkyl, OH, carboxyl, etc.; R<1> -R<3> are each H, an alkyl, allyl, propargyl, benzyl, phenyl, an alkoxycarbonylmethyl), e.g. 7-10-dihydro-1,3,9- trimethoxycarbonyl-7-oxo-imidazo[4,5,1-ij] pyrrolo[2,3-f]quinoline. The compound of formula I is obtained by treating a pyrroloquinone ester compound with glycine or formalin/ammonium chloride.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to novel ester compounds of imidazopyrroloquinolines, and more particularly to unsubstituted and 5-substituted 7,10-dihydroester compounds. Mono, di or triester compounds of -7-oxo-imidazo [4,5,1-ij] pyrrolo [2,3-f] quinoline-1,3,9-tricarboxylic acid (sometimes referred to as IPQ esters) )
About. As the imidazopyrroloquinoline compound, 7,10-dihydro-7-oxo-imidazo [4,
5,1-ij] pyrrolo [2,3-f] quinoline-1,
Only 3,9-tricarboxylic acid is known, but its physiological activity is not yet sufficient for practical use. Therefore, development of an imidazopyrroloquinoline compound having more excellent physiological activity has been desired. An object of the present invention is to obtain an imidazopyrroloquinoline compound having such a superior physiological activity.

[0002]

The present inventors have conducted various studies to obtain a novel imidazopyrroloquinoline compound, and found that an ester compound of pyrroloquinoline (hereinafter referred to as PQQ) and various amines and amino acids or ammonia and various compounds were obtained. Reaction of aldehydes under aerobic conditions under acidic conditions, or reaction of PQQ with various aldehydes or various amino acids to obtain unsubstituted or 5-substituted IP
Q compound is obtained and then esterified to obtain IP
The inventors have found that a Q-type ester compound can be obtained, and have completed the present invention. That is, the present invention provides a compound represented by the general formula (I)

[0003]

Embedded image [Where R is hydrogen, carbamoyl group, phenyl group, 4
-Methylphenyl group, alkyl group having 1 to 4 carbon atoms, or hydroxyl group, carboxyl group, carbamoyl group, methylmercapto group, phenyl group, 4-hydroxyphenyl group, mercapto group, imidazolyl group, amino group, guanidino group, methoxy group Or an alkyl group having 1 to 4 carbon atoms substituted with a phosphoric acid group. Where R ¹ , R ² ,
R ³ represents hydrogen, an alkyl group, an allyl group, a propargyl group, a benzyl group, a phenyl group, or an alkoxycarbonylmethyl group, except for the case of all hydrogen atoms], and is a novel imidazopyrroloquinoline tricarboxylic acid ester compound represented by the formula:

[0004]

BEST MODE FOR CARRYING OUT THE INVENTION As a method for producing a novel IPQ ester of the present invention, an ester compound of PQQ and various amines, amino acids or ammonia and various aldehydes are aerobically reacted under acidic conditions. There is a way.
Further, PQQ and various amines, amino acids or ammonia and various aldehydes are aerobically reacted under acidic conditions,
Then, there is a method of esterification. In this case, R of the general formula (I) can be variously changed depending on the drug to be used, and IPQ ester compound (R = H), alanine by using methylamine, glycine, tryptophan, proline, or ammonia and formaldehyde By using a methyl IPQ ester compound (R
= CH ₃ ), a hydroxymethyl IPQ ester compound (R = CH ₂ OH) by using serine, a methylethyl IPQ ester compound (R = CH (CH ₃ ) ₂ ) by using valine, and ₂ by using leucine. -Methylpropyl IPQ ester compound (R = CH
_{2 CH (CH 3) 2)} , by using isoleucine methylpropyl IPQ ester compound (R = CH
By using (CH ₃ ) CH ₂ CH ₃ ) and glutamic acid, a 2-carboxyethyl IPQ ester compound (R
_{= CH 2 CH 2 CO 2 H} ), by using a lysine 4-hydroxyphenyl methyl IPQ ester compound

[0005] Mercaptomethyl IP by using cysteine
Q ester compound (R = CH ₂ SH), carboxymethyl IPQ ester compound (R = CH ₂ CO ₂ H) by using aspartic acid, 4-imidazolyl methyl IPQ ester compound by using histidine

[0006] -Guanidinopropyl IPQ ester compound by using arginine

[0007]Carbamoylmethyl by using asparagine
IPQ ester compound (R = CH_TwoCONH_Two), O-
By using methylserine, methoxymethyl IPQ
Ester compound (R = CH_TwoOCH_Three), O-phosphoryl
Phosphoryloxymethyl IP by using Lucerin
Q ester compound (R = CH_TwoOPO_ThreeH _Two), Serine
Carbamoyl IPQ ester by using amide
Compound (R = CONH_Two), Ammonia and propiona
Ethyl IPQ ester compound by using aldehyde
Object (R = CH_TwoCH_Three), Ammonia and butylaldehyde
Propyl IPQ ester compound by using
(R = CH_TwoCH_TwoCH_Three), Ammonia and benzal
Phenyl IPQ ester compound
Object (R = C₆H_Five) Can be obtained.

On the other hand, R ¹ , R ² and R ³ in the general formula I represent hydrogen, alkyl, allyl, propargyl, benzyl, phenyl and alkoxycarbonylmethyl groups, except that all of them are hydrogen. -1, 3, 9
-Triesters, IPQs-1,3-diesters (R ³
ＨH), IPQs-1,9-diester (R ² ＨH),
IPQ such -3,9 diester (R ¹ = H), IPQ compound 1-ester ^{(R 2 = R 3 = H} ), IPQ compound 3- ester ^{(R 1 = R 3 = H} ), IPQ acids - There are 9-esters (R ¹ = R ² = H), and the type of the ester is
They may be the same or different. I according to the present invention
The following compounds can be mentioned as ester compounds of PQs.

Compound 1: IPQ-1,3,9-trimethyl ester (IPQ-1,3,9-TME) 7,10-dihydro-1,3,9-trimethoxycarbonyl-7-oxo-imidazo [4 , 5,1-ij] pyrrolo [2,3-f] quinoline Compound 2: IPQ-3,9-dimethyl ester (IPQ
-3,9-DME) 1-carboxy-7,10-dihydro-3,9-dimethoxycarbonyl-7-oxo-imidazo [4,5,1-
ij] pyrrolo [2,3-f] quinoline Compound 3: IPQ-1,9-dimethyl ester (IPQ
-1,9-DME) 3-carboxy-7,10-dihydro-1,9-dimethoxycarbonyl-7-oxo-imidazo [4,5,1-
ij] pyrrolo [2,3-f] quinoline Compound 4: IPQ-9-methyl ester (IPQ-9-
ME) 1,3-Dicarboxy-7,10-dihydro-9-methoxycarbonyl-7-oxo-imidazo [4,5,1-
ij] pyrrolo [2,3-f] quinoline Compound 5: IPQ-3-methyl ester (IPQ-3-
ME) 1,9-dicarboxy-7,10-dihydro-3-methoxycarbonyl-7-oxo-imidazo [4,5,1-
ij] pyrrolo [2,3-f] quinoline Compound 6: IPQ-1,3,9-triallyl ester (IPQ-1,3,9-TAE) 1,3,9-triaryloxycarbonyl-7,10 -Dihydro-7-oxo-imidazo [4,5,1-ij] pyrrolo [2,3-f] quinoline Compound 7: IPQ-9-allyl ester (IPQ-9-
AE) 9-Allyloxycarbonyl-1,3-dicarboxy-
7,10-dihydro-7-oxo-imidazo [4,5
1-ij] pyrrolo [2,3-f] quinoline Compound 8: IPQ-1,3,9-tristearyl ester (IPQ-1,3,9-TSE) 7,10-dihydro-1,3,9- Trioctadecyloxycarbonyl-7-oxo-imidazo [4,5,1-i
j] pyrrolo [2,3-f] quinoline Compound 9: IPQ-9-stearyl ester (IPQ-
9-SE) 1,3-dicarboxy-7,10-dihydro-9-octadecyloxycarbonyl-7-oxo-imidazo [4,
5,1-ij] pyrrolo [2,3-f] quinoline Compound 10: IPQ-1,3-diisopropyl ester (IPQ-1,3-DIPE) 9-carboxy-7,10-dihydro-1,3-bis (1-Methylethyloxycarbonyl) -7-oxo-imidazo [4,5,1-ij] pyrrolo [2,3-f] quinoline

The method for producing the above compound is described in detail below. The IPQ esters of compounds 1 to 9 correspond to the corresponding P
The ester compound of QQ is glycine or formalin /
It can be synthesized by treating with ammonium chloride. The synthesis of these PQQ esters can be obtained by selective esterification or hydrolysis from PQQ or a triester of PQQ, and furthermore, an appropriate combination thereof. In the esterification, an acid-catalyzed reaction using an alcohol, a reaction using an alkyl halide and a base, and a reaction aid such as an alcohol or an alkoxide and a 2-halobiridinium salt, dicarbonylimidazole, or dicyclohexylcarbodiimide are used. The reaction can be performed depending on the reaction used. For the hydrolysis reaction, a reaction reagent such as trimethylsilyl iodide, lithium iodide, aluminum / alkylthiol halide, boron bromide, potassium cyanide and the like can be used in addition to the reaction under a base or acidic condition.

IPQ triesters such as Compounds 1, 6, and 8 can be prepared by the same method as PQQ triester.
And IPQ esters such as compounds 4, 7, and 9 can also be synthesized from IPQ triesters by their selective hydrolysis. Compound 10 can be synthesized by selectively hydrolyzing IPQ monomethyldiisopropyl ester derived from compound 4. IP
Purification of the Q-type ester compound is appropriately performed by extraction, recrystallization, silica gel chromatography, reverse phase chromatography,
This can be achieved by performing operations such as gel filtration, concentration, centrifugation, and drying. Means such as elemental analysis, nuclear magnetic resonance spectrum, infrared absorption spectrum, and ultraviolet / visible absorption spectrum are used to identify the IPQ ester compound. The quantitative determination of the IPQ ester compound is
It can be performed by high performance liquid chromatography. The physical properties of the compound are shown in Tables 1, 2, and 3 below.

[0012]

[Table 1] (a) Decomposition was observed during the measurement for compounds 1, 2, 3, 4, 5, and 10.

[0013]

[Table 2]

[0014]

[Table 3] (a) Tetramethylsilane in heavy dimethylsulfoxide, heavy chloroform or heavy dimethylformamide was used as an internal standard.

[0015]

EXAMPLES The present invention will be described more specifically with reference to examples, but the present invention is not limited to these examples.

Example 1 IPQ-1,3,9-trimethyl ester (compound 1)
Dissolved IPQ21.1mg of producing (61.9μmol) in dry dimethylformamide 10 ml, this 350mg
(2.54 mmol) potassium carbonate and 600 μl
(4.71 mmol) of dimethyl sulfuric acid was added. This solution was vigorously stirred at 25 ° C. for 18 hours under a nitrogen stream. The reaction mixture was poured into 10 ml of water, and then concentrated with concentrated hydrochloric acid.
And 2. The solid produced by cooling was centrifuged, and further dried under reduced pressure to obtain 16.2 mg (yield: 68%) of compound 1 as orange crystals. Mass spectrum (EI) of compound 1; m / e = 383 (M
⁺ ), 338 (M ⁺ -Me × 3), 324 (M ⁺ -CO ₂ Me), 206 (M ^-- CO ₂
Me x 3).

Example 2 IPQ-1,3,9-trimethyl ester (Compound 1)
Dissolved IPQ3.46g of preparing (10.1 mmol) in dry dimethylformamide 350ml, 88.0m thereto
1 (0.566 mol) of ethyldiisopropylamine was added. This solution was cooled on ice, and 96.2 m
1 (1.14 mol) of dimethyl sulfuric acid was added dropwise. After the dropwise addition, the reaction solution was vigorously stirred at 25 ° C. for 23 hours under a nitrogen stream. Pour the reaction mixture into 500 ml of 2N sulfuric acid,
The resulting orange solid was left at 5 ° C. for 20 hours and separated by filtration. After thoroughly washing with distilled water, the residue was dried under reduced pressure to obtain 3.19 g (yield: 82%) of compound 1 (HPLC purity: 99.0).
%).

Example 3 Preparation of IPQ-3,9-dimethyl ester (compound 2) The compound was synthesized from PQQ trimethyl ester in three steps as follows. (1) 7,9-dicarboxy-4,5-dihydro-2-
Synthesis of methoxycarbonyl-4,5-dioxo-1H-pyrrolo [2,3-f] quinoline (PQQ-2-ME) PQQ trimethyl ester 150 mg (0.403 mm
ol) in 75 ml of acetonitrile and 75 ml of 0.1
Dissolved in a mixed solvent with aqueous potassium carbonate solution
The mixture was stirred at 5 ° C for 4 hours. PH of the reaction mixture with concentrated hydrochloric acid
The mixture was adjusted to 1 and extracted with ethyl acetate. After drying over sodium sulfate, the solvent was distilled off, and the resulting orange solid was thoroughly washed with ether. After drying under reduced pressure, 98 mg (yield 64)
%) Of PQQ-2-ME as red crystals. The physical properties of this compound were as follows. Melting point;> 300 ° C (decomposition) UV-visible absorption spectrum (in methanol); 250, 27
8 ^sh 323 (nm) infrared absorption spectrum (KBr method); ν _max = 3448
^{br, m} , 1713 ^vs , 1683 ^s , 1653 ^s , 1503 ^m , 1278 ^s , 12
57 ^s , 1192 ^s (cm ^-1 ) ¹ H-NMR spectrum (deuterated dimethyl sulfoxide solvent, tetramethylsilane internal standard); δ = 3.87 (s, 3
H), 7.27 (s, 1H), 8.61 (s, 1H), 13.49 (s, 1H) ppm. (2) 2,7-dimethoxycarbonyl-9-carboxy-4,5-dihydro-4,5-dioxo Synthesis of -1H-pyrrolo [2,3-f] quinoline (PQQ-2,7-DME) 15 mg of PQQ-2-ME (0.247 mol)
Dissolved in ml of methanol, 0.3 ml of concentrated sulfuric acid was added dropwise and the mixture was heated at 60 ° C. for 4 hours. After the completion of the reaction, the pH was adjusted to 5 with 0.1 M potassium carbonate and extracted with ethyl acetate. After drying over sodium sulfate, the solvent was distilled off, and the resulting red solid was purified by silica gel chromatography (developing solvent, ethyl acetate / acetic acid = 1/2), and recrystallized from ethyl acetate to give 36 mg (yield). (41%) of PQQ-2,7-DME as red crystals. The physical properties of this compound were as follows. Melting point: 243-244 ° C. (decomposition) UV-visible absorption spectrum (in methanol); λ _max =
258 (ε = 23,500), 279 ^sh , 354 (ε = 12,600) nm infrared absorption spectrum (KBr method); ν _max = 3415
^{br, m, 1728 vs, 1616} s, 1433 m, 1261 s, 1236 s (cm -1) 1 H-NMR spectrum (deuterated dimethyl sulfoxide solvent, tetramethylsilane internal standard); δ = 3.87 (s, 3
H), 3.95 (s, 3H ), 7.27 (d, J = 2H 2, 1H), 8.63 (s, 1H), 14.
52 (s, 1H) ppm. (3) IPQ-3,9-dimethyl ester (compound 2)
Synthesis of PQQ-2,7-DME 362 mg (1.01 mmol)
l) was dissolved in 90 ml of dimethylformamide and 200 ml of methanol, and 66 ml of 37% formalin was added thereto.
And 40 ml of 20% ammonium chloride. After heating at 60 ° C. for 19 hours, the solid precipitated by cooling on ice was separated by filtration,
It was washed with 0.1N hydrochloric acid and dried under reduced pressure to obtain 280 mg of a crude solid. Further, the filtrate was concentrated and then acid precipitated to obtain 27 mg of a crude solid. The solids were combined and recrystallized from dimethyl sulfoxide to obtain 221 mg (yield: 71.8%) of Compound 2 as an orange solid.

Example 4 Preparation of IPQ-1,9-dimethyl ester (compound 3) PQQ was synthesized in two steps from trimethyl ester as follows. (1) Synthesis of 7-carboxy-4,5-dihydro-2,9-dimethoxycarbonyl-4,5-dioxo-1H-pyrrolo [2,3-f] quinoline (PQQ-2,9-DME) PQQ trimethyl 100 mg of ester (0.269 mm
ol) was dissolved in 5 ml of a mixed solvent of trichloroacetic acid-water (trifluoroacetic acid / water = 3/1) and heated at 60 ° C. for 12 hours. After cooling, 15 ml of water was added and extracted with chloroform. After drying over sodium sulfate,
The orange solid obtained by evaporating the solvent was thoroughly washed with ether. After drying under reduced pressure, 64 mg (yield 67%) of PQQ-
2,9-DME was obtained as orange-red crystals. The physical properties of this compound were as follows. Melting point: 219 to 221 ° C. UV-visible absorption spectrum (in methanol); λ _max =
258 (ε = 23,700), 279, 357 (ε = 12,900) nm infrared absorption spectrum (KBr method); ν _max = 312
2 ^{br, m} , 1747 ^s , 1716 ^vs , 1687 ^s , 1294 ^vs , 1243 ^s ,
1218 ^s (cm ^-1 ) ¹ H-NMR spectrum (deuterated dimethyl sulfoxide solvent, tetramethylsilane internal standard); δ = 3.89 (s, 3
H), 4.05 (s, 3H ), 7.28 (d, J = 2H 2, 1H), 8.56 (s, 1H),
12.52 (s, 1H) ppm. (2) IPQ-1,9-dimethyl ester (Compound 3)
Synthesis of PQQ-2,9-DME 35.8 mg (0.100 mm
ol) in 15 ml of methanol, and 37%
5 ml of formalin and 3 ml of 20% ammonium chloride were added. While stirring the reaction mixture at room temperature, p
H was adjusted to 5-6 with 4N sodium hydroxide and stirred for 5 hours. After adjusting the pH of the reaction solution to 1.5 with 2N hydrochloric acid, the solution was concentrated to half the volume using an evaporator. The precipitated solid was separated by filtration and washed with 0.1N hydrochloric acid, ethanol and ether. Dry under reduced pressure to give compound 3.
30.1 mg (81.6% yield) was obtained as an orange solid.

Example 5 Preparation of IPQ-9-methyl ester (compound 4) IPQ-1,3,9-trimethyl ester (compound 1)
76.6 mg (0.200 mmol) were suspended in 300 ml of acetonitrile, and 180 ml of a 0.1 M aqueous potassium carbonate solution was added thereto while stirring at 25 ° C.
After vigorous stirring for 28 minutes, the reaction was stopped by adding 30 ml of 1N hydrochloric acid. After the reaction mixture was concentrated to 120 ml, the precipitated solid was separated by filtration and recrystallized from dimethylformamide-isopropyl ether to give 61.2 mg.
The title compound (yield 86.2%) was obtained as orange crystals.

Example 6 Preparation of IPQ-3-methyl ester (compound 5) The compound was synthesized in two steps starting from PQQ as follows. (1) 2,9-dicarboxy-4,5-dihydro-7-
Synthesis of methoxycarbonyl-4,5-dioxo-1H-pyrrolo [2,3-f] quinoline (PQQ-7-ME) 201 mg of PQQ disodium salt (0.537 mmol
l) was dissolved in 150 ml of methanol, to which 1.5 ml of concentrated sulfuric acid was added dropwise. This solution was stirred at 35 ° C. for 3 hours, then poured into 350 ml of distilled water, adjusted to pH 1 with a 20% aqueous sodium hydroxide solution, and treated with ethyl acetate (200 ml).
× 1, 100 ml × 4). 100 organic layers
After concentration to 300 ml, diluted with 300 ml of acetonitrile,
Then, it was dried with 200 g of anhydrous sodium sulfate. After concentration, the solid was washed with ether to obtain 201 mg of a crude product. This was suspended in 25 ml of dimethylformamide and filtered to remove unnecessary substances. 200 ml in the filtrate
The precipitated red crystals were filtered off, washed with chloroform, and 165 mg (yield 89.3%) of P
QQ-7-ME was obtained. Melting point;> 250 ° C. (decomposition) UV-visible absorption spectrum (in methanol); λ _max =
275, 335 (nm) infrared absorption spectrum (KBr method); ν _max = 3417
^{br, w} , 3128 ^w , 1734 ^s , 1701 ^m , 1678 ^s , 1294 ^m (c
m ^-1 ) ¹ H-NMR spectrum (deuterated dimethyl sulfoxide solvent, tetramethylsilane internal standard); δ = 3.95 (s, 3
H), 7.19 (d, J = 2H ₂ , 1H), 8.61 (s, 1H), 13.77 (br, 1H) pp
m. 2) Synthesis of IPQ-3-methyl ester 141 mg (0.41 mmol) of PQQ-7-ME was added to 6
Dissolve in 0 ml of methanol, add 25 ml of 37% formalin and 16 ml of 20% ammonium chloride to this,
Heated to 50 ° C. for 10.5 hours. After cooling on ice, the solid was filtered off and recrystallized from dimethylformamide to give the title compound 7
9.3 mg (54.9% yield) were obtained as an orange solid.

Example 7 IPQ-1,3,9-triallyl ester (compound 6)
Dissolved manufacturing glycine 1.0g of water 30 ml, this 4
A 10 ml methanol solution in which 5.0 mg (0.10 mmol) of PQQ triallyl ester was dissolved was added (p
H4.0). This solution was vigorously stirred at 25 ° C. for 72 hours under air exposure. The reaction mixture was poured into 100 ml of water, extracted with chloroform (20 ml × 4), and the organic layer was washed with aqueous sodium bicarbonate. After drying over magnesium sulfate, the mixture was concentrated, and the residue was purified by silica gel column chromatography (developing agent: ethyl acetate / chloroform = 1/4) to give 2.9 mg (yield 6.3%) of compound 6 as orange crystals. As obtained.

Example 8 IPQ-1,3,9-triallyl ester (compound 6)
Dissolved methylamine hydrochloride 1.50g of manufacturing (22.0 mm) in water 30 ml, which in 40.0g (0.0868m
mol) of PQQ triallyl ester
1 methanol solution was added. After the pH of this solution was adjusted to 2.6 with 1N hydrochloric acid, the solution was vigorously stirred at 25 ° C. for 7 days under air exposure. The reaction mixture was poured into 100 ml of water, extracted with chloroform (20 ml × 4), and the organic layer was washed with aqueous sodium bicarbonate. After drying over magnesium sulfate, the mixture was concentrated, and the residue was purified by silica gel column chromatography (developing agent: ethyl acetate / chloroform = 1/4) to obtain 6.5 mg (yield 16%) of compound 6 as orange crystals. Was.

Example 9 IPQ-1,3,9-triallyl ester (compound 6)
Dissolved PQQ triallyl ester 52.0g of manufacture (0.116mM) in methanol 15 ml, 10 to the solution
15% aqueous formalin solution and 20% aqueous ammonium chloride solution were added. After stirring vigorously for 2 days at room temperature under air exposure, the reaction mixture was poured into 30 ml of water and extracted with chloroform (10 ml × 3). After drying and concentrating the organic layer, silica gel column chromatography (developing agent:
(Ether / chloroform = 1/4) and purified to 31.3.
mg (yield 59%) of compound 6 was obtained as orange crystals.

Example 10 IPQ-1,3,9-triallyl ester (compound 6)
2 g (5.9 mmol) of IPQ was dissolved in 200 ml of hexamethylphosphoric triamide, and silver oxide was added thereto.
1 g (26.4 mmol), 3.2 g of allyl bromide (2
6.4 mmol) and reacted at 60 ° C. for 3 hours. After the reaction solution reached room temperature, it was filtered and further concentrated. To this, 1000 ml of ethyl acetate and 800 ml of water were added, and the mixture was shaken well. After standing, the aqueous layer was removed. The organic layer was washed four times with 400 ml of water, and the organic layer was collected, concentrated,
Dried. The obtained concentrate was purified by column chromatography (silica gel 100 g, developing solvent chloroform) to obtain 1.16 g (yield 42.9%) of compound 6 as orange crystals.

Example 11 Synthesis of IPQ- 9-allyl ester (compound 7) IPQ-1,3,9-triallyl ester (compound 6)
1.0 g (2.15 mmol) of tetrahydrofuran 2
The solution was dissolved in 00 ml, and 200 ml of a 0.1 M potassium carbonate aqueous solution was further added, followed by a reaction at 25 ° C. for 3 hours. 5 ml of concentrated hydrochloric acid was added to the reaction solution, and tetrahydrofuran was distilled off under reduced pressure. 100 ml of distilled water was added thereto, and the precipitated crystals were filtered. The crystals were washed with isopropyl alcohol, methanol and diethyl ether, and then dried to obtain 0.43 g of compound 7 as orange crystals.

Example 12 IPQ-1,3,9-tristearyl ester (compound
1 g (2.9 mmol) of IPQ synthesized in 8) was dissolved in 33 ml of hexamethylphosphoric triamide, and silver oxide was added thereto.
06 g (13.2 mmol), stearyl bromide4.
4 g (13.2 mmol) was added and reacted at 60 ° C. for 7 hours. After the reaction solution reached room temperature, it was filtered and
Then, the mixture was extracted three times with 150 ml of chloroform. The extract was collected and concentrated, and methanol was added to the concentrated residue.
l was added, and the precipitated crystals were collected by filtration. The obtained crystals were purified by column chromatography (silica gel 200 g, developing solvent chloroform), further washed with methanol 1 l, and dried under vacuum to obtain 1.21 g (yield 37.6%) of compound 8 as yellow crystals. .

Example 13 Synthesis of IPQ-9-stearyl ester (compound 9 ) 0.91 g (0.5 mmol) of IPQ-1,3,9-tristearyl ester (compound 8) was dissolved in 180 ml of tetrahydrofuran. 180 ml of a 1M aqueous potassium carbonate solution was added, and the mixture was reacted at 40 ° C. for 5 hours.
4.5 ml of concentrated hydrochloric acid was added to the reaction solution, tetrahydrofuran was distilled off under reduced pressure, 100 ml of distilled water was added thereto, and the precipitated crystals were filtered. The crystals were washed with isopropyl alcohol, methanol, and diethyl ether, and then dried to obtain 0.46 g of compound 9 as yellow crystals.

Example 14 IPQ-1,3-diisopropyl ester (Compound 1
Preparation of 0) Synthesized in two steps starting from compound 4 as follows. (1) 7,10-dihydro-9-methoxycarbonyl-
1,3-bis (1-methylethyloxycarbonyl) -7
-Oxo-imidazo [4,5,1-ij] pyrrolo [2
Synthesis of 3-f] quinoline IPQ-9-methyl ester (compound 4) 10 mg
(0.028 mmol) was suspended in 5 ml of acetonitrile, and 300 μl of isopropanol and 90 μl of ethyldiisopropylamine were added thereto.
77.0 mg of chloro-1-methylpyridinium (0.3
00 mmol) was added. The mixture was stirred at room temperature for 2 hours under a nitrogen stream, and the mixture was poured into 50 ml of 0.1N hydrochloric acid and extracted with chloroform. After drying the organic layer, the solvent is distilled off, and the residue is separated by silica gel preparative thin-layer chromatography (developing agent:
Purified with chloroform: methanol = 9: 1),
11.4 mg of 0-dihydro-9-methoxycarbonyl-1,3-bis (1-methylethyloxycarbonyl) -7-oxo-imidazo [4,5,1-ij] pyrrolo [2,3-f] quinoline. (92.0% yield) as an orange solid. 266-267 ° C (decomposition) Infrared absorption spectrum (KBr method); ν _max = 2985
^w , 1726 ^s , 1660 ^s , 1242 ^vs , 1103 ^s (m ^-1 ) ¹ H-NMR spectrum (deuterated chloroform solvent, tetramethylsilane internal standard); δ = 1.46 (d, J = 6 Hz, 12
H), 3.91 (s, 3H), 5.39 (m, 2H), 7.52 (d, J = 2Hz, 1H),
8.34 (s, 1H), 9.24 (s, 1H), 12.70 (br, 1H) ppm. (2) Synthesis of IPQ-1,3-diisopropyl ester (compound 10) 7,10-dihydro-9-methoxycarbonyl- 1,3
-Bis (1-methylethyloxycarbonyl) -7-oxo-imidazo [4,5,1-ij] pyrrolo [2,3-
f] Quinoline (154 mg, 0.35 mmol)
l of dimethylformamide and add 1.41 g
(10.5 mmol) of lithium iodide was added, and the mixture was heated at 140 ° C. for 6 hours under a nitrogen atmosphere. After cooling, the reaction mixture was poured into 200 ml of 0.1N hydrochloric acid and extracted with chloroform. After drying over sodium sulfate, the solvent was distilled off under reduced pressure, and the residual solid was suspended in 30 ml of acetonitrile. This was partially dissolved by sonication and further filtered to remove insoluble solids. The filtrate was concentrated and purified by preparative thin-layer chromatography on silica gel (developing agent: chloroform: methanol = 4: 1), and recrystallized from dimethylformamide to give 33.1 mg (yield: 22.1%) of the title. The compound was obtained as an orange solid.

According to the present invention, there is provided an imidazopyrroloquinoline compound which is expected to be a drug having a higher physiological activity than conventionally known imidazopyrroloquinoline compounds.

Claims (1)

[Claims] 1. A novel imidazopyrroloquinoline tricarboxylic acid ester compound represented by the general formula (I). Embedded image [Where R is hydrogen, carbamoyl group, phenyl group, 4
-Methylphenyl group, alkyl group having 1 to 4 carbon atoms, or hydroxyl group, carboxyl group, carbamoyl group, methylmercapto group, phenyl group, 4-hydroxyphenyl group, mercapto group, imidazolyl group, amino group, guanidino group, methoxy group Or an alkyl group having 1 to 4 carbon atoms substituted with a phosphoric acid group. Where R ¹ , R ² ,
R ³ represents hydrogen, an alkyl group, an allyl group, a propargyl group, a benzyl group, a phenyl group or an alkoxycarbonylmethyl group, except in the case of hydrogen.