JPH11180980A - 1-furoyl-substituted piperazine derivative, medicine containing the same as active ingredient and intermediate for producing the same - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject new compound capable of expressing a strong inhibiting action against the bonding of secretin to sialyl Le<x> and useful for medicines for treating and preventing inflammatory dermatitis, chronic nephritis, chronic thyroiditis, etc. SOLUTION: A compound of formula I (R<1> is H or a lower alkyl), its inorganic acid salt, monocarboxylic acid salt or organic sulfonic acid salt. For example, 1-(2-furoyl)-4-[2-oxo-2-(1-phenyl-2,3-dihydro-1H-pyrrolo[2,3-b]quinoli n-4- ylamino)ethyl]piperazine. The compound of formula I is obtained by condensing a compound of formula II with a compound of the formula: XCH2 COCl (X is a halogen) and subsequently reacting the obtained compound of formula III with 1-(2-furoyl)piperazine.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

[0001] The present invention relates to a cell adhesion molecule, selectin, and sialyl Lewis x (hereinafter referred to as sialyl Le).
The following formula (I) useful as a compound that inhibits the binding to a sugar chain (abbreviated as x)

[0002]

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(Wherein R ¹ represents a hydrogen atom or a lower alkyl group) or a pharmaceutically acceptable inorganic acid salt, monocarboxylate or organic sulfonate thereof, and The present invention relates to a drug as an active ingredient and an intermediate for producing the drug.

[0004]

2. Description of the Related Art Recently, the role of selectin, a cell adhesion molecule, in various inflammatory diseases has attracted attention. Selectins include E-selectin (sometimes called ELAM-1), P-selectin (GMP-140, PA
DGEM, etc.) or L-selectin (LAM-1, LECAM-1, gp90Mel)
-14, etc.) are known, and these selectins are expressed in various cells during the process of inflammation. For example, E-selectin is TNF-
α (Tumor Necrosis Factor-α), IL-1 (Interleu
It is expressed on vascular endothelial cells near the site of inflammation by stimulation such as kin-1). P-selectin is mainly expressed in platelet α-granules and Weibel-Parade bodies of vascular endothelial cells by stimulation with thrombin, histamine and the like. Also, L
-Selectin is expressed on white blood cells.

[0005] In general, cell invasion is one of the most important findings of inflammation. In the infiltration of cells during inflammation, it is known that inflammatory cells in blood adhere to vascular endothelial cells and then infiltrate into tissues. Prior to this cell adhesion, it has been shown that a phenomenon called rolling, in which inflammatory cells roll along the blood vessel wall, occurs. This rolling is mediated by the interaction between the various selectins described above and the sialyl Lex sugar chain (ligand of selectin) present on the inflammatory cells, and as a first step of the infiltration of the inflammatory cells into the tissue. This is a very important process.

Therefore, these selectins and sialyl L
Compounds that inhibit binding to ex sugar chains are useful as preventive or therapeutic agents for various inflammatory diseases by inhibiting the adhesion between inflammatory cells and vascular endothelial cells. That is, selectin inhibitors are used for various inflammations, for example, inflammatory dermatitis such as atopic dermatitis, contact hypersensitivity, photosensitivity, chronic nephritis, asthma, etc. It is useful for the prevention or treatment of chronic immune diseases.

[0007] Also, in ischemia-reperfusion injury, it has been reported that various selectins are involved in endothelial cell damage accompanying neutrophil infiltration [Stroke, 25, 202-210 (199).
Four)〕. In fact, selectin ligand sialyl Le
It has been reported that the x derivative can suppress the impairment of the reperfusion model [J. Clin. Invest., 93, 1140-1148 (199
Four)〕. Therefore, a selectin inhibitor has an effective inhibitory effect also on ischemia-reperfusion injury (for example, US Pat.
P5,444,050).

[0008] In addition, in angiogenesis observed during the growth of cancer cells, sialyl Le, a ligand of selectin, is used.
It has been reported that x derivatives can inhibit angiogenesis in various tests (in vitro and in vivo) [Biochem. Bi
ophys. Res. Commun, 228, 716-723 (1996)]. Therefore, the selectin inhibitor can be an inhibitor for diseases involving angiogenesis, for example, cancer growth.

Further, it has been reported that selectin plays an important role in cancer metastasis [Science, 246, 1303].
-1306 (1989)]. Therefore, selectin inhibitors can also be inhibitors of cancer metastasis.

Although various compounds that inhibit selectin are already known, 1-furoyl-substituted piperazine derivatives are
unknown.

[0011]

SUMMARY OF THE INVENTION An object of the present invention is to provide a novel compound which strongly inhibits the binding between selectin and sialyl Lex, a process for producing the same, and a drug containing the same as an active ingredient.

[0012]

As a result of various studies, the present inventors have found that the 1-furoyl-substituted piperazine derivative represented by the general formula (I) strongly inhibits the binding between selectin and sialyl Lex. The present invention has been found to have an effect, and the present invention has been completed.

[0013]

BEST MODE FOR CARRYING OUT THE INVENTION The compound of the present invention has the following formula (I)

[0014]

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(Wherein R ¹ represents a hydrogen atom or a lower alkyl group) or a pharmaceutically acceptable inorganic acid salt, monocarboxylate or organic sulfonate thereof.

In the specification of the present application, a lower alkyl group means a linear or branched alkyl group having 1 to 4 carbon atoms,
Specifically, a methyl group, an ethyl group, an n-propyl group, is
Examples thereof include an o-propyl group, an n-butyl group, a sec-butyl group and a tert-butyl group.

The pharmaceutically acceptable inorganic, monocarboxylate or organic sulfonate includes, for example, hydrochloride, hydrobromide, acetate, methanesulfonate and p-toluenesulfonic acid. Salts and the like can be exemplified. Further, the present invention includes the compound represented by the formula (I) and an inorganic acid salt, a monocarboxylic acid salt or an organic sulfonate thereof, and also a hydrate thereof.

The lower alkyl group is preferably a methyl group. Further, as the pharmaceutically acceptable inorganic acid salt, monocarboxylate or organic sulfonate, inorganic acid salt or organic sulfonate is preferable, and among them, hydrochloride, methanesulfonic acid salt or p-toluenesulfonic acid salt is preferable. Is particularly preferred.

Specific examples of the compound (I) of the present invention are listed below. 1- (2-furoyl) -4- [2-oxo-2- (1
-Phenyl-2,3-dihydro-1H-pyrrolo [2,3
-B] quinolin-4-ylamino) ethyl] piperazine 1- (2-furoyl) -4- [2-oxo-2- (1
-Phenyl-2,3-dihydro-1H-pyrrolo [2,3
-B] quinolin-4-ylamino) ethyl] piperazine hydrochloride 1- (2-furoyl) -4- [2-oxo-2- (1
-Phenyl-2,3-dihydro-1H-pyrrolo [2,3
-B] quinolin-4-ylamino) ethyl] piperazine methanesulfonate 1- (2-furoyl) -4- [2-oxo-2- (1
-Phenyl-2,3-dihydro-7-methyl-1H-pyrrolo [2,3-b] quinolin-4-ylamino) ethyl] piperazine The meanings of the abbreviations and symbols used herein are shown below. DMF: N, N-dimethylformamide DMAP: 4-dimethylaminopyridine THF: tetrahydrofuran TEA: triethylamine LDA: lithium diisopropylamide DMSO: dimethylsulfoxide The method for producing compound (I) is described below. 1. Method for producing compound (I) Compound (I) is prepared, for example, by the following method (Scheme 1)

[0020]

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Wherein X represents a halogen atom, and R ¹ is the same as described above.

First, the compound (III) is condensed with the tricyclic amine derivative (II) to obtain a compound (IV). The reaction is performed by dissolving the tricyclic amino derivative (II) in an aprotic solvent such as THF, chloroform, acetone or DMF,
1.2 to 3 equivalents of an organic base such as TEA, pyridine or DMAP or an inorganic base such as potassium carbonate or sodium carbonate is added, and a halogenated acetyl chloride (III) such as chloroacetyl chloride is added. 2
The target compound (I) was reacted at 0 ° C. to 70 ° C. for 4 hours.
V).

Next, the compound (IV) and the compound (V) are condensed to obtain the desired compound (I). The reaction is carried out by dissolving compound (V) and compound (IV) in an aprotic solvent such as DMF and adding 1.2 to 3 equivalents of an inorganic base such as potassium carbonate, preferably for 1 to 10 hours. React at 70 ° C. After completion of the reaction, the target compound (I) is obtained by purification by recrystallization or column chromatography according to a conventional method.

The compound (I) thus produced can be converted into the pharmaceutically acceptable acid addition salt by a conventional method. 2. Production method of intermediate (II) : Intermediate (II) is a novel compound, and is, for example, of the following formula (Scheme 2)

[0025]

Embedded image (Wherein R ¹ is the same as described above).

First, the compound (VIII) is obtained by condensing 1-phenyl-2-pyrrolidinone (VI) and a 2-cyanoaniline derivative (VII). The reaction is performed by dissolving 1-phenyl-2-pyrrolidinone (VI) in an inert solvent such as chloroform or toluene, and adding a condensing agent such as phosphorus oxychloride, phosphorus pentachloride, or thionyl chloride in an amount of usually 0.5 to 10 moles, Preferably, 1.0 to 4 times mol is added, and the mixture is reacted at 0 ° C to 50 ° C for 10 minutes to 3 hours. Then, the cyanoanilino derivative (VII) is added, and the mixture is reacted at 0 ° C to 150 ° C to convert the amidine derivative (VIII). obtain.

Next, the target compound (II) is obtained by a cyclization reaction of the amidine derivative (VIII). The reaction is performed in the presence of an acid or a base.

When the reaction is carried out in the presence of an acid, a Lewis acid such as zinc chloride, zinc bromide or aluminum chloride is used as the acid, and the reaction is carried out at 50 ° C. to 200 ° C. in an inert solvent such as nitrobenzene, chlorobenzene or toluene. Let it.

When the reaction is carried out in the presence of a base, lithium diisopropylamide, butyl lithium,
The reaction is carried out at −50 ° C. to 100 ° C. in an inert solvent such as THF or ether using sodium ethoxide or the like.

The compound (II) thus produced can be converted into a salt of an inorganic acid or an organic acid, for example, a hydrochloride, a sulfate, a methanesulfonate, a p-toluenesulfonate or the like by a conventional method. .

The compounds of the present invention are useful as selectin inhibitors as described below, and can be used for the prevention or treatment of various inflammatory diseases, cancer or ischemia-reperfusion injury.

The drug containing the compound (I) of the present invention or a pharmaceutically acceptable inorganic salt, monocarboxylate or organic sulfonate as an active ingredient is orally or parenterally administered to a patient. The dose varies depending on the disease to be applied, the method of administration, the age, weight or condition of the patient, and the like. Generally, the range of 1 to 600 mg / day as the compound (I) of the present invention is appropriate. Alternatively, it is administered in 2 to 4 times a day.

As the dosage form, tablets, granules, fine granules, capsules, injections, liposomes and the like are used depending on the administration form.

Such a preparation is manufactured by a conventional method, and tablets, granules and fine granules are prepared by mixing the compound (I) of the present invention or the pharmaceutically acceptable acid addition salt thereof with a usual pharmaceutical additive, for example, Lactose, synthetic aluminum silicate, glucose, mannitol, crystalline cellulose, excipients such as starch, carboxymethyl cellulose, disintegrants such as sodium alginate, magnesium stearate, lubricants such as talc, or hydroxymethyl cellulose, hydroxypropyl cellulose, Capsules are prepared by mixing a binder such as hydroxypropylmethylcellulose and polyvinylpyrrolidone, and capsules are prepared by appropriately filling the above granules and powders into capsules.

For injection, compound (I) of the present invention or the pharmaceutically acceptable acid addition salt thereof is dissolved or suspended in sterile water, and mannitol, sodium chloride, glucose, sorbit, glycerol, xylitol, By adding an isotonic agent such as fructose, maltose and mannose, and, if necessary, further adding a stabilizer such as sodium sulfite and albumin and a preservative such as benzyl alcohol, and aseptically encapsulating in ampoules or vials. Manufactured.

[0036]

The compound of the general formula (I) of the present invention or the pharmaceutically acceptable acid addition salt thereof has a strong bond between E-selectin, P-selectin and / or L-selectin and sialyl Lex. Inhibits (see Test Example 1),
Inhibits cell infiltration in an inflammation animal model (see Test Example 2). Furthermore, the compounds of the general formula (I) of the present invention and the pharmaceutically acceptable acid addition salts thereof have low toxicity. Therefore, the compound of the present invention is useful as a selectin inhibitor, various inflammations such as atopic dermatitis, contact hypersensitivity, inflammatory dermatitis such as photosensitivity, rheumatoid arthritis,
It is suitably used for treating or preventing autoimmune chronic diseases such as chronic thyroiditis and ischemia-reperfusion injury, cancer and the like. (Test Example 1) Binding inhibition test between E-, P- and L-selectin and sialyl Lex (1) Test compound ・ Compound of the present invention a (compound of Example 3) ・ Compound of the present invention b (Compound of Example 4 Compound)-Compound c of the present invention (compound of Example 5)-Compound d of the present invention (compound of Example 6)-Known compound X Sialyl Lex Test method 2-1) Test for inhibition of binding between E-selectin and sialyl Lex (Foxall, C.) et al.
Method using gG chimera [J. Cell Biol., 117, 895-902
(1992)].

After dissolving a sialyl Lex pentasaccharide derivative (see Reference Example below) in 50% methanol / distilled water,
100 pmol / well was placed in a 6-well plate, allowed to stand at room temperature overnight, and the solvent was evaporated. 5% BSA (Bovi
ne Serum Albumin) and 50 mM imidazole buffer (pH 7.2) containing 1 mM calcium chloride for 1 hour at room temperature.

On the other hand, biotin-labeled anti-human IgG (Fc)
And streptavidin-labeled alkaline phosphatase containing 1% BSA and 1 mM calcium chloride.
50 mM each in mM imidazole buffer (pH 7.2)
After adding 0-fold dilution, E-
A complex solution was prepared by adding a selectin IgG chimera.

The test compound was dissolved in DMSO and 10 mM
A solution was prepared and this was added to a 50 mM imidazole buffer (pH 7.0) containing 1% BSA and 1 mM calcium chloride.
By diluting sequentially in 2), a solution having eight concentrations (from 1 mM to 2-fold dilution) was prepared. Equal volumes of each concentration solution of the test compound and the above complex solution were mixed and incubated at room temperature for 30 minutes to prepare a reaction solution.

After the completion of the blocking, the blocking solution of the plate is discarded and 50 mM imidazole buffer solution (pH
After washing in 7.2), the above reaction solution (50 μl / well)
Was added and incubated at 37 ° C. for 45 minutes. next,
Plates are washed with 50 mM imidazole buffer (pH 7.2)
And 3 times each with distilled water, and 50 μl of 1M diethanolamine (pH 9.8) containing 0.01% magnesium chloride and 1 mg / ml paranitrophenyl phosphate.
/ Well put and color was developed for 1-2 hours. Then 405
The absorbance at nm was measured. Using the absorbance (A) of the well containing no test compound as a control, the absorbance (X) of the well containing each concentration of the test compound was measured, and the following formula was used.

[0041]

## EQU1 ## After calculating the binding ratio (%) at each concentration according to the binding ratio (%) = (X / A) × 100, the IC ₅₀ value was calculated by the probit method.

The absorbances A and X are values obtained by subtracting the absorbance of the well containing no E-selectin IgG chimera and the test compound as the background. 2-2) Binding inhibition test between P-selectin and sialyl Lex E-selectin IgG chimera (10 μg / ml) was
The test was conducted in the same manner as in 2-1) except that the selectin IgG chimera (10 μg / ml) was used. 2-3) Test for inhibition of binding between L-selectin and sialyl Lex E-selectin IgG chimera (10 μg / ml) was
The test was conducted in the same manner as in 2-1) except that the selectin IgG chimera (10 μg / ml) was used. (3) Test results The results are shown in Table 1.

[0043]

[Table 1]

Test Example 2 Cell Invasion Inhibiting Effect Report of Bradley (PP) and others [Journal of I
nvestigative Dermatology, 78, 206-209 (1982))
According to myeloperoxidase (hereinafter MP
O) activity was used as an indicator of cell invasion. (1) Test compound Compound of the present invention a (compound of Example 3) (2) Test method A physiological saline solution containing 3 g of ovalbumin and 4 mg of aluminum hydroxide gel was added to an 8-week-old female BALB / c mouse. It was sensitized by intraperitoneal injection of 5 ml. Two weeks later, an inflammatory reaction was induced by injecting 10 μl of ovalbumin, which was adjusted to 1 mg / ml using phosphate buffered saline, into the auricles of both sides of the mouse. In the non-inflammation group, the same solution was intradermally injected into both auricles of a non-sensitized animal.
The test compound was added to a concentration of 1 mg / ml in 0.0
It was dissolved in 017N hydrochloric acid and administered intravenously in a volume of 0.1 ml / 10 g body weight 2, 5 and 8 hours after the induction of inflammation.
The control group received 0.0017N hydrochloric acid intravenously. Twenty-four hours after the induction of the reaction, both ears were cut out to a diameter of 6 mm, homogenized and centrifuged, and the MPO activity of the supernatant was determined according to the method of Bradley et al.
-Absorbance of dianisidine at 450 nm (hereinafter referred to as OD)
Was measured as an index.

The inhibition rate of cell infiltration was determined by the following equation.

[0046]

(Equation 2) ODexp: average OD of the test compound-administered group OD nega: average OD of the non-inflammation-inducing group ODcont: average OD of the control group A significant difference test of the test compound-administered group to the control group was performed by the Dunnett method. (3) Test results The results are shown in Table 2.

[0047]

[Table 2]

[0048]

EXAMPLES The present invention will be described more specifically with reference to the following Reference Examples and Examples. Reference Example Sialyl Lex pentasaccharide derivative: 3-tridecyl hexadeci
O- (5-acetamido-3,5-dideoxy-D
-Glycero-α-D-galact-2-nonulopyranosiro
Acid)-(2 → 3) -O- (β-D-galactopyranosi
)-(1 → 4) -O-[(α-L-fucopyranosyl)
-(1 → 3)]-O- (2-acetamido-2-deoxy
C-β-D-glucopyranosyl)-(1 → 3) -β-D
-Production of galactopyranoside (1) 3-tridecylhexadecanol: 3-tridecylhexadecanoic acid (439 mg) in THF (10.0 m
l) 1 M borane-THF complex / THF solution (2.0 ml) was added to the solution at 0 ° C, and the mixture was stirred at room temperature for 15 hours. The reaction mixture was poured into a mixed solution of water / THF (80 ml / 40 ml) and neutralized with sodium hydrogen carbonate. The reaction mixture was extracted with ethyl acetate, the organic layers were combined, washed with saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue is subjected to silica gel medium pressure liquid chromatography (n-hexane: ethyl acetate = 20: 1).
And 392 mg of the title compound was obtained. ¹ H-NMR (CDCl ₃ ) δ: 0.89 (t, J = 7 Hz, 6H), 1.2
0-1.40 (m, 48H), 1.50-1.60 (m, 3H), 3.67 (t, J = 7 Hz, 2H). (2) 3-tridecylhexadecyl O- (methyl 5
-Acetamido-4,7,8,9-tetra-O-acetyl-3,5-dideoxy-D-glycero-α-D-galact-2-nonulopyranosylonate)-(2 → 3) -O
-(2,4,6-tri-O-benzoyl-β-D-galactopyranosyl)-(1 → 4) -O-[(2,3,4-
Tri-O-acetyl-α-L-fucopyranosyl)-(1
→ 3)]-O- (2-acetamido-6-O-acetyl-2-deoxy-β-D-glucopyranosyl)-(1 →
3) -2,4,6-Tri-O-acetyl-β-D-galactopyranoside: a method known in the literature [J. Carbohydr. Chem., 11, 645-658 (199)
2)], the O- (methyl 5-acetamido-4,
7,8,9-tetra-O-acetyl-3,5-dideoxy-D-glycero-α-D-galact-2-nonulopyranosylonate)-(2 → 3) -O- (2,4, 6-tri-O-benzoyl-β-D-galactopyranosyl)-
(1 → 4) -O-[(2,3,4-tri-O-acetyl-α-L-fucopyranosyl)-(1 → 3)]-O- (2
-Acetamide-6-O-acetyl-2-deoxy-β
-D-glucopyranosyl)-(1 → 3) -2,4,6-
Molecular sieves 4 was added to a solution of 25 mg of tri-O-acetyl-α-D-galactopyranosyl trichloroacetimidate and 28 mg of 3-tridecylhexadecanol [see (1) above] in methylene chloride (0.3 ml).
Add A type AW300 (56 mg) and add 4
After stirring for an hour, boron trifluoride diethyl ether complex (8 mg) was added at 0 ° C., and the mixture was stirred at the same temperature for 18 hours. Ethyl acetate was added to the reaction mixture, and the insoluble material was removed by filtration.
The organic layer was washed with saturated aqueous sodium hydrogen carbonate and water, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel medium pressure liquid chromatography (n-hexane: ethyl acetate = 1: 1 to ethyl acetate) to obtain 21 mg of the title compound.

[Α] _D -10} (c = 0.59, CH
Cl ₃ ) ¹ H-NMR (CDCl ₃ ) δ: 0.89 (t, J = 7 Hz, 6H), 1.15
1.40 (m, 48H), 1.21 (d, J = 7Hz, 3H), 1.78 (s, 3H), 1.82 (s, 3
H), 1.90 (s, 3H), 1.93 (s, 3H), 2.00 (s, 3H), 2.03 (s, 3H), 2.0
5 (s, 3H), 2.07 (s, 3H), 2.08 (s, 3H), 2.09 (s, 3H), 2.12 (s, 3
H), 2.41 (dd, J = 4,13Hz, 1H), 3.81 (s, 3H), 5.60-5.70 (m, 1
H), 7.40-8.20 (m, 15H). (3) 3-tridecylhexadecyl O- (5-acetamido-3,5-dideoxy-D-glycero-α-D-
Galact-2-nonulopyranosylonic acid)-(2 → 3)-
O- (β-D-galactopyranosyl)-(1 → 4) -O
-[(Α-L-fucopyranosyl)-(1 → 3)]-O-
(2-acetamido-2-deoxy-β-D-glucopyranosyl)-(1 → 3) -β-D-galactopyranoside: 46 mg of the compound of the above (2) in methanol (10 m
l) 8 mg of sodium methoxide was added to the solution, and the mixture was stirred at 50 ° C for 14 hours. 1 ml of water was added to the reaction mixture, and the mixture was further stirred at the same temperature for 24 hours. The reaction mixture was returned to room temperature and ion-exchange resin [DOWEX ^™ (50W-X8, H
⁺ Form)] and purified by column chromatography (Sephadex ^™ LH-20, chloroform: methanol = 5: 4) to obtain 29 mg of the title compound.

[Α] _D -15 ゜ [c = 0.49, CH
Cl ₃ -MeOH (1: 1)]. ¹ H-NMR (CD ₃ OD) δ: 0.90 (t, J = 6 Hz, 6H), 1.17
(d, J = 7Hz, 3H), 1.20-1.40 (m, 48H), 1.89 (t, J = 12Hz, 1H), 1.
98 (s, 3H), 2.00 (s, 3H), 2.78 (dd, J = 4,13Hz, 1H), 4.22 (d, J =
7 Hz, 1 H), 4.52 (d, J = 8 Hz, 1 H), 5.06 (d, J = 4 Hz, 1 H). Mass spectrum (m / e): 1413 (M + Na) ⁺ Example 1 4-amino-1-phenyl -2,3-dihydro-1H-
Pyrrolo [2,3-b] quinoline [of the general formula (II)
R ¹ Te production of a compound] a hydrogen atom: 1) 2 - [(1-phenyl-2-pyrrolidinylidene) amino] benzonitrile: N- phenyl-pyrrolidone (1
5.0 g) was dissolved in chloroform (50 ml), phosphorus oxychloride (9.54 ml) was added under ice-cooling, and the mixture was stirred at room temperature for 30 minutes. Then, a solution of 2-aminobenzonitrile (10.99 g) in chloroform (40 ml) was added. Was added. After the reaction mixture was heated under reflux for 2 hours, ice water was added under ice cooling. further,
A 20% aqueous NaOH solution was added to neutralize, extracted with chloroform, and washed with saturated saline. After drying over anhydrous sodium sulfate and evaporating the solvent under reduced pressure, diethyl ether 100
The precipitated yellow plate-like crystals were collected by filtration, and the target compound was removed.
(19.4 g) was obtained.

Melting point: 104-106 ° C. ¹ H-NMR (CDCl ₃ ) d: 2.00-2.20 (m, 2H), 2.61 (t,
2H, J = 7.8Hz), 3.92 (t, J = 6.9Hz, 2H), 6.88 (d, J = 7.6Hz, 1H),
6.95-7.05 (m, 1H), 7.05-7.20 (m, 1H), 7.35-7.50 (m, 3H), 7.
50-7.60 (m, 1H), 7.75 to 7.85 (m, 2H). Mass spectrum (m / e): 262 (M + H) ⁺ 2) 4-Amino-1-phenyl-2,3-dihydro-1.
H-pyrrolo [2,3-b] quinoline: Under argon atmosphere, the compound (1.31 g) of the above compound (1.31 g) in THF (20 m
l) The suspension was cooled to -28 ° C. LDA with stirring at the same temperature
-THF complex (1.5 M cyclohexane solution; 4 ml) was slowly added dropwise. Thereafter, the temperature of the reaction solution was gradually increased to 35
Minutes. Ice water was added to the reaction solution, which was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and the solvent was concentrated under reduced pressure. Toluene was added to the residue, and the precipitated crystals were collected by filtration to give the desired compound.
(1.0 g) was obtained as a yellow powder.

Melting point: 226-229 ° C. (decomposition) ¹ H-NMR (CDCl ₃ ) d: 3.08 (t, J = 8.1 Hz, 2H), 4.1
6 (t, 2H, J = 8.1Hz), 4.30 (br s, 2H), 7.02 (t, J = 7.3Hz, 1H),
7.15-7.30 (m, 1H), 7.35-7.60 (m, 4H), 7.70-7.80 (m, 1H), 8.
00-8.05 (m, 2H). Mass spectrum (m / e): 261 (M ⁺ ). Example 2 4-Amino-7-methyl-1-phenyl-2,3-diphenyl
Dro-1H-pyrrolo [2,3-b] quinoline [general formula (I
I) a compound wherein R ¹ is a 7-methyl group]
Production : 1) 4-Methyl-2-[(1-phenyl-2-pyrrolidinylidene) amino] benzonitrile: N-phenylpyrrolidone (6.1 g) was dissolved in chloroform (15 ml), and phosphorus oxychloride (3 .88 ml) at room temperature.
After stirring for 2 minutes, 2-amino-4-methylbenzonitrile
(5 g) in chloroform (15 ml) was added. After the reaction mixture was refluxed under heating for 2 hours, ice water was added under ice cooling. Further, the mixture was neutralized by adding a 20% aqueous NaOH solution, extracted with chloroform, and washed with saturated saline. After drying over anhydrous sodium sulfate and evaporating the solvent under reduced pressure, 30 ml of diethyl ether was added, and the precipitated pale yellow plate crystals were collected by filtration to obtain the desired compound (6.68 g).

Melting point: 177-179 ° C. ¹ H-NMR (CDCl ₃ ) d; 2.00-2.25 (m, 2H), 2.33 (s,
3H), 2.61 (t, J = 7.8Hz, 2H), 3.91 (t, J = 6.9Hz, 2H), 6.71 (s, 1
H), 6.80-6.90 (m, 1H), 7.10-7.20 (m, 1H), 7.30-7.50 (m, 3
H), 7.78 (dd, J = 0.9, 8.6 Hz, 2H). Mass spectrum (m / e): 276 (M + H) ⁺ 2) 4-amino-7-methyl-1-phenyl-2,3-
Dihydro-1H-pyrrolo [2,3-b] quinoline: The compound (2 g) of the above 1) was dissolved in nitrobenzene (5 ml), zinc chloride (1.39 g) was added, and the mixture was heated and stirred at 140 ° C. for 2 hours. . The reaction mixture was returned to room temperature, ethyl acetate was added, and a 20% aqueous NaOH solution was added to adjust the pH to 10. After extraction with ethyl acetate, the extract was washed with saturated saline. After drying over anhydrous sodium sulfate and evaporating the solvent under reduced pressure, diethyl ether (30 ml) was added and the precipitated light brown plate-like crystals were collected by filtration to obtain the title compound (1.02 g). The filtrate obtained by crystallization by adding diethyl ether was subjected to silica gel medium pressure column chromatography (n-hexane / ethyl acetate = 3/1 → 1/1 → ethyl acetate only) to give the target compound (103 mg). Obtained.

Melting point: 202-206 ° C. (decomposition)¹ H-NMR (CDCl_Three) D; 2.47 (s, 3H), 3.06 (t, J = 8.1
Hz, 2H), 4.15 (t, J = 8.1Hz, 2H), 4.27 (br, 2H), 7.00-7.15 (m,
2H), 7.35-7.55 (m, 3H), 7.60 (br, 1H), 8.00-8.10 (m, 2H). Mass spectrum (m / e): 276 (M + H)⁺  Example 31- (2-furoyl) -4- [2-oxo-2- (1-
Phenyl-2,3-dihydro-1H-pyrrolo [2,3-
b] Quinolin-4-ylamino) ethyl] piperazine
[In the general formula (I), R ¹ Is a hydrogen atom)
Manufacturing of: 1) 4-chloroacetylamino-1-phenyl-2,3
-Dihydro-1H-pyrrolo [2,3-b] quinoline: working
Compound of Example 1 (523 mg) in chloroform (12 ml)
, 0.396 ml of pyridine, 24.4 m of DMAP
g, chloroacetyl chloride (0.24 ml)
Stirred at room temperature for 1 hour. To the reaction mixture was added saturated aqueous sodium bicarbonate
After extraction with loroform, the extract was washed with saturated saline. Sulfuric anhydride
After drying over sodium and distilling off the solvent under reduced pressure,
Chill (4 ml) and diethyl ether (20 ml) were added for precipitation.
The obtained light brown plate-like crystals were collected by filtration, and the target compound (532 mg) was obtained.
Obtained.

Melting point: 146-148 ° C. ¹ H-NMR (CDCl ₃ ) d; 3.24 (t, J = 7.9 Hz, 2H), 4.17
(t, J = 7.9 Hz, 2H), 4.35 (s, 3H), 7.08 (t, J = 7.3Hz, 1H), 7.20
-7.35 (m, 1H), 7.40-7.75 (m, 4H), 7.80-7.90 (m, 1H), 8.00-
8.10 (m, 2H), 8.50 (br, 1H). Mass spectrum (m / e): 338 (M + H) ⁺ 2) 1- (2-furoyl) -4- [2-oxo-2-
(1-Phenyl-2,3-dihydro-1H-pyrrolo [2,3-b] quinolin-4-ylamino) ethyl] piperazine: The compound of the above 1) (200 mg) was added to DMF (7
ml) and 1- (2-furoyl) piperazine (17
2 mg) and potassium carbonate (245 mg) were added, and the mixture was stirred at 50 ° C. for 2 hours. Water and saturated aqueous sodium hydrogen carbonate were added to the reaction mixture, extracted with ethyl acetate, and washed with saturated saline. After drying over anhydrous sodium sulfate, purification was performed by silica gel medium pressure column chromatography (chloroform only → chloroform / methanol = 40/1) to obtain 205 mg of the desired compound.

Melting point: 95-97 ° C. ¹ H-NMR (CDCl ₃ ) d; 2.85 (t, J = 5 Hz, 4H), 3.26
(t, J = 7.9Hz, 2H), 3.36 (s, 2H), 3.95-4.10 (m, 4H), 4.17 (t, J
= 8Hz, 2H), 6.52 (dd, J = 1.8,3.5Hz, 1H), 7.05-7.15 (m, 2H),
7.30-7.40 (m, 1H), 7.40-7.50 (m, 2H), 7.55-7.65 (m, 3H), 7.
84 (d, J = 8.3Hz, 1H), 8.00-8.15 (m, 2H), 9.34 (brs, 1H). Mass spectrum (m / e): 482 (M + H) ⁺ Example 4 1- (2-furoyl ) -4- [2-oxo-2- (1-
Phenyl-2,3-dihydro-1H-pyrrolo [2,3-
b] quinolin-4-ylamino) ethyl] piperazine.
1 methanesulfonic acid salt [In the general formula (I), R ¹ is water
Production of methanesulfonate of compound which is an element atom]: The compound of Example 3 (40 mg) was dissolved in chloroform (2 ml), and methanesulfonic acid (8 mg) in chloroform (0.
33 ml) solution and stirred at room temperature for 10 minutes. The solvent was distilled off under reduced pressure, 1 ml of diethyl ether was added, and the precipitated pale yellow plate crystals were collected by filtration to obtain the title compound (44.2 mg).

Melting point: 183-186 ° C. (decomposition) ¹ H-NMR (CDCl ₃ ) d; 2.62 (s, 2H), 3.00-3.20 (m,
4H), 3.27 (t, J = 7.8Hz, 2H), 4.00-4.25 (m, 4H), 4.15 (t, J = 7.
8Hz, 2H), 6.52 (dd, J = 1.8,3.5Hz, 1H), 7.10 (dd, J = 0.8,3.5H
z, 1H), 7.30-7.65 (m, 6H), 7.70-7.90 (m, 3H), 7.90-8.00 (m,
1H). Example 5 1- (2-furoyl) -4- [2-oxo-2- (1-
Phenyl-2,3-dihydro-1H-pyrrolo [2,3-
b] quinolin-4-ylamino) ethyl] piperazine.
Monohydrochloride [In the general formula (I), R ¹ is a hydrogen atom
Preparation of Compound Hydrochloride]: Compound of Example 3 (40 mg)
Was dissolved in chloroform (2 ml), and acetyl chloride was dissolved.
(6.6 mg) and a mixture of methanol (0.44 ml) were added, and the mixture was stirred at room temperature for 10 minutes. The solvent was distilled off under reduced pressure,
Diethyl ether (2 ml) was added, and the precipitated pale yellow plate-like crystals were collected by filtration to obtain the title compound (42.5 mg).

Melting point: 195-200 ° C. (decomposition) ¹ H-NMR (CDCl ₃ ) d; 2.90-3.20 (m, 4H), 3.30 (t,
J = 7.8Hz, 2H), 4.10-4.30 (m, 6H), 6.52 (dd, J = 1.8,3.5Hz, 1
H), 7.10-7.20 (m, 1H), 7.30-8.10 (m, 10H). Example 6 1- (2-furoyl) -4- [2-oxo-2- (7-
Methyl-1-phenyl-2,3-dihydro-1H-pyro
B [2,3-b] quinolin-4-ylamino) ethyl]
Piperazine [in the formula (I), R ¹ is a 7-methyl group;
Preparation of a compound] is: 1) 4-Chloro-acetylamino-7-methyl-1-phenyl-2,3-dihydro -1H- pyrrolo [2,3-b] quinoline: The compound of Example 2 (275 mg) Chloroform
(6 ml), pyridine (0.198 ml), DM
AP (12.2 mg), chloroacetyl chloride (0.
119 ml) and stirred at room temperature for 1 hour. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform and washed with saturated saline. After drying over anhydrous sodium sulfate and evaporating the solvent under reduced pressure, ethyl acetate (5 ml) was added and the precipitated pale yellow plate-like crystals were collected by filtration to obtain the title compound (211 mg).
The filtrate obtained by adding ethyl acetate for crystallization was subjected to silica gel medium pressure column chromatography (n-hexane / ethyl acetate = 3/1 → 2/1 → 1/1) to give the desired compound (57 mg). Obtained.

Melting point: 219-221 ° C. ¹ H-NMR (CDCl ₃ ) d; 2.49 (s, 3H), 3.22 (t, J = 7.9)
Hz, 2H), 4.16 (t, J = 7.9Hz, 2H), 4.34 (s, 2H), 7.00-7.20 (m, 2
H), 7.40-7.50 (m, 2H), 7.53 (d, J = 8.3Hz, 1H), 7.65 (br, 1H),
8.02 (d, J = 7.9 Hz, 2H), 8.44 (brs, 1H). Mass spectrum (m / e): 351 (M ⁺ ) 2) 1- (2-Floyl) -4- [2-oxo-2 −
(7-methyl-1-phenyl-2,3-dihydro-1H
-Pyrrolo [2,3-b] quinolin-4-ylamino) ethyl] piperazine: The compound of the above 1) (100 mg) was added to D
Dissolve in MF (3 ml), add 1- (2-furoyl) piperazine (83 mg) and potassium carbonate (118 mg), and add
Stirred at C for 2 hours. Water and saturated aqueous sodium hydrogen carbonate were added to the reaction mixture, extracted with ethyl acetate, and washed with saturated saline.
After drying over anhydrous sodium sulfate, ethyl acetate (2 ml) was added, and the precipitated light brown plate-like crystals were collected by filtration, and the target compound (29 m
g) was obtained.

Melting point: 177-181 ° C.¹ H-NMR (CDCl_Three) D; 2.49 (s, 3H), 2.80-2.90 (m,
4H), 3.24 (t, J = 7.8Hz, 2H), 3.35 (s, 2H), 3.95-4.05 (m, 4H),
4.16 (t, J = 7.9Hz, 2H), 6.52 (dd, J = 1.7,3.5Hz, 1H), 7.05-7.
20 (m, 3H), 7.40-7.60 (m, 4H), 7.65 (brs, 1H), 8.00-8.10 (m,
2H), 9.31 (brs, 1H). Mass spectrum (m / e): 496 (M + H)⁺  Example 7Tablet manufacturing As described below, the compound of Example 3 (compound a) 1 in one tablet
A tablet containing 00 mg is obtained. [Prescription][Operation] Main drug, corn starch and microcrystalline cellulose
After mixing, the hydroxypro dissolved in 50 parts by weight of water was added.
Add pill cellulose and knead well. Sieve the kneaded material
After passing through and granulating on granules and drying, the resulting granules
Mix with magnesium stearate and press into a tablet.
Lock. Example 8Manufacture of granules As described below, the compound of Example 3 (compound
a) A granule containing 200 mg is obtained. [Prescription][Operation] Mix the active ingredient, lactose and corn starch
Hydroxypropyl cellulose dissolved in 120 parts by weight of water
And knead well. This kneaded material is 20 mesh
Granulated through a sieve, dried and sized to obtain granules
You. Example 9Manufacture of capsules As described below, the compound of Example 3 (compound
a) Obtain a capsule containing 100 mg. [Prescription][Operation] Thoroughly mix the above components, and mix 2
A capsule is obtained by filling the capsule with the amount of 00 mg. Example 10Production of injections 0.5 parts by weight of the compound of Example 3 (compound a) and sol
Dissolve by adding distilled water for injection to a mixture of 5 parts by weight of bit
To 100 parts by weight.
Filter with a filter. 5 g in the ampoule of which the filtrate was replaced with nitrogen
After filling, sealing and sterilizing at 120 ° C for 15 minutes,
Injection containing 25 mg of compound a in ampoule
You.

Claims (5)

[Claims] (1) The following formula (I): (In the formula, R ¹ represents a hydrogen atom or a lower alkyl group.)
Or a pharmaceutically acceptable inorganic, monocarboxylate or organic sulfonate thereof. 2. A drug comprising the compound (I) according to claim 1 or a pharmaceutically acceptable inorganic salt, monocarboxylate or organic sulfonate thereof as an active ingredient. 3. A selectin inhibitor comprising the compound (I) according to claim 1 or a pharmaceutically acceptable inorganic salt, monocarboxylate or organic sulfonate thereof as an active ingredient. 4. An inflammatory disease, cancer or cancer comprising the compound (I) according to claim 1 or a pharmaceutically acceptable inorganic, monocarboxylate or organic sulfonate thereof as an active ingredient. Drug for preventing or treating ischemia-reperfusion injury. 5. A compound represented by the following formula (II): (In the formula, R ¹ represents a hydrogen atom or a lower alkyl group.)
Or the organic acid salt or the inorganic acid salt thereof.