JP2008247878A - Imidazopyridine or imidazopyrimidine compound and narcotic or sedative composition containing the same - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a new water-soluble or water-miscible compound useful for producing a narcotic, especially a venous narcotic, and to provide a narcotic composition using such a compound. <P>SOLUTION: The useful new compound is an imidazopyridine or imidazopyrimidine compound represented by general formula (I) or a pharmaceutically acceptable salt thereof. <P>COPYRIGHT: (C)2009,JPO&INPIT

Description

  The present invention relates to novel imidazopyridine and imidazopyrimidine compounds. The imidazopyridine and imidazopyrimidine compounds of the present invention are useful for the manufacture of pharmaceuticals, particularly anesthetics.

  Many drugs for central nervous system have been reported so far as imidazopyridine and imidazopyrimidine derivatives, and there are also commercially available compounds as sleep-inducing agents for imidazopyridine derivatives.

  For example, an imidazopyridine compound that is said to have an anesthetic action is described in Patent Document 1, but the imidazopyridine compound does not have an anesthetic action sufficiently, and a reflex action by stimulation is also observed. Further, although other imidazopyridine compounds are shown in Non-Patent Document 1, Patent Document 2, and the like, none of them has been reported to have an anesthetic action.

  In general, it is desired that intravenous anesthetics have a rapid action and that recovery from anesthesia is quick. In addition, in order to prepare an injectable dosage form, it is more desirable to be water-soluble. For example, since propofol (2,6-diisopropylphenol), which is currently used as an anesthetic, is hardly soluble in water, a formulation designed to be emulsified in an emulsion of soybean oil, glycerin, and purified egg phospholipid has been applied. It is used clinically as an anesthetic. For this reason, side effects such as vascular pain at the time of injection, lipid accumulation, and infectivity are pointed out. In recent years, highly concentrated preparations are also commercially available for the purpose of alleviating these side effects.

From the above, it is a compound that is still satisfactory from the viewpoint that it is fast acting when used as an intravenous anesthetic, has quick recovery, has few side effects, and can be dissolved in water or miscible with water. Is not found.
Guiseppe et al., J Med Chem, 40, 3109-3118 (1997). JP-A-3-181419 International Patent Publication No. WO2005 / 044818

  An object of the present invention is to provide a novel compound that is water-soluble or water-miscible and useful for the production of anesthetics, particularly intravenous anesthetics, and an anesthetic composition using such compounds.

  As a result of diligent research, the present inventors have found imidazopyridine and imidazopyrimidine compounds having specific structures not disclosed in the above-mentioned literature, and it seems that such compounds are different from the mechanism of action of conventional imidazopyridine compounds. The present inventors have found that an excellent anesthetic action is exhibited with a mechanism of action, and further studies have been made to complete the present invention.

［式（Ｉ）中、２個のＲ_１は同一または相異なって水素原子、炭素数１〜５の直鎖または分岐鎖状アルキル、２個のＲ_１が結合して形成する置換基を有していてもよい炭素数２〜５のアルキレン基、あるいは２個のＲ_１が結合して硫黄、窒素および酸素原子からなる群から選択される１または２のヘテロ原子を含んでいてもよい飽和または不飽和の５員から７員の環状基を示し、Ｒ_２は

（式中、ｎは０〜２の整数であり、Ｒ_４は炭素数１〜５の直鎖または分岐鎖状アルキル、炭素数１〜５の１以上のフッ素で置換されているアルキル、炭素数３〜５の直鎖または分岐鎖状アルケニルまたはアルキニル、５から７員のシクロアルキルまたはシクロアルキルメチル、炭素数１〜５のアルコキシアルキル、アルキルアミノアルキル、シアノアルキルあるいは置換基を有していてもよいフェニル基またはフェニルアルキル基を示す。）；

（式中、ｎ’は１〜２の整数であり、Ｒ_４は前記と同意義を示す。）；または

（式中、Ａは−ＯＣＯ−あるいは−Ｏ−を示し、Ｒ_４は前記と同意義を示す。）で表される基を示し、
Ｒ_３は、炭素数１〜６のアルキル、置換基を有していてもよいフェニル、ベンジル、ピリジル、シクロヘキシル、ナフチル、チオフェニル、フラニル基から成る群より選択される基を示し、
Ｘは炭素原子または窒素原子を示す。ただし、２個のＲ_１がともに水素原子であることはない。］
［２］ 一般式（Ｉ）中の２個のＲ_１がメチル、エチル、プロピルおよびイソプロピル基からなる群より選択される同一または相異なる２個の基である、前項［１］記載の化合物あるいはその医薬上許容される塩。
［３］ 一般式（Ｉ）中の２個のＲ_１の組み合わせが６−メチル−７−エチル、６−エチル−７−メチルまたは６−イソプロピル−７−メチルである前項［２］記載の化合物あるいはその医薬上許容される塩。
［４］ ２個のＲ_１がいずれもメチル基である、前項［２］記載の化合物あるいはその医薬上許容される塩。
［５］ 下記一般式（Ｉ−１）で表される、前項［１］記載の化合物あるいはその医薬上許容される塩。

［式（Ｉ−１）中、Ｍはイミダゾピリジンまたはイミダゾピリミジン環と共に、置換基を有していてもよい飽和または不飽和の５員、６員または７員の環状基を形成する基を示し、Ｘ、Ｒ_２およびＲ_３は前記と同意義を示す。］
［６］ 一般式（Ｉ−１）中のＭが、
−ＣＨ_２ＣＨ_２ＣＨ_２−、
−ＣＨ_２ＣＨ（ＣＨ_３）ＣＨ_２−、
−ＣＨ_２ＣＨ_２ＣＨ_２ＣＨ_２−および
−ＣＨ_２ＣＨ_２ＣＨ_２ＣＨ_２ＣＨ_２−
からなる群より選択される基である、前項［５］記載の化合物またはその医薬上許容される塩。
［７］ 一般式（Ｉ）または（Ｉ−１）中のＲ_２が、式
−（ＣＨ_２）_ｎ−ＣＯ_２−Ｑ
（式中、ｎは０〜２の整数であり、Ｑは炭素数１〜５の直鎖または分岐鎖状アルキル、炭素数１〜５の１以上のフッ素で置換されているアルキル、あるいは２−メチル−２−プロペニル、２−プロピニル、シクロペンチル、シクロペンチルメチルまたはフェニル基を示す。）
で示される基である前項［１］〜［６］いずれかに記載の化合物またはその医薬上許容される塩。
［８］ 一般式（Ｉ）または（Ｉ−１）中のＲ_２が、式
−ＣＨ_２−ＣＯ−Ｔ
（式中、Ｔは炭素数１〜５のアルキル基を示す。）
で示される基である前項［１］〜［６］いずれかに記載の化合物またはその医薬上許容される塩。
［９］ 一般式（Ｉ）または（Ｉ−１）中のＲ_２が、式
−（ＣＨ_２）_２−Ａ−Ｚ
（式中、Ａは−ＯＣＯ−あるいは−Ｏ−を示し、Ｚは炭素数１〜３のアルキル基を示す。）
で示される基である前項［１］〜［６］いずれかに記載の化合物またはその医薬上許容される塩。
［１０］ 一般式（Ｉ）または（Ｉ−１）中のＲ_３が、置換されていてもよいフェニル基である、前項［１］〜［９］いずれかに記載の化合物またはその医薬上許容される塩。
［１１］ 麻酔有効量の前項［１］〜［１０］いずれかに記載の化合物またはその医薬上許容される塩、および医薬上許容されるキャリアを含有する、哺乳動物のための麻酔または鎮静薬組成物。
［１２］ 静脈投与して用いられる、前項［１１］記載の麻酔または鎮静薬組成物。
［１３］ 全身麻酔の導入および維持に用いられる、前項［１１］または［１２］記載の麻酔または鎮静薬組成物。
［１４］ 術後の鎮静管理、検査時の鎮静管理、局所麻酔時の鎮静管理または集中治療時の鎮静管理に用いられる、前項［１１］または［１２］記載の麻酔または鎮静薬組成物。
［１５］ 前項［１］〜［１０］いずれかに記載の化合物またはその医薬上許容される塩の、哺乳動物用麻酔または鎮静薬組成物を製造するための使用。
［１６］ 麻酔有効量の前項［１］〜［１０］いずれかに記載の化合物またはその医薬上許容される塩を、麻酔または鎮静を必要とする対象の哺乳動物へ投与することを含む、哺乳動物の麻酔または鎮静方法。 That is, the gist of the present invention is as follows.
[1] An imidazopyridine or imidazopyrimidine compound represented by the following general formula (I), or a pharmaceutically acceptable salt thereof.

[In the formula (I), two R _{1 s} are the same or different and each has a hydrogen atom, a linear or branched alkyl having 1 to 5 carbon atoms, and a substituent formed by combining two R _{1 s.} An optionally substituted alkylene group having 2 to 5 carbon atoms, or two R ₁ bonded together and containing 1 or 2 heteroatoms selected from the group consisting of sulfur, nitrogen and oxygen atoms Or an unsaturated 5- to 7-membered cyclic group, wherein R ₂ is

(In the formula, n is an integer of 0 to 2, R ₄ is linear or branched alkyl having 1 to 5 carbon atoms, alkyl substituted with 1 or more fluorine atoms having 1 to 5 carbon atoms, carbon number 3 to 5 linear or branched alkenyl or alkynyl, 5 to 7-membered cycloalkyl or cycloalkylmethyl, alkoxyalkyl having 1 to 5 carbon atoms, alkylaminoalkyl, cyanoalkyl or a substituent. A good phenyl or phenylalkyl group).

(Wherein n ′ is an integer of 1 to 2 and R ₄ is as defined above); or

In the formula, A represents —OCO— or —O—, and R ₄ represents the same meaning as described above.
R ₃ represents a group selected from the group consisting of alkyl having 1 to 6 carbon atoms, optionally substituted phenyl, benzyl, pyridyl, cyclohexyl, naphthyl, thiophenyl, furanyl group;
X represents a carbon atom or a nitrogen atom. However, the two R _{1 s} are not both hydrogen atoms. ]
[2] The compound according to the above item [1], wherein two R ₁ in the general formula (I) are the same or different two groups selected from the group consisting of methyl, ethyl, propyl and isopropyl groups. Its pharmaceutically acceptable salt.
[3] The compound according to item [2], wherein the combination of two R ₁ in general formula (I) is 6-methyl-7-ethyl, 6-ethyl-7-methyl or 6-isopropyl-7-methyl. Or a pharmaceutically acceptable salt thereof.
[4] The compound of the above-mentioned [2] or a pharmaceutically acceptable salt thereof, wherein each of the two R _{1 's} is a methyl group.
[5] The compound of the above-mentioned item [1] represented by the following general formula (I-1) or a pharmaceutically acceptable salt thereof.

[In the formula (I-1), M represents a group which forms a saturated or unsaturated 5-membered, 6-membered or 7-membered cyclic group which may have a substituent together with an imidazopyridine or imidazopyrimidine ring. , X, R ₂ and R ₃ are as defined above. ]
[6] M in the general formula (I-1) is
-CH ₂ CH ₂ CH ₂ -,
_{-CH 2 CH (CH 3) CH} 2 -,
_{-CH 2 CH 2 CH 2 CH 2} - and _{-CH 2 CH 2 CH 2 CH 2} CH 2 -
The compound or a pharmaceutically acceptable salt thereof according to [5] above, which is a group selected from the group consisting of:
[7] R ₂ in the general formula (I) or (I-1) is represented by the formula — (CH ₂ ) _n —CO ₂ —Q
(In the formula, n is an integer of 0 to 2, and Q is a linear or branched alkyl having 1 to 5 carbon atoms, an alkyl substituted with one or more fluorines having 1 to 5 carbon atoms, or 2- Methyl-2-propenyl, 2-propynyl, cyclopentyl, cyclopentylmethyl or phenyl group is shown.)
Or a pharmaceutically acceptable salt thereof according to any one of [1] to [6] above.
[8] R ₂ in the general formula (I) or (I-1) is represented by the formula —CH ₂ —CO—T.
(In the formula, T represents an alkyl group having 1 to 5 carbon atoms.)
Or a pharmaceutically acceptable salt thereof according to any one of [1] to [6] above.
[9] R ₂ in the general formula (I) or (I-1) is represented by the formula — (CH ₂ ) ₂ —AZ.
(In the formula, A represents —OCO— or —O—, and Z represents an alkyl group having 1 to 3 carbon atoms.)
Or a pharmaceutically acceptable salt thereof according to any one of [1] to [6] above.
[10] The compound according to any one of [1] to [9] above or a pharmaceutically acceptable salt thereof, wherein R ₃ in the general formula (I) or (I-1) is an optionally substituted phenyl group Salt.
[11] An anesthesia or sedative for mammals containing the compound according to any one of [1] to [10] above or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier in an effective amount of anesthesia Composition.
[12] The anesthetic or sedative composition according to [11], which is used by intravenous administration.
[13] The anesthetic or sedative composition according to [11] or [12] above, which is used for the induction and maintenance of general anesthesia.
[14] The anesthesia or sedative composition according to [11] or [12] above, which is used for postoperative sedation management, sedation management during examination, sedation management during local anesthesia, or sedation management during intensive care.
[15] Use of the compound according to any one of [1] to [10] or a pharmaceutically acceptable salt thereof for producing an anesthetic or sedative composition for mammals.
[16] A mammal comprising administering an effective anesthetic amount of the compound according to any one of [1] to [10] above or a pharmaceutically acceptable salt thereof to a mammal in need of anesthesia or sedation Animal anesthesia or sedation method.

に従って記載する。 In the description of the present specification and claims, unless otherwise specified, the names of imidazopyridine and imidazopyrimidine compounds are the following imidazopyridine and imidazopyrimidine skeleton numbering systems:

Follow the instructions.

  The compound of the present invention and a pharmaceutically acceptable salt thereof have a suitable anesthetic / sedative action for mammals and can be suitably used for the production of anesthetics.

  An anesthetic or sedative composition comprising a compound of the present invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier (vehicle) is useful as an anesthetic or sedative composition for mammals, It is suitably used for general anesthesia as a venous anesthetic.

In one preferred embodiment of the present invention, in the formula (I), two R ₁ bonded to the 6,7-position may be the same or different, and are composed of methyl, ethyl, propyl and isopropyl. A group selected from the group; In particular, among the compounds represented by the formula (I), 6,7-dimethyl compounds in which two R ₁ are both methyl are preferably used. A compound in which the combination of two R ₁ bonded to the 6,7-position is 6-methyl-7-ethyl, 6-ethyl-7-methyl or 6-isopropyl-7-methyl is also preferably used. . Needless to say, when the above combination is, for example, 6-methyl-7-ethyl, R ₁ bonded to the 6-position is a methyl group and R ₁ bonded to the 7-position is an ethyl group. It means that. In another preferred embodiment of the present invention, two R ₁ bonded to the 6,7-position together with an imidazopyridine or imidazopyrimidine ring form a 5-membered, 6-membered or 7-membered cyclic group.

  In the formula (I), X represents a carbon atom or a nitrogen atom, and a carbon atom is particularly preferable.

（式中、ｎは０〜２の整数であり、Ｒ_４は炭素数１〜５の直鎖または分岐鎖状アルキル、炭素数１〜５の１以上のフッ素で置換されているアルキル、炭素数３〜５の直鎖または分岐鎖状アルケニルまたはアルキニル、５から７員のシクロアルキルまたはシクロアルキルメチル、炭素数１〜５のアルコキシアルキル、アルキルアミノアルキル、シアノアルキルあるいは置換基を有していてもよいフェニル基またはフェニルアルキル基を示す。）
で表される基が挙げられる。 In the formula (I), examples of the group represented by R ₂ include

(In the formula, n is an integer of 0 to 2, R ₄ is linear or branched alkyl having 1 to 5 carbon atoms, alkyl substituted with 1 or more fluorine atoms having 1 to 5 carbon atoms, carbon number 3 to 5 linear or branched alkenyl or alkynyl, 5 to 7-membered cycloalkyl or cycloalkylmethyl, alkoxyalkyl having 1 to 5 carbon atoms, alkylaminoalkyl, cyanoalkyl or a substituent. A good phenyl or phenylalkyl group.)
The group represented by these is mentioned.

（式中、ｎ’は１〜２の整数であり、Ｒ_４は前記と同意義を示す。）
で表される基が挙げられる。 In the formula (I), examples of the group represented by R ₂ include

(In the formula, n ′ is an integer of 1 to 2, and R ₄ is as defined above.)
The group represented by these is mentioned.

（式中、ＡおよびＲ_４は前記と同意義を示す。）
で表される基が挙げられる。 In the formula (I), examples of the group represented by R ₂ include

(In the formula, A and R ₄ are as defined above.)
The group represented by these is mentioned.

（式中、ｎ、Ｒ_４は前記と同意義である。）
で表される基が好ましく、かかる好ましい態様において、式中のｎが１〜２の整数であることが特に好ましく、Ｒ_４は炭素数３〜５の直鎖状アルキルであるか、炭素数１〜３の１以上のフッ素で置換されているアルキルであることが特に好ましい。 Among the above examples, in the formula (I), as the group represented by R ₂ ,

(In the formula, n and R ₄ are as defined above.)
In the preferred embodiment, n in the formula is particularly preferably an integer of 1 to 2, and R ₄ is a linear alkyl having 3 to 5 carbon atoms or 1 carbon atom. It is particularly preferable that the alkyl is substituted with one or more fluorine atoms of ˜3.

In the formula (I), examples of the group represented by R ₃ include phenyl, benzyl, pyridyl, cyclohexyl, thiophenyl and furanyl groups which may have a substituent. Among these, as the group represented by R ₃ , a phenyl group which may have a substituent is particularly preferable.

As described above, groups such as phenyl, benzyl, pyridyl, cyclohexyl, thiophenyl and furanyl represented by R ₃ may have a substituent, and the number of substituents in the case of having a substituent is 1 to 1. Three, more preferably one or two. Examples of such substituents for R ₃ include halogen [eg, fluorine, chlorine, bromine, iodine], hydroxy, alkyl having 1 to 5 carbons [eg: methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, Isopentyl], alkoxy having 1 to 4 carbon atoms [e.g., methoxy, ethoxy, propoxy, isopropoxy, butoxy), trifluoromethyl, alkoxy substituted with one or more fluorine atoms having 1 to 3 carbon atoms [e.g., trifluoro Methoxy, trifluoroethoxy and trifluoropropoxy], amide, carboxy, cyano, alkylthio having 1 to 4 carbon atoms [eg, methylthio, ethylthio, propylthio, butylthio], nitro, amino, methylamino, dimethylamino, dimethylaminomethyl, Dipropylaminomethyl, methylenedi Oxy, phenoxy, benzyloxy, alkanoyloxy having 2 to 5 carbon atoms [Example: acetoxy, propionyloxy, butyryloxy], ω-hydroxyalkyl having 1 to 3 carbon atoms [example: hydroxymethyl, hydroxyethyl], alkanoyloxy (carbon 2-5) -alkyl (C1-C3) [Example: acetyloxymethyl, acetyloxyethyl, propionyloxymethyl], C2-C5 alkanoylamino [Example: acetylamino, propionylamino], alkoxycarbonyl [Examples: methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl], phenoxycarbonyl, benzyloxycarbonyl group and the like.

When R ₃ has a substituent, the substituent may be substituted at any position of R ₃ . When R ₃ is a phenyl group, an unsubstituted phenyl group or a phenyl group substituted at the 2-position or 4-position with a fluorine atom or a methyl group is preferred. The 2nd or 4th position here is not determined by the numbering system of the imidazopyridine and imidazopyrimidine skeletons described above.

Moreover, when the phenyl group or alkylphenyl group which may have a substituent represented by R ₄ has a substituent, examples of the substituent in R ₄ are the same as the examples of the substituent in R ₃ described above. An example is given.

  Pharmaceutically acceptable salts of the compounds of the present invention are salts with alkali metals, alkaline earth metals, ammonium, alkylammonium, etc., salts with mineral acids or organic acids. These salts include, for example, sodium, potassium, calcium, ammonium, triethylammonium, acetate, propionate, butyrate, formate, trifluoroacetate, maleate, tartrate, citric acid. Acid, stearate, succinate, ethyl succinate, lactobionate, gluconate, glucoheptonate, benzoate, methanesulfonate, ethanesulfonate, 2-hydroxyethanesulfonate, benzene Sulfonate, paratoluenesulfonate, lauryl sulfate, malate, aspartate, glutamate, adipate, salt with cysteine, salt with N-acetylcysteine, hydrochloride, hydrobromide , Phosphate, sulfate, hydroiodide, nicotinate, oxalate, picrate, thiocyanate Salt, undecanoate, a salt with an acrylic acid polymer, and salts with carboxyvinyl polymers and the like.

[Synthesis method]
Hereinafter, the synthesis method of the compound of the present invention will be described with examples. The following method is exemplary, and the compound of the present invention may be obtained by applying any known method.

（式中、ｎおよびＲ_４は前記と同意義を示す。）
で表される基である場合、例えば式（II）：

（式中、Ｒ_１、Ｒ_３、Ｒ_４、Ｘおよびｎは前記と同意義を示す。）
で表される化合物は、例えば以下のａ）およびｂ）に示す方法により製造し得る。 ・ Method (i)
Compound (I) of the present invention [The compound represented by the formula (I) may be referred to in this way, and the same applies to the compounds represented by the formulas identified by other numbers or symbols. ] In which R ₂ represents the formula:

(In the formula, n and R ₄ are as defined above.)
In the case of a group represented by formula (II), for example:

(Wherein R ₁ , R _3, R _4, X and n are as defined above.)
Can be produced by, for example, the methods shown in the following a) and b).

a) When n = 1 Using the compound of formula (III) as a starting material, compound (II-a) in which n is 1 can be produced by the reaction shown in the following scheme. In the reaction formulas in the scheme, R ₁ , R ₃ , R ₄ and X are as defined above (where R ₄ is a group other than ethyl or propyl group), and R ₅ is ethyl or propyl group. .

  The compounds represented by the above (III) as starting materials in the above scheme, for example, the following compounds (III-1) to (III-3) can be obtained as follows.

  2-Amino-4,5-dimethylpyridine (III-1) is described in J. Am. Heterocyclic Chem. , 18, 1613-1618 (1981), by heating a mixture of 3,4-dimethylpyridine and sodium amide.

  6,7-Dihydro-5H-cyclopenta [c] pyridin-3-amine (III-2) is described in J. Am. AM. Chem. SOC. 2003, 125, 11460-11461, Khemia getteri sichliskiskih soedinenii, 1983, No 9, 1279-1282 and khimiko-farmatsevichskii zhurnal, 1984, 18, 35. In addition, 5,6,7,8-tetrahydro-3-isoquinolinamine, 6,7,8,9-tetrahydro-5H-cyclohepta [c] pyridin-3-amine and the like can be obtained with reference to the above documents.

  6,7-Dihydro-5H-cyclopenta [d] pyrimidin-2-amine (III-3) is described in J. Am. AM. Chem. SOC. 1959, 81, 3108-3114. 4,5-dimethyl-2-pyrimidinamine and the like can also be obtained with reference to the above literature.

A scheme for obtaining the above compounds (III-1) to (III-3) is shown below.

As described above, a suitable compound (III) was obtained as a starting material, which was prepared in the presence of sodium hydrogen carbonate in an ethanol solvent and represented by the formula: R ₃ —CO—CH ₂ —Br (wherein R ₃ is as defined above). The compound (IV) can be produced by reacting with a bromo compound represented by The bromo compound can be reacted with bromine in the formula: R ₃ —CO—CH ₃ (wherein R ₃ is as defined above) in dichloromethane or acetic acid solvent.

  The compound (IV) obtained above was converted to Aust. J. et al. Chem. , 1997, 50, 719-725, in the presence of p-toluenesulfonic acid in a mixed solvent of toluene and ethanol, in the presence of paratoluenesulfonic acid, or in International Patent Publication No. WO1999 / 055388. Compound (V) can be produced by reacting with propylglyoxalate produced according to the described method under heating.

  Subsequently, thionyl chloride, N, N-dimethylformamide and sodium hydroxymethanesulfinate dihydrate were added to compound (V) in a chloroform solvent in accordance with the method described in International Patent Publication WO2005 / 08021. The compound (II-a-1) can be obtained by acting.

  Further, if necessary, the compound (II-a-1) is hydrolyzed with an alkali to obtain the compound (II-a-2), which is converted into the corresponding alcohol, phenol or hydroxyl compound and WSC [1-ethyl-3]. Compound (II-a) can be produced by esterification in the presence of-(3-dimethylaminopropyl) carbodiimide hydrochloride] and DMAP (4-dimethylaminopyridine).

（反応式中、Ｒ_１、Ｒ_３、Ｒ_４、Ｒ_５およびＸは前記と同意義を示し、ｎ’’は０または２を示す。） b) When n = 0 or 2 Using the compound of formula (III) as a starting material, compound (II-b) in which n is 0 or 2 can be produced by the reaction shown in the following scheme.

(In the reaction formula, R ₁ , R ₃ , R ₄ , R ₅ and X are as defined above, and n ″ represents 0 or 2.)

  That is, J. et al. Med. According to the method described in Chem, 1997, 40, 3109-3118, Compound (III) is heated with Compound (VI) in butanol to give Compound (II-b-1). The compound (II-b) in which n is 0 or 2 can be produced by hydrolysis and esterification.

Here, the compound (VI) is a carboxyl represented by the formula: R ₃ —CO—CH ₂ — (CH ₂ ) _{n ″} —COOH (wherein R ₃ and n ″ are as defined above). The acid can be obtained by esterification in the same manner as described above in the presence of ethanol or propanol and then reacting with bromine in a dichloromethane solvent.

［式中、ｎ’およびＲ_４は前記と同意義（但しＲ_４は水素原子ではない）を示す。］
で表される基である場合、例えば式（VII）：

［式中、Ｒ_１、Ｒ_３、Ｒ_４、Ｘおよびｎ’は前記と同意義（但しＲ_４は水素原子ではない）を示す。］
で表される化合物は、以下の方法により製造し得る。 ・ Method (ii)
In the present compound (I), R ₂ has the formula:

[Wherein, n ′ and R ₄ have the same meaning as described above (where R ₄ is not a hydrogen atom). ]
In the case of a group represented by formula (VII), for example:

[Wherein, R ₁ , R _3, R _4, X and n ′ represent the same meaning as described above (provided that R ₄ is not a hydrogen atom). ]
Can be produced by the following method.

［反応式中、Ｒ_１、Ｒ_３、Ｒ_４、Ｒ_５、Ｘおよびｎ’は前記と同意義（但しＲ_４は水素原子ではない）を示す。］ Specifically, compound (VII) can be produced by the reaction shown in the following scheme.

[In the reaction formula, R ₁ , R ₃ , R ₄ , R ₅ , X and n ′ are as defined above (provided that R ₄ is not a hydrogen atom). ]

  In the above scheme, compound (VIII) can be produced by a synthesis method similar to the synthesis method of compound (2-a-1) or (2-a-2) described above.

For this compound (VIII), with reference to the synthesis method described in International Patent Publication WO2005 / 044818, in the presence of sodium hexamethyldisilazane in anhydrous tetrahydrofuran solvent, the formula: R ₄ —CO—Cl 2 ₄ represents the same meaning as described above.) Compound (IX) can be obtained by acting an acid chloride represented by the following formula, and then it is heated and stirred with a mixed solution of acetic acid and hydrochloric acid to give compound (IX). VI) can be obtained.

［式中、Ａ、Ｒ_４は前記と同意義（但しＲ_４は水素原子ではない）を示す。］
で表される基である場合、例えば式（Ｘ）：

［式中、Ｒ_１、Ｒ_３、Ｒ_４およびＸは前記と同意義（但しＲ_４は水素原子ではない）を示す。］
で表される化合物は、例えば以下のａ）およびｂ）に示す方法により製造し得る。 ・ Method (iii)
In the present compound (I), R ₂ is

[Wherein, A and R ₄ represent the same meaning as described above (provided that R ₄ is not a hydrogen atom). ]
Is a group represented by formula (X):

[Wherein, R ₁ , R ₃ , R ₄ and X are as defined above (where R ₄ is not a hydrogen atom). ]
Can be produced by, for example, the methods shown in the following a) and b).

［式中、Ｒ_１、Ｒ_３、Ｒ_４、Ｒ_５およびＸは前記と同意義（但しＲ_４は水素原子ではない）を示す。］ a) In the case of A = -OCO- A compound (X-a) can be manufactured by reaction shown by the following scheme.

[Wherein, R ₁ , R ₃ , R ₄ , R ₅ and X are as defined above (provided that R ₄ is not a hydrogen atom). ]

  In the above scheme, compound (XI) is obtained by reducing compound (XI) with lithium tetrahydroborate in an anhydrous tetrahydrofuran solvent using compound (II-a-1) obtained by the above-described method as a starting material. Is esterified with carboxylic acid in the same manner as described above to give compound (X-a).

［式中、Ｒ_１、Ｒ_３、Ｒ_４およびＸは前記と同意義（但しＲ_４は水素原子ではない）を示し、Ｍｓはメタンスルホニル基を示す。］ b) In the case of A = -O- Compound (Xa) can be produced by the reaction shown in the following scheme.

[Wherein, R ₁ , R _3, R ₄ and X are as defined above (where R ₄ is not a hydrogen atom), and Ms represents a methanesulfonyl group. ]

  In the above scheme, compound (Xb) is obtained by reacting compound (XI) with methanesulfonyl chloride in the presence of triethylamine in dichloromethane solvent to give compound (XII), which is heated with the corresponding alcohol, phenol or hydroxyl compound. It can be obtained by stirring.

[Anesthetic or sedative composition]
The compounds of the present invention and pharmaceutically acceptable salts thereof can be used as active ingredients for anesthetics or sedatives for mammals.

Currently marketed anesthetics such as propofol are said to act on central nerve GABA _A receptors, enhance potentiation of inhibitory neurotransmission and develop anesthesia or sedation. Since the imidazopyridine compound, imidazopyrimidine compound and salts thereof of the present invention also act on the central nerve GABA _A receptor of mammals including humans and exhibit the same action as described above, anesthesia or sedation for mammals Useful as a medicine.

Zirpidem and imidazopyridine and pyrimidine derivatives that have been published so far in Non-Patent Document 1, Patent Documents 1 and 2, and the like described above have sedation or hypnosis by acting on the benzodiazepine site of the central nerve GABA _A receptor. It is supposed to be expressed. These effects can be antagonized by using flumazenil, which is a benzodiazepine antagonist. On the other hand, sedation or anesthetic action of propofol and thiopental currently marketed as anesthetics acts on the same central nerve GABA _A receptor, but is not antagonized by flumazenil, and these anesthetic sedatives and sedative hypnotics are different It is thought to have a mechanism of action. The sedative or anesthetic action of the compounds of the present invention is not antagonized by flumazenil, and is considered to have a different mechanism of action from the published imidazopyridine and pyrimidine compounds. It is observed in compounds having an ester, a ketone, and an ether, and the substituent at the 6 to 8 position is enhanced by making it a disubstitution rather than a monosubstitution.

  The compound of the present invention has a strong action compared with commercially available intravenous anesthetics such as propofol, and has a high safety as well as not only having an equivalent or faster rapid introduction and rapid wakefulness profile. is there.

  Since the compound of the present invention has an imidazopyridine or imidazopyrimidine skeleton and has a basic nitrogen atom in the mother nucleus, it can be converted into a pharmaceutically acceptable salt or a dissolution aid can be used. Can easily be made water-soluble or water-miscible. For this reason, the compounds of the present invention are useful and ideal for the production of intravenous anesthetics. As the pharmaceutically acceptable salt, any of the above-mentioned salts can be suitably used.

  The anesthetic or sedative composition of the present invention is a composition comprising an anesthetic effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, and is a tablet, granule, capsule , Injections, eye drops, ointments, poultices, suppositories, and other oral forms or mammals including humans (eg intravenous, epidural, intraspinal, subcutaneous, intramuscular) Etc.) and can be used.

  Particularly preferred as the anesthetic or sedative composition of the present invention is a intravenous anesthetic obtained by dissolving directly in a pharmaceutically acceptable vehicle or using a solubilizing agent. Here, examples of the pharmaceutically acceptable vehicle that can be suitably used include purified water, physiological saline, water for injection, Ringer's solution, and the like, and physiological saline is particularly preferable.

  Most of the compounds represented by the formula (I) of the present invention are easily water-soluble when in the form of a pharmaceutically acceptable salt. Moreover, in the case of a compound which is hardly soluble in water, an aqueous solution can be obtained by using a solubilizing agent. Examples of such a solubilizer include inorganic acids, organic acids, polyoxyethylene hydrogenated castor oil, dimethyl sulfoxide, cyclodextrin, glycerin, ethanol, propylene glycol, polyethylene glycol and the like.

  The anesthetic or sedative composition of the present invention may be provided as a solution composition previously dissolved in a vehicle, and is used in a powder form for mixing with an appropriate vehicle such as water or physiological saline immediately before use. It may be provided as a composition.

  In addition to the above, the anesthetic or sedative composition of the present invention may contain an additive added to a normal anesthetic or sedative composition. Examples of such additives include, but are not limited to, isotonic agents (eg, sodium chloride and glucose), buffers (eg, calcium citrate, sodium citrate, potassium acetate, sodium acetate, phosphorus Sodium hydrogen hydrate and potassium dihydrogen phosphate), preservatives (eg benzyl alcohol and phenol), antioxidants (eg sodium pyrosulfite, sodium hydrogen sulfite and ascorbic acid), preservatives (eg benzethonium chloride, benzaza chloride) Luconium, phenol, cresol, chlorobutanol and benzyl alcohol.) And chelating agents such as EDTA, thioglycolic acid, thiolactic acid and thioglycerin.

  Other medicinal ingredients may be added to the anesthetic or sedative composition of the present invention as long as the object of the present invention is not adversely affected.

  The anesthetic or sedative composition of the present invention is suitably used particularly for general anesthesia by intravenous administration. For example, it is suitably used for introduction of anesthesia during surgical operation, maintenance of anesthesia and postoperative sedation management, sedation management during artificial respiration in intensive care, sedation management during examination, and sedation management during local anesthesia. The anesthetic or sedative composition of the present invention can be used in appropriate combination with other analgesics and / or muscle relaxants as necessary at each stage of the anesthesia.

  The effective amount of anesthesia of the compound represented by the formula (I) or a salt thereof of the present invention is not particularly limited, and is appropriately determined depending on the age, sex, body weight, health condition, etc. of the administration target and the intended depth of anesthesia and duration of anesthesia. Just choose.

  As a typical example of the dosage according to the purpose when the compound of the present invention or a salt thereof is used as a intravenous anesthetic, the imidazopyridine or the imidazopyrimidine compound of the present invention or a salt thereof is about 0.1 to 40 mg / kg, preferably 1.0 to 20.0 mg / kg is administered. For maintenance of anesthesia, intravenous administration is continuously performed at 0.5 to 25 mg / kg / hour, preferably 1.0 to 15 mg / kg / hour. In the maintenance of sedation during intensive care or postoperative sedation management, there is a mode in which 0.05 to 10 mg / kg / hour, preferably 0.1 to 5.0 mg / kg / hour is continuously administered intravenously, Such dosage is not limited to the numerical ranges exemplified above.

  EXAMPLES Hereinafter, the present invention will be described more specifically with reference to test examples and reference examples, but the present invention is not limited to these ranges.

Reference Example 1: Production Example of 4,5-dimethyl-2-pyridinamine 3,4-dimethylpyridine (20 g, 0.19 mol) and sodium amide (7.8 g, 0.2 mol) were added to N, N-dimethylaniline ( In 47.4 mL, 0.37 mol), the mixture was heated and stirred at 150 ° C. for 6.5 hours under argon substitution. Thereafter, ice water was added to the reaction solution, extracted with chloroform, and the organic layer was concentrated under reduced pressure to obtain 6.8 g of a mixture of 4,5-dimethyl-2-pyridinamine and 3,4-dimethyl-2-pyridinamine. (Mixing ratio approx. 1: 2.5)

Reference Example 2: Production Example of 6,7-dihydro-5H-cyclopenta [c] pyridin-3-amine The title compound was produced by the following synthesis procedures (a) to (e).

(A) Synthesis of 2-cyclopentylidenemalononitrile Malononitrile (6.6 g, 0.1 mol), cyclopentanone (8.4 g, 0.1 mol) and AM. Chem. SOC. RuHAP (II) (500 mg) synthesized with reference to 2003, 125, 11460-11461 was heated and stirred at 80 ° C. for 20 hours in water (50 mL). Thereafter, the reaction solution was suction filtered, the filtrate was extracted with chloroform, and then the organic layer was concentrated under reduced pressure. The obtained oil was purified by NH-type silica gel column chromatography (chloroform) to obtain 13 g of 2-cyclopentylidenemalononitrile.

(B) Synthesis of 2- {2-[(E)-(dimethylamino) methylidene] cyclopentylidene} malononitrile The product of (a) above (873 mg, 6.6 mmol) and aluminum chloride (88 mg, 0.66 mmol) Was stirred at 50 ° C. under argon substitution in anhydrous benzene (10 mL), and diethoxy-N, N-dimethylmethanamide (1.6 mL, 9.9 mmol) was added dropwise thereto, followed by heating to reflux for 30 minutes. Thereafter, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform) to obtain 363 mg of 2- {2-[(E)-(dimethylamino) methylidene] cyclopentylidene} malononitrile.

(C) Synthesis of 3-amino-6,7-dihydro-5H-cyclopenta [c] pyridine-4-carbonitrile The product of (b) above (2.3 g, 12.3 mmol) and 2.0 M ammonia-ethanol The solution (18 mL) was heated and stirred under pressure at 130 ° C. for 2 hours in a portable reactor (manufactured by Pressure Glass Industrial Co., Ltd.). Thereafter, the precipitated solid was subjected to suction filtration, and the obtained solid was dried to obtain 1.2 g of 3-amino-6,7-dihydro-5H-cyclopenta [c] pyridine-4-carbonitrile.

(D) Synthesis of 3-amino-6,7-dihydro-5H-cyclopenta [c] pyridine-4-carboxylic acid and 6,7-dihydro-5H-cyclopenta [c] pyridin-3-amine The product (3.9 g, 24.5 mmol) was heated to reflux in 47% aqueous hydrobromic acid (20 mL) for 100 hours. Thereafter, sodium hydroxide was added to the reaction solution until the pH of the solution reached 6 to 7, the precipitated solid was suction filtered, and the obtained solid was dried to give 3-amino-6,7-dihydro-5H-. 2.0 g of cyclopenta [c] pyridine-4-carboxylic acid was obtained. Further, sodium hydroxide was added to the filtrate obtained above until the liquid pH was about 9, and then the precipitated solid was suction filtered, and the obtained solid was dried to obtain 6,7-dihydro 348 mg of -5H-cyclopenta [c] pyridin-3-amine was obtained.

(E) Synthesis of 6,7-dihydro-5H-cyclopenta [c] pyridin-3-amine 3-amino-6,7-dihydro-5H-cyclopenta [c] pyridine-4-carboxylic acid produced in (d) above The acid (2.0 g, 11.4 mmol) was heated at 270 ° C. for 5 minutes using a glass tube oven (manufactured by Shibata Scientific Instruments Co., Ltd.). Thereafter, a mixed solvent of chloroform and methanol (mixing ratio = 1: 1) was added to the reaction product to separate the soluble material and the insoluble material by suction filtration, and the soluble material was concentrated under reduced pressure and dried to obtain 6,7. -724 mg of dihydro-5H-cyclopenta [c] pyridin-3-amine was obtained.

Reference Example 3: Production Example of 5,6,7,8-Tetrahydro-3-isoquinolinamine Substituting cyclohexanone as the starting material for cyclopentanone in Reference Example 2 above, (a)-( The title compound was obtained in the same manner as shown in e).

Reference Example 4: Production Example of 6,7,8,9-Tetrahydro-5H-cyclohepta [c] pyridin-3-amine By using cycloheptanone instead of cyclopentanone in Reference Example 2 as a starting material, The title compound was obtained in the same manner as shown in (a) to (e) of Reference Example 2.

Reference Example 5: Production Example of 4-ethyl-2-pyridinamine As shown in (a) to (e) of Reference Example 2, using 2-butanone instead of cyclopentanone in Reference Example 2 as a starting material. The title compound was obtained in the same manner as described above.

Reference Example 6: Production Example of 4-Ethyl-5-methyl-2-pyridinamine Substituting 3-pentanone instead of cyclopentanone in Reference Example 2 as a starting material, The title compound was obtained in the same manner as shown in e).

Reference Example 7 Production Example of 5,5-dimethyl-6,7-dihydro-5H-cyclopenta [c] pyridin-3-amine (a) Synthesis of 2- (2,2-dimethylcyclopentylidene) malononitrile Malononitrile ( 4.8 g, 73.2 mmol), 2,2-dimethylcyclopentanone (5.47 g, 48.8 mol), ammonium acetate (2.44 g, 31.6 mmol) and 4.86 mL of acetic acid in toluene (72 mL). Heated to reflux overnight using a Dean-Stark instrument. Thereafter, the reaction solution was decanted, washed with water, dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 9: 1) to obtain 6.47 g of 2- (2,2-dimethylcyclopentylidene) malononitrile.
(B)-(e)
2- (2,2-dimethylcyclopentylidene) malononitrile, which is the product of (a) above, was used in place of the product of (a) in Reference Example 2 above, and (b) to (B) of Reference Example 2 were used. The title compound was obtained in the same manner as shown in (e).

Reference Example 8: Preparation Example of 6-Methyl-6,7-dihydro-5H-cyclopenta [c] pyridin-3-amine 3-methyl instead of 2,2-dimethylcyclopentanone in Reference Example 7 as a starting material Using cyclopentanone, the title compound was obtained in the same manner as shown in (a) to (e) of Reference Example 7.

Reference Example 9: Production Example of 6,7-Dihydro-5H-cyclopenta [d] pyrimidin-2-amine The title compound was produced by the following synthetic procedures (a) to (d).

(A) Synthesis of 2-amino-6,7-dihydro-5H-cyclopenta [d] pyrimidin-4-ol 2-oxocyclopentanecarboxylic acid ethyl ester (21.7 g, 139 mmol) and guanidine carbonate (25.0 g, 139 mmol) was heated to reflux for 18 hours under argon substitution in absolute ethanol. Thereafter, the solvent was distilled off under reduced pressure, acetic acid was added to the residue so that the pH was 6 to 7, and the precipitated solid was suction filtered. The obtained solid was dried to obtain 10.4 g of 2-amino-6,7-dihydro-5H-cyclopenta [d] pyrimidin-4-ol.

(B) Synthesis of 4-chloro-6,7-dihydro-5H-cyclopenta [d] pyrimidin-2-amine The product of (a) above (10.4 g, 68.7 mmol) was converted to argon in phosphoryl chloride (25 mL). Heated to reflux for 45 minutes under displacement. Thereafter, ice water is added to the reaction solution under ice cooling, neutralized with an aqueous sodium hydroxide solution, the precipitated solid is suction filtered, and the obtained solid is purified by silica gel column chromatography (chloroform: methanol = 19: 1). As a result, 8.2 g of 4-chloro-6,7-dihydro-5H-cyclopenta [d] pyrimidin-2-amine was obtained.

(C) Synthesis of 2-amino-6,7-dihydro-5H-cyclopenta [d] pyrimidine-4-thiol The product of above (b) (8.2 g, 48.1 mmol) and thiourea (7.3 g, 96.2 mmol) was heated to reflux in absolute ethanol (50 mL) for 2.5 hours under argon substitution. Thereafter, the solvent was distilled off under reduced pressure, water was added to the residue, and the solution was made acidic (pH = 1 to 2) with 1N hydrochloric acid, and then the solution was made alkaline again (pH = 11 to 12) with potassium carbonate. The precipitated solid is suction filtered. The obtained solid was dried to obtain 7.9 g of 2-amino-6,7-dihydro-5H-cyclopenta [d] pyrimidine-4-thiol.

(D) Synthesis of 6,7-dihydro-5H-cyclopenta [d] pyrimidin-2-amine The product of above (c) (7.9 g, 47.2 mmol) and Raney nickel (23.7 g: as an aqueous suspension) Was heated to reflux in water (100 mL) for 6.5 hours. Thereafter, the suspension was naturally filtered, the filtrate obtained was distilled off under reduced pressure, and the residue was purified by NH-type silica gel column chromatography (chloroform) to obtain 6,7-dihydro-5H-cyclopenta [d] pyrimidine. 4.5 g of -2-amine was obtained.

Reference Example 10: Production Example of 5,6,7,8-Tetrahydro-2-quinazolinamine 2-oxocyclohexanecarboxylic acid ethyl ester in place of 2-oxocyclopentanecarboxylic acid ethyl ester in Reference Example 9 as a starting material And the title compound was obtained in the same manner as shown in (a) to (d) of Reference Example 9.

Reference Example 11 Production Example of 6,7,8,9-Tetrahydro-5H-cyclohepta [d] pyrimidin-2-amine As a starting material, instead of 2-oxocyclopentanecarboxylic acid ethyl ester in Reference Example 9 above, 2- The title compound was obtained in the same manner as shown in (a) to (d) of Reference Example 9 using oxocycloheptanecarboxylic acid ethyl ester.

Reference Example 12: Production Example of 4,5-dimethyl-2-pyrimidineamine As a starting material, 2-methyl-3-oxobutyric acid ethyl ester instead of 2-oxocyclopentanecarboxylic acid ethyl ester in Reference Example 9 was used as a starting material. To give the title compound in the same manner as shown in (a) to (d) of Reference Example 9.

Reference Example 13: Production Example of 5-Isopropyl-4-methyl-2-pyrimidinamine In place of 2-oxocyclopentanecarboxylic acid ethyl ester in Reference Example 9 as a starting material, 2-acetyl-3-methylbutyric acid ethyl ester was used. And the title compound was obtained in the same manner as shown in (a) to (d) of Reference Example 9.

Reference Example 14: Production Example of 5-ethyl-4-methyl-2-pyrimidinamine In place of 2-oxocyclopentanecarboxylic acid ethyl ester in Reference Example 9 as a starting material, 2-ethyl-3-oxobutyric acid ethyl ester was used. And the title compound was obtained in the same manner as shown in (a) to (d) of Reference Example 9.

Reference Example 15: Preparation Example of 4-Ethyl-5-methyl-2-pyrimidinamine (a) Synthesis of 2-methyl-3-oxo-pentanecarboxylic acid methyl ester Methyl 3-keto-n-valerate (3.0 g) , 23.1 mmol) was added with sodium ethoxide (1.5 g, 27.7 mmol) at 0 ° C. under argon substitution in anhydrous tetrahydrofuran, and the mixture was stirred for 30 minutes. Thereafter, methyl iodide (3.6 g, 25.4 mmol) was added to the reaction solution, and the mixture was further stirred for 2 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, chloroform was added to the residue, and the insoluble matter was separated by suction filtration. The obtained solution was distilled off under reduced pressure to obtain 3.1 g of 2-methyl-3-oxo-pentanecarboxylic acid methyl ester.
(B)-(d)
2-methyl-3-oxo-pentanecarboxylic acid methyl ester, which is the product of (a) above, was used instead of the product of (a) in Reference Example 9, and The title compound was obtained in the same manner as shown in (d).

Reference Example 16 Production Example of 2-bromo-1- (2-fluorophenyl) -1-ethanone 2′-fluoroacetophenone (5 g, 36.2 mmol) was dissolved in acetic acid (13 mL), and bromine (1 .86 mL, 36.2 mmol) in acetic acid (13 mL) was added dropwise over 30 minutes. Thereafter, the mixture was stirred overnight at room temperature, and the reaction solution was concentrated under reduced pressure. The residue was dissolved in chloroform, washed with 5% NaHCO ₃ , washed with water, dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: chloroform = 3: 1) to give 2-bromo-1- (2-fluorophenyl) -1-ethanone.

Example 1: 6,7-dimethyl-2-phenyl-3- (propoxycarbonylmethyl) imidazo [1,2-a] pyridine [IUPAC name: 2- (6,7-dimethyl-2-phenylimidazo [1, 2-a] pyridin-3-yl) acetic acid propyl ester]
The title compound was obtained by the following synthesis procedures (1-a) to (1-e).

(1-a) Synthesis of 6,7-dimethyl-2-phenylimidazo [1,2-a] pyridine 4,5-dimethyl-2-pyridinamine obtained in Reference Example 1 and 3,4-dimethyl- A mixture of 2-pyridinamine (2.0 g, 16.4 mmol), phenacyl bromide (3.26 g, 16.4 mmol) and sodium bicarbonate (2.75 g, 32.7 mmol) was replaced with argon in absolute ethanol (10 mL). Under reflux for 3 hours. Thereafter, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane: chloroform = 2: 1) to give 6,7-dimethyl-2-phenylimidazo [1,2-a] pyridine. 717 mg of was obtained. The physical property data is shown below.
¹ H-NMR (400 MHz, CDCl ₃ ) δ ppm: 2.20 (3H, s), 2.30 (3H, s), 7.28-7.32 (1H, m), 7.36 (1H, s), 7.39-7.43 (2H, m), 7.69 (1H, s), 7.82 (1H, s), 7.91-7.94 (2H, s)

(1-b) Synthesis of 2- (6,7-dimethyl-2-phenylimidazo [1,2-a] pyridin-3-yl) -2-hydroxyacetic acid ethyl ester Product of (1-a) above ( 462 mg, 2.1 mmol), ethylglyoxalate 40% toluene solution (2.6 mL, 10.3 mmol) and paratoluenesulfonic acid monohydrate (47 mg, 0.25 mmol) under argon substitution in absolute ethanol (5 mL) And heated at reflux for 3 hours. Thereafter, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform) to give 2- (6,7-dimethyl-2-phenylimidazo [1,2-a] pyridine-3- Yl) -2-hydroxyacetic acid ethyl ester was obtained. The physical property data is shown below.
¹ H-NMR (400 MHz, CDCl ₃ ) δ ppm: 1.16 (3H, t, J = 7.2 Hz), 2.24 (3H, s), 2.32 (3H, s), 3.77 (1H, brs), 4.09-4.29 (2H, m), 5.77 (1H, s), 7.36-7.44 (4H, m), 7.71-7.73 (2H , M), 7.94 (1H, s)

(1-c) Synthesis of 2- (6,7-dimethyl-2-phenylimidazo [1,2-a] pyridin-3-yl) acetic acid ethyl ester A chloroform solution of thionyl chloride (110 mg, 0.9 mmol) was added to argon. Under substitution, the mixture was stirred at 0 ° C., a chloroform solution of N, N-dimethylformamide (64 mg, 0.9 mmol) was added dropwise thereto, and the mixture was stirred at room temperature for 50 minutes. Thereafter, the reaction temperature was again set to 0 ° C., and a chloroform solution of the product (1-b) (200 mg, 0.6 mmol) was added dropwise thereto. After the dropwise addition, the mixture was stirred at room temperature for 3 hours, sodium hydroxymethanesulfinate dihydrate (475 mg, 3.1 mmol) was added, the reaction temperature was raised to 40 ° C., and the mixture was further stirred with heating for 4 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, an aqueous sodium hydroxide solution was added, and the mixture was extracted with chloroform. The obtained organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform) to give 2- (6,7-dimethyl-2-phenylimidazo [1,2-a] pyridine-3- Yl) 168 mg of acetic acid ethyl ester was obtained. The physical property data is shown below.
¹ H-NMR (400 MHz, CDCl ₃ ) δ ppm: 1.29 (3H, t, J = 7.2 Hz), 2.29 (3H, m), 2.35 (3H, m), 4.01 (2H, s), 4.23 (2H, q, J = 7.1 Hz), 7.35-7.39 (1H, m), 7.41 (1H, s), 7.45-7. 49 (2H, m), 7.81-7.84 (2H, m), 7.86 (1H, s)

(1-d) Synthesis of 2- (6,7-dimethyl-2-phenylimidazo [1,2-a] pyridin-3-yl) acetic acid Product of (1-c) above (871 mg, 2.8 mmol) And 15% potassium carbonate aqueous solution (4.5 mL) was heated and stirred at 80 ° C. for 1 hour under replacement with argon in methanol (10 mL). Thereafter, the solvent was distilled off, water was added, and the mixture was extracted with chloroform. 1N Hydrochloric acid was added to the obtained aqueous layer so that the pH was 6, and the mixture was cooled to 4 ° C. Thereafter, the precipitated solid was subjected to suction filtration, and the obtained solid was dried to obtain 631 mg of 2- (6,7-dimethyl-2-phenylimidazo [1,2-a] pyridin-3-yl) acetic acid. . The physical property data is shown below.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ ppm: 2.25 (3H, s), 2.32 (3H, s), 4.09 (2H, s), 7.33-7.37 ( 1H, m), 7.38 (1H, s), 7.45-7.49 (2H, m), 7.72-7.74 (2H, m), 8.19 (1H, s)

(1-e) Synthesis of 2- (6,7-dimethyl-2-phenylimidazo [1,2-a] pyridin-3-yl) acetic acid propyl ester Product of (1-d) above (100 mg, 0. 4 mmol), 1-propanol (25.8 mg, 0.4 mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (73.0 mg, 0.4 mmol) and 4-dimethylaminopyridine (5. 2 mg, 0.4 mmol) was stirred for 22 hours at room temperature under argon substitution in anhydrous dichloromethane (3.6 mL). Thereafter, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform: methanol = 49: 1) to give 2- (6,7-dimethyl-2-phenylimidazo [1,2-a] pyridine. 71 mg of -3-yl) acetic acid propyl ester was obtained. The physical property data is shown below.
¹ H-NMR (400 MHz, CDCl ₃ ) δ ppm: 0.91 (3H, t, J = 7.4 Hz), 1.66 (2H, sext, J = 7.1 Hz), 2.25 (3H , S), 2.32 (3H, s), 3.99 (2H, s), 4.12 (2H, t, J = 6.6 Hz), 7.33-7.37 (1H, m) 7.39 (1H, s), 7.44-7.47 (2H, m), 7.83-7.85 (3H, m)

Example 2: 3- (6,7-Dimethyl-2-phenylimidazo [1,2-a] pyridin-3-yl) propionic acid ethyl ester Synthesis procedure of the following (2-a) to (2-c) To give the title compound.

(2-a) Synthesis of 5-oxo-5-phenylvaleric acid ethyl ester 5-oxo-5-phenylvaleric acid (3.0 g, 15.6 mmol), ethanol (1.4 g, 31.2 mmol), 1- Ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (3.6 g, 18.7 mmol) and 4-dimethylaminopyridine (232 mg, 1.9 mmol) were substituted with argon in anhydrous dichloromethane (44 mL) at room temperature for 4 hours. Stir for hours. Thereafter, the solvent was distilled off under reduced pressure, the residue was dissolved in chloroform, washed with aqueous ammonium chloride solution, aqueous sodium hydrogen carbonate solution and saturated brine, dried over sodium sulfate, and then the solvent was distilled off under reduced pressure to give 5-oxo- 4.2 g of 5-phenylvaleric acid ethyl ester was obtained. The physical property data is shown below.
¹ H-NMR (400 MHz, CDCl ₃ ) δ ppm: 1.26 (3H, t, J = 7.2 Hz), 2.08 (2H, quin, J = 7.2 Hz), 2.44 (2H , T, J = 7.2 Hz), 3.06 (2H, t, J = 7.2 Hz), 4.14 (2H, t, J = 7.1 Hz), 7.44-7.49. (2H, m), 7.54-7.58 (1H, m), 7.96-7.98 (2H, m),

(2-b) Synthesis of 4-bromo-5-oxo-5-phenylvaleric acid ethyl ester Bromine (0.8 mL) was added to the acetic acid solution of the product of (2-a) (4.2 g, 15.6 mmol). , 15.6 mmol) of acetic acid was added dropwise and stirred at room temperature for 18 hours under argon substitution. Thereafter, the solvent was distilled off under reduced pressure, 5% aqueous sodium hydrogen carbonate solution was added to the residue, extracted with chloroform, dried over sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1) to obtain 3.5 g of 4-bromo-5-oxo-5-phenylvaleric acid ethyl ester. The physical property data is shown below.
¹ H-NMR (400 MHz, CDCl ₃ ) δ ppm: 1.26 (3H, t, J = 7.1 Hz), 2.35-2.67 (4H, m), 4.16 (2H, t, J = 7.2 Hz), 5.39 (1H, dd, J = 8.5 Hz, 5.6 Hz), 7.48-7.52 (2H, m), 7.59-7.63 ( 1H, m), 8.02-8.04 (2H, m)

(2-c) Synthesis of 3- (6,7-dimethyl-2-phenylimidazo [1,2-a] pyridin-3-yl) propionic acid ethyl ester 4,5-dimethyl obtained in Reference Example 1 A mixture of 2-pyridinamine and 3,4-dimethyl-2-pyridinamine (600 mg, 4.9 mmol), the product of (2-b) above (1.5 g, 4.9 mmol) and sodium bicarbonate (825 mg) , 9.8 mmol) was heated to reflux for 19 hours under argon substitution in absolute ethanol (12.5 mL). Thereafter, the solvent was distilled off under reduced pressure, water was added to the residue, extracted with chloroform, dried over sodium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1 to 1: 1) to give 3- (6,7-dimethyl-2-phenylimidazo [1,2-a] pyridine- 154 mg of 3-yl) propionic acid ethyl ester was obtained. The physical property data is shown below.
¹ H-NMR (400 MHz, CDCl ₃ ) δ ppm: 1.23 (3H, t, J = 7.1 Hz), 2.29 (3H, s), 2.33 (3H, s), 2.65 -2.69 (2H, m), 3.39-3.43 (2H, m), 4.14 (2H, q, J = 7.2 Hz), 7.32-7.47 (4H, m ), 7.75-7.77 (3H, m)

Example 3: 6,7-Dimethyl-2-phenylimidazo [1,2-a] pyridine-3-carboxylic acid propyl ester The title compound was synthesized by the following synthesis procedures of (3-a) to (3-d). Got.

(3-a) Synthesis of 2-bromo-3-oxo-3-phenylpropionic acid ethyl ester 3-oxo-3-phenylpropionic acid ethyl ester (8.0 g, 41.6 mmol) in acetic acid solution with bromine (2. 1 mL, 41.6 mmol) of acetic acid was added dropwise, and the mixture was stirred at room temperature for 22 hours under argon substitution. Thereafter, the solvent was distilled off under reduced pressure, a 5% aqueous sodium hydrogen carbonate solution was added to the residue, the mixture was extracted with chloroform, dried over sodium sulfate, and the solvent was distilled off under reduced pressure to give 2-bromo-3-oxo-3-phenylpropylene. 11.1 g of ethyl on acid was obtained. The physical property data is shown below.
¹ H-NMR (400 MHz, CDCl ₃ ) δ ppm: 1.24 (3H, t, J = 7.1 Hz), 4.28 (2H, q, J = 7.2 Hz), 5.71 (1H , S), 7.48-7.65 (3H, m), 7.98-8.04 (2H, m)

(3-b) Synthesis of 6,7-dimethyl-2-phenylimidazo [1,2-a] pyridine-3-carboxylic acid ethyl ester 4,5-dimethyl-2-pyridinamine obtained in Reference Example 1 And a mixture of 3,4-dimethyl-2-pyridinamine (2.3 g, 18.4 mmol) and the product of (3-a) above (5.0 g, 18.4 mmol) with argon in anhydrous propanol (47 mL) The mixture was heated to reflux for 16.5 hours. Thereafter, the solvent was distilled off under reduced pressure, 5% aqueous sodium hydrogen carbonate solution was added, the mixture was extracted with chloroform, dried over sodium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) to give 6,7-dimethyl-2-phenylimidazo [1,2-a] pyridine-3-carboxylic acid ethyl ester. 325 mg was obtained. The physical property data is shown below.
¹ H-NMR (400 MHz, CDCl ₃ ) δ ppm: 1.21 (3H, t, J = 7.2 Hz), 2.29 (3H, s), 2.35 (3H, s), 4.28 (2H, q, J = 7.1 Hz), 7.36-7.45 (4H, m), 7.72-7.77 (2H, m), 9.15 (1H, s)

(3-c) Synthesis of 6,7-dimethyl-2-phenylimidazo [1,2-a] pyridine-3-carboxylic acid Product (325 mg, 1.1 mmol) of the above (3-b) and 15% carbonic acid Aqueous potassium solution (0.9 mL) was heated and stirred at 80 ° C. for 23 hours under argon substitution in methanol (2.3 mL). Thereafter, the solvent was distilled off, water was added and suction filtration was performed. Hydrochloric acid is added to the filtrate to make the solution acidic, and the precipitated solid is collected by filtration, washed with water and dried, and the resulting solid is purified by silica gel column chromatography (chloroform: methanol = 100: 0 to 49: 1). Gave 149 mg of 6,7-dimethyl-2-phenylimidazo [1,2-a] pyridine-3-carboxylic acid. The physical property data is shown below.
¹ H-NMR (400 MHz, CDCl ₃ ) δ ppm: 2.29 (3H, s), 2.36 (3H, s), 7.26-7.34 (3H, m), 7.52 (1H, s), 7.77-7.79 (2H, m), 9.20 (1H, s)

(3-d) Synthesis of 6,7-dimethyl-2-phenylimidazo [1,2-a] pyridine-3-carboxylic acid propyl ester Product of (3-c) above (149 mg, 0.6 mmol), 1 -Propanol (64.3 mg, 1.1 mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (128.8 mg, 0.7 mmol) and 4-dimethylaminopyridine (8.2 mg, 0.2 mmol). 07 mmol) was stirred for 6 hours at room temperature under argon substitution in anhydrous dichloromethane (1.6 mL). Thereafter, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 9: 1 to 4: 1), whereby 6,7-dimethyl-2-phenylimidazo [1,2-a ] 130 mg of pyridine-3-carboxylic acid propyl ester was obtained. The physical property data is shown below.
¹ H-NMR (400 MHz, CDCl ₃ ) δ ppm: 0.78 (3H, t, J = 7.4 Hz), 1.58 (2H, sext, J = 7.1 Hz), 2.33 (3H , S), 2.39 (3H, s), 4.18 (2H, t, J = 6.6 Hz), 7.37-7.44 (3H, m), 7.47 (1H, s) , 7.71-7.74 (2H, m), 9.20 (1H, s)

Examples (4-1) to (4-14)
In the same manner as in Example 1, No. 1 shown in Table 1 was obtained. 1-No. 14 compounds were obtained.

Examples (4-15) to (4-90)
In the same manner as in Examples 1, 2, or 3, No. 2 shown in Tables 2 and 3 were used. 15-No. 90 compounds were obtained.

Example 5: 6,7-dimethyl-2-phenyl-3- (2-oxohexyl) imidazo [1,2-a] pyridine [IUPAC name: 1- (6,7-dimethyl-2-phenylimidazo [1] , 2-a] pyridin-3-yl) -2-hexanone]
2- (6,7-dimethyl-2-phenylimidazo [1,2-a] pyridin-3-yl) acetic acid ethyl ester (404 mg, 1.31 mmol) in anhydrous tetrahydrofuran (8 mL) was placed in a three-necked flask. To the three-necked flask, a dropping funnel containing valeric chloride (0.17 mL, 1.44 mmol) in tetrahydrofuran (3 mL) and 15% hexamethyldisilazane potassium-toluene solution (1.92 g, 1.44 mmol) in tetrahydrofuran ( 3 mL) was placed, and the mixture was stirred for 30 minutes at −78 ° C. under argon substitution, and then the hexamethyldisilazane potassium solution was dropped into the reaction solution and stirred for 1.5 hours. Thereafter, a valeric acid chloride solution was dropped, and the mixture was further stirred for 1.5 hours. After completion of the reaction, water was added, extracted with ethyl acetate, and the organic layer was concentrated under reduced pressure. Acetic acid (4 mL) and concentrated hydrochloric acid (4 mL) were added to the residue, and the mixture was heated to reflux for 3 hours. After completion of the reaction, the reaction solution was cooled to near room temperature, and an aqueous sodium carbonate solution was added thereto so that the pH of the solution was 10 to 11, followed by extraction with chloroform. After the organic layer was concentrated, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 19: 1 to 0: 100) to obtain 6,7-dimethyl-2-phenyl-3- (2-oxohexyl). 85 mg of imidazo [1,2-a] pyridine was obtained. The physical property data is shown below.
¹ H-NMR (400 MHz, CDCl ₃ ) δ ppm: 0.83 (3H, t, J = 7.3 Hz), 1.23 (2H, sext, J = 7.5 Hz), 1.52 (2H , Quin, J = 7.5 Hz), 2.26 (3H, m), 2.34 (3H, m), 2.42 (2H, t, J = 7.5 Hz), 4.09 (2H , S), 7.37-7.39 (1H, m), 7.40 (1H, s), 7.44-7.48 (2H, m), 7.61 (1H, s), 7. 66-7.69 (2H, m)

Example 6: 6,7-Dimethyl-2-phenyl-3- (2-propoxyethyl) imidazo [1,2-a] pyridine In the synthesis procedure of (6-a) to (6-c) below, The title compound was obtained.

(6-a) 6,7-dimethyl-3- (2-hydroxyethyl) -2-phenylimidazo [1,2-a] pyridine [IUPAC name: 2- (6,7-dimethyl-2-phenylimidazo [ 1,2-a] pyridin-3-yl) -1-ethanol] 2- (6,7-dimethyl-2-phenylimidazo [1,2-a], which is the product of (1-c) above A solution of pyridin-3-yl) acetic acid in anhydrous tetrahydrofuran (2 mL) was stirred at 0 ° C., and a borane-tetrahydrofuran complex tetrahydrofuran solution (1.0 mol / L) was added dropwise thereto. Thereafter, the mixture was stirred for 2.25 hours while gradually raising the reaction temperature to room temperature. After completion of the reaction, the solution was cooled again to 0 ° C., 1N hydrochloric acid was added until no bubbles were generated, and the mixture was stirred at room temperature for 30 minutes. Thereafter, the reaction solution was concentrated, and 1N sodium hydroxide solution was added so that the solution became alkaline, followed by extraction with dichloromethane. The obtained organic layer was dried over sodium sulfate and concentrated, and the residue was purified by silica gel column chromatography (chloroform) to give 6,7-dimethyl-3- (2-hydroxyethyl) -2-phenylimidazo [1 , 2-a] pyridine was obtained. The physical property data is shown below.
¹ H-NMR (400 MHz, CDCl ₃ ) δ ppm: 2.23 to 2.24 (3H, m), 2.27 (3H, m), 3.21 (2H, t, J = 6.2 Hz) , 4.02 (2H, t, J = 6.2 Hz), 7.16 (1H, s), 7.25-7.35 (3H, m), 7.66-7.69 (2H, m ), 7.82 (1H, s)

(6-b) Synthesis of 6,7-dimethyl-2-phenyl-3-mesyloxyethylimidazo [1,2-a] pyridine Product of above (6-a) (129 mg, 0.48 mmol), methanesulfonyl Chloride (61 mg, 0.53 mmol) and triethylamine (74 mg, 0.73 mmol) were stirred at room temperature for 2.5 hours under argon substitution in dichloromethane (5 mL). After completion of the reaction, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform) to give 6,7-dimethyl-2-phenyl-3-mesyloxyethylimidazo [1,2-a] pyridine. 144 mg was obtained. The physical property data is shown below.
¹ H-NMR (400 MHz, CDCl ₃ ) δ ppm: 2.30 (3H, s), 2.35 (3H, s), 2.85 (3H, s), 3.56 (2H, t, J = 7.1 Hz), 4.48 (2H, t, J = 7.2 Hz), 7.35-7.38 (1H, m), 7.40 (1H, s), 7.45-7. 49 (2H, m), 7.74-7.76 (2H, m), 7.84 (1H, s)

(6-c) Synthesis of 6,7-dimethyl-2-phenyl-3- (2-propoxyethyl) imidazo [1,2-a] pyridine Product of (6-b) above (80 mg, 0.23 mmol) Was heated to reflux in 1-propanol (5 mL) under argon substitution for 23 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform: methanol = 99: 1) to obtain 6,7-dimethyl-2-phenyl-3- (2-propoxyethyl). 50 mg of imidazo [1,2-a] pyridine was obtained. The physical property data is shown below.
¹ H-NMR (400 MHz, CDCl ₃ ) δ ppm: 0.87-0.91 (3H, m), 1.54-1.59 (2H, m), 2.25 (3H, s), 32 (3H, s), 3.28-3.30 (2H, m), 3.36-3.40 (2H, m), 3.74-3.77 (2H, m), 7.30- 7.36 (2H, m), 7.41-7.46 (2H, m), 7.78-7.80 (2H, m), 7.94 (1H, s)

Example 7: 6,7-Dimethyl-3-ethylcarbonyloxyethyl-2-phenylimidazo [1,2-a] pyridine [IUPAC name: Propionic acid 2- (6,7-dimethyl-2-phenylimidazo [1 , 2-a] pyridin-3-yl) ethyl ester]
The product of (5-a), 6,7-dimethyl-3- (2-hydroxyethyl) -2-phenylimidazo [1,2-a] pyridine (170 mg, 0.64 mmol), propionic acid (57 mg) , 0.77 mmol), WSC [1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride] (147 mg, 0.77 mmol) and DMAP [4-dimethylaminopyridine] (9 mg, 0.08 mmol) in dichloromethane. The mixture was stirred at room temperature for 14 hours under medium argon substitution. After completion of the reaction, the solvent was distilled off, and the residue was purified by silica gel column chromatography (chloroform: methanol = 99: 1) to give 6,7-dimethyl-3-ethylcarbonyloxyethyl-2-phenylimidazo [1, 198 mg of 2-a] pyridine was obtained. The physical property data is shown below.
¹ H-NMR (400 MHz, CDCl ₃ ) δ ppm: 1.12 (3H, t, J = 7.6 Hz), 2.30 (2H, q, J = 7.6 Hz), 2.30 (3H M), 2.34-2.35 (3H, m), 3.40 (2H, t, J = 7.2 Hz), 4.38 (2H, t, J = 7.3 Hz), 7 .33-7.37 (1H, m), 7.39 (1H, s), 7.44-7.48 (2H, m), 7.78-7.80 (2H, m), 7.91 (1H, s)

Examples (8-1) to (8-3)
In the same manner as in Example 5, No. 4 shown in Table 4 was obtained. 91-93 compounds were obtained.

Examples (8-4) to (8-5)
In the same manner as in Example 6 or 7, No. 94-95 compounds were obtained.

Example 9-a: Formulation for injection 18.0 mg of the compound obtained in (1-e) of Example 1, 0.56 mL of 0.1N hydrochloric acid and 45.0 mg of sodium chloride were dissolved in distilled water for injection, and the total amount was obtained. Was 5.0 mL. This aqueous solution was aseptically filtered to obtain a clear injection.

Example 9-b: Formulation for injection 18.0 mg of the compound obtained in (1-e) of Example 1, 0.56 mL of 0.1N hydrochloric acid and 250.0 mg of glucose were dissolved in distilled water for injection. 5.0 mL. This aqueous solution was aseptically filtered to obtain a clear injection.

[Pharmacological test example]
The anesthetic action of the compound of the present invention was examined by the following method.

Test Example 1: Forward reflection disappearance test using a mouse (Test solution preparation method)
The compounds obtained in the above examples were hydrochlorides in the case of hydrochlorides, and those other than those were converted to hydrochlorides using hydrochloric acid and then dissolved in physiological saline at a predetermined concentration to obtain test solutions.
For compounds that do not dissolve in physiological saline as hydrochloride, polyoxyethylene hydrogenated castor oil (final concentration 5%) / glucose (final concentration 5%) / dimethyl sulfoxide (final concentration 1%) aqueous solution, or polyoxyethylene Ethylene hydrogenated castor oil (final concentration 5%) / glucose (final concentration 5%) / dimethyl sulfoxide (final concentration 1%) was dissolved in 0.1N HCl solution at a predetermined concentration to prepare a test solution. In addition, propofol was mixed with soybean oil of the same weight, and then 10% intralipid (manufactured by Terumo Corporation) was added and used as an emulsion in the test.

(Administration and evaluation methods)
The test solution was intravenously administered to the tail vein of ICR male mice (4-5 weeks old) at a dose rate of 1 mL / min. The anesthetic effect is confirmed to be effective for an individual in which the disappearance of the direct reflex is recognized for 30 seconds or more after the administration and the pinna reflex has disappeared, and the time (Onset) from the completion of the administration until the direct reflex disappears Observed. The administration group was 3 cases per group, and starting from 40 mg / kg (volume: 0.1 mL per 10 g of mice), if there was an anesthetic effect of 2 or more cases, serial dilution was administered at a common ratio of 1/2. The anesthetic effect is assessed by an estimate of the dose (HD ₅₀ ) that eliminates the right reflex in half of the mice, Onset is the time at which the reflex disappears at the lowest dose at which more than half of the mice lose the right reflex, A case where the specular reflection disappeared 0 to 5 seconds after the completion of administration was determined in three stages: ++ that disappeared after 5 to 10 seconds, + that which disappeared after 10 seconds or more, and −. In addition, as a safety evaluation item, an approximate value of the dose (LD ₅₀ ) at which half of the mice die was also determined.

(result)
Table 6 shows the HD ₅₀ value, LD ₅₀ value and Onset of the compounds of the present invention.

Test Example 2: EEG test using rats (administration / evaluation method)
After grounding the electroencephalogram electrode to the cortical area, the test solution was intravenously administered at a dosing rate of 1.0 mL / min into the tail vein of SD male rats (6-7 weeks old) acclimatized for 4 days or more. Measurements were made. The measurement is continuously performed before the start of administration and after the completion of administration until a wakeful wave (low amplitude fast wave) can be confirmed, and the evaluation is performed by visually observing an electroencephalogram chart, which is a characteristic electroencephalogram expressed during deep anesthesia. The presence or absence of the expression of the suppression and the time from the completion of administration to the return to the wakefulness wave (action time) were used as indices. Dose starts at _{2HD 50} of study drug, if the _{2HD 50} Burst suppression is not observed administered _{3HD 50,} administration volume was 0.1mL per rat 10g. The test liquid was prepared in the same manner as in Test Example 1.
(result)
All compounds studied induced BS at 2HD ₅₀ or 3HD ₅₀ .
In addition, the duration of action of these compounds was almost the same as or shorter than that of propofol.
Table 7 shows the action time of the compounds of the present invention.

Test Example 3: Antagonism test with flumazenil in mice (administration / evaluation method)
Changes in anesthesia and sedation hypnotic action of these compounds by combining benzodiazepine receptor antagonist flumazenil with the compounds of the present invention, sedative hypnotic drug zolpidem, which is a commercially available drug, and anesthesia sedative drug propofol (ICR) System: 4-5 weeks old) was examined using the loss of direct reflex as an index. As the evaluation method, the antagonistic action of flumazenil in each test drug was evaluated by two test methods: a method in which each test drug was administered 5 minutes after pre-administration of flumazenil and a method in which flumazenil was administered after the test drug was administered. The dose of each test drug was as follows, and the dose volume was 0.1 mL per 10 g of rat. Moreover, the test liquid was prepared in the same manner as in Test Example 1.
Compound of the present invention (No. 19 and No. 23): 10 mg / kg [solvent: physiological saline]
Zolpidem: 20 mg / kg [Solvent: Polyoxyethylene hydrogenated castor oil (final concentration 5%) / glucose (final concentration 5%) / dimethyl sulfoxide (final concentration 1%) 0.05N HCl solution]
Propofol: 29.4 mg / kg [soybean oil / intralipid emulsion]
Patent document 1 listed compound: 2.5 mg / kg [solvent: polyoxyethylene hydrogenated castor oil (final concentration 5%) / glucose (final concentration 5%) / dimethyl sulfoxide (final concentration 1%) 0.05N HCl solution ]
Flumazenil: 1 or 5 mg / kg [solvent: aqueous solution of propylene glycol (final concentration 10%) / polyethylene glycol (final concentration 10%) / sodium chloride (final concentration 0.9%)]

(result)
In the zolpidem 20 mg / kg administration group, when flumazenil 1 mg / kg or 5 mg / kg was pre-administered, no disappearance of the right-angle reflex was observed at any dose. In addition, when zolpidem was pre-administered, recovery from disappearance of the right-angled reflex was recognized immediately after administration of flumazenil 5 mg / kg. Further, the same tendency as zolpidem was observed in the 2.5 mg / kg administration group of the compound described in Patent Document 1.
On the other hand, in the compound of the present invention and propofol administration group, the flarezenil pre-administration and post-administration methods and doses did not affect the reflex loss time of these test drugs.

Test Example 4: Two-electrode potential fixation method (administration / evaluation method) using Xenopus laevis oocytes expressing GABA _A receptor
Using human brain cDNA library (Takara) as a template, PCR was performed using primers specific to the human GABA _A receptor subunit α ₁ , β ₂ , γ _2s gene, and the entire coding sequence of each gene was TA cloned. Inserted into vector (Invitrogen). Each gene specific primer is shown below.
α1 (Accession # NM — 09806.3): 5′-CCC GCG ATG AGG AAA AGT CCA GGT CTG TC-3 ′ and 5′-AAA TTC CCA GTG CAG AGG ACT GAA CAA CAG-3 ′
β2 (Accession # NM_000813.1): 5'-CCA TCA AAA ACT AAAGGG ATG TGG AGA GTC-3 'and 5'-GCT TCC AGT GGG AGG CCA TGT TTA GTT CAC-3
γ2s (Accession # NM_000816.2): 5'-AAA GCG ATG AGT TCG CCA AAT ATA TGG AGC-3 'and 5'-CAT ATC AGT AAA ACC CAT ACC TCC TCA CAG-3'.

Next, human clone GABA _A receptor subunits α ₁ , β ₂ , and γ _2s were subcloned into a translation vector (modified pBluescript MXT), then linearized with appropriate restriction enzymes, and T3 RNA message machine kit (Ambion) The capped cRNA was synthesized in vitro. Xenopus laevis oocytes treated with collagenase from these cRNAs were microinjected to express the α ₁ β ₂ γ _2s recombinant GABA _A receptor. After the injection, incubation was carried out at 18 ° C. for 48-72 hours, and the Cl ion current induced by exogenous GABA was measured with a two-electrode potential-clamp amplifier (Warner, OC725) using a glass electrode containing a 3 molar KCL solution. It was measured. The current value was recorded on a computer using software (Pulse) manufactured by HEKA. The recording cell in which the oocyte was placed was refluxed with a frog Ringer's solution, and administration drugs such as GABA, a test drug, and a benzodiazepine antagonist (flumazenil) were dissolved in the reflux solution and administered to the oocyte.

(result)
In the human GABA _A receptor composed of α ₁ β ₂ γ ₂ subunits, any of the compounds of Patent Document 1, the zolpidem and the compound of the present invention (No. 60) has an effect of enhancing the current induced by GABA. Admitted. Moreover, by using together with flumazenil, which is a benzodiazepine receptor antagonist, these current enhancing actions disappeared in the compound of Patent Document 1 and zolpidem administration, but this disappearance was not observed in the compound group of the present invention.
FIG. 1 shows the induced currents of the compound of the present invention (No. 60), the compound of Patent Document 1 and zolpidem.

  As the above results show, the compound of the present invention is a compound having a different mechanism of action from zolpidem marketed as a sedative hypnotic drug having the same skeleton and the compound listed in Patent Document 1, and is commercially available. It has a strong action compared with conventional intravenous anesthetics such as propofol, sodium thiopental, etc. is there.

It is a graph which shows the result of the antagonistic test by flumazenil using the mouse.

Claims (16)

An imidazopyridine or imidazopyrimidine compound represented by the following general formula (I), or a pharmaceutically acceptable salt thereof.

[In the formula (I), two R _{1 s} are the same or different and each has a hydrogen atom, a linear or branched alkyl having 1 to 5 carbon atoms, and a substituent formed by combining two R _{1 s.} An optionally substituted alkylene group having 2 to 5 carbon atoms, or two R ₁ bonded together and containing 1 or 2 heteroatoms selected from the group consisting of sulfur, nitrogen and oxygen atoms Or an unsaturated 5- to 7-membered cyclic group, wherein R ₂ is

(In the formula, n is an integer of 0 to 2, R ₄ is linear or branched alkyl having 1 to 5 carbon atoms, alkyl substituted with 1 or more fluorine atoms having 1 to 5 carbon atoms, carbon number 3 to 5 linear or branched alkenyl or alkynyl, 5 to 7-membered cycloalkyl or cycloalkylmethyl, alkoxyalkyl having 1 to 5 carbon atoms, alkylaminoalkyl, cyanoalkyl or a substituent. A good phenyl or phenylalkyl group).

(Wherein n ′ is an integer of 1 to 2 and R ₄ is as defined above); or

In the formula, A represents —OCO— or —O—, and R ₄ represents the same meaning as described above.
R ₃ represents a group selected from the group consisting of alkyl having 1 to 6 carbon atoms, optionally substituted phenyl, benzyl, pyridyl, cyclohexyl, thiophenyl, and furanyl group;
X represents a carbon atom or a nitrogen atom. However, the two R _{1 s} are not both hydrogen atoms. ] Is two of R ₁ are methyl, ethyl, the same or different two groups selected from the group consisting of propyl and isopropyl groups in the general formula (I), the compounds or pharmaceutically acceptable thereof according to claim 1, wherein Salt. Formula two combinations of 6-methyl-7-ethyl _{R 1} in (I), 6-ethyl-7-methyl or 6-isopropyl-7 compound methyl a is claim 2, wherein or their pharmaceutically Acceptable salt. The compound according to claim 2 or a pharmaceutically acceptable salt thereof, wherein two R _{1 s} are both methyl groups. The compound of Claim 1 represented by the following general formula (I-1) or a pharmaceutically acceptable salt thereof.

[In the formula (I-1), M represents a group which forms a saturated or unsaturated 5-membered, 6-membered or 7-membered cyclic group which may have a substituent together with an imidazopyridine or imidazopyrimidine ring. , X, R ₂ and R ₃ are as defined above. ] M in the general formula (I-1) is
-CH ₂ CH ₂ CH ₂ -,
_{-CH 2 CH (CH 3) CH} 2 -,
_{-CH 2 CH 2 CH 2 CH 2} - and _{-CH 2 CH 2 CH 2 CH 2} CH 2 -
The compound according to claim 5 or a pharmaceutically acceptable salt thereof, which is a group selected from the group consisting of: R ₂ in the general formula (I) or (I-1) is represented by the formula — (CH ₂ ) _n —CO ₂ —Q
(In the formula, n is an integer of 0 to 2, and Q is a linear or branched alkyl having 1 to 5 carbon atoms, an alkyl substituted with one or more fluorines having 1 to 5 carbon atoms, or 2- Methyl-2-propenyl, 2-propynyl, cyclopentyl, cyclopentylmethyl or phenyl group is shown.)
The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof. R ₂ in the general formula (I) or (I-1) is represented by the formula —CH ₂ —CO—T.
(In the formula, T represents an alkyl group having 1 to 5 carbon atoms.)
The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof. R ₂ in the general formula (I) or (I-1) is represented by the formula — (CH ₂ ) ₂ —A—Z.
(In the formula, A represents —OCO— or —O—, and Z represents an alkyl group having 1 to 3 carbon atoms.)
The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 9, wherein R ₃ in the general formula (I) or (I-1) is an optionally substituted phenyl group.   An anesthetic or sedative composition for mammals containing an anesthetic effective amount of the compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.   The anesthetic or sedative composition according to claim 11, which is used by intravenous administration.   The anesthetic or sedative composition according to claim 11 or 12, which is used for introduction and maintenance of general anesthesia.   The anesthesia or sedative composition according to claim 11 or 12, which is used for postoperative sedation management, sedation management during examination, sedation management during local anesthesia, or sedation management during intensive care.   Use of the compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof for producing an anesthetic or sedative composition for mammals.   A method for anesthesia or sedation of a mammal, comprising administering an effective anesthetic amount of the compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof to a mammal of a subject in need of anesthesia or sedation. .

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