JPWO2006080284A1 - 2-substituted imino-1,3-oxazine derivatives - Google Patents

Abstract

Provided are a 2-substituted imino-1,3-oxazine derivative having a cannabinoid receptor agonistic action and a pharmaceutical composition containing the compound as an active ingredient. General formula (I): (wherein R1 is optionally substituted aryl, etc .; R2 is C1-C6 alkyl, etc .; R3 is C1-C6 alkyl, etc .; or R2 and R3 together are adjacent carbons Containing atoms, may form a 3-8 membered cycloalkane optionally substituted with C1-C4 alkyl, etc .; R4 is of the formula: -C (= X) -Y-R5 where R5 is a substituted A group represented by C1-C4 alkyl, etc., which may be used; X is a sulfur atom, etc .; Y is a sulfur atom, etc.), an optically active substance thereof, a pharmaceutically acceptable salt thereof, or Their solvates.

Description

  The present invention relates to a 2-substituted imino-1,3-oxazine derivative having a cannabinoid receptor agonistic action and a pharmaceutical composition thereof.

Cannabinoids were discovered in 1960 as the main body of marijuana actives, and their effects include central nervous system effects (such as hallucinations, euphoria, and spatiotemporal perturbations), and peripheral cell system effects (immunosuppression, anti-inflammatory, It was found to be an analgesic action.
Subsequently, anandamide and 2-arachidonoylglycerol produced from arachidonic acid-containing phospholipids were discovered as endogenous cannabinoid receptor agonists. Although these endogenous agonists are known to express central nervous system effects and peripheral cell system effects, Non-patent Document 1 also reports the cardiovascular effects of anandamide.
As a cannabinoid receptor, a cannabinoid type 1 receptor was discovered in 1990 and found to be distributed in the central nervous system such as the brain. Its agonist suppresses the release of neurotransmitters and exhibits central effects such as hallucinations. I understood it. Further, in 1993, a cannabinoid type 2 receptor was discovered and found to be distributed in immune system tissues such as the spleen, and its agonists suppress the activation of immune system cells and inflammatory cells, and suppress the immunosuppressive action, It was found to show inflammatory action and analgesic action (Non-patent Document 2). Non-Patent Document 3 discloses that cannabinoid receptor agonists Δ ⁹ -tetrahydrocannabinol and the like have a bronchodilator action. Furthermore, it is disclosed that a cannabinoid receptor agonist has an antipruritic action (Patent Document 1) and an analgesic action (Patent Document 2).
Patent Literature 3, Patent Literature 4, and Patent Literature 5 disclose thiazine derivatives having cannabinoid receptor agonist activity.
International Publication No. 03/035109 Pamphlet International Publication No. 02/42248 Pamphlet International Publication No. 01/19807 Pamphlet International Publication No. 02/072562 Pamphlet International Publication No. 03/070277 Pamphlet Hypertension 1997, Vol. 29, p. 1204-1210 Nature 1993, 365, p. 61-65. Journal of Cannabis Therapeutics 2002, Vol. 2, No. 1, p. 59-71

  Provided are a compound having a cannabinoid receptor agonist activity, particularly a compound excellent in stability and pharmacokinetics, and a pharmaceutical composition containing the compound as an active ingredient.

（式中、Ｒ^１は置換されていてもよいアリール又は置換されていてもよいヘテロアリール；
Ｒ^２はＣ１−Ｃ６アルキル、Ｃ２−Ｃ４アルケニル、又はＣ２−Ｃ４アルキニル；
Ｒ^３はＣ１−Ｃ６アルキル、Ｃ２−Ｃ４アルケニル、又はＣ２−Ｃ４アルキニル；又は
Ｒ^２及びＲ^３は一緒になって、隣接する炭素原子を含む、Ｃ１−Ｃ４アルキルで置換されていてもよい３〜８員のシクロアルカン又は隣接する炭素原子を含む、Ｃ１−Ｃ４アルキルで置換されていてもよい３〜８員の含酸素ヘテロ環を形成してもよい；
Ｒ⁴は置換されていてもよいアリール、置換されていてもよいヘテロアリール、又は式：−Ｃ（＝Ｘ）−Ｙ−Ｒ^５（式中、Ｒ^５は置換されていてもよいＣ１−Ｃ４アルキル、置換されていてもよいＣ２−Ｃ４アルケニル、又は置換されていてもよいＣ２−Ｃ４アルキニル；Ｘは酸素原子又は硫黄原子；Ｙは酸素原子又は硫黄原子）で表される基）で示される化合物、その光学活性体、その製薬上許容される塩、又はそれらの溶媒和物、
２）Ｒ⁴が式：−Ｃ（＝Ｘ）−Ｙ−Ｒ^５（式中、Ｒ^５は置換されていてもよいＣ１−Ｃ４アルキル又は置換されていてもよいＣ２−Ｃ４アルケニル；Ｘは酸素原子又は硫黄原子；Ｙは硫黄原子）で表される基である１）記載の化合物、その光学活性体、その製薬上許容される塩、又はそれらの溶媒和物、
３）Ｒ²がＣ１−Ｃ４アルキル、及びＲ³がＣ１−Ｃ４アルキルである１）または２）記載の化合物、その光学活性体、その製薬上許容される塩、又はそれらの溶媒和物、
４）Ｒ²がＣ１−Ｃ４アルキル、及びＲ³がＣ１−Ｃ４アルキル（ただし、Ｒ²とＲ³は同じではない）である１）または２）記載の化合物、その光学活性体、その製薬上許容される塩、又はそれらの溶媒和物、
５）Ｒ²及びＲ³は一緒になって隣接する炭素原子を含む、Ｃ１−Ｃ４アルキルで置換されていてもよい５〜７員のシクロアルカンである１）または２）記載の化合物、その光学活性体、その製薬上許容される塩、又はそれらの溶媒和物、
６）Ｒ^１が置換されていてもよいナフチル、置換されていてもよいテトラヒドロナフチル、置換されていてもよいインダニル、置換されていてもよいイソオキサゾリル、又は置換されていてもよいピラゾリルである１）〜５）のいずれかに記載の化合物、その光学活性体、その製薬上許容される塩、又はそれらの溶媒和物、
７）Ｒ^１が置換されていてもよい１−ナフチル、置換されていてもよい５，６，７，８−テトラヒドロ−１−ナフチル、置換されていてもよい４−インダニル、置換されていてもよい５−イソオキサゾリル、又は置換されていてもよい５−ピラゾリルである１）〜５）のいずれかに記載の化合物、その光学活性体、その製薬上許容される塩、又はそれらの溶媒和物、
８）Ｒ^１が置換基群Ａから選択される１〜２個の置換基で置換されていてもよい１−ナフチル、置換基群Ａから選択される１〜２個の置換基で置換されていてもよい５，６，７，８−テトラヒドロ−１−ナフチル、置換基群Ａから選択される１〜２個の置換基で置換されていてもよい４−インダニル、置換基群Ａから選択される１〜２個の置換基で置換されていてもよい５−イソオキサゾリル、又は置換基群Ａから選択される１〜２個の置換基で置換されていてもよい５−ピラゾリル；
置換基群Ａ：ハロゲン原子、Ｃ１−Ｃ８アルキル、Ｃ２−Ｃ６アルケニル、Ｃ２−Ｃ６アルキニル、ハロＣ１−Ｃ８アルキル、Ｃ１−Ｃ６アルコキシＣ１−Ｃ８アルキル、Ｃ１−Ｃ６アルキルチオＣ１−Ｃ８アルキル、Ｃ１−Ｃ６アルキルアミノＣ１−Ｃ８アルキル、Ｃ３−Ｃ６シクロアルキル、ヒドロキシ、Ｃ１−Ｃ６アルコキシ、Ｃ２−Ｃ６アルケニルオキシ、ハロＣ１−Ｃ６アルコキシ、Ｃ１−Ｃ６アルキルチオＣ１−Ｃ６アルコキシ、Ｃ１−Ｃ６アルコキシＣ１−Ｃ６アルコキシ、カルボキシＣ１−Ｃ６アルコキシ、Ｃ１−Ｃ６アルコキシカルボニルＣ１−Ｃ６アルコキシ、シアノＣ１−Ｃ６アルコキシ、Ｃ１−Ｃ６アルキルチオ、アミノ、モノ（Ｃ１−Ｃ６アルキル）アミノ、ジ（Ｃ１−Ｃ６アルキル）アミノ、Ｎ−Ｃ１−Ｃ６アルキル−アラルキルアミノ、Ｎ−Ｃ１−Ｃ６アルキル−アリールアミノ、Ｃ１−Ｃ６アルキルカルボニルアミノ、Ｃ１−Ｃ６アルキルスルホニルアミノ、ニトロ、カルボキシ、Ｃ１−Ｃ６アルキルカルボニル、Ｃ１−Ｃ６アルコキシカルボニル、シアノ、Ｃ１−Ｃ６アルキルスルホニルオキシ、フェニル、２−ピリジル、フェノキシ、及びベンジルオキシ；
である１）〜５）のいずれかに記載の化合物、その光学活性体、その製薬上許容される塩、又はそれらの溶媒和物、
９）１）〜８）のいずれかに記載の化合物を有効成分として含有する医薬組成物、
１０）鎮痛剤である８）記載の医薬組成物、
１１）疼痛治療剤である８）記載の医薬組成物、
１２）抗掻痒剤である８）記載の医薬組成物、
１３）１）〜８）のいずれかに記載の化合物、その製薬上許容される塩又はそれ
らの溶媒和物を投与することを特徴とする痛み、疼痛、および／または掻痒の予防又は治療方法、
１４）痛み、疼痛、および／または掻痒の予防剤又は治療剤を製造するための１）〜８）のいずれかに記載の化合物、その光学活性体、その製薬上許容される塩、又はそれらの溶媒和物の使用、に関する。The present inventors have the following 2-substituted imino-1,3-oxazine derivatives having a strong cannabinoid receptor agonist activity and excellent stability and pharmacokinetics, and pharmaceutical compositions containing the compounds as active ingredients I found it.
That is, the present invention relates to 1) general formula (I):

Wherein R ¹ is an optionally substituted aryl or an optionally substituted heteroaryl;
R ² is C1-C6 alkyl, C2-C4 alkenyl, or C2-C4 alkynyl;
R ³ is C 1 -C 6 alkyl, C 2 -C 4 alkenyl, or C 2 -C 4 alkynyl; or R ² and R ³ together are optionally substituted with C 1 -C 4 alkyl containing adjacent carbon atoms 3 May form a 3-8 membered oxygenated heterocycle optionally substituted with a C1-C4 alkyl, containing a ˜8 membered cycloalkane or an adjacent carbon atom;
R ⁴ is an optionally substituted aryl, an optionally substituted heteroaryl, or a formula: —C (═X) —Y—R ⁵ , wherein R ⁵ is an optionally substituted C 1 -C 4 An alkyl, an optionally substituted C2-C4 alkenyl, or an optionally substituted C2-C4 alkynyl; X is an oxygen atom or a sulfur atom; Y is an oxygen atom or a sulfur atom) A compound, an optically active isomer thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof,
2) R ⁴ is a formula: —C (═X) —Y—R ⁵ , wherein R ⁵ is an optionally substituted C1-C4 alkyl or an optionally substituted C2-C4 alkenyl; X is oxygen 1) the compound represented by 1), an optically active isomer, a pharmaceutically acceptable salt thereof, or a solvate thereof;
3) The compound according to 1) or 2), wherein R ² is C1-C4 alkyl, and R ³ is C1-C4 alkyl, an optically active isomer, a pharmaceutically acceptable salt thereof, or a solvate thereof,
4) The compound according to 1) or 2), wherein R ² is C1-C4 alkyl, and R ³ is C1-C4 alkyl (where R ² and R ³ are not the same), its optically active substance, its pharmaceutical Acceptable salts, or solvates thereof,
5) The compound according to 1) or 2), wherein R ² and R ³ are a 5- to 7-membered cycloalkane which may be substituted with C1-C4 alkyl, together containing adjacent carbon atoms, the optical An active form, a pharmaceutically acceptable salt thereof, or a solvate thereof,
6) R ¹ is an optionally substituted naphthyl, an optionally substituted tetrahydronaphthyl, an optionally substituted indanyl, an optionally substituted isoxazolyl, or an optionally substituted pyrazolyl 1) To 5), an optically active isomer, a pharmaceutically acceptable salt thereof, or a solvate thereof,
7) R ¹ may be substituted 1-naphthyl, may be substituted 5,6,7,8-tetrahydro-1-naphthyl, may be substituted 4-indanyl, may be substituted The compound according to any one of 1) to 5), which is a good 5-isoxazolyl or an optionally substituted 5-pyrazolyl, an optically active isomer, a pharmaceutically acceptable salt thereof, or a solvate thereof,
8) R ¹ is substituted with ¹ to 2 substituents selected from the substituent group A, 1-naphthyl optionally substituted with 1 to 2 substituents selected from the substituent group A, Optionally selected from 5,6,7,8-tetrahydro-1-naphthyl, 4-indanyl optionally substituted with one or two substituents selected from substituent group A, selected from substituent group A 5-isoxazolyl optionally substituted with 1 to 2 substituents, or 5-pyrazolyl optionally substituted with 1 to 2 substituents selected from Substituent Group A;
Substituent group A: halogen atom, C1-C8 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo C1-C8 alkyl, C1-C6 alkoxy C1-C8 alkyl, C1-C6 alkylthio C1-C8 alkyl, C1-C6 Alkylamino C1-C8 alkyl, C3-C6 cycloalkyl, hydroxy, C1-C6 alkoxy, C2-C6 alkenyloxy, halo C1-C6 alkoxy, C1-C6 alkylthio C1-C6 alkoxy, C1-C6 alkoxy C1-C6 alkoxy, Carboxy C1-C6 alkoxy, C1-C6 alkoxycarbonyl C1-C6 alkoxy, cyano C1-C6 alkoxy, C1-C6 alkylthio, amino, mono (C1-C6 alkyl) amino, di (C1-C6 alkyl) amino, N-C1 -C6 Kill-aralkylamino, N-C1-C6 alkyl-arylamino, C1-C6 alkylcarbonylamino, C1-C6 alkylsulfonylamino, nitro, carboxy, C1-C6 alkylcarbonyl, C1-C6 alkoxycarbonyl, cyano, C1-C6 Alkylsulfonyloxy, phenyl, 2-pyridyl, phenoxy, and benzyloxy;
The compound according to any one of 1) to 5), an optically active isomer, a pharmaceutically acceptable salt thereof, or a solvate thereof,
9) A pharmaceutical composition comprising the compound according to any one of 1) to 8) as an active ingredient,
10) The pharmaceutical composition according to 8), which is an analgesic.
11) The pharmaceutical composition according to 8), which is a pain therapeutic agent,
12) The pharmaceutical composition according to 8), which is an anti-pruritic agent,
13) A method for preventing or treating pain, pain, and / or pruritus, comprising administering the compound according to any one of 1) to 8), a pharmaceutically acceptable salt thereof, or a solvate thereof,
14) The compound according to any one of 1) to 8) for producing a prophylactic or therapeutic agent for pain, pain, and / or pruritus, an optically active isomer, a pharmaceutically acceptable salt thereof, or a Use of solvates.

The meaning of each term is explained below. In the present specification, each term is used in a unified meaning, and is used in the same meaning when used alone or in combination with other terms.
“Halogen atom” means a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.
“Heteroatom” includes oxygen atom, sulfur atom, nitrogen atom and the like.
“Alkyl” includes a straight-chain or branched monovalent aliphatic hydrocarbon group having a specified number of carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec -Butyl, t-butyl, n-pentyl, isopentyl, neo-pentyl, 2-methyl-2-butyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl and the like. C1-C8 linear or branched alkyl is preferable, specifically, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, Examples include isopentyl, neo-pentyl, 2-methyl-2-butyl, n-hexyl, n-heptyl, n-octyl and the like. Furthermore, linear or branched alkyl having 1 to 4 carbon atoms is more preferable, and specific examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and t-butyl. It is done.
“Alkoxyalkyl” includes the above “alkyl” substituted with 1 to 3 of the following “alkoxy” and includes, for example, methoxymethyl, 2-methoxyethyl, 2-ethoxyethyl, 3-methoxypropyl and the like. . In particular, when a carbon number is specified, it means “alkoxyalkyl” having a carbon number within the range of the number.
“Alkylthioalkyl” includes the above “alkyl” substituted with 1 to 3 of the following “alkylthio” and includes, for example, methylthiomethyl, 2-methylthioethyl, 2-ethylthioethyl, 3-methylthiopropyl and the like. It is done. In particular, when a carbon number is specified, it means “alkylthioalkyl” having a carbon number within that range.
“Alkylaminoalkyl” includes the above “alkyl” substituted with 1 to 3 of the following “alkylamino”, for example, methylaminomethyl, 2-dimethylaminoethyl, 2-diethylaminoethyl, 3-dimethylamino. And propyl. In particular, when a carbon number is specified, it means “alkylaminoalkyl” having a carbon number within the range.
“Alkylcarbonylaminoalkyl” includes the above “alkyl” substituted with 1 to 3 of the following “alkylcarbonylamino”, for example, methylcarbonylaminomethyl, 2- (ethylcarbonylamino) ethyl, 2- ( Propylcarbonylamino) ethyl and the like. When the number of carbon atoms is specified, it means “alkylcarbonylaminoalkyl” having a carbon number within the range.
“Alkenyl” includes a straight-chain or branched monovalent aliphatic hydrocarbon group having a specified number of carbon atoms having 1 to 3 double bonds, such as vinyl, 1-propenyl, allyl. , Isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 1,3-butadienyl, 3-methyl-2-butenyl, 2,3-dimethyl-2-hexenyl and the like. A straight chain or branched alkenyl having 2 to 6 carbon atoms is preferable, and specifically, vinyl, 1-propenyl, allyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 1 , 3-butadienyl, 3-methyl-2-butenyl. Furthermore, straight chain or branched alkenyl having 2 to 4 carbon atoms is more preferable, and specific examples include allyl, isopropenyl, and 3-butenyl.
“Alkynyl” includes a linear or branched monovalent aliphatic hydrocarbon group having 1 to 3 triple bonds and having a specified number of carbons, and examples thereof include ethynyl and propargyl. A linear or branched alkynyl having 2 to 6 carbon atoms is preferable, and specific examples include propargyl. In particular, linear or branched alkynyl having 2 to 4 carbon atoms is more preferable, and specific examples include propargyl.
“Haloalkyl” means a group obtained by substituting 1 to 5 of the above “alkyl” with the above “halogen atom”, for example, chloromethyl, dichloromethyl, difluoromethyl, trifluoromethyl, chloroethyl (for example, 2-chloroethyl). Etc.), dichloroethyl (for example, 1,2-dichloroethyl, 2,2-dichloroethyl and the like), chloropropyl (for example, 2-chloropropyl, 3-chloropropyl and the like) and the like. In particular, a haloalkyl having 1 to 6 carbon atoms is preferred. Specifically, chloromethyl, dichloromethyl, difluoromethyl, trifluoromethyl, 2-chloroethyl, 1,2-dichloroethyl, 2,2-dichloroethyl, 2-chloro And propyl and 3-chloropropyl. When the number of carbons is specified, it means “haloalkyl” having the number of carbons within the range.
“Cycloalkane” includes 3- to 10-membered cycloalkane, and examples thereof include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, and cyclooctane. A 3- to 8-membered cycloalkane is preferred, and specific examples include cyclopentane, cyclohexane, cycloheptane, and cyclooctane. Furthermore, a 5- to 7-membered cycloalkane is more preferable, and specific examples include cyclopentane, cyclohexane, and cycloheptane. In particular, when the number of carbon atoms forming the ring is designated, it means “cycloalkane” within the range of the number of carbon atoms forming the ring.
“Cycloalkyl” includes cycloalkyl having 3 to 10 carbon atoms, and examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like. C3-C6 cycloalkyl is preferable, and specific examples include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. When the number of carbons is specified, it means “cycloalkyl” having the number of carbons within the range.
The alkyl part of “alkoxy” has the same meaning as the above “alkyl”. Examples of “alkoxy” include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, t-butoxy, n-pentyloxy, n-hexyloxy, n-heptyloxy, n- Examples include octyloxy. In particular, alkoxy having 1 to 6 carbon atoms is preferable. Specifically, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, t-butoxy, n-pentyloxy, n-hexyloxy Is mentioned. In particular, when a carbon number is specified, it means “alkoxy” having a carbon number within the range.
The alkenyl part of “alkenyloxy” has the same meaning as the above “alkenyl”. Examples of “alkenyloxy” include vinyloxy, allyloxy, 2-butenyloxy, 3-butenyloxy, 2-pentenyloxy, 5-pentenyloxy, 3-methyl-2-butenyloxy, 2,3dimethyl-2-hexenyloxy and the like. Can be mentioned. Particularly, alkenyloxy having 1 to 6 carbon atoms is preferable, and specific examples include vinyloxy, allyloxy, 2-butenyloxy, 3-butenyloxy, 2-pentenyloxy, 5-pentenyloxy, and 3-methyl-2-butenyloxy. In particular, when a carbon number is specified, it means “alkenyloxy” having a carbon number within the range of the number.
“Haloalkoxy” means a group in which 1 to 5 of the above “halogen atoms” are substituted on the above “alkoxy”, for example, dichloromethoxy, difluoromethoxy, trifluoromethoxy, trifluoroethoxy (2,2,2 -Trifluoroethoxy) and the like. In particular, difluoromethoxy and trifluoromethoxy are preferable. In particular, when a carbon number is specified, it means “haloalkoxy” having a carbon number within the range of the number.
“Alkoxyalkoxy” includes the above “alkoxy” substituted with 1 to 3 of “alkoxy” and includes, for example, methoxymethoxy, ethoxymethoxy, n-propoxymethoxy, isopropoxymethoxy, 1-methoxyethoxy, 2 -Methoxyethoxy and the like. In particular, 1-methoxyethoxy and 2-methoxyethoxy are preferable. In particular, when the number of carbons is specified, it means “alkoxyalkoxy” having the number of carbons within the range.
“Alkylthioalkoxy” includes the above “alkoxy” substituted with 1 to 3 of the following “alkylthio” and includes, for example, methylthiomethoxy, ethylthiomethoxy, n-propylthiomethoxy, isopropylthiomethoxy, 1-methylthioethoxy , 2-methylthioethoxy and the like. In particular, 1-methylthioethoxy and 2-methylthioethoxy are preferable. In particular, when a carbon number is specified, it means “alkylthioalkoxy” having a carbon number within that range.
“Carboxyalkoxy” means a group in which 1 to 3 carboxy are substituted on the above “alkoxy”, and examples thereof include 2-carboxyethoxy, 3-carboxypropoxy, 4-carboxybutoxy and the like. In particular, when the number of carbons is specified, it means “carboxyalkoxy” having the number of carbons within the range.
“Cyanoalkoxy” means a group in which 1 to 3 cyanos are substituted on the above “alkoxy”, and examples thereof include 2-cyanoethoxy, 3-cyanopropoxy, 4-cyanobutoxy and the like. In particular, when a carbon number is specified, it means “cyanoalkoxy” having a carbon number within the range of the number.
“Alkoxycarbonylalkoxy” means a group in which 1 to 3 of the following “alkoxycarbonyl” is substituted on the above “alkoxy”, and examples thereof include methoxycarbonylmethoxy, ethoxycarbonylmethoxy, n-propoxycarbonylmethoxy, isopropoxycarbonylmethoxy. , N-butoxycarbonylmethoxy, isobutoxycarbonylmethoxy, sec-butoxycarbonylmethoxy, t-butoxycarbonylmethoxy, 2- (t-butoxycarbonyl) ethoxy, 2- (n-pentyloxycarbonyl) ethoxy, 2- (n- Hexyloxycarbonyl) ethoxy, n-heptyloxycarbonylmethoxy, n-octyloxycarbonylmethoxy and the like. In particular, t-butoxycarbonylmethoxy and 2- (t-butoxycarbonyl) ethoxy are preferable. In particular, when a carbon number is specified, it means “alkoxycarbonylalkoxy” having a carbon number within the range of the number.
The alkyl part of “alkylthio” has the same meaning as the above “alkyl”. Examples of “alkylthio” include methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, sec-butylthio, t-butylthio, n-pentylthio, n-hexylthio and the like. In particular, linear or branched alkylthio having 1 to 4 carbon atoms is preferable, and specific examples include methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, sec-butylthio, and t-butylthio. It is done. In particular, when a carbon number is specified, it means “alkylthio” having a carbon number within the range of the number.
The alkyl part of “mono (alkyl) amino” has the same meaning as the above “alkyl”. Examples of “mono (alkyl) amino” include methylamino, ethylamino, n-propylamino, isopropylamino and the like. In particular, methylamino and ethylamino are preferable. In particular, when a carbon number is specified, it means “mono (alkyl) amino” having a carbon number within the range.
The alkyl part of “di (alkyl) amino” is the same or different and has the same meaning as the above “alkyl”. Examples of “di (alkyl) amino” include dimethylamino, diethylamino, ethylmethylamino, propylmethylamino and the like. In particular, dimethylamino and diethylamino are preferable. In particular, when a carbon number is specified, it means “alkylamino” having a carbon number within the range.
The alkyl part of “N-alkyl-arylamino” has the same meaning as the above “alkyl”, and the aryl part has the same meaning as “aryl” below. Examples of “N-alkyl-arylamino” include N-methyl-phenylamino, N-ethyl-phenylamino, Nn-propyl-phenylamino, N-isopropyl-phenylamino and the like. In particular, N-methyl-phenylamino and N-ethyl-phenylamino are preferable. In particular, when the number of carbons is specified, it means “N-alkyl-arylamino” having the number of carbons within the range.
The alkyl part of “N-alkyl-aralkylamino” has the same meaning as the above “alkyl”, and the aralkyl part has the same meaning as the following “aralkyl”. Examples of “N-alkyl-aralkylamino” include N-methyl-benzylamino, N-ethyl-benzylamino, Nn-propyl-benzylamino, N-isopropyl-benzylamino and the like. In particular, N-methyl-benzylamino and N-ethyl-benzylamino are preferable. In particular, when a carbon number is specified, it means “N-alkyl-aralkylamino” having a carbon number within the range.
“Alkylcarbonylamino” includes amino substituted with 1 to 2 of the following “alkylcarbonyl” and includes, for example, methylcarbonylamino, ethylcarbonylamino, propylcarbonylamino and the like. In particular, when a carbon number is designated, it means “alkylcarbonylamino” having a carbon number within the range of the number.
The “alkylsulfonylamino” includes amino substituted with 1 to 2 of the following “alkylsulfonyl”, and examples thereof include methylsulfonylamino and ethylsulfonylamino. In particular, when a carbon number is specified, it means “alkylsulfonylamino” having a carbon number within the range.
“Alkylcarbonyl” means a group obtained by substituting the above “alkyl” with carbonyl, for example, methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, isopropylcarbonyl, n-butylcarbonyl, isobutylcarbonyl, sec-butylcarbonyl, Examples include t-butylcarbonyl, n-pentylcarbonyl, n-hexylcarbonyl, n-heptylcarbonyl, n-octylcarbonyl and the like. In particular, methylcarbonyl, ethylcarbonyl and the like are preferable. In particular, when the number of carbon atoms of “alkyl” is designated, it means “alkylcarbonyl” having “alkyl” in the number range of carbon atoms.
“Alkoxycarbonyl” means a group obtained by substituting the above “alkoxy” with carbonyl, such as methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, isobutoxycarbonyl, sec-butoxy. Examples include carbonyl, t-butoxycarbonyl, n-pentyloxycarbonyl, n-hexyloxycarbonyl, n-heptyloxycarbonyl, n-octyloxycarbonyl and the like. In particular, methoxycarbonyl, ethoxycarbonyl and the like are preferable. In particular, when the number of carbon atoms of “alkoxy” is specified, it means “alkoxycarbonyl” having “alkoxy” in the number range of carbon atoms.
“Alkylthiocarbonyl” means a group in which the above “alkylthio” is substituted on carbonyl, such as methylthiocarbonyl, ethylthiocarbonyl, n-propylthiocarbonyl, isopropylthiocarbonyl, n-butylthiocarbonyl, isobutylthiocarbonyl, and sec-butylthiocarbonyl, t-butylthiocarbonyl, n-pentylthiocarbonyl, n-hexylthiocarbonyl, n-heptylthiocarbonyl, n-octylthiocarbonyl and the like. In particular, methylthiocarbonyl, ethylthiocarbonyl and the like are preferable. In particular, when the number of carbon atoms of “alkylthio” is designated, it means “alkylthiocarbonyl” having “alkylthio” having the number of carbon atoms within the range.
The alkyl part of “alkylsulfonyl” has the same meaning as the above “alkyl”. Examples of “alkylsulfonyl” include methylsulfonyl, ethylsulfonyl and the like. When the number of carbons is specified, it means “alkylsulfonyl” having the number of carbons within the range.
The alkylsulfonyl moiety of “alkylsulfonyloxy” has the same meaning as the above “alkylsulfonyl”. Examples of “alkylsulfonyloxy” include methanesulfonyloxy, ethanesulfonyloxy and the like. In particular, when a carbon number is specified, it means “alkylsulfonyloxy” having a carbon number within the range of the number.

“Aryl” includes aryl having 6 to 14 carbon atoms, and examples thereof include phenyl, naphthyl, 4-indanyl, 5,6,7,8-tetrahydronaphthyl, anthryl, phenanthryl and the like. In particular, phenyl, naphthyl, 4-indanyl, and 5,6,7,8-tetrahydronaphthyl are preferable.
“Aralkyl” includes a group in which the above “alkyl” is substituted with the above “aryl” and includes, for example, benzyl, phenylethyl (eg, 1-phenylethyl, 2-phenylethyl), phenylpropyl (eg, 1-phenyl). Phenylpropyl, 2-phenylpropyl, 3-phenylpropyl, etc.), naphthylmethyl (eg, 1-naphthylmethyl, 2-naphthylmethyl, etc.) and the like. In particular, benzyl and naphthylmethyl are preferable.
“Heteroaryl” includes C 1-9 heteroaryl containing 1 to 4 nitrogen, oxygen and / or sulfur atoms, for example, furyl (eg, 2-furyl, 3-furyl). , Thienyl (eg, 2-thienyl, 3-thienyl), pyrrolyl (eg, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), imidazolyl (eg, 1-imidazolyl, 2-imidazolyl, 4-imidazolyl), pyrazolyl ( For example, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl), triazolyl (eg, 1,2,4-triazol-1-yl, 1,2,4-triazolyl-3-yl, 1,2 , 4-triazol-4-yl), tetrazolyl (eg, 1-tetrazolyl, 2-tetrazolyl, 5-tetrazolyl), oxazolyl ( For example, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl), isoxazolyl (eg, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl), thiazolyl (eg, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl), thiadiazolyl , Isothiazolyl (eg, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl), pyridyl (eg, 2-pyridyl, 3-pyridyl, 4-pyridyl), pyridazinyl (eg, 3-pyridazinyl, 4-pyridazinyl), pyrimidinyl ( For example, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl), furazanyl (eg, 3-furazinyl), pyrazinyl (eg, 2-pyrazinyl), oxadiazolyl (eg, 1,3,4-oxadiazol-2-yl) ), , 3-benzodioxolyl, 1,4-benzodioxanyl, benzofuryl (for example, 2-benzo [b] furyl, 3-benzo [b] furyl, 4-benzo [b] furyl, 5-benzo [b ] Furyl, 6-benzo [b] furyl, 7-benzo [b] furyl), benzothienyl (for example, 2-benzo [b] thienyl, 3-benzo [b] thienyl, 4-benzo [b] thienyl, 5 -Benzo [b] thienyl, 6-benzo [b] thienyl, 7-benzo [b] thienyl), benzimidazolyl (for example, 1-benzoimidazolyl, 2-benzoimidazolyl, 4-benzoimidazolyl, 5-benzoimidazolyl), dibenzofuryl, benzo Oxazolyl, quinoxalyl (eg 2-quinoxalinyl, 5-quinoxalinyl, 6-quinoxalinyl), cinnolinyl (eg For example, 3-cinnolinyl, 4-cinnolinyl, 5-cinnolinyl, 6-cinnolinyl, 7-cinnolinyl, 8-cinnolinyl), quinazolyl (eg, 2-quinazolinyl, 4-quinazolinyl, 5-quinazolinyl, 6-quinazolinyl, 7-quinazolinyl , 8-quinazolinyl), quinolyl (eg, 2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 6-quinolyl, 7-quinolyl, 8-quinolyl), phthalazinyl (eg, 1-phthalazinyl, 5-phthalazinyl) 6-phthalazinyl), isoquinolyl (eg, 1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl, 6-isoquinolyl, 7-isoquinolyl, 8-isoquinolyl), prill, pteridinyl (eg, 2-pteridinyl, 4 -Pteridinyl, 6-pte Dinyl, 7-pteridinyl), carbazolyl, phenanthridinyl, acridinyl (eg 1-acridinyl, 2-acridinyl, 3-acridinyl, 4-acridinyl, 9-acridinyl), indolyl (eg 1-indolyl, 2-indolyl) , 3-indolyl, 4-indolyl, 5-indolyl, 6-indolyl, 7-indolyl), isoindolyl, phenazinyl (eg, 1-phenazinyl, 2-phenazinyl), or phenothiazinyl (eg, 1-phenothiazinyl, 2- Phenothiazinyl, 3-phenothiazinyl, 4-phenothiazinyl) and the like.
“Oxygen-containing heterocycle” includes a 3- to 8-membered non-aromatic heterocycle containing only one or two oxygen atoms as a heteroatom, and includes oxirane, oxetane, oxolane, dioxolane, oxane, dioxane, Oxepane, oxocane and the like. In particular, oxolane, oxane and oxepane are preferable.
The “non-aromatic heterocyclic group” includes a non-aromatic ring having 1 to 9 carbon atoms containing 1 to 4 nitrogen atoms, oxygen atoms, and / or sulfur atoms, such as 1-pyrrolinyl, 2- Pyrrolinyl, 3-pyrrolinyl, pyrrolidino, 2-pyrrolidinyl, 3-pyrrolidinyl, 1-imidazolinyl, 2-imidazolinyl, 4-imidazolinyl, 1-imidazolidinyl, 2-imidazolidinyl, 4-imidazolidinyl, 1-pyrazolinyl, 3-pyrazolinyl, 4- Examples include pyrazolinyl, 1-pyrazolidinyl, 3-pyrazolidinyl, 4-pyrazolidinyl, piperidino, 2-piperidyl, 3-piperidyl, 4-piperidyl, piperazino, 2-piperazinyl, 2-morpholinyl, 3-morpholinyl, morpholino, tetrahydropyranyl and the like. It is done. In particular, morpholino, pyrrolidino, piperidino and piperazino are preferred.
The aryl part of “aryloxy” has the same meaning as the above “aryl”. Examples of “aryloxy” include phenoxy, naphthoxy (eg, 1-naphthoxy, 2-naphthoxy, etc.), anthryloxy (eg, 1-anthryloxy, 2-anthryloxy, etc.), phenanthryloxy ( For example, 1-phenanthryloxy, 2-phenanthryloxy and the like). In particular, phenoxy and naphthoxy are preferable.
The aralkyl part of “aralkyloxy” has the same meaning as the above “aralkyl”. Examples of “aralkyloxy” include benzyloxy, phenethyloxy and the like. In particular, benzyloxy is preferred.
“Arylcarbonylamino” includes amino substituted with 1 to 2 of the following “arylcarbonyl”, for example, phenylcarbonylamino, naphthylcarbonylamino (eg, 1-naphthylcarbonylamino, 2-naphthylcarbonylamino) Etc. When the number of carbons is specified, it means “arylcarbonylamino” having the number of carbons within the range.
The aryl part of “arylsulfonyl” has the same meaning as the above “aryl”. Examples of “arylsulfonyl” include phenylsulfonyl, naphthylsulfonyl (eg, 1-naphthylsulfonyl, 2-naphthylsulfonyl) and the like. In particular, when a carbon number is specified, it means “arylsulfonyl” having a carbon number within the range of the number.

“Optionally substituted alkyl”, “optionally substituted alkenyl”, “optionally substituted alkynyl”, “optionally substituted aryl”, “optionally substituted heteroaryl” , “Optionally substituted 1-naphthyl”, “optionally substituted 5,6,7,8-tetrahydro-1-naphthyl”, “optionally substituted 4-indanyl”, “substituted Optionally substituted 5-isooxolyl "," optionally substituted 5-pyrazolyl "," optionally substituted non-aromatic heterocyclic group "," optionally substituted aryloxy " , Any position may be substituted with 1 to 4 substituents which are the same or different. In particular, when the number of carbons is specified, it means a group including carbon atoms within the range of the number.
Examples of the substituent include a halogen atom (fluorine atom, chlorine atom, bromine atom, iodine atom), C1-C6 alkyl (eg, methyl, ethyl, isopropyl, t-butyl etc.), C2-C6 alkenyl (eg, vinyl Etc.), C2-C6 alkynyl (eg ethynyl etc.), halo C1-C6 alkyl (eg CF ₃ , CH ₂ CF ₃ , CH ₂ CCl ₃ etc.), C1-C6 alkoxy C1-C6 alkyl (eg 2-methoxy) Ethyl, 2-ethoxyethyl, etc.), C1-C6 alkylthio C1-C6 alkyl (eg 2-methylthioethyl, 2-ethylthioethyl etc.), C1-C6 alkylamino C1-C6 alkyl (eg 2-dimethylaminoethyl, 2 -Diethylaminoethyl, etc.), C3-C6 cycloalkyl (eg cyclopropyl, Cyclopentyl, cyclohexyl etc.), aryl (eg phenyl etc.), heteroaryl (eg 2-pyridyl etc.), hydroxy, C1-C6 alkoxy (eg methoxy, ethoxy, propoxy, butoxy etc.), C2-C6 alkenyl Oxy (eg, allyloxy, etc.), halo C1-C6 alkoxy (eg, difluoromethoxy, trifluoromethoxy, etc.), C1-C6 alkylthio C1-C6 alkoxy (eg, 2-methylthioethoxy, etc.), aralkyloxy (eg, benzyloxy, etc.) ), C1-C6 alkoxy C1-C6 alkoxy (eg 2-methoxyethoxy, 2-ethoxyethoxy etc.), carboxy C1-C6 alkoxy (eg 2-carboxyethoxy etc.), C1-C6 alkoxycarbonyl C1-C6 al Xy (for example, 2-ethoxycarbonylethoxy, etc.), cyano C1-C6 alkoxy (for example, 2-cyanoethoxy, etc.), aryloxy (for example, phenoxy), C1-C6 alkylsulfonyloxy (for example, methylsulfonyloxy, etc.), C1-C6 alkylthio (eg, methylthio, ethylthio, etc.), carboxy, C1-C6 alkylcarbonyl (eg, methylcarbonyl, ethylcarbonyl, etc.), C1-C6 alkoxycarbonyl (eg, methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, etc.) ), Amino, C1-C6 alkylamino (eg, methylamino, dimethylamino, diethylamino, etc.), C1-C6 alkylcarbonylamino (eg, methylcarbonylamino, etc.), C1-C6 alkylsulfur Nylamino (eg, methylsulfonylamino, etc.), nitro, cyano, formyl, oxo, aralkyl (eg, benzyl, etc.), non-aromatic heterocyclic group (eg, morpholino, piperidino, etc.), arylcarbonylamino (eg, phenylsulfonyl) Amino), azide, C1-C6 alkylcarbonylamino C1-C6 alkyl (eg 2-methylcarbonylaminoethyl etc.), C1-C6 alkylthiocarbonyl (eg methylthiocarbonyl etc.), mercapto, alkylsulfonyl (eg methylsulfonyl) And arylsulfonyl (for example, phenylsulfonyl) and the like.
The “optically active substance” includes a specific optical isomer when the compound of the present invention has an asymmetric carbon.
“Racemic” means a compound having equal amounts of enantiomers.

特に、以下に示すＲ^２及びＲ^３が一緒になって隣接する炭素原子を含む５〜７員のシクロアルカンが好ましい。

Ｒ^４としては、式：−Ｃ（＝Ｘ）−Ｙ−Ｒ^５が好ましく、特に−Ｃ（＝Ｏ）−Ｓ−ＣＨ_３、−Ｃ（＝Ｓ）−Ｓ−ＣＨ_３、−Ｃ（＝Ｏ）−Ｓ−Ｃ_２Ｈ_５、−Ｃ（＝Ｓ）−Ｓ−Ｃ_２Ｈ_５、−Ｃ（＝Ｏ）−Ｓ−ＣＨ_２ＣＨ＝ＣＨ_２、または−Ｃ（＝Ｓ）−Ｓ−ＣＨ_２ＣＨ＝ＣＨ_２が好ましい。
Ｒ^４の置換されていてもよいアリールとしては、置換されていてもよいフェニルが好ましく、該置換基としては、トリフルオロメチルまたはニトロが好ましい。
Ｒ^４の置換されていてもよいヘテロアリールとしては、置換されていてもよいピリジルが好ましく、該置換基としては、トリフルオロメチルまたはニトロが好ましい。Among the compounds represented by the formula (I), compounds having preferable substituents shown below are particularly preferable compounds.
R ¹ is optionally substituted phenyl, optionally substituted 1-naphthyl, optionally substituted 5,6,7,8-tetrahydro-1-naphthyl, optionally substituted 4-indanyl, substituted Preferred is 5-isoxazolyl which may be substituted or 5-pyrazolyl which may be substituted. In particular, 1-naphthyl which may be substituted or 5,6,7,8-tetrahydro-1-naphthyl which may be substituted is more preferable.
Here, as each substituent, 1-2 substituents selected from the substituent represented by the substituent group A are preferable.
Substituent group A: halogen atom, C1-C8 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo C1-C8 alkyl, C1-C6 alkoxy C1-C8 alkyl, C1-C6 alkylthio C1-C8 alkyl, C1-C6 Alkylamino C1-C8 alkyl, C3-C6 cycloalkyl, hydroxy, C1-C6 alkoxy, C2-C6 alkenyloxy, halo C1-C6 alkoxy, C1-C6 alkylthio C1-C6 alkoxy, C1-C6 alkoxy C1-C6 alkoxy, Carboxy C1-C6 alkoxy, C1-C6 alkoxycarbonyl C1-C6 alkoxy, cyano C1-C6 alkoxy, C1-C6 alkylthio, amino, mono (C1-C6 alkyl) amino, di (C1-C6 alkyl) amino, N-C1 -C6 Kill-aralkylamino, N-C1-C6 alkyl-arylamino, C1-C6 alkylcarbonylamino, C1-C6 alkylsulfonylamino, nitro, carboxy, C1-C6 alkylcarbonyl, C1-C6 alkoxycarbonyl, cyano, C1-C6 Alkylsulfonyloxy, phenyl, 2-pyridyl, phenoxy, and benzyloxy.
Furthermore, 1 or 2 substituents selected from the substituents represented by the substituent group B are more preferable.
Substituent group B: halogen atom, C1-C8 alkyl, halo C1-C8 alkyl, hydroxy, C1-C6 alkoxy, di (C1-C6 alkyl) amino, nitro, and cyano.
R ² and R ³ are the same and are preferably C2-C3 alkyl, or differently one being C2-C4 alkyl and the other being C1-C4 alkyl.
Examples of the ^3- to 8-membered cycloalkane of the 3- to 8-membered cycloalkane in which R ² and R ³ are combined and the C1-C4 alkyl containing an adjacent carbon atom may be substituted include the following groups: It is done. The cycloalkane may be substituted with 1 to 4 C1-C4 alkyls, and the substituent is preferably methyl or ethyl.

In particular, a 5- to 7-membered cycloalkane in which R ² and R ³ shown below together contain adjacent carbon atoms is preferable.

As R ⁴ , the formula: —C (═X) —Y—R ⁵ is preferable, and in particular, —C (═O) —S—CH ₃ , —C (═S) —S—CH ₃ , —C (= _{O) -S-C 2 H 5} , -C (= S) -S-C 2 H 5, -C (= O) -S-CH 2 CH = CH 2 or -C, (= S) -S- CH ₂ CH═CH ₂ is preferred.
The aryl which may be substituted for R ⁴ is preferably an optionally substituted phenyl, and the substituent is preferably trifluoromethyl or nitro.
The optionally substituted heteroaryl of R ⁴ is preferably an optionally substituted pyridyl, and the substituent is preferably trifluoromethyl or nitro.

  A compound having a cannabinoid receptor agonistic action, particularly a 2-substituted imino-1,3-oxazine derivative excellent in activity, stability and pharmacokinetics is also useful as a pharmaceutical because of its high safety.

（式中、Ｒ^１は置換されていてもよいアリール又は置換されていてもよいヘテロアリール；
Ｒ^２はＣ１−Ｃ６アルキル、Ｃ２−Ｃ４アルケニル、又はＣ２−Ｃ４アルキニル；
Ｒ^３はＣ１−Ｃ６アルキル、Ｃ２−Ｃ４アルケニル、又はＣ２−Ｃ４アルキニル；又は
Ｒ^２及びＲ^３は一緒になって、隣接する炭素原子を含む、Ｃ１−Ｃ４アルキルで置換されていてもよい３〜８員のシクロアルカン又は隣接する炭素原子を含む、Ｃ１−Ｃ４アルキルで置換されていてもよい３〜８員の含酸素ヘテロ環を形成してもよい；
Ｒ⁴は置換されていてもよいアリール、置換されていてもよいヘテロアリール、又は式：−Ｃ（＝Ｘ）−Ｙ−Ｒ^５（式中、Ｒ^５は置換されていてもよいＣ１−Ｃ４アルキル、置換されていてもよいＣ２−Ｃ４アルケニル、又は置換されていてもよいＣ２−Ｃ４アルキニル；Ｘは酸素原子又は硫黄原子；Ｙは酸素原子又は硫黄原子）で表される基）
第１工程
式（ＩＩ）で示される化合物のアミノ基をイソチオシアン酸エステル（イソチオシアネート）に変換し、式（ＩＩＩ）で示される化合物を製造する工程である。
アミノ基からイソチオシアン酸エステル（イソチオシアネート）への変換法としては、（１）アンモニア（ＮＨ_３、ＮＨ_４ＯＨ）やトリエチルアミン（Ｅｔ_３Ｎ）などの塩基の存在下にニ硫化炭素（ＣＳ_２）を作用させて得られるジチオカルバミド酸塩を、クロロ炭酸エチル（ＣｌＣＯ_２Ｅｔ）、トリエチルアミン（Ｅｔ_３Ｎ）で処理する方法、（２）前記ジチオカルバミド酸塩を、硝酸鉛等の金属塩で処理する方法、（３）チオホスゲン（ＣＳＣｌ_２）を作用させる方法、（４）チオカルボニルジイミダゾールを作用させる方法等が挙げられる。
（１）の場合、塩基（１．０〜１．５当量）及び二硫化炭素（１．０〜１．５当量）を化合物（ＩＩ）に加え、非プロトン性溶媒（例えば、ジエチルエーテル、テトラヒドロフラン、ジメチルホルムアミド、ベンゼン、トルエン、ジクロロメタン、クロロホルム等）中で０．５時間〜１０時間攪拌する。その後、クロロ炭酸エチル（１．０〜１．５当量）及びトリエチルアミン（１．０〜１．５当量）を加え、非プロトン性溶媒（例えば、ジエチルエーテル、テトラヒドロフラン、ジメチルホルムアミド、ベンゼン、トルエン、ジクロロメタン、クロロホルム等）中で０．５時間〜１０時間攪拌する。反応温度としては０℃〜１００℃が好ましく、特に０℃〜室温が好ましい。
（３）の場合、チオホスゲン（１．０〜１．５当量）を化合物（ＩＩ）に加え、非プロトン性溶媒（例えば、ジエチルエーテル、テトラヒドロフラン、ジメチルホルムアミド、ベンゼン、トルエン、ジクロロメタン、クロロホルム等）中で０．５時間〜１０時間攪拌する。反応温度としては０℃〜１００℃が好ましく、特に０℃〜室温が好ましい。
（４）の場合、チオカルボニルジイミダゾール（１．０〜１．５当量）を化合物（ＩＩ）に加え、非プロトン性溶媒（例えば、ジエチルエーテル、テトラヒドロフラン、ジメチルホルムアミド、ベンゼン、トルエン、ジクロロメタン、クロロホルム等）中で０．５時間〜１０時間攪拌する。反応温度としては０℃〜１００℃が好ましく、特に０℃〜室温が好ましい。
式（ＩＩ）で示される化合物として、アニリン、２−トリフルオロメチルアニリン、３−トリフルオロメチルアニリン、ｏ−アニシジン、３−ジメチルアミノ−２−メチルアミノベンゼン、１−アミノ−３−フルオロナフタレン、１−アミノ−４−フルオロナフタレン、１−アミノ−５−フルオロナフタレン、１−アミノ−６−フルオロナフタレン、１−アミノ−７−フルオロナフタレン、１−アミノ−３−クロロナフタレン、１−アミノ−４−クロロナフタレン、１−アミノ−５−クロロナフタレン、１−アミノ−６−クロロナフタレン、１−アミノ−７−クロロナフタレン、１−アミノ−３−ブロモナフタレン、１−アミノ−４−ブロモナフタレン、１−アミノ−５−ブロモナフタレン、１−アミノ−６−ブロモナフタレン、１−アミノ−７−ブロモナフタレン、１−アミノ−３−メチルナフタレン、１−アミノ−４−メチルナフタレン、１−アミノ−５−メチルナフタレン、１−アミノ−６−メチルナフタレン、１−アミノ−７−メチルナフタレン、１−アミノ−３−メトキシナフタレン、１−アミノ−４−メトキシナフタレン、１−アミノ−５−メトキシナフタレン、１−アミノ−６−メトキシナフタレン、１−アミノ−７−メトキシナフタレン、１−アミノ−３−シアノナフタレン、１−アミノ−４−シアノナフタレン、１−アミノ−５−シアノナフタレン、１−アミノ−６−シアノナフタレン、１−アミノ−７−シアノナフタレン、１−アミノ−３−Ｎ，Ｎ−ジメチルアミノナフタレン、１−アミノ−４−Ｎ，Ｎ−ジメチルアミノナフタレン、１−アミノ−５−（ジメチルアミノ）ナフタレン、１−アミノ−６−（ジメチルアミノ）ナフタレン、１−アミノ−７−（ジメチルアミノ）ナフタレン、１−アミノ−３−ニトロナフタレン、１−アミノ−４−ニトロナフタレン、１−アミノ−５−ニトロナフタレン、１−アミノ−６−ニトロナフタレン、１−アミノ−７−ニトロナフタレン、１−アミノ−３−ベンジルオキシナフタレン、１−アミノ−４−ベンジルオキシナフタレン、１−アミノ−５−ベンジルオキシナフタレン、１−アミノ−６−ベンジルオキシナフタレン、１−アミノ−７−ベンジルオキシナフタレン、１−アミノ−４−（２−ピリジル）ナフタレン、１−アミノ−５，６，７，８−テトラヒドロナフタレン、１−アミノ−７−ヒドロキシ−５，６，７，８−テトラヒドロナフタレン、４−アミノ−ベンゾジオキソール、５−アミノ−１，４−ベンゾジオキサン、５−アミノ−３−イソプロピルイソオキサゾール、５−アミノ−３−ｔ−ブチルイソオキサゾール、５−アミノ−３−（２−メチルブチル−２−イル）イソオキサゾール、２−アミノ−４−ｔ−ブチルチアゾール、５−アミノ−３−ｔ−ブチル−１−メチルピラゾール、５−アミノ−３−（２−メチルブチル−２−イル）−１−メチルピラゾール等が挙げられる。
第２工程
式（ＩＩＩ）で示される化合物のイソチオシアン酸エステル（イソチオシアネート）に、ＮＨ_２−ＣＨ_２Ｃ（Ｒ^２Ｒ^３）ＣＨ_２−ＯＨ（Ｒ^２及びＲ^３は前記と同意語）を反応させ、式（ＩＶ）で示される化合物を製造する工程である。
本工程は、非プロトン性溶媒（例えば、ジエチルエーテル、テトラヒドロフラン、ジメチルホルムアミド、ベンゼン、トルエン、ジクロロメタン、クロロホルム等）中で行うことができる。
反応温度としては、０℃〜１００℃が好ましく、特に０℃〜室温が好ましく、反応時間としては、０．５時間〜１０時間が好ましい。
ＮＨ_２−ＣＨ_２Ｃ（Ｒ^２Ｒ^３）ＣＨ_２−ＯＨは、化合物（ＩＩＩ）に対して１．０〜１．５当量用いればよい。
ＮＨ_２−ＣＨ_２Ｃ（Ｒ^２Ｒ^３）ＣＨ_２−ＯＨとしては、３−アミノ−２−メチル−２−ｎ−プロピルプロパノール、３−アミノ−２−イソプロピル−２−メチルプロパノール、３−アミノ−２−エチル−２−ｎ−プロピルプロパノール、３−アミノ−２−エチル−２−イソプロピルプロパノール、３−アミノ−２−イソプロピル−２−ｎ−プロピルプロパノール、３−アミノ−２，２−ジ−ｎ−プロピルプロパノール、３−アミノ−２，２−ジイソプロピルプロパノール、３−アミノ−２，２−エチレンプロパノール、３−アミノ−２，２−トリメチレンプロパノール、３−アミノ−２，２−テトラメチレンプロパノール、３−アミノ−２，２−ペンタメチレンプロパノール、３−アミノ−２，２−ヘキサメチレンプロパノール、３−アミノ−２，２−ヘプタメチレンプロパノール等が挙げられる。
なお、Ｒ^２とＲ^３が異なる場合はＲ^２とＲ^３が置換した炭素原子は不斉炭素であり、光学異性体が存在する。光学異性体の製造法の一例として、ｉ）ＮＣ−Ｃ（Ｒ^２Ｒ^３）−ＣＯＯＨであるシアノ酢酸誘導体と光学活性なアミン誘導体（例えば、（１Ｒ，２Ｒ）−（−）−２−アミノ−１−フェニル−１，３−プロパンジオール、（１Ｓ，２Ｓ）−（＋）−２−アミノ−１−フェニル−１，３−プロパンジオール等）の塩を、再結晶等の方法で精製する工程、ｉｉ）ヒドリド試薬（例えば、ＬｉＡｌＨ_４等）等による還元反応の工程による方法を用いることができる。
第３工程
式（ＩＶ）で示される化合物を閉環させ、式（Ｖ）で示される化合物を製造する工程である。
閉環方法としては、（１）アルコール中、アルキルハライドで処理する方法、（２）アルコール中、アルキルハライドで処理後、塩基で処理する方法等が挙げられる。
（１）の場合は、アルコールとしてメタノール、エタノール等を用い、０℃〜溶媒の還流温度で０．５時間〜７２時間行えばよい。アルキルハライドとして、メチルヨーダイド、エチルヨーダイド等を用い、化合物（ＩＶ）に対して０．５〜３当量用いればよい。
（２）の場合は、アルキルハライドとして、ヨードメタン、ヨードエタン等を用い、化合物（ＩＶ）に対して０．５〜３当量用いればよい。アルコールとしてメタノール、エタノール等を用い、０℃〜溶媒の還流温度で０．５時間〜７２時間反応後、塩基として水酸化ナトリウム、水酸化カリウム等を用いて、アルコールとしてメタノール、エタノール等を用い、０℃〜溶媒の還流温度で０．５時間〜２４時間反応を行うことができる。
第４工程
式（Ｖ）で示される化合物に、Ｈａｌ−Ｒ^４（式中、Ｒ^４は前記と同意義、Ｈａｌはハロゲン原子）を導入し、式（Ｉ）で示される化合物を製造する工程である。
本工程は、（１）Ｒ^４が置換されていてもよいアリール又置換されていてもよいアリールの場合は、塩基（例えば、水素化ナトリウム、水酸化ナトリウム、水酸化カリウム等）の存在下、Ｈａｌ−Ｒ^４（式中、Ｒ^４は置換されていてもよいアリール又置換されていてもよいアリール）で示される化合物を反応させることにより行うことができる。溶媒として非プロトン性溶媒（例えば、ジエチルエーテル、テトラヒドロフラン、ジメチルホルムアミド、ベンゼン、トルエン、ジクロロメタン、クロロホルム等）等を使用し、０℃〜溶媒の還流温度で０．５時間〜７２時間反応を行うことができる。
（２）Ｒ^４が式：−Ｃ（＝Ｘ）−Ｙ−Ｒ^５（式中、Ｒ^５、Ｘ及びＹは前記と同意義）である場合は、塩基（例えば、トリエチルアミン、ピリジン、Ｎ，Ｎ−ジメチルアミノピリジン等）の存在下、式：Ｈａｌ−Ｃ（＝Ｘ）−Ｙ−Ｒ^５（式中、Ｒ^５、Ｘ及びＹは前記と同意義、Ｈａｌはハロゲン原子）で示される化合物を反応させることにより行うことができる。通常のＮ−アシル化の条件に従って行えばよく、例えば、溶媒として非プロトン性溶媒（例えば、ジエチルエーテル、テトラヒドロフラン、ジメチルホルムアミド、ベンゼン、トルエン、ジクロロメタン、クロロホルム等）等を使用し、０℃〜１００℃で、０．５時間〜１０時間、反応を行うことができる。
また、塩基（例えば、水素化ナトリウム等）の存在下、二硫化炭素（ＣＳ_２）を反応させ、次いで、アルキルハライド（例えば、ヨードメタン、ヨードエタン等）又はアルコキシアルキルハライド（例えば、クロロメチルメチルエーテル等）を反応させることによっても得ることができる。この場合、溶媒としては、非プロトン性溶媒（例えば、ジエチルエーテル、テトラヒドロフラン、ジメチルホルムアミド、ベンゼン、トルエン、ジクロロメタン、クロロホルム等）を用いることができ、０℃〜室温で反応は進行する。
なお、 Ｒ^１、Ｒ^４及びＲ^５が保護基で保護されている基を有する場合、ａ）脱保護またはｂ）脱保護後、アルキル化を行うことができる。
脱保護は、Protective Groups in Organic Synthesis, Theodora W Green (John Wiley & Sons)等に記載の方法で除去することができる。
アルキル化は、塩基（例えば、水素化ナトリウム等）の存在下、アルキルハライド（例えば、ヨードメタン、ヨードエタン等）又は（アルコキシカルボニル）アルキルハライド（例えば、ｔ−ブトキシカルボニルメチルブロミド等）を反応させることによって得ることができる。この場合、溶媒としては、非プロトン性溶媒（例えば、ジエチルエーテル、テトラヒドロフラン、ジメチルホルムアミド、ベンゼン、トルエン、ジクロロメタン、クロロホルム等）を用いることができ、０℃〜室温で反応を行うことができる。
なお、各工程で得られた化合物は、そのまま次の工程に用いることができるが、必要であれば蒸留、再結晶、カラムクロマトグラフィー等で精製することができる。The compound according to the present invention can be produced by the steps shown below with reference to WO01 / 19807 and WO02 / 072562. The structural formulas of formulas (I) to (V) indicate racemic or optically active substances.

Wherein R ¹ is an optionally substituted aryl or an optionally substituted heteroaryl;
R ² is C1-C6 alkyl, C2-C4 alkenyl, or C2-C4 alkynyl;
R ³ is C 1 -C 6 alkyl, C 2 -C 4 alkenyl, or C 2 -C 4 alkynyl; or R ² and R ³ together are optionally substituted with C 1 -C 4 alkyl containing adjacent carbon atoms 3 May form a 3-8 membered oxygenated heterocycle optionally substituted with a C1-C4 alkyl, containing a ˜8 membered cycloalkane or an adjacent carbon atom;
R ⁴ is an optionally substituted aryl, an optionally substituted heteroaryl, or a formula: —C (═X) —Y—R ⁵ , wherein R ⁵ is an optionally substituted C 1 -C 4 An alkyl, an optionally substituted C2-C4 alkenyl, or an optionally substituted C2-C4 alkynyl; X is an oxygen atom or a sulfur atom; Y is an oxygen atom or a sulfur atom))
1st process It is the process of converting the amino group of the compound shown by Formula (II) into an isothiocyanate (isothiocyanate), and manufacturing the compound shown by Formula (III).
The conversion method from amino group to isothiocyanate (isothiocyanate) includes (1) carbon disulfide (CS ₂ ) in the presence of a base such as ammonia (NH ₃ , NH ₄ OH) or triethylamine (Et ₃ N). A method of treating a dithiocarbamate obtained by the action of ethyl chlorocarbonate (ClCO ₂ Et) or triethylamine (Et ₃ N), (2) treating the dithiocarbamate with a metal salt such as lead nitrate (3) a method of allowing thiophosgene (CSCl ₂ ) to act, (4) a method of causing thiocarbonyldiimidazole to act, and the like.
In the case of (1), a base (1.0 to 1.5 equivalents) and carbon disulfide (1.0 to 1.5 equivalents) are added to compound (II) and an aprotic solvent (eg, diethyl ether, tetrahydrofuran). , Dimethylformamide, benzene, toluene, dichloromethane, chloroform, etc.) for 0.5 to 10 hours. Thereafter, ethyl chlorocarbonate (1.0-1.5 equivalents) and triethylamine (1.0-1.5 equivalents) are added and an aprotic solvent (eg, diethyl ether, tetrahydrofuran, dimethylformamide, benzene, toluene, dichloromethane). In chloroform, etc.) for 0.5 to 10 hours. The reaction temperature is preferably 0 ° C to 100 ° C, particularly preferably 0 ° C to room temperature.
In the case of (3), thiophosgene (1.0 to 1.5 equivalents) is added to compound (II) and in an aprotic solvent (eg, diethyl ether, tetrahydrofuran, dimethylformamide, benzene, toluene, dichloromethane, chloroform, etc.) At 0.5 to 10 hours. The reaction temperature is preferably 0 ° C to 100 ° C, particularly preferably 0 ° C to room temperature.
In the case of (4), thiocarbonyldiimidazole (1.0 to 1.5 equivalents) is added to compound (II), and an aprotic solvent (for example, diethyl ether, tetrahydrofuran, dimethylformamide, benzene, toluene, dichloromethane, chloroform) Etc.) and stir for 0.5 to 10 hours. The reaction temperature is preferably 0 ° C to 100 ° C, particularly preferably 0 ° C to room temperature.
Examples of the compound represented by the formula (II) include aniline, 2-trifluoromethylaniline, 3-trifluoromethylaniline, o-anisidine, 3-dimethylamino-2-methylaminobenzene, 1-amino-3-fluoronaphthalene, 1-amino-4-fluoronaphthalene, 1-amino-5-fluoronaphthalene, 1-amino-6-fluoronaphthalene, 1-amino-7-fluoronaphthalene, 1-amino-3-chloronaphthalene, 1-amino-4 -Chloronaphthalene, 1-amino-5-chloronaphthalene, 1-amino-6-chloronaphthalene, 1-amino-7-chloronaphthalene, 1-amino-3-bromonaphthalene, 1-amino-4-bromonaphthalene, 1 -Amino-5-bromonaphthalene, 1-amino-6-bromonaphthalene, 1-amino 7-bromonaphthalene, 1-amino-3-methylnaphthalene, 1-amino-4-methylnaphthalene, 1-amino-5-methylnaphthalene, 1-amino-6-methylnaphthalene, 1-amino-7-methylnaphthalene, 1-amino-3-methoxynaphthalene, 1-amino-4-methoxynaphthalene, 1-amino-5-methoxynaphthalene, 1-amino-6-methoxynaphthalene, 1-amino-7-methoxynaphthalene, 1-amino-3 -Cyanonaphthalene, 1-amino-4-cyanonaphthalene, 1-amino-5-cyanonaphthalene, 1-amino-6-cyanonaphthalene, 1-amino-7-cyanonaphthalene, 1-amino-3-N, N- Dimethylaminonaphthalene, 1-amino-4-N, N-dimethylaminonaphthalene, 1-amino-5- (dimethyl) Ruamino) naphthalene, 1-amino-6- (dimethylamino) naphthalene, 1-amino-7- (dimethylamino) naphthalene, 1-amino-3-nitronaphthalene, 1-amino-4-nitronaphthalene, 1-amino- 5-nitronaphthalene, 1-amino-6-nitronaphthalene, 1-amino-7-nitronaphthalene, 1-amino-3-benzyloxynaphthalene, 1-amino-4-benzyloxynaphthalene, 1-amino-5-benzyl Oxynaphthalene, 1-amino-6-benzyloxynaphthalene, 1-amino-7-benzyloxynaphthalene, 1-amino-4- (2-pyridyl) naphthalene, 1-amino-5,6,7,8-tetrahydronaphthalene 1-amino-7-hydroxy-5,6,7,8-tetrahydronaphthalene, 4-amino No-benzodioxole, 5-amino-1,4-benzodioxan, 5-amino-3-isopropylisoxazole, 5-amino-3-t-butylisoxazole, 5-amino-3- (2-methylbutyl) -2-yl) isoxazole, 2-amino-4-tert-butylthiazole, 5-amino-3-tert-butyl-1-methylpyrazole, 5-amino-3- (2-methylbutyl-2-yl)- Examples thereof include 1-methylpyrazole.
Second Step To the isothiocyanate ester (isothiocyanate) of the compound represented by the formula (III), NH ₂ —CH ₂ C (R ² R ³ ) CH ₂ —OH (R ² and R ³ are synonymous with the above). It is a step of reacting to produce a compound represented by the formula (IV).
This step can be performed in an aprotic solvent (eg, diethyl ether, tetrahydrofuran, dimethylformamide, benzene, toluene, dichloromethane, chloroform, etc.).
The reaction temperature is preferably 0 ° C to 100 ° C, particularly preferably 0 ° C to room temperature, and the reaction time is preferably 0.5 hours to 10 hours.
NH ₂ —CH ₂ C (R ² R ³ ) CH ₂ —OH may be used in an amount of 1.0 to 1.5 equivalents relative to compound (III).
NH ₂ The _{^{-CH 2 C (R 2 R 3}} ) CH 2 -OH, 3- amino-2-methyl -2-n-propyl-propanol, 3-amino-2-isopropyl-2-methyl propanol, 3-amino 2-ethyl-2-n-propylpropanol, 3-amino-2-ethyl-2-isopropylpropanol, 3-amino-2-isopropyl-2-n-propylpropanol, 3-amino-2,2-di- n-propylpropanol, 3-amino-2,2-diisopropylpropanol, 3-amino-2,2-ethylenepropanol, 3-amino-2,2-trimethylenepropanol, 3-amino-2,2-tetramethylenepropanol 3-amino-2,2-pentamethylene propanol, 3-amino-2,2-hexamethylene propanol, 3- Examples include amino-2,2-heptamethylene propanol.
When R ² and R ³ are different, the carbon atom substituted by R ² and R ³ is an asymmetric carbon, and an optical isomer exists. As an example of a method for producing an optical isomer, i) a cyanoacetic acid derivative which is NC-C (R ² R ³ ) —COOH and an optically active amine derivative (for example, (1R, 2R)-(−)-2-amino Salt of -1-phenyl-1,3-propanediol, (1S, 2S)-(+)-2-amino-1-phenyl-1,3-propanediol, etc.) is purified by a method such as recrystallization. Step, ii) A method using a reduction reaction step with a hydride reagent (for example, LiAlH ₄ or the like) can be used.
Third Step This is a step for producing a compound represented by the formula (V) by ring-closing the compound represented by the formula (IV).
Examples of the ring closure method include (1) a method of treating with an alkyl halide in an alcohol, and (2) a method of treating with an alkyl halide in an alcohol and then treating with a base.
In the case of (1), methanol, ethanol or the like may be used as the alcohol, and the reaction may be performed at 0 ° C. to the solvent reflux temperature for 0.5 hour to 72 hours. As the alkyl halide, methyl iodide, ethyl iodide or the like may be used, and 0.5 to 3 equivalents may be used relative to compound (IV).
In the case of (2), iodomethane, iodoethane or the like may be used as the alkyl halide, and 0.5 to 3 equivalents may be used relative to compound (IV). Using methanol, ethanol, etc. as the alcohol, reacting at 0 ° C. to the reflux temperature of the solvent for 0.5 hours-72 hours, using sodium hydroxide, potassium hydroxide, etc. as the base, using methanol, ethanol, etc. as the alcohol, The reaction can be carried out at 0 ° C. to the reflux temperature of the solvent for 0.5 to 24 hours.
A compound represented by the fourth step formula (V), (wherein, ^{R 4} are as defined above, Hal is a halogen atom) ^{Hal-R 4} steps introduced to produce the compound of formula (I) It is.
In this step, (1) when R ⁴ is an optionally substituted aryl or an optionally substituted aryl, in the presence of a base (for example, sodium hydride, sodium hydroxide, potassium hydroxide, etc.) The reaction can be carried out by reacting a compound represented by Hal-R ⁴ (wherein R ⁴ is aryl which may be substituted or aryl which may be substituted). Using an aprotic solvent (for example, diethyl ether, tetrahydrofuran, dimethylformamide, benzene, toluene, dichloromethane, chloroform, etc.) as the solvent, the reaction is performed at 0 ° C. to the reflux temperature of the solvent for 0.5 hours to 72 hours. Can do.
(2) When R ⁴ is a formula: —C (═X) —Y—R ⁵ (wherein R ⁵ , X and Y are as defined above), a base (eg, triethylamine, pyridine, N, A compound represented by the formula: Hal-C (= X) -Y-R ⁵ (wherein R ⁵ , X and Y are as defined above, Hal is a halogen atom) in the presence of N-dimethylaminopyridine and the like). It can be performed by reacting. For example, an aprotic solvent (for example, diethyl ether, tetrahydrofuran, dimethylformamide, benzene, toluene, dichloromethane, chloroform, etc.) or the like is used as a solvent. The reaction can be carried out at a temperature of 0.5 to 10 hours.
In addition, carbon disulfide (CS ₂ ) is reacted in the presence of a base (eg, sodium hydride), and then an alkyl halide (eg, iodomethane, iodoethane, etc.) or an alkoxyalkyl halide (eg, chloromethyl methyl ether, etc.) ) Can also be obtained by reacting. In this case, an aprotic solvent (for example, diethyl ether, tetrahydrofuran, dimethylformamide, benzene, toluene, dichloromethane, chloroform, etc.) can be used as the solvent, and the reaction proceeds at 0 ° C. to room temperature.
In addition, when R ¹ , R ⁴ and R ⁵ have a group protected by a protecting group, alkylation can be performed after a) deprotection or b) deprotection.
Deprotection can be removed by the method described in Protective Groups in Organic Synthesis, Theodora W Green (John Wiley & Sons) and the like.
Alkylation is accomplished by reacting an alkyl halide (eg, iodomethane, iodoethane, etc.) or (alkoxycarbonyl) alkyl halide (eg, t-butoxycarbonylmethyl bromide, etc.) in the presence of a base (eg, sodium hydride, etc.). Obtainable. In this case, an aprotic solvent (for example, diethyl ether, tetrahydrofuran, dimethylformamide, benzene, toluene, dichloromethane, chloroform, etc.) can be used as the solvent, and the reaction can be performed at 0 ° C. to room temperature.
In addition, although the compound obtained at each process can be used for the next process as it is, if necessary, it can be purified by distillation, recrystallization, column chromatography or the like.

Examples of the pharmaceutically acceptable salt include basic salts such as alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; ammonium salt; trimethylamine salt, triethylamine salt and dicyclohexyl. Aliphatic amine salts such as amine salts, ethanolamine salts, diethanolamine salts, triethanolamine salts, brocaine salts; aralkylamine salts such as N, N-dibenzylethylenediamine; pyridine salts, picoline salts, quinoline salts, isoquinoline salts, etc. Heterocyclic aromatic amine salt; tetramethylammonium salt, tetraethylammonium salt, benzyltrimethylammonium salt, benzyltriethylammonium salt, benzyltributylammonium salt, methyltrioctylammonium salt, tetrabutylammonium Quaternary ammonium salts such as nium salts; basic amino acid salts such as arginine salts and lysine salts. Examples of the acid salt include inorganic acid salts such as hydrochloride, sulfate, nitrate, phosphate, carbonate, bicarbonate, perchlorate; acetate, propionate, lactate, maleate, Organic acid salts such as fumarate, tartrate, malate, citrate and ascorbate; sulfonates such as methanesulfonate, isethionate, benzenesulfonate and p-toluenesulfonate; Examples include acidic amino acids such as aspartate and glutamate.
Solvates include organic solvates that coordinate any number of organic solvent molecules and hydrates that coordinate any number of water molecules. The solvate means a solvate of the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof, for example, a monosolvate, a disolvate, a monohydrate, a dihydrate Thing etc. are mentioned.

The compound of the present invention is excellent in stability and pharmacokinetics (hHERG, CL, T _1/2 , BA, AUC, etc.), has low toxicity, and is used for the purpose of treatment or prevention for diseases involving cannabinoid receptor agonists. be able to. For example, Nature, 1993, 365, p. 61-65, states that cannabinoid receptor agonists have anti-inflammatory and analgesic effects, Journal of Cannabis Therapeutics. 2002, Vol. 2, No. 1, p. 59-71 describes that cannabinoid receptor agonists have bronchodilator activity and WO 03/035109 pamphlet has anti-pruritic activity.
That is, the compound of the present invention is an anti-inflammatory agent, antiallergic agent, analgesic agent, pain therapeutic agent (nociceptive pain therapeutic agent, neuropathic pain therapeutic agent, psychogenic pain therapeutic agent, acute pain therapeutic agent, chronic pain therapeutic agent. Agent), immunodeficiency treatment agent, immunosuppressant, immunomodulator, autoimmune disease treatment agent, rheumatoid arthritis treatment agent, multiple sclerosis treatment agent, airway inflammatory cell infiltration inhibitor, airway hypersensitivity inhibitor It can be used as a bronchodilator, a mucus secretion inhibitor, an anti-pruritic agent and the like.
In order to use the compound of the present invention for treatment, it is formulated as a usual preparation for oral or parenteral administration. The pharmaceutical composition containing the compound of the present invention can take a dosage form for oral and parenteral administration. That is, oral preparations such as tablets, capsules, granules, powders, syrups, or injection solutions or suspensions such as intravenous injections, intramuscular injections, subcutaneous injections, inhalants, eye drops, nasal drops, suppositories Or a parenteral preparation such as a preparation for transdermal administration such as an ointment or ointment.
These preparations can be produced using appropriate carriers, excipients, solvents, bases and the like known to those skilled in the art. For example, in the case of a tablet, the active ingredient and auxiliary ingredients are compressed or molded together. Auxiliary ingredients include pharmaceutically acceptable excipients such as binders (eg, corn starch), fillers (eg, lactose, microcrystalline cellulose, etc.), disintegrants (eg, sodium starch glycolate, etc.) ) Or a lubricant (for example, magnesium stearate) or the like is used. The tablet may be appropriately coated. In the case of liquid preparations such as syrups, solutions and suspensions, for example, suspending agents (for example, methylcellulose), emulsifiers (for example, lecithin), preservatives, and the like are used. In the case of an injectable preparation, it may be in the form of a solution, a suspension or an oily or aqueous emulsion, and these may contain a suspension stabilizer or a dispersing agent. When used as an inhaler, it is used as a liquid that can be applied to an inhaler, and when used as an eye drop, it is also used as a liquid or suspending agent.
The dose of the compound of the present invention varies depending on the administration form, patient's symptoms, age, body weight, sex, or concomitant drugs (if any), and ultimately depends on the judgment of a doctor. In the case of administration, 0.01-100 mg / kg body weight per day, preferably 0.01-10 mg, more preferably 0.1-10 mg, in the case of parenteral administration, 0.001-100 mg / kg body weight per day Preferably, 0.001 to 1 mg, more preferably 0.01 to 1 mg is administered. This may be divided into 1 to 4 times.

Hereinafter, the present invention will be described in detail with reference to examples. However, these are merely examples, and the present invention is not limited thereto.
Each abbreviation has the meaning shown below.
Me: methyl,
Et: ethyl,
DMF: N, N-dimethylformamide

１）５，５−ジイソプロピル−２−（３−トリフルオロメチルフェニルイミノ）ペルヒドロ−１，３−オキサジン（１）の合成
１−（３−ヒドロキシ−２，２−ジイソプロピルプロピル）−３−（３−トリフルオロメチルフェニル）チオウレア（１；０．６５ｇ）のメタノール（６ ｍＬ）溶液にヨウ化メチル（０．５６ ｍＬ）を加え、室温で４時間攪拌した。反応液を減圧濃縮して得られた残渣をメタノール（６ ｍＬ）で溶解し、氷冷化で水酸化カリウム（０．５０ ｇ）のメタノール（４ ｍＬ）溶液を加え、室温で３時間攪拌した。反応後、水（１５０ ｍＬ）を加え、ジクロロメタン（５０ ｍＬ）で２回抽出した。抽出液を無水硫酸マグネシウムで乾燥後、減圧濃縮して得られた結晶を再結晶（酢酸エチル／ｎ−ヘキサン）して５，５−ジイソプロピル−２−（３−トリフルオロメチルフェニルイミノ）ペルヒドロ−１，３−オキサジン（２；０．４９ ｇ、収率８３％）を無色結晶として得た。
融点：１０３〜１０４℃、
¹Ｈ−ＮＭＲ（ＣＤＣｌ₃）δｐｐｍ：0.97 (6H, d, J=6.9), 0.99 (6H, d, J=6.9), 1.90 (2H, sept, J=6.9), 3.23 (2H, s), 4.07 (2H, s), 7.13-7.50 (4H, m).
２）５，５−ジイソプロピル−３−［(メチルチオ)カルボニル］−２−（３−トリフルオロメチルフェニルイミノ）ペルヒドロ−１，３−オキサジン（I−５６）の合成
５，５−ジイソプロピル−２−（３−トリフルオロメチルフェニルイミノ）ペルヒドロ−１，３−オキサジン（２；０．２３ ｇ）とトリエチルアミン（０．１１ ｇ）のジクロロメタン（２ ｍＬ）溶液に、氷冷下でメチルクロロチオールホーメート（０．０９ ｍＬ）を加え、０℃で１時間攪拌した。反応後、水（８０ ｍＬ）を加え、ジエチルエーテル（１００ ｍＬ）で抽出した。抽出液を食塩水（８０ ｍＬ）で洗浄して無水硫酸マグネシウムで乾燥後、減圧濃縮して得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル：ｎ−ヘキサン：トリエチルアミン＝７：９２：１）で精製を行ない５，５−ジイソプロピル−３−［(メチルチオ)カルボニル］−２−（３−トリフルオロメチルフェニルイミノ）ペルヒドロ−１，３−オキサジン（I−５６；０．２４ ｇ、収率８５％）を無色油状物として得た。Example 1 Synthesis of 5,5-diisopropyl-3-[(methylthio) carbonyl] -2- (3-trifluoromethylphenylimino) perhydro-1,3-oxazine (I-56)

1) Synthesis of 5,5-diisopropyl-2- (3-trifluoromethylphenylimino) perhydro-1,3-oxazine (1) 1- (3-hydroxy-2,2-diisopropylpropyl) -3- (3 -Trifluoromethylphenyl) thiourea (1; 0.65 g) in methanol (6 mL) was added with methyl iodide (0.56 mL) and stirred at room temperature for 4 hours. The residue obtained by concentrating the reaction solution under reduced pressure was dissolved in methanol (6 mL), and a solution of potassium hydroxide (0.50 g) in methanol (4 mL) was added with ice cooling, followed by stirring at room temperature for 3 hours. . After the reaction, water (150 mL) was added and extracted twice with dichloromethane (50 mL). The extract is dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The crystals obtained are recrystallized (ethyl acetate / n-hexane) to give 5,5-diisopropyl-2- (3-trifluoromethylphenylimino) perhydro- 1,3-oxazine (2; 0.49 g, yield 83%) was obtained as colorless crystals.
Melting point: 103-104 ° C
¹ H-NMR (CDCl ₃ ) δ ppm: 0.97 (6H, d, J = 6.9), 0.99 (6H, d, J = 6.9), 1.90 (2H, sept, J = 6.9), 3.23 (2H, s), 4.07 (2H, s), 7.13-7.50 (4H, m).
2) Synthesis of 5,5-diisopropyl-3-[(methylthio) carbonyl] -2- (3-trifluoromethylphenylimino) perhydro-1,3-oxazine (I-56) To a solution of (3-trifluoromethylphenylimino) perhydro-1,3-oxazine (2; 0.23 g) and triethylamine (0.11 g) in dichloromethane (2 mL) was added methyl chlorothiolformate under ice-cooling. (0.09 mL) was added, and the mixture was stirred at 0 ° C. for 1 hr. After the reaction, water (80 mL) was added and extracted with diethyl ether (100 mL). The extract was washed with brine (80 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (ethyl acetate: n-hexane: triethylamine = 7: 92: 1). Purification was performed and 5,5-diisopropyl-3-[(methylthio) carbonyl] -2- (3-trifluoromethylphenylimino) perhydro-1,3-oxazine (I-56; 0.24 g, 85% yield) ) Was obtained as a colorless oil.

１）２−[３−（１，１−ジメチルプロピル）−５−イソオキサゾリルイミノ]−５，５−ペンタメチレンペルヒドロ−１，３−オキサジン（４）の合成
１−［３−（１，１−ジメチルプロピル）−５−イソオキサゾリル］−３−（３−ヒドロキシ−２，２−ペンタメチレンプロピル）チオウレア（３；１．０２ ｇ） のメタノール（１８ ｍＬ）溶液にヨウ化メチル（１．０３ ｍＬ）を加え、室温で３日間攪拌した。反応液を減圧濃縮して得られた残渣に飽和炭酸水素ナトリウム水溶液（６０ ｍＬ）を加え、酢酸エチル（１００ ｍＬ）で抽出した。抽出液を食塩水（８０ ｍＬ）で洗浄して無水硫酸マグネシウムで乾燥後、減圧濃縮して得られた結晶を洗浄（ジイソプロピルエーテル：ｎ−ヘキサン＝２：１）して２−[３−（１，１−ジメチルプロピル）−５−イソオキサゾリルイミノ]−５，５−ペンタメチレンペルヒドロ−１，３−オキサジン（４；０．５５ ｇ、収率６０％）を淡褐色結晶として得た。
融点：１９６．５〜１９８℃、
¹Ｈ−ＮＭＲ（ＣＤＣｌ₃）δｐｐｍ：0.81 (3H, t, J=7.6), 1.26 (6H, s), 1.49-1.65 (12H, m), 3.32 (2H, m), 4.12 (2H, s), 5.43 (1H, s).
２）２−[３−（１，１−ジメチルプロピル）−５−イソオキサゾリルイミノ]−３−［(メチルチオ)チオカルボニル］−５，５−ペンタメチレンペルヒドロ−１，３−オキサジン（Ｉ−５２）の合成
２−[３−（１，１−ジメチルプロピル）−５−イソオキサゾリルイミノ]−５，５−ペンタメチレンペルヒドロ−１，３−オキサジン（４；０．２１ ｇ）と二硫化炭素（０．０６５ ｍＬ）およびＤＭＦ（２．１ ｍＬ）の混合液に６０％水素化ナトリウム（０．０４２ ｇ）を氷冷化で加え、０℃で３０分間攪拌した後、ヨウ化メチル（０．０６５ ｍＬ）を氷冷下で加え、０℃で１時間攪拌した。反応液を氷水（８０ ｍＬ）に加え、ジエチルエーテル（１００ ｍＬ）で抽出した。抽出液を食塩水（８０ ｍＬ）で洗浄し、無水硫酸マグネシウムで乾燥後、減圧濃縮して得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル：ｎ−ヘキサン：トリエチルアミン＝７：９２：１）で精製して得られた結晶を再結晶（酢酸エチル／ｎ−ヘキサン）して２−[３−（１，１−ジメチルプロピル）−５−イソオキサゾリルイミノ]−３−［(メチルチオ)チオカルボニル］−５，５−ペンタメチレンペルヒドロ−１，３−オキサジン（Ｉ−５２；０．１７ ｇ、収率６０％）を黄色結晶として得た。
融点：１１７〜１１８℃。Example 2 2- [3- (1,1-Dimethylpropyl) -5-isoxazolylimino] -3-[(methylthio) thiocarbonyl] -5,5-pentamethyleneperhydro-1,3-oxazine Synthesis of (I-52)

1) Synthesis of 2- [3- (1,1-dimethylpropyl) -5-isoxazolylimino] -5,5-pentamethyleneperhydro-1,3-oxazine (4) 1- [3- ( 1,1-dimethylpropyl) -5-isoxazolyl] -3- (3-hydroxy-2,2-pentamethylenepropyl) thiourea (3; 1.02 g) in methanol (18 mL) with methyl iodide (1 0.03 mL) was added and stirred at room temperature for 3 days. Saturated aqueous sodium hydrogen carbonate solution (60 mL) was added to the residue obtained by concentrating the reaction solution under reduced pressure, and the mixture was extracted with ethyl acetate (100 mL). The extract was washed with brine (80 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to wash the crystals (diisopropyl ether: n-hexane = 2: 1) to give 2- [3- ( 1,1-dimethylpropyl) -5-isoxazolylimino] -5,5-pentamethyleneperhydro-1,3-oxazine (4; 0.55 g, 60% yield) was obtained as light brown crystals. It was.
Melting point: 196.5-198 ° C.
¹ H-NMR (CDCl ₃ ) δ ppm: 0.81 (3H, t, J = 7.6), 1.26 (6H, s), 1.49-1.65 (12H, m), 3.32 (2H, m), 4.12 (2H, s) , 5.43 (1H, s).
2) 2- [3- (1,1-Dimethylpropyl) -5-isoxazolylimino] -3-[(methylthio) thiocarbonyl] -5,5-pentamethyleneperhydro-1,3-oxazine ( Synthesis of I-52) 2- [3- (1,1-dimethylpropyl) -5-isoxazolylimino] -5,5-pentamethyleneperhydro-1,3-oxazine (4; 0.21 g ), Carbon disulfide (0.065 mL) and DMF (2.1 mL) were mixed with 60% sodium hydride (0.042 g) under ice-cooling and stirred at 0 ° C. for 30 minutes. Methyl iodide (0.065 mL) was added under ice cooling, and the mixture was stirred at 0 ° C. for 1 hr. The reaction mixture was added to ice water (80 mL) and extracted with diethyl ether (100 mL). The extract was washed with brine (80 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (ethyl acetate: n-hexane: triethylamine = 7: 92: 1). The crystal obtained by purification was recrystallized (ethyl acetate / n-hexane) to give 2- [3- (1,1-dimethylpropyl) -5-isoxazolylimino] -3-[(methylthio) thio. Carbonyl] -5,5-pentamethyleneperhydro-1,3-oxazine (I-52; 0.17 g, yield 60%) was obtained as yellow crystals.
Melting point: 117-118 ° C.

１）（Ｓ）−２−シアノ−２−イソプロピル吉草酸の合成
２−シアノ−２−イソプロピル吉草酸（５；７．６１ ｇ、４５ ｍｍｏｌ）のエタノール（２０ ｍＬ）溶液に（１Ｒ，２Ｒ）−（−）−２−アミノ−１−フェニル−１，３−プロパンジオール（７．５２ ｇ、４５ ｍｍｏｌ）のエタノール（５０ ｍＬ）の溶液を加えた。混合液を減圧濃縮し、得られた塩を水（６０ ｍＬ）から再結晶を行ない、（Ｓ）−２−シアノ−２−イソプロピル吉草酸の（１Ｒ，２Ｒ）−（−）−２−アミノ−１−フェニル−１，３−プロパン塩（４．３０ ｇ）を無色結晶として得た。
得られたＳ体の塩（４．０４ ｇ、１２ ｍｍｏｌ）を水（１５０ ｍＬ）に溶解し、濃塩酸（６ ｍＬ）で中和後、クロロホルム（１００ｍｌ）で２回抽出した。抽出液を０．５％塩酸（１００ｍｌ）で水洗し、無水硫酸マグネシウムで乾燥後、減圧濃縮して（Ｓ）−２−シアノ−２−イソプロピル吉草酸（６；２．００ ｇ）を無色結晶として得た。
融点：７２−７８℃、［α］_Ｄ＋３．５±０．４°

２）（Ｓ）−２−アミノメチル−２−イソプロピル−１−ペンタノール（７）の合成
リチウムアルミニウムヒドリド（０．７３ ｇ、１９ ｍｍｏｌ）のテトラヒドロフラン（１１ ｍＬ）懸濁液に（Ｓ）−２−シアノ−２−イソプロピル吉草酸（６；１．８６ ｇ、１１ ｍｍｏｌ）のテトラヒドロフラン（１１ ｍＬ）溶液を氷冷下で２５分間で滴下した。室温で１時間攪拌後、５５℃で３時間攪拌した。反応液に水（５ｍｌ）を氷冷下で１５分間で滴下した。析出した不溶物を除去し、減圧濃縮して得られた残渣にエタノール（４０ ｍＬ）を加え、再び析出した不溶物を除去した。減圧濃縮して得られた残渣をエーテル（４０ ｍＬ）で抽出し、抽出液を減圧濃縮して（Ｓ）−２−アミノメチル−２−イソプロピル−１−ペンタノール（７；１．１５ ｇ、収率：６６％）を無色油状物として得た。

３）（Ｓ）−Ｎ−（４−クロロ−１−ナフチル）−Ｎ’−（２−ヒドロキシメチル−２−イソプロピルペンチル）チオウレア（８）の合成
（Ｓ）−２−アミノメチル−２−イソプロピル−１−ペンタノール（７；１．１１ ｇ、７ ｍｍｏｌ）のジクロロメタン（７ ｍＬ）溶液に４−クロロ−１−ナフチルイソチオシアネート（１．５４ ｇ、７ ｍｍｏｌ）のジクロロメタン（７ ｍＬ）溶液を氷冷下で加え、室温で４時間攪拌した。反応液をシリカゲルカラムクロマトグラフィー（酢酸エチル／n-ヘキサン）で精製し、（Ｓ）−Ｎ−（４−クロロ−１−ナフチル）−Ｎ’−（２−ヒドロキシメチル−２−イソプロピルペンチル）チオウレア（８；１．６６ ｇ、収率：６３％）を無色結晶として得た。

４）（Ｓ）−２−（４−クロロ−１−ナフチル）イミノ−５−イソプロピル−５−プロピルペルヒドロ−１，３−オキサジン（９）の合成
（Ｓ）−Ｎ−（４−クロロナフチル）−Ｎ’−（２−ヒドロキシメチル−２−イソプロピルペンチル）チオウレア（８；０．７６ ｇ、２ ｍｍｏｌ）のメタノール（８ ｍＬ）溶液にヨウ化メチル（０．６２ ｍＬ、１０ ｍｍｏｌ）を加え、室温で３時間攪拌した。反応液を減圧濃縮し、得られた残渣をメタノール（６ｍＬ）で溶解し、氷冷化で水酸化カリウム（０．５６ｇ，１０ｍｍｏｌ）のメタノール（６ｍＬ）溶液を加え、室温で一夜攪拌した。反応後に水（１５０ｍＬ）を加え、クロロホルム（８０ ｍＬ）で２回抽出した。抽出液を無水硫酸マグネシウムで乾燥後、減圧濃縮して得られた結晶を再結晶（酢酸エチル／ｎ−ヘキサン）して（Ｓ）−２−（４−クロロ−１−ナフチル）イミノ−５−イソプロピル−５−プロピルペルヒドロ−１，３−オキサジン（９；０．３４ ｇ、収率：４９％、光学純度：９９％ｅｅ）を無色結晶として得た。

５）（Ｓ）-３−［（メチルチオ）チオカルボニル］−２−（４−クロロ−１−ナフチル）イミノ−５−イソプロピル−５−プロピルペルヒドロー１，３−オキサジン（Ｉ−２２５Ａ）の合成
（Ｓ）−２−（４−クロロ−１−ナフチル）イミノ−５−イソプロピル−５−プロピルペルヒドロ−１，３−オキサジン（９；０．２４ ｇ、０．７ ｍｍｏｌ）および二硫化炭素（０．０８ ｍＬ、１．４ ｍｍｏｌ）のＤＭＦ（３ ｍＬ）の溶液に６０％水素化ナトリウム（０．０６ ｇ、１．４ ｍｍｏｌ）を氷冷化で加え、０℃で３０分間攪拌した後、ヨウ化メチル（０．０９ ｍＬ、１．４ ｍｍｏｌ）を氷冷下で加え、０℃で１時間攪拌した。反応液を氷水（８０ｍＬ）に加え、ジエチルエーテル（１００ ｍＬ）で抽出した。抽出液を食塩水（８０ ｍｌ）で洗浄し、無水硫酸マグネシウムで乾燥後、減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル：ｎ−ヘキサン：トリエチルアミン＝７：９２：１）で精製し、得られた結晶を再結晶（ｎ−ヘキサン）して（Ｓ）-３−［（メチルチオ）チオカルボニル］−２−（４−クロロ−１−ナフチル）イミノ−５−イソプロピル−５−プロピルペルヒドロー１，３−オキサジン（Ｉ−２２５Ａ；０．１２ｇ、収率：３９％）を無色結晶として得た。
融点：１０３−１０５℃、［α］_Ｄ＋２３．５±１．０°
¹Ｈ−ＮＭＲ（ＣＤＣｌ₃）δｐｐｍ：0.88-0.99 (9H, m), 1.25-1.50 (4H, m), 1.87 (1H, sept, J=6.9), 2.65 (3H, s), 3.86 (1H, d, J=11.2), 3.99 (1H, d, J=11.2), 4.32 (1H, d, J=13.5), 4.43 (1H, d, J=13.5), 7.08 (1H, d, J=7.9), 7.48-7.62 (3H, m), 8.19-8.26 (2H, m)

上記と同様な方法を用いて、化合物Ｉ−１〜Ｉ−５１、Ｉ−５３〜Ｉ−５５、Ｉ−５７〜Ｉ−８１、Ｉ−８４、Ｉ−８５、Ｉ−９４〜Ｉ−Ｉ−１０５、Ｉ−１１３〜Ｉ−１１５、Ｉ−１１８〜Ｉ−２２５およびＩ−２２５Ｂを合成した。化合物Ｉ−８２、Ｉ−８３、Ｉ−８６〜Ｉ−９３、Ｉ−１０６〜Ｉ−１１２、Ｉ−１１６、Ｉ−１１７、およびＩ−Ａ１〜Ｉ−Ｂ９は、上記実施例と同様に合成することができる。構造式および物性は表１〜２６に示した。Example 3 Synthesis of (S) -2- (4-chloronaphthylimino) -5-isopropyl-5-propyl-3- (methylthio) carbonyl-1,3-oxazine (I-225A)

1) Synthesis of (S) -2-cyano-2-isopropylvaleric acid To a solution of 2-cyano-2-isopropylvaleric acid (5; 7.61 g, 45 mmol) in ethanol (20 mL) (1R, 2R) A solution of-(-)-2-amino-1-phenyl-1,3-propanediol (7.52 g, 45 mmol) in ethanol (50 mL) was added. The mixture was concentrated under reduced pressure, and the resulting salt was recrystallized from water (60 mL) to give (S) -2-cyano-2-isopropylvaleric acid (1R, 2R)-(−)-2-amino. -1-Phenyl-1,3-propane salt (4.30 g) was obtained as colorless crystals.
The obtained salt of S form (4.04 g, 12 mmol) was dissolved in water (150 mL), neutralized with concentrated hydrochloric acid (6 mL), and extracted twice with chloroform (100 ml). The extract was washed with 0.5% hydrochloric acid (100 ml), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give (S) -2-cyano-2-isopropylvaleric acid (6; 2.00 g) as colorless crystals. Got as.
Melting point: 72-78 ° C., [α] _D + 3.5 ± 0.4 °

2) Synthesis of (S) -2-aminomethyl-2-isopropyl-1-pentanol (7) To a suspension of lithium aluminum hydride (0.73 g, 19 mmol) in tetrahydrofuran (11 mL) (S)- A solution of 2-cyano-2-isopropylvaleric acid (6; 1.86 g, 11 mmol) in tetrahydrofuran (11 mL) was added dropwise over 25 minutes under ice cooling. After stirring at room temperature for 1 hour, the mixture was stirred at 55 ° C. for 3 hours. Water (5 ml) was added dropwise to the reaction solution over 15 minutes under ice cooling. The precipitated insoluble matter was removed, and ethanol (40 mL) was added to the residue obtained by concentration under reduced pressure to remove the precipitated insoluble matter again. The residue obtained by concentration under reduced pressure was extracted with ether (40 mL), and the extract was concentrated under reduced pressure to give (S) -2-aminomethyl-2-isopropyl-1-pentanol (7; 1.15 g, (Yield: 66%) was obtained as a colorless oil.

3) Synthesis of (S) -N- (4-chloro-1-naphthyl) -N ′-(2-hydroxymethyl-2-isopropylpentyl) thiourea (8) (S) -2-aminomethyl-2-isopropyl A solution of 4-chloro-1-naphthylisothiocyanate (1.54 g, 7 mmol) in dichloromethane (7 mL) was added to a solution of -1-pentanol (7; 1.11 g, 7 mmol) in dichloromethane (7 mL). The mixture was added under ice cooling and stirred at room temperature for 4 hours. The reaction solution was purified by silica gel column chromatography (ethyl acetate / n-hexane), and (S) -N- (4-chloro-1-naphthyl) -N ′-(2-hydroxymethyl-2-isopropylpentyl) thiourea. (8; 1.66 g, yield: 63%) was obtained as colorless crystals.

4) Synthesis of (S) -2- (4-chloro-1-naphthyl) imino-5-isopropyl-5-propylperhydro-1,3-oxazine (9) (S) -N- (4-chloronaphthyl) ) -N ′-(2-hydroxymethyl-2-isopropylpentyl) thiourea (8; 0.76 g, 2 mmol) in methanol (8 mL) was added methyl iodide (0.62 mL, 10 mmol). And stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was dissolved in methanol (6 mL). A solution of potassium hydroxide (0.56 g, 10 mmol) in methanol (6 mL) was added with ice cooling, and the mixture was stirred overnight at room temperature. After the reaction, water (150 mL) was added, and the mixture was extracted twice with chloroform (80 mL). The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The crystals obtained were recrystallized (ethyl acetate / n-hexane) to give (S) -2- (4-chloro-1-naphthyl) imino-5. Isopropyl-5-propylperhydro-1,3-oxazine (9; 0.34 g, yield: 49%, optical purity: 99% ee) was obtained as colorless crystals.

5) of (S) -3-[(methylthio) thiocarbonyl] -2- (4-chloro-1-naphthyl) imino-5-isopropyl-5-propylperhydro-1,3-oxazine (I-225A) Synthesis (S) -2- (4-Chloro-1-naphthyl) imino-5-isopropyl-5-propylperhydro-1,3-oxazine (9; 0.24 g, 0.7 mmol) and carbon disulfide 60% sodium hydride (0.06 g, 1.4 mmol) was added to a solution of (0.08 mL, 1.4 mmol) in DMF (3 mL) with ice cooling, and the mixture was stirred at 0 ° C. for 30 minutes. Thereafter, methyl iodide (0.09 mL, 1.4 mmol) was added under ice cooling, and the mixture was stirred at 0 ° C. for 1 hour. The reaction mixture was added to ice water (80 mL) and extracted with diethyl ether (100 mL). The extract was washed with brine (80 ml), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate: n-hexane: triethylamine = 7: 92: 1), and the obtained crystal was recrystallized (n-hexane) to give (S) -3- [ (Methylthio) thiocarbonyl] -2- (4-chloro-1-naphthyl) imino-5-isopropyl-5-propylperhydro-1,3-oxazine (I-225A; 0.12 g, yield: 39%) Was obtained as colorless crystals.
Melting point: 103-105 ° C., [α] _D + 23.5 ± 1.0 °
¹ H-NMR (CDCl ₃ ) δ ppm: 0.88-0.99 (9H, m), 1.25-1.50 (4H, m), 1.87 (1H, sept, J = 6.9), 2.65 (3H, s), 3.86 (1H, d, J = 11.2), 3.99 (1H, d, J = 11.2), 4.32 (1H, d, J = 13.5), 4.43 (1H, d, J = 13.5), 7.08 (1H, d, J = 7.9) , 7.48-7.62 (3H, m), 8.19-8.26 (2H, m)

Using methods similar to those described above, compounds I-1 to I-51, I-53 to I-55, I-57 to I-81, I-84, I-85, I-94 to I-I- 105, I-113 to I-115, I-118 to I-225 and I-225B were synthesized. Compounds I-82, I-83, I-86 to I-93, I-106 to I-112, I-116, I-117, and I-A1 to I-B9 were synthesized in the same manner as in the above examples. can do. Structural formulas and physical properties are shown in Tables 1 to 26.

Test examples of the compounds of the present invention are shown below.
Test Example 1 Human Cannabinoid Receptor Binding Inhibition Experiment As a human cannabinoid receptor, a membrane fraction of CHO cells in which CB1 or CB2 receptor was stably expressed was used. Prepared membrane preparation and test compound, and 38,000 dpm [ ³ H] CP55940 (final concentration 0.5 nM: PerkinElmer Life & Analytical Sciences) assay buffer (50 mM Tris-HCl containing 0.5% bovine serum albumin) Incubation was carried out in a buffer solution (pH 7.4), 1 mM EDTA, 3 mM MgCl ₂ ) at 25 ° C. for 2 hours. After incubation, filter with a glass filter treated with 1% polyethyleneimine, wash with 50 mM Tris-HCl buffer (pH 7.4) containing 0.1% BSA, and then determine the radioactivity on the glass filter with a liquid scintillation counter. It was. Nonspecific binding was measured in the presence of 10 μM WIN552122-2 (Cannabinoid receptor agonist described in US50881122, manufactured by Sigma), and the 50% inhibitory concentration (IC ₅₀ value) of the test compound against specific binding was determined. The Ki value of the test compound was calculated from the obtained IC ₅₀ value and the Kd value of [ ³ H] CP55940.

Test Example 2 CAMP Production Inhibition Experiment via Cannabinoid Receptor A test compound was added to CHO cells expressing human CB1 or CB2 receptor, incubated for 15 minutes, and then forskolin (final concentration 4 μM, SIGMA) was added. In addition, it was incubated for 20 minutes. After stopping the reaction by adding 1N HCl, the amount of cAMP in the supernatant was measured using Cyclic AMP kit (CIS bio international). The cAMP production by forskolin stimulation was set to 100% with respect to no forskolin stimulation, and the concentration (IC ₅₀ value) of the test compound exhibiting a 50% inhibitory action was determined.

Test Example 3 Inhibitory Effect on Formalin Noxious Stimulation in ICR Type Mice ICR type male mice (5 weeks old) were used for the experiment, and the inhibitory effect of the compound of the present invention on formalin noxious stimuli was examined. The test compound was dissolved in sesame oil and orally administered to mice 2 hours before formalin administration, and then formalin (2%, 20 μL) was subcutaneously administered to the right hind limb. In this experiment, measurement was performed for 30 minutes after formalin administration, and was divided into 5 minutes (first phase) immediately after formalin administration and 20 minutes (second phase) from 10 to 30 minutes. For the intensity of pain, the inhibitory effect of the test compound was measured using the total time of licking and biting behavior for the right hind limb as an index, and the ED ₅₀ value was calculated.

The results of Test Examples 1 to 3 are shown in Tables 27 to 32.

Formulation Examples Formulation Examples 1 to 10 shown below are merely examples, and are not intended to limit the scope of the invention. The term “active ingredient” means a compound of the present invention, a tautomer thereof, a prodrug thereof, a pharmaceutically acceptable salt thereof or a solvate thereof.
Formulation Example 1
Hard gelatin capsules are manufactured using the following ingredients:
dose
(Mg / capsule)
Active ingredient 250
Starch (dried) 200
Magnesium stearate 10
Total 460mg
Formulation Example 2
Tablets are manufactured using the following ingredients:
dose
(Mg / tablet)
Active ingredient 250
Cellulose (microcrystal) 400
Silicon dioxide (fume) 10
Stearic acid 5
665mg total
The ingredients are mixed and compressed into tablets each weighing 665 mg.
Formulation Example 3
An aerosol solution is prepared containing the following ingredients:
weight
Active ingredient 0.25
Ethanol 25.75
Propellant 22 (chlorodifluoromethane) 74.00
Total 100.00
The active ingredient and ethanol are mixed and this mixture is added to a portion of the propellant 22, cooled to -30 ° C and transferred to a filling device. The required amount is then fed into a stainless steel container and diluted with the remaining propellant. Attach the bubble unit to the container.
Formulation Example 4
A tablet containing 60 mg of active ingredient is prepared as follows:
Active ingredient 60mg
45mg starch
Microcrystalline cellulose 35mg
Polyvinylpyrrolidone (10% solution in water) 4mg
Sodium carboxymethyl starch 4.5mg
Magnesium stearate 0.5mg
Talc 1mg
150mg total
Active ingredients, starch, and cellulose are no. 45 mesh U.V. S. And mix well. An aqueous solution containing polyvinylpyrrolidone was mixed with the obtained powder, and the mixture was 14 mesh U.S. S. Pass through a sieve. The granules thus obtained were dried at 50 ° C. 18 mesh U.F. S. Pass through a sieve. No. 60 mesh U.S. S. Sodium carboxymethyl starch, magnesium stearate, and talc passed through a sieve are added to the granules, mixed and then compressed on a tablet press to obtain tablets each weighing 150 mg.
Formulation Example 5
Capsules containing 80 mg of active ingredient are prepared as follows:
Active ingredient 80mg
Starch 59mg
Microcrystalline cellulose 59mg
Magnesium stearate 2mg
Total 200mg
Mix the active ingredient, starch, cellulose and magnesium stearate; 45 mesh U.V. S. Through the sieve and filled into hard gelatin capsules 200 mg each.
Formulation Example 6
A suppository containing 225 mg of active ingredient is prepared as follows:
Active ingredient 225mg
Saturated fatty acid glyceride 2000mg
Total 2225mg
The active ingredient is No. 60 mesh U.S. S. And suspended in a saturated fatty acid glyceride that has been heated and melted to the minimum necessary. The mixture is then cooled in an apparent 2 g mold.
Formulation Example 7
A suspension containing 50 mg of active ingredient is prepared as follows:
Active ingredient 50mg
Sodium carboxymethylcellulose 50mg
Syrup 1.25ml
Benzoic acid solution 0.10ml
Fragrance q. v.
Dye q. v.
5ml in total with purified water
The active ingredient is No. 45 mesh U.V. S. And is mixed with sodium carboxymethylcellulose and syrup to give a smooth paste. Add the benzoic acid solution and perfume diluted with a portion of the water and stir. Then add a sufficient amount of water to the required volume.
Formulation Example 8
The intravenous formulation is manufactured as follows:
Active ingredient 100mg
Saturated fatty acid glyceride 1000ml
Solutions of the above components are usually administered intravenously to the patient at a rate of 1 ml per minute.
Formulation Example 9 A gel is prepared as follows:
Active ingredient 100mg
Isopropanol 500mg
Partially hydrophobized hydroxymethylcellulose 150mg
Purified water added for a total of 10,000 mg
The active ingredient is dissolved in isopropanol, added to the partially dispersed hydrophobized hydroxymethylcellulose, water is added, and the mixture is uniformly mixed with a stirrer to dissolve all ingredients.
Formulation Example 10 A droplet-dispersed ointment is produced as follows:
Active ingredient 100mg
Benzyl alcohol 400mg
Sorbitan sesquistearate 400mg
Liquid paraffin 500mg
White petrolatum 8600mg
Total 10,000mg
The active ingredient is dissolved in benzyl alcohol, added to a mixture of sorbitan sesquistearate, liquid paraffin, and white petrolatum, and mixed with a stirrer to prepare.

  The present inventors have found a 2-substituted imino-1,3-oxazine derivative having a strong cannabinoid receptor agonist activity and excellent stability and pharmacokinetics and a pharmaceutical composition containing the compound as an active ingredient.

Claims (11)

Formula (I):

Wherein R ¹ is an optionally substituted aryl or an optionally substituted heteroaryl;
R ² is C1-C6 alkyl, C2-C4 alkenyl, or C2-C4 alkynyl;
R ³ is C 1 -C 6 alkyl, C 2 -C 4 alkenyl, or C 2 -C 4 alkynyl; or R ² and R ³ together are optionally substituted with C 1 -C 4 alkyl containing adjacent carbon atoms 3 May form a 3-8 membered oxygenated heterocycle optionally substituted with a C1-C4 alkyl, containing a ˜8 membered cycloalkane or an adjacent carbon atom;
R ⁴ is an optionally substituted aryl, an optionally substituted heteroaryl, or a formula: —C (═X) —Y—R ⁵ , wherein R ⁵ is an optionally substituted C 1 -C 4 An alkyl, an optionally substituted C2-C4 alkenyl, or an optionally substituted C2-C4 alkynyl; X is an oxygen atom or a sulfur atom; Y is an oxygen atom or a sulfur atom) Compound, optically active form thereof, pharmaceutically acceptable salt thereof, or solvate thereof. R ⁴ is represented by the formula: —C (═X) —Y—R ⁵ , wherein R ⁵ is an optionally substituted C1-C4 alkyl or an optionally substituted C2-C4 alkenyl; X is an oxygen atom or The compound according to claim 1, an optically active form thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof. The compound according to claim 1, wherein R ² is C1-C4 alkyl, and R ³ is C1-C4 alkyl, an optically active form thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof. ^2. The compound according to claim 1, wherein R ² is C1-C4 alkyl, and R ³ is C1-C4 alkyl (wherein R ² and R ³ are not the same), optically active form thereof, and pharmaceutically acceptable salt thereof Or a solvate thereof. The compound according to claim 1, wherein R ² and R ³ together are a 5- to 7-membered cycloalkane optionally containing a C1-C4 alkyl containing an adjacent carbon atom, its optically active substance, its A pharmaceutically acceptable salt, or a solvate thereof. R ¹ may be substituted 1-naphthyl, optionally substituted 5,6,7,8-tetrahydro-1-naphthyl, optionally substituted 4-indanyl, optionally substituted 5 The compound according to claim 1, which is isoxazolyl, or optionally substituted 5-pyrazolyl, an optically active form thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof. R ¹ may be substituted with ¹ to 2 substituents selected from Substituent Group A 1-naphthyl, or may be substituted with 1 to 2 substituents selected from Substituent Group A Good 5,6,7,8-tetrahydro-1-naphthyl, 4-indanyl optionally substituted with 1 to 2 substituents selected from Substituent Group A, 1 selected from Substituent Group A 5-isoxazolyl optionally substituted with 2 substituents, or 5-pyrazolyl optionally substituted with 1 to 2 substituents selected from Substituent Group A;
Substituent group A: halogen atom, C1-C8 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo C1-C8 alkyl, C1-C6 alkoxy C1-C8 alkyl, C1-C6 alkylthio C1-C8 alkyl, C1-C6 Alkylamino C1-C8 alkyl, C3-C6 cycloalkyl, hydroxy, C1-C6 alkoxy, C2-C6 alkenyloxy, halo C1-C6 alkoxy, C1-C6 alkylthio C1-C6 alkoxy, C1-C6 alkoxy C1-C6 alkoxy, Carboxy C1-C6 alkoxy, C1-C6 alkoxycarbonyl C1-C6 alkoxy, cyano C1-C6 alkoxy, C1-C6 alkylthio, amino, mono (C1-C6 alkyl) amino, di (C1-C6 alkyl) amino, N-C1 -C6 Kill-aralkylamino, N-C1-C6 alkyl-arylamino, C1-C6 alkylcarbonylamino, C1-C6 alkylsulfonylamino, nitro, carboxy, C1-C6 alkylcarbonyl, C1-C6 alkoxycarbonyl, cyano, C1-C6 Alkylsulfonyloxy, phenyl, 2-pyridyl, phenoxy and benzyloxy;
The compound according to any one of claims 1 to 5, an optically active form thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof. The pharmaceutical composition which contains the compound in any one of Claims 1-7 as an active ingredient. The pharmaceutical composition according to claim 8, which is a pain therapeutic agent. A method for preventing or treating pain or pain, comprising administering the compound according to any one of claims 1 to 7, an optically active isomer thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof. Use of the compound according to any one of claims 1 to 7, an optically active isomer thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof for producing a prophylactic or therapeutic agent for pain or pain.