JP2007262022A - Novel 2-thiophenecarboxamide derivatives - Google Patents

Abstract

（式中、ＶはＯ、ＯＨ；Ｒ₁はＨ、ＣＦ₃、脂肪族炭化水素等；Ｒ₂は、Ｈ、ハロゲン、脂肪族炭化水素等； Ｒ₃は一〜三環式炭素環、アリールアルキル等；ＷはＮ、Ｓ；ｎは０−２；Ｒ₄、Ｒ₄'はＨ、脂肪族炭化水素；Ｒ₅、Ｒ₆はＨ、トリハロメタンスルホニル等；環Ｐ、環Ｑは脂環式複素炭化水素基等。）で示される化合物、その塩、その溶媒和物、これらを有効成分とする医薬組成物。
【選択図】なしThe present invention provides a preventive and / or therapeutic agent for a disease involving cannabinoid 2 receptor (CB2).
Formula (I)

(Wherein V is O, OH; R ₁ is H, CF ₃ , aliphatic hydrocarbon, etc .; R ₂ is H, halogen, aliphatic hydrocarbon, etc .; R ₃ is a mono- to tricyclic carbocycle, aryl W is N, S; n is 0-2; R ₄ and R ₄ ′ are H, aliphatic hydrocarbons; R ₅ and R ₆ are H, trihalomethanesulfonyl, etc .; ring P and ring Q are alicyclic Heterohydrocarbon groups, etc.), salts thereof, solvates thereof, and pharmaceutical compositions containing these as active ingredients.
[Selection figure] None

Description

  The present invention relates to a novel 2-thiophenecarboxamide derivative or a pharmaceutically acceptable salt thereof, or a solvate thereof. The present invention also relates to a novel pharmaceutical composition comprising a 2-thiophenecarboxamide derivative or a pharmaceutically acceptable salt thereof, or a solvate thereof as an active ingredient. Further, a cannabinoid 2 receptor (hereinafter sometimes referred to as CB2) characterized by containing a 2-thiophenecarboxamide derivative or a pharmaceutically acceptable salt thereof, or a solvate thereof as an active ingredient. The present invention relates to a novel preventive and / or therapeutic agent for a disease involved, particularly a novel preventive and / or therapeutic agent for neuropathic pain, inflammatory pain, inflammatory disease, allergic disease and autoimmune disease.

Cannabinoid is a generic name for Δ9-tetrahydrocannabinol (Δ9-THC), which is the main active ingredient of cannabis, and its similar compounds (Non-patent Document 1). It is known to cause various effects such as feeling, hallucination, somnolence, increased appetite, decreased pain sensation, immunosuppression, and anti-inflammatory (Non-Patent Document 2).
As a cannabinoid (CB) receptor, two subtypes of cannabinoid 1 receptor (hereinafter sometimes referred to as CB1) and CB2 have been cloned. Among these, CB1 was first identified and was cloned from rat cerebral cortex cDNA in 1990 by Matsuda et al. (Non-patent Document 3). On the other hand, in 1993, another CB2 gene was cloned from HL-60 cells, a human promyelocytic leukemia cell line, by Munro et al. (Non-patent Document 4). CB1 is expressed in most nervous tissues, whereas CB2 is hardly expressed in the central nervous system and is abundantly expressed in tissues and cells mainly involved in inflammation or immune response. It has become clear. Recently, in addition to tissues and cells of the immune system, microglia (Non-patent Document 5),
It has been reported that CB2 is expressed even in peripheral nerves (Non-Patent Document 6) and skin keratinocytes (Non-Patent Document 7).

Recent studies reveal that among the various actions of Δ9-THC, actions such as euphoria, hallucinations, somnolence, disruption of temporal and spatial sensations, and increased appetite are effects via CB1 in the central nervous system It has become. On the other hand, among the actions of Δ9-THC, anti-inflammatory action, immunosuppressive action, and pain sensation reduction are considered to be actions through cells that are involved in inflammation or immune reaction expressing CB2. Therefore, if a substance that does not bind to CB1 but selectively binds only to CB2 is found, it is expected to exert analgesic, anti-inflammatory and immunomodulating effects while avoiding central effects. Many drug discovery studies have been conducted so far.

  Actually, Patent Documents 1 to 31 show specific compounds and target diseases of substances that bind to CB2 (hereinafter sometimes referred to as CB2 ligands), and particularly Patent Document 7 or Patent Document 8 , 20, 27, 28, and 29 show the effectiveness in various experimental models. The target diseases of CB2 ligand described in these patent documents include pain, inflammatory diseases (such as rheumatoid arthritis, knee osteoarthritis), autoimmune diseases (such as scleroderma, Crohn's disease, systemic lupus erythematosus), allergic Disease (asthma, atopic dermatitis, urticaria, etc.), neurological disease (multiple sclerosis, amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease, Huntington's disease, etc.), cardiovascular disease, renal disease, osteoporosis Etc. are mentioned.

Among CB2 ligands exogenously administered to mammals, particularly inverse agonists mainly have anti-inflammatory effects and immunomodulation by antagonizing the physiological effects of endogenous CB2 ligands such as 2-arachidonoylglycerol (2-AG). It is thought to show pharmacological actions such as action. That is, endogenous CB2 ligand is locally produced during inflammation, which activates microglia and monocytic cells via CB2 to cause inflammation and immune response, and CB2 ligand including inverse agonist is It antagonizes the action of the ligand (Non-patent Documents 8 and 9). Actually CB2-selective inverse agonists JTE-907, SR144528 and Sch. 336 has been reported to show efficacy by oral administration in various animal models of inflammation, atopic dermatitis, and allergic asthma (Non-patent Documents 10-12).

On the other hand, among CB2 ligands exogenously administered to mammals, agonists, in particular, are considered to exhibit pharmacological effects mainly by stimulating CB2 receptors as agonists themselves and modifying cell and nerve functions. ing. That is, the expression of CB2 in the microglia and nervous system is increased in the pathological state, and the agonist suppresses the excitation and activation of these cells and nerves (Non-patent Documents 13-15). In fact, the selective CB2 agonist AM1241 shows allodynia due to nerve injury (feeling pain with stimuli that do not normally feel pain), inflammatory pain sensation in mammals without showing side effects related to the central nervous system. It has been reported that hypersensitivity (feeling painful stimulation stronger than usual) and suppressing an inflammatory reaction (Non-Patent Documents 7, 16, and 17). In addition, JWH133, which is a selective CB2 agonist, has been reported to show antitussive action in mammals without showing side effects on the central nervous system caused by CB1 (Non-patent Document 18). The nonselective CB2 agonist WIN55212-2 suppresses airway hypersensitivity and neurogenic inflammation in mammals, and its pharmacological action is antagonized by a CB2 selective inverse agonist (Non-patent Documents 14 and 19). As these reports indicate, CB2 agonists are effective in vivo against pathologies such as pain, cough, and airway hyperresponsiveness based on direct / indirect effects on the nervous system. In addition to these nervous system diseases, CB2 agonists act directly on monocytes / macrophages and show their efficacy in an arteriosclerosis model through the inhibition of migration by their chemokines (Non-patent Document 20), CB2 without central effects It has been reported that selective agonists show efficacy in mouse osteoporosis models through osteoblast activation and osteoclast proliferation inhibition (Non-patent Document 21).

From the reports of the above-mentioned patent documents and non-patent documents, a substance that binds selectively to CB2 without binding to CB1 (CB2 selective ligand) shows pain, inflammatory disease (rheumatoid arthritis, Knee osteoarthritis), autoimmune disease (scleroderma, Crohn's disease, systemic lupus erythematosus, etc.), allergic disease (asthma, atopic dermatitis, urticaria, etc.), neurological disease (multiple sclerosis, muscle, etc.) It is expected to be useful as a therapeutic agent for amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease, Huntington's disease, etc.), cardiovascular disease, renal disease, and osteoporosis.
Among CB2 selective ligands, agonists are particularly useful as analgesics for neuropathic pain (postherpetic neuralgia, painful diabetic neuropathy, etc.) and inflammatory pain (rheumatoid arthritis, knee osteoarthritis, etc.) Sex is expected. In addition, as an antitussive for cough (bronchitis, cold syndrome, asthma, obstructive pulmonary disease, etc.) based on increased airway hypersensitivity, or cardiovascular disease (unstable angina, myocardial infarction or stroke) based on arteriosclerosis It is also considered useful as a prophylactic agent for osteoporosis.
Furthermore, autoimmune diseases, inflammation, kidney diseases, other neurological diseases (stroke, Alzheimer, migraine, Parkinson's disease, amyotrophic lateral sclerosis, etc.), cardiovascular diseases (arrhythmia, hypertension, cerebral ischemia), It is considered useful as a preventive and / or therapeutic agent for allergies, cancer, gastrointestinal diseases, obesity, multiple sclerosis, Huntington's disease, pruritus, arteriosclerosis and other neuropathic pain (such as diabetic pain).
Further, among the CB2 selective ligands, particularly inverse agonists are considered useful as preventive and / or therapeutic agents for allergic diseases such as allergic asthma, atopic dermatitis and urticaria.
Furthermore, prevention against T cell lymphoma, rheumatoid arthritis, allergy, scleroderma, Crohn's disease, systemic lupus erythematosus, multiple sclerosis, diabetes, glaucoma, osteoporosis, renal ischemia, nephritis, cerebral ischemia, stroke and / or It is considered useful as a therapeutic agent.

  On the other hand, the application of the 2-thiophenecarboxamide derivative to the above-mentioned diseases has not been known so far, and further, the pharmacological action via CB2 of the 2-thiophenecarboxamide derivative containing the compound has not been known at all.

WO 97/860 pamphlet International Publication No. 97/29079 Pamphlet WO 02/72562 pamphlet International Publication No. 01/28329 Pamphlet WO 02/72562 pamphlet International Publication No. 02/85866 pamphlet WO03 / 61699 pamphlet International Publication No. 03/63758 Pamphlet International Publication No. 03/97597 Pamphlet International Publication No. 04/807 Pamphlet

International Publication No. 04/29027 Pamphlet International Publication No. 04/35548 Pamphlet JP 2001-151779 A JP 2001-151780 A International Publication No. 04/18433 Pamphlet International Publication No. 04/50086 pamphlet International Publication No. 04/87704 Pamphlet International Publication No. 04/10400 Pamphlet International Publication No. 04/103974 Pamphlet International Publication No. 05/21547 Pamphlet

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  As described above, CB2 selective ligands are being studied as preventive and / or therapeutic agents for neuropathic pain, neurological diseases, inflammation or allergic diseases, autoimmune diseases, etc. that do not affect the central nervous system. However, it has not yet succeeded as a pharmaceutical product, and its effective use is being sought. Therefore, development of a novel therapeutic agent containing a cannabinoid selective ligand, particularly a ligand selective for CB2 as an active ingredient is still desired.

  As a result of intensive studies on compounds having binding activity to CB2, the present inventors have found that a 2-thiophenecarboxamide compound of the formula (I) described later or a pharmaceutically acceptable salt thereof directly binds to CB2. It has been found that it has an action of regulating its function and / or has an action of binding directly to CB2 and inhibiting binding of an endogenous or exogenous CB2 ligand. In addition, a novel preventive and / or therapeutic agent for a disease involving CB2, characterized by containing the compound or the salt as an active ingredient, particularly a novel preventive and therapeutic agent for neurological diseases, inflammation or allergic diseases and autoimmune diseases A therapeutic agent was found.

CB2 selective ligands show no central side effects, such as pain, inflammatory diseases (such as rheumatoid arthritis, knee osteoarthritis), autoimmune diseases (such as scleroderma, Crohn's disease, systemic lupus erythematosus), allergies Diseases (asthma, atopic dermatitis, urticaria, etc.), neurological diseases (multiple sclerosis, amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease, Huntington's disease, etc.), cardiovascular disease, kidney disease, Its usefulness is expected as an agent for preventing and / or treating osteoporosis.
Among CB2 selective ligands, agonists are particularly useful as analgesics for neuropathic pain (postherpetic neuralgia, painful diabetic neuropathy, etc.) and inflammatory pain (rheumatoid arthritis, knee osteoarthritis, etc.) Sex is expected. In addition, as an antitussive for cough (bronchitis, cold syndrome, asthma, obstructive pulmonary disease, etc.) based on increased airway hypersensitivity, or cardiovascular disease (unstable angina, myocardial infarction or stroke) based on arteriosclerosis It is also considered useful as a prophylactic agent for osteoporosis.
Furthermore, autoimmune diseases, inflammation, kidney diseases, other neurological diseases (stroke, Alzheimer, migraine, Parkinson's disease, amyotrophic lateral sclerosis, etc.), cardiovascular diseases (arrhythmia, hypertension, cerebral ischemia), It is considered useful as a preventive and / or therapeutic agent for allergies, cancer, gastrointestinal diseases, obesity, multiple sclerosis, Huntington's disease, pruritus, arteriosclerosis and other neuropathic pain (such as diabetic pain).
Further, among the CB2 selective ligands, particularly inverse agonists are considered useful as preventive and / or therapeutic agents for allergic diseases such as allergic asthma, atopic dermatitis and urticaria.
Furthermore, prevention against T cell lymphoma, rheumatoid arthritis, allergy, scleroderma, Crohn's disease, systemic lupus erythematosus, multiple sclerosis, diabetes, glaucoma, osteoporosis, renal ischemia, nephritis, cerebral ischemia, stroke and / or It is considered useful as a therapeutic agent.

A functional assay for determining agonist / inverse agonist activity of a test substance having human CB2 receptor binding activity includes guanosine triphosphate (GTP) binding reaction (“Assay and Drug Development Technologies (Assay and Drug Development Technologies)”. ) "2003, Vol. 1, No. 2, p. 275-280). In this system, the CB2 ligand that increases the binding amount of GTP is an agonist, and the ligand that decreases it is an inverse agonist.
As another determination method, a system in which cells forcibly expressing human CB2 receptor are stimulated with forskolin and intracellular cAMP is measured can be mentioned. In this system, the ligand that decreases the intracellular cAMP concentration is an agonist, and the ligand that increases the intracellular cAMP concentration is an inverse agonist.

The present invention is described in detail below. The abbreviations and definitions described in the general formula (I) for each group such as R ₁ and R ₂ shown here show a common range in the present specification even when described in other general formulas.
In this specification, “•” is sometimes used in the meaning of “,”, but is used in a concept concept different from other “,” in the context.
The “C ₁ -C ₆ aliphatic hydrocarbon group” refers to a saturated or unsaturated hydrocarbon group having 1 to 6 straight or branched carbon atoms, such as a C ₁ -C ₆ alkyl group, C ₂ -C ₆ alkenyl group, C ₂ -C ₆ alkynyl group and the like can be mentioned.
Examples of the “C ₁ -C ₆ alkyl group” include methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, tert-butyl group, pentyl group, isopentyl group, neopentyl group, tert-pentyl group, 1-methylbutyl group, 2-methylbutyl group, 1,2-dimethylpropyl group, hexyl group, isohexyl group, 1-methylpentyl group, 2-methylpentyl group, 3-methylpentyl group, 1,1 -Dimethylbutyl group, 1,2-dimethylbutyl group, 2,2-dimethylbutyl group, 1,3-dimethylbutyl group, 2,3-dimethylbutyl group, 3,3-dimethylbutyl group, 1-ethylbutyl group, 2-ethylbutyl group, 1,1,2-trimethylpropyl group, 1,2,2-trimethylpropyl group, 1-ethyl-1-methylpropylene Group, 1-ethyl-2-methylpropyl group and the like.

Examples of the “C ₂ -C ₆ alkenyl group” include vinyl group, allyl group, propenyl group, isopropenyl group, 2-methylallyl group, butenyl group, pentenyl group, hexenyl group and the like.
Examples of the “C ₂ -C ₆ alkynyl group” include ethynyl group, 1-propynyl group, 2-propynyl group, butynyl group, pentynyl group, hexynyl group and the like.
The “aryl group” represents a 6 to 10 membered aryl group, and examples thereof include a phenyl group, an α or β naphthyl group, and the like.
The “alicyclic hydrocarbon group” refers to a saturated or partially unsaturated monocyclic, condensed or bridged cyclic alicyclic hydrocarbon group having 3 to 10 carbon atoms, such as a cyclopropyl group, Examples thereof include a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cyclohexenyl group, a bicyclooctyl group, a noradamantyl group, an adamantyl group, and α-pinene.
“Heteroaryl group” means a 5- to 10-membered heteroaryl group containing 1 to 4 heteroatoms arbitrarily selected from a nitrogen atom, an oxygen atom, and a sulfur atom, such as an oxadiazolyl group, pyrrolyl group, furyl Group, thienyl group, oxazolyl group, imidazolyl group, isoxazolyl group, thiazolyl group, isothiazolyl group, pyrazolyl group, tetrazolyl group, pyridyl group, pyridazinyl group, pyrimidinyl group, pyrazinyl group, thiadiazinyl group, quinolyl group, indolyl group, etc. .

The “alicyclic heterohydrocarbon group” contains 1 to 4 heteroatoms arbitrarily selected from a nitrogen atom, an oxygen atom and a sulfur atom, and has a partially unsaturated bond or aromatic ring in the ring. Represents an optionally substituted 3 to 10-membered alicyclic heterohydrocarbon group, such as 1-aza-2-thiacyclopentane-2,2-dione-5-yl group, 1-aza-2-thiacyclo Pentane-2,2-dione-1-yl group, 1-thiacyclopentane-1,1-dione-2-yl group, azetidinyl group, oxiranyl group, oxetanyl group, pyrrolidinyl group, tetrahydrofuryl group, thiolanyl group, pyrazolinyl Group, pyrazolidinyl group, piperidyl group, tetrahydropyranyl group, morpholinyl group, piperazinyl group, tetrahydroquinolyl group, decahydroquinolyl group,
A dihydrobenzofuranyl group, a tetrahydropyranyl group, etc. are mentioned.
Examples of the “halogen atom” include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
Examples of the “C ₁ -C ₆ alkoxy group” include methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, sec-butoxy group, tert-butoxy group, pentyloxy group, 1,2-dimethylpropyloxy Group, 1,1-dimethylpropyloxy group, 2,2-dimethylpropyloxy group, 2-ethylpropyloxy group, hexyloxy group, 1,2-dimethylbutyloxy group, 2,3-dimethylbutyloxy group, 1 , 3-dimethylbutyloxy group, 1-ethyl-2-methylpropyloxy group, 1-methyl-2-ethylpropyloxy group and the like.

Examples of the “C ₁ -C ₃ alkylsulfonyl group” include a methanesulfonyl group, an ethanesulfonyl group, a propanesulfonyl group, and the like.
Examples of the “trihalomethanesulfonyl group” include a trifluoromethanesulfonyl group.
The “arylthio group” represents a 6-10 membered arylthio group, and examples thereof include a phenylthio group, an α- or β-naphthylthio group, and the like.
The “arylsulfonyl group” represents a 6-10 membered arylsulfonyl group, and examples thereof include a phenylsulfonyl group and an α- or β-naphthylsulfonyl group.
Examples of the “C ₁ -C ₆ alkylcarbonyl group” include linear or branched fatty acids having 2 to 6 carbon atoms such as acetyl group, propionyl group, butyryl group, valeryl group, isovaleryl group, pivaloyl group, caproyl group and the like. A group derived from a linear or branched aliphatic unsaturated carboxylic acid having 3 to 6 carbon atoms, such as a group derived from an aromatic saturated carboxylic acid, an acryloyl group, a propioroyl group, a methacryloyl group, a crotonoyl group, an isocrotonoyl group Etc.
Examples of the “C ₁ -C ₆ alkoxycarbonyl group” include methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, isopropoxycarbonyl group, butoxycarbonyl group, sec-butoxycarbonyl group, tert-butoxycarbonyl group, pentoxycarbonyl Groups and the like.
Examples of the “aryl C ₁ -C ₆ alkyl group” include benzyl group, phenethyl group, α or β-naphthylmethyl group, and the like.

  The present invention relates to a novel 2-thiophenecarboxamide derivative or a pharmaceutically acceptable salt thereof, or a solvate thereof. The present invention also relates to a novel pharmaceutical composition comprising a 2-thiophenecarboxamide derivative or a pharmaceutically acceptable salt thereof, or a solvate thereof as an active ingredient. Further, a cannabinoid 2 receptor (hereinafter sometimes referred to as CB2) characterized by containing a 2-thiophenecarboxamide derivative or a pharmaceutically acceptable salt thereof, or a solvate thereof as an active ingredient. The present invention relates to a novel preventive and / or therapeutic agent for diseases involved, and particularly to a novel preventive and / or therapeutic agent for neuropathic pain, neurological diseases, inflammation or allergic diseases and autoimmune diseases.

（式中、
Ｖは酸素原子（オキソ基）または水酸基を表し、実線と破線で表される結合は単結合若しくは二重結合を表し、

Ｒ₁は、
水素原子、トリハロメチル基、水酸基で置換されていてもよい直鎖若しくは分枝鎖のC₁−C₆脂肪族炭化水素基、脂環式炭化水素基、アリール基、カルボキシル基、C₁−C₆アルキルカルボニル基、C₁−C₆アルコキシカルボニル基、カルバモイル基であり、 The present invention is a novel compound, a pharmaceutical composition, or a pharmaceutical use thereof shown in the following embodiments.
The present invention will be described in detail by the following embodiments.
<Aspect 1>
Formula (I)

(Where
V represents an oxygen atom (oxo group) or a hydroxyl group, and a bond represented by a solid line and a broken line represents a single bond or a double bond,

R ₁ is
Linear or branched C ₁ -C ₆ aliphatic hydrocarbon group, alicyclic hydrocarbon group, aryl group, carboxyl group, C ₁ -C optionally substituted with hydrogen atom, trihalomethyl group, hydroxyl group ₆ alkylcarbonyl group, C ₁ -C ₆ alkoxycarbonyl group, carbamoyl group,

R ₂ is selected from R2a), R2b), R2c)
R2a)
Linear or branched C ₁ -C which may be substituted with 1 to 3 groups optionally selected from a hydrogen atom, halogen atom, nitro group, cyano group, amino group / hydroxyl group / oxo group / halogen atom ₃ aliphatic hydrocarbon group or C ₃ alicyclic hydrocarbon group,
R2b)
A linear or branched C ₄ aliphatic hydrocarbon group optionally substituted by 1-3 groups selected from an amino group, a hydroxyl group, an oxo group, and a halogen atom,
R2c)
1-3 substituted with an amino group-hydroxyl group, a halogen atom, C ₁ -C ₆ alkyl group, C ₁ -C ₆ alkoxy group, a carboxyl group, C ₁ -C ₆ alkoxycarbonyl group, an aryl group chosen arbitrarily from the base which may be an aryl group, optionally selected from an amino group, a hydroxyl group, a halogen atom, C ₁ -C ₆ alkyl group, C ₁ -C ₆ alkoxy group, a carboxyl group, C ₁ -C ₆ alkoxycarbonyl group, an aryl group is 1-3 optionally substituted heteroaryl group group, an amino group, a hydroxyl group, a halogen atom, C ₁ -C ₆ alkyl group, C ₁ -C ₆ alkoxy group, a carboxyl group, C ₁ -C ₆ alkoxy Aryl C ₁ -C ₆ alkyl group, arylthio group, arylsulfonyl group, amino group / hydroxyl group / oxo group / halogen atom optionally substituted by 1 to 3 groups optionally selected from carbonyl group and aryl group A linear or branched C ₅ -C ₆ aliphatic hydrocarbon group optionally substituted with 1 to 3 groups arbitrarily selected from a group, an amino group, a hydroxyl group, an oxo group, and a halogen atom. A C ₄ -C ₆ alicyclic hydrocarbon group optionally substituted by 1 to 3 groups,

R ₃ is
C ₃ -C ₁₀ monocyclic, bicyclic (fused or spiro ring), tricyclic (fused or spiro ring) carbocycle,
3-10 membered monocyclic, bicyclic (fused or spiro ring), tricyclic (fused or spiro ring) hetero, containing 1-4 heteroatoms arbitrarily selected from oxygen, nitrogen and sulfur atoms A ring, an aryl C ₁ -C ₂ alkyl group, and the cyclic group may be substituted with 1-3 groups arbitrarily selected from a halogen atom, a hydroxyl group, a trifluoromethyl group, and a C ₁ -C ₃ alkyl group Often,

W represents a nitrogen atom or a sulfur atom,
When W is a nitrogen atom,
n represents an integer of 0-2,
R ₄ and R ₄ ′ are the same or different,
A hydrogen atom, a linear or branched C ₁ -C ₃ aliphatic hydrocarbon group optionally substituted with a hydroxyl group,
R ₅ and R ₆ are the same or different,
Hydrogen atom, a trihalomethanesulfonyl group, C ₁ -C ₃ alkylsulfonyl group or a C ₁ -C ₃ aliphatic hydrocarbon group which may linear be substituted by hydroxyl or oxo groups or branched,
However, R ₅ and R ₆ are not simultaneously a trihalomethanesulfonyl group or a C ₁ -C ₃ alkylsulfonyl group,
Alternatively, an alicyclic heterohydrocarbon group or a heteroaryl group is formed as a ring P containing R ₄ , R ₅ , and W as constituent elements,
Alternatively, an alicyclic heterohydrocarbon group or a heteroaryl group is formed as a ring Q containing R ₅ , R ₆ , and W as constituent elements,
Here, when ring P is a heteroaryl group, R ₄ ′ and R ₆ may not form a substituent, or R ₆ may represent an oxygen atom (N-oxide);
However, ring P and ring Q do not form a ring at the same time,

When W is a sulfur atom,
n represents an integer of 0-2,
R ₄ and R ₄ ′ are the same or different,
A hydrogen atom, a linear or branched C ₁ -C ₃ aliphatic hydrocarbon group optionally substituted with a hydroxyl group,
R ₅ is
C ₁ -C ₃ aliphatic hydrocarbon group optionally substituted straight or branched chain with a hydroxyl group, trihalomethyl group, with C ₁ -C ₃ mono- or disubstituted amino group which may be alkyl group Yes,
Alternatively, a 3-6 membered alicyclic heterohydrocarbon group is formed as a ring P containing R ₄ , R ₅ , and W as components,
R ₆ is
W—R ₆ is a sulfinyl group or a sulfonyl group. )
Or a pharmaceutically acceptable salt thereof, or a solvate thereof.

（式中、
Ｖは酸素原子（オキソ基）または水酸基を表し、実線と破線で表される結合は単結合若しくは二重結合を表し、
Ｒ₁は、
水素原子、トリハロメチル基、水酸基で置換されていてもよい直鎖若しくは分枝鎖のC₁−
C₆脂肪族炭化水素基、脂環式炭化水素基、アリール基、カルボキシル基、C₁−C₆アルキルカルボニル基、C₁−C₆アルコキシカルボニル基、カルバモイル基であり、

Ｒ₁として好ましくは、
水素原子、トリフルオロメチル基、直鎖若しくは分枝鎖のC₁−C₃脂肪族炭化水素基であり、 <Aspect 2>
Formula (I)

(Where
V represents an oxygen atom (oxo group) or a hydroxyl group, and a bond represented by a solid line and a broken line represents a single bond or a double bond,
R ₁ is
Linear or branched C _1- which may be substituted with a hydrogen atom, trihalomethyl group or hydroxyl group
C ₆ aliphatic hydrocarbon group, alicyclic hydrocarbon group, an aryl group, a carboxyl group, C ₁ -C ₆ alkylcarbonyl group, C ₁ -C ₆ alkoxycarbonyl group, a carbamoyl group,

R ₁ is preferably
A hydrogen atom, a trifluoromethyl group, a linear or branched C ₁ -C ₃ aliphatic hydrocarbon group,

R ₂ is selected from R2a) and R2b)
R2a)
Linear or branched C ₁ -C which may be substituted with 1 to 3 groups optionally selected from a hydrogen atom, halogen atom, nitro group, cyano group, amino group / hydroxyl group / oxo group / halogen atom _{3 is an} aliphatic hydrocarbon group,
R2b)
A linear or branched C ₄ aliphatic hydrocarbon group optionally substituted by 1-3 groups selected from an amino group, a hydroxyl group, an oxo group, and a halogen atom,

R ₂ is preferably R 2a), especially a hydrogen atom, a halogen atom, a linear or branched C ₁ -C ₃ aliphatic hydrocarbon group,

R ₃ is
C ₃ -C ₁₀ monocyclic, bicyclic (fused or spiro ring), tricyclic (fused or spiro ring) carbocycle,
3-10 membered monocyclic, bicyclic (fused or spiro ring), tricyclic (fused or spiro ring) hetero, containing 1-4 heteroatoms arbitrarily selected from oxygen, nitrogen and sulfur atoms A ring, an aryl C ₁ -C ₂ alkyl group, and the cyclic group may be substituted with 1-3 groups arbitrarily selected from a halogen atom, a hydroxyl group, a trifluoromethyl group, and a C ₁ -C ₃ alkyl group Often,

R ₃ is preferably
A C ₃ -C ₁₀ monocyclic, bicyclic, or tricyclic (fused or spirocyclic) carbocycle optionally substituted with 1-3 groups selected from halogen atoms and hydroxyl groups,

W represents a nitrogen atom or a sulfur atom,
When W is a nitrogen atom,
n represents an integer of 0-2,
Preferably n is 0,

R ₄ and R ₄ ′ are the same or different,
A hydrogen atom, a linear or branched C ₁ -C ₃ aliphatic hydrocarbon group optionally substituted with a hydroxyl group,
R ₅ and R ₆ are the same or different,
Hydrogen atom, a trihalomethanesulfonyl group, C ₁ -C ₃ alkylsulfonyl group or a C ₁ -C ₃ aliphatic hydrocarbon group which may linear be substituted by hydroxyl or oxo groups or branched,
Alternatively, an alicyclic heterohydrocarbon group or a heteroaryl group is formed as ring P,
Alternatively, an alicyclic heterohydrocarbon group is formed as ring Q,
Here, when ring P is a heteroaryl group, R ₄ ′ and R ₆ may not form a substituent, or R ₆ may represent an oxygen atom (N-oxide);

R ₅ and R ₆ are preferably the same or different,
Hydrogen atom, trihalomethanesulfonyl group, a C ₁ -C ₃ alkylsulfonyl groups,
However, R ₅ and R ₆ are not simultaneously a trihalomethanesulfonyl group or a C ₁ -C ₃ alkylsulfonyl group,
Ring P is preferably a 3-6 membered alicyclic heterohydrocarbon group,
However, ring P and ring Q do not form a ring at the same time,

When W is a sulfur atom,
n represents an integer of 0-2,
R ₄ and R ₄ ′ are the same or different,
A hydrogen atom, a linear or branched C ₁ -C ₃ aliphatic hydrocarbon group optionally substituted with a hydroxyl group,
R ₅ is
C ₁ -C ₃ aliphatic hydrocarbon group optionally substituted straight or branched chain with a hydroxyl group, trihalomethyl group, with C ₁ -C ₃ mono- or disubstituted amino group which may be alkyl group Yes,
R ₆ is
W—R ₆ is a sulfinyl group or a sulfonyl group,
Alternatively, a 3-6 membered alicyclic heterohydrocarbon group is formed as ring P,
However, ring P and ring Q do not form a ring at the same time. )
Or a pharmaceutically acceptable salt thereof, or a solvate thereof.

（式中、
Ｖは、酸素原子（オキソ基）または水酸基を表し、実線と破線で表される結合は単結合若しくは二重結合を表し、
Ｒ₁は、
水素原子、トリハロメチル基、水酸基で置換されていてもよい直鎖若しくは分枝鎖のC₁−C₆脂肪族炭化水素基、脂環式炭化水素基、アリール基、カルボキシル基、C₁−C₆アルキルカルボニル基、C₁−C₆アルコキシカルボニル基、カルバモイル基であり、 <Aspect 3>
Formula (I)

(Where
V represents an oxygen atom (oxo group) or a hydroxyl group, and a bond represented by a solid line and a broken line represents a single bond or a double bond,
R ₁ is
Linear or branched C ₁ -C ₆ aliphatic hydrocarbon group, alicyclic hydrocarbon group, aryl group, carboxyl group, C ₁ -C optionally substituted with hydrogen atom, trihalomethyl group, hydroxyl group ₆ alkylcarbonyl group, C ₁ -C ₆ alkoxycarbonyl group, carbamoyl group,

R ₁ is preferably
A hydrogen atom,

R ₂ is selected from R2b) and R2c)
R2b)
A linear or branched C ₄ aliphatic hydrocarbon group optionally substituted by 1-3 groups selected from an amino group, a hydroxyl group, an oxo group, and a halogen atom,
R2c)
1-3 substituted with an amino group-hydroxyl group, a halogen atom, C ₁ -C ₆ alkyl group, C ₁ -C ₆ alkoxy group, a carboxyl group, C ₁ -C ₆ alkoxycarbonyl group, an aryl group chosen arbitrarily from the base Aryl group, amino group, hydroxyl group, halogen atom, C ₁ -C ₆ alkyl group, C ₁
A heteroaryl group optionally substituted by a group arbitrarily selected from -C ₆ alkoxy group, carboxyl group, C ₁ -C ₆ alkoxycarbonyl group, aryl group, amino group, hydroxyl group, halogen atom, C Aryl C _1- which may be substituted with 1 to 3 groups optionally selected from _1- C ₆ alkyl group, C ₁ -C ₆ alkoxy group, carboxyl group, C ₁ -C ₆ alkoxycarbonyl group and aryl group A linear or branched C ₅ -C which may be substituted with 1-3 groups optionally selected from C ₆ alkyl group, arylthio group, arylsulfonyl group, amino group / hydroxyl group / oxo group / halogen atom _{A 6-} aliphatic hydrocarbon group, a C ₄ -C _6- membered alicyclic hydrocarbon group which may be substituted with 1-3 groups arbitrarily selected from an amino group, a hydroxyl group, an oxo group and a halogen atom,

R ₂ is preferably
1-3 substituted with an amino group-hydroxyl group, a halogen atom, C ₁ -C ₆ alkyl group, C ₁ -C ₆ alkoxy group, a carboxyl group, C ₁ -C ₆ alkoxycarbonyl group, an aryl group chosen arbitrarily from the base which may be an aryl or heteroaryl group, a C ₅ -C ₆ aliphatic hydrocarbon group having a straight-chain or branched,

R ₃ is
C ₃ -C ₁₀ monocyclic, bicyclic (fused or spiro ring), tricyclic (fused or spiro ring) carbocycle,
3-10 membered monocyclic, bicyclic (fused or spiro ring), tricyclic (fused or spiro ring) hetero, containing 1-4 heteroatoms arbitrarily selected from oxygen, nitrogen and sulfur atoms A ring, an aryl C ₁ -C ₂ alkyl group, and the cyclic group may be substituted with 1-3 groups arbitrarily selected from a halogen atom, a hydroxyl group, a trifluoromethyl group, and a C ₁ -C ₃ alkyl group Often,

R ₃ is preferably
Monocyclic, bicyclic (fused or spiro ring) tricyclic radical with 1-3 substituents which do good C ₃ -C ₁₀ be selected arbitrarily from a halogen atom, a hydroxyl group (fused or spiro ring) carbocyclic And

W represents a nitrogen atom or a sulfur atom,
When W is a nitrogen atom,
n represents an integer of 0-2,
Preferably n is 0,

R ₄ and R ₄ ′ are the same or different,
A hydrogen atom, a linear or branched C ₁ -C ₃ aliphatic hydrocarbon group optionally substituted with a hydroxyl group,
R ₅ and R ₆ are the same or different,
Hydrogen atom, a trihalomethanesulfonyl group, C ₁ -C ₃ alkylsulfonyl group or a C ₁ -C ₃ aliphatic hydrocarbon group which may linear be substituted by hydroxyl or oxo groups or branched,
Alternatively, an alicyclic heterohydrocarbon group or a heteroaryl group is formed as ring P,
Alternatively, an alicyclic heterohydrocarbon group is formed as ring Q,
Here, when ring P is a heteroaryl group, R ₄ ′ and R ₆ may not form a substituent, or R ₆ may represent an oxygen atom (N-oxide);

R ₅ and R ₆ are preferably the same or different,
A linear or branched C ₁ -C ₃ aliphatic hydrocarbon group optionally substituted with a hydroxyl group or an oxo group,
However, R ₅ and R ₆ are not simultaneously a trihalomethanesulfonyl group or a C ₁ -C ₃ alkylsulfonyl group,
Ring P is preferably a 5-6 membered alicyclic heterohydrocarbon group,
However, ring P and ring Q do not form a ring at the same time,

When W is a sulfur atom,
n represents an integer of 0-2,
Preferably n is 0,

R ₄ and R ₄ ′ are the same or different,
A hydrogen atom, a linear or branched C ₁ -C ₃ aliphatic hydrocarbon group optionally substituted with a hydroxyl group,
R ₅ is
C ₁ -C ₃ aliphatic hydrocarbon group optionally substituted straight or branched chain with a hydroxyl group, trihalomethyl group, with C ₁ -C ₃ mono- or disubstituted amino group which may be alkyl group Yes,
R ₆ is
W—R ₆ is a sulfinyl group or a sulfonyl group,
Alternatively, a 3-6 membered alicyclic heterohydrocarbon group is formed as ring P,
However, ring P and ring Q do not form a ring at the same time. )
Or a pharmaceutically acceptable salt thereof, or a solvate thereof.

Hereinafter, preferred functional groups and preferred compounds in the compound of formula (I) as an active ingredient of a preventive and / or therapeutic agent for a disease involving CB2 of the present invention will be described.
R ₁ is
A hydrogen atom, a methyl group, an ethyl group, an isopropyl group, a cyclopropyl group, and a trifluoromethyl group are preferable.

R ₂ is
A hydrogen atom, methyl group, isopropyl group, t-butyl group, trifluoromethyl group, chlorine atom, bromine atom and iodine atom are preferred.

R ₃ is
Menthyl group, 4,7,7-trimethyl-3-oxo-2-oxabicyclo [2.2.1] heptan-1-yl group, indan-1-yl group, indan-2-yl group, tetralin-1 -Yl group, tetralin-2-yl group,
Difluorocyclohexyl group, adamantyl group, 3-fluoroadamantyl group, 3,5-
A difluoroadamantyl group, a 3,5,7-trifluoroadamantyl group, and a 3-chloroadamantyl group are preferable.
More preferably, a difluorocyclohexyl group, an adamantyl group, a 3-fluoroadamantyl group, a 3,5-difluoroadamantyl group, a 3,5,7-trifluoroadamantyl group,
3-Chloroadamantyl group.

は、(トリフルオロメチルスルホニルアミノ）メチル基、(メチルスルホニルアミノ)メチ
ル基、（エチルスルホニルアミノ）メチル基、（Ｎ−メチルメチルスルホニルアミノ）メチル基、[Ｎ−（２−ヒドロキシエチル）メチルスルホニルアミノ]メチル基、（１，１−ジオキシチアゾリジン−２−イル）メチル基、１−（トリフルオロメチルスルホニルアミノ）エチル基、１−（メチルスルホニルアミノ）エチル基、２−ヒドロキシ−１−（トリフルオロメチルスルホニルアミノ）エチル基、２−ヒドロキシ−１−（メチルスルホニル
アミノ）エチル基、１−トリフルオロメチルスルホニル−２−アジリジニル基、１−メチルスルホニル−２−アジリジニル基、1−メチルスルホニル−２−アゼチジニル基、1−メチルスルホニル−２−ピロリジニル基、（１，１−ジオキシチアゾリジン−３−イル）メチル基、
（メチルスルホニル）メチル基、（トリフルオロメチルスルホニル）メチル基、１−（メチルスルホニル）エチル基、2−ヒドロキシ−１−（メチルスルホニル）エチル基、（１
，１−ジオキシテトラヒドロチオフェン−２−イル）メチル基、（メチルスルフィニル）メチル基、（ｔｅｒｔ−ブチルスルホニル）メチル基、（２−ヒドロキシエチルスルホニル）メチル基、（ジメチルアミノスルホニル）メチル基が好ましい。

Are (trifluoromethylsulfonylamino) methyl group, (methylsulfonylamino) methyl group, (ethylsulfonylamino) methyl group, (N-methylmethylsulfonylamino) methyl group, [N- (2-hydroxyethyl) methylsulfonyl Amino] methyl group, (1,1-dioxythiazolidin-2-yl) methyl group, 1- (trifluoromethylsulfonylamino) ethyl group, 1- (methylsulfonylamino) ethyl group, 2-hydroxy-1- ( Trifluoromethylsulfonylamino) ethyl group, 2-hydroxy-1- (methylsulfonylamino) ethyl group, 1-trifluoromethylsulfonyl-2-aziridinyl group, 1-methylsulfonyl-2-aziridinyl group, 1-methylsulfonyl- 2-azetidinyl group, 1-methylsulfonyl-2-pyrrolidini Group, (1,1-dioxythiazolidin-3-yl) methyl group,
(Methylsulfonyl) methyl group, (trifluoromethylsulfonyl) methyl group, 1- (methylsulfonyl) ethyl group, 2-hydroxy-1- (methylsulfonyl) ethyl group, (1
, 1-Dioxytetrahydrothiophen-2-yl) methyl group, (methylsulfinyl) methyl group, (tert-butylsulfonyl) methyl group, (2-hydroxyethylsulfonyl) methyl group, (dimethylaminosulfonyl) methyl group are preferred. .

Further particularly preferred compounds of the formula (I) are
N- {3- [1-hydroxy-2- (methylsulfonyl) ethyl] thiophen-2-yl} adamantane-1-carboxamide N- {5-chloro-3- [1-hydroxy-2- (methylsulfonyl) ethyl ] Thiophen-2-yl} adamantane-1-carboxamide N- {3- [1-hydroxy-2- (methylsulfonyl) ethyl] thiophen-2-yl} 3-fluoroadamantane-1-carboxamide N- {3- [ 1-hydroxy-2- (methylsulfonyl) ethyl] thiophen-2-yl} 3,5,7-trifluoroadamantane-1-carboxamide N- {3- [2- (trifluoromethylsulfonylamino) acetyl] thiophene- 2-yl} adamantane-1-carboxamide N- {3- [2- (methylsulfonylamino) acetyl] thio Fen-2-yl} adamantane-1-carboxamide N- {3- [2- (trifluoromethylsulfonylamino) acetyl] thiophen-2-yl} 3-fluoroadamantane-1-carboxamide N- {5-methyl-3 -[2- (Trifluoromethylsulfonylamino) acetyl] thiophen-2-yl} 3-fluoroadamantane-1-carboxamide N- {4-methyl-3- [2- (trifluoromethylsulfonylamino) acetyl] thiophene- 2-yl} 3-fluoroadamantane-1-carboxamide N- {3- [2- (trifluoromethylsulfonylamino) acetyl] thiophen-2-yl} 3,5-difluoroadamantane-1-carboxamide

N- {3- [2- (methylsulfonylamino) acetyl] thiophen-2-yl} 3,5,7-trifluoroadamantane-1-carboxamide N- {3- [2- (trifluoromethylsulfonylamino) acetyl ] Thiophen-2-yl} 3,5,7-trifluoroadamantane-1-carboxamide N- {5-chloro-3- [2- (methylsulfonylamino) acetyl] thiophen-2-yl} 3,5,7 -Trifluoroadamantane-1-carboxamide N- {3- [1-hydroxy-2- (methylsulfonylamino) ethyl] thiophen-2-yl} adamantane-1-carboxamide N- {3- [1-hydroxy-2- (Trifluoromethylsulfonylamino) ethyl] thiophen-2-yl} 3,5,7-trifluoroadamantane-1- Ruboxamide N- [5-Bromo-3- (2-dimethylamino-1-hydroxyethyl) thiophen-2-yl] adamantane-1-carboxamide N- [3- (2-dimethylamino-1-hydroxyethyl) -5 -Phenylthiophen-2-yl] adamantane-1-carboxamide N- [3- (2-dimethylamino-1-hydroxyethyl) -5- (3-pyridyl) thiophen-2-yl] adamantane-1-carboxamide N- [3- (2-Dimethylamino-1-hydroxyethyl) -5- (2-hydroxyphenyl) thiophen-2-yl] adamantane-1-carboxamide N- [3- (2-dimethylamino-1-hydroxyethyl) -5- (8-quinolyl) thiophen-2-yl] adamantane-1-carboxamide

N- [5- (1-butyl) -3- (2-dimethylamino-1-hydroxyethyl) thiophen-2-yl] adamantane-1-carboxamide N- {3- [hydroxy (N-methyl- (S) -Pyrrolidin-2-yl) methyl] -5-phenylthiophen-2-yl} adamantane-1-carboxamide N- {5- (tert-butyl) -3- [2- (methylsulfonylamino) acetyl] thiophene-2 -Yl} adamantane-1-carboxamide N- {3- [2- (S) -methyl-2- (methylsulfonylamino) acetyl] thiophen-2-yl} adamantane-1-carboxamide N- {3- [2- (S) -Hydroxymethyl-2- (methylsulfonylamino) acetyl] thiophen-2-yl} adamantane-1-carboxamide N- [3 (N-methylsulfonyl- (S) -aziridin-2-yl) carbonylthiophen-2-yl] adamantane-1-carboxamide N- {3- [2- (methylsulfonylamino) acetyl] thiophen-2-yl} 3 -Fluoroadamantane-1-carboxamide N- {3- [2- (methylsulfonylamino) acetyl] thiophen-2-yl} 4,4-difluorocyclohexane-1-carboxamide N- {3- [1-hydroxy-2- (Methylsulfonyl) ethyl] -5-methylthiophen-2-yl} adamantane-1-carboxamide N- {3- [1-hydroxy-2- (methylsulfonyl) ethyl] thiophen-2-yl} 3-chloroadamantane- 1-carboxamide

N- {3- [1-hydroxy-2- (methylsulfonyl) ethyl] -4-isopropylthiophen-2-yl} adamantane-1-carboxamide N- {3- [1-hydroxy-2-methyl-2- ( Methylsulfonyl) ethyl] thiophen-2-yl} adamantane-1-carboxamide N- {3- [1-hydroxy-3- (methylsulfonyl) propyl] thiophen-2-yl} adamantane-1-carboxamide N- {5- Chloro-3- [1-hydroxy-2- (methylsulfonyl) ethyl] thiophen-2-yl} 3-fluoroadamantane-1-carboxamide N- {3- [1-hydroxy-2- (methylsulfonyl) ethyl]- 5-methylthiophen-2-yl} 3-fluoroadamantane-1-carboxamide N- {3- [1-hydroxy- 2- (Methylsulfonyl) ethyl] -4-methylthiophen-2-yl} 3-fluoroadamantane-1-carboxamide N- {3- [1-hydroxy-2- (methylsulfonyl) ethyl] -5- (trifluoro Methyl) thiophen-2-yl} 3-fluoroadamantane-1-carboxamide N- {5-chloro-3- [1-hydroxy-2- (methylsulfonyl) ethyl] -4-methylthiophen-2-yl} 3- Fluoroadamantane-1-carboxamide N- {3- [1-hydroxy-2- (methylsulfonyl) ethyl] thiophen-2-yl} 3,5-difluoroadamantane-1-carboxamide N- {3- [1-hydroxy- 2- (Methylsulfonyl) ethyl] -5-methylthiophen-2-yl} 3,5,7-trifluoroadamantane -1-carboxamide

N- {3- [1-hydroxy-2- (methylsulfonyl) ethyl] -4-isopropylthiophen-2-yl} 3,5,7-trifluoroadamantane-1-carboxamide N- {5-chloro-3- [1-Hydroxy-2- (methylsulfonyl) ethyl] thiophen-2-yl} 3,5,7-trifluoroadamantane-1-carboxamide N- {3- [1-hydroxy-2- (methylsulfonyl) ethyl] -5- (trifluoromethyl) thiophen-2-yl} 3,5,7-trifluoroadamantane-1-carboxamide N- {3- [1-hydroxy-2- (methylsulfonyl) ethyl] -4- (tri Fluoromethyl) thiophen-2-yl} 3,5,7-trifluoroadamantane-1-carboxamide N- {3- [1-hydroxy-2- (methyl) Sulfonyl) ethyl] -4-methylthiophen-2-yl} 3,5,7-trifluoroadamantane-1-carboxamide N- {3- [hydroxy (N-methylsulfonyl- (S) -aziridin-2-yl)] Methyl] thiophen-2-yl] adamantane-1-carboxami N- {3- [1-hydroxy-2- (methylsulfonylamino) ethyl] thiophen-2-yl} 3-fluoroadamantane-1-carboxamide N- {5 -Bromo-3- [hydroxy (N-methylsulfonyl- (S) -pyrrolidin-2-yl) methyl] thiophen-2-yl] adamantane-1-carboxami N- [5-chloro-3- (2-dimethylamino) -1-hydroxyethyl) thiophen-2-yl] adamantane-1-carboxamide N- [3- (2-dimethyl) Amino-1-hydroxyethyl) -5- (4-fluorophenyl) thiophene-2-yl] adamantane-l-carboxamide

N- [3- (2-Dimethylamino-1-hydroxyethyl) -5- (3-hydroxyphenyl) thiophen-2-yl] adamantane-1-carboxamide N- [5- (3-aminophenyl) -3- (2-Dimethylamino-1-hydroxyethyl) thiophen-2-yl] adamantane-1-carboxamide N- [3- (2-dimethylamino-1-hydroxyethyl) -5- (2-propoxyphenyl) thiophene-2 -Yl] adamantane-1-carboxamide N- [3- (2-dimethylamino-1-hydroxyethyl) -5- (3-propoxyphenyl) thiophen-2-yl] adamantane-1-carboxamide N- [3- ( 2-Dimethylamino-1-hydroxyethyl) -5- (4-propoxyphenyl) thiophen-2-yl] Mantan-1-carboxamide N- [3- (2-dimethylamino-1-hydroxyethyl) -5- (1-naphthyl) thiophen-2-yl] adamantane-1-carboxamide N- [3- (2-dimethylamino -1-hydroxyethyl) -5- (2-naphthyl) thiophen-2-yl] adamantane-1-carboxamide N- [5- (2-biphenyl) -3- (2-dimethylamino-1-hydroxyethyl) thiophene -2-yl] adamantane-1-carboxamide N- [5- (3-biphenyl) -3- (2-dimethylamino-1-hydroxyethyl) thiophen-2-yl] adamantane-1-carboxamide N- [5- (4-Biphenyl) -3- (2-dimethylamino-1-hydroxyethyl) thiophen-2-yl] adamantane 1-carboxamide N- is [3- (2-diethylamino-1-hydroxyethyl) -5-phenyl-2-yl] adamantane-l-carboxamide.

<Aspect 4>
A pharmaceutical composition comprising the compound according to any one of aspects 1 to 3, a pharmaceutically acceptable salt or a solvate thereof as an active ingredient.

<Aspect 5>
A prophylactic and / or therapeutic agent for a disease involving a CB2 receptor, comprising as an active ingredient the compound of any one of aspects 1 to 3, a pharmaceutically acceptable salt, or a solvate thereof .
Diseases involving CB2 include, for example, neurological diseases caused by CB2, inflammation or allergic diseases caused by CB2, autoimmune diseases caused by CB2, cardiovascular disorders caused by CB2, etc. Thus, the preventive and / or therapeutic agent of Embodiment 5 of the present invention is effective for the prevention and / or treatment of these diseases. A compound of formula (I), or a pharmaceutically acceptable salt thereof, binds to CB2 and modulates its function, or directly binds to CB2 to bind an endogenous or exogenous CB2 ligand to CB2. Inhibiting binding demonstrates a prophylactic and / or therapeutic effect.
In the present invention, “a neurological disease involving CB2” refers to neuropathic pain such as postherpetic neuralgia, painful diabetic neuropathy, cancer pain, postoperative pain, low back pain, headache, migraine And cough diseases including bronchitis, pneumonia, spontaneous pneumothorax, cold syndrome, pulmonary tuberculosis and lung cancer, neurodegeneration, epilepsy, vomiting, Parkinson's disease and Alzheimer's disease.

The term “inflammatory or allergic disease involving CB2” in the present invention refers to inflammatory bowel disease, nephritis, gastritis, peptic ulcer, pancreatitis, myocarditis, pneumonia, hepatitis, cirrhosis, encephalitis, osteoarthritis, allergic contact skin Inflammation, allergic rhinitis, reflux esophagitis, ankylosing spondylitis, bronchial asthma, fever, atopic dermatitis, hives, knee osteoarthritis, cough based on airway hyperresponsiveness (bronchitis, cold syndrome, asthma , Obstructive pulmonary disease, etc.).
The term “autoimmune disease involving CB2” in the present invention refers to rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus (SLE), refractory colitis, ulcerative colitis, Crohn's disease, glomerulonephritis, strong Examples include dermatoses, Sjogren's syndrome, and tissue damage and rejection after organ transplantation.
The “cardiovascular disorder involving CB2” in the present invention includes angina pectoris, unstable angina pectoris, myocardial infarction, heart failure, stroke and the like.
Specific examples of the disease for which the preventive and / or therapeutic agent of aspect 5 of the present invention is effective are shown above, but the disease involving CB2 is not limited thereto.
Preferably, the preventive and / or therapeutic agent according to aspect 5 of the present invention is a prophylactic and / or therapeutic agent characterized in that the disease involving CB2 is a neurological disease, an inflammatory or allergic disease and an autoimmune disease. . More preferably, it is a prophylactic and / or therapeutic agent characterized in that the disease involving CB2 is a pain disease. Particularly preferred is a prophylactic and / or therapeutic agent characterized in that the disease involving CB2 is neuropathic pain.

<Aspect 6>
A CB2 function regulator comprising the compound of formula (I) or a pharmaceutically acceptable salt thereof and a solvate thereof as an active ingredient. A function regulator of CB2 is a reagent that, when administered in vivo, directly binds to CB2 and regulates its function, and has an effect on diseases involving CB2 and physiological actions. The CB2 function regulator is not limited to a reagent administered in vivo, but also includes a reagent that regulates the action of CB2 for a test for confirming the action of CB2 ligand in vitro. Moreover, the reagent for the purpose of adjusting the effect | action of the CB2 ligand added as a 3rd reagent is included.
Furthermore, Embodiment 6 of the present invention includes an embodiment of an inhibitor of binding of endogenous or exogenous CB2 ligand to CB2, which comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient. The binding inhibitor of CB2 ligand to CB2 is a reagent that inhibits binding of CB2 ligand to CB2 in vivo or in vitro.
The CB2 ligand is, for example, an endogenous CB2 ligand under physiological conditions, and a typical example is 2-AG. Examples of exogenous CB2 ligands administered in vivo include cannabinoids, which are cannabis components.
Diseases caused by these CB2 ligands binding to CB2 and adversely affecting the body, such as 2-AG produced by microglia and monocyte cells at the time of nerve injury, act on CB2 and cause pain (mainly The binding inhibitor of the present invention is effective against diseases caused by exerting neuropathic pain), inflammation and immune response. Further, for example, it is also effective for a disease caused by a cause such as when an exogenous CB2 ligand that has been ingested or administered is bound to CB2 in vivo.

  The compound of the formula (I) (hereinafter sometimes referred to as the compound of the present invention) used as an active ingredient of the preventive and / or therapeutic agent of the present invention may have an asymmetric carbon, and is optically active or stereoisomeric ( Enantiomers, diastereomers, etc.) may exist. The compounds of the present invention include a mixture of various stereoisomers such as geometric isomers and optical isomers, and isolated isomers. Isolation and purification of such geometric isomers can be achieved by recrystallization and column chromatography, and stereoisomers can be isolated and purified by optical resolution or asymmetric synthesis using preferential crystallization and column chromatography. Both of these can be achieved by those skilled in the art using conventional techniques.

The compounds of the present invention may form acid addition salts. Depending on the type of substituent, a salt with a base may be formed. Such a salt is not particularly limited as long as it is a pharmaceutically acceptable salt, and specific examples thereof include mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, and the like. , Propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, formic acid, malic acid, tartaric acid, citric acid, mandelic acid and other organic carboxylic acids, methanesulfonic acid, ethanesulfonic acid, p-toluene Acid addition salts with organic sulfonic acids such as sulfonic acid and 2-hydroxyethanesulfonic acid, acidic amino acids such as aspartic acid and glutamic acid; bases of alkali metals or alkaline earth metals such as sodium, potassium, magnesium and calcium; Salts with organic bases such as methylamine, ethylamine, ethanolamine, pyridine, lysine, arginine, ornithine; Moniumu salts and the like.

The salt of the compound of the present invention includes a mono salt, a di salt and the like. Or depending on the substituent of a side chain, both the salt of an acid addition salt and a base can be formed. Further, hydrates of the compounds of the present invention, various pharmaceutically acceptable solvates and crystal polymorphs, and the like are also included in the compounds and pharmaceutical compositions of the present invention. Of course, the present invention is not limited to the compounds described in the examples below, but 2-thiophenecarboxamide derivatives represented by the formula (I) or pharmaceutically acceptable salts thereof or their It includes all solvates.

[Method for producing compound of the present invention]
Although the manufacturing method of 2-thiophene carboxamide derivative (I) or its salt of this invention is shown below and each reaction process is demonstrated, this invention is not limited to the manufacturing method demonstrated below at all.

（式中、Ｒ₁、Ｒ₂、Ｒ₃、Ｒ₄、Ｒ₄’、Ｒ₅、Ｒ₆、ｎは前記と同じ意味を表し、Ｒ₅’、Ｒ₆’は異なってアルキルオキシカルボニル基に代表されるアミノ基の保護基または水素原
子、或いは環を形成した場合、環Ｐ，Ｑを表す。） [Production method 1]
The compound of formula (Ia), a salt thereof or a solvate thereof can be produced by the method of the following (Reaction Scheme 1).

(Wherein R ₁ , R ₂ , R ₃ , R ₄ , R ₄ ′, R ₅ , R ₆ , n represent the same meaning as described above, and R ₅ ′ and R ₆ ′ are different and represent an alkyloxycarbonyl group. When a representative amino-protecting group or hydrogen atom or a ring is formed, it represents rings P and Q.)

<Step 1>
When a compound of formula (II) and a compound of formula (III) are used and a method known in the literature, for example, when the compound of formula (III) is an acid halide, [New Experimental Chemistry Lecture 14 Synthesis and Reaction of Organic Compounds [II],
1142, 1977, Maruzen], etc., in the presence of a base such as triethylamine or pyridine in the presence of a base such as triethylamine or pyridine, a halogenated solvent such as dichloromethane or chloroform, diethyl ether, By reacting at a temperature at which the solvent is refluxed from 0 ° C. in a solvent not involved in the reaction such as an ether solvent such as tetrahydrofuran, a hydrocarbon solvent such as toluene and benzene, and a polar solvent such as N, N-dimethylformamide, Compounds of formula (IV) can be prepared. When the compound of formula (III) is a carboxylic acid, [New Experimental Chemistry Course 14 Synthesis and Reaction of Organic Compounds [II], 1104, 1977, Maruzen]
In accordance with the method described in [Synthesis of acid halide], an acid halide is prepared and reacted in the same manner as described above, or [New Experimental Chemistry Lecture 14 Synthesis and Reaction of Organic Compounds [II], 1
136, 1977, Maruzen], etc., according to the method [condensation reaction of carboxylic acid and amine], 1,3-dicyclohexylcarbodiimide (DCC), 1-ethyl-3- (3 ′
-Dimethylaminopropyl) carbodiimide hydrochloride (WSC.HCl), benzotriazole-1-iroxytris (dimethylamino) phosphonium hexafluorophosphate (BOP reagent), bis (2-oxo-3-oxazolidinyl) phosphinic chloride (BOP) In the presence of a condensing agent such as -Cl), halogen solvents such as dichloromethane and chloroform, ether solvents such as diethyl ether and tetrahydrofuran, hydrocarbon solvents such as toluene and benzene, and polar solvents such as N, N-dimethylformamide. The compound of the formula (IV) can be produced by reacting at a temperature at which the solvent refluxes from −78 ° C. in the presence or absence of a base such as triethylamine or pyridine in a solvent that does not participate in the reaction. .

<Step 2>
After deprotecting the amino-protecting group using the compound of formula (IV), alkyl or halomethanesulfonic acid chloride such as methanesulfonic acid chloride, trifluoromethanesulfonic acid chloride, etc. In the presence of a base such as triethylamine or pyridine in a solvent that does not participate in the reaction of alkyl and halomethanesulfonic anhydride such as methanesulfonic anhydride and trifluoromethanesulfonic anhydride with halogen solvents such as dichloromethane and chloroform Alternatively, the compound of formula (Ia) can be produced by reaction at a temperature at which the solvent is refluxed from 0 ° C. in the absence.
Alternatively, after deprotecting the protecting group of the amino group, in the presence of a reducing agent such as alkyl aldehyde such as formaldehyde and acetaldehyde and sodium triacetoxyborohydride or sodium cyanoborohydride, according to a known method in the literature or in accordance therewith, Using a solvent that does not participate in the reaction, such as a protic solvent such as methanol, ethanol or isopropanol, an ether solvent such as diethyl ether, tetrahydrofuran, dimethoxyethane or dioxane, a halogen solvent such as dichloromethane or chloroform, or a mixed solvent thereof. The compound of formula (Ia) can be produced by performing the reaction at a temperature at which the solvent is refluxed from 0 ° C.

式（Ｖ）の化合物、式（VI）の化合物、および硫黄もしくはジチアンを用い、文献公知の方法、例えばサブニス（ＳＡＢＮＩＳ）の総説（「サルファー レポート（Ｓｕｌｆｕｒ Ｒｅｐｏｒｔｓ）」、（米国）、１９９４年、第１６巻、ｐ．１−１７）などに記載された方法[ゲワルド合成（ＧＥＷＡＬＤ ｓｙｎｔｈｅｓｉｓ）]に準じて、ジエチルアミン、モルホリン、トリエチルアミン等の塩基存在下、エタノール、Ｎ，Ｎ−ジメチルホルムアミド、ジオキサン、テトラヒドロフラン等の反応に不活性な溶媒、もしくはこれらの混合溶媒を用いて、室温から溶媒が還流する温度で反応を行い、式（II）の化合物を製造することができる。 The compound of the formula (II) used as a raw material of the (reaction formula 1) can be produced according to a method known in the literature or according to, for example, the following (reaction formula 2).

Using compounds of formula (V), compounds of formula (VI), and sulfur or dithiane, methods known in the literature, such as a review of SABNIS ("Sulfur Reports", (USA), 1994, Vol. 16, p. 1-17) and the like [GEwald synthesis] in the presence of a base such as diethylamine, morpholine, triethylamine, etc., ethanol, N, N-dimethylformamide, dioxane, Using a solvent inert to the reaction, such as tetrahydrofuran, or a mixed solvent thereof, the reaction can be carried out at a temperature at which the solvent is refluxed from room temperature to produce the compound of formula (II).

式（VII）の化合物および式（VIII）の化合物を用い、文献公知の方法、またはそれに
準じて、例えばジエチルエーテル、テトラヒドロフラン、ジメトキシエタン等のエーテル系溶媒等の反応に関与しない溶媒中、−７８℃から０℃で、式（VIII）とｎ−ブチルリチウム、ｓｅｃ−ブチルリチウム、水素化ナトリウム等の塩基から生成させたアニオンを、式（VIII）の化合物に−７８℃から室温で加え、−７８℃から溶媒が還流する温度で反応を行い、式（Ｉｂ）の化合物を製造することができる。 [Production method 2]
The compound of formula (Ib), a salt thereof or a solvate thereof can also be produced by the method of the following (Reaction Scheme 3).
(Wherein R ₁ , R ₂ , R ₃ , R ₄ , R ₄ ′, R ₅ , ring P represents the same meaning as described above, R ₇ represents a lower alkyl group represented by a methyl group and an ethyl group, m represents an integer of 1 to 2)

-78 using a compound of formula (VII) and a compound of formula (VIII) in a solvent not involved in the reaction such as ether solvents such as diethyl ether, tetrahydrofuran, dimethoxyethane, etc. At 0 to 0 ° C., an anion generated from the formula (VIII) and a base such as n-butyllithium, sec-butyllithium, sodium hydride and the like is added to the compound of the formula (VIII) at −78 ° C. to room temperature, The reaction can be carried out at a temperature at which the solvent is refluxed from 78 ° C. to produce the compound of formula (Ib).

＜工程１＞
式（IX）の化合物および式（VI）の化合物を用い、[製造法１]の式（II）の化合物の製造法と同様の方法により、式（Ｘ）の化合物を製造することができる。
＜工程２＞
式（Ｘ）の化合物および式（III）の化合物を用い、[製造法１]の＜工程１＞と同様の方
法により、式（VII）の化合物を製造することができる。 The compound of the formula (VII) used as a raw material of the (reaction formula 3) can be produced according to a method known in the literature or according to, for example, the following (reaction formula 4).

<Step 1>
Using the compound of formula (IX) and the compound of formula (VI), the compound of formula (X) can be produced by a method similar to the production method of the compound of formula (II) in [Production Method 1].
<Step 2>
Using the compound of formula (X) and the compound of formula (III), the compound of formula (VII) can be produced by the same method as in <Step 1> of [Production Method 1].

（式中、Ｒ₁、Ｒ₂、Ｒ₃、Ｒ₄、Ｒ₄’、Ｒ₅、Ｒ₆、Ｗ、ｎ、環Ｐ、環Ｑは前記と同じ意味
を表す。）
式（Ｉｃ）の化合物（式（Ｉ）のＶがオキソ基である化合物）を用い、文献公知の方法、例えば[新実験化学講座 １４ 酸化と還元[II]、１８３頁、１９７７年、丸善]などに記載された方法[ケトンの還元反応]に準じて、例えばメタノール、エタノール、イソプロパノール等のプロトン性溶媒、ジエチルエーテル、テトラヒドロフラン、ジメトキシエタン、ジオキサン等のエーテル系溶媒、もしくはこれらの混合溶媒等の反応に関与しない溶媒を用いて、−７８℃から室温で、水素化ホウ素ナトリウム、水素化ホウ素リチウム、トリアセトキシ水素化ホウ素ナトリウム、シアノ水素化ホウ素ナトリウム等の還元剤を加え、−７８℃から溶媒が還流する温度で反応を行い、式（Ｉｄ）の化合物（式（Ｉ）のＶが水酸基である化合物）を製造することができる。 [Production method 3]
The compound of formula (Id), a salt thereof or a solvate thereof can also be produced by the method of the following (Scheme 5).

(In the formula, R ₁ , R ₂ , R ₃ , R ₄ , R ₄ ′, R ₅ , R ₆ , W, n, ring P, and ring Q have the same meanings as described above.)
Using compounds of formula (Ic) (compounds of formula (I) where V is an oxo group), methods known in the literature, such as [New Experimental Chemistry Course 14 Oxidation and Reduction [II], page 183, 1977, Maruzen] In accordance with the method described in [Reduction reaction of ketone], for example, a protic solvent such as methanol, ethanol, isopropanol, an ether solvent such as diethyl ether, tetrahydrofuran, dimethoxyethane, dioxane, or a mixed solvent thereof. Using a solvent that does not participate in the reaction, a reducing agent such as sodium borohydride, lithium borohydride, sodium triacetoxyborohydride, sodium cyanoborohydride, and the like is added at −78 ° C. to room temperature, and from −78 ° C. to the solvent To produce a compound of formula (Id) (a compound in which V in formula (I) is a hydroxyl group) Can do.

（式中、Ｒ₁、Ｒ₃、Ｒ₄、Ｒ₄’、Ｒ₅、Ｒ₆、Ｗ、ｎ、環Ｐ、環Ｑは前記と同じ意味を表し、Ｒ₂’はアリール基もしくはヘテロアリール基を表す。）
＜工程１＞
式（Ｉｅ）の化合物（式（Ｉ）のＲ₂が水素，Ｖがオキソ基である化合物）を用い、文
献公知の方法、例えば[新実験化学講座 １４ 有機化合物の合成と反応[Ｉ]、３０７頁
、１９７７年、丸善]などに記載された方法[ハロゲン化反応]に準じて、Ｎ−クロロコハ
ク酸イミド、Ｎ−ブロモコハク酸イミド、Ｎ−ヨードコハク酸イミド、臭素、ヨウ素、塩化銅等のハロゲン化剤存在下、ジクロロメタン、クロロホルム、四塩化炭素等のハロゲン系溶媒等の反応に関与しない溶媒中、酢酸等の酸の存在下または非存在下、０℃から溶媒が還流する温度で反応させることにより、Ｙが塩素、臭素、ヨウ素である式（Ｉｆ）の化合物を製造できる。 [Production Method 4]
The compound of formula (Ie), formula (If), formula (Ig), a salt thereof or a solvate thereof can also be produced by the method of the following (Scheme 6).

(Wherein R ₁ , R ₃ , R ₄ , R ₄ ′, R ₅ , R ₆ , W, n, ring P, and ring Q represent the same meaning as described above, and R ₂ ′ represents an aryl group or heteroaryl group. Represents.)
<Step 1>
Using compounds of formula (Ie) (compounds of formula (I) where R ₂ is hydrogen and V is an oxo group), methods known in the literature, for example, [New Experimental Chemistry Course 14 Synthesis and Reaction [I] of Organic Compounds, 307, 1977, Maruzen], etc., halogens such as N-chlorosuccinimide, N-bromosuccinimide, N-iodosuccinimide, bromine, iodine, copper chloride, etc. In the presence of an agent, the reaction is carried out at a temperature at which the solvent is refluxed from 0 ° C. in the presence or absence of an acid such as acetic acid in a solvent such as dichloromethane, chloroform, carbon tetrachloride and the like that is not involved in the reaction. Can produce a compound of formula (If) where Y is chlorine, bromine or iodine.

<Step 2>
Using a compound of the formula (If) and a boronic acid or boronic ester of the formula (XI) (R ₂ ′ is an aryl or heteroaryl group), a method known from the literature, for example, a review by SUZUKI et al. (“Chemical Review ( CHEM.REV.) "(USA), 1995, p. 2457) and the like [Suzuki-Miyaura cross-coupling reaction] under a non-oxygen atmosphere, tetrakis (triphenylphosphine) palladium, In the presence of palladium catalysts such as bis (triphenylphosphine) palladium chloride and palladium tetraacetate, sodium carbonate, barium hydroxide, potassium phosphate and aqueous solutions thereof, and bases such as triethylamine and morpholine, toluene, diethyl ether, tetrahydrofuran, dioxane , Ethers such as 1,2-dimethoxyethane Using a solvent, a solvent inert to the reaction such as an aromatic hydrocarbon solvent such as benzene and toluene, or a mixed solvent thereof, the reaction is performed at a temperature at which the solvent is refluxed from 0 ° C., and the compound of the formula (Ig) is obtained. Can be manufactured.
<Step 3>
Using the compound of formula (Ig), the compound of formula (Ih) can be produced by the same method as in [Production Method 3].

When each compound synthesized by each of the above production methods has a reactive group such as a hydroxyl group, an amino group, or a carboxyl group as a substituent, these groups are appropriately protected in each production process, and the protection is performed at an appropriate stage. Groups can also be removed. Such a method for introducing / removing a protecting group is appropriately performed depending on the group to be protected or the type of protecting group. For example, Green et al., “Protective Groups in Organic Synthesis”. ) ", (USA), 3rd edition, 1999, etc.
In addition, the compounds represented by the above formula (III), formula (V), formula (VI), formula (VIII), and formula (IX) are commercially available products or are prepared from commercially available compounds by known methods. be able to.

The preventive / therapeutic agent and pharmaceutical composition of the fourth aspect of the present invention (hereinafter sometimes collectively referred to as the present pharmaceutical composition) will be described.
This pharmaceutical composition is effective not only for intravenous administration but also for oral administration. Therefore, the pharmaceutical composition and the preventive / therapeutic agent of the present invention are considered to have a wide range of applications without being limited to administration applications.
In addition, the compound which is an active ingredient of the pharmaceutical composition and preventive / therapeutic agent of the present invention is not toxic at a concentration that sufficiently shows the efficacy in vivo. That is, the pharmaceutical composition and the preventive / therapeutic agent of the present invention are excellent in safety.

  The present pharmaceutical composition only needs to contain at least one compound represented by the compound of formula (I), and is prepared in combination with a pharmaceutically acceptable additive. More specifically, excipients (eg; lactose, sucrose, mannitol, crystalline cellulose, silicic acid, corn starch, potato starch), binders (eg; celluloses (hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose ( HPMC)), crystalline cellulose, saccharides (lactose, mannitol, sucrose, sorbitol, erythritol, xylitol), starches (corn starch, potato starch), pregelatinized starch, dextrin, polyvinylpyrrolidone (PVP), macrogol, polyvinyl alcohol (PVA)), lubricant (eg; magnesium stearate, calcium stearate, talc, carboxymethylcellulose), disintegrant (eg; starches (corn starch, potato starch), carbox Methyl starch sodium, carmellose, carmellose calcium, croscarmellose sodium, crospovidone), coating agent (eg, celluloses (hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC)), aminoalkyl methacrylate copolymer E, methacrylic acid Copolymer LD), plasticizers (eg triethyl citrate, macrogol), masking agents (eg titanium oxide), colorants, flavoring agents, preservatives (eg benzalkonium chloride, paraoxybenzoic acid esters), isotonic Agents (eg, glycerin, sodium chloride, calcium chloride, mannitol, glucose), pH regulators (eg, buffers such as sodium hydroxide, potassium hydroxide, sodium carbonate, hydrochloric acid, sulfuric acid, phosphate buffer), stable Agent (eg, sugar, sugar a) (Alcohol, xanthan gum), dispersant, antioxidant (eg; ascorbic acid, butylhydroxyanisole (BHA), propyl gallate, dl-α-tocopherol), buffer, preservative (eg; paraben, benzyl alcohol, benzal chloride) Luconium), fragrance (eg, vanillin, 1-menthol, rose oil), solubilizer (eg, polyoxyethylene hydrogenated castor oil, polysorbate 80, polyethylene glycol, phospholipid cholesterol, triethanolamine), absorption enhancer (E.g., sodium glycolate, sodium edetate, sodium caprate, acylcarnitines, limonene), gelling agents, suspending agents or emulsifiers, commonly used suitable additives or solvents It can be combined with the compounds of the invention as appropriate to form various dosage forms. Come.

Various dosage forms include tablets, capsules, granules, powders, pills, ointments, patches, suppositories, injections, sublingual, liquids, powders, suspensions, nasal administration, slow Examples include release preparations. Oral, subcutaneous administration, intramuscular administration, transdermal administration, intravenous administration, intraarterial administration, perineural administration, epidural administration, intradural administration, intraventricular administration, intrarectal administration, intranasal administration Etc. and can be administered to patients.
The clinical dose of the compound of the present invention to humans is appropriately determined in consideration of the symptoms, weight, age, sex, etc. of the patient to which it is applied, but is usually 0.005 mg to 3.0 g, preferably 0. It is 05 mg to 2.5 g, more preferably 0.1 mg to 1.5 g. This is divided into one time or several times, orally or parenterally, preferably orally. Since the dosage varies depending on various conditions, an amount smaller than the above dosage range may be sufficient. Depending on the patient's condition, the administration period is not limited to one day but may be several consecutive days or weeks, but can be appropriately increased or decreased depending on the symptoms or administration route.

<Formulation example>
Although the formulation example of the pharmaceutical composition of this invention is given to the following, this invention is not limited to these. Unless otherwise specified,% is mass%.

Formulation Example 1 Tablet Example 3 Compound 100 g
137g of lactose
Crystalline cellulose 30g
Hydroxypropylcellulose 15g
Carboxymethyl starch sodium 15g
Magnesium stearate 3g
Weigh the above ingredients and mix evenly. This mixture is compressed into tablets having a weight of 150 mg.

Formulation Example 2 Film Coating Hydroxypropylmethylcellulose 9g
Macrogol 6000 1g
Titanium oxide 2g
After weighing the above components, hydroxypropylmethylcellulose and macrogol 6000 are dissolved in water and titanium oxide is dispersed. This liquid is film-coated on 300 g of the tablet of Preparation Example 1 to obtain film-coated tablets.

Formulation Example 3 Capsule Example 10 Compound 50g
Lactose 435g
Magnesium stearate 15g
The above ingredients are weighed and mixed uniformly. The mixture is filled into an appropriate hard capsule in an amount of 300 mg in a capsule encapsulator to obtain a capsule.

Formulation Example 4 Capsule Example 10 Compound 100g
Lactose 63g
Corn starch 25g
Hydroxypropylcellulose 10g
Talc 2g
After weighing the above components, the compound of Example 48, lactose and corn starch are uniformly mixed, an aqueous solution of hydroxypropylcellulose is added, and granules are produced by wet granulation.
Talc is uniformly mixed with the granules, and 200 mg each is filled into a suitable hard capsule to form a capsule.

Formulation Example 5 Powder Example 10 Compound 200g
790 g of lactose
Magnesium stearate 10g
After weighing each of the above components, they are mixed uniformly to form a 20% powder.

Formulation Example 6 Granules, Fine Granules Example 14 Compound 100g
Lactose 200g
Crystalline cellulose 100g
Partially pregelatinized starch 50g
Hydroxypropylcellulose 50g
After weighing the above components, add the compound of Example 27, lactose, crystalline cellulose, and partially pregelatinized starch, and mix uniformly. To manufacture. The granules or fine granules are dried to obtain granules or fine granules.

Formulation Example 7 Injection Example 15 Compound 2g
Propylene glycol 200g
Distilled water for injection Appropriate amount After weighing the above components, the compound of Example 48 is dissolved in propylene glycol. Add sterilized water for injection to a total volume of 1000 mL, and after sterilizing by filtration, dispense 5 mL each into a 10 mL ampoule and seal to make an injection.

Formulation Example 8 Suppository Example 15 Compound 100g
Polyethylene glycol 1500 180g
Polyethylene glycol 4000 720g
Example 56 The compound was sufficiently polished in a mortar to make a fine powder, and then made into 1 g suppositories by the melting method.

<Pharmacological experiment example>
Hereinafter, the present invention will be specifically described with reference to experimental examples of pharmacological tests, but the present invention is not limited thereto.

Experimental Example 1 Human CB2 Receptor Binding Assay Human CB2 receptor forced expression CHO-K1 cells (Euroscreen) were 10% inactivated fetal bovine serum (FBS), 400 μg / mL neomycin (G-418), 100 U / mL. The cells were cultured in HAM'sF-12 medium containing penicillin, 100 μg / mL streptomycin and 2.5 μg / mL fungison. Ice-cold phosphate buffered saline (PB
After washing with S), the cells were detached with a cell scraper and collected by centrifugation, and then a binding assay buffer (50 mM Tris / hydrochloric acid pH 7.4, 2.5 mM ethylenediaminetetraacetic acid (EDTA), 100 mM NaCl, 0.1%) Bovine serum albumin (BSA)) was prepared to 100,000 cells / mL.
4 nM of radioligand [ ³ H] -WIN55212-2 in binding assay buffer
A solution and an unlabeled WIN552122-2 10 μM solution were prepared. The test substance was dissolved in dimethyl sulfoxide (DMSO) at a concentration 1000 times the final concentration, and this DMSO solution was added to the binding assay buffer at a concentration of 1% and dissolved.
Add 100 μL of binding assay buffer to the tube, 25 μL of binding assay buffer containing 1% DMSO for total binding, and 25 μL of unlabeled WIN55212-2 10 μM for nonspecific binding. Concentration 1 μM), or 25 μL of a test substance preparation solution prepared to an appropriate concentration was added. [ ³ H] -WIN5 in all the above tubes
25 μL of 4nM solution of 5212-2 was added (final concentration 0.4 nM), and cell solution 100 μl
L was added (10,000 cells / tube, total liquid volume 250 μL, 0.1% DMSO), and incubated at 30 ° C. for 60 minutes.
Immediately after the incubation, the reaction solution was added to a multi-screen FC 96-well plate (Millipore), aspirated, and washed 3 times with 300 μL of ice-cooled binding assay buffer. After washing, the filter was removed from the plate and placed in a vial filled with 2 mL of scintillation cocktail (AQUASOL-2, Packard). Radioactivity of all samples was measured using a liquid scintillation counter (LS6000TA, Beckman) (5 minutes / sample). The radioligand binding inhibition Ki value of each test substance is calculated using the analysis software Sigma
It calculated using aPlot (HULLINKS company).

Table 1 shows the Ki value of each Example compound. The Ki value of the thiophenecarboxamide derivative of the present invention was in the range of 1 nM to 1000 nM, and showed a good binding activity for the CB2 receptor.

(Experimental example 2) Human CB1 receptor binding assay Human CB1 receptor forced expression HEK cell membrane fraction was purchased from Perkin Elmer,
After dissolution at 37 ° C., an appropriate protein concentration was prepared with a binding assay buffer (50 mM Tris / hydrochloric acid pH 7.4, 2.5 mM EDTA, 5 mM MgCl ₂ , 0.1% BSA).
A 2 nM solution of radioligand [ ³ H] -CP55,940 and an unlabeled CP55,940 10 μM solution were prepared in a binding assay buffer. The test substance was dissolved in dimethyl sulfoxide (DMSO), and this DMSO solution was added to the binding assay buffer.
Add 100 μL of binding assay buffer to the tube, 25 μL of binding assay buffer containing 1% DMSO for total binding, and 25 μL of unlabeled CP55,940 10 μM for nonspecific binding. Concentration 1 μM), or 25 μL of a test substance preparation solution prepared to an appropriate concentration was added. 25 μL of a 2 nM solution of [ ³ H] -CP55,940 is added to all the above tubes (final concentration 0.2 nM), 100 μL of CB1 membrane fraction is added (total liquid volume 250 μL, 0.1% DMSO), 30 ° C. Incubated for 90 minutes.
Multi-screen FC 96-well plate (Millipore) immediately after incubation
The sample was aspirated and washed three times with 300 μL of ice-cold binding assay buffer. After washing, the filter was removed from the plate and placed in a vial filled with 2 mL of scintillation cocktail (AQUASOL-2, Packard). Radioactivity of all samples was measured using a liquid scintillation counter (LS6000TA, Beckman) (5 minutes / sample). The radioligand binding inhibition Ki value of each test substance is calculated using the analysis software Sigma
It calculated using aPlot (HULLINKS company).

The hCB1 receptor binding activity of the thiophenecarboxamide derivative of the present invention is hCB2 receptor binding activity Ki value in which Ki = 573 nM in Example Compound 16, Ki> 10000 nM in Example Compound 19, and Ki value is 1.0-20 nM. Higher values were shown and good selectivity for the hCB1 receptor.

(Experimental example 3) Human CB2 receptor functional assay 1. GTP binding assay As one of functional assays for determining agonist / inverse agonist activity of a test substance having human CB2 receptor binding activity, guanosine triphosphate (GTP) A binding reaction system was performed.
The precipitate of human CB2 receptor forced expression CHO-K1 cells cultured and recovered by the method of Experimental Example 1 was added to a Tris / EDTA buffer (10 mM Tris / hydrochloric acid p containing 0.32 mM sucrose).
H7.5, 0.1 mM EDTA) was added and homogenized. The supernatant obtained by centrifugation at 4 ° C. for 15 minutes was collected in an ultracentrifuge tube (33PC Atsumi Kumi, Hitachi, Ltd.) and 45000 g, 4 ° C. in an ultracentrifuge Himac CP70G (Hitachi, RP70T175 roter). For 30 minutes. The obtained precipitate was suspended in Tris / EDTA buffer and centrifuged again at 45000 g at 4 ° C. for 30 minutes. This precipitate was suspended in Tris / EDTA buffer and adjusted to 1 mg / mL after protein quantification. The membrane fraction thus obtained was snap-frozen in liquid nitrogen and stored at −80 ° C. until use.
The influence of the test substance on GTP binding was measured using DELFIA (GTP-binding Kit (Perkin Elmer)) 7.5 μM guanosine diphosphate (GDP) was added to each well of a polypropylene 96-well round bottom plate, 0.1% BS
40 μL of 50 mM HEPES buffer containing A,, 125 mM NaCl, 7.5 mM MgCl ₂ and 50 mM HEPES buffer 2 containing 500 μg / mL saponin
0 μL was added. 20 μL of 50 mM HEPES buffer containing the test drug, solvent (DMSO final concentration 0.1%) or GTP-γ-s (final concentration 10 μM) in each well
Added one by one. The membrane fraction was diluted 4-fold with 50 mM HEPES buffer, and each we
20 μL was added to ll (final concentration 50 μg protein / mL) and incubated at room temperature for 30 minutes with stirring.
After the incubation, 10 μL of 50 mM HEPES buffer containing 100 nM Europium-labeled GTP (GTP-Eu) was added and incubated at room temperature for 30 minutes with stirring. The entire amount of the reaction solution was transferred to a 96-well filter, and the washing solution was added 300 μL × 3 times with suction. This plate was placed in an ARVO plate reader (Wallac), and the amount of GTP-Eu was counted at 615 nm. The value obtained by subtracting the count value of the GTP-γ-s added well from the count value of each well as non-specific binding is defined as the GTP-Eu binding amount, and the increase or decrease from the binding amount of the well added with the solvent (0.1% DMSO) is increased or decreased. Calculated in%.
In this GTP binding assay system, the CB2 ligand that increases the amount of GTP-Eu binding is an agonist, and the ligand that decreases it is an inverse agonist. HU210 (Sigma) was used as the agonist control substance, and SR144528 was used as the inverse agonist control substance.

Of the thiophenecarboxamide derivatives of the present invention, the effects of Example compounds 16 and 19 on the GTP binding reaction are shown in FIGS. 1 and 2, respectively. Example compound 16 increased the amount of GTP-Eu binding in a concentration-dependent manner and showed agonistic activity similar to HU210. On the other hand, Example Compound 19 decreased the amount of GTP-Eu binding in a concentration-dependent manner, and showed the same inverse agonist activity as SR144528.

(Experimental example 4) Human CB2 receptor functional assay 2. Intracellular cAMP concentration measurement system Intracellular cAMP concentration as one of functional assays for determining agonist / inverse agonist activity of a test substance having human CB2 receptor binding activity Implement the measurement system. LANCE cAMP 384 Kit (Perkin Elmer) is used for quantification of cAMP concentration.
After culturing human CB2-expressing cells by the method described in Experimental Example 1, ice-cooled Hanks-bala
Nced Salt Solution (HBSS) is added, and the cells are detached with a cell scraper and collected by centrifugation. The resulting cell suspension is washed twice with HBSS, and then adjusted to 100,000 cells / mL with Stimulation buffer (pH 7.4 HBSS containing 5 mM HEPES, 0.1% BSA, 0.5 mM IBMX). To this, Alexa Fluor (registered trademark) 647-anti-cAMP antibody attached to Kit was added to 1/100 of the cell suspension amount.
Add amount.
Swell containing Forskolin (final concentration 3M) and test substance (solvent: DMSO final concentration 0.1%) in an appropriate concentration range in a 96-well half area plate (Coaster)
24 μL of mulation buffer is added, the same amount of the cell suspension is added, and the mixture is incubated at room temperature for 30 minutes with stirring. After incubation, europium labeled streptavidin, biotin labeled cAMP, 10 mM CaCl ₂ , 0.35% Titon X
48 μL of 50 mM HEPES buffer pH 7.4 containing 100 is added and incubated at room temperature for 60 minutes with agitation. The cAMP standard solution attached to the kit is appropriately diluted, added to the well in the same manner as described above under conditions that do not contain cells, test substances, etc., and used for preparing a cAMP concentration calibration curve. After the incubation, all wells of the test substance and standard solution are measured using wallac Envision (Perkin Elmer) at an excitation wavelength of 320 nm, a fluorescence wavelength of 665 nm, and a reference wavelength of 615 nm, and the cAMP concentration is quantified.
In this intracellular cAMP concentration measurement system, the CB2 ligand that decreases the cAMP concentration is an agonist, and the ligand that increases the concentration is an inverse agonist. HU210 and CP55,940 are used as agonist control substances, and SR144528 is used as an inverse agonist control substance.

(Experimental Example 5) Rat Carrageenin-Induced Pain Model All experimental procedures were performed using the International Association fort.
It can be carried out according to the ethical rules described in he Study of Pain (Zimmermann, M., 1983. Pain 16, vol. 109). Five-week-old male Wistar rats are purchased from Japan SLC, and raised in a room maintained at a room temperature of 21-25 ° C., a humidity of 45-55%, and a 12-hour day / night cycle. Feed and drink freely during the acclimatization period. Animals are subjected to experiments at 6 weeks of age and fasted for at least 18 hours from the day before measurement.
The test substance is dissolved or suspended in a 2% carboxymethylcellulose Na (Wako Pure Chemical Industries) solution, and is orally administered to rats by a volume of 10 mL / kg. One hour after administration of the test substance, 0.1 mL of carrageenin (Zushi Chemical) physiological saline suspended at 1 w / v% is subcutaneously subcutaneously injected into the right hind paw of the animal to induce inflammation. The analgesic action of the test substance is examined using the Randall-Selitto method (Randall, LO and Selitto, JJ, 1957. Arch. Int. Pharmacodyn, 111, 409). That is, 3 to 4 hours after administration of carrageenan,
A pressure stimulus is applied by eter (TK-201, Unicom), and the pressure at which the animal causes the limb withdrawal behavior is measured as a pain threshold.

In this model animal, one of the thiophenecarboxamide derivatives of the present invention showed an analgesic effect by increasing the pain threshold in a dose-dependent manner by oral administration of 10 to 100 mg / kg. From the above, it can be confirmed that the compound of the present invention is useful as an analgesic in inflammatory pain.

(Experimental example 6) Streptozotocin-induced rat diabetic pain model All experimental procedures were conducted according to the ethical rules of International Association for the Study of Pain (Zimmermann, M., 1983.
Pain 16 volume, page 109). Male Sprague-Dawley rats administered intraperitoneally with 50 mg / kg streptozotocin were purchased from Japan SLC and kept in a room kept at a room temperature of 21-25 ° C., a humidity of 45-55%, and a 12 hour day / night cycle. During the habituation period, they were allowed to feed and drink freely. The animals were subjected to the experiment after 3 weeks or more of streptozotocin administration, and fasted for 18 hours or more from the day before the measurement.
The test substance was dissolved or suspended in a 0.5% strength hydroxypropylmethylcellulose Na solution and orally administered to rats in a volume of 10 mL / kg. Allodynia, which is characteristically observed in neuropathic pain, was measured according to the method of Seltzer et al. (1990. Pain 43, 205). That is, an animal is placed in a plastic cage placed on a net, a series of von Frey Filament (Stoelting) is pressed against the rat hind footpad, and the threshold (g) is calculated from the filament diameter used when the paw is quickly retracted. It was measured.

In this model animal, the compound of Example 7 of the present invention increased the threshold in a dose-dependent manner by oral administration of 10 to 30 mg / kg, and showed an antiallodynic action. From the above, it was confirmed that the representative compound of the present invention is useful as an analgesic in neuropathic pain.

From the results of these pharmacological experimental examples, it was confirmed that the compound of the present invention not only shows CB2 binding activity in vitro, but also can be used as a prophylactic and / or therapeutic agent for diseases involving CB2 when administered in vivo. The

<Synthesis Example>
Next, synthesis examples are given to describe the present invention in more detail, but the present invention is not limited thereto.
For the measurement of nuclear magnetic resonance spectrum (NMR), Geol JNM-LA300 (JEOL
JNM-LA300) FT-NMR (manufactured by JEOL Ltd.) or JEOL JNM-EX270 (JEOL JNM-EX270) FT-NMR (manufactured by JEOL Ltd.) was used.

Example 1
Synthesis of N- {3- [1-hydroxy-2- (methylsulfonyl) ethyl] thiophen-2-yl} adamantane-1-carboxamide <Step 1> 2- (1-adamantanecarbonylamino) thiophene-3-carboxylic acid Synthesis of ethyl Pyridine (11.76 mL) and 1-adamantanecarbonyl chloride (14.45 g) were sequentially added to a solution of ethyl 2-aminothiophene-3-carboxylate (8.30 g) in dichloromethane (170 mL). Stir for hours. Water was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed successively with 0.5N hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (eluent: n-hexane: ethyl acetate = 100: 0 to 9: 1), and the resulting solid was purified with n-hexane. Washing gave the title compound (10.4 g) as a colorless solid.
<Step 2> Synthesis of N- {3- [2- (methylsulfonyl) acetyl] thiophen-2-yl} adamantane-1-carboxamide In a suspension of dimethylsulfone (39.29 g) in tetrahydrofuran (240 mL), -78 N-Butyllithium (200 mL 1.58 M n-hexane solution) was added dropwise at 0 ° C., and after dropping, the temperature was returned to room temperature, followed by heating under reflux for 1 hour. A solution of the compound obtained in Step 1 (8.00 g) in tetrahydrofuran (80 mL) was added dropwise to this reaction solution at room temperature, and the mixture was stirred for 10 minutes. Water was added to the reaction solution under ice-cooling, neutralized with 1N hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and then dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was washed with diethyl ether to obtain the title compound (8.00 g) as a pale yellow solid.
<Step 3> Synthesis of N- {3- [1-hydroxy-2- (methylsulfonyl) ethyl] thiophen-2-yl} adamantane-1-carboxamide in Step 2 (0.55 g) of tetrahydrofuran ( To a 5 mL) -methanol (5 mL) solution was added sodium tetrahydroborate (81.8 mg), and the mixture was stirred at room temperature for 30 minutes. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and then dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (eluent; n-hexane: ethyl acetate = 2: 1 to 1: 2) to give the title compound (0.46 g) as a colorless amorphous product. Got as.

(Example 2)
Synthesis of N- {5-chloro-3- [1-hydroxy-2- (methylsulfonyl) ethyl] thiophen-2-yl} adamantane-1-carboxamide <Step 1> N- {5-Chloro-3- [2 Synthesis of-(methylsulfonyl) acetyl] thiophen-2-yl} adamantane-1-carboxamide Example 1 <Step 2> In a chloroform (4 mL) solution of the compound (0.20 g) obtained in acetic acid (2 mL), N-chlorosuccinimide (77 mg) was sequentially added, and the mixture was stirred at room temperature for 1 hour. 1N sodium hydroxide was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (eluent; n-hexane: ethyl acetate = 100: 0 to 2: 1), and the resulting solid was washed with diethyl ether. The title compound (93 mg) was obtained as a white powder.
<Step 2> Synthesis of N- {5-chloro-3- [1-hydroxy-2- (methylsulfonyl) ethyl] thiophen-2-yl} adamantane-1-carboxamide Example 1 <Method 3> The title compound (65 mg) was obtained as a white powder from the compound obtained in Step 1 (80 mg).

(Example 3)
Synthesis of N- {3- [1-hydroxy-2- (methylsulfonyl) ethyl] thiophen-2-yl} 3-fluoroadamantane-1-carboxamide <Step 1> 2- (3-Fluoroadamantane-1-carbonylamino ) Synthesis of ethyl thiophene-3-carboxylate In the same manner as in Example 1 <Step 1>, in accordance with the method described in methyl 2-aminothiophene-3-carboxylate (400 mg) and EP 870757. Using 3-fluoro-1-adamantanecarbonyl chloride prepared from synthesized 3-fluoro-1-adamantanecarboxylic acid (717 mg), the title compound (694 mg) was obtained as a white powder.
<Step 2> N- {3- [2- (methylsulfonyl) acetyl] thiophen-2-yl} 3
Synthesis of -fluoroadamantane-1-carboxamide In the same manner as in Example 1 <Step 2>, the title compound (322 mg) was obtained as a white powder from the compound obtained in Step 1 (200 mg).
<Step 3> N- {3- [1-hydroxy-2- (methylsulfonyl) ethyl] thiophene-
Synthesis of 2-yl} 3-fluoroadamantane-1-carboxamide In the same manner as in Example 1 <Step 3>, the title compound (91 mg) was obtained as colorless crystals from the compound (155 mg) obtained in Step 2.

Example 4
Synthesis of N- {3- [1-hydroxy-2- (methylsulfonyl) ethyl] thiophen-2-yl} 3,5,7-trifluoroadamantane-1-carboxamide <Step 1> 2- (3, 5, Synthesis of ethyl 7-trifluoroadamantane-1-carbonylamino) thiophene-3-carboxylate In the same manner as in Example 1 <Step 1>, methyl 2-aminothiophene-3-carboxylate (93 mg) and European Patent No. Using 3,5,7-trifluoro-1-adamantanecarbonyl chloride prepared from 3,5,7-trifluoro-1-adamantanecarboxylic acid (180 mg) synthesized according to the method described in pamphlet of 870757, The title compound (122 mg) was obtained as a pale yellow solid.
<Step 2> Synthesis of N- {3- [2- (methylsulfonyl) acetyl] thiophen-2-yl} 3,5,7-trifluoroadamantane-1-carboxamide Example 1 <Method 2> The title compound (200 mg) was obtained as a pale yellow solid from the compound (110 mg) obtained in Step 1.
<Step 3> Synthesis of N- {3- [1-hydroxy-2- (methylsulfonyl) ethyl] thiophen-2-yl} 3,5,7-trifluoroadamantane-1-carboxamide Example 1 <Step 3> In the same manner as described above, the title compound (90 mg) was obtained as a colorless solid from the compound (200 mg) obtained in Step 2.

(Example 5)
Synthesis of N- {3- [2- (trifluoromethylsulfonylamino) acetyl] thiophen-2-yl} adamantane-1-carboxamide <Step 1> Synthesis of tert-butyl N- (2-cyanoacetyl) carbamate Tetrahydrofuran ( 200 mL) and n-butyllithium (136 mL) at -60 ° C. or lower.
1.56M n-hexane solution) was added, and a solution of acetonitrile (12.4 mL) in tetrahydrofuran (20 mL) was added dropwise to the solution at −65 ° C. or lower. The reaction solution was stirred at the same temperature for 10 minutes, and then a solution of N- (tert-butoxycarbonyl) glycine methyl ester in tetrahydrofuran (20 mL) was added dropwise at −65 ° C. or lower. Take 1 hour after dropping
After heating up to 35 degreeC, it stirred at the same temperature for further 2 hours. The reaction mixture was neutralized by adding 1N hydrochloric acid (250 mL) at once, and extracted with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (14.49 g) as a pale red oil.
<Step 2> Synthesis of 2-amino-3- [2- (tert-butoxycarbonylamino) acetyl] thiophene In a solution of the compound obtained in Step 1 (13.0 g) in ethanol (400 mL), 2,5-dihydroxy- 1,4-dithiane (12.0 g) was added and heated to 50 ° C., then triethylamine (21.9 mL) was added all at once and stirred at 60 to 70 ° C. for 30 minutes. After standing to cool, the insoluble material was filtered off, and the filtrate was concentrated to about 100 mL. Water was added to this concentrated solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was washed with diethyl ether to obtain the title compound (7.5 g) as a pale yellow solid.

<Step 3> Synthesis of N- {3- [2- (tert-butoxycarbonylamino) acetyl] thiophen-2-yl} adamantane-1-carboxamide Compound (7.0 g) in dichloromethane (140 mL) ) After sequentially adding pyridine (4.73 mL) and 1-adamantanecarbonyl chloride (8.3 g) to the solution,
The mixture was stirred at room temperature for 2 hours and at 40 ° C. for 2 hours. Water was added to the reaction mixture, and the mixture was made alkaline with 1N sodium hydroxide and extracted with dichloromethane. The organic layer was washed successively with dilute hydrochloric acid (pH 3-4) and saturated brine, and then dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (eluent; n-hexane: ethyl acetate = 9: 1 to 6: 4) to give the title compound (6.66 g) as pale yellow Obtained as amorphous.
<Step 4> Synthesis of N- {3- [2- (trifluoromethylsulfonylamino) acetyl] thiophen-2-yl} adamantane-1-carboxamide 4N hydrochloric acid was added to the compound (0.1 g) obtained in Step 3 -An ethyl acetate solution (5 mL) was added, and the mixture was stirred at room temperature for 30 minutes and at 50 ° C for 30 minutes. After distilling off the solvent, water was added, and the mixture was made alkaline with 1N sodium hydroxide and extracted with dichloromethane. The organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was dissolved in dichloromethane (5 mL), and trifluoromethanesulfonic anhydride (57 μL) and pyridine (68 μL) were successively added under ice cooling, followed by stirring at room temperature for 15 minutes. Water was added to the reaction mixture, and the mixture was made alkaline with saturated aqueous sodium hydrogen carbonate solution and extracted with dichloromethane. The organic layer was washed successively with 1N hydrochloric acid and saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (eluent; n-hexane: ethyl acetate = 4: 1 to 2: 1) to give the title compound (47 mg) as a pale yellow amorphous product. Obtained.

(Example 6)
Synthesis of N- {3- [2- (methylsulfonylamino) acetyl] thiophen-2-yl} adamantane-1-carboxamide obtained in the same manner as Example 5 <Step 4>, obtained in Example 5 <Step 3>. The title compound (0.24 mg) was obtained as a white powder from the obtained compound (0.40 g) and methanesulfonyl chloride (96 μL).

(Example 7)
Synthesis of N- {3- [2- (trifluoromethylsulfonylamino) acetyl] thiophen-2-yl} 3-fluoroadamantane-1-carboxamide <Step 1> N- {3- [2- (tert-butoxycarbonyl) Synthesis of (amino) acetyl] thiophen-2-yl} 3-fluoroadamantane-1-carboxamide Compound (1.2 g) obtained in Example 5 <Step 2> in the same manner as in Example 5 <Step 3>. And 3-fluoroadamantane-1-carbonyl chloride prepared from 3-fluoroadamantane-1-carboxylic acid (1.32 g) gave the title compound (1.45 g) as a colorless solid.
<Step 2> Synthesis of N- {3- [2- (trifluoromethylsulfonylamino) acetyl] thiophen-2-yl} 3-fluoroadamantane-1-carboxamide Example 5 In the same manner as in <Step 4>, The title compound (880 mg) was obtained as a pale yellow amorphous product from the compound (1.3 g) obtained in Step 1.

(Example 8)
Synthesis of N- {5-methyl-3- [2- (trifluoromethylsulfonylamino) acetyl] thiophen-2-yl} 3-fluoroadamantane-1-carboxamide <Step 1> 2-amino-3- [2- Synthesis of (tert-butoxycarbonylamino) acetyl] -5-methylthiophene In the same manner as in Example 5 <Step 2>, the compound (5.0 g) obtained in Example 5 <Step 1>, propionaldehyde ( 2.2 mL) and sulfur powder (806 mg) gave the title compound (317 mg) as a light brown solid.
<Step 2> N- {3- [2- (tert-butoxycarbonylamino) acetyl] -5-
Synthesis of methylthiophen-2-yl} 3-fluoroadamantane-1-carboxamide In the same manner as in Example 5 <Step 3>, the compound (300 mg) obtained in Step 1 and 3-fluoro-1-adamantanecarbonyl chloride (380 mg) was used to give the title compound (445 mg) as a pale yellow amorphous.
<Step 3> Synthesis of N- {5-methyl-3- [2- (trifluoromethylsulfonylamino) acetyl] thiophen-2-yl} 3-fluoroadamantane-1-carboxamide Same as Example 5 <Step 4> In this manner, the title compound (0.17 g) was obtained as a pale orange solid from the compound (0.39 g) obtained in Step 2.

Example 9
Synthesis of N- {4-methyl-3- [2- (trifluoromethylsulfonylamino) acetyl] thiophen-2-yl} 3-fluoroadamantane-1-carboxamide <Step 1> 2-amino-3- [2- Synthesis of (tert-butoxycarbonylamino) acetyl] -4-methylthiophene In the same manner as in Example 5 <Step 2>, the compound (5.0 g) obtained in Example 5 <Step 1>, acetone (37 mL) ) And sulfur powder (806 mg) to give the title compound (818 mg) as a pale yellow amorphous.
<Step 2> N- {3- [2- (tert-butoxycarbonylamino) acetyl] -4-
Synthesis of methylthiophen-2-yl} 3-fluoroadamantane-1-carboxamide In the same manner as in Example 5 <Step 3>, the compound (0.20 g) obtained in Step 1 and 3-fluoro-1-adamantane The title compound (0.19 g) was obtained as a colorless solid using carbonyl chloride (0.24 g).
<Step 3> Synthesis of N- {4-methyl-3- [2- (trifluoromethylsulfonylamino) acetyl] thiophen-2-yl} 3-fluoroadamantane-1-carboxamide Same as Example 5 <Step 4> The title compound (0.12 g) was obtained as a pale yellow amorphous product from the compound (0.18 g) obtained in Step 2.

(Example 10)
Synthesis of N- {3- [2- (trifluoromethylsulfonylamino) acetyl] thiophen-2-yl} 3,5-difluoroadamantane-1-carboxamide <Step 1> N- {3- [2- (tert- Synthesis of butoxycarbonylamino) acetyl] thiophen-2-yl} 3,5-difluoroadamantane-1-carboxamide In the same manner as in Example 5 <Step 3>, the compound obtained in Example 5 <Step 2> ( 137 mg) and 3,5-difluoroadamantane-1-carbonyl chloride prepared from 3,5-difluoroadamantane-1-carboxylic acid (173 mg) synthesized according to the method described in the pamphlet of European Patent No. 870757, The title compound (160 mg) was obtained as a pale yellow solid.
<Step 2> Synthesis of N- {3- [2- (trifluoromethylsulfonylamino) acetyl] thiophen-2-yl} 3,5-difluoroadamantane-1-carboxamide Example 5 <Method similar to Step 4> The title compound (93 mg) was obtained as a yellow solid from the compound (160 mg) obtained in Step 1.

(Example 11)
Synthesis of N- {3- [2- (methylsulfonylamino) acetyl] thiophen-2-yl} 3,5,7-trifluoroadamantane-1-carboxamide <Step 1> N- {3- [2- (tert Synthesis of -butoxycarbonylamino) acetyl] thiophen-2-yl} 3,5,7-trifluoroadamantane-1-carboxamide obtained in the same manner as Example 5 <Step 3>, obtained in Example 5 <Step 2>. By using the obtained compound (0.16 g) and 3,5,7-trifluoroadamantane-1-carbonyl chloride (0.20 g), the title compound (0.16 g) was obtained as a pale yellow amorphous.
<Step 2> Synthesis of N- {3- [2- (methylsulfonylamino) acetyl] thiophen-2-yl} 3,5,7-trifluoroadamantane-1-carboxamide Similar to Example 5 <Step 4> The title compound (38 mg) was obtained as a pale yellow solid from the compound obtained in step 1 (72 mg) and methanesulfonyl chloride (24 μL).

(Example 12)
Synthesis of N- {3- [2- (trifluoromethylsulfonylamino) acetyl] thiophen-2-yl} 3,5,7-trifluoroadamantane-1-carboxamide In the same manner as in Example 5 <Step 4>. The title compound (30 mg) was obtained as a yellow solid from the compound (51 mg) obtained in Example 11 <Step 1>.

(Example 13)
Synthesis of N- {5-chloro-3- [2- (methylsulfonylamino) acetyl] thiophen-2-yl} 3,5,7-trifluoroadamantane-1-carboxamide <Step 1> N- {5-Chloro Synthesis of -3- [2- (tert-butoxycarbonylamino) acetyl] thiophen-2-yl} 3,5,7-trifluoroadamantane-1-carboxamide Example 2 <Step 1> The title compound (80 mg) was obtained as a pale yellow solid from the compound (80 mg) obtained in Example 11 <Step 1>.
<Step 2> Synthesis Example 5 of N- {5-chloro-3- [2- (methylsulfonylamino) acetyl] thiophen-2-yl} 3,5,7-trifluoroadamantane-1-carboxamide <Step 4 The title compound (39 mg) was obtained as a pale yellow solid from the compound obtained in Step 1 (73 mg) and methanesulfonyl chloride (22 μL) in the same manner as above.

(Example 14)
Synthesis of N- {3- [1-hydroxy-2- (methylsulfonylamino) ethyl] thiophen-2-yl} adamantane-1-carboxamide In the same manner as Example 1 <Step 3>, Example 6 <Step From the compound obtained in 4> (0.10 g), the title compound (90 mg) was obtained as a white powder.

(Example 15)
Synthesis of N- {3- [1-hydroxy-2- (trifluoromethylsulfonylamino) ethyl] thiophen-2-yl} 3,5,7-trifluoroadamantane-1-carboxamide Example 1 <Step 3> In the same manner, the title compound (14 mg) was obtained as a pale yellow amorphous product from the compound (20 mg) obtained in Example 12.

(Example 16)
Synthesis of N- [5-bromo-3- (2-dimethylamino-1-hydroxyethyl) thiophen-2-yl] adamantane-1-carboxamide <Step 1> N- {5-Bromo-3- [2- ( Synthesis of tert-butoxycarbonylamino) acetyl] thiophen-2-yl} adamantane-1-carboxamide In the same manner as in Example 2 <Step 1>, the compound (6.3 g) obtained in Example 5 <Step 3> ) And N-bromosuccinimide (2.68 g) gave the title compound (7.05 g) as a light brown solid.
<Step 2> Synthesis of N- [5-bromo-3- (2-dimethylaminoacetyl) thiophen-2-yl] adamantane-1-carboxamide Compound 1 (0.50 g) obtained in ethyl acetate (10 mL) 4N hydrochloric acid-ethyl acetate solution (2 mL) was added to the solution, and the mixture was stirred at room temperature for 2 hours. 4N hydrochloric acid-ethyl acetate solution (
3 mL) was added, and the mixture was stirred at room temperature for 2 hours. Further, 4N hydrochloric acid-ethyl acetate solution (3 mL) was added, and the mixture was stirred at room temperature for 2 hours. After distilling off the solvent, the solution was made alkaline with 1N sodium hydroxide and extracted with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was dissolved in dichloromethane (9 mL), and 37% formaldehyde solution (0.69 mL) and sodium triacetoxyborohydride (0.54 g) were successively added under ice cooling. The mixture was stirred for 2 hours under ice cooling. 1N sodium hydroxide was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (0.36 g) as a yellow amorphous.
<Step 3> Synthesis of N- [5-bromo-3- (2-dimethylamino-1-hydroxyethyl) thiophen-2-yl] adamantane-1-carboxamide In the same manner as in Example 1 <Step 3> The title compound (44 mg) was obtained as a colorless solid from the compound obtained in Step 2 (0.10 g).

(Example 17)
Synthesis of N- [3- (2-dimethylamino-1-hydroxyethyl) -5-phenylthiophen-2-yl] adamantane-1-carboxamide <Step 1> N- {3- [2- (tert-butoxycarbonyl) Synthesis of Aminoacetyl)]-5-Phenylthiophen-2-yl} adamantane-1-carboxamide Example 16, <1>, 2-dimethoxy of compound (0.30 g) obtained in <Step 1> and phenylboric acid (93 mg) After degassing the ethane (1.2 mL) suspension, a 2 M aqueous sodium carbonate solution (1.2 mL) and tetrakis (triphenylphosphine) palladium (0) (70 mg) were sequentially added under a nitrogen atmosphere. Stir for hours. After allowing to cool, ethyl acetate was added, and the organic layer was washed successively with 1N sodium hydroxide and saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (eluent: n-hexane: ethyl acetate = 9: 1 to 4: 1), and the resulting solid was purified with n-hexane. Washing gave the title compound (0.20 g) as a pale yellow solid.
<Step 2> N- [3- (2-dimethylaminoacetyl) -5-phenylthiophene-2-
Synthesis of [Il] adamantane-1-carboxamide In the same manner as in Example 16 <Step 2>, the title compound (0.14 g) was obtained as a yellow solid from the compound (0.23 g) obtained in Step 1.
<Step 3> Synthesis of N- [3- (2-dimethylamino-1-hydroxyethyl) -5-phenylthiophen-2-yl] adamantane-1-carboxamide In the same manner as in Example 1 <Step 3> The title compound (89 mg) was obtained as a colorless solid from the compound (0.14 g) obtained in Step 2.

(Example 18)
Synthesis of N- [3- (2-dimethylamino-1-hydroxyethyl) -5- (3-pyridyl) thiophen-2-yl] adamantane-1-carboxamide <Step 1> N- {3- [2- ( tert-Butoxycarbonylaminoacetyl)]-5- (3-pyridyl) thiophen-2-yl} adamantane-1-carboxamide In a manner similar to Example 17 <Step 1>, in Example 16 <Step 1> The title compound (124 mg) was obtained as a yellow amorphous form from the obtained compound (150 mg) and 3-pyridylboric acid (37 mg).
<Step 2> Synthesis of N- [3- (2-dimethylaminoacetyl) -5- (3-pyridyl) thiophen-2-yl] adamantane-1-carboxamide In the same manner as in Example 16 <Step 2> The title compound (87 mg) was obtained as a yellow amorphous form from the compound (124 mg) obtained in Step 1.
<Step 3> Synthesis of N- [3- (2-dimethylamino-1-hydroxyethyl) -5- (3-pyridyl) thiophen-2-yl] adamantane-1-carboxamide Same as Example 1 <Step 3> By the method, the title compound (49 mg) was obtained as a pale yellow amorphous from the compound (67 mg) obtained in Step 2.

Example 19
Synthesis of N- [3- (2-dimethylamino-1-hydroxyethyl) -5- (2-hydroxyphenyl) thiophen-2-yl] adamantane-1-carboxamide <Step 1> N- [3- (2- Synthesis of (dimethylaminoacetyl) -5- (2-hydroxyphenyl) thiophen-2-yl] adamantane-1-carboxamide obtained in Example 16 <Step 2> in a manner similar to Example 17 <Step 1>. The title compound (462 mg) was obtained as an orange-yellow solid from the compound (760 mg) and 2- (4,4,5,5, -tetramethyl-1,3,2-dioxaborolan-2-yl) phenol (472 mg). .
<Step 2> Synthesis of N- [3- (2-dimethylamino-1-hydroxyethyl) -5- (2-hydroxyphenyl) thiophen-2-yl] adamantane-1-carboxamide Example 1 <Step 3> In the same manner, the title compound (306 mg) was obtained as a white powder from the compound (450 mg) obtained in Step 1.

(Example 20)
Synthesis of N- [3- (2-dimethylamino-1-hydroxyethyl) -5- (8-quinolyl) thiophen-2-yl] adamantane-1-carboxamide <Step 1> N- [3- (2-dimethyl) Synthesis of aminoacetyl) -5- (8-quinolyl) thiophen-2-yl] adamantane-1-carboxamide The compound obtained in Example 16 <Step 2> was prepared in the same manner as in Example 17 <Step 1>. The title compound (35 mg) was obtained as yellow crystals from 100 mg) and 8-quinolylboric acid (49 mg).
<Step 2> Synthesis of N- [3- (2-dimethylamino-1-hydroxyethyl) -5- (8-quinolyl) thiophen-2-yl] adamantane-1-carboxamide Same as Example 1 <Step 3> By the method, the title compound (25 mg) was obtained as a yellow powder from the compound (30 mg) obtained in Step 1.

(Example 21)
Synthesis of N- [5- (1-butyl) -3- (2-dimethylamino-1-hydroxyethyl) thiophen-2-yl] adamantane-1-carboxamide <Step 1> 2-amino-3- [2- Synthesis of (tert-butoxycarbonylamino) acetyl] -5- (1-butyl) thiophene In the same manner as in Example 5 <Step 2>, the compound (400 mg) obtained in Example 5 <Step 1>, hexanal (0.24 mL) and sulfur powder (83 mg) gave the title compound (153 mg) as a brown amorphous.
<Step 2> N- {3- [2- (tert-butoxycarbonylamino) acetyl] -5-
Synthesis of (1-butyl) thiophen-2-yl} 3-fluoroadamantane-1-carboxamide In the same manner as in Example 5 <Step 3>, the compound (153 mg) obtained in Step 1 and 1-adamantanecarbonyl chloride were used. (146 mg) was used to give the title compound (142 mg) as a yellow amorphous.
<Step 3> Synthesis of N- [5- (1-butyl) -3- (2-dimethylaminoacetyl) thiophen-2-yl] adamantane-1-carboxamide In the same manner as in Example 16 <Step 2> From the compound (93 mg) obtained in Step 2, the title compound (54 mg) was obtained as a pale orange amorphous.
<Step 4> Synthesis of N- [5- (1-butyl) -3- (2-dimethylamino-1-hydroxyethyl) thiophen-2-yl] adamantane-1-carboxamide Similar to Example 1 <Step 3> By the method, the title compound (42 mg) was obtained as a yellow amorphous form from the compound (51 mg) obtained in Step 3.

(Example 22)
Synthesis of N- {3- [hydroxy (N-methyl- (S) -pyrrolidin-2-yl) methyl] -5-phenylthiophen-2-yl] adamantane-1-carboxamide <Step 1> N-tert-butoxy Synthesis of carbonyl-2- (2-cyanoacetyl)-(S) -pyrrolidine In the same manner as in Example 5 <Step 1>, N-tert-butoxycarbonyl- (S) -proline methyl ester (9.00 g) Gave the title compound (5.46 g) as a yellow oil.
<Step 2> Synthesis of 2-amino-3- (N-tert-butoxycarbonyl- (S) -pyrrolidin-2-yl) acetyl-5-phenylthiophene In the same manner as in Example 5 <Step 2>, The title compound (1.43 g) was obtained as an ocher solid from the compound obtained in 1 (1.0 g), phenylacetaldehyde (0.55 mL), and sulfur powder (134 mg).
<Step 3> N- [3- (N-tert-butoxycarbonyl- (S) -pyrrolidine-2-
Yl) Synthesis of carbonyl-5-phenylthiophen-2-yl] adamantane-1-carboxamide In the same manner as in Example 5 <Step 3>, the compound (1.0 g) obtained in Step 2 and 1-adamantanecarbonyl The title compound (1.26 g) was obtained as a yellow solid using chloride (800 mg).

<Step 4> N- [5-Phenyl-3-((S) -pyrrolidin-2-yl) carbonylthiophen-2-yl] adamantane-1-carboxamide synthesized in Step 3 (1.0 g) Trifluoroacetic acid (1.44 mL) was added to a dichloromethane solution (25 mL), and the mixture was stirred at room temperature overnight. The reaction solution was made alkaline by adding 25% aqueous ammonia, and extracted with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (810 mg) as a pale yellow solid.
<Step 5> N- [3- (N-methyl- (S) -pyrrolidin-2-yl) carbonyl-5
Phenylthiophen-2-yl] adamantane-1-carboxamide Synthesis Step 4 Into a 1,2-dichloroethane (5 mL) solution of the compound (120 mg), 37% formaldehyde solution (136 μL), triacetoxyborohydride Sodium (88 mg) was sequentially added, and the mixture was stirred for 30 minutes under ice cooling. Water was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was washed with a mixed solvent of n-hexane-diethyl ether to obtain the title compound (107 mg) as a pale yellow solid.
<Step 6> Synthesis of N- {3- [hydroxy (N-methyl- (S) -pyrrolidin-2-yl) methyl] -5-phenylthiophen-2-yl} adamantane-1-carboxamide Example 1 <Step In the same manner as in 3>, the low-polar diastereomer (30 mg) and the high-polar diastereomer (38 mg) of the title compound were each obtained as a colorless solid from the compound (100 mg) obtained in Step 5.

The following compounds from Example 23 to Example 61 were synthesized by the same method as described above or a method analogous thereto.

(Example 23)
N- {5- (tert-butyl) -3- [2- (methylsulfonylamino) acetyl] thiophen-2-yl} adamantane-1-carboxamide (Example 24)
N- {3- [2- (S) -methyl-2- (methylsulfonylamino) acetyl] thiophen-2-yl} adamantane-1-carboxamide (Example 25)
N- {3- [2- (S) -hydroxymethyl-2- (methylsulfonylamino) acetyl] thiophen-2-yl} adamantane-1-carboxamide (Example 26)
N- [3- (N-methylsulfonyl- (S) -aziridin-2-yl) carbonylthiophen-2-yl] adamantane-1-carboxamide (Example 27)
N- {3- [2- (methylsulfonylamino) acetyl] thiophen-2-yl} 3-fluoroadamantane-1-carboxamide (Example 28)
N- {3- [2- (methylsulfonylamino) acetyl] thiophen-2-yl} 4,4-difluorocyclohexane-1-carboxamide (Example 29)
N- {3- [1-hydroxy-2- (methylsulfonyl) ethyl] -5-methylthiophen-2-yl} adamantane-1-carboxamide (Example 30)
N- {3- [1-hydroxy-2- (methylsulfonyl) ethyl] thiophen-2-yl} 3-chloroadamantane-1-carboxamide (Example 31)
N- {3- [1-hydroxy-2- (methylsulfonyl) ethyl] -4-isopropylthiophen-2-yl} adamantane-1-carboxamide (Example 32)
N- {3- [1-hydroxy-2-methyl-2- (methylsulfonyl) ethyl] thiophen-2-yl} adamantane-1-carboxamide

(Example 33)
N- {3- [1-hydroxy-3- (methylsulfonyl) propyl] thiophen-2-yl} adamantane-1-carboxamide (Example 34)
N- {5-chloro-3- [1-hydroxy-2- (methylsulfonyl) ethyl] thiophen-2-yl} 3-fluoroadamantane-1-carboxamide (Example 35)
N- {3- [1-hydroxy-2- (methylsulfonyl) ethyl] -5-methylthiophen-2-yl} 3-fluoroadamantane-1-carboxamide (Example 36)
N- {3- [1-hydroxy-2- (methylsulfonyl) ethyl] -4-methylthiophen-2-yl} 3-fluoroadamantane-1-carboxamide (Example 37)
N- {3- [1-hydroxy-2- (methylsulfonyl) ethyl] -5- (trifluoromethyl) thiophen-2-yl} 3-fluoroadamantane-1-carboxamide (Example 38)
N- {5-chloro-3- [1-hydroxy-2- (methylsulfonyl) ethyl] -4-methylthiophen-2-yl} 3-fluoroadamantane-1-carboxamide (Example 39)
N- {3- [1-hydroxy-2- (methylsulfonyl) ethyl] thiophen-2-yl} 3,5-difluoroadamantane-1-carboxamide (Example 40)
N- {3- [1-hydroxy-2- (methylsulfonyl) ethyl] -5-methylthiophen-2-yl} 3,5,7-trifluoroadamantane-1-carboxamide (Example 41)
N- {3- [1-hydroxy-2- (methylsulfonyl) ethyl] -4-isopropylthiophen-2-yl} 3,5,7-trifluoroadamantane-1-carboxamide (Example 42)
N- {5-chloro-3- [1-hydroxy-2- (methylsulfonyl) ethyl] thiophen-2-yl} 3,5,7-trifluoroadamantane-1-carboxamide

(Example 43)
N- {3- [1-hydroxy-2- (methylsulfonyl) ethyl] -5- (trifluoromethyl) thiophen-2-yl} 3,5,7-trifluoroadamantane-1-carboxamide (Example 44)
N- {3- [1-hydroxy-2- (methylsulfonyl) ethyl] -4- (trifluoromethyl) thiophen-2-yl} 3,5,7-trifluoroadamantane-1-carboxamide (Example 45)
N- {3- [1-hydroxy-2- (methylsulfonyl) ethyl] -4-methylthiophen-2-yl} 3,5,7-trifluoroadamantane-1-carboxamide (Example 46)
N- {3- [Hydroxy (N-methylsulfonyl- (S) -aziridin-2-yl) methyl] thiophen-2-yl] adamantane-1-carboxami (Example 47)
N- {3- [1-hydroxy-2- (methylsulfonylamino) ethyl] thiophen-2-yl} 3-fluoroadamantane-1-carboxamide (Example 48)
N- {5-Bromo-3- [hydroxy (N-methylsulfonyl- (S) -pyrrolidin-2-yl) methyl] thiophen-2-yl] adamantane-1-carboxami (Example 49)
N- [5-Chloro-3- (2-dimethylamino-1-hydroxyethyl) thiophen-2-yl] adamantane-1-carboxamide (Example 50)
N- [3- (2-Dimethylamino-1-hydroxyethyl) -5- (4-fluorophenyl) thiophen-2-yl] adamantane-1-carboxamide (Example 51)
N- [3- (2-Dimethylamino-1-hydroxyethyl) -5- (3-hydroxyphenyl) thiophen-2-yl] adamantane-1-carboxamide (Example 52)
N- [5- (3-aminophenyl) -3- (2-dimethylamino-1-hydroxyethyl) thiophen-2-yl] adamantane-1-carboxamide

(Example 53)
N- [3- (2-Dimethylamino-1-hydroxyethyl) -5- (2-propoxyphenyl) thiophen-2-yl] adamantane-1-carboxamide (Example 54)
N- [3- (2-Dimethylamino-1-hydroxyethyl) -5- (3-propoxyphenyl) thiophen-2-yl] adamantane-1-carboxamide (Example 55)
N- [3- (2-Dimethylamino-1-hydroxyethyl) -5- (4-propoxyphenyl) thiophen-2-yl] adamantane-1-carboxamide (Example 56)
N- [3- (2-Dimethylamino-1-hydroxyethyl) -5- (1-naphthyl) thiophen-2-yl] adamantane-1-carboxamide (Example 57)
N- [3- (2-Dimethylamino-1-hydroxyethyl) -5- (2-naphthyl) thiophen-2-yl] adamantane-1-carboxamide (Example 58)
N- [5- (2-biphenyl) -3- (2-dimethylamino-1-hydroxyethyl) thiophen-2-yl] adamantane-1-carboxamide (Example 59)
N- [5- (3-biphenyl) -3- (2-dimethylamino-1-hydroxyethyl) thiophen-2-yl] adamantane-1-carboxamide (Example 60)
N- [5- (4-biphenyl) -3- (2-dimethylamino-1-hydroxyethyl) thiophen-2-yl] adamantane-1-carboxamide (Example 61)
N- [3- (2-Diethylamino-1-hydroxyethyl) -5-phenylthiophen-2-yl] adamantane-1-carboxamide

Table 2 shows the structures of the compounds synthesized in Examples 1 to 61 described above.
In addition, Table 3 shows the NMR spectrum data of Examples 1 to 22. In the abbreviations of substituents used in Table 1, Me represents a methyl group, Et represents an ethyl group, Pr represents an n-propyl group, Bu represents an n-butyl group, and Ph represents a phenyl group.

The CB2 ligand supplied by the present invention includes various pains, inflammatory diseases (such as rheumatoid arthritis and knee osteoarthritis), autoimmune diseases (such as scleroderma, Crohn's disease, and systemic lupus erythematosus), allergic diseases (asthma). , Atopic dermatitis, urticaria, etc.), neurological diseases (multiple sclerosis, amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease, Huntington's disease, etc.), cardiovascular disease, kidney disease, osteoporosis Can be used as
Among the CB2 ligands provided by the present invention, in particular, the inverse agonist is allergic asthma,
It can be used as a therapeutic agent for allergic diseases such as atopic dermatitis and urticaria.
On the other hand, among the CB2 ligands provided by the present invention, particularly agonists are for neuropathic pain (postherpetic neuralgia, painful diabetic neuropathy, etc.) and inflammatory pain (rheumatoid arthritis, knee osteoarthritis, etc.). Can be used as an analgesic. It can also be used as an antitussive for cough (bronchitis, cold syndrome, asthma, obstructive pulmonary disease, etc.) based on increased airway hypersensitivity. It can also be used as a preventive agent for cardiovascular diseases (unstable angina, myocardial infarction and stroke) and osteoporosis based on arteriosclerosis.

2 is a graph showing the effect of Example Compound 16 on GTP binding reaction. 4 is a graph showing the effect of Example Compound 19 on GTP binding reaction.

Claims (3)

Formula (I)

(Where
V represents an oxygen atom (oxo group) or a hydroxyl group, and a bond represented by a solid line and a broken line represents a single bond or a double bond,

R ₁ is
Linear or branched C ₁ -C ₆ aliphatic hydrocarbon group, alicyclic hydrocarbon group, aryl group, carboxyl group, C ₁ -C optionally substituted with hydrogen atom, trihalomethyl group, hydroxyl group ₆ alkylcarbonyl group, C ₁ -C ₆ alkoxycarbonyl group, carbamoyl group,

R ₂ is selected from R2a), R2b), R2c)
R2a)
Linear or branched C ₁ -C which may be substituted with 1 to 3 groups optionally selected from a hydrogen atom, halogen atom, nitro group, cyano group, amino group / hydroxyl group / oxo group / halogen atom ₃ aliphatic hydrocarbon group or C ₃ alicyclic hydrocarbon group,
R2b)
A linear or branched C ₄ aliphatic hydrocarbon group optionally substituted by 1-3 groups selected from an amino group, a hydroxyl group, an oxo group, and a halogen atom,
R2c)
1-3 substituted with an amino group-hydroxyl group, a halogen atom, C ₁ -C ₆ alkyl group, C ₁ -C ₆ alkoxy group, a carboxyl group, C ₁ -C ₆ alkoxycarbonyl group, an aryl group chosen arbitrarily from the base which may be an aryl group, optionally selected from an amino group, a hydroxyl group, a halogen atom, C ₁ -C ₆ alkyl group, C ₁ -C ₆ alkoxy group, a carboxyl group, C ₁ -C ₆ alkoxycarbonyl group, an aryl group is 1-3 optionally substituted heteroaryl group group, an amino group, a hydroxyl group, a halogen atom, C ₁ -C ₆ alkyl group, C ₁ -C ₆ alkoxy group, a carboxyl group, C ₁ -C ₆ alkoxy Aryl C ₁ -C ₆ alkyl group, arylthio group, arylsulfonyl group, amino group / hydroxyl group / oxo group / halogen atom optionally substituted by 1 to 3 groups optionally selected from carbonyl group and aryl group A linear or branched C ₅ -C ₆ aliphatic hydrocarbon group optionally substituted with 1 to 3 groups arbitrarily selected from a group, an amino group, a hydroxyl group, an oxo group, and a halogen atom. A C ₄ -C ₆ membered alicyclic hydrocarbon group which may be substituted by 1-3 groups,

R ₃ is
C ₃ -C ₁₀ monocyclic, bicyclic (fused or spiro ring), tricyclic (fused or spiro ring) carbocycle,
3-10 membered monocyclic, bicyclic (fused or spiro ring), tricyclic (fused or spiro ring) hetero, containing 1-4 heteroatoms arbitrarily selected from oxygen, nitrogen and sulfur atoms A ring, an aryl C ₁ -C ₂ alkyl group, and the cyclic group may be substituted with 1-3 groups arbitrarily selected from a halogen atom, a hydroxyl group, a trifluoromethyl group, and a C ₁ -C ₃ alkyl group Often,

W represents a nitrogen atom or a sulfur atom,
When W is a nitrogen atom,
n represents an integer of 0-2,
R ₄ and R ₄ ′ are the same or different,
A hydrogen atom, a linear or branched C ₁ -C ₃ aliphatic hydrocarbon group optionally substituted with a hydroxyl group,
R ₅ and R ₆ are the same or different,
Hydrogen atom, a trihalomethanesulfonyl group, C ₁ -C ₃ alkylsulfonyl group or a C ₁ -C ₃ aliphatic hydrocarbon group which may linear be substituted by hydroxyl or oxo groups or branched,
However, R ₅ and R ₆ are not simultaneously a trihalomethanesulfonyl group or a C ₁ -C ₃ alkylsulfonyl group,
Alternatively, an alicyclic heterohydrocarbon group or a heteroaryl group is formed as a ring P containing R ₄ , R ₅ , and W as constituent elements,
Alternatively, an alicyclic heterohydrocarbon group or a heteroaryl group is formed as a ring Q containing R ₅ , R ₆ , and W as constituent elements,
Here, when ring P is a heteroaryl group, R ₄ ′ and R ₆ may not form a substituent, or R ₆ may represent an oxygen atom (N-oxide);
However, ring P and ring Q do not form a ring at the same time,

When W is a sulfur atom,
n represents an integer of 0-2,
R ₄ and R ₄ ′ are the same or different,
A hydrogen atom, a linear or branched C ₁ -C ₃ aliphatic hydrocarbon group optionally substituted with a hydroxyl group,
R ₅ is
C ₁ -C ₃ aliphatic hydrocarbon group optionally substituted straight or branched chain with a hydroxyl group, trihalomethyl group, with C ₁ -C ₃ mono- or disubstituted amino group which may be alkyl group Yes,
Alternatively, a 3-6 membered alicyclic heterohydrocarbon group is formed as a ring P containing R ₄ , R ₅ , and W as components,
R ₆ is
W—R ₆ is a sulfinyl group or a sulfonyl group. )
Or a pharmaceutically acceptable salt thereof, or a solvate thereof.
A pharmaceutical composition comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof, or a solvate thereof as an active ingredient.
A prophylactic and / or therapeutic treatment for a disease involving cannabinoid 2 receptor (CB2), comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof, or a solvate thereof as an active ingredient. Agent.

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