JP2008222557A - PYRROLO[3,2-d]PYRIMIDINE DERIVATIVE AND PHARMACEUTICAL COMPOSITION COMPRISING THE SAME AS EFFECTIVE COMPONENT - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a compound that suppresses gastric acid secretion and has an antimicrobial action on Helicobacter pylori. <P>SOLUTION: A compound represented by formula (I) [wherein R<SP>1</SP>represents a hydrogen atom, an alkyl group, an arylmethyl group, a trimethylsylilethoxymethyl group or the like; R<SP>2</SP>, R<SP>3</SP>may be the same or different and each represents a hydrogen atom, an alkyl group, an alkoxycarbonyl group, a carboxyl group, a carbamoyl group, an alkanoyl group, a cyano group, a halogen atom or the like; R<SP>4</SP>represents a hydrogen atom, an alkyl group, an alkoxy group, an alkoxycarbonyl group, a halogen atom, a hydroxy group, a carboxy group, a cyano group, a nitro group or the like; and R<SP>5</SP>represents an arylmethyl group, a heteroarylmethyl group or the like], a pharmacologically acceptable salt thereof, and a medicine comprising the compound as an effective component, are disclosed. <P>COPYRIGHT: (C)2008,JPO&INPIT

Description

The present invention is a novel pyrrolo [3,2-d] useful as a medicament, particularly a prophylactic or therapeutic agent for ulcer disease, which has an excellent acid secretion inhibitory action and an excellent antibacterial action against Helicobacter pylori. The present invention relates to a pyrimidine derivative or a pharmacologically acceptable salt thereof, and to a pharmaceutical composition containing the pyrrolopyrimidine derivative as an active ingredient.

It has been reported that peptic ulcer occurs when the balance between an attack factor and a defense factor against the gastric mucosa is lost, and suppression of gastric acid secretion, which is an attack factor, is useful for ulcer prevention and treatment. Conventionally, proton pump inhibitors typified by omeprazole have been widely used in clinical practice to suppress gastric acid secretion. However, existing proton pump inhibitors have problems in terms of effects and side effects. That is, existing proton pump inhibitors are often formulated as enteric preparations because they are unstable under acidic conditions, and in that case, several hours are required for the onset of action. Moreover, since the existing proton pump inhibitor is covalently bonded to the protein, it takes time to dissociate between the protein and the drug, and the disappearance from the body is delayed. Therefore, there are concerns about side effects and recurrence due to the rebound effect after drug disappearance, and an improved proton pump inhibitor is desired.

In recent years, the relationship between Helicobacter pylori infection and gastric ulcers and gastric cancer is becoming clear. In the treatment of ulcers, especially from the viewpoint of preventing recurrence, ulcer treatment agents and antibacterial agents such as amoxicillin have been used in combination. From this point of view, it is desired to develop a compound having an antibacterial action against Helicobacter pylori as a preventive or therapeutic agent for anti-ulcer disease while strongly suppressing gastric acid secretion, which is an attack factor for the gastric mucosa. .

In recent years, condensed nitrogen-containing heterocycles have attracted attention as compounds having proton / potassium-adenosine triphosphatase (H ⁺ , K ⁺ -ATPase) inhibitory activity and compounds having antibacterial activity against Helicobacter pylori. For example, pyrrolo [2,3-d] pyridazine compounds (Patent Document 1), imidazo [1,2-a] pyridine compounds (Patent Document 2), imidazo [1,2-a] pyrazine compounds (Patent Document 3) Pyrrolo [3,2-b] pyridine compounds (Patent Document 4), pyrrolo [2,3-c] pyridine compounds (Patent Document 5), pyrrolo [3,2-c] pyridine compounds (Patent Document 6), etc. Although proposed, the development of more powerful and safe drugs is desired.

International Publication No. 00/77003 Pamphlet WO99 / 55706 pamphlet International Publication No. 2004/074289 Pamphlet International Publication No. 2006/013195 Pamphlet International Publication No. 2006/011670 Pamphlet International Publication No. 2006/025715 Pamphlet

The present invention has been made in view of the above circumstances, and provides a compound having an antibacterial action against Helicobacter pylori while strongly suppressing gastric acid secretion, which is an attack factor against the gastric mucosa of warm-blooded animals (particularly humans). In addition, an object of the present invention is to provide a pharmaceutical comprising this as an active ingredient, particularly a prophylactic or therapeutic agent for ulcer disease.

As a result of intensive studies to solve the above-mentioned problems, the present inventors have found that a specific pyrrolo [3,2-d] pyrimidine derivative strongly suppresses gastric acid secretion and further has excellent antibacterial activity against Helicobacter pylori. It has been found that it has activity, and the present invention has been completed.
That is, the compound of the present invention is represented by the following general formula (I):

[Wherein R ¹ includes a hydrogen atom, an alkyl group that may be branched (1 to 10 carbon atoms), an alkyl group that may be branched including a double bond (2 to 10 carbon atoms), or a triple bond. A branched alkyl group (2-10 carbon atoms), a branched alkyl group containing a saturated carbocyclic ring (3-10 carbon atoms), a branched haloalkyl group (1-10 carbon atoms), An alkoxyalkyl group (2-10 carbon atoms) which may be branched, a hydroxyalkyl group (1-10 carbon atoms) which may be branched, an arylmethyl group which may have a substituent, or a trimethylsilylethoxymethyl group. Show.

R ² and R ³ may be the same or different and are each a hydrogen atom, an alkyl group that may be branched (1 to 10 carbon atoms), or an alkyl group that may be branched including a saturated carbocyclic ring (3 carbon atoms). -10), haloalkyl group which may be branched (1-10 carbon atoms), alkoxyalkyl group which may be branched (2-10 carbon atoms), hydroxyalkyl group which may be branched (1-10 carbon atoms) Represents an alkoxycarbonyl group (2-10 carbon atoms) which may be branched, a carboxyl group, an amino group, a carbamoyl group, an alkanoyl group, a cyano group or a halogen atom.

R ⁴ is a hydrogen atom, an optionally branched alkyl group (1-10 carbon atoms), an optionally branched alkyl group containing a saturated carbocyclic ring (3-10 carbon atoms), an optionally branched haloalkyl group ( 1-10) carbon, branched alkoxy group (1-10 carbon atoms), branched alkoxyalkyl group (2-10 carbon atoms), branched hydroxyalkyl group (1 carbon atoms) -10), an alkoxyalkoxyalkyl group that may be branched (3 to 10 carbon atoms), an alkoxycarbonyl group that may be branched (2 to 10 carbon atoms), a halogen atom, a hydroxyl group, a carboxyl group, a cyano group, a nitro group , —CONR ⁶ R ⁷ group (provided that R ⁶ and R ⁷ may be the same or different and each is a hydrogen atom, a branched alkyl group (having 1 to 10 carbon atoms), or a branched chain containing a saturated carbocyclic ring. Alkyl group 3-10 carbon atoms), optionally branched alkoxyalkyl group optionally (2-10 carbon atoms), indicating a branch to be good hydroxyalkyl group (1-10 carbon atoms). }, —NR ⁸ R ⁹ group {provided that R ⁸ and R ⁹ may be the same or different, and each represents a hydrogen atom, an alkyl group which may be branched (1-10 carbon atoms), or an alkanoyl which may be branched Group (carbon number 2-10), optionally substituted arylcarbonyl group, optionally substituted heteroarylcarbonyl group, branched alkylsulfonyl group (carbon number 1-10), A hydroxyalkylsulfonyl group (1-10 carbon atoms), an alkylsulfinyl group (1-10 carbon atoms), an arylsulfonyl group which may have a substituent, and a heteroarylsulfonyl group which may have a substituent are shown. }, Or —S (O) nR ¹⁰ {wherein R ¹⁰ is an alkyl group (1-10 carbon atoms) which may be branched, and n is 0-2. }.

R ⁵ represents an arylmethyl group which may have a substituent, a heteroarylmethyl group which may have a substituent, or a substituent represented by the following formula (a).

{However, R ¹¹ may be branched alkyl group (1-5 carbon atoms), may be branched haloalkyl group (1-5 carbon atoms), may be branched alkoxy group (1-5 carbon atoms). Represents a halogen atom or a hydroxyl group. Z represents a —CHR ¹² — group or a —CHR ¹² CHR ¹³ — group. In the formula, R ¹² and R ¹³ may be the same or different, and each represents a hydrogen atom, an alkyl group that may be branched (1-5 carbon atoms), or an alkyl group that may be branched including a saturated carbocycle ( 3-10) carbon atoms, haloalkyl groups that may be branched (1-5 carbon atoms), alkoxy groups that may be branched (1-5 carbon atoms), alkoxyalkyl groups that may be branched (2 carbon atoms) 5), a hydroxyalkyl group (1-5 carbon atoms) that may be branched, an alkoxycarbonyl group (2-5 carbon atoms) that may be branched, a halogen atom, a hydroxyl group, a carboxyl group, a cyano group, a nitro group,- CONR ¹⁴ R ¹⁵ group or —NR ¹⁶ R ¹⁷ group is shown. In the formula, R ¹⁴ and R ¹⁵ may be the same or different and each represents a hydrogen atom, a branched alkyl group (1-5 carbon atoms), or a branched alkyl group containing a saturated carbocyclic ring. (C3-5), an alkoxyalkyl group (C2-5) which may be branched, and a hydroxyalkyl group (C1-5) which may be branched. R ¹⁶ and R ¹⁷ may be the same or different and are each a hydrogen atom, a branched alkyl group (1-5 carbon atoms), a branched alkanoyl group (2-5 carbon atoms), Arylcarbonyl group which may have a substituent, heteroarylcarbonyl group which may have a substituent, alkylsulfonyl group which may be branched (1-5 carbon atoms), aryl which may have a substituent A sulfonyl group and a heteroarylsulfonyl group which may have a substituent are shown. }
X represents —O—, —NH—, or —CH ₂ —. ]
Or a pharmacologically acceptable salt thereof.

The compound represented by the general formula (I) of the present invention strongly suppresses gastric acid secretion and has excellent antibacterial activity against Helicobacter pylori. Thus, since the compound represented by the general formula (I) of the present invention has an action of suppressing gastric acid secretion and an antibacterial action against Helicobacter pylori, it is a pharmaceutical, particularly a prophylactic agent for ulcer disease. Alternatively, it can be expected to be useful as a therapeutic agent for preventing or treating gastritis, reflux esophagitis, gastric ulcer, gastric cancer, gastric malignant lymphoma, gastric MALT lymphoma, duodenal ulcer, duodenal cancer or enteritis.

The compound of the present invention represented by the general formula (I) will be described in detail. For R ^{1 in} formula (I), an alkyl group that may be branched (1-10 carbon atoms: the carbon number in the present invention refers to the carbon number of the entire group) is, for example, a methyl group, ethyl Group, propyl group, isopropyl group, butyl group, isobutyl group, pentyl group, hexyl group, heptyl group, octyl group, nonyl group, decanyl group and the like. Examples of the alkyl group (2-10 carbon atoms) that may be branched including a double bond include a vinyl group, an allyl group, a propenyl group, an isopropenyl group, a butenyl group, an isobutenyl group, a pentenyl group, a hexenyl group, and a heptenyl group. Octenyl group, nonenyl group, decenyl group and the like. Examples of the alkyl group (2-10 carbon atoms) that may be branched including a triple bond include ethynyl group, propynyl group, butynyl group, pentynyl group, hexynyl group, octynyl group, and the like. The haloalkyl group (1-10 carbon atoms) which may be branched includes, for example, monofluoromethyl group, difluoromethyl group, trifluoromethyl group, 2,2,2-trifluoroethyl group, pentafluoroethyl group, monochloromethyl Group, dichloromethyl group, trichloromethyl group, 2,2,2-trichloroethyl group and the like. Examples of the branched alkyl group containing 3 to 10 carbon atoms (3 to 10 carbon atoms) include cyclopropyl group, cyclopropylmethyl group, 2-cyclopropylethyl group, 2-methylcyclopropylmethyl group, 2- ( 2-methylcyclopropyl) ethyl group, 3- (2-methylcyclopropyl) propyl group, 6- (2-methylcyclopropyl) hexyl group, 2-ethylcyclopropylmethyl group, 2-propylcyclopropylmethyl group, 2 -Hexylcyclopropylmethyl group, cyclobutylmethyl group, 2-methylcyclobutylmethyl group, cyclopentylmethyl group, 2-cyclopentylethyl group, 2-methylcyclopentylmethyl group, 2- (2-methylcyclopentyl) ethyl group, 2- Ethylcyclopentylmethyl group, cyclohexylmethyl group, 2-cyclohexylethyl group, 2-methylcyclohexylmethyl group, 2- (2-methylcyclohexyl Xyl) ethyl group, cycloheptylmethyl group and the like. Examples of the alkoxyalkyl group (having 2 to 10 carbon atoms) that may be branched include a methoxymethyl group, an ethoxymethyl group, and a methoxyethyl group. Examples of the branched hydroxyalkyl group (having 1 to 10 carbon atoms) include a hydroxymethyl group and a hydroxyethyl group.

For R ² and R ^{3 in} the general formula (I), the alkyl group (1-10 carbon atoms) which may be branched is, for example, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, pentyl Group, hexyl group, heptyl group, octyl group, nonyl group, decanyl group and the like. The alkyl group having 3 to 10 carbon atoms containing a saturated carbocyclic ring (3 to 10 carbon atoms) is, for example, a cyclopropyl group, a cyclopropylmethyl group, a 2-cyclopropylethyl group, a 2-methylcyclopropylmethyl group, 2- ( 2-methylcyclopropyl) ethyl group, 3- (2-methylcyclopropyl) propyl group, 6- (2-methylcyclopropyl) hexyl group, 2-ethylcyclopropylmethyl group, 2-propylcyclopropylmethyl group, 2 -Hexylcyclopropylmethyl group, cyclobutylmethyl group, 2-methylcyclobutylmethyl group, cyclopentylmethyl group, 2-cyclopentylethyl group, 2-methylcyclopentylmethyl group, 2- (2-methylcyclopentyl) ethyl group, 2- Ethylcyclopentylmethyl group, cyclohexylmethyl group, 2-cyclohexylethyl group, 2-methylcyclohexylmethyl group, 2- (2-methylcyclohexyl Sill) ethyl group, a cycloheptylmethyl group. Examples of the haloalkyl group (1-10 carbon atoms) that may be branched include a monofluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a 2,2,2-trifluoroethyl group, a pentafluoroethyl group, and a monochloromethyl group. Group, dichloromethyl group, trichloromethyl group, 2,2,2-trichloroethyl group and the like. Examples of the alkoxyalkyl group (2-10 carbon atoms) that may be branched include a methoxymethyl group, an ethoxymethyl group, and a methoxyethyl group. Examples of the branched hydroxyalkyl group (having 1 to 10 carbon atoms) include a hydroxymethyl group and a hydroxyethyl group. Examples of the alkoxycarbonyl group (2-10 carbon atoms) that may be branched include a methoxycarbonyl group and an ethoxycarbonyl group. The alkanoyl group is, for example, an acetyl group or a propionyl group. The halogen atom is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.

For R ^{4 in the} general formula (I), the alkyl group (having 1 to 10 carbon atoms) which may be branched is, for example, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, pentyl group, hexyl. Group, heptyl group, octyl group, nonyl group, decanyl group and the like. The alkyl group having 3 to 10 carbon atoms containing a saturated carbocyclic ring (3 to 10 carbon atoms) is, for example, a cyclopropyl group, a cyclopropylmethyl group, a 2-cyclopropylethyl group, a 2-methylcyclopropylmethyl group, 2- ( 2-methylcyclopropyl) ethyl group, 3- (2-methylcyclopropyl) propyl group, 6- (2-methylcyclopropyl) hexyl group, 2-ethylcyclopropylmethyl group, 2-propylcyclopropylmethyl group, 2 -Hexylcyclopropylmethyl group, cyclobutylmethyl group, 2-methylcyclobutylmethyl group, cyclopentylmethyl group, 2-cyclopentylethyl group, 2-methylcyclopentylmethyl group, 2- (2-methylcyclopentyl) ethyl group, 2- Ethylcyclopentylmethyl group, cyclohexylmethyl group, 2-cyclohexylethyl group, 2-methylcyclohexylmethyl group, 2- (2-methylcyclohexyl Sill) ethyl group, a cycloheptylmethyl group. Examples of the haloalkyl group (1-10 carbon atoms) that may be branched include a monofluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a 2,2,2-trifluoroethyl group, a pentafluoroethyl group, and a monochloromethyl group. Group, dichloromethyl group, trichloromethyl group, 2,2,2-trichloroethyl group and the like. Examples of the alkoxy group (1-10 carbon atoms) that may be branched include a methoxy group, an ethoxy group, a propoxy group, and an isopropoxy group. Examples of the alkoxyalkyl group (having 1 to 10 carbon atoms) that may be branched include a methoxymethyl group, an ethoxymethyl group, and a methoxyethyl group. Examples of the branched hydroxyalkyl group (having 1 to 10 carbon atoms) include a hydroxymethyl group and a hydroxyethyl group. Examples of the alkoxyalkoxyalkyl group (having 1 to 10 carbon atoms) that may be branched include a methoxymethoxymethyl group and a methoxyethoxymethyl group. Examples of the alkoxycarbonyl group (1-10 carbon atoms) that may be branched include a methoxycarbonyl group and an ethoxycarbonyl group. The halogen atom is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.

The alkyl group (C1-10) which may be branched with respect to R ⁶ and R ^{7 in} the —CONR ⁶ R ⁷ group is, for example, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, A pentyl group, a hexyl group, a heptyl group, an octyl group, a nonyl group, a decanyl group, and the like. The alkyl group having 3 to 10 carbon atoms containing a saturated carbocyclic ring (3 to 10 carbon atoms) is, for example, a cyclopropyl group, a cyclopropylmethyl group, a 2-cyclopropylethyl group, a 2-methylcyclopropylmethyl group, 2- ( 2-methylcyclopropyl) ethyl group, 3- (2-methylcyclopropyl) propyl group, 6- (2-methylcyclopropyl) hexyl group, 2-ethylcyclopropylmethyl group, 2-propylcyclopropylmethyl group, 2 -Hexylcyclopropylmethyl group, cyclobutylmethyl group, 2-methylcyclobutylmethyl group, cyclopentylmethyl group, 2-cyclopentylethyl group, 2-methylcyclopentylmethyl group, 2- (2-methylcyclopentyl) ethyl group, 2- Ethylcyclopentylmethyl group, cyclohexylmethyl group, 2-cyclohexylethyl group, 2-methylcyclohexylmethyl group, 2- (2-methylcyclohexyl Sill) ethyl group, a cycloheptylmethyl group. Examples of the alkoxyalkyl group (2-10 carbon atoms) that may be branched include a methoxymethyl group, an ethoxymethyl group, and a methoxyethyl group. The hydroxyalkyl group (C1-10) which may be branched is, for example, a hydroxymethyl group, a hydroxyethyl group or the like.

For R ⁸ and R ^{9 in} —NR ⁸ R ⁹ group, the alkyl group (C 1-10) that may be branched is, for example, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, A pentyl group, a hexyl group, a heptyl group, an octyl group, a nonyl group, a decanyl group, and the like. Examples of the alkanoyl group (2-10 carbon atoms) which may be branched include an acetyl group and a propionyl group. The arylcarbonyl group which may have a substituent is, for example, a benzoyl group. Examples of the heteroarylcarbonyl group that may have a substituent include a 2-nicotinoyl group, a 3-nicotinoyl group, and a 4-nicotinoyl group. Examples of the alkylsulfonyl group (having 1 to 10 carbon atoms) that may be branched include a methanesulfonyl group and an ethanesulfonyl group. Examples of the arylsulfonyl group that may have a substituent include a benzenesulfonyl group and a toluenesulfonyl group. The heteroarylsulfonyl group which may have a substituent is, for example, a pyridylsulfonyl group.

-S (O) nR ¹⁰ R ¹⁰ may be branched and the alkyl group (1-10 carbon atoms) may be, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl Group, hexyl group, heptyl group, octyl group, nonyl group, decanyl group and the like.

For R ⁵ of the general formula (I), the arylmethyl group which may have a substituent is, for example, a benzyl group, a 4-fluorobenzyl group, a 2,6-dimethylbenzyl group, a 2,6-dimethoxybenzyl group, or the like. It is. Examples of the heteroarylmethyl group which may have a substituent include a 2-pyridylmethyl group, a 3-pyridylmethyl group, and a 4-pyridylmethyl group. In addition, for R ¹¹ of the substituent represented by the general formula (a), the alkyl group (1-5 carbon atoms) that may be branched is, for example, a methyl group, an ethyl group, a propyl group, an isopropyl group, or a butyl group. , Isobutyl group and pentyl group. Examples of the haloalkyl group (1-5 carbon atoms) that may be branched include a monofluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a 2,2,2-trifluoroethyl group, a pentafluoroethyl group, and a monochloromethyl group. Group, dichloromethyl group, trichloromethyl group, 2,2,2-trichloroethyl group and the like. Examples of the alkoxy group (1-5 carbon atoms) that may be branched include a methoxy group, an ethoxy group, a propoxy group, and an isopropoxy group. The halogen atom is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.

For R ¹² and R ¹³ of the —CHR ¹² — group and —CHR ¹² CHR ¹³ — group, the alkyl group (1-5 carbon atoms) that may be branched is, for example, a methyl group, an ethyl group, a propyl group, or an isopropyl group. Butyl group, isobutyl group, pentyl group and the like. Examples of the alkyl group having 3 to 5 carbon atoms containing a saturated carbocyclic ring (C3-5) include a cyclopropyl group, a cyclopropylmethyl group, a 2-cyclopropylethyl group, a 2-methylcyclopropylmethyl group, and the like. Examples of the haloalkyl group (1-5 carbon atoms) that may be branched include a monofluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a 2,2,2-trifluoroethyl group, a pentafluoroethyl group, and a monochloromethyl group. Group, dichloromethyl group, trichloromethyl group, 2,2,2-trichloroethyl group and the like. Examples of the alkoxy group (1-5 carbon atoms) that may be branched include a methoxy group, an ethoxy group, a propoxy group, and an isopropoxy group. Examples of the alkoxyalkyl group (2-5 carbon atoms) that may be branched include a methoxymethyl group, an ethoxymethyl group, and a methoxyethyl group. Examples of the branched hydroxyalkyl group (having 1 to 5 carbon atoms) include a hydroxymethyl group and a hydroxyethyl group. Examples of the alkoxycarbonyl group (2-5 carbon atoms) that may be branched include a methoxycarbonyl group and an ethoxycarbonyl group. The halogen atom is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.

The alkyl group (C1-5) which may be branched with respect to R ¹⁴ and R ¹⁵ of the —CONR ¹⁴ R ¹⁵ group is, for example, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, A pentyl group and the like. Examples of the alkyl group having 3 to 5 carbon atoms containing a saturated carbocyclic ring (C3-5) include a cyclopropyl group, a cyclopropylmethyl group, a 2-cyclopropylethyl group, a 2-methylcyclopropylmethyl group, and the like. Examples of the alkoxyalkyl group (2-5 carbon atoms) that may be branched include a methoxymethyl group, an ethoxymethyl group, and a methoxyethyl group. Examples of the branched hydroxyalkyl group (having 1 to 5 carbon atoms) include a hydroxymethyl group and a hydroxyethyl group.

For R ¹⁶ and R ^{17 in} the —NR ¹⁶ R ¹⁷ group, the alkyl group (having 1 to 5 carbon atoms) which may be branched is, for example, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, A pentyl group and the like. Examples of the alkanoyl group (2-5 carbon atoms) that may be branched include an acetyl group and a propionyl group. The arylcarbonyl group (C 1-5) that may have a substituent (for example, benzoyl group), and the heteroarylcarbonyl group that may have a substituent include, for example, 2-nicotinoyl group, 3-nicotinoyl Group, 4-nicotinoyl group and the like. Examples of the alkylsulfonyl group (having 1 to 5 carbon atoms) that may be branched include a methanesulfonyl group and an ethanesulfonyl group. Examples of the arylsulfonyl group which may have a substituent include a benzenesulfonyl group and a toluenesulfonyl group. The heteroarylsulfonyl group which may have a substituent is, for example, a pyridylsulfonyl group.

In the above description of the group, the substituent in the arylmethyl group which may have a substituent may be a branched alkyl group (for example, a methyl group, an ethyl group, a propyl group, an isopropyl group, Butyl group, isobutyl group, pentyl group), haloalkyl group which may be branched (for example, monofluoromethyl group, difluoromethyl group, trifluoromethyl group, 2,2,2-trifluoroethyl group, pentafluoroethyl group, Monochloromethyl group, dichloromethyl group, trichloromethyl group, 2,2,2-trichloroethyl group, etc.), branched alkoxy group (for example, methoxy group, ethoxy group, propoxy group, isopropoxy group, etc.), halogen An atom (a fluorine atom, a chlorine atom, a bromine atom, an iodine atom), a hydroxyl group, etc. are mentioned.

The compound of the present invention includes any stereoisomer, optical isomer, tautomer, any mixture thereof and the like. In addition, the compound of the present invention includes all compounds that are metabolized in vivo and converted into the general formula (I) and compounds that are converted into salts, so-called prodrugs. Examples of the group that forms a prodrug of the compound of the present invention include those described in Prog. Med., 5 , 2157, 1985. and those described in Hirokawa Shoten 1990, “Development of Drugs”, Volume 7, Molecular Design, page 163. Group.

  The term “pharmacologically acceptable salt” refers to a book that retains the biological effectiveness and properties of the compounds of the invention represented by general formula (I) and is not biologically or otherwise inconvenient. Refers to a salt of an inventive compound. Examples of the addition salt of the compound of the present invention include those described in WILEY-VCH publication “Hondbook of Pharmaceutical Salts (2002, Camille G. Wermuth and P. Heinrich Stahl)”. For example, acid addition salts include hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, formic acid, acetic acid, trifluoroacetic acid, oxalic acid, Citric acid, malonic acid, fumaric acid, glutaric acid, adipic acid, maleic acid, tartaric acid, succinic acid, mandelic acid, malic acid, pantothenic acid, glutamic acid, aspartic acid and the like can be mentioned. Base addition salts are lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, ammonia, isopropylamine, diethylamine, triethylamine, ethanolamine, piperidine, pyridine, tris (hydroxymethyl) methylamine, tris ( Hydroxyethyl) methylamine, lysine, arginine, choline and the like.

The compounds represented by the above general formula (I) are exemplified below.
(1) 4- (4-Fluorobenzyloxy) -6,7-dimethyl-5-propyl-5H-pyrrolo [3,2-d] pyrimidine (2) 4- (2,6-dimethylbenzyloxy) -6 , 7-Dimethyl-5-propyl-5H-pyrrolo [3,2-d] pyrimidine (3) 4- (4-Fluorobenzyloxy) -6,7-dimethyl-5- (2-methylcyclopropylmethyl)- 5H-pyrrolo [3,2-d] pyrimidine (4) 4- (2,6-dimethylbenzyloxy) -6,7-dimethyl-5- (2-methylcyclopropylmethyl) -5H-pyrrolo [3,2 -d] pyrimidine (5) 4- (4-fluorobenzyloxy) -6,7-dimethyl-5-propenyl-5H-pyrrolo [3,2-d] pyrimidine (6) 4- (4-fluorobenzyloxy) -5-Methoxymethyl-6,7-dimethyl-5H-pyrrolo [3,2-d] pyrimidine (7) 4- (2,6-dimethylbenzyloxy) -5-methoxymethyl-6,7-dimethyl-5H -Pyrrolo [3,2-d] pyrimidine (8) 4- (4-fluorobenzyloxy) -6,7-dimethyl-5- (2-trimethylsilanyl eth Cymethyl) -5H-pyrrolo [3,2-d] pyrimidine (9) 4- (2,6-dimethylbenzyloxy) -6,7-dimethyl-5- (2-trimethylsilanylethoxymethyl) -5H-pyrrolo [3,2-d] pyrimidine (10) 4-(-fluorobenzyloxy) -6,7-dimethyl-5H-pyrrolo [3,2-d] pyrimidine

(11) 4- (2,6-dimethylbenzyloxy) -6,7-dimethyl-5H-pyrrolo [3,2-d] pyrimidine (12) 2-chloro-4- (4-fluorobenzyloxy) -6 , 7-Dimethyl-5-propyl-5H-pyrrolo [3,2-d] pyrimidine (13) 4- (4-Fluorobenzyloxy) -6,7-dimethyl-5-propyl-5H-pyrrolo [3,2 -d] pyrimidine-2-carbonitrile (14) 4- (4-fluorobenzyloxy) -6,7-dimethyl-5-propyl-5H-pyrrolo [3,2-d] pyrimidine-2-carboxylic acid dimethylamide (15) 4- (4-Fluorobenzyloxy) -6,7-dimethyl-5-propyl-5H-pyrrolo [3,2-d] pyrimidine-2-carboxylic acid (2-hydroxypropyl) amide
(16) 2-amino-4- (4-fluorobenzyloxy) -6,7-dimethyl-5-propyl-5H-pyrrolo [3,2-d] pyrimidine (17) N- [4- (4-fluoro (Benzyloxy) -6,7-dimethyl-5-propyl-5H-pyrrolo [3,2-d] pyrimidin-2-yl] acetamide (18) N- [4- (4-fluorobenzyloxy) -6,7 -Dimethyl-5-propyl-5H-pyrrolo [3,2-d] pyrimidin-2-yl] propionamide (19) N- [4- (4-fluorobenzyloxy) -6,7-dimethyl-5-propyl -5H-pyrrolo [3,2-d] pyrimidin-2-yl] benzamide (20) N- [4- (4-fluorobenzyloxy) -6,7-dimethyl-5-propyl-5H-pyrrolo [3, 2-d] pyrimidin-2-yl] methanesulfonamide

(21) N- [4- (4-Fluorobenzyloxy) -6,7-dimethyl-5-propyl-5H-pyrrolo [3,2-d] pyrimidin-2-yl] ethanesulfonamide (22) N- [4- (4-Fluorobenzyloxy) -6,7-dimethyl-5-propyl-5H-pyrrolo [3,2-d] pyrimidin-2-yl] benzenesulfonamide (23) 2-amino-4- ( 4-Fluorobenzyloxy) -6,7-dimethyl-5- (2-methylcyclopropylmethyl) -5H-pyrrolo [3,2-d] pyrimidine (24) N- [4- (4-fluorobenzyloxy) -6,7-dimethyl-5- (2-methylcyclopropylmethyl) -5H-pyrrolo [3,2-d] pyrimidin-2-yl] methanesulfonamide (25) 2-amino-4- (2,6 -Dimethylbenzyloxy) -6,7-dimethyl-5-propyl-5H-pyrrolo [3,2-d] pyrimidine (26) N- [4- (2,6-dimethylbenzyloxy) -6,7-dimethyl -5-propyl-5H-pyrrolo [3,2-d] pyrimidin-2-yl] methanesulfonamide (27) 2-amino-4- ( 2,6-Dimethylbenzyloxy) -6,7-dimethyl-5- (2-methylcyclopropylmethyl) -5H-pyrrolo [3,2-d] pyrimidine (28) N- [4- (2,6- (Dimethylbenzyloxy) -6,7-dimethyl-5- (2-methylcyclopropylmethyl) -5H-pyrrolo [3,2-d] pyrimidin-2-yl] methanesulfonamide (29) N- [4- ( 2,6-Dimethoxybenzyloxy) -6,7-dimethyl-5-propyl-5H-pyrrolo [3,2-d] pyrimidin-2-yl] methanesulfonamide (30) N- [4- (Indan-1 -Yloxy) -6,7-dimethyl-5-propyl-5H-pyrrolo [3,2-d] pyrimidin-2-yl] methanesulfonamide

(31) N- [4- (5-Fluoroindan-1-yloxy) -6,7-dimethyl-5-propyl-5H-pyrrolo [3,2-d] pyrimidin-2-yl] methanesulfonamide (32 ) N- [6,7-Dimethyl-4- (2-methylindan-1-yloxy) -5-propyl-5H-pyrrolo [3,2-d] pyrimidin-2-yl] methanesulfonamide (33) N -[4- (7-Methoxyindan-1-yloxy) -6,7-dimethyl-5-propyl-5H-pyrrolo [3,2-d] pyrimidin-2-yl] methanesulfonamide (34) N- [ 6,7-dimethyl-5-propyl-4- (1,2,3,4-tetrahydronaphthalen-1-yloxy) -5H-pyrrolo [3,2-d] pyrimidin-2-yl] methanesulfonamide (35 ) 4- (4-Fluorobenzyloxy) -6,7-dimethyl-2-methylsulfanyl-5-propyl-5H-pyrrolo [3,2-d] pyrimidine (36) 4- (4-fluorobenzyloxy)- 2-Methanesulfinyl-6,7-dimethyl-5-propyl-5H-pyrrolo [3,2-d] pyrimidine (37) 4- (4-Fluorobenzyloxy) -2-methanesulfonyl-6,7-dimethyl-5-propyl-5H-pyrrolo [3,2-d] pyrimidine (38) 4- (4-fluorobenzylamino) -6 , 7-dimethyl-5H-pyrrolo [3,2-d] pyrimidine (39) 4- (2,6-dimethylbenzylamino) -6,7-dimethyl-5H-pyrrolo [3,2-d] pyrimidine (40 ) 4- (4-Fluorobenzylamino) -6,7-dimethyl-5-propyl-5H-pyrrolo [3,2-d] pyrimidine

(41) 4- (2,6-dimethylbenzylamino) -6,7-dimethyl-5-propyl-5H-pyrrolo [3,2-d] pyrimidine (42) N- [4- (4-fluorobenzylamino) ) -6,7-dimethyl-5-propyl-5H-pyrrolo [3,2-d] pyrimidin-2-yl] methanesulfonamide (43) N- [4- (2,6-dimethylbenzylamino) -6 , 7-Dimethyl-5-propyl-5H-pyrrolo [3,2-d] pyrimidin-2-yl] methanesulfonamide (44) N- [4- (indan-1-ylamino) -6,7-dimethyl- 5-propyl-5H-pyrrolo [3,2-d] pyrimidin-2-yl] methanesulfonamide (45) 4- (4-fluorobenzylamino) -6,7-dimethyl-2-methylsulfanyl-5-propyl -5H-pyrrolo [3,2-d] pyrimidine (46) 4- (4-fluorobenzylamino) -2-methanesulfinyl-6,7-dimethyl-5-propyl-5H-pyrrolo [3,2-d] Pyrimidine (47) 4- (4-fluorobenzylamino) -2-methanesulfonyl-6,7-dimethyl-5-propyl Lopyl-5H-pyrrolo [3,2-d] pyrimidine (48) 4- [2- (4-fluorophenyl) ethyl] -6,7-dimethyl-5-propyl-5H-pyrrolo [3,2-d] Pyrimidine (49) 4- [2- (2,6-dimethylphenyl) ethyl] -6,7-dimethyl-5-propyl-5H-pyrrolo [3,2-d] pyrimidine (50) 4- [2- ( 4-Fluorophenyl) ethyl] -5-methoxymethyl-6,7-dimethyl-5H-pyrrolo [3,2-d] pyrimidine

(51) 4- [2- (2,6-Dimethylphenyl) ethyl] -5-methoxymethyl-6,7-dimethyl-5H-pyrrolo [3,2-d] pyrimidine (52) 4- [2- ( 4-Fluorophenyl) ethyl] -6,7-dimethyl-5- (2-trimethylsilanylethoxymethyl) -5H-pyrrolo [3,2-d] pyrimidine (53) 4- [2- (2,6- Dimethylphenyl) ethyl] -6,7-dimethyl-5- (2-trimethylsilanylethoxymethyl) -5H-pyrrolo [3,2-d] pyrimidine (54) 4- [2- (4-fluorophenyl) ethyl ] -6,7-dimethyl-5H-pyrrolo [3,2-d] pyrimidine (55) 4- [2- (2,6-dimethylphenyl) ethyl] -6,7-dimethyl-5H-pyrrolo [3, 2-d] pyrimidine (56) N- {4- [2- (4-fluorophenyl) ethyl] -6,7-dimethyl-5-propyl-5H-pyrrolo [3,2-d] pyrimidin-2-yl } Methanesulfonamide (57) 4- [2- (4-fluorophenyl) ethyl] -6,7-dimethyl-2-methylsulfanyl-5-propyl-5H-pyrrolo [3,2-d] pyrimidine 58) 4- [2- (4-Fluorophenyl) ethyl] -2-methanesulfinyl-6,7-dimethyl-5-propyl-5H-pyrrolo [3,2-d] pyrimidine (59) 4- [2- (4-Fluorophenyl) ethyl] -2-methanesulfonyl-6,7-dimethyl-5-propyl-5H-pyrrolo [3,2-d] pyrimidine

  The compound of the present invention can be produced by the following method. Examples of the protective group used in the production include the protective groups described in “Protective Groups in Organic Synthesis (1999, Theodora W. Greene and Peter G. M. Wuts)” published by WILEY-Interscience.

A. The synthesis of the pyrrolo [3,2-d] pyrimidine derivative in which R ² and R ³ in the general formula (I) are methyl groups and R ⁴ is a hydrogen atom is synthesized via a synthesis intermediate (X). A production example of this synthetic intermediate (X) is shown in the following scheme 1. The starting compound 3-cyano-2-butanone (VI) can be prepared according to the method described in the literature (for example, International Publication No. 03/014067 pamphlet, J. Pharm. Soc. Japan, 1956, 76 , 60).

First step: A step of obtaining enamine (VII) by reaction of 3-cyano-2-butanone (VI) and diethyl aminomalonate. The reaction is performed in the presence of sodium acetate in a mixture of alcohols such as methanol and ethanol and water, or in an inert solvent such as benzene, toluene, ether, tetrahydrofuran (THF), and 1,4-dioxane. The reaction is carried out at 0 ° C. to the solvent reflux temperature.
Second step: A step of obtaining pyrrole derivative (VIII) from enamine (VII). The reaction is usually sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium hydride, potassium hydride, triethylamine, 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), lithium diisopropylamide The reaction is carried out in the presence of a base such as (LDA), potassium carbonate, sodium carbonate and the like in an inert solvent, and preferable examples include methanol, ethanol, ether, THF, 1,4-dioxane, benzene, toluene and the like. The reaction is carried out at 0 ° C. to the solvent reflux temperature.

Third step: A step of obtaining pyrrolo [3,2-d] pyrimidone (IX) by reaction of pyrrole derivative (VIII) with formamidine. The reaction is carried out in an inert solvent, and preferred examples include methanol, ethanol, ether, THF, 1,4-dioxane, benzene, toluene and the like. The reaction is carried out at 0 ° C. to the solvent reflux temperature.
In addition, the 1st-3rd process can be performed according to the method of literature (for example, J. Org. Chem., 1999, 64 , 8411 etc.).
Fourth step: This is a method of obtaining intermediate compound (X) by reaction of compound (IX) with phosphorus oxychloride. The reaction is usually carried out without solvent or in an inert solvent such as benzene or toluene. The reaction is usually performed at room temperature to the solvent reflux temperature.

B. In formula (I), R ² and R ³ are methyl groups, and R ⁴ may be branched alkyl group, —NR ⁸ R ⁹ (provided that R ⁸ and R ⁹ are the same as above) or chlorine atom A pyrrolo [3,2-d] pyrimidine derivative is synthesized via a synthetic intermediate (XII). A production example of this synthetic intermediate (XII) is shown in the following scheme 2. The starting compound (XII) can be produced according to the method described in the literature (for example, J. Med. Chem., 2000, 43 , 4288, etc.).

Fifth step: A step of obtaining a pyrrolo [3,2-d] pyrimidine derivative (XI) (wherein R ²⁰ is a branched alkyl group, —NH ₂ or a hydroxyl group) from the pyrrole derivative (VIII). . In the reaction, pyrrole derivative (VIII) is branched in the presence of an alkyl nitrile (where R ²⁰ is an alkyl group which may be branched) or cyanamide (where R ²⁰ is —NH ₂ ) and hydrogen chloride. The reaction is performed, or after reacting with potassium cyanate (wherein R ²⁰ is a hydroxyl group), treatment is performed with an aqueous alkali solution such as sodium hydroxide, potassium hydroxide, calcium hydroxide or the like. The reaction is usually carried out without solvent or in an inert solvent such as benzene, toluene, ether, THF, 1,4-dioxane. The reaction is usually performed at room temperature to the solvent reflux temperature.
Step 6: Step of obtaining compound (XII) (wherein R ²¹ is an alkyl group which may be branched, —NH ₂ or a chlorine atom) by reaction of compound (XI) with phosphorus oxychloride. The reaction is usually carried out without solvent or in an inert solvent such as benzene or toluene. The reaction is usually performed at room temperature to the solvent reflux temperature.

C. In general formula (I), R ² and R ³ are methyl groups, and R ⁴ is —S (O) nR ¹⁰ (where R ¹⁰ and n are the same as defined above). The pyrimidine derivative is synthesized via a synthetic intermediate (XV). This synthetic intermediate (XV) can be produced by the method of Scheme 3 below.

Seventh step: A step of obtaining pyrrolo [3,2-d] pyrimidine derivative (XIII) from pyrrole derivative (VIII). The reaction is carried out according to the method described in the literature (for example, J. Med. Chem., 2000, 43 , 4288, etc.). The reaction is carried out by reacting the pyrrole derivative (VIII) with ethoxycarbonyl isothiocyanate and then treating with an alkaline aqueous solution such as sodium hydroxide, potassium hydroxide or calcium hydroxide. The reaction is usually carried out from room temperature to the solvent reflux temperature in the absence of solvent or in an inert solvent such as benzene, toluene, ether, THF, 1,4-dioxane.

Eighth step: In this step, compound (XIV) is obtained by reacting compound (XIII) with R ¹⁰ -A. The reaction is usually carried out in an inert solvent in the presence of a base such as sodium methoxide, sodium ethoxide, potassium-t-butoxide, sodium hydride, potassium hydride, triethylamine, DBU, LDA, potassium carbonate, sodium carbonate, etc. . Preferred examples of the inert solvent include ether, THF, 1,4-dioxane, dichloromethane, acetone, benzene, toluene, N, N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO) and the like. Further, a crown ether compound such as 18-crown-6 may be added. The reaction is usually performed at −78 ° C. to solvent reflux temperature. (In the formula, A represents a halogen atom, a methanesulfonyloxy group, a toluenesulfonyloxy group, or a trifluoromethanesulfonyloxy group, and R ¹⁰ is the same as described above.)
Ninth step: In this step, compound (XV) is obtained by reacting compound (XIV) with N-chlorosuccinimide (NCS). The reaction is usually carried out without solvent or in an inert solvent such as ether, THF, 1,4-dioxane and the like. The reaction is usually performed at room temperature to the solvent reflux temperature.

D. Next, a method for producing the pyrrolo [3,2-d] pyrimidine derivative represented by the general formula (I) of the present invention from the aforementioned synthetic intermediate will be described.
D-1. A pyrrolo [3,2-d] pyrimidine derivative in which R ² and R ³ in the general formula (I) are a methyl group and the —X— group is an —O— group can be produced according to the method of Scheme 4 below. .

Tenth step: In this step, compound (XVII) is obtained by reacting 7-chloropyrrolo [3,2-d] pyrimidine derivative (XVI) with R ¹ -A. The reaction is usually carried out in an inert solvent in the presence of a base such as sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium hydride, potassium hydride, triethylamine, DBU, LDA, potassium carbonate, sodium carbonate. Preferable examples include ether, THF, 1,4-dioxane, dichloromethane, acetone, benzene, toluene, DMF, DMSO and the like. Further, a crown ether compound such as 18-crown-6 may be added. The reaction is usually carried out at the reflux temperature of the solvent from -78 ° C. (provided that, A, ^{R 1} is synonymous with the aforementioned.).

Eleventh step: Step for obtaining compound (XVIII) by reacting compound (XVII) with R ⁵ —OH. The reaction is usually carried out in an inert solvent in the presence of a base such as sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium hydride, potassium hydride, triethylamine, DBU, LDA, potassium carbonate, sodium carbonate. Preferable examples include ether, THF, 1,4-dioxane, dichloromethane, acetone, benzene, toluene, DMF, DMSO and the like. Further, a crown ether compound such as 18-crown-6 may be added. The reaction is usually carried out at −78 ° C. to solvent reflux temperature (provided that R ⁵ is as defined above).

Twelfth step: In the case where R ¹ is an allyl group, a methoxymethyl group, a benzyl group, a p-methoxybenzyl group, a trimethylsilylethoxymethyl group or the like, this is a step for obtaining a compound (XVIII) under deprotection conditions. As deprotection conditions, for example, a potassium-t-butoxide / DMSO reaction system (R ¹ is an allyl group), a proton acid and Lewis acid reaction system (R ¹ is a methoxymethyl group), a catalyst such as palladium carbon is used. Catalytic hydrocracking reaction (R ¹ is benzyl group), reaction system using diammonium cerium nitrate (R ¹ is p-methoxybenzyl group), reaction system using tetrabutylammonium fluoride, hydrofluoric acid, etc. (R ¹ is a trimethylsilylethoxymethyl group) and the like.

D-2. A pyrrolo [3,2-d] pyrimidine derivative in which R ² and R ³ in the general formula (I) are a methyl group and the —X— group is a —NH— group can be produced according to the method of Scheme 5 below. .

Thirteenth step: A step of obtaining compound (XX) by reaction of 7-chloropyrrolo [3,2-d] pyrimidine derivative (XVII) with R ⁵ —NH ₂ . The reaction is usually carried out without solvent or in an inert solvent such as ether, THF, 1,4-dioxane, dichloromethane, acetone, benzene, toluene, xylene, DMF, DMSO. The reaction is usually performed at room temperature to the solvent reflux temperature.

D-3. A pyrrolo [3,2-d] pyrimidine derivative in which R ² and R ³ in the general formula (I) are a methyl group and the —X— group is a —CH ₂ — group can be produced according to the method of Scheme 6 below. it can.

14th step: A step of obtaining a compound (XXI) by a Suzuki-Miyaura reaction between a 7-chloropyrrolo [3,2-d] pyrimidine derivative (XVII) and a boron compound such as R ⁵ —CH ₂ -9-BBN. . The reaction was carried out using an aqueous alkali solution such as sodium carbonate or potassium phosphate, tetrakis (triphenylphosphine) palladium, bis (triphenylphosphine) palladium dichloride, [1,1'-bis (diphenylphosphino) ferrocene] palladium dichloride, tris (di Benzylideneacetone) dipalladium, palladium acetate, palladium chloride, palladium carbon and the like, in the presence of a palladium catalyst, in an inert solvent such as THF, 1,4-dioxane, benzene, toluene, DMF, DMSO. The reaction is usually performed at room temperature to the solvent reflux temperature.

15th step: When R ¹ is an allyl group, a methoxymethyl group, a benzyl group, a p-methoxybenzyl group, a trimethylsilylethoxymethyl group or the like, this is a step for obtaining a compound (XXII) under deprotection conditions. As deprotection conditions, for example, a potassium-t-butoxide / DMSO reaction system (R ¹ is an allyl group), a proton acid and Lewis acid reaction system (R ¹ is a methoxymethyl group), a catalyst such as palladium carbon is used. Catalytic hydrocracking reaction (R ¹ is benzyl group), reaction system using diammonium cerium nitrate (R ¹ is p-methoxybenzyl group), reaction system using tetrabutylammonium fluoride, hydrofluoric acid, etc. (R ¹ is a trimethylsilylethoxymethyl group) and the like.

After completion of each reaction, the target compound of each reaction is collected from the reaction mixture according to a conventional method. For example, if insolubles are present, filter appropriately and remove the solvent under reduced pressure or after removing the solvent under reduced pressure, add water to the residue and extract with a water-immiscible organic solvent such as ethyl acetate. After drying with anhydrous magnesium sulfate or the like, it can be obtained by distilling off the solvent. If necessary, it can be further purified by conventional methods such as recrystallization and column chromatography.

The pyrrolo [3,2-d] pyrimidine derivative of the present invention has excellent acid secretion inhibitory action and excellent antibacterial activity against Helicobacter pylori, peptic ulcer, acute or chronic gastric ulcer, duodenal ulcer, gastritis, reflux esophagus It is useful as a prophylactic agent for inflammation, gastroesophageal reflex disease, dyspepsia, gastric hyperacidity, a therapeutic agent or an ulcer disease during surgery, or an antibacterial agent against Helicobacter pylori.

When the compound represented by the general formula (I) of the present invention or a pharmacologically acceptable salt thereof is used as the above pharmaceutical product, an appropriate pharmacologically acceptable carrier, excipient (for example, starch, lactose, etc.) Sucrose, calcium carbonate, calcium phosphate, etc.), binders (eg starch, gum arabic, carboxymethylcellulose, hydroxypropylcellulose, crystalline cellulose, alginic acid, gelatin, polyvinylpyridone etc.), lubricants (eg stearic acid, stearic acid) Magnesium, calcium stearate, talc, etc.), disintegrating agents (eg, carboxymethylcellulose, talc, etc.), diluents (eg, physiological saline, etc.), etc., and powders, fine granules, capsules, tablets, It can be administered orally or parenterally in the form of external preparations or injections.

  The dosage of the composition of the present invention varies depending on the administration route, target disease, patient symptom, body weight or age, and the compound to be used, and can be appropriately set according to the purpose of administration. Usually, in the case of oral administration to adults, 0.01 to 1000 mg / kg body weight / day, preferably 0.05 to 500 mg / kg body weight / day, is preferably administered in one to several times a day.

The compound represented by the general formula (I) of the present invention or a pharmacologically acceptable salt thereof is also used in combination with other drugs, particularly therapeutic agents used for digestive diseases, for the prevention or treatment of ulcerative diseases. Can be used. Other drugs include, for example, sedatives such as diazepam and chlordiazepoxide: antacids such as sodium bicarbonate, magnesium oxide, magnesium hydroxide, magnesium silicate, aluminum hydroxide, and aluminum silicate: cimetidine, ranitidine Histamine H ₂ blockers such as omeprazole, esomeprazole, pantoprazole, rabeprazole, tenatoprazole, ilaprazole, lansoprazole: trospium, solifenacin, tolterodine, famotidine, lafutidine, nizatidine, roxatidine , Muscarinic receptor blockers such as tiotropium, citropium, oxitropium, ipratropium, tiquidium, darifenacin, imidafenacin: urogastron , Proglumide, secretin and other anti-gastrin drugs: sodium azulene sulfonate, azuroxa, L-glutamine, teprenone, rebamipide, polaprezinc, ecabet, praunotol, cetraxate, sucralfate, etc .: Misoprostol Prostaglandins such as enprostil: dolasetron, palonosetron, allosetron, azasetron, ramosetron, mitrazapine, granisetron, tropisetron, ondansetron, serotonin 5-HT ₃ receptor blockers such as indisetron: tegaserod, mosapride, Shinitapurido, serotonin 5-HT ₄ receptor agonists, such as oxy triptans: metoclopramide, Donpe pyrrolidone, shielding dopamine D ₂ receptors, such as levo sulpiride Drugs: Motilin agonists such as erythromycin, mitensinal, SLV-305, and acylmotine: GIPs such as diacetylglycerol, 3-bromo-5-methyl-2-phenylpyrazolo [1,5-a] pyrimidin-7-ol Inhibitors: alanidipine, lacidipine, falodipine, azelnidipine, clinidipine, lomerizine, diltiazem, gallopamil, efonidipine, nisoldipine, amlodipine, lercanidipine, bevantolol, nicardipine, isradipine, benidipine, verapamil, nitrendipine, fenidipine, valendipin, protidipine Calcium channel antagonists such as nilvadipine, nimodipine, and fasudil: potassium channels such as pinacidil, tirisolol, nicorandil, NS-8, retigabine Mouth drugs: baclofen, GABA _B agonists such as AZD-3355: GAS-360, GABA B blockers such as SGS-742: Nepadeyutanto, TAK-637, MK-869 , Ranepitanto tachykinins blockers such as Dapitanto : NO synthase inhibitors such as GW-274150, Tyrarginine, Guanidioethyl disulfide, Nitroflurbiprofen: Vanilloid receptor 1 blockers such as AMG-517 and GW-705498: Squalamine, DY-9760 Calmodulin blockers such as: Dobutamine, Denopamine, Xamoterol, β1 agonists such as Denopamine, Docarpamine, Xamoterol: Salbutamol, Terbutaline, Alformoterol, Meladrin, Mabuterol, Ritodrine, Fenoterol, Cle Β2 agonists such as nbuterol, formoterol, procaterol, pyrbuterol, bambuterol, tulobuterol, dopexamine, levosalbutamol: β-agonists such as isoproterenol, terbutaline: clonidine, medetomidine, lofexidine, moxonidine, tizanidine, guanfacine, riguanazole, , Α2 agonists such as dexmedetomidine: Endothelin A blockers such as boncetane, atrasentan, ambrisentan, clazosentan, sitaxsentan, fundsentan, darsentan: opioid μ agonists such as morphine, fentanyl, loperamide, naloxone Opioid μ blockers such as buprenorphine and albimopan: acetylcholine such as Z-338 and KW-5092 Esterase release stimulants: CCK-B blockers such as YF-476 and S-0509: Glucagon blockers such as NN-2501 and A-770077: clarithromycin, roxithromycin, rokitamicin, flurithromycin, teri And anti-Helicobacter pylori drugs such as thromycin, amoxicillin, ampicillin, temocillin, bacampicillin, aspoxillin, sultamicillin, piperacillin, lenampicillin, tetracycline, metronidazole, bismuth hypocitrate, and bismuth subsalicylate.

The following are reference examples and general examples showing test examples of the pharmacological action of the compound represented by the general formula (I) of the present invention and production examples of synthetic intermediates of the compound represented by the general formula (I) of the present invention. The present invention will be described more specifically with reference to examples showing production examples of the compound represented by formula (I).
[Test example]
Test Example 1: Evaluation of inhibitory action of H ⁺ -K ⁺ ATPase According to the method of Hongo et al. {Japan J. Pharmacol., 52, 295 (1990)}, a microsomal fraction prepared from a gastric mucosa layer of a fresh pig was extracted with H ⁺ -K. ⁺ Used as ATPase preparation. Add 0.01 mL of the test compound solution dissolved in DMSO to 0.49 mL of 2 mM BIS-Tris acetate buffer (pH 5.5 or 7.4) containing 20-40 μg / mL enzyme preparation in terms of protein concentration, and add it to 37 ° C. Incubated for 30 minutes. The enzymatic reaction was initiated by adding 0.5 mL of 4 mM adenosine triphosphate disodium solution adjusted with 75 mM BIS-Tris acetate buffer (containing 10 mM KCl, 4 mM MgCl ₂ , pH 7.4). The enzyme reaction was performed for 15 minutes, and 1 mL of 15% trichloroacetic acid solution was added to stop the reaction. After centrifuging the reaction solution at 2000 g for 10 minutes, the inorganic phosphate produced by hydrolysis of adenosine triphosphate in the supernatant was colorimetrically determined by the Fiske-Subbarow method {J. Biol. Chem., 66, 375 (1925)}. Quantified. In addition, the amount of inorganic phosphoric acid in the reaction solution without KCl was measured in the same manner, and this difference was defined as H ⁺ -K ⁺ ATPase activity by subtracting from the amount of inorganic phosphoric acid in the presence of KCl. The inhibition rate (%) was determined from the control activity value and the activity value at each concentration of the test compound, and the 50% inhibitory concentration (IC ₅₀ ) against H ⁺ -K ⁺ ATPase was determined. The results are shown in Table 1.

Test Example 2: Helicobacter pylori growth inhibitory action
H.pylori bacterial solution pre-cultured in Brain Heart Infusion Broth (BHI-broth) containing 10% Fetal Bovine Serum (FBS) containing test compound solution dissolved in DMSO (DMSO final concentration in culture medium is 1%) (ATCC43504 strain, viable cell count: 2.5 × 10 ⁶ CFU / mL) was added and shaken for 24 hours at 37 ° C under microaerobic conditions (5% O ₂ , 10% CO ₂ , 85% N ₂ ). Culture was performed. In addition, what added DMSO which does not contain a test substance was implemented similarly as control. Prepare appropriate dilution series with BHI-broth from the cultured bacterial solution, apply 0.1mL of each diluted bacterial solution on equine blood agar medium, and culture for 7 days at 37 ° C under microaerobic condition did. Count the number of colonies of H.pylori formed on the agar medium, multiply by the dilution factor, determine the number of viable bacteria in each bacterial solution, and reduce the number of viable H.pylori bacteria in the control by 90% The concentration of the substance (MIC ₉₀ ) was calculated. The results are shown in Table 1.

[Reference example]
Reference example 1
Production example of 3-amino-4,5-dimethyl-1H-pyrrole-2-carboxylic acid ethyl ester
112.4 g of aminomalonic acid diethyl ester hydrochloride and 43.6 g of sodium acetate were added to a mixture of 1500 mL of 3-cyano-2-butanone in 1500 mL of methanol and 300 mL of water, and the mixture was stirred at room temperature for 20 hours. The reaction solution was concentrated under reduced pressure, methanol was distilled off, and the residual aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. 14.5 g of sodium ethoxide was added to a 1500 mL solution of the crude product in ethanol, and the mixture was stirred at 80 ° C. for 4 hours. The reaction mixture was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate / hexane) to give 52.3 g of the title compound as yellow crystals.
¹ H-NMR (CDCl ₃ ) δ = 1.29-1.33 (m, 3H), 1.84 (s, 3H), 2.13 (s, 3H), 4.02-4.26 (m, 4H), 4.25 (m, 2H), 7.63 -7.96 (br, 1H).

Reference example 2
Production example of 6,7-dimethyl-3,5-dihydropyrrolo [3,2-d] pyrimidin-4-one
6.40 g of formamidine acetate was added to a 60 mL ethanol solution of 7.50 g of 3-amino-4,5-dimethyl-1H-pyrrole-2-carboxylic acid ethyl ester, and the mixture was heated to reflux for 16 hours. The reaction mixture was allowed to cool, and the precipitated crystals were collected by filtration. The obtained crystals were washed with ethanol and dried to give the title compound (5.24 g) as gray crystals.
¹ H-NMR (DMSO-d ₆ ) δ = 2.06 (s, 3H), 2.25 (s. 3H), 7.71 (s, 1H), 11.47 (br-s, 2H).
Reference example 3
Production example of 4-chloro-6,7-dimethyl-5H-pyrrolo [3,2-d] pyrimidine
A mixture of 5.24 g of 6,7-dimethyl-3,5-dihydropyrrolo [3,2-d] pyrimidin-4-one and 75 mL of phosphorus oxychloride was stirred at 130 ° C. for 20 hours. The reaction mixture was concentrated under reduced pressure, and ice and saturated aqueous sodium hydrogen carbonate were added to the residue to adjust the pH to about 8. Extraction was performed with ethyl acetate, and the organic layer was washed with saturated brine. The extract was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to give 5.26 g of the title compound as yellow crystals.
¹ H-NMR (CDCl ₃ ) δ = 2.29 (s, 3H), 2.50 (s, 3H), 8.65 (br-s, 1H), 8.69 (s, 1H).

Reference example 4
Production example of 4-chloro-6,7-dimethyl-5-propyl-5H-pyrrolo [3,2-d] pyrimidine
To a solution of 411 mg of 4-chloro-6,7-dimethyl-5H-pyrrolo [3,2-d] pyrimidine in 6 mL of DMF was added 110 mg of sodium hydride under ice cooling, and the mixture was stirred for 30 minutes. To the reaction solution, 0.23 mL of n-propane bromide was added and stirred at room temperature for 5 hours. The reaction mixture was poured into saturated aqueous ammonium chloride and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate / hexane) to give 434 mg of the title compound as pale yellow crystals.
¹ H-NMR (CDCl ₃ ) δ = 0.98 (t, 3H, J = 7.6Hz), 1.76-1.82 (m, 2H), 2.30 (s, 3H), 2.44 (s, 3H), 4.36 (t, J = 8.2Hz, 2H), 8.61 (s, 1H).
Reference Example 5
Production example of 4-chloro-6,7-dimethyl-5- (2-methylcyclopropylmethyl) -5H-pyrrolo [3,2-d] pyrimidine
Use 4-chloro-6,7-dimethyl-5H-pyrrolo [3,2-d] pyrimidine and 1-bromomethyl-2-methylcyclopropane in the same manner as in Reference Example 4 to give the title compound as a yellow oil. Obtained.
¹ H-NMR (CDCl ₃ ) δ = 0.27-0.31 (m, 1H), 0.50-0.55 (m, 1H), 0.76-0.91 (m, 2H), 0.99 (d, J = 5.6Hz, 3H), 2.31 (s, 3H), 2.46 (s, 3H), 4.39 (d, J = 6.3Hz, 2H), 8.62 (s, 1H).

Reference Example 6
Production example of 5-allyl-4-chloro-6,7-dimethyl-5H-pyrrolo [3,2-d] pyrimidine
The title compound was obtained as a yellow oil in the same manner as in Reference Example 4 using 4-chloro-6,7-dimethyl-5H-pyrrolo [3,2-d] pyrimidine and allyl bromide.
¹ H-NMR (CDCl ₃ ) δ = 2.32 (s, 3H), 2.41 (s, 3H), 4.66 (d, J = 16.8Hz, 1H), 5.07-5.09 (m, 1H), 5.16 (d, J = 10.7Hz, 1H), 5.96-6.03
(m, 1H), 8.63 (s, 1H).
Reference Example 7
Production example of 4-chloro-5-methoxymethyl-6,7-dimethyl-5H-pyrrolo [3,2-d] pyrimidine
The title compound was obtained as yellow crystals in the same manner as in Reference Example 4 using 4-chloro-6,7-dimethyl-5H-pyrrolo [3,2-d] pyrimidine and chloromethyl methyl ether.
¹ H-NMR (CDCl ₃ ) δ = 2.31 (s, 3H), 2.51 (s, 3H), 3.32 (s, 3H), 5.80 (s, 2H), 8.68 (s, 1H).

Reference Example 8
Production example of 4-chloro-6,7-dimethyl-5- (2-trimethylsilanylethoxymethyl) -5H-pyrrolo [3,2-d] pyrimidine
Using 4-chloro-6,7-dimethyl-5H-pyrrolo [3,2-d] pyrimidine and 2- (chloromethoxy) ethyltrimethylsilane in the same manner as in Reference Example 4, the title compound as a yellow oil Obtained.
¹ H-NMR (CDCl ₃ ) δ = −0.01 (s, 9H), 0.94 (t, J = 8.3Hz, 2H), 2.35 (s, 3H), 2.56 (s, 3H), 3.62 (t, J = 8.1Hz, 2H), 5.86 (s, 2H), 8.71 (s, 1H).
Reference Example 9
Production example of 6,7-dimethyl-5H-pyrrolo [3,2-d] pyrimidine-2,4-diol
To a solution of 4.64 g of 3-amino-4,5-dimethyl-1H-pyrrole-2-carboxylic acid ethyl ester in 100 mL of acetic acid and 10 mL of water was added a 20 mL solution of 6.21 g of potassium cyanate in water, and the mixture was stirred at room temperature for 22 hours. The reaction solution was allowed to cool, and the precipitated crystals were collected by filtration. The crystals were washed with diethyl ether and water and dried. A mixture of 6% sodium hydroxide in 100 mL obtained was heated to reflux for 3 hours. 12N hydrochloric acid was added to the reaction solution to adjust the pH to about 6. The precipitated crystals were collected by filtration, washed with water and dried to give 1.87 g of the title compound as purple crystals.
¹ H-NMR (DMSO-d ₆ ) δ = 1.92 (s, 3H), 2.13 (s, 3H), 10.36 (br-s, 1H), 10.67 (br-s, 1H), 11.39 (br-s, 1H).

Reference Example 10
Production example of 2,4-dichloro-6,7-dimethyl-5H-pyrrolo [3,2-d] pyrimidine
The title compound was obtained as yellow crystals in the same manner as in Reference Example 3 using 6,7-dimethyl-5H-pyrrolo [3,2-d] pyrimidine-2,4-diol and phosphorus oxychloride.
¹ H-NMR (CDCl ₃ ) δ = 2.25 (s, 3H), 2.51 (s, 3H), 8.65 (br-s, 1H).
Reference Example 11
Example of production of 2,4-dichloro-6,7-dimethyl-5-propyl-5H-pyrrolo [3,2-d] pyrimidine
The title compound was obtained as white crystals in the same manner as in Reference Example 4 using 2,4-dichloro-6,7-dimethyl-5H-pyrrolo [3,2-d] pyrimidine and n-propane bromide.
¹ H-NMR (CDCl ₃ ) δ = 0.66 (t, J = 7.3Hz, 3H), 1.41-1.51 (m, 2H), 1.94 (s, 3H), 2.12 (s, 3H), 4.01 (t, J = 7.8Hz, 2H).

Reference Example 12
Production example of 2-amino-6,7-dimethyl-5H-pyrrolo [3,2-d] pyrimidin-4-ol
3-amino-4,5-dimethyl-1H-pyrrole-2-carboxylic acid ethyl ester 17.21 g in methanol 110 mL solution 1,3-bis (tert-butoxycarbonyl) -2-methyl-2-thiopseurea 34.28 g And acetic acid 34mL was added and it stirred at room temperature for 21.5 hours. The precipitated crystals were collected by filtration, washed with water, and dried. 115 mL of trifluoroacetic acid was added to a 230 mL solution of this crystal in methylene chloride, and the mixture was stirred at room temperature for 15 hours. The reaction solution was concentrated under reduced pressure, and a mixed solution of 230 mL of ethanol and 230 mL of 1N sodium hydroxide was heated to reflux for 3.5 hours. The reaction solution was concentrated under reduced pressure, and ethanol was distilled off. 10% hydrochloric acid was added to the residual aqueous layer to adjust the pH to about 6. The precipitated crystals were collected by filtration, washed with water and dried to give 16.82 g of the title compound as white crystals.
¹ H-NMR (DMSO-d ₆ ) δ = 1.99 (s, 3H), 2.20 (s, 3H), 7.36 (br-s, 2H), 11.72 (br-s, 1H).

Reference Example 13
Production example of 2-amino-4-chloro-6,7-dimethyl-5H-pyrrolo [3,2-d] pyrimidine
The title compound was obtained as yellow crystals in the same manner as in Reference Example 3 using 2-amino-6,7-dimethyl-5H-pyrrolo [3,2-d] pyrimidin-4-ol and phosphorus oxychloride.
¹ H-NMR (DMSO-d ₆ ) δ = 2.02 (s, 3H), 2.31 (s, 3H), 6.08 (br-s, 2H), 11.14 (br-s, 1H).
Reference Example 14
Production example of 2-amino-4-chloro-6,7-dimethyl-5-propyl-5H-pyrrolo [3,2-d] pyrimidine
2-amino-4-chloro-6,7-dimethyl-5H-pyrrolo [3,2-d] pyrimidine (3.50 g) in DMF (45 mL) was added n-propane bromide (0.23 mL), potassium carbonate, and potassium iodide (0.296 g). And stirred at 80 ° C. for 15.5 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate / hexane) to give 3.48 g of the title compound as yellow crystals.
¹ H-NMR (CDCl ₃ ) δ = 0.94 (t, J = 7.3Hz, 3H), 1.70-1.78 (m, 2H), 2.16 (s, 3H), 2.34 (s, 3H), 4.22 (t, J = 7.8Hz, 2H), 4.81 (br-s, 2H).

Reference Example 15
Preparation of 2-amino-4-chloro-6,7-dimethyl-5- (2-methylcyclopropylmethyl) -5H-pyrrolo [3,2-d] pyrimidine
The title compound was prepared in the same manner as in Reference Example 14 using 2-amino-4-chloro-6,7-dimethyl-5H-pyrrolo [3,2-d] pyrimidine and 1-bromomethyl-2-methylcyclopropane. Obtained as yellow crystals.
¹ H-NMR (CDCl ₃ ) δ = 0.23-0.28 (m, 1H), 0.46-0.51 (m, 1H), 0.83-0.87 (m, 2H), 0.98 (d, J = 5.9Hz, 3H), 2.17 (s, 3H), 2.36 (s.3H), 4.24 (d, J = 6.3Hz, 2H), 4.77 (br-s, 2H).
Reference Example 16
Production example of N- (4-chloro-6,7-dimethyl-5H-pyrrolo [3,2-d] pyrimidin-2-yl) methanesulfonamide
To a solution of 2.00 g of 2-amino-4-chloro-6,7-dimethyl-5H-pyrrolo [3,2-d] pyrimidine in 50 mL of pyridine is added 1.6 mL of methanesulfonyl chloride under ice-cooling, and the mixture is 4.5 hours at room temperature. Stir. The reaction mixture was concentrated under reduced pressure, and the residue was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate / hexane) to give 0.48 g of the title compound as white crystals.
¹ H-NMR (CDCl ₃ ) δ = 2.19 (s, 3H), 2.45 (s, 3H), 3.54 (s, 3H), 8.12 (br-s, 1H).

Reference Example 17
Production example of 2-mercapto-6,7-dimethyl-5H-pyrrolo [3,2-d] pyrimidin-4-ol
A 270 mL benzene solution of 10.00 g of 3-amino-4,5-dimethyl-1H-pyrrole-2-carboxylic acid ethyl ester and 7.20 g of ethoxycarbonyl isothiocyanate was heated to reflux for 2.5 hours. The reaction solution was concentrated under reduced pressure, and the precipitated crystals were collected by filtration, washed with n-hexane and dried. A mixture of 450% of the obtained crystals in 6% potassium hydroxide was heated to reflux for 16 hours. After allowing the reaction solution to cool, concentrated hydrochloric acid was added to adjust the pH to about 5. The precipitated crystals were collected by filtration, washed with water and dried to give 7.69 g of the title compound as purple crystals.
¹ H-NMR (DMSO-d ₆ ) δ = 2.00 (s, 3H), 2.17 (s.3H), 11.77 (br-s, 1H), 11.82 (br-s, 1H), 12.43 (br-s, 1H).
Reference Example 18
Production example of 6,7-dimethyl-2-methylsulfanyl-5H-pyrrolo [3,2-d] pyrimidin-4-ol
To a suspension of 7.69 g of 2-mercapto-6,7-dimethyl-5H-pyrrolo [3,2-d] pyrimidin-4-ol in 700 mL of acetone, add 4.40 g of potassium carbonate and 3.9 mL of iodomethane, and at room temperature for 21 hours Stir. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate / hexane) to give 3.83 g of the title compound as gray crystals.
¹ H-NMR (DMSO-d ₆ ) δ = 2.03 (s, 3H), 2.22 (s.3H), 2.52 (s, 3H), 11.50 (br-s, 1H), 11.85 (br-s, 1H) .

Reference Example 19
Example of production of 4-chloro-6,7-dimethyl-2-methylsulfanyl-5H-pyrrolo [3,2-d] pyrimidine To a solution of triphenylphosphine 18.58g in THF 145mL, add N-chlorosuccinimide 9.46g at room temperature. Stir for 1 hour. To the reaction solution was added a THF 95 mL solution of 6.94 g of 6,7-dimethyl-2-methylsulfanyl-5H-pyrrolo [3,2-d] pyrimidin-4-ol, and the mixture was heated to reflux for 15 hours. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate / hexane) to give 4.43 g of the title compound as yellow crystals.
¹ H-NMR (CDCl ₃ ) δ = 2.22 (s, 3H), 2.45 (s. 3H), 2.64 (s, 3H), 8.03 (br-s, 1H).
Reference Example 20
Production example of 4-chloro-6,7-dimethyl-2-methylsulfanyl-5-propyl-5H-pyrrolo [3,2-d] pyrimidine
4-Chloro-6,7-dimethyl-2-methylsulfanyl-5H-pyrrolo [3,2-d] pyrimidine and n-propane bromide were used in the same manner as in Reference Example 4 to give the title compound as yellow crystals. Obtained.
¹ H-NMR (CDCl ₃ ) δ = 0.95 (t, J = 7.2Hz, 3H), 1.72-1.78 (m, 2H), 2.23 (S, 3H), 2.39 (S, 3H), 2.63 (S, 3H ), 4.29 (t, J = 7.2Hz, 2H).

〔Example〕
Example 1
Preparation of 4- (4-fluorobenzyloxy) -6,7-dimethyl-5-propyl-5H-pyrrolo [3,2-d] pyrimidine
220 mg of 4-fluorobenzyl alcohol and 50 mg of 18-crown-6-ether were dissolved in 8 mL of THF, 400 mg of potassium t-butoxide was added, and the mixture was stirred at room temperature for 40 minutes. To the reaction solution, 200 mg of 4-chloro-6,7-dimethyl-5-propyl-5H-pyrrolo [3,2-d] pyrimidine obtained in Reference Example 4 was added, and the mixture was stirred at room temperature for 18.5 hours. The reaction mixture was poured into saturated aqueous ammonium chloride and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate / hexane) to give 170 mg of the title compound as pale yellow crystals.
¹ H-NMR (CDCl ₃ ) δ = 0.79 (t, J = 7.3Hz, 3H), 1.61-1.69 (m, 2H), 2.27 (S, 3H), .35 (S, 3H), 4.14-4.17 ( m, 2H), 5.53 (S, 2H),
7.05-7.09 (m, 2H), 7.43-7.47 (m, 2H), 8.43 (S, 1H).

Example 2
4- (2,6-Dimethylbenzyloxy) -6,7-dimethyl-5-propyl-5H-pyrrolo [3,2-d] pyrimidine 4-chloro-6,7-dimethyl obtained in Reference Example 4 The title compound was obtained as white crystals in the same manner as in Example 1 using -5-propyl-5H-pyrrolo [3,2-d] pyrimidine and 2,6-dimethylbenzyl alcohol.
¹ H-NMR (CDCl ₃ ) δ = 0.61 (t, J = 7.3Hz, 3H), 1.55 (m, 2H), 2.27 (s, 3H), 2.32 (s, 3H), 2.43 (s, 6H), 4.01 (t, J = 7.6Hz, 2H),
5.61 (s, 2H), 7.08 (d, J = 7.3Hz, 2H), 7.16 (m, 1H), 8.50 (s, 1H).
Example 3
Production of 4- (4-fluorobenzyloxy) -6,7-dimethyl-5- (2-methylcyclopropylmethyl) -5H-pyrrolo [3,2-d] pyrimidine 4-chloro- obtained in Reference Example 5 Using 6,7-dimethyl-5- (2-methylcyclopropylmethyl) -5H-pyrrolo [3,2-d] pyrimidine and 4-fluorobenzyl alcohol in the same manner as in Example 1, the title compound was white. Obtained as crystals.
¹ H-NMR (CDCl ₃ ) δ = 0.12-0.17 (m, 1H), 0.36-0.41 (m, 1H), 0.62 (m, 1H), 0.79-0.81 (m, 1H), 0.90 (d, J = 5.6Hz, 3H), 2.29 (s, 3H), 2.38 (s, 3H), 4.09 (dd, J = 7.2Hz, 14.6Hz, 1H), 4.21 (dd, J = 6.3Hz, 14.6Hz, 1H), 5.50-5.59 (m, 2H), 7.04-7.10 (m, 2H), 7.44-7.48 (m, 2H), 8.47 (s, 1H).

Example 4
Production of 4- (2,6-dimethylbenzyloxy) -6,7-dimethyl-5- (2-methylcyclopropylmethyl) -5H-pyrrolo [3,2-d] pyrimidine 4-obtained in Reference Example 5 Chloro-6,7-dimethyl-5- (2-methylcyclopropylmethyl) -5H-pyrrolo [3,2-d] pyrimidine and 2,6-dimethylbenzyl alcohol were used in the same manner as in Example 1, The title compound was obtained as white crystals.
¹ H-NMR (CDCl ₃ ) δ = 0.03-0.06 (m, 1H), 0.20-0.25 (m1H), 0.45 (m, 1H), 0.64-0.70 (m, IH), 0.80 (d, 3H, J = 5.8Hz), 2.28
(s, 3H), 2.35 (s, 3H), 2.44 (s, 6H), 3.93 (dd, J = 7.0Hz, 1H), 4.11 (dd, J = 6.3Hz, 14.6Hz, 1H), 5.60-5.68 (m, 1H), 7.07 (d,
J = 7.3Hz, 1H), 7.18 (t, J = 6.8Hz, 1H), 8.50 (s, 1H).
Example 5
4- (4-Fluorobenzyloxy) -6,7-dimethyl-5-propenyl-5H-pyrrolo [3,2-d] pyrimidine 5-allyl-4-chloro-6,7 obtained in Reference Example 6 The title compound was obtained as a pale yellow oil in the same manner as in Example 1 using -dimethyl-5H-pyrrolo [3,2-d] pyrimidine and 4-fluorobenzyl alcohol.
¹ H-NMR (CDCl ₃ ) δ = 1.46 (dd, J = 1.7Hz, 6.8Hz, 3H), 2.27 (s, 3H), 2.32 (s, 3H), 5.51 (s, 2H), 5.83-5.86 ( m, 1H), 6.65 (dd,
J = 2.0Hz, 8.1Hz, 1H), 7.02-7.07 (m, 2H), 7.39-7.43 (m, 2H), 8.48 (s, 1H).

Example 6
4- (4-Fluorobenzyloxy) -5-methoxymethyl-6,7-dimethyl-5H-pyrrolo [3,2-d] pyrimidine 4-chloro-5-methoxymethyl-6 obtained in Reference Example 7 , 7-Dimethyl-5H-pyrrolo [3,2-d] pyrimidine and 4-fluorobenzyl alcohol were used in the same manner as in Example 1 to obtain the title compound as yellow crystals.
¹ H-NMR (CDCl ₃ ) δ = 2.28 (s.3H), 2.42 (s, 3H), 3.14 (s, 3H), 5.58 (s, 2H), 5.61 (s, 2H), 7.05-7.10 (m , 2H), 7,45-7,49
(m, 2H), 8,51 (s, 1H).
Example 7
4- (2,6-Dimethylbenzyloxy) -5-methoxymethyl-6,7-dimethyl-5H-pyrrolo [3,2-d] pyrimidine 4-chloro-5-methoxymethyl obtained in Reference Example 7 The title compound was obtained as yellow crystals in the same manner as in Example 1 using -6,7-dimethyl-5H-pyrrolo [3,2-d] pyrimidine and 2,6-dimethylbenzyl alcohol.
¹ H-NMR (CDCl ₃ ) δ = 2.28 (s.3H), 2.40 (s, 3H), 2.44 (s.6H), 3.03 (s, 3H), 5.47 (s, 2H), 5.65 (s, 2H ), 7.08 (d, J = 7.6Hz, 2H),
7.19 (m, 1H), 8.55 (s, 1H).

Example 8
4- (4-Fluorobenzyloxy) -6,7-dimethyl-5- (2-trimethylsilanylethoxymethyl) -5H-pyrrolo [3,2-d] pyrimidine 4-chloro obtained in Reference Example 8 -6,7-dimethyl-5- (2-trimethylsilanylethoxymethyl) -5H-pyrrolo [3,2-d] pyrimidine and 4-fluorobenzyl alcohol were used in the same manner as in Example 1 to obtain the title compound. Was obtained as a yellow oil.
¹ H-NMR (CDCl ₃ ) δ = −0.12 (s, 9H), 0.77 (t, J = 8.1Hz, 2H), 2.28 (s, 3H), 2.43 (s, 3H), 3.39 (t, J = 8.1Hz, 2H), 5.57 (s.2H), 5.64 (s.2H), 7.02-7.09 (m, 2H), 7.45-7.49 (m, 2H), 8.51 (s, 1H).
Example 9
4- (2,6-Dimethylbenzyloxy) -6,7-dimethyl-5- (2-trimethylsilanylethoxymethyl) -5H-pyrrolo [3,2-d] pyrimidine obtained in Reference Example 8 -Chloro-6,7-dimethyl-5- (2-trimethylsilanylethoxymethyl) -5H-pyrrolo [3,2-d] pyrimidine and 2,6-dimethylbenzyl alcohol were used in the same manner as in Example 1. To give the title compound as a yellow oil.
¹ H-NMR (CDCl ₃ ) δ = −0.13 (s, 9H), 0.69 (t, J = 8.3Hz, 2H), 2.28 (s, 3H), 2.40 (s, 3H), 2.44 (s, 6H) , 3.27 (t, J = 7.8Hz, 2H), 5.50 (s, 2H), 5.64 (s.2H), 7.05-7.20 (m, 3H), 8.54 (s, 1H).

Example 10
Preparation of 4- (4-fluorobenzyloxy) -6,7-dimethyl-5H-pyrrolo [3,2-d] pyrimidine 150 mg of the compound obtained in Example 8 was dissolved in 1 mL of THF, and a solution of tetrabutylammonium fluoride in THF. 1.1 mL was added and heated to reflux for 5 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate / hexane) to give 53 mg of the title compound as white crystals.
¹ H-NMR (CDCl ₃ ) δ = 2.27 (s, 3H), 2.41 (s, 3H), 5.53 (s.2H), 7.05-7.09 (m, 2H), 7.44-7.48 (m, 2H), 8.13 (br-s, 1H), 8.52 (s, 1H).
Example 11
Preparation of 4- (2,6-dimethylbenzyloxy) -6,7-dimethyl-5H-pyrrolo [3,2-d] pyrimidine Using the compound obtained in Example 9 and tetrabutylammonium fluoride THF solution, In the same manner as in Example 10, the title compound was obtained as white crystals.
¹ H-NMR (CDCl ₃ ) δ = 2.27 (s, 3H), 2.38 (s, 3H), 2.43 (s, 6H), 5.61 (s, 2H), 7.09 (d, J = 7.3Hz, 2H), 7.20 (t, J = 8.1Hz, 1H), 8.04 (br-s, 1H), 8.56 (s, 1H).

Example 12
Production of 2-chloro-4- (4-fluorobenzyloxy) -6,7-dimethyl-5-propyl-5H-pyrrolo [3,2-d] pyrimidine 2,4-dichloro-6 obtained in Reference Example 11 , 7-Dimethyl-5-propyl-5H-pyrrolo [3,2-d] pyrimidine and 4-fluorobenzyl alcohol were used in the same manner as in Example 1 to obtain the title compound as yellow crystals.
¹ H-NMR (CDCl ₃ ) δ = 0.78 (t, J = 7.6Hz, 3H), 1.60-1.67 (m, 2H), 2.22 (s, 3H), 2.33 (s, 3H), 4.11 (t, J = 7.5Hz, 2H), 5.52 (s, 2H), 7.08 (t, 2H, J = 8.5Hz), 7.44-7.47 (m, 2H).
Example 13
4- (4-Fluorobenzyloxy) -6,7-dimethyl-5-propyl-5H-pyrrolo [3,2-d] pyrimidine-2-carbonitrile 1.74 g of the compound obtained in Example 12 To a 20 mL solution of N-dimethylacetamide, add 500 mg of zinc cyanide, 100 mg of zinc powder, 280 mg of 1,1'-bis (diphenylphosphino) ferrocene, 230 mg of tris (dibenzylideneacetone) dipalladium under an argon stream at 130 ° C. Stir for 3 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate / hexane) to give 510 mg of the title compound as white crystals.
¹ H-NMR (CDCl ₃ ) δ = 0.81 (t, J = 7.6Hz, 3H), 1.64-1.70 (m, 2H), 2.27 (s, 3H), 2.38 (s, 3H), 4.18 (t, J = 7.6Hz, 2H), 5.55 (s, 2H), 7.07-7.11 (m, 2H), 7.45-7.49 (m, 2H).

Example 14
4- (4-Fluorobenzyloxy) -6,7-dimethyl-5-propyl-5H-pyrrolo [3,2-d] pyrimidine-2-carboxylic acid dimethylamide 113 mg of the compound obtained in Example 13 To 3 mL solution, 1 mL of 10% aqueous sodium hydroxide was added and heated to reflux for 3 hours. The reaction mixture was poured into saturated aqueous ammonium chloride and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. To a DMF 3 mL solution of the residue, 81 mg of dimethylamine hydrochloride, 96 mg of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, 138 mg of potassium carbonate, 78 mg of 1-hydroxy-1H-benzotriazole monohydrate were added, Stir at room temperature for 2 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate) to obtain 77 mg of the title compound as pale yellow crystals.
¹ H-NMR (CDCl ₃ ) δ = 0.79 (t, J = 7.2 Hz, 3H), 1.66 (m, 2H), 2.27 (s, 3H), 2.36 (s, 3H), 2.97 (s, 3H), 3.16 (s, 3H), 4.17 (t, J = 7.2Hz,
2H), 5.55 (s, 2H), 7.04-7.09 (m, 2H), 7.43-7.46 (m, 2H).
Example 15
Preparation of 4- (4-fluorobenzyloxy) -6,7-dimethyl-5-propyl-5H-pyrrolo [3,2-d] pyrimidine-2-carboxylic acid (2-hydroxypropyl) amide obtained in Example 13 The title compound was obtained as pale brown crystals in the same manner as in Example 14 using 1-amino-2-propanol.
¹ H-NMR (CDCl ₃ ) δ = 0.79 (t, J = 7.6Hz, 3H), 1.27 (d, J = 6.0Hz, 3H), 1.64-1.70 (m, 2H), 2.29 (s, 3H), 2.37 (s, 3H), 3.22 (br-s, 1H), 3.41-3.47 (m, 1H), 3.62-3.68 (m, 1H), 4.11 (br-s, 1H), 4.18 (t, J = 7.6 Hz, 2H), 5.62 (s, 2H), 7.05-7.09 (m, 2H), 7.47-7.50 (m, 2H), 8.44 (br-s, 1H).

Example 16
Production of 2-amino-4- (4-fluorobenzyloxy) -6,7-dimethyl-5-propyl-5H-pyrrolo [3,2-d] pyrimidine 2-amino-4-chloro obtained in Reference Example 14 The title compound was obtained as yellow crystals in the same manner as in Example 1 using -6,7-dimethyl-5-propyl-5H-pyrrolo [3,2-d] pyrimidine and 4-fluorobenzyl alcohol.
¹ H-NMR (CDCl ₃ ) δ = 0.76 (t, J = 7.3Hz, 3H), 1.57-1.66 (m, 2H), 2.15 (s, 3H), 2.27 (s, 3H), 4.04 (t, J = 7.3Hz, 3H), 4.64 (br-s,
2H), 5.43 (s, 2H), 7.04-7.08 (m, 2H), 7.40-7.44 (m, 2H).
Example 17
Production of N- [4- (4-fluorobenzyloxy) -6,7-dimethyl-5-propyl-5H-pyrrolo [3,2-d] pyrimidin-2-yl] acetamide 198 mg of the compound obtained in Example 16 To a 6 mL solution of pyridine was added 0.09 mL of acetic anhydride, and the mixture was heated to reflux for 15 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate / hexane) to give 143 mg of the title compound as white crystals.
¹ H-NMR (DMSO-d ₆ ) δ = 0.72 (t, J = 7.3 Hz, 3H), 1.54-1.60 (m, 2H), 2.10 (s, 3H), 2.19 (s, 3H), 2.32 (s , 3H), 4.11 (t, 2H,
J = 7.6Hz), 5.52 (s, 2H), 7.22 (t, J = 8.8Hz, 2H), 7.61-7.65 (m, 2H), 10.03 (br-s, 1H).

Example 18
Production of N- [4- (4-fluorobenzyloxy) -6,7-dimethyl-5-propyl-5H-pyrrolo [3,2-d] pyrimidin-2-yl] propionamide Compound obtained in Example 16 And propionic anhydride were used in the same manner as in Example 17 to obtain the title compound as white crystals.
¹ H-NMR (CDCl ₃ ) δ = 0.79 (t, J = 7.3Hz, 3H), 1.26 (t, J = 7.6Hz, 3H), 1.61-1.70 (m, 2H), 2.19 (s, 3H), 2.32 (s, 3H), 2.85 (br-s, 2H),
4.11 (t, J = 7.6Hz, 2H), 5.50 (s, 2H), 7.07 (t, J = 8.5Hz, 2H), 7.43-7.47 (m, 2H), 7.78 (br-s, 1H).
Example 19
Production of N- [4- (4-fluorobenzyloxy) -6,7-dimethyl-5-propyl-5H-pyrrolo [3,2-d] pyrimidin-2-yl] benzamide Compound of Example 16 and benzoic anhydride The title compound was obtained as white crystals in the same manner as in Example 17 using acid.
¹ H-NMR (CDCl ₃ ) δ = 0.79 (t, J = 7.3Hz, 3H), 1.62-1.68 (m, 2H), 2.22 (s, 3H), 2.33 (s, 3H), 4.13 (t, J = 7.6Hz, 3H), 5.56 (s, 2H), 7.06 (t, J = 8.8Hz, 2H), 7.46-7.54 (m, 5H), 7.94 (d, J = 7.3Hz, 2H), 8.48 (br -s, 1H).

Example 20
Preparation of N- [4- (4-fluorobenzyloxy) -6,7-dimethyl-5-propyl-5H-pyrrolo [3,2-d] pyrimidin-2-yl] methanesulfonamide obtained in Example 16 To a solution of 300 mg of the compound in 3 mL of methylene chloride was added 0.25 mL of triethylamine and 0.14 mL of methanesulfonyl chloride under ice cooling, and the mixture was stirred for 45 minutes under ice cooling. The reaction solution was poured into water and extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. To a 10 mL solution of the residue in methanol, 2.5 mL of 10% sodium hydroxide was added and stirred at room temperature for 3 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate / hexane) to give 363 mg of the title compound as yellow crystals.
¹ H-NMR (CDCl ₃ ) δ = 0.76 (t, J = 11.2Hz, 18,5Hz, 3H), 1.60-1.63 (m, 2H), 2.11 (s, 3H), 2.27 (s, 3H), 3.32 (s, 3H), 4.04 (m, 2H), 5.48 (s, 2H), 7.04 (t, J = 9.0Hz, 2H), 7.41 (m, 2H).

Example 21
Preparation of N- [4- (4-fluorobenzyloxy) -6,7-dimethyl-5-propyl-5H-pyrrolo [3,2-d] pyrimidin-2-yl] ethanesulfonamide obtained in Example 16 Triethylamine 0.1 mL and ethanesulfonyl chloride 0.14 mL were added to a solution of the compound 200 mg in 2 mL of methylene chloride, and the mixture was stirred for 1.5 hours under ice cooling and 40 minutes at room temperature. The reaction solution was poured into water and extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate / hexane) to give 72 mg of the title compound as white crystals.
¹ H-NMR (CDCl ₃ ) δ = 0.78 (t, J = 7.6 Hz, 3H), 1.41 (t, J = 7.6 Hz, 3H), 1.60-1.66 (m, 2H), 2.14 (s, 3H), 2.30 (s, 3H), 3.52 (m, 2H), 4.08 (t, J = 7.6Hz, 2H), 5.50 (s, 2H), 7.07 (t, J = 8.8Hz, 2H), 7.41-7.45 (m , 2H).
Example 22
Preparation of N- [4- (4-fluorobenzyloxy) -6,7-dimethyl-5-propyl-5H-pyrrolo [3,2-d] pyrimidin-2-yl] benzenesulfonamide obtained in Example 16 The title compound was obtained as yellow crystals in the same manner as in Example 21 using the compound and benzenesulfonyl chloride.
¹ H-NMR (CDCl ₃ ) δ = 0.73 (t, J = 7.6Hz, 3H), 1.53-1.59 (m, 2H), 2.12 (s, 3H), 2.27 (s, 3H), 4.00 (t, J = 7.3Hz, 2H), 5.32 (s, 2H),
7.05 (t, J = 8.8Hz, 2H), 7.33-7.36 (m, 2H), 7.42-7.51 (m, 3H), 8.10-8.12 (m, 2H).

Example 23
Production of 2-amino-4- (4-fluorobenzyloxy) -6,7-dimethyl-5- (2-methylcyclopropylmethyl) -5H-pyrrolo [3,2-d] pyrimidine Obtained in Reference Example 15 Example 1 with 2-amino-4-chloro-6,7-dimethyl-5- (2-methylcyclopropylmethyl) -5H-pyrrolo [3,2-d] pyrimidine and 4-fluorobenzyl alcohol In the same manner, the title compound was obtained as yellow crystals.
¹ H-NMR (CDCl ₃ ) δ = 0.11-0.14 (m, 1H), 0.32-0.37 (m, 1H), 0.58 (m, 1H), 0.75 (m, 1H), 0.89 (d, J = 6.0Hz , 3H), 2.18 (s, 3H), 2.29 (s, 3H), 3.97 (dd, J = 6.8Hz, 14.8Hz, 1H), 4.10 (dd, J = 4.8Hz, 14.8Hz, 1H), 4.89 ( br-s, 2H), 5.41-5.50 (m, 2H), 7.04-7.09 (m, 2H), 7.26-7.45 (m, 2H).
Example 24
N- [4- (4-Fluorobenzyloxy) -6,7-dimethyl-5- (2-methylcyclopropylmethyl) -5H-pyrrolo [3,2-d] pyrimidin-2-yl] methanesulfonamide The title compound was obtained as yellow crystals in the same manner as in Example 20 using the compound obtained in Production Example 23 and methanesulfonyl chloride.
¹ H-NMR (CDCl ₃ ) δ = 0.14-0.18 (m, 1H), 0.34-0.36 (m, 1H), 0.59 (m, 1H), 0.75 (m, 1H), 0.90 (d, J = 6.0Hz , 3H), 2,15 (s, 3H), 2.33 (s, 3H), 3.36 (s, 3H), 4.01 (dd, J = 6.8Hz, 14.8Hz, 1H), 4.13 (dd, J = 6.4Hz , 14.8Hz, 1H), 5.48-5.57 (m, 2H), 7.05-7.10 (m, 2H), 7.24-7.46 (m, 2H).

Example 25
Production of 2-amino-4- (2,6-dimethylbenzyloxy) -6,7-dimethyl-5-propyl-5H-pyrrolo [3,2-d] pyrimidine 2-amino-4 obtained in Reference Example 14 -Chloro-6,7-dimethyl-5-propyl-5H-pyrrolo [3,2-d] pyrimidine and 2,6-dimethylbenzyl alcohol were used in the same manner as in Example 1 to give the title compound as yellow crystals. Obtained.
¹ H-NMR (CDCl ₃ ) δ = 0.59 (t, J = 7.3Hz, 3H), 1.46-1.55 (m, 2H), 2.15 (s, 3H), 2.24 (s, 3H), 2.42 (s, 6H ,) 3.90 (t, J = 7.6Hz, 2H), 4.62 (br-s, 2H), 5.51 (s, 2H), 7.06 (d, J = 7.6Hz, 2H), 7.13-7.17 (m, 1H) .
Example 26
Preparation of N- [4- (2,6-dimethylbenzyloxy) -6,7-dimethyl-5-propyl-5H-pyrrolo [3,2-d] pyrimidin-2-yl] methanesulfonamide In Example 25 The title compound was obtained as pale-yellow crystals in the same manner as in Example 20 using the obtained compound and methanesulfonyl chloride.
¹ H-NMR (CDCl ₃ ) δ = 0.59 (t, J = 7.3 Hz, 3H), 1.48-1.55 (m, 2H), 2.13 (s, 3H), 2.27 (s, 3H), 2.40 (s, 6H ), 3.41 (s, 3H), 3.93 (t, J = 7.6Hz, 2H), 5.59 (s, 2H), 7.07 (d, J = 7.3Hz, 2H), 7.16-7.19 (m, 1H).

Example 27
Production of 2-amino-4- (2,6-dimethylbenzyloxy) -6,7-dimethyl-5- (2-methylcyclopropylmethyl) -5H-pyrrolo [3,2-d] pyrimidine In Reference Example 15 Using the obtained 2-amino-4-chloro-6,7-dimethyl-5- (2-methylcyclopropylmethyl) -5H-pyrrolo [3,2-d] pyrimidine and 2,6-dimethylbenzyl alcohol, In the same manner as in Example 1, the title compound was obtained as pale yellow crystals.
¹ H-NMR (CDCl ₃ ) δ = −0.01-0.04 (m, 1H), 0.18-0.22 (m, 1H), 0.40-0.46 (m, 1H), 0.61-0.67 (m, 1H), 0.79 (d , J = 5.9Hz, 3H), 2.16 (s, 3H), 2.26 (s, 3H), 2.43 (s, 6H), 3.82 (dd, J = 7.1Hz, 14.6Hz, 1H), 3.99 (dd, J = 6.3Hz, 14.9Hz, 1H), 4.61 (br-s, 2H), 5.53 (m, 2H), 7.05-7.18 (m, 3H).
Example 28
N- [4- (2,6-Dimethylbenzyloxy) -6,7-dimethyl-5- (2-methylcyclopropylmethyl) -5H-pyrrolo [3,2-d] pyrimidin-2-yl] methanesulfone Preparation of amide Using the compound of Example 27 and methanesulfonyl chloride, the title compound was obtained as yellow crystals in the same manner as in Example 20.
¹ H-NMR (CDCl ₃ ) δ = −0.01-0.06 (m, 1H), 0.16-0.21 (m, 1H), 0.39-0.43 (m, 1H), 0.61-0.65 (m, 1H), 0.79 (d , J = 5.9Hz, 3H), 2.14 (s, 3H), 2.29 (s, 3H), 2.41 (s, 6H), 3.42 (s, 3H), 3.84 (dd, J = 7.3Hz, 14.9Hz, 1H ), 4.01 (dd, J = 6.3Hz, 14.6Hz, 1H), 5.62 (m, 2H), 7.07-7.20 (m, 3H).

Example 29
Production of N- [4- (2,6-dimethoxybenzyloxy) -6,7-dimethyl-5-propyl-5H-pyrrolo [3,2-d] pyrimidin-2-yl] methanesulfonamide In Reference Example 14 The obtained 2-amino-4-chloro-6,7-dimethyl-5-propyl-5H-pyrrolo [3,2-d] pyrimidine and 2,6-dimethoxybenzyl alcohol were used in the same manner as in Example 1. The obtained 2-amino-4- (2,6-dimethoxybenzyloxy) -6,7-dimethyl-5-propyl-5H-pyrrolo [3,2-d] pyrimidine was used in the same manner as in Example 20. The title compound was obtained as pale red crystals.
¹ H-NMR (CDCl ₃ ) δ = 0.61 (t, J = 7.3Hz, 3H), 1.55 (m, 2H), 2.12 (s, 3H), 2.25 (s, 3H), 3.42 (s, 3H), 3.80 (s, 6H), 3.93 (t, J = 7.6Hz, 2H), 5.61 (s, 2H), 6.57 (d, J = 8.5Hz, 2H), 7.30 (t, J = 8.5Hz, 1H).
Example 30
Production of N- [4- (indan-1-yloxy) -6,7-dimethyl-5-propyl-5H-pyrrolo [3,2-d] pyrimidin-2-yl] methanesulfonamide obtained in Reference Example 14 2-Amino-4-chloro-6,7-dimethyl-5-propyl-5H-pyrrolo [3,2-d] pyrimidine and 1-indanol were used in the same manner as in Example 29 to give the title compound as white crystals Got as.
¹ H-NMR (CDCl ₃ ) δ = 0.71 (t, J = 7.6 Hz, 3H), 1.54-1.59 (m, 2H), 2.14 (s, 3H), 2.28 (s, 3H), 2.23-2.31 (m , 1H), 2.67-2.76 (m, 1H), 2.93-3.01 (m, 1H), 3.11-3.18 (m, 1H), 3.43 (s, 3H), 3.97-4.02 (m, 2H), 6.72-6.74 (m, 1H), 7.20-7.32 (m, 3H), 7.50 (d, J = 7.8Hz, 1H).

Example 31
Reference Example 14 for Production of N- [4- (5-Fluoroindan-1-yloxy) -6,7-dimethyl-5-propyl-5H-pyrrolo [3,2-d] pyrimidin-2-yl] methanesulfonamide 14 Using 2-amino-4-chloro-6,7-dimethyl-5-propyl-5H-pyrrolo [3,2-d] pyrimidine and 5-fluoro-1-indanol obtained in the same manner as in Example 29, To give the title compound as a red oil.
¹ H-NMR (CDCl ₃ ) δ = 0.72 (t, J = 7.5 Hz, 3H), 1.53-1.59 (m, 2H), 2.13 (s, 3H), 2.28 (s, 3H), 2.30-2.35 (m , 1H), 2.69-2.75
(m, 1H), 2.96-2.97 (m, 1H), 3.10-3.16 (m, 1H), 3.42 (s, 3H), 3.97-4.02 (m, 2H), 6.66-6.69 (m, 1H), 6.92 (t, J = 8.8Hz, 1H), 6.98 (d, J = 8.8Hz, 1H), 7.47-7.50 (m, 1H).
Example 32
Reference Example 14 for Production of N- [6,7-dimethyl-4- (2-methylindan-1-yloxy) -5-propyl-5H-pyrrolo [3,2-d] pyrimidin-2-yl] methanesulfonamide 14 Using 2-amino-4-chloro-6,7-dimethyl-5-propyl-5H-pyrrolo [3,2-d] pyrimidine and 2-methyl-1-indanol obtained in the same manner as in Example 29, The title compound was obtained as yellow crystals.
¹ H-NMR (CDCl ₃ ) δ = 0.72 (t, J = 7.5 Hz, 3H), 1.25 (d, J = 6.8 Hz, 3H), 1.55-1.60 (m, 2H), 2.15 (s, 3H), 2.29 (s, 3H), 2.58-2.63 (m, 1H), 2.71-2.76 (m, 1H), 3.26-3.31 (m, 1H), 3.41 (s, 3H), 3.98-4.06 (m, 2H), 6.41 (d, J = 4.4Hz, 1H), 7.18-7.20 (m, 1H), 7.26-
7.30 (m, 1H), 7.42 (d, J = 8.8Hz, 1H).

Example 33
Reference Example 14 for Production of N- [4- (7-Methoxyindan-1-yloxy) -6,7-dimethyl-5-propyl-5H-pyrrolo [3,2-d] pyrimidin-2-yl] methanesulfonamide 14 Using 2-amino-4-chloro-6,7-dimethyl-5-propyl-5H-pyrrolo [3,2-d] pyrimidine and 7-methoxy-1-indanol obtained in the same manner as in Example 29, To give the title compound as a yellow oil.
¹ H-NMR (CDCl ₃ ) δ = 0.95 (t, J = 7.3Hz, 3H), 1.72-1.78 (m, 2H), 2.14 (s, 3H), 2.21-2.27 (m, 1H), 2.33 (s , 3H), 2.40-2.47 (m, 1H), 2.81-2.88 (m, 1H), 3.06-3.14 (m, 1H), 3.70 (s, 3H), 3.76 (s, 3H), 4.09-4.15 (m , 2H), 5.10 (d, J = 5.8Hz, 1H), 5.45 (m, 1H), 6.69 (d, J = 8.1Hz, 1H), 6.87 (d, J = 7.3Hz, 1H), 7.23 (t , J = 8.0Hz, 1H).
Example 34
N- [6,7-Dimethyl-5-propyl-4- (1,2,3,4-tetrahydronaphthalen-1-yloxy) -5H-pyrrolo [3,2-d] pyrimidin-2-yl] methanesulfone Preparation of Amide 2-amino-4-chloro-6,7-dimethyl-5-propyl-5H-pyrrolo [3,2-d] pyrimidine obtained in Reference Example 14 and 1,2,3,4-tetrahydronaphthol Were used to give the title compound as pale yellow crystals in the same manner as Example 29.
¹ H-NMR (CDCl ₃ ) δ = 0.63 (t, J = 7.6 Hz, 3H), 1.46-1.55 (m, 2H), 1.91-2.02 (m, 2H), 2.13-2.27 (m, 2H), 2.13 (s, 3H), 2.27 (s, 3H), 2.78-2.95 (m, 2H), 3.40 (s, 3H), 3.96-4.01 (m, 2H), 6.55-6.57 (m, 1H), 7.13-7.16 (m, 2H), 7.21-7.26 (m, 1H), 7.37 (d,
J = 7.3Hz, 1H).

Example 35
Production of 4- (4-fluorobenzyloxy) -6,7-dimethyl-2-methylsulfanyl-5-propyl-5H-pyrrolo [3,2-d] pyrimidine 4-chloro-6, obtained in Reference Example 20 The title compound was obtained as white crystals in the same manner as in Example 1, using 7-dimethyl-2-methylsulfanyl-5-propyl-5H-pyrrolo [3,2-d] pyrimidine and 4-fluorobenzyl alcohol. .
¹ H-NMR (CDCl ₃ ) δ = 0.77 (t, J = 7.3Hz, 3H), 1.60-1.66 (m, 2H), 2.21 (s, 3H), 2.31 (s, 3H), 2.63 (s, 3H ), 4.10 (t, J = 7.3Hz, 2H), 5.52 (s, 2H), 7.04-7.08 (m, 2H), 7.41-7.45 (m, 2H).
Example 36
Preparation of 4- (4-fluorobenzyloxy) -2-methanesulfinyl-6,7-dimethyl-5-propyl-5H-pyrrolo [3,2-d] pyrimidine To a solution of 300 mg of the compound obtained in Example 35 in 4 mL of THF Under ice cooling, 216 mg of m-chloroperbenzoic acid was added and stirred for 2 hours. 20% Sodium bisulfite was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated sodium bicarbonate and saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (chloroform / methanol) to obtain 222 mg of the title compound as pale yellow crystals.
¹ H-NMR (CDCl ₃ ) δ = 0.81 (t, J = 7.3Hz, 3H), 1.65-1.71 (m, 2H), 2.28 (s, 3H), 2.37 (s, 3H), 2.92 (s, 3H ), 4.19 (t, J = 7.6Hz, 2H), 5.61 (s, 2H), 7.06-7.10 (m, 2H), 7.46-7.50 (m, 2H).

Example 37
Preparation of 4- (4-fluorobenzyloxy) -2-methanesulfonyl-6,7-dimethyl-5-propyl-5H-pyrrolo [3,2-d] pyrimidine To a solution of 300 mg of the compound obtained in Example 35 in 4 mL of THF Under ice-cooling, 721 mg of m-chloroperbenzoic acid was added and stirred at room temperature for 17 hours. 20% Sodium bisulfite was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated sodium hydrogen carbonate and saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate / hexane) to give 218 mg of the title compound as white crystals.
¹ H-NMR (CDCl ₃ ) δ = 0.80 (t, J = 7.3Hz, 3H), 1.64-1.69 (m, 2H), 2.72 (s, 3H), 2.38 (s, 3H), 3.38 (s, 3H ), 4.20 (t, J = 7.3Hz, 2H),
5.62 (s, 2H), 7.06-7.10 (m, 2H), 7.48-7.51 (m, 2H).
Example 38
4- (4-Fluorobenzylamino) -6,7-dimethyl-5H-pyrrolo [3,2-d] pyrimidine 4-chloro-6,7-dimethyl-5H-pyrrolo [3] obtained in Reference Example 3 , 2-d] pyrimidine 200 mg and 4-fluorobenzylamine 151 mg in 4 mL of xylene were heated to reflux for 15 hours. The reaction solution was poured into saturated sodium hydrogen carbonate water and extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (chloroform / methanol) to obtain 290 mg of the title compound as yellow crystals.
¹ H-NMR (CDCl ₃ ) δ = 2.12 (s, 3H), 2.30 (s, 3H), 4.75 (d, J = 5.6Hz, 2H), 6.78 (t, J = 8.8Hz, 2H), 7.23 ( m, 2H), 8.20 (s, 1H), 8.84
(br-s, 1H), 11.76 (br-s, 1H).

Example 39
4- (2,6-Dimethylbenzylamino) -6,7-dimethyl-5H-pyrrolo [3,2-d] pyrimidine 4-chloro-6,7-dimethyl-5H-pyrrolo obtained in Reference Example 3 The title compound was obtained as yellow crystals in the same manner as in Example 38, using [3,2-d] pyrimidine and 2,6-dimethylbenzylamine.
¹ H-NMR (CDCl ₃ ) δ = 2.15 (s, 3H), 2.30 (s, 3H), 2.36 (s.6H), 4.83 (d, J = 4.9Hz, 2H), 6.74-6.81 (m, 3H ), 8.14 (br-s, 1H), 8.02 (s, 1H), 11.93 (br-s, 1H).
Example 40
4- (4-Fluorobenzylamino) -6,7-dimethyl-5-propyl-5H-pyrrolo [3,2-d] pyrimidine 4-chloro-6,7-dimethyl-5 obtained in Reference Example 4 The title compound was obtained as white crystals in the same manner as in Example 38 using -propyl-5H-pyrrolo [3,2-d] pyrimidine and 4-fluorobenzylamine.
¹ H-NMR (CDCl ₃ ) δ = 0.86 (t, J = 7.3Hz, 3H), 1.66-1.76 (m, 2H), 2.25 (s, 3H), 2.33 (s, 3H), 4.02 (t, 2H , J = 7.6Hz), 4.79 (d, 2H, J = 4.4Hz), 4.82 (br-s, 1H), 7.04 (t, 2H, J = 8.5Hz), 7.34-7.38 (m, 2H), 8.43 (s, 1H).

Example 41
4- (2,6-Dimethylbenzylamino) -6,7-dimethyl-5-propyl-5H-pyrrolo [3,2-d] pyrimidine 4-chloro-6,7-dimethyl obtained in Reference Example 4 The title compound was obtained as yellow crystals in the same manner as in Example 38, using -5-propyl-5H-pyrrolo [3,2-d] pyrimidine and 2,6-dimethylbenzylamine.
¹ H-NMR (CDCl ₃ ) δ = 0.72 (t, J = 7.3Hz, 3H), 1.60-1.65 (m, 2H), 2.24 (s, 3H), 2.30 (s, 3H), 2.42 (s, 6H ), 3.88 (t, 2H,
J = 7.3Hz), 4.37 (br-s, 1H), 4.76 (d, J = 3.7Hz, 2H), 7.08-7.17 (m, 3H), 8,49 (s, 1H).
Example 42
Preparation of N- [4- (4-fluorobenzylamino) -6,7-dimethyl-5-propyl-5H-pyrrolo [3,2-d] pyrimidin-2-yl] methanesulfonamide
Example 38 with N- (4-chloro-6,7-dimethyl-5-propyl-5H-pyrrolo [3,2-d] pyrimidin-2-yl) methanesulfonamide and 4-fluorobenzylamine In the same manner, the title compound was obtained as white crystals.
¹ H-NMR (DMSO-d ₆ ) δ = 0.76 (t, J = 7.3Hz, 3H), 1.52-1.57 (m, 2H), 2.02 (s, 3H), 2.26 (s, 3H), 2.78 (br -s, 3H), 4.21 (t, J = 7.1Hz, 2H), 4.76 (d, J = 5.4Hz, 2H), 7.09-7.13 (m, 2H), 7.41-7.45 (m, 2H).

Example 43
Preparation of N- [4- (2,6-dimethylbenzylamino) -6,7-dimethyl-5-propyl-5H-pyrrolo [3,2-d] pyrimidin-2-yl] methanesulfonamide
Examples using N- (4-chloro-6,7-dimethyl-5-propyl-5H-pyrrolo [3,2-d] pyrimidin-2-yl) methanesulfonamide and 2,6-dimethylbenzylamine In the same manner as in 38, the title compound was obtained as pale yellow crystals.
¹ H-NMR (CD ₃ OD) δ = 0.67 (t, J = 7.3Hz, 3H), 1.51-1.56 (m, 2H), 2.09 (s, 3H), 2.28 (s, 3H), 2.40 (s, 6H), 3.25 (s, 3H), 4.04 (t, J = 7.6Hz, 2H), 4.91 (s, 2H), 7.06-7.14 (m, 3H).
Example 44
Preparation of N- [4- (indan-1-ylamino) -6,7-dimethyl-5-propyl-5H-pyrrolo [3,2-d] pyrimidin-2-yl] methanesulfonamide
Same as Example 38, using N- (4-chloro-6,7-dimethyl-5-propyl-5H-pyrrolo [3,2-d] pyrimidin-2-yl) methanesulfonamide and 1-aminoindan To give the title compound as white crystals.
¹ H-NMR (CDCl ₃ ) δ = 0.84 (t, J = 7.3Hz, 3H), 1.70-1.75 (m, 2H), 1.87-1.96 (m, 1H), 2.09 (s, 3H), 2.27 (s , 3H), 2.80-3.02 (m, 3H), 3.26 (s, 3H), 3.90-3.93 (m, 2H), 5.17 (d, J = 7.8Hz, 1H), 5.92-5.98 (m, 1H), 7.20-7.33 (m, 4H).

Example 45
Production of 4- (4-fluorobenzylamino) -6,7-dimethyl-2-methylsulfanyl-5-propyl-5H-pyrrolo [3,2-d] pyrimidine 4-chloro-6, obtained in Reference Example 20 The title compound was obtained as yellow crystals in the same manner as in Example 38 using 7-dimethyl-2-methylsulfanyl-5-propyl-5H-pyrrolo [3,2-d] pyrimidine and 4-fluorobenzylamine. .
¹ H-NMR (CDCl ₃ ) δ = 0.83 (t, J = 7.6Hz, 3H), 1.67-1.72 (m, 2H), 2.19 (s, 3H), 2.29 (s, 3H), 2.56 (s, 3H ), 3.96 (t, J = 7.6Hz, 2H), 4.77-4.83 (m, 3H), 7.00-7.04 (m, 2H), 7.32-7.36 (m, 2H).
Example 46
4- (4-Fluorobenzylamino) -2-methanesulfinyl-6,7-dimethyl-5-propyl-5H-pyrrolo [3,2-d] pyrimidine Compound of Example 45 and m-chloroperbenzoic acid In the same manner as in Example 36, the title compound was obtained as pale yellow crystals.
¹ H-NMR (CDCl ₃ ) δ = 0.89 (t, J = 7.3Hz, 3H), 1.72-1.78 (m, 2H), 2.26 (s, 3H), 2.34 (s, 3H), 2.84 (s, 3H ), 4.05 (t, J = 7.6Hz, 2H), 4.80-4.83 (m, 2H), 5.13 (m, 1H), 7.01-7.05 (m, 2H), 7.34-7.38 (m, 2H).

Example 47
4- (4-Fluorobenzylamino) -2-methanesulfonyl-6,7-dimethyl-5-propyl-5H-pyrrolo [3,2-d] pyrimidine Compound of Example 45 and m-chloroperbenzoic acid In the same manner as in Example 37, the title compound was obtained as pale yellow crystals.
¹ H-NMR (CDCl ₃ ) δ = 0.87 (t, J = 7.3Hz, 3H), 1.72-1.77 (m, 2H), 2.25 (s, 3H), 2.36 (s, 3H), 3.29 (s, 3H ), 4.06 (t, J = 7.6Hz, 2H), 4.82 (d, J = 5.1Hz, 2H), 5.12 (m, 1H), 7.02-7.06 (m, 2H), 7.36-7.40 (m, 2H) .
Example 48
Preparation of 4- [2- (4-fluorophenyl) ethyl] -6,7-dimethyl-5-propyl-5H-pyrrolo [3,2-d] pyrimidine
To a 15 mL THF solution of 287 mg of 4-fluorostyrene, 11.2 mL of 9-borabicyclo [3.3.1] / nonane / THF solution was added under a stream of argon, and the mixture was heated to reflux for 3 hours. The reaction mixture was allowed to cool to room temperature, 3M potassium phosphate 2.3 mL and DMF 17.8 mL were added, and the mixture was stirred at room temperature for 20 min. To the reaction solution was added 500 mg of 4-chloro-6,7-dimethyl-5-propyl-5H-pyrrolo [3,2-d] pyrimidine obtained in Reference Example 4 and 161 mg of diphenylphosphinoferrocene palladium dichloride at 50 ° C. Stir for 1.5 hours. Water and ethyl acetate were added to the reaction solution, insoluble materials were removed by filtration, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate / hexane) to give 316 mg of the title compound as yellow crystals.
¹ H-NMR (CDCl ₃ ) δ = 0.92 (t, J = 7.6Hz, 3H), 1.62-1.71 (m, 2H), 2.30 (s, 3H), 2.41 (s, 3H), 3.14-3.18 (m , 2H), 3.30-3.34 (m, 2H), 4.06 (t, J = 8.1Hz, 2H), 6.94-6.98 (m, 2H), 7.14-7.18 (m, 2H), 8.84 (s, 1H).

Example 49
Preparation of 4- [2- (2,6-dimethylphenyl) ethyl] -6,7-dimethyl-5-propyl-5H-pyrrolo [3,2-d] pyrimidine
In the same manner as in Example 48, using 2,6-dimethylstyrene and 4-chloro-6,7-dimethyl-5-propyl-5H-pyrrolo [3,2-d] pyrimidine obtained in Reference Example 4, The title compound was obtained as a yellow oil.
¹ H-NMR (CDCl ₃ ) δ = 0.89 (t, J = 7.3Hz, 3H), 1.61-1.67 (m, 2H), 2.30 (s, 3H), 2.34 (s, 6H), 2.39 (s, 3H ), 3.21-3.28 (m, 4H), 4.02 (t, J = 7.8Hz, 2H), 7.03-7.04 (m, 3H), 8.88 (s, 1H).
Example 50
Preparation of 4- [2- (4-fluorophenyl) ethyl] -5-methoxymethyl-6,7-dimethyl-5H-pyrrolo [3,2-d] pyrimidine
Using 4-fluorostyrene and 4-chloro-5-methoxymethyl-6,7-dimethyl-5H-pyrrolo [3,2-d] pyrimidine obtained in Reference Example 7 in the same manner as in Example 48, the title The compound was obtained as a yellow oil.
¹ H-NMR (CDCl ₃ ) δ = 2.30 (s, 3H), 2.47 (s, 3H), 3.13-3.17 (m, 2H), 3.25 (s, 3H), 3.38-3.42 (m, 2H), 5.39 (s, 2H), 6.94-6.98 (m, 2H), 7.17-7.21 (m, 2H), 8.89 (s, 1H).

Example 51
Preparation of 4- [2- (2,6-dimethylphenyl) ethyl] -5-methoxymethyl-6,7-dimethyl-5H-pyrrolo [3,2-d] pyrimidine
In the same manner as in Example 48, using 2,6-dimethylstyrene and 4-chloro-5-methoxymethyl-6,7-dimethyl-5H-pyrrolo [3,2-d] pyrimidine obtained in Reference Example 7 The title compound was obtained as a yellow oil.
¹ H-NMR (CDCl ₃ ) δ = 2.30 (s, 3H), 2.32 (s, 6H), 2.45 (s, 3H), 3.21 (s, 3H), 3.24-3.34 (m, 4H), 5.30 (s , 2H), 7.00-7.03 (m, 3H), 8.94 (s, 1H).
Example 52
Preparation of 4- [2- (4-fluorophenyl) ethyl] -6,7-dimethyl-5- (2-trimethylsilanylethoxymethyl) -5H-pyrrolo [3,2-d] pyrimidine
Example using 4-fluorostyrene and 4-chloro-6,7-dimethyl-5- (2-trimethylsilanylethoxymethyl) -5H-pyrrolo [3,2-d] pyrimidine obtained in Example 8 In the same manner as 48, the title compound was obtained as a yellow oil.
¹ H-NMR (CDCl ₃ ) δ = −0.05 (s, 9H), 0.87 (t, J = 8.3Hz, 2H), 2.30 (s, 3H), 2.46 (s, 3H), 3.16 (t, J = 8.5Hz, 2H), 3.40-3.49 (m, 4H), 5.40 (s. 2H), 6.96 (m, 2H), 7.18-7.21 (m, 2H), 8.88 (s, 1H).

Example 53
Preparation of 4- [2- (2,6-dimethylphenyl) ethyl] -6,7-dimethyl-5- (2-trimethylsilanylethoxymethyl) -5H-pyrrolo [3,2-d] pyrimidine
Using 2,6-dimethylstyrene and 4-chloro-6,7-dimethyl-5- (2-trimethylsilanylethoxymethyl) -5H-pyrrolo [3,2-d] pyrimidine obtained in Example 8, In the same manner as in Example 48, the title compound was obtained as a yellow oil.
¹ H-NMR (CDCl ₃ ) δ = −0.06 (s, 9H), 0.83 (t, J = 7.3Hz, 2H), 2.30 (s, 3H), 2.33 (s, 6H), 2.44 (s, 3H) , 3.29-3.44 (m, 6H), 5.30 (s, .2H), 6.99-7.02 (m, 3H), 8.93 (s, 1H).
Example 54
4- [2- (4-Fluorophenyl) ethyl] -6,7-dimethyl-5H-pyrrolo [3,2-d] pyrimidine Using the compound obtained in Example 52 and a tetrabutylammonium fluoride THF solution In the same manner as in Example 10, the title compound was obtained as white crystals.
¹ H-NMR (CDCl ₃ ) δ = 2.25 (s, 3H), 2.35 (s, 3H), 3.13-3.21 (m, 4H), 6.92 (t, J = 8.8Hz, 2H), 7.06-7.10 (m , 2H), 7.40 (br-s, 1H), 8.88 (s, 1H).

Example 55
Preparation of 4- [2- (2,6-dimethylphenyl) ethyl] -6,7-dimethyl-5H-pyrrolo [3,2-d] pyrimidine Compound obtained in Example 53 and tetrabutylammonium fluoride THF solution In the same manner as in Example 10, the title compound was obtained as white crystals.
¹ H-NMR (CDCl ₃ ) δ = 2.16 (s, 6H), 2.23 (s, 3H), 2.24 (s, 3H), 3.12- 3.22 (m, 4H), 6.81 (br-s, 1H), 6.96 (d, J = 7.8Hz, 2H), 7.04 (t, J = 8.3Hz, 1H), 8.87 (s, 1H).
Example 56
Preparation of N- {4- [2- (4-fluorophenyl) ethyl] -6,7-dimethyl-5-propyl-5H-pyrrolo [3,2-d] pyrimidin-2-yl} methanesulfonamide
As in Example 48, using 4-fluorostyrene and N- (4-chloro-6,7-dimethyl-5-propyl-5H-pyrrolo [3,2-d] pyrimidin-2-yl) methanesulfonamide To give the title compound as white crystals.
¹ H-NMR (CDCl ₃ ) δ = 0.90 (t, J = 7.3 Hz, 3H), 1.59-1.64 (m, 2H), 2.20 (s, 3H), 2.36 (s, 3H), 3.14-3.18 (m , 2H), 3.25-3.29 (m, 2H), 3.50 (s, 3H), 4.01 (t, J = 7.8Hz, 2H), 6.93-6.98 (m, 2H), 7.12-7.16 (m, 2H).

Example 57
Preparation of 4- [2- (4-fluorophenyl) ethyl] -6,7-dimethyl-2-methylsulfanyl-5-propyl-5H-pyrrolo [3,2-d] pyrimidine
Similar to Example 48, using 4-fluorostyrene and 4-chloro-6,7-dimethyl-2-methylsulfanyl-5-propyl-5H-pyrrolo [3,2-d] pyrimidine obtained in Reference Example 20. To give the title compound as white crystals.
¹ H-NMR (CDCl ₃ ) δ = 0.88 (t, J = 7.6Hz, 3H), 1.53-1.64 (m, 2H), 2.23 (s, 3H), 2.35 (s, 3H), 2.66 (s, 3H ), 3.14-3.28 (m, 4H), 4.00 (t, J = 8.1Hz, 2H), 6.93-6.97 (m, 2H), 7.13-7.17 (m, 2H).
Example 58
4- [2- (4-Fluorophenyl) ethyl] -2-methanesulfinyl-6,7-dimethyl-5-propyl-5H-pyrrolo [3,2-d] pyrimidine Preparation Example 57 and m-chloroperoxide The title compound was obtained as yellow crystals in the same manner as in Example 36 using benzoic acid.
¹ H-NMR (CDCl ₃ ) δ = 0.94 (t, J = 7.6Hz, 3H), 1.65-1.71 (m, 2H), 2.32 (s, 3H), 2.43 (s, 3H), 2.92 (s, 3H ), 3.19-3.23 (m, 2H), 3.39-3.43 (m, 2H), 4.09 (t, J = 7.8Hz, 2H), 6.93-6.97 (m, 2H), 7.12-7.16 (m, 2H).

Example 59
4- [2- (4-Fluorophenyl) ethyl] -2-methanesulfonyl-6,7-dimethyl-5-propyl-5H-pyrrolo [3,2-d] pyrimidine Preparation Example 57 and m-chloroperoxide The title compound was obtained as pale-yellow crystals in the same manner as Example 37 using benzoic acid.
¹ H-NMR (CDCl ₃ ) δ = 0.93 (t, J = 7.3Hz, 3H), 1.64-1.70 (m, 2H), 2.31 (s, 3H), 2.44 (s, 3H), 3.21-3.25 (m , 2H), 3.38 (s, 3H), 3.40-3.44 (m, 2H), 4.11 (t, J = 8.1Hz, 2H), 6.93-6.97 (m, 2H), 7.13-7.17 (m, 2H).
The compounds listed in Table 2 can also be produced in the same manner as the methods described in the above examples or production methods.

Claims (11)

The following general formula (I):

[Wherein R ¹ includes a hydrogen atom, an alkyl group that may be branched (1 to 10 carbon atoms), an alkyl group that may be branched including a double bond (2 to 10 carbon atoms), or a triple bond. A branched alkyl group (2-10 carbon atoms), a branched alkyl group containing a saturated carbocyclic ring (3-10 carbon atoms), a branched haloalkyl group (1-10 carbon atoms), An alkoxyalkyl group (2-10 carbon atoms) which may be branched, a hydroxyalkyl group (1-10 carbon atoms) which may be branched, an arylmethyl group which may have a substituent, or a trimethylsilylethoxymethyl group. Show.
R ² and R ³ may be the same or different and are each a hydrogen atom, an alkyl group that may be branched (1 to 10 carbon atoms), or an alkyl group that may be branched including a saturated carbocyclic ring (3 carbon atoms). -10), haloalkyl group which may be branched (1-10 carbon atoms), alkoxyalkyl group which may be branched (2-10 carbon atoms), hydroxyalkyl group which may be branched (1-10 carbon atoms) Represents an alkoxycarbonyl group (2-10 carbon atoms) which may be branched, a carboxyl group, an amino group, a carbamoyl group, an alkanoyl group, a cyano group or a halogen atom.
R ⁴ is a hydrogen atom, an optionally branched alkyl group (1-10 carbon atoms), an optionally branched alkyl group containing a saturated carbocyclic ring (3-10 carbon atoms), an optionally branched haloalkyl group ( 1-10) carbon, branched alkoxy group (1-10 carbon atoms), branched alkoxyalkyl group (2-10 carbon atoms), branched hydroxyalkyl group (1 carbon atoms) -10), an alkoxyalkoxyalkyl group that may be branched (3 to 10 carbon atoms), an alkoxycarbonyl group that may be branched (2 to 10 carbon atoms), a halogen atom, a hydroxyl group, a carboxyl group, a cyano group, a nitro group , —CONR ⁶ R ⁷ group (provided that R ⁶ and R ⁷ may be the same or different and each is a hydrogen atom, a branched alkyl group (having 1 to 10 carbon atoms), or a branched chain containing a saturated carbocyclic ring. Alkyl group 3-10 carbon atoms), optionally branched alkoxyalkyl group optionally (2-10 carbon atoms), indicating a branch to be good hydroxyalkyl group (1-10 carbon atoms). }, —NR ⁸ R ⁹ group {provided that R ⁸ and R ⁹ may be the same or different, and each represents a hydrogen atom, an alkyl group which may be branched (1-10 carbon atoms), or an alkanoyl which may be branched Group (carbon number 2-10), optionally substituted arylcarbonyl group, optionally substituted heteroarylcarbonyl group, branched alkylsulfonyl group (carbon number 1-10), A hydroxyalkylsulfonyl group (1-10 carbon atoms), an alkylsulfinyl group (1-10 carbon atoms), an arylsulfonyl group which may have a substituent, and a heteroarylsulfonyl group which may have a substituent are shown. }, Or —S (O) nR ¹⁰ {wherein R ¹⁰ is an alkyl group (1-10 carbon atoms) which may be branched, and n is 0-2. }.
R ⁵ represents an arylmethyl group which may have a substituent, a heteroarylmethyl group which may have a substituent, or a substituent represented by the following formula (a).

{However, R ¹¹ is an alkyl group (1-5 carbon atoms) which may be branched, a haloalkyl group (1-5 carbon atoms) which may be branched, or an alkoxy group (1-5 carbon atoms) which may be branched. Represents a halogen atom or a hydroxyl group. Z represents a —CHR ¹² — group or a —CHR ¹² CHR ¹³ — group. In the formula, R ¹² and R ¹³ may be the same or different, and each represents a hydrogen atom, an alkyl group that may be branched (1-5 carbon atoms), or an alkyl group that may be branched including a saturated carbocycle ( 3-10) carbon atoms, haloalkyl groups that may be branched (1-5 carbon atoms), alkoxy groups that may be branched (1-5 carbon atoms), alkoxyalkyl groups that may be branched (2 carbon atoms) 5), a hydroxyalkyl group (1-5 carbon atoms) that may be branched, an alkoxycarbonyl group (2-5 carbon atoms) that may be branched, a halogen atom, a hydroxyl group, a carboxyl group, a cyano group, a nitro group,- CONR ¹⁴ R ¹⁵ group or —NR ¹⁶ R ¹⁷ group is shown. In the formula, R ¹⁴ and R ¹⁵ may be the same or different, and each represents a hydrogen atom, an alkyl group which may be branched (1-5 carbon atoms), or an alkyl group which may contain a saturated carbocyclic ring. (C3-10), an alkoxyalkyl group that may be branched (C2-5), and a hydroxyalkyl group that may be branched (C1-5). R ¹⁶ and R ¹⁷ may be the same or different and are each a hydrogen atom, an alkyl group that may be branched (1-5 carbon atoms), an alkanoyl group that may be branched (2-5 carbon atoms), Arylcarbonyl group which may have a substituent, heteroarylcarbonyl group which may have a substituent, alkylsulfonyl group which may be branched (1-5 carbon atoms), aryl which may have a substituent A sulfonyl group and a heteroarylsulfonyl group which may have a substituent are shown. }
X represents —O—, —NH—, or —CH ₂ —. ]
Or a pharmacologically acceptable salt thereof. General formula (II):

[Wherein R ¹ and R ⁵ are the same as described above. R ² and R ³ may be the same or different and are each a hydrogen atom, an optionally branched alkyl group (1-5 carbon atoms), an optionally branched alkyl group containing a saturated carbocyclic ring (3 carbon atoms). -10) represents a haloalkyl group (carbon number 1-5) which may be branched.
R ⁴ represents a hydrogen atom, a —NHSO ₂ R ¹⁸ group (provided that R ¹⁸ represents a branched alkyl group (carbon number 1-5) and an aryl group which may have a substituent). } Or —S (O) nCH ₃ group {provided that n represents 0-2. }. ]
Or a pharmacologically acceptable salt thereof. General formula (III):

[Wherein R ¹ and R ⁵ are the same as described above. R ² and R ³ may be the same or different and are each a hydrogen atom, an optionally branched alkyl group (1-5 carbon atoms), an optionally branched alkyl group containing a saturated carbocyclic ring (3 carbon atoms). -10) represents a haloalkyl group (carbon number 1-5) which may be branched.
R ⁴ represents a hydrogen atom, a —NHSO ₂ R ¹⁸ group (provided that R ¹⁸ represents a branched alkyl group (carbon number 1-5) and an aryl group which may have a substituent). } Or —S (O) nCH ₃ group {provided that n represents 0-2. }. ]
Or a pharmacologically acceptable salt thereof. Formula (IV):

[Wherein R ¹ and R ⁵ are the same as described above. R ² and R ³ may be the same or different and are each a hydrogen atom, an optionally branched alkyl group (1-5 carbon atoms), an optionally branched alkyl group containing a saturated carbocyclic ring (3 carbon atoms). -10) represents a haloalkyl group (carbon number 1-5) which may be branched.
R ⁴ represents a hydrogen atom, a —NHSO ₂ R ¹⁸ group (provided that R ¹⁸ represents a branched alkyl group (carbon number 1-5) and an aryl group which may have a substituent). } Or —S (O) nCH ₃ group {provided that n represents 0-2. }. ]
Or a pharmacologically acceptable salt thereof. General formula (V):

[Wherein R ¹ and R ⁵ are the same as described above. R ¹⁹ represents an alkyl group (1-5 carbon atoms) which may be branched. ]
Or a pharmacologically acceptable salt thereof. A pharmaceutical composition comprising the compound according to any one of claims 1 to 5 or a pharmacologically acceptable salt thereof as an active ingredient. A prophylactic or therapeutic agent for ulcerative diseases comprising the compound according to any one of claims 1 to 5 or a pharmacologically acceptable salt thereof as an active ingredient. A prophylactic or therapeutic agent for a disease associated with infection by Helicobacter pylori comprising the compound according to any one of claims 1 to 5 or a pharmacologically acceptable salt thereof as an active ingredient. Compound or a pharmacologically acceptable salt thereof according to any one of claims 1 to 5, sedatives, antacids, histamine H ₂ receptor blockers, proton pump inhibitors, muscarinic receptor blocking agents, anti-gastrin Drugs, mucosal protective / tissue repair promoters, prostaglandin drugs, gastrointestinal motility activators, GIP (Gastric inhibitory polypeptide) inhibitors, calcium channel antagonists, potassium channel openers, GABA _B agonists, GABA _B blockers , Tachykinin blocker, NO synthase inhibitor, vanilloid receptor 1 blocker, calmodulin blocker, β1 agonist, β2 agonist, β agonist, α2 agonist, endothelin A blocker, opioid μ agonist, opioid μ Select from blockers, acetylcholinesterase release stimulants, CCK-B blockers, glucagon blockers, anti-Helicobacter pylori drugs It is a pharmaceutical composition containing at least one drug. A prophylactic or therapeutic agent for ulcer disease comprising the pharmaceutical composition according to claim 9 as an active ingredient. A prophylactic or therapeutic agent for a disease associated with infection by Helicobacter pylori comprising the pharmaceutical composition according to claim 9 as an active ingredient.