2-imino-1,3-thiazine derivatives

专利摘要:
Compounds of formula (I) of the invention specifically bind to cannabinoid 2 receptor (CB2R) and exhibit antagonistic or agonistic activity against CB2R: [Formula I] [Wherein, R 1 represents an optionally substituted alkylene; R 2 is hydrogen, alkyl, a group represented by the formula -C (= R 5 ) -R 6 (wherein R 5 represents O or S; R 6 represents alkyl, alkoxy, alkylthio, etc.), or a formula A group represented by -SO 2 R 7 (wherein R 7 represents alkyl or the like); m is an integer from 0 to 2; A represents an optionally substituted aryl or the like].
公开号:KR20020027646A
申请号:KR1020027003364
申请日:2000-09-11
公开日:2002-04-13
发明作者:하나사끼고지；무라시다까미；가이히로유끼
申请人:시오노 요시히코；시오노기세이야쿠가부시키가이샤；
IPC主号:

专利说明:

2-imino-1,3-thiazine derivative {2-IMINO-1,3-THIAZINE DERIVATIVES}
[2] Cannabinoids were found to be the main active substances contained in marijuana in 1960, and their activity on the central nervous system (hallucinations, fortunateness, confusion of time and space sensation) and activity on the peripheral cell system (immunosuppressive activity, anti-inflammatory activity, Analgesic activity).
[3] Thereafter, anandamide and 2-arachidonoylglycerols produced from phospholipids containing arachidonic acid were found as endogenous agonists for the carbinoid receptor. Such endogenous agonists are known to exhibit activity on the central nervous system and activity on the peripheral cell system. Hypertension (1997) 29 1204-1210 describes that anandamide exhibits cardiovascular activity.
[4] Cannabinoid type 1 receptors discovered in 1990 were found to be distributed in the central nervous system such as the brain. Agonists for these receptors have been found to inhibit the release of neurotransmitters and cause central action such as hallucinations. Cannabinoid type 2 receptors discovered in 1993 were found to be distributed in immune tissues such as spleen and the like. Agonists for these receptors have been shown to exhibit immunosuppressive, anti-inflammatory and analgesic activity by inhibiting the activation of immune or inflammatory cells (Nature, 1993, 365, 61-65).
[5] Thus, selective antagonists or agonists for cannabinoid type 2 receptors are expected to be immunosuppressants, anti-inflammatory agents, analgesics without side effects on the central nervous system such as drug dependence or hallucinations associated with cannabinoid type 1 receptors (Nature, 1998, 349, 277). -281).
[6] Isoindolinone derivatives (WO97 / 29079 and WO99 / 02499), pyrazole derivatives (WO98 / 41519) and the like are known as compounds having antagonistic or agonistic activity on cannabinoid type 2 receptors.
[7] On the other hand, Japanese Patent Publication (Kokai 1986-65894, Kokai 1987-29594) describes that organophosphorus compounds having a 2-imino-1,3-thiazine skeleton are useful as insecticides.
[8] However, it is not known that 2-imino-1,3-thiazine derivatives have antagonistic or agonistic activity on cannabinoid type 2 receptors.
[9] Summary of the Invention
[10] The present invention provides 2-imino-1,3-thiazine derivatives and the like as novel compounds having selective antagonistic or agonistic activity on cannabinoid type 2 receptors.
[11] The present invention includes the following:
[12] 1) A pharmaceutical composition comprising a compound of formula (I), a prodrug thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof:
[13]
[14] [Wherein, R ¹ is an optionally substituted alkylene,
[15] R ² is alkyl; Formula -C (= R ⁵ ) -R ⁶ , wherein R ⁵ is O or S; R ⁶ is alkyl, alkoxy, alkylthio, optionally substituted amino, optionally substituted aralkyloxy, optionally substituted aralkylthio , Optionally substituted aralkylamino, alkoxyalkyl, alkylthioalkyl or optionally substituted aminoalkyl); Or a group of the formula -SO ₂ R ⁷ , wherein R ⁷ is alkyl, optionally substituted amino, optionally substituted aryl or optionally substituted heteroaryl,
[16] m is an integer from 0 to 2,
[17] A is an optionally substituted aromatic carbon ring or an optionally substituted aromatic hetero ring],
[18] 2) The chemical formula of 1) above Pharmaceutical compositions wherein the group is of the formula
[19]
[20] [Wherein R ³ and R ⁴ are each independently hydrogen, alkyl, alkoxy, alkylthio, optionally substituted amino, optionally substituted aryl, optionally substituted aryloxy, cycloalkyl, halogen, hydroxy, nitro, haloalkyl, Haloalkoxy, optionally substituted carbamoyl, carboxy, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, alkoxyalkyl, alkylthioalkyl, optionally substituted aminoalkyl, alkoxyalkoxy, alkylthioalkoxy, optionally substituted heteroaryl, An optionally substituted non-aromatic heterocyclic group, alkoxyiminoalkyl or a formula -C (= 0) -R ^H , wherein R ^H is hydrogen, alkyl, optionally substituted aryl or optionally substituted non-aromatic heterocyclic group Or)
[21] Or R ³ and R ⁴ together may form an alkylenedioxy,
[22] A is an optionally substituted aromatic carbon ring or an optionally substituted aromatic hetero ring],
[23] 3) The pharmaceutical composition according to 1) or 2), having a binding activity to a cannabinoid type 2 receptor,
[24] 4) The pharmaceutical composition according to 3), wherein the pharmaceutical composition has an agonistic activity on cannabinoid type 2 receptors,
[25] 5) The pharmaceutical composition according to 3), which is useful as an anti-inflammatory agent,
[26] 6) The pharmaceutical composition according to 3), which is useful as an immunosuppressive agent,
[27] 7) The pharmaceutical composition of 3), useful as a nephritis therapeutic agent,
[28] 8) A compound of formula II, a prodrug thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof:
[29]
[30] [Wherein, R ¹ is an optionally substituted alkylene,
[31] R ² is of the formula —C (═R ⁵ ) —R ⁶ wherein R ⁵ is O or S, R ⁶ is alkyl, alkoxy, alkylthio, optionally substituted amino, optionally substituted aralkyloxy, optionally substituted Aralkylthio, an optionally substituted aralkylamino, alkoxyalkyl, alkylthioalkyl or an optionally substituted aminoalkyl), or a formula -SO ₂ R ⁷ , wherein R ⁷ is alkyl, optionally substituted amino, optionally substituted Aryl or optionally substituted heteroaryl),
[32] R ³ and R ⁴ are each independently hydrogen, alkyl, alkoxy, alkylthio, optionally substituted amino, optionally substituted aryl, optionally substituted aryloxy, cycloalkyl, halogen, hydroxy, nitro, haloalkyl, haloalkoxy, Optionally substituted carbamoyl, carboxy, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, alkoxyalkyl, alkylthioalkyl, optionally substituted aminoalkyl, alkoxyalkoxy, alkylthioalkoxy, optionally substituted heteroaryl, optionally substituted Non-aromatic heterocyclic group, alkoxyiminoalkyl, or formula -C (= 0) -R ^H , wherein R ^H is hydrogen, alkyl, optionally substituted aryl or optionally substituted non-aromatic heterocyclic group Is a group of
[33] Or R ³ and R ⁴ together may form an alkylenedioxy,
[34] m is an integer from 0 to 2,
[35] A is an optionally substituted aromatic carbon ring or an optionally substituted aromatic hetero ring],
[36] 9) The compound according to 8), wherein m is 0, a prodrug thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof,
[37] 10) The compound according to 8) or 9), wherein R ¹ is C2-C9 linear or branched alkylene optionally substituted with alkylene, prodrugs thereof, pharmaceutically acceptable salts or solvates thereof,
[38] 11) The compound according to any one of 8) to 10), wherein R ¹ is C2-C9 linear alkylene substituted with alkylene, or C2-C9 branched alkylene, prodrug thereof, pharmaceutically acceptable Salts or solvates thereof,
[39] 12) The compound according to any one of 8) to 11), wherein R ⁶ is alkoxy or alkylthio, R ⁷ is optionally substituted aryl, prodrugs thereof, pharmaceutically acceptable salts or solvates thereof,
[40] 13) The compound according to any one of 8) to 12), wherein R ³ and R ⁴ are each independently hydrogen, alkyl, alkoxy or alkylthio, and A is an optionally substituted aromatic carbon ring, a prodrug thereof, or a pharmaceutical thereof Or acceptable salts thereof, or solvates thereof,
[41] 14) The process according to 8), wherein R ¹ is 2,2-dimethyltrimethylene, 2,2-diethyltrimethylene, 2,2-ethylenetrimethylene, 1-methyltrimethylene, 2-methyltrimethylene, trimethylene , 2,2-di-n-propyltrimethylene, 2,2-tetramethylenetrimethylene, 2,2-pentamethylenetrimethylene, 1,1-dimethylethylene or 1-methylethylene, R ⁶ is methyl, ethyl , n-propyl, i-propyl, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, methylthio, ethylthio, n-propylthio, i-propylthio, i-butylthio , see-butylthio, benzyloxy, benzylthio, methoxymethyl, ethoxymethyl, methylthiomethyl, ethylthiomethyl or ethylamino, R ⁷ is methyl, ethyl, 4-tolyl, 4-nitrophenyl, 3- Nitrophenyl, 2-nitrophenyl, 4-methoxyphenyl, 4-trifluoromethylphenyl, 2-thienyl or 2-naphthyl, and R ³ is hydrogen, methyl, ethyl, n-propyl, i-propyl, n -Butyl, i-butyl, see-butyl, t-butyl, methoxy, Ethoxy, n-propoxy, i-propoxy, n-butoxy, methylthio, ethylthio, n-propylthio, i-propylthio, dimethylamino, acetylamino, N-acetylmethylamino, diethylamino, Ethylmethylamino, propylmethylamino, phenyl, phenoxy, fluoro, chloro, bromo, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, N-methylcarbamoyl, methoxycarbonyl, Methanesulfinyl, ethanesulfinyl, methanesulfonyl, ethanesulfonyl, acetyl, methoxymethyl, 1-methoxyethyl, 3-pyridyl, morpholino, pyrrolidino, piperidino, 2-oxopyrroli Dino, 1-methoxyiminoethyl or morpholinocarbonyl and R ⁴ is hydrogen, methyl, ethyl, fluoro, chloro, nitro, methoxy or ethoxy, or R ³ and R ⁴ together are -O-CH ₂ -O-, wherein A is benzene, naphthalene, pyridine or quinoline, prodrugs thereof, Pharmaceutically acceptable salts or solvates thereof,
[42] 15) A pharmaceutical composition comprising a compound according to any one of 8) to 14), a prodrug thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof,
[43] 16) The pharmaceutical composition according to 15), wherein the pharmaceutical composition has binding activity to cannabinoid type 2 receptors,
[44] 17) The pharmaceutical composition according to 16), wherein the pharmaceutical composition has an agonistic activity on cannabinoid type 2 receptors,
[45] 18) The pharmaceutical composition according to the above 16), which is useful as an anti-inflammatory agent,
[46] 19) The pharmaceutical composition according to the above 16), which is useful as an immunosuppressive agent,
[47] 20) The pharmaceutical composition according to the above 16), which is useful as a nephritis therapeutic agent,
[48] 21) A method for treating inflammation comprising administering the pharmaceutical composition according to 1),
[49] 22) An immunosuppressive method comprising administering the pharmaceutical composition according to 1),
[50] 23) a nephritis treatment method comprising administering the pharmaceutical composition according to 1),
[51] 24) use of the compound according to 1) for the preparation of an anti-inflammatory agent,
[52] 25) use of a compound according to 1) for the preparation of an immunosuppressive agent, and
[53] 26) Use of a compound according to 1) above for the preparation of a therapeutic agent for nephritis.
[1] The present invention relates to 2-imino-1,3-thiazine derivatives, in particular 2-imino-1,3-thiazine derivatives having selective antagonistic or agonistic activity against cannabinoid type 2 receptors, and pharmaceuticals thereof It is about a use.
[54] The meanings of the respective terms used in the compounds of the formulas (I) and (II) are described below. Each term is used in the specification to indicate the same meaning.
[55] The term "alkylene" includes C2-C10 linear or branched alkylene, for example ethylene, 1-methylethylene, 1-ethylethylene, 1,1-dimethylethylene, 1,2-dimethylethylene, 1,1- Diethylethylene, 1,2-diethylethylene, 1-ethyl-2-methylethylene, trimethylene, 1-methyltrimethylene, 2-methyltrimethylene, 1,1-dimethyltrimethylene, 1,2-dimethyltri Methylene, 2,2-dimethyltrimethylene, 1-ethyltrimethylene, 2-ethyltrimethylene, 1,1-diethyltrimethylene, 1,2-diethyltrimethylene, 2,2-diethyltrimethylene, 2 -Ethyl-2-methyltrimethylene, tetramethylene, 1-methyltetramethylene, 2-methyltetramethylene, 1,1-dimethyltetramethylene, 1,2-dimethyltetramethylene, 2,2-dimethyltetramethylene, 2, 2-di-n-propyltrimethylene and the like. Preference is given to C2-C9 linear or branched alkylenes. C2-C9 branched alkylene, for example 2,2-dimethyltrimethylene, 2,2-diethyltrimethylene, 1-methyltrimethylene, 2-methyltrimethylene, trimethylene, 2,2-di- More preferred are n-propyltrimethylene, 1,1-dimethylethylene or 1-methylethylene. The position number of these substituents is based on the order of NR ¹ -S or the order of SR ¹ -N.
[56] Examples of substituents of “optionally substituted alkylene” include alkylene (eg methylene, ethylene, trimethylene, tetramethylene, pentamethylene, etc.), cycloalkyl (eg cyclopropyl, cyclobutyl, cyclopentyl, Cyclohexyl, etc.), alkoxy (eg, methoxy, ethoxy, etc.), alkylthio (eg, methylthio, ethylthio, etc.), alkylamino (eg, methylamino, ethylamino, dimethylamino, etc.) ), Acylamino (eg, acetylamino, etc.), aryl (eg, phenyl, etc.), aryloxy (eg, phenoxy, etc.), halogen (fluoro, chloro, bromo, iodo), Hydroxy, amino, nitro, alkylsulfonyl (eg methanesulfonyl, ethanesulfonyl, etc.), arylsulfonyl (eg, benzenesulfonyl, etc.), cyano, hydroxyamino, carboxy, alkoxycar Carbonyl (eg, methoxycarbonyl, ethoxycarbonyl, etc.), acyl (eg, ace , The benzoyl and the like), aralkyl (e.g., benzyl, and the like, etc.), mercapto, hydrazino, amidino, guanidino. One to four such substituents may be substituted at any position. Alkylene is preferred as a substituent of "optionally substituted alkylene".
[57] Alkylene substituted with alkylene includes alkylene substituted with alkylene via spiro atoms (eg, 2,2-ethylenetrimethylene, 2,2-trimethylenetrimethylene, 2,2-tetramethylenetrimethylene, 2,2-pentamethylenetrimethylene and the like) and alkylene substituted with alkylene at different positions (eg, 1,2-tetramethyleneethylene, 1,2-ethylenetrimethylene and the like). Preferred examples include 2,2-ethylenetrimethylene, 2,2-trimethylenetrimethylene, 2,2-tetramethylenetrimethylene, 2,2-pentamethylenetrimethylene, especially 2,2-ethylenetrimethylene, 2, 2-tetramethylenetrimethylene and 2,2-pentamethylenetrimethylene are included.
[58] The term "alkyl" includes C1-C10 linear or branched alkyl such as methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, tert-butyl, n-pentyl, i-pentyl, neo-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl and the like. Preferred are C1-C4 linear or branched alkyls such as methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, see-butyl and tert-butyl.
[59] The term "alkoxy" includes an oxygen atom substituted with said "alkyl", for example methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, sec-butoxy, tert-butoxy, n-pentyloxy, n-hexyloxy, n-heptyloxy, n-octyloxy and the like. Preferred are C1-C4 linear or branched alkoxy, for example methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, sec-butoxy and tert-butoxy Do.
[60] The term "alkylthio" includes sulfur atoms substituted with "alkyl", for example methylthio, ethylthio, n-propylthio, i-propylthio, n-butylthio, i-butylthio, see-butylthio , tert-butylthio, n-pentylthio, n-hexylthio, and the like. C1-C4 linear or branched alkylthio, for example methylthio, ethylthio, n-propylthio, i-propylthio, n-butylthio, i-butylthio, sec-butylthio and tert-butylthio desirable.
[61] Examples of substituents of “optionally substituted amino” include alkyl (eg, methyl, ethyl, n-propyl, i-propyl, etc.), acyl (eg, formyl, acetyl, propionyl, benzoyl, etc.), and the like. Included. The nitrogen atom of the amino group may be 1- or 2-substituted with such substituents.
[62] Examples of "optionally substituted amino" include amino, methylamino, ethylamino, n-propylamino, i-propylamino, dimethylamino, diethylamino, ethylmethylamino, acetylamino, N-acetylmethylamino, propylmethylamino Etc. are included.
[63] The term “aryl” includes C 6 -C 14 aromatic carbocyclic groups such as phenyl, naphthyl, anthryl, phenanthryl and the like.
[64] The term "aralkyl" includes the "alkyl" substituted with "aryl", eg benzyl, phenylethyl (eg 1-phenylethyl, 2-phenylethyl), phenylpropyl (eg 1 -Phenylpropyl, 2-phenylpropyl, 3-phenylpropyl, and the like), naphthylmethyl (eg, 1-naphthylmethyl, 2. naphthylmethyl, etc.) and the like.
[65] The term "aralkyloxy" includes an oxygen atom substituted with said "aralkyl" such as benzyloxy, phenylethyloxy (eg 1-phenylethyloxy, 2-phenylethyloxy), phenylpropoxy ( For example, 1-phenylpropyloxy, 2-phenylpropyloxy, 3-phenylpropyloxy, etc.), naphthyl methoxy (for example, 1-naphthyl methoxy, 2-naphthyl methoxy etc.) etc. are contained.
[66] The term "aralkylthio" includes sulfur atoms substituted with "aralkyl" such as benzylthio, phenylethylthio (eg, 1-phenylethylthio, 2-phenylethylthio), phenylpropylthio ( For example, 1-phenylpropylthio, 2-phenylpropylthio, 3-phenylpropylthio, etc.), naphthylmethylthio (for example, 1-naphthylmethylthio, 2-naphthylmethylthio, etc.), etc. are mentioned. Included.
[67] The term "aralkylamino" includes a nitrogen atom substituted with one or two such "aralkyl" such as benzylamino, phenylethylamino (eg 1-phenylethylamino, 2-phenylethylamino), Phenylpropylamino (eg 1-phenylpropylamino, 2-phenylpropylamino, 3-phenylpropylamino), naphthylmethylamino (eg 1-naphthylmethylamino, 2-naphthylmethylamino, etc. ), Dibenzylamino and the like.
[68] The term "alkoxyalkyl" includes the "alkyl" substituted with "alkoxy", eg methoxymethyl, ethoxymethyl, n-propoxymethyl, 1-methoxyethyl, 2-methoxyethyl, 1- Ethoxyethyl, 2-ethoxyethyl, 1-n-propoxyethyl, 2-n-propoxyethyl, 1-methoxy-n-propyl, 2-methoxy-n-propyl, 3-methoxy-n -Propyl, 1-ethoxy-n-propyl, 2-ethoxy-n-propyl, 3-ethoxy-n-propyl, 1-n-propoxy-n-propyl, 2-n-propoxy-n- Propyl, 3-n-propoxy-n-propyl, and the like.
[69] The term "alkylthioalkyl" includes "alkyl" substituted with "alkylthio" such as methylthiomethyl, ethylthiomethyl, n-propylthiomethyl, 1-methylthioethyl, 2-methylthioethyl, 1-ethylthioethyl, 2-ethylthioethyl, 1-n-propylthioethyl, 2-n-propylthioethyl, 3-n-propylthioethyl, 1-methylthio-n-propyl, 2-methylthio- n-propyl, 3-methylthio-n-propyl, 1-ethylthio-n-propyl, 2-ethylthio-n-propyl, 3-ethylthio-n-propyl, 1-n-propylthio-n-propyl , 2-n-propylthio-n-propyl, 3-n-propylthio-n-propyl and the like.
[70] The term “optionally substituted aminoalkyl” includes such “alkyl” substituted with “optionally substituted amino”, eg, N-methylaminomethyl, N-acetylaminomethyl, N, N-dimethylaminomethyl, and the like. do.
[71] The term "alkoxyalkoxy" includes the "alkoxy" substituted with said "alkoxy", for example methoxymethoxy, ethoxymethoxy, n-propoxymethoxy, isopropoxymethoxy, 1-methoxy Methoxy, 2-methoxyethoxy and the like.
[72] The term "alkylthioalkoxy" includes the "alkoxy" substituted with "alkylthio" such as methylthiomethoxy, ethylthiomethoxy, n-propylthiomethoxy, isopropylthiomethoxy, 1-methyl Thioethoxy, 2-methoxyethoxy and the like.
[73] The term “heteroaryl” includes C 1 -C 9 heteroaryl having 1 to 4 nitrogen atom (s), oxygen atom (s) and / or sulfur atom (s) such as furyl (eg 2-furyl). , 3-furyl), thienyl (eg 2-thienyl, 3-thienyl), pyrrolyl (eg 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), imidazolyl (Eg 1-imidazolyl, 2-imidazolyl, 4-imidazolyl), pyrazolyl (eg 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl), triazolyl ( Eg, 1,2,4-triazol-1-yl, 1,2,4-triazol-3-yl, 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 For example, 3- Sothiazolyl, 4-isothiazolyl, 5-isothiazolyl), pyridyl (eg, 2-pyridyl, 3-pyridyl, 4-pyridyl), pyridazinyl (eg, 3- Pyridazinyl, 4-pyridazinyl), pyrimidinyl (eg 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl), furazanyl (eg 3-furazanyl) , Pyrazinyl (eg 2-pyrazinyl), oxdiazolyl (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), benzothienyl (eg , 2-benzo [b] thienyl, 3-benzo [b] thienyl, 4-benzo [b] thienyl, 5-benzo [b] thienyl, 6-benzo [b] thienyl, 7-benzo [ b] thienyl), benzimidazolyl (eg 1-benzimidazolyl, 2-benzimidazolyl, 4-benzimidazolyl, 5-benzimidazolyl), dibenzofuryl, benzoxa Zolyl, quinoxalinyl (eg, 2-quinoxalinyl, 5-quinoxalinyl, 6-quinoxalinyl), cinnolinyl (e.g. 3-cinnolinyl, 4-cinnolinyl, 5-cinnolinyl, 6-cinnolinyl, 7-cinnolinyl, 8-cinnolinyl ), Quinazolinyl (e.g., 2-quinazolinyl, 4-quinazolinyl, 5-quinazolinyl, 6-quinazolinyl, 7-quinazolinyl, 8-quinazolinyl), quinolyl ( For example, 2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 6-quinolyl, 7-quinolyl, 8-quinolyl), phthalazinyl (eg 1- Phthalazinyl, 5-phthalazinyl, 6-phthalazinyl), isoquinolyl (eg 1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl, 6 -Isoquinolyl, 7-isoquinolyl, 8-isoquinolyl), furyl, pterridinyl (eg, 2-pteridinyl, 4-pteridinyl, 6-pteridinyl, 7-pteriyl) Dinil), carbazolyl, phenanthridinyl, acridinyl (eg 1-acridinyl, 2-acridinyl, 3-acridinyl, 4-acridinyl, 9-acridinyl), Indolyl (eg 1-indolyl, 2-indole , 3-indolyl, 4-indolyl, 5-indolyl, 6-indolyl, 7-indolyl), isoindolyl, phenazinyl (eg 1-phenazinyl, 2-phenazinyl) or phen Nothiadinyl (eg, 1-phenothiadinyl, 2-phenothiadinyl, 3-phenothiadinyl, 4-phenothiadinyl), and the like.
[74] 3-pyridyl is preferred as heteroaryl of R ³ and R ⁴ . 2-thienyl is preferred as heteroaryl of R ⁷ .
[75] Ring A includes “optionally substituted aromatic carbon rings” or “optionally substituted aromatic hetero rings”.
[76] The term "aromatic carbon ring" includes C6-C14 aromatic carbon ring, such as benzene, naphthalene, anthracene, phenanthrene, and the like. Preference is given to benzene or naphthalene.
[77] The term "aromatic heterocycle" includes a C1-C9 aromatic ring having 1 to 4 nitrogen atom (s), oxygen atom (s) and / or sulfur atom (s), for example furan, thiophene, pyrrole, Dazole, pyrazole, triazole, tetrazole, oxazole, isoxazole, thiazole, thiadiazole, isothiazole, pyridine, pyridazine, pyrimidine, furazane, pyrazine, benzofuran, benzothiophene, benzimi Dazole, dibenzofuran, benzoxazole, quinoxaline, cinnoline, quinazoline, quinoline, phthalazine, isoquinoline, purine, pteridine, carbazole, phenanthridine, acridine, indole, isoindole or phena Jeans are included. Pyridine, quinoline or isoquinoline are preferred.
[78] "Optionally substituted aralkyloxy", "optionally substituted aralkylthio", "optionally substituted aralkylamino", optionally substituted aryl "," optionally substituted heteroaryl "," optionally substituted aryloxy "," Examples of substituents of "optionally substituted aromatic cyclic", "optionally substituted aromatic heterocycle" and "optionally substituted non-aromatic heterocyclic group" include alkyl, alkoxy, alkylthio, optionally substituted amino, optionally substituted aryl , Optionally substituted aryloxy, cycloalkyl, halogen, hydroxy, nitro, haloalkyl, haloalkoxy, optionally substituted carbamoyl, carboxy, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, alkoxyalkyl, alkylthioalkyl , Optionally substituted aminoalkyl, alkoxyalkoxy, alkylthioalkoxy, optionally substituted heteroaryl, optionally substituted non-aromatic heterocyclic group, alkoxyiminoalkyl, formula -C (= 0) -R ^H (wherein R ^H Is hydrogen, alkyl, optionally substituted aryl or Arylsulfonyl (e.g., benzenesulfonyl, etc.), cyano, hydroxy amino, aralkyl (e.g., benzyl, etc.), mercapto, hydra Gino, Amidino, Guanidino, Isocyano, Isocyanato, Tiocyanato, Isothiocyanato, Sulfamoyl, Formyloxy, Haloformyl, Oxalo, Tioformyl, Tiocarboxy, Dithiocarboxy, thiocarbamoyl, sulfino, sulfo, sulfoamino, azido, eureido, amidino, guanidino, oxo, thioxo and the like.
[79] Such substituents may be substituted at any substitutable position. Alkylenedioxy may be substituted at the same or different position on the ring. Examples of alkylenedioxy include —O—CH ₂ —O—, —O—CH ₂ —CH ₂ —O—, —O—CH ₂ —CH ₂ —CH ₂ —O—.
[80] The term "aryloxy" includes oxygen atoms substituted with "aryl" such as phenoxy, naphthoxy (eg, 1-naphthoxy, 2-naphthoxy, etc.), anthryloxy (eg, 1-anthryloxy, 2-anthryloxy, and the like), phenanthryl (eg, 1-phenanthryl, 2-phenanthryl, etc.), and the like.
[81] The term "cycloalkyl" includes C3-C7 cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
[82] The term "halogen" includes fluoro, chloro, bromo and iodo. Fluoro, chloro or bromo are preferred.
[83] The term "haloalkyl" includes "alkyl", eg, chloromethyl, dichloromethyl, difluoromethyl, trifluoromethyl, chloroethyl (eg, 1-chloroethyl, 2, substituted with one or more halogens). -Chloroethyl and the like), dichloroethyl (for example, 1,1-dichloroethyl, 1,2-dichloroethyl, 2,2-dichloroethyl and the like) and the like.
[84] The term "haloalkoxy" includes the above "alkoxy" substituted with one or more halogens, eg, dichloromethoxy, difluoromethoxy, trifluoromethoxy, trifluoroethoxy (2,2,2-trifluoro Ethoxy, etc.), and the like.
[85] Examples of substituents of “optionally substituted carbamoyl” include alkyl (eg, methyl, ethyl, n-propyl, i-propyl, etc.), acyl (eg, formyl, acetyl, propionyl, benzoyl, etc.) Etc. are included. The nitrogen atom of the carbamoyl group may be 1- or 2-substituted with such substituents.
[86] Carbamoyl, N-methylcarbamoyl or N-ethylcarbamoyl are preferred as “optionally substituted carbamoyl”.
[87] The term "alkoxycarbonyl" includes carbonyl substituted with "alkoxy". Methoxycarbonyl, ethoxycarbonyl and the like are preferable.
[88] The term "alkylsulfinyl" includes sulfinyl substituted with "alkyl" above. Methanesulfinyl, ethanesulfinyl, and the like are preferable.
[89] The term "alkylsulfonyl" includes sulfonyl substituted with "alkyl" above. Methanesulfonyl, ethanesulfonyl, etc. are preferable.
[90] The term "non-aromatic heterocyclic group" includes a C1-C9 non-aromatic ring, eg 1-, having from 1 to 4 nitrogen atom (s), oxygen atom (s) and / or sulfur atom (s). Pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrrolidino, 2-pyrrolidinyl, 3-pyrrolidinyl, 1-imidazolinyl, 2-imidazolinyl, 4-imida Zolinyl, 1-imidazolidinyl, 2-imidazolidinyl, 4-imidazolidinyl, 1-pyrazolinyl, 3-pyrazolinyl, 4-pyrazolinyl, 1-pyrazolidinyl, 3- Pyrazolidinyl, 4-pyrazolidinyl, piperidino, 2-piperidyl, 3-piperidyl, 4-piperidyl, piperazino, 2-piperazinyl, 2-morpholinyl, 3- Morpholinyl, morpholino, tetrahydropyranyl and the like. Preference is given to morpholino, pyrrolidino, piperidino or piperazino.
[91] The term "alkoxyiminoalkyl" includes such "alkyl" substituted with alkoxyimino, such as methoxyiminomethyl, ethoxyiminomethyl, 1-methoxyiminoethyl, and the like.
[92] Examples of groups of the formula -C (= 0) -R ^H , wherein R ^H is hydrogen, alkyl, optionally substituted aryl or optionally substituted non-aromatic heterocyclic group, include formyl, acetyl, benzoyl, tolu Oils, morpholinocarbonyl and the like.
[93] The term "m" is an integer from 0 to 2. 0 is preferred as "m".
[94] The term “acting activity on cannabinoid type 2 receptors” includes actuating cannabinoid type 2 receptors.
[95] The compounds of the present invention can be prepared according to the following process.
[96]
[97] [Wherein, R ¹ is an optionally substituted alkylene,
[98] R ² is alkyl; Formula -C (= R ⁵ ) -R ⁶ , wherein R ⁵ is O or S, R ⁶ is alkyl, alkoxy, alkylthio, optionally substituted amino, optionally substituted aralkyloxy, optionally substituted aralkylthio , Optionally substituted aralkylamino, alkoxyalkyl, alkylthioalkyl or optionally substituted aminoalkyl); Or a group of the formula -SO ₂ R ⁷ , wherein R ⁷ is alkyl, optionally substituted amino, optionally substituted aryl or optionally substituted heteroaryl,
[99] R ³ and R ⁴ are each independently hydrogen, alkyl, alkoxy, alkylthio, optionally substituted amino, optionally substituted aryl, optionally substituted aryloxy, cycloalkyl, halogen, hydroxy, nitro, haloalkyl, haloalkoxy, Optionally substituted carbamoyl, carboxy, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, alkoxyalkyl, alkylthioalkyl, optionally substituted aminoalkyl, alkoxyalkoxy, alkylthioalkoxy, optionally substituted heteroaryl, optionally substituted A non-aromatic heterocyclic group, alkoxyiminoalkyl, or of the formula -C (= 0) -R ^H , wherein R ^H is hydrogen, alkyl, optionally substituted aryl or optionally substituted non-aromatic heterocyclic group Or
[100] Or R ³ and R ⁴ together may form —O—CH ₂ —O—,
[101] m is an integer from 0 to 2,
[102] A is an optionally substituted aromatic carbon ring or an optionally substituted aromatic hetero ring.
[103] Process 1
[104] Process 1 is a process for preparing a compound of formula IV comprising converting the amino group of the compound of formula III to isothiocyanic acid ester (isothiocyanate).
[105] Methods for converting amino groups to isothiocyanate esters (isothiocyanates) include the following methods: 1) Base compounds such as ammonia (NH ₃ , NH ₄ OH), triethylamine (Et ₃ N) Reacting with carbon disulfide in the presence of and reacting the dithiocarbamate obtained with ethyl chlorocarboxylate (ClCO ₂ Et) and triethylamine (Et ₃ N), 2) the dithiocar A method comprising reacting a barmate with an acid metalate such as lead nitrate, 3) a method of reacting thiophosgen (CSCl ₂ ), and 4) a method of reacting thiocarbonyldiimidazole and the like.
[106] In the above 1), a base (1.0 to 1.5 molar equivalents) and carbon disulfide (1.0 to 1.5 molar equivalents) are added to an aprotic solvent (for example, diethyl ether, tetrahydrofuran, dimethylformamide, benzene, toluene, dichloro To a solution of the compound of formula III in methane, chloroform, etc.) and the mixture is stirred for 0.5 to 10 hours. Then ethyl chlorocarboxylate (1.0-1.5 molar equivalents) and triethylamine (1.0-1.5 molar equivalents) are added and the mixture is stirred in the same solvent for 0.5-10 hours. The reaction temperature is preferably 0 to 100 ° C, in particular 0 ° C to room temperature.
[107] In the above 3), the thiophosgen (1.0 to 1.5 molar equivalents) is added to the compound of formula III in an aprotic solvent (e.g., diethyl ether, tetrahydrofuran, dimethylformamide, benzene, toluene, dichloromethane, chloroform, etc.). Add to solution of compound and stir for 0.5 to 10 hours. The reaction temperature is preferably 0 to 100 ° C, in particular 0 ° C to room temperature.
[108] In the above 4), thiocarbonyldiimidazole (1.0 to 1.5 molar equivalents) is added to an aprotic solvent (eg, diethyl ether, tetrahydrofuran, dimethylformamide, benzene, toluene, dichloromethane, chloroform, etc.). Is added to a solution of the compound of formula III in and stirred for 0.5 to 10 hours. The reaction temperature is preferably 0 to 100 ° C, in particular 0 ° C to room temperature.
[109] Examples of compounds of formula III wherein m is 0 include aniline, 2-methylaniline, 2-ethylaniline, 2-n-propylaniline, 2-i-propylaniline, 2-n-butylaniline, 2-sec-butylaniline 2-t-butylaniline, 3-methylaniline, 3-i-propylaniline, 3-i-propyl-4-methylaniline, 3-t-butylaniline, 4-methylaniline, 4-i-propylaniline, 2,6-dimethylaniline, 2,3-dimethylaniline, 2,4-dimethylaniline, 3,4-dimethylaniline, 2,5-dimethylaniline, 3,4-dimethylaniline, 3,5-dimethylaniline, 2 , 6-diethylaniline, 2,6-di-i-propylaniline, 2-methoxyaniline, 2-ethoxyaniline, 2-i-propoxyaniline, 3-methoxyaniline, 3,5-dimethoxy Aniline, 3-n-butoxyaniline, 4-n-butoxyaniline, 4-ethoxyaniline, 3,4-dimethoxyaniline, 2-methylthioaniline, 2-ethylthioaniline, 2-i-propylthio Aniline, 2-N, N-dimethylaminoaniline, 2-phenylaniline, 3-phenylaniline, 4-phenoxyaniline, 2-cyclohexylaniline, 2-hour Lopentylaniline, 2-nitroaniline, 2,4-dinitroaniline, 2-fluoroaniline, 2-chloroaniline, 4-chloroaniline, 2,3-dichloroaniline, 3,4-dichloroaniline, 2-i -Propyl-4-nitroaniline, 2-i-propyl-6-methylaniline, 2-hydroxyaniline, 2-N, N-dimethylaminocarbonylaniline, 2-N-acetylaniline, 2- (1-ethyl Propyl) aniline, 2-i-propyl-4-methylaniline, 2-i-propyl-4-hydroxyaniline, 2-i-propyl-4-chloroaniline, 2-i-propyl-4-aminoaniline, 2 -i-propyl-5-methylaniline, 2-i-propyl-5-hydroxyaniline, 2-i-propyl-5-chloroaniline, 4-chloro-3-methylaniline, 3,4-methylenedioxyaniline Etc. are included.
[110] Examples of compounds of formula III wherein m is 1 include benzylamine, 2-methylbenzylamine, 2-ethylbenzylamine, 2-n-propylbenzylamine, 2-i-propylbenzylamine, 2-n-butylbenzylamine, 2-sec-butylbenzylamine, 2-t-butylbenzylamine, 3-methylbenzylamine, 3-i-propylbenzylamine, 3-i-propyl-4-methylbenzylamine, 3-t-butylbenzylamine, 4-methylbenzylamine, 4-i-propylbenzylamine, 2,6-dimethylbenzylamine, 2,3-dimethylbenzylamine, 2,4-dimethylbenzylamine, 3,4-diethylbenzylamine, 2,5 -Dimethylbenzylamine, 3,4-dimethylbenzylamine, 3,5-dimethylbenzylamine, 2,6-diethylbenzylamine, 2,6-di-i-propylbenzylamine, 2-methoxybenzylamine, 2 -Ethoxybenzylamine, 2-i-propoxybenzylamine, 3-methoxybenzylamine, 3,5-dimethoxybenzylamine, 3-n-butoxybenzylamine, 4-n-butoxybenzylamine, 4 -Ethoxybenzylamine, 3,4-dimethoxybenzylamine, 2-methylthiobenzylamine, 2-ethylthiobenzylamine, 2-i-propylthiobenzylamine, 2-N, N-dimethylami Benzylamine, 2-phenylbenzylamine, 3-phenylbenzylamine, 4-phenoxybenzylamine, 2-cyclohexylbenzylamine, 2-cyclopentylbenzylamine, 2-nitrobenzylamine, 2,4-dinitrobenzylamine , 2-fluorobenzylamine, 2-chlorobenzylamine, 4-chlorobenzylamine, 2,3-dichlorobenzylamine, 3,4-dichlorobenzylamine, 2-i-propyl-4-nitrobenzylamine, 2- i-propyl-6-nitrobenzylamine, 2-hydroxybenzylamine, 2-N, N-dimethylaminocarbonylbenzylamine, 2-N-acetylbenzylamine, 2- (1-ethylpropyl) benzylamine, 2 -i-propyl-4-methylbenzylamine, 2-i-propyl-4-hydroxybenzylamine, 2-i-propyl-4-chlorobenzylamine, 2-i-propyl-4-aminobenzylamine, 2- i-propyl-5-methylbenzylamine, 2-i-propyl-5-hydroxybenzylamine, 2-i-propyl-5-chlorobenzylamine, 4-chloro-3-methylbenzylamine, 3,4-methylene Dioxybenzylamine and the like.
[111] Examples of compounds of formula III wherein m is 2 include phenethylamine, 2-methylphenethylamine, 2-ethylphenethylamine, 2-n-propylphenethylamine, 2-i-propylphenethylamine, 2-n -Butylphenethylamine, 2-sec-butylphenethylamine, 2-t-butylphenethylamine, 3-methylphenethylamine, 3-i-propylphenethylamine, 3-i-propyl-4-methylphene Netylamine, 3-t-butylphenethylamine, 4-methylphenethylamine, 4-i-propylphenethylamine, 2,6-dimethylphenethylamine, 2,3-dimethylphenethylamine, 2,4- Dimethylphenethylamine, 3,4-diethylphenethylamine, 2,5-dimethylphenethylamine, 3,4-dimethylphenethylamine, 3,5-dimethylphenethylamine, 2,6-diethylphenethyl Amines, 2,6-di-i-propylphenethylamine, 2-methoxyphenethylamine, 2-ethoxyphenethylamine, 2-i-propoxyphenethylamine, 3-methoxyphenethylamine, 3 , 5-dimethoxyphenethylamine, 3-n-butoxyphenethylamine, 4-n-butoxyphenethylamine, 4-ethoxyphenethylamine, 3,4-dimethoxyphenethylamine, 2-methyl Thiope Tylamine, 2-ethylthiophenethylamine, 2-i-propylthiophenethylamine, 2-N, N-dimethylaminophenethylamine, 2-phenylphenethylamine, 3-phenylphenethylamine, 4-phenoxy Cyphenethylamine, 2-cyclohexylphenethylamine, 2-cyclopentylphenethylamine, 2-nitrophenethylamine, 2,4-dinitrophenethylamine, 2-fluorophenethylamine, 2-chlorophen Netylamine, 4-chlorophenethylamine, 2,3-dichlorophenethylamine, 3,4-dichlorophenethylamine, 2-i-propyl-4-nitrophenethylamine, 2-i-propyl-6-nitro Phenethylamine, 2-hydroxyphenethylamine, 2-N, N-dimethylaminocarbonylphenethylamine, 2-N-acetylphenethylamine, 2- (1-ethylpropyl) phenethylamine, 2-i -Propyl-4-methylphenethylamine, 2-i-propyl-4-hydroxyphenethylamine, 2-i-propyl-4-chlorophenethylamine, 2-i-propyl-4-aminophenethylamine, 2-i-propyl-5-methylphenethylamine, 2-i-propyl-5-hydroxyphenethylamine, 2-i-propyl-5-chlorophen Butyl amine, and the like 4-chloro-3-methyl-phenethylamine, 3,4-methylenedioxy phenethylamine.
[112] Process 2
[113] Process 2 is a process for preparing the compound of formula V comprising reacting isothiocyanate of the compound of formula IV with NH ₂ -R ¹ -OH.
[114] This process may be carried out in an aprotic solvent (eg, diethyl ether, tetrahydrofuran, dimethylformamide, benzene, toluene, dichloromethane, chloroform, etc.).
[115] The reaction temperature is preferably 0 to 100 ° C, in particular 0 ° C to room temperature. The reaction time is 0.5 to 10 hours.
[116] The amount of NH ₂ -R ¹ -OH (wherein R ¹ is optionally substituted alkylene) is 1.0 to 1.5 molar equivalents of the compound of formula IV.
[117] Examples of NH ₂ -R ¹ -OH include 2-aminoethanol, 2-amino-2-methylethanol, 2-amino-1-methylethanol, 2-amino-1,1-dimethylethanol, 3-aminopropanol, 3 -Amino-2,2-dimethylpropanol, 3-amino-1-methylpropanol, 3-amino-2-methylpropanol, 3-amino-3-methylpropanol, 3-amino-2,2-diethylpropanol, 1 -Aminomethyl-1-hydroxymethylcyclopropane, 1-aminomethyl-1- (hydroxymethyl) cyclobutane, 2- (aminomethyl) cyclopentanol and the like.
[118] Process 3
[119] Process 3 is a process for preparing a compound of Formula VI, including cyclization of a compound of Formula V.
[120] Cyclization methods include 1) a method comprising reacting with diethylazodicarboxylate (DEAD) and triphenylphosphine (Ph ₃ P), and 2) a method comprising reacting with hydrochloric acid and the like.
[121] In 1), in an aprotic solvent (eg, diethyl ether, tetrahydrofuran, dimethylformamide, benzene, toluene, dichloromethane, chloroform, etc.) while stirring at 0 ° C. to room temperature for 0.5 to 5 hours. The reaction can be carried out. The amount of diethylazodicarboxylate (DEAD) and triphenylphosphine (Ph ₃ P) is 1.0 to 1.5 molar equivalents of compound V.
[122] In 2), the reaction may be carried out in concentrated hydrochloric acid while refluxing for 0.5 to 10 hours.
[123] Process 4
[124] Step 4 is a group of R ² (Formula-C (= R ⁵ ) -R ⁶ or a group of formula -SO ₂ R ⁷ wherein R ⁵ is O or S, R ⁶ is alkyl, alkoxy, alkylthio, optionally Substituted amino, optionally substituted aralkyloxy, optionally substituted aralkylthio, optionally substituted aralkylamino, alkoxyalkyl, alkylthioalkyl or optionally substituted aminoalkyl, R ⁷ is alkyl, optionally substituted amino, optionally Substituted aryl or optionally substituted heteroaryl]) in the process of preparing a compound of Formula II.
[125] This process is a base (e.g., triethylamine, pyridine, N, N- dimethylaminopyridine, etc.), the general formula XC (= R ⁵⁾ -R ⁶ in the presence of a (wherein, R ⁵ and R ⁶ are as defined above, And X is halogen. This process can be carried out under generally known conditions of N-acylation. For example, the reaction may be carried out in an aprotic solvent (eg, diethyl ether, tetrahydrofuran, dimethylformamide, benzene, toluene, dichloromethane, chloroform, etc.) while stirring at 0-100 ° C. for 0.5-10 hours. This can be done at
[126] A thioacid ester, wherein R ⁵ is S and R ⁶ is alkylthio or optionally substituted aralkylthio, is reacted with carbon disulfide (CS ₂ ) in the presence of a base (eg sodium hydride, etc.) and halogenated alkyl (eg For example, methyl iodide, ethyl iodide and the like) or halogenated aralkyl (e.g., benzyl bromide and the like). The reaction can be carried out in an aprotic solvent (eg diethyl ether, tetrahydrofuran, dimethylformamide, benzene, toluene, dichloromethane, chloroform, etc.) with stirring at 0 ° C. to room temperature.
[127] When R ² introduced is a group of the formula —SO ₂ R ⁷ wherein R ⁷ is alkyl, optionally substituted amino, optionally substituted aryl or optionally substituted heteroaryl, the compound of formula VI is added to the formula R in the presence of a base ⁷ SO ₂ X (wherein X is a halogen or the like).
[128] Prodrugs are derivatives which are converted into pharmaceutically active compounds of the invention under physiological conditions. Methods of selecting and preparing suitable prodrug derivatives are described in literature such as Design of Prodrugs, Elsevier, Amsterdam 1985.
[129] Prodrugs of the invention can be prepared by introducing a leaving group into a substituent on a substitutable ring A (eg, amino, hydroxy, etc.). Examples of prodrugs derived from compounds having amino groups include carbamate derivatives (eg, methylcarbamate, cyclopropylmethylcarbamate, t-butylcarbamate, benzylcarbamate, etc.), amide derivatives ( For example, formamide, acetamide and the like), N-alkyl derivatives (eg, N-allylamine, N-methoxymethylamine, etc.) and the like. Examples of prodrugs derived from compounds having hydroxy groups include ether derivatives (methoxymethylether, methoxyethoxymethylether, etc.), ester derivatives (eg, acetate, pivaloate, benzoate, etc.), and the like. do.
[130] Examples of pharmaceutically acceptable salts include basic salts (e.g., alkali metal salts such as sodium or potassium salts; alkaline earth metal salts such as calcium or magnesium salts; ammonium salts; aliphatic amine salts such as trimethylamine, triethylamine, dicyclohexyl) Amine, ethanolamine, diethanolamine, triethanolamine or procaine salts; aralkyl amine salts such as N, N-dibenzylethylenediamine salts; heterocyclic aromatic amine salts such as pyridine salts, picoline salts, quinoline salts or isoquinoline Salts; quaternary ammonium salts such as tetramethylammonium salts, tetraethylammonium salts, benzyltrimethylammonium salts, benzyltriethylammonium salts, benzyltributylammonium salts, methyltrioctylammonium salts or tetrabutylammonium salts; and basic amino acid salts such as Arginine salts or lysine salts). Acid addition salts include, for example, mineral acid salts such as hydrochloride salts, sulfate salts, nitrate salts, phosphate salts, carbonate salts, hydrogen carbonate salts or perchlorate salts; Organic acid salts such as acetate, propionate, lactate, maleate, fumarate, tartrate, maleate, succinate, or ascorbate; Sulfonates such as methanesulfonate, isethionate, benzenesulfonate, or p-toluenesulfonate; And acidic amino acid salts such as aspartate or glutamate.
[131] Solvates include solvates of compounds of formula (I) or (II), prodrugs thereof or pharmaceutically acceptable salts thereof, for example, solvates, solvates, monohydrates, dihydrates, and the like.
[132] The compounds of the present invention have binding activity to cannabinoid type 2 receptors (CB2R) and specifically bind to cannabinoid type 2 receptors (CB2R) to exhibit antagonistic or agonistic activity on CB2R, in particular agonistic activity on CB2R.
[133] Since the compounds of the present invention do not have binding activity on cannabinoid type 1 receptors (CB1R), the compounds of the present invention do not cause side effects on the central nervous system such as drug dependence or hallucinations associated with cannabinoid type 1 receptors.
[134] Thus, the compounds of the present invention can be used for the treatment or prevention of diseases associated with cannabinoid type 2 receptors (CB2R). For example, [Proc. Natl. Acad. Sci. USA 96, 14228-14233 describes that CB2R agonists have anti-inflammatory and analgesic activity. Nature, 1998, 349, 277-281 describes that CB2R agonists have analgesic activity. The European Journal of Pharmacology 396 (2000) 85-92 describes that CB2R antagonists have analgesic activity.
[135] The compounds of the present invention inhibit the activation of immune cells or inflammatory cells, thereby exhibiting activity on the peripheral cell system (eg, immunosuppressive activity, anti-inflammatory activity and analgesic activity). Accordingly, the compounds of the present invention can be used as anti-inflammatory agents, anti-allergic agents, analgesics, immunodeficiency agents, immunosuppressants, immunomodulators, autoimmune diseases, chronic rheumatoid arthritis, multiple sclerosis, and the like.
[136] Agonists for cannabinoid type 2 receptors are known to inhibit nephritis caused by rat Thy-1 antibodies (WO97 / 29079). Thus, the compounds of the present invention are useful as nephritis therapeutics.
[137] When the compounds of the present invention are used in therapy, they can be formulated in general oral and parenteral formulations. Pharmaceutical compositions containing a compound of the present invention may be in a form for oral or parenteral administration. Specifically, oral formulations such as tablets, capsules, granules, powders, syrups, and the like; It may be formulated as a parenteral formulation such as intravenous, intramuscular or subcutaneous injection solutions or suspensions, inhalants, eye drops, nasal drops, suppositories, or ointments such as ointments.
[138] In the preparation of the formulations, carriers, excipients, solvents and bases known to those skilled in the art can be used. Tablets can be made by compressing or molding the active ingredient with the auxiliary ingredient. Examples of useful auxiliary ingredients include pharmaceutically acceptable excipients such as binders (eg corn starch), fillers (eg lactose, microcrystalline cellulose), disintegrants (eg sodium starch glycolate), Or lubricants (eg magnesium stearate). Tablets may be appropriately coated. In the case of liquid formulations such as syrups, solutions or suspensions, they may contain suspending agents (eg methyl cellulose), emulsifiers (eg lecithin), preservatives and the like. In the case of injectable formulations, they may be in the form of solutions or suspensions, or oily or aqueous emulsions, and may contain suspension-stabilizers or dispersants and the like. In the case of inhalants, it is formulated in a liquid formulation applicable to the inhaler. In the case of eye drops, they are formulated in solution or suspension.
[139] Appropriate dosages of the compounds of the present invention will vary depending on the route of administration, the age, weight, sex or condition of the patient, and the type of drug (s) used, if any, and should be ultimately determined by the physician, orally. For administration, the daily dosage may generally be about 0.01-100 mg, preferably about 0.01-10 mg, more preferably about 0.01-1 mg per kg body weight. For parenteral administration, the daily dosage may generally be about 0.001-100 mg, preferably about 0.001-1 mg, more preferably about 0.001-0.1 mg per kg body weight. The daily dose may be administered in 1-4 divided doses.
[140] The following examples are provided to further illustrate the invention and should not be construed as limiting the scope of the invention.
[141] The meaning of each abbreviation is as follows.
[142] Me: methyl, Et: ethyl, Pr: propyl, Pr ⁱ : i-propyl,
[143] Bu: butyl, Bu ⁱ : i-butyl, Bu ^s : sec-butyl,
[144] Bu ^t : t-butyl
[145] Ph: phenyl, Ac: acetyl, Bn: benzyl
[146] DMF: N, N-dimethylformamide. THF: tetrahydrofuran,
[147] DEAD: diethyl azodicarboxylate.
[148] Reference Example 1-1 Preparation of (2-isopropylphenyl) isothiocyanate (Compound 2)
[149]
[150] To the mixture of 2-isopropylaniline (5.00 g), triethylamine (3,74 g) and toluene (10 mL) was added dropwise carbon disulfide (2.81 g) for 10 minutes. The mixture was stirred at rt for 1 h and left for 12 h. The reaction mixture was concentrated under reduced pressure. Dichloromethane (20 mL) and triethylamine (3.74 g) were added. To the solution was added ethyl chlorocarbonate (4.01 g) for 10 minutes under ice cooling. The mixture was stirred at rt for 1 h. 10% hydrochloric acid (20 mL) was added to the reaction mixture. The mixture was extracted with dichloromethane (60 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give (2-isopropylphenyl) isothiocyanate (6.55 g, yield: 99%) as a yellow oil. .
[151]
[152] Reference Example 1-2 Preparation of (2-isopropylphenyl) isothiocyanate (Compound 2)
[153]
[154] To a solution of 2-isopropylaniline (1.81 g) in diethyl ether (20 mL) was added dropwise thiophosgene (1.54 g) for 10 minutes under ice-cooling. The mixture was stirred at rt for 1 h.
[155] Water (30 mL) was added to the reaction mixture. The mixture was extracted with diethyl ether (60 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give (2-isopropylphenyl) isothiocyanate (2.35 g, yield: 99%) as a brown oil. It was.
[156] Reference Example 2 Preparation of N- (2-isopropylphenyl) -N '-(1-hydroxy-2,2-dimethyl) propylthiourea (Compound 3)
[157]
[158] To a solution of (2-isopropylphenyl) isothiocyanate (3.30 g) in diethyl ether (20 mL) was added 3-amino-2,2-dimethylpropanol (1.92 g). The mixture was stirred at rt for 1 h and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane / ethyl acetate) to give N- (2-isopropylphenyl) -N '-(1-hydroxy-2,2-dimethyl) propylthiourea (4.60 g, yield: 88%) was obtained as a yellow oil.
[159]
[160] Reference Example 3 Preparation of 2- (2-isopropylphenyl) imino-5,5-dimethyl-1,3-thiazine (Compound 4)
[161]
[162] Concentrated hydrochloric acid (5 mL) was added to N- (2-isopropylphenyl) -N '-(1-hydroxy-2,2-dimethyl) propylthiourea (10.37 g). The mixture was refluxed for 3 hours. The reaction solution was cooled to room temperature and poured into 20% aqueous sodium hydroxide solution (25 mL). The precipitated crystals were filtered and recrystallized with ethyl acetate to give 2- (2-isopropylphenyl) imino-5,5-dimethyl-1,3-thiazine (4.80 g, yield: 50%) as white crystals. Obtained as.
[163] Melting point 155-157 ℃
[164]
[165] Reference Example 4 Preparation of 2- (2-isopropylphenyl) imino-5,5-dimethyl-1,3-thiazine (Compound 4)
[166]
[167] Thionyl chloride (0.60 g) in a solution of N- (2-isopropylphenyl) -N '-(1-hydroxy-2,2-dimethyl) propylthiourea (1.00 g) in tetrahydrofuran (6 mL) Was added dropwise. The mixture was stirred at rt for 1 h and concentrated under reduced pressure. Acetonitrile (20 mL) and potassium carbonate (0.93 g) were added to the solution. The mixture was refluxed for 2 hours. Water (40 mL) was added to the solution. The mixture was extracted with dichloromethane (60 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane / ethyl acetate) to give 2- (2-isopropylphenyl) imino-5,5-dimethyl-1,3-thiazine (0.45 g, Yield: 48%) was obtained as white crystals.
[168] Examples 1 to 5 below were carried out using 2- (2-isopropylphenyl) imino-5,5-dimethyl-1,3-thiazine prepared in Reference Examples 3 and 4.
[169] Example 1 Preparation of 3-ethyl-2- (2-isopropylphenyl) imino-5,5-dimethyl-1,3-thiazine (Compound I-1)
[170]
[171] 60% sodium hydride (0.05 g) in a solution of 2- (2-isopropylphenyl) imino-5,5-dimethyl-1,3-thiazine (0.26 g) in N, N-dimethylformamide (2 mL) ) Was added under ice cooling. The mixture was stirred for 30 minutes. Ethyl iodide (0.17 g) was added. The mixture was stirred at rt for 2 h. Water (30 mL) was added to the reaction mixture, extracted with diethyl ether (60 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (n-hexane / ethyl acetate) to give 3-ethyl-2- (2-isopropylphenyl) imino-5,5-dimethyl-1,3-thiazine (0.21 g, yield: 71%) was obtained as a colorless oil.
[172]
[173] Example 2 Preparation of 2- (2-isopropylphenyl) imino-3-propionyl-5,5-dimethyl-1,3-thiazine (Compound I-2)
[174]
[175] Propionyl chloride in a mixture of 2- (2-isopropylphenyl) imino-5,5-dimethyl-1,3-thiazine (0.26 g), triethylamine (0.15 g) and dichloromethane (5 mL) 0.13 g) was added dropwise for 5 minutes. The mixture was stirred at rt for 2 h. Water (30 mL) was added to the solution. The mixture was extracted with diethyl ether (60 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane / ethyl acetate) to give 2- (2-isopropylphenyl) imino-3-propionyl-5,5-dimethyl-1,3-thia Gin (0.18 g, yield: 56%) was obtained as a colorless oil.
[176]
[177] Example 3 Preparation of 3- (ethoxycarbonyl) -2- (2-isopropylphenyl) imino-5,5-dimethyl-1,3-thiazine (Compound I-3)
[178]
[179] Ethyl chlorocarbobo in a mixture of 2- (2-isopropylphenyl) imino-5,5-dimethyl-1,3-thiazine (0.26 g), triethylamine (0.15 g) and dichloromethane (5 mL) Nate (0.13 g) was added dropwise for 5 minutes. The mixture was stirred at rt for 2 h. Water (30 mL) was added to the solution. The mixture was extracted with diethyl ether (60 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (n-hexane / ethyl acetate) to give 3- (ethoxycarbonyl) -2- (2-isopropylphenyl) imino-5,5-dimethyl-1 , 3-thiazine (0.23 g, yield: 68%) was obtained as white crystals. Melting point 84-86 ° C .;
[180]
[181] Example 4 Preparation of 3- (ethylthiocarbonyl) -2- (2-isopropylphenyl) imino-5,5-dimethyl-1,3-thiazine (Compound I-4)
[182]
[183] Ethyl chlorothiocar in a mixture of 2- (2-isopropylphenyl) imino-5,5-dimethyl-1,3-thiazine (1.00 g), triethylamine (0.58 g) and dichloromethane (5 mL) Bonate (0.56 g) was added dropwise over 5 minutes. The mixture was stirred at rt for 1 h. Water (30 mL) was added to the solution. The mixture was extracted with diethyl ether (60 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane / ethyl acetate) to give 3- (ethylthiocarbonyl) -2- (2-isopropylphenyl) imino-5,5-dimethyl-1 , 3-thiazine (0.74 g, yield: 56%) was obtained as a colorless oil.
[184]
[185] Example 5 Preparation of 2- (2-isopropylphenyl) imino-3- (methylthio) thiocarbonyl-5,5-dimethyl-1,3-thiazine (Compound I-5)
[186]
[187] To a mixture of 2- (2-isopropylphenyl) imino-5,5-dimethyl-1,3-thiazine (0.26 g), carbon disulfide (0.09 g) and N, N-dimethylformamide (2 mL) 60% sodium hydride (0.05 g) was added under ice cooling. The mixture was stirred for 30 minutes. Methyl iodide (0.17 g) was added. The mixture was stirred at rt for 2 h. Water (30 mL) was added to the solution, extracted with diethyl ether (60 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane / ethyl acetate) to give 2- (2-isopropylphenyl) imino-3- (methylthio) thiocarbonyl-5,5-dimethyl- 1,3-thiazine (0.14 g, yield: 40%) was obtained as yellow crystals. Melting point 77-79 ° C.
[188]
[189] Reference Example 5 below was carried out according to Reference Examples 2 and 3.
[190] Reference Example 5 Preparation of 2- (2-isopropylphenyl) imino-1,3-thiazolidine (Compound 6)
[191]
[192] To a solution of (2-isopropylphenyl) isothiocyanate (2.00 g) in diethyl ether (20 mL) was added 2-aminoethanol (0.69 g). The mixture was stirred at rt for 1 h and concentrated under reduced pressure. To the obtained oil was added concentrated hydrochloric acid (5 mL). The mixture was refluxed for 3 hours. The reaction mixture was cooled to room temperature and poured into 20% aqueous sodium hydroxide solution (25 mL). The mixture was extracted with dichloromethane (60 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane / ethyl acetate) to give 2- (2-isopropylphenyl) imino-1,3-thiazolidine (1.80 g, yield: 73%) Was obtained as white crystals. Melting point 76-77 ° C.
[193]
[194] Examples 6 and 7 below were carried out using 2- (2-isopropylphenyl) imino-1,3-thiazolidine prepared in Reference Example 5.
[195] Example 6 Preparation of 3- (ethylthiocarbonyl) -2- (2-isopropylphenyl) imino-1,3-thiazolidine (Compound I-6)
[196]
[197] Ethyl chlorothiocarboxylate (0.15 g) in a mixture of 2- (2-isopropylphenyl) imino-1,3-thiazolidine (0.25 g), triethylamine (0.15 g) and dichloromethane (5 mL) ) Was added dropwise for 5 minutes. The mixture was stirred for 2 hours. Water (30 mL) was added to the solution. The mixture was extracted with diethyl ether (60 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane / ethyl acetate) to give 3- (ethylthiocarbonyl) -2- (2-isopropylphenyl) imino-1,3-thiazolidine (0.27 g, yield: 77%) was obtained as white crystals. Melting point 79-81 ° C.
[198]
[199] Example 7 Preparation of 2- (2-isopropylphenyl) imino-3- (methylthio) thiocarbonyl-1,3-thiazolidine (Compound I-7)
[200]
[201] 60% sodium hydride in a mixture of 2- (2-isopropylphenyl) imino-1,3-thiazolidine (0.22 g), carbon disulfide (0.09 g) and N, N-dimethylformamide (2 mL) 0.05 g) was added under ice cooling. The mixture was stirred for 30 minutes. Methyl iodide (0.17 g) was added. The mixture was stirred at rt for 2 h. Water (30 mL) was added to the mixture. The mixture was extracted with diethyl ether (60 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (n-hexane / ethyl acetate) to give 2- (2-isopropylphenyl) imino-3- (methylthio) thiocarbonyl-1,3-thiazoli Dean (0.14 g, yield: 45%) was obtained as a colorless oil.
[202]
[203] Reference Example 6 Preparation of (2-methoxybenzyl) isothiocyanate (Compound 8)
[204]
[205] To a solution of 2-methoxybenzylamine (1.80 g) in diethyl ether (20 mL) was added dropwise thiophosgene (1.54 g) for 10 minutes under ice-cooling. The mixture was stirred at rt for 1 h. Water (30 mL) was added to the reaction solution, extracted with diethyl ether (60 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give (2-methoxybenzyl) isothiocyanate (2.35 g, Yield: 99%) was obtained as a brown oil.
[206]
[207] Reference Example 7 Preparation of N- (2-methoxybenzyl) -N '-(1-hydroxy-2,2-dimethyl) propylthiourea (Compound 9)
[208]
[209] To a solution of (2-methoxybenzyl) isothiocyanate (2.35 g) in diethyl ether (20 mL) was added 3-amino-2,2-dimethylpropanol (1.34 g). The mixture was stirred at rt for 1 h. The mixture was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane / ethyl acetate) to give N- (2-methoxybenzyl) -N '-(1-hydroxy-2,2-dimethyl) propylthiourea. (3.70 g, yield: 99%) was obtained as a colorless oil.
[210]
[211] Reference Example 8 Preparation of 2- (2-methoxybenzyl) imino-5,5-dimethyl-1,3-thiazine (Compound 10)
[212]
[213] Of N- (2-methoxybenzyl) -N '-(1-hydroxy-2,2-dimethyl) propylthiourea (3.70 g), triphenylphosphine (3.44 g) and tetrahydrofuran (20 mL) Azodicarboxylate (2.28 g) was added dropwise to the mixture for 10 minutes. The mixture was stirred at rt for 2 h. Water (40 mL) was added to the solution. The mixture was extracted with dichloromethane (90 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane / ethyl acetate) to give 2- (2-methoxybenzyl) imino-5,5-dimethyl-1,3-thiazine (0.87 g, Yield: 25%) was obtained as a colorless oil.
[214]
[215] Examples 8 and 9 below were carried out using 2- (2-methoxybenzyl) imino-5,5-dimethyl-1,3-thiazine prepared in Reference Example 8.
[216] Example 8 Preparation of 3- (ethylthiocarbonyl) -2- (2-methoxybenzyl) imino-5,5-dimethyl-1,3-thiazine (Compound I-8)
[217]
[218] Ethyl chlorothiocar in a mixture of 2- (2-methoxybenzyl) imino-5,5-dimethyl-1,3-thiazine (0.28 g), triethylamine (0.15 g) and dichloromethane (5 mL) Voxylate (0.17 g) was added dropwise for 5 minutes. The mixture was stirred at rt for 1 h. Water (30 mL) was added to the reaction solution, extracted with diethyl ether (60 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane / ethyl acetate) to give 3- (ethylthiocarbonyl) -2- (2-methoxybenzyl) imino-5,5-dimethyl-1 , 3-thiazine (0.20 g, yield: 57%) was obtained as a colorless oil.
[219]
[220] Example 9 Preparation of 2- (2-methoxybenzyl) imino-3- (methylthio) thiocarbonyl-5,5-dimethyl-1,3-thiazine (Compound I-9)
[221]
[222] To a mixture of 2- (2-methoxybenzyl) imino-5,5-dimethyl-1,3-thiazine (0.27 g), carbon disulfide (0.09 g) and N, N-dimethylformamide (2 mL) 60% sodium hydride (0.05 g) was added under ice cooling. The mixture was stirred for 30 minutes. Methyl iodide (0.17 g) was added. The mixture was stirred at rt for 2 h. Water (30 mL) was added to the solution. The mixture was extracted with diethyl ether (60 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane / ethyl acetate) to give 2- (2-methoxybenzyl) imino-3- (methylthio) thiocarbonyl-5,5-dimethyl- 1,3-thiazine (0.20 g, yield: 57%) was obtained as a colorless oil.
[223]
[224] Reference Example 9 Preparation of (2-methoxyphenethyl) isothiocyanate (Compound 12)
[225]
[226] Thiophosgene (1.54 g) was added dropwise under ice-cooling to a solution of 2-methoxyphenethylamine (1.98 g) in diethyl ether (20 mL). The mixture was stirred at rt for 1 h. Water (30 mL) was added to the solution. The mixture was extracted with diethyl ether (60 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure to afford (2-methoxyphenethyl) isothiocyanate (1.80 g, yield: 71%) as a brown oil. Obtained.
[227]
[228] Reference Example 10 Preparation of N- (2-methoxyphenethyl) -N '-(1-hydroxy-2,2-dimethyl) propylthiourea (Compound 13)
[229]
[230] To a solution of (2-methoxyphenethyl) isothiocyanate (2.35 g) in diethyl ether (20 mL) was added 3-amino-2,2-dimethylpropanol (1.34 g). The mixture was stirred at rt for 1 h. The mixture was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane / ethyl acetate) to give N- (2-methoxyphenethyl) -N '-(1-hydroxy-2,2-dimethyl) propylthio Urea (2.45 g, yield: 89%) was obtained as a colorless oil.
[231]
[232] Reference Example 11 Preparation of 2- (2-methoxyphenethyl) imino-5,5-dimethyl-1,3-thiazine (Compound 14)
[233]
[234] N- (2-methoxyphenethyl) -N '-(1-hydroxy-2,2-dimethyl) propylthiourea (2.40 g), triphenylphosphine (2.12 g) and tetrahydrofuran (20 mL) To the mixture of diethyl azodicarboxylate (2.28 g) was added dropwise for 10 minutes. The mixture was stirred at rt for 2 h. Water (40 mL) was added to the solution. The mixture was extracted with dichloromethane (90 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane / ethyl acetate) to give 2- (2-methoxyphenethyl) imino-5,5-dimethyl-1,3-thiazine (0.70 g , Yield: 31%) was obtained as a colorless oil.
[235]
[236] Examples 10 and 11 below were carried out using 2- (2-methoxyphenethyl) imino-5,5-dimethyl-1,3-thiazine prepared in Reference Example 11.
[237] Example 10 Preparation of 3- (ethylthiocarbonyl) -2- (2-methoxyphenethyl) imino-5,5-dimethyl-1,3-thiazine (Compound I-10)
[238]
[239] Ethyl chlorothio in a mixture of 2- (2-methoxyphenethyl) imino-5,5-dimethyl-1,3-thiazine (0.28 g), triethylamine (0.15 g) and dichloromethane (5 mL) Carboxylate (0.15 g) was added dropwise for 3 minutes. The mixture was stirred at rt for 2 h. Water (30 mL) was added to the solution. The mixture was extracted with diethyl ether (60 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane / ethyl acetate) to give 2- (2-methoxyphenethyl) imino-N- (ethylthiocarbamoyl) -5,5-dimethyl -1,3-thiazine (0.21 g, yield: 60%) was obtained as a colorless oil.
[240]
[241] Example 11 Preparation of 2- (2-methoxyphenethyl) imino-3- (methylthio) thiocarbonyl-5,5-dimethyl-1,3-thiazine (Compound I-11)
[242]
[243] Mixture of 1- (1-methoxyphenethyl) imino-5,5-dimethyl-1,3-thiazine (0.28 g), carbon disulfide (0.09 g) and N, N-dimethylformamide (2 mL) To 60% sodium hydride (0.05 g) was added under ice cooling. The mixture was stirred for 30 minutes. Methyl iodide (0.17 g) was added. The mixture was stirred at rt for 2 h. Water (30 mL) was added to the solution. The mixture was extracted with diethyl ether (60 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was chromatographed (n-hexane / ethyl acetate) to give 2- (2-methoxyphenethyl) imino-3- (methylthio) thiocarbonyl-5,5-dimethyl-1,3- Thiazine (0.18 g, yield: 50%) was obtained as a colorless oil.
[244]
[245] The compounds shown in the following table were prepared according to the above examples. The numbers in the left column of the table represent the compound numbers.
[246]
[247]
[248]
[249]
[250]
[251]
[252]
[253]
[254]
[255]
[256]
[257]
[258]
[259]
[260] Physical data (melting point, ¹ H-NMR) of the compounds of the table are shown in the table below.
[261]
[262]
[263]
[264]
[265]
[266]
[267]
[268]
[269]
[270]
[271]
[272]
[273]
[274]
[275]
[276]
[277]
[278]
[279]
[280]
[281]
[282]
[283]
[284]
[285]
[286]
[287] The following compounds are within the scope of the present invention. Such compounds may be prepared according to the above examples. The numbers in the left column of the table represent the compound numbers.
[288]
[289]
[290]
[291]
[292]
[293]
[294]
[295]
[296]
[297]
[298]
[299]
[300]
[301]
[302]
[303]
[304]
[305]
[306]
[307]
[308]
[309]
[310]
[311]
[312]
[313]
[314]
[315]
[316]
[317]
[318]
[319]
[320]
[321]
[322]
[323]
[324]
[325]
[326]
[327]
[328]
[329]
[330]
[331]
[332]
[333]
[334]
[335]
[336]
[337]
[338] The compounds of the present invention were tested as follows.
[339] Test Example 1 Experiment for Inhibiting Human CB2 Receptor (CB2R) Binding
[340] The coding region of human CB2R cDNA (Munro et al., 1993, 365, 61-65) was inserted into the mammalian expression vector pSVL SV40 Late Promoter Expression Vector (Amersham Pharmacia Biotech Inc.). The prepared vector was transfected into Chinese Hamster Ovary (CHO) cells using LipofectAMINE reagent (Gibco BRL) and a stable CB2R-expressing clone was selected.
[341] A crude membrane fraction was then prepared from CB2R-expressing CHO cells. Receptor binding assays were performed with the respective test compounds and [ ³ H] CP55940 (50 mM Tris-HCl, 1 mM EDTA, 3 mM MgCl ₂ , pH 7.4) membranes in assay buffer containing 0.5% bovine serum albumin (BSA). Final concentration 0.5 nM: NEN Life Science Products) was incubated for 2 hours at 25 ℃. The incubation mixture was filtered through a 1% polyethyleneimine (PEI) -treated GF / C glass filter and washed with 50 mM Tris-HCl (pH 7.4) containing 0.1% BSA. Radioactivity was then counted with a liquid scintillation counter. Nonspecific binding was determined in the presence of 10 μM WIN55212-2 (CB agonist described in Patent US508122, Research Biochemicals International), and specific binding was calculated by subtracting nonspecific binding from total binding. IC ₅₀ values for each test compound were determined as concentrations at which 50% specific binding was inhibited.
[342] For receptor binding assays to human CB1 receptor (CB1R), stable CB1R-expressing CHO cells were prepared as described above and binding assays were performed using their membrane fractions. As a result of this study, the K _i values of each test compound for both cannabinoid receptors were determined and are shown in Table 89. As shown in Table 89, the series of compounds described herein were found to selectively block the binding of CP55940 (CB agonist described in US Pat. No. 43,717,20) to CB2R more effectively than CB1R.
[343]
[344] Test Example 2: Inhibition experiment on CB2R-mediated inhibition of cAMP synthesis
[345] CHO cells expressing human CB2R were incubated with the test compound for 15 minutes. After incubation, 4 μM forskolin (Sigma) was added and the cells were incubated at 37 ° C. for 20 minutes. The reaction was stopped by the addition of 1N HCl and the amount of cAMP in the cell supernatant was measured using the EIA kit (Amersham Pharmacia Biotech) according to the instructions. The amount of cAMP increased by forskolin compared to the absence of forskolin was 100% and the IC ₅₀ value of each test compound was determined at a concentration at which 50% of forskolin-stimulated cAMP synthesis was inhibited. . As a result of this study, the IC ₅₀ values of each test compound are shown in Table 90. As shown in Table 90, the compounds described in the present invention were found to have functional activity on CB2R.
[346] The antagonistic activity of each compound was also evaluated in this assay.
[347]
[348] Test Example 3 Experiment for Positive Red Blood Cell (SRBC) -Induced Delayed Hypersensitivity (DTH) Response
[349] Female ddY mice (7 weeks old) were used for sheep erythrocyte (SRBC) -induced delayed hypersensitivity (DTH) reactions.
[350] The cannabinoid receptor agonists I-6, I-60, I-77 and I-118 were suspended in 0.6% Arabian rubber solution. Mice were sensitized by intradermal injection of 10 ⁷ cells of SRBC (40 μl / foot) into the left hind paw of the mouse. Five days later, DTH responses were induced by intradermal injection of 10 ⁸ cells of SRBC into the right hind paw of mice. Test compounds were administered orally 1 hour before and 5 hours after DTH reaction induction (10 mL / kg). Twenty four hours after SRBC injection, the volumes of the left and right hind paws were measured by numerical method. Plantar swelling was calculated from the volume difference between the right and left hind paws and used as an indicator of DTH response.
[351] Data is shown as percent inhibition of each compound. Statistical analysis was performed by Welch's t-test, where a value of P <0.05 is considered a significant difference.
[352]
[353] Compounds of formulas (I) and (II) of the present invention selectively bind to cannabinoid type 2 receptors (CB2R) to exhibit antagonistic or agonistic activity against CB2R. Thus, the compounds of the present invention can be used for the treatment or prevention of diseases associated with cannabinoid type 2 receptors (CB2R) without causing side effects on the central nervous system such as drug dependence or hallucinations associated with cannabinoid type 1 receptors (CB1R).

权利要求:
Claims (26)
[1" claim-type="Currently amended] A pharmaceutical composition comprising a compound of formula (I), a prodrug thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof:
[Formula I]
[Wherein, R ¹ is an optionally substituted alkylene,
R ² is alkyl; Formula -C (= R ⁵ ) -R ⁶ , wherein R ⁵ is O or S; R ⁶ is alkyl, alkoxy, alkylthio, optionally substituted amino, optionally substituted aralkyloxy, optionally substituted aralkylthio , Optionally substituted aralkylamino, alkoxyalkyl, alkylthioalkyl or optionally substituted aminoalkyl); Or a group of the formula -SO ₂ R ⁷ , wherein R ⁷ is alkyl, optionally substituted amino, optionally substituted aryl or optionally substituted heteroaryl,
m is an integer from 0 to 2,
A is an optionally substituted aromatic carbon ring or an optionally substituted aromatic hetero ring.
[2" claim-type="Currently amended] The compound of claim 1 wherein Pharmaceutical compositions wherein the group is of the formula

[Wherein R ³ and R ⁴ are each independently hydrogen, alkyl, alkoxy, alkylthio, optionally substituted amino, optionally substituted aryl, optionally substituted aryloxy, cycloalkyl, halogen, hydroxy, nitro, haloalkyl, Haloalkoxy, optionally substituted carbamoyl, carboxy, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, alkoxyalkyl, alkylthioalkyl, optionally substituted aminoalkyl, alkoxyalkoxy, alkylthioalkoxy, optionally substituted heteroaryl, An optionally substituted non-aromatic heterocyclic group, alkoxyiminoalkyl or a formula -C (= 0) -R ^H , wherein R ^H is hydrogen, alkyl, optionally substituted aryl or optionally substituted non-aromatic heterocyclic group Or)
Or R ³ and R ⁴ together may form an alkylenedioxy,
A is an optionally substituted aromatic carbon ring or an optionally substituted aromatic hetero ring.
[3" claim-type="Currently amended] The pharmaceutical composition according to claim 1 or 2, having binding activity to cannabinoid type 2 receptors.
[4" claim-type="Currently amended] 4. A pharmaceutical composition according to claim 3 having an agonistic activity on cannabinoid type 2 receptors.
[5" claim-type="Currently amended] The pharmaceutical composition according to claim 3, which is useful as an anti-inflammatory agent.
[6" claim-type="Currently amended] The pharmaceutical composition according to claim 3, which is useful as an immunosuppressive agent.
[7" claim-type="Currently amended] 4. The pharmaceutical composition according to claim 3, which is useful as an agent for treating nephritis.
[8" claim-type="Currently amended] A compound of formula II, a prodrug thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof:
[Formula II]
[Wherein, R ¹ is an optionally substituted alkylene,
R ² is of the formula —C (═R ⁵ ) —R ⁶ , wherein R ⁵ is O or S, R ⁶ is alkyl, alkoxy, alkylthio, optionally substituted amino, optionally substituted aralkyloxy, optionally substituted Aralkylthio, an optionally substituted aralkylamino, alkoxyalkyl, alkylthioalkyl or an optionally substituted aminoalkyl), or a formula -SO ₂ R ⁷ , wherein R ⁷ is alkyl, optionally substituted amino, optionally substituted Aryl or optionally substituted heteroaryl),
R ³ and R ⁴ are each independently hydrogen, alkyl, alkoxy, alkylthio, optionally substituted amino, optionally substituted aryl, optionally substituted aryloxy, cycloalkyl, halogen, hydroxy, nitro, haloalkyl, haloalkoxy, Optionally substituted carbamoyl, carboxy, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, alkoxyalkyl, alkylthioalkyl, optionally substituted aminoalkyl, alkoxyalkoxy, alkylthioalkoxy, optionally substituted heteroaryl, optionally substituted Non-aromatic heterocyclic group, alkoxyiminoalkyl, or formula -C (= 0) -R ^H , wherein R ^H is hydrogen, alkyl, optionally substituted aryl or optionally substituted non-aromatic heterocyclic group Is a group of
Or R ³ and R ⁴ together may form an alkylenedioxy,
m is an integer from 0 to 2,
A is an optionally substituted aromatic carbon ring or an optionally substituted aromatic hetero ring.
[9" claim-type="Currently amended] The compound of claim 8, wherein m is 0, a prodrug thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof.
[10" claim-type="Currently amended] 10. A compound according to claim 8 or 9, wherein R ¹ is C2-C9 linear or branched alkylene optionally substituted with alkylene, prodrugs thereof, pharmaceutically acceptable salts or solvates thereof.
[11" claim-type="Currently amended] The compound according to any one of claims 8 to 10, wherein R ¹ is C2-C9 linear alkylene substituted with alkylene, or C2-C9 branched alkylene, prodrug thereof, pharmaceutically acceptable thereof. Salts or solvates thereof.
[12" claim-type="Currently amended] The compound according to any one of claims 8 to 11, wherein R ⁶ is alkoxy or alkylthio and R ⁷ is optionally substituted aryl, a prodrug thereof, a pharmaceutically acceptable salt thereof or a solvate thereof.
[13" claim-type="Currently amended] The compound according to any one of claims 8 to 12, wherein R ³ and R ⁴ are each independently hydrogen, alkyl, alkoxy or alkylthio, and A is an optionally substituted aromatic carbon ring, a prodrug thereof, or a pharmaceutical thereof. Optionally acceptable salts or solvates thereof.
[14" claim-type="Currently amended] The compound of claim 8, wherein R ¹ is 2,2-dimethyltrimethylene, 2,2-diethyltrimethylene, 2,2-ethylenetrimethylene, 1-methyltrimethylene, 2-methyltrimethylene, trimethylene, 2 , 2-di-n-propyltrimethylene, 2,2-tetramethylenetrimethylene, 2,2-pentamethylenetrimethylene, 1,1-dimethylethylene or 1-methylethylene, R ⁶ is methyl, ethyl, n -Propyl, i-propyl, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, methylthio, ethylthio, n-propylthio, i-propylthio, i-butylthio, see -Butylthio, benzyloxy, benzylthio, methoxymethyl, ethoxymethyl, methylthiomethyl, ethylthiomethyl or ethylamino, and R ⁷ is methyl, ethyl, 4-tolyl, 4-nitrophenyl, 3-nitrophenyl , 2-nitrophenyl, 4-methoxyphenyl, 4-trifluoromethylphenyl, 2-thienyl or 2-naphthyl, R ³ is hydrogen, methyl, ethyl, n-propyl, i-propyl, n-butyl , i-butyl, see-butyl, t-butyl, methoxy, to C, n-propoxy, i-propoxy, n-butoxy, methylthio, ethylthio, n-propylthio, i-propylthio, dimethylamino, acetylamino, N-acetylmethylamino, diethylamino, ethyl Methylamino, propylmethylamino, phenyl, phenoxy, fluoro, chloro, bromo, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, N-methylcarbamoyl, methoxycarbonyl, methane Sulfinyl, ethanesulfinyl, methanesulfonyl, ethanesulfonyl, acetyl, methoxymethyl, 1-methoxyethyl, 3-pyridyl, morpholino, pyrrolidino, piperidino, 2-oxopyrrolidino , 1-methoxyiminoethyl or morpholinocarbonyl and R ⁴ is hydrogen, methyl, ethyl, fluoro, chloro, nitro, methoxy or ethoxy, or R ³ and R ⁴ together are —O—CH ₂ -O-, wherein A is benzene, naphthalene, pyridine or quinoline, a prodrug thereof, a drug thereof Acceptable salt or solvate thereof.
[15" claim-type="Currently amended] A pharmaceutical composition comprising a compound according to claim 8, a prodrug thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof.
[16" claim-type="Currently amended] The pharmaceutical composition of claim 15 having binding activity to cannabinoid type 2 receptors.
[17" claim-type="Currently amended] The pharmaceutical composition of claim 16 having an agonistic activity on cannabinoid type 2 receptors.
[18" claim-type="Currently amended] The pharmaceutical composition according to claim 16, which is useful as an anti-inflammatory agent.
[19" claim-type="Currently amended] The pharmaceutical composition of claim 16, wherein the pharmaceutical composition is useful as an immunosuppressive agent.
[20" claim-type="Currently amended] The pharmaceutical composition according to claim 16, which is useful as a nephritis agent.
[21" claim-type="Currently amended] A method for treating inflammation comprising administering a pharmaceutical composition according to claim 1.
[22" claim-type="Currently amended] An immunosuppressive method comprising administering the pharmaceutical composition according to claim 1.
[23" claim-type="Currently amended] A method of treating nephritis comprising administering a pharmaceutical composition according to claim 1.
[24" claim-type="Currently amended] Use of a compound according to claim 1 for the manufacture of anti-inflammatory agents.
[25" claim-type="Currently amended] Use of a compound according to claim 1 for the preparation of an immunosuppressive agent.
[26" claim-type="Currently amended] Use of a compound according to claim 1 for the preparation of a therapeutic agent for nephritis.

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同族专利:

---

公开号 | 公开日

---

US7420053B2|2008-09-02|

---

DE60038687D1|2008-06-05|

---

CN1387519A|2002-12-25|

---

JP3936189B2|2007-06-27|

---

EP1219612B1|2008-04-23|

---

US6818640B1|2004-11-16|

---

AU6877300A|2001-04-17|

---

EP1219612A4|2002-10-16|

---

US7183275B2|2007-02-27|

---

US20070088020A1|2007-04-19|

---

WO2001019807A1|2001-03-22|

---

CA2384757A1|2001-03-22|

---

US20050124617A1|2005-06-09|

---

CN1247553C|2006-03-29|

---

DE60038687T2|2009-05-28|

---

TWI285199B|2007-08-11|

---

KR100509401B1|2005-08-22|

---

AT393150T|2008-05-15|

---

EP1219612A1|2002-07-03|

引用文献:

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公开号 | 申请日 | 公开日 | 申请人 | 专利标题

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法律状态:
1999-09-14|Priority to JPJP-P-1999-00260780

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1999-09-14|Priority to JP26078099

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2000-09-11|Application filed by 시오노 요시히코, 시오노기세이야쿠가부시키가이샤

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2002-04-13|Publication of KR20020027646A

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2005-08-22|Application granted

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2005-08-22|Publication of KR100509401B1

优先权:

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申请号 | 申请日 | 专利标题

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JPJP-P-1999-00260780|1999-09-14|

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JP26078099|1999-09-14|