WO2000001696A1 - 3-ALKYLPYRROLO[3,2-c]QUINOLINE DERIVATIVES - Google Patents

Abstract

The present invention relates to 3-alkylpyrrolo[3,2-c]quinoline derivatives represented by formula (1), their pharmaceutically acceptable salts, process for preparation thereof, and pharmaceutical composition thereof for treating gastric ulcer. 3-Alkylpyrrolo[3,2-c]quinoline derivatives of the present invention and their salts which inhibit gastric acid secretion of mammal, can be used effectively as a treatment for gastric ulcer.

Description

3 -ALKYLPYRROLO [3 , 2 -c] QUINOLINE DERIVATIVES

BACKGROUND OF THE INVENTION

The present invention relates to 3-alkylpyrrolo [3 , 2-c] quinoline derivatives represented

by the formula 1, their pharmaceutically acceptable salts, process for preparation thereof, and pharmaceutical composition thereof for treating gastric ulcer.

More particularly, the present invention relates to 3-alkylpyrrolo [3 , 2-c] quinoline derivatives which

inhibit gastric acid secretion of mammal; their salts; and process for preparation thereof. The pharmaceutical composition comprising quinoline derivatives of the present invention as an active ingredient is effective for inhibiting gastric acid secretion and treating gastric ulcer. FORMULA 1

Wherein, R is an alkyl group of C ₄, may be substituted with hydroxy group, alkoxycarbonyl group of C ₄ , alkylcarbonyl group of C_x_ , arylcarbonyl group, aldehyde, alkoxy group of G ₄, amino group, aminoalcohol, carboxy group, or halogen;

R_τ is hydrogen, alkyl of C_τ._{b l} phenyl group, hydroxymethyl group, halogen, alkylthio group of C^, alkoxy group of C^, or amino group of Cχ_, substituted or unsubstituted with hydroxy group; R; is hydrogen, alkyl group of C_ι_₆, alkoxy group of Ci_, substituted or unsubstituted with hydroxy group or fluorine, hydroxy group, hydroxymethyl group, or amino group of C_:_,; and

Ar is a phenyl or benzyl group substituted or unsubstituted with hydrogen, alkyl group of CV, substituted or unsubstituted with halogen, haloalkoxy group of C-_ substituted or unsubstituted with halogen, alkylthio group of C^, halogen, cyano group, amino group, nitro group, hydroxy group, etc.

So far, benzimidazole derivatives containing pyridine, as represented by the Omeprazole, have been commonly used as inhibitors of gastric acid secretion. Benzimidazole derivatives containing pyridine have displayed a prominent remedial result, but have raised a problem in long term administration because of their irreversible reaction mechanism. That is, there have been a sustained effect of medicine after stopping administration or a side effect of stomach wall thickening by administration, etc.

On the one hand, quinoline derivatives have been known as an inhibitor for gastric acid secretion of mammal, and there have been attempts to develop them as a reversible inhibitor for gastric acid secretion. [EP Appl. 87-307824.0; USP 5,362,743; PCT/KR 94-29274; EP Appl. 89-301801.0; EP Appl. 89-301805.1; EP Appl. 89-301802.8; EP Appl . 88-306583.1; PCT/KR 97-00074; KR Pat. Appl. 96-38314; KR Pat. Appl. 97-30692; KR Pat. Appl. 97-30693; J. Med . Chem . , 1992, 35, 3413; and J.

Med. Chem . , 1995, 38, 2742].

For example, EP Appl. 88-306583.1 describes pyrrolo [3 , 2-c] quinoline derivatives of the following structure .

Wherein,

A is -CH=CH-, -(CH₂h~ or -(CH₂),-;

Rj to R_ are hydrogen, alkyl group of C^ , alkoxy group of C__,, phenyl group, alkylthio group of C_x__fe, alkanoyl group of C-,-,, amino group, alkylamino group of

C_ι-₆, dialkylamino group of C_α_₆, halogen, trifluoromethyl group or nitro group, respectively;

R- to R„ are hydrogen, alkyl group of -_C , alkoxy group of C__ , alkylthio group of C^, halogen, cyano group, amino group, hydroxy group, carbamoyl group, carbonyl group, alkanoyl group of C^, trifluoromethyl group or nitro group, respectively; and

R₁₀ is hydrogen, alkyl group of C^, halogen, hydroxy group, -CH₂0H, alkylthio group of C^, NH(CH _r,OH (wherein n is 0 to 4) or -NR_nR₁₂.

The literature mentioned above described that compounds of the above formula and their salts acted as an inhibitor for gastric acid secretion by inhibiting gastric H^T/K^~-ATPase, and are useful for treating ulcers in mammal, particularly in human.

Also, in J. Med. Chem., 1992, 35, 1845-1852, it was described 1-arylpyrrolo [3 , 2-c] quinoline derivatives

as a reversible inhibitor for gastric acid secretion, particularly on the effect of substituent R₁₀. And KR Pat. Appl. 97-38512 describes the use of haloalkyl groups as R_α . Despite of a good deal of effect, however, there has been no report about the introduction of substituent into 3-position since it is difficult to synthesize such compounds.

We, the inventors of the present invention, have investigated to develop a novel inhibitors for gastric acid secretion, and synthesized novel 3-alkylpyrrolo [3 , 2-c] quinoline derivatives and their salts by introducing various substituents into 3-position, which display an excellent inhibition of gastric acid secretion and stability. The synthesis was based on the application of a new synthetic method developed recently using palladium catalyst ( Tetrahedron Letter, 1998, 39, 627 and Heterocycles,

1996, 43 , 1641) .

SUMMARY OF THE INVENTION

It is the object of the present invention to provide 3-alkylpyrrolo [3 , 2-c] quinoline derivatives

represented by the formula 1 and their pharmaceutically acceptable salts.

It is another objective of the present invention to provide process for preparing 3-alkylpyrrolo [3 , 2- c] quinoline derivatives represented by the formula 1.

It is still another objective of the present invention to provide pharmaceutical composition for treating gastric ulcer, which comprises 3- alkylpyrrolo [3 , 2-c] quinoline derivatives represented by the formula 1 and their pharmaceutically acceptable salts as an active ingredient.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides 3-alkylpyrrolo [3 , 2- c] quinoline derivatives of formula 1, and their

pharmaceutically acceptable salts : FORMULA 1

wherein,

R is an alkyl group of C^, may be substituted with hydroxy group, alkoxycarbonyl group of C^, alkylcarbonyl group of C₂-, , arylcarbonyl group, aldehyde, alkoxy group of C^, amino group, aminoalcohol, carboxy group, or halogen;

Ri is hydrogen, alkyl of C _λ._t phenyl group, hydroxymethyl group, halogen, alkylthio group of C_τ._{6 l} alkoxy group of C^, or amino group of C^ substituted or unsubstituted with hydroxy group;

R_^ is hydrogen, alkyl group of C₁-_b , alkoxy group of C _„ substituted or unsubstituted with hydroxy group or fluorine, hydroxy group, hydroxymethyl group, or amino group of C_^ ; and Ar is a phenyl or benzyl group substituted or unsubstituted with hydrogen, alkyl group of

substituted or unsubstituted with halogen, haloalkoxy group of C _ substituted or unsubstituted with halogen, alkylthio group of C^, halogen, cyano group, amino group, nitro group, hydroxy group, etc.

In addition, the present invention provides process for preparation of 3-alkylpyrrolo [3 , 2- c] quinoline derivatives. The compounds of the present

invention can be prepared by two methods, process I represented by the following reaction scheme 1, and process II represented by the following reaction scheme 2.

REACTION SCHEME 1

REACTION SCHEME 2

ArIH ₂(V)

(«V)

(III)

(I) The process for preparation according to the present invention, by the foregoing reaction scheme 1, comprises the steps of:

1) chlorinating a compound of formula (III) to give the quinoline substituted with chlorine, of formula (IV) (step 1) ;

2) reacting the quinoline substituted with chlorine, of formula (IV) , with the aryl amine of formula (V) to give the quinoline of formula (VI) (step 2);

3) reacting the quinoline of formula (VI) with an allyl halide (AX) in the presence of a base to give the compound of formula (VII) (step 3) ; and

4) cyclizing the compound of formula (VII) with palladium catalyst to give the compound of formula 1

(step 4) .

Also, the process for preparation according to the present invention, by the foregoing reaction scheme 2, comprises the steps of:

1) chlorinating a compound of formula (III) to give the quinoline substituted with chlorine, of formula (IV) (step 1) ;

2) reacting the quinoline substituted with chlorine, of formula (IV) , with the aryl amine of formula (V) to give the quinoline of formula (VI) (step 2);

3) reacting the quinoline of formula (VI) with the alkynes substituted with alkylsilane, of formula

(VIII) , to give the compound of formula (IX) (step 3) ; and

4) removing silyl group in the compound of formula

(IX) to give the compound of formula 1 (step 4) .

The compound of formula (III) used as a starting material in the process of the present invention, was obtained from the compound of the following formula

(II) by the known method [ Synthesis , 1977, 865] by

introducing iodine into 3-position of quinolone . FORMULA 2

(ll)

Wherein, R_τ and R₂ are defined as above.

The starting materials used in the present invention were synthesized according to a known method [Heterocyclic compounds, Quinolines , Vol. 32, PART 1] .

The process of each step according to the present invention will be described below in more detail.

At first, in the process I represented by the reaction scheme 1:

1) In the said reaction scheme 1, the compound of formula (III) is chlorinated with phosphoryl chloride

(POCl,) , thionyl chloride (S0C1₂) , phosphorus pentachloride (PC1₅) , etc. to give the compound of formula (IV) . In this reaction 1-10 equivalent of chlorinating reagent can be used, the reaction solvent may be selected from the group consisting of 1, 2-dichloroethane, methylene chloride, etc. or the reaction can be performed without solvent.

2) The compound of formula (IV) and aryl amine (V) are reacted in 1,4 -dioxane or in the absence of solvent, at 100-150 °C for 1-2 hours to give the compound of formula (VI) . Here, the number of equivalents of aryl amine is preferably 1-10.

3) The compound of formula (VI) is reacted with various allyl halides in the presence of a base at room temperature for 2-3 hours to give the compound of formula (VII) . Here, a solvent may be selected from the group consisting of tetrahydrofuran, methylene chloride, chloroform, diethyl ether, etc. 4) 3 -Alkylpyrrolo [3 , 2-c] quinoline of formula 1 is

obtained from the compound of formula (VII) by a cyclization reaction using palladium catalyst, a new heterocycle synthetic method [Heterocycles , 1996, 43 ,

1641] . In this reaction, 1-10 mol% of palladium catalyst, 1-5 equivalents of a base, and an organic or inorganic chloride salt are used, and the reactants are reacted in various solvents at 80-150 °C for 3-4 hours to give cyclized quinoline derivatives. It is preferable to use palladium acetate [ (CH₃COO) ₂Pd] , potassium acetate (CH,COOK) , tetrabutylammonium chloride [ (n-Bu) ₄NC1] in tetrahydrofuran (THF).

Also, in the process II represented by the reaction scheme 2 :

1) In the said reaction scheme 2, the compound of formula (III) is chlorinated with phosphoryl chloride (P0C1₃) , thionyl chloride (S0C1 , phosphorus penta- chloride (PC1=) , etc. to give the compound of formula (IV) . In this reaction 1-10 equivalents of chlorinating reagent can be used, the reaction solvent may be selected from the group consisting of 1, 2-dichloroethane, methylene chloride, etc. or the reaction can be performed without solvent .

2) The compound of formula (IV) and aryl amine (V) are reacted in 1,4-dioxane or in the absence of solvent, at 100-150 °C for 1-2 hours to give the compound of formula (VI) . Here, the number of equivalents of aryl amine is preferably 1-10.

3) The compound of formula (VI) and various alkynes of formula (VIII) substituted with alkylsilane, are reacted in various solvents by using a new heterocycle synthetic method [ Tetrahedron Letters, 1998, 39 , 627] to give a compound of formula (IX) . At this time, 1-10 mol% of palladium catalyst, 1-5 equivalents of a base, and an organic or inorganic chloride are used, and the reactants are reacted by using various solvents at 80-150 °C for 4-8 hours to give a cyclized compound of formula (IX) . The compound of formula (IX) is obtained easily by using preferably, palladium acetate, potassium acetate, lithium chloride (LiCl) in dimethylformamide (DMF) .

4) Silyl group in the compound of formula (IX) is removed in the presence of acid catalyst in various solvents, to give the compound of formula 1.

3 -Alkyl-2 , 3 -dihydro-lH-pyrrolo [3 , 2-c] quinoline,

the compound of formula 1 of which 2- and 3 -positioned carbon are saturated with hydrogen, is prepared by selective hydr ogena t ion reaction of

3-alkylpyrrolo [3, 2-c] quinoline prepared according to the above processes I and II, with catalyst such as platinum oxide (Pt0₂) , sodium borohydride (NaBH₄) , sodium cyanoborohydride (NaBH₃CN) , etc. [.Reaction in

Orgainc Chemistry, 1984, M. Hudlicky, Ellis Horwood

Ltd. , pp 55-57] .

On the one hand, _τ in the compound of formula 1 can be transformed into various functional groups by the known method [Heterocyclic Compound, Quinolines, Vol 32, Part I, II] . That is, in case of R_τ being CH₃, nitrogen at 5-position is oxidized with hydrogen peroxide to give 5-oxide, and the rearrangement in the presence of acetic anhydride and the hydrolysis transform the functional group into CH,OH [J. Am. Chem.

Soc. 1954, 76, 1286] . In addition, in case of R_: being

hydrogen, chlorine is introduced into 4 -position by reacting 5-oxide with phosphoryl chloride, sulfonyl halide, thionyl chloride, etc., and the compound in which chlorine is introduced into 4-position is reacted with various nucleophiles to give compounds wherein substituted amino, alkylthio or alkoxy is introduced into R_: of the said formula 1 [Chem. Abstr . , 1951, 45,

8525; Chem. Abstr., 1957, 51, 8742; Chem. Abstr., 1958,

52, 14605] . Pharmaceutically acceptable salts of 3- alkylpyrrolo [3, 2-c] quinoline derivatives prepared according to the above, can be prepared by using suitable organic or inorganic acids according to the general method. At this time, acids can be selected from the group consisting of hydrochloric acid, sulfuric acid, phosphoric acid, citric acid, maleic acid, formic acid, etc.

3-Alkylpyrrolo [3 , 2-c] quinoline derivatives of the

present invention and their pharmaceutically acceptable salts inhibit reversibly gastric acid secretion, therefore pharmaceutical composition comprising them as an active ingredient is useful for inhibiting gastric acid secretion and treating gastric or duodenal ulcer. Pharmaceutical composition for treatment of gastric ulcer, comprising 3-alkylpyrrolo [3 , 2- c] quinoline derivatives of the present invention and their salts as an active ingredient, can be prepared for oral or non-oral administration by mixing with generally-used nontoxic and pharmaceutically acceptable carrier and diluent in addition to the compound of the formula 1.

Pharmaceutical composition of the present invention can be prepared in type of oral administrable forms such as pill, troche, water-soluble or oil-soluble suspension, powder, granule, emulsion, hard or soft capsule, syrup, or elixirs. For preparation of pill or capsule, binding agent such as lactose, sucrose, sorbitol, mannitol, starch, amylopectin, cellulose or gelatin; diluent such as dicalcium phosphate; dissolute such as corn starch or sweet potato starch; and lubricant such as magnesium stearate, calcium stearate, sodium stearyl fumarate or polyethylene glycol, etc. can be included. In case of preparation of capsule, liquid carrier like fatty oil can be included in addition to the above mentioned substances .

Also, pharmaceutical composition comprising the compound of the formula 1 as an active ingredient, can be prepared for injection, and such a preparation is administered by the method of hypodermic injection, intravenous injection, intramuscular injection or intrathoracic injection. To prepare such a preparation, the compound of the formula 1 and a stabilizer or damping agent in the water is mixed to make in the form of an aqueous solution or a suspension, and ampule or vial for unit dosage is prepared by using them.

3 -Alkylpyrrolo [3 , 2-c] quinoline derivatives of the

present invention and their pharmaceutically acceptable salts show a prominent inhibition on gastric acid secretion, and can solve a problem in long term administration because of their reversible action mechanism in inhibiting gastric acid secretion, and therefore those can be used effectively as a new treatment for gastric ulcer.

Practically and presently preferred embodiments of the present invention are illustrative as shown in the following examples . However, it will be appreciated that those skilled in the art, on consideration of this disclosure, may make modification and improvements within the spirit and scope of the present invention.

In the following examples, the process I was applied to examples 1-22, and the process II was applied to example 23 to prepare the compound of example 1. The compounds of examples 1-31 can be easily prepared by the process II described in the example 23.

<Example 1> Preparation of 6 -methoxy- 3 -methyl - 1- (2 -

me hylphenyl) -Iff-pyrrolo [3 , 2 -c] quinoline

(Step 1) Preparation of 3 - iodo-4 - (2 -methylphenylamino) -

8 -methoxyquinoline

4 -Chloro-3 - iodo- 8 -methoxyquinoline (41 . 47 g, 0 . 13 mol) and 2 -methylaniline ( 41 g, 0 . 4 mol ) were ref luxed at 125 °C for 4 hours. The reaction mixture was dissolved in methylene chloride (600 ml) and washed with sodium bicarbonate aqueous solution, the organic layer was separated, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo, and the

residue was purified by silica gel column chromatography to give the desired compound (42 g, 83%) .

^'Η NMR(CDC1₃) δ 2.45(s, 3H) , 4.07(s, 3H) , 6.08(brs, 1H) , 6.51(m, 1H) , 6.96-7.30(m, 6H) , 9.07(s, 1H) . m/e_; 390 (M⁺) . m.p. ; 155-156 °C .

(Step 2) Preparation of 6-methoxy-3-methyl-l- (2-

methylphenyl) -lff-pyrrolo [3, 2-c] quinoline

To 3-iodo-4- (2-methylphenylamino) - 8 - methoxyquinoline (2.8 g, 7.1 mmol) in anhydrous tetrahydrofuran (20 ml) was added 60%-sodium hydride

(NaH, 1 g) , and the reaction mixture was stirred at room temperature for 1 hour. Allyl iodide (CH₂CHCH₂I, 2.8 g, 16 mmol) was added, and the mixture was stirred for 5 hours. To the intermediate obtained by adding saline to the reaction mixture and separating the organic layer were added tetrabutylammonium chloride [ (n-Bu) ₄NC1, 2.37 g, 6 mmol], sodium formate (0.84 g,

12 mmol), potassium acetate (1.34 g, 12 mmol) and palladium acetate (80 mg) and the mixture in tetrahydrofuran (20 ml) was refluxed at 120 °C for 2 hours. The reaction mixture was concentrated and extracted with ethyl acetate, and the organic layer was separated. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo,

and the residue was purified by silica gel column chromatography to give the desired compound (1.4 g, 77%) , and the compound was crystallized with a small amount of diethyl ether. H NMR(CDC1₃) δ 1.91(s, 3H) , 2.52(s, 3H) , 4.08(s, 3H) , 6.66-7.49(m, 8H) , 9.21(s, 1H) . m/e; 302 (M⁺) . m.p. ; 131-133 °C .

<Example 2> Preparation of 3 -ethyl- 6 -methoxy-1- (2-

methylphenyl) -lff-pyrrolo [3, 2-c] uinoline

To 3-iodo-4- ( 2 - me t hy lpheny 1 amino ) -8- methoxyquinoline (1.17 g, 3.0 mmol) prepared by the process of the step 1 of example 1 in anhydrous tetrahydrofuran (20 ml) was added 60%-sodium hydride (NaH, 0.75 g) and the reaction mixture was stirred at room temperature for 1 hour. To this solution crotyl bromide (CH_:.CHCHCH₂Br, 1.02 g, 7.5 mmol) was added, and the mixture was stirred for 5 hours. To the intermediate obtained by adding saline to the reaction mixture and separating the organic layer were added tetrabutylammonium chloride (0.72 g, 3 mmol), sodium formate (0.42 g, 6 mmol), potassium acetate (0.61 g, 6 mmol) and palladium acetate (40 mg) and the mixture in tetrahydrofuran (15 ml) was refluxed at 120 °C for 2 hours . The reaction mixture was concentrated and extracted with ethyl acetate, and the organic layer was separated, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo, and the residue was

purified by silica gel column chromatography to give the desired compound (0.4 g, 43%) . E NMR(CDC1₃) δ 1.43(t, 3H) , 1.92(s, 3H) , 3.00(q, 2H) , 6.67-7.49(m, 8H) , 9.24(s, 1H) . m/e ; 316 (M⁺) .

<Example 3> Preparation of 3-isopropyl-6-methoxy-l- (2-

methylphenyl) -lff-pyrrolo [3, 2-c] quinoline

To 3-iodo-4- (2-methylphenylamino) - 8 - methoxyquinoline (0.78 g, 2 mmol) prepared by the process of the step 1 of example 1 dissolved in anhydrous tetrahydrofuran (20 ml) was added 60%-sodium hydride (NaH, 0.24 g) , and the reaction mixture was stirred at room temperature for 1 hour. To this solution 4-bromo-2-methyl-l-butene (0.59 g, 4 mmol) was added, and the mixture was stirred for 5 hours. To the intermediate obtained by adding saline to the reaction mixture and separating the organic layer were added tetrabutylammonium chloride (0.22 g, 1 mmol), sodium formate (0.14 g, 2 mmol), potassium acetate (0.2 g, 2 mmol) and palladium acetate (20 mg) , and the mixture in tetrahydrofuran (15 ml) was refluxed at 120 'C for 2 hours. The reaction mixture was concentrated and extracted with ethyl acetate, and the organic layer was separated, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo, and the residue was

purified by silica gel column chromatography to give the desired compound (0.18 g, 55%).

^XH NMR(CDC1₃) δ 1.45 (d, J=6.9Hz, 6H) , 1.89 (s, 3H) ,

3.43 (m, 1H) , 4.07(s, 3H) , 6.67-7.47(m, 8H) , 9.29(s, 1H) . m/e; 330 (M⁺) .

<Example 4> Preparation of 1- (4-fluoro-2-methylphenyl) -

6-me hoxy-3 -methyl-lff-pyrrolo [3, 2-c] quinoline

(Step 1) Preparation of 4- (4-fluoro-2 -

methylphenylamino) -3-iodo-8-methoxyquinoline

4 -Chloro-3-iodo- 8 -methoxyquinoline (3.83 g, 12 mmol) and 4- fluoro- 2-methylaniline (2.3 g, 18 mmol) were refluxed at 125 °C for 4 hours. The mixture was dissolved in methylene chloride (70 ml) and washed with sodium bicarbonate aqueous solution, the organic layer was separated, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo, and the residue was

purified by silica gel column chromatography to give the desired compound (4.67 g, 95%) . Η NMR(CDC1₃) δ 2.39(s, 3H) , 4.05(s, 3H) , 5.97 (brs,

1H) , 6.47-7.20(m, 6H) , 9.02(ε, 1H) . m/e; 408 (M⁺) . m.p. ; 150-151 °C .

(Step 2) Preparation of 1- (4-fluoro-2-methylphenyl) -6-

methoxy-3 -methyl-lff-pyrrolo [3, 2-c] quinoline

4- ( 4 - Fluoro- 2 -methylphenylamino ) -3-iodo- 8-methoxyquinoline (0.5 g, 1.2 mmol) in anhydrous tetrahydrofuran (20 ml) was added 60%-sodium hydride (NaH, 0.2 g) , and the reaction mixture was stirred at room temperature for 1 hour. To this solution was added allyl iodide (CH₂CHCH₂I, 0.55 g, 4 mmol), and the mixture was stirred for 5 hours. To the intermediate obtained by adding saline to the reaction mixture and separating the organic layer were added tetrabutylammonium chloride (0.22 g, 1 mmol), sodium formate (0.14 g, 2 mmol), potassium acetate (0.2 g, 2 mmol) and palladium acetate (40 mg) and the mixture in tetrahydrofuran (15 ml) was refluxed at 120 ''C for 2 hours. The reaction mixture was concentrated and extracted with ethyl acetate, and the organic layer was separated, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo, and the residue was

purified by silica gel column chromatography to give the desired compound (0.18 g, 64%), and the compound was crystallized with a small amount of diethyl ether. H NMR(CDC1₃) δ 1.88(s, 3H) , 2.49(s, 3H) , 4.06(s, 3H) , 6.64-7.37(m, 7H) , 9.18(s, 1H) . m/e; 320 (M⁺) . m.p. ; 156-158 °C .

<Example 5> Preparation of 3-ethyl-l- (4-fluoro-2-

methylphenyl) -6-methoxy-lff-pyrrolo [3, 2-c] quinoline

To 4- (4-fluoro-2-methylphenylamino) -3-iodo-8- methoxyquinoline (0.55 g, 1.36 mmol), prepared by the process of the step 1 of example 4 in anhydrous tetrahydrofuran (20 ml) was added 60%-sodium hydride (NaH, 0.2 g) , and the reaction mixture was stirred at room temperature for 1 hour. To this solution an excess of crotyl bromide (CH₃CHCHCH₂Br) was added dropwise, and the mixture was stirred for 5 hours. To the intermediate (0.5 g, 80%) obtained by adding saline to the reaction mixture and separating the organic layer were added tetrabutylammonium chloride (0.25 g, 1.08 mmol), sodium formate (0.15 g, 2.16 mmol), potassium acetate (0.25 g, 2.16 mmol) and palladium acetate (20 mg) , and the mixture in tetrahydrofuran (10 ml) was refluxed at 120 °C for 2 hours. The reaction mixture was concentrated and extracted with ethyl acetate, and the organic layer was separated, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo,

and the residue was purified by silica gel column chromatography to give the desired compound (0.2 g, 56%) , and the compound was crystallized with a small amount of diethyl ether.

^'Η NMR(CDC1₃) δ 1.42(t, 3H) , 1.89(s, 3H) , 2.97(q, 2H) , 4.08(s, 3H) , 6.63-7.41(m, 7H) , 9.22(s, 1H) . m/e; 334 (M⁺) . m.p. ; 174-175 °C.

<Example 6> Preparation of 1- (4-hydroxy-2-

methylphenyl) -6 -methoxy- 3 -methyl- lff-pyrrolo [3,2-

c] quinoline

(Step 1) Preparation of 4- (4-benzyloxy-2-

methylphenylamino) -3 -iodo- 8-methoxyquinoline

4-Chloro-3-iodo-8-methoxyquinoline (5.1 g, 16 mmol) and 4-benzyloxy-2-methylaniline (6.8 g, 32 mmol) were refluxed at 125 °C for 4 hours. The reaction mixture was dissolved in methylene chloride (100 ml) and washed with sodium bicarbonate aqueous solution, the organic layer was separated, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo, and the residue was purified by silica gel column chromatography to give the desired compound (6.5 g, 82%) .

^"XH NMR(CDC1₃) δ 2.38(s, 3H) , 4.08(s, 3H) , 5.06(s, 2H) , 6.10 (brs, 1H) , 6.61-7.48(m, 11H) , 9.02(s, 1H) m/e; 496 (M⁺) . m.p. ,- 162-163 °C .

(Step 2) Preparation of 3 -methyl- 6 -methoxy-1- (4-

benzyloxy-2-methylphenyl) -lff-pyrrolo [3 , 2-c] quinoline

To 4- (4-benzyloxy-2-methylphenylamino) -3-iodo-8- methoxyquinoline (1 g, 2 mmol) in anhydrous tetrahydrofuran (20ml) was added 60%-sodium hydride

(NaH, 0.5 g) , and the reaction mixture was stirred at room temperature for 1 hour. To this solution was added allyl iodide (0.7 g, 4 mmol), and the mixture was stirred for 5 hours . To the intermediate obtained by adding saline to the reaction mixture and separating the organic layer were added tetrabutylammonium chloride (0.47 g, 2 mmol), sodium formate (0.27 g, 4 mmol), potassium acetate (0.4 g, 4 mmol) and palladium acetate (23 mg) , and the mixture in tetrahydrofuran (20 ml) was refluxed at 120 °C for 2 hours. The reaction mixture was concentrated and extracted with ethyl acetate, and the organic layer was separated, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo, and the residue was purified by

silica gel column chromatography to give the desired compound (0.56 g, 68%), and the compound was crystallized with a small amount of diethyl ether. -H NMR(CDC1₃) δ 1.86(s, 3H) , 2.50(s, 3H) , 4.08(s, 3H) , 5.16(Ξ, 2H) , 6.72-7.52(m, 12H) , 9.18(s, 1H) . m/e; 408 (M⁺) . m.p. ; 163-164 °C .

(Step 3) Preparation of 1- (4-hydroxy-2-methylphenyl) -6-

methoxy-3 -methyl-lff-pyrrolo [3, 2-c] quinoline

3 -Methyl-6-methoxy-1- (4-benzyloxy-2-methylphenyl) - lH-pyrrolo [3, 2-c] quinoline (0.45 g, 1.1 mmol) in

methanol (20 ml) was stirred in the presence of 5%-palladium catalyst and hydrogen (H₂, 40 psi) at room temperature for 2 hours . The reaction mixture was filtered and concentrated to give the desired compound

(50 mg, 15%) .

^:H NMR(CDC1₃) δ 1.08(s, 3H) , 2.49(s, 3H) , 4.02(s, 3H) , 6.76-7.18 (m, 7H) , 9.16(s, 1H) . m/e; 318 (M⁺) . m.p. ; 270 °C.

<Example 7> Preparation of 1- (4-hydroxy-2-

methylphenyl) -3-ethyl-6 -methoxy- lff-pyrrolo [3,2- c] quinoline

(Step 1) Preparation of 1- (4-benzyloxy-2-methylphenyl) -

3 -ethyl-6 -methoxy-lff-pyrrolo [3 , 2 -c] quinoline

To 4- (4-benzyloxy-2-methylphenylamino) -3-iodo-8- methoxyquinoline (1 g, 2 mmol) in anhydrous tetrahydrofuran (20 ml) was added 60%-sodium hydride (NaH, 0.5 g) , and the mixture was stirred at room temperature for 1 hour. To this solution crotyl bromide (CH₃CHCHCH_:Br, 0.63 g, 4 mmol) was added, and the mixture was stirred for 5 hours . To the intermediate obtained by adding saline to the reaction mixture and separating the organic layer were added tetrabutylammonium chloride (0.47 g, 2 mmol), sodium formate (0.27 g, 4 mmol), potassium acetate (0.4 g, 4 mmol) and palladium acetate (23 mg) , and the mixture in tetrahydrofuran (20 ml) was refluxed at 120 ^&C for 2 hours . The reaction mixture was concentrated and extracted with ethyl acetate, and the organic layer was separated, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo, and the residue was

purified by silica gel column chromatography to give the desired compound (0.25 g, 30%), and the compound was crystallized with a small amount of diethyl ether. ^"JH NMR(CDC1₃) δ 1.42(t, 3H) , 1.87(s, 3H) , 2.97(q, 2H) , 4.08(s, 3H) , 5.17(s, 2H) , 6.75-7.50(m, 12H) , 9.18(s, 1H) . m/e ; 422 (M ) . m . p . ; 55 - 57 °C .

(Step 2) Preparation of 1- (4-hydroxy-2-methylphenyl) -3-

ethyl-6 -methoxy-lff-pyrrolo [3, 2-c] quinoline

1- (4-Benzyloxy-2-methylphenyl) -3 -ethyl-6 -methoxy- lH-pyrrolo [3, 2-c] quinoline (0.25 g, 0.59 mmol) prepared

in the step 1 of example 7 in methanol (10 ml) was stirred in the presence of 5%-palladium catalyst and hydrogen (H_, 40 psi) at room temperature for 2 hours. The reaction mixture was filtered and concentrated to give the desired compound (0.12 g, 62%) . ^lE NMR(DMSO-d₆) δ 1.45(t, 3H) , 1.82(s, 3H) , 2.98(s, 2H) , 4.07(s, 3H) , 6.80-7.25(m, 7H) , 9.15(s, 1H) . m/e; 332 (M⁺) . m.p. ; 247-250 °C .

<Example 8> Preparation of 1- (4-hydroxy-2-

methylphenyl) -3 -isopropyl- 6 -methoxy- lff-pyrrolo [3,2-

c] quinoline

1- (4-Benzyloxy-2-methylphenyl) -3 - isopropyl-6 - methoxy-lH-pyrrolo [3, 2-c] quinoline (448 mg, 1.03 mmol)

prepared by the process of the step 1 of example 7 in methanol (10 ml) was stirred in the presence of 5%-palladium catalyst and hydrogen (H₂, 40 psi) at room temperature for 2 hours. The reaction mixture was filtered and concentrated to give the desired compound (240 mg, 69%) .

^"Η NMR(DMSO-d₆) δ 1.45(d, 6H) , 1.78(s, 3H) , 3.41(m, 1H) , 4.08(s, 3H) , 6.76-7.23(m, 7H) , 9.23(s, 1H) . m/e; 346 (M⁺) . m.p. ; 264-266 °C .

<Example 9> Preparation of 6 -methoxy-3 -methyl-1- (1-

phenylethyl) -lff-pyrrolo [3 , 2-c] quinoline

(Step 1) Preparation of 3-iodo-8-methoxy-4- (1-

phenylethylamino) quinoline

4-Chloro-3-iodo-8-methoxyquinoline (2 g, 6.2 mmol) and 1-phenyl-1-ethylamine (2 g, 16 mmol) were refluxed at 125 ^CC for 4 hours. The reaction mixture was dissolved in methylene chloride (50 ml) and washed with sodium bicarbonate aqueous solution, the organic layer was separated, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo, and the residue was

purified by silica gel column chromatography to give the desired compound (1.6 g, 63%) .

Η NMR(CDC1₃) δ 1.64(d, 3H) , 4.04(s, 3H) , 4.70(brd, 1H) , 5.10 (m, 1H) , 6.97-7.53(m, 8H) , 8.87(s, 1H) . m/e; 404 (M") . m.p. ; 166-167 °C . (Step 2) Preparation of 6-methoxy-3-methyl-l- (1-

phenylethyl) -lff-pyrrolo [3 , 2-c] quinoline

To 3 -iodo-8-methoxy-4- ( 1-phenylethylamino) quinoline (0.6 g, 4.4 mmol) in anhydrous tetrahydrofuran (20 ml) was added 60%-sodium hydride (NaH, 0.2 g) , and the mixture was stirred at room temperature for 1 hour. To this solution was added an excess of allyl iodide, and the mixture was stirred for 5 hours. To the intermediate obtained by adding saline to the reaction mixture and separating the organic layer were added tetrabutylammonium chloride (0.39 g, 1.7 mmol), sodium formate (0.23 g, 3.4 mmol), potassium acetate (0.34 g, 3.4 mmol) and palladium acetate (20 mg) , and the mixture in tetrahydrofuran (10 ml) was refluxed at 120 °C for 2 hours. The reaction mixture was concentrated and extracted with ethyl acetate, and the organic layer was separated, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo,

and the residue was purified by silica gel column chromatography to give the desired compound (0.4 g, 70%) , and the compound was crystallized with a small amount of diethyl ether.

^:H NMR(CDC1₃) δ 1.96(s, 3H) , 2.45(s, 3H) , 4.05(s, 3H) , 6.29(q, 1H) , 6.92-7.71 (m, 9H) , 9.13(s, 1H) . m/e; 316 (M⁺) . m.p. ; 142-144 ^ϋC . <Example 10> Preparation of 3 -ethyl-6-methoxy-1- (1-

phenylethyl) -lff-pyrrolo [3, 2-c] quinoline

The reaction with 4-chloro- 3 -iodo-8- ethoxyquinoline in place of 4-chloro-3-iodo-8- methoxyquinoline as a starting material, was performed by the same method in the example 9 to give the desired compound .

'H NMR(CDC1₃) δ 1.42(t, 3H) , 2.04(d, 3H) , 2.96(q, 2H) , 4.07(s, 3H) , 6.34(q, 1H) , 6.97-7.76(m, 9H) , 9.22 (s, 1H) . m/e; 330 (M⁺) . m.p. ; 89-90 °C.

<Example 11> Preparation of 6-methoxy-3 , 4-dimethyl-l-

(2-methylphenyl) -lff-pyrrolo [3, 2-c] quinoline

(Step 1) Preparation of 3-iodo-8-methoxy-2-methyl-4- (2-

methylphenylamino) quinoline

4-Chloro-3-iodo-8-methoxy-2-methylquinoline (33 g, 0.1 mol) and 2-methylaniline (30 g, 0.27 mol) were refluxed at 125 °C for 4 hours. The reaction mixture was dissolved in methylene chloride (400 ml) and washed with sodium bicarbonate aqueous solution, the organic layer was separated, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo, and the

residue was purified by silica gel column chromatography to give the desired compound (30 g, 75%) .

^:H NMR(CDC1₃) δ 2.45(s, 3H) , 3.04(s, 3H) , 4.06(s, 3H) , 6.13 (brs, 1H) , 6.41(m, 1H) , 6.93-7.28(m, 6H) . m/e; 404 (M⁺) .

(Step 2) Preparation of 6-methoxy-3 , 4-dimethyl-l- (2-

methylphenyl) -lff-pyrrolo [3, 2-c] quinoline

To 3-iodo-8-methoxy-2-methyl-4- ( 2 - methylphenylamino) quinoline (2.8 g, 7.1 mmol) in anhydrous tetrahydrofuran (30 ml) was added 60%-sodium hydride (NaH, 1 g) , and the mixture was stirred at room temperature for 1 hour. To this solution was added an excess of allyl iodide, and the mixture was stirred for 5 hours . To the intermediate obtained by adding saline to the reaction mixture and separating the organic layer were added tetrabutylammonium chloride (2.37 g, 6 mmol), sodium formate (0.84 g, 12 mmol), potassium acetate (1.34 g, 12 mmol) and palladium acetate (80 mg) , and the mixture in tetrahydrofuran (20 ml) were refluxed at 120 ^CC for 2 hours. The reaction mixture was concentrated and extracted with ethyl acetate, and the organic layer was separated, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo,

and the residue was purified by silica gel column chromatography to give the desired compound (1.4 g, 77%) , and the compound was crystallized with a small amount of diethyl ether . H NMR(CDC1₃) δ 1.92(s, 3H) , 2.61(s, 3H) , 3.10(s, 3H) , 4.05(s, 3H) , 6.60-7.50(m, 8H) . m/e; 316 (M⁺) .

<Example 12> Preparation of 3-ethyl-6-methoxy-4 -methyl-

1- (2-methylphenyl) -lff-pyrrolo [3, 2-c] quinoline

The reaction with crotyl bromide in place of allyl halide, was performed by the same process of the example 11 to give the desired compound.

^ΎE NMR(CDC1₃) δ 1.40(t, J=7.3Hz, 3H) , 1.91(s, 3H) ,

3.09(q, J=7.3Hz, 2H) , 3.10(s, 3H) , 4.05(s, 3H) , 6.60-

7.52 (m, 8H) . m/e; 330 (NT) .

<Example 13> Preparation of 1- (4-fluoro-2-

methylphenyl) - 6 -methoxy-3 , 4 -dimethyl -lff-pyrrolo [3,2-

c] quinoline

(Step 1) Preparation of 4- (4-fluoro-2-

methylphenylamino) -3 -iodo- 8-methoxy-2 -methylquinoline

4-Chloro-3-iodo-8-methoxy-2-methylquinoline (7 g, 20.9 mmol) and 4-fluoro-2-methylaniline (5 g, 40 mmol) were refluxed at 125 °C for 4 hours. The mixture was dissolved in methylene chloride (100 ml) and washed with sodium bicarbonate aqueous solution, the organic layer was separated, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo, and the

residue was purified by silica gel column chromatography to give the desired compound (6 g, 68%) .

-H NMR(CDC1₃) δ 2.42(s, 3H) , 3.04(s, 3H) , 4.05(s, 3H) , 6.04(brs, 1H) , 6.37-7.17 (m, 6H) . m/e; 422 (M⁺) . m.p. ; 180-181 °C .

(Step 2) Preparation of 1- (4-fluoro-2-methylphenyl) -6-

methoxy-3,4-dimethyl-lff-pyrrolo [3, 2-c] quinoline

To 4- (4-fluoro-2-methylphenylamino) -3-iodo-8- methoxy-2-methylquinoline (0.89 g, 1.2 mmol) in anhydrous tetrahydrofuran (30 ml) was added 60%-sodium hydride (NaH, 0.3 g) , and the mixture was stirred at room temperature for 1 hour. To this solution was added an excess of allyl iodide, and the mixture was stirred for 5 hours. To the intermediate obtained by adding saline to the reaction mixture and separating the organic layer were added tetrabutylammonium chloride

(0.48 g, 2.1 mmol), sodium formate (0.28 g, 4.2 mmol), potassium acetate (0.41 g, 4.2 mmol) and palladium acetate (23 mg) , and the mixture in tetrahydrofuran (20 ml) was refluxed at 120 °C for 2 hours. The reaction mixture was concentrated and extracted with ethyl acetate, and the organic layer was separated, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo, and the residue was purified by

silica gel column chromatography to give the desired compound (0.33 g, 47%), and the compound was crystallized with a small amount of diethyl ether.

^:H NMR(CDC1₃) δ 1.86(s, 3H) , 2.57(s, 3H) , 3.06(s, 3H) , 4.01(Ξ, 3H) , 6.55-7.33(m, 7H) . m/e; 334 (M⁺) . m.p. ; 199-200 °C .

<Example 14> Preparation of 3-ethyl-4-methyl-6-methoxy-

1- (4-fluoro-2-methylphenyl) -lff-pyrrolo [3 , 2-c] quinoline

To 4- (4-fluoro-2-methylphenylamino) -3-iodo-8- methoxy-2 -methylquinoline (0.89 g, 1.2 mmol) prepared by the process of the step 1 of example 13 in anhydrous tetrahydrofuran (30 ml) was added 60%-sodium hydride

(NaH, 0.5 g) , and the reaction mixture was stirred at room temperature for 1 hour. To this solution was added crotyl bromide (CH,CHCHCH₂Br, 0.67 g, 5.0 mmol), and the mixture was stirred for 5 hours . To the intermediate obtained by adding saline to the reaction mixture and separating the organic layer were added tetrabutylammonium chloride (0.48 g, 2.1 mmol), sodium formate (0.28 g, 4.2 mmol), potassium acetate (0.41 g,

4.2 mmol) and palladium acetate (23 mg) , and the mixture in tetrahydrofuran (20 ml) was refluxed at 120 °C for 2 hours. The reaction mixture was concentrated and extracted with ethyl acetate, and the organic layer was separated, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo, and the residue was

purified by silica gel column chromatography to give the desired compound (0.37 g, 51%), and the compound was crystallized with a small amount of diethyl ether.

Ε NMR(CDC1₃) δ 1.39(t, 3H) , 1.89(s, 3H) , 3.09(q, 2H) , 3.10(s, 3H) , 4.04(s, 3H) , 6.61-7.39(m, 7H) . m/e ; 348 (M^1") m.p. ; 162.5-136.5 °C .

<Example 15> Preparation of 6-hydroxy-3-methyl-l- (2-

methylphenyl) -lff-pyrrolo [3 , 2-c] quinoline

To 6 -methoxy-3 -methyl- 1- (2 -methylphenyl) -lff-

pyrrolo [3, 2-c] quinoline (0.86 g, 2.84 mmol) prepared by

the process of step 1 and 2 of example 11 with 3-iodo- 8-methoxy-4- (2-methylphenylamino) quinoline in place of 3-iodo-8-methoxy-2-methyl-4- (2 -methylphenylamino) quinoline in methylene chloride (20 ml) was added dropwise slowly boron tribromide (BBr-,, 1 g, 3.9 mmol), and the reaction mixture was stirred at room temperature for 2 hours . The mixture was washed with dilute aqueous soda solution, the organic layer was separated, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo, and the residue was

purified by silica gel column chromatography to give the desired compound (0.57 g, 70%) . Η NMR(CDC1₃) δ 1.89(s, 3H) , 2.49(s, 3H) , 6.49(dd, 1H) , 6.89-7.50(m, 7H) , 9.00(s, 1H) . m/e ; 228 (M^τ) . m.p. ; 137-139 °C .

<Example 16> Preparation of 6- (2 -hydroxyethoxy) -3-

methyl-1- (2 -methylphenyl) -lff-pyrrolo [3, 2-c] quinoline

6 - Hydroxy- 3 -me thy1 - 1 - ( 2 -methylphenyl ) -lff-

pyrrolo [3 , 2-c] quinoline (0.29 g, 1 mmol) prepared by

the process of step 1 and 2 of example 11 with 3-iodo- 8 -hydroxy-4- (2 -methylphenyl) quinoline in place of 3- iodo- 8 -methoxy- 2-methy1-4- (2 -methylphenylamino) quinoline, ethylene carbonate (1, 3-dioxolan-2-one, 3 g) and potassium carbonate (K₂C0₃, 0.3 g) were refluxed at 130 °C for 3 hours. The reaction mixture was dissolved in methylene chloride (20 ml) , washed with distilled water, the organic layer was separated, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo, and the residue was purified by silica gel

column chromatography to give the desired compound (0.3 g, 90%) . ^:H NMR(CDC1₃) δ 1.93(s, 3H) , 2.54(s, 3H) , 4.04(t, J=4.3Hz,2H), 4.32(t, J=4.3Hz, 2H) , 6.72-7.52(m, 8H) ,

9.16(s, 1H) . m/e; 332 (M⁺) .

<Example 17> Preparation of 6- trifluoromethoxy-3-

methyl-1- (2 -methylphenyl) -lff-pyrrolo [3, 2-c] quinoline

(Step 1) Preparation of ethyl 4-oxo-8-trifluoromethoxy-

l,4-dihydro-3-quinolinecarboxylate

The mixture of 2-trifluoromethoxyaniline (17.7 g, 0.1 mol) and diethyl ethoxy methylene malonate (17.7 g, 0.1 mol) was refluxed at 90 °C for 30 minutes. The intermediate obtained by concentrating the mixture in

vacuo to remove the ethanol produced during reaction,

was dissolved in diphenyl ether (200 ml) , and the mixture was refluxed at 260 °C for 2 hours. The mixture was allowed to cool to room temperature, petroleum ether (200 ml) was added, and the mixture was stirred for 30 minutes. The solid produced was filtered to give the desired compound (23.1 g, 77%).

^~Η NMR(DMS0-d₆) δ 1.30(t, 3H) , 4.25(q, 2H) , 7.50(t, 1H) , 7.82(d, 1H) , 8.18(d, 1H) , 8.42(d, 1H) , 12.38(d, 1H) . m/e; 301 (M⁺) m.p. ; 228-230 °C . (Step 2) Preparation of 8-trifluoromethoxy-l,4-dihydro-

4-quinolinone

140 ml of 10%-soda aqueous solution was added to ethyl 4 -oxo- 8 - trifluoromethoxy- 1 , 4 -dihydro-3 - quinolinecarboxylate (30.1 g, 0.1 mol), and the reaction mixture was refluxed for 3 hours. The mixture was allowed to cool to room temperature, neutralized

(pH= 2) with dilute hydrochloric acid to give a white solid, and the solid was separated and dried. Diphenyl ether (250 ml) was added to the solid, and the solution was refluxed at 260 °C for 3 hours. The mixture was allowed to cool to room temperature, poured into petroleum ether (250 ml) and stirred for 30 minutes. The solid produced was filtered to give the desired compound (22 g, 96%) .

H NMR (DMSO-d δ 6.15(d, 1H) , 7.40-8.10 (m, 4H) , 11.85 (brs, 1H) . m/e; 229 (M⁺) . m.p. ; 145-146 °C .

(Step 3) Preparation of 3 -iodo-8-trifluoromethoxy-1,4-

dihydro-4-quinolinone

8-Trifluoromethoxy-l,4-dihydro-4-quinolinone (22.9 g, 0.1 mol) was dissolved in 10%-soda solution (200 ml), iodine (36.5 g) was dissolved in 20%-potassium iodide aqueous solution, and the latter solution was added dropwise slowly to the former. The mixture was stirred at room temperature for 3 hours. The solid produced by adding the excess of acetic acid and distilled water (300 ml) to the mixture, was filtered to give the desired compound (27.6 g, 79%)

"H NMR(DMSO-d_e) δ 7.50(t, 1H) , 7.83(d, 1H) , 8.18(d, 1H) , 8.43 (d, 1H) , 12.40(br, 1H) . m/e; 355 (M⁺) m.p. ; 278-279 °C .

(Step 4) Preparation of 4-chloro-3-iodo-8-

trifluoromethoxyquino1ine

The mixture of 3 -iodo- 8 -trifluoromethoxy-1, 4- dihydro-4-quinolinone (33 g) and phosphorus oxychloride

(80 ml) was refluxed at 110 °C for 1 hour, the mixture was poured slowly into ice water, neutralized with dilute soda solution to give a solid, and the solid produced was filtered to give the desired compound (33.5 g, 95%) .

^AH NMR(CDC1 δ 7.60-7.75(m, 2H) , 8.25(dd, 1H) , 9.21(s, 1H) . m/e; 373 (M⁺) m.p. ; 95-96 °C .

(Step 5) Preparation of 3 -iodo-4- (2-methylphenylamino) 8- trifluoromethoxyquinoline

The mixture of 4 - chloro - 3 - iodo - 8 - trifluoromethoxyquinoline (10 g, 26.8 mmol) and 2- methylaniline (10 g) was refluxed at 125 °C for 4 hours. The mixture was dissolved in methylene chloride (100 ml), washed with sodium bicarbonate aqueous solution, the organic layer was separated, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo, and the residue was purified by silica gel

column chromatography to give the desired compound (9 g, 76%) .

^'lE NMR(CDC1₃) δ 2.42(s, 3H) , 6.18(s, 1H) , 6.59(m, 1H) , 7.00-7.56(m, 6H) , 9.12(s, 1H) . m/e; 444 (M") . m.p. ; 104-106 °C .

(Step 6) Preparation of 6-trifluoromethoxy-3 -methyl-1-

(2 -methylphenyl) -lff-pyrrolo [3 , 2-c] quinoline

To 3-iodo-4- (2-methylphenylamino) - 8 - trifluoromethoxyquinoline (1.14 g, 2.5 mmol) in anhydrous tetrahydrofuran (20 ml) was added 60%-sodium hydride (NaH, 0.3 g) , and the mixture was stirred at room temperature for 1 hour. To this solution was added ally iodide (2.8 g, 16 mmol), and the mixture was stirred for 5 hours. To the intermediate obtained by adding saline to the mixture and separating the organic layer were added tetrabutylammonium chloride (0.45 g, 2 mmol), sodium formate (0.28 g, 4 mmol), potassium acetate (0.45 g, 4 mmol) and palladium acetate (30 mg) , and the mixture in tetrahydrofuran (10 ml) was refluxed at 120 °C for 2 hours. The mixture was concentrated and extracted with ethyl acetate, and the organic layer was separated, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo, and the residue was

purified by silica gel column chromatography to give the desired compound (0.25 g, 28%), and the compound was crystallized with a small amount of diethyl ether. ^λE NMR(CDC1₃) δ 1.92(s, 3H) , 2.52(s, 3H) , 6.95-

7.50(m, 8H) , 9.28 (s, 1H) . m/e; 356(M⁺), 341(15.6), 271(11.8), 257(11.8), 255 (19.8) , 69(79.2) . m.p. ; 103-105 °C .

<Example 18> Preparation of 3-ethyl-6-trifluoromethoxy-

1- (2 -methylphenyl) -lff-pyrrolo [3, 2-c] quinoline To 3 - iodo - 4 - ( 2 -me thylpheny lamino ) - 8 - trifluoromethoxyquinoline (1.14 g, 2.5 mmol) prepared by the process of step 1-5 of example 17 in anhydrous tetrahydrofuran (20 ml) was added 60%-sodium hydride

(NaH, 0.3 g) , and the mixture was stirred at room temperature for 1 hour. To this solution was added crotyl bromide (CH₃CHCHCH₂Br, 2.8 g, 16 mmol), and the mixture was stirred for 5 hours. To the intermediate obtained by adding saline to the mixture and separating the organic layer were added tetrabutylammonium chloride (0.45 g, 2 mmol), sodium formate (0.28 g, 4 mmol), potassium acetate (0.45 g, 4 mmol) and palladium acetate (30 mg) , and the mixture in tetrahydrofuran (10 ml) was refluxed at 120 °C for 2 hours. The mixture was concentrated and extracted with ethyl acetate, and the organic layer was separated, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo,

and the residue was purified by silica gel column chromatography to give the desired compound (0.33 g, 35%) .

Η NMR(CDC1₃) δ 1.42(t, 3H) , 1.95(s, 3H) , 2.98(q, 2H) , 6.95-7.55(m, 8H) , 9.31(s, 1H) . m/e ; 370 (M⁺), 355(100), 69(60).

<Example 19> Preparation of 3 -isopropyl-β-

trifluoromethoxy-1- (2 -methylphenyl) -lff-pyrrolo [3 , 2-

c] quinoline

To 3-iodo-4- (2-methylphenylamino) - 8 - trifluoromethoxyquinoline (1.14 g, 2.5 mmol) prepared by the process of step 1-5 of example 17 in anhydrous tetrahydrofuran (20 ml) was added 60%-sodium hydride (NaH, 0.3 g) , and the mixture was stirred at room temperature for 1 hour. To this solution was added 4- bromo-2-methyl-l-butene (2.8 g, 16 mmol), and the mixture was stirred for 5 hours. To the intermediate obtained by adding saline to the reaction mixture and separating the organic layer were added tetrabutylammonium chloride (0.45 g, 2 mmol), sodium formate (0.28 g, 4 mmol), potassium acetate (0.45 g, 4 mmol) and palladium acetate (30 mg) , and the mixture in tetrahydrofuran (10 ml) was refluxed at 120 °C for 2 hours . The mixture was concentrated and extracted with ethyl acetate, and the organic layer was separated, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo, and the residue was purified by

silica gel column chromatography to give the desired compound (0.23 g, 24%), and the compound was crystallized with a small amount of diethyl ether.

^:H NMR(CDC1₃) δ 1.45(d, 6H) , 1.92(s, 3H) , 3.41(m, 1H) , 6.94(s, 1H) , 7.00-7.55(m, 7H) , 9.37(s, 1H) . m/e; 384(M⁺), 370(24.2), 369(100), 69(31.5). m.p. ; 111-112 °C.

<Example 20> Preparation of 1- (4-fluoro-2-

ethyl henyl) - 6 - trif luoromethoxy- 3 -methyl -lff-

pyrrolo [3 , 2 -c] quinoline

(Step 1) Preparation of 4- (4-fluoro-2-

methylphenylamino) -3-iodo-8-trifluoromethoxyquinoline 4-Chloro-3-iodo-8-trifluoromethoxyquinoline (4.25 g, 11.3 mmol) and 4-fluoro-2-methylaniline (4.25 g) were refluxed at 125 °C for 36 hours. The mixture was dissolved in methylene chloride (100 ml) and washed with sodium bicarbonate, the organic layer was separated , dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo, and the residue was

purified by silica gel column chromatography to give the desired compound (4.5 g, 86%) . ^"'H NMR(CDC1₃) δ 2.40(s, 3H) , 6.10(brs, 1H) , 6.55- 7.55 (m, 6H) , 9.10(s, 1H) . m/e; 462 (M⁺) . m.p. ; 116-117 °C .

(Step 2) Preparation of 1- (4-fluoro-2 -methylphenyl) -6-

trifluoromethoxy-3 -methyl-lff-pyrrolo [3, 2-c] quinoline

To 4- (4-fluoro-2-methylphenylamino) -3 -iodo- 8- trifluoromethoxyquinoline (1.14 g, 2.5 mmol) in anhydrous tetrahydrofuran (20 ml) was added 60%-sodium hydride (NaH, 0.3 g) , and the mixture was stirred at room temperature for 1 hour. To this solution was added allyl iodide (2.8 g, 16 mmol), and the mixture was stirred for 5 hours. To the intermediate obtained by adding saline to the mixture and separating the organic layer were added tetrabutylammonium chloride (0.45 g, 2 mmol), sodium formate (0.28 g, 4 mmol), potassium acetate (0.45 g, 4 mmol) and palladium acetate (30 mg) , and the mixture in tetrahydrofuran (10 ml) was refluxed at 120 °C for 2 hours. The mixture was concentrated and extracted with ethyl acetate, and the organic layer was separated, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo, and the residue was

purified by silica gel column chromatography to give the desired compound (0.25 g, 27%), and the compound was crystallized with a small amount of diethyl ether. ^:H NMR(CDC1₃) δ 1.90(s, 3H) , 2.54(s, 3H) , 6.92(s, 1H) , 7.00-7.47(m, 6H) , 9.26(s, 1H) . m/e; 374(M⁺, 100), 359(7.4), 69(72.4). m.p. ; 129-131 °C .

<Example 21> Preparation of 3-ethyl-l- (4-fluoro-2-

methylphenyl) -6 - trifluoromethoxy- lff-pyrrolo [3,2-

c] quinoline

To 4- (4-fluoro-2 -methylphenylamino) -3-iodo-8- trifluoromethoxyquinoline (1.14 g, 2.5 mmol) prepared by the process of step 1 of example 20 in anhydrous tetrahydrofuran (20 ml) was added 60%-sodium hydride (NaH, 0.3 g) , and the mixture was stirred at room temperature for 1 hour. To this solution was added crotyl bromide (CH₃CHCHCH₂Br, 2.8 g, 16 mmol), and the mixture was stirred for 5 hours. To the intermediate obtained by adding saline to the mixture and separating the organic layer were added tetrabutylammonium chloride (0.45 g, 2 mmol), sodium formate (0.28 g, 4 mmol), potassium acetate (0.45 g, 4 mmol) and palladium acetate (30 mg) , and the mixture in tetrahydrofuran (10 ml) was refluxed at 120 °C for 2 hours. The mixture was concentrated and extracted with ethyl acetate, and the organic layer was separated, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo,

and the residue was purified by silica gel column chromatography to give the desired compound (0.24 g, 25%) , and the compound was crystallized with a small amount of diethyl ether. ^lE NMR(CDC1₃) δ 1.42(t, 3H) , 1.91(s, 3H) , 2.97(q, 2H) , 7.02-7.47(m, 6H) , 9.30(s, 1H) . m/e; 389(M⁺+1, 54.7), 388 (M⁺) , 373(100), 358(5.7), 303(14.5), 287(10), 273(11.4), 69(34.2). m.p. ; 155-156 °C .

<Example 22> Preparation of 6- (2, 2, 2 -trifluoroethoxy) 3-

methyl-1- (2 -methylphenyl) -lff-pyrrolo [3 , 2-c] quinoline

(Step 1) Preparation of ethyl 4-oxo-8- (2, 2,2-

trifluoroethoxy) -1, 4-dihydro-3-quinolinecarboxylate

The mixture of 2- (2, 2, 2 -trifluoroethoxy) aniline

(19.1 g, 0.1 mol) and diethyl ethoxy methylene malonate (17.7 g, 0.1 mol) was refluxed at 90 "C for 30 minutes. The intermediate obtained by concentrating the mixture in vacuo to remove the ethnaol produced during

reaction, was dissolved in diphenyl ether (200 ml) , and the mixture was refluxed at 260 °C for 2 hours. The mixture was allowed to cool to room temperature, petroleum ether (200 ml) was added, and the mixture was stirred for 30 minutes. The solid produced was filtered to give the desired compound (25.2 g, 80%) .

^:H NMR(DMS0-d₆) δ 1.30 (t, 3H) , 4.24 (q, 2H) , 5.05 (q, 2H) , 7.35-7.85(m, 3H) , 8.42(br, 1H) , 11.80 (brd, 1H) . m/e; 315 (M⁺) . m.p. ; 236-238 °C .

(Step 2) Preparation of 8- (2, 2, 2-trifluoroethoxy) -1,4-

dihydro-4-quinolinone

10%-soda aqueous solution (140 ml) was added to ethyl 4-0x0-8- (2,2, 2-trifluoroethoxy) -1 , 4-dihydro-3 - quinolinecarboxylate (31.5 g, 0.1 mol) and the reaction mixture was refluxed for 3 hours . The mixture was allowed to cool to room temperature, neutralized to pH 2 with dilute hydrochloric acid to give a white solid, and the solid was separated and dried. Diphenyl ether (250 ml) was added to the solid, and the solution was refluxed at 260 °C for 3 hours. The mixture was allowed to cool to room temperature, poured into petroleum ether (250 ml) and stirred for 30 minutes. The solid produced was filtered to give the desired compound (23 g, 95%) .

^:H NMR(DMSO-d₆) δ 4.98(q, 2H) , 6.07(d, 1H) , 7.21- 7.85(m, 4H) , 11.25 (brs, 1H) . m/e; 243 (M⁺) . m.p. ; 173-175 ^ϋC .

(Step 3) Preparation of 3 -iodo-8- (2 , 2, 2-

trifluoroethoxy) -1, 4-dihydro-4-quinolinone

8 - (2 , 2 , 2 -Trif luoroethoxy) -l,4-dihydro-4- quinolinone (24.3 g, 0.1 mol) was dissolved in 10%-soda solution (200 ml), iodine (36.5 g) was dissolved in 20%-potassium iodide aqueous solution, and the latter solution was added dropwise slowly to the former. The reaction mixture was stirred at room temperature for 3 hours. The solid produced by adding the excess of acetic acid and distilled water (300 ml) to the mixture, was filtered to give the desired compound (30.6 g, 83%) ^'XE NMR(DMS0-d) δ 5.00(q, 2H) , 7.29-8.30(m, 4H) , 11.65 (br, 1H) . m/e; 369 (M⁺) . m.p. ; 187-189 °C.

(Step 4) Preparation of 4-chloro-3-iodo-8- (2, 2, 2-

trifluoroethoxy) quinoline The mixture of 3 -iodo- 8- (2 , 2 , 2-trifluoroethoxy) - 1, 4-dihydro-4-quinolinone (9.2 g, 24.9 mmol) and phosphorus oxychloride (20 ml) was refluxed at 110 °C . After the reaction for 1 hour, the mixture was poured slowly into ice water and neutralized with dilute soda solution, and the organic layer was extracted with ethyl acetate and separated. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrate in vacuo, and the residue was purified by

silica gel column chromatography to give the desired compound (8.0 g, 83%).

^:H NMR(CDC1₃) δ 4.47(q, 2H) , 7.30(d, 1H) , 7.56(t, 1H) , 7.99(q, 1H) , 9.13(s, 1H) . m/e; 387 (M⁺) . m.p. ; 135-136 °C.

(Step 5) Preparation of 3 -iodo-4- (2 -methylphenylamino) -

8- (2,2, 2 -trifluoroethoxy) quinoline

The mixture of 4-chloro-3-iodo-8- (2 , 2 , 2- trifluoroethoxy) quinoline (6.9 g, 17.8 mmol) and 2- methylaniline (8.0 g) was refluxed at 125 °C for 4 hours. The mixture was dissolved in methylene chloride

(100 ml) and washed with sodium bicarbonate aqueous solution, and the organic layer was separated. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo, and the residue was purified by silica gel column chromatography to give the desired compound (7.0 g, 85%) .

^:H NMR(CDC1₃) δ 2.42 (s, 3H) , 4.72 (q, 2H) , 6.10 (brs, 1H) , 6.50-7.30(m, 7H) , 9.07(s, 1H) . m/e; 458 (M⁺) . m.p. ; 115-117 °C.

(Step 6) Preparation of 6- (2, 2, 2- trifluoroethoxy) -3-

methyl-1- (2 -methylphenyl) -lff-pyrrolo [3, 2-c] quinoline

To 3 -iodo-4- (2 -methylphenylamino) -8- (2,2,2- trifluoroethoxy) quinoline (1.15 g, 2.5 mmol) in anhydrous tetrahydrofuran (20 ml) was added 60%-sodium hydride (NaH, 0.3 g) , and the reaction mixture was stirred at room temperature for 1 hour. To this solution was added ally iodide (2.8 g, 16 mmol), and the mixture was stirred for 5 hours . To the intermediate obtained by adding saline to the mixture and separating the organic layer were added tetrabutylammonium chloride (0.45 g, 2 mmol), sodium formate (0.28 g, 4 mmol), potassium acetate (0.45 g, 4 mmol) and palladium acetate (30 mg) , and the mixture in tetrahydrofuran (10 ml) was refluxed at 120 °C for 2 hours . The mixture was concentrated and extracted with ethyl acetate, and the organic layer was separated. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo, and the

residue was purified by silica gel column chromatography to give the desired compound (0.5 g, 54%) . ^:H NMR(CDC1₃) δ 1.90(s, 3H) , 2.52(s, 3H) , 4.78(q, 2H) , 6.80-7.50(m, 8H) , 9.22(s, 1H) . m/e; 370 (M") .

The following examples 23-31 relates to the preparation of 3 -alkylpyrrolo [3 , 2 - c] quinoline

derivatives according to the process II.

<Example 23> Preparation of 6-methoxy-3-methyl-l- (2-

methylphenyl) -lff-pyrrolo [3, 2-c] quinoline

(Step 1) Preparation of 6-methoxy-3 -methyl-1- (2-

methyl) -2-trimethylsilyl-lff-pyrrolo [3, 2-c] quinoline

3-Iodo-4- (2-methylphenylamino) -8 -methoxyquinoline

(2 g, 5.3 mmol), trimethylsilyl-1-propyne (1.8 g, 16 mmol), lithium chloride (0.22 g, 5.3 mmol), potassium acetate (1 g, 10.6 mmol) and palladium acetate (59 mg,

5 mmol%) in dimethylformamide (50 ml) , were refluxed at

100 °C for 4 hours. The mixture was concentrated in

vacuo and the organic layer was extracted with diethyl

ether. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo, the residue was purified by silica gel column chromatography to give the desired compound (1.51 g, 72%) , and the compound was crystallized with a small amount of diethyl ether . ^XH NMR(CDC1₃) δ 0.10(s, 9H) , 1.85(s, 3H) , 2.64(s, 3H) , 4.08(s, 3H) , 6.45-7.49(m, 7H) , 9.20(s, 1H) . m/e; 376 (M⁺) .

(Step 2) Preparation of 6-methoxy-3 -methyd-1- (2-

methylphenyl) -lff-pyrrolo [3 , 2-c] quinoline

6-Methoxy-3 -methyl- 1- (2-methyl) -2-trimethylsilyl- lff-pyrrolo [3 , 2-c] quinoline (1.51 g, 4 mmol) in

trifluoroacetic acid (TFA, 8 ml) was refluxed for 3 hours . The mixture was concentrated and the organic layer was separated by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo, the

residue was purified by silica gel column chromatography to give the desired compound (1.1 g, 92%) , and the compound was crystallized with a small amount of diethyl ether .

The compounds of examples 24-31 were prepared by the same process of example 23, with 3-trimethylsilyl- 2-propyn-l-ol in place of trimethylsilyl-1-propyne . <Example 24> Preparation of 6 -methoxy- 3 -hydroxymethyl -

1- (2 -methylphenyl) -lff-pyrrolo [3 , 2-c] quinoline

Yield=82%. ^λE NMR(CDC1₃) δ 1.91(s, 3H) , 2.10 (brs , 1H) , 4.08(s, 3H) , 5.10 (s, 2H) , 6.66-7.49(m, 8H) , 9.21(s, 1H) . m/e; 318 (M⁺) . m.p. _; 96-98 °C .

<Example 25> Preparation of 1- (4-fluoro-2-

methylphenyl) -6-methoxy-3-hydroxymethyl-lff-pyrrolo [3,2-

c] quinoline

Yield=80%.

^XH NMR(CDC1₃) δ 1.88(s, 3H) , 2.25(brs, 1H) , 4.06(s, 3H) , 5.10(s, 2H) , 6.64-7.37(m, 7H) , 9.18(s, 1H) . m/e; 336 (M⁺) . m.p. ; 168-170 °C .

<Example 26> Preparation of 1- (4-methoxy-2-

methylphenyl) -6-methoxy-3 -hydroxymethyl-lff-pyrrolo [3,2-

c] quinoline

Yield=78%.

^:H NMR(CDC1₃) δ 1.80(s, 3H) , 2.25(s, 1H) , 4.02(s, 3H) , 5.10(s,2H) , 6.76-7.18(m, 7H) , 9.16(s, 1H) . m/e; 334 (M⁺) . m.p. ; 198-200 °C . <Example 27> Preparation of 6-methoxy-3- (2-

hydroxy ethyl) -1- (2 -methylphenyl) -lff-pyrrolo [3,2-

c] quinoline

Yield=75%.

^:H NMR(CDC1₃) δ 1.91(s, 3H) , 2.10 (brs, 1H) , 3.20(t, 2H) , 4.00(t, 2H) , 4.08 (s, 3H) , 6.66-7.49(m, 8H) , 9.21(s, 1H) . m/e; 332 (M⁺) . m.p. ; 86-88 °C .

<Example 28> Preparation of 1- (4-f luoro-2-

methylphenyl ) - 6 -methoxy- 3 - ( 2 -hydroxyethy 1 ) -lff-

pyrrolo [3, 2-c] quinoline

Yield=79%. ^:H NMR(CDC1₃) δ 1.88 (s, 3H) , 2.25 (brs, 1H) ,

3.20(t,2H) , 4.00(t,2H) , 4.06(s, 3H) , 6.64-7.37(m, 7H) , 9.18 (s, 1H) . m/e; 350 (M⁺) . m.p. ; 150-152 °C .

<Example 29> Preparation of 1- (4-methoxy-2-

methylphenyl) - 6 -me thoxy- 3 - ( 2 - hydroxyethy 1 ) -lff-

pyrrolo [3, 2-c] quinoline

Yield=73%. ^:H NMR(CDC1₃) δ 1.80(s, 3H) , 2.25(s, 1H) , 3.20(t, 2H) , 4.00(t, 2H) , 4.02(s, 3H) , 6.76-7.18(m, 7H) , 9.16(s, 1H) . m/e; 348 (M⁺) . m.p. ; 170-172 °C .

<Example 30> Preparation of 1- (4-methoxy-2-

methylphenyl) - 6 -methoxy -3 -methyl - lff-pyrrolo [3,2-

c] quinoline

Yield=74%. ^XH NMR(CDC1₃) δ 1.88(s, 3H) , 2.51(s, 3H) , 3.92(s,

3H) , 4.09(s, 3H) , 6.73-7.31 (m, 7H) , 9.19(s, 1H) . m/e; 332 (M⁺) . m.p. ; 192.5-193.5 °C .

<Example 31> Preparation of 1- (4 -me thoxy -2 -

methylphenyl) - 6 -methoxy- 3 -ethyl- lff-pyrrolo [3,2-

c] quinoline

Yield=78%. ^αH NMR(CDC1₃) δ 1.39(t, 3H) , 1.84(s, 3H, J = 7.5 Hz), 2.95(q, 2H, J = 7.5 Hz), 3.88(ε, 3H) , 4.05(s, 3H) , 6.70-7.30(m, 7H) , 9.19(s, 1H) . m/e; 346 (M⁺) . m.p. ; 138-140 °C .

3 -Alkylpyrrolo [3, 2-c] quinoline derivatives of the present invention as well as the compounds of examples 1-31, can be prepared easily by the processes I and II.

The preparation examples of pharmaceutical composition comprising 3-alkylpyrrolo [3 , 2-c] quinoline

derivatives of the present invention and their pharmaceutically acceptable salts as an active ingredient, are described below.

The following preparation examples are just representative examples of the present invention, and never limit the scope of the present invention.

<Preparation Example 1> Preparation of syrup comprising

3 -alkylpyrrolo [3, 2-c] quinoline derivatives as an active

ingredient

Syrup comprising 2 % (wt/vol.) of 3- alkylpyrrolo [3, 2-c] quinoline derivatives of the present

invention and their pharmaceutically acceptable salts, was prepared by the following process . Acid salt of 3-alkylpyrrolo [3 , 2-c] quinoline derivatives, sugar and saccharin were dissolved in 80 g of warm distilled water, the solution was allowed to cool, and then the solution consisting of glycerin, saccharin, sweetener, sorbic acid and distilled water was added to the above solution. Distilled water was added to the solution until the volume of the solution was 100 ml. The acid part of 3-alkylpyrrolo [3 , 2-c] quinoline derivatives can be substituted with another acid. The followings are the components of the syrup.

6-Methoxy-3-methyl-l- (2 -methylphenyl) -lff-pyrrolo [3,2-

c] quinoline -HCI salt . . . . . 2 g

Saccharin . . . . . . . . 0.8 g Sugar • 25.4 g

Glycerin 8.0 g Sweetener . . 0.04 g Ethanol 4.0 g Sorbic acid 0.4 g Distilled water q.s.

<Preparation Example 2> Preparation of pill comprising

3 -alkylpyrrolo [3, 2-c] quinoline derivatives as an active

ingredient

Pill comprising 15 mg of 3-alkylpyrrolo [3 , 2- c] quinoline derivatives and their pharmaceutically

acceptable salts, was prepared by the following process .

250 g of 6-methoxy-3 -methyl-1- (2 -methylphenyl) -lff-

pyrrolo [3 , 2-c] quinoline -HCI salt was mixed with 175.9 g of lactose, 180 g of corn starch and 32 g of colloidal silicic acid. 10% Gelatin solution was added to the mixture, and the mixture was pulverized, filtered with No. 14 mesh sieve and dried. Hereto was added 160 g of potato starch, 50 g of talc and 5 g of magnesium stearate to obtain the mixture, and the mixture was prepared in type of pill. The followings are the components of the pill prepared by the above process .

6-Methoxy-3-methyl-l- (2-methylphenyl) -lff-pyrrolo [3,2-

c] quinoline -HCI salt . . . . . 250 g

Lactose . . . . . . . . 175.9 g

Corn starch . . . . . . . 180 g Colloidal silicic acid . . . . . 32 g

Potato starch . . . . . . . 160 g

Talc . . . . . . . . 50 g

Magnesium stearate . . . . . . 5 g

10 % Gelatin solution

<Preparation Example 3> Preparation of ampule

comprising 3-alkylpyrrolo [3, 2-c] quinoline derivatives

as an active ingredient

Ampule comprising 10 mg of 3-alkylpyrrolo [3 , 2- c] quinoline derivatives and their pharmaceutically acceptable salts, was prepared by the following process .

1 g of 6 -methoxy-3 -methyl- 1- (2 -methylphenyl) -lff-

pyrrolo [3 , 2-c] quinoline -HCI salt, 0.6 g of sodium

chloride and 0.1 g of ascorbic acid were dissolved in distilled water, to prepare 100 ml of solution. This solution was put into the bottle, and pasteurized by heating at 20 °C for 30 minutes. The followings are the components of the ampule prepared by the above process .

6 -Methoxy- 3 -methyl-1- (2 -methylphenyl) -lff-pyrrolo [3,2-

c] quinoline -HCI salt . . . . . 1 g

Sodium chloride . . . . . . 0.6 g

Ascorbic acid . . . . . . 0.1 g Distilled water . . . . . . q.s.

Dose of 3-alkylpyrrolo [3, 2-c] quinoline derivatives

represented by the formula 1 according to the present invention, can be varied in accordance with the age, weight, gender, type of administration, health of patient and severity of disease, however, dose per day is preferably 15-25 mg on the basis of adult male.

To confirm the prominent effect on inhibiting gastric acid secretion of 3-alkylpyrrolo [3 , 2- c] quinoline derivatives represented by the formula 1

according to the present invention, in vivo assay of

pharmacological activity was performed.

<Experiment 1> In vivo assay of pharmacological

activity

In vi tro enzyme assay of H⁺/K"-ATPase collected

from a pig stomach was carried out, wherein the negative control was the activity of H⁺/K⁺-ATPase stimulated by Mg^,÷ and the positive control was the activity of HVK⁺-ATPase stimulated by Mg²⁺ and K⁺ .

Sprague Dawley male rats (150-200 g, 6 weak-old) were fasted for 24 hours, and the compound of the present invention suspended in 0.5% CMC, was orally administered in 30, 100, 300 mg/kg dose. After 1 hour, 1 ml of 97% ethanol was orally administered, and the mouse was sacrificed an hour later with ether. Stomach was resected, 13 ml of 1% formalin was injected into stomach, and the stomach was put into 1% formalin solution and fixed for 1 hour. The stomach was incised along greater curvature and opened, and the length of gastric ulcer was measured and compared with that of the control to which only solvent was administered, to calculate % protection and to determine the 50% protection dose. The result was shown in the following table 1.

TABLE 1

As a result, it was confirmed that 3- alkylpyrrolo [3 , 2-c] quinoline derivatives according to the present invention and their pharmaceutically acceptable salts inhibit more prominently the gastric acid secretion than Omeprazole.

<Experiment 2> Toxicity test

3000 g/kg of the compound of example 5, which had been suspended in 5% CMC, was administered to 5 white mice, the acute toxicity did not appear and any abnormality was not found for 2 weeks. 300 mg/kg/day of the compound of example 1 was administered to 5 Sprague Dawley male rats (150-200 g) for 3 weeks. The rats grew without any abnormality, and there was no abnormality in the rats sectioned after stopping administration.

Claims

What is claimed is :

1. 3 -Alkylpyrrolo [3 , 2-c] quinoline derivatives

represented by the formula 1, and their pharmaceutically acceptable salts: FORMULA 1

wherein

R is an alkyl group of C^, may be substituted with hydroxy group, alkoxycarbonyl group of C_╬╣_₄ alkylcarbonyl group of C_x_₄ , arylcarbonyl group, aldehyde, alkoxy group of C_╬╗-₄ , amino group, aminoalcohol, carboxy group, or halogen;

Ri is hydrogen, alkyl of C^, phenyl group, hydroxymethyl group, halogen, alkylthio group of C_╧ä.₍ , alkoxy group of C^, or amino group of CI_P substituted or unsubstituted with hydroxy group;

R₂ is hydrogen, alkyl group of C^, alkoxy group of

C_:_ΓÇ₧ substituted or unsubstituted with hydroxy group or fluorine, hydroxy group, hydroxymethyl group, or amino group of C_:ΓÇ₧ ; and

Ar is a phenyl or benzyl group substituted or unsubstituted with hydrogen, alkyl group of Cj.₆ substituted or unsubstituted with halogen, haloalkoxy group of C_:_,~ substituted or unsubstituted with halogen, alkylthio group of

halogen, cyano group, amino group, nitro group, hydroxy group, etc.

2. 3 -Alkylpyrrolo [3, 2-c] quinoline derivatives and

their pharmaceutically acceptable salts according to claim 1, wherein

R is an alkyl group of C_╬╣_₄ and may be substituted with hydroxy group, alkoxycarbonyl group of C^, alkylcarbonyl group of C╧ç_₄, arylcarbonyl group or aldehyde;

Ri is hydrogen or methyl group;

R is hydrogen, alkoxy group of C^ substituted or unsubstituted with fluorine, hydroxy group, or 2- hydroxyethoxy group; and Ar is a phenyl or benzyl group substituted or unsubstituted with hydrogen, alkyl group of C^ substituted or unsubstituted with halogen, or hydroxy group .

3. 3 -Alkylpyrrolo [3 , 2-c] quinoline derivatives and

their pharmaceutically acceptable salts according to claim 1, wherein the compound of formula 1 is 6- methoxy-3 -methyl-1- (2 -methylphenyl) -lff-pyrrolo [3,2-

c] quinoline.

4. 3-Alkylpyrrolo [3 , 2-c] quinoline derivatives and their pharmaceutically acceptable salts according to claim 1, wherein the compound of formula 1 is l-(4- fluoro- 2 -methylphenyl) -6 -methoxy -3 -methyl - lff-

pyrrolo [3 , 2- c] quinoline .

5. 3-Alkylpyrrolo [3, 2-c] quinoline derivatives and

their pharmaceutically acceptable salts according to claim 1, wherein the compound of formula 1 is 3-ethyl- 1- (4-fluoro-2 -methylphenyl) -6-methoxy-lff-pyrrolo [3,2-

c] quinoline.

6. A process for preparing 3-alkylpyrrolo [3 , 2-

c] quinoline derivatives, represented by reaction scheme

3, characterized by comprising the steps of: 1) reacting the compound of formula (VI) with allyl halide (AX) in the presence of a base to give N- allyl quinoline derivative of formula (VII) ; and

2) cyclizing the compound of formula (VII) using palladium catalyst (cat-Pd) to give the compound of formula 1.

REACTION SCHEME 3

Wherein, R, R_1; R₂ and Ar are defined as above.

7. A process for preparing 3-alkylpyrrolo [3 , 2-

c] quinoline derivatives, represented by reaction scheme

4, comprising the steps of:

1) cyclizing the quinoline compound of formula (VI) and silyl alkyne of formula (VIII) using palladium catalyst to give the compound of formula (IX) ; and

2) removing silyl group in the compound of formula (IX) to give the compound of formula 1.

REACTION SCHEME 4

d╬╕silylation

(i) Wherein, R, R_l7 R₂ and Ar are defined as above.

8. A pharmaceutical composition for treating gastric ulcer, which comprises 3-alkylpyrrolo [3 , 2- c] quinoline derivatives represented by the formula 1 and their pharmaceutically acceptable salts as an active ingredient.