WO2006129609A1

WO2006129609A1 - 2-naphthylimino-5,5-disubstituted-1,3-thiazin derivative

Info

Publication number: WO2006129609A1
Application number: PCT/JP2006/310679
Authority: WO
Inventors: Hiroyuki Kai
Original assignee: Shionogi & Co., Ltd.
Priority date: 2005-05-30
Filing date: 2006-05-29
Publication date: 2006-12-07
Also published as: JPWO2006129609A1

Abstract

The object is to prepare a 2-naphthylimino-5,5-disubstituted-1,3-thiazin derivative and a pharmaceutical composition comprising the compound as an active ingredient and to provide an analgesic agent, a therapeutic agent for pain, an anti-pruritic agent or a bronchodilator. A compound represented by the general formula (I) or an optically active form or pharmaceutically acceptable salt of the compound or a solvate of the compound, optically active form or salt: (I) wherein R1 independently represents an alkyl or the like; R2 and R3 are different from each other and represent a C1-C6 alkyl or the lie, or R2 and R3 may together form a 5- to 8-membered cycloalkane which has a adjacent carbon atom and is substituted by a C1-C4 alkyl, or the like; R4 represents a C1-C4 alkyl or the like; X represents an oxygen or sulfur atom; W represents -CH=CH-CH=CH- or the like; and n is an integer of 0 to 7.

Description

Specification

2_Naphthylimino-5,5-disubstituted-1,3-thiazine derivatives

Technical field

[0001] The present invention relates to a 2-naphthylimino 5,5-disubstituted-1,3-thiazine derivative having a cannapinoid receptor agonistic action and a pharmaceutical use thereof.

Background art

[0002] Cannapinoids were discovered in 1960 as the main active substance of marijuana, and their effects include central nervous system effects (such as hallucinations, euphoria, and spatiotemporal sensations) 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. Sarako and Patent Document 1 disclose that a cannapinoid receptor agonist has an anti-epileptic action. Patent Document 2 discloses that cannapinoid receptor agonists have an anti-asthma effect.

Examples of cannapinoid receptor agonists include isoindolinone derivatives (Patent Document 3), pyrazole derivatives (Patent Document 4), quinolone derivatives (Patent Documents 5 and 6), pyridone derivatives (Patent Document 7), etc. Thiazine derivatives (Patent Document 8, Patent Document 9 and Patent Document 10) having a structure similar to the inventive compound are known. Patent Document 1: International Publication No. 03Z035109 Pamphlet

Patent Document 2: Pamphlet of International Publication No. 2005Z016351

Patent Document 3: International Publication No. 97Z29079 Pamphlet

Patent Document 4: International Publication No.98Z41519 Pamphlet

Patent Document 5: Pamphlet of International Publication No. 99Z02499

Patent Document 6: Pamphlet of International Publication No. 00Z40562

Patent Document 7: Pamphlet of International Publication No. 02Z053543

Patent Document 8: International Publication No.01Z19807 Pamphlet

Patent Document 9: Pamphlet of International Publication No. 02Z072562

Patent Document 10: International Publication 2005Z026138 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 and a pharmaceutical composition containing the compound as an active ingredient are created to provide an analgesic agent, a pain therapeutic agent, an antidepressant, or a bronchodilator.

Means for solving the problem

[0004] The present inventors show that the following 2 naphthylimino 5,5 disubstituted 1,3 thiazine derivatives have a strong cannapinoid receptor agonist action, and analgesics and pains containing them as an active ingredient It was found to be effective as a therapeutic agent, an antidepressant, or a bronchodilator.

[0005] That is, the present invention provides: 1) General formula (I):

[Chemical 1] (I)

Wherein R ¹ is the same or different and is alkyl, alkoxy, alkylthio, optionally substituted amide-substituted aryl, optionally substituted aryloxy, optionally substituted aralkyloxy; Cycloalkyl, halogen atom, hydroxy, nitro, haloalkyl, haloalkoxy, optionally substituted rubamoyl, carboxyl, alkoxycarbonyl, alkylsulfiel, alkylsulfonyl, anoleoxyalkyl, alkylthioalkyl, optionally substituted amino Alkyl, alkoxyiminoalkyl, alkoxyalkoxy, alkylthioalkoxy, alkoxycarboalkoxy, carboxyalkoxy, alkylsulfo-loxy, optionally substituted heteroaryl, substituted Any non-aromatic heterocyclic group, cyano-cyanoxylated, or formula: -di (= 0)-! ^ (1 ^ is hydrogen, alkyl, optionally substituted aryl, or substituted ヽOr a non-aromatic heterocyclic group);

R ² and R ³ are different and are C 1 C 6 alkyl, C 2 -C 4 alkenyl, or C 2 -C 4 alkynyl; or

R ² and R ³ together are 5 to 8 membered cycloalkanes containing adjacent carbon atoms and substituted with C1 C4 alkyl or adjacent carbon atoms and substituted with C1—C4 alkyl and 5 8 membered May form an oxygen-containing heterocycle ヽ;

R ⁴ is CI—C4 alkyl, C2—C4 alkyl, C2—C4 alkyl, or CI—C4 alkyl C 1—C4 alkyl;

X is an oxygen atom or a sulfur atom;

W CH CH CH CH CHCH CH CH OCH O OCH CH O

2 2 2 2 2 2 2 2 2 2 or CH = CH— CH = CH—;

n is an integer of 0 7), an optically active isomer, a pharmaceutically acceptable salt thereof, or a solvate thereof,

2) The compounds according to 1), wherein R ² and R ³ are different from each other and CI-C4 alkyl, and optically active forms thereof , A pharmaceutically acceptable salt thereof, or a solvate thereof,

3) R ² and R ³ together form a 5- to 7-membered cycloalkane containing an adjacent carbon atom and substituted with C1 C4 alkyl, the compound according to 1), an optically active form thereof, a product thereof A pharmaceutically acceptable salt, or a solvate thereof,

4) R ⁴ is methyl, ethyl, or aryl, the compound according to any one of 1) to 3), an optically active isomer, a pharmaceutically acceptable salt thereof, or a solvate thereof,

5) General formula (Π):

[Chemical 2]

Wherein R ¹ is the same or different and is alkyl, alkoxy, an optionally substituted amino-substituted halogen atom, hydroxy, haloalkyl, haloalkoxy, silane-containing or alkoxy force norboninoleanoloxy;

R ² and R ³ together may form a 5-8 membered cycloalkane containing an adjacent carbon atom and substituted with C1 C4 alkyl! / ヽ;

R ⁴ is C 1 C4 alkyl or C2-C4 alkenyl;

X is an oxygen atom or a sulfur atom;

n is an integer of 0 to 4), an optically active form thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof,

6) The compound according to 5), wherein R ² and R ³ are different from each other and CI-C4 alkyl, an optically active isomer, a pharmaceutically acceptable salt thereof, or a solvate thereof,

7) R ² and R ³ together form a 5- to 7-membered cycloalkane containing an adjacent carbon atom and substituted with C1 C4 alkyl, the compound according to 5), an optically active substance thereof, a product thereof A pharmaceutically acceptable salt, or a solvate thereof, 8) The compound according to any one of 5) to 7), wherein R ⁴ is methyl, ethyl, or allyl, an optically active isomer, a pharmaceutically acceptable salt thereof, or a solvate thereof,

9) General formula (III):

[Chemical 3]

R ⁴ is C 1 C4 alkyl or C2-C4 alkenyl;

X is an oxygen atom or a sulfur atom;

n is an integer of 0 to 3), its optically active form, its pharmaceutically acceptable

Or a solvate thereof,

10) The compound according to 9), wherein R ² and R ³ are different from each other and CI-C4 alkyl, an optically active compound thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof,

11) R ² and R ³ together form a 5- to 7-membered cycloalkane containing an adjacent carbon atom and substituted with C1 C4 alkyl. 9) The compound, its optically active substance, its pharmaceutical Acceptable salts, or solvates thereof,

12) R ⁴ force methyl, ethyl, or aryl, the compound according to any one of 9) to 11), an optically active form thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof,

13) Formula:

[Chemical 4]

(Wherein Me is methyl), a pharmaceutically acceptable salt thereof, or a solvate thereof,

14) A pharmaceutical composition comprising the compound according to any one of 1) to 13), an optically active isomer thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof as an active ingredient,

15) The pharmaceutical composition according to 14), which is a pain therapeutic agent,

16) A pharmaceutical composition according to 14) which is an analgesic,

17) The pharmaceutical composition according to 14), which is an antidepressant,

18) The pharmaceutical composition according to 14), which is a bronchodilator

19) A method for treating pain, comprising administering the compound according to any one of 1) to 13), a pharmaceutically acceptable salt thereof, or a solvate thereof,

20) Use of the compound according to any one of 1) to 13), a pharmaceutically acceptable salt thereof, or a solvate thereof for producing a pain therapeutic agent.

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. “Alkyl” includes straight-chain or branched alkyl having 1 to 10 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butylene, n-pentinoles, isopentinoles, neo-pentinoles, n-hexynole, n-heptyl, n-octyl, n-noel, n-decyl and the like. In particular, straight-chain or branched alkyl having 1 to 6 carbon atoms is preferred. Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n- Pentyl, isopentyl, neo-pentyl and n-hexyl are preferred. In particular, when a carbon number is specified, it means “alkyl” having a carbon number within the range of the number.

“Alkoxyalkyl” includes the above “alkyl” substituted with one or more 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 “alkoxy” having the number of carbons in the number range and “alkyl” having the number of carbons in the number range. The

“Alkylthioalkyl” includes the above “alkyl” substituted with one or more of the following “alkylthio”, for example, methylthiomethyl, 2-methylthioethyl, 2-ethylthioethyl, 3-methylthiopropyl, etc. It is done.

“Substituted, optionally, aminoamino” includes the above “alkyl” substituted by one or more of the following “substituted, optionally, amino”, for example, methylaminomethyl, 2-dimethyl And ruaminoethyl, 2-jetylaminoethyl, 3-dimethylaminopropyl and the like.

“Alkoxyiminoalkyl” includes the above “alkyl” substituted with one or more imino groups substituted with the following “alkoxy” and includes, for example, methoxyiminomethyl, 2-methoxyiminoethyl, 2-ethoxyimino. Examples thereof include ethyl and 2-methoxyiminopropyl.

“Alkenyl” includes linear or branched alkenyl having 2 to 8 carbon atoms having one or more double bonds to the above “alkyl”, and includes, for example, vinyl, 1-probe. -L, allyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 1,3-butagel, 3-methyl-2-butul and the like. In particular, straight chain or branched alkaryl having 2 to 4 carbon atoms is preferred, and allyl, iso-probe, and 3_butul are preferred. In particular, when a carbon number is specified, it means “alkell” having a carbon number within that range.

“Alkynyl” includes linear or branched alkynyl having 2 to 8 carbon atoms having one or more triple bonds in the above “alkyl”, and examples thereof include ethynyl, propargyl and the like. It is done. In particular, a linear or branched alkyl having 2 to 4 carbon atoms is preferable, and specifically, propargyl is preferable.

“Haloalkyl” means a group in which one or more halogens are substituted on the above “alkyl”. For example, chloromethyl, dichloromethyl, difluoromethyl, trifluoromethyl, chloroethyl (for example, 2-chloroethyl) , Dichloroethyl (for example, 1,2-dichloroethyl, 2,2-dichloroethinole, etc.), black-mouthed propinole (f-row separation, 2-black-headed propinole, 3-black-headed propylene, etc.) and the like. C1-C3 haloalkyl is preferred.

“Cycloalkane” includes a cycloalkane having 3 to 10 carbon atoms. Pan, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane and the like. Preferably, it is a C5-C8 cycloalkane, for example, cyclopentane, cyclohexane, cycloheptane, and cyclooctane. In particular, when the number of carbons is specified, it means “cycloalkane” having members within the range of the number.

“Cycloalkyl” includes cycloalkyl having 3 to 10 carbon atoms, and examples thereof include cyclopropinole, cyclobutinole, cyclopentinole, cyclohexinole, cycloheptinole, cyclooctyl and the like. Preferred is cycloalkyl having 3 to 6 carbon atoms, and examples thereof include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In particular, when the number of carbons is specified, it means “cycloalkyl” having the number of carbons within the range.

The “aryl” includes aryl having 6 to 14 carbon atoms, and examples thereof include phenol, naphthyl, anthryl, phenanthryl and the like. In particular, phenol and naphthyl are preferable.

“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). ), Chael (eg, 2-chael, 3-chael), pyrrolyl (eg, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), imidazolyl (eg, 1-imidazolyl, 2-imidazolyl, 4-imidazolyl), pyrazolyl (eg 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl), triazolyl (eg 1, 2, 4-triazol-1-yl, 1, 2, 4-triazolyl-3- 1,2,4-triazol-4-yl), tetrazolyl (eg 1-tetrazolyl, 2-tetrazolyl, 5-tetrazolyl), oxazolyl (eg 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), pyridazyl (eg, 3-pyridazil, 4-pyridazil), pyrimidyl (eg, 2-pyrimidyl, 4-pyrimidyl, 5- Pyrimidyl), furazal (eg 3-furazal), virazil (eg 2-pyrazur), oxadiazolyl (eg 1, 3, 4-oxadiazol-2-yl), benzofuryl (eg 2-benzo [b] furyl, 3-benzo [b] furyl, 4-benzo [b] furyl, 5-benzo [b] furyl, 6-benzo [b] furyl, 7-benzo [b] furyl) , Benzo chales (eg 2-benzo [b] chael, 3-benzo [b] chael, 4-benzo [b] chael, 5-benzo [b] chael, 6-benzo [b] chael, 7-benzo [b] chael), benzimidazolyl (eg, 1-benzimidazolyl, 2-benzoimidazolyl, 4-benzoimidazolyl, 5-benzo Midazolyl), dibenzofuryl, benzoxazolyl, quinoxalyl (eg 2-quinoxalinyl, 5-quinoxalinyl, 6-quinoxalinyl), cinnolinyl (eg 3-cinnolyl, 4-cinnolyl, 5-cinnolyl- , 6-cinnolyl, 7-cinnolyl, 8-cinnolyl), quinazolyl (eg 2-quinazolyl, 4-quinazolyl, 5-quinazolyl, 6-quinazolyl, 7 -Quinazolyl, 8-quinazolyl), quinolyl (eg, 2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 6-quinolyl, 7-quinolyl, 8-quinolyl), phthalajur (eg, 1 -Phthaladulyl, 5-phthaladulyl, 6-phthaladuryl), isoquinolyl (eg, 1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl, 6-isoquinolyl, 7-isoquinolyl, 8-isoquinolyl), Prill, pteridyl (eg, 2-pteridyl, 4-pteridinyl, 6-pteridinyl, 7-pteridinyl), carbazolyl, phenanthridinyl, ataridyl (eg, 1-ataridyl, 2-ataridyl-) 3 drills, 3 drills, 4 drills, 9 drills, in-drills (eg 1-in drill, 2-in drill, 3-in drill, 4-in drill, 5-in drill, 6-in drill, 7 -Indolyl), isoindolyl, fanadyl (eg 1-phenadyl, 2-phenadyl) or phenothiazil (eg 1-phenothiazole, 2-phenothiazole, 3-phenothiazole) 4-phenothiazole) and the like.

The term “oxygen-containing heterocycle” includes a 3- to 8-membered heterocycle in which one or two oxygen atoms may be present, and includes oxolan, oxetane, oxolan, dioxolan, oxane, dioxane, oxepane, oxocan Etc. In particular, oxolan, oxane and oxepane are preferred. “Non-aromatic heterocyclic group” means a nitrogen atom, an oxygen atom, and 1 to

Includes 4 non-aromatic cyclic groups containing 1 to 9 carbon atoms, such as 1-pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrrolidino, 2-pyrrolidinyl, 3-pyrrolidinyl, piperidino, 2-piperidyl, 3- Examples include piperidyl, 4-piperidyl, piperazino, 2-piperazinyl, 2-morpholinyl, 3-morpholinyl, morpholinated tetrahydrobiral and the like. In particular, morpholy-containing pyrrolidi-containing piperidino-containing piperazino is preferred.

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, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, and t-butoxy are preferred, where C 1-4 alkoxy is preferred. In particular, when a carbon number is specified, it means “alkoxy” having a carbon number within the range of the number.

“Haloalkoxy” means a group in which one or more halogens 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 preferred.

“Aryloxy” includes a group in which one of the above “aryl” is substituted on an oxygen atom. For example, phenoxy, naphthoxy (eg, 1-naphthoxy, 2-naphthoxy, etc.), anthrinoloxy (eg, 1— Anthryloxy, 2-anthryloxy, etc.), phenanthrylloxy (for example, 1-phenanthroxy, 2-phenanthroxy), and the like. In particular, phenoxy and naphthoxy are preferable.

“Aralkyloxy” includes a group in which one above-mentioned “aralkyl” is substituted on an oxygen atom, and examples thereof include benzyloxy and phenethyloxy. In particular, benzyloxy is preferred.

“Alkoxyalkoxy” includes the above “alkoxy” substituted with the above “alkoxy”, for example, methoxymethoxy, ethoxymethoxy, n-propoxymethoxy, isopropoxymethoxy, 1-methoxyethoxy, 2-methoxyethoxy and the like. Is mentioned. In particular, 1-methoxyethoxy and 2-methoxyethoxy are preferable.

“Alkylthioalkoxy” includes the above “alkoxy” substituted with the following “alkylthio” and includes, for example, methylthiomethoxy, ethylthiomethoxy, n-propylthiomethoxy, isopropylthiomethoxy, 1-methylthioethoxy, Examples include 2-methylthioethoxy. In particular, 1-methylthioethoxy and 2-methylthioethoxy are preferable.

“Carboxyalkoxy” includes the above “alkoxy” substituted with one or more of “carboxy” and includes, for example, carboxymethoxy, 2-carboxyethoxy and the like.

“Alkoxycarbonalkoxy” means a group in which the above “alkoxy” is substituted by the following “alkoxycarbol”, and includes, for example, methoxycarbonylmethoxy, ethoxycarbonylmethoxy, n-propoxycarbonylaminoremethoxy, Topropoxy carbonyl methoxy, n-butoxy carbonyl methoxy, i-butoxy carbonyl methoxy, sec-butoxy carbonyl methoxy, tert-butoxy carbonyl methoxy, 2- (tert-butoxy carbonyl) ethoxy, 2— ( n-pentyloxycarbol) ethoxy, 2- (n-hexyloxycarboro) ethoxy, n-heptyloxycarboromethoxy, n-octyloxycarboromethoxy and the like. In particular, tert-butoxycarboromethoxy and 2- (tert-butoxycarboro) ethoxy are preferable.

The “cyanalkoxy” includes the above “alkoxy” substituted with one or more “ciano” and includes, for example, cyanomethoxy, 2-cyanethoxy and the like.

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, straight chain or branched alkylthio having 1 to 4 carbon atoms is preferred, and methylthio, ethylthio, n propylthio, isopropylthio, n-butinoreio, isobutinoreio, sec butinoreio, and tbutinoreio are preferred.

Examples of “optionally substituted amino” include unsubstituted C1 C4 alkylamino, (C 1 C4 alkyl) carborylaminocarbonylcarbonylamino, N— (C1—C4 alkyl) carbol CI— C4 alkylamine-containing alkylalkylamino, CI—C4 alkylsulfo Nylamino, C2—C4 alkenylcarboxylamine (CI—C4 alkoxy) carboninoreamino, C2—C4 anorekeninoreamino, arenorecanenoboninoreamino, heteroarino carbo-lamino. Especially preferred are unsubstituted amino-containing C1 C4 alkylamino, (C1-C4 alkyl) carbolumino, and (C1-C4 alkoxy) carbolumino! /.

Examples of CI-C4 alkylamino include methylamino, ethylamino, n-propylamino, i-propylamino-containing dimethylamino-containing ketylamino-containing ethylmethylamino, and propylmethylamino. Examples of (C1-C4 alkyl) carboamino include acetylamino, formylamino, and propio-lumino. Examples of aryl carbonates include benzoylamino. Examples of N— (CI—C4 alkyl) carboalkylamino include N-acetylmethylamino. Aralkylamino includes, for example, benzylamino-containing 1-phenylamino-containing 2-phenylethyl-containing 1-phenylpropylamino-containing 2-phenylpropylamino-containing 3-phenylpropylamino-containing 1-naphthylmethylamino-containing dibenzylamino. Can be mentioned. Examples of the C1-C4 alkyl sulforamino include methanesulfo-amid ethane sulforamino. Examples of the C2-C4 alkenylcarbolumino include bicarboxylamine-containing carboxycarboxylamino. Examples of (C1-C4alkoxy) carbolamino include methoxycarbolamylated ethoxycarbolamino and tert-butoxycarbolamino. Examples of the C2—C4 alkamino include buramino and allylamino. An example of aryl carbonamino is benzoylamino. Examples of the heteroaryl carbolumino include pyridine carbolumino.

“Acyl” means a carbo group substituted with a group other than hydrogen, such as an alkyl carboyl (eg, acetyl, propiol, butyryl, isobutyryl, valeryl, isovaleryl, bivaloyl, hexanoyl, Otatanyl, lauroyl, etc.), alkaryl carbo yl (eg, atalyloyl, meta atalyloyl), cycloalkyl carbo yl (eg, cyclopropane carbonyl, cyclobutane carbonyl, cyclopentane carbonyl, cyclohexane carbonyl, etc.), aryl carbo -Lole (benzoyl, naphthoyl, etc.), heteroaryl carbole (pyridyl carbole, etc.). These groups are further alkylated And may be substituted with a substituent such as halogen. For example, arylalkyl substituted with alkyl includes a toluoyl group, and alkylcarbonyl substituted with halogen includes a trifluoroacetyl group.

“Alkoxycarbon” means a group in which the above “alkoxy” is substituted on the carbocycle, and includes, for example, methoxycarbonyl, ethoxycarbonyl, n_propoxy carbonylbonole, i-poxoxy carbonylbonole, n -Butoxycarbonyl, i-butoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, n-pentyloxycarbonyl, n-hexynoleoxy carbo yl, n-heptyloxy carbo yl, n-octyloxy carbo -Le. In particular, methoxycarbol, ethoxycarbol and the like are preferable.

Examples of the substituent of “optionally substituted rubamoyl” include alkyl (for example, methyl, ethyl, n-propyl, i-propyl, etc.), isyl (for example, formyl, acetyl, propionyl, benzoyl, etc.) and the like. Can be mentioned. Nitrogen nuclear power of the rubermoyl group may be mono- or di-substituted with these substituents. As the “substituted but optionally rubamoyl”, rubamoyl, N-methylcarbamoyl, N-ethylcarbamoyl and the like are preferable.

The alkyl part of “alkylsulfiel” has the same meaning as the above “alkyl”, and examples of “alkylsulfiel” include methanesulfiel, ethanesulfiel and the like.

The alkyl part of the “alkylsulfol” has the same meaning as the above “alkyl”, and examples of the “alkylsulfol” include methanesulfol, ethanesulfol and the like.

The alkyl sulfol moiety of the “alkyl sulfo-oxy” has the same meaning as the above “alkyl sulfo”, and examples of the “alkyl sulfo-oxy” include methane sulfo-oxy, ethane sulfo-oxy and the like.

“Optionally substituted aryl”, “optionally substituted heteroaryl”, “substituted, may be non-aromatic heterocyclic group”, “substituted, may be aryloxy” Or when “optionally substituted aralkyloxy” has a substituent, any one to four substituents may be substituted at any position. Examples of the substituent include hydroxy, carboxy, halogen atom (fluorine atom, chlorine atom, bromine atom, iodine atom), haloalkyl (for example, CF, CHCF, CHCC1, etc.),

3 2 3 2 3 Haloalkoxy, alkyl (eg, methyl, ethyl, isopropyl, tert-butyl, etc.), alkyl (eg, butyl), formyl, isyl (eg, acetyl, propiol, butyryl, pivalol, benzoyl) , Pyridinecarbonyl, cyclopentanecarbonyl, cyclohexanecarbon, etc.), alkyl (eg, etul), cycloalkyl (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.), alkoxy (eg, methoxy, Ethoxy, propoxy, butoxy, etc.), alkoxy carbs (eg, methoxy carbol, ethoxy carbol, tert-butoxy carbol etc.), nitro, -toroso, oxo, optionally substituted amino ( For example, amided alkylamino (eg, methylamino, ethyl Dimethylamino, etc.), formylamino acylamine (eg, acetylamino benzoylamino), azide, aryl (eg, phenol), aryloxy (eg, phenol), sheared isocyanate, thiocyanato, isothiocyanate, Mercapto, alkylthio (for example, methylthio, ethylthio, etc.), alkylsulfol (for example, methanesulfol, ethanesulfol), arylsulfol (for example, benzenesulfol, etc.), optionally substituted rubamoyl , Sulfamoyl, formyloxy, noroformyl, oxaza, mercapto, thioformyl, thiocarboxy, dithiocarboxy, thiocarbamoyl, sulfi-containing sulfo, sulfoamido hydrazino, ureido, amidino, gua-dino, holmi Okishi, Chiokiso, alkoxyalkoxy, § Ruki Lucio alkoxy, 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.

R ² and R ^{3 taken} together include the following groups as 5- to 8-membered cycloalkanes containing adjacent carbon atoms and substituted with C 1 C 4 alkyl. A cycloalkane in which 1 to 4 C 1 C4 alkyl is substituted at the substitutable position of the cycloalkane is preferred. As C1-C4 alkyl, methyl and ethyl are preferred.

[Chemical 5]

In particular, the 5- to 7-membered cycloalkane shown below is preferable. Preference is given to cycloalkanes substituted with 1 to 2 CI—C4 alkyl at the substitutable positions of the cycloalkane! /. As C 1 -C 4 alkyl, methyl is particularly preferred.

[Chemical 6]

Preference is given to (R ¹ ), R ^{2 to} R ⁴ , X, W, and n of the compounds represented by the general formulas (I) to (III)! / ヽ Substituent groups are represented by (la) to (In) Show. Preferable compounds of those possible combinations.

(R ¹ ) is preferably (la) a hydrogen atom, a halogen atom, alkyl, haloalkyl, hydroxy, alkoxy, haloalkoxy, an optionally substituted amino or alkoxycarboalkoxy, and (lb) hydrogen. Atom, halogen atom, alkyl, alkoxy, optionally substituted amino or alkoxy carboalkoxy are preferred, although (Ic

) A hydrogen atom, a halogen atom, an optionally substituted amino or alkoxycarboalkoxy is preferred.

R ² and R ³ are different, (Id) —preferably C2—C4 alkyl or C2—C3 alkenyl and the other is C1—C4 alkyl or C2—C3 alkenyl. — Is preferably C2—C4 alkyl and the other is CI—C4 alkyl.

R ⁴ is preferably (1 £) 1 to 4 alkyl or 2 to 4 alkyl, and (ig) Cl C4 alkyl is preferred! /.

X is (Ih) an oxygen atom or a sulfur atom.

W is (Ii) —CH 2 CH 2 CH 1, OCH 2 O, or —CH = CH—CH = CH

2 2 2 2 2

Furthermore, —I is preferred. (Ij) —CH═CH—CH═CH is preferred.

Or R ² and R ^{3 taken} together are preferably 5-8 membered cycloalkanes containing adjacent carbon atoms and substituted with (Ik) C1 C4 alkyl, and (I1) C1—C4 alkyl substituted. The converted 5- to 7-membered cycloalkane is preferred! n is preferably an integer of (Im) 0 to 2, and more preferably an integer of (In) 0 to 1.

The invention's effect

[0009] The compound of the present invention has an excellent cannapinoid receptor agonist action and high safety, and is therefore useful as a pharmaceutical, particularly as a therapeutic agent for pain.

BEST MODE FOR CARRYING OUT THE INVENTION

[0010] The compound according to the present invention can be produced by the following steps. The structural formulas of the formulas (I) to (V) indicate a racemate or an optically active substance.

[Chemical 7]

Wherein R ¹ is the same or different and is alkyl, alkoxy, alkylthio, optionally substituted amide-substituted aryl, optionally substituted aryloxy, optionally substituted aralkyloxy; Cycloalkyl, halogen atom, hydroxy, nitro, haloalkyl, haloalkoxy, optionally substituted rubamoyl, carboxyl, alkoxycarbonyl, alkylsulfiel, alkylsulfonyl, anoleoxyalkyl, alkylthioalkyl, optionally substituted amino Alkyl, alkoxy Ciminoalkyl, alkoxyalkoxy, alkylthioalkoxy, alkoxycarboalkoxy, carboxyalkoxy, alkylsulfoxyloxy, optionally substituted heteroaryl, optionally substituted non-aromatic heterocyclic group, cyanosilane Lucoxy or the formula: -di (= 0)-! ^ (1 ^ is hydrogen, alkyl, optionally substituted aryl, or optionally substituted non-aromatic heterocyclic group) Group

R ² and R ^{3 taken} together include an adjacent carbon atom and may be substituted with C1 C4 alkyl, or include an 8-membered cycloalkane or an adjacent carbon atom and substituted with C1-C4 alkyl; However, it may form a 58-membered oxygenated heterocycle.

R ^{5 s} are the same or different and are alkyl, alkoxy, alkylthio, optionally substituted amide-substituted aryl, substituted with an optionally substituted amide-substituted protecting group. Optionally substituted aryloxy, optionally substituted aralkyloxy, cycloalkyl, halogen atom, protected with hydroxy, nitro, haloalkyl, haloalkoxy, optionally substituted rubamoyl, protected with a protecting group Carbonoxy, Anolexoxynoreboninole, Anolequinoles norefininore, Anolequinoles nolehoninole, Anoleoxy alkyl, Alkylthioalkyl, An optionally substituted aminoalkyl, Alkoxyiminoalkyl, Alkoxyalkoxy , Alkylthioalkoxy, alkoxy carboalkoxy Carboxyalkoxy, alkylsulfonyl - Ruokishi, Teroariru to optionally substituted, may be substituted non-aromatic heterocyclic group, or ^{formula: -c (= 0) -R H} (R H is hydrogen, alkyl An optionally substituted aryl, or an optionally substituted non-aromatic heterocyclic group);

X is an oxygen atom or a sulfur atom;

W CH CH CH CH CHCH CH CH OCH O OCH CH O

2 2 2 2 2 2 2 2 2 2 or CH = CH— CH = CH—;

n is an integer of 0 7) 1st process

In this step, the amino group of the compound represented by the formula (IV) is converted to an isothiocyanate (isothiocynate) to produce a compound represented by the formula (V).

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

1) 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 added to the compound (IV) and an aprotic solvent (for example, , Jetyl ether, tetrahydrofuran, dimethylformamide, benzene, toluene, dichloromethane, black mouth form, etc.) for 0.5 to 10 hours. 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 (IV) and an aprotic solvent (for example, 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 0 ° C to room temperature.

In the case of (4), thiocarbodiimidazole (1.0 to 1.5 equivalents) is added to compound (IV), 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 (IV) include 1-aminonaphthalene, 1-amino-2-fluoronaphtalene, 1-amino-3-funole-old ronaphthalene, 1-amino-4-funole-aged naphthaphthalene, 1-amino-1-fluoronaphthalene, 1-- Amino 1 Fluoronaphthalene, 1—Amino 1— Funole-old Lonaphthalene, 1 Amino-8 Funole-old Lonaphthalene, 1 Amino-2 Chloronaphthalene, 1 Amino-3 Chloronaphthalene, 1 Amino-4 Chloronaphthalene, 1 Amino-5 Chloronaphthalene, 1 Amino-6 Chloronaphthalene, 1 Amino-7 Chloronaphthalene 1 amino-8 chloronaphthalene, 1 amino-2 bromonaphthalene, 1 amino-3-bromonaphthalene, 1 amino-4-bromonaphthalene, 1 amino-5 bromonaphthalene, 1-amino-6 bromonaphthalene, 1-amino-7 bromonaphthalene, 1-amino 8 Bromonaphthalene, 1-amino-2-methylnaphthalene, 1-amino-3-methylnaphthalene, 1-amino-4-methylnaphthalene, 1-amino-5-methylnaphthalene, 1-amino 6-methylnaphthalene, 1 amino-7-methylna Phthalene, 1-amino-8-methylnaphthalene, 1-amino-2-methoxynaphthalene, 1-amino-3-methoxynaphthalene, 1-amino-4-methoxynaphthalene, 1-amino-5-methoxynaphthalene, 1-amino-6-methoxynaphthalene, 1-amino-7-methoxynaphthalene, 1-amino-8-methoxynaphthalene, 1-amino-2-N, N dimethylaminonaphthalene, 1-amino-3-N, N dimethylaminonaphthalene, 1-amino 4-N, N dimethylaminonaphthalene, 1 —Amino 1-N, N Dimethylamino naphthalene, 1-Amino 1-amino 6- N, N Dimethylamino naphthalene, 1-amino-7-N, N Dimethylaminonaphthalene, 1-amino-8- N, N Dimethylaminonaphthalene, 1-amino-2-benzyloxynaphthalene, 1-amino-3-benziloxynaphthalene 1 amino-4 benzyloxynaphthalene, 1 amino-5 benzyloxynaphthalene, 1 amino-6 benzyloxynaphthalene, 1 amino-7-benzyloxynaphthalene, 1 amino-8 benzyloxynaphthalene, 1 amino-4 (2 Pyridyl) naphthalene and their 5, 6, 7, 8-tetrahydro compounds.

Second step

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

2 2 2

This is a process for producing a compound.

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

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 (V).

2 2 2

That's fine.

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

2 2 2

Propanol, 3 amino-2-ethyl-2-isopropylpropanol, 3-amino-2-isopropyl 2-aminopropyl, 3-amino-2-i-butyl 2-isopropylpropyl, 3-amino-2-tert-butyl 2-isopropylpropanol, 3-amino-2-methyl 2- n Propylpropanol, 3-amino-2-ethyl 2-n-propyl propanol, 3-amino 2-isopropyl 2 n-propyl propanol, 3-amino-2-i-butyl 2-n-propylpropanol, 3-amino-2-t-butyl 2-— n Propylpropanol, 3 amino-2- i-butyl 2-methyl propanol, 3-amino 2- i-butyl 2-ethyl 2-propanol, 3-amino 2-t-butyl 2-methyl propanol, 3-amino-2 s butyl 2-ethyl propanol, 3-amino 2, 2— (2-Methylteto Methylene) propanol, 3 amino-2, 2- (2,2 dimethyltetramethylene) propanol, 3 amino-2, 2- (2 dimethylpentamethylene) propanol, 3 amino-2, 2- (2,2 dimethylpentamethylene) propanol , And their optically active pairs.

3rd process

In this step, the compound represented by the formula (VI) is cyclized to produce the compound represented by the formula (VII).

Ring closure methods include: (1) after treatment with tetrasalt carbon and triphenylphosphine (Ph P),

Three

Examples include a method of treating with a base such as potassium carbonate, and a method of treating with (2) hydrochloric acid.

In the case of (1), an aprotic solvent (for example, jetyl ether, tetrahydrofuran, dimethylformamide, benzene, toluene, dichloromethane, black mouthform, etc.) is used as the solvent, and 0.5 hours to 5 hours. What is necessary is just to perform at 0 degreeC-room temperature. Tetrasalt carbon and triphenylphosphine (Ph P) should be used in an amount of 1.0 to 1.5 equivalents to the compound (VI), respectively. Yes.

In the case of (2), the mixture may be heated to reflux in concentrated hydrochloric acid for 0.5 to 10 hours.

4th process

In this step, C (= X) —SR ⁴ is introduced into the compound represented by the formula (VII) to produce the compound represented by the formula (la).

This step is carried out in the presence of a base (eg, triethylamine, pyridine, N, N-dimethylaminopyridine, etc.) in the formula: Hal—C (= X) —SR ⁴ (wherein R ⁴ and X are as defined above). Significance, Hal represents a halogen atom) and can be carried out by reacting a compound represented by For example, an aprotic solvent (for example, jetyl ether, tetrahydrofuran, dimethylformamide, benzene, toluene, dichloromethane, black mouth form, etc.) is used as the solvent. The reaction may be performed at 0 ° C to 100 ° C for 0.5 hour 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.

5th process

In the case where R ⁵ has a group protected by a protecting group, a) deprotection or b) deprotection followed by alkylation to produce a compound represented by formula (I).

It can be removed by the methods described in Deprotection, Protective uroups in urganic Synthesis, Theodora Wureen (John Wiley & Sons), etc.

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, the solvent may be an aprotic solvent (e.g., jetyl ether, tetrahydrofuran, dimethylformamide, benzene, toluene, dichloromethane, Etc.), and the reaction proceeds from o ° c to room temperature.

In each step, it can be purified by a usual method such as recrystallization, distillation, column chromatography (when a chiral column is used, an optically active substance can be obtained) and used in the next step.

The compounds of the present invention can be converted into prodrugs. A prodrug is a compound that becomes a pharmaceutically active compound of the present invention in vivo under physiological conditions. Methods for selecting and producing suitable prodrug derivatives can be found, for example, in Design of Prodrugs, Elsevier, Amsterdam 1985.

The prodrug of the compound according to the present invention can be produced by introducing a leaving group into a substituent on the A ring that can introduce a leaving group (for example, amino-containing hydroxy). Examples of prodrugs of amino groups include force rubamates (eg, methyl carbamate, cyclopropylmethyl carbamate, t-butyl carbamate, benzyl carbamate, etc.), amides (eg, formamide, acetamide, etc.), N-alkyls (eg, , N-arylamine, N-methoxymethylamine, etc.). Examples of the hydroxy group prodrug include an ether form (methoxymethyl ether, methoxyethoxymethyl ether, etc.), an ester form (eg, acetate, pivaloate, benzoate, etc.) and 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. , Aliphatic amine salts such as triethylamine salt, dicyclohexylamine salt, ethanolamine salt, diethanolamine salt, triethanolamine salt, brocaine salt; aralkylamine salts such as Ν, Ν-dibenzylethylenediamine; pyridine salt, picoline Heterocyclic aromatic amine salts such as salts, quinoline salts and isoquinoline salts; tetramethylammonium salt, tetraethylammonium salt, benzyltrimethylammonium salt, benzyltriethylammonium salt, benzyltributyl Ammonium salt, methyl trioctyl ammonium salt, tetraptyl ammonium Quaternary ammonia salts such as -um salts; 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 , Fumarate, tartrate, malate, kenate Organic salts such as ascorbate; sulfonates such as methanesulfonate, isethionate, benzenesulfonate, and P-toluenesulfonate; acidic amino acids such as aspartate and glutamate Can be mentioned.

Solvate means a solvate of a compound represented by formula (I) or formula (式), a prodrug thereof, or a pharmaceutically acceptable salt thereof, for example, a monosolvate, a disolvate Japanese hydrate, monohydrate, dihydrate and the like can be mentioned.

The compound of the present invention can be used for the purpose of treatment or prevention for diseases involving cannapinoid receptor agonists. For example, in Nature 1993, pp. 365, p. 61-65, Cannapinoid receptor agonists have anti-inflammatory and analgesic effects, and the journal of Cannabis Thetas (Journal of Cannabis The (rapeutics) 2002, 2-1, p. 59-71 states that the cannapinoid receptor agonist has bronchodilator activity and that WO 03Z035109 has an anti-epileptic activity. Has been.

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, orally administered 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 an 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 tablets, the active ingredient and auxiliary ingredients are compressed or molded together. Auxiliary ingredients include pharmaceutically acceptable excipients such as binders (e.g. Rocco starch etc.), fillers (eg latatose, microcrystalline cellulose etc.), disintegrants (eg sodium starch glycolate etc.) or lubricants (eg magnesium stearate etc.) etc. are 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.

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: Mechinole

Example

Example 1 5 Isobutyl-5 Isopropyl 3 [(Methylthio) thiocarbol] 2 Naphthylimino 1, 3 Synthesis of thiazine (1-48)

[Chemical 8]

To a solution of naphthyl isothiocyanate (1, 3.71 g) in dichloromethane (20 mL) was added 3 amino-2-ethyl-2-isopropylpropanol (3.47 g) in dichloromethane (20 mL) under ice-cooling, and the mixture was stirred overnight at room temperature. . The residue obtained by concentrating the reaction under reduced pressure was purified by silica gel column chromatography (ethyl acetate: _n- hexane = 2: 8) 1 1 (3-hydroxy-2 isobutyl-2 isopropylpropyl) 3 naphthylthiourea ( 2, 5.51 g, yield 77%) was obtained as colorless crystals.

NMR (CDC1) δ ppm: 0.58 (3H, d, J = 6.6), 0.69—1.00 (11H, m), 1.46—1.70 (3

Three

H, m), 3.30-3.47 (3H, m), 3.90 (IH, dd, J = 13.9, 6.6), 6.53 (IH, s), 7.43-7.63 (5H, m), 7.70 (IH, s), 7.87-7.93 (2H, m), 8.03 (IH, m).

1- (3-hydroxy-1-2-isobutyl 2-isopropylpropyl) 3-naphthylthiourea (2, 2.15 g), triphenylphosphine (3.15 g) and acetonitrile (18 mL) 1.85 g) was added under ice cooling, and the mixture was stirred at room temperature for 2 hours. Potassium carbonate (1.66 g) was added, and the mixture was stirred at room temperature overnight. Water (30 mL) was added to the reaction mixture, and the precipitated crystals were collected by filtration with washing with n-hexane, and 5-isobutyl-5-isopropyl-2-naphthyliminone 1,3 thiazine (3, 1.63 g, collected). 80%) was obtained as colorless crystals.

NMR (CDC1) δ ppm: 0.90-0.97 (12H, m), 1.37—1.54 (2H, m), 1.73 (IH, m),

Three

2.12 (IH, sept, J = 6.6), 2.58-3.34 (4H, m), 5.78 (IH, br s), 7.00 (IH, d, J = 7.3), 7.35 -7.48 (3H, m), 7.55 ( IH, d, J = 8.2), 7.81 (IH, m), 8.02 (IH, m).

5 Isobutyl-5 Isopropyl-2 Naphthylimino 1,3 Thiazine (3, 0.272 g), carbon disulfide (0.1 mL) and DMF (2.4 mL) in a mixture of 60% sodium hydride (0.064 g) in ice After cooling and stirring at 0 ° C for 30 minutes, methyl iodide (0.1 mL) was added under ice-cooling. = ['PP' Ηΐ) Ζε · ΐ '(ω ΉΖ \) ΐΟ · ΐ- S6'0: radcJ9 ( ^S raa) Ν Ν Η _τ , one. 68 ~ ^

. 《雜 ¾ (% 9Ζ? Ί) ί § 32, 6 1 I)

-έ-ε Ί- ^ y ^-^-^ -z- [^ / (^ ^)] ε ci i g—

: S, (Be ^ ^u ) f ^ ^) w ^-^ mm ^ (96: = Be ^^

w ^m iw, ^ a ^ a ^m ro)

Stop ^

^ E (Η ( ^s

[6 ^] ^ α) (6 ^ -ι) ^ J .- ^-ε 'x- ^ y ^-^-^

-Ζ- [/-^ / ^ {^ Λ ^)] —ε / cl l / s / ^: s z m [woo]

• (ω 'Ηΐ) Ζ0 · 8' (ω 'Ηΐ) 38 "Ζ' · 8 = ί"'Ρ' Ηΐ) 99 "Ζ '(ω Ήε)

'(6 · ει = ί "'

Ρ 'Ηΐ)% VZ' (6 · εΐ = ί "'Ρ' Ηΐ) ZVZ '( ^s Ήε) 69' (6 · 9 = ί"'s Ήΐ) WZ' (ω 'ΗΖ) Ζ8 "ΐ — SS 'I'(9'S'^ = [' PP 'Ηΐ) W \' (ω 'ΗΖΙ) 0 · ΐ— 68'0: mdcJ9 OoaO) H NH _T

,. _o m ~ SIldui

§ ZZ'O, 8 — I)

-έ-ε ^ ー [-^ / ^ (^ / ^)] — ε— / ci i

-s— s, (Be ^ u) f ^ ^) w ^-^ mm ^ (86: s = be ^

—U: Ye S) — ^^ Mumah ½ = tsu S Sui ui OS / Ie /

, "¾ ^

6.90TC / 900Zdf / X3d LZ 6096ΖΪ / 900Ζ OAV

°: _n "τ ~ τ

^^ M ^ ^^ osi— ι〜εοΐ— i 呦 ^ : Tsu ^^ soi— i ~ os— I, ι〜τ— I 呦 ^ ^ ^^ MM ^ i [sioo]

• (ω 'Ηΐ) ZVS' (ω 'Ηΐ) WL' (6''Ζ = Γ 'Ρ' Ηΐ) WL '(ω Ήε) WL-OVL' (9 · 9 = Γ 'Ρ' Ηΐ) 86 · 9 '(6 · εΐ = ί "' Ρ 'Ηΐ) 9Vf' (6" ST = f 'Ρ' Ηΐ) 8 · ε τΐ = ί 'Ρ' Ηΐ) 08 '(S

τι = ί 'ρ' ΗΙ) ε9 '( ^s Ήε) 8ε' (6 · 9 = ί "'s' _Ηΐ ) ₉₆ '(m' _HS ) ss'i— IS'I '(6's' e-

6.90TC / 900Zdf / X3d 83 6096ΖΪ / 900Ζ OAV

6.90TC / 900Zdf / X3d 63 6096ΖΪ / 900Ζ OAV

6.90TC / 900Zdf / X3d οε 6096ΖΪ / 900Ζ OAV

6.90TC / 900 ^ df / X3d 6096ΖΪ / 900Ζ: OAV [9¾

6.90TC / 900Zdf / X3d εε 6096ΖΪ / 900Ζ OAV a

6.90Tf / 900Zdf / X3d 6096ΖΪ / 900Ζ 0Λ \ [8¾

6.90TC / 900Zdf / X3d 9ε 6096ΖΪ / 900Ζ OAV 關

6.90TC / 900Zdf / X3d 9ε 6096Π / 900Ζ O / A [Οΐ 挲]

6.90TC / 900Zdf / X3d ζε 6096ΖΪ / 900Ζ OAV

OAV 60962§pu 0 inch is ^ s

[I] mm

6Z.90lC / 900Zdf / X3d 6096 / 900Ζ OAV

6Z, 90Tf / 900Zdf / X3d zv 6096ΖΪ / 900Ζ OAV

[Table 17] Compounds

Structural formula f

1-115

chiral ^Me _v ^Me

— Me

1-116

^

₀ Me chiral ^{e Me}

PI 17

chiral ^Me _v ^Me

1-118 Li o s' ^Me chiral ^M V ^Me

1-119

C people N

chiral ^Me _v ^Me

1-120

(W people

[0, e F Test examples of the above compounds of the present invention are shown below.

Test Example 1 Human cannapinoid receptor binding inhibition experiment

As the 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 of [ 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 MgC12). After incubation, 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 use a liquid scintillation counter to top the glass filter. The radioactivity of was determined. Nonspecific binding was measured in the presence of 10 / z M of WIN55212-2 (Cannapinoid receptor antigen described in US 5081122, Sigma), and 50% inhibition of the test compound for specific binding. The concentration (IC value) was determined. The Ki value of the test compound was obtained as I

50

It was calculated from the C 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 and incubated for 15 minutes, followed by incubation with forskolin (final concentration 4 M, SIGMA) for 20 minutes. After IN HC1 was added to stop the reaction, the amount of cAMP in the supernatant was measured using a Cy clic AMP kit (CIS bio international). The concentration of cAMP (IC value) showing a 50% inhibitory effect was determined by setting cAMP production by stimulation with forskolin as 100% against no stimulation with forskolin.

50

Test Example 3 Inhibitory effect on formalin-noxious stimuli in ddy mice

In the experiment, ddy male mice (5 weeks old) were used, 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 (first) 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 actions on the right hind limb as an index, and the ED value was calculated.

50 calculated. The results of Test Examples 1 to 3 are shown in Tables 18 to 20.

[Table 18]

[Table 19]

[Table 20]

Test Example 4 Inhibitory effect on Compound 48 / 80-induced itch in ddy mice An experiment was carried out by partially modifying the method of Inagaki et al. (Eur J Pharmacol 1999; 367: 361-371). Specifically, compound 48/80 (3 μg / 50 μ 1 / site) was injected intradermally into a pre-shaved back of a female ddy mouse to induce a reaction, and the hind limbs to the injection site observed immediately thereafter I counted the number of whirlings in I for 30 minutes. After the test compound was dissolved in sesame oil and orally administered to mice, itching was induced by inoculation with compound 48/80 at the time when the maximum blood concentration set in advance was obtained. The evaluation of itch control is performed by comparing the number of pulls in the compound administration group with the number of pulls in the vehicle administration group, and the ED value is calculated. It was.

Formulation example

Formulation Examples 1 to 8 shown below are merely examples, and are 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 Active ingredient 250

Cellulose (microcrystal) 400

Diacid silicate (Hume) 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:

_

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 oOmg

Starch 45mg

Microcrystalline cellulose d5mg

Polyburpyrrolidone (10% solution in water) 4mg

Sodium carboxymethyl starch 4.5mg

Magnesium stearate 0.5mg

Talc lmg _

A doo

O B I 150mg

The active ingredient, starch, and cellulose are sifted through a No. 45 mesh US sieve and mixed thoroughly. The aqueous solution containing polybulurpyrrolidone is mixed with the resulting powder, and the mixture is then passed through a No. 14 mesh U.S. sieve. The granules so 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 2mg 200mg total

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

Sodium carboxymethyl cell mouth

Syrup

Benzoic acid solution

Fragrance

Pigment

Add purified water and total

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

Intravenous preparations are 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.

Industrial applicability

The present inventors have found that 2-naphthylimino 5,5 disubstituted 1,3 thiazine derivatives having cannapinoid receptor agonist activity show an analgesic effect, a pain treatment effect, an antidepressant effect, or a bronchodilator effect.

Claims

The scope of the claims

[1] General formula (I)

[Chemical 1]

R ² and R ³ together are 5- to 8-membered cycloalkanes containing adjacent carbon atoms and substituted with C1 C4 alkyl or adjacent carbon atoms and substituted with C1-C4 alkyl 5-8 May form a member's oxygenated heterocycle ヽ;

X is an oxygen atom or a sulfur atom;

W CH CH CH-CH CH CH CH-OCH O OCH CH O

Or CH = CH— CH = CH- n is an integer of 0 to 7), an optically active form thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof.

[2] The compound according to claim 1, wherein R ² and R ³ are differently CI—C4 alkyl, an optically active substance thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof.

[3] The compound according to claim 1, wherein R ² and R ³ are combined to form a 5- to 7-membered cycloalkane containing an adjacent carbon atom and substituted with C1-C4 alkyl. The pharmaceutically acceptable salt or solvate thereof.

[4] The compound according to any one of claims 1 to 3, which is R ⁴ acetyl, ethyl, or allyl, an optically active isomer, a pharmaceutically acceptable salt thereof, or a solvate thereof.

[5] General formula (II):

[Chemical 2]

R ⁴ is C 1 C4 alkyl or C2-C4 alkenyl;

X is an oxygen atom or a sulfur atom;

n is an integer of 0 to 4), an optically active form thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof.

6. The compound according to claim 5, wherein R ² and R ³ are different from each other and C 1 C 4 alkyl, an optically active substance thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof. [7] The compound according to claim 5, wherein R ² and R ³ are taken together to form a 5- to 7-membered cycloalkane containing an adjacent carbon atom and substituted with CI—C4 alkyl, its optically active form, The pharmaceutically acceptable salt or solvate thereof.

[8] The compound according to any one of claims 5 to 7, which is R ⁴ carbyl, ethyl, or allyl, an optically active isomer, a pharmaceutically acceptable salt thereof, or a solvate thereof.

[9] General formula (ΠΙ):

[Chemical 3]

R ⁴ is C 1 C4 alkyl or C2-C4 alkenyl;

X is an oxygen atom or a sulfur atom;

n is an integer of 0 to 3), an optically active form thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof.

[10] The compound according to claim 9, wherein R ² and R ³ are different from each other and are C1 C4 alkyl, an optically active substance thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof.

[11] The compound according to claim 9, wherein R ² and R ³ are combined to form a 5- to 7-membered cycloalkane containing an adjacent carbon atom and substituted with C 1 C 4 alkyl. Or a solvate thereof.

[12] R ⁴ is methyl, Echiru, or claim 9 which is Ariru: A compound according to any one of L 1, An optically active substance thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof.

[13] A pharmaceutical composition comprising the compound according to any one of claims 1 to 12 as an active ingredient.

14. The pharmaceutical composition according to claim 13, which is a pain therapeutic agent.

[15] A method for treating pain, comprising administering the compound according to any one of claims 1 to 12, a pharmaceutically acceptable salt thereof, or a solvate thereof.

[16] Use of the compound according to any one of claims 1 to 12, a pharmaceutically acceptable salt thereof, or a solvate thereof for the manufacture of a therapeutic agent for pain.