Medicinal composition containing 1,3-thiazine derivative

专利摘要:
The present invention relates to compounds of formula (I) having a binding action to cannabinoid type 2 receptors: [Formula I] Wherein R 1 is an optionally substituted heterocyclic group or the like; each of R 2 and R 3 is independently hydrogen or the like; m is an integer from 0 to 2; A is an optionally substituted aromatic carbocyclic group or the like).
公开号:KR20040007462A
申请号:KR10-2003-7011711
申请日:2002-02-14
公开日:2004-01-24
发明作者:가이히로유끼；무라시다까미；도미다미노루
申请人:시오노기세이야쿠가부시키가이샤；
IPC主号:

专利说明:

Pharmaceutical composition containing a 1,3-thiazine derivative {MEDICINAL COMPOSITION CONTAINING 1,3-THIAZINE DERIVATIVE}
[2] Cannabinoids were discovered in 1960 as the main active substance contained in marijuana, whose actions are central nervous system actions (psychedelic, fortunate, confusion of time-space appreciation), and peripheral cell system actions (immunosuppressive, anti Inflammation, analgesic).
[3] Then, anandamide and 2-arachidonoylglycerol produced from arachidonic acid-containing phospholipids were found as endogenous cannabinoid receptor agonists. These endogenous agonists are known to express central nervous system and peripheral cell system functions. Hypertension (1997) 29, 1204-1210 also reports the action of anandamide on the cardiovascular system.
[4] Cannabinoid type 1 receptors discovered in 1990 were found to be distributed in the central nervous system such as the brain. Agonists to these receptors are known to inhibit the release of neurotransmitters and cause central effects such as analgesic or hallucinations. Cannabinoid type 2 receptors discovered in 1993 are known to be distributed in immune system tissues such as the spleen. Agonists for this receptor have been shown to exhibit immunosuppressive, anti-inflammatory, and analgesic effects by inhibiting the activation of immune or inflammatory cells (Nature, 1993, 365, 61-65).
[5] Therefore, agonists for cannabinoid type 2 receptors are expected as immunosuppressants, anti-inflammatory agents, and analgesics (Nature, 1998, 349, 277-281).
[6] Isoindolidon derivatives (WO97 / 29079 and WO99 / 02499), pyrazole derivatives (WO98 / 41519) and the like are known as compounds having agonist action on cannabinoid type 2 receptors.
[7] See also J. Pharmacol. Exp. Ther., 2001, 296, 420-425 disclose that compounds having a binding action (agonist action and / or antagonist action) to cannabinoid type 2 receptors have an anti-inflammatory effect.
[8] On the other hand, Japanese Patent Publication (Publication 1986-65894, Published 1987-29594) discloses that an organic phosphorus compound having a 2-imino-1,3-thiazine skeleton is useful as an insecticide.
[9] WO 00/42031 also discloses that compounds similar to the compounds of the present invention have a binding action to progesterone receptors.
[10] However, it is not known that 2-imino-1,3-thiazine derivatives have a binding action (antagonist action and / or agonist action) to cannabinoid type 2 receptors.
[11] Disclosure of the Invention
[12] The present invention seeks to find a compound having a binding action (antagonist action and / or agonist action) to cannabinoid type 2 receptors.
[13] The present invention provides 2-imino-1,3-thiazine derivatives as novel compounds having a binding action on cannabinoid type 2 receptors.
[14] The present invention includes the following:
[15] (1) a compound of formula (I), a prodrug thereof, a pharmaceutically acceptable salt thereof or a solvate thereof:
[16]
[17] [In the meal,
[18] R ¹ is an optionally substituted heterocyclic group or formula: -C (= Z) WR ⁴ (where Z is an oxygen atom or a sulfur atom; W is an oxygen atom or a sulfur atom; R ⁴ is optionally substituted alkyl, optionally substituted Alkenyl or optionally substituted alkynyl);
[19] Each of R ² and R ³ is independently hydrogen, optionally substituted alkyl, optionally substituted alkoxyalkyl, optionally substituted aminoalkyl, or optionally substituted cycloalkyl; or
[20] R ² and R ³ together form a substituted alkylene which may contain heteroatom (s);
[21] m is an integer from 0 to 2;
[22] A is an optionally substituted aromatic carbocyclic group or an optionally substituted aromatic heterocyclic group;
[23] Provided that when R ¹ is a group represented by the formula: -C (= Z) WR ⁴ (where Z is an oxygen atom or a sulfur atom; W is an oxygen atom or a sulfur atom; R ⁴ is an unsubstituted alkyl), ² and R ³ together form an optionally substituted alkylene containing heteroatom (s);
[24] (2) The compound according to (1) above, a prodrug thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof:
[25]
[26] Is an equation represented by:
[27]
[28] [In the meal,
[29] Each of R ⁵ and R ⁶ is 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 Group of; or
[30] R ⁵ and R ⁶ together form an alkylenedioxy;
[31] A is an aromatic carbocyclic group or aromatic heterocyclic group;
[32] (3) The compound according to the above (2), a prodrug thereof, a pharmaceutically acceptable salt thereof or a solvate thereof:
[33] R ⁵ is hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy , Methylthio, ethylthio, n-propylthio, isopropylthio, 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-oxopyrrolidino, 1-methoxyiminoethyl or morpholinocarbonyl;
[34] R ⁶ is hydrogen, methyl, ethyl, fluoro, chloro, nitro, methoxy or ethoxy; or
[35] R ⁵ and R ⁶ together form —O—CH ₂ —O—;
[36] A is phenyl, naphthyl, pyridyl or quinolyl;
[37] (4) The compound according to the above (2), a prodrug thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof:
[38] Each of R ⁵ and R ⁶ is independently hydrogen, alkyl, alkoxy, or alkylthio;
[39] A is an aromatic carbocyclic group;
[40] (5) The compound according to any one of the above (1) to (4), a prodrug thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof:
[41] m is 0;
[42] (6) The compound according to (5) above, a prodrug thereof, a pharmaceutically acceptable salt thereof or a solvate thereof:
[43] R ¹ is an optionally substituted heterocyclic group.
[44] (7) The compound according to (6) above, a prodrug thereof, a pharmaceutically acceptable salt thereof or a solvate thereof:
[45] R ¹ is optionally substituted pyridyl, optionally substituted benzothiazolyl, optionally substituted benzoxazolyl or optionally substituted thiadiazolyl.
[46] (8) The compound according to (5) above, a prodrug thereof, a pharmaceutically acceptable salt thereof or a solvate thereof:
[47] R ¹ is a formula: -C (= Z) WR ⁴ where Z is an oxygen atom or a sulfur atom; W is an oxygen atom or a sulfur atom; R ⁴ is optionally substituted alkyl, optionally substituted alkenyl or optionally substituted alkoxy Nil);
[48] (9) The compound according to the above (8), a prodrug thereof, a pharmaceutically acceptable salt thereof or a solvate thereof:
[49] Z and W are sulfur atoms;
[50] (10) The compound according to any one of the above (1) to (9), a prodrug thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof:
[51] Each of R ² and R ³ is independently methyl, ethyl, propyl or methoxymethyl; or
[52] R ² and R ³ together form ethylene, trimethylene, tetramethylene, pentamethylene or ethyleneoxyethylene;
[53] (11) The compound according to (1), which is represented by the following formula, a prodrug thereof, a pharmaceutically acceptable salt thereof or a solvate thereof:
[54]
[55] [In the meal,
[56] Each of R ² and R ³ is independently optionally substituted alkyl;
[57] R ² and R ³ together form an optionally substituted alkylene which may contain heteroatoms;
[58] R ⁴ is optionally substituted alkyl, optionally substituted alkenyl or optionally substituted alkynyl;
[59] R ⁵ is alkyl, alkoxy, or optionally substituted amino;
[60] R ⁶ is hydrogen, alkyl, alkoxy, optionally substituted amino or haloalkoxy;
[61] (12) The compound according to the above (11), a prodrug thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof:
[62] R ⁴ is optionally substituted alkyl [substituents are cyano, alkoxy, alkylcarbonyl, carboxy, alkoxycarbonyl, alkenyloxycarbonyl, alkoxyalkoxycarbonyl, optionally substituted carbamoyl (substituent is alkyl or alkoxy) , Halogen, alkylcarbonyloxy, aryloxy, optionally substituted non-aromatic heterocyclic group (substituent is alkyl), optionally substituted aromatic heterocyclic group (substituent is alkyl or aryl), or formula: -OR ^I Wherein R ^I is a group represented by a non-aromatic heterocyclic group), alkenyl or alkynyl;
[63] (13) The compound according to (1) above, a prodrug thereof, a pharmaceutically acceptable salt thereof or a solvate thereof:
[64] A is optionally substituted phenyl, optionally substituted naphthyl, or optionally substituted quinolyl;
[65] (14) A pharmaceutical composition comprising the compound according to any one of (1) to (13), a prodrug thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof;
[66] (15) The pharmaceutical composition according to the above (14), which has a binding action to the cannabinoid type 2 receptor;
[67] (16) The pharmaceutical composition according to the above (15), which has an agonist action on the cannabinoid type 2 receptor;
[68] (17) The pharmaceutical composition according to any of the above (14) to (16), which is useful as an anti-inflammatory agent;
[69] (18) A method of treating inflammation comprising administering a pharmaceutical composition according to (1) above;
[70] (19) the use of a compound according to the above (1) to prepare an anti-inflammatory agent;
[71] (20) The pharmaceutical composition according to any one of (14) to (16) above, which is useful as an immunosuppressive agent;
[72] (21) The pharmaceutical composition according to any one of (14) to (16) above, which is useful as a nephritis therapeutic agent;
[73] (22) The pharmaceutical composition according to any of the above (14) to (16), which is useful as an analgesic agent;
[74] (23) A method of treating immunosuppression, comprising administering the pharmaceutical composition according to (1) above;
[75] (24) A method for treating nephritis, comprising administering the pharmaceutical composition according to (1) above;
[76] (25) A method for treating pain, comprising administering the pharmaceutical composition according to (1) above;
[77] (26) use of a compound according to (1) above for preparing an immunosuppressive agent;
[78] (27) use of a compound according to the above (1) for the preparation of a nephritis therapeutic agent;
[79] (28) Use of a compound according to the above (1) to prepare an analgesic agent.
[80] Compounds represented by formula (I) include the following:
[81] 1) The 1,3-thiazine ring is an optionally substituted heterocyclic group or a formula -C (= Z) WR ⁴ (where Z is an oxygen atom or a sulfur atom; W is an oxygen atom or a sulfur atom; R ⁴ is an optionally substituted Alkyl, optionally substituted alkenyl, or optionally substituted alkynyl)
[82] 2) The 1,3-thiazine ring is represented by the formula = N- (CH ₂ ) _m -A, wherein m is an integer from 0 to 2; A is an optionally substituted aromatic carbocyclic group or an optionally substituted aromatic heterocyclic group) Substituted at position 2 with the indicated groups;
[83] As the compound represented by the formula (I), the following cases are preferable:
[84] 1) Substituents on A ring are 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 nonaromatic A heterocyclic group, or a group represented by the formula: -C (= 0) -R ^H , wherein R ^H is hydrogen, alkyl, optionally substituted aryl or optionally substituted non-aromatic heterocyclic group Occation,
[85] 2) when the A ring is substituted with an alkylenedioxy at an adjacent position,
[86] 3) If m is 0,
[87] 4) when R ¹ is optionally substituted pyridyl, optionally substituted benzothiazolyl, optionally substituted benzoxazolyl, or optionally substituted thiazolyl,
[88] 5) R ¹ is a formula -C (= Z) WR ⁴ where Z is an oxygen atom or a sulfur atom; W is an oxygen atom or a sulfur atom; R ⁴ is optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted Is alkynyl),
[89] 6) R ¹ is a formula -C (= Z) WR ⁴ where Z is an oxygen atom or a sulfur atom; W is an oxygen atom or a sulfur atom; R ⁴ is substituted alkyl, optionally substituted alkenyl, or optionally substituted Alkynyl),
[90] 7) R ¹ and R ² are each independently methyl, ethyl, propyl, or methoxymethyl; Or when R ¹ and R ² together form ethylene, trimethylene, tetramethylene, pentamethylene, or ethyleneoxyethylene,
[91] 8) when the A ring is monocyclic aromatic, wherein the atoms adjacent to the bonding position are substituted with branched alkyl,
[92] 9) when R ² and R ³ together form an optionally substituted alkylene which may contain hetero atom (s).
[93] The meaning of each term used for the compound of formula (I) is explained below. Each term used alone or in combination with other terms is used to express the same meaning.
[94] The term “alkyl” means C 1 -C 10 straight or branched alkyl, examples of which are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl Isopentyl, neopentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl and the like. Preferred are C1-C4 straight or branched alkyls such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl.
[95] The term "alkenyl" refers to a C2-C8 straight or branched alkenyl having at least one double bond in said "alkyl", examples of which are vinyl, 1-propenyl, allyl, isopropenyl, 1-. Butenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 1,3-butadienyl, 3-methyl-2-butenyl and the like.
[96] The term "alkynyl" refers to a C2-C8 straight or branched alkynyl having at least one triple bond to said "alkyl", examples of which are ethynyl and the like.
[97] The term "alkoxy" means a group in which "alkyl" is substituted for an oxygen atom, examples of which are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentyloxy, n-hexyloxy, n-heptyloxy, n-octyloxy and the like. Preferred are C1-C4 straight or branched alkoxy, for example methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and tert-butoxy.
[98] The term "alkoxyalkyl" refers to a group in which "alkyl" is substituted for "alkoxy", examples of which are 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-meth Oxy-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.
[99] Examples of substituents of “optionally substituted amino” include alkyl (eg, methyl, ethyl, n-propyl, isopropyl, etc.), acyl (eg, formyl, acetyl, propionyl, benzoyl, etc.) and the like. The nitrogen atom of the amino group may be mono- or di-substituted with these substituents.
[100] Examples of "optionally substituted amino" include amino, methylamino, ethylamino, n-propylamino, isopropylamino, dimethylamino, diethylamino, ethylmethylamino, acetylamino, N-acetylmethylamino, propylmethylamino and the like. There is this.
[101] The term "optionally substituted aminoalkyl" refers to "alkyl" substituted with "optionally substituted amino", examples of which are aminomethyl, methylaminomethyl, ethylaminomethyl, n-propylaminomethyl, isopropylamino Methyl, N, N-dimethylaminomethyl, N, N-diethylaminomethyl, N-ethyl-N-methylaminomethyl, acetylaminomethyl, N-acetylmethylaminomethyl, N-propyl-N-methylaminomethyl and the like There is this.
[102] The term "cycloalkyl" refers to a C3-C10 saturated carbocyclic group, examples of which are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like. Preferred are C3-C6 cycloalkyl, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.
[103] The term "alkylene which may contain heteroatoms" means C2-C10 straight or branched alkylene which may contain 1 to 3 heteroatom (s), examples of which are ethylene, trimethylene, tetra Methylene, pentamethylene, methylenedioxy, ethylenedioxy, ethyleneoxyethylene and the like. Especially preferred are C3-C5 straight chain alkylenes which may contain one heteroatom, examples being tetramethylene, pentamethylene, ethyleneoxyethylene, ethyleneaminoethylene, ethylenethioethylene.
[104] The term "aromatic carbocyclic group" means a C6-C14 aromatic carbocyclic group, examples of which are phenyl, naphthyl (1-naphthyl, 2-naphthyl) anthryl, phenanthryl and the like. Preferred are phenyl or naphthyl (1-naphthyl, 2-naphthyl).
[105] The term "aromatic heterocyclic group" refers to a C1-C14 monocyclic aromatic heterocyclic group or 2 containing 1 to 4 nitrogen atom (s), oxygen atom (s) and / or sulfur atom (s) as constituent atoms of the ring. Group derived from a dog or three condensed rings, examples of which are as follows: furyl (eg 2-furyl, 3-furyl), thienyl (eg 2-thienyl, 3-thienyl), blood Rollyl (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-oxa Zolyl), isoxazolyl (eg, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl), thiazole (Eg 2-thiazolyl, 4-thiazolyl, 5-thiazolyl), thiadiazolyl, isothiazolyl (eg 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl), pyridyl (Eg 2-pyridyl, 3-pyridyl, 4-pyridyl), pyridazinyl (eg 3-pyridazinyl, 4-pyridazinyl), pyrimidinyl (eg 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl), furazanyl (eg 3-furazanyl), pyrazinyl (eg 2-pyrazinyl), oxadiazolyl (eg 1,3,4-oxadiazole -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] thier Nilyl, 6-benzo [b] thienyl, 7-benzo [b] thienyl), benzimidazolyl (eg 1-benzimidazolyl, 2-benzimidazolyl, 4-benzimidazolyl, 5 -Benzimidazolyl), dibenzofuryl, benzone Sazolyl, quinoxalinyl (eg, 2-quinoxalinyl, 5-quinoxalinyl, 6-quinoxalinyl), cinnolinyl (eg, 3-cinnolinyl, 4-cinnolinyl, 5-cinnolyl) Nil, 6-cinnolinyl, 7-cinnolinyl, 8-cinnolinyl), quinazolinyl (eg, 2-quinazolinyl, 4-quinazolinyl, 5-quinazolinyl, 6-quinazolinyl , 7-quinazolinyl, 8-quinazolinyl), quinolyl (eg, 2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 6-quinolyl, 7-quinolyl, 8 -Quinolyl), phthalazinyl (eg 1-phthalazinyl, 5-phthalazinyl, 6-phthalazinyl), isoquinolyl (eg 1-isoquinolyl, 3-isoquinolyl, 4- Isoquinolyl, 5-isoquinolyl, 6-isoquinolyl, 7-isoquinolyl, 8-isoquinolyl), furyl, pteridinyl (eg, 2-pteridinyl, 4-pteridinyl, 6 -Putridinyl, 7-putridinyl), carbazolyl, phenanthridinyl, acridinyl (eg 1-acridinyl, 2-acridinyl, 3-acridinyl, 4-acridinyl, 9-acridinyl), Doryl (eg 1-indolyl, 2-indolyl, 3-indolyl, 4-indolyl, 5-indolyl, 6-indolyl, 7-indolyl), isoindoleyl, phenazinyl (eg 1 -Phenazinyl, 2-phenazinyl) or penothiadinyl (e.g., 1-phenothiadinyl, 2-phenothiadinyl, 3-phenothiadinyl, 4-phenothiadinyl) and the like.
[106] Particularly preferred as "aromatic heterocyclic groups" of A are pyridyl, quinolyl (particularly 5-quinolyl) or isoquinolyl.
[107] The term "heterocyclic group" refers to a C1-C14 monocyclic heterocyclic group or two or three condensed rings containing 1 to 4 nitrogen atom (s), oxygen atom (s) and / or sulfur atom (s). Group derived from, examples of which are “the aromatic heterocyclic group” or a nonaromatic heterocyclic group.
[108] The term "non-aromatic heterocyclic group" means a C1-C14 non-aromatic heterocyclic group containing 1 to 4 nitrogen atom (s), oxygen atom (s) and / or sulfur atom (s) or two or three groups. Group derived from a condensed ring, examples of which are 1-pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrrolidino, 2-pyrrolidinyl, 3-pyrrolidinyl, 1-imida Zolinyl, 2-imidazolinyl, 4-imidazolinyl, 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. Preferred are morpholino, pyrrolidino, piperidino or piperazino.
[109] When R ¹ is a heterocyclic group, preference is given to aromatic heterocyclic groups, in particular monocyclic or bicyclic aromatic heterocyclic groups. Particularly preferred are pyridyls (eg pyridin-2-yl and the like), thiazolyl (eg thiazol-2-yl and the like), benzothiazolyl (eg benzothiazol-2-yl and the like), benzoxazolyl ( Benzoxazol-2-yl and the like).
[110] "Optionally substituted heterocyclic group", "optionally substituted alkyl", "optionally substituted alkenyl", "optionally substituted alkynyl", "optionally substituted alkoxyalkyl", "optionally substituted cycloalkyl", "hetero Examples of substituents of "optionally substituted alkylene which may contain atoms", "optionally substituted aromatic carbocyclic groups" and "optionally substituted aromatic heterocyclic groups" are alkyl, alkoxy, alkenyloxy, alkylthio, optionally substituted Amino, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted non-aromatic heterocyclic group, optionally substituted aryloxy, cycloalkyl, halogen, hydroxy, nitro, haloalkyl, haloalkoxy, optionally substituted carba Moyl, carboxy, alkoxycarbonyl, alkenyloxycarbonyl, alkylsulfinyl, alkylsulfonyl, alkoxyalkyl, alkylthioalkyl, optionally substituted aminoalkyl, alkoxyalkoxy, alkoxyalkoxycarbonyl, 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 optionally substituted non-aromatic heterocyclic group Groups, arylsulfonyl (such as benzenesulfonyl, etc.), cyano, hydroxy amino, aralkyl (such as benzyl, etc.), mercapto, hydrazino, amidino, guanidino, isociano, isocyanato , Thiocyanato, isothiocyanato, sulfamoyl, formyloxy, haloformyl, oxalo, thioformyl, thiocarboxy, dithiocarboxy, thiocarbamoyl, sulfino, sulfo, sulfoamino, azido , Ureido, amidino, guanidino, oxo, thioxo, alkylcarbonyloxy, alkylenedioxy, a group represented by -OR ^I (wherein R ^I is a non-aromatic heterocyclic group), aralkyloxy , Aralkylthio, aralkylamino and the like.
[111] These substituents may be substituted at any substitutable position. The divalent groups described above may be substituted at the same or different positions on the ring.
[112] Among the above substituents, as the substituent of the "optionally substituted heterocyclic group" of R ¹ , particularly preferred are alkyl (eg, methyl, etc.), alkoxy (eg, methoxy, etc.), alkylthio (eg, methylthio, etc.), Optionally substituted amino, cycloalkyl, halogen, hydroxy, nitro, haloalkyl, haloalkoxy, optionally substituted carbamoyl, carboxy, alkoxycarbonyl, optionally substituted aminoalkyl, formula: -C (= 0) -R ^{Group represented by H} (wherein R ^H is hydrogen or alkyl), cyano, hydroxyamino, mercapto and the like.
[113] Of R ⁴ in the substituent of "optionally substituted alkyl", "optionally substituted alkenyl", an optionally substituted alkynyl "," optionally substituted alkoxyalkyl "and" optionally as a substituent of the substituted cycloalkyl ", particularly preferred Alkoxy (eg, methoxy, etc.), alkenyloxy (eg, vinyloxy, etc.), optionally substituted heteroaryl [eg, alkyl (eg, methyl, isopropyl, isobutyl, tert-butyl, etc.) or aryl (eg, Heteroaryl optionally substituted with phenyl) (eg isoxazolyl, oxazolyl, etc.), non-aromatic heterocyclic group optionally substituted with alkyl (eg methyl) (eg morpholino, 4,5-dihydroi) Soxazol-3-yl, 1,3-dioxolane, etc.), aryloxy (eg, phenoxy, etc.), halogen (eg, fluoro), hydroxy, haloalkyl (eg, trifluoromethyl, etc.), optionally Substituted carbamoyl (eg, unsubstituted carbamoyl, N, N-dimethylcarbamoyl, N-methyl-N -Methoxycarbamoyl, etc.), carboxy, alkoxycarbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl, etc.), al Kenyloxycarbonyl (eg, vinyloxycarbonyl, allyloxycarbonyl, etc.), alkoxyalkoxycarbonyl (eg, 2-methoxyethyloxycarbonyl, etc.), formula: -C (= 0) -R ^H (formula Wherein R ^H is hydrogen or alkyl (eg, formyl, acetyl, etc.), cyano, oxo, alkylcarbonyloxy (eg, acetyloxy, etc.), alkylenedioxy (eg, ethylenedioxy Etc.), a group represented by -OR ^I (wherein R ^I is a non-aromatic heterocyclic group) (e.g., tetrahydropyran-2-yloxy and the like).
[114] Of the above substituents, substituents of "optionally substituted alkylene which may contain a heteroatom" of A, "optionally substituted aromatic carbocyclic group" and "optionally substituted aromatic heterocyclic group" are particularly preferably alkyl (e.g., , Methyl, ethyl, isopropyl, sec-butyl, etc.), alkoxy (eg, methoxy, ethoxy, isopropoxy, etc.), optionally substituted amino (eg, dimethylamino, diethylamino, ethylmethylamino, etc.), Haloalkyl (eg, trifluoromethyl, etc.), haloalkoxy (eg, trifluoromethoxy, etc.), aralkyl (eg, benzyl, etc.). Substituents of "alkylene which may contain heteroatoms" and "aromatic heterocyclic groups" may be substituted on heteroatoms (nitrogen atoms).
[115] In particular, A is monocyclic aromatic (e.g., phenyl, furyl, thienyl, pyrrolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, etc.) At that time, it is preferable that the atoms adjacent to the bonding position be substituted with branched alkyl. Branched alkyl refers to C1-C10 branched alkyl, examples of which are isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, neopentyl, tert-pentyl, isohexyl and the like. Especially preferred are C3 or C4 branched alkyls such as isopropyl, isobutyl, sec-butyl, or tert-butyl.
[116] The term "halogen" means fluoro, chloro, bromo and iodo. Preferred are fluoro, chloro or bromo.
[117] The term "alkenyloxy" refers to a group in which "alkenyl" is substituted for an oxygen atom, examples of which are vinyloxy, 1-propenyloxy, allyloxy, isopropenyloxy, 1-butenyloxy, 2- Butenyloxy, 3-butenyloxy, 2-pentenyloxy, 1,3-butadienyloxy, 3-methyl-2-butenyloxy and the like.
[118] The term "alkylthio" means a group substituted by "alkyl" with a sulfur atom, examples of which are methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, sec-butyl Thio, t-butylthio, n-pentylthio, n-hexylthio, and the like. Preferred are C1-C4 straight or branched alkylthio, for example methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, sec-butylthio and t-butylthio to be.
[119] The term "aryl" has the same meaning as the "aromatic carbocyclic group", examples of which are phenyl, naphthyl (1-naphthyl or 2-naphthyl), anthryl, phenanthryl and the like. Especially preferred are phenyl or naphthyl (1-naphthyl or 2-naphthyl).
[120] The term "heteroaryl" has the same meaning as the "aromatic heterocyclic group", examples of which are furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thia Zolyl, thiadiazolyl, isothiazolyl, pyridyl, pyridazinyl, pyrimidinyl, furazanyl, pyrazinyl, benzofuryl, benzothienyl, benzimidazolyl, dibenzofuryl, benzoxazolyl, quinoxalinyl Cinnalinyl, quinazolinyl, quinolinyl, phthalazinyl, isoquinolinyl, furyl, pterridinyl, carbazolyl, phenanthridinyl, acridinyl, indolyl, isoindolinyl, phenazinyl, Penothiadinyl and the like. Preferred is pyridine, quinoline or isoquinoline.
[121] The term "aryloxy" refers to a group in which "aryl" is substituted for an oxygen atom, examples of which include 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.
[122] The term "haloalkyl" means said "alkyl" substituted with one or more halogens, with particular preference being given to C1-C3 haloalkyl, for example trifluoromethyl, chloromethyl, dichloromethyl, difluoromethyl, 1-chloroethyl, 2-chloroethyl, 1,1-dichloroethyl, 1,2-dichloroethyl, 2,2-dichloroethyl, 2,2,2-trichloroethyl and the like.
[123] The term "haloalkoxy" means a group in which "haloalkyl" is substituted for an oxygen atom, examples of which are dichloromethoxy, difluoromethoxy, trifluoromethoxy, trifluoroethoxy (2,2,2- Trifluoroethoxy and the like).
[124] Examples of substituents of “optionally substituted carbamoyl” are alkyl (eg, methyl, ethyl, n-propyl, isopropyl, etc.), acyl (eg, formyl, acetyl, propionyl, benzoyl, etc.) and the like. The nitrogen atom of the carbamoyl group may be monosubstituted or disubstituted with these substituents. Preferred as “optionally substituted carbamoyl” are carbamoyl, N-methylcarbamoyl or N-ethylcarbamoyl.
[125] The term "alkoxycarbonyl" refers to a carbonyl group substituted with "alkoxy", examples of which are methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbon Carbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, n-pentyloxycarbonyl, n-hexyloxycarbonyl, n-heptylcarbonyl, n-octyloxycarbonyl and the like. .
[126] The term "alkenyloxycarbonyl" refers to a carbonyl group substituted with "alkenyloxy", examples of which are vinyloxycarbonyl, 1-propenyloxycarbonyl, allyloxycarbonyl, isopropenyloxycarbon Bonyl, 1-butenyloxycarbonyl, 2-butenyloxycarbonyl, 3-butenyloxycarbonyl, 2-pentenyloxycarbonyl, 1,3-butadienyloxycarbonyl, 3-methyl-2 Butenyloxycarbonyl and the like.
[127] The term "alkylsulfinyl" refers to a sulfinyl group substituted with "alkyl" above. Preferred are methanesulfinyl, ethanesulfinyl and the like.
[128] The term "alkylsulfonyl" refers to a sulfonyl group substituted with "alkyl" above. Preferred are methanesulfonyl, ethanesulfonyl and the like.
[129] The term "alkylthioalkyl" means "alkyl" substituted with "alkylthio", examples of which are 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.
[130] The term "alkoxyalkoxy" means said "alkoxy" substituted with said "alkoxy", examples of which are methoxymethoxy, ethoxymethoxy, n-propoxymethoxy, isopropoxymethoxy, 1-methoxy Methoxyethoxy, 2-methoxyethoxy and the like.
[131] The term "alkoxyalkoxycarbonyl" means "carbonyl" substituted with "alkoxyalkoxy", examples of which are methoxymethoxycarbonyl, ethoxymethoxycarbonyl, n-propoxymethoxycarbonyl, Isopropoxymethoxycarbonyl, 1-methoxyethoxycarbonyl, 2-methoxyethoxycarbonyl and the like.
[132] The term "alkylthioalkoxy" means "alkoxy" substituted with "alkylthio", examples of which are methylthiomethoxy, ethylthiomethoxy, n-propylthiomethoxy, isopropylthiomethoxy, 1- Methylthioethoxy, 2-methoxyethoxy and the like.
[133] The term "alkoxyiminoalkyl" refers to alkyl substituted with "alkoxyimino", examples of which are methoxyiminomethyl, ethoxyiminomethyl, 1-methoxyiminoethyl and the like.
[134] Formula: Examples of groups of —C (═O) —R ^H , wherein R ^H is hydrogen, alkyl, optionally substituted aryl or optionally substituted non-aromatic heterocyclic group, include formyl, acetyl, benzoyl, toluoyl Morpholinocarbonyl and the like.
[135] The term "arylsulfonyl" means "sulfonyl" substituted with "aryl", with benzenesulfonyl being particularly preferred.
[136] The term "aralkyl" refers to "alkyl" substituted with "aryl", examples of which are benzyl, phenylethyl (eg 1-phenylethyl, 2-phenylethyl), phenylpropyl (eg 1-phenyl Propyl, 2-phenylpropyl, 3-phenylpropyl, and the like), naphthylmethyl (eg, 1-naphthylmethyl, 2-naphthylmethyl, and the like).
[137] The term "alkylcarbonyloxy" means carbonyloxy substituted with said "alkyl", examples of which are methylcarbonyloxy, ethylcarbonyloxy, n-propylcarbonyloxy, isopropylcarbonyloxy, n- Butylcarbonyloxy, isobutylcarbonyloxy, sec-butylcarbonyloxy, tert-butylcarbonyloxy, n-pentylcarbonyloxy, isopentylcarbonyloxy, neopentylcarbonyloxy, tert-pentylcarbonyloxy , n-hexylcarbonyloxy, isohexylcarbonyloxy, n-heptylcarbonyloxy, n-octylcarbonyloxy, n-nonylcarbonyloxy, n-dodecylcarbonyloxy and the like.
[138] The term "alkylenedioxy" means deoxy substituted with C1-C6 straight or branched alkylene and may be substituted on the same or different atoms. For example, preferred are methylenedioxy (-O-CH ₂ -O-), ethylenedioxy (-O-CH ₂ -CH ₂ -O-), propylenedioxy (-O-CH ₂ -CH _2- CH ₂ -O-) and the like.
[139] Examples of groups represented by the formula: -OR ^I wherein R ^I is a non-aromatic heterocyclic group include 1-pyrrolinyloxy, 2-pyrrolinyloxy, 3-pyrrolinyloxy, pyrrolidinoxy , 2-pyrrolidinoxy, 3-pyrrolidinoxy, 1-imidazolinyloxy, 2-imidazolinyloxy, 4-imidazolinyloxy, 1-pyrazolinyloxy, 3-pyrazoli Nyloxy, 4-pyrazolinyloxy, 1-pyrazolidinyloxy, 3-pyrazolidinyloxy, 4-pyrazolidinyloxy, piperidinoxy, 2-piperidinoxy, 3-piperidinoxy, 4-piperidinoxy, piperadinoxy, 2-piperadinoxy, 2-morpholinyloxy, 3-morpholinyloxy, morpholinoxy, tetrahydropyran-2-yloxy and the like.
[140] The term "aralkyloxy" refers to a group in which "aralkyl" is substituted for an oxygen atom, examples of which are benzyloxy, phenylethyloxy (eg 1-phenylethyloxy, 2-phenylethyloxy), phenylpropoxy (Eg, 1-phenylpropyloxy, 2-phenylpropyloxy, 3-phenylpropyloxy, and the like), naphthylmethoxy (eg, 1-naphthylmethoxy, 2-naphthylmethoxy, and the like).
[141] The term "aralkylthio" refers to a group in which "aralkyl" is substituted for a sulfur atom, examples of which are benzylthio, phenylethylthio (eg, 1-phenylethylthio, 2-phenylethylthio), phenylpropylthio (Eg, 1-phenylpropylthio, 2-phenylpropylthio, 3-phenylpropylthio, etc.), naphthylmethylthio (eg, 1-naphthylmethylthio, 2-naphthylmethylthio, etc.).
[142] The term "aralkylamino" means a group substituted by one or two of said "aralkyl" to a nitrogen atom, examples of which include 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.
[143] "m" is an integer of 0-2. "m" is preferably 0.
[144] The term "agonist action on cannabinoid type 2 receptor" means agonist action on cannabinoid type 2 receptor.
[145] The compounds of the present invention can be prepared by the following process.
[146]
[147] Process 1
[148] This is a process for preparing the compound of formula (IV) comprising converting the amino group of the compound of formula (III) to isothiocyanic acid ester (isothiocyanate).
[149] Processes for converting amino groups to isothiocyanic acid esters (isothiocyanates) include the following methods: 1) in the presence of a base such as ammonia (NH ₃ , NH ₄ OH) or triethylamine (Et ₃ N) Reacting the starting compound with carbon disulfide and reacting the obtained dithiocarbamate with ethyl chlorocarboxylate (ClCO ₂ Et) and triethylamine (Et ₃ N), 2) the dithiocarba A method comprising treating the mate with a metal salt such as lead nitrate, 3) a method of reacting thiophosgen (CSCl ₂ ), 4) a method of reacting thiocarbonyldiimidazole, and the like.
[150] In the case of 1), a base (1.0 to 1.5 equivalents) and carbon disulfide (1.0 to 1.5 equivalents) are added to a protic solvent (eg, diethyl ether, tetrahydrofuran, dimethylformamide, benzene, toluene, dichloromethane, chloroform, etc.). ) To a solution of the compound of formula (III), and the mixture was stirred for 0.5 to 10 hours. Thereafter, ethyl chlorocarboxylate (1.0-1.5 equivalents) and triethylamine (1.0-1.5 equivalents) were added thereto, and the mixture was 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.
[151] In the case of 3) above, the thiophosgene (1.0 to 1.5 equivalents) is added to the compound of formula (III) in a protic solvent (e.g., diethyl ether, tetrahydrofuran, dimethylformamide, benzene, toluene, dichloromethane, chloroform, etc.). Was added to the solution of and stirred for 0.5 to 10 hours. The reaction temperature is preferably 0 to 100 ° C, in particular 0 ° C to room temperature.
[152] In the case of 4), thiocarbonyldiimidazole (1.0 to 1.5 equivalents) is converted into an aprotic solvent (e.g., diethyl ether, tetrahydrofuran, dimethylformamide, benzene, toluene, dichloromethane, chloroform, etc.). To the solution of the compound of (III) was added and stirred for 0.5 to 10 hours. The reaction temperature is preferably 0 to 100 ° C, in particular 0 ° C to room temperature.
[153] Examples of compounds of formula (III) wherein m is 0 are: aniline, 2-methylaniline, 2-ethylaniline, 2-n-propylaniline, 2-isopropylaniline, 2-n-butylaniline, 2 sec-butylaniline, 2-t-butylaniline, 3-methylaniline, 3-isopropylaniline, 3-isopropyl-4-methylaniline, 3-t-butylaniline, 4-methylaniline, 4-i- Propylaniline, 2,6-dimethylaniline, 2,3-dimethylaniline, 2,4-dimethylaniline, 3,4-diethylaniline, 2,5-dimethylaniline, 3,4-dimethylaniline, 3,5- Dimethylaniline, 2,6-diethylaniline, 2,6-di-isopropylaniline, 2-methoxyaniline, 2-ethoxyaniline, 2-isopropoxyaniline, 3-methoxyaniline, 3,5- Dimethoxyaniline, 3-n-butoxyaniline, 4-n-butoxyaniline, 4-ethoxyaniline, 3,4-dimethoxyaniline, 2-methylthioaniline, 2-ethylthioaniline, 2-isopropyl Thioaniline, 2-N, N-dimethylaminoaniline, 2-phenylaniline, 3-phenylaniline, 4-phenoxycyanyl , 2-cyclohexylaniline, 2-cyclopentylaniline, 2-nitroaniline, 2,4-dinitroaniline, 2-fluoroaniline, 2-chloroaniline, 4-chloroaniline, 2,3-dichloroaniline, 3 , 4-dichloroaniline, 2-isopropyl-4-nitroaniline, 2-isopropyl-6-nitroaniline, 2-hydroxyaniline, 2-N, N-dimethylaminocarbonylaniline, 2-N-acetylaniline , 2- (1-ethylpropyl) aniline, 2-isopropyl4-methylaniline, 2-isopropyl-4-hydroxyaniline, 2-isopropyl-4-chloroaniline, 2-isopropyl-4-aminoaniline 2-isopropyl-5-methylaniline, 2-isopropyl-5-hydroxy aniline, 2-isopropyl-5-chloroaniline, 4-chloro-3-methylaniline, 3,4-methylenedioxyaniline, and the like .
[154] Examples of compounds of formula (III) wherein m is 1 are: benzylamine, 2-methylbenzylamine, 2-ethylbenzylamine, 2-n-propylbenzylamine, 2-isopropylbenzylamine, 2-n -Butylbenzylamine, 2-sec-butylbenzylamine, 2-t-butylbenzylamine, 3-methylbenzylamine, 3-isopropylbenzylamine, 3-isopropyl-4-methylbenzylamine, 3-t-butyl Benzylamine, 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-isopropylbenzylamine, 2-methoxybenzylamine 2-ethoxybenzylamine, 2-isopropoxybenzylamine, 3-methoxybenzylamine, 3,5-dimethoxybenzylamine, 3-n-butoxybenzylamine, 4-n-butoxybenzylamine, 4-ethoxybenzylamine, 3,4-dimethoxybenzylamine, 2-methylthiobenzylamine, 2-ethylthiobenzylamine, 2-isopropylthio Nitrogenamine, 2-N, N-dimethylaminobenzylamine, 2-phenylbenzylamine, 3-phenylbenzylamine, 4-phenoxybenzylamine, 2-cyclohexylbenzylamine, 2-cyclopentylbenzylamine, 2-nitro Benzylamine, 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-isopropyl4-methylbenzylamine, 2-isopropyl-4-hydroxybenzylamine, 2-isopropyl-4-chlorobenzylamine, 2-isopropyl-4- Aminobenzylamine, 2-isopropyl-5-methylbenzylamine, 2-isopropyl-5-hydroxybenzylamine, 2-isopropyl-5-chlorobenzylamine, 4-chloro-3-methylbenzylamine, 3, 4-methylenedioxybenzylamine and the like.
[155] m is 2. Examples of the compound of formula (III) are as follows: phenethylamine, 2-methylphenethylamine, 2-ethylphenethylamine, 2-n-propylphenethylamine, 2-isopropylphenethyl Amine, 2-n-butylphenethylamine, 2-sec-butylphenethylamine, 2-t-butylphenethylamine, 3-methylphenethylamine, 3-isopropylphenethylamine, 3-isopropyl-4 -Methylphenethylamine, 3-t-butylphenethylamine, 4-methylphenethylamine, 4-isopropylphenethylamine, 2,6-dimethylphenethylamine, 2,3-dimethylphenethylamine, 2, 4-dimethylphenethylamine, 3,4-diethylphenethylamine, 2,5-dimethylphenethylamine, 3,4-dimethylphenethylamine, 3,5-dimethylphenethylamine, 2,6-diethyl Phenethylamine, 2,6-di-isopropylphenethylamine, 2-methoxyphenethylamine, 2-ethoxyphenethylamine, 2-i-propoxyphenethylamine, 3-methoxyphenethylamine, 3,5-dimethoxyphenethylamine, 3-n-butoxyphenethylamine, 4-n-butoxyphenethylamine, 4-ethoxyphenethylamine, 3,4-dimethoxy Phenethylamine, 2-methylthiophenethylamine, 2-ethylthiophenethylamine, 2-isopropylthiophenethylamine, 2-N, N-dimethylaminophenethylamine, 2-phenylphenethylamine, 3-phenyl Phenethylamine, 4-phenoxyphenethylamine, 2-cyclohexylphenethylamine, 2-cyclopentylphenethylamine, 2-nitrophenethylamine, 2,4-dinitrophenethylamine, 2-fluorophene Ethylamine, 2-chlorophenethylamine, 4-chlorophenethylamine, 2,3-dichlorophenethylamine, 3,4-dichlorophenethylamine, 2-i-propyl-4-nitrophenethylamine, 2- Isopropyl-6-nitrophenethylamine, 2-hydroxyphenethylamine, 2-N, N-dimethylaminocarbonylphenethylamine, 2-N-acetylphenethylamine, 2- (1-ethylpropyl) phene Ethylamine, 2-isopropyl4-methylphenethylamine, 2-isopropyl-4-hydroxyphenethylamine, 2-isopropyl-4-chlorophenethylamine, 2-isopropyl-4-aminophenethylamine, 2-isopropyl-5-methylphenethylamine, 2-isopro Phil-5-hydroxyphenethylamine, 2-isopropyl-5-chlorophenethylamine, 4-chloro-3-methylphenethylamine, 3,4-methylenedioxyphenethylamine and the like.
[156] Process 2
[157] This is a process for preparing a compound of formula (V) comprising reacting isothiocyanate of a compound of formula (IV) with NH ₂ -CH ₂ C (R ² ) R ³ CH ₂ -OH.
[158] This process can be carried out in the presence of an aprotic solvent (eg, diethyl ether, tetrahydrofuran, dimethylformamide, benzene, toluene, dichloromethane, chloroform and the like).
[159] 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.
[160] The amount of NH ₂ -CH ₂ C (R ² ) R ³ CH ₂ -OH is 1.0 to 1.5 equivalents based on compound (IV).
[161] Examples of NH ₂ -CH ₂ C (R ² ) R ³ CH ₂ -OH include 3-aminopropanol, 3-amino-2,2-dimethylethanol, 3-amino-1-methylpropanol, 3-amino-2- Methylpropanol, 3-amino-3-methylpropanol, 3-amino-2,2-diethylpropanol, 1-aminomethyl-1-hydroxymethylcyclopropane, 1-aminomethyl-1-hydroxymethylcyclopentane, 1-aminomethyl-1-hydroxymethylcyclohexane, 1-aminomethyl-1-hydroxymethyl-4-oxacyclohexane, and the like.
[162] Process 3
[163] This is a process for the preparation of the compound of formula (VI) which comprises cyclization of the compound of formula (V).
[164] The cyclization method may include 1) a method comprising reacting diethylazodicarboxylate (DEAD) and triphenylphosphine (Ph ₃ P), 2) a method comprising reacting with hydrochloric acid, and the like.
[165] In the case of 1), the reaction is carried out 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. Can be performed in presence. The amount of diethylazodicarboxylate (DEAD) and triphenylphosphine (Ph ₃ P) is 1.0 to 1.5 equivalents relative to compound (V).
[166] In the case of 2), the reaction can be carried out in concentrated hydrochloric acid while refluxing for 0.5 to 10 hours.
[167] Process 4
[168] Which R ² in the compound of formula (VI) [formula: -C (= R ⁵⁾ or a group of the formula -R ^6: -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 Is a group of amino, optionally substituted aryl or optionally substituted heteroaryl).
[169] This process is carried out in the presence of a base (e.g. triethylamine, pyridine, N, N-dimethylaminopyridine, etc.) with the formula: XC (= R ⁵ ) -R ⁶ wherein R ⁵ and R ⁶ are as defined above. And X is halogen. This process can be carried out under the usual 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.) with stirring at 0-100 ° C. for 0.5-10 hours. Can be.
[170] Compounds of thioacid esters wherein R ⁵ is S and R ⁶ is alkylthio or optionally substituted aralkylthio are reacted with carbon disulfide (CS ₂ ) in the presence of a base (eg, sodium hydride, etc.), and a halogenated alkyl ( 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 the presence of an aprotic solvent (eg diethylether, tetrahydrofuran, dimethylformamide, benzene, toluene, dichloromethane, chloroform, etc.) with stirring at 0 ° C. to room temperature.
[171] When R ² to be 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 a base Can be reacted with a compound of the formula: R ⁷ SO ₂ X, wherein X is halogen or the like.
[172] Prodrugs are derivatives that are converted to pharmaceutically active compounds of the present invention under physiological conditions. Methods of selecting and preparing suitable prodrug derivatives are described in the Design of Prodrugs, Elsevier, Amsterdam 1985.
[173] 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 (eg, Formamide, acetamide and the like), N-alkyl derivatives (e.g., N-allylamine, N-methoxymethylamine, etc.). Examples of prodrugs derived from compounds having hydroxy groups are ether derivatives (methoxymethyl ether, methoxyethoxymethyl ether, etc.), ester derivatives (eg, acetate, pivaloate, benzoate and the like) and the like.
[174] Examples of pharmaceutically acceptable salts are as follows: basic salts (eg 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, triethyl Amine, dicyclohexylamine, 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. Examples of acid addition salts are: inorganic acid salts such as hydrochloride, sulfate, nitrate, phosphate, carbonate, hydrogen carbonate or perchlorate; 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.
[175] Solvates are solvates of a compound of formula (I), a prodrug thereof or a pharmaceutically acceptable salt thereof, examples of which are monosorbates, dissolves, monohydrates, dihydrates and the like.
[176] The compounds of the present invention have a binding action on cannabinoid type 2 receptors (CB2R), and bind to cannabinoid type 2 receptors (CB2R) to antagonist action or agonist action on CB2R, in particular agonist action on CB2R. Indicates.
[177] 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 effects. Nature, 1998, 349, 277-281 describes that CB2R agonists have analgesic action. European Journal of Pharmacology 396 (2000) 85-92 describes that CB2R antagonists have analgesic action. Cancer Research 61 (2001) 5784-5789 also describes that agonists for cannabinoid type 2 receptors have a constrictive effect on brain tumors, and European Journal of Pharmacology 396 (2000) 85-92 describes cannes. It has been described that the antagonists for the butterfly type 2 receptor have analgesic action. J Pharmacol Exp Ther, 2001, 296, 420-425 also describes that compounds having a binding action (agonist action and / or antagonist action) to cannabinoid type 2 receptors have anti-inflammatory action. Pain, 2001, 93, 239-245 describes that compounds having agonist action on cannabinoid type 2 receptors have analgesic action.
[178] The compounds of the present invention are believed to express peripheral nervous system action (eg, immunosuppression, anti-inflammatory action and analgesic action) by inhibiting the activation of immune system cells, inflammatory cells and peripheral neurons. Therefore, the compound of the present invention can be used as an anti-inflammatory agent, anti-allergic agent, analgesic agent, immunodeficiency treatment agent, immunosuppressive agent, immunomodulatory agent, autoimmune disease treatment agent, chronic rheumatic joint treatment agent, multiple sclerosis treatment agent and the like.
[179] Agonists for cannabinoid type 2 receptors are known to inhibit nephritis caused by rat Thy-1 antibodies (WO 97/29079). Thus, the present compounds are useful as therapeutic agents for nephritis.
[180] When the compounds of the present invention are used for treatment, they may be formulated in conventional oral or parenteral formulations. Pharmaceutical compositions containing a compound of the present invention may be oral and parenteral dosage forms. In particular, oral administration such as tablets, capsules, granules, powders, syrups and the like, or parenteral administration such as intravenous, intramuscular or subcutaneous injections, solutions or suspensions for inhalation, instillation, eye drops, nasal drops, suppositories, Or percutaneous administrations, such as ointments.
[181] In preparing the formulations, carriers, excipients, solvents and bases known to those skilled in the art can be used. In the case of tablets, the active and auxiliary ingredients are compressed or molded together. Examples of auxiliary ingredients that can be used include pharmaceutically acceptable excipients such as binders (eg corn starch), fillers (eg lactose, microcrystalline cellulose), disintegrants (eg starch sodium glycolate) ) Or a lubricant (eg, manganese 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. In the case of injectable preparations, they may be in the form of solutions or suspensions, or oily or aqueous emulsions, which 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, it may be formulated as a liquid or suspending agent.
[182] Suitable dosages of the compounds of the present invention depend on the dosage form, the age, weight, sex or symptoms of the patient, and the type of drug (s) used, if present, and finally at the discretion of the physician. In this case, the daily dose is about 0.01-100 mg, preferably about 0.01-10 mg, more preferably about 0.01-1 mg per 1 kg of body weight. For parenteral administration, the daily dose is about 0.001-100 mg, preferably about 0.001-1 mg, more preferably about 0.001-0.1 mg per 1 kg of body weight. The daily dose may be administered in 1-4 divided doses.
[1] The present invention relates to 2-amino-1,3-thiazine derivatives, and more specifically to imino-1,3-thiazine derivatives having a binding action on cannabinoid type 2 receptors and to their use in medicine.
[183] The invention is further illustrated by the following examples, but is not intended to limit the scope of the invention.
[184] The meaning of each abbreviation is as follows.
[185] Me: methyl, Et: ethyl, Pr: propyl, Pr ⁱ : isopropyl,
[186] Bu: butyl, Bu ⁱ : isobutyl, Bu ^s : sec-butyl,
[187] Bu ^t : t-butyl,
[188] Ph: phenyl,
[189] DMF: N, N-dimethylformamide, THF: tetrahydrofuran,
[190] Reference Example 1-1 Preparation of (2-isopropylphenyl) isothiocyanate (Compound 2)
[191]
[192] Carbon dioxide (2.81 g) was added dropwise to the mixture of 2-isopropylaniline (5.00 g), triethylamine (3.74 g) and toluene (10 ml) for 10 minutes. The reaction mixture was stirred at rt for 1 h and left for 12 h. The reaction mixture was concentrated under reduced pressure. To this was added dichloromethane (20 ml) and triethylamine (3.74 g). To the reaction mixture was added ethyl chlorocarbonate (4.01 g) under ice cooling for 10 minutes. The reaction mixture was stirred at rt for 1 h. 10% hydrochloric acid (20 ml) was added to the reaction mixture. The reaction mixture was extracted with dichloromethane (60 ml), dried over aqueous magnesium sulfate and concentrated under reduced pressure to give (2-isopropylphenyl) isothiocyanate (6.55 g, yield: 99%) as a yellow oil. .
[193] ¹ H-NMR (δ ppm TMS / CDCl ₃ ) 1.25 (6H, d, J = 6.7), 3.25 (1H, q, J = 6.7), 7.14-7.30 (4H, m).
[194] Reference Example 1-2 : Preparation of (2-isopropylphenyl) isothiocyanate (Compound 2)
[195]
[196] Thiophosgene (1.54 g) was added dropwise to the solution of 2-isopropylaniline (1.81 g) in diethyl ether (20 ml) under ice cooling for 10 minutes. The reaction mixture was stirred at rt for 1 h.
[197] Water (30 ml) was added to the reaction mixture. The reaction mixture is extracted with diethyl ether (60 ml), dried over aqueous magnesium sulfate and concentrated under reduced pressure to give (2-isopropylphenyl) isothiocyanate (2.35 g, yield: 99%) as a brown oil. did.
[198] Reference Example 2 : Preparation of N- (2-isopropylphenyl) -N '-(1-hydroxy-2,2-dimethyl) propylthiourea (Compound 3)
[199]
[200] 3-amino-2,2-dimethylpropanol (1.92 g) was added to a solution of (2-isopropylphenyl) isothiocyanate (3.30 g) in diethyl ether (20 ml). The reaction 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.
[201] ¹ H-NMR (δ ppm TMS / CDCl ₃ ) 0.82 (6H, s), 1.25 (6H, d, J = 6.7), 3.11 (1H, q, J = 6.7), 3.25 (2H, s), 3.55 (2H , d, J = 6.3), 6.05 (1H, m), 7.17-7.40 (4H, m).
[202] Reference Example 3 : Preparation of 2- (2-isopropylphenyl) imino-5,5-dimethyl-1,3-thiazine (Compound 4)
[203]
[204] Concentrated hydrochloric acid (5 ml) was added to N- (2-isopropylphenyl) -N '-(1-hydroxy-2,2-dimethyl) propylthiourea (10.37 g). The reaction mixture was refluxed for 3 hours. The reaction mixture was cooled to room temperature and poured into 20% aqueous sodium hydroxide (25 ml) solution. 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. did.
[205] M.p. 155-157 ℃
[206] ¹ H-NMR (δ ppm TMS / CDCl ₃ ) 1.15 (6H, s), 1.20 (6H, d, J = 6.7), 2.67 (2H, s), 3.09 (2H, s), 3.15 (1H, q, J = 6.7), 6.88 (1H, m), 7.05-7.11 (2H, m), 7.20 (1H, m).
[207] Reference Example 4 : Preparation of 2- (2-isopropylphenyl) imino-5,5-dimethyl-1,3-thiazine (Compound 4)
[208]
[209] Thionylchloride (0.60 g) in a solution of N- (2-isopropylphenyl) -N '-(1-hydroxy-2,2-dimethyl) propylthiourea (1.00 g) in tetrahydrofuran (6 ml) Dropped. The reaction 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 reaction mixture. The reaction mixture was refluxed for 2 hours. (40 ml) was added to the reaction mixture. The reaction mixture was extracted with dichloromethane (60 ml), dried over aqueous 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.
[210] The following examples were prepared using 2- (2-isopropylphenyl) imino-5,5-dimethyl-1,3-thiazine prepared in Reference Examples 3 and 4.
[211] Example 1 Preparation of 2- (2-isopropylphenyl) imino-3- (allylthio) thiocarbonyl-5,5-dimethyl-1,3-thiazine (Compound I-1)
[212]
[213] Of 2- (2-isopropylphenyl) imino-5,5-dimethyl-1,3-thiazine (0.26 g) and carbonisulfide (0.10 g) in N, N-dimethylformamide (3 ml) To the solution was added 60% sodium hydride (0.05 g) under ice cooling. The reaction mixture was stirred for 30 minutes. To this was added allyl chloride (0.10 g). The reaction mixture was stirred at 0 ° C for 1 h. Water (80 ml) was added to the reaction mixture, extracted with diethyl ether (100 ml), dried over aqueous 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- (allylthio) thiocarbonyl-5,5-dimethyl-1, 3-thiazine (0.26 g, yield: 69%) was obtained as a pale yellow oil.
[214] Example 2 : 2- (2-isopropylphenyl) imino-3- (5-trifluoromethyl-2-pyridyl) -5,5-dimethyl-1,3-thiazine (Compound I-106) Manufacture
[215]
[216] 2- (2-isopropylphenyl) imino-5,5-dimethyl-1,3-thiazine (0.26 g) and 5-trifluoromethyl-2- in N, N-dimethylformamide (3 ml) 60% sodium hydride (0.05 g) was added to a solution of chloropyridine (0.24 g) under ice cooling. The mixture was stirred at rt for 2 h. (80 ml) was added to the reaction mixture, extracted with diethyl ether (100 ml), dried over aqueous 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- (5-trifluoromethyl-2-pyridyl) -5, 5-Dimethyl-1,3-thiazine (0.13 g, yield: 32%) was obtained as a colorless oil.
[217] The compounds shown in the following table were prepared according to the above examples. The numbers in the left column of the table indicate the compound numbers and together describe the compounds obtained in the above examples.
[218]
[219]
[220]
[221]
[222]
[223]
[224]
[225]
[226]
[227] The compound physical data described in the table is shown in the table below.
[228]
[229]
[230]
[231]
[232]
[233]
[234]
[235]
[236]
[237]
[238]
[239]
[240]
[241]
[242]
[243] Compounds of the present invention also include compounds shown in the following table.
[244] These compounds are synthesize | combined by the method similar to the said Example.
[245] Numbers in the left column of the table indicate compound numbers.
[246]
[247]
[248]
[249]
[250]
[251]
[252]
[253]
[254]
[255]
[256]
[257]
[258]
[259]
[260]
[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]
[288]
[289]
[290]
[291]
[292]
[293]
[294]
[295]
[296]
[297]
[298]
[299]
[300]
[301]
[302]
[303]
[304]
[305]
[306] In the table above, Me and methyl = methyl, Et = ethyl, Allyl = allyl, isoxazolyl = isoxazolyl
[307] The compounds of the present invention were tested as follows.
[308] Test Example 1 Inhibition of Human CB2 Receptor (CB2R) Binding
[309] The coding region of the human CB2 receptor (CB2R) cDNA (Munro et al., 1993, 365, 61-65) was inserted into the mammalian expression vector pSVL SV40 Late Promotor Expression Vector (Amersham Pharmacia Biotech Inc.). The obtained vector was transcribed into Chinese Hamster Ovary (CHO) cells using LipofectAMINE reagent (Gibco BRL) according to the manufacturer's protocol, and stable CB2R expression clones were selected.
[310] Crude membrane fractions were prepared from CB2R expressing CHO cells. Receptor binding assay was performed with each test compound and [ ³ H] CP55940 (final concentration 0.5 nM: NEN Life Science Products) with 50 mM Tris-HCl (pH 7.4) containing assay buffer (0.5% bovine serum albumin (BSA), 1 mM EDTA, 3 mM MgCl ₂ ) was performed by incubating the membrane for 2 hours at 25 ° C. The culture mixture was filtered through a 1% polyethyleneimine treated GF / C glass filter and washed with 50 mM Tris-HCl (pH 7.4) containing 0.1% BSA. Then, radioactivity was calculated | required by the liquid scintillation counter. Nonspecific binding was measured in the presence of 10 μM WIN55212-2 (cannabinoid receptor agonist, US Pat. No. 508122, Research Biochemicals International), and specific binding was calculated by subtracting nonspecific binding from total binding. The IC ₅₀ value of each test compound was determined as the concentration at which 50% of the specific binding was inhibited.
[311] For receptor binding assays of human CB1 receptor (CB1R), stable CB1R expressing CHO cells were prepared by the above method, and binding assays were performed using membrane fractions. As a result of these binding experiments, the K _i values of each test compound for all cannabinoid receptors are shown in a table. As shown in the table, a series of compounds of the present invention inhibited the binding of cannabinoid receptor agonists described in CP55940 (US Pat. No. 4371720) to CB2R.
[312]
[313] Experimental Example 2: cAMP synthesis inhibition experiment mediated by CB2R
[314] Human CB2R expressing CHO cells were incubated with the test compound for 15 minutes. After incubation, forskolin (final concentration 4 μM, Sigma) was added and the cells were incubated at 37 ° C. for 20 minutes. The reaction was stopped by addition of 1N HCl and the amount of cAMP in the cell supernatant was measured with an EIA kit (Amersham Pharmacia Biotech Inc.) according to the manufacturer's protocol. The amount of cAMP increased by forskolin compared to that in the absence of forskolin was defined as 100% and the IC ₅₀ value of each test compound was determined as the concentration at which 50% of the forskolin stimulated cAMP synthesis was inhibited. As a result of this, the IC ₅₀ value of each test compound is shown in the table. As shown in the table, the compounds of the present invention exhibited agonist action on CB2R.
[315] In addition, the antagonist action of each compound was evaluated in the same assay.
[316]
[317] Compounds of the present invention, except for the compounds described above, showed binding activity to the same or more cannabinoid type 2 receptors as described above and agonist action to the cannabinoid type 2 receptors.
[318] On the other hand, the compounds of the present invention can be evaluated for anti-inflammatory effects according to the following in vivo studies.
[319] Example 3: Positive Red Blood Cell (SRBC) Induced Delayed Type Hypersensitivity (DTH) Response Experiment
[320] Female ddY mice (7 weeks old) were used for positive red blood cell (SRBC) induced delayed-type hypersensitivity (DTH) responses.
[321] 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 SRBCs (40 μl / 1 foot) into the left posterior plantar. After 5 days, 10 ⁸ SRBCs were injected intradermal into the right posterior plantar to elicit a DTH response. Test compounds were administered orally (po; 10 ml / kg) 1 hour before and 5 hours after induction of the DTH response. 24 hours after SRBC injection, the left and right plantar volumes were measured according to the water replacement method. The paw edema dose was calculated as the difference between the right hind paw and left hind paw volume and used as an indicator of DTH response.
[322] Data is expressed as% inhibition of each compound.
[323] In addition, statistical analysis was performed by Welch t test, where the value P <0.05 is considered as significant difference.
[324] In addition, the compound of the present invention is a pharmaceutical composition having high metabolic stability and excellent.
[325] Formulation example
[326] Formulation Examples 1 to 8 below are for illustration only and do not limit the scope of the invention. The term "active ingredient" means a compound represented by the formula (I), a tautomer, a prodrug thereof, a pharmaceutically acceptable salt thereof or a solvate thereof.
[327] Formulation Example 1
[328] Hard gelatin capsules are prepared from the following ingredients:
[329] Dose (mg / capsule) Active Ingredient Starch (Dry) Magnesium Stearate25020010 Sum460 mg
[330] Formulation Example 2
[331] Tablets are made with the following ingredients:
[332] Dose (mg / capsule) Active ingredient Cellulose (fine crystal) Silicon dioxide (fume) Stearic acid250400105 Sum665 mg
[333] Mixing and compressing the above ingredients yields tablets of 665 mg weight.
[334] Formulation Example 3
[335] An aerosol solution containing the following ingredients is prepared:
[336] weight Active Ingredients Ethanol Propelant 22 (Chlorodifluoromethane)0.2525.7574.00 Sum100.00
[337] The active ingredient is mixed with ethanol, the mixture is added to a portion of Propellant 22 and cooled to -30 ° C and transferred to the filling device. The required amount is then supplied to a stainless steel vessel and diluted with the residual liquid foaming agent. Attach a value unit to the container.
[338] Formulation Example 4
[339] Each tablet containing 60 mg of active ingredient is prepared as follows:
[340] Active ingredient Starch microcrystalline cellulose polyvinylpyrrolidone (10% solution in water) sodium carboxymethyl starch magnesium stearate60 mg45 mg35 mg4 mg4.5 mg0.5 mg1 mg Sum150 mg
[341] Active ingredients, starch, and cellulose; 45 mesh U.S. Pass through a sieve and mix thoroughly. After mixing an aqueous solution containing polyvinylpyrrolidone with the obtained powder, the mixture was No. 14 mesh U.S. Pass it through a sieve. The obtained granules were dried at 50 deg. 18 mesh U.S. Pass it through a sieve. No. 60 mesh U.S. Sodium carboxymethyl starch, magnesium stearate, and talc, which were previously passed through a sieve, are added to the granules, mixed, and then compressed with a tablet press to obtain tablets of 150 mg in weight each.
[342] Formulation Example 5
[343] Each tablet containing 80 mg of active ingredient is prepared as follows:
[344] Active ingredient Starch microcrystalline magnesium cellulose stearate80 mg59 mg59 mg2 mg Sum200 mg
[345] The active ingredient, cellulose, starch, and magnesium stearate are mixed, 45 mesh U.S. Pass through a sieve and fill 200 mg of hard gelatin capsules.
[346] Formulation Example 6
[347] Each suppository containing 225 mg of the active ingredient is prepared as follows:
[348] Saturated Fatty Acid Glycerides225 mg2000 mg Sum2225 mg
[349] Active ingredient No. 60 mesh U.S. It is passed through a sieve and preheated to the minimum necessary and suspended in the molten saturated fatty acid glycerides and glycerides. The mixture is then poured into a suppository mold of 2 g of appearance and cooled.
[350] Formulation Example 7
[351] Each suspension containing 50 mg of active ingredient per 5 ml dose is prepared as follows:
[352] Active Ingredients Sodium Carboxymethyl Cellulose Syrup Benzoic Acid Solution50 mg 50 mg 1.25 ml 0.10 mlq.v.q.v. Total added purified water5 ml
[353] Active ingredient No. 45 U.S. Pass through a sieve and mix with sodium carboxymethyl cellulose and syrup to form a soft paste. The benzoic acid solution, flavor and pigment are diluted with a portion of water and added with stirring. Then enough water is added to make the required volume.
[354] Formulation Example 8
[355] Intravenous preparations are prepared as follows:
[356] Active ingredient Physiological saline100 mg 1000 ml
[357] A solution of this component is usually administered intravenously to a patient at a rate of 1 ml per minute.
[358] In the present invention represented by the formula (I), the compound binds to the cannabinoid type 2 receptor (CB2R) and exhibits an antagonist action or agonist action on 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).

权利要求:
Claims (19)
[1" claim-type="Currently amended] A compound of formula (I), a prodrug thereof, a pharmaceutically acceptable salt thereof or a solvate thereof:
[Formula I]
[In the meal,
R ¹ is an optionally substituted heterocyclic group or formula: -C (= Z) WR ⁴ (where Z is an oxygen atom or a sulfur atom; W is an oxygen atom or a sulfur atom; R ⁴ is optionally substituted alkyl, optionally substituted Alkenyl or optionally substituted alkynyl);
Each of R ² and R ³ is independently hydrogen, optionally substituted alkyl, optionally substituted alkoxyalkyl, optionally substituted aminoalkyl, or optionally substituted cycloalkyl; or
R ² and R ³ together form a substituted alkylene which may contain heteroatom (s);
m is an integer from 0 to 2;
A is an optionally substituted aromatic carbocyclic group or an optionally substituted aromatic heterocyclic group;
Provided that when R ¹ is a group represented by the formula: -C (= Z) WR ⁴ (where Z is an oxygen atom or a sulfur atom; W is an oxygen atom or a sulfur atom; R ⁴ is an unsubstituted alkyl), ² and R ³ together form an optionally substituted alkylene containing heteroatom (s).
[2" claim-type="Currently amended] A compound according to claim 1, a prodrug thereof, a pharmaceutically acceptable salt thereof or a solvate thereof:

Is an equation represented by:

[In the meal,
Each of R ⁵ and R ⁶ is 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 Group of; or
R ⁵ and R ⁶ together form an alkylenedioxy;
A is an aromatic carbocyclic group or aromatic heterocyclic group.
[3" claim-type="Currently amended] A compound according to claim 2, a prodrug thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof:
R ⁵ is hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy , Methylthio, ethylthio, n-propylthio, isopropylthio, 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-oxopyrrolidino, 1-methoxyiminoethyl or morpholinocarbonyl;
R ⁶ is hydrogen, methyl, ethyl, fluoro, chloro, nitro, methoxy or ethoxy; or
R ⁵ and R ⁶ together form —O—CH ₂ —O—;
A is phenyl, naphthyl, pyridyl or quinolyl.
[4" claim-type="Currently amended] A compound according to claim 2, a prodrug thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof:
Each of R ⁵ and R ⁶ is independently hydrogen, alkyl, alkoxy, or alkylthio;
A is an aromatic carbocyclic group.
[5" claim-type="Currently amended] The compound according to any one of claims 1 to 4, characterized in that: a prodrug thereof, a pharmaceutically acceptable salt thereof or a solvate thereof:
m is 0.
[6" claim-type="Currently amended] A compound according to claim 5, a prodrug thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof:
R ¹ is an optionally substituted heterocyclic group.
[7" claim-type="Currently amended] 7. A compound according to claim 6, a prodrug thereof, a pharmaceutically acceptable salt thereof or a solvate thereof:
R ¹ is optionally substituted pyridyl, optionally substituted benzothiazolyl, optionally substituted benzoxazolyl or optionally substituted thiadiazolyl.
[8" claim-type="Currently amended] A compound according to claim 5, a prodrug thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof:
R ¹ is a formula: -C (= Z) WR ⁴ where Z is an oxygen atom or a sulfur atom; W is an oxygen atom or a sulfur atom; R ⁴ is optionally substituted alkyl, optionally substituted alkenyl or optionally substituted alkoxy Nil).
[9" claim-type="Currently amended] A compound according to claim 8, a prodrug thereof, a pharmaceutically acceptable salt thereof or a solvate thereof, characterized in that:
Z and W are sulfur atoms.
[10" claim-type="Currently amended] 10. A compound according to any one of claims 1 to 9, a prodrug thereof, a pharmaceutically acceptable salt thereof or a solvate thereof:
Each of R ² and R ³ is independently methyl, ethyl, propyl or methoxymethyl; or
R ² and R ³ together form ethylene, trimethylene, tetramethylene, pentamethylene or ethyleneoxyethylene.
[11" claim-type="Currently amended] A compound according to claim 1, represented by the following formula, a prodrug thereof, a pharmaceutically acceptable salt thereof or a solvate thereof:

[In the meal,
Each of R ² and R ³ is independently optionally substituted alkyl;
R ² and R ³ together form an optionally substituted alkylene which may contain heteroatoms;
R ⁴ is optionally substituted alkyl, optionally substituted alkenyl or optionally substituted alkynyl;
R ⁵ is alkyl, alkoxy, or optionally substituted amino;
R ⁶ is hydrogen, alkyl, alkoxy, optionally substituted amino or haloalkoxy.
[12" claim-type="Currently amended] 12. A compound according to claim 11, a prodrug thereof, a pharmaceutically acceptable salt thereof or solvate thereof:
R ⁴ is optionally substituted alkyl [substituents are cyano, alkoxy, alkylcarbonyl, carboxy, alkoxycarbonyl, alkenyloxycarbonyl, alkoxyalkoxycarbonyl, optionally substituted carbamoyl (substituent is alkyl or alkoxy) , Halogen, alkylcarbonyloxy, aryloxy, optionally substituted non-aromatic heterocyclic group (substituent is alkyl), optionally substituted aromatic heterocyclic group (substituent is alkyl or aryl), or formula: -OR ^I Wherein R ^I is a non-aromatic heterocyclic group), alkenyl or alkynyl.
[13" claim-type="Currently amended] A compound according to claim 1, a prodrug thereof, a pharmaceutically acceptable salt thereof or a solvate thereof:
A is optionally substituted phenyl, optionally substituted naphthyl, or optionally substituted quinolyl.
[14" claim-type="Currently amended] A pharmaceutical composition comprising a compound according to any one of claims 1 to 13, a prodrug thereof, a pharmaceutically acceptable salt thereof or a solvate thereof.
[15" claim-type="Currently amended] The pharmaceutical composition according to claim 14, which has a binding action to cannabinoid type 2 receptors.
[16" claim-type="Currently amended] The pharmaceutical composition according to claim 15, which has an agonist action on the cannabinoid type 2 receptor.
[17" claim-type="Currently amended] The pharmaceutical composition according to any one of claims 14 to 16, which is useful as an anti-inflammatory agent.
[18" claim-type="Currently amended] A method of treating inflammation comprising administering a pharmaceutical composition according to claim 1.
[19" claim-type="Currently amended] Use of a compound according to claim 1 for the preparation of an anti-inflammatory agent.

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RU2455285C2|2012-07-10|NITROGEN CONTAINING HETEROCYCLIC DERIVATIVE SHOWING TYPE I 11β -HYDROXYSTEROIDDEHYDROGENASE INHIBITORY ACTIVITY

同族专利:

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公开号 | 公开日

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US6916806B2|2005-07-12|

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EP1375489A1|2004-01-02|

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DE60228429D1|2008-10-02|

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CA2440186C|2009-01-13|

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KR100642570B1|2006-11-10|

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WO2002072562A1|2002-09-19|

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AT405555T|2008-09-15|

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JPWO2002072562A1|2004-07-02|

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EP1375489B1|2008-08-20|

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CN1301981C|2007-02-28|

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BR0207966A|2004-06-15|

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CN1514831A|2004-07-21|

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CA2440186A1|2002-09-19|

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KR20060029296A|2006-04-05|

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US20040116326A1|2004-06-17|

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JP4188694B2|2008-11-26|

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EP1375489A4|2005-03-02|

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MXPA03008033A|2003-12-04|

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:
2001-03-08|Priority to JP2001065386

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2001-03-08|Priority to JPJP-P-2001-00065386

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2002-02-14|Application filed by 시오노기세이야쿠가부시키가이샤

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2002-02-14|Priority to PCT/JP2002/001229

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2004-01-24|Publication of KR20040007462A

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2006-11-10|Application granted

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2006-11-10|Publication of KR100642570B1

优先权:

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申请号 | 申请日 | 专利标题

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JP2001065386|2001-03-08|

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JPJP-P-2001-00065386|2001-03-08|

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PCT/JP2002/001229|WO2002072562A1|2001-03-08|2002-02-14|Medicinal composition containing 1,3-thiazine derivative|