JPH11343289A - N-(imidazo(2,1-a)isoquinolin-9-yl)carbamic acid ester - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a new compound having an inhibitory action on H<+> /K<+> - ATPase activity, an inhibitory action on secretion of acid in the stomach and antibacterial action on Helicobacter pylori, useful as a medicine. SOLUTION: This compound is shown by formula I (R<1> is a lower alkyl which may be substituted with a halogen or the like; Ar is phenyl which may be substituted with a halogen or the like; R<2> is H or the like; R<3> is H or the like; R<4> is H or the like; a broken line forms a double bond or the like with a solid line) such as 9-methoxycarbonylamino-2-(2methylphenyl)imidazo [2,1- a]isoquinoline. The compound of formula I is obtained, for example, by reacting a compound of formula II (e.g. 1-amino-7-nitroisoquinoline or the like) with a compound of formula III (Z is a halogen; R<11> is H or the like) (e.g. 2-bromo-2'- methylacetophenone or the like) in the presence of a base in an alcohol under heating, reducing the reaction product and further reacting the resulting product with a compound of the formula: ClCO2 R<1> (e.g. methyl chlorocarbonate) in the presence of a base.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

FIELD OF THE INVENTION The present invention relates to a novel and useful pharmaceutically useful N- (imidazo [2,1-a] isoquinoline-
9-yl) carbamic acid ester and its pharmaceutically acceptable salts and solvates thereof.

[0002]

2. Description of the Related Art Compounds having an imidazo [2,1-a] isoquinoline skeleton, characterized in that the 2-position is substituted by phenyl which may be substituted, and which has an anti-pregnancy effect No. 51-75098),
Or a compound characterized by being substituted at the 2-position with phenyl or phenylalkylene which may be substituted and having an anti-inflammatory action, an immunomodulatory action, etc. (JP-A-7-291972); Is substituted with lower alkyl, and has an anti-ulcer effect (European Patent Application No. 165545),
Or a compound having an amino which may be substituted at the 2-position and having an amino optionally substituted at the 3-position, and having an anti-ulcer effect (European Patent Application No. 822194) Although imidazo [2, which has a carbamic acid ester at the 9-position as in the present application, is known.
No 1-a] isoquinoline derivatives are known.

[0003]

DISCLOSURE OF THE INVENTION The present invention relates to a useful medicine,
In particular, H ⁺ / K ⁺ -ATPase activity inhibitory action, gastric acid secretion inhibitory action, and Helicobacter pylori
lori), a new imidazo [2,
1-a] It is intended to provide an isoquinoline derivative.

[0004]

The present inventors have previously found a novel imidazo [2,1-a] isoquinoline derivative having an antiulcer action (European Patent Application No. 822194).
No.), as a result of intensive studies to solve the above-mentioned problems for the purpose of developing more excellent pharmaceuticals, a new N-type compound different from the conventional imidazo [2,1-a] isoquinoline derivatives
-(Imidazo [2,1-a] isoquinolin-9-yl)
Carbamic acid esters and their pharmaceutically acceptable salts and solvates thereof are H ⁺ / K ⁺ -ATPase
The present inventors have found that they have an activity inhibiting effect, a gastric acid secretion suppressing effect, and an antibacterial effect against Helicobacter pylori, and completed the present invention. That is, the present invention provides N- (imidazo [2,1-a] isoquinolin-9-yl) carbamic acid ester represented by the following general formula (I), a pharmaceutically acceptable salt thereof, and a solvent thereof. Regarding Japanese:

Embedded image Wherein R ¹ is halogen, cyano, lower alkylthio,
Lower alkyl optionally having a substituent selected from lower alkylsulfonyl or phenyl; or lower alkenyl: Ar is halogen; lower alkoxy; or lower alkyl optionally substituted with hydroxyl, lower alkoxy or acyloxy. Optionally substituted phenyl, pyridyl, furyl or thienyl: R ² is hydrogen; cyano; nitroso; halogen; lower alkyl; lower alkylthio; lower alkoxy; protected carboxy; amino; acylamino; lower alkylamino, lower alkylideneamino; lower alkanoyl; is -CH = NR ⁵ [R ⁵ hydroxyl; cyano, lower alkoxy, lower alkenyl which may be substituted with a lower alkanoyl or optionally protected carboxy lower alkoxy A; lower alkyl optionally substituted by hydroxyl, lower alkoxy or protected carboxy]; or -AR ⁶ [A is lower alkylene: R ⁶ is halogen; cyano; amino; lower alkylideneamino; hydroxyl or lower A lower alkylamino optionally substituted with alkoxy; an acylamino; a lower alkoxycarbonylamino; a protected carboxy; -XR ⁷ [X is oxygen or sulfur: R ⁷ is hydrogen; a lower alkyl; a lower alkenyl;

Embedded image (Wherein R ⁸ , R ⁹ , and R ¹⁰ are lower alkyl; Y represents an acid residue)]]: R ³ is hydrogen or lower alkyl: R ⁴ is hydrogen; halogen; lower alkoxy; lower Alkyl; or lower alkoxycarbonylamino;
The broken line portion represents a double bond or a single bond integrally with the solid line. ].

[0005] The terms used in the present specification are defined below. Regarding the substituents of the compound (I) of the present invention, it is determined whether the substituents are present independently or in other groups. Regardless, the following meanings are used in this specification. "Lower" means 1 to 1 carbon atoms unless otherwise indicated.
Means six.

Suitable "halogens" include fluorine, chlorine, bromine and iodine.

"Halogen, cyano, lower alkylthio,
Lower alkyl optionally having a substituent selected from lower alkylsulfonyl or phenyl "," phenyl optionally having a substituent selected from lower alkyl optionally substituted by hydroxyl, lower alkoxy or acyloxy " , Pyridyl, furyl or thienyl ",
In "lower alkylthio", "lower alkylamino", "lower alkyl optionally substituted with hydroxyl, lower alkoxy or protected carboxy" and "lower alkylamino optionally substituted with hydroxyl or lower alkoxy" The "lower alkyl moiety" and "lower alkyl" mean a linear, branched or cyclic alkyl group, specifically, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl Tert-butyl, 1,1-dimethylethyl, pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl ,
3-methylpentyl, 1,1-dimethylbutyl, 1,2
-Dimethylbutyl, 2,2-dimethylbutyl, 1,3-
Dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl,
Examples thereof include 1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, cyclopropyl, cyclobutyl, cyclopentyl, 2-methylcyclopentyl, and 3-ethylcyclohexyl. Among them, an alkyl group having 1 to 3 carbon atoms is preferable.

Suitable examples of "lower alkenyl moiety" and "lower alkenyl" in "cyano, lower alkoxy, lower alkanoyl or lower alkenyl optionally substituted with carboxy" include vinyl, allyl. , 1-propenyl, 2-propenyl, isopropenyl, 2-methyl-1-propenyl, 1
-Butenyl, 2-butenyl, 3-butenyl, 2-ethyl-1-butenyl, 3-methyl-2-butenyl, 1,3-
Butanedienyl, 1-pentenyl, 2-pentenyl, 3
-Pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl and the like.

"Phenyl, pyridyl, furyl or thienyl optionally having a substituent selected from hydroxyl, lower alkoxy or lower alkyl optionally substituted with acyloxy", "cyano, lower alkoxy, lower alkanoyl or protected Lower alkenyl optionally substituted with carboxy, "hydroxyl, lower alkoxy or lower alkyl optionally substituted with protected carboxy", "optionally substituted with hydroxyl or lower alkoxy "Lower alkylamino" and "lower alkoxycarbonylamino"
In the "lower alkoxy moiety" and "lower alkoxy", methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy, neopentyloxy, tert- Pentyloxy, 1-methylbutoxy, 2-methylbutoxy, 1,
2-dimethylpropoxy, hexyloxy, isohexyloxy, 1-methylpentyloxy, 2-methylpentyloxy, 3-methylpentyloxy, 1-ethylbutoxy, 2-ethylbutoxy, 1,2,2, -trimethylpropoxy, 1-ethyl-1-methylpropoxy, 1
And alkoxy groups such as -ethyl-2-methylpropoxy and methylenedioxy. Among them, an alkoxy group having 1 to 3 carbon atoms is preferable.

"Halogen, cyano, lower alkylthio,
"Lower alkylthio moiety" and "lower alkylthio" in "lower alkyl optionally having substituent (s) selected from lower alkylsulfonyl or phenyl" include methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, sec- Butylthio, tert-butylthio, pentylthio, isopentylthio, neopentylthio, tert-pentylthio, 1-methylbutylthio, 2-methylbutylthio and the like.

"Cyano, lower alkoxy, lower alkanoyl or lower alkenyl optionally substituted with optionally protected carboxy" and "hydroxyl,
Preferred examples of "protected carboxy moiety" and "protected carboxy" in "lower alkyl optionally substituted with lower alkoxy or protected carboxy" include esterified carboxy and the like. . Suitable examples of the “ester moiety” in the “esterified carboxy” include lower alkyl esters (eg, methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester, tert-butyl ester, pentyl ester , Hexyl ester, 1-cyclopropylethyl ester, etc.) [The lower alkyl ester may have at least one suitable substituent (for example,
Lower alkanoyloxy (lower) alkyl esters [e.g., acetoxymethyl ester, propionyloxymethyl ester, butyryloxymethyl ester, isobutyryloxymethyl ester, hexanoyloxymethyl ester, 1 (or 2) -acetoxyethyl ester, (Or 2 or 3) -acetoxypropyl ester, 1 (or 2 or 3 or 4) -acetoxybutyl ester, 1 (or 2) -propionyloxyethyl ester, 1 (or 2 or 3) -propionyloxypropyl ester, 1 (Or 2) -butyryloxyethyl ester, 1 (or 2) -isobutyryloxyethyl ester, 1 (or 2) -hexanoyloxyethyl ester, isobutyryloxymethyl ester, 2-ethyl Styryl oxymethyl ester, 3,
3-dimethylbutyryloxymethyl ester, 1 (or 2) -pentanoyloxyethyl ester, etc.], lower alkanesulfonyl (lower) alkyl ester [eg, 2-mesylethyl ester, etc.], mono (or di or tri or ) Halo (lower) alkyl esters [for example,
2-chloroethyl ester, 2-iodoethyl ester, 2,2,2-trichloroethyl ester, etc.], lower alkoxycarbonyloxy (lower) alkyl ester [for example, methoxycarbonyloxymethyl ester, ethoxycarbonyloxymethyl ester, -Methoxycarbonyloxyethyl ester, 1-ethoxycarbonyloxyethyl ester, 1-isopropoxycarbonyloxyethyl ester, etc.])]; lower alkenyl esters (eg, vinyl esters, allyl esters, etc.); lower alkynyl esters (eg, Ethynyl ester, propynyl ester, etc.); al (lower)
Alkyl esters [eg, mono (or di or tri) phenyl (lower) alkyl esters, etc.] [the ar (lower) alkyl esters may have at least one suitable substituent (eg, benzyl esters,
4-methoxybenzyl ester, 4-nitrobenzyl ester, phenethyl ester, 3,4-dimethoxybenzyl ester, etc.)]; an aryl ester optionally having at least one suitable substituent (e.g., phenyl ester, 4 -Chlorophenyl ester, tolyl ester, tert-butylphenyl ester, xylyl ester, mesityl ester, etc.).

The “lower alkanoyl moiety” and “lower alkanoyl” in “cyano, lower alkoxy, lower alkanoyl or lower alkenyl optionally substituted with optionally protected carboxy” may be substituted or unsubstituted. Examples of good aliphatic saturated carboxylic acid residues include, for example, formyl, acetyl, propionyl, butyryl, isobutyryl, hexanoyl, bromoacetyl, trifluoroacetyl, methoxyacetyl, butoxyacetyl, phenoxyacetyl, Bromomethylphenylacetyl, 4-methoxyphenylacetyl, 1-naphthylacetyl, 3-pyridylacetyl,
3-chloropropionyl, 3-bromopropionyl, 3
-(Methylthio) propionyl, 3-ethoxypropionyl, 3- (3,4-dimethoxyphenyl) propionyl, 3-carboxypropionyl, 3-benzoylpropionyl, 4-chlorobutyryl, 3-acetylbutyryl, succinyl, cyclopentylacetyl, 6- Bromohexanoyl, and the like.

As the “acyl moiety” in “phenyl, pyridyl, furyl or thienyl optionally having a substituent selected from hydroxyl, lower alkoxy or lower alkyl optionally substituted with acyloxy” and “acylamino” Is a residue of an organic acid such as an aliphatic unsaturated carboxylic acid, a carbocyclic carboxylic acid, a heterocyclic carboxylic acid, or a sulfonic acid, in addition to the above-mentioned "lower alkanoyl". , Acryloyl, 2-furylacryloyl, crotonoyl, 3-methylcrotonoyl, cinnamoyl, 4-methoxycinnamoyl, methoxymaleoyl, methoxyfumaroyl, and the like.
-Pentylbenzoyl, p-anisoyl, o-anisoyl, 3,5-bis (trifluoromethyl) benzoyl,
4-bromobenzoyl, 4-butoxybenzoyl, 4-
Chlorobenzoyl, 3-chlorobenzoyl, 4-chloromethylbenzoyl, 4-cyanobenzoyl, 3,4-dichlorobenzoyl, 3,5-dichlorobenzoyl, 2,
4-difluorobenzoyl, 3,4-dimethoxybenzoyl, 4-ethoxybenzoyl, 3-fluorobenzoyl, 4-isopropylbenzoyl, 3- (trifluoromethyl) benzoyl, 3,4,5-trimethoxybenzoyl, 3,4- Dimethylbenzoyl, m-toluoyl,
o-tolu oil, p-tolu oil, 1-naphthoyl, 2
-Naphthoyl, a residue of a carbocyclic carboxylic acid such as 1-bromo-2-naphthoyl, 4-morpholinecarbonyl,
Piperidinecarbonyl, 2-thenoyl, 3-thenoyl,
5-methyl-2-thenoyl, 2-furoyl, 5-bromo-2-furoyl, nicotinoyl, isonicotinoyl, 6
-Methylpicolinoyl, 3-methyl-2-benzo [b]
Examples include residues of heterocyclic carboxylic acids such as furoyl and quinoline-2-carbonyl, and residues of sulfonic acids such as mesyl, tosyl and isopropylsulfonyl. Of these, a residue of an aliphatic carboxylic acid, particularly a residue of an aliphatic saturated carboxylic acid, is preferred.

Suitable examples of "lower alkylideneamino" include ethylideneamino, propylideneamino, butylideneamino, isobutylideneamino, isopropylideneamino, neopentylideneamino, 2-methylbutylideneamino, 2-methylbutylideneamino, Methylpentylideneamino, 3,3-
Dimethylbutylideneamino, 2-ethylbutylideneamino and the like can be mentioned.

Suitable "lower alkylenes" include methylene, ethylene, trimethylene, tetramethylene, pentamethylene or hexamethylene.

Preferred "acid residues" include residues of alkyl and hydrohalic acids [ie, halogens (eg, chlorine, bromine, fluorine or iodine)], (lower) alkyl sulfates (eg, methyl Sulfuric acid, ethyl sulfuric acid,
And the like).

Preferred examples of "Ar" include phenyl,
2-chlorophenyl, 2-fluorophenyl, 4-bromophenyl, 3-chlorophenyl, 4-chlorophenyl, 2,4-dichlorophenyl, 3,4-dichlorophenyl, 4-fluorophenyl, 3-fluorophenyl,
3,4-difluorophenyl, 3-bromo-4-fluorophenyl, 3,4-difluorophenyl, 2,5-difluorophenyl, 2,4,5-trifluorophenyl, o-tolyl, m-tolyl, p- Tolyl, 2-ethylphenyl, 4-ethylphenyl, 4-isopropylphenyl, 3-butylphenyl, 4-tert-butylphenyl, 4-hexylphenyl, 3,4-dimethylphenyl, 2,4-dimethylphenyl, 2- Methyl-3-propylphenyl, 4-ethyl-2-methylphenyl, 2,
4,6-trimethylphenyl, 3-chloro-6-methylphenyl, 3-bromo-6-methylphenyl, 3-fluoro-6-methylphenyl, 4-chloro-2-methylphenyl, 4-bromo-2-methyl Phenyl, 4-fluoro-2-methylphenyl, 4-chloro-3-methylphenyl, 4-bromo-3-methylphenyl, 2-chloro-
5-methylphenyl, 2-bromo-5-methylphenyl, 3-chloro-4-methylphenyl, 3-bromo-4
-Methylphenyl, 2-chloro-4-methylphenyl,
2-bromo-4-methylphenyl, 4-methoxyphenyl, 2-methoxyphenyl, 4-ethoxyphenyl, 2
-Methoxy-6-methylphenyl, 2-fluoro-4-
Methylphenyl, 2- (hydroxymethyl) phenyl,
2- (acetoxymethyl) phenyl, 2- (methoxymethyl) phenyl, 3,4-methylenedioxyphenyl,

2-thienyl, 3-methyl-2-thienyl, 2-methyl-3-thienyl, 2-methyl-5-thienyl, 3-methyl-5-thienyl, 2-ethyl-3-thienyl, 2-propyl -3-thienyl, 2-butyl-5
-Thienyl, 3-isobutyl-5-thienyl, 2,3-
Dimethyl-5-thienyl, 2,5-dimethyl-3-thienyl, 2,3,5-trimethyl-4-thienyl, 2-ethyl-5-methyl-3-thienyl, 2-methyl-3-isopropyl-5 Thienyl, 2-butyl-5-ethyl-
4-thienyl, 2-chloro-5-thienyl, 2-bromo-5-thienyl, 2-chloro-3-methyl-4-thienyl, 5-chloro-2-methyl-3-thienyl, 3-bromo-2- Methyl-5-thienyl, 3-bromo-4-methyl-5-thienyl, 3-methyl-4-thienyl, 3-bromo-4-methyl-2-thienyl,

2-furyl, 2-methyl-3-furyl, 3
-Methyl-2-furyl, 2-methyl-5-furyl, 2-
Butyl-5-methyl-4-furyl, 3-ethyl-5-methyl-2-furyl, 2,3-dimethyl-5-furyl,
2,4-dimethyl-3-furyl, 2,4-dimethyl-5
-Furyl, 2,5-dimethyl-3-furyl, 2-methyl-3-pyridyl, 3-methyl-4-pyridyl, 3-methyl-6-pyridyl, 2,3-dimethyl-4-pyridyl,
2,4-dimethyl-3-pyridyl, 4-methyl-2-pyridyl, 2-methyl-4-pyridyl, 3,4-dimethyl-2-pyridyl, 3,5-dimethyl-2-pyridyl,
2,6-dimethyl-3-pyridyl, 3-methyl-2-pyridyl, 2-methyl-3-pyridyl, 2-chloro-6
Methyl-3-pyridyl and the like.

In a preferred group of the compounds of the invention of the formula (I), R ¹ represents lower alkyl or lower alkenyl. Particularly preferably, it represents lower alkyl or lower alkenyl having 1 to 3 carbon atoms. Another preferred group of the compounds of the present invention of formula (I) is that wherein Ar has a substituent selected from halogen; lower alkoxy; or lower alkyl optionally substituted by hydroxyl, lower alkoxy or acyloxy. Is a compound representing phenyl or thienyl which may be substituted. Particularly preferably, Ar is halogen,
Represents phenyl having one or two substituents selected from lower alkoxy or lower alkyl, or thienyl having one or two substituents selected from halogen or lower alkyl.

Another preferred group of the compounds of the present invention of the formula (I) is that R ² is lower alkyl; lower alkenyl optionally substituted by lower alkoxy;
⁵ [R ⁵ is hydroxyl; lower alkoxy; lower alkyl optionally substituted by hydroxyl, lower alkoxy or protected carboxy]; or -AR
⁶ [A is lower alkylene: R ⁶ is amino; lower alkylamino optionally substituted by hydroxyl or lower alkoxy; acylamino; -XR ⁷ [X is oxygen or sulfur; R ⁷ is hydrogen; lower alkyl; Alkenyl;
Acyl]]. Particularly preferred are lower alkyl, lower alkenyl and lower alkylene of -AR ⁶ having 1 to 3 carbon atoms. Another preferred group of the compounds of the invention of formula (I) is
² is a compound representing amino, acylamino, lower alkylamino or lower alkylideneamino. Formula (I)
Another preferred group of the compounds of the present invention represented by are those in which the dashed line represents a double bond with the solid line.

A preferred group of compounds of the present invention represented by formula (I) are lower alkyl, wherein R ¹ may have a substituent selected from halogen, cyano, lower alkylthio, lower alkylsulfonyl or phenyl; Lower alkenyl, wherein Ar is halogen; lower alkoxy;
Or phenyl or thienyl which may have a substituent selected from lower alkyl which may be substituted with hydroxyl, lower alkoxy or acyloxy,
R ² is hydrogen; lower alkyl; lower alkylthio; lower alkoxy; amino; acylamino; lower alkylamino; lower alkylideneamino; ; -CH
= NR ⁵ [R ⁵ is hydroxyl, lower alkoxy, hydroxyl, lower alkyl which may be substituted with lower alkoxy or protected carboxy; or -A-R
⁶ [A is lower alkylene: R ⁶ is halogen; amino; lower alkylideneamino; lower alkylamino optionally substituted with hydroxyl or lower alkoxy; acylamino; lower alkoxycarbonylamino; protected carboxy; ⁷ [X is oxygen or sulfur: R ⁷ is hydrogen; lower alkyl; lower alkenyl; or acyl], and R ³ is hydrogen or lower alkyl, R ⁴
Is hydrogen, and the dashed line is a compound group that represents a double bond integrally with the solid line.

A particularly preferred group of the compounds of the present invention of the formula (I) is that R ¹ is lower alkyl or lower alkenyl and Ar is 1 or 2 substituents selected from halogen; lower alkoxy; or lower alkyl. 2-phenyl or thienyl, wherein R ² is hydrogen; lower alkyl; amino; acylamino; lower alkylamino; lower alkylideneamino; cyano, lower alkoxy, lower alkanoyl or optionally protected carboxy. Good lower alkenyl; -CH
= NR ⁵ [R ⁵ is hydroxyl, lower alkoxy, hydroxyl, lower alkyl which may be substituted with lower alkoxy or protected carboxy; or -A-R
⁶ [A is lower alkylene: R ⁶ is halogen; amino; alkylideneamino; lower alkylamino optionally substituted by hydroxyl or lower alkoxy; acylamino; lower alkoxycarbonylamino; protected carboxy; or -XR ⁷ [X is oxygen: R ⁷ is hydrogen; lower alkyl; lower alkenyl; or acyl]],
R ³ is hydrogen or methyl, R ⁴ is hydrogen, and the dashed line is a compound group that represents a double bond integrally with the solid line.

A further particularly preferred group of the compounds of the invention of the formula (I) is that R ¹ is lower alkyl or lower alkenyl having 1 to 3 carbon atoms and Ar is halogen;
Lower alkoxy; or phenyl or thienyl having one or two substituents selected from lower alkyl, wherein R ² is lower alkyl having 1 to 3 carbon atoms; amino; acylamino; lower alkylamino; lower alkylideneamino; , Lower alkoxy, lower alkanoyl or lower alkenyl having 1 to 3 carbon atoms which may be substituted by optionally protected carboxy; -CH = NR
⁵ [R ⁵ is hydroxyl; lower alkoxy; lower alkyl optionally substituted by hydroxyl, lower alkoxy or protected carboxy]; or -AR
⁶ [A is lower alkylene having 1 to 3 carbon atoms: R ⁶ is amino;
Alkylideneamino; hydroxyl or lower alkoxy optionally substituted by lower alkyl amino; acylamino; lower alkoxycarbonylamino; protected carboxy; or -X-R ⁷ [X is oxygen: R ⁷ is hydrogen;
Lower alkyl; lower alkenyl; or acyl]], wherein R ³ is hydrogen or methyl, R ⁴ is hydrogen, and the dashed line is a group of compounds which, together with the solid line, represent a double bond.

Among the compounds of the present invention, representative compounds are shown below. For example, 3-acetyl-9-methoxycarbonylamino-2-phenylimidazo [2,1-
a] isoquinoline, 3-ethyl-9-methoxycarbonylamino-2-phenylimidazo [2,1-a] isoquinoline, 3- (2-chloroethyl) -9-methoxycarbonylamino-2-phenylimidazo [2,1- a] isoquinoline, 9-methoxycarbonylamino-3- [2
-(Methylthio) ethyl] -2-phenylimidazo [2,1-a] isoquinoline, 8-chloro-3-formyl-9-methoxycarbonylamino-2-phenylimidazo [2,1-a] isoquinoline, 3-hydroxy Methyl-9-methoxycarbonylamino-2-phenylimidazo [2,1-a] isoquinoline, 3-amino-9-methoxycarbonylamino-2-phenylimidazo [2
1-a] isoquinoline, 9-methoxycarbonylamino-3-methylamino-2-phenylimidazo [2,1-
a] isoquinoline, 2- (2-fluorophenyl) -9
-Methoxycarbonylamino-3-methylimidazo [2,1-a] isoquinoline, 2- (2-fluorophenyl) -3-hydroxymethyl-9- (methoxycarbonylamino) imidazo [2,1-a] isoquinoline,
-Amino-2- (2-fluorophenyl) -9- (methoxycarbonylamino) imidazo [2,1-a] isoquinoline, 2- (3-fluorophenyl) -3-hydroxymethyl-9- (methoxycarbonylamino) Imidazo [2,1-a] isoquinoline, 3-amino-2- (3-
Fluorophenyl) -9- (methoxycarbonylamino) imidazo [2,1-a] isoquinoline, 2- (3-
Fluorophenyl) -9-methoxycarbonylamino-
3- (methylthio) imidazo [2,1-a] isoquinoline, 2- (4-fluorophenyl) -3-hydroxymethyl-9- (methoxycarbonylamino) imidazo [2,1-a] isoquinoline, 3-ethoxymethyl -2
-(4-fluorophenyl) -9- (methoxycarbonylamino) imidazo [2,1-a] isoquinoline, 3-
Acetylamino-2- (4-fluorophenyl) -9-
(Methoxycarbonylamino) imidazo [2,1-a]
Isoquinoline, 2- (4-fluorophenyl) -9-methoxycarbonylamino-3- (methylthio) imidazo [2,1-a] isoquinoline, 3-amino-2- (4-
(Fluorophenyl) -9- (n-propoxycarbonylamino) imidazo [2,1-a] isoquinoline, 3-
(2-aminoethyl) -2- (2-chlorophenyl)-
9- (methoxycarbonylamino) imidazo [2,1-
a] Isoquinoline, 2- (2-chlorophenyl) -3-
Formyl-9- (methoxycarbonylamino) imidazo [2,1-a] isoquinoline,

2- (2-chlorophenyl) -3-hydroxymethyl-9- (methoxycarbonylamino) imidazo [2,1-a] isoquinoline, 2- (2-chlorophenyl) -9-methoxycarbonylamino-3- ( Methoxymethyl) imidazo [2,1-a] isoquinoline, 3-
Acetoxymethyl-2- (2-chlorophenyl) -9-
(Methoxycarbonylamino) imidazo [2,1-a]
Isoquinoline, 3-aminomethyl-2- (2-chlorophenyl) -9- (methoxycarbonylamino) imidazo [2,1-a] isoquinoline, 2- (2-chlorophenyl) -3-ethylamino-9- (methoxycarbonyl Amino) imidazo [2,1-a] isoquinoline, 2- (2
-Chlorophenyl) -9-methoxycarbonylamino-
3- (methylthio) imidazo [2,1-a] isoquinoline, 3-amino-2- (3-chlorophenyl) -9-
(Methoxycarbonylamino) imidazo [2,1-a]
Isoquinoline, 2- (4-chlorophenyl) -9-methoxycarbonylamino-3-methylimidazo [2,1-
a] isoquinoline, 3-amino-2- (4-chlorophenyl) -9- (methoxycarbonylamino) imidazo [2,1-a] isoquinoline, 2- (2-fluoro-4
-Methylphenyl) -3-hydroxymethyl-9- (methoxycarbonylamino) imidazo [2,1-a] isoquinoline, 3-amino-2- (2-fluoro-4-methylphenyl) -9- (methoxycarbonylamino ) Imidazo [2,1-a] isoquinoline, 2- (2-fluoro-4-methoxyphenyl) -3-hydroxymethyl-9
-(Methoxycarbonylamino) imidazo [2,1-
a] isoquinoline, 3-amino-2- (2-fluoro-
4-methoxyphenyl) -9- (methoxycarbonylamino) imidazo [2,1-a] isoquinoline, 3-ethylideneamino-2- (2-fluoro-4-methoxyphenyl) -9- (methoxycarbonylamino) imidazo [ 2,1-a] isoquinoline, 3-ethylamino-2-
(2-fluoro-4-methoxyphenyl) -9- (methoxycarbonylamino) imidazo [2,1-a] isoquinoline, 2- (2-fluoro-4-methoxyphenyl)
-9-methoxycarbonylamino-3- (methylthio)
Imidazo [2,1-a] isoquinoline, 2- (2,4-
Dichlorophenyl) -3-hydroxymethyl-9- (methoxycarbonylamino) imidazo [2,1-a] isoquinoline, 3-amino-2- (2,4-dichlorophenyl) -9- (methoxycarbonylamino) imidazo [2 1-a] isoquinoline, 9-methoxycarbonylamino-2- (2-methylphenyl) imidazo [2,1
-A] isoquinoline, 9-methoxycarbonylamino-
5-methyl-2- (2-methylphenyl) imidazo [2,1-a] isoquinoline, 9-methoxycarbonylamino-7-methyl-2- (2-methylphenyl) imidazo [2,1-a] isoquinoline,

7,9-bis (methoxycarbonylamino) -2- (2-methylphenyl) imidazo [2,1-
a] isoquinoline, 9-methoxycarbonylamino-2
-(2-methylphenyl) -3- (vinyl) imidazo [2,1-a] isoquinoline, 9-methoxycarbonylamino-2- (2-methylphenyl) imidazo [2,1
-A] isoquinoline-3-aldoxime, 3- (2-cyanovinyl) -9-methoxycarbonylamino-2-
(2-methylphenyl) imidazo [2,1-a] isoquinoline, 9-methoxycarbonylamino-2- (2-methylphenyl) -3-[(methylthio) methyl] imidazo [2,1-a] isoquinoline, 9 -Methoxycarbonylamino-2- (2-methylphenyl) -3- (1-propenyl) imidazo [2,1-a] isoquinoline, [9
-Methoxycarbonylamino-2- (2-methylphenyl) imidazo [2,1-a] isoquinolin-3-yl]
-O-methylaldoxime, 9-methoxycarbonylamino-3- (2-methoxyvinyl) -2- (2-methylphenyl) imidazo [2,1-a] isoquinoline, 3-
Ethoxycarbonyl-9-methoxycarbonylamino-
2- (2-methylphenyl) imidazo [2,1-a] isoquinoline, 3- (2-acetylvinyl) -9-methoxycarbonylamino-2- (2-methylphenyl) imidazo [2,1-a] isoquinoline N-[(9-methoxycarbonylamino-2- (2-methylphenyl) imidazo [2,1-a] isoquinolin-3-yl) methylidene] -n-propylamine, N-[(9-methoxycarbonylamino -2- (2-Methylphenyl) imidazo [2,1-a] isoquinolin-3-yl) methylidene]
Glycine methyl ester, N-[(9-methoxycarbonylamino-2- (2-methylphenyl) imidazo [2,1-a] isoquinolin-3-yl) methylidene]
2-methoxyethylamine, 9-methoxycarbonylamino-3- (2-methoxyethyl) -2- (2-methylphenyl) imidazo [2,1-a] isoquinoline, 3
-[2- (acetylamino) ethyl] -9-methoxycarbonylamino-2- (2-methylphenyl) imidazo [2,1-a] isoquinoline, 3-hydroxymethyl-
9-methoxycarbonylamino-2- (2-methylphenyl) imidazo [2,1-a] isoquinoline, 3-hydroxymethyl-9-methoxycarbonylamino-5-methyl-2- (2-methylphenyl) imidazo [2 , 1-
a] isoquinoline, 9-methoxycarbonylamino-3
-Methoxymethyl-2- (2-methylphenyl) imidazo [2,1-a] isoquinoline, 3-acetoxymethyl-9-methoxycarbonylamino-5-methyl-2-
(2-methylphenyl) imidazo [2,1-a] isoquinoline, 3-allyloxymethyl-9-methoxycarbonylamino-2- (2-methylphenyl) imidazo [2,1-a] isoquinoline,

3-aminomethyl-9-methoxycarbonylamino-2- (2-methylphenyl) imidazo [2
1-a] isoquinoline, 3-ethylideneaminomethyl-
9-methoxycarbonylamino-2- (2-methylphenyl) imidazo [2,1-a] isoquinoline, 3-ethylaminomethyl-9-methoxycarbonylamino-2-
(2-methylphenyl) imidazo [2,1-a] isoquinoline, 9-methoxycarbonylamino-3- (methoxycarbonylamino) methyl-2- (2-methylphenyl) imidazo [2,1-a] isoquinoline, 9 -Methoxycarbonylamino-2- (2-methylphenyl) -3
-(Methylsulfonylaminomethyl) imidazo [2,1
-A] isoquinoline, 9-methoxycarbonylamino-
3- (2-methoxyethyl) aminomethyl-2- (2-
Methylphenyl) imidazo [2,1-a] isoquinoline, 9-methoxycarbonylamino-2- (2-methylphenyl) -3- (nitroso) imidazo [2,1-a]
Isoquinoline, 3-amino-9-methoxycarbonylamino-2- (2-methylphenyl) imidazo [2,1-
a] isoquinoline, 3-amino-9-methoxycarbonylamino-5-methyl-2- (2-methylphenyl) imidazo [2,1-a] isoquinoline, 3-amino-9-
Methoxycarbonylamino-8-methyl-2- (2-methylphenyl) imidazo [2,1-a] isoquinoline,
3-amino-8-chloro-9-methoxycarbonylamino-2- (2-methylphenyl) imidazo [2,1-
a] isoquinoline, 3-amino-8-methoxy-9-methoxycarbonylamino-2- (2-methylphenyl)
Imidazo [2,1-a] isoquinoline, 8-chloro-3
-Ethylideneamino-9-methoxycarbonylamino-
2- (2-methylphenyl) imidazo [2,1-a] isoquinoline, 3-ethylideneamino-8-methoxy-9
-Methoxycarbonylamino-2- (2-methylphenyl) imidazo [2,1-a] isoquinoline, 9-methoxycarbonylamino-2- (2-methylphenyl) -3
-(N-propylideneamino) imidazo [2,1-a]
Isoquinoline, 3-ethylamino-9-methoxycarbonylamino-2- (2-methylphenyl) imidazo [2,1-a] isoquinoline, 9-methoxycarbonylamino-2- (2-methylphenyl) -3- (n -Propylamino) imidazo [2,1-a] isoquinoline, 9
-Methoxycarbonylamino-5-methyl-2- (2-
Methylphenyl) -3- (methylthio) imidazo [2
1-a] isoquinoline, 3- (ethylthio) -9-methoxycarbonylamino-2- (2-methylphenyl) imidazo [2,1-a] isoquinoline, 9-ethoxycarbonylamino-2- (2-methylphenyl) Imidazo [2,1-a] isoquinoline,

2- (2-methylphenyl) -9- [2-
(Methylsulfonyl) ethoxycarbonylamino] imidazo [2,1-a] isoquinoline, 2- (2-methylphenyl) -9- [2- (methylthio) ethoxycarbonylamino] imidazo [2,1-a] isoquinoline, 3 −
Ethylideneamino-2- (2-methylphenyl) -9-
(N-propoxycarbonylamino) imidazo [2,1
-A] isoquinoline, 9- (1,1-dimethyl-2-cyanoethoxy) carbonylamino-2- (2-methylphenyl) imidazo [2,1-a] isoquinoline, 9-allyloxycarbonylamino-2- ( 2-methylphenyl) imidazo [2,1-a] isoquinoline, 3-amino-9-methoxycarbonylamino-2- (3-methylphenyl) imidazo [2,1-a] isoquinoline, 3-amino-9-methoxy Carbonylamino-2- (4-methylphenyl) imidazo [2,1-a] isoquinoline, 2
-(2-ethylphenyl) -3-hydroxymethyl-9
-(Methoxycarbonylamino) imidazo [2,1-
a] isoquinoline, 3-amino-2- (2-ethylphenyl) -9- (methoxycarbonylamino) imidazo [2,1-a] isoquinoline, 9-methoxycarbonylamino-2- [2- (methoxymethyl) phenyl ] Imidazo [2,1-a] isoquinoline, 3-amino-9-methoxycarbonylamino-2- [2- (methoxymethyl) phenyl] imidazo [2,1-a] isoquinoline,
3-hydroxymethyl-9-methoxycarbonylamino-2- [2- (methoxymethyl) phenyl] imidazo [2,1-a] isoquinoline, 9-methoxycarbonylamino-3-methoxymethyl-2- [2- (methoxy Methyl) phenyl] imidazo [2,1-a] isoquinoline, 2- [2- (acetoxymethyl) phenyl] -3-
Amino-9- (methoxycarbonylamino) imidazo [2,1-a] isoquinoline, 2- [2- (acetoxymethyl) phenyl] -3-ethylamino-9- (methoxycarbonylamino) imidazo [2,1-a Isoquinoline, 3-amino-2- [2- (hydroxymethyl) phenyl] -9- (methoxycarbonylamino) imidazo [2,1-a] isoquinoline, 3-ethylamino-2-
[2- (Hydroxymethyl) phenyl] -9- (methoxycarbonylamino) imidazo [2,1-a] isoquinoline, 3-amino-2- (2,4-dimethylphenyl)
-9- (methoxycarbonylamino) imidazo [2,1
-A] isoquinoline, 3-ethylamino-2- (2,4
-Dimethylphenyl) -9- (methoxycarbonylamino) imidazo [2,1-a] isoquinoline, 3-amino-9-methoxycarbonylamino-2- (2,4,6-
Trimethylphenyl) imidazo [2,1-a] isoquinoline, 2- (4-chloro-2-methylphenyl) -3-
Hydroxymethyl-9- (methoxycarbonylamino)
Imidazo [2,1-a] isoquinoline, 2- (4-chloro-2-methylphenyl) -9-methoxycarbonylamino-3- (methoxymethyl) imidazo [2,1-a]
Isoquinoline, 3-amino-2- (4-chloro-2-methylphenyl) -9- (methoxycarbonylamino) imidazo [2,1-a] isoquinoline,

2- (4-chloro-2-methylphenyl)
-9-methoxycarbonylamino-3- (methylthio)
Imidazo [2,1-a] isoquinoline, 2- (4-fluoro-2-methylphenyl) -9- (methoxycarbonylamino) imidazo [2,1-a] isoquinoline, 3-
[2- (4-fluoro-2-methylphenyl) -9-
(Methoxycarbonylamino) imidazo [2,1-a]
Isoquinolin-3-yl] ethyl acrylate, 3- (2
-Aminoethyl) -2- (4-fluoro-2-methylphenyl) -9- (methoxycarbonylamino) imidazo [2,1-a] isoquinoline, 2- (4-fluoro-2
-Methylphenyl) -3-hydroxymethyl-9- (methoxycarbonylamino) imidazo [2,1-a] isoquinoline, 8-chloro-2- (4-fluoro-2-methylphenyl) -3-hydroxymethyl-9 -(Methoxycarbonylamino) imidazo [2,1-a] isoquinoline, 2- (4-fluoro-2-methylphenyl) -3-
Hydroxymethyl-8-methoxy-9- (methoxycarbonylamino) imidazo [2,1-a] isoquinoline,
2- (4-fluoro-2-methylphenyl) -9-methoxycarbonylamino-3- (methoxymethyl) imidazo [2,1-a] isoquinoline, 3-aminomethyl-2
-(4-Fluoro-2-methylphenyl) -9- (methoxycarbonylamino) imidazo [2,1-a] isoquinoline, 3-ethylaminomethyl-2- (4-fluoro-2-methylphenyl) -9- (Methoxycarbonylamino) imidazo [2,1-a] isoquinoline, 3-amino-2- (4-fluoro-2-methylphenyl) -9-
(Methoxycarbonylamino) imidazo [2,1-a]
Isoquinoline, 3-ethylideneamino-2- (4-fluoro-2-methylphenyl) -9-methoxycarbonylamino-5-methylimidazo [2,1-a] isoquinoline, 3-ethylamino-2- (4-fluoro -2-methylphenyl) -9- (methoxycarbonylamino) imidazo [2,1-a] isoquinoline, 2- (4-fluoro-2-methylphenyl) -9- (n-propoxycarbonylamino) imidazo [2 1-a] isoquinoline, 3
-Amino-2- (4-fluoro-2-methylphenyl)
-9- (n-propoxycarbonylamino) imidazo [2,1-a] isoquinoline, 3-hydroxymethyl-
9-methoxycarbonylamino-2- (2-methoxyphenyl) imidazo [2,1-a] isoquinoline, 9-methoxycarbonylamino-2- (2-methoxyphenyl) -3- (methylamino) imidazo [2,1 -A] isoquinoline, 9-methoxycarbonylamino-2- (4
-Methoxyphenyl) -3-methylimidazo [2,1-
a] isoquinoline, 3-amino-9-methoxycarbonylamino-2- (4-methoxyphenyl) imidazo [2,1-a] isoquinoline, 2- (4-ethoxyphenyl) -3-hydroxymethyl-9- (methoxy Carbonylamino) imidazo [2,1-a] isoquinoline,

3-amino-9-methoxycarbonylamino-2- (3,4-methylenedioxyphenyl) imidazo [2,1-a] isoquinoline, 3-ethylamino-9
-Methoxycarbonylamino-2- (3,4-methylenedioxyphenyl) imidazo [2,1-a] isoquinoline, 3-formyl-9-methoxycarbonylamino-2
-(3-methyl-2-pyridyl) imidazo [2,1-
a] isoquinoline, 9-methoxycarbonylamino-2
-(3-methyl-2-pyridyl) -3- (methylthio)
Imidazo [2,1-a] isoquinoline, 3-hydroxymethyl-9-methoxycarbonylamino-2- (3-methyl-2-furyl) imidazo [2,1-a] isoquinoline, 3-amino-9-methoxycarbonyl Amino-2-
(3-methyl-2-furyl) imidazo [2,1-a] isoquinoline, 9-methoxycarbonylamino-2- (3
-Methyl-2-furyl) -3- (methylthio) imidazo [2,1-a] isoquinoline, 2- (2,5-dimethyl-3-furyl) -9- (methoxycarbonylamino)-
3-methylimidazo [2,1-a] isoquinoline, 3-
Amino-2- (2,5-dimethyl-3-furyl) -9-
(Methoxycarbonylamino) imidazo [2,1-a]
Isoquinoline, 3- [9-methoxycarbonylamino-
2- (2-methyl-3-thienyl) imidazo [2,1-
a] Isoquinolin-3-yl] ethyl acrylate, 3-
Aminomethyl-9-methoxycarbonylamino-2-
(2-methyl-3-thienyl) imidazo [2,1-a]
Isoquinoline, 3-amino-8-methoxy-9- (methoxycarbonylamino) -2- (2-methyl-3-thienyl) imidazo [2,1-a] isoquinoline, 9-methoxycarbonylamino-2- (2- Methyl-3-thienyl) -3- (methylthio) imidazo [2,1-a] isoquinoline, 3-ethylideneamino-9-methoxycarbonylamino-2- (3-methyl-2-thienyl) imidazo [2,1- a] isoquinoline, 3-ethylamino-9
-Methoxycarbonylamino-2- (3-methyl-2-
Thienyl) imidazo [2,1-a] isoquinoline, 2-
(2,5-dimethyl-3-thienyl) -3-hydroxymethyl-9- (methoxycarbonylamino) imidazo [2,1-a] isoquinoline, 3-amino-2- (2
5-dimethyl-3-thienyl) -9- (methoxycarbonylamino) imidazo [2,1-a] isoquinoline,
-Ethylamino-2- (2,5-dimethyl-3-thienyl) -9- (methoxycarbonylamino) imidazo [2,1-a] isoquinoline, 2- (2,5-dimethyl-3-thienyl) -9 -Methoxycarbonylamino-3
-(Methylthio) imidazo [2,1-a] isoquinoline, 2- (5-chloro-2-methyl-3-thienyl)-
3-hydroxymethyl-9- (methoxycarbonylamino) imidazo [2,1-a] isoquinoline,

3-amino-2- (5-chloro-2-methyl-3-thienyl) -9- (methoxycarbonylamino) imidazo [2,1-a] isoquinoline, 3-amino-9-methoxycarbonylamino- 2- (2-methylphenyl) -5,6-dihydroimidazo [2,1-a] isoquinoline, 2- (4-fluoro-2-methylphenyl) -3-hydroxymethyl-9-methoxycarbonylamino-5 6-dihydroimidazo [2,1-a] isoquinoline, 3-amino-9-methoxycarbonylamino-2- (2-methyl-3-thienyl) -5,6-dihydroimidazo [2,1-a] isoquinoline, 9-methoxycarbonylamino-2- (2-methyl-3-thienyl)
-3- (methylthio) -5,6-dihydroimidazo [2,1-a] isoquinoline, and the like.

As the pharmaceutically acceptable salt of the compound (I) of the present invention, any salt generally used in medicine can be used, and examples thereof include alkali metals such as sodium and potassium, magnesium, and the like. Salts with inorganic bases such as alkaline earth metals such as calcium, salts with organic bases such as ethylamine, propylamine, diethylamine, triethylamine, morpholine, pyridine, piperidine, N-ethylpiperidine, diethanolamine, cyclohexylamine, lysine; Salts with basic amino acids such as ornithine, ammonium salts, mineral salts such as hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, acetic acid, oxalic acid, succinic acid, citric acid, maleic acid, malic acid, fumaric acid, Salts with organic acids such as tartaric acid, picric acid, methanesulfonic acid and ethanesulfonic acid, glutamic acid Salts with acidic amino acids such as aspartic acid. Further, the compound (I) of the present invention or a pharmaceutically acceptable salt thereof may be isolated as a solvate such as water or ethanol or a polymorphic substance, and the present invention also includes these. . The compound (I) of the present invention includes all stereoisomers, optical isomers, geometric isomers and the like.

Although various methods for producing the compound of the present invention are conceivable, typical methods are shown below. The compound of the present invention can be produced by a method generally known for producing a compound having a similar structure. A typical method consists of the following reactions. (Production method 1)

Embedded image [Wherein Ar, R ¹ , R ³ and R ⁴ are the same as above; Z means halogen; R ¹¹ means hydrogen, optionally substituted lower alkyl or protected carboxy and the like. 1-Amino-7-nitroisoquinolines represented by the formula (II) can be prepared by a known method (for example, EP 0143001).
) Or a method analogous thereto, and can be produced from phenethylamine and β- (or α-) methylphenethylamine. Further, o- (or m-) xylyl cyanide, 2-chloro (or 3-chloro) benzyl cyanide or 2-methoxy (or 3-methoxy) benzyl cyanide is reduced, and the resulting phenethylamine derivative is used as a raw material. can do. Further, the compound can be produced from a dinitro compound obtained by nitrating tetrahydroisoquinoline. Further, 2-halogenoethanones represented by the formula (III) can be prepared by a known method (for example,
JP-A-61-152677, Journal of
Medicinal Chemistry (J.Med.Chem.), 37
Vol. 57, 1994) or a method analogous thereto. Compound (IV) or a salt thereof,
It can be produced by reacting compound (II) or a salt thereof with compound (III) under standard reaction conditions known for producing similar compounds. For example, heating in alcohol in the presence of an inorganic or organic base.
Compound (V) or a salt thereof can be produced by subjecting compound (IV) or a salt thereof to a standard reduction reaction. For example, reduction with hydrogen in the presence of a palladium catalyst. The reaction is usually performed at room temperature. Further, the compound (V) in which the broken line portion represents a single bond integrally with the solid line is obtained by heating the compound (IV) or a salt thereof under an acidic condition using a palladium catalyst. Compound (Ia)
Alternatively, a salt thereof can be produced by reacting compound (V) or a salt thereof with chlorocarbonate (VI). The reaction is usually performed in the presence of a base.

(Production method 2)

Embedded image Wherein, Ar, R ^1, R ³ and R ⁴ are as defined above; R ¹²
Represents cyano, lower alkoxy, lower alkanoyl or lower alkenyl optionally substituted by optionally protected carboxy; R ¹³ represents cyano, lower alkyl, —CH ＝ NR ⁵ or —A—R ⁶ I do. -CH
= NR ⁵ and -A-R ⁶ is as defined above. Compound (Ib) or a salt thereof is compound (Ia ′) (R ¹¹
(Ia)) or a salt thereof is subjected to a nitrosation reaction (first step), followed by a reduction reaction (second step)
Can be produced. (1) First step: This reaction can be performed under standard conditions. For example, the reaction can be carried out by reacting with a nitrite (eg, isopentyl nitrite or the like) in a solvent that does not adversely affect the reaction. (2) Second step: This reduction reaction can be performed by a standard method. For example, catalytic reduction using palladium / carbon, platinum oxide or the like as a catalyst or reduction using a combination of a metal such as titanium, iron or zinc and an inorganic or organic acid such as hydrochloric acid, acetic acid or propionic acid can be mentioned.

Compound (Ic) or a salt thereof can be produced by subjecting compound (Ia ') or a salt thereof to a formylation reaction. This formylation can be carried out by a conventional method, for example, using compound (Ia ') or a salt thereof with Vilsmeier (Vi
lsmeier) reagent (prepared by reaction of N, N-dimethylformamide with phosphorus oxychloride or the like) (first step), and then hydrolyzes the resulting compound (second step)
It can be done by doing. (1) First step: This reaction can be usually performed in a solvent such as N, N-dimethylformamide, tetrahydrofuran, diethyl ether or other solvents that do not adversely influence the reaction. The reaction temperature is not particularly limited, and the reaction is usually performed with heating or heating. (2) Second step: The hydrolysis can be performed by a conventional method.

The compound (Id) or a salt thereof can be produced by subjecting the compound (Ia ') or a salt thereof to a desired di (lower) alkylamine by a Mannich reaction. This reaction is usually performed in the presence of a conventional acid. Suitable acids include organic acids (eg, formic acid, acetic acid, propionic acid, trifluoroacetic acid, etc.) and inorganic acids (eg, hydrochloric acid, hydrobromic acid, etc.). This reaction can be usually performed in a solvent such as methylene chloride, N, N-dimethylformamide, or other solvents that do not adversely influence the reaction. Liquid acids can also be used as solvents.

Compound (Ie) or a salt thereof can be prepared by a conventional method using compound (Ic) or a salt thereof and a phosphorane prepared by base treatment of an organic phosphonium salt such as an alkyltriphenylphosphonium salt or a β-carbonylphosphonium salt. It can be produced by the Wittig reaction or a modification thereof.

Compound (Ic), compound (Id), compound (Ie) or compound (If) having a suitable substituent is used as a starting material for the compound represented by the formula (If) or a salt thereof. It is produced by conversion in a manner well known to those skilled in the art. Preferred examples of these are shown below.

[Table 1]

(Production method 3)

Embedded image Wherein, Ar, R ^1, R ³ and R ⁴ are as defined above; R ¹⁴
Represents lower alkyl; R ¹⁵ represents lower alkylthio and acylamino; R ¹⁶ represents lower alkyl. Compound (Ig) or a salt thereof can be produced by subjecting compound (Ib) or a salt thereof and a desired aldehyde (VII) to a dehydration condensation reaction. This reaction can be performed under well-known standard conditions.

Compound (Ih) or a salt thereof can be obtained from compound (Ib) or a salt thereof according to a standard substitution reaction carried out via a diazonium salt. Also,
The compound represented by the formula (Ih) or a salt thereof can also be produced by using a compound (Ih) having an appropriate substituent as a raw material and partially converting the compound by an appropriate means. Compound (Ih) or a salt thereof can be produced by subjecting compound (Ib) or a salt thereof to a standard acylation reaction. As the acylating agent used in this reaction,
The desired carboxylic acid or carboxylic anhydride or acyl halide or a combination thereof with a suitable condensing agent may be mentioned.

Compound (Ii) or a salt thereof can be produced by subjecting compound (Ig) or a salt thereof to a reduction reaction. These reduction reactions can be performed under standard conditions. For example, reduction with a metal hydride complex compound (eg, sodium borohydride, etc.) or catalytic reduction using a catalyst (eg, palladium / carbon, platinum oxide, etc.) can be mentioned.

In order to obtain the compound of the present invention, the order of a specific reaction can be appropriately changed.

Compounds (Ia) to (Ii), compound (II),
Suitable salts of compound (IV) and compound (V) include acid addition salts as exemplified for compound (I).

When it is desired to obtain a salt of compound (I), if compound (I) is obtained in the form of a salt, it may be purified as it is. The salt may be dissolved or suspended in an organic solvent, and an acid may be added to form a salt. The compound (I) and a pharmaceutically acceptable salt thereof may be present in the form of adducts with water or various solvents, and these adducts are also included in the present invention. Intermediates and target compounds in the above-mentioned production methods are isolated and purified by appropriately using purification methods commonly used in organic synthetic chemistry, for example, filtration, extraction, washing, concentration, drying, recrystallization, and various types of chromatography. Can be. In addition, the intermediate can be subjected to the next reaction without purification.

Hereinafter, the present invention will be described in detail with reference to Examples.
The present invention is not limited to these. In the examples, IR indicates an infrared absorption spectrum, and the unit is cm ^-1 and the measurement method is shown in parentheses. NMR represents a proton nuclear magnetic resonance spectrum, the unit is ppm, and the solvent in the parentheses is represented by the following abbreviation. CDCL chloroform-d DMSO dimethylsulfoxide-d ₆ METH methanol-d _{4 In} the tables of the examples, when the broken line of the formula (I) is integrated with the solid line to represent a double bond, the column 5-6 is used. "2" and "1" when representing a single bond.

Example 1 9-methoxycarbonylamino-2- (2-methylphen
Nyl) imidazo [2,1-a] isoquinoline 1-amino-7-nitroisoquinoline (10 g), 2-
Bromo-2'-methylacetophenone (13.5 g),
Sodium bicarbonate (13.3 g) and ethanol (12
(0 mL) is heated at reflux for 15 hours. After cooling, the reaction solution was poured into water, and the precipitated crystals were collected by filtration, washed with water and dried to give 9-nitro-2- (2-methylphenyl) imidazo [2,1-a] isoquinoline (10.6 g) as a yellow powder. obtain. A solution of 9-nitro-2- (2-methylphenyl) imidazo [2,1-a] isoquinoline (10.6 g) in ethanol (120 mL) was treated with 10% palladium on carbon (1.0%).
g) and hydrogenate with stirring at room temperature. After stirring for 13 hours, the catalyst was filtered off and the solvent was distilled off under reduced pressure to give 9 as yellow powder.
-Amino-2- (2-methylphenyl) imidazo [2,
1-a] Isoquinoline (9.5 g) is obtained. 9-amino-2- (2-methylphenyl) imidazo [2,1-a] isoquinoline (9.5) was added to a solution of sodium hydride (3 g, 60% in oil.) In tetrahydrofuran (300 mL).
g) A solution of tetrahydrofuran (100 mL) is added dropwise. After 20 minutes, methyl chlorocarbonate (2.9 mL) is added dropwise. After completion of the dropwise addition, the mixture is stirred at room temperature for 2 hours. The reaction solution is poured into ice water and extracted with chloroform. The organic layer is washed successively with water and brine and dried over anhydrous magnesium sulfate. The drying agent was removed by filtration, the solvent was distilled off under reduced pressure, and the residue obtained was purified by silica gel column chromatography, and then recrystallized from ethyl acetate to give the title compound 1 as pale yellow columnar crystals.
(6.9 g) are obtained. Melting point: 157.0-158.0 ° C IR (KBr): 3260, 2950, 1720, 1620, 1580, 1522, 1240, 1225, 1
068,730 NMR (CDCL): 8.43 (1H, d, J = 2.0Hz), 8.12-7.82 (1H, m), 7.9
9 (1H, dd, J = 2.0Hz, 8.4Hz), 7.82 (1H, d, J = 7.6Hz), 7.63 (1
H, s), 7.62 (1H, d, J = 8.4Hz), 7.44-7.20 (4H, m), 6.94 (1H, d,
J = 7.6Hz), 3.80 (3H, s), 2.70 (1H, brs), 2.58 (3H, s)

Example 2 The compounds of Table 1 are obtained by substituting the corresponding chlorocarbonate for the methyl chlorocarbonate of Example 1.

[Table 2]

Example 3 By substituting 2-bromo-2'-methylacetophenone of Example 1 with the corresponding 2-halogenoethanone, the compounds in Table 2 are obtained.

[Table 3]

Example 4 9-methoxycarbonylamino-2- (2-methylphen
Nyl) -5,6-dihydroimidazo [2,1-a] iso
Quinoline 9-nitro-2- (2-methylphenyl) imidazo [2,1-a] isoquinoline (3.0 g) in acetic acid (50 g).
Sodium acetate (2.5 g) and 10% palladium on carbon (0.3 g) were added to the solution and hydrogenated at 70 ° C. with stirring. After stirring for 19 hours, the catalyst is filtered off, and the solvent is distilled off under reduced pressure. Ethanol (60 mL) and a 2N aqueous sodium hydroxide solution (40 mL) are added to the residue, and the mixture is refluxed for 5 hours. After cooling, pour into water and extract with chloroform. The organic layer is washed successively with water and brine and dried over anhydrous magnesium sulfate. The drying agent was separated by filtration, and the solvent was distilled off under reduced pressure to obtain 9-amino-2- (2-methylphenyl) -5, a yellow powder.
6-Dihydroimidazo [2,1-a] isoquinoline (2.7 g) is obtained. Sodium hydride (1g, 60% i
n oil.) in tetrahydrofuran (30 mL) solution
-Amino-2- (2-methylphenyl) -5,6-dihydroimidazo [2,1-a] isoquinoline (2.7 g)
Of tetrahydrofuran (30 mL) is added dropwise. 3
After 0 min, methyl chlorocarbonate (1.5 mL) is added dropwise.
After the addition, the mixture is stirred at 60 ° C. for 2 hours. After cooling, the reaction solution is poured into ice water and extracted with ethyl acetate. The organic layer is washed with water and dried over anhydrous magnesium sulfate. The desiccant was filtered off, the solvent was distilled off under reduced pressure, and the residue obtained was purified by silica gel column chromatography, and then recrystallized from ethyl acetate-diisopropyl ether to give the title compound 4 as a pale yellowish white powder. 2.9 g) are obtained. Melting point: 156.0-157.0 ° C IR (KBr): 3260,3060,2950,1730,1622,1598,1553,1527,1
230,1070,736 NMR (CDCL): 8.01-7.80 (1H, m), 7.84 (1H, d, J = 2.0Hz), 7.6
6 (1H, dd, J = 2.0Hz, 8.2Hz), 7.32-7.19 (3H, m), 7.11-6.94 (2
H, m), 4.16 (2H, t, J = 7.0Hz), 3.75 (3H, s), 3.09 (2H, t, J = 7.0Hz)
Hz), 2.50 (3H, s)

Example 5 A yellow powder was synthesized according to the method of Example 1 except that 1-amino-7-nitro-5-methylisoquinoline was used in place of 1-amino-7-nitroisoquinoline of Example 1. 9-methoxycarbonylamino-7-methyl-2-
(2-Methylphenyl) imidazo [2,1-a] isoquinoline (compound 5a) is obtained. Melting point: 191.5-192.5 ° C IR (KBr): 3220, 2960, 1701, 1615, 1074, 770, 741 NMR (DMSO): 9.99 (1H, s), 8.67 (1H, d, J = 2.0 Hz), 8.29 (1H, d,
J = 7.0Hz), 8.19 (1H, s), 8.16-7.92 (1H, m), 7.59 (1H, d, J = 2.
0Hz), 7.31 (3H, brs), 7.23 (1H, d, J = 7.0Hz), 3.76 (3H, s), 2.
58 (6H, s) The compounds shown in Table 3 are obtained in the same manner as in Example 5 and Examples 1-4.

[Table 4]

[Table 5]

Example 6 3-amino-9-methoxycarbonylamino-2- (2
-Methylphenyl) -5,6-dihydroimidazo [2,
1-a] isoquinoline hydrochloride 9-methoxycarbonylamino-2- (2-methylphenyl) -5,6-dihydroimidazo [2,1-a] isoquinoline (1.0 g) in dioxane (12 mL) at 80 ° C. And stir. Then, isopentyl nitrite (1.2 mL) is added dropwise and stirred for 30 minutes under the same conditions. After cooling, the precipitated precipitate was collected by filtration, washed with ethanol, and green powdered 3-nitroso-9-methoxycarbonylamino-2-
(2-Methylphenyl) -5,6-dihydroimidazo [2,1-a] isoquinoline (0.4 g) is obtained. 3-
Nitroso-9-methoxycarbonylamino-2- (2-
Methylphenyl) -5,6-dihydroimidazo [2,1
-A] isoquinoline (0.4 g) in ethanol (25 m
L) 10% palladium on carbon (0.1 g) is added to the suspension and hydrogenated at room temperature with stirring. After stirring for 1 hour, the catalyst was filtered off and the solvent was distilled off under reduced pressure. The residue obtained was purified by silica gel column chromatography to give a brown amorphous solid, 3-amino-9-methoxycarbonylamino-2-yl.
(2-Methylphenyl) -5,6-dihydroimidazo [2,1-a] isoquinoline (0.3 g) is obtained. 3-
Amino-9-methoxycarbonylamino-2- (2-methylphenyl) -5,6-dihydroimidazo [2,1-
a] Isoquinoline (0.3 g) was dissolved in ethyl acetate-ether (18 mL), ether saturated with hydrogen chloride gas was added, and the resulting precipitate was collected by filtration and recrystallized from ethanol-ether to give an orange-yellow powder. Compound 6 (0.1
g). Melting point: 175.0-178.0 ° C IR (KBr): 3400,3050,2950,2840-2640,1724,1650,1621,1
602,1540,1234,1068,760 NMR (DMSO): 9.98 (1H, s), 8.29 (1H, d, J = 1.0Hz), 7.39 (6H,
s), 4.29 (2H, t, J = 7.0Hz), 3.70 (3H, s), 3.32-3.01 (2H, m),
2.35 (3H, s)

Example 7 3-amino-9-methoxycarbonylamino-2- (2
-Methyl-3-thienyl) imidazo [2,1-a] iso
Quinoline 9-methoxycarbonylamino-2- (2-methyl-3
A solution of -thienyl) imidazo [2,1-a] isoquinoline (1.6 g) in dioxane (30 mL) is heated and stirred at 80 ° C. Then, isopentyl nitrite (1.9m
L) is added dropwise and stirred under the same conditions for 15 minutes. After cooling, the precipitated precipitate was collected by filtration, washed with ether, and brown powdered 3-nitroso-9-methoxycarbonylamino-2- (2-methyl-3-thienyl) imidazo [2,1-a] isoquinoline (1. 7g, melting point: 245.0-249.0 ° C (decomposition)).
3-nitroso-9-methoxycarbonylamino-2-
(2-methyl-3-thienyl) imidazo [2,1-a]
10% palladium on carbon (0.2 g) is added to a suspension of isoquinoline (1.7 g) in ethanol (40 mL) and hydrogenated at room temperature with stirring. After stirring for 15 hours, the catalyst was filtered off and the solvent was distilled off under reduced pressure. The residue obtained was purified by silica gel column chromatography, and then recrystallized from methanol to give the title compound 7 (1. 0 g). Melting point: 109.0-111.0 ° C IR (KBr): 3410,3325,2960,1711,1620,1585,1524,1240,1
070 NMR (CDCL): 8.35 (1H, brs), 8.14 (1H, brd, J = 2.0Hz), 7.99
(1H, dd, J = 2.0Hz, 8.5Hz), 7.62 (1H, d, J = 7.0Hz), 7.50 (1H,
d, J = 8.5Hz), 7.30-7.05 (2H, m), 6.86 (1H, d, J = 7.0Hz), 3.75
(3H, s), 3.58 (2H, brs), 2.57 (3H, s)

Example 8 9-methoxycarbonylamino-2- (2-
Methylphenyl) -5,6-dihydroimidazo "2.1
-A "Instead of isoquinoline or 9-methoxycarbonylamino-2- (2-methyl-3-thienyl) imidazo [2,1-a] isoquinoline of Example 7, the corresponding (5,6-dihydro) imidazo [ The compounds shown in Table 4 are obtained by performing a nitrosation reaction and a reduction reaction using [2,1-a] isoquinoline.

[Table 6]

[Table 7]

Example 9 3-acetylamino-9-methoxycarbonylamino-
2- (2-methylphenyl) imidazo [2,1-a] i
Soquinoline 3-amino-9-methoxycarbonylamino-2- (2
Acetic anhydride (10 mL) is added to a suspension of (-methylphenyl) imidazo [2,1-a] isoquinoline (5.0 g) in methanol (100 mL), and the mixture is stirred at room temperature for 2 hours. The reaction solution is poured into water and extracted with ethyl acetate. The organic layer is washed with water and dried over anhydrous magnesium sulfate. The drying agent was filtered off, and the solvent was distilled off under reduced pressure to give the title compound 9a (2.
7 g) are obtained. Melting point: 257.0-258.5 ° C IR (KBr): 3260, 3140, 3080, 2950, 1730, 1676, 1620, 1580, 1
525,1245,1225,1068,760 NMR (DMSO): 10.01 (1H, s), 9.92 (1H, s), 8.71 (7.97-7.70 (3
H, m), 7.50-7.13 (5H, m), 3.73 (3H, s), 2.40 (3H, s), 2.121H,
s), (3H, s) In a similar manner, the compounds in Table 5 are obtained.

[Table 8]

Example 10 3-ethylideneamino-2- (2-methylphenyl)-
9- (n-propoxycarbonylamino) imidazo
[2,1-a] isoquinoline 3-amino-2- (2-methylphenyl) -9- (n-
Propoxycarbonylamino) imidazo [2,1-a]
Acetaldehyde (1.3 g) is added to a suspension of isoquinoline (2.0 g) in methanol (30 mL), and the mixture is stirred at room temperature for 3 hours. The residue obtained by evaporating the reaction solution under reduced pressure was recrystallized from ethyl acetate-diisopropyl ether to obtain the title compound 10a (2.7 g) as an orange powder. Melting point: 133.0-136.0 ° C IR (KBr): 3430-3200, 2980, 1725, 1620, 1580, 1521, 1230, 1
068,759 NMR (CDCL): 8.35 (1H, d, J = 2.0Hz), 8.18 (1H, d, J = 7.6Hz),
8.06 (1H, dd, J = 2.0Hz, 9.0Hz) 7.81 (1H, q, J = 5.0Hz), 7.70 (1
(H, d, J = 9.0Hz), 7.48-7.20 (4H, m), 7.09 (1H, d, J = 7.6Hz), 4.
18 (2H, t, J = 6.2Hz), 2.24 (3H, s), 2.09 (3H, d, J = 5.0Hz), 1.9
7-1.42 (2H, m), 0.96 (3H, t, J = 7.0Hz) By the same method, the compounds shown in Table 6 are obtained.

[Table 9]

Example 11 3-Ethylamino-2- (4-fluoro-2-methylphenol)
Enyl) -9- (methoxycarbonylamino) imidazo
[2,1-a] isoquinoline 3-amino-2- (4-fluoro-2-methylphenyl) -9- (methoxycarbonylamino) imidazo [2,1-a] isoquinoline (1.0 g) in methanol (20 mL) ) Acetaldehyde (0.5mL) in suspension
And stirred at room temperature for 1 hour. Methanol (30 mL) is added to the residue obtained by evaporating the reaction solution under reduced pressure, and sodium borohydride (0.5 g) is added over 10 minutes with stirring at room temperature. The reaction solution is heated under reflux for 30 minutes, poured into ice water and extracted with ethyl acetate. The organic layer is washed with water and dried over anhydrous magnesium sulfate. The drying agent is filtered off, and the solvent is distilled off under reduced pressure. The residue obtained is recrystallized from methanol to obtain the title compound 11a (1.0 g) as a white powder. Melting point: 177.0-178.5 ° C IR (KBr): 3310,3150,3080,2960,2870,1713,1620,1588,1
520,1244,1230,1070,823 NMR (CDCL): 8.25 (1H, brd, J = 2.0Hz), 8.20-7.96 (2H, m),
7.81 (1H, d, J = 7.0Hz), 7.63 (1H, d, J = 8.6Hz), 7.49-7.20 (1
H, m), 7.10-6.87 (3H, m), 3.74 (3H, s), 2.92 (2H, q, J = 7.0H
z), 2.32 (3H, s), 1.04 (3H, t, J = 7.0 Hz) By the same method, the compounds shown in Table 7 are obtained.

[Table 10]

[Table 11]

Example 12 3- (N, N-dimethylaminomethyl) -9-methoxy
Carbonylamino-2- (2-methylphenyl) imida
Zo [2,1-a] isoquinoline 9-methoxycarbonylamino-2- (2-methylphenyl) imidazo [2,1-a] isoquinoline (3.3
g) in methanol (30 mL) solution, dimethylamine hydrochloride (1.6 g), paraformaldehyde (0.6 g)
Are sequentially added and heated to reflux. After cooling, the mixture is poured into an aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer is washed with water and dried over anhydrous magnesium sulfate. The drying agent is filtered off and the solvent is distilled off under reduced pressure. The residue obtained is purified by silica gel column chromatography to obtain the title compound 12a (2.8 g) as a pale yellow amorphous solid. IR (KBr): 3300,3080,3020,2980,2960,2870,2830,2780,1
720,1640,1620,1580,1520,1444,1385,1230,1068,750 NMR (CDCL): 8.23 (1H, d, J = 2.0Hz), 8.11 (1H, d, J = 7.0Hz), 7.
92 (1H, dd, J = 2.0Hz, 8.0Hz), 7.59 (1H, d, J = 8.0Hz), 7.22 (4
H, brs), 7.09 (1H, brs), 6.93 (1H, d, J = 7.0Hz), 3.75 (3H, s),
3.62 (2H, s), 2.28 (3H, s), 2.15 (6H, s) In a similar manner, the compounds in Table 8 are obtained.

[Table 12]

Example 13 3-cyanomethyl-9-methoxycarbonylamino-2
-(2-methylphenyl) imidazo [2,1-a] iso
Quinoline 3- (N, N-dimethylaminomethyl) -9-methoxycarbonylamino-2- (2-methylphenyl) imidazo [2,1-a] isoquinoline (2.8 g) iodide in a methanol (30 mL) solution Add methyl (2.1 g) and stir at room temperature for 4 hours. Ether was added and the resulting precipitate was collected by filtration and recrystallized from methanol-ether to give 3-trimethylammoniomethyl-9-methoxycarbonylamino-2- (2-methylphenyl) imidazo [2,1-a] as a white powder. There is obtained isoquinoline iodide (2.9 g, melting point: 280 ° C. or higher). 3-Trimethylammoniomethyl-9-methoxycarbonylamino-2- (2-methylphenyl) imidazo [2,1-a] isoquinoline iodide (2.7 g) in dimethylformamide (30 mL)
Sodium cyanide (0.5 g) is added to the solution, and the mixture is heated and stirred at 80 ° C. for 2 hours. After cooling, the mixture is poured into an aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer is washed with water and dried over anhydrous magnesium sulfate. The desiccant was filtered off, the solvent was distilled off under reduced pressure, and the residue obtained was purified by silica gel column chromatography and then recrystallized from ethyl acetate-hexane to give the title compound 13a (0%) as pale yellow needles. .
4 g) are obtained. Melting point: 206.0-208.0 ° C IR (KBr): 3300,3150,3070,2960,2270,1722,1640,1620,
1580,1520,1447,1410,1380,1230,1070,765 NMR (CDCL + DMSO): 9.78 (1H, brs), 8.73 (1H, brs), 8.08 (1
H, d, J = 7.0Hz), 7.77 (2H, brs), 7.33 (4H, s), 7.23 (1H, d, J =
7.0 Hz), 4.18 (2H, s), 3.79 (3H, s), 2.38 (3H, s) In a similar manner, the compounds in Table 9 are obtained.

[Table 13]

Example 14 3- (2-aminoethyl) -9-methoxycarbonyla
Mino-2- (2-methylphenyl) imidazo [2,1-
a] Isoquinoline hydrochloride 3-cyanomethyl-9-methoxycarbonylamino-2
Platinum oxide (30 mg) is added to a solution of-(2-methylphenyl) imidazo [2,1-a] isoquinoline (2.4 g) in ethanol (100 mL), and the mixture is hydrogenated with stirring at room temperature. After stirring for 24 hours, the catalyst was filtered off and the solvent was distilled off under reduced pressure. The residue obtained was purified by silica gel column chromatography to give brown amorphous solid 3- (2-aminoethyl) -9-methoxycarbonylamino- 2- (2-Methylphenyl) imidazo [2,1-a] isoquinoline (1.3 g) is obtained. 3- (2-aminoethyl) -9-
Methoxycarbonylamino-2- (2-methylphenyl) imidazo [2,1-a] isoquinoline (1.3 g)
Was dissolved in chloroform (50 mL), ether saturated with hydrogen chloride gas was added, and the resulting precipitate was collected by filtration and recrystallized from methanol-ether to give the title compound 14a (0.6 g) as a brown powder. Melting point: 249.0-251.0 ° C (decomposition) IR (KBr): 3400,3100-2700,1730,1620,1513,1440,1235,
1070,767 NMR (DMSO): 10.45 (1H, brs), 9.08-8.80 (2H, m), 8.79-8.3
0 (2H, brs), 8.16 (1H, brd, J = 8.0Hz), 8.01 (1H, d, J = 7.6Hz),
7.85 (1H, d, J = 8.0Hz), 7.50 (4H, brs), 3.78 (3H, s), 3.60-2.
70 (4H, m), 2.33 (3H, s) In a similar manner, the compounds in Table 10 are obtained.

[Table 14]

Example 15 3-Formyl-9-methoxycarbonylamino-2-
(2-methylphenyl) imidazo [2,1-a] isoki
In dimethylformamide (30 mL) solution of Norin phosphorus oxychloride (2.5 mL) 9-methoxy-carbonyl-amino-2
-(2-methylphenyl) imidazo [2,1-a] isoquinoline (6.6 g) in dimethylformamide (30 m
L) Add the solution dropwise. After completion of the dropwise addition, the mixture is stirred at room temperature for 2 hours. The reaction solution was poured into water, an aqueous sodium carbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer is washed successively with water and brine and dried over anhydrous magnesium sulfate. The drying agent is filtered off, and the solvent is distilled off under reduced pressure. The obtained residue is recrystallized from methanol to obtain the title compound 15a (1.1 g) as a pale yellow powder. Melting point: 156.0-158.0 ° C IR (KBr): 3350-3290,3150,3080,2960,2850,1732,1642,
1619,1522,1358,1230,1068,766 NMR (CDCL): 9.82 (1H, s), 9.25 (1H, d, J = 7.0Hz), 8.60 (1H,
d, J = 2.0Hz), 8.10 (1H, dd, J = 2.0Hz, 9.0Hz), 7.80 (1H, d, J =
9.0Hz), 7.58-7.25 (5H, m), 3.84 (3H, s), 2.46 (3H, s) In a similar manner, the compounds in Table 11 are obtained.

[Table 15]

Example 16 3-Hydroxymethyl-9-methoxycarbonylamino
-2- (2-methylphenyl) imidazo [2,1-a]
Isoquinoline 3-formyl-9-methoxycarbonylamino-2-
To a solution of (2-methylphenyl) imidazo [2,1-a] isoquinoline (1.2 g) in methanol (100 mL) was added sodium borohydride (0.2 g) under stirring at room temperature.
Add over 0 minutes. The reaction solution is heated under reflux for 30 minutes, poured into ice water and extracted with ethyl acetate. The organic layer is washed with water and dried over anhydrous magnesium sulfate. The drying agent is filtered off and the solvent is distilled off under reduced pressure. The residue obtained is recrystallized from ethyl acetate to give the title compound 16a (1.0 g) as a white powder. Melting point: 187.0-188.5 ° C (decomposition) IR (KBr): 3450,3110,2960,2850,1752,1622,1528,1210,
1070,763 NMR (CDCL): 8.21 (1H, brs), 8.02 (1H, dd, J = 2.0Hz, 9.0H
z), 7.91 (1H, d, J = 7.0Hz), 7.60 (1H, d, J = 9.0Hz), 7.26-7.08
(4H, m), 6.94 (1H, d, J = 7.0Hz), 4.70 (2H, s), 3.71 (3H, s), 2.
22 (3H, s) In a similar manner, the compounds in Table 12 are obtained.

[Table 16]

Example 17 3-acetoxymethyl-9-methoxycarbonylamino
-2- (2-methylphenyl) imidazo [2,1-a]
Isoquinoline 3-hydroxymethyl-9-methoxycarbonylamino-2- (2-methylphenyl) imidazo [2,1-a]
Acetic anhydride (5 mL) is added to a solution of isoquinoline (2.1 g) in pyridine (20 mL), and the mixture is stirred at room temperature for 2 hours. The reaction solution is poured into an aqueous solution of sodium carbonate and extracted with ethyl acetate. The organic layer is washed with water and dried over anhydrous magnesium sulfate.
The drying agent was separated by filtration, and the residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography and recrystallized from ethyl acetate-diisopropyl ether to give the title compound 17a (1. 0 g). Melting point: 161.0-162.0 ° C IR (KBr): 3340,3150,3080,2960,1732,1622,1528,1230,
1070,768 NMR (CDCL): 8.41 (1H, d, J = 2.0Hz), 8.05 (1H, dd, J = 2.0Hz,
9.0Hz), 7.93 (1H, d, J = 7.0Hz), 7.69 (1H, d, J = 9.0Hz), 7.32
(4H, s), 7.09 (1H, d, J = 7.0Hz), 5.37 (2H, s), 3.78 (3H, s), 2.
36 (3H, s), 2.09 (3H, s) In a similar manner, the compounds in Table 13 are obtained.

[Table 17]

Example 18 9-methoxycarbonylamino-2- (2-methylphen
Nyl) -3- (methylthio) imidazo [2,1-a] i
Soquinoline 3-amino-9-methoxycarbonylamino-2- (2
A mixture of -methylphenyl) imidazo [2,1-a] isoquinoline (1.3 g) and acetic acid (12 mL) and water (6 mL) is cooled to -10 ° C. Then, an aqueous solution (4 mL) of sodium nitrite (0.3 g) is added dropwise. 1
After 0 min, 15% aqueous sodium methyl mercaptan (2 mL) is added dropwise. After completion of the dropwise addition, the mixture is stirred for 20 minutes. The reaction solution is poured into an aqueous solution of sodium carbonate and extracted with ethyl acetate. The organic layer is washed with water and dried over anhydrous magnesium sulfate. The drying agent is filtered off, the solvent is distilled off under reduced pressure, and the residue obtained is purified by silica gel column chromatography, and then washed with methanol to obtain the title compound 18a (1.0 g) as a yellow powder. Melting point: 137.0-138.0 ° C IR (KBr): 3290,3150,2950,1730,1619,1522,1370,1245,
1229,1192,1070,730 NMR (CDCL + METH): 8.87 (1H, d, J = 7.4Hz), 8.40-8.15 (2H,
m), 7.78 (1H, d, J = 10.0 Hz), 7.69-7.35 (4H, m), 7.24 (1H, d, J
= 7.4Hz), 3.78 (3H, s), 2.75 (3H, s), 2.40 (3H, s) In a similar manner, the compounds in Table 14 are obtained.

[Table 18]

Example 19 3-bromo-2- (4-fluoro-2-methylphenyi
Ru) -9- (methoxycarbonylamino) imidazo
[2,1-a] isoquinoline 2- (4-fluoro-2-methylphenyl) -9- (methoxycarbonylamino) imidazo [2,1-a] isoquinoline (0.7 g) in chloroform (10 mL) solution Under cold stirring, add bromine (0.4 mL). After 15 minutes, the reaction solution is diluted with chloroform, and the organic layer is washed with an aqueous sodium carbonate solution and dried over anhydrous magnesium sulfate. The drying agent is separated by filtration, the solvent is distilled off under reduced pressure, and the residue obtained is purified by silica gel column chromatography and recrystallized from methanol to obtain the title compound 19a (0.5 g) as pale orange needles. . Melting point: 174.0-175.0 ° C IR (KBr): 3380,3290,2960,2830,1739,1709,1620,1525,
1444,1232,1070,828 NMR (CDCL): 8.31 (1H, d, J = 2.0Hz), 8.12 (1H, dd, J = 2.0Hz,
9.0Hz), 7.91 (1H, d, J = 7.0Hz), 7.70 (1H, d, J = 9.0Hz), 7.52-
7.30 (1H, m), 7.20-6.85 (2H, m), 7.15 (1H, d, J = 7.0Hz), 3.80
(3H, s), 2.38 (3H, s) In a similar manner, the compounds in Table 15 are obtained.

[Table 19]

Example 20 9-methoxycarbonylamino-3-methoxymethyl-
2- (2-methylphenyl) imidazo [2,1-a] i
Soquinoline 3-hydroxymethyl-9-methoxycarbonylamino-2- (2-methylphenyl) imidazo [2,1-a]
4-Dimethylaminopyridine (1.5 g) is added to a solution of isoquinoline (2.0 g) in pyridine (10 mL), and methanesulfonyl chloride (0.5 mL) is added dropwise with stirring at room temperature. After completion of the dropwise addition, the mixture is stirred for 30 minutes. Then, a solution obtained by adding methanol (30 mL) to the reaction solution is added to a methanol (30 mL) solution of sodium metal (0.4 g).
The reaction mixture is heated under reflux for 2 hours, poured into ice water and extracted with ethyl acetate. The organic layer is washed successively with water and brine and dried over anhydrous magnesium sulfate. The drying agent is filtered off, the solvent is distilled off under reduced pressure, and the residue obtained is purified by silica gel column chromatography to obtain the title compound 20a (0.9 g) as a white amorphous solid. IR (KBr): 3310,3080,2960,2940,2830,1732,1621,1580,
1528,1231,1077,764 NMR (CDCL): 8.40 (1H, d, J = 2.0Hz), 8.02 (1H, dd, J = 2.0Hz,
9.0Hz), 8.00 (1H, d, J = 7.0Hz), 7.67 (1H, d, J = 9.0Hz), 7.44-
7.20 (4H, m), 7.07 (1H, d, J = 7.0Hz), 4.67 (2H, s), 3.78 (3H,
s), 3.31 (3H, s), 2.37 (3H, s) In a similar manner, the compounds in Table 16 are obtained.

[Table 20]

Example 21 3-cyano-9-methoxycarbonylamino-2- (2
-Methylphenyl) imidazo [2,1-a] isoquinol
Down 3-formyl-9-methoxy-carbonylamino-2-
To a solution of (2-methylphenyl) imidazo [2,1-a] isoquinoline (2.0 g) in methanol (50 mL) was added an aqueous solution (5 mL) of sodium acetate (0.8 g) and hydroxylamine hydrochloride (0.4 g). Heat it under reflux for 4 hours. After cooling, the reaction solution was poured into an aqueous solution of sodium hydrogen carbonate, and the deposited precipitate was collected by filtration, washed with water, and dried to give 9-methoxycarbonylamino-2- (2-methylphenyl) imidazo [2,1-a] as a yellow powder. Isoquinoline-3-
Aldoxime (Compound 21a) (1.8 g, melting point: 224.0-
227.0 ° C). 9-methoxycarbonylamino-2
Acetic acid (50 g) of-(2-methylphenyl) imidazo [2,1-a] isoquinoline-3-aldoxime (1.8 g)
Sodium acetate (0.5 g) was added to the solution, and the mixture was refluxed for 21 hours. After cooling, the reaction solution is poured into an aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer is washed with an aqueous solution of sodium hydrogen carbonate and dried over anhydrous magnesium sulfate. The drying agent was removed by filtration, the solvent was distilled off under reduced pressure, and the residue obtained was purified by silica gel column chromatography and then recrystallized from hexane-ethyl acetate to give the title compound 21b (0%) as pale yellow needles. .8 g). Melting point: 207.0-208.0 ° C IR (KBr): 3350,3080,2960,2240,1740,1621,1575,1528,
1227,1056,760,723 NMR (DMSO): 10.20 (1H, brs), 8.82 (1H, brs), 8.31 (1H, d, J
= 7.0Hz), 7.93 (2H, brs), 7.80-7.30 (5H, m), 3.77 (3H, s), 2.
55 (3H, s) In a similar manner, the compounds in Table 17 are obtained.

[Table 21]

Example 22 N-[(9-methoxycarbonylamino-2- (2-meth
Tylphenyl) imidazo [2,1-a] isoquinoline-
3-yl) methylidene] -2-hydroxyethylamine 3-formyl-9-methoxycarbonylamino-2-
A mixture of (2-methylphenyl) imidazo [2,1-a] isoquinoline (5.0 g) and ethanolamine (30 mL) is heated and stirred at 110 ° C. for 30 minutes. After cooling, chloroform was added and the resulting precipitate was collected by filtration and recrystallized from ethyl acetate to give the title compound 22 (1.1 g) as a white powder. Melting point: 199.0-201.0 ° C IR (KBr): 3260,3100,2960,2850,1741,1640,1620,1525,
1400,1250,1230,1069,764 NMR (CDCL + DMSO): 9.41 (1H, d, J = 7.0Hz), 8.72 (1H, s), 8.1
8 (1H, s), 7.78 (2H, s), 7.45-7.15 (5H, m), 4.75-4.45 (1H, br
s), 3.90-3.50 (4H, m), 3.75 (3H, s), 2.35 (3H, s)

Example 23 3-[(2-hydroxyethyl) aminomethyl] -9-
Methoxycarbonylamino-2- (2-methylphenyi
L) Imidazo [2,1-a] isoquinoline N-[(9-methoxycarbonylamino-2- (2-methylphenyl) imidazo [2,1-a] isoquinoline-
Sodium borohydride (1.2 g) is added to a suspension of 3-yl) methylidene] -2-hydroxyethylamine (5.4 g) in methanol (100 mL) at room temperature over 10 minutes. The reaction solution is refluxed for 2 hours, poured into ice water and extracted with ethyl acetate. The organic layer is washed with water and dried over anhydrous magnesium sulfate. The drying agent is filtered off and the solvent is distilled off under reduced pressure. The residue obtained is recrystallized from ethyl acetate to give the title compound 23 (1.5 g) as a yellow powder. Melting point: 126.0-127.0 ° C IR (KBr): 3250,3150,3080,2950,2840,1735,1620,1525,
1230,1070,760 NMR (CDCL + DMSO): 9.79 (1H, s), 8.67 (1H, brs), 8.25 (1H,
d, J = 7.0Hz), 7.71 (2H, brs), 7.30 (4H, s), 7.09 (1H, d, J = 7.0
Hz), 4.00 (2H, brs), 3.72 (3H, s), 3.48 (2H, brt, J = 5.0Hz),
2.59 (2H, brt, J = 5.0Hz), 2.36 (3H, s)

Example 24 3- [9-methoxycarbonylamino-2- (2-methyl
Ruphenyl) imidazo [2,1-a] isoquinoline-3
-Yl] ethyl acrylate Ethyl diethylphosphonoacetate (7.6 g) is slowly added dropwise to a solution of sodium hydride (1.3 g, 60% in oil) in tetrahydrofuran (60 mL). After the addition,
Stir for 30 minutes at room temperature. Then, 3-formyl-9-methoxycarbonylamino-2- (2-methylphenyl) imidazo [2,1-a] isoquinoline (6.
A solution of 2 g) in tetrahydrofuran (30 mL) is added dropwise. After 2 hours, the reaction solution is poured into aqueous sodium carbonate solution and extracted with ethyl acetate. The organic layer is washed with water and dried over anhydrous magnesium sulfate. The drying agent was filtered off, and the solvent was distilled off under reduced pressure. The residue obtained was recrystallized from methanol to obtain the title compound 24a (5.8 g) as a pale yellow powder. Melting point: 205.0-206.0 ° C IR (KBr): 3350,3150,3080,2960,1732,1697,1620,1270,
1232,1169,1065,763 NMR (CDCL): 8.40 (1H, d, J = 2.0Hz), 8.12 (1H, d, J = 7.0Hz),
8.09 (1H, dd, J = 2.0Hz, 9.0Hz), 7.87 (1H, d, J = 16.0Hz), 7.71
(1H, d, J = 9.0Hz), 7.36 (4H, s), 7.19 (1H, d, J = 7.0Hz), 6.00
(1H, d, J = 16.0Hz), 4.22 (2H, q, J = 7.0Hz), 3.80 (3H, s), 2.28
(3H, s), 1.30 (3H, t, J = 7.0Hz) By the same method, the compounds shown in Table 18 are obtained.

[Table 22]

Example 25 3- [9-methoxycarbonylamino-2- (2-methyl
Ruphenyl) imidazo [2,1-a] isoquinoline-3
-Ethyl- propionate 3- [9-methoxycarbonylamino-2- (2-methylphenyl) imidazo [2,1-a] isoquinoline-3
-Yl] ethyl acrylate (0.6 g) in ethanol (20 mL) solution, acetic acid (4 mL) and platinum oxide (60 m
g) and hydrogenate with stirring at room temperature. After 20 hours, the catalyst is filtered off, water is added to the filtrate, the solution is made alkaline with an aqueous sodium carbonate solution, and the mixture is extracted with chloroform. The organic layer is washed with water and dried over anhydrous magnesium sulfate. The drying agent is filtered off, the solvent is distilled off under reduced pressure, and the residue obtained is purified by silica gel column chromatography to give the title compound 25 (0.4 g) as a pale yellow amorphous solid. IR (KBr): 3320,3070,2990,2960,1740,1720,1620,1525,
1230,1064,760 NMR (CDCL): 8.32 (1H, d, J = 1.6Hz), 8.15-7.55 (3H, m), 7.4
0-7.10 (5H, m), 7.07 (1H, d, J = 8.0Hz), 4.08 (2H, q, J = 7.0H
z), 3.78 (3H, s), 3.40-3.05 (2H, m), 2.70-2.38 (2H, m), 2.31
(3H, s), 1.18 (3H, t, J = 7.0Hz)

Test Example 1 H ⁺ / K ⁺ -ATPase Activity Inhibitory Activity Hongo et al.'S method (The Japanese Journal of
Pharmacology (Japan.J.Pharmacol.), Volume 52,
295, 1990), a microsomal fraction prepared from pig gastric mucosa was used as an enzyme preparation. An enzyme preparation (13 μg protein) and a test compound (0.1-100 μm)
M) in a 50 mM Tris / acetate buffer (2 mM magnesium chloride, 5 mM potassium chloride, pH
The reaction was carried out at 37 ° C. for 30 minutes in the solution containing 7.4).
The enzymatic reaction was started by adding 2 mM final concentration of adenosine triphosphate (ATP) Tris, 37
The reaction was carried out at 150C for 15 minutes. The reaction was stopped by cooling 10
Performed by adding% trichloroacetic acid. The inorganic phosphorus released by the hydrolysis of ATP during this reaction time was analyzed by the method of Fiske-Subbarow (The
Journal of biological chemistry
(J. Biol. Chem.), 66, 375, 1925)
Colorimetrically. The H ⁺ / K ⁺ -ATPase activity was determined by subtracting the activity in the absence of potassium chloride from the total activity. The 50% inhibitory concentration (IC ₅₀ ) was calculated from the enzyme inhibition rate at each concentration for the enzyme inhibitory activity of the drug, and the results are shown in Table 19.

[Table 23] Compound A: 3-amino-7-methoxycarbonylamino-2- (2-methylphenyl) imidazo [2,1-a]
Isoquinoline

Test Example 2 Gastric Acid Secretion Inhibiting Effect by Perfusion Method SD male rats (6 to 7 weeks old) were used after a 24-hour fast (however, water was freely taken). 1.25g / kg
The rats were anesthetized by intraperitoneal administration of urethane. The abdomen was opened and the stomach cavity was perfused with saline throughout the study. A 10 mM sodium hydroxide solution was used as a titrant, and the perfusate was titrated by an automatic titrator by a stat method so as to maintain pH 5.5. Gastric acid secretion was induced by continuous infusion of histamine dihydrochloride (8 mg / kg / hour) intravenously. Two hours after the start of histamine infusion, the test compound (0.3 to 10 mg / kg) was intraperitoneally administered. The compound was mixed with a small amount of polysorbate 80 and then suspended in physiological saline. The drug efficacy was represented by ID ₅₀ (dose that inhibits acid secretion by 50%) calculated from the acid secretion inhibition rate 1 hour after administration, and the results are shown in Table 20.

[Table 24]

Test Example 3 Helicobacter pylori (Heli
Antibacterial activity test against Helicobacter pylori From the antibacterial activity test against Helicobacter pylori, the minimum inhibitory concentration (MIC; Mini)
mum Inhibitory Concentration) was calculated. Helicobacter pylori is ATCC43
504 was used. To 4.85 mL of Brucella broth medium containing 10% calf serum, 50 μL of a compound dissolved in a solvent (dimethyl sulfoxide) was added.
^{0 8 CFU / mL (CFU;} colony forming unit) Helicobacter pylori (Helicobacter pylori) suspension 100μL added and 85% nitrogen, 5% oxygen, under the conditions of 10% carbon dioxide, and cultured with shaking at 37 ° C.. The MIC was determined from the turbidity of the medium three days later. The results are shown in Table 21.

[Table 25]

Test Example 4 Acute Toxicity Test Examples 1 and 3 were performed using ICR male mice (6 weeks old).
The acute toxicity of the compounds a, 8d and 8h by intraperitoneal administration was examined. Three animals were each administered at a dose of 500 mg / kg, and no deaths were observed until 7 days after the administration. Next, acute toxicity of the compounds of Examples 1 and 8d by oral administration was examined using ICR male mice (6 weeks old). Five animals were each administered at a dose of 2,000 mg / kg, but no deaths were observed until 2 weeks after the administration.

As apparent from Test Examples 1, 2, 3 and 4, the compound (I) of the present invention is useful as an antiulcer agent.
When administering the compound (I) of the present invention and a pharmaceutically acceptable salt thereof or a solvate thereof for therapeutic purposes, the above compound is used as an active ingredient and a pharmaceutically acceptable carrier such as It can be used in the form of a formulation with organic or inorganic, solid or liquid excipients suitable for oral or parenteral use. Pharmaceutical preparations may be made into capsules, tablets, dragees, solutions, suspensions, emulsions and the like. Such formulations are prepared by standard methods well known to those skilled in the art. The dose of the compound varies depending on the age and condition of the patient.
mg, preferably within the range of 5 to 800 mg.
Administration once or several times a day is effective in treating ulcers. Suitably, the compounds will be administered for a period of continuous treatment, for example for a week or more.

[0077]

As is clear from the above test results, the compound (I) of the present invention has excellent H ⁺ / K ⁺ -ATPase activity inhibitory activity, gastric acid secretion inhibitory activity and antibacterial activity against Helicobacter pylori. Show,
Moreover, it has been revealed that it has low toxicity. Therefore, the present invention has provided a novel chemical substance having excellent properties as an anti-ulcer agent.

Claims (7)

[Claims] 1. A compound of the general formula (I) Wherein R ¹ is halogen, cyano, lower alkylthio,
Lower alkyl optionally having a substituent selected from lower alkylsulfonyl or phenyl; or lower alkenyl: Ar is halogen; lower alkoxy; or lower alkyl optionally substituted with hydroxyl, lower alkoxy or acyloxy. Optionally substituted phenyl, pyridyl, furyl or thienyl: R ² is hydrogen; cyano; nitroso; halogen; lower alkyl; lower alkylthio; lower alkoxy; protected carboxy; amino; acylamino; lower alkylamino, lower alkylideneamino; lower alkanoyl; is -CH = NR ⁵ [R ⁵ hydroxyl; cyano, lower alkoxy, lower alkenyl which may be substituted with a lower alkanoyl or optionally protected carboxy lower alkoxy A; lower alkyl optionally substituted by hydroxyl, lower alkoxy or protected carboxy]; or -AR ⁶ [A is lower alkylene: R ⁶ is halogen; cyano; amino; lower alkylideneamino; hydroxyl or lower A lower alkylamino optionally substituted with alkoxy; an acylamino; a lower alkoxycarbonylamino; a protected carboxy; -XR ⁷ [X is oxygen or sulfur: R ⁷ is hydrogen; a lower alkyl; a lower alkenyl; Embedded image (Wherein R ⁸ , R ⁹ , and R ¹⁰ are lower alkyl; Y represents an acid residue)]]: R ³ is hydrogen or lower alkyl: R ⁴ is hydrogen; halogen; lower alkoxy; lower Alkyl; or lower alkoxycarbonylamino;
N- (imidazo [2,1-a] isoquinolin-9-yl) carbamic acid ester represented by the dashed line represents a double bond or a single bond integrally with the solid line, and pharmaceutically acceptable salts thereof. Salts and solvates thereof. Wherein R ² is hydrogen; lower alkyl; lower alkylthio; lower alkoxy; amino; acylamino; lower alkylamino, lower alkylideneamino, cyano, lower alkoxy, substituted with even better carboxy optionally be lower alkanoyl or protected which may be lower alkenyl; -CH = NR ⁵ [R ⁵ is hydroxyl, lower alkoxy, hydroxyl, lower alkyl which may be substituted with lower alkoxy or protected carboxy; or -A-R ⁶ [A lower Alkylene: R ⁶ is halogen; amino; lower alkylideneamino; lower alkylamino optionally substituted by hydroxyl or lower alkoxy; acylamino; lower alkoxycarbonylamino;
Protected carboxy; or -X-R ⁷ [X is oxygen or sulfur: R ⁷ is hydrogen; lower alkyl; lower alkenyl; or acyl]] is a compound of claim 1. 3. Ar is phenyl or thienyl which may have a substituent selected from halogen; lower alkoxy; or lower alkyl which may be substituted with hydroxyl, lower alkoxy or acyloxy; 3. The compound according to claim 2, wherein said compound represents a double bond together with said compound. 4. The compound according to claim 2, wherein R ¹ is lower alkyl or lower alkenyl: the dashed line represents a double bond together with the solid line. 5. R ¹ is lower alkyl or lower alkenyl: Ar has a substituent selected from halogen; lower alkoxy; or lower alkyl optionally substituted by hydroxyl, lower alkoxy or acyloxy. good phenyl or thienyl: R ³ is hydrogen or methyl: R ⁴ is hydrogen or methyl: the dashed line portion of the compound of claim 2, wherein represents a double bond becomes solid and integral. 6. The compound according to claim 4, wherein R ² is amino; acylamino; lower alkylamino; or lower alkylideneamino. 7. R ² is lower alkyl; lower alkenyl optionally substituted by cyano, lower alkoxy, lower alkanoyl or optionally protected carboxy;
CH = NR ⁵ [R ⁵ is hydroxyl; lower alkoxy; lower alkyl optionally substituted with hydroxyl, lower alkoxy or protected carboxy]; or —A
-R ⁶ [A is lower alkylene: R ⁶ is halogen; cyano;
Amino; lower alkylamino optionally substituted with hydroxyl or lower alkoxy; acylamino; protected carboxy; -XR ⁷ [X is oxygen or sulfur; R ⁷ is hydrogen; lower alkyl; lower alkenyl; or acyl] 5. The compound according to claim 4, wherein