JPH1180156A - 1- (substituted aryl) alkyl-1H-imidazopyridin-4-amine derivatives - Google Patents

Abstract

(57) [Summary] (Modified) [PROBLEMS] To provide a compound having excellent interferon-inducing ability. The general formula (I) (Wherein R ¹ is COR ⁷ , SO ₂ NR ⁸ R ⁹ , NR ¹⁰ R
A group represented by ¹¹ or the like, R ² and R ³ is a hydrogen atom or an alkyl group, R ⁴ is such as a hydrogen atom or an alkyl group, R ⁵ is a hydrogen atom or an alkyl group, R ⁶ is a hydrogen atom, an alkyl group, R ⁷
Is a hydroxyl group, an alkyl group or an alkoxy group, R ⁸ and R ⁹ are a hydrogen atom or an alkyl group, R ¹⁰ is a hydrogen atom, an alkyl group, etc., R ¹¹ is a hydrogen atom, an alkyl group, an alkane sulfonyl group, etc., m is 0 to 1 , N is an integer of 1 to 3, X is an alkylene chain or a carbon chain represented by CH = CH, Y is a sulfur atom or a carbon chain represented by CH = CH, and the bond represented by the solid line and the dotted line is a single bond or a double bond. Represents a heavy bond. 1)
(Substituted aryl) alkyl-1H-imidazo [4,5-
c] A quinolin-4-amine derivative or a pharmacologically acceptable salt thereof.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a novel 1- (substituted aryl) alkyl-1H-imidazopyridin-4-amine derivative which induces interferon biosynthesis and is useful as an antiviral or anticancer agent, or a drug thereof. It relates to a physically acceptable salt.

[0002]

2. Description of the Related Art As a compound having a 1H-imidazopyridine-4-amine skeleton, JP-A-60-123488 is known.
No. 1-isobutyl-1H-imidazo [4,5-c] quinolin-4-amine (generic name: imiquimod, imiquimod), 1- (2-
Phenylethyl) -1H-imidazo [4,5-c] quinolin-4-amine and the like are disclosed, but a sulfamoyl group, carbamoyl group, Amino group, amide group, sulfonamide group, cyano group, carboxyl group, ureide group,
1H-imidazopyridin-4-amine derivatives having a substituent having a functional group such as a thioureido group, a hydroxyiminomethyl group or a hydroxyl group have not been known at all.

[0003]

The above-mentioned imiquimod has an effect of inducing the biosynthesis of interferon. It has been reported that Journal of Interferon Research, vol. ), And other compounds having the same action as 2-amino-5-bromo-6-
Phenyl-4 (3H) -pyrimidinone (generic name: bropir
imine, bropirimine) [Journal of Medicinal Chemistr
y), 23, 237 (1980)] and 2, 7-
Bis [2- (diethylamino) ethoxy] -9H-fluoren-9-one (generic name: tilorone, tilorone) [The Merck Index, 12
Edition, 9581], etc., but their activity is not yet sufficient.

[0004] It is an object of the present invention to have excellent interferon-inducing ability, and to have rheumatoid arthritis, wart, hepatitis B, C
It is an object of the present invention to provide novel compounds useful for diseases caused by the involvement of viruses such as hepatitis hepatitis and cancers and other neoplastic diseases.

[0005]

Means for Solving the Problems The inventors of the present invention have made intensive studies to solve such problems, and as a result, have found that a sulfamoyl group, a carbamoyl group, an amino group, an amide group are formed on the aromatic ring of the arylalkyl group at position 1. Novel 1- (substituted aryl) alkyl- having a substituent having a functional group such as a sulfonamide group, a cyano group, a carboxyl group, a ureido group, a thioureido group, a hydroxyiminomethyl group or a hydroxyl group
The present inventors have found that a 1H-imidazopyridine-4-amine derivative or a pharmacologically acceptable salt thereof has excellent interferon-inducing ability, and completed the present invention.

That is, the present invention provides the following general formula (I)

Embedded image(Where R¹Is COR⁷, SO_TwoNR⁸R⁹, CONR
⁸R⁹, NR^TenR¹¹, C (R¹²) = NOH
Group, hydroxyl group or cyano group is represented by R^TwoAnd R^ThreeAre the same or different
Represents a hydrogen atom or a lower alkyl group;^FourIs hydrogen field
Or one or more hydroxyl groups, lower alkoxy
Substituted with a group, cyclic alkyl group or halogen atom
Good linear or branched alkyl having 1 to 10 carbon atoms
R represents a group^FiveRepresents a hydrogen atom or a lower alkyl group;⁶
Represents a hydrogen atom, a lower alkyl group, a lower alkoxy group or
The logen atom is represented by R⁷Is hydroxyl group, lower alkyl group or lower
Represents an alkoxy group;⁸And R⁹Are the same or different
An atom or lower alkyl group is represented by R ^TenIs a hydrogen atom, lower
Represents a alkyl group or a benzyl group;¹¹Is a hydrogen atom, lower
Alkyl group, benzyl group, lower alkane sulfonyl group, low
Alkanoyl group, substituted or unsubstituted carbamoyl
Group, substituted or unsubstituted thiocarbamoyl group or substituted
Or an unsubstituted benzenesulfonyl group;¹²Is
A hydrogen atom or a lower alkyl group, m is an integer of 0 to 1 and n is
Represents an integer of 1 to 3, X is an alkylene having 1 to 3 carbon atoms
Represents a chain or a carbon chain represented by CH = CH, and Y represents a sulfur atom
And a carbon chain represented by CH = CH, a solid line and a dotted line
The bond represented by represents a single bond or a double bond. )
1- (substituted aryl) alkyl-1H-imidazo
Pyridine-4-amine derivatives or pharmacologically acceptable thereof
It relates to possible salts.

[0007]

BEST MODE FOR CARRYING OUT THE INVENTION In the general formula (I),
R ² , R ³ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R
Examples of the lower alkyl group represented by ¹¹ or R ¹² include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group and a tert-
Butyl group and the like, carbon atoms represented by R ⁴ 1 to 10
Examples of the linear or branched alkyl group include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl.
Butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, n-heptyl, n-octyl, n-
Nonyl group, n-decyl group and the like. Examples of the lower alkoxy group which may be substituted on the alkyl group include, for example, methoxy group, ethoxy group, n-propoxy group, isopropoxy group, n-butoxy group, Examples thereof include an isobutoxy group, a sec-butoxy group, and a tert-butoxy group. Examples of the cyclic alkyl group which may be substituted on the alkyl group include, for example, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, and cycloheptyl. And a halogen atom which may be substituted on the alkyl group, for example, a fluorine atom, a chlorine atom, a bromine atom,
And iodine atoms. The lower alkoxy group represented by R ⁶ or R ⁷ includes, for example, methoxy group, ethoxy group, n-propoxy group, isopropoxy group, n-butoxy group, isobutoxy group, sec-butoxy group, tert-butoxy group And the halogen atom represented by R ⁶ includes, for example, a fluorine atom, a chlorine atom, a bromine atom and an iodine atom. Examples of the lower alkanesulfonyl group represented by R ¹¹ include a methanesulfonyl group, a propanesulfonyl group, and a butanesulfonyl group. Examples of the lower alkanoyl group represented by R ¹¹ include an acetyl group, a propionyl group, and a butyryl group. Examples of the substituted or unsubstituted carbamoyl group, substituted or unsubstituted thiocarbamoyl group, or substituted or unsubstituted benzenesulfonyl group represented by R ¹¹ include lower alkyl groups, lower alkoxy groups and halogen atoms. And the like.

The compound represented by the above general formula (I) of the present invention can be converted into a pharmacologically acceptable salt or a base can be liberated from the formed salt as required.

The pharmacologically acceptable salts of the compounds represented by the above general formula (I) of the present invention include, for example, acid addition salts, such as hydrochloric acid, hydrobromic acid, hydroiodic acid and nitric acid. , Sulfuric acid, phosphoric acid, etc., or acetic acid, maleic acid, fumaric acid, citric acid, oxalic acid, malic acid, methanesulfonic acid, p-toluenesulfonic acid, mandelic acid, 10-
Organic acid salts such as camphorsulfonic acid and tartaric acid are exemplified.

The compound having an asymmetric carbon in the compound represented by formula (I) of the present invention may have optical isomers, and the present invention also includes these optically active isomers and mixtures thereof. .

The compound of the present invention represented by the above general formula (I) or a pharmaceutically acceptable salt thereof can exist in any crystal form depending on the production conditions, and can exist as an arbitrary hydrate. Although they can be present, these crystal forms, hydrates and mixtures thereof are also included in the scope of the present invention.

The 1- (substituted aryl) alkyl- of the present invention
Preferred embodiments of the 1H-imidazopyridine-4-amine derivative include the compounds described in Examples described below, the following compounds, or pharmacologically acceptable salts thereof, and the present invention relates to these examples. It is not limited to. (1) 1- [2- [4- (1-aminoethyl) phenyl] ethyl] -1H-imidazo [4,5-c] quinolin-4-amine (2) 1- [2- [4- (1 -Aminoethyl) phenyl] ethyl] -2-methyl-1H-imidazo [4,5-
c] Quinolin-4-amine (3) 1- [2- [4- (1-aminoethyl) phenyl] ethyl] -2-ethyl-1H-imidazo [4,5-
c] Quinolin-4-amine (4) 1- [2- [4- (1-aminoethyl) phenyl] ethyl] -2-n-propyl-1H-imidazo [4,
5-c] quinolin-4-amine (5) 1- [2- [4- (1-aminoethyl) phenyl] ethyl] -2-n-butyl-1H-imidazo [4,5
-C] quinoline-4-amine (6) 1- [2- [4- (1-aminoethyl) phenyl] ethyl] -2-cyclopropylmethyl-1H-imidazo [4,5-c] quinoline-4- Amine (7) 1- [2- [4- (1-Aminoethyl) phenyl] ethyl] -2-ethoxymethyl-1H-imidazo [4,5-c] quinolin-4-amine (8) 1- [2 -[4- (1-aminoethyl) phenyl] ethyl] -6,7,8,9-tetrahydro-1H-
Imidazo [4,5-c] quinolin-4-amine (9) 1- [2- [4- (1-aminoethyl) phenyl] ethyl] -6,7,8,9-tetrahydro-2-methyl-1H -Imidazo [4,5-c] quinolin-4-amine (10) 1- [2- [4- (1-aminoethyl) phenyl] ethyl] -2-ethyl-6,7,8,9-tetrahydro- 1H-imidazo [4,5-c] quinolin-4-amine (11) 1- [2- [4- (1-aminoethyl) phenyl] ethyl] -6,7,8,9-tetrahydro-2-n -
Propyl-1H-imidazo [4,5-c] quinoline-4
-Amine (12) 1- [2- [4- (1-aminoethyl) phenyl] ethyl] -2-n-butyl-6,7,8,9-tetrahydro-1H-imidazo [4,5-c] Quinoline-4-
Amine (13) 1- [2- [4- (1-aminoethyl) phenyl] ethyl] -2-cyclopropylmethyl-6,7,7
8,9-tetrahydro-1H-imidazo [4,5-c]
Quinoline-4-amine (14) 1- [2- [4- (1-aminoethyl) phenyl] ethyl] -2-ethoxymethyl-6,7,8,9-
Tetrahydro-1H-imidazo [4,5-c] quinolin-4-amine (15) 1- [2- [4- (1-aminoethyl) phenyl] ethyl] -1,6,7,8-tetrahydrocyclopenta [B] Imidazo [4,5-d] pyridin-4-amine (16) 1- [2- [4- (1-aminoethyl) phenyl] ethyl] -1,6,7,8-tetrahydro-2- Methylcyclopenta [b] imidazo [4,5-d] pyridin-4-amine (17) 1- [2- [4- (1-aminoethyl) phenyl] ethyl] -2-ethyl-1,6,7 , 8-Tetrahydrocyclopenta [b] imidazo [4,5-d] pyridin-4-amine (18) 1- [2- [4- (1-aminoethyl) phenyl] ethyl] -1,6,7, 8-tetrahydro-2-n-
Propylcyclopenta [b] imidazo [4,5-d] pyridin-4-amine (19) 1- [2- [4- (1-aminoethyl) phenyl] ethyl] -2-n-butyl-1,6 , 7,8-Tetrahydrocyclopenta [b] imidazo [4,5-d] pyridin-4-amine (20) 1- [2- [4- (1-aminoethyl) phenyl] ethyl] -2-cyclopropyl Methyl-1,6
7,8-tetrahydrocyclopenta [b] imidazo [4,5-d] pyridin-4-amine

(21) 1- [2- [4- (1-aminoethyl) phenyl] ethyl] -2-ethoxymethyl-1,
6,7,8-tetrahydrocyclopenta [b] imidazo [4,5-d] pyridin-4-amine (22) 1- [2- [4- (1-aminoethyl) phenyl] ethyl] -1,6 , 7,8,9,10-Hexahydrocyclohepta [b] imidazo [4,5-d] pyridin-4-amine (23) 1- [2- [4- (1-aminoethyl) phenyl] ethyl] -1,6,7,8,9,10-Hexahydro-2-methylcyclohepta [b] imidazo [4,5-
d] pyridine-4-amine (24) 1- [2- [4- (1-aminoethyl) phenyl] ethyl] -2-ethyl-1,6,7,8,9,10
-Hexahydrocyclohepta [b] imidazo [4,5-
d] pyridin-4-amine (25) 1- [2- [4- (1-aminoethyl) phenyl] ethyl] -1,6,7,8,9,10-hexahydro-2-n-propylcyclohepta [B] Imidazo [4,
5-d] pyridin-4-amine (26) 1- [2- [4- (1-aminoethyl) phenyl] ethyl] -2-n-butyl-1,6,7,8,9,1
0-hexahydrocyclohepta [b] imidazo [4,5
-D] pyridin-4-amine (27) 1- [2- [4- (1-aminoethyl) phenyl] ethyl] -2-cyclopropylmethyl-1,6,
7,8,9,10-Hexahydrocyclohepta [b] imidazo [4,5-d] pyridin-4-amine (28) 1- [2- [4- (1-aminoethyl) phenyl] ethyl]- 2-ethoxymethyl-1,6,7,8,
9,10-hexahydrocyclohepta [b] imidazo [4,5-d] pyridin-4-amine (29) N- [1- [4- [2- (4-amino-1H-imidazo [4,5 -C] quinolin-1-yl) ethyl] phenyl] ethyl] acetamide (30) N- [1- [4- [2- (4-amino-2-methyl-1H-imidazo [4,5-c] quinoline -1-yl) ethyl] phenyl] ethyl] acetamide (31) N- [1- [4- [2- (4-amino-2-ethyl-1H-imidazo [4,5-c] quinolin-1-yl) ) Ethyl] phenyl] ethyl] acetamide (32) N- [1- [4- [2- (4-amino-2-n-propyl-1H-imidazo [4,5-c] quinoline-1-)
Yl) ethyl] phenyl] ethyl] acetamide (33) N- [1- [4- [2- (4-amino-2-n-butyl-1H-imidazo [4,5-c] quinolin-1-yl) Ethyl] phenyl] ethyl] acetamide (34) N- [1- [4- [2- (4-amino-2-cyclopropylmethyl-1H-imidazo [4,5-c] quinolin-1-yl) ethyl] Phenyl] ethyl] acetamide (35) N- [1- [4- [2- (4-amino-2-ethoxymethyl-1H-imidazo [4,5-c] quinoline-
1-yl) ethyl] phenyl] ethyl] acetamide (36) N- [1- [4- [2- (4-amino-6,7,7,
8,9-tetrahydro-1H-imidazo [4,5-c]
Quinolin-1-yl) ethyl] phenyl] ethyl] acetamide (37) N- [1- [4- [2- (4-amino-6,7,
8,9-tetrahydro-2-methyl-1H-imidazo [4,5-c] quinolin-1-yl) ethyl] phenyl] ethyl] acetamide (38) N- [1- [4- [2- (4- Amino-2-ethyl-6,7,8,9-tetrahydro-1H-imidazo [4,5-c] quinolin-1-yl) ethyl] phenyl] ethyl] acetamide (39) N- [1- [4- [2- (4-amino-6,7,
8,9-tetrahydro-2-n-propyl-1H-imidazo [4,5-c] quinolin-1-yl) ethyl] phenyl] ethyl] acetamide (40) N- [1- [4- [2- ( 4-Amino-2-n-butyl-6,7,8,9-tetrahydro-1H-imidazo [4,5-c] quinolin-1-yl) ethyl] phenyl] ethyl] acetamide

(41) N- [1- [4- [2- (4-amino-2-cyclopropylmethyl-6,7,8,9-tetrahydro-1H-imidazo [4,5-c] quinoline- 1
-Yl) ethyl] phenyl] ethyl] acetamide (42) N- [1- [4- [2- (4-amino-2-ethoxymethyl-6,7,8,9-tetrahydro-1H-imidazo [4, 5-c] quinolin-1-yl) ethyl] phenyl] ethyl] acetamide (43) N- [1- [4- [2- (4-amino-1,6,6)
7,8-tetrahydrocyclopenta [b] imidazo [4,5-d] pyridin-1-yl) ethyl] phenyl] ethyl] acetamide (44) N- [1- [4- [2- (4-amino- 1,6
7,8-tetrahydro-2-methylcyclopenta [b]
Imidazo [4,5-d] pyridin-1-yl) ethyl
Phenyl] ethyl] acetamide (45) N- [1- [4- [2- (4-amino-2-ethyl-1,6,7,8-tetrahydrocyclopenta [b]
Imidazo [4,5-d] pyridin-1-yl) ethyl
Phenyl] ethyl] acetamide (46) N- [1- [4- [2- (4-amino-1,6,
7,8-tetrahydro-2-n-propylcyclopenta [b] imidazo [4,5-d] pyridin-1-yl) ethyl] phenyl] ethyl] acetamide (47) N- [1- [4- [2 -(4-Amino-2-n-butyl-1,6,7,8-tetrahydrocyclopenta [b] imidazo [4,5-d] pyridin-1-yl) ethyl] phenyl] ethyl] acetamide (48) N- [1- [4- [2- (4-amino-2-cyclopropylmethyl-1,6,7,8-tetrahydrocyclopenta [b] imidazo [4,5-d] pyridine-1-
Yl) ethyl] phenyl] ethyl] acetamide (49) N- [1- [4- [2- (4-amino-2-ethoxymethyl-1,6,7,8-tetrahydrocyclopenta [b] imidazo [4 , 5-d] pyridin-1-yl)
Ethyl] phenyl] ethyl] acetamide (50) N- [1- [4- [2- (4-amino-1,6,6)
7,8,9,10-hexahydrocyclohepta [b] imidazo [4,5-d] pyridin-1-yl) ethyl] phenyl] ethyl] acetamide (51) N- [1- [4- [2- (4-amino-1,6,
7,8,9,10-Hexahydro-2-methylcyclohepta [b] imidazo [4,5-d] pyridin-1-yl) ethyl] phenyl] ethyl] acetamide (52)
N- [1- [4- [2- (4-amino-2-ethyl-
1,6,7,8,9,10-hexahydrocyclohepta [b] imidazo [4,5-d] pyridin-1-yl) ethyl] phenyl] ethyl] acetamide (53) N- [1- [4 -[2- (4-amino-1,6,6
7,8,9,10-Hexahydro-2-n-propylcyclohepta [b] imidazo [4,5-d] pyridine-1-
Yl) ethyl] phenyl] ethyl] acetamide (54) N- [1- [4- [2- (4-amino-2-n-butyl-1,6,7,8,9,10-hexahydrocyclohepta) [B] Imidazo [4,5-d] pyridin-1-yl) ethyl] phenyl] ethyl] acetamide (55) N- [1- [4- [2- (4-amino-2-cyclopropylmethyl-1) , 6,7,8,9,10-Hexahydrocyclohepta [b] imidazo [4,5-d] pyridin-1-yl) ethyl] phenyl] ethyl] acetamide (56) N- [1- [4- [2- (4-amino-2-ethoxymethyl-1,6,7,8,9,10-hexahydrocyclohepta [b] imidazo [4,5-d] pyridine-
1-yl) ethyl] phenyl] ethyl] acetamide (57) 1- [2- [4- (aminomethyl) phenyl] ethyl] -1H-imidazo [4,5-c] quinoline-4-
Amine (58) 1- [2- [4- (aminomethyl) phenyl] ethyl] -2-methyl-1H-imidazo [4,5-c] quinolin-4-amine (59) 1- [2- [4 -(Aminomethyl) phenyl] ethyl] -2-ethyl-1H-imidazo [4,5-c] quinolin-4-amine (60) 1- [2- [4- (aminomethyl) phenyl] ethyl] -2 -N-propyl-1H-imidazo [4,5-
c] Quinoline-4-amine

(61) 1- [2- [4- (aminomethyl)
Phenyl] ethyl] -2-n-butyl-1H-imidazo [4,5-c] quinolin-4-amine (62) 1- [2- [4- (aminomethyl) phenyl] ethyl] -2-cyclopropyl Methyl-1H-imidazo [4,5-c] quinolin-4-amine (63) 1- [2- [4- (aminomethyl) phenyl] ethyl] -2-ethoxymethyl-1H-imidazo [4,5
-C] quinolin-4-amine (64) 1- [2- [4- (aminomethyl) phenyl] ethyl] -6,7,8,9-tetrahydro-1H-imidazo [4,5-c] quinoline- 4-amine (65) 1- [2- [4- (aminomethyl) phenyl] ethyl] -6,7,8,9-tetrahydro-2-methyl-
1H-imidazo [4,5-c] quinolin-4-amine (66) 1- [2- [4- (aminomethyl) phenyl] ethyl] -2-ethyl-6,7,8,9-tetrahydro-
1H-imidazo [4,5-c] quinolin-4-amine (67) 1- [2- [4- (aminomethyl) phenyl] ethyl] -6,7,8,9-tetrahydro-2-n-propyl -1H-imidazo [4,5-c] quinolin-4-amine (68) 1- [2- [4- (aminomethyl) phenyl] ethyl] -2-n-butyl-6,7,8,9- Tetrahydro-1H-imidazo [4,5-c] quinolin-4-amine (69) 1- [2- [4- (aminomethyl) phenyl] ethyl] -2-cyclopropylmethyl-6,7,8,9 −
Tetrahydro-1H-imidazo [4,5-c] quinolin-4-amine (70) 1- [2- [4- (aminomethyl) phenyl] ethyl] -2-ethoxymethyl-6,7,8,9- Tetrahydro-1H-imidazo [4,5-c] quinoline-4-
Amine (71) 1- [2- [4- (aminomethyl) phenyl] ethyl] -1,6,7,8-tetrahydrocyclopenta [b] imidazo [4,5-d] pyridin-4-amine (72 ) 1- [2- [4- (Aminomethyl) phenyl] ethyl] -1,6,7,8-tetrahydro-2-methylcyclopenta [b] imidazo [4,5-d] pyridine-4
-Amine (73) 1- [2- [4- (aminomethyl) phenyl] ethyl] -2-ethyl-1,6,7,8-tetrahydrocyclopenta [b] imidazo [4,5-d] pyridine- 4
-Amine (74) 1- [2- [4- (aminomethyl) phenyl] ethyl] -1,6,7,8-tetrahydro-2-n-propylcyclopenta [b] imidazo [4,5-d] Pyridin-4-amine (75) 1- [2- [4- (aminomethyl) phenyl] ethyl] -2-n-butyl-1,6,7,8-tetrahydrocyclopenta [b] imidazo [4,5 -D] pyridine-
4-amine (76) 1- [2- [4- (aminomethyl) phenyl] ethyl] -2-cyclopropylmethyl-1,6,7,8-
Tetrahydrocyclopenta [b] imidazo [4,5-
d] pyridine-4-amine (77) 1- [2- [4- (aminomethyl) phenyl] ethyl] -2-ethoxymethyl-1,6,7,8-tetrahydrocyclopenta [b] imidazo [4, 5-d] pyridin-4-amine (78) 1- [2- [4- (aminomethyl) phenyl] ethyl] -1,6,7,8,9,10-hexahydrocyclohepta [b] imidazo [ 4,5-d] pyridine-4-
Amine (79) 1- [2- [4- (aminomethyl) phenyl] ethyl] -1,6,7,8,9,10-hexahydro-2
-Methylcyclohepta [b] imidazo [4,5-d] pyridin-4-amine (80) 1- [2- [4- (aminomethyl) phenyl] ethyl] -2-ethyl-1,6,7, 8,9,10-hexahydrocyclohepta [b] imidazo [4,5-d] pyridin-4-amine

(81) 1- [2- [4- (aminomethyl)
[Phenyl] ethyl] -1,6,7,8,9,10-hexahydro-2-n-propylcyclohepta [b] imidazo [4,5-d] pyridin-4-amine (82) 1- [2- [4- (Aminomethyl) phenyl] ethyl] -2-n-butyl-1,6,7,8,9,10-hexahydrocyclohepta [b] imidazo [4,5-d]
Pyridin-4-amine (83) 1- [2- [4- (aminomethyl) phenyl] ethyl] -2-cyclopropylmethyl-1,6,7,8,
9,10-hexahydrocyclohepta [b] imidazo [4,5-d] pyridin-4-amine (84) 1- [2- [4- (aminomethyl) phenyl] ethyl] -2-ethoxymethyl-1 , 6,7,8,9,1
0-hexahydrocyclohepta [b] imidazo [4,5
-D] pyridin-4-amine (85) 1- [2- (4-aminophenyl) ethyl] -1
H-imidazo [4,5-c] quinolin-4-amine (86) 1- [2- (4-aminophenyl) ethyl] -2
-Methyl-1H-imidazo [4,5-c] quinoline-4
-Amine (87) 1- [2- (4-aminophenyl) ethyl] -2
-Ethyl-1H-imidazo [4,5-c] quinoline-4
-Amine (88) 1- [2- (4-aminophenyl) ethyl] -2
-N-propyl-1H-imidazo [4,5-c] quinolin-4-amine (89) 1- [2- (4-aminophenyl) ethyl] -2
-N-butyl-1H-imidazo [4,5-c] quinoline-
4-amine (90) 1- [2- (4-aminophenyl) ethyl] -2
-Cyclopropylmethyl-1H-imidazo [4,5-
c] Quinolin-4-amine (91) 1- [2- (4-aminophenyl) ethyl] -2
-Ethoxymethyl-1H-imidazo [4,5-c] quinolin-4-amine (92) 1- [2- (4-aminophenyl) ethyl]-
6, 7, 8, 9-tetrahydro-1H-imidazo [4,
5-c] quinolin-4-amine (93) 1- [2- (4-aminophenyl) ethyl]-
6,7,8,9-Tetrahydro-2-methyl-1H-imidazo [4,5-c] quinolin-4-amine (94) 1- [2- (4-aminophenyl) ethyl] -2
-Ethyl-6,7,8,9-tetrahydro-1H-imidazo [4,5-c] quinolin-4-amine (95) 1- [2- (4-aminophenyl) ethyl]-
6,7,8,9-tetrahydro-2-n-propyl-1H
-Imidazo [4,5-c] quinolin-4-amine (96) 1- [2- (4-aminophenyl) ethyl] -2
-N-butyl-6,7,8,9-tetrahydro-1H-imidazo [4,5-c] quinolin-4-amine (97) 1- [2- (4-aminophenyl) ethyl] -2
-Cyclopropylmethyl-6,7,8,9-tetrahydro-1H-imidazo [4,5-c] quinolin-4-amine (98) 1- [2- (4-aminophenyl) ethyl] -2
-Ethoxymethyl-6,7,8,9-tetrahydro-1
H-imidazo [4,5-c] quinolin-4-amine (99) 1- [2- (4-aminophenyl) ethyl]-
1,6,7,8-tetrahydrocyclopenta [b] imidazo [4,5-d] pyridin-4-amine (100) 1- [2- (4-aminophenyl) ethyl]-
1,6,7,8-tetrahydro-2-methylcyclopenta [b] imidazo [4,5-d] pyridin-4-amine

(101) 1- [2- (4-aminophenyl) ethyl] -2-ethyl-1,6,7,8-tetrahydrocyclopenta [b] imidazo [4,5-d] pyridine-4- Amine (102) 1- [2- (4-aminophenyl) ethyl]-
1,6,7,8-tetrahydro-2-n-propylcyclopenta [b] imidazo [4,5-d] pyridin-4-amine (103) 1- [2- (4-aminophenyl) ethyl]-
2-n-butyl-1,6,7,8-tetrahydrocyclopenta [b] imidazo [4,5-d] pyridin-4-amine (104) 1- [2- (4-aminophenyl) ethyl]-
2-cyclopropylmethyl-1,6,7,8-tetrahydrocyclopenta [b] imidazo [4,5-d] pyridin-4-amine (105) 1- [2- (4-aminophenyl) ethyl]-
2-ethoxymethyl-1,6,7,8-tetrahydrocyclopenta [b] imidazo [4,5-d] pyridine-4
-Amine (106) 1- [2- (4-aminophenyl) ethyl]-
1,6,7,8,9,10-hexahydrocyclohepta [b] imidazo [4,5-d] pyridin-4-amine (107) 1- [2- (4-aminophenyl) ethyl]-
1,6,7,8,9,10-hexahydro-2-methylcyclohepta [b] imidazo [4,5-d] pyridine-
4-amine (108) 1- [2- (4-aminophenyl) ethyl]-
2-ethyl-1,6,7,8,9,10-hexahydrocyclohepta [b] imidazo [4,5-d] pyridine-
4-amine (109) 1- [2- (4-aminophenyl) ethyl]-
1,6,7,8,9,10-Hexahydro-2-n-propylcyclohepta [b] imidazo [4,5-d] pyridin-4-amine (110) 1- [2- (4-aminophenyl ) Ethyl]-
2-n-butyl-1,6,7,8,9,10-hexahydrocyclohepta [b] imidazo [4,5-d] pyridin-4-amine (111) 1- [2- (4-amino Phenyl) ethyl]-
2-cyclopropylmethyl-1,6,7,8,9,10
-Hexahydrocyclohepta [b] imidazo [4,5-
d] pyridine-4-amine (112) 1- [2- (4-aminophenyl) ethyl]-
2-ethoxymethyl-1,6,7,8,9,10-hexahydrocyclohepta [b] imidazo [4,5-d] pyridin-4-amine (113) N- [4- [2- (4 -Amino-1H-imidazo [4,5-c] quinolin-1-yl) ethyl] phenyl] acetamide (114) N- [4- [2- (4-amino-2-methyl-
1H-imidazo [4,5-c] quinolin-1-yl) ethyl] phenyl] acetamide (115) N- [4- [2- (4-amino-2-ethyl-
1H-imidazo [4,5-c] quinolin-1-yl) ethyl] phenyl] acetamide (116) N- [4- [2- (4-amino-2-n-propyl-1H-imidazo [4,5 -C] quinolin-1-yl) ethyl] phenyl] acetamide (117) N- [4- [2- (4-amino-2-n-butyl-1H-imidazo [4,5-c] quinolin-1-) Ill)
Ethyl] phenyl] acetamide (118) N- [4- [2- (4-Amino-2-cyclopropylmethyl-1H-imidazo [4,5-c] quinolin-1-yl) ethyl] phenyl] acetamide (119 ) N- [4- [2- (4-Amino-2-ethoxymethyl-1H-imidazo [4,5-c] quinoline-1-
Yl) ethyl] phenyl] acetamide (120) N- [4- [2- (4-amino-6,7,8,
9-tetrahydro-1H-imidazo [4,5-c] quinolin-1-yl) ethyl] phenyl] acetamide

(121) N- [4- [2- (4-amino-
6,7,8,9-Tetrahydro-2-methyl-1H-imidazo [4,5-c] quinolin-1-yl) ethyl] phenyl] acetamide (122) N- [4- [2- (4-amino -2-ethyl-
6, 7, 8, 9-tetrahydro-1H-imidazo [4,
5-c] quinolin-1-yl) ethyl] phenyl] acetamide (123) N- [4- [2- (4-amino-6,7,8,
9-tetrahydro-2-n-propyl-1H-imidazo [4,5-c] quinolin-1-yl) ethyl] phenyl] acetamide (124) N- [4- [2- (4-amino-2-n -Butyl-6,7,8,9-tetrahydro-1H-imidazo [4,5-c] quinolin-1-yl) ethyl] phenyl] acetamide (125) N- [4- [2- (4-amino- 2-cyclopropylmethyl-6,7,8,9-tetrahydro-1H-
Imidazo [4,5-c] quinolin-1-yl) ethyl
Phenyl] acetamide (126) N- [4- [2- (4-amino-2-ethoxymethyl-6,7,8,9-tetrahydro-1H-imidazo [4,5-c] quinolin-1-yl) Ethyl] phenyl] acetamide (127) N- [4- [2- (4-amino-1,6,7,
8-tetrahydrocyclopenta [b] imidazo [4,5
-D] pyridin-1-yl) ethyl] phenyl] acetamide (128) N- [4- [2- (4-amino-1,6,7,
8-tetrahydro-2-methylcyclopenta [b] imidazo [4,5-d] pyridin-1-yl) ethyl] phenyl] acetamide (129) N- [4- [2- (4-amino-2-ethyl) −
1,6,7,8-tetrahydrocyclopenta [b] imidazo [4,5-d] pyridin-1-yl) ethyl] phenyl] acetamide (130) N- [4- [2- (4-amino-1 , 6,7,
8-tetrahydro-2-n-propylcyclopenta [b]
Imidazo [4,5-d] pyridin-1-yl) ethyl
Phenyl] acetamide (131) N- [4- [2- (4-amino-2-n-butyl-1,6,7,8-tetrahydro-2-cyclopenta [b] imidazo [4,5-d] pyridine -1-yl) ethyl] phenyl] acetamide (132) N- [4- [2- (4-amino-2-cyclopropylmethyl-1,6,7,8-tetrahydrocyclopenta [b] imidazo [4, 5-d] pyridin-1-yl) ethyl] phenyl] acetamide (133) N- [4- [2- (4-amino-2-ethoxymethyl-1,6,7,8-tetrahydrocyclopenta [b] Imidazo [4,5-d] pyridin-1-yl) ethyl] phenyl] acetamide (134) N- [4- [2- (4-amino-1,6,7,
8,9,10-hexahydrocyclohepta [b] imidazo [4,5-d] pyridin-1-yl) ethyl] phenyl] acetamide (135) N- [4- [2- (4-amino-1, 6,7,
8,9,10-Hexahydro-2-methylcyclohepta [b] imidazo [4,5-d] pyridin-1-yl) ethyl] phenyl] acetamide (136) N- [4- [2- (4-amino) -2-ethyl-
1,6,7,8,9,10-hexahydrocyclohepta [b] imidazo [4,5-d] pyridin-1-yl) ethyl] phenyl] acetamide (137) N- [4- [2- ( 4-amino-1,6,7,
8,9,10-Hexahydro-2-n-propylcyclohepta [b] imidazo [4,5-d] pyridin-1-yl) ethyl] phenyl] acetamide (138) N- [4- [2- (4 -Amino-2-n-butyl-1,6,7,8,9,10-hexahydrocyclohepta [b] imidazo [4,5-d] pyridin-1-yl)
Ethyl] phenyl] acetamide (139) N- [4- [2- (4-amino-2-cyclopropylmethyl-1,6,7,8,9,10-hexahydrocyclohepta [b] imidazo [4, 5-d] pyridin-1-yl) ethyl] phenyl] acetamide (140) N- [4- [2- (4-amino-2-ethoxymethyl-1,6,7,8,9,10-hexahydro) Cyclohepta [b] imidazo [4,5-d] pyridine-1-
Yl) ethyl] phenyl] acetamide

(141) 1- [2- [4- (methylamino) phenyl] ethyl] -1H-imidazo [4,5-
c] Quinolin-4-amine (142) 2-methyl-1- [2- [4- (methylamino) phenyl] ethyl] -1H-imidazo [4,5-
c] Quinolin-4-amine (143) 2-ethyl-1- [2- [4- (methylamino) phenyl] ethyl] -1H-imidazo [4,5-
c] Quinolin-4-amine (144) [2- [4- (methylamino) phenyl] ethyl] -2-n-propyl-1H-imidazo [4,5-c]
Quinoline-4-amine (145) 2-n-butyl-1- [2- [4- (methylamino) phenyl] ethyl] -1H-imidazo [4,5-
c] Quinolin-4-amine (146) 2-cyclopropylmethyl-1- [2- [4-
(Methylamino) phenyl] ethyl] -1H-imidazo [4,5-c] quinolin-4-amine (147) 2-ethoxymethyl-1- [2- [4- (methylamino) phenyl] ethyl] -1H −Imidazo [4,
5-c] quinolin-4-amine (148) 6,7,8,9-tetrahydro-1- [2-
[4- (Methylamino) phenyl] ethyl] -1H-imidazo [4,5-c] quinolin-4-amine (149) 6,7,8,9-tetrahydro-2-methyl-
1- [2- [4- (methylamino) phenyl] ethyl]
-1H-imidazo [4,5-c] quinolin-4-amine (150) 2-ethyl-6,7,8,9-tetrahydro-
1- [2- [4- (methylamino) phenyl] ethyl]
-1H-imidazo [4,5-c] quinolin-4-amine (151) 6,7,8,9-tetrahydro-1- [2-
[4- (Methylamino) phenyl] ethyl] -2-n-propyl-1H-imidazo [4,5-c] quinoline-4-
Amine (152) 2-n-butyl-6,7,8,9-tetrahydro-1- [2- [4- (methylamino) phenyl] ethyl] -1H-imidazo [4,5-c] quinoline-4 -Amine (153) 2-cyclopropylmethyl-6,7,8,9-
Tetrahydro-1- [2- [4- (methylamino) phenyl] ethyl] -1H-imidazo [4,5-c] quinolin-4-amine (154) 2-ethoxymethyl-6,7,8,9- Tetrahydro-1- [2- [4- (methylamino) phenyl]
Ethyl] -1H-imidazo [4,5-c] quinoline-4
-Amine (155) 1,6,7,8-tetrahydro-1- [2-
[4- (Methylamino) phenyl] ethyl] cyclopenta [b] imidazo [4,5-d] pyridin-4-amine (156) 1,6,7,8-tetrahydro-2-methyl-
1- [2- [4- (methylamino) phenyl] ethyl]
Cyclopenta [b] imidazo [4,5-d] pyridine-
4-amine (157) 2-ethyl-1,6,7,8-tetrahydro-
1- [2- [4- (methylamino) phenyl] ethyl]
Cyclopenta [b] imidazo [4,5-d] pyridine-
4-amine (158) 1,6,7,8-tetrahydro-1- [2-
[4- (Methylamino) phenyl] ethyl] -2-n-propylcyclopenta [b] imidazo [4,5-d] pyridin-4-amine (159) 2-n-butyl-1,6,7, 8-tetrahydro-1- [2- [4- (methylamino) phenyl] ethyl] cyclopenta [b] imidazo [4,5-d] pyridin-4-amine (160) 2-cyclopropylmethyl-1,6, 7,8-
Tetrahydro-1- [2- [4- (methylamino) phenyl] ethyl] cyclopenta [b] imidazo [4,5-
d] pyridine-4-amine

(161) 2-ethoxymethyl-1,6,
7,8-tetrahydro-1- [2- [4- (methylamino) phenyl] ethyl] cyclopenta [b] imidazo [4,5-d] pyridin-4-amine (162) 1,6,7,8, 9,10-hexahydro-1
-[2- [4- (methylamino) phenyl] ethyl] cyclohepta [b] imidazo [4,5-d] pyridine-4
-Amine (163) 1,6,7,8,9,10-hexahydro-2
-Methyl-1- [2- [4- (methylamino) phenyl] ethyl] cyclohepta [b] imidazo [4,5-
d] pyridine-4-amine (164) 2-ethyl-1,6,7,8,9,10-hexahydro-1- [2- [4- (methylamino) phenyl] ethyl] cyclohepta [b] imidazo [ 4, 5-
d] pyridin-4-amine (165) 1,6,7,8,9,10-hexahydro-1
-[2- [4- (methylamino) phenyl] ethyl]-
2-n-propylcyclohepta [b] imidazo [4,5-
d] pyridin-4-amine (166) 2-n-butyl-1,6,7,8,9,10-hexahydro-1- [2- [4- (methylamino) phenyl] ethyl] cyclohepta [b] Imidazo [4,5-
d] pyridine-4-amine (167) 2-cyclopropylmethyl-1,6,7,8,
9,10-hexahydro-1- [2- [4- (methylamino) phenyl] ethyl] cyclohepta [b] imidazo [4,5-d] pyridin-4-amine (168) 2-ethoxymethyl-1,6 , 7,8,9,1
0-hexahydro-1- [2- [4- (methylamino)
[Phenyl] ethyl] cyclohepta [b] imidazo [4,
5-d] pyridine-4-amine

The novel 1- (substituted aryl) alkyl-1H-imidazopyridin-4-amine derivatives represented by the above general formula (I) of the present invention can be produced by various methods. The first mode of the manufacturing method of the present invention, there may be mentioned the following manufacturing method according to the method disclosed in JP-A-3-206078, in the general formula (I) by this manufacturing method, R ¹ Is SO ₂ NR ⁸ R ⁹ ,
Or hydroxyl group represented by ^{CONR 8 R 9, NR 10 R} 11,
R ⁵ is a hydrogen atom, wherein R ¹⁰ is a lower alkyl group or a benzyl group, and R ¹¹ is a lower alkyl group, a benzyl group, a lower alkanesulfonyl group, a lower alkanoyl group or a substituted or unsubstituted benzenesulfonyl group. Certain compounds can be synthesized.

[0022]

Embedded image (Wherein R ¹ ′ is SO ₂ NR ⁸ R ⁹ , CONR ⁸ R ⁹ , N
R ¹⁰ ′ represents a group represented by R ¹¹ ′ or a hydroxyl group, and when R ¹⁰ ′ is a hydrogen atom, R ¹¹ ′ is a lower alkanesulfonyl group;
Represents a lower alkanoyl group, a lower alkyl group or a substituted or unsubstituted benzenesulfonyl group, and when R ¹⁰ ′ is a lower alkyl group or a benzyl group, R ¹¹ ′ is a lower alkyl group, a benzyl group, a lower alkane sulfonyl group, a lower alkanoyl group; Represents a group or a substituted or unsubstituted benzenesulfonyl group, and represents R ² , R ³ , R ⁴ , R ⁶ , R ⁸ , R ⁹ ,
The bonds indicated by m, n, X, Y and the dotted and solid lines have the same meanings as described above. )

The compounds represented by the general formulas (II) and (III) as starting materials in the production method of the present invention are known compounds or commercially available compounds.
l of Medicinal Chemistry, 18, p. 726 (197
5 years).

That is, in the step 1, the compound represented by the general formula (II) is treated with a nitrating agent such as fuming nitric acid in the presence or absence of a solvent such as acetic acid and the like. The reaction can be carried out between to obtain a compound of the general formula (III).

In step 2, the compound of the general formula (III) is converted to a chlorinating agent such as phosphorus oxychloride, thionyl chloride,
Using phosgene, oxalyl chloride, phosphorus pentachloride, etc.
The compound of the general formula (IV) can be obtained by performing the reaction between 0 ° C. and the reflux temperature of the solvent in the presence or absence of an inert solvent such as N, N-dimethylformamide or methylene chloride. .

In the step 3, the method disclosed in
JP-A-62-116575, JP-A-59-484
No. 47, JP-A-52-85137 and Journal of Med
icinalChemistry, 20, 1212 (1977)
The following general formula (IX) whose production method is disclosed in

Embedded image (Wherein R ¹ ′, R ² , R ³ , m, n and Y have the same meanings as described above) and a compound of the general formula (IV), and N, N-dimethylformamide or chloride By reacting in an inert solvent such as methylene in the presence or absence of a base such as triethylamine or potassium carbonate at a temperature between −10 ° C. and the reflux temperature of the solvent, a compound of the general formula (V) is obtained. Can be.

In the step 4, the nitro group of the compound of the formula (V) is reduced by an appropriate method, for example, a catalytic reduction method using a catalyst such as platinum, Raney nickel, palladium carbon, etc.
Reduction by a reduction method using nickel chloride and sodium borohydride, a reduction method using iron powder and hydrochloric acid, etc.
The compound of I) can be obtained.

In step 5, the compound of the general formula (VI) is reacted with the following general formula (X) R ⁴ C (OR) ₃ (X) (wherein R is a lower alkyl group, and R ⁴ is the same as defined above) In the presence or absence of an acid catalyst such as hydrochloric acid or sulfuric acid, in the presence or absence of an inert solvent such as N, N-dimethylformamide or methylene chloride, together with the trialkyl orthoester represented by From 0 ° C to 2
By reaction between 00 ° C., the general formula (VII) (where 'if is SO ₂ NH ₂ group, depending on the reaction conditions R ^1' R ¹ of the general formula (VI) SO ₂ N = C ( OR) represents a R ⁴ group). However, depending on the compound, the following general formula (XI) which is a reaction intermediate from the general formula (VI) to the general formula (VII)

Embedded image (Where R, R ¹ ′, R ² , R ³ , R ⁴ , R ⁶ , m, n,
X and Y have the same meaning as described above. )), The reaction may be difficult to proceed, in which case the resulting intermediate (XI)
Reaction between 0 ° C and 200 ° C in the presence or absence of an acid catalyst such as p-toluenesulfonic acid or in the presence or absence of an inert solvent such as N, N-dimethylformamide, acetonitrile or toluene By the general formula
The compound of the formula (VII) can be obtained.

As another method, a compound of the general formula (VI) is converted to a compound of the following general formula (XII) R ⁴ COZ (XII) (where Z is a chlorine atom or a bromine atom, and R ⁴ is the same as defined above) Together with the compound of formula (I), N, N in the presence or absence of an acid catalyst such as p-toluenesulfonic acid.
-Reaction in the presence or absence of an inert solvent such as dimethylformamide, acetonitrile or toluene at a temperature between 0 ° C. and 200 ° C. to obtain a compound represented by the general formula (VII) (wherein R ¹ ′ When R is a hydroxyl group, R ¹ ′ is OC
OR ⁴ represents a group. ) Can be obtained.

Further, as another method, the compound represented by the general formula (VI)
Together with a compound represented by the following general formula (XIII) R ⁴ COOH (XIII) (wherein R ⁴ has the same meaning as described above) in the presence or absence of an acid catalyst such as hydrochloric acid or sulfuric acid. By reacting at 0 ° C. to 200 ° C. in the presence or absence of an inert solvent such as N, N-dimethylformamide or methylene chloride, the following general formula (XIV)

Embedded image (In the formula, R ¹ 'when the hydroxyl group R ^1' is OC of formula (VI)
OR ⁴ group, R ¹ ′, R ² , R ³ , R
^{4, R 6, m, n} , X and Y has the same meanings as that described above. )
After obtaining the compound of formula (II), the compound of formula (VII) can be obtained by treating this compound with a chlorinating agent. In the chlorination reaction, when R ⁴ of the compound of the general formula (XIV) is a hydrogen atom or a linear or branched alkyl group substituted by a lower alkoxy group, a halogen atom or a cyclic alkyl group, The compound of formula (XIV) is reacted directly with the chlorinating agent, while the compound of formula (XIV) R ⁴
Is a linear or branched alkyl group having one or more hydroxyl groups, after protecting the hydroxyl group with a protecting group such as an acetyl group (in this case, R ⁴ is a protecting group such as an acetyl group). Represents a linear or branched alkyl group having one or more hydroxyl groups protected with a group.), And reacting with a chlorinating agent.

In this chlorination reaction, a suitable chlorinating agent, for example, phosphorus oxychloride, thionyl chloride, phosgene, oxalyl chloride, phosphorus pentachloride or the like is added to an inert solvent such as N, N-dimethylformamide or methylene chloride. By reacting at 0 ° C. to the reflux temperature of the solvent in the presence or absence of the compound of formula (VII) (wherein R ^{4 in} formula (XIV) has one or more hydroxyl groups. When it is a linear or branched alkyl group, R ⁴ represents a linear or branched alkyl group having one or more hydroxyl groups protected by a protecting group such as an acetyl group.) Can be obtained.

In step 6, the compound of the formula (VII) and phenol are combined with an alkali such as sodium hydroxide or potassium hydroxide in the presence or absence of an inert solvent such as N, N-dimethylformamide or methylene chloride. The compound of the general formula (VIII) can be obtained by reacting at 0 ° C. to 200 ° C. in the presence.

In Step 7, the compound of the general formula (VIII) is added together with ammonium acetate in the presence or absence of an inert solvent such as N, N-dimethylformamide or methylene chloride at a temperature between 0 ° C. and 200 ° C. To give a compound of the general formula (I).

The second mode of the production method includes the following production method.

Embedded image (Wherein, R ¹³ represents a lower alkyl group or a benzyl group,
R ¹ ′, R ² , R ³ , R ⁴ , R ⁶ , m, n, X and Y have the same meanings as described above. That is, in the step 8, the compound of the general formula (V) obtained by the above-mentioned first mode and dibenzylamine or N
Lower alkyl-N-benzylamine at 0 ° C. in the presence or absence of an inert solvent such as N, N-dimethylformamide or methylene chloride, in the presence or absence of a base such as triethylamine or potassium carbonate; From 20
By reacting at 0 ° C., the compound of the general formula (XV) can be obtained.

In step 9, the nitro group of the compound of the formula (XV) is reduced by an appropriate reduction method, for example, a reduction method using nickel chloride and sodium borohydride, or a reduction method using iron powder and hydrochloric acid. Thus, the compound of the general formula (XVI) can be obtained.

In step 10, the compound of the general formula (XVI) is converted to a compound of the general formula (XVI) in the same manner as in step 5 described above.
Alternatively, the compound of the general formula (XVII) can be obtained by reacting with the compound of the general formula (XIII) under the same conditions.

In step 11, the compound of the general formula (XVII) is subjected to an appropriate debenzylation reaction, for example, by catalytic reduction using a catalyst such as palladium carbon or Pearlman's reagent in the presence of a hydrogen donor such as ammonium formate or formic acid. The compound of general formula (I) can be obtained by performing a debenzylation reaction.

As a third mode of the production method, R
^A method for producing a compound of the general formula (I) wherein ¹ is a group represented by NR ¹⁰ R ¹¹ and R ¹¹ is a hydrogen atom can be mentioned. That is, the compound of the general formula (I) wherein R ^1, which can be obtained in the above-mentioned first mode, is a group represented by NR ¹⁰ R ¹¹ and R ¹¹ is a lower alkanoyl group, is converted into water or methanol or ethanol. Acids such as hydrochloric acid and sulfuric acid and alkalis such as sodium hydroxide and potassium hydroxide in alcoholic solvents such as n-propanol, isopropanol, n-butanol, sec-butanol, tert-butanol or mixed solvents of water and alcohol. And hydrolysis at room temperature to the reflux temperature of the solvent.

In the fourth mode of the production method, R ¹ is N
A group represented by R ¹⁰ R ^11, and at least one hydrogen atom of R ¹⁰ and R ^11, the other methods for the preparation of compounds of general formula (I) is a hydrogen atom or a lower alkyl group. That is, the following general formula (XVIII) which can be obtained by the first or second mode of the above-mentioned production method

Embedded image (Wherein, R ¹⁴ is a lower alkyl group or a benzyl group, R ¹⁵
Represents a hydrogen atom or a benzyl group, R ¹⁶ represents a hydrogen atom, a lower alkyl group or a benzyl group, and R ² , R ³ , R ⁴ , R
⁶ , m, n, X or Y has the same meaning as described above. ) Is debenzylated by catalytic reduction using a catalyst such as palladium carbon or Perlman's reagent in the presence of hydrogen, a hydrogen donor such as formic acid or ammonium formate, and the like. Can be obtained.

As a fifth mode of the manufacturing method, the following manufacturing method can be mentioned.

Embedded image (Wherein, R ¹⁷ represents a hydrogen atom or a lower alkyl group, W represents an oxygen atom or a sulfur atom, and R ² , R ³ , R ⁴ , R ⁵ ,
R ⁶ , m, n, X or Y has the same meaning as described above. That is, the compound of the general formula (XIX) which can be obtained in the step 12 by the third or fourth mode of the above-mentioned production method is combined with an appropriate urea-forming agent or thiourea-forming agent to form N, N
-The compound represented by the general formula (XX) can be obtained by performing the reaction at 0 ° C to 200 ° C in the presence or absence of an inert solvent such as dimethylformamide, acetonitrile or toluene. Suitable ureating agents include, for example, urea, cyanic acid, sodium cyanate,
Potassium cyanate, urethane, alkyl urethane, alkyl isocyanate and the like can be mentioned. Examples of the thiourea agent include thiourethane, alkyl thiourethane, alkyl isothiocyanate and the like.

As a sixth mode of the manufacturing method, the following manufacturing method can be mentioned.

Embedded image (Wherein, R ² , R ³ , R ⁴ , R ⁶ , m, n, X or Y have the same meanings as described above.) That is, in step 13, the first or second mode of the above-mentioned production method By reacting the compound of the general formula (XXI) obtained by the above with a suitable dehydrating agent at 0 ° C. to 200 ° C., the compound of the general formula (XXII) can be obtained. Suitable dehydrating agents include, for example, phosphorus oxychloride, thionyl chloride, diphosphorus pentoxide, p-toluenesulfonyl chloride, methanesulfonyl chloride, N,
N'-dicyclohexylcarbodiimide, acetic anhydride, trifluoroacetic anhydride and the like can be mentioned.

In step 14, the compound represented by the general formula (XXIII) can be obtained by reacting the compound represented by the general formula (XXII) in the same manner as in step 7 described above.

As a seventh mode of the production method, the following production method can be mentioned.

Embedded image (Wherein, R ¹⁸ represents a lower alkyl group, and R ² , R ³ , R
^{4, R 6, m, n} , X or Y has the same meanings as that described above. That is, in the step 15, the compound of the general formula (XXIV), which can be obtained by the first mode of the above-mentioned production method, is reacted in the same manner as in the above-mentioned step 6, to give a compound of the general formula
In step 16, a compound represented by the general formula (XXV) is obtained by reacting the compound represented by the general formula (XXV) in the same manner as in the above step 7. Can be.

In step 17, the compound of the general formula (XXVII) is reacted with an alcohol such as methanol or ethanol in the presence of a suitable acid catalyst at room temperature to the reflux temperature of the solvent. ) Can be obtained. Suitable acid catalysts include, for example,
Examples thereof include concentrated hydrochloric acid, concentrated sulfuric acid, thionyl chloride, and alcoholic hydrogen chloride.

As an eighth mode of the manufacturing method, the following manufacturing method can be mentioned.

Embedded image (Wherein, R ¹⁹ represents a lower alkyl group, and R ² , R ³ , R
^{4, R 6, m, n} , X or Y has the same meanings as that described above. That is, in the step 18, the compound of the general formula (XXVIII), which can be obtained by the first mode of the above-mentioned production method, is reacted in the same manner as in the above-mentioned step 7, to give the compound of the general formula (XXIX) Can be obtained.

In step 19, the compound of the formula (XXIX) and hydroxylamine hydrochloride are reacted with N, N-dimethylformamide, methanol, ethanol in the presence or absence of a base such as sodium acetate, triethylamine, potassium carbonate and the like. 0 ° C to 200 ° C in the presence or absence of an inert solvent such as alcohol or methylene chloride.
By performing the reaction within the range, the compound represented by the general formula (XXX) can be obtained.

In step 20, the compound represented by the general formula (XXXI) can be obtained by reducing the oxime group of the compound represented by the general formula (XXX) by a catalytic reduction method using a suitable catalyst. Suitable catalysts include, for example, platinum, Raney nickel, palladium carbon, and the like. The reaction is carried out in a solvent such as water or an alcoholic solvent such as methanol or ethanol, or a mixture of water and an alcoholic solvent. The reaction can be carried out in the presence or absence thereof at a temperature of room temperature to 200 ° C. in a range of normal pressure to 100 atm.

The general formula (I) thus produced
1- (substituted aryl) alkyl-1H represented by the formula:
Pharmaceuticals containing an imidazopyridine-4-amine derivative or a pharmacologically acceptable salt thereof as an active ingredient are usually orally administered preparations such as capsules, tablets, fine granules, granules, powders, and syrups. Or parenteral preparations such as injections, suppositories, eye drops, eye ointments, ear drops, and dermatological agents. These preparations can be produced by a conventional method by adding pharmacologically and pharmaceutically acceptable additives. That is, for oral preparations and suppositories, excipients (lactose, D-mannitol, corn starch, crystalline cellulose, etc.), disintegrants (carboxymethylcellulose, carboxymethylcellulose calcium, etc.), binders (hydroxypropylcellulose, hydroxypropyl) Pharmaceutical components such as methylcellulose, polyvinylpyrrolidone, etc.), lubricants (magnesium stearate, talc, etc.), coating agents (hydroxypropylmethylcellulose, sucrose, titanium oxide, etc.), bases (polyethylene glycol, hard fat, etc.) For injections, eye drops, and ear drops, solubilizers or solubilizers (aqueous or distilled water for injection, physiological saline, propylene glycol, etc.), pH adjusters (inorganic) Or organic acids or bases), isotonic Preparations (eg, salt, glucose, glycerin, etc.) and stabilizers, and ophthalmic ointments and dermatological agents, ophthalmic ointments, creams, and patch preparations (white petrolatum, Macrogol, glycerin, cotton cloth, etc.).

The dose of the present compound to a treated patient depends on the condition of the patient, but is usually about 0.1 to 1000 mg for oral administration and 0.01 to 1000 mg for parenteral administration as a daily dose for adults.
It is about 500 mg.

[0050]

EXAMPLES The present invention will be described below with reference to Examples and Examples, but the present invention is not limited to these Examples.

Reference Example 1 2- [4- (methylamino) phenyl] ethylamine
Hydrochloride (1) N- [4- (cyanomethyl) phenyl] formamide A mixture of 71 ml of acetic anhydride and 40 ml of formic acid was stirred at 50 ° C. for 30 minutes, and then 20.0 g of 4-aminobenzylcyanide was added under ice-cooling and stirring. And stirred at room temperature for 30 minutes. A 20% aqueous sodium hydroxide solution was added to the reaction solution to adjust the pH to pH 8. The precipitated crystals were collected by filtration, washed with water, and washed with 19.0 g of N
-[4- (Cyanomethyl) phenyl] formamide (melting point: 103.0 to 105.0 ° C) was obtained. (2) 2- [4- (Methylamino) phenyl] ethylamine hydrochloride 29.5 g of concentrated sulfuric acid and anhydrous solution of 22.8 g of lithium aluminum hydride and 500 ml of anhydrous tetrahydrofuran were stirred under ice-cooling under a nitrogen stream. Tetrahydrofuran 10
0 ml of the mixture was added dropwise over 30 minutes. After warming the mixture to room temperature, N- [4- (cyanomethyl) phenyl]
19.3 g of formamide in anhydrous tetrahydrofuran 40
0 ml of the solution was added dropwise over 1 hour. After stirring at room temperature for 1 hour, under ice-cooling, 60 ml of water and 120 ml of tetrahydrofuran.
Was added dropwise. After adding 9.5 g of potassium carbonate,
Stirred at room temperature for 14 hours. The insolubles were removed by filtration and washed with tetrahydrofuran and methylene chloride. After drying the filtrate,
The pH of the solution was adjusted to pH 2 by adding ethanolic hydrogen chloride.
The precipitated crystals were collected by filtration and washed with tetrahydrofuran to obtain 18.9 g of pale brown crystals. Recrystallization from ethanol gave light brown crystals with a melting point of 215.0-220.0 ° C. Elemental analysis C ₉ H ₁₄ N ₂ .2HCl Theoretical C, 48.44; H, 7.23; N, 12.55 Experimental C, 48.39; H, 7.29; N, 12.59

Reference Example 2 2- [4- (2-aminoethyl) phenyl] -2-methyl-1,3-dioxolane (1) N- [2- [4- (2-methyl-1,3-dioxolane) -2-yl) phenyl] ethyl] trifluoroacetamide 10.0 g of N- [2- (4-acetylphenyl) ethyl] trifluoroacetamide was dissolved in 100 ml of toluene, and 12.0 g of ethylene glycol and p-toluenesulfonic acid were dissolved. -0.4 g of monohydrate was added, and the mixture was refluxed for 15 hours using a Dean-Stark apparatus. After cooling the reaction,
After washing with water and dehydration, the solvent was distilled off under reduced pressure to obtain 11.0 g of N-
[2- [4- (2-methyl-1,3-dioxolan-2)
-Yl) phenyl] ethyl] trifluoroacetamide (melting point: 72.0-74.0 ° C) was obtained. (2) 2- [4- (2-aminoethyl) phenyl] -2-
Methyl-1,3-dioxolane 11.0 g of N- [2- [4- (2-methyl-1,3-dioxolan-2-yl) phenyl] ethyl] trifluoroacetamide was dissolved in 30 ml of methanol, and 10%
20 ml of an aqueous sodium hydroxide solution was added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, extracted with a mixture of methylene chloride and methanol (10: 1), dried, and the solvent was distilled off under reduced pressure to obtain 7.20 g of a brown liquid. Mass spectrum m / z: 207 (M ⁺ ) NMR spectrum δ (CDCl ₃ ) ppm: 1.65 (3H, s), 2.
74 (2H, t, J = 6.5Hz), 2.97-3.00 (2H, m), 3.79 (2H, t, J = 2Hz),
4.03 (2H, t, J = 2Hz), 7.18 (2H, d, J = 8Hz), 7.41 (2H, d, J = 8Hz)

Reference Example 3 N- [1- [4- (2-aminoethyl) phenyl] ethyl] acetamide hydrochloride (1) N- [1- [4- [2- (tert-butoxycarbonylamino) ethyl] [Phenyl] ethyl] acetamide To 10.0 g of 4- [2- (tert-butoxycarbonylamino) ethyl] acetophenone was added 100 ml of 10% methanolic ammonia and 1 ml of Raney nickel, and the mixture was stirred under a hydrogen atmosphere at 60 ° C. and 80 atm for 48 hours. . After cooling the reaction solution, the catalyst was removed by filtration and concentrated under reduced pressure. The obtained green liquid was dissolved in 70 ml of methylene chloride, and 5.8 ml of triethylamine and 3.9 ml of acetic anhydride were added under ice-cooling and stirring.
Stirred for 0 minutes. Water was added, extracted with methylene chloride, dried and concentrated under reduced pressure. The residue was washed with diethyl ether, and 9.30 g of N- [1- [4- [2- (tert.
-Butoxycarbonylamino) ethyl] phenyl] ethyl] acetamide (mp 138.0-140.0 ° C) was obtained. (2) N- [1- [4- (2-aminoethyl) phenyl]
Ethyl] acetamide hydrochloride N- [1- [4- [2- (tert-butoxycarbonylamino) ethyl] phenyl] ethyl] acetamide 9.0
0 g was dissolved in methanol (18 ml), 15% ethyl acetate-based hydrogen chloride (27 ml) was added, and the mixture was stirred at room temperature for 1 hour. After the reaction solution was concentrated under reduced pressure, 10 ml of isopropyl alcohol was added,
The mixture was stirred under ice cooling and the precipitated crystals were collected by filtration to give colorless crystals.
0 g was obtained. Recrystallized from ethanol, melting point 212.
Colorless crystals of 0 to 214.0 ° C were obtained. Elemental analysis C ₁₂ H ₁₈ N ₂ O.HCl Theoretical C, 59.37; H, 7.89; N, 11.54 Experimental C, 59.25; H, 7.61; N, 11.48

Reference Example 4 2- [4- (dibenzylamino) phenyl] ethylamine hydrochloride (1) N- [2- [4- (dibenzylamino) phenyl]
Ethyl] trifluoroacetamide N- [2- (4-aminophenyl) ethyl] trifluoroacetamide (1.00 g), potassium carbonate (600 mg),
10 ml of N, N-dimethylformamide and 1.1 ml of benzyl bromide were added, and the mixture was stirred at 50 ° C. for 1 hour. After adding water, the mixture was extracted with diethyl ether, dried and concentrated under reduced pressure.
The residue was washed with isopropyl ether, and 1.10 g of N- [2- [4- (dibenzylamino) phenyl] ethyl] trifluoroacetamide (mp 142.0-14)
4.0 ° C.). (2) 2- [4- (dibenzylamino) phenyl] ethylamine hydrochloride N- [2- [4- (dibenzylamino) phenyl] ethyl] trifluoroacetamide (1.00 g) is mixed with 3 ml of methanol and 10% hydroxylation. Add 2 ml of aqueous sodium solution and add
Stirred at 0 ° C. for 30 minutes. After the reaction solution was concentrated under reduced pressure, water was added, extracted with methylene chloride and dried. After adding ethanolic hydrogen chloride to the methylene chloride layer and stirring with ice cooling, the precipitated crystals were collected by filtration to obtain 1.00 g of colorless crystals. Recrystallized from a mixture of methylene chloride and ethanol, melting point 168.
Colorless crystals of 0 to 170.0 ° C were obtained. Elemental analysis _{C 22 H 24 N 2 · 2HCl} · 1 / 4H 2 O Theoretical value C, 67.09; H, 6.78; N, 7.11 Found C, 67.01; H, 6.81; N, 7.23

Reference Example 5 4- (2-Aminoethyl) -α-methylbenzyl alcohol hydrochloride 10.0 g of 4- (2-azidoethyl) acetophenone was dissolved in 50 ml of methanol, and 2.0 g of sodium borohydride was added. The mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, water was added, extracted with diethyl ether, dried and concentrated under reduced pressure. The obtained slightly yellow liquid was dissolved in 150 ml of tetrahydrofuran, and triphenylphosphine 2 was dissolved.
1.7 g and 2.5 ml of water were added, and the mixture was stirred at room temperature for 10 hours. The reaction solution was concentrated under reduced pressure, dissolved in 100 ml of ethanol, ethanolic hydrogen chloride was added, and the mixture was stirred under ice cooling. The precipitated crystals were collected by filtration to obtain 9.00 g of colorless crystals. Recrystallization from ethanol gave colorless crystals having a melting point of 171.0-172.0 ° C. Elemental analysis C ₁₀ H ₁₅ NO.HCl Theoretical C, 59.55; H, 8.00; N, 6.94 Experimental C, 59.29; H, 8.27; N, 6.85

Reference Example 6 4- (3-aminopropyl) benzenesulfonamide
Hydrochloride (1) N- (3-phenylpropyl) acetamide 3-phenylpropylamine 1.00 g of pyridine 25
To the ml solution, 3.8 ml of acetic anhydride was added dropwise under ice cooling, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, and ethyl acetate and 10% hydrochloric acid were added to the residue to adjust the pH of the solution to 3-4, followed by separation. The organic layer was washed successively with water and saturated saline and dehydrated, and then the solvent was distilled off under reduced pressure to obtain 6.20 g of N- (3-phenylpropyl) acetamide. (2) 1.00 g of 4- [3- (acetylamino) propyl] benzenesulfonyl chloride N- (3-phenylpropyl) acetamide
Then, 3.40 g of chlorosulfonic acid was added dropwise to a 10 ml solution of methylene chloride under ice cooling, and the mixture was refluxed for 1 hour. The reaction mixture was poured into ice water, and after liquid separation, the organic layer was washed with saturated saline. After dehydration of the organic layer, the solvent was distilled off under reduced pressure to obtain 1.20 g of 4
-[3- (Acetylamino) propyl] benzenesulfonyl chloride was obtained. (3) 4- [3- (acetylamino) propyl] benzenesulfonamide A mixture of 1.20 g of 4- [3- (acetylamino) propyl] benzenesulfonyl chloride, 6 ml of tetrahydrofuran and 3.0 g of aqueous ammonia was added at room temperature for 7 minutes. Stirred for hours. The solvent was distilled off under reduced pressure, methanol was added to the residue, and the insoluble matter was removed by filtration. The filtrate was concentrated to give 0.50 g of 4- [3- (acetylamino) propyl] benzenesulfonamide. (4) 4- (3-Aminopropyl) benzenesulfonamide hydrochloride A mixture of 1.95 g of 4- [3- (acetylamino) propyl] benzenesulfonamide and 20 ml of 6N hydrochloric acid is heated at 110 to 120 ° C. for 6 hours. Stirred. The reaction mixture was concentrated under reduced pressure, and the residue was washed with ethanol to obtain 0.95 g of colorless crystals. NMR spectrum δ (DMSO) ppm: 1.89 (2H, quint, J
= 8Hz), 2.74 (2H, t, J = 8Hz), 2.80 (2H, t, J = 8Hz), 7.20 (2H, br
-s), 7.40 (2H, d, J = 8.5 Hz), 7.76 (2H, d, J = 8.5 Hz), 7.93 (2H,
br-s)

Reference Example 7 N- [4- (2-aminoethyl) phenyl] -4-methylbenzenesulfonamide (1) N- [2- (4-nitrophenyl) ethyl] trifluoroacetamide 2- (4- To a mixture of 5.00 g of (nitrophenyl) ethylamine hydrochloride and 50 ml of methylene chloride, 3.4 ml of triethylamine and 10.5 ml of trifluoroacetic anhydride were added under ice-cooling, followed by stirring at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with methylene chloride. The extract was washed with saturated saline, dehydrated, and the solvent was distilled off under reduced pressure.
[2- (4-Nitrophenyl) ethyl] trifluoroacetamide was obtained. (2) N- [2- (4-aminophenyl) ethyl] trifluoroacetamide N- [2- (4-nitrophenyl)
Ethyl] trifluoroacetamide (36.3 g) was dissolved in methanol (180 ml), and 5% palladium-carbon (1.8 g) was dissolved.
Was added thereto and subjected to catalytic reduction under normal temperature and normal pressure for 17 hours. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure to give 33.4 g of N- [2- (4-aminophenyl) ethyl] trifluoroacetamide.
I got (3) N- [4- [2- (trifluoroacetylamino)
Ethyl] phenyl] -4-methylbenzenesulfonamide In a mixture of 10.0 g of N- [2- (4-aminophenyl) ethyl] trifluoroacetamide, 50 ml of methylene chloride and 7.9 ml of triethylamine under ice-cooling and stirring.
A solution of 10.8 g of p-toluenesulfonyl chloride in 10 ml of methylene chloride was added dropwise, and the mixture was stirred for 1 hour. Water was added to the reaction mixture, and the precipitated crystals were collected by filtration.
N- [4- [2- (trifluoroacetylamino) ethyl] phenyl] -4-methylbenzenesulfonamide was obtained. (4) N- [4- (2-aminoethyl) phenyl] -4-
Methylbenzenesulfonamide N- [4- [2- (trifluoroacetylamino) ethyl] phenyl] -4-methylbenzenesulfonamide 1
A mixture of 3.4 g, 130 ml of methanol and 80 ml of a 10% aqueous sodium hydroxide solution was stirred at room temperature for 30 minutes.
After adding 10% hydrochloric acid to the reaction mixture to adjust the pH to pH 7, the mixture was concentrated under reduced pressure. After adding ethanol to the residue and filtering off insolubles, the filtrate was concentrated under reduced pressure to obtain 12.0 g of a pale yellow liquid.
I got NMR spectrum δ (DMSO) ppm: 2.33 (3H, s), 2.76
(2H, t, J = 8.5Hz), 2.96 (2H, t, J = 8.5Hz), 7.05 (2H, d, J = 8.5H
z), 7.10 (2H, d, J = 8.5 Hz), 7.34 (2H, d, J = 8 Hz), 7.65 (2H, d, J
= 8Hz), 8.40 (2H, br-s)

Reference Example 8 4- (2-aminoethyl) -N-methylbenzenesulfonamide hydrochloride (1) N- (2-phenylethyl) acetamide 2-phenylethylamine 15.0 g of pyridine 75 ml
12.8 ml of acetic anhydride was added dropwise to the solution under ice cooling, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure.
The solution was adjusted to pH 3 to 4 by adding hydrochloric acid, and extracted with ethyl acetate. The extract was washed successively with water and saturated saline, then dehydrated, and the solvent was distilled off under reduced pressure to obtain 27.7 g of N-
(2-Phenylethyl) acetamide was obtained. (2) 4- [2- (Acetylamino) ethyl] benzenesulfonyl chloride To a mixture of 98.2 g of N- (2-phenylethyl) acetamide and 500 ml of methylene chloride, 362 g of chlorosulfonic acid was added dropwise under ice-cooling. After refluxing for 2 hours, the reaction solution was poured into ice water. 88. The precipitated crystals were collected by filtration and washed with water.
3 g of 4- [2- (acetylamino) ethyl] benzenesulfonyl chloride were obtained. (3) 4- [2- (acetylamino) ethyl] -N-methylbenzenesulfonamide A solution of 5.00 g of 4- [2- (acetylamino) ethyl] benzenesulfonyl chloride in 25 ml of tetrahydrofuran at room temperature was treated with 40% methyl 14.8 g of an aqueous amine solution was added. After refluxing for 5 hours, the mixture was concentrated under reduced pressure to obtain 5.90 g of 4- [2- (acetylamino) ethyl] -N-methylbenzenesulfonamide. (4) 4- (2-Aminoethyl) -N-methylbenzenesulfonamide hydrochloride 34.0 g of 4- [2- (acetylamino) ethyl] -N-methylbenzenesulfonamide and 170 N hydrochloric acid 170
The ml mixture was stirred at 110 ° C. for 5 hours. The reaction mixture was concentrated under reduced pressure, and the residue was washed with methanol to obtain 10.6 g of colorless crystals. NMR spectrum δ (DMSO) ppm: 2.42 (3H, s), 3.02
(2H, t, J = 5Hz), 3.07 (2H, t, J = 5Hz), 7.40 (1H, br-s), 7.57 (2H, t, J = 5Hz)
(H, d, J = 8Hz), 7.74 (2H, d, J = 8Hz), 8.08 (2H, br-s)

Reference Example 9 4- (2-aminoethyl) -N-propylbenzenesulfonamide (1) N-propyl-4- [2- (trifluoroacetylamino) ethyl] benzenesulfonamide 4- [2- ( To a solution of 13.4 g of trifluoroacetylamino) ethyl] benzenesulfonyl chloride in 20 ml of tetrahydrofuran was added 6.9 ml of propylamine under ice cooling, followed by stirring for 3 hours under ice cooling. The reaction mixture was concentrated under reduced pressure, and water and methylene chloride were added to the residue. The precipitated crystals were collected by filtration to obtain 15.3 g of N-propyl-4- [2- (trifluoroacetylamino) ethyl] benzenesulfonamide. (2) 4- (2-Aminoethyl) -N-propylbenzenesulfonamide A solution of 15.3 g of N-propyl-4- [2- (trifluoroacetylamino) ethyl] benzenesulfonamide in 150 ml of methanol was added at room temperature to 10 A 92% aqueous sodium hydroxide solution was added, and the mixture was stirred for 30 minutes. After adding 10% hydrochloric acid to the reaction mixture to adjust the pH to 7 to 8, the solution was concentrated under reduced pressure. After adding ethanol to the residue and filtering off insolubles, the filtrate was concentrated under reduced pressure to obtain 12.7 g of a colorless liquid. NMR spectrum δ (DMSO) ppm: 0.80 (3H, t, J = 7H
z), 1.40 (2H, sextet, J = 7Hz), 2.70 (2H, t, J = 7Hz), 2.97 (2H,
t, J = 7.5Hz), 3.09 (2H, t, J = 7.5Hz), 4.23 (1H, br-s), 7.46 (2H
(H, d, J = 8Hz), 7.74 (2H, d, J = 8Hz), 7.80-8.00 (2H, br-s)

Reference Example 10 4- (2-Aminoethyl) -N, N-dimethylbenzenesulfonamide hydrochloride (1) 4- [2- (acetylamino) ethyl] -N, N-
Dimethylbenzenesulfonamide 4- [2- (acetylamino) ethyl] benzenesulfonyl chloride (5.00 g) in a tetrahydrofuran (25 ml) solution at room temperature is a 50% dimethylamine aqueous solution (17.2 g).
Was added and refluxed for 5 hours. The reaction mixture was concentrated under reduced pressure,
4.10 g of 4- [2- (acetylamino) ethyl]-
N, N-dimethylbenzenesulfonamide was obtained. (2) 4- (2-aminoethyl) -N, N-dimethylbenzenesulfonamide hydrochloride 4.10 g of 4- [2- (acetylamino) ethyl] -N, N-dimethylbenzenesulfonamide and 6 N hydrochloric acid 40 ml of the mixture was stirred at 100 ° C. for 6 hours. The reaction mixture was concentrated under reduced pressure, and the residue was washed with methanol to obtain 1.00 g of colorless crystals. NMR spectrum δ (DMSO) ppm: 2.62 (6H, s), 3.01
(2H, t, J = 8.5Hz), 3.11 (2H, t, J = 8.5Hz), 7.54 (2H, d, J = 8H
z), 7.70 (2H, d, J = 8Hz), 8.00 (2H, br-s)

Reference Example 11 2- (2-aminoethyl) benzenesulfonamide (1) 5-bromo-2- [2- (trifluoroacetylamino) ethyl] benzenesulfonyl chloride N- [2- (4-bromophenyl) ) Ethyl] To a solution of 15.5 g of trifluoroacetamide in 45 ml of methylene chloride was added 10 ml of chlorosulfonic acid under ice-cooling, and the mixture was refluxed for 2 days. After the reaction mixture was poured into ice water and separated, the organic layer was washed successively with water and saturated saline. After dehydrating the organic layer, the solvent was distilled off under reduced pressure. A mixture of n-hexane and ethyl acetate (6: 1) was added to the residue, and insolubles were removed by filtration. After the filtrate was concentrated under reduced pressure, the residue was purified by column chromatography [silica gel, n-hexane-ethyl acetate (6: 1)] to give 4.90 g of 5-bromo-2- [2- (trifluoroacetylamino). ) Ethyl] benzenesulfonyl chloride was obtained. (2) 5-bromo-2- [2- (trifluoroacetylamino) ethyl] benzenesulfonamide A solution of 25.5 g of 5-bromo-2- [2- (trifluoroacetylamino) ethyl] benzenesulfonyl chloride in 38 ml of tetrahydrofuran To the mixture was added 45 ml of aqueous ammonia under ice cooling, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, the residue was washed with methylene chloride, and washed with 22.0
g of 5-bromo-2- [2- (trifluoroacetylamino) ethyl] benzenesulfonamide was obtained. (3) 2- [2- (trifluoroacetylamino) ethyl] benzenesulfonamide 12.0 g of 5-bromo-2- [2- (trifluoroacetylamino) ethyl] benzenesulfonamide, 120 ml of methanol and 10% palladium- A mixture of 1.2 g of carbon was subjected to catalytic reduction under normal temperature and normal pressure for 4 hours. After removing the catalyst by filtration, the filtrate was concentrated under reduced pressure to obtain 11.0 g of 2- [2
-(Trifluoroacetylamino) ethyl] benzenesulfonamide. (4) 2- (2-aminoethyl) benzenesulfonamide 11.0 g of 2- [2- (trifluoroacetylamino) ethyl] benzenesulfonamide, 110 ml of methanol
And a mixture of 66 ml of a 10% aqueous sodium hydroxide solution,
Stirred at room temperature for 1 hour. After adding 10% hydrochloric acid to the reaction mixture to adjust the pH to 7 to 8, the solution was concentrated under reduced pressure. Ethanol was added to the residue, the insolubles were removed by filtration, and the filtrate was evaporated under reduced pressure to obtain 8.0 g of colorless crystals. NMR spectrum δ (DMSO) ppm: 3.10 (2H, t, J = 7H
z), 3.30 (2H, t, J = 7Hz), 7.43-7.47 (2H, m), 7.50-7.60 (5H,
m), 7.90-7.93 (1H, m)

REFERENCE EXAMPLE 12 3- (2-Aminoethyl) benzenesulfonamide (1) N- [2- (4-bromophenyl) ethyl] trifluoroacetamide 2- (4-bromophenyl) ethylamine 10.0 g of chloride To a 100 ml solution of methylene was added 21 ml of trifluoroacetic anhydride under ice-cooling, followed by stirring at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, the residue was washed with isopropyl ether, and 13.7 g of N- [2- (4-bromophenyl)
[Ethyl] trifluoroacetamide was obtained. (2) 2-bromo-5- [2- (trifluoroacetylamino) ethyl] benzenesulfonyl chloride N- [2- (4-bromophenyl) ethyl] trifluoroacetamide (15.5 g) was added to a solution of methylene chloride (45 ml) in ice, Under cooling, 10 ml of chlorosulfonic acid was added, and the mixture was refluxed for 2 days. After the reaction mixture was poured into ice water and separated, the organic layer was washed successively with water and saturated saline. After dehydrating the organic layer, the solvent was distilled off under reduced pressure. The residue was washed with a mixture of n-hexane and ethyl acetate (6: 1) to obtain 8.20 g of 2-bromo-5- [2- (trifluoroacetylamino) ethyl] benzenesulfonyl chloride. (3) 2-Bromo-5- [2- (trifluoroacetylamino) ethyl] benzenesulfonamide A solution of 8.20 g of 2-bromo-5- [2- (trifluoroacetylamino) ethyl] benzenesulfonyl chloride in 12 ml of tetrahydrofuran To the mixture was added 14.4 ml of aqueous ammonia under ice cooling, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was washed with ethanol.
0 g of 2-bromo-5- [2- (trifluoroacetylamino) ethyl] benzenesulfonamide was obtained. (4) 3- [2- (trifluoroacetylamino) ethyl] benzenesulfonamide 5.30 g of 2-bromo-5- [2- (trifluoroacetylamino) ethyl] benzenesulfonamide, 50 ml of methanol and 10% palladium- A mixture of 0.5 g of carbon was subjected to catalytic reduction under normal temperature and normal pressure for 11 hours. After removing the catalyst by filtration, the filtrate was concentrated under reduced pressure to obtain 4.00 g of 3-
[2- (Trifluoroacetylamino) ethyl] benzenesulfonamide was obtained. (5) 3- (2-Aminoethyl) benzenesulfonamide A mixture of 4.00 g of 3- [2- (trifluoroacetylamino) ethyl] benzenesulfonamide, 40 ml of methanol and 24 ml of a 10% aqueous sodium hydroxide solution was added at room temperature for 3 hours. Stirred for hours. After adding 10% hydrochloric acid to the reaction mixture to adjust the pH to 7 to 8, the solution was concentrated under reduced pressure. After adding ethanol to the residue and filtering off insolubles, the filtrate was concentrated under reduced pressure to obtain 4.30 g of colorless crystals. NMR spectrum δ (DMSO) ppm: 2.98 (2H, t, J = 8H
z), 3.08 (2H, t, J = 8Hz), 7.25 (2H, br-s), 7.48-7.58 (2H, m),
7.70-7.78 (2H, m), 7.81 (2H, br-s)

Reference Example 13 4- [2-[(2-chloro-3-nitroquinoline-4-
Yl) amino] ethyl] benzamide 4- (2-aminoethyl) was added to a solution of 8.03 g of 2,4-dichloro-3-nitroquinoline and 18.5 ml of triethylamine in N, N-dimethylformamide under ice-cooling and stirring.
4.35 g of benzamide was added, and the mixture was stirred under ice cooling for 5 hours. Water and 10% hydrochloric acid were added to the reaction solution to adjust the pH to pH 8, and then extracted with ethyl acetate. The organic layer was washed with saturated saline and then dehydrated, and the solvent was distilled off under reduced pressure. The residue was washed with isopropyl ether to give brown crystals (5.89 g). Recrystallized from ethanol, melting point 217.5-218.5
A yellow-brown prism crystal of ° C. was obtained. Elemental analysis C ₁₈ H ₁₅ ClN ₄ O ₃ Theoretical C, 58.31; H, 4.08; N, 15.11 Experimental C, 58.32; H, 3.88; N, 15.04

According to the method of Reference Example 13, the compounds of Reference Examples 14 to 46 shown in Tables 1 to 9 were obtained.

[0065]

[Table 1]

[0066]

[Table 2]

[0067]

[Table 3]

[0068]

[Table 4]

[0069]

[Table 5]

[0070]

[Table 6]

[0071]

[Table 7]

[0072]

[Table 8]

[0073]

[Table 9]

Reference Example 47 N- [4- [2-[(2-chloro-3-nitroquinolin-4-yl) amino] ethyl] phenyl] -N-methylacetamide 2-chloro-N- [2- [ 4- (methylamino) phenyl] ethyl] -3-nitroquinolin-4-amine 2.5
To 9 g, 26 ml of pyridine and 6.9 ml of acetic anhydride were added, and the mixture was stirred at room temperature for 1.5 hours. The solvent was distilled off under reduced pressure, and the residue was washed with isopropyl ether to obtain 2.72 g of yellow crystals. Recrystallized from ethanol, melting point 176.5-1
77.0 ° C. yellow prism crystals were obtained. Elemental analysis C ₂₀ H ₁₉ ClN ₄ O ₃ Theoretical C, 60.23; H, 4.80; N, 14.05 Experimental C, 60.28; H, 4.70; N, 14.01

According to the method of Reference Example 47, the compound of Reference Example 48 shown in Table 10 was obtained.

[0076]

[Table 10]

Reference Example 49 2-chloro-5,6,7,8-tetrahydro-N- [2
-[4- (N-methylbenzylamino) phenyl] ethyl] -3-nitroquinolin-4-amine 2-chloro-
5,6,7,8-Tetrahydro-N- [2- [4- (methylamino) phenyl] ethyl] -3-nitroquinolin-4-amine 36.8 g, potassium carbonate 14.1 g and N, N-dimethyl In a suspension of 370 ml of formamide,
Under stirring at room temperature, 12.4 ml of benzyl bromide was added dropwise. After stirring at room temperature for 14 hours, the reaction mixture was added to ice water and extracted with methylene chloride. The extract was washed with water, dehydrated, and concentrated under reduced pressure. The residue was purified by column chromatography [silica gel, methylene chloride-n-hexane (1: 1)] to obtain 41.9 g of a red liquid. IR spectrum ν (liq) cm ^-1 : 3432, 1580
, 1522 Mass spectrum m / z: 450, 452 (M ⁺ , 3: 1), 210
(BP) NMR spectrum δ (CDCl ₃ ) ppm: 1.65-1.80 (4H,
m), 2.02-2.15 (2H, m), 2.70-2.85 (4H, m), 3.03 (3H, s), 3.30
(2H, q, J = 6Hz), 4.33 (1H, br-s), 4.53 (2H, s), 6.71 (2H, d, J =
8.5Hz), 7.01 (2H, d, J = 8.5Hz), 7.15-7.38 (5H, m), 7.22 (2H,
d, J = 7.5Hz), 7.24 (1H, t, J = 7.5Hz), 7.31 (2H, t, J = 7.5Hz)

Reference Example 50 N- [4- [2-[(2-Dibenzylamino-3-nitroquinolin-4-yl) amino] ethyl] phenyl] acetamide N- [4- [2-[(3- A mixture of 5.75 g of amino-2-chloroquinolin-4-yl) amino] ethyl] phenyl] acetamide and 11.9 ml of dibenzylamine was stirred at 100 ° C. for 10 hours. Water and 10
% Hydrochloric acid was added, the precipitate was filtered off, and the mother liquor was extracted with methylene chloride. The extract was washed with water and then dehydrated, and the solvent was distilled off. The resulting red-orange oily residue was subjected to column chromatography [silica gel, ethyl acetate-n-hexane (1: 2-2:
1)] to obtain 6.37 g of a red-orange liquid. IR spectrum ν (liq) cm ^-1 : 3320, 1668
, 1522 NMR spectrum δ (CDCl ₃ ) ppm: 2.15 (3H, s), 2.
88 (2H, t, J = 7Hz), 4.03 (2H, q, J = 7Hz), 4.50 (4H, s), 7.00-7.
30 (13H, m), 7.42 (2H, d, J = 8Hz), 7.50-7.60 (3H, m), 7.92 (1
(H, d, J = 8Hz)

According to the method of Reference Example 50, Tables 11 to 1
The compounds of Reference Examples 51 to 54 shown in FIG. 2 were obtained.

[0080]

[Table 11]

[0081]

[Table 12]

Reference Example 55 4- [2-[(2-N-methylbenzylamino-3-nitroquinolin-4-yl) amino] ethyl] benzenesulfonamide 4- [2-[(2-chloro-3- Nitroquinoline-4-
Yl) amino] ethyl] benzenesulfonamide 2.4
1 g was dissolved in 7.6 ml of N-methylbenzylamine.
The mixture was stirred at 00 ° C for 1 hour. After cooling the reaction mixture to room temperature, 5% hydrochloric acid was added, and the mixture was extracted with methylene chloride. The extract was washed successively with water and saturated saline and dehydrated, and then the solvent was distilled off under reduced pressure. The residue was subjected to column chromatography [silica gel, methylene chloride-methanol (50: 1 to 40:
1)] to obtain 2.34 g of red-orange crystals. Recrystallized from methanol, melting point 156.0-157.5 ° C
Red-orange crystals were obtained. Elemental analysis C ₂₅ H ₂₇ N ₅ O ₂ S Theoretical C, 65.05; H, 5.90; N, 15.17 Experimental C, 64.81; H, 5.91; N, 14.90

Reference Example 56 4- [2-[(3-amino-2-chloroquinoline-4-
Yl) amino] ethyl] benzamide nickel chloride hexahydrate (2.05 g) in methanol (32 ml)
After adding 1.18 g of sodium borohydride at room temperature, 4- [2-[(2-chloro-3-nitroquinolin-4-yl) amino] ethyl] benzamide 6.4 was added.
1 g of N, N-dimethylformamide solution was added. Further, 0.65 g of sodium borohydride was added little by little. After filtering off the insoluble matter, the solvent was distilled off under reduced pressure, and the obtained residue was extracted by adding a mixed solution of water, ethyl acetate and methanol. The organic layer was washed with saturated saline and dehydrated, and the solvent was distilled off under reduced pressure. The residue was subjected to column chromatography [silica gel, methylene chloride-methanol (30: 1 to 10:
1)] to obtain 2.88 g of pale brown crystals. Recrystallization from ethanol gave pale yellow crystals having a melting point of 220.0-220.5 ° C. Elemental analysis C ₁₈ H ₁₇ ClN ₄ O Theoretical C, 63.44; H, 5.03; N, 16.44 Experimental C, 63.28; H, 4.93; N, 16.24

According to the method of Reference Example 56, Tables 13 and 2
The compounds of Reference Examples 57 to 94 shown in FIG. 5 were obtained.

[0085]

[Table 13]

[0086]

[Table 14]

[0087]

[Table 15]

[0088]

[Table 16]

[0089]

[Table 17]

[0090]

[Table 18]

[0091]

[Table 19]

[0092]

[Table 20]

[0093]

[Table 21]

[0094]

[Table 22]

[0095]

[Table 23]

[0096]

[Table 24]

[0097]

[Table 25]

Reference Example 95 4- [2- (4-chloro-1H-imidazo [4,5-
c] Quinolin-1-yl) ethyl] benzamide 4- [2-[(3-amino-2-chloroquinoline-4-
10 ml of ethyl orthoformate was added to 2.45 g of yl) amino] ethyl] benzamide, and the mixture was stirred at 80 to 120 ° C for 5 hours. N-Hexane was added at room temperature, and the precipitated crystals were collected by filtration.
After washing with isopropyl ether, 2.29 g of pale brown crystals were obtained.
I got Recrystallized from acetonitrile, mp 287.
Colorless crystals of 0 to 288.0 ° C were obtained. Elemental analysis C ₁₉ H ₁₅ ClN ₄ O Theoretical C, 65.05; H, 4.31; N, 15.97 Experimental C, 64.80; H, 4.08; N, 16.15

According to the method of Reference Example 95, Tables 26 to 3
The compounds of Reference Examples 96 to 147 shown in FIG. 4 were obtained.

[0100]

[Table 26]

[0101]

[Table 27]

[0102]

[Table 28]

[0103]

[Table 29]

[0104]

[Table 30]

[0105]

[Table 31]

[0106]

[Table 32]

[0107]

[Table 33]

[0108]

[Table 34]

Reference Example 148 4- [2- (4-Chloro-2-methyl-1H-imidazo [4,5-c] quinolin-1-yl) ethyl] -N-
(1-ethoxyethylidene) benzenesulfonamide 4- [2-[(3-amino-2-chloroquinoline-4-
Yl) amino] ethyl] benzenesulfonamide 2.3
9.4 ml of ethyl orthoformate was added to 4 g, and the mixture was added at 140 ° C. for 1 hour.
Stirred overnight. After cooling the reaction solution, n-hexane was added and decanted, and the residue was purified by column chromatography [silica gel, ethyl acetate-n-hexane (1: 1 to 4: 1)]. Crystallization from a mixed solution of ethyl acetate and n-hexane gave 1.67 g of crystals. Recrystallization from ethyl acetate gave yellow needles having a melting point of 151.0 to 152.0 ° C. Elemental analysis C ₂₃ H ₂₃ ClN ₄ O ₃ S Theoretical C, 58.65; H, 4.92; N, 11.90 Experimental C, 58.59; H, 4.70; N, 11.71

According to the method of Reference Example 148, the compounds of Reference Examples 149 to 152 shown in Tables 35 to 36 were obtained.

[0111]

[Table 35]

[0112]

[Table 36]

Reference Example 153 4- [2- (4-chloro-2-ethyl-propionic acid)
1H-imidazo [4,5-c] quinolin-1-yl) ethyl] benzyl 4- [2-[(3-amino-2-chloroquinoline-4-
Il) amino] ethyl] benzyl alcohol 3.00 g
Was dissolved in 75 ml of toluene, and propionyl chloride was dissolved in 75 ml of toluene.
1 ml was added. After stirring at room temperature for 3 hours, 0.17 g of p-toluenesulfonic acid monohydrate was added, and the mixture was refluxed for 6 hours. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in methylene chloride. , Water and saturated saline were successively performed. After dehydration of the methylene chloride layer, the solvent was distilled off under reduced pressure. The residue was subjected to column chromatography [silica gel,
Methylene chloride-methanol (50: 1)]
1.70 g of light brown crystals were obtained. Recrystallization from isopropyl alcohol gave pale brown crystals having a melting point of 144.0 to 145.5 ° C. Elemental analysis C ₂₄ H ₂₄ ClN ₃ O ₂ Theoretical C, 68.32; H, 5.73; N, 9.96 Experimental C, 68.32; H, 5.74; N, 9.98

According to the method of Reference Example 153, the compounds of Reference Examples 154 to 156 shown in Tables 37 to 38 were obtained.

[0115]

[Table 37]

[0116]

[Table 38]

Reference Example 157 4- [2- (2-ethoxymethyl-4-hydroxy-1)
H-imidazo [4,5-c] quinolin-1-yl) ethyl] benzenesulfonamide 4- [2-[(3-amino-2-chloroquinoline-4-
Il) amino] ethyl] benzenesulfonamide 5.9
23.7 ml of ethoxyacetic acid was added to 2 g, and the temperature was 80 to 130 ° C.
For 6 hours. After the reaction, the precipitated crystals were collected by filtration and washed with methylene chloride to obtain 3.90 g of crystals. N, N
-Recrystallization from a mixed solution of dimethylformamide and water gave colorless crystals having a melting point of 300 ° C or higher. Elemental analysis C ₂₁ H ₂₂ N ₄ O ₄ .1 / 2H ₂ O Theoretical C, 58.52; H, 5.26; N, 13.00 Experimental C, 58.41; H, 5.00; N, 12.75

According to the method of Reference Example 157, the compounds of Reference Examples 158 to 178 shown in Tables 39 to 46 were obtained.

[0119]

[Table 39]

[0120]

[Table 40]

[0121]

[Table 41]

[0122]

[Table 42]

[0123]

[Table 43]

[0124]

[Table 44]

[0125]

[Table 45]

[0126]

[Table 46]

Reference Example 179 4- [2- (4-chloro-2-ethoxymethyl-1H-
Imidazo [4,5-c] quinolin-1-yl) ethyl
Benzenesulfonamide 4- [2- (2-ethoxymethyl-4-hydroxy-1
To a suspension containing 3.03 g of H-imidazo [4,5-c] quinolin-1-yl) ethyl] benzenesulfonamide, 1.5 ml of triethylamine and 30 ml of toluene were added 2.8 ml of phosphorus oxychloride at room temperature. After dropping, at 120 ° C 5
Stirred for hours. The reaction solution was poured into ice water, the precipitated crystals were collected by filtration, and the obtained crystals were purified by column chromatography [silica gel, methylene chloride-methanol (20: 1)] to obtain 1.89 g of pale brown crystals. . IR spectrum ν (KBr) cm ^-1 : 3360, 1332
, 1160 Mass spectrum m / z: 444 (M ⁺ ) NMR spectrum δ (DMSO) ppm: 1.16 (3H, t, J = 7H
z), 3.30 (2H, t, J = 8Hz), 3.56 (2H, q, J = 7Hz), 4.59 (2H, s), 4.
99 (2H, t, J = 8Hz), 7.24 (2H, br-s), 7.41 (2H, d, J = 8Hz), 7.77
-7.82 (4H, m), 8.11-8.13 (1H, m), 8.45-8.47 (1H, m)

According to the method of Reference Example 179, the compounds of Reference Examples 180 to 196 shown in Tables 47 to 51 were obtained.

[0129]

[Table 47]

[0130]

[Table 48]

[0131]

[Table 49]

[0132]

[Table 50]

[0133]

[Table 51]

Reference Example 197 N- [4- [2- (4-dibenzylamino) -2-ethoxymethyl-1H-imidazo [4,5-c] quinoline-
1-yl) ethyl] phenyl] acetamide 5.21 g of N- [4- [2-[(3-amino-2-dibenzylaminoquinolin-4-yl) amino] ethyl] phenyl] acetamide and 4.21 g of ethoxyacetic acid Was stirred at 140 ° C. for 10 hours. Ethyl acetate and 10
% Aqueous sodium hydroxide solution was added to the reaction mixture, and the mixture was separated, and the aqueous layer was extracted with ethyl acetate. The ethyl acetate layers were combined, washed with saturated saline and then dehydrated, and the solvent was distilled off. The residue was purified by column chromatography [silica gel, ethyl acetate-n-hexane (1: 2 to 1: 1)] and washed with a mixed solution of ethyl acetate and isopropyl ether to obtain 2.35 g of pale brown crystals. Recrystallization from ethyl acetate gave colorless needles having a melting point of 171.0-171.5 ° C. Elemental analysis C ₃₇ H ₃₇ N ₅ O ₂ Theoretical C, 76.13; H, 6.39; N, 12.00 Experimental C, 76.23; H, 6.32; N, 11.98

According to the method of Reference Example 197, the compounds of Reference Examples 198 to 204 shown in Tables 52 to 56 were obtained.

[0136]

[Table 52]

[0137]

[Table 53]

[0138]

[Table 54]

[0139]

[Table 55]

[0140]

[Table 56]

Reference Example 205 4- [2- (2-acetoxymethyl-4-hydroxy-
1H-imidazo [4,5-c] quinolin-1-yl) ethyl] benzenesulfonamide 4- [2- (4-hydroxy-2-hydroxymethyl-
1H-imidazo [4,5-c] quinolin-1-yl) ethyl] benzenesulfonamide
25 ml and 17.8 ml of acetic anhydride were added and stirred at room temperature for 1 hour. After the reaction solution was concentrated under reduced pressure, water was added, and the precipitated crystals were collected by filtration, washed successively with water and ethyl acetate, and then washed at 7.8.
1 g of crystals were obtained. Recrystallized from a mixture of N, N-dimethylformamide and water, melting point 275.0-276.0 ° C.
To give pale brown crystals. Elemental analysis C ₂₁ H ₂₀ N ₄ O ₅ S Theoretical C, 57.26; H, 4.58; N, 12.72 Experimental C, 56.94; H, 4.50; N, 12.63

According to the method of Reference Example 205, the compound of Reference Example 206 shown in Table 57 was obtained.

[0143]

[Table 57]

Reference Example 207 4- [2- (2-hydroxymethyl-4-phenoxy-
1H-imidazo [4,5-c] quinolin-1-yl) ethyl] benzenesulfonamide 4- [2- (2-acetoxymethyl-4-hydroxy-
A mixture of 3.00 g of [1H-imidazo [4,5-c] quinolin-1-yl) ethyl] benzenesulfonamide and 45 ml of phosphorus oxychloride was refluxed for 1 hour. After cooling, the crystals were collected by filtration and washed with ethyl acetate to obtain 2.30 g of pale brown crystals. 4.71 g of phenol and 1.72 g of potassium hydroxide were added to the obtained light brown crystals, and the mixture was stirred at 120 ° C. for 1 hour. After cooling, 10% hydrochloric acid and ethyl acetate were added,
After filtering off the insolubles, the layers were separated, the ethyl acetate layer was dehydrated and concentrated under reduced pressure. Diethyl ether was added to the residue, and the precipitated crystals were collected by filtration to obtain 1.39 g of crystals. Recrystallization from a mixture of N, N-dimethylformamide and water gave a melting point of 2.
Light brown crystals of 61.0-263.0 ° C were obtained. Elemental analysis C ₂₅ H ₂₂ N ₄ O ₄ S Theoretical C, 63.28; H, 4.67; N, 11.81 Experimental C, 63.24; H, 4.58; N, 11.71

According to the method of Reference Example 207, the compound of Reference Example 208 shown in Table 58 was obtained.

[0146]

[Table 58]

Reference Example 209 4- [2- (4-phenoxy-1H-imidazo [4,5
-C] quinolin-1-yl) ethyl] benzamide 4- [2- (4-chloro-1H-imidazo [4,5-
c] Quinolin-1-yl) ethyl] benzamide 1.6
0.81 g of potassium hydroxide and 4.4 of phenol are added to 5 g.
3 g was added, and the mixture was stirred at 120 ° C. for 4.5 hours. Water and 10% hydrochloric acid were added to the reaction mixture to adjust the pH to pH 8, and then ethyl acetate was added. The precipitated crystals were collected by filtration to obtain 1.29 g of pale brown crystals. Recrystallization from ethanol gave yellow needles with a melting point of 265.0-266.0 ° C. Elemental analysis C ₂₅ H ₂₀ N ₄ O ₂ Theoretical C, 73.51; H, 4.94; N, 13.72 Experimental C, 73.33; H, 4.85; N, 13.43

According to the method of Reference Example 209, the compounds of Reference Examples 210 to 287 shown in Tables 59 to 71 were obtained.

[0149]

[Table 59]

[0150]

[Table 60]

[0151]

[Table 61]

[0152]

[Table 62]

[0153]

[Table 63]

[0154]

[Table 64]

[0155]

[Table 65]

[0156]

[Table 66]

[0157]

[Table 67]

[0158]

[Table 68]

[0159]

[Table 69]

[0160]

[Table 70]

[0161]

[Table 71]

Reference Example 288 4- [2- (2-n-butyl-4-phenoxy-6,7,
8,9-tetrahydro-1H-imidazo [4,5-c]
(Quinolin-1-yl) ethyl] benzenesulfonamide (1) 4- [2- (2-n-butyl-4-chloro-6,7,
8,9-tetrahydro-1H-imidazo [4,5-c]
Quinolin-1-yl) ethyl-N- (1-ethoxypentylidene) benzenesulfonamide 4- [2-[(3-amino-2-chloro-5,6,7,
12-mL of triethyl orthovalerate was added to 3.04 g of 8-tetrahydroquinolin-4-yl) amino] ethyl] benzenesulfonamide, and the mixture was stirred at 120 to 140 ° C for 25 hours. n-Hexane was added, triethyl orthovalerate was removed by decantation, and the residue was stirred at 140 ° C for 19 hours. This was purified by column chromatography [silica gel, methylene chloride-methanol (100: 1)] to obtain 1.67 g of pale brown crystals. (2) 4- [2- (2-n-butyl-4-phenoxy-6,
7,8,9-tetrahydro-1H-imidazo [4,5-
c] Quinolin-1-yl) ethyl] benzenesulfonamide 4- [2- (2-n-butyl-4-chloro-6,7,8,
To 1.35 g of 9-tetrahydro-1H-imidazo [4,5-c] quinolin-1-yl) ethyl-N- (1-ethoxypentylidene) benzenesulfonamide, 0.43 g of potassium hydroxide and 2.33 g of phenol And add 12
Stirred at 0 ° C. for 5 hours. Water and a 10% aqueous sodium hydroxide solution were added to the reaction mixture to adjust the pH to 10, and then methylene chloride was added for extraction. The extract was washed successively with a 10% aqueous sodium hydroxide solution, water and saturated saline, dehydrated, and methylene chloride was distilled off. The residue was subjected to column chromatography [silica gel, methylene chloride-methanol (1
00: 1-30: 1)] to give a pale brown crystal 0.68
g was obtained. Recrystallization from ethyl acetate gave a melting point of 224.5.
~ 225.5 ° C colorless crystals were obtained. Elemental analysis C ₂₈ H ₃₂ N ₄ O ₃ S Theoretical C, 66.64; H, 6.39; N, 11.10 Experimental C, 66.43; H, 6.41; N, 10.84

Reference Example 289 4- [2- (2-cyclopropylmethyl-4-phenoxy-1H-imidazo [4,5-c] quinolin-1-yl) ethyl] benzyl alcohol (1) cyclopropylacetic acid 4- [2- (4-chloro-2
-Cyclopropylmethyl-1H-imidazo [4,5-
c] Quinolin-1-yl) ethyl] benzyl cyclopropylacetic acid 4- [2- (2-cyclopropylmethyl-4-hydroxy-1H-imidazo [4,5-
c] quinolin-1-yl) ethyl] benzyl 1.33 g
To the mixture was added 20 ml of phosphorus oxychloride and the mixture was stirred at 120 ° C for 1 hour. The reaction solution was poured into water, and extracted by adding methylene chloride. The extract was washed successively with water and saturated saline, dehydrated, and the solvent was distilled off. The residue was subjected to column chromatography [silica gel, methylene chloride-methanol (100: 1 to 3).
0: 1)] to give 0.36 g of colorless crystals. (2) 4- [2- (2-cyclopropylmethyl-4-phenoxy-1H-imidazo [4,5-c] quinoline-1-
Yl) ethyl] benzyl alcohol cyclopropylacetic acid 4- [2- (4-chloro-2-cyclopropylmethyl-1H-imidazo [4,5-c] quinolin-1-yl) ethyl] benzyl 0.25 g and water 0.09 g of potassium oxide and 0.50 g of phenol were added, and the mixture was stirred at 120 ° C. for 4 hours. After the reaction, water, a 10% aqueous sodium hydroxide solution and ethyl acetate were added, and the mixture was stirred under ice cooling. The precipitated crystals were collected by filtration to obtain 0.14 g of slightly brown crystals. Recrystallization from ethyl acetate gave a melting point of 185.0-1.
0.10 g of colorless crystals at 85.5 ° C. was obtained. Elemental analysis C ₂₉ H ₂₇ N ₃ O ₂ Theoretical C, 77.48; H, 6.05; N, 9.35 Experimental C, 77.22; H, 6.09; N, 9.11

According to the method of Reference Example 289, the compounds of Reference Examples 290 to 291 shown in Tables 72 to 73 were obtained.

[0165]

[Table 72]

[0166]

[Table 73]

Reference Example 292 4- [2- [2- (2-methylpropyl) -4-phenoxy-1H-imidazo [4,5-c] quinolin-1-yl] ethyl] benzenesulfonamide (1) 4 -[2- [4-hydroxy-2- (2-methylpropyl) -1H-imidazo [4,5-c] quinoline-1
-Yl] ethyl] benzenesulfonamide 4- [2-[(3-amino-2-chloroquinoline-4-
Il) amino] ethyl] benzenesulfonamide 8.0
11.6 ml of isovaleric acid was added to 0 g, and the mixture was stirred at 130 ° C. for 24 hours. The precipitated crystals were collected by filtration and washed with methylene chloride to obtain 9.31 g of crystals. (2) 4- [2- [4-Chloro-2- (2-methylpropyl) -1H-imidazo [4,5-c] quinolin-1-yl] ethyl] benzenesulfonamide 4- [2- [4 135 ml of phosphorus oxychloride was added to 9.00 g of -hydroxy-2- (2-methylpropyl) -1H-imidazo [4,5-c] quinolin-1-yl] ethyl] benzenesulfonamide, and the mixture was stirred at 120 ° C for 9 hours. did. The reaction solution was concentrated under reduced pressure, ethyl acetate was added, and the precipitated crystals were collected by filtration to obtain 5.10 g of crystals. (3) 4- [2- [2- (2-methylpropyl) -4-phenoxy-1H-imidazo [4,5-c] quinoline-1
-Yl] ethyl] benzenesulfonamide 4- [2- [4-chloro-2- (2-methylpropyl)
-1H-imidazo [4,5-c] quinolin-1-yl]
[Ethyl] benzenesulfonamide (4.80 g), potassium hydroxide (1.86 g) and phenol (10.2 g) were added.
Stirred at 20 ° C. for 5 hours. Water and 10%
After adjusting the pH of the solution to pH 8 by adding hydrochloric acid, ethyl acetate was added and the precipitated crystals were collected by filtration to obtain 2.16 g of pale brown crystals. Recrystallization from ethyl acetate gave a melting point of 221.0-22.
2.0 ° C. pale brown needles were obtained. Elemental analysis C ₂₈ H ₂₈ N ₄ O ₃ S Theoretical C, 67.18; H, 5.64; N, 11.19 Experimental C, 67.08; H, 5.47; N, 11.40

According to the method of Reference Example 292, the compound of Reference Example 293 shown in Table 74 was obtained.

[0169]

[Table 74]

Reference Example 294 1- [2- (4-cyanophenyl) ethyl] -4-phenoxy-1H-imidazo [4,5-c] quinoline 4- [2- (4-phenoxy-1H-imidazo [4 , 5
-C] quinolin-1-yl) ethyl] benzamide
33 g of N, N-dimethylformamide was dissolved in 33 ml of the solution, and 1.05 ml of pyridine and 0.92 ml of trifluoroacetic anhydride were added thereto under ice cooling and stirring, followed by stirring with ice for 30 minutes.
100 ml of ice water and 20 ml of diethyl ether were added to the reaction solution, and the mixture was stirred. The precipitated crystals were collected by filtration to obtain 0.89 g of crystals. Recrystallization from ethyl acetate gave a melting point of 196.0.
Light yellow needles at 198.0 ° C. were obtained. Elemental analysis C ₂₅ H ₁₈ N ₄ O Theoretical C, 76.91; H, 4.65; N, 14.35 Experimental C, 76.97; H, 4.35; N, 14.45

Reference Example 295 4- [2- (4-phenoxy-1H-imidazo [4,5
-C] quinolin-1-yl) ethyl] benzoic acid 4- [2- (4-chloro-1H-imidazo [4,5-
c) quinolin-1-yl) ethyl] ethyl benzoate
To 31 g, 5.67 g of phenol and potassium hydroxide 2.
After adding 02 g, the mixture was stirred at 120 ° C. for 3 hours. Water and 10% hydrochloric acid were added to the reaction mixture to adjust the liquid property to pH 8, and then ethyl acetate was added, and the precipitated crystals were collected by filtration.
9 g of crystals were obtained. Recrystallized from a mixture of N, N-dimethylformamide and water, melting point 265.0-267.0 ° C.
To obtain colorless crystals. Elemental analysis C ₂₅ H ₁₉ N ₃ O ₃ Theoretical C, 73.34; H, 4.68; N, 10.26 Experimental C, 73.34; H, 4.38; N, 10.38

Example 1 4- [2- (4-amino-1H-imidazo [4,5-
c] Quinolin-1-yl) ethyl] benzamide 4- [2- (4-phenoxy-1H-imidazo [4,5
-C] quinolin-1-yl) ethyl] benzamide
9.87 g of ammonium acetate was added to 09 g,
For 5 hours. A 10% aqueous sodium hydroxide solution was added to the reaction mixture to adjust the liquid property to pH 8, and the precipitated crystals were collected by filtration and washed with water to obtain 0.82 g of light brown crystals. Recrystallized from ethanol, melting point 267.0-26
8.0 ° C. pale brown crystals were obtained. Elemental analysis C ₁₉ H ₁₇ N ₅ O Theoretical C, 68.87; H, 5.17; N, 21.13 Experimental C, 68.58; H, 4.94; N, 20.87

According to the method of Example 1, Tables 75 to 78
The compounds of Examples 2 to 50 shown in Table 1 were obtained.

[0174]

[Table 75]

[0175]

[Table 76]

[0176]

[Table 77]

[0177]

[Table 78]

Example 51 4- [2- (4-Amino-2-methyl-1H-imidazo [4,5-c] quinolin-1-yl) ethyl] benzyl alcohol (1) 4- [2- (4 -Chloro-2-methyl-1H-imidazo [4,5-c] quinolin-1-yl) ethyl] benzyl alcohol 4- [2-[(3-amino-2-chloroquinolin-4-
Yl) amino] ethyl] benzyl alcohol 2.57 g
Was added to 7.2 ml of triethyl orthoacetate.
Stirred at 0 ° C. for 28 hours. After adding n-hexane to the reaction mixture and removing it by decanting, the residue was subjected to column chromatography [silica gel, methylene chloride-methanol (1: 1).
0-30: 1)] to obtain 1.66 g of pale yellow crystals. (2) 4- [2- (2-methyl-4-phenoxy-1H-
Imidazo [4,5-c] quinolin-1-yl) ethyl
Benzyl alcohol 4- [2- (4-Chloro-2-methyl-1H-imidazo [4,5-c] quinolin-1-yl) ethyl] benzyl alcohol 1.50 g, potassium hydroxide 0.73 g and phenol 4. After adding 02 g, the mixture was stirred at 120 ° C. for 6 hours. Water and a 10% aqueous sodium hydroxide solution were added to the reaction mixture to adjust the pH thereof to pH 10, and then methylene chloride was added for extraction. The methylene chloride layer was washed successively with a 10% aqueous sodium hydroxide solution, water and saturated saline, and after dehydration, the solvent was distilled off under reduced pressure to obtain 1.20 g of pale brown crystals. (3) 4- [2- (4-amino-2-methyl-1H-imidazo [4,5-c] quinolin-1-yl) ethyl] benzyl alcohol 4- [2- (2-methyl-4-phenoxy) -1H-imidazo [4,5-c] quinolin-1-yl) ethyl] benzyl alcohol to 1.00 g and ammonium acetate 4.52
g was added and stirred at 140 ° C. for 6 hours. 10% after reaction
After adjusting the pH of the solution to pH 8 by adding an aqueous sodium hydroxide solution, the mixture was extracted with a mixture of methylene chloride and methanol (10: 1). The organic layer was concentrated under reduced pressure, and methanol 3.8 was added to the residue.
and 0.2 ml of 2N aqueous sodium hydroxide solution.
Stirred at 50 ° C. for 1 hour. The reaction solution was stirred under ice-cooling.
26 g of crystals were obtained. Recrystallization from ethanol gave colorless crystals having a melting point of 236.0 to 237.0 ° C. Elemental analysis C ₂₀ H ₂₀ N ₄ O theory C, 72.27; H, 6.06; N, 16.86 Found C, 72.05; H, 6.07; N, 16.64

According to the method of Example 1, Tables 79 to 84
The compounds of Examples 52 to 79 shown in the above were obtained.

[0180]

[Table 79]

[0181]

[Table 80]

[0182]

[Table 81]

[0183]

[Table 82]

[0184]

[Table 83]

[0185]

[Table 84]

Example 80 N- [4- [2- (4-amino-2-ethoxymethyl-
1H-imidazo [4,5-c] quinolin-1-yl) ethyl] phenyl] acetamide N- [4- [2- (4-dibenzylamino-2-ethoxymethyl-1H-imidazo [4,5-c Quinoline-1
-Yl) ethyl] phenyl] acetamide 2.20 g,
4.00 g of Pearlman's reagent and ammonium formate 1
A suspension of 4.28 g of methanol in 70 ml was refluxed for 53 hours. The catalyst was removed by filtration, and the solvent was distilled off under reduced pressure. Water and saturated saline were added to the residue, and extracted with methylene chloride. After dehydration of the extract, the solvent was distilled off under reduced pressure. The obtained residue was washed with isopropyl ether to obtain 1.24 g of colorless crystals.
Recrystallization from isopropanol gives a melting point of 207.0-2.
Colorless crystals of 08.0 ° C. were obtained. Elemental analysis _{C 23 H 25 N 5 O 2} · 1 / 2H 2 O Theoretical value C, 66.97; H, 6.35; N, 16.98 Found C, 66.90; H, 6.28; N, 16.81

According to the method of Example 80, Tables 85 to 8
The compounds of Examples 81 to 84 shown in FIG. 7 were obtained.

[0188]

[Table 85]

[0189]

[Table 86]

[0190]

[Table 87]

Example 85 1- [2- (4-Aminophenyl) ethyl] -1H-imidazo [4,5-c] quinolin-4-amine hydrochloride N- [4- [2- (4-amino) -1H-imidazo [4,
To 8.00 g of 5-c] quinolin-1-yl) ethyl] phenyl] acetamide was added 40 ml of 2N hydrochloric acid, and
Stirred at C for 1 hour. After the reaction, a 10% aqueous sodium hydroxide solution was added to adjust the solution to pH 7, and the precipitated crystals were collected by filtration, purified by column chromatography [silica gel, methylene chloride-methanol (20: 1)], and then ethanol. Hydrogen chloride was added, and the precipitated crystals were collected by filtration to obtain 3.50 g of colorless crystals. Recrystallization from a mixture of methanol and water gave colorless crystals having a melting point of 275.0-283.0 ° C. Elemental analysis _{C 18 H 17 N 5 · 2HCl} · 1 / 4H 2 O Theoretical value C, 56.78; H, 5.16; N, 18.39 Found C, 56.78; H, 5.11; N, 18.22

According to the method of Example 85, Tables 88 to 8
The compounds of Examples 86 to 104 shown in Example 9 were obtained.

[0193]

[Table 88]

[0194]

[Table 89]

Example 105 1- [2- (4-Aminophenyl) ethyl] -2-n-butyl-1H-imidazo [4,5-c] quinolin-4-amine 1- [2- [4- ( 2. dibenzylamino) phenyl] ethyl] -2-n-butyl-1H-imidazo [4,5-c] quinolin-4-amine 18.8 g, Pearlman's reagent
76 g, ammonium formate 33.0 g and methanol 6
00 ml of the suspension were refluxed for 7 hours. The catalyst was removed by filtration and the solvent was distilled off. Water was added to the obtained residue, and the pH was adjusted to 9 with a 10% aqueous sodium hydroxide solution, followed by extraction with methylene chloride. The extract is washed with water and dehydrated, and the solvent is distilled off.
The obtained residue was washed with ethyl acetate and recrystallized from isopropanol to obtain colorless crystals having a melting point of 191.0 to 192.0 ° C. Elemental analysis C ₂₂ H ₂₅ N ₅ theory C, 73.51; H, 7.01; N, 19.48 Found C, 73.41; H, 6.90; N, 19.22

According to the procedure of Example 105, the compounds of Example 106 shown in Table 90 were obtained.

[0197]

[Table 90]

Example 107 1- [2- (4-aminophenyl) ethyl] -1,6,
7,8-tetrahydro-cyclopenta [b] imidazo [4,5-d] pyridin-4-amine hydrochloride N, N-dibenzyl-1- [2- [4- (dibenzylamino) phenyl] ethyl]- 0.81 g of 1,6,7,8-tetrahydrocyclopenta [b] imidazo [4,5-d] pyridin-4-amine, 0.16 of Pearlman's reagent
g, ammonium formate 1.56 g and methanol 40 ml
Was refluxed for 30.5 hours. The catalyst was removed by filtration and the solvent was distilled off. Water was added to the residue, the solution was adjusted to pH 9 with a 10% aqueous potassium carbonate solution, and methylene chloride was added. The precipitated crystals were collected by filtration, the methylene chloride layer was separated, and the aqueous layer was further extracted with methylene chloride. After dehydration of the methylene chloride layer, the solvent was distilled off to obtain colorless crystals. 0.41 g of colorless crystals were obtained as a hydrochloride by a conventional method together with the above crystals. Recrystallized from methanol, melting point 259.0-260.0 ° C
Colorless crystals of (decomposition) were obtained. Elemental analysis C ₁₇ H ₁₉ N ₅ · 2HCl theory C, 55.74; H, 5.78; N, 19.12 Found C, 55.76; H, 5.89; N, 19.07

According to the method of Example 107, the compounds of Examples 108 to 109 shown in Table 91 were obtained.

[0200]

[Table 91]

Example 110 1- [2- (4-Ureidophenyl) ethyl] -1H-
1. 800 mg of imidazo [4,5-c] quinolin-4-amine 1- [2- (4-aminophenyl) ethyl] -1H-imidazo [4,5-c] quinolin-4-amine was dissolved in 8 ml of acetic acid and 4 ml of water. The mixture was dissolved in 8 ml of a mixed solution, and while stirring at room temperature, a solution of sodium cyanate (400 mg) in water (4.8 ml) was added.
Stirred at room temperature for 2 hours. A 10% aqueous solution of sodium hydroxide was added to the reaction solution to adjust the solution to pH 9, and the crystals were collected by filtration.
After washing with water, 790 mg of crystals were obtained. Recrystallization from a mixed solution of ethanol and water gave light brown crystals having a melting point of 300 ° C. or higher. Elemental analysis C ₁₉ H ₁₈ N ₆ O Theoretical C, 65.88; H, 5.24; N, 24.26 Experimental C, 66.00; H, 5.14; N, 24.07

Example 111 1- [2- [4- (N'-methylthioureido) phenyl] ethyl] -1H-imidazo [4,5-c] quinolin-4-amine 1- [2- (4-amino Phenyl) ethyl] -1H-imidazo [4,5-c] quinolin-4-amine in 800 mg of methanol 24 ml and methyl isothiocyanate 0.6
0 ml was added and the mixture was stirred at 40 ° C. for 15 hours. After cooling the reaction solution, the precipitated crystals were collected by filtration to obtain 770 mg of crystals.
Recrystallization from a mixture of ethanol and water gave a melting point of 220.0.
Light brown crystals of ２２221.5 ° C. were obtained. Elemental analysis C ₂₀ H ₂₀ N ₆ S Theoretical C, 63.81; H, 5.35; N, 22.32 Experimental C, 63.60; H, 5.13; N, 22.05

Example 112 1- [2- (4-acetylphenyl) ethyl] -1H-
Imidazo [4,5-c] quinolin-4-amine 2- [4- [2- (4-phenoxy-1H-imidazo [4,5-c] quinolin-1-yl) ethyl] phenyl] -2-methyl To 3.89 g of -1,3-dioxolane was added 33.2 g of ammonium acetate, and the mixture was stirred at 140 ° C. for 3 hours. After the reaction, a 10% aqueous sodium hydroxide solution was added to adjust the solution to pH 8, and the precipitated crystals were collected by filtration and washed with water to obtain 2.83 g of pale brown crystals. Recrystallization from a mixture of methylene chloride and methanol gave a melting point of 267.0-2.
Colorless crystals of 69.0 ° C. were obtained. Elemental analysis C ₂₀ H ₁₈ N ₄ O Theoretical C, 72.71; H, 5.49; N, 16.96 Experimental C, 72.41; H, 5.34; N, 16.70

Example 113 1- [2- [4- (1-Hydroxyiminoethyl) phenyl] ethyl] -1H-imidazo [4,5-c] quinolin-4-amine 1- [2- (4-acetyl) Phenyl) ethyl] -1H-
Imidazo [4,5-c] quinolin-4-amine 1.63
0.38 g of hydroxylamine hydrochloride, 1.34 g of sodium acetate trihydrate and 16 ml of ethanol were added to the resulting mixture.
Refluxed for 2 hours. After the reaction solution was concentrated under reduced pressure, water was added and the precipitated crystals were collected by filtration to obtain 1.47 g of crystals. Recrystallized from a mixture of ethanol and water, melting point 269.0-270.5
C. Light brown crystals were obtained. Elemental analysis C ₂₀ H ₁₉ N ₅ O theory C, 69.55; H, 5.54; N, 20.28 Found C, 69.34; H, 5.54; N, 20.11

Example 114 1- [2- [4- (1-Aminoethyl) phenyl] ethyl] -1H-imidazo [4,5-c] quinolin-4-amine 1- [2- [4- (1 -Hydroxyiminoethyl) phenyl] ethyl] -1H-imidazo [4,5-c] quinolin-4-amine (500 mg) was mixed with 10% methanolic ammonia (150 ml) and Raney nickel (1 ml), and the mixture was stirred at 50 atm. . After cooling the reaction solution, the solvent was filtered and concentrated under reduced pressure to obtain 300 mg of crystals. Recrystallization from ethanol gave pale brown crystals with a melting point of 222.0-224.0 ° C. Elemental analysis C ₂₀ H ₂₁ N ₅ theory C, 72.48; H, 6.39; N, 21.13 Found C, 72.46; H, 6.39; N, 20.86

Example 115 4- [2- (4-amino-1H-imidazo [4,5-
c] Quinolin-1-yl) ethyl] ethyl benzoate 4- [2- (4-amino-1H-imidazo [4,5-
c] Quinolin-1-yl) ethyl] benzoic acid (550 mg) was added with ethanol (28 ml) and concentrated sulfuric acid (2.8 ml), and the mixture was refluxed for 5 hours. After the reaction solution was concentrated under reduced pressure, water and a 10% aqueous sodium hydroxide solution were added to adjust the solution to pH 9, and the precipitated crystals were collected by filtration to obtain 550 mg of pale brown crystals. Recrystallization from methanol gave pale brown needles having a melting point of 180.0-182.0 ° C. Elemental analysis C ₂₁ H ₂₀ N ₄ O ₂ Theoretical C, 69.98; H, 5.59; N, 15.55 Experimental C, 69.98; H, 5.39; N, 15.62

Test Example 1: Interferon α-inducing ability in human cells As an example showing the excellent effect of the compound of the present invention, the interferon α-inducing ability in human cells is shown in Table 1. The following compounds were used as control drugs. Control drug A: 1-isobutyl-1H-imidazo [4,5
-C] quinolin-4-amine (generic name: imiquimod) Control drug B: 1- (2-phenylethyl) -1H-imidazo [4,5-c] quinolin-4-amine

1. Preparation of blood cells for culture 17 Novo Heparin Injection 1000 (Novo Nordisk A / S)
Whole blood was collected by venipuncture into a 50 ml centrifuge tube containing 0 μl. Peripheral blood mononuclear cells (PBMCs) were converted to Leuco PREPTM (Becton D
ickinson; Reorder No. 2751) adjusted with a cell separation tube and adjusted to 2 mM L-glutamine (LIFE TECHNOLOGIS; Cat. No.
25030-016), penicillin-streptomycin solution (final concentration penicillin 100 U / ml, streptomycin 100 μg / m
l, LIFE TECHNOLOGIS; Cat. No. 15145-014) and 10% fetal bovine serum (INTERGEN COMPANY; Cat. No. 102)
0-90) (Nissui Pharmaceutical Co., Ltd .; Co.
de 05918), and cultured at a cell density of 1 × 10 6 cells / ml.

[0209] 2. Preparation of Compound The compound was suspended in 0.1 N hydrochloric acid to a concentration of 1 mg / ml, and diluted with physiological saline to solubilize it. 0.03 μg / ml compound
Tested in the concentration range of 3.0 μg / ml. 3. Incubate 50 μl of test compound solution or solvent in 96 wells (flat bottom).
cro Test III TM (Becton Dickinson; FALCON 3072)
The plate was added to a cell culture plate, and 200 μl of PBMC in the medium was added to the well containing the plate. Cover the plate with a plastic lid and place in a 5% carbon dioxide atmosphere.
Incubated at 2 ° C. for 2 days.

[0210] 4. Subsequent to the incubation, place the plate in the PLATE SEALER
After coating with S (Coster Corporation; Cat. No. 3095), a universal cooling centrifuge (Kubota Manufacturing; KUBOTA 5)
800) at 4 ° C. for 5 minutes at 2,000 rpm (740 × g, rotor; RS-96SA / 6). Each culture supernatant was used as a sample.

[0211] 5. Quantification of interferon α was performed by enzyme immunoassay. Cyto scree
n TM Human Interferon α Quantitation Kit (BIOSOURCE; C
At. # ASY-05), a mouse anti-human interferon α monoclonal antibody (first antibody) is immobilized.
The well plate was bound to interferon α in a 100 μl sample by an antigen-antibody reaction. Next, after binding a rabbit anti-human interferon α polyclonal antibody (secondary antibody), a peroxidase-labeled anti-rabbit antibody was bound. Color was developed using tetramethylbenzidine to stop the reaction. Next, the absorbance at 450 nm was measured using V max kinetics.
The measurement was performed using a tic microplate reader (Molecular Devices). All results were expressed as pg / ml according to an interferon α standard curve. Table 92 shows the results.
And Table 93.

[0212]

[Table 92]

[0213]

[Table 93] The compound of the present invention exhibits excellent interferon α-inducing ability as compared with a control drug, and diseases caused by the involvement of viruses such as rheumatoid arthritis, warts, hepatitis B, hepatitis C, and cancer and other neoplastic diseases. It is extremely useful for the treatment of

[0214]

Industrial Applicability The compounds of the present invention have excellent interferon-inducing ability, and are diseases caused by the involvement of viruses such as rheumatoid arthritis, warts, hepatitis B, hepatitis C, and cancers and other tumors. It is extremely useful for treating sexual diseases.

 ────────────────────────────────────────────────── ─── Continued on the front page (72) Inventor Katsutoshi Tsubouchi 37-1 Inoguchi 37, Katsuyama-shi, Fukui Prefecture Hokuriku Pharmaceutical Co., Ltd.

Claims (1)

[Claims] (1) The following general formula (I): (Wherein R ¹ is COR ⁷ , SO ₂ NR ⁸ R ⁹ , CONR
⁸ R ⁹ , NR ¹⁰ R ¹¹ , a group represented by C (R ¹² ) = NOH, a hydroxyl group or a cyano group, R ² and R ³ are the same or different and represent a hydrogen atom or a lower alkyl group, and R ⁴ represents hydrogen R ⁵ represents a hydrogen atom, a linear or branched alkyl group having 1 to 10 carbon atoms which may be substituted with one or more hydroxyl groups, lower alkoxy groups, cyclic alkyl groups or halogen atoms; the atom or a lower alkyl group, R ⁶
Represents a hydrogen atom, a lower alkyl group, a lower alkoxy group or a halogen atom; R ⁷ represents a hydroxyl group, a lower alkyl group or a lower alkoxy group; R ⁸ and R ⁹ may be the same or different and represent a hydrogen atom or a lower alkyl group; ¹⁰ is a hydrogen atom, a lower alkyl group, a benzyl group, R ¹¹ is a hydrogen atom, a lower alkyl group, a benzyl group, a lower alkanesulfonyl group, a lower alkanoyl group, a substituted or unsubstituted carbamoyl group, a substituted or unsubstituted thio A carbamoyl group or a substituted or unsubstituted benzenesulfonyl group; R ¹² represents a hydrogen atom or a lower alkyl group; m represents an integer of 0 to 1; n represents an integer of 1 to 3; Represents an alkylene chain or a carbon chain represented by CH = CH, Y represents a sulfur atom or a carbon chain represented by CH = CH, and a bond represented by a solid line and a dotted line is Bond or a double bond. 1)-(substituted aryl) alkyl-1H-imidazopyridin-4-amine derivatives represented by the following formulas: or a pharmacologically acceptable salt thereof.