WO2006080284A1 - 2-substituted imino-1,3-oxazine derivative - Google Patents

Abstract

Disclosed are a 2-substituted imino-1,3-oxazine derivative having a cannabinoid receptor agonist effect, and a pharmaceutical composition containing such a compound as an active constituent. Specifically disclosed is a compound represented by the general formula (I) below, an optically active substance thereof, a pharmaceutically acceptable salt thereof, or a solvate of any one of them. (I) (In the formula, R1 represents an optionally substituted aryl or the like; R2 represents a C1-C6 alkyl or the like, R3 represents a C1-C6 alkyl or the like, or alternatively R2 and R3 may form a 3-8 membered cycloalkane together with an adjacent carbon atom which may be substituted by a C1-C4 alkyl; and R4 represents a group represented by the following formula: -C(=X)-Y-R5 (wherein R5 represents an optionally substituted C1-C4 alkyl or the like, X represents a sulfur atom or the like, and Y represents a sulfur atom or the like) or the like.)

Description

 2_Substituted imino _ 1,3_oxazine derivatives

 Technical field

 [0001] The present invention relates to a 2-substituted imino 1,3-years old xazine derivative having a cannapinoid receptor agonistic action and a pharmaceutical composition thereof.

 Background art

 [0002] Cannapinoids were discovered in 1960 as the main active substance of marijuana, and their actions are related to central nervous system effects (such as hallucinations, euphoria, and spatiotemporal perturbations), and peripheral cell system effects (immunosuppression). , Anti-inflammatory, analgesic action, etc.).

Later, anandamide and 2-arachidonolglycerol produced from arachidonic acid-containing phospholipids were discovered as endogenous cannapinoid receptor agonists. These endogenous agonists are known to express central nervous system effects and peripheral cell system effects. Furthermore, Non-Patent Document 1 reports the effects of anandamide on the cardiovascular system. As a cannapinoid receptor, a cannapinoid type 1 receptor was discovered in 1990 and found to be distributed in the central nervous system such as the brain, and its agonist suppresses the release of neurotransmitters and is central to hallucinations. It was very powerful to show the action. In 1993, the 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 and inflammatory cells, and It has been shown to exhibit inhibitory action, anti-inflammatory action, and analgesic action (Non-patent Document 2). Non-patent document 3 discloses that the cannapinoid receptor agonist Δ ⁹ -tetrahydrocannabinol and the like have a bronchodilator action. Furthermore, it has been disclosed that a cannapinoid receptor agonist has an antidepressant action (Patent Document 1) and an analgesic action (Patent Document 2). Patent Document 3, Patent Document 4, and Patent Document 5 disclose thiazine derivatives having cannapinoid receptor agonist activity.

 Patent Document 1: International Publication No. 03Z035109 Pamphlet

 Patent Document 2: Pamphlet of International Publication No. 02Z42248

Patent Document 3: Pamphlet of International Publication No. 01Z19807 Patent Document 4: International Publication No. 02Z072562 Pamphlet

 Patent Document 5: International Publication No. 03Z070277 Pamphlet

 Non-Patent Document 1: Hypertension 1997, 29th, p. 1204—12 10

 Non-Patent Document 2: Nature 1993, 365, p. 61-65

 Non-Patent Document 3: Journal of Cannabi s Therapeutics 2002, No. 2-1, p. 59—71

 Disclosure of the invention

 Problems to be solved by the invention

[0003] A compound having a cannapinoid receptor agonist action, particularly a compound having excellent stability and pharmacokinetics, and a pharmaceutical composition comprising the compound as an active ingredient

[0004] The present inventors have the following 2-substituted imino-1,3-oxazine derivatives having a strong cannapinoid receptor agonist action and excellent stability and pharmacokinetics, and the compounds as active ingredients. A pharmaceutical composition was found.

 That is, the present invention provides: 1) General formula (I):

 [Chemical 1]

(Wherein R ¹ may be substituted, aryl, or substituted, heteroaryl.

R ² is C1-C6 alkyl, C2-C4 alkenyl, or C2-C4 alkynyl;

R ³ is C1-C6 alkyl, C2-C4 alkenyl, or C2-C4 alkynyl; or

R ² and R ³ together are substituted with C1-C4 alkyl, containing adjacent carbon atoms. It may be substituted with a C1-C4 alkyl containing a 3-8 membered cycloalkane or an adjacent carbon atom, and may form a 3-8 membered oxygenated heterocycle. ;

R ⁴ is an optionally substituted aryl, an optionally substituted heteroaryl, or a formula: — C (= X) — Y— R ⁵ (where R ⁵ is an optionally substituted CI— C 4 Alkyl, substituted, optionally C2-C4 alkyl, or substituted, C2-C4 alkyl; X is an oxygen atom or sulfur atom; Y is an oxygen atom or sulfur atom) A compound represented by (group represented), an optically active isomer, a pharmaceutically acceptable salt thereof, or a solvate thereof,

2) R ⁴ is represented by the formula: — C (= X) — Y— R ⁵ (wherein R ⁵ is an optionally substituted CI—C4 alkyl, or may be a substituted C2—C4 alkyl). X is an oxygen atom or a sulfur atom; Y is a group represented by 1) a compound represented by 1), an optically active substance thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof,

3) 1 ^ is 1 to 4 alkyl, and R ³ is CI—C4 alkyl 1) or 2) The compound, its optically active compound, its pharmaceutically acceptable salt, or their solvent Japanese,

4) 1 ^ is 1 to 4 alkyl, and R ³ is CI—C4 alkyl (where R ² and R ³ are not the same) 1) or 2), the optically active compound thereof, A pharmaceutically acceptable salt thereof, or a solvate thereof,

5) Compounds according to 1) or 2), wherein R ² and R ³ together are adjacent carbon atoms, substituted with CI—C4 alkyl, and are 5- to 7-membered cycloalkanes , An optically active form thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof,

6) R ¹ is substituted !, may! /, Naphthyl, substituted !, may be tetrahydronaphthyl, optionally substituted indanyl, optionally substituted isoxazolyl, or substituted However, it is virazolyl, the compound according to any one of 1) to 5), its optically active substance, its pharmaceutically acceptable salt, or a solvate thereof,

7) 1 ^ optionally substituted 1-naphthyl, optionally substituted 5, 6, 7, 8-tetrahydro 1-naphthyl, optionally substituted 4 indanyl, optionally substituted 5 Isoxazolyl, or substituted and may be 5 pyrazolyl 1) to 5), a compound according to any one of the compounds, an optically active form thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof, 8 ¹ may be substituted with ¹ to 2 substituents selected from Substituent Group A ^1- naphthyl, substituted with 1 to 2 substituents selected from Substituent Group A Optionally substituted 5, 6, 7, 8-tetrahydro 1-naphthyl, optionally substituted with 1-2 substituents selected from substituent group A 4-indanyl, substituent group A force selected Substituted with 1 to 2 substituents, 5 isoxazolyl, or substituted with 1 to 2 substituents selected from Substituent Group A, and may be 5-pyrazolyl;

Substituent group A: Neurogenic atom, C1-C8 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo C1-C8 alkyl, C1-C6 alkoxy C1-C8 alkyl, C1-C6 alkylthio CI-C8 Alkyl, C1 C6 alkylamino C1 C8 alkyl, C3— C6 cycloalkyl, hydroxy, C1— C6 alkoxy, C2— C6 alkoxy, halo C 1 C6 alkoxy, CI— C6 alkylthio CI— C6 alkoxy, CI— C6 alkoxy C1 — C6 alkoxy, carboxy C1— C6 alkoxy, C1— C6 alkoxycarbole C1— C6 alkoxy, cyano C1— C6 alkoxy, C1— C6 alkylthio, amino, mono (CI— C6 alkyl) amide di (CI— C6 alkyl) ) N-CI-C6 alkyl aralkyl-containing N— C1 C6 alkyl-aryl containing C1 C6 alkyl carboamino, CI- C6 alkyl sulfo-amino Toro, carboxy, CI- C6 al kills carbonyl, CI- C6 alkoxycarbonyl - le, ShiaIri CI- C6 alkylsulfonyl - Ruokishi, Hue - Le, 2-pyridyl, phenoxy, and Benjiruokishi;

The compound according to any one of 1) to 5), an optically active form thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof,

 9) A pharmaceutical composition containing the compound according to any one of 1) to 8) as an active ingredient,

10) A pharmaceutical composition according to 8) which is an analgesic,

 11) A pharmaceutical composition according to 8) which is a pain therapeutic agent,

 12) The pharmaceutical composition according to 8), which is an antidepressant,

 13) Prevention or treatment of pain, pain, and Z or epilepsy characterized by administering the compound according to any one of 1) to 8), a pharmaceutically acceptable salt thereof, or a solvate thereof. Method,

14) 1) to 8 for producing a prophylactic or therapeutic agent for pain, pain, and Z or hemorrhoids ), An optically active form thereof, a pharmaceutically acceptable salt thereof, or use of a solvate thereof.

 The meaning of each term is explained below. In this specification, each term is used in a unified meaning, and is used in the same meaning whether 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, isoptinole, sec Butinole, t-butinole, n-pentinole, isopentinole, neo-pentinole, 2-methyl-2-butyl, n-hexyl, n-heptyl, n-octyl, n-noel, n-decyl and the like. Specific examples of straight-chain or branched alkyl having 1 to 8 carbon atoms are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec butyl, t-butyl, n-pentyl, Examples include isopentyl, neo pentyl, 2-methyl-2-butyl, n-xyl, n-ptyl, and n-octyl. Furthermore, specific examples of straight-chain or branched alkyl having 1 to 4 carbon atoms are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec butyl, and t-butyl.

“Alkoxyalkyl” includes the above “alkyl” substituted with 13 “alkoxy” below, 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 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 the following “alkylamino” and includes, for example, methylaminomethyl, 2-dimethylaminoethyl, 2-jetyl. And ruaminoethyl, 3-dimethylaminopropyl and the like. In particular, when a carbon number is specified, it means “alkylaminoalkyl” having a carbon number within the range.

“Alkylcarbo-laminoalkyl” includes the above-mentioned “alkyl” substituted with 1 to 3 of the following “alkylcarbo-lamino” and includes, for example, methylcarbolaminomethyl, 2 (ethylcarbolumino) ethyl, 2- (propyl) Carbo-Lamino) etil. In particular, when a carbon number is designated, it means “alkyl carboaminoalkyl” having a carbon number within the range.

 “Alkenyl” includes a linear or branched monovalent aliphatic hydrocarbon group having a specified number of carbon atoms having 1 to 3 double bonds, such as vinyl, 1 probe, and the like. , Aryl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 1,3-butenyl, 3-methyl-2-butenyl, 2,3-dimethyl-2-hexenyl, and the like. Specific examples of straight-chain or branched alkenyl having 2 to 6 carbon atoms are vinyl, 1-propenyl, allyl, isopropenyl, 1-butenyl, 2 butenyl, 3 butenyl, 2 Examples include pental, 1,3 butagel, and 3-methyl-2-butyr. Furthermore, specific examples of straight-chain or branched alkaryl having 2 to 4 carbon atoms are aralkyl, iso-probe, and 3-butyl.

 “Alkynyl” includes a straight-chain or branched monovalent aliphatic hydrocarbon group having 1 to 3 triple bonds and having a specified number of carbons, and examples thereof include ethynyl, propargyl and the like. . Specific examples of straight chain or branched alkynyl having 2 to 6 carbon atoms are preferred. In particular, specific examples of straight-chain or branched alkynyl having 2 to 4 carbon atoms are more preferred.

“Haloalkyl” means a group in which the above “alkyl” is substituted with 1 to 5 of the above “halogen atoms”, and examples thereof include chloromethyl, dichloromethyl, difluoromethyl, trifluoromethyl, chloroethyl (eg, 2-chloroethyl). And ethyl), dichloroethyl (eg, 1,2-dichloroethyl, 2,2-dichloroethyl), black propyl (eg, 2-chloropropyl, 3-chloropropyl) and the like. In particular, haloalkyls having 1 to 6 carbon atoms are preferred, such as chloromethyl, dichloromethyl, difluoromethyl, trifluoromethyl, 2-chloroethinole, 1,2 dichloroethinole, 2,2 dichloroethinole, 2 black mouth propinole, 3 The Rolopropyl is mentioned. In particular, when a carbon number is specified, it means “haloalkyl” having a carbon number within that range.

 “Cycloalkane” includes 3- to 10-membered cycloalkane, and examples thereof include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, and cyclooctane. Specific examples of preferred 3-8 membered cycloalkanes include cyclopentane, cyclohexane, cycloheptane, and cyclooctane. Furthermore, 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 a ring is specified, 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 cyclopropinole, cyclobutinole, cyclopentinole, cyclohexinole, cycloheptinole, cyclooctyl and the like. Specific examples of preferred cycloalkyl having 3 to 6 carbon atoms include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. In particular, when a carbon number is specified, it means “cycloalkyl” having a carbon number 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-octyloxy and the like. Can be mentioned. In particular, alkoxy having 1 to 6 carbon atoms is preferred. Specifically, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec butoxy, t-butoxy, n-pentyloxy, n-hexoxy Luoxy is mentioned. In particular, when a carbon number is specified, it means “alkoxy” having a carbon number within that range.

The alkell portion of “alkalkoxy” has the same meaning as the above “alkell”. Examples of the “alkyloxy” include buroxy, allyloxy, 2-butyroxy, 3-butenyloxy, 2-pentenyloxy, 5-pentenyloxy, 3-methyl-2-butyroxy, 2,3dimethyl-2-hexoxy and the like. In particular, alkoxy having 1 to 6 carbon atoms is preferred. Specifically, buroxy, allyloxy, 2 butenyloxy, 3 butenyloxy, 2 pentenyloxy, and 5 pentenyloxy. Xyl, 3-methyl-2-butenyloxy. In particular, when a carbon number is specified, it means “alkenyloxy” having a carbon number within the range.

 “Haloalkoxy” means a group in which the above “alkoxy” is substituted with 1 to 5 of the above “norogen atom”, and examples thereof include dichloromethoxy, difluoromethoxy, trifluoromethoxy, trifluoroethoxy (2 , 2, 2-trifluoroethoxy etc.). In particular, difluoromethoxy and trifluoromethoxy are preferred. In particular, when a carbon number is specified, it means “haloalkoxy” having a carbon number within that range.

 “Alkoxyalkoxy” includes the above “alkoxy” substituted with 1 to 3 of the above “alkoxy”, and includes, for example, methoxymethoxy, ethoxymethoxy, n-propoxymethoxy, isopropoxymethoxy, 1- Examples include methoxyethoxy and 2-methoxyethoxy. In particular, 1-methoxyethoxy and 2-methoxyethoxy are preferable. In particular, when a carbon number is specified, it means “alkoxyalkoxy” having a carbon number within the range of the number.

 “Alkylthioalkoxy” includes the above “alkoxy” substituted with 1 to 3 of the following “alkylthio” and includes, for example, methylthiomethoxy, ethylthiomethoxy, n-propylthiomethoxy, isopropylthiomethoxy, 1-methylthio. Examples include ethoxy and 2-methylthioethoxy. Particularly, 1-methylthioethoxy and 2-methylthioethoxy are preferable.

. In particular, when a carbon number is specified, it means “alkylthioalkoxy” having a carbon number within the range.

 “Carboxyalkoxy” means a group in which 1 to 3 carboxys are substituted on the above “alkoxy”, and examples thereof include 2-carboxyethoxy, 3-carboxypropoxy, 4-carboxybutoxy and the like. In particular, when a carbon number is specified, it means “carboxyalkoxy” having a carbon number within that range.

 The “cyanalkoxy” means a group in which 1 to 3 cyanos are substituted on the above “alkoxy”, and examples thereof include 2-cyanethoxy, 3-cyanpropoxy, 4-cyanoboxy and the like. In particular, when a carbon number is specified, it means “Cyanalkoxy” having a carbon number within that range.

The term “alkoxycarboalkoxy” means a group in which the above “alkoxy” is substituted with 1 to 3 of the following “alkoxycarbole”, for example, methoxycarboromethoxy, ethoxy Carbonylmethoxy, _n -propoxycarbonylmethoxy, isopropoxycarbonylmethoxy, n-butoxycarbonylmethoxy, isobutoxycarbonylmethoxy, sec-butoxycarbonylmethoxy, t-butoxycarbonylmethoxy, 2- (t-butoxycarbonyl) ethoxy, Examples include 2- (n-pentyloxycarbonyl) ethoxy, 2- (nxyloxycarbonyl) ethoxy, _n- ptyloxycarbonylmethoxy, _n- octyloxycarbonylmethoxy, and the like. In particular, t-butoxycarboromethoxy and 2- (t-butoxycarbonyl) ethoxy are preferable. In particular, when a carbon number is specified, it means “alkoxycarboxalkoxy” having a carbon number within that range.

 The alkyl part of “alkylthio” has the same meaning as the above “alkyl”. Examples of the “alkylthio” include methylthio, ethylthio, n-propylthio, isopropylthio n-butylthio, isobutylthio, sec-butylthio, t-butylthio, n-pentylthio, n xylthio and the like. In particular, straight chain or branched alkylthio having 14 carbon atoms is preferred. 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 the “mono (alkyl) amino” include methylamino, ethylamino, n-propylamino, isopropylamino and the like. In particular, methylamidoethylamino is preferable. In particular, when a number of carbons is specified, it means “mono (alkyl) amino” having a number of carbons within that range.

 The alkyl part of “di (alkyl) amino” is the same or different and is synonymous with the above “alkyl”. “Di (alkyl) amino” includes, for example, dimethylamino-containing ethylamino-containing propylmethylamino. In particular, dimethylamino-containing germanamino is preferred. In particular, when a carbon number is specified, it means “alkylamino” having a carbon number within that range.

The alkyl part of “N-alkyl-arylamino” has the same meaning as “alkyl” above, and the aryl part has the same meaning as “aryl” below. "N-alkyl-arylamino" Examples of the compound include N-methyl-phenol-containing N-ethyl-phenol-containing N—n-propyl-phenol-containing N-isopropyl-phenol-amino and the like. In particular, N-methyl-fluoroamino containing N-methyl-phenol is preferred. In particular, when a carbon number is specified, it means “N-alkyl-arylamino” having a carbon number within that 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-alkylalkylamino” include N-methyl-benzylamido-containing N-ethyl-benzylaminy-containing N-n-propylmonobenzylamido-N-isopropylmonobenzylamino. In particular, N-methyl-benzylamino-containing N-ethyl-benzylamino is preferable. In particular, when a carbon number is specified, it means “N-alkyl-alkylalkylamino” having a carbon number within the range.

 “Alkylcarbolamino” includes amino substituted with 1 to 2 of the following “alkylcarbole” and includes, for example, methylcarbolamido-ethylamidopropyl-carbonylcarbonylamino and the like. In particular, when a carbon number is specified, it means “alkylcarbonylamino” having a carbon number within that range.

 “Alkylsulfolamino” includes aminos substituted with 1 to 2 of the following “alkylsulfol”, and examples thereof include methylsulfol-aminoethylsulfolamino. In particular, when the number of carbon atoms is specified, it means “alkylsulfo-lumino” having a carbon number within the range of the number.

“Alkylcarbon” means a group in which the above “alkyl” is substituted on a carbocycle, such as methyl carbo yl, ethyl carbo ol, n-propyl carbo ol, isopropyleno levono renole, n— Butinorecanolé Boninole, Isobutinorecanolé Boninole, sec—Butinorecanolé Ninore, Tobutinorecanolé Boninole, n—Pentinorecanolé Boninole, n—Hexinorecanolé Boninole, n-Heptylcarbol , N-octylcarbol and the like. In particular, methylcarbonyl, ethylcarbonyl and the like are preferable. In particular, when the number of carbon atoms of “alkyl” is specified, it means “alkylcarbonyl” having “alkyl” in the range of the number of carbon atoms. “Alkoxycarbon” means a group in which the above “alkoxy” is substituted on a carbocycle, such as methoxycarbol, ethoxycarbol, n-propoxycarbol, isopropoxycarbonyl, _n -butoxy. Examples thereof include carbonyl, isobutoxycarbonyl, sec butoxycarbonyl, t-butoxycarbonyl, n-pentyloxycarbonyl, n-xyloxycarbonyl, n-ptyloxycarbonyl, n-octyloxycarbonyl and the like. In particular, methoxycarbol, ethoxycarbol and the like are preferable. In particular, when the number of carbon atoms of “alkoxy” is designated, it means “alkoxycarbol” having “alkoxy” having the number of carbon atoms within the range.

 “Alkylthiocarbol” means a group in which the above “alkylthio” is substituted on a carbocycle, such as methylthiocarbol, ethylthiocarbol, n-propylthiocarbonyl, isopropylthiocarbonyl, n-butylthiocarbonyl, Isobutylthiocanenopononole, sec butinorethiocanoleboninole, t-butinorenocanonobononire, n pentinorecananobononire, n Examples include luthiocarbol. In particular, methylthiocarbol, ethylthiocarbonyl and the like are preferable. In particular, when the number of carbon atoms of “alkylthio” is specified, it means “alkylthiocarbonyl” having “alkylthio” of carbon number within the range.

 The alkyl part of “alkylsulfol” has the same meaning as the above “alkyl”. Examples of “alkylsulfol” include methylsulfol, ethylsulfol and the like. In particular, when a carbon number is specified, it means “alkylsulfur” having a carbon number within that range.

 The alkylsulfol moiety of “alkylsulfuroxy” has the same meaning as the above “alkylsulfol”. Examples of “alkylsulfoxy-oxy” include methanesulfoloxy, ethanesulfonyloxy and the like. In particular, when a carbon number is specified, it means “alkylsulfonyloxy” having a carbon number within the range.

The “aryl” includes aryl having 614 carbon atoms, and examples thereof include phenol, naphthyl, 4-indanyl, 5, 6, 7, 8-tetrahydronaphthyl, anthryl, phenanthryl and the like. In particular, phenyl, naphthyl, 4 indanyl, 5, 6, 7, 8-tetrahydronaphthyl Is preferred.

 “Aralkyl” includes a group in which the above “alkyl” is substituted with the above “aryl”, and examples thereof include benzyl, ferroethyl (for example, 1-phenyl, 2-phenyl), propyl ( For example, 1-propylpropyl, 2-phenylpropyl, 3-phenylpropyl, etc.), naphthylmethyl (eg, 1-naphthylmethyl, 2-naphthylmethyl, etc.) and the like can be mentioned. In particular, benzyl and naphthylmethyl are preferable.

“Heteroaryl” includes a nitrogen atom, an oxygen atom, and a heteroaryl having 1 to 9 carbon atoms containing 1 to 4 Z or sulfur atoms, such as furyl (eg, 2 furyl, 3 furyl), Chaels (eg, 2 chails, 3 chaels), pyrrolyl (eg, 1 pyrrolyl, 2 pyrrolyl, 3 pyrrolyl), imidazolyl (eg, 1 imidazolyl, 2-imidazolyl, 4-imidazolyl), pyrazolyl (Eg, 1-pyrazolyl, 3 pyrazolyl, 4-virazolyl, 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 (eg, 2-oxazolyl, 4-oxazolyl, 5-oxa) Lyl), 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), pyridazyl (eg, 3-pyridazil, 4-pyridazil), pyrimidyl (eg, 2 pyrimidyl, 4 pyrimidyl) , 5 pyrimidyl), frazale (eg, 3 frazale), virazile (eg, 2 pyrajur), oxadiazole (eg, 1, 3, 4 oxadiazole, 2-il), 1,3 Benzodioxolyl, 1,4 Benzodioxal, Benzofuryl (eg 2 Benzo [b] furyl, 3 Benzo [b ] Frills, 4 benzo [b] furyl, 5-benzo [b] furyl, 6-benzo [b] furyl, 7-benzo [b] furyl), benzochel (e.g., 2 Benzo [b] Chael, 3 Benzo [b] Chael, 4 One Benzo [b] Chael, 5—Benzo [b] Chael, 6—Ven Zo [b] chael, 7-benzo [b] chael), benzimidazolyl (eg, 1-benzoimidazolyl, 2-benzoimidazolyl, 4-benzoimidazolyl, 5-benzozo) Imidazolyl), dibenzofuryl, benzo Oxazolyl, quinoxalyl (eg, 2 quinoxalinyl, 5 quinoxalinyl, 6 quinoxalinyl), cinnanol (eg, 3-cinnolyl, 4 cinnolyl, 5-cinnolyl, 6 cinnolyl, 7 cinnolyl, 8 cinnolyl), quinazolyl (eg 2 quinazolinyl, 4-quinazolinyl, 5-quinazolinyl, 6-quinazolinyl, 7-quinazolinyl, 8 quinazolyl), quinolyl (eg 2 quinolyl, 3 quinolyl, 4 quinolyl, 5 quinolyl) Noryl, 6 quinolyl, 7 quinolyl, 8 quinolyl), phthaladyl (eg, 1-phthaladyl, 5 phthaladur, 6 phthaladyl), isoquinolyl (eg, 1-isoquinolyl, 3-isoquinolyl, 4 isoquinolyl, 5-isoquinolyl, 6-isoquinolyl) 7-isoquinolyl, 8-isoquinolyl), prill, pute Diethyls (eg, 2 pteridinyl, 4 pteridyl, 6-pteridyl, 7-pteridyl), carbazolyl, phenanthridinyl, attalizyl (eg, 1-atarizinole, 2-atarizyl-) Nore, 3—Atarid-Nore, 4—Ataridiz-Nore, 9 Ataridizil), Indrill (eg 1 Indrill, 2 Indrill, 3 Indrill, 4 Indrill, 5—Indrill, 6—Indrill, 7—Indrill), Isoindrill , Phenyl (eg, 1 phenadyl, 2-phenadyl), or phenothiazole (eg, 1 phenothiazyl, 2 phenothiazyl, 3 phenothiazyl, 4 phenothiazine). .

 “Oxygen-containing heterocycle” refers to a non-aromatic heterocycle of 3 to 8 members containing only one or two oxygen atoms as a heteroatom, and includes oxolan, oxetane, oxolan, dioxolan, oxan , Dioxane, oxepane, oxocan and the like. In particular, oxolan, oxan, and oxepane are preferable.

The “non-aromatic heterocyclic group” includes a nitrogen atom, an oxygen atom, and a non-aromatic ring having 1 to 9 carbon atoms containing 1 to 4 Z or sulfur atoms, such as 1 pyrrolinyl, 2 pyrrolinyl, 3 pyrrolinyl, pyrrolidino, 2 pyrrolidyl, 3 pyrrolidyl, 1 imidazolinyl, 2 — imidazolyl, 4 — imidazolyl, 1 — imidazolidyl, 2 — imidazolidyl, 4 — imidazolidinyl, 1 — virazolinyl, 3-Virazolinyl, 4-Virazolinyl, 1-Virazolidyl, 3-Virazolidyl, 4-Virazolidyl, Piperidino, 2 Piperidyl, 3 Piperidyl, 4-Piperidyl, Piperazin-containing 2 Piperazinyl, 2 Morpholinyl, 3 Morpholinyl , Morpholino, tetrahydrobiral and the like. In particular, morpholino, pyrrolidino, Piperidino-filled piperazino is preferred.

 The aryl part of “aryloxy” has the same meaning as the above “aryl”. “Aryloxy” includes, for example, phenoxy, naphthoxy (eg, 1-naphthoxy, 2-naphthoxy, etc.), anthrinoreoxy (eg, 1-anthrinoleoxy, 2-anthrinoleoxy, etc.), phenol, etc. And trinoreoxy (for example, 1-phenanthrinoreoxy, 2-phenanthrinoreoxy, etc.). 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.

 “Aryl carboamino” includes amino substituted with 1 to 2 of the following “aryl carbo”, and includes, for example, naphthyl carbolamino (for example, 1 naphthyl carboamiami 2). —Naphthylcarbolumino) and the like. In particular, when a carbon number is specified, it means “aryl carbonamino” having a carbon number within that range.

The aryl part of “aryl reel” has the same meaning as the above “aryl”. Examples of “arylsulfol” include phenylsulfol, naphthylsulfol (eg, 1-naphthylsulfol, 2-naphthylsulfol) and the like. In particular, when a carbon number is specified, it means “arylsulfonyl” having a carbon number within the range of “optionally substituted alkyl”, “optionally substituted alkyl”, “substituted” Optionally substituted alkyl "," optionally substituted aryl "," optionally substituted heteroaryl "," optionally substituted 1 naphthyl "," optionally substituted 5, 6, 7, 8-tetrahydro-1-naphthyl ”,“ optionally substituted 4-indanyl ”,“ optionally substituted 5-isoxolyl ”,“ optionally substituted 5-pyrazolyl ”,“ substituted ” In the case where “non-aromatic heterocyclic group” or “substituted, or aryloxy” has a substituent, an arbitrary position is substituted with 1 to 4 substituents which are the same or different from each other. May be In particular, when the number of carbons is specified, it means a group that includes the number of carbons within the range. Examples of the substituent include a halogen atom (fluorine atom, chlorine atom, bromine atom, iodine atom), CI—C6 alkyl (eg, methyl, ethyl, isopropyl, t-butyl, etc.), C 2 -C6 alkenyl ( For example, bur etc.), C2-C6 alkyl (eg Etul), halo CI-C6 alkyl (eg CF, CH CF, CH CC1, etc.), CI-C6 alkoxy

 3 2 3 2 3

C1-C6 alkyl (eg 2-methoxyethyl, 2-ethoxyethyl), CI-C6 alkylthio C1 C6 alkyl (eg 2-methylthioethyl, 2-ethylthioethyl), CI-C6 alkylamino CI-C6 alkyl (eg 2-dimethyl) Aminoethyl, 2-jetylaminoethyl, etc.), C3-C6 cycloalkyl (eg, cyclopropyl, cyclopentyl, cyclohexyl, etc.), aryl (eg, phenol, etc.), heteroaryl (eg, 2-pyridyl, etc.) Etc.), hydroxy, CI—C6 alkoxy (eg, methoxy, ethoxy, propoxy, butoxy, etc.), C2—C6 alkoxy (eg, aryloxy, etc.), halo CI—C6 alkoxy (eg, difluoromethoxy, trifluoro) Romethoxy etc.), CI—C6 alkylthio C1 C6 alkoxy (eg 2-methylthioe) ), Aralkyloxy (eg, benzyloxy, etc.), CI—C6 alkoxy CI—C6 alkoxy (eg, 2-methoxyethoxy, 2 ethoxyethoxy, etc.), carboxy C1 C6 alkoxy (eg, 2 carboxyethoxy, etc.), C1 — C6 alkoxycarbole C1— C6 alkoxy (eg, 2 ethoxycarbo ethoxy), cyano C1—C6 alkoxy (eg, 2—cyanethoxy), aryloxy (eg, phenoxy), CI—C6 alkylsulfo-loxy ( For example, methylsulfo-loxy, etc.), C1 C6 alkylthio (eg, methylthio, ethylthio, etc.), carboxy, C1 C6 alkylcarbole (eg, methylcarbonyl, ethylcarbole, etc.), C1-C6 alkoxycarbole (eg, For example, methoxycarbonyl, ethoxycarbonyl, t- C1-C6 alkylamino (for example, methylamino, dimethylamido-demethylamino), CI-C6 alkylcarbolumino (for example, methylcarbolamino), C1 C6 alkylsulfo-lamino (for example, methylsulfo-) Lumino, etc.), nitro, sheared formyl, oxo, aralkyl (eg, benzyl, etc.), non-aromatic heterocyclic groups (eg, morpholine-containing piperidino, etc.), aryl carboluminos (eg, phenylsulfo-luamino, etc.) ), Azide, C1-C6 alkylcarbolumino CI-C6 alkyl (eg, 2-methylcarbolumino) Ethyl), CI C6 alkylthiocarbol (for example, methylthiocarbol, etc.), mercapto, alkylsulfol (for example, methylsulfol), and arylsulfol (for example, phenolsulfol), etc. Can be mentioned.

 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.

 Of the compounds represented by the formula (I), compounds having the following preferred substituents are particularly preferred, and examples thereof include compounds.

As R ¹ , an optionally substituted phenyl, an optionally substituted 1 naphthyl, an optionally substituted 5, 6, 7, 8-tetrahydro-1 naphthyl, an optionally substituted 4 indanyl, a substituted Preference is given to 5-isoxazolyl or, if substituted, 5-pyrazolyl. 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 to 2 substituents selected from the substituent group represented by the substituent group A are preferable.

Substituent group A: Neurogenic atom, C1-C8 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo C1-C8 alkyl, C1-C6 alkoxy C1-C8 alkyl, C1-C6 alkylthio CI-C8 Alkyl, C1 C6 alkylamino C1 C8 alkyl, C3— C6 cycloalkyl, hydroxy, C1— C6 alkoxy, C2— C6 alkoxy, halo C 1 C6 alkoxy, CI— C6 alkylthio CI— C6 alkoxy, CI— C6 alkoxy C1 — C6 alkoxy, carboxy C1— C6 alkoxy, C1— C6 alkoxycarbole C1— C6 alkoxy, cyano C1— C6 alkoxy, C1— C6 alkylthio, amino, mono (CI— C6 alkyl) amide di (CI— C6 alkyl) ) N-CI-C6 alkyl aralkyl-containing N— C1 C6 alkyl-aryl containing C1 C6 alkyl carboamino, CI- C6 alkyl sulfo-amino Toro, carboxy, CI- C6 al kills carbonyl, CI- C6 alkoxycarbonyl - le, ShiaIri CI- C6 alkylsulfonyl - Ruokishi, Hue - Le, 2-pyridyl, phenoxy, and Benjiruokishi.

Furthermore, 1 to 2 substituents selected by the substituent power represented by the substituent group B are more preferred. That's right.

Substituent group B: halogen atom, C1 C8 alkyl, halo CI—C8 alkyl, hydroxy, C 1 C6 alkoxy, di (CI—C6 alkyl) amidonitro, and cyan.

Preferably, R ² and R ³ are the same and are C2-C3 alkyl, or differently one is C2-C4 alkyl and the other is C1 C4 alkyl.

The C1-C4 alkyl containing the adjacent carbon atom in which R ² and R ³ are joined together may be substituted. Examples of the 3-8 membered cycloalkane of the 3-8 membered cycloalkane include the following groups: It is done. The cycloalkane may be substituted with 1 to 4 C1-C4 alkyl. The substituent is preferably methyl or ethyl.

[Chemical 2]

特に、以下に示す R²及び R³が一緒になつ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。

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

[Chemical 3]

R ⁴ is preferably represented by the formula: 1 C (= X) —Y—R ⁵ , particularly 1 C (= 0) —S—CH 2, 1 C (

 Three

= S) -S-CH, 1 C (= 0) — S— C H, 1 C (= S) — S— C H, 1 C (= 0) — S

 3 2 5 2 5

— CH 2 CH = CH or one C (= S) —S 2 —CH 2 CH = CH is preferred.

 2 2 2 2

R ⁴ may be substituted or aryl, and may be substituted, but the substituent is preferably trifluoromethyl or -tro.

R ⁴ may be substituted or heteroaryl may be substituted or pyridyl Preferred as the substituent is trifluoromethyl or -tro.

 The invention's effect

 [0009] A compound having a cannapinoid receptor agonist action, particularly a 2-positioned amino-1,3-oxazine derivative excellent in activity, stability and internal kinetics, is also useful as a pharmaceutical because of its high safety.

 BEST MODE FOR CARRYING OUT THE INVENTION

[0010] The compound according to the present invention can be produced by the following steps with reference to WO01Z19807 and WO02Z072562. The structural formulas of formulas (I) to (V) indicate racemic bodies or optically active bodies.

 [Chemical 4]

R ¹

 (IV)

 (V) (I)

(Wherein R ¹ may be substituted, aryl, or substituted, heteroaryl.

R ² is C1-C6 alkyl, C2-C4 alkenyl, or C2-C4 alkynyl;

R ³ is C1-C6 alkyl, C2-C4 alkenyl, or C2-C4 alkynyl; or

R ² and R ^{3 taken} together include a C1-C4 alkyl containing a C1-C4 alkyl optionally containing a C1-C4 alkyl, or a C1-C4 alkyl containing a C-C4 alkyl containing an adjacent carbon atom. May be substituted to form a 3-8 membered oxygenated heterocycle;

R ⁴ is an optionally substituted aryl, an optionally substituted heteroaryl, or the formula:

— C (= X) — Y— R ⁵ (where R ⁵ is an optionally substituted CI—C 4 alkyl, substituted Or a C2-C4 alkyl, or a substituted C2-C4 alkyl; X is an oxygen atom or a sulfur atom; Y is an oxygen atom or a sulfur atom) )

1st process

 In this step, the amino group of the compound represented by the formula (Π) is converted to an isothiocyanate (isothiocyanate) to produce the compound represented by the formula (ΠΙ).

 The conversion method from an amino group to an isothiocyanate (isothiocyanate) includes (

I) In the presence of bases such as ammonia (NH, NH OH) triethylamine (Et N)-

3 4 3

Dithiol rubamide obtained by the action of carbon sulfide (CS) is converted into ketyl carbonate (C

 2

 ICO Et), a method of treating with triethylamine (Et N), (2) the dithiocarbamate

twenty three

A method of treating selenium with a metal salt such as lead nitrate, and (3) a method of using thiophosgene (CSC1)

 2

And (4) a method of reacting thiocarbodiimidazole.

 In the case of (1), a base (1.0 to 1.5 equivalents) and carbon dioxide (1.0 to 1.5 equivalents) are combined with a compound (

In addition to II), the mixture is stirred for 0.5 to 10 hours in an aprotic solvent (for example, jetyl ether, tetrahydrofuran, dimethylformamide, benzene, toluene, dichloromethane, chloroform, etc.). Thereafter, ketyl carbonate (1.0 to 1.5 equivalents) and triethylamine (1.0 to 1.5 equivalents) are added, and an aprotic solvent (eg, jetyl ether, tetrahydrofuran, dimethylformamide) is added. , Benzene, toluene, dichloromethane, 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 the compound (II) and an aprotic solvent (for example, jetyl ether, tetrahydrofuran, dimethylformamide, benzene, toluene, etc.). The mixture is stirred for 0.5 to 10 hours in (Ruen, dichloromethane, black mouth form, etc.). The reaction temperature is preferably 0 ° C to 100 ° C, particularly preferably 0 ° C to room temperature.

In the case of (4), thiocarbodiimidazole (1.0 to 1.5 equivalents) is added to the compound (Π) and an aprotic solvent (eg, jetyl ether, tetrahydrofuran, dimethylformamide, benzene, toluene, Stir in dichloromethane, chloroform, etc.) for 0.5-10 hours. The reaction temperature is preferably 0 ° C to 100 ° C, particularly preferably o ° c to room temperature. Compounds represented by the formula (II) include aline, 2-trifluoromethylaline, 3-trifluoro Fluoromethylaniline, o-anisidine, 3 dimethylamino-2-methylaminobenzene, 1-amino-1 fluoronaphthalene, 1-amino-1 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 bu-monaphthalene, 1 amino-3-methylnaphthalene, 1 amino-4-methylnaphthalene, 1-amino 5-methylnaphthalene, 1-amino-6-me Lunaphthalene, 1-amino-1-7-methylnaphthalene, 1-amino-3-methoxynaphthalene, 1-amino-4-methoxynaphthalene, 1-amino-5-methoxynaphthalene, 1-amino-6-methoxynaphthalene, 1-amino-7-methoxynaphthalene, 1 Amino-3 cyananophthalene, 1 amino-4-cyanononphthalene, 1 amino-5 cyananophthalene, 1 amino-6 cyananophthalene, 1 amino no 7 cyananophthalene, 1 amino 3—N, N dimethylamino naphthalene, 1 amino no 4 — N, N Dimethylaminonaphthalene, 1-Amino-5- (Dimethylamino) naphthalene, 1-Amino-6- (Dimethylamino) naphthalene, 1-Amino-1- 7- (Dimethylamino) naphthalene, 1 Amino-3 ditronaphthalene, 1 Amino 4-12 Tronaphthalene, 1 Amino-5 Nito Naphthalene, 1 amino-6 ditronaphthalene, 1 amino-7 ditronaphthalene, 1 amino-3 benzyloxynaphthalene, 1 amino-4 monobenzyloxynaphthalene, 1 amino-5 benzyloxynaphthalene, 1 amino-6 benzyloxynaphthalene , 1-amino-1-benzyloxynaphthalene, 1-amino-4- (2-pyridinole) naphthalene, 1 amino-5, 6, 7, 8-tetrahydronaphthalene, 1 amino-7 hydroxy 5, 6, 7, 8— Tetrahydronaphthalene, 4 Amino-benzodioxol, 5-Amino-1,4 monobenzodioxane, 5-Amino-3-isopropylisoxazole, 5-Amino-3-tert-butylisoxazole, 5 Amino-3 — (2-Methylbutyl 2-yl) isoxazole, 2 amino-4-tert-butylthiazole, 5 amino-3 t— Chill -1-methyl Vila tetrazole, 5-amino-3- (2-Mechirubuchiru 2 I le) 1-methyl-pyrazole, and the like. Second step

NH ³ —CH ² C ³ (R ² R ³ ) CH ² —OH (R ² and R ³ are synonymous with the above) is reacted with the isothiocyanate ester (isothiocyanate) of the compound represented by the formula (ΠΙ), and the formula Indicated by (IV)

2 2 2

This is a process for producing a compound.

 This step can be performed in an aprotic solvent (for example, jetyl ether, tetrahydrofuran, dimethylformamide, benzene, toluene, dichloromethane, black mouth form, etc.).

 The reaction temperature is preferably 0 ° C to 100 ° C, and the reaction time is particularly preferably o ° c to room temperature, and is preferably 0.5 hours to 10 hours.

NH ² —CH ² C ³ (R ² R ³ ) CH—OH is used in an amount of 1.0 to 1.5 equivalents relative to compound (III).

2 2 2

That's fine.

NH ² —CH ² C ³ (R ² R ³ ) CH—OH includes 3-amino-2-methyl-2-n-propyl

2 2 2

1-propanol, 3-amino-2-isopropyl-2-methylpropanol, 3-amino-2-ethyl-2-aminopropyl, 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-1,2,2 ethylenepropanol, 3 amino-1,2,2 trimethylenepropanol, 3 amino-2,2-tetramethylenepropanol, 3 amino-2,2 pentame Tylene propanol, 3 amino-2,2 hexamethylene propanol, 3 amino-2,2 heptamethylene propanol and the like can be mentioned.

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. Examples of optical isomer production methods include: i) NC-C (R ² R ³ ) -COOH cyanoacetic acid derivatives and optically active amine derivatives (eg (1R, 2R) — (1) 2 —Amino 1 (Ii) 1,3 propanediol, (IS, 2S) — (+) — 2 Amino 1 phenol 1,3 propanediol, etc.) Use a method based on a reduction reaction step with a hydride reagent (for example, L1A1H, etc.)

 Four

be able to.

3rd process In this step, the compound represented by the formula (IV) is cyclized to produce the compound represented by the formula (V).

 Examples of the ring-closing method include (1) a method of treating with an alcohol in an alcohol, and an alkylide and a ride, and (2) a method of treating with an alkylno and a ride in an alcohol and then a base.

 In the case of (1), methanol, ethanol or the like is used as the alcohol, and the reaction may be performed at 0 ° C. to the solvent reflux temperature for 0.5 to 72 hours. Methyl iodide, ethyl iodide and the like may be used as the alkyl halide, and 0.5 to 3 equivalents may be used relative to compound (IV).

 In the case of (2), it is sufficient to use 0.5 to 3 equivalents of the compound (IV) by using odomethane, odoethane or the like as the alkyl halide. Methanol, ethanol, etc. are used as alcohol, and reaction is carried out at 0 ° C. to the reflux temperature of the solvent for 0.5 hours to 72 hours. Then, sodium hydroxide, potassium hydroxide, etc. are used as bases, and methanol, ethanol, etc. are used as alcohols. Use

The reaction can be carried out at 0 ° C. to the reflux temperature of the solvent for 0.5 to 24 hours.

4th process

In this step, Hal—R ⁴ (wherein R ⁴ is as defined above and Hal is a halogen atom) is introduced into the compound represented by the formula (V) to produce the compound represented by the formula (I).

In this step, (1) R ⁴ may be substituted, aryl or substituted, and in the case of aryl, a base (for example, sodium hydride, sodium hydroxide, potassium hydroxide, potassium hydroxide) Etc.) in the presence of Hal-R ⁴ (wherein R ⁴ is an optionally substituted aryl or optionally substituted V, aryl). Use an aprotic solvent (eg, jetyl ether, tetrahydrofuran, dimethylformamide, benzene, toluene, dichloromethane, black mouth form, etc.) as the solvent, and 0.5 to 72 hours at 0 ° C to the reflux temperature of the solvent. The reaction can be performed.

(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, N-dimethylaminopyridine etc.) in the presence of the formula: Hal—C (= X) —Y—R ⁵ (where R ⁵ , X and Y are as defined above, Hal is a halogen atom) The reaction can be carried out by reacting the compound. For example, an aprotic solvent (e.g., diethyl ether, tetrahydrofuran, dimethylformamide, benzene, toluene, dichloromethane) may be used according to the usual N-acylation conditions. The reaction can be carried out at 0 ° C to 100 ° C for 0.5 to 10 hours.

 Also, react with carbon dioxide (CS 2) in the presence of a base (for example, sodium hydride).

Then, it can also be obtained by reacting an alkyl halide (for example, odomethane, odoethane, etc.) or an alkoxyalkyl halide (for example, chloromethyl methyl ether). In this case, an aprotic solvent (for example, jetyl ether, tetrahydrofuran, dimethylformamide, benzene, toluene, dichloromethane, chloroform, etc.) can be used as the solvent, and the reaction proceeds from o ° c to room temperature.

In addition, when R ¹ R ⁴ and R ⁵ have a group protected by a protecting group, a) deprotection or b) deprotection can be followed by alkylation.

 jtefesi i, Protective Groups in Organic Synthesis, Theodora W Green (John Wiley & Sons) and the like.

 Alkylation is carried out in the presence of a base (for example, sodium hydride) in the presence of an alkylno, a ride (for example, odomethane, odoethane, or the like) or an (alkoxycarbon) alkyl halide (for example, t-butoxycarbonylmethyl bromide). It can be obtained by reacting. In this case, an aprotic solvent (for example, jetyl ether, tetrahydrofuran, dimethylformamide, benzene, toluene, dichloromethane, black mouth form, etc.) can be used as the solvent, and the reaction is performed at 0 ° C to room temperature. be able to.

 The compound obtained in each step can be used as it is in the next step, and can be purified by distillation, recrystallization, column chromatography or the like if necessary.

Examples of pharmaceutically acceptable salts include basic salts such as alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as calcium salts and magnesium salts; ammonium salts; trimethylamine salts. , Triethylamine salts, dicyclohexylamine salts, ethanolamine salts, diethanolamine salts, triethanolamine salts, aliphatic amine salts such as brocaine salts; aralkylamine salts such as Ν, Ν-dibenzylethylenediamine; pyridine salts, picoline Heterocyclic aromatic amine salts such as salts, quinoline salts, isoquinoline salts; tetramethyl ammonium salt, tetraethyl ammonium salt, benzyltrimethyl ammonium salt, benzyltriethyl ammonium salt, benzyltributyl Ammo salt, methyl trioctyl ammo Quaternary ammonium salts such as chlorinated salts and tetraptyl ammonium salts; and basic amino acid salts such as arginine salts and lysine salts. Examples of acidic salts 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, kenate, and ascorbate; sulfonates such as methanesulfonate, isethionate, benzenesulfonate, and P-toluenesulfonate And 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. Solvate means a solvate of a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, for example, monosolvate, disolvate, monohydrate, dihydrate. Thing etc. are mentioned.

 The compound of the present invention has stability and pharmacokinetics (hHERG, CL, T, BA, AUC, etc.)

 1/2

It can be used for the treatment or prevention of diseases that are superior and have low toxicity and involve cannapinoid receptor agonists. For example, in Nature 1993, Vol. 365, p. 61-65, the cannapinoid receptor agonist has anti-inflammatory and analgesic effects, and the Journal of Cannabis Thera peutics) 2002, No. 2-1, p. 59-71, that the cannapinoid receptor agonist has an effect of expanding the trachea, and WO 03Z035109 has an antidepressant action The effect is described.

 That is, the compound of the present invention is an anti-inflammatory agent, antiallergic agent, analgesic agent, pain treatment agent (invasive pain treatment agent, neuropathic pain treatment agent, psychogenic pain treatment agent, acute pain treatment agent, chronicity Pain treatment, etc.), immunodeficiency treatment, immunosuppressant, immunomodulator, autoimmune disease treatment, rheumatoid arthritis treatment, multiple sclerosis treatment, airway inflammatory cell infiltration inhibitor, airway hypersensitivity It can be used as an hyperinhibitory agent, bronchodilator, mucus secretion inhibitor, antidepressant, 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, tablets, capsules, granules, powders, syrups, etc. Parenterals such as orally administered preparations, or solutions for injection such as intravenous injection, intramuscular injection, and subcutaneous injection, suspensions, inhalants, eye drops, nasal drops, suppositories, ointments, etc. It can also be a dosage formulation.

 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 tablets, the active ingredient and auxiliary ingredients are compressed or molded together. Auxiliary ingredients include pharmaceutically acceptable excipients such as binders (e.g. corn starch), fillers (e.g. latatoses, microcrystalline cellulose etc.), disintegrants (e.g. starch glycolic acid). Sodium) 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, etc. are used. In the case of injectable preparations, they may be in the form of solutions, suspensions or oily or aqueous emulsions, which may contain suspension stabilizers or dispersants. When used as an inhaler, it is used as a solution that can be applied to an inhaler, and when used as an eye drop, it is also used as a solution or suspending agent. The dose of the compound of the present invention varies depending on the administration form, patient symptom, age, body weight, sex, or concomitant drug (if any), and is ultimately left to the judgment of the doctor. For oral administration, per day per kg body weight: 0.01 to: LOOmg, preferably 0.01 to 10 mg, more preferably 0.1 to: LOmg, for parenteral administration, per kg body weight, 0.001 to 10 Omg per day, preferably 0.001 to 1 mg, more preferably 0.01 to 1 mg is administered. This should be divided into 1 to 4 doses.

[0013] Hereinafter, the present invention will be described in detail with reference to examples, but these are merely examples, and the present invention is not limited thereto.

 Each abbreviation has the meaning shown below.

 Me: Mechinole,

 Et:

 DMF: N, N-dimethylformamide

 Example

[0014] Example 1 5,5-diisopropyl-3-[(methylthio) carbol]-2-- (3-trifl) Synthesis of olomethylfeu-rimino) perhydro 1,3-oxazine (I 56)

[Chemical 5]

1) Synthesis of 5, 5 Diisopropyl 1- (3 (Trifluoromethyl Fe-Rimino) Perhydro 1,3 Oxazine (1)

 1— (3 Hydroxy-1,2,2 diisopropylpropyl) 3— (3 Trifluoromethyl phenol) thiourea (1; 0.665 g) in methanol (6 mL) with methyl iodide (0.56 mL) The mixture was further 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. did. 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 resulting crystals are recrystallized (ethyl acetate Zn-hexane) to give 5,5 diisopropyl-2- (3-trifluoromethylphenol-mino). Perhydro 1,3-oxazine (2; 0.49 g, yield 83%) was obtained as colorless crystals.

Melting point: 103-104 ° C

 — NMR (CDC1) δ ppm: 0.97 (6H, d, J = 6.9), 0.99 (6H, d, J = 6.9), 1.90 (2H, sep

 Three

t, J = 6.9), 3.23 (2H, s), 4.07 (2H, s), 7.13-7.50 (4H, m).

 2) 5, 5 Diisopropyl— 3 [(Methylthio) carbol] — 2— (3 Trifluoromethyl leumino) perhydro 1,3-oxazine (I 56)

5, 5 Diisopropyl-1-2- (3 trifluoromethylfeu-rimino) perhydro-1,3-oxazine (2; 0.23 g) and triethylamine (0.11 g) in dichloromethane (2 mL) Methylchlorothiolformate (0.09 mL) was added to the solution under ice-cooling, and the mixture was stirred at 0 ° C for 1 hr. After the reaction, water (80 mL) was added and extracted with jetyl ether (100 mL). The extract was washed with brine (80 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography (ethyl acetate: n-hexane: triethylamine = 7:92: Purified in 1) 5,5 Diisopropyl 3 [(methylthio) carbol] -2- (3 trifluoromethylfeurimino) perhydro 1,3oxazine (I 56; 0.24 g, yield 85 %) As a colorless oil.

Example 2 2- [3— (1,1 dimethylpropyl) -5isoxazolylimino] 3 [(methylthio) thiocarbonyl] 5,5 pentamethylene perhydro-1,3 oxazine (I 52) Composition

[Chemical 6]

 1-52

1) Synthesis of 2- [3- (1, 1-dimethylpropyl) -5 isoxazolylimino] 5, 5 pentamethylene perhydro-1,3oxazine (4)

1— [3— (1, 1-Dimethylpropyl) -5-isoxazolyl] — 3— (3 Hydroxy-2,2 pentamethylenepropyl) thiourea (3; 1.02 g) in methanol (18 mL) Methyl iodide (1.03 mL) was added, and the mixture was stirred at room temperature for 3 days. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution (60 mL) was added to the residue, 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) and 2- [3- (1,1-dimethylpropyl) -5-isoxazolylimino] 5,5 pentamethylene perhydro-1,3oxazine (4; 0.55 g, Yield 60%) was obtained as light brown crystals.

Melting point: 196.5-198. C,

 NMR (CDC1) δ ppm: 0.81 (3H, t, .1 = 7.6), 1.26 (6H, s), 1.49-1.65 (12H, m),

 Three

 3.32 (2H, m), 4.12 (2H, s), 5.43 (1H, s).

 2) 2— [3- (1,1 Dimethylpropyl) 5 isoxazolylimino] 3 [(Methylthio) thiocarbol] —5,5 Pentamethylene perhydro-1,3oxazine (1-52) Synthesis of

 2— [3- (1,1 dimethylpropyl) 5 isoxazolylimino] 5,5 pentamethylene perhydro-1,3oxazine (4; 0.21 g) and carbon disulfide (0.065 mL) And 60% sodium hydride (0.042 g) was added to a mixture of DMF (2.1 mL) with ice cooling, stirred at 0 ° C for 30 minutes, and then methyl iodide (0.065 mL). ) 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 jetyl ether (100 mL). The extract was washed with brine (80 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography (ethyl acetate: n-hexane: triethylamine = 7: 92: 1 ) And then recrystallize (ethyl acetate Zn—hexane) to give 2- [3— (1,1 dimethylpropyl) -5isoxazolylimino] 3 — [(methylthio) thio Carbonyl] 5,5 pentamethylene perhydro-1,3-oxazine (1-52; 0.17 g, yield 60%) was obtained as yellow crystals.

Melting point: 117-118 ° C.

Example 3 Synthesis of (3) -2- (4-Chloronaphthylimino) -5-isopropyl-5-propyl-3 (methylthio) carbolulu 1,3 oxazine (I 225A)

[Chemical 7]

1) Synthesis of (S) 2-cyan 2-isopropylvaleric acid

 2 Cyan 2 Isopropylvaleric acid (5; 7.61 g, 45 mmol) in ethanol (20 mL) in (1R, 2R) — (—) — 2 amino 1-phenol 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), and (S) -2 cyano-2-isopropylvaleric acid (1R, 2R) — (—) — 2 amino 1— Ferreux 1,3 propane salt (4.30 g) was obtained as colorless crystals.

 The obtained salt of the S form (4.04 g, 12 mmol) was dissolved in water (150 mL), neutralized with concentrated hydrochloric acid (6 mL), and extracted twice with black mouth form (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-isopropyl valeric acid (6; 2.00 g) as colorless crystals. Got as.

Melting point: 72-78. C, [α] + 3.5 ± 0.4 °

 D

 2) Synthesis of (S) 2 aminomethyl-2-isopropyl 1 pentanol (7)

Lithium aluminum hydride (0.73 g, 19 mmol) in tetrahydrofuran (11 mL) in a suspension of (S) —2 cyano-2-isopropylvaleric acid (6; 1.86 g, ll mmol) in tetrahydrofuran (11 mL) The solution 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. Precipitated Solvent 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 obtain (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 Black 1-naphthyl) N,-(2 Hydroxymethyl 2-isopropylpropyl) thiourea (8)

 (S) —2 aminomethyl-2-isopropyl-1-1-pentanol (7; 1.11 g, 7 mm ol) in dichloromethane (7 mL) with 4 chloro-1 naphthinoreisothiocyanate (1.54 g, 7 mmol) in dichloromethane (7 mL) was cooled under ice-cooling and stirred at room temperature for 4 hours. The reaction solution was purified by silica gel column chromatography (ethyl acetate Zn-hexane), and (S) -N- (4 1-naphthyl) N,-(2 hydroxymethyl-2-isopentylpentyl) 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-1,3oxazine (9)

 (S) -N- (4 Black naphthyl) N,-(2 Hydroxymethyl-2-isopropylbenzyl) thiourea (8; 0.76 g, 2 mmol) in methanol (8 mL) in methyl iodide (0.62 mL, 10 mmol) was added 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 overnight at room temperature. Stir. After the reaction, water (150 mL) was added, and the mixture was extracted twice with black mouth form (80 mL). The extract is dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The crystals obtained are recrystallized (ethyl acetate Zn—hexane) to give (S) —2 -— (4-Naphthinole) imino 5 Isopropyl 5 propinolepenolehydro 1,3 oxazine (9; 0.34 g, yield: 49%, optical purity: 99% ee) was obtained as colorless crystals.

 5) Synthesis of (S) -3 [(Methylthio) thiocarbol] -2- (4-chloro-1-naphthyl) imino-5 isopropyl 5 propylperhydro-1,3-oxazine (I-225A)

(S)-2- (4—Black mouth 1-naphthyl) imino 5—Isopropyl 1-5 propyl perhydro 1,3 oxazine (9; 0. 24 g, 0.7 mmol) and carbon disulfide (0.08 mL) , 1.4 mmol) in DMF (3 mL) was added 60% sodium hydride (0.06 g, 1.4 mmol) with ice-cooled water, stirred at 0 ° C for 30 min, Methyl chloride (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 resulting residue was purified by silica gel column chromatography (ethyl acetate: n-hexane: triethylamine = 7: 92: 1), and the resulting crystals were recrystallized (n-hexane) to give (S) -3 [(Methylthio) thiocarbonyl] 2- (4 1-naphthinole) imino 5 isopropyl 5 propyl perhydro-1,3-oxazine (I-225A; 0.12 g, yield: 39%) as colorless crystals Obtained.

Melting point: 103-105. C, [α] + 23.5 ± 1.0 °

 D

NMR (CDC1) δ ppm: 0.88-0.99 (9Η, m), 1.25-1.50 (4H, m), 1.87 (IH, sept,

 Three

 J = 6.9), 2.65 (3H, s), 3.86 (IH, d, J = 11.2), 3.99 (IH, d, J = 11.2), 4.32 (IH, d, J = 13.5), 4.43 (IH, d , J = 13.5), 7.08 (IH, d, J = 7.9), 7.48-7.62 (3H, m), 8.19-8.26 (2H, m) Using a method similar to the above, compound I—1-1— 51, I 53-1 55, I 57-1 81, 1-84, 1-85, 1-94 to G 1-105, 1-113 to G 115, I-118 to G 225 and I-225B did. 1-82, 1-83, 1-86 to 93, 1-106 to 112, I-116, I 117, and 1-8-1 to 9 are It can be synthesized in the same way. The structural formula and physical properties are shown in Tables 1-26.

[table 1]

[Table 2]

[Table 3]

[Table 4]

[Table 5]

[Table 6]

[Table 7]

[Table 8]

[Table 9]

[Table 10]

[Table 11]

[Table 12]

14]

[Table 13]

14]

[Table 15]

[Table 16] 8.4),

 J = 6.3 m), 1.81- = 8.4), J = 7.6 2.13-2.02 d J =

8.4), J = 7.6 d, J =

[Table 17]

[Table 18]

[Table 19]

[Table 20]

IS

.6600C / 900Zdf / X3d 080 / 900Z OAV (3H, t, q, (2H, s),

= 8.2), 3.92

[Table 22]

[Table 23]

[Table 24]

[Table 25]

[Table 26] Compound

 Structural formula Melting point. Optical rotation and N M R

J=13.5), 4.43 (1H, d, J=13.5), 7.08 (1H， d,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,

1-225 108-110 J = 7.9), 7.48-7.62 (3H, m), 8.19-8.26 (2H, m)

 Me No Me [a] D + 23.5 ± 1. O ° 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),

I- s ^ s' ^Me 7.08 (1H, d, J = 7.9), 7.48-7.62 (3H, m), 8.19-

225A 103-105 8.26 (2H, m)

 Me [a] D— 43. 1 ± 0. 8 °

 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,

I- s _s ' ^Me J = 13.5), 4.43 (1H, d, J = 13.5), 7.08 (1H, d,

225B 72-76 J = 7.9), 7.48-7.62 (3H, m), 8.19-8.26 (2H, m) Test examples of the compounds of the present invention are shown below.

Test Example 1 Human cannapinoid receptor binding inhibition experiment

As a human cannapinoid receptor, a membrane fraction of CHO cells stably expressing CB1 or CB2 receptor was used. Prepared membrane preparation and test compound, and 38,000 dpm [ ³ H] CP55940 (final concentration 0.5 nM: PerkinElmer Life & Analytical Sciences) with Atsy buffer (50 mM Tris-HC1 containing 0.5% bovine serum albumin) Incubation was performed at 25 ° C for 2 hours in a buffer solution (pH 7.4), 1 mM EDTA, 3 mM MgCI). After incubation, 1

2

 Filter with a glass filter treated with 1% polyethyleneimine, wash with 50 mM Tris-HC1 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 M WIN55212-2 (Cannapinoid receptor antigen described in US5081 122, Sigma), and 50% inhibitory concentration (IC value) of the test compound for specific binding. ) The Ki value of the test compound was obtained

 50

It was calculated from the obtained IC value and the Kd value of [ ³ H] CP55940.

 50

Test Example 2 cAMP production inhibition experiment via cannapinoid receptor

A test compound was added to CHO cells expressing human CB1 or CB2 receptor, incubated for 15 minutes, and then incubated for 20 minutes with the addition of forskolin (final concentration 4 M, SIGMA). After stopping the reaction by adding IN HC1, the amount of cAMP in the supernatant was determined. Measurement was performed using Cyclic AMP kit (CIS bio international). The concentration of cAMP (IC value) exhibiting a 50% inhibitory effect was determined by setting cAMP production upon stimulation with forskolin as 100% against no stimulation with forskolin.

 50

Test Example 3 Inhibitory effect on noxious formalin stimulation in ICR mice

 ICR male mice (5 weeks of age) were used in the experiment, and the inhibitory effect of the compound of the present invention on formalin noxious stimulation 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 L) 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 immediately after formalin administration (phase 1) and 20 minutes from 10 to 30 minutes (phase 2). The intensity of pain was measured by measuring the inhibitory effect of the test compound using the total time of liking and biting behavior on the right hind limb as an index.

 Five

A zero value was calculated.

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

[Table 27]

6ξ

f / 13d ^ 81080/9001 ΟΛ \ [Table 28]

[Table 29]

m

19

.6600C / 900Zdf / X3d 080 / 900Z OAV

£ 9

00Zdf / X3d 080 / 900Z OAV [Table 31]

[表 32]

[Table 32]

製剤例

Formulation example

 Formulation examples 1- shown below: L0 is merely illustrative and is not intended to limit the scope of the invention in any way. 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 / capsenore)

 Active ingredient 250

 Starch (dried) 200

 Magnesium stearate

 Total 460mg

Formulation Example 2 Tablets are manufactured using the following ingredients:

 Dose

 (mg / tablet)

 Active ingredient 250

 Cellulose (microcrystal) 400

 Diacid-key element (Fume) 10

 Stearic acid 5_

 Total 665mg

 The ingredients are mixed and compressed into tablets each weighing 665 mg.

Formulation Example 3

 An aerosol solution is prepared containing the following ingredients:

 MM. _

 Active ingredient 0.25

 Ethanore 25. 75

 Propellant 22 (Chlorodifluoromethane) 74. 00

 Total 100.00

 Mix the active ingredient and ethanol, place the mixture in a portion of propellant 22, cool to -30 ° C, and transfer to a filling device. Then feed the required amount into a stainless steel container and dilute 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

 Starch 45mg

 Microcrystalline cellulose d5mg

 Polyburpyrrolidone (10% solution in water) 4mg

 Sodium carboxymethyl starch 4.5mg

 Magnesium stearate 0.5mg

Talc Img _ 150mg total

 The active ingredient, starch, and cellulose are sifted through a No. 45 mesh U.S. sieve and mixed thoroughly. The aqueous solution containing polybulurpyrrolidone is mixed with the resulting powder and then the mixture is passed through a No. 14 mesh U.S. sieve. The granules thus obtained are dried at 50 ° C and passed through a No. 18 mesh U.S. sieve. Sodium carboxymethyl starch, magnesium stearate, and talc passed through a No. 60 mesh U.S. sieve in advance are added to the granules, mixed, and compressed by a tableting machine 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

 A

 O doo B I 200mg

 The active ingredient, starch, cellulose, and magnesium stearate are mixed and passed through a No. 45 mesh U.S. sieve to fill 200 mg of hard gelatin capsules. 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

 Pass the active ingredient through a No. 60 mesh U.S. sieve and suspend in saturated fatty acid glycerides that have 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 0.1 ml

 Material q. V.

 Dye q. V.

 Add purified water and total 5ml

 The active ingredient is sieved through No. 45 mesh U.S. and mixed with sodium carboxymethyl cellulose and syrup to form a smooth paste. Add benzoic acid solution and fragrance diluted with a portion of water and stir. Next, add a sufficient amount of water to the required volume Formulation Example 8

 The intravenous formulation is manufactured as follows:

 Active ingredient lOOmg

 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 Gels are manufactured as follows:

 Active ingredient lOOmg

 Isopropanol 500mg

 Partially hydrophobized hydroxymethylcellulose 150mg

 Add purified water and total lOOOOmg

 The active ingredient is dissolved in isopropanol and added to the partially dispersed hydrophobized hydroxymethylcellulose. Further, after adding water, mix uniformly with a stirrer to dissolve all ingredients.

Formulation Example 10 A drop-dispersed ointment is manufactured as follows:

 Active ingredient lOOmg

 Penzino Reano Reconole 400mg

 Sonorbitan sesquistearate 400mg

 Liquid paraffin 500mg

White petrolatum 8600mg Total lOOOOmg

 Dissolve the active ingredient in benzyl alcohol, add sorbitan sesquistearate, fluid paraffin, and white petrolatum, and mix with a stirrer to adjust.

Industrial applicability

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

Claims

Claims [1] General formula (I):  [Chemical 1]

(Wherein R ¹ may be substituted, aryl, or substituted, heteroaryl. R ² is C1-C6 alkyl, C2-C4 alkenyl, or C2-C4 alkynyl; R ³ is C1-C6 alkyl, C2-C4 alkenyl, or C2-C4 alkynyl; or R ² and R ^{3 taken} together include a C1-C4 alkyl containing a C1-C4 alkyl optionally containing a C1-C4 alkyl, or a C1-C4 alkyl containing a C-C4 alkyl containing an adjacent carbon atom. May be substituted to form a 3-8 membered oxygenated heterocycle; R ⁴ is an optionally substituted aryl, an optionally substituted heteroaryl, or the formula: — C (= X) — Y— R ⁵ (wherein R ⁵ is an optionally substituted CI—C4 alkyl, substituted, may be a C2—C4 alkyl, or substituted, C2-C4 alkyl; X is an oxygen atom or a sulfur atom; Y is a group represented by an oxygen atom or a sulfur atom), an optically active substance thereof, a pharmaceutically acceptable salt thereof, Or a solvate thereof. [2] R ⁴ is represented by the formula: -C (= X) -YR ⁵ (wherein R ⁵ is substituted !, may be! /, C1-C4 alkyl or substituted, may be C2 The compound according to claim 1, an optically active form thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, or a group represented by —C4 alkenyl; X is an oxygen atom or sulfur atom; Y is a sulfur atom) Solvate. [3] The compound according to claim 1, wherein R ² is C1-C4 alkyl, and R ³ is CI-C4 alkyl, an optically active form thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof. [4] 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! / ヽ), the optically active substance thereof, Pharmaceutically acceptable salts or solvates thereof. [5] R ² and R ³ together are substituted with CI—C4 alkyl containing adjacent carbon atoms! 2. The compound according to claim 1, which is a 5- to 7-membered cycloalkane, an optically active form thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof. [6] 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 2. The compound according to claim 1, which is 5-isoxazolyl or optionally substituted 5 pyrazolyl, an optically active form thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof. [7] R ¹ may be substituted with ¹ to 2 substituents selected from substituent group A 1-naphthyl, 1 to 2 substituents selected from substituent group A 5,6,7,8-tetrahydro-1-naphthyl, which may be substituted with 4-indanyl which may be substituted with 1 to 2 substituents selected from substituent group A Optionally substituted with 1 to 2 substituents selected from group A, 5 isoxazolyl, or substituted with 1 to 2 substituents selected from substituent group A, 5 —Pyrazolyl;  Substituent group A: Neurogenic atom, C1-C8 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo C1-C8 alkyl, C1-C6 alkoxy C1-C8 alkyl, C1-C6 alkylthio CI-C8 Alkyl, C1 C6 alkylamino C1 C8 alkyl, C3— C6 cycloalkyl, hydroxy, C1— C6 alkoxy, C2— C6 alkoxy, halo C 1 C6 alkoxy, CI— C6 alkylthio CI— C6 alkoxy, CI— C6 alkoxy C1 — C6 alkoxy, carboxy C1— C6 alkoxy, C1— C6 alkoxycarbole C1— C6 alkoxy, cyano C1— C6 alkoxy, C1— C6 alkylthio, amino, mono (CI— C6 alkyl) amide di (CI— C6 alkyl) ) N-CI-C6 alkyl aralkyl-containing N— C1 C6 alkyl-aryl containing C1 C6 alkyl carboamino, CI- C6 alkyl sulfo-amino Toro, carboxy, CI- C6 al kills carbonyl, CI- C6 alkoxycarbonyl - le, ShiaIri CI- C6 alkylsulfonyl - Ruokishi, Hue - Le, 2-pyridyl, phenoxy and Benjiruokishi;  The compound according to any one of claims 1 to 5, an optically active isomer, a pharmaceutically acceptable salt thereof, or a solvate thereof. [8] A pharmaceutical composition comprising the compound according to any one of claims 1 to 7 as an active ingredient. 9. The pharmaceutical composition according to claim 8, which is a pain therapeutic agent.  [10] Prevention or treatment of pain or pain, comprising administering the compound according to any one of claims 1 to 7, an optically active form thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof. Method.  [11] A compound according to any one of claims 1 to 7, an optically active isomer, a pharmaceutically acceptable salt thereof, or a solvate thereof, for producing a prophylactic or therapeutic agent for pain or pain use.