CA2301510A1 - 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-ALKYLPYRROLOI3,2-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-alkylpyrrolof3,2-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.
FORMUL:: 1 ~~ 1 2 N'~:1 y y -a- w N 4 Ra R2 (I) Wherein, R is an alkyl group of C,_4, may be substituted with hydroxy group, alkoxycarbonyl group of C1_4, alkylcarbonyl group of C1_y, arylcarbonyl group, aldehyde, alkoxy group of C1_4, amino group, aminoalcohol, carboxy group, or halogen;
R; is hydrogen, alkyl of C1_~, phenyl group, hydroxymethyl group, halogen, alkylthio group of C1_r, alkoxy group of C1_6, or amino group of C1_substituted or unsubstituted with hydroxy group;
R- is hydrogen, alkyl group of Cl_~, alkoxy group of C1_r substituted or unsubstituted with hydro~y 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 C1_~
substituted or unsubstituted with halogen, haloalkoxy group of C__~ substituted or unsubstituted with halogen, alkylthio group of Cl_6, 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.
~o Wherein, A is -CH=CH-, - (CHz) ~- or - (CHZ) ~-;
R1 to R_ are hydrogen, alkyl group of C,_4, alkoxy group of C__~, phenyl group, alkylthio group of C1_e, alkanoyl group of C;_4, amino group, alkylamino group of C1_6, dialkylamino group of Cl_~, halogen, trifluoromethyl group or nitro group, respectively;
R~, to R~ are hydrogen, alkyl group of C1_~, alkoxy group of C:_: , alkylthio group of C1_~, halogen, cyano group, amino group, hydroxy group, carbamoyl group, carbonyl group, alkanoyl group of C1_~, trifluoromethyl group or nitro group, respectively; and Rlo is hydrogen, alkyl group of C1_E, halogen, hydroxy group, -CH~OH, alkylthio group of C1_~, Z5 NH(CH.)r,OH (wherein n is 0 to 4) or -NR1;R1~.
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'/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 R,o.
And KR Pat. Appl. 97-38512 describes the use of haloalkyl groups as R,.

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) .
SU~~ARY OF TSE 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 pharnlaceutically 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:

N
8 / , \ 3 R

S
wherein, R is an alkyl group of C1_s, may be substituted with hydroxy group, alkoxycarbonyl group of C1_4, alkylcarbonyl group of C,_~, arylcarbonyl group, aldehyde, alkoxy group of C1-4, amino group, *rB

aminoalcohol, carboxy group, or halogen;
R1 is hydrogen, alkyl of C 1_,; phenyl group, hydroxymethyl group, halogen, alkylthio group of C1_6, alkoxy group of Cl_b, or amino group of C,_; substituted or unsubstituted with hydroxy group;
R~ is hydrogen, alkyl group of Cl_e, 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 Cl_E
substituted or unsubstituted with halogen, haloalkoxy group of C,_~ substituted or unsubstituted with halogen, alkylthio group of C1_e, 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.

WO 00/01696 ' PCT/KR99/00346 o ' AriV~l,(~
AN Rt _ RZ
M.,~R~A
Cit~tl -N

C!
I
ArNH 2(1~
R, R H ~s (ill) Ar a IfA~ aSIC ~ iNlll) detilyrlativn C~t-Pd ~1 M) fix) (I) WO 00/Oi696 PCT/KR99/00346 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 WO 00/01696 a PCT/KR99/00346 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.

Wherein, R1 and R~ 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 (POClz), thionyl chloride (SOC1~), 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.

*rB

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 molo 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 [(CH~C00)=Pd], 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 (POC13), thionyl chloride (SOC1-~), 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 fornlula (IX) is obtained easily by using preferably, palladium acetate, potassium acetate, lithium chloride (LiCl) in dimethy~.formamide (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-1H-pyrrolo[3,2-c]quinoline, the compound of formula 1 of which 2- and 3-positioned carbon are saturated with hydrogen, is prepared by *rB

selective hydrogenation reaction of 3-alkylpyrrolo[3,2-c]quinoline prepared according to the above processes I and II, with catalyst such as platinum oxide (PtOz), sodium borohydride (NaBH~), sodium cyanoborohydride (NaBH~CN), etc. [Reaction in Orgainc Chemistry, 1984, M. Hudlicky, Ellis Horwood Ltd., pp 55-57].
On the one hand, R1 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 R1 being CHz, 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 CHZOH [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] .

*rB

WO 00/01696 ~ PCT/KR99/00346 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, malefic 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-methylphenyl)-1H-pyrrolol3,2-clquinoline (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 refluxed *rB

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%).
'H NMR(CDC1~) s 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-1-(2-methylphenyl)-1H-pyrrolo[3,2-c7quinoline 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 (CH~CHCHZI, 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)qNCl, 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 tet rahydrofuran ( 2 0 ml ) was ref luxed at 12 0 °C f or 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, 770), and the compound was crystallized with a small amount of diethyl ether.
1H NMR(CDClz) b 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-methylpheayl)-1H-pyrrolol3,2-clquinoliae To 3-iodo-4-(2-methylphenylamino)-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:CHCHCH~Br, 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 fortnate (0.42 g, 6 mmol), potassium acetate (0.61 g, 5 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%).
'H NMR(CDClz) b 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-1-(2-methylphenyl)-1H-pyrrolo[3,2-clquinoline 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-1-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%).
1H NMR(CDC13) b 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-methoxy-3-methyl-1H-pyrrolo[3,2-clquinoline ( Step 1) Preparation of 4- (4-fluoro-2-methylpheaylamino)-3-iodo-8-methoxyquinoline 4-Chloro-3-iodo-8-methoxyquinoline 13.83 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%).
-H NMR(CDC13) b 2.39(s, 3H), 4.05(s, 3H), 5.97(brs, 1H), 6.47-7.20(m, 6H), 9.02(s, 1H).
m/e; 408 (M+) .
m.p. ; 150-151 °C.
(Step 2) Preparation of 1-(4-fluoro-2-methylphenyl)-6-methoxy-3-methyl-1H-pyrrolol3,2-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 (CH~CHCH1I, 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.
1H NMR(CDC13) ~ 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> Preparatioa of 3-ethyl-1-(4-fluoro-2-methylphenyl)-6-methoxy-1H-pyrroloL3,2-clquinoline 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 (CH,CHCHCH,Br) 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.
1H NMR(CDC1:) b 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-methylpheayl)-6-methoxy-3-methyl-1H-pyrrolo(3,2-c~quinoliae (Step 1) Preparation of 4-(4-beazyloxy-2-methylphenylamino)-3-iodo-8-methoxyquinoliae -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, 820) .
'H NMR(CDC1,) ~ 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)-1H-pyrrolo(3,2-clquinoline To 4-(4-benzyloxy-2-methylphenylamino)-3-iodo-8-methoxyquinoline (1 g, 2 mmol) in anhydrous tetrahydrofuran (20m1) was added 60o-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 ref luxed 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 *rB

concentrated in vacuo, and the residue was purified by silica gel column chromatography to give the desired compound (0.56 g, 680), and the compound was crystallized with a small amount of diethyl ether.
'H NMR(CDC1,) b 1.86 (s, 3H) , 2.50 (s, 3H) , 4.08 (s, 3H), 5.16(s, 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-lIi-pyrrolo I3, 2-c~ quinoliae 3-Methyl-6-methoxy-1-(4-benzyloxy-2-methylphenyl)-1H-pyrrolo[3,2-c]quinoline (0.45 g, 1.1 mmol) in methanol (20 ml) was stirred in the presence of 5o-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 (50 mg, 15%).
1H NMR(CDC1,) b 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-1H-pyrrolo[3,2-c]quinoliae (Step 1) Preparation of 1-(4-beazyloxy-2-methylphenyl)-3-ethyl-&-methoxy-1H-pyrrolo[3~2-clquinoline 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 (CH~CHCHCH~,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.
-H NMR(CDC13) b 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-1H-pyrrolo[3,2-c]quinoline 1-(4-Benzyloxy-2-methylphenyl)-3-ethyl-6-methoxy-1H-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 5o-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, &2%).
1H NMR(DMSO-d6) b 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-1H-pyrrolo[3,2-c] quinoline 1-(4-Benzyloxy-2-methylphenyl)-3-isopropyl-6-methoxy-1H-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 5o-palladium catalyst and hydrogen (H~, 40 psi) at room *rB

temperature for 2 hours. The reaction mixture was filtered and concentrated to give the desired compound (240 mg, 690) .
'H NMR(DMSO-d6) b 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)-1H-pyrroloL3,2-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 'C 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%).
'H NMR(CDC1~) b 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.

*rB

(Step 2) Preparation of 6-methoxy-3-methyl-1-(1-phenylethyl)-1H-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 foxmate (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 ref luxed 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(CDClz) ~ 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 °C.

<Example 10> Preparation of 3-ethyl-6-methoxy-1-(1-phenylethyl)-1H-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 (CDClz) b 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 il> Preparation of 6-methoxy-3,4-dimethyl-1-(2-methylphenyl)-1X-pyrrolo[3,2-c]quinoline (Step 1) Preparation of 3-iodo-8-methoxy-2-methyl-4-(2-methylphenylamino)quiaoline 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(CDC1,) ~ 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-1-(2-methylphenyl)-1H-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 °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 (1.4 g, 77%), and the compound was crystallized with a small amount of diethyl ether.
1H NMR(CDC1,) ~ 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)-1H-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.
'H NMR(CDCl~) b 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 (M') .
<Example 13> Preparation of 1-(4-fluoro-2-methylphenyl)-6-methoxy-3,4-dimethyl-1H-pyrrolo(3,2-c]quinoline ( S tep 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, 680).
iH NMR(CDC1,) b 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-1H-pyrrolo[3,2-c]quinoline To 4-(4-fluoro-2-methyiphenylamino)-3-iodo-8-methoxy-2-methylquinoline (0.89 g, 1.2 mmol) in anhydrous tetrahydrofuran (30 ml) was added 60o-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, 47s), and the compound was crystallized with a small amount of diethyl ether.
'H NMR(CDClz) ~ 1.86 (s, 3H) , 2.57 (s, 3H) , 3 .06 (s, 3H), 4.01(s, 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)-1H-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~CHCHCH~Br, 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 fozmate (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.
iH NMR(CDClz) b 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+) m.p. ; 162.5-136.5 °C.
<Example 15> Preparation of 6-hydroxy-3-methyl-1-(2-methylphenyl)-1H-pyrrolo[3,2-c~quinoline To 6-methoxy-3-methyl-1-(2-methylphenyl)-1H-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%).
'H NMR(CDC1,) ~ 1.89 (S, 3H) , 2 .49 (S, 3H) , 6 .49 (dd, i 1H), 6.89-7.50(m, 7H), 9.00(s, 1H).
m/e ; 228 (M') .
m.p.; 137-139 °C.
<Example 16> Preparation of 6-(2-hydroxyethoxy)-3-methyl-1-(2-methylphenyl)-1H-pyrroloL3~2-c]quinoline 6-Hydroxy-3-methyl-1-(2-methylphenyl)-1H-pyrrolo [ 3 , 2 - c] quinaline ( 0 . 2 9 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-methyl-4-(2-methylphenylamino) quinoline, ethylene carbonate (1,3-dioxolan-2-one, 3 g) and potassium carbonate (KzC03, 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%) .

*rB

'H NMR(CDClz) ~ 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)-1H-pyrrolo[3,2-c7quinoline (Step 1) Preparation of ethyl 4-oxo-8-trifluoromethoxy-1,4-dihydro-3-quinoliaecarboxylate 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%).
'H NMR (DMSO-dd) b 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-1,4-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. biphenyl 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~) b 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-1,4-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%) 1H NMR(DMSO-db) ~ 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-trifluoromethoxyquinoline The mixture of 3-iodo-8-trifluoromethoxy-1,4-dihydro-4-quinolinone (33 g) and phosphorus oxychloride ( 80 ml ) was ref luxed at 110 °C far 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%).
'H NMR(CDCI;) ~ 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, 760) .
iH NMR(CDC1,) b 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)-1H-pyrroloL3~2-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 0 ) , and the compound was crystallized with a small amount of diethyl ether.
iH NMR(CDC13) b 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) -1.H-pyrrolo L3, 2-c7 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 crotyl bromide (CH~CHCHCHZBr, 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%) .
~H NMR(CDC13) b 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-6-trifluoromethoxy-1-(2-methylphenyl)-1H-pyrrolol3,2-c~ quiaoliae 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-*rB

bromo-2-methyl-1-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 fox 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(CDC1~) b 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-methylphenyl)-6-trifluoromethoxy-3-methyl-iH-pyrrolo t3, 2-c] quinoliae (Step 1) Preparation of 4-(4-fluoro-2-methylphenylamiao)-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 (CDClz) b 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-1H-pyrrolol3~2-clquinoline 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 (D.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.
1H NMR(CDClz) ~ 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-1-(4-fluoro-2-methylphenyl)-6-trifluoromethoxy-iH-pyrroloL3,2-c1 quiaoline 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 (CH~CHCHCH~Br, 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 . 2 8 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.
1H NMR(CDClz) 5 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)-1H-pyrroloL3,2-c]quinoline (Step 1) Preparation of ethyl 4-oxo-8-(2,2,2-trifluoroethoxy)-1,4-dihydro-3-quinoliaecarboxylate The mixture of 2-(2,2,2-trifluoroethoxy)aniline (19.1 g, 0.1 mol) and diethyl ethoxy methylene malonate (I7.7 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(DMSO-d~) b 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-oxo-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. biphenyl 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 0 ) .
'H NMR (DMSO-db) ~ 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 °C.
(Step 3> Preparation of 3-iodo-8-(2,2,2-trifluoroethoxy)-1,4-dihydro-4-quinolinone 8-(2,2,2-Trifluoroethoxy)-1,4-dihydro-4-quinolinone (24.3 g, 0.1 mol) was dissolved in 10s-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, 83a) -'H NMR(DMSO-dr) ~ 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)quiaoline 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) b 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-I2-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 *rB

residue was purified by silica gel column chromatography to give the desired compound (7.0 g, 85%) .
'H NMR(CDC1~) b 2.42 (s, 3H) , 4.72 (q, 2H) , -6.10(brs, iH), 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)-1H-pyrroloL3,2-c]quinoline T o 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 fozmate (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 0 ) lH NMR(CDClz) b 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-1-(2-methylphenyl)-1H-pyrrolo[3,2-c~quinoline (Step 1) Preparation of 6-methoxy-3-methyl-1-(2-methyl)-2-trimethylsilyl-1H-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 dimethylfortnamide (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, 720), and the compound was crystallized with a small amount of diethyl ether. -'H NMR(CDCl~) b 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)-1X-pyrroloL3,2-cJquinoline 6-Methoxy-3-methyl-1-(2-methyl)-2-trimethylsilyl-1H-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°s), 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-1-of in place of trimethylsilyl-1-propyne.

<Example 24> Preparation of 6-methoxy-3-hydroxymethyl-1- (2-methylphenyl) -1H-pyrrolo L3.2-c] quinoline Yield=82o.
1H NMR(CDCl~) ~ 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-1H-pyrroloL3,2 c]quinoline Yield=80~.
1H NMFt (CDC13) b 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-1H-pyrrolo(3~2-c]quinoliae Yield=78o.
'H NMR(CDCla) b 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-hydroxyethyl)-1-(2-methylphenyl)-iH-pyrrolo(3,2-c1 quinoline Yield=75%.
'H NMR(CDC13) b 1.91(5, 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(5, 1H).
m/e; 332 (M+) .
m.p.; 86-88 °C.
<Example 28> Preparation of 1-(4-fluoro-2-methylpheayl)-6-methoxy-3-(2-hydroxyethyl)-1H-pyrrolo(3,2-c~quiaoliae Yield=79%.
-H NMR (CDC13) b 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(5, 1H).
m/e; 350 (M+) .
m.p.; 150-152 °C.
<Example 29> Preparation of 1-(4-methoxy-2-methylphenyl)-6-methoxy-3-(2-hydroxyethyl)-1H-pyrrolo(3,2-c]quinoliae Yield=73%.
-H NMR(CDC1,) b 1.80 (S, 3H) , 2 .25 (S, 1H) , 3.20 (t, 2H), 4.00(t, 2H), 4.02(5, 3H), 6.76-7.18(m, 7H), 9.16(5, 1H).
m/e; 348 (M+) .
m.p.; 170-172 "C.
<Example 30> Preparation of 1-(4-methoxy-2-methylphenyl)-6-methoxy-3-methyl-1H-pyrroloL3,2-c1 quinoline Yield=74%.
'H NMR(CDC13) b 1.88 (s, 3H) , 2.51 (s, 3H) , 3 .92 (s, 3H), 4.09(5, 3H), 6.73-7.31(m, 7H), 9.19(5, 1H).
m/e; 332 (M+) .
m.p.; 192.5-193.5 °C.
<Example 31> Preparation of 1-(4-methoxy-2-methylphenyl)-6-methoxy-3-ethyl-1H-pyrrolo[3,2-c1 quinoline Yield=78°s.
1H NMR(CDC1~) ~ 1.39 (t, 3H) , 1.84 (s, 3H, J = 7.5 Hz), 2.95(q, 2H, J - 7.5 Hz), 3.88(5, 3H), 4.05(s, 3H), 6.70-7.30(m, 7H), 9.19(5, 1H).
m/e; 346 (M+) .
m.p. ; 138-140 °C.
3-Alkyipyrrolo[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 8xample 1> Preparation of syrup comprising 3-alkylpyrrolot3,2-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-1-(2-methylphenyl)-1H-pyrrolo[3,2-c] quinoline HC1 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-alkylpyrroloL3,2-clquinoline 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)-1H-pyrrolo[3,2-c]quinoline~HCl 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-1-(2-methylphenyl)-1H-pyrrolo[3,2-c]quinolineHCl 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 o Gelatin solution <Preparation Example 3> Preparation of ampule comprising 3-alkylpyrrolo[3,2-clquinoline 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)-1H
pyrrolo[3,2-c]quinoline~HC1 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)-1H-pyrrolo[3,2-c]quinoline~HC1 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-alkyipyrrolo[3,2-c]quinoline derivatives represented by the formula 1 according to the present invention, in vivo assay of pharmacological activity was performed.
<Experimeat 1> In vivo assay of pharmacological activity In vitro enzyme assay of H+/Ki-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 H-/K+-ATPase stimulated by Mg'+ 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 0.5o 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 inj ected into stomach, and the stomach was put into 1o 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 o protection and to determine the 50%
protection dose.

The result was shown in the following table 1.

Inhibition rate of In vitro Example No.
gastric ulcer enzymatic of compound relative to Omeprazole reaction 1 +++ +++

2 ++ +

3 + ++

4 +++ ++

5 +++ +++

7 + +++

8 + +++

+ +++

* Relative 15 in vivo pharmaceutical efficacy to comparative compound;
+++(strong), ++(similar), +(weak) * Omeprazole;
compound of EP No.
9105959.0 As a result, it was confirmed that 3 alkylpyrrolo[3,2-cJquinoline derivatives according to the present invention and their pharmaceutically acceptable salts inhibit more prominently the gastric acid secretion than Omeprazole.
<Experimeat 2> Toxicity test 3000 mg/kg of the compound of example 5, which had been suspended in 5% CMC, was administered to 5 white *rB

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 (8)

What is claimed is:

1. 3-Alkylpyrrolo[3,2-c]quinoline derivatives represented by the formula 1, and their pharmaceutically acceptable salts:
wherein R is an alkyl group of C1-4, may be substituted with hydroxy group, alkoxycarbonyl group of C1-4, alkylcarbonyl group of C1-4, arylcarbonyl group, aldehyde, alkoxy group of C1-4, amino group, aminoalcohol, carboxy group, or halogen;
R1 is hydrogen, alkyl of C1-6, phenyl group, hydroxymethyl group, halogen, alkylthio group of C1-6, alkoxy group of C1-6, or amino group of C1-8 substituted or unsubstituted with hydroxy group;
R2 is hydrogen, alkyl group of C1-6, alkoxy group of C1-6 substituted or unsubstituted with hydroxy group or fluorine, hydroxy group, hydroxymethyl group, or amino group of C1-~; and Ar is a phenyl or benzyl group substituted or unsubstituted with hydrogen, alkyl group of C1-6 substituted or unsubstituted with halogen, haloalkoxy group of C1-6 substituted or unsubstituted with halogen, alkylthio group of C1-6, 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 C1-4, and may be substituted with hydroxy group, alkoxycarbonyl group of C1-4, alkylcarbonyl group of C1-4, arylcarbonyl group or aldehyde;
R1 is hydrogen or methyl group;
R2 is hydrogen, alkoxy group of C1-3 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 C1-3 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)-1H-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 1-(4-fluoro-2-methylphenyl)-6-methoxy-3-methyl-1H-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-1H-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.

Wherein, R, R1, 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.
Wherein, R, R1, 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.