JP2006117568A - New amide derivative having thiophene ring and its application as medicine - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide an amide derivative useful for preventing and/or treating C5a-concerned diseases and the like, its salt allowable in pharmaceutical preparation, its hydrate and solvate, and their medicinal application. <P>SOLUTION: There are provided an amide derivative represented by formula (1), its pharmaceutically allowable salt, and its hydrate and solvate. These compounds of this invention have a C5a acceptor antagonism, are useful as a prophylactic and/or a therapeutic agent against C5a-concerned diseases and as an anti-inflammatory agent, and are also useful as a prophylactic and/or a therapeutic agent against infectious diseases by bacteria or viruses penetrating through a C5a receptor. <P>COPYRIGHT: (C)2006,JPO&NCIPI

Description

  The present invention relates to an amide derivative useful for prevention and / or treatment of a disease involving C5a or the like, a pharmaceutically acceptable salt thereof, a hydrate or a solvate thereof, and a pharmaceutical use thereof.

  When the complement system is activated, the complement system protein is enzymatically degraded to produce fragments having various physiological activities. One of them, complement component C5a, is a glycoprotein composed of 74 amino acids and having a molecular weight of about 11,000, and has a strong inflammation-inducing action. C5a has various actions such as smooth muscle contraction, increased vascular permeability, leukocyte migration, leukocyte degranulation, reactive oxygen species production, enhancement of antibody production and induction of cytokine, TNF or leukotriene production. Autoimmune diseases such as systemic lupus erythematosus, sepsis, adult respiratory distress syndrome, allergic diseases such as asthma, atherosclerosis, myocardial infarction, cerebral infarction, psoriasis, Alzheimer's disease or ischemia reperfusion and trauma, burns, surgical invasion It is said to be a causative agent of diseases such as organ damage (eg, pneumonia, nephritis, hepatitis, pancreatitis, etc.) due to leukocyte activation caused by the above [Annu. Rev. Immunol. 12, 775-808 (1994) (Non-patent document 1), Immunopharmacology, 38, 3-15 (1997) (Non-patent document 2), Curr. Pharm. Des. 5, 737-755 (1999) (non-patent document 3) and IDrugs, 2, 686-693 (1999) (non-patent document 4)].

  Regarding C5a receptor antagonists, for example, the following patent applications have been published. JP-A-10-182648 (Patent Document 1) discloses a TAN-2474-related compound having a C5a antagonistic action. WO94 / 07815 (Patent Document 2) discloses a peptide derivative having a C5a receptor antagonistic action, and WO99 / 00406 (Patent Document 3) discloses a cyclic peptide derivative having a C5a receptor antagonistic action. It is disclosed. Furthermore, WO02 / 14265 (Patent Document 4) and WO02 / 22556 (Patent Document 5) disclose urea derivatives having C5a receptor antagonistic activity and amide derivatives not containing a thiophene ring.

  However, until now, no drug has been developed to prevent and / or treat diseases involving C5a or infections caused by bacteria or viruses that invade through the C5a receptor by inhibiting the action of C5a.

Annu. Rev. Immunol. 12, 775-808 (1994) Immunopharmacology, 38, 3-15 (1997) Curr. Pharm. Des. 5: 737-755 (1999) IDrugs, Vol. 2, pages 686-693 (1999) Japanese Patent Laid-Open No. 10-182648 WO94 / 07815 WO99 / 00406 Publication WO02 / 14265 WO02 / 22556

  A non-peptide low molecular weight compound having a C5a receptor antagonistic activity can be expected as a prophylactic and / or therapeutic agent for diseases associated with C5a, and can also be expected as a novel non-steroidal anti-inflammatory drug. It can also be expected as a prophylactic and / or therapeutic agent for infectious diseases caused by bacteria and viruses that enter via the C5a receptor. Accordingly, an object of the present invention is to provide a novel non-peptidic low molecular weight compound having a C5a receptor antagonistic action.

  In view of the above circumstances, the present inventors have conducted extensive research for the purpose of finding a non-peptide compound that exhibits C5a receptor antagonistic activity and has a novel skeleton. As a result, the present inventors have found that the amide derivative having a thiophene ring according to the present invention exhibits C5a receptor antagonistic activity, and completed the present invention.

  That is, the gist of the present invention is as follows.

  1. General formula (1)

[Wherein, R ¹ , R ² and R ³ are the same or different and each has a hydrogen atom, an alkyl which may have a substituent, an alkenyl which may have a substituent, or a substituent. Alkynyl which may have a substituent, cycloalkyl which may have a substituent, alkoxy which may have a substituent, acyl which may have a substituent, acyloxy which may have a substituent, Halogen atom, hydroxyl group, nitro, cyano, mercapto, optionally substituted alkylthio, optionally substituted alkylsulfonyl, amino, optionally substituted alkylamino, substituent Dialkylamino which may have a substituent, cyclic amino which may have a substituent, carbamoyl, alkoxycarbonyl which may have a substituent, carboxyl, sulfamoyl or Shows the mill,
a, b, c, d and e all represent carbon atoms, or any one or two of a, b, c, d and e represent nitrogen atoms and the rest represent carbon atoms,
A represents a hydrogen atom, an optionally substituted cycloalkyl, an optionally substituted aryl, an optionally substituted heteroaryl, or an optionally substituted cyclic. Indicates amino,

Is the following formula

(Wherein R ⁴ and R ⁵ are the same or different, and each may have a hydrogen atom, an optionally substituted alkyl, an optionally substituted alkenyl, or an optionally substituted group. Alkynyl, cycloalkyl which may have a substituent, alkoxy which may have a substituent, acyl which may have a substituent, acyloxy which may have a substituent, a halogen atom, Hydroxyl group, nitro, cyano, mercapto, optionally substituted alkylthio, optionally substituted alkylsulfonyl, amino, optionally substituted alkylamino, substituted Dialkylamino which may have a substituent, cyclic amino which may have a substituent, carbamoyl, alkoxycarbonyl which may have a substituent, carboxyl, sulfamoyl or formyl Indicates bicyclic sulfur-containing heterocyclic ring group selected from the group consisting of indicating),
X represents an oxygen atom or a sulfur atom,
Y represents methylene or alkylene which may have a substituent,
Z represents methylene or alkylene which may have a bond or a substituent. Or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof.

2. R ¹ , R ² and R ^{3 in the} general formula (1) are the same or different and each has 1 to 3 carbon atoms substituted with a hydrogen atom, alkyl having 2 to 4 carbon atoms, methoxy, halogen atom, or halogen atom 2. The amide derivative according to 1, which is alkyl, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof.

  3. The amide derivative or the pharmaceutically acceptable salt thereof according to 1 or 2, wherein the ring composed of a, b, c, d, e and the carbon atom of the general formula (1) is phenyl or pyridyl, or a hydrate thereof Product or solvate.

  4). The amide derivative or the pharmaceutically acceptable salt thereof according to 1 to 3, wherein A in the general formula (1) is an optionally substituted phenyl, or an optionally substituted heteroaryl. Hydrate or solvate of

  5. Of general formula (1)

4. The amide derivative according to 1 to 4, wherein the amide derivative is a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof.

Or

6). R ⁴ and R ^{5 in} the general formula (1) are the same or different and each has a hydrogen atom, an optionally substituted alkyl, a halogen atom, an optionally substituted alkoxy, or a substituted group. The amide derivative according to 1 to 5, which is acyl, formyl or cyano, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof.

  7. The amide derivative according to 1 to 6, wherein X in the general formula (1) is an oxygen atom, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof.

8). The amide derivative according to 1 to 7, wherein —Y— in the general formula (1) is — (CH ₂ ) —, — (CH ₂ ) ₂ —, — (CH ₂ ) ₃ —, or a pharmaceutically acceptable salt thereof. Or a hydrate or solvate thereof.

  9. The amide derivative according to 1 to 8, wherein Z in the general formula (1) is methylene, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof.

10. N- (4-dimethylaminophenylmethyl) -N- (4-isopropylphenyl) -4,5,6,7-tetrahydrobenzo [b] thiophene-4-carboxamide,
N- (4-dimethylaminophenylmethyl) -N- (4-isopropylphenyl) -2-methyl-4,5,6,7-tetrahydrobenzo [b] thiophene-4-carboxamide;
N- (4-dimethylaminophenylmethyl) -N- (4-isopropylphenyl) -3-methyl-4,5,6,7-tetrahydrobenzo [b] thiophene-4-carboxamide;
1,3-dimethyl-N- (4-dimethylaminophenylmethyl) -N- (4-isopropylphenyl) -4,5,6,7-tetrahydrobenzo [c] thiophene-4-carboxamide,
Or N- (4-dimethylaminophenylmethyl) -N- (4-isopropylphenyl) -2-methyl-5,6,7,8-tetrahydro-4H-cyclohepta [b] thiophene-4-carboxamide or a pharmaceutical thereof Acceptable salts or hydrates or solvates thereof.

  11. A pharmaceutical composition comprising the amide derivative according to any one of 11.1 to 10 or a pharmaceutically acceptable salt or hydrate or solvate thereof and a pharmaceutically acceptable additive.

  12. A prophylactic and / or therapeutic drug for a disease involving C5a comprising the amide derivative according to any one of 12.1 to 10 or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof.

  13. Diseases involving C5a are autoimmune diseases, sepsis, adult respiratory distress syndrome, allergic diseases, atherosclerosis, myocardial infarction, cerebral infarction, psoriasis, Alzheimer's disease or ischemia reperfusion or trauma, burns, surgical invasion, etc. 13. The prophylactic and / or therapeutic agent according to 12, which is an organ injury caused by leukocyte activation caused by the disease.

  14. An anti-inflammatory drug comprising the amide derivative according to any one of 1 to 10 or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof.

  15. A C5a receptor antagonist comprising the amide derivative according to any one of 1 to 10 or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof.

  16. 16. The C5a receptor antagonist according to 15, which is a prophylactic and / or therapeutic agent for infectious diseases caused by bacteria or viruses that enter via the C5a receptor.

  The compound of the present invention represented by the general formula (1) or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof has a C5a receptor antagonistic action, and a disease involving C5a [for example, , Autoimmune diseases such as rheumatism and systemic lupus erythematosus, sepsis, adult respiratory distress syndrome, allergic diseases such as asthma, atherosclerosis, myocardial infarction, cerebral infarction, psoriasis, Alzheimer's disease or ischemia reperfusion and trauma, It is useful as a prophylactic and / or therapeutic agent or anti-inflammatory agent for important organ injuries (eg, pneumonia, nephritis, hepatitis, pancreatitis, etc.) caused by leukocyte activation resulting from burns, surgical invasion, etc. It is useful as a prophylactic and / or therapeutic agent for infectious diseases caused by bacteria and viruses that invade through the body.

  In the present specification, alkyl means straight or branched alkyl having 1 to 6 carbon atoms, and is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, secondary butyl, tertiary. Butyl, n-pentyl, isopentyl, neopentyl, tertiary pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl, 1-methylpentyl, 2- Methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl 1-ethyl-2-methylpropyl, 1-ethyl-1-methylpropyl, etc., and preferred examples include methyl, ethyl, - it can be mentioned propyl, isopropyl, n- butyl, isobutyl, secondary butyl, tertiary butyl. Alkyl may have a substituent shown below, and preferred substituents include alkoxy, halogen atom, hydroxyl group, cyclic amino optionally substituted with alkyl, alkyl optionally substituted with halogen atom. Mention may be made of amino.

  Alkenyl is straight or branched alkenyl having 2 to 6 carbon atoms, and is vinyl, allyl, 1-propenyl, isopropenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 4-pentenyl, 3- Examples include methyl-2-butenyl, 5-hexenyl, 4-methyl-3-pentenyl and the like. Further, alkenyl may have a substituent shown below.

  Alkynyl represents straight or branched alkynyl having 2 to 6 carbon atoms, and is ethynyl, propynyl, butynyl, 1-methyl-2-propynyl, pentynyl, 3-methyl-1-butynyl, 1-methyl-2 -Butynyl, 2-methyl-3-butynyl, hexynyl, 3-methyl-1-pentynyl, 1-methyl-2-pentynyl, 2,2-dimethyl-3-butynyl and the like. Moreover, alkynyl may have the substituent shown below.

  Cycloalkyl represents cycloalkyl having 3 to 6 carbon atoms, and examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like. Cycloalkyl may have a substituent shown below.

  Alkoxy is a straight or branched alkoxy having 1 to 6 carbon atoms, and includes methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, secondary butoxy, tertiary butoxy, n- Pentyloxy, isopentyloxy, neopentyloxy, tertiary pentyloxy, 1-methylbutoxy, 2-methylbutoxy, 1,2-dimethylpropoxy, 1-ethylpropoxy, n-hexyloxy, isohexyloxy, 1- Methylpentyloxy, 2-methylpentyloxy, 3-methylpentyloxy, 1,1-dimethylbutyloxy, 1,2-dimethylbutyloxy, 2,2-dimethylbutyloxy, 1-ethylbutyloxy, 1,1, 2-trimethylpropyloxy, 1,2,2-trimethylpropyloxy, 1-ethyl 2-methylpropyloxy, 1-ethyl-1-methylpropyloxy and the like, and preferable examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, secondary butoxy and tertiary butoxy. Can be mentioned. Further, alkoxy may have a substituent shown below.

  Acyl is a linear or branched alkanoyl having 2 to 7 carbon atoms or cyclic cycloalkylcarbonyl, aroyl or heteroarylcarbonyl, and includes acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, hexanoyl, cyclopropylcarbonyl , Cyclopentylcarbonyl, cyclohexylcarbonyl, benzoyl, nicotinoyl, thenoyl, furoyl and the like. Acyl may have the following substituents.

  Acyloxy is a linear, branched or cyclic acyloxy having 2 to 7 carbon atoms, and includes acetoxy, ethylcarbonyloxy, propylcarbonyloxy, isopropylcarbonyloxy, butylcarbonyloxy, isobutylcarbonyloxy, secondary butylcarbonyl Examples include oxy, tertiary butylcarbonyloxy, n-pentylcarbonyloxy, neopentylcarbonyloxy, n-hexylcarbonyloxy, cyclopentylcarbonyloxy, cyclohexylcarbonyloxy, benzoyloxy, nicotinoyloxy, tenoyloxy, furoyloxy and the like. Acyloxy may have the following substituents.

  The halogen atom is fluorine, chlorine, bromine or iodine.

  Alkylthio means an alkylthio group having 1 to 6 carbon atoms, methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, secondary butylthio, tertiary butylthio, n-pentylthio, isopentylthio, neopentylthio, Examples include 1-ethylpentylthio, n-hexylthio, 2-ethylbutylthio and the like. In addition, alkylthio may have a substituent shown below.

  Alkylsulfonyl means alkylsulfonyl having 1 to 6 carbon atoms, and examples thereof include methylsulfonyl, ethylsulfonyl, propylsulfonyl and the like. Moreover, alkylsulfonyl may have the substituent shown below.

  Alkylamino means alkylamino having 1 to 6 carbon atoms, methylamino, ethylamino, n-propylamino, isopropylamino, n-butylamino, isobutylamino, secondary butylamino, tertiary butylamino, n -Pentylamino, isopentylamino, neopentylamino, tertiary pentylamino, 1-methylbutylamino, 2-methylbutylamino, 1,2-dimethylpropylamino, 1-ethylpropylamino, n-hexylamino, iso Hexylamino, 1-methylpentylamino, 2-methylpentylamino, 3-methylpentylamino, 1,1-dimethylbutylamino, 1,2-dimethylbutylamino, 2,2-dimethylbutylamino, 1-ethylbutylamino 1,1,2-trimethylpropylamino, 1,2,2 Trimethyl-propylamino, 1-ethyl-2-methylpropylamino, 1-ethyl-1, methyl propylamino, and the like, may be mentioned as preferred examples ethylamino. Alkylamino may have a substituent shown below, and a preferred substituent includes a halogen atom.

  Dialkylamino refers to dialkylamino having 2 to 6 carbon atoms, such as dimethylamino, ethylmethylamino, diethylamino, methyl n-propylamino, methylisopropylamino, n-butylmethylamino, isobutylmethylamino, secondary butylmethylamino. , Tertiary butylmethylamino, ethylpropylamino, ethylisopropylamino, di-n-propylamino, diisopropylamino, n-propylisopropylamino, n-butylethylamino, isobutylethylamino, secondary butylethylamino, tertiary Primary butylethylamino, methyl n-pentylamino, methylisopentylamino, methylneopentylamino, methyl tertiary pentyl, (1-methylbutyl) methylamino, (2-methylbutyl) methylamino, (1,2-di- Chirupuropiru) methylamino, (1-ethylpropyl) such as methylamino, and the like, may be mentioned dimethylamino preferred examples, ethylmethylamino, diethylamino. Moreover, dialkylamino may have the substituent shown below.

  Examples of cyclic amino include aziridinyl, azetidinyl, pyrrolidinyl, piperidyl, piperazinyl, azepinyl, morpholinyl, thiomorpholinyl and the like, and preferred examples include pyrrolidinyl, piperazinyl and morpholinyl. Moreover, cyclic amino may have the substituent shown below, and can mention alkyl as a preferable substituent.

  Alkoxycarbonyl represents an alkoxycarbonyl having 2 to 7 carbon atoms, and examples thereof include methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, and tertiary butoxycarbonyl. Moreover, alkoxycarbonyl may have the substituent shown below.

  Aryl refers to aryl having 6 to 10 carbon atoms, and examples thereof include phenyl, 1-naphthyl, 2-naphthyl, and the like. Preferred examples include phenyl. Aryl may have the following substituents, and preferred substituents include dialkylamino.

  Heteroaryl is a 5- to 7-membered heteroaryl containing 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom as a ring atom, and these heteroaryls And 1 or 2 benzene fused ring, pyridyl, thienyl, furyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, indolinyl, benzofuranyl, 2,3-dihydrobenzofuran Nyl, benzothienyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, quinolyl, isoquinolyl, quinoxalinyl, quinazolinyl and the like are preferable, and pyrazolyl and pyridyl are preferable. Further, the heteroaryl may have a substituent shown below, and preferred substituents include methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy and isopropoxy.

  Alkylene means alkylene having 2 to 6 carbon atoms, and examples thereof include ethylene, trimethylene, tetramethylene, pentamethylene, and hexamethylene. Methylene and alkylene may have the following substituents.

  Of the substituents that the above-mentioned alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, acyl, acyloxy, alkylthio, alkylsulfonyl, alkylamino, dialkylamino, cyclic amino, alkoxycarbonyl, aryl, heteroaryl and alkylene may have Specific examples include alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, acyl, acyloxy, halogen, alkylthio, alkylsulfonyl, alkylamino, dialkylamino, cyclic amino, alkoxycarbonyl, sulfamoyl, aryl, heteroaryl as defined above. In addition to formyl, hydroxyl group, nitro, cyano, mercapto, amino, carbamoyl, carboxyl, amide, sulfonamide and the like can be mentioned. Examples of preferred substituents include alkyl, alkoxy, halogen atom, hydroxyl group, optionally substituted alkylamino, dialkylamino, and optionally substituted cyclic amino.

In the general formula (1), R ¹ , R ² and R ³ are the same or different and each represents a hydrogen atom, an alkyl which may have a substituent, an alkenyl which may have a substituent, or a substituent. Alkynyl, cycloalkyl, optionally substituted alkoxy, optionally substituted acyl, optionally substituted acyloxy, optionally substituted acyloxy, halogen atom, hydroxyl group, nitro , Cyano, mercapto, optionally substituted alkylthio, optionally substituted alkylsulfonyl, amino, optionally substituted alkylamino, optionally substituted Good dialkylamino, optionally substituted cyclic amino, carbamoyl, optionally substituted alkoxycarbonyl, carboxyl or sulfamoyl are shown. Preferable examples of R ¹ , R ² and R ³ include a hydrogen atom, an alkyl optionally having a substituent, an alkoxy optionally having a substituent, a halogen atom, and a substituent. Mention may be made of good dialkylamino. Specific examples of the alkyl which may have a substituent include methyl, ethyl, n-propyl and isopropyl which may be substituted with a halogen atom. Preferred examples include trifluoromethyl and isopropyl. Can be mentioned. Specific examples of the alkoxy which may have a substituent include methoxy, ethoxy, n-propoxy, and isopropoxy, and methoxy is preferable. A preferred example of the halogen atom is bromine. Specific examples of the dialkylamino which may have a substituent include dimethylamino, ethylmethylamino and diethylamino, and dimethylamino is preferred. Specific examples of particularly preferred R ¹ include trifluoromethyl, isopropyl, methoxy, and bromine, and more preferably isopropyl. Specific examples of particularly preferable R ² include a hydrogen atom and dimethylamino, and a hydrogen atom is more preferable. A particularly preferred specific example of R ² is a hydrogen atom.

  In the general formula (1), a, b, c, d and e all represent carbon atoms, or any one or two of a, b, c, d and e represent nitrogen atoms and the rest are carbon atoms. Indicates. Preferred examples of a, b, c, d and e are all a, b, c, d and e are carbon atoms, or any one of a, b, c, d and e is a nitrogen atom, and the rest All can mention carbon atoms. More preferable examples include a, b, c, d and e are all carbon atoms, or b is a nitrogen atom and a, c, d and e are carbon atoms, and a, b, c, d and e are It is particularly preferred that all are carbon atoms.

  In the general formula (1), A represents a hydrogen atom, an optionally substituted cycloalkyl, an optionally substituted aryl, an optionally substituted heteroaryl or a substituent. The cyclic amino which may have is shown. Preferred examples of A include aryl optionally having substituent (s) and heteroaryl optionally having substituent (s), more preferably phenyl optionally having substituent (s), substituent (s) May be mentioned, pyrazole which may have a substituent and pyridyl which may have a substituent, and phenyl which may have a substituent is particularly preferable. Preferred examples of the substituent of A include alkyl, alkoxy, and dialkylamino. More preferred examples include ethyl, methoxy, and dimethylamino, and more preferred is dimethylamino. Although there is no restriction | limiting in the number of the substituent which A has, 1 or 2 is preferable and 1 is more preferable. Preferred examples of A include 4-dimethylaminophenyl, 1-ethyl-1H-pyrazol-4-yl, 2,6-dimethoxy-3-pyridyl, 6-methyl-3-pyridyl, and 6-dimethylamino-3. -Pyridyl can be mentioned, More preferably, 4-dimethylaminophenyl can be mentioned.

  In general formula (1),

Is the following formula

Preferred examples include the formula (Ba) and the formula (Bb).

In the general formula (1), R ⁴ and R ⁵ are the same or different and each has a hydrogen atom, an alkyl which may have a substituent, an alkenyl which may have a substituent, or a substituent. Alkynyl which may have a substituent, cycloalkyl which may have a substituent, alkoxy which may have a substituent, acyl which may have a substituent, acyloxy which may have a substituent, Halogen atom, hydroxyl group, nitro, cyano, mercapto, optionally substituted alkylthio, optionally substituted alkylsulfonyl, amino, optionally substituted alkylamino, substituent Dialkylamino which may have a substituent, cyclic amino which may have a substituent, carbamoyl, alkoxycarbonyl which may have a substituent, carboxyl, sulfamoyl Or show a formyl. Preferred examples of R ⁴ include a hydrogen atom and alkyl optionally having a substituent. More preferred examples include a hydrogen atom, methyl and ethyl, and particularly preferred examples include a hydrogen atom and methyl. Preferred examples of R ⁵ include a hydrogen atom, alkyl optionally having substituent (s), acyl optionally having substituent (s), halogen atom, cyano, and formyl. More preferred examples are hydrogen. Examples thereof include methyl, ethyl, acetyl, halogen atom, cyano and formyl, which may have an atom or a substituent, and particularly preferred examples include a hydrogen atom and methyl. Specific examples of the substituent that may be substituted on alkyl, acyl, and methyl in R ⁵ include alkoxy, a hydroxyl group, an alkylamino that may have a substituent, and a cyclic amino that may have a substituent. Preferred examples include methoxy, hydroxyl group, 2,2,2-trifluoroethylamino, morpholinyl, 4-methylpiperazinyl, and pyrrolidinyl.

  In General formula (1), X shows an oxygen atom or a sulfur atom, and an oxygen atom is preferable.

  In the general formula (1), Y represents an optionally substituted methylene or alkylene, preferably an optionally substituted methylene, ethylene or trimethylene, more preferably methylene, ethylene or trimethylene. Even more preferred is ethylene or trimethylene.

  In the general formula (1), Z represents methylene or alkylene which may have a bond or a substituent, preferably methylene which may have a substituent, and more preferably methylene.

As a preferable specific compound of the general formula (1),
N- (4-dimethylaminophenylmethyl) -N- (4-isopropylphenyl) -4,5,6,7-tetrahydrobenzo [b] thiophene-4-carboxamide,
N- (4-dimethylaminophenylmethyl) -N- (4-isopropylphenyl) -2-methyl-4,5,6,7-tetrahydrobenzo [b] thiophene-4-carboxamide;
N- (4-dimethylaminophenylmethyl) -N- (4-isopropylphenyl) -3-methyl-4,5,6,7-tetrahydrobenzo [b] thiophene-4-carboxamide;
1,3-dimethyl-N- (4-dimethylaminophenylmethyl) -N- (4-isopropylphenyl) -4,5,6,7-tetrahydrobenzo [c] thiophene-4-carboxamide, and N- (4 -Dimethylaminophenylmethyl) -N- (4-isopropylphenyl) -2-methyl-5,6,7,8-tetrahydro-4H-cyclohepta [b] thiophene-4-carboxamide.

  Examples of the pharmaceutically acceptable salt of the compound of the general formula (1) include a salt with an inorganic acid, a salt with an organic acid, a salt with a metal, and a salt with an organic base. Can be converted into a salt by treating with an inorganic acid, organic acid or the like by a conventional method.

  The compound of the general formula (1) and a pharmaceutically acceptable salt thereof may exist in the form of a hydrate or a solvate (for example, an ethanol solvate). Also included in the present invention. Further, since the compound of the general formula (1) has an asymmetric atom, at least two kinds of optical isomers exist. These optical isomers and their racemates are included in the present invention. Furthermore, it includes a prodrug that is metabolized in vivo and converted to the compound of the general formula (1), or an active metabolite of the compound of the general formula (1).

  Although the compound of this invention can be manufactured with the following method, the manufacturing method is not limited to these.

  When X represents an oxygen atom in the compound of the general formula (1), the compound (1a) can be produced according to the following method 1 or 2.

Method 1

(Wherein R ¹ , R ² , R ³ , a, b, c, d, e, A, B, Y, and Z are as defined above.)
For the step 1, a known amidation method or peptide synthesis method can be applied, for example, carbodiimides (N, N-dicyclohexylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide, etc.), diphenylphosphoryl azide , Carbonyldiimidazole, 1-benzotriazolyloxytris (dimethylamino) phosphonium hexafluorophosphate (Bop reagent), 2-chloro-N-methylpyridinium iodide-tributylamine system (Mukoyama method), etc. It can be carried out in the presence of an inert solvent or without a solvent, preferably at -20 ° C to 80 ° C. In step 1, an organic base such as triethylamine, N-methylmorpholine, pyridine, dimethylaniline, or a deoxidizer of an inorganic base such as sodium hydrogen carbonate, potassium carbonate, or sodium hydroxide may be present. Usually these reactions are completed within 24 hours.

  In addition, compound (1a) in step 1 can also be produced by converting compound (3) into another reactive derivative. When the reactive derivative of compound (3) is an acid halide (acid chloride, acid bromide, etc.) or an acid anhydride (symmetric acid anhydride, lower alkyl carbonate mixed acid anhydride, alkyl phosphoric acid mixed acid anhydride, etc.) The reaction is usually carried out in an inert solvent or without solvent at -20 ° C to 80 ° C.

  Furthermore, as reactive derivatives of the compound (3), so-called active esters (4-nitrophenyl ester, 4-chlorobenzyl ester, 4-chlorophenyl ester, pentafluorophenyl ester, succinimide ester, benzotriazole ester, 4-dimethyl ester) In the case of using a sulfonium phenyl ester or the like, the reaction is usually carried out in an inert solvent or without a solvent from −20 ° C. to the reflux temperature of the solvent.

  Examples of the inert solvent used in the amidation reaction described above include hydrocarbons such as hexane, benzene and toluene, halogenated hydrocarbons such as chloroform, dichloromethane and dichloroethane, tetrahydrofuran (hereinafter abbreviated as THF), and the like. Ethers such as dioxane, esters such as acetate, ketones such as acetone and methyl ethyl ketone, alcohols such as methanol, ethanol and isopropyl alcohol, dimethylformamide (hereinafter abbreviated as DMF), dimethylacetamide (hereinafter referred to as Amides such as DMA, acetonitrile, dimethyl sulfoxide (hereinafter abbreviated as DMSO), water, or a mixed solvent thereof.

  (1-ethyl-1H-pyrazol-4-ylmethyl) (6-isopropylpyridin-3-yl) amine, [(1-ethyl-1H-pyrazol-4-yl) methyl] (4 -Methoxyphenyl) amine and [(6-dimethylaminopyridin-3-yl) methyl] (4-isopropylphenyl) amine are used to produce 3-ethyl-N-[(1- Ethyl-1H-pyrazol-4-yl) methyl] -N- (6-isopropylpyridin-3-yl) -2-methyl-4,5,6,7-tetrahydrobenzo [b] thiophene-4-carboxamide (implemented) Example 13), 1,3-dimethyl-N-[(1-ethyl-1H-pyrazol-4-yl) methyl] -N- (4-methoxyphenyl) -5,6,7,8-tetrahydride -4H-cyclohepta [c] thiophene-4-carboxamide (Example 29), 1,3-dimethyl-N-[(6-dimethylaminopyridin-3-yl) methyl] -N- (4-isopropylphenyl)- 5,6,7,8-Tetrahydro-4H-cyclohepta [c] thiophene-4-carboxamide (Example 30) can be obtained.

  Method 2

Wherein R ¹ , R ² , R ³ , a, b, c, d, e, A, Y, Z are as defined above, and L is a halogen atom, methanesulfonyloxy, paratoluenesulfonyloxy, etc. Represents a leaving group.)
Compound (1a) can be produced by reacting compound (4) with compound (5).

  Step 2 is a deoxidizer of an organic base such as triethylamine, N-methylmorpholine, pyridine, dimethylaniline or an inorganic base such as sodium hydride, sodium bicarbonate, potassium carbonate, sodium hydroxide in a solvent that does not inhibit the reaction In the presence of -20 ° C to the reflux temperature of the solvent. Examples of the solvent used in Step 2 include hydrocarbons such as hexane, benzene and toluene, halogenated hydrocarbons such as chloroform, dichloromethane and dichloroethane, ethers such as THF and dioxane, esters such as acetate, acetone, Examples thereof include ketones such as methyl ethyl ketone, alcohols such as methanol, ethanol and isopropyl alcohol, amides such as DMF and DMA, acetonitrile, DMSO, water or a mixed solvent thereof.

Synthesis Method of Raw Material Compound Compound (2) as a raw material can be produced according to the following Method 3.

Method 3

(Wherein T represents an amino-protecting group such as acetyl and t-butoxycarbonyl, and R ¹ , R ² , R ³ , a, b, c, d, e, A, Z and L are as defined above. is there.)
That is, compound (2) can be produced by reacting compound (6) and compound (5) in the presence of a base in an appropriate solvent to give compound (7), and then removing the protecting group. (Steps 3 and 4).

  Examples of the solvent used in Step 3 include methanol, ethanol, propanol, isopropyl alcohol, methylene chloride, chloroform, THF, dioxane, benzene, toluene, xylene, DMF, DMSO and the like. Examples of the base used include sodium hydride, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, sodium hydroxide, potassium hydroxide, triethylamine, diisopropylethylamine, pyridine and the like. The reaction temperature varies depending on the solvent, but is usually 0 to 140 ° C., and the reaction time varies depending on the reaction temperature, but is usually 1 hour to 24 hours.

  This reaction can also be carried out in the absence of the protecting group T (when T represents a hydrogen atom), whereby the compound (2) can be produced.

  The removal of the protecting group in step 4 can be carried out by a usual method such as hydrolysis, acid treatment or the like according to a conventional method depending on the kind of the protecting group.

The compound (11) in which —Z— of the starting compound (2) is —CH ₂ — can be produced by the following methods 4 and 5.

  Method 4

(In the formula, R ¹ , R ² , R ³ , a, b, c, d, e, A are as defined above, U represents alkylene which may have a substituent, and R ⁷ represents hydrogen. (Atom, alkyl, aryl or heteroaryl optionally having substituent (s))
Compound (11) can be produced by dehydrating and condensing compound (8) and compound (9) in the absence of solvent or in an appropriate solvent to give compound (10), and subsequently reducing this compound in an appropriate solvent. Yes (steps 5 and 6).

  The dehydration condensation reaction of the compound (8) and the compound (9) in step 5 can be carried out in the presence of a dehydrating agent or by removing generated water from the reaction system using a Dean-Stark apparatus.

  As the dehydrating agent used in this reaction, a normal dehydrating agent can be used. Examples of the dehydrating agent include anhydrous magnesium sulfate and molecular sieves. Examples of the solvent used for the reaction include methylene chloride, chloroform, benzene, toluene, xylene and the like. The reaction temperature varies depending on the solvent, but is usually 0 to 150 ° C., and the reaction time varies depending on the reaction temperature, but is usually 1 hour to 24 hours.

  Examples of the reducing agent used in Step 6 include sodium borohydride, sodium triacetoxyborohydride, sodium cyanoborohydride, formic acid and sodium formate. Examples of the solvent used in the reaction include water, methanol, ethanol, propanol, THF, dioxane, acetic acid and the like, or a mixed solvent thereof. The reaction temperature varies depending on the solvent, but is usually 0 to 80 ° C., and the reaction time varies depending on the reaction temperature, but is usually 1 to 24 hours.

  Method 5

(Wherein R ¹ , R ² , R ³ , a, b, c, d, e, A are as defined above.)
Compound (8) or a salt thereof and compound (12) or a reactive derivative thereof are reacted in the absence of a solvent or in an appropriate solvent to obtain compound (13), followed by reaction with a reducing agent in an appropriate solvent. Can produce compound (14) (steps 7 and 8).

  The reaction of compound (8) or a salt thereof and compound (12) in step 7 can be carried out in the same manner as in step 1.

  Examples of the reducing agent used in the reduction reaction in Step 8 include lithium aluminum hydride and borane. Examples of the solvent used for the reduction reaction include THF, diethyl ether, hexane, and the like, or a mixed solvent thereof. The reaction temperature varies depending on the solvent, but is usually 0 to 65 ° C., and the reaction time varies depending on the reaction temperature, but is usually 1 to 24 hours.

Method 6
Compound (3) used in Method 1 is compound (15) according to the method described in the literature (Synthetic Communications, 12 (10), pp. 763-770, 1982). It is synonymous with the above.) (Step 9).

Method 7
Moreover, the compound (3) used by the method 1 can be manufactured through the following process (process 10-13).

(In the formula, Y, B, and L are as defined above.)
Examples of the reducing agent used in the reduction reaction in Step 10 include sodium borohydride. Examples of the solvent used in the reaction include water, methanol, ethanol, propanol, THF, dioxane, or a mixed solvent thereof. The reaction temperature varies depending on the solvent, but is usually 0 to 30 ° C., and the reaction time varies depending on the reaction temperature, but is usually 1 to 24 hours.

  The conversion reaction from the hydroxyl group to the leaving group (L) in Step 11 can be performed using a known chemical reaction. As a typical example, reaction with thionyl chloride in a solvent that does not inhibit the reaction (L = chloro), reaction in a solvent that does not inhibit the reaction, reaction with methanesulfonyl chloride in the presence of an organic base such as ethylamine (L = mesyl) ) Etc.

  Examples of the cyanating agent used in the cyanation reaction in Step 12 include sodium cyanide and potassium cyanide, and the reaction solvent is preferably DMSO. The reaction temperature is suitably from room temperature to about 80 ° C., and the reaction time is about 1 to 5 hours.

  The hydrolysis reaction in step 13 can be performed by a conventional method such as acid hydrolysis or alcal hydrolysis according to a conventional method.

Method 8
Compound (4) used in Method 2 can be produced from compound (8) and compound (3).

(Wherein R ¹ , R ² , R ³ , a, b, c, d, e, B, Y are as defined above.)
That is, compound (4) can be produced by reacting compound (8) or a salt thereof with compound (3) or a reactive derivative thereof in the absence of a solvent or in an appropriate solvent (step 14).

  The reaction of compound (3) with compound (8) or a salt thereof in step 14 can be carried out in the same manner as in step 1.

  The compound of the present invention represented by the general formula (1), a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof shows C5a receptor antagonistic action.

Here, “C5a receptor antagonism” means that “a substance that binds to C5a receptor” binds to a cell expressing C5a receptor via C5a receptor and causes some physiological change (for example, intracellular Ca ^2+). The “substance that binds to the C5a receptor” is a degradation product of C5a and C5a (for example, C5a desArg lacking the arginine at the carboxy terminus of C5a). Furthermore, it is a substance having affinity for known or unknown C5a receptors other than C5a.

  In the present invention, the “C5a receptor antagonist” is a substance that inhibits the binding between the C5a receptor and the “substance that binds to the C5a receptor”.

  In the present invention, the disease involving C5a is a disease considered to be caused by binding of C5a to the C5a receptor, for example, autoimmune diseases such as rheumatism and systemic lupus erythematosus, sepsis, adult respiratory distress syndrome, asthma Allergic diseases such as atherosclerosis, myocardial infarction, cerebral infarction, psoriasis, Alzheimer's disease or organ damage caused by leukocyte activation caused by ischemia reperfusion or trauma, burns, surgical invasion, etc. (e.g., pneumonia, Nephritis, hepatitis, pancreatitis, etc.), and the compounds of the present invention have C5a receptor antagonistic activity, and thus are considered useful as preventive and / or therapeutic agents for these diseases.

  In addition, since C5a is known to induce a strong inflammatory reaction by binding to C5a receptor, the compound of the present invention having C5a receptor antagonistic activity is considered to be useful as an anti-inflammatory drug.

  Furthermore, since the compounds of the present invention have an affinity for the C5a receptor, they bind to the C5a receptor. This inhibits the invasion of bacteria and viruses that enter via the C5a receptor, and thus is useful as a preventive and / or therapeutic agent for infections caused by these bacteria and viruses.

  When the compound of the present invention represented by the general formula (1), a pharmaceutically acceptable salt thereof or a solvate thereof is used for the above-mentioned prevention / treatment, it is usually systemically or locally, orally or parenterally. It is administered in the form. The dose to the patient varies depending on age, weight, sex, general health condition, therapeutic effect, diet, administration time, administration method, excretion rate, combination of drugs, degree of disease being treated, and the like. Usually, it is orally administered once to several times a day, in the range of 0.1 mg to 500 mg per adult, or once daily in the range of 0.01 mg to 200 mg per adult. Administer parenterally several times.

  The compound of the present invention represented by the general formula (1) or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof can be used orally or parenterally, and can be used as a pharmaceutical composition or formulation. (For example, tablets, injections, etc.), and at least one compound of the present invention can be used alone or mixed with a pharmaceutically acceptable carrier (excipient etc.).

  Hereinafter, the present invention will be specifically described with reference to Preparation Examples, Examples, Formulation Formulation Examples, Formulation Examples, and Test Examples, but the present invention is not limited thereto.

About the physical property data of the compound, ¹ H-NMR was measured at 300 MHz. ^For the chemical shift value of ¹ H-NMR, tetramethylsilane (TMS) was used as an internal standard, and the relative delta (δ) value was expressed in parts per million (ppm). Coupling constants indicate trivial multiplicity in hertz (Hz), s (singlet), d (doublet), t (triplet), q (quartet), sept (septet), m (multiplet), dd (double) (Doublet), brs (broad singlet) and the like.
About mass spectrometry value (m / z), EIS was used as the ionization method, and it described with MS (EIS) m / z: (OO) [M + H] ^< +>.
Further, thin layer chromatography was performed using Merck and column chromatography was performed using silica gel manufactured by Fuji Silysia Chemical Co. The abbreviations used in the examples are shown below.
IPE (diisopropyl ether)
THF (tetrahydrofuran)
DMF (dimethylformamide)
DMSO (dimethyl sulfoxide)

Preparation Example 1
A suspension of 264 g of 2-hydroxy-6-isopropylnicotinonitrile and 500 g of phosphorus oxychloride was dissolved by heating under stirring and refluxed for 2 hours. The reaction solution was cooled, poured into 3 L of ice water, stirred for a while, and then subjected to liquid separation extraction with toluene. The organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was distilled off to obtain 313.6 g of 2-chloro-6-isopropylnicotinonitrile as a brown oil.
¹ H-NMR (CDCl ₃ ) δ: 1.32 (6H, d, J = 6.9 Hz), 3.12 (1H, sept, J = 6.9 Hz), 7.28 (1H, d, J = 8.1 Hz), 7.94 (1H, d, J = 8.1 Hz)

Preparation Example 2
313.6 g of 2-chloro-6-isopropylnicotinonitrile and 800 mL of 75% sulfuric acid were stirred at an internal temperature of 110 ° C. for 2.5 hours. The reaction solution was cooled, poured into 4 L of ice water, stirred for a while, and then subjected to liquid separation extraction with toluene. The organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was distilled off, and the solid matter precipitated after inoculation was suspended in hexane and a small amount of IPE and collected by filtration to obtain 285 g of 2-chloro-6-isopropylnicotinic acid as brown powder crystals.
¹ H-NMR (CDCl ₃ ) δ: 1.31 (6H, d, J = 6.9 Hz), 3.13 (1H, sept, J = 6.9 Hz), 7.20 (1H, d, J = 8.1 Hz), 8.29 (1 H, d, J = 8.1 Hz), 12.40 (1 H, brs)

Preparation Example 3
312 g of 2-chloro-6-isopropylnicotinic acid, 16.0 g of palladium carbon (10%), and 2000 mL of ethanol-water (6: 1) were stirred at room temperature for 3 days in a hydrogen atmosphere. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. Ethyl acetate and a small amount of ethanol were added to the residue, and the precipitated solid was collected by filtration. This solid was added to 1130 mL of a cooled 1N-sodium hydroxide aqueous solution, and the solid that precipitated after dissolution was collected by filtration. This was dissolved in chloroform and then dried over magnesium sulfate. The solvent was distilled off, and the residual solid was suspended in hexane and collected by filtration to obtain 152 g of 6-isopropylnicotinic acid as white powder crystals.
¹ H-NMR (CDCl ₃ ) δ: 1.37 (6H, d, J = 6.9 Hz), 3.29 (1H, sept, J = 6.9 Hz), 7.38 (1H, d, J = 8.1 Hz), 8.40 (1H, dd, J = 2.1, 8.1 Hz), 9.33 (1H, d, J = 2.1 Hz)

Preparation Example 4
To 148 g of 6-isopropylnicotinic acid and 250 mL of tert-butanol (1800 mL) in 250 mL of triethylamine, 212 mL of diphenylphosphoryl azide was added dropwise at room temperature, and the mixture was heated to reflux for 2 hours with stirring. The reaction mixture was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was concentrated under reduced pressure, water was added to the residual solid, suspended and collected by filtration to obtain 137 g of tert-butyl (6-isopropylpyridin-3-yl) carbamate as pale yellow powder crystals.
¹ H-NMR (CDCl ₃ ) δ: 1.27 (6H, d, J = 6.9 Hz), 1.51 (9H, s), 3.03 (1H, sept, J = 6.9 Hz), 6 .90-7.03 (1H, m), 7.12 (1H, d, J = 8.4 Hz), 7.85-8.01 (1H, brs), 8.35 (1H, d, J = 2.4Hz)

Preparation Example 5
To 50.0 g of tert-butyl (6-isopropylpyridin-3-yl) carbamate, 432 mL of 4 mol / L-hydrochloric acid / dioxane was added and stirred for one day at room temperature. To the reaction solution in which a solid was deposited, 500 mL of diethyl ether was added and collected by filtration. This solid was added to an aqueous sodium hydrogen carbonate solution and subjected to liquid separation extraction with diethyl ether. The organic layer was washed with saturated brine and dried over sodium sulfate. The solvent was distilled off to obtain 26.4 g of 6-isopropylpyridin-3-amine as a brown oil.
¹ H-NMR (CDCl ₃ ) δ: 1.26 (6H, d, J = 6.9 Hz), 2.96 (1H, sept, J = 6.9 Hz), 3.35-3.68 (2H, brs), 6.95 (2H, m), 8.03 (1H, m)

Preparation Example 6
A DMF-toluene mixed solution (1: 1, 400 mL) of 80 g of ethyl 1H-pyrazole-4-carboxylate, 54.8 mL of iodoethane and 78.7 g of potassium carbonate was stirred at 50 to 60 ° C. for 8 hours. After filtering the reaction solution, the solvent was distilled off under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain 106.4 g of ethyl 1-ethyl-1H-pyrazole-4-carboxylate as a yellow oil.
¹ H-NMR (CDCl ₃ ) δ: 1.34 (3H, t, J = 7.2 Hz), 1.51 (3H, t, J = 7.2 Hz), 4.19 (2H, q, J = 7.2 Hz), 4.29 (2H, q, J = 7.2 Hz), 7.90 (2H, s).

Preparation Example 7
106.4 g of ethyl 1-ethyl-1H-pyrazole-4-carboxylate was added to a mixed solution of 760 mL of ethanol and 760 mL of 1N sodium hydroxide aqueous solution, and the mixture was stirred at 50 to 60 ° C. for 3 hours. The solvent was distilled off, water and 1N aqueous sodium hydroxide solution (100 mL) were added to the residue, and the aqueous layer was washed with ethyl acetate. The aqueous layer was acidified with hydrochloric acid and extracted with chloroform and ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was distilled off, and the residual solid was suspended in hexane and collected by filtration to obtain 152 g of 1-ethyl-1H-pyrazole-4-carboxylic acid as pale yellow powder crystals.

Preparation Example 8
To a solution of 9.80 g of 1-ethyl-1H-pyrazole-4-carboxylic acid in 1,2-dichloroethane (50 mL) was added 7.66 mL of thionyl chloride, and the mixture was stirred at 60 ° C. for 3 hours. The reaction mixture was concentrated under reduced pressure, toluene was added to the residue, and the mixture was concentrated again under reduced pressure. A solution of this residue in 1,2-dichloroethane (25 mL) was added to a solution of 9.52 g of 3-amino-6-isopropylpyridine in 1,2-dichloroethane (100 mL) under ice cooling. The mixture was warmed to room temperature and stirred at the same temperature for 2 hours. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate and extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the solid residue was suspended in IPE and collected by filtration to give N- (6-isopropylpyridin-3-yl) -1-ethyl-1H-pyrazole-4-carboxamide 11 0.4 g was obtained as brown powder crystals.
¹ H-NMR (CDCl ₃ ) δ: 1.27 (6H, d, J = 6.9 Hz), 1.46 (3H, t, J = 7.2 Hz), 3.02 (1H, sept, J = 6.9 Hz), 4.14 (2H, q, J = 7.2 Hz), 7.13 (1H, d, J = 8.6 Hz), 7.93 (1H, s), 7.98 (1H, s), 8.12 (1H, dd, J = 2.6, 8.6 Hz), 8.53-8.57 (2H, m)

Preparation Example 9
11.4 g of N- (6-isopropylpyridin-3-yl) -1-ethyl-1H-pyrazole-4-carboxamide was dissolved in borane / THF complex / 1 mol / L-THF solution (BH ₃ .THF complex / 1M THF solution). Dissolved in 100 mL and heated to reflux for 4 hours. After cooling the reaction solution, it was added to 200 mL of 1 mol / L-hydrochloric acid, and this mixed solution was heated to reflux for several minutes. The reaction mixture was cooled, poured into saturated aqueous sodium bicarbonate, and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain 9.86 g of (1-ethyl-1H-pyrazol-4-ylmethyl) (6-isopropylpyridin-3-yl) amine as a pale yellow oil. It was.
¹ H-NMR (CDCl ₃ ) δ: 1.27 (6H, d, J = 6.9 Hz), 1.46 (3H, t, J = 7.2 Hz), 2.96 (1H, sept, J = 6.9 Hz), 3.77-3.90 (1H, brs), 4.08-4.20 (4H, m), 6.89 (1H, dd, J = 2.6, 8.6 Hz), 6.98 (1H, d, J = 8.6 Hz), 7.37 (1H, s), 7.47 (1H, s), 8.01 (1H, d, J = 2.6 Hz)

Preparation Example 10
By reacting in the same manner as in Preparation Example 8 using 4.93 g of 1-ethyl-1H-pyrazole-4-carboxylic acid and 4.34 g of p-anisidine as starting materials, N- (4-methoxyphenyl) -1-ethyl 8.21 g of -1H-pyrazole-4-carboxamide was obtained as brown powder crystals.
¹ H-NMR (CDCl ₃ ) δ: 1.48 (3H, t, J = 7.2 Hz), 3.79 (3H, s), 4.16 (2H, q, J = 7.2 Hz), 6 .86 (2H, d, J = 8.9 Hz), 7.48 (2H, d, J = 8.9 Hz), 7.73 (1H, brs), 7.85 (1H, brs), 7.92 (1H, s)

Preparation Example 11
N- (4-Methoxyphenyl) -1-ethyl-1H-pyrazole-4-carboxamide 8.21 g The starting material was reacted in the same manner as in Preparation Example 9 to give [(1-ethyl-1H-pyrazole-4- Yl) methyl] (4-methoxyphenyl) amine 6.19 g was obtained as white powder crystals.
¹ H-NMR (CDCl ₃ ) δ: 1.47 (3H, t, J = 7.2 Hz), 3.48-3.65 (1H, brs), 3.75 (3H, s), 4.14 (2H, q, J = 7.2 Hz), 6.63 (2H, d, J = 8.9 Hz), 6.80 (2H, d, J = 8.9 Hz), 7.34 (1H, s) , 7.47 (1H, s)

Preparation Example 12
To a toluene (200 mL) solution of 11 g of 4-dimethylaminobenzaldehyde, 10 g of 4-isopropylaniline and 20 g of Molecular Sieves 4A were added under ice-cooling, and the mixture was stirred overnight at room temperature. Molecular sieves 4A was removed from the reaction solution by filtration, and the resulting filtrate was concentrated under reduced pressure. The residue was dissolved in 200 mL of methanol, added with 2.3 g of sodium borohydride under ice cooling, and stirred at room temperature for 5 hours. After distilling off methanol, water was added to the residue, followed by separation / extraction with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated to obtain 13.6 g of (4-dimethylaminophenylmethyl) (4-isopropylphenyl) amine. Melting point 71-73 ° C

Preparation Example 13
To a 1,2-dichloroethane solution (200 mL) of 8.7 g of 4-dimethylaminobenzaldehyde and 10 g of 4-bromoaniline were added 3.3 mL of acetic acid and 25 g of triacetoxyborohydride, and the mixture was stirred at room temperature overnight. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated to give a white solid. This was suspended in IPE, and then collected by filtration to obtain 13.6 g of (4-bromophenyl) (4-dimethylaminophenylmethyl) amine as white crystals.
MS (ESI) m / z: 305 [M + H] ⁺

Preparation Example 14
By reacting 10.0 g of 4-dimethylaminobenzaldehyde and 8.25 g of p-anisidine in the same manner as in Preparation Example 12, 5.0 g of (4-dimethylaminophenylmethyl) (4-methoxyphenyl) amine was obtained. Obtained.
Melting point 92-94 ° C

Preparation Example 15
To a solution of 2.34 g of 1-ethyl-1H-pyrazole-4-carboxylic acid in 1,2-dichloroethane (50 mL) were added 1.83 mL of thionyl chloride and several drops of DMF, and the mixture was stirred at 70 ° C. for 1.5 hours. The reaction solution was concentrated under reduced pressure, 20 mL of methylene chloride was added to the residue, and a solution of 2.29 mL of 4-isopropylaniline in methylene chloride (20 mL) was added to the solution under ice cooling. The mixture was warmed to room temperature and stirred at the same temperature for 1 hour. The reaction mixture was added to saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off, ether was added to the residue, and the precipitated solid was collected by filtration to obtain 3.76 g of N- (4-isopropylphenyl) -1-ethyl-1H-pyrazole-4-carboxamide (melting point). 141.0 ° C). To 3.75 g of this compound was added 29 mL of borane / THF complex / 1 mol / L-THF solution (BH ₃ .THF complex / 1M THF solution), and the mixture was heated to reflux for 4 hours. After cooling the reaction solution, 60 mL of 1 mol / L-hydrochloric acid was added, and the mixture was stirred overnight at room temperature. The reaction mixture was added to saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain 1.95 g of [(1-ethyl-1H-pyrazol-4-yl) methyl] (4-isopropylphenyl) amine.
¹ H-NMR (CDCl ₃ ) δ: 1.21 (6H, d, J = 6.9 Hz), 1.47 (3H, t, J = 7.3 Hz), 2.81 (1H, sept, 6. 9 Hz), 3.57-3.78 (1H, brs), 4.14 (2H, q, J = 7.3 Hz), 4.15 (2H, s), 6.62 (2H, d, J = 8.4 Hz), 7.06 (2H, d, J = 8.4 Hz), 7.36 (1H, s), 7.47 (1H, s).

Preparation Example 16
To a solution of 2.10 g of 2-fluoro-5-nitrobenzotrifluoride in DMF (12 mL) was added 2.70 g of a 50% dimethylamine aqueous solution under ice cooling, and the mixture was stirred at room temperature for 1 hour. 30 mL of water was added to the reaction solution, and the precipitated solid was collected by filtration and dried to obtain 2.34 g of dimethyl [(4-nitro-2-trifluoromethyl) phenyl] amine as pale yellow powder crystals.
¹ H-NMR (DMSO-d ₆ ) δ: 3.02 (6H, s), 7.27 (1H, d, J = 9.4 Hz), 8.27 (1H, dd, J = 2.9, 9.4 Hz), 8.36 (1H, d, J = 2.9 Hz)

Preparation Example 17
2.34 g of dimethyl [(4-nitro-2-trifluoromethyl) phenyl] amine, 0.2 g of palladium carbon (10%), and 20 mL of ethanol-THF (1: 1) were stirred at room temperature for 2 hours under a hydrogen atmosphere. did. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain 2.04 g of N ¹ , N ¹ -dimethyl-2-trifluoromethyl-benzene-1,4-diamine as a red oil.
¹ H-NMR (DMSO-d ₆ ) δ: 2.51 (6H, s), 5.31 (2H, s), 6.78 (1H, d, J = 8.3 Hz), 6.79 (1H , S), 7.27 (1H, d, J = 8.3 Hz)

Preparation Example 18
To a DMF (6 mL) solution of 0.55 g of 6-methylnicotinic acid, 0.714 g of 1,1′-carbonylbis-1H-imidazole was added and stirred at room temperature for 1 hour. To this reaction solution, 0.65 g of N ¹ , N ¹ -dimethyl-2-trifluoromethyl-benzene-1,4-diamine was added, the temperature was raised to 140 ° C., and the mixture was stirred at the same temperature for 2 hours. After cooling the reaction solution to room temperature, 20 mL of water was added, and the precipitated solid was collected by filtration and dried to give N-[(4-dimethylamino-3-trifluoromethyl) phenyl]-(6-methylpyridine- 0.95 g of 3-yl) carboxamide was obtained as brown powder crystals.
¹ H-NMR (DMSO-d ₆ ) δ: 2.56 (3H, s), 2.64 (6H, s), 7.44 (1H, d, J = 8.1 Hz), 7.58 (1H , D, J = 9 Hz), 8.01 (1H, dd, J = 2, 9 Hz), 8.12 (1H, d, J = 2 Hz), 8.21 (1H, dd, J = 2, 8. 1 Hz), 9.01 (1 H, d, J = 2 Hz), 10.5 (1 H, s)

Preparation Example 19
N-[(4-dimethylamino-3-trifluoromethyl) phenyl] -6-methylpyridine-3-carboxamide was reacted in the same manner as in Preparation Example 9 using 0.95 g of N-[(4 0.89 g of -dimethylamino-3-trifluoromethyl) phenyl] -N-[(6-methylpyridin-3-yl) methyl] amine was obtained as white powder crystals.

Preparation Example 20
As in Preparation Example 8, using 0.70 g of 1-ethyl-1H-pyrazole-4-carboxylic acid and 1.02 g of N ¹ , N ¹ -dimethyl-2-trifluoromethyl-benzene-1,4-diamine as starting materials By the reaction treatment, 1.43 g of N-[(4-dimethylamino-3-trifluoromethyl) phenyl] -1-ethyl-1H-pyrazole-4-carboxamide was obtained as white powder crystals.
¹ H-NMR (DMSO-d ₆ ) δ: 1.40 (3H, t, J = 7.2 Hz), 2.62 (6H, s), 4.19 (2H, q, J = 7.2 Hz) 7.55 (1H, d, J = 9.0 Hz), 7.97 (1H, dd, J = 2.4, 9.0 Hz), 8.03 (1H, s), 8.04 (1H, d, J = 2.4 Hz), 8.36 (1H, s), 9.82 (1H, s)

Preparation Example 21
By reacting N-[(4-dimethylamino-3-trifluoromethyl) phenyl] -1-ethyl-1H-pyrazole-4-carboxamide as a starting material in the same manner as in Preparation Example 9, 1.36 g of (4-dimethylamino-3-trifluoromethylphenyl) -N-[(1-ethyl-1H-pyrazol-4-yl) methyl] amine was obtained as white powder crystals.
¹ H-NMR (DMSO-d ₆ ) δ: 1.33 (3H, t, J = 7.2 Hz), 2.51 (6H, s), 4.03-4.12 (4H, m), 6 .13 (1H, t, J = 5.5 Hz), 6.82 (1H, s), 6.83 (1H, d, J = 8.4 Hz), 7.33 (1H, d, J = 8. 4Hz), 7.38 (1H, s), 7.66 (1H, s)

Preparation Example 22
60 g of 4- (2-thienyl) butyric acid was added to 330 mL of acetic anhydride, 2 mL of phosphoric acid was further added, and the mixture was heated to reflux for 3 hours. The reaction solution was neutralized with a saturated aqueous ammonia solution, extracted with chloroform, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was distilled under reduced pressure at 105 ° C./2 mmHg to obtain 29 g of 6,7-dihydro-5H-4-oxo-benzo [b] thiophene as a black oil.

Preparation Example 23
After adding 55.3 mL of trimethylsilylcyanide and 0.84 g of zinc iodide to 25 g of 6,7-dihydro-5H-4-oxo-benzo [b] thiophene and stirring at room temperature for 12 hours, the reaction solution was separated with chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After distilling off the solvent, the residue was dissolved in a mixed solvent of 160 mL of acetic acid and 160 mL of concentrated hydrochloric acid, 120 g of stannous chloride was added thereto, and the mixture was heated to reflux for 4 hours. The reaction solution was cooled and extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain 11 g of 4,5,6,7-tetrahydrobenzo [b] thiophene-4-carboxylic acid.
¹ H-NMR (CDCl ₃ ) δ: 1.83-2.15 (4H, m), 2.70-2.82 (2H, m), 3.73-3.76 (1H, m), 6 .94 (1H, d, J = 5.1 Hz), 7.08 (1H, d, J = 5.1 Hz).

Preparation Example 24
11 g of 4,5,6,7-tetrahydrobenzo [b] thiophene-4-carboxylic acid was dissolved in 40 mL of ethanol, 2 mL of concentrated sulfuric acid was added, and the mixture was heated to reflux for 5 hours. The reaction mixture was poured into ice water and extracted with diethyl ether. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off to give 10.8 g of ethyl 4,5,6,7-tetrahydrobenzo [b] thiophene-4-carboxylate brown Obtained as an oil.
¹ H-NMR (CDCl ₃ ) δ: 1.27 (3H, t, J = 7.2 Hz) 1.83-2.13 (4H, m), 2.71-2.81 (2H, m), 3.69-3.71 (1H, m), 4.17 (2H, q, J = 7.2 Hz), 6.90 (1H, d, J = 5.1 Hz), 7.04 (1H, d , J = 5.1 Hz).
MS (ESI) m / z: 211 [M + H] ⁺

Preparation Example 25
To 15 mL of 1,2-dichloroethane, 0.88 mL of acetyl chloride was added under ice cooling, 2.03 g of anhydrous aluminum chloride was further added, and the mixture was stirred for 30 minutes, and then 4,5,6,7-tetrahydrobenzo [b] thiophene-4 -10 mL of a 1,2-dichloroethane solution of ethyl carboxylate was added dropwise. After warming up to room temperature, it stirred for 3 hours. The reaction solution was poured into ice and extracted with chloroform. The organic layer was washed with saturated brine and saturated aqueous sodium hydrogen carbonate, dried over anhydrous magnesium sulfate, and the solvent was evaporated to give 2-acetyl-4,5,6,7-tetrahydrobenzo [b] thiophene-4- 2.9 g of ethyl carboxylate was obtained as a brown oil.
¹ H-NMR (CDCl ₃ ) δ: 1.30 (3H, t, J = 7.2 Hz) 1.80-2.18 (4H, m), 2.50 (3H, S), 2.75- 2.89 (2H, m), 3.69 (1H, t, J = 5.4 Hz), 4.21 (2H, q, J = 7.2 Hz), 7.53 (1H, S).

Preparation Example 26
2.9 g of ethyl 2-acetyl-4,5,6,7-tetrahydrobenzo [b] thiophene-4-carboxylate was dissolved in 27 mL of ethanol, 14 mL of 1M aqueous sodium hydroxide solution was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was acidified with hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off to give 2-acetyl-4,5,6,7-tetrahydrobenzo [b] thiophene-4-carboxylic acid as 2 0.0 g was obtained.
MS (ESI) m / z: 225 [M + H] ⁺

Preparation Example 27
6.7 g of ethyl 4,5,6,7-tetrahydrobenzo [b] thiophene-4-carboxylate was dissolved in 5 mL of DMF, and 3.6 mL of phosphorus oxychloride was slowly added dropwise under water cooling. The reaction was warmed to 60 ° C. and stirred for 2 hours. The reaction mixture was poured onto ice, neutralized with aqueous sodium bicarbonate, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off to give ethyl 2-formyl-4,5,6,7-tetrahydrobenzo [b] thiophene-4-carboxylate 7 0.1 g was obtained as a yellow oil.
¹ H-NMR (CDCl ₃ ) δ: 1.30 (3H, t, J = 7.2 Hz) 1.86-2.16 (4H, m), 2.83-2.89 (2H, m), 3.72 (1H, t, J = 5.7 Hz), 4.20 (2H, q, J = 7.2 Hz), 7.20 (1H, s), 9.81 (1H, s).
MS (ESI) m / z: 239 [M + H] ⁺

Preparation Example 28
The same procedure as in Preparation Example 26 was performed using 6.5 g of ethyl 2-formyl-4,5,6,7-tetrahydrobenzo [b] thiophene-4-carboxylate as the starting material, and 2-formyl-4,5, 5.7 g of 6,7-tetrahydrobenzo [b] thiophene-4-carboxylic acid was obtained as a pale yellow oil.
¹ H-NMR (CDCl ₃ ) δ: 1.88-2.21 (4H, m), 2.85-2.91 (2H, m), 3.79 (1H, t, J = 5.7 Hz) , 7.68 (1H, s), 9.82 (1H, s).
MS (ESI) m / z: 211 [M + H] ⁺

Preparation Example 29
166 g of aluminum chloride was dissolved in 500 g of nitrobenzene, and 78 g of succinic anhydride was added under ice cooling. 2-methylthiophene 50mL was dripped at the reaction liquid over 25 minutes, and it stirred under ice-cooling for 4 hours. The reaction solution was poured into 700 g of ice, 340 mL of concentrated hydrochloric acid was added, and the mixture was stirred at 50 ° C., followed by separation and extraction with chloroform. A sodium hydroxide aqueous solution was added to the organic layer for separation and extraction. The obtained aqueous layer was washed with toluene, and then acidified with concentrated hydrochloric acid. The precipitated crystals were collected by filtration to obtain 89 g of 4- (5-methylthiophen-2-yl) -4-oxobutyric acid as a yellow oil.
¹ H-NMR (CDCl ₃ ) δ: 2.53 (3H, s), 2.73-2.80 (2H, m), 3.16-3.22 (2H, m), 6.80 (1H , T, J = 3.6 Hz), 7.58 (1H, t, J = 3.6 Hz)
MS (ESI) m / z: 199 [M + H] ⁺

Preparation Example 30
To 89 g of 4- (5-methylthiophen-2-yl) -4-oxobutyric acid and 65 mL of hydrazine monohydrate in an ethylene glycol (320 mL) solution, 58 g of potassium hydroxide was added while maintaining the temperature at 50 ° C. or lower. The reaction solution was heated to 100 ° C. and stirred for 2 hours, and then heated to 150 ° C. and stirred for 3 hours. The reaction mixture was poured into ice, acidified with concentrated hydrochloric acid, and extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off to obtain 75 g of 4- (5-methylthiophen-2-yl) butyric acid.

Preparation Example 31
By using 75 g of 4- (5-methylthiophen-2-yl) butyric acid as a starting material and carrying out a reaction treatment in the same manner as in Preparation Example 22, 2-methyl-6,7-dihydro-5H-4-oxo-benzo [b ] 44 g of thiophene was obtained as a yellow oil.
¹ H-NMR (DMSO-d ₆ ) δ: 2.04-2.13 (2H, m), 2.38 (3H, s), 2.42 (2H, t, J = 6.9 Hz), 2 .93 (1H, t, J = 6.0 Hz), 6.94 (1H, s)
MS (ESI) m / z: 167 [M + H] ⁺

Preparation Example 32
The reaction was conducted in the same manner as in Preparation Example 23 using 44 g of 2-methyl-6,7-dihydro-5H-4-oxo-benzo [b] thiophene as a starting material to give 2-methyl-4,5,6,7. -43 g of tetrahydro-benzo [b] thiophene-4-carboxylic acid was obtained as pale yellow crystals.
MS (ESI) m / z: 197 [M + H] ⁺

Preparation Example 33
The reaction was conducted in the same manner as in Preparation Example 29 using 50 g of 3-methylthiophene as a starting material to obtain 94 g of 4- (4-methylthiophen-2-yl) -4-oxobutyric acid as white crystals.
MS (ESI) m / z: 199 [M + H] ⁺

Preparation Example 34
Using 94 g of 4- (4-methylthiophen-2-yl) -4-oxobutyric acid as a starting material, the reaction treatment was performed in the same manner as in Preparation Example 30 to obtain 88 g of 4- (4-methylthiophen-2-yl) butyric acid. Obtained as a brown oil.

Preparation Example 35
The residue obtained by reacting in the same manner as in Preparation Example 22 using 88 g of 4- (4-methylthiophen-2-yl) butyric acid as a starting material was purified by silica gel column chromatography to obtain 3-methyl-6. , 7-dihydro-5H-4-oxo-benzo [b] thiophene was obtained as a brown oil.
¹ H-NMR (DMSO-d ₆ ) δ: 2.04-2.12 (2H, m), 2.34 (3H, s), 2.44-2.52 (2H, m), 3.00 (1H, t, J = 6.0 Hz), 6.96 (1H, s)
MS (ESI) m / z: 167 [M + H] ⁺

Preparation Example 36
By using 17 g of 3-methyl-6,7-dihydro-5H-4-oxo-benzo [b] thiophene as a starting material and reacting in the same manner as in Preparation Example 23, 3-methyl-4,5,6,7 -2.8 g of tetrahydro-benzo [b] thiophene-4-carboxylic acid was obtained as white crystals.
¹ H-NMR (CDCl ₃ ) δ: 1.87-2.00 (2H, m), 2.11 (3H, s), 2.21-2.28 (2H, m), 2.70-2 .88 (2H, m), 6.72 (1H, s)
MS (ESI) m / z: 197 [M + H] ⁺

Preparation Example 37
By using 34 g of 2-methyl-4,5,6,7-tetrahydro-benzo [b] thiophene-4-carboxylic acid as a starting material and reacting in the same manner as in Preparation Example 24, 2-methyl-4,5, 35 g of ethyl 6,7-tetrahydro-benzo [b] thiophene-4-carboxylate was obtained as a yellow oil.
¹ H-NMR (CDCl ₃ ) δ: 1.28 (3H, t, J = 6.9 Hz), 1.70-2.09 (4H, m), 2.39 (3H, s), 2.68 -2.71 (2H, m), 3.51-3.62 (1H, m), 4.14 (2H, q, J = 6.9 Hz),
6.52 (1H, s)

Preparation Example 38
By using 3 g of ethyl 2-methyl-4,5,6,7-tetrahydro-benzo [b] thiophene-4-carboxylate as a starting material, the reaction treatment was conducted in the same manner as in Preparation Example 25 to obtain 3-acetyl-2-methyl. 3.4 g of ethyl -4,5,6,7-tetrahydro-benzo [b] thiophene-4-carboxylate was obtained as a yellow oil.
¹ H-NMR (CDCl ₃ ) δ: 1.25 (3H, t, J = 6.9 Hz), 1.80-2.04 (4H, m), 2.45 (3H, s), 2.61 (3H, s), 2.66-2.70 (2H, m), 3.97 (1H, t, J = 5.4 Hz), 4.14 (2H, q, J = 6.9 Hz)

Preparation Example 39
Ethyl 3-acetyl-2-methyl-4,5,6,7-tetrahydro-benzo [b] thiophene-4-carboxylate (2.2 g) was dissolved in ethanol (50 mL), and sodium borohydride (0.65 g) was cooled with ice. The mixture was warmed to room temperature and stirred for 2 hours. The reaction mixture was poured into ice and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography to obtain 1.7 g of ethyl 3- (1-hydroxyethyl) -2-methyl-4,5,6,7-tetrahydro-benzo [b] thiophene-4-carboxylate as a yellow oil. Got as.

Preparation Example 40
5.7 g of sodium iodide was dissolved in 50 mL of acetonitrile, and 4.9 mL of trimethylsilyl chloride was added dropwise at room temperature. Further, an acetonitrile solution (5 mL) of 1.7 g of ethyl 3- (1-hydroxyethyl) -2-methyl-4,5,6,7-tetrahydro-benzo [b] thiophene-4-carboxylate was added dropwise. Heated to reflux for hours. After allowing to cool to room temperature, hydrosulfite was added until the color disappeared, and potassium carbonate water was further added to make it weakly alkaline. The reaction solution was subjected to separation / extraction with chloroform, and the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography to obtain 0.9 g of ethyl 3-ethyl-2-methyl-4,5,6,7-tetrahydro-benzo [b] thiophene-4-carboxylate as a colorless oil.
¹ H-NMR (CDCl ₃ ) δ: 1.01 (3H, t, J = 7.5 Hz), 1.26 (3H, t, J = 6.9 Hz), 1.82-2.11 (4H, m), 2.30 (3H, s), 2.32-2.41 (2H, m), 2.65-2.80 (2H, m), 3.61 (1H, t, J = 3. 9 Hz), 4.17 (2H, q, J = 6.9 Hz)
MS (ESI) m / z: 253 [M + H] ⁺

Preparation Example 41
By using 0.83 g of ethyl 3-ethyl-2-methyl-4,5,6,7-tetrahydro-benzo [b] thiophene-4-carboxylate as a starting material, a reaction treatment was conducted in the same manner as in Preparation Example 26 to obtain 3 -0.72 g of ethyl-2-methyl-4,5,6,7-tetrahydro-benzo [b] thiophene-4-carboxylic acid was obtained as white crystals.
¹ H-NMR (CDCl ₃ ) δ: 1.03 (3H, t, J = 7.5 Hz), 1.86-1.97 (3H, m), 2.16-2.20 (1H, m) , 2.31 (3H, s), 2.40 (2H, q, J = 7.5 Hz), 2.67-2.81 (2H, m), 3.65 (1H, t, J = 3. 9Hz)
MS (ESI) m / z: 225 [M + H] ⁺

Preparation Example 42
To 3.27 g of ethyl 2-formyl-4,5,6,7-tetrahydrobenzo [b] thiophene-4-carboxylate, add 15 mL of formic acid, 3 drops of concentrated sulfuric acid, and 1,24 g of hydroxylamine hydrochloride, and heat to reflux for 2 hours. did. The reaction solution was neutralized and then extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography to obtain 1.43 g of ethyl 2-carbamoyl-4,5,6,7-tetrahydro-benzo [b] thiophene-4-carboxylate as a yellow oil.
MS (ESI) m / z: 254 [M + H] ⁺

Preparation Example 43
By using 1.43 g of ethyl 2-carbamoyl-4,5,6,7-tetrahydro-benzo [b] thiophene-4-carboxylate as a starting material, the reaction treatment was carried out in the same manner as in Preparation Example 26, whereby 2-carbamoyl-4 , 5,6,7-tetrahydro-benzo [b] thiophene-4-carboxylic acid 0.7 g was obtained as pale yellow crystals.
¹ H-NMR (DMSO-d ₆ ) δ: 1.75-1.99 (4H, m), 2.62-2.79 (2H, m), 3.61 (1H, t, J = 5. 4Hz), 7.23 (1H, brs), 7.54 (1H, s), 7.87 (1H, brs), 12.5 (1H, brs)

Preparation Example 44
To 10.0 g of ethyl 4,5,6,7-tetrahydrobenzo [b] thiophene-4-carboxylate, 350 mL of acetic acid and 350 mL of water were added and stirred under ice cooling. Bromine 3.0mL was dripped at the reaction liquid, and it stirred under ice-cooling for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography to obtain a colorless oil. By reacting in the same manner as in Preparation Example 26 using 1.3 g of the obtained oil as a starting material, 2-bromo-4,5,6,7-tetrahydro-benzo [b] thiophene-4-carboxylic acid 1.2 g was obtained.
¹ H-NMR (CDCl ₃ ) δ: 1.86-2.11 (4H, m), 2.61-2.72 (2H, m), 3.67 (1H, t, J = 5.4 Hz) , 6.91 (1H, s)

Preparation Example 45
By reacting in the same manner as in Preparation Example 27 using 10.0 g of 2-methylthiophene as a starting material, 5.4 g of 2-formyl-5-methylthiophene was obtained as a yellow oil.

Preparation Example 46
Sodium hydride (2.0 g) was added to 50 mL of tetrahydrofuran under ice-cooling, and a tetrahydrofuran solution (10 mL) of 11.5 g of ethyl diethylphosphonoacetate was added dropwise, followed by stirring under ice-cooling. To the reaction solution, a tetrahydrofuran solution (40 mL) of 5.4 g of 2-formyl-5-methylthiophene was added dropwise and stirred for 20 minutes under ice cooling. Saturated brine was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The obtained residue was used as a starting material and reacted in the same manner as in Preparation Example 26 to give 3- (5-methylthiophen-2-yl) acrylic acid as white crystals.

Preparation Example 47
The total amount of 3- (5-methylthiophen-2-yl) acrylic acid obtained in Preparation Example 46 was dissolved in 200 mL of methanol, 0.7 g of 10% palladium / carbon was added, and the mixture was stirred at room temperature for 10 hours in a hydrogen stream. . The reaction solution was filtered through Celite, and the filtrate was concentrated to obtain 0.9 g of 3- (5-methylthiophen-2-yl) propionic acid as white crystals.
¹ H-NMR (DMSO-d ₆ ) δ: 2.36 (3H, s), 2.52 (2H, t, J = 7.2 Hz), 2.92 (2H, t, J = 7.2 Hz) , 6.58 (1H, s), 6.61 (1H, s), 12.2 (1H, brs)

Preparation Example 48
0.88 g of 3- (5-methylthiophen-2-yl) propionic acid was dissolved in 15 mL of dichloroethane, a drop of DMF was added, 0.45 mL of thionyl chloride was added, and the mixture was heated for 30 minutes. After cooling to room temperature, the solvent and thionyl chloride were distilled off under reduced pressure. To the residue was added 30 mL of 1,2-dichloroethane, and 0.82 g of anhydrous aluminum chloride was added under ice cooling, followed by stirring for 30 minutes. The mixture was warmed to room temperature and stirred for 1 hour. The reaction solution was poured onto ice and extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography to obtain 0.6 g of 2-methyl-4-oxo-5,6, -dihydrocyclopenta [b] thiophene as pale yellow crystals.
¹ H-NMR (DMSO-d ₆ ) δ: 2.46 (3H, s), 2.81 (2H, t, J = 4.8 Hz), 3.10 (2H, t, J = 4.8 Hz) , 6.81 (1H, s)

Preparation Example 49
By using 0.6 g of 2-methyl-4-oxo-5,6, -dihydrocyclopenta [b] thiophene as a starting material and reacting in the same manner as in Preparation Example 23, 2-methyl-5,6, -dihydro 0.33 g of -4H-cyclopenta [b] thiophene-4-carboxylic acid was obtained as pale yellow crystals.
¹ H-NMR (DMSO-d ₆ ) δ: 2.39 (3H, s), 2.45-2.59 (2H, m), 2.78-2.84 (2H, m), 3.78 (1H, t, J = 7.2 Hz), 6.59 (1H, s), 12.3 (1H, brs)

Preparation Example 50
10 g of 2-methylthiophene and 17.9 g of ethylglucaryl chloride were dissolved in 300 mL of 1,2-dichloroethane, and 16.0 g of aluminum chloride was added under ice cooling, followed by stirring for 1 hour, followed by warming to room temperature and stirring for 1 hour. . The reaction solution was poured onto ice and extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography to obtain 22.6 g of ethyl 5- (5-methylthiophen-2-yl) -5-oxo-valerate as a yellow oil.

Preparation Example 51
19.8 g of ethyl 5- (5-methylthiophen-2-yl) -5-oxo-valerate was dissolved in 200 mL of methanol, and 3.4 g of sodium borohydride was added under ice cooling. After stirring for 20 minutes under ice-cooling, saturated brine was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography to obtain 13.8 g of ethyl 5-hydroxy-5- (5-methylthiophen-2-yl) valerate as a pale yellow oil.
¹ H-NMR (DMSO-d ₆ ) δ: 1.16 (3H, t, J = 6.9 Hz), 1.43-1.63 (4H, m), 2.28 (2H, t, J = 6.9 Hz), 2.39 (3 H, s), 4.03 (2 H, q, J = 6.9 Hz), 4.62-4.67 (1 H, m), 5.41 (1 H, d, J = 4.5 Hz), 6.60 (1H, d, J = 3.6 Hz), 6.67 (1H, d, J = 3.6 Hz)

Preparation Example 52
1.5 g of ethyl 5-hydroxy-5- (5-methylthiophen-2-yl) valerate was dissolved in 30 mL of toluene, a catalytic amount of p-toluenesulfonic acid was added, and the mixture was heated to reflux for 1 hour. After the solvent was distilled off, the residue was purified by silica gel column chromatography to obtain 0.87 g of ethyl 5- (5-methylthiophen-2-yl) -4-pentenoate as a colorless oil.
¹ H-NMR (DMSO-d ₆ ) δ: 1.17 (3H, t, J = 6.9 Hz), 2.38 (3H, s), 2.36-2.51 (4H, m), 4 .06 (2H, q, J = 6.9 Hz), 5.82-5.89 (1H, m), 6.50 (1H, d, J = 15.9 Hz), 6.64 (1H, d, J = 3.0 Hz), 6.74 (1H, d, J = 3.0 Hz)
MS (ESI) m / z: 225 [M + H] ⁺

Preparation Example 53
By using 7.2 g of ethyl 5- (5-methylthiophen-2-yl) -4-pentenoate as a starting material, the reaction treatment was conducted in the same manner as in Preparation Example 26 to obtain 5- (5-methylthiophen-2-yl). 6.5 g of -4-pentenoic acid was obtained as yellow crystals.

Preparation Example 54
By reacting in the same manner as in Preparation Example 47 using 6.5 g of 5- (5-methylthiophen-2-yl) -4-pentenoic acid as a starting material, 5- (5-methylthiophen-2-yl) yoshi 6.4 g of valeric acid was obtained as white crystals.

Preparation Example 55
By using 6.4 g of 5- (5-methylthiophen-2-yl) valeric acid as a starting material and reacting in the same manner as in Preparation Example 48, 2-methyl-4-oxo-5,6,7,8- 4.0 g of tetrahydrocyclohepta [b] thiophene was obtained as a yellow oil.
¹ H-NMR (DMSO-d ₆ ) δ: 1.74-1.86 (4H, m), 2.35 (3H, s), 2.62 (2H, t, J = 6.0 Hz), 3 .02 (2H, t, J = 6.0 Hz), 6.96 (1H, s)

Preparation Example 56
By using 3.9 g of 2-methyl-4-oxo-5,6,7,8-tetrahydrocyclohepta [b] thiophene as a starting material and reacting in the same manner as in Preparation Example 23, 2-methyl-5,6 , 7,8-Tetrahydro-4H-cyclohepta [b] thiophene-4-carboxylic acid 1.6 g was obtained as a brown oil.
¹ H-NMR (DMSO-d ₆ ) δ: 1.40-1.98 (6H, m), 2.29 (3H, s), 2.67 (1H, t, J = 4.5 Hz), 3 71-3.74 (1H, m), 6.45 (1H, s), 12.6 (1H, brs)

Preparation Example 57
By using 10 g of 2,5-dimethylthiophene as a starting material and carrying out a reaction treatment in the same manner as in Preparation Example 25, 17.5 g of ethyl 4- (2,5-dimethylthiophen-3-yl) -4-oxo-butyrate is diluted lightly. Obtained as a yellow oil.
¹ H-NMR (CDCl ₃ ) δ: 1.26 (3H, t, J = 6.9 Hz), 2.40 (3H, s), 2.66 (3H, s), 2.68 (2H, t , J = 6.6 Hz), 3.11 (2H, t, J = 6.6 Hz), 4.14 (2H, q, J = 6.9 Hz), 7.04 (1H, s)

Preparation Example 58
By using 17.4 g of ethyl 4- (2,5-dimethylthiophen-3-yl) -4-oxo-butyrate as a starting material and reacting in the same manner as in Preparation Example 26, 4- (2,5-dimethylthiophene) 13.4 g of -3-yl) -4-oxo-butyric acid was obtained as white crystals.
¹ H-NMR (CDCl ₃ ) δ: 2.40 (3H, s), 2.66 (3H, s), 2.74 (2H, t, J = 6.6 Hz), 3.12 (2H, t , J = 6.6 Hz), 7.02 (1H, s)

Preparation Example 59
By using 12.2 g of 4- (2,5-dimethylthiophen-3-yl) -4-oxo-butyric acid as a starting material and reacting in the same manner as in Preparation Example 30, 4- (2,5-dimethylthiophene- 11.4 g of 3-yl) butyric acid was obtained as white crystals.
¹ H-NMR (CDCl ₃ ) δ: 1.82-1.92 (2H, m), 2.27 (3H, s), 2.34 (2H, t, J = 3.9 Hz), 2.37 (3H, s), 2.49 (2H, t, J = 7.6 Hz), 6.44 (1H, s)

Preparation Example 60
By using 11.3 g of 4- (2,5-dimethylthiophen-3-yl) butyric acid as a starting material and reacting in the same manner as in Preparation Example 48, 1,3-dimethyl-6,7-dihydro-5H-4 There were obtained 8.44 g of -oxo-benzo [c] thiophene as yellow crystals.
¹ H-NMR (DMSO-d ₆ ) δ: 1.87-1.96 (2H, m), 2.26 (3H, s), 2.41 (2H, t, J = 6.6 Hz), 2 .61-2.66 (2H, m), 2.63 (3H, s)

Preparation Example 61
By reacting 1,3-dimethyl-6,7-dihydro-5H-4-oxo-benzo [c] thiophene (6.44 g) as a starting material in the same manner as in Preparation Example 23, 1,3-dimethyl-4 , 5,6,7-tetrahydrobenzo [c] thiophene-4-carboxylic acid 0.2 g was obtained as white crystals.
¹ H-NMR (DMSO-d ₆ ) δ: 1.64-1.76 (3H, m), 1.98-2.04 (1H, m), 2.16 (3H, s), 2.19 (3H, s), 2.34-2.51 (2H, m), 12.3 (1H, brs)

Preparation Example 62
To a solution of 100 g of 6-chloronicotinic acid in 1,2-dichloroethane (400 mL), 48.6 mL of thionyl chloride and a catalytic amount of dimethylformamide were added, and the mixture was heated to reflux with stirring for 2 hours. The reaction mixture was concentrated under reduced pressure, toluene was added to the residue, and the mixture was concentrated again under reduced pressure. A methylene chloride (200 mL) solution of this residue was appropriately added to a solution of 8-5.9 g of 4-isopropylaniline in methylene chloride (800 mL) under ice cooling, and the mixture was stirred at room temperature for 1 hour. To the reaction solution, 700 mL of a 1N sodium hydroxide aqueous solution was added, followed by separation and extraction with chloroform. The organic layer was washed with brine and dried over magnesium sulfate. After the solvent was distilled off, 1000 mL of a mixed solvent of isopropyl ether / hexane (1: 1) was added to the residue, and the solid was collected by filtration to give 6-chloropyridine-N- (4-isopropylphenyl) -3-carboxamide. 167 g was obtained as powder crystals.
¹ H-NMR (CDCl ₃ ) δ: 1.24 (6H, d, J = 6.9 Hz), 2.90 (1H, sept, J = 6.9 Hz), 7.21 (2H, d, J = 8.4 Hz), 7.40 (1 H, d, J = 8.4 Hz), 7.50 (2 H, d, J = 8.4 Hz), 8.02 (1 H, brs), 8.13 (1 H, dd, J = 2.7, 8.4 Hz), 8.82 (1H, d, J = 2.4 Hz)

Preparation Example 63
To a solution of 147 g of 6-chloropyridine-N- (4-isopropylphenyl) -3-carboxamide in DMF (880 mL) were added 130.9 g of dimethylamine hydrochloride and 443 g of potassium carbonate, and the mixture was stirred at 80 ° C. for 18 hours. The reaction solution was poured into 1800 mL of water and stirred at room temperature for 4 hours. The precipitated solid was collected by filtration to obtain 150 g of 6- (dimethylamino) pyridine-N- (4-isopropylphenyl) -3-carboxamide as powder crystals.
¹ H-NMR (CDCl ₃ ) δ: 1.24 (6H, d, J = 6.9 Hz), 2.90 (1H, sept, J = 6.9 Hz), 3.17 (6H, s), 6 .53 (1H, d, J = 6.9 Hz), 7.21 (2H, d, J = 8.4 Hz), 7.51 (2H, d, J = 5.1 Hz), 7.62 (1H, brs), 7.96 (1H, dd, J = 2.4, 9.0 Hz), 8.67 (1H, d, J = 2.4 Hz)

Preparation Example 64
64.1 g of 6- (dimethylamino) pyridine-N- (4-isopropylphenyl) -3-carboxamide was dissolved in 500 mL of borane / THF complex / 1 mol / L-THF solution (BH ₃ .THF complex / 1M THF solution). And heated to reflux for 7 hours. After cooling the reaction solution, 690 mL of 1 mol / L-hydrochloric acid was carefully added, and the mixed solution was stirred overnight at room temperature. The reaction solution was neutralized with 400 mL of a 2 mol / L-sodium hydroxide aqueous solution and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off, and purification by silica column chromatography yielded 44.0 g of [(6-dimethylaminopyridin-3-yl) methyl] (4-isopropylphenyl) amine as white powder crystals.
¹ H-NMR (CDCl ₃ ) δ: 1.20 (6H, d, J = 6.9 Hz), 2.80 (1H, sept, J = 6.9 Hz), 3.09 (6H, s), 4 .14 (2H, s), 6.51 (1H, d, J = 8.7 Hz), 6.61 (2H, d, J = 8.4 Hz), 7.05 (2H, d, J = 8. 4 Hz), 7.49 (1H, dd, J = 8.7 Hz), 8.15 (1H, d, J = 2.3 Hz)

Preparation Example 65
By using 7.8 g of 2,5-dimethylthiophene as a starting material and carrying out a reaction treatment in the same manner as in Preparation Example 50, ethyl 5- (2,5-dimethylthiophen-3-yl) -5-oxo-valerate is yellow. Obtained as an oil.

Preparation Example 66
By using the total amount of ethyl 5- (2,5-dimethylthiophen-3-yl) -5-oxo-valerate obtained in Preparation Example 65 as a starting material, the reaction was conducted in the same manner as in Preparation Example 51 to give 5-hydroxy Ethyl 5- (2,5-dimethylthiophen-3-yl) valerate was obtained as a brown oil.

Preparation Example 67
The total amount of ethyl 5-hydroxy-5- (2,5-dimethylthiophen-3-yl) valerate obtained in Preparation Example 66 was used as a starting material, and the reaction was carried out in the same manner as in Preparation Example 52 to give 5- (2 , 5-Dimethylthiophen-3-yl) -4-pentenoate was obtained as a brown oil.

Preparation Example 68
By using the total amount of ethyl 5- (2,5-dimethylthiophen-3-yl) -4-pentenoate obtained in Preparation Example 67 as a starting material, the reaction was conducted in the same manner as in Preparation Example 26 to obtain 5- (2, 9.5 g of 5-dimethylthiophen-3-yl) -4-pentenoic acid was obtained as colorless crystals.
¹ H-NMR (DMSO-d ₆ ) δ: 2.25-2.36 (10H, m), 5.91-5.98 (1H, m), 6.34 (1H, d, J = 15. 9Hz), 6.81 (1H, s), 12.1 (1H, s)

Preparation Example 69
5- (2,5-dimethylthiophen-3-yl) -4-pentenoic acid 9.5 g was used as a starting material, and reacted in the same manner as in Preparation Example 47 to give 5- (2,5-dimethylthiophene-3 -Ill) 7.3 g of valeric acid was obtained as white crystals.
¹ H-NMR (DMSO-d ₆ ) δ: 1.43-1.53 (4H, m), 2.23 (3H, s), 2.31 (3H, s), 2.18-2.40 (4H, m), 6.49 (1H, s), 12.0 (1H, brs)

Preparation Example 70
By using 7.3 g of 5- (2,5-dimethylthiophen-3-yl) valeric acid as a starting material and subjecting to a reaction treatment in the same manner as in Preparation Example 48, 1,3-dimethyl-4-oxo-5,6, 4.5 g of 7,8-tetrahydrocyclohepta [c] thiophene was obtained as a yellow oil.
¹ H-NMR (DMSO-d ₆ ) δ: 2.27 (3H, s), 2.21-2.41 (4H, m), 2.46 (3H, s), 2.50-2.60 (2H, m), 2.67-2.71 (2H, m)

Preparation Example 71
By reacting in the same manner as in Preparation Example 51 using 3.0 g of 1,3-dimethyl-4-oxo-5,6,7,8-tetrahydrocyclohepta [c] thiophene as a starting material, 4-hydroxy-1 , 3-Dimethyl-5,6,7,8-tetrahydro-4H-cyclohepta [c] thiophene 2.1 g was obtained as white crystals.
¹ H-NMR (DMSO-d ₆ ) δ: 1.9-1.17 (1H, m), 1.22-1.40 (1H, m), 1.51-1.63 (1H, m) 1.78-1.85 (1H, m), 1.96-2.05 (2H, m), 2.18 (3H, s), 2.26 (3H, s), 2.49-2. .53 (1H, m), 2.61-2.68 (1H, m), 4.69 (1H, d, J = 3.0 Hz), 4.78-4.81 (1H, m)

Preparation Example 72
2.1 g of 4-hydroxy-1,3-dimethyl-5,6,7,8-tetrahydro-4H-cyclohepta [c] thiophene was dissolved in 25 mL of dichloromethane and stirred under ice cooling. To the reaction solution, 0.83 mL of thionyl chloride was added dropwise and stirred for 30 minutes under ice-cooling, and then the solvent was distilled off under reduced pressure. The obtained brown oil was dissolved in 2 mL of DMSO and added dropwise to a DMSO solution (10 mL) of 1.5 g of sodium cyanide under stirring at 80 ° C. After stirring at 80 ° C. for 6 hours, the reaction solution was allowed to cool to room temperature. Saturated brine was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography to obtain 1.4 g of 4-cyano-1,3-dimethyl-5,6,7,8-tetrahydro-4H-cyclohepta [c] thiophene as a pale yellow oil.
¹ H-NMR (DMSO-d ₆ ) δ: 2.23 (3H, s), 2.30 (3H, s), 1.13-2.82 (8H, m), 4.46-4.48 (1H, m)

Preparation Example 73
1.4 g of 4-cyano-1,3-dimethyl-5,6,7,8-tetrahydro-4H-cyclohepta [c] thiophene and 2 g of potassium hydroxide were dissolved in 12 mL of ethylene glycol and stirred at 180 ° C. for 5 hours. . The reaction solution was allowed to cool to room temperature, acidified with concentrated hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography to obtain 0.61 g of 1,3-dimethyl-5,6,7,8-tetrahydro-4H-cyclohepta [c] thiophene-4-carboxylic acid as white crystals.
¹ H-NMR (DMSO-d ₆ ) δ: 1.10-1.15 (1H, m), 1.40-1.48 (1H, m), 1.63-1.68 (1H, m) 1.79-1.84 (2H, m), 2.20 (6H, s), 2.24-2.29 (2H, m), 2.69-2.72 (1H, m), 3 .87-3.90 (1H, m), 12.3 (1H, brs)

Example 1

  Add a drop of DMF to a solution of 1.4 g of 4,5,6,7-tetrahydrobenzo [b] thiophene-4-carboxylic acid in methylene chloride (20 mL), add 0.83 mL of thionyl chloride, and heat for 2 hours with stirring. Refluxed. The reaction mixture was concentrated under reduced pressure, 5 mL of methylene chloride was added to the residue, and a solution of 2.4 g of (4-dimethylaminophenylmethyl) (4-isopropylphenyl) amine in methylene chloride (5 mL) was added. Stir. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off, the residue was purified by silica gel column chromatography, and the resulting crystals were recrystallized from IPE to give N- (4-dimethylaminophenylmethyl) -N- (4-isopropylphenyl) -4, 1.1 g of 5,6,7-tetrahydrobenzo [b] thiophene-4-carboxamide was obtained as white crystals.

¹ H-NMR (CDCl ₃ ) δ: 1.23 (6H, d, J = 6.9 Hz), 1.50-1.59 (1H, m), 1.87-2.08 (3H, m) , 2.65-2.91 (3H, m), 2, 94 (6H, s), 3.60 (1H, t, J = 7.1 Hz), 4.64 (1H, d, J = 14. 0 Hz), 4.97 (1H, d, J = 14.0 Hz), 6.64-6.70 (3H, m), 6.94 (2H, d, J = 8.4 Hz), 7.03 ( 1H, d, J = 5.1 Hz), 7.10 (2H, d, J = 8.4 Hz), 7.16 (2H, d, J = 8.4 Hz).
MS (ESI) m / z: 433 [M + H] ⁺

Example 2

Starting from 2.0 g of 2-acetyl-4,5,6,7-tetrahydrobenzo [b] thiophene-4-carboxylic acid and 2.4 g of (4-dimethylaminophenylmethyl) (4-isopropylphenyl) amine By reacting in the same manner as in Example 1, 2-acetyl-N- (4-dimethylaminophenylmethyl) -N- (4-isopropylphenyl) -4,5,6,7-tetrahydrobenzo [b] 0.64 g of thiophene-4-carboxamide was obtained as a white amorphous.

¹ H-NMR (CDCl ₃ ) δ: 1.24 (6H, d, J = 7.2 Hz), 1.55-1.58 (1H, m), 1.87-2.10 (3H, m) , 2.45 (3H, s), 2.69-2.91 (3H, m), 2.94 (6H, s), 3.58 (1H, t, J = 7.0 Hz), 4.65. (1H, d, J = 13.8 Hz), 4.96 (1H, d, J = 13.8 Hz), 6.65 (2H, d, J = 8.4 Hz), 6.96 (2H, d, J = 8.4 Hz), 7.13 (2H, d, J = 8.4 Hz), 7.20 (2H, d, J = 8.4 Hz), 7.22 (1H, s).
MS (ESI) m / z: 475 [M + H] ⁺

Example 3

Starting from 2.14 g of 2-formyl-4,5,6,7-tetrahydrobenzo [b] thiophene-4-carboxylic acid and 2.74 g of (4-dimethylaminophenylmethyl) (4-isopropylphenyl) amine, By reacting in the same manner as in Example 1, N- (4-dimethylaminophenylmethyl) -2-formyl-N- (4-isopropylphenyl) -4,5,6,7-tetrahydrobenzo [b] thiophene 1.15 g of -4-carboxamide was obtained as a pale yellow amorphous.

¹ H-NMR (CDCl ₃ ) δ: 1.24 (6H, d, J = 6.9 Hz), 1.50-1.59 (1H, m), 1.87-2.08 (3H, m) , 2.65-2.91 (3H, m), 2.95 (6H, s), 3.59 (1H, t, J = 7.2 Hz), 4.69 (1H, d, J = 14. 0 Hz), 4.92 (1 H, d, J = 14.0 Hz), 6.64-7.21 (9 H, m), 9.76 (1 H, s).
MS (ESI) m / z: 461 [M + H] ⁺

Example 4

Starting from 0.75 g of N- (4-dimethylaminophenylmethyl) -2-formyl-N- (4-isopropylphenyl) -4,5,6,7-tetrahydrobenzo [b] thiophene-4-carboxamide, By reacting in the same manner as in Preparation Example 39, N- (4-dimethylaminophenylmethyl) -2-hydroxymethyl-N- (4-isopropylphenyl) -4,5,6,7-tetrahydrobenzo [b] 0.41 g of thiophene-4-carboxamide was obtained as yellow crystals.

¹ H-NMR (CDCl ₃ ) δ: 1.24 (6H, d, J = 6.9 Hz), 1.51-1.56 (1H, m), 1.85-1.95 (2H, m) , 2.00-2.08 (1H, m), 2.62-2.76 (2H, m), 2.91 (1H, sept, J = 6.9 Hz), 3.03 (6H, s) 3.33 (1H, brs), 4.69 (2H, s), 4.75 (1H, d, J = 14.1 Hz), 4.92 (1H, d, J = 14.1 Hz), 6 .56 (1H, s), 6.95 (2H, d, J = 8.4 Hz), 6.99 (2H, d, J = 8.4 Hz), 7.18-7.25 (4H, m) .
MS (ESI) m / z: 463 [M + H] ⁺

Example 5

1.2 g of 2-acetyl-N- (4-dimethylaminophenylmethyl) -N- (4-isopropylphenyl) -4,5,6,7-tetrahydrobenzo [b] thiophene-4-carboxamide was added to trifluoroacetic acid 3 Then, 3.2 mL of triethylsilane was added with stirring under ice-cooling. The mixture was warmed to room temperature, stirred for a whole day and night, and then heated to reflux for 7 hours. The reaction solution was poured onto ice, neutralized with 1M aqueous sodium hydroxide solution, and extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off, the residue was purified by silica gel column chromatography, and N- (4-dimethylaminophenylmethyl) -2-ethyl-N- (4-isopropylphenyl) -4,5,6,7-tetrahydrobenzo [ b] 0.47 g of thiophene-4-carboxamide was obtained as a yellow oil.

¹ H-NMR (CDCl ₃ ) δ: 1.21-1.26 (9H, m), 1.50-1.55 (1H, m), 1.83-2.10 (3H, m), 2 .65-2.91 (5H, m), 2.95 (6H, s), 3.53 (1H, t, J = 8.1 Hz), 4.66 (1H, d, J = 14.1 Hz) , 4.96 (1H, d, J = 14.1 Hz), 6.34 (1H, s), 6.66 (2H, d, J = 8.4 Hz), 6.93 (2H, d, J = 8.4 Hz), 7.11-7.17 (4H, m).
MS (ESI) m / z: 461 [M + H] ⁺

Example 6

0.55 g of 4,5,6,7-tetrahydrobenzo [b] thiophene-4-carboxylic acid, 0.73 g of [(1-ethyl-1H-pyrazol-4-yl) methyl] (4-isopropylphenyl) amine The starting material was reacted in the same manner as in Example 1 to give N-[(1-ethyl-1H-pyrazol-4-yl) methyl] -N- (4-isopropylphenyl) -4,5,6, 0.39 g of 7-tetrahydrobenzo [b] thiophene-4-carboxamide was obtained as a yellow oil.

¹ H-NMR (CDCl ₃ ) δ: 1.25 (6H, d, J = 6.9 Hz), 1.45 (3H, t, J = 7.2 Hz), 1.51-1.60 (1H, m), 1.85-2.10 (3H, m), 2.70-2.90 (2H, m), 2.92 (1H, sept, J = 6.9 Hz), 3.59 (1H, t, J = 7.0 Hz), 4.13 (2H, q, J = 7.2 Hz), 4.56 (1H, d, J = 14.4 Hz), 4.83 (1H, d, J = 14) .4 Hz), 6.59 (1H, d, J = 5.1 Hz), 7.00-7.04 (3H, m), 7.22 (2H, d, J = 8.4 Hz), 7.32 (1H, s), 7.40 (1H, s).
MS (ESI) m / z: 408 [M + H] ⁺

Example 7

Starting from 1.0 g of 2-methyl-4,5,6,7-tetrahydrobenzo [b] thiophene-4-carboxylic acid and 1.37 g of (4-dimethylaminophenylmethyl) (4-isopropylphenyl) amine, By carrying out the reaction treatment in the same manner as in Example 1, N- (4-dimethylaminophenylmethyl) -N- (4-isopropylphenyl) -2-methyl-4,5,6,7-tetrahydrobenzo [b] thiophene Obtained 1.29 g of -4-carboxamide as a brown oil.
MS (ESI) m / z: 447 [MH] ⁺

1.29 g of N- (4-dimethylaminophenylmethyl) -N- (4-isopropylphenyl) -2-methyl-4,5,6,7-tetrahydrobenzo [b] thiophene-4-carboxamide in 5 mL of ethyl acetate After dissolution, 0.79 mL of 4M hydrochloric acid / ethyl acetate was added to make a homogeneous solution, and then the solvent was distilled off under reduced pressure. The obtained crystals were suspended in IPE and collected by filtration to give N- (4-dimethylaminophenylmethyl) -N- (4-isopropylphenyl) -2-methyl-4,5,6,7-tetrahydro 1.26 g of benzo [b] thiophene-4-carboxamide monohydrochloride was obtained as yellow crystals.

¹ H-NMR (CDCl ₃ ) δ: 1.25 (6H, d, J = 6.9 Hz), 1.51-1.57 (1H, m), 1.83-1.88 (2H, m) 1.90-2.05 (1H, m), 2.39 (3H, s), 2.58-2.80 (2H, m), 2.92 (1H, sept, J = 6.9 Hz). 3.16 (6H, s), 3.58 (1H, t, J = 7.0 Hz), 4.86 (1H, d, J = 14.4 Hz), 4.95 (1H, d, J = 14.4 Hz), 6.29 (1H, s), 6.97 (2H, d, J = 8.4 Hz), 7.22 (2H, d, J = 8.4 Hz), 7.41 (2H, d, J = 8.4 Hz), 7.69 (2H, d, J = 8.4 Hz).

Example 8

0.3 g of 2-methyl-4,5,6,7-tetrahydrobenzo [b] thiophene-4-carboxylic acid, [(2,6-dimethoxy-3-pyridyl) methyl] (4-isopropylphenyl) amine By reacting 43 g as a starting material in the same manner as in Example 1, N-[(2,6-dimethoxy-3-pyridyl) methyl] -N- (4-isopropylphenyl) -2-methyl-4, 0.19 g of 5,6,7-tetrahydrobenzo [b] thiophene-4-carboxamide was obtained as a pale yellow amorphous.

¹ H-NMR (CDCl ₃ ) δ: 1.22 (6H, d, J = 6.9 Hz), 1.49-1.53 (1H, m), 1.83 to 2.04 (3H, m) , 2.38 (3H, s), 2.56-2.80 (2H, m), 2.87 (1H, sept, J = 6.9 Hz), 3.56 (1H, t, J = 7. 2 Hz), 3.70 (3 H, s), 3.89 (3 H, s), 4.75 (1 H, d, J = 14.1 Hz), 4.94 (1 H, d, J = 14.1 Hz) 6.24 (1H, d, J = 8.1 Hz), 6.33 (1H, s), 6.96 (1H, d, J = 8.1 Hz).
MS (ESI) m / z: 465 [M + H] ⁺

Example 9

Starting from 0.5 g of 2-methyl-4,5,6,7-tetrahydrobenzo [b] thiophene-4-carboxylic acid and 0.78 g of (4-bromophenyl) (4-dimethylaminophenylmethyl) amine, By reacting in the same manner as in Example 7, N- (4-bromophenyl) -N- (4-dimethylaminophenylmethyl) -2-methyl-4,5,6,7-tetrahydrobenzo [b] thiophene 0.88 g of -4-carboxamide monohydrochloride was obtained as yellow crystals.

¹ H-NMR (CDCl ₃ ) δ: 1.50-1.59 (1H, m), 1.81-1.90 (2H, m), 2.01-2.04 (1H, m), 2 .39 (3H, s), 2.57-2.77 (2H, m), 3.15 (6H, s), 3.53 (1H, t, J = 6.9 Hz), 4.88 (1H , D, J = 15.0 Hz), 4.93 (1H, d, J = 15.0 Hz), 6.26 (1H, s), 6.94 (2H, d, J = 8.4 Hz), 7 .38 (2H, d, J = 8.1 Hz), 7.52 (2H, d, J = 8.4 Hz), 7.65 (2H, s).
MS (ESI) m / z: 483 [M + H] ⁺

Example 10

Starting from 0.3 g of 2-methyl-4,5,6,7-tetrahydrobenzo [b] thiophene-4-carboxylic acid and 0.39 g of (4-dimethylaminophenylmethyl) (4-methoxyphenyl) amine, By reacting in the same manner as in Example 7, N- (4-dimethylaminophenylmethyl) -N- (4-methoxyphenyl) -2-methyl-4,5,6,7-tetrahydrobenzo [b] thiophene 0.6 g of -4-carboxamide monohydrochloride was obtained as yellow crystals.

¹ H-NMR (CDCl ₃ ) δ: 1.50-1.56 (1H, m), 1.81-2.05 (3H, m), 2.62-2.75 (2H, m), 3 .17 (6H, s), 3.81 (3H, s), 4.87 (1H, d, J = 14.4 Hz), 4.93 (1H, d, J = 14.4 Hz), 6.28 (1H, s), 6.87 (2H, d, J = 8.7 Hz), 6.96 (2H, d, J = 8.7 Hz), 7.40 (2H, d, J = 8.4 Hz) , 7.70 (2H, d, J = 8.4 Hz).
MS (ESI) m / z: 435 [M + H] ⁺

Example 11

Starting from 0.5 g of 3-methyl-4,5,6,7-tetrahydrobenzo [b] thiophene-4-carboxylic acid and 0.68 g of (4-dimethylaminophenylmethyl) (4-isopropylphenyl) amine, By reacting in the same manner as in Example 7, N- (4-dimethylaminophenylmethyl) -N- (4-isopropylphenyl) -3-methyl-4,5,6,7-tetrahydrobenzo [b] thiophene 0.5 g of -4-carboxamide / 1 hydrochloride was obtained as yellow crystals.

¹ H-NMR (CDCl ₃ ) δ: 1.26 (6H, d, J = 6.9 Hz), 1.60-1.70 (1H, m), 1.78-1.88 (2H, m) , 2.00 (3H, s), 2.64-2.70 (1H, m), 2.80-2.89 (1H, m), 2.92 (1H, sept, J = 6.9 Hz) 3.14 (6H, s), 3.52 (1H, t, J = 6.0 Hz), 4.87 (2H, s), 6.64 (1H, s), 7.02 (2H, d) , J = 8.4 Hz), 7.24 (2H, d, J = 8.4 Hz), 7.39 (2H, d, J = 8.4 Hz), 7.62 (2H, brs).
MS (ESI) m / z: 447 [M + H] ⁺

Example 12

3-ethyl-2-methyl-4,5,6,7-tetrahydro-benzo [b] thiophene-4-carboxylic acid 1.04 g, (4-dimethylaminophenylmethyl) (4-isopropylphenyl) amine 1.37 g Was used as a starting material and reacted in the same manner as in Example 1 to give N- (4-dimethylaminophenylmethyl) -3-ethyl-N- (4-isopropylphenyl) -2-methyl-4,5,6. , 7-tetrahydrobenzo [b] thiophene-4-carboxamide was obtained as white crystals.

¹ H-NMR (CDCl ₃ ) δ: 0.93 (3H, t, J = 7.6 Hz), 1.24 (6H, d, J = 6.9 Hz), 1.60-1.69 (2H, m), 1.86-1.95 (1H, m), 2.00-2.04 (1H, m), 2.26 (3H, s), 2.29-2.36 (2H, m) 2.56-2.59 (1H, m), 2.75-2.92 (2H, m), 2.92 (6H, s), 3.44 (1H, t, J = 5.1 Hz) , 4.71 (1H, d, J = 13.8 Hz), 4.82 (1H, d, J = 13.8 Hz), 6.61 (2H, d, J = 8.4 Hz), 6.98 ( 2H, d, J = 8.4 Hz), 7.07 (2H, d, J = 8.4 Hz), 7.18 (2H, d, J = 8.4 Hz).
MS (ESI) m / z: 475 [M + H] ⁺

Example 13

0.69 g of 3-ethyl-2-methyl-4,5,6,7-tetrahydro-benzo [b] thiophene-4-carboxylic acid, (1-ethyl-1H-pyrazol-4-ylmethyl) (6-isopropylpyridine By reacting in the same manner as in Example 1 using 0.75 g of -3-yl) amine as a starting material, 3-ethyl-N-[(1-ethyl-1H-pyrazol-4-yl) methyl] -N 0.26 g of-(6-isopropylpyridin-3-yl) -2-methyl-4,5,6,7-tetrahydrobenzo [b] thiophene-4-carboxamide was obtained as a yellow oil.

¹ H-NMR (CDCl ₃ ) δ: 0.89 (3H, t, J = 7.5 Hz), 1.32 (6H, d, J = 6.9 Hz), 1.43 (3H, t, J = 7.2Hz), 1.62-1.80 (2H, m), 1.82-1.90 (1H, m), 1.97-2.08 (1H, m), 2.20-2. 27 (2H, m), 2.26 (3H, s), 2.50-2.62 (1H, m), 2.70-2.80 (1H, m), 3.11 (1H, sept, J = 6.9 Hz), 3.36 (1H, t, J = 5.1 Hz), 4.11 (2H, q, J = 7.2 Hz), 4.51 (1H, d, J = 14.4 Hz) ), 4.81 (1H, d, J = 14.4 Hz), 7.20-7.38 (4H, m,), 8.39 (1H, d, J = 2.1 Hz).
MS (ESI) m / z: 451 [M + H] ⁺

Example 14

0.7 g of 2-carbamoyl-4,5,6,7-tetrahydro-benzo [b] thiophene-4-carboxylic acid, [(1-ethyl-1H-pyrazol-4-yl) methyl] (4-isopropylphenyl) The reaction was conducted in the same manner as in Example 1 using 1.07 g of the amine as a starting material, whereby 2-carbamoyl-N-[(1-ethyl-1H-pyrazol-4-yl) methyl] -N- (4-isopropyl 1.1 g of phenyl) -4,5,6,7-tetrahydrobenzo [b] thiophene-4-carboxamide was obtained as a brown amorphous.
MS (ESI) m / z: 451 [MH] ⁺

1.1 g of the obtained brown amorphous was dissolved in 15 mL of tetrahydrofuran, and 1.0 g of pyridine was added and stirred under ice cooling. To the reaction solution was added dropwise a tetrahydrofuran solution (5 mL) of 2.77 g of trifluoroacetic anhydride, and the mixture was stirred for 2 hours under ice cooling. The reaction mixture was neutralized with saturated aqueous sodium hydrogen carbonate, and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off, the residue was purified by silica gel column chromatography, and 2-cyano-N-[(1-ethylpyrazol-4-yl) methyl] -N- (4-isopropylphenyl) -4,5,6, 0.4 g of 7-tetrahydrobenzo [b] thiophene-4-carboxamide was obtained as white crystals.

¹ H-NMR (DMSO-d ₆ ) δ: 1.20 (6H, d, J = 6.9 Hz), 1.31 (3H, t, J = 7.2 Hz), 1.40-1.55 ( 1H, m), 1.76-1.87 (2H, m), 1.90-2.00 (1H, m), 2.75 (2H, brs), 2.90 (1H, sept, J = 6.9 Hz), 3.49 (1H, t, J = 5.1 Hz), 4.06 (2H, q, J = 7.2 Hz), 4.58 (1H, d, J = 14.7 Hz), 4.71 (1H, d, J = 14.7 Hz), 7.21 (1H, s,), 7.24 (2H, d, J = 8.4 Hz), 7.31 (2H, d, J = 8.4 Hz), 7.50 (1H, s), 7.62 (1H, s).
MS (ESI) m / z: 433 [M + H] ⁺

Example 15

1.18 g of 2-bromo-4,5,6,7-tetrahydro-benzo [b] thiophene-4-carboxylic acid, [(1-ethylpyrazol-4-yl) methyl] (4-isopropylphenyl) amine By reacting in the same manner as in Example 1 using 65 g as a starting material, 2-bromo-N-[(1-ethylpyrazol-4-yl) methyl] -N- (4-isopropylphenyl) -4,5 , 6,7-Tetrahydrobenzo [b] thiophene-4-carboxamide 0.78 g was obtained as a yellow oil.

¹ H-NMR (DMSO-d ₆ ) δ: 1.20 (6H, d, J = 6.9 Hz), 1.31 (3H, t, J = 7.2 Hz), 1.41-1.50 ( 1H, m), 1.72-1.79 (2H, m), 1.88-1.95 (1H, m), 2.50-2.61 (2H, m), 2.91 (1H, sept, J = 6.9 Hz), 3.42 (1H, t, J = 6.9 Hz), 4.06 (2H, q, J = 7.2 Hz), 4.59 (1H, d, J = 14) .7 Hz), 4.69 (1 H, d, J = 14.7 Hz), 6.75 (1 H, s,), 7.19 (2 H, d, J = 8.1 Hz), 7.20 (1 H, s), 7.30 (2H, d, J = 8.1 Hz), 7.50 (1H, s).
MS (ESI) m / z: 486 [M] ⁺

Example 16

2-Bromo-N-[(1-ethyl-1H-pyrazol-4-yl) methyl] -N- (4-isopropylphenyl) -4,5,6,7-tetrahydrobenzo [b] thiophene-4-carboxamide 7.8g was melt | dissolved in THF80mL, and it cooled and stirred to -40 degreeC. To the reaction solution, 20 mL of 2.0 M isopropyl magnesium chloride (tetrahydrofuran solution) was added dropwise, and the temperature was raised to 0 ° C. and stirred for 1 hour. To the reaction solution, 20 mL of DMF was quickly poured, and the mixture was further separated with saturated brine and ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off, the residue was purified by silica gel column chromatography, and N-[(1-ethyl-1H-pyrazol-4-yl) methyl] -2-formyl-N- (4-isopropylphenyl) -4,5 , 6,7-Tetrahydrobenzo [b] thiophene-4-carboxamide was obtained as a yellow oil.
MS (ESI) m / z: 436 [M + H] ⁺

Example 17

N-[(1-ethyl-1H-pyrazol-4-yl) methyl] -2-formyl-N- (4-isopropylphenyl) -4,5,6,7-tetrahydrobenzo [b] thiophene-4-carboxamide 0.65 g, morpholine 0.16 g, acetic acid 0.52 mL, triacetoxyborohydride 0.64 g was dissolved in 1,2-dichloroethane 5 mL, and the mixture was stirred at room temperature for 1 hour. The reaction solution was neutralized with saturated aqueous sodium bicarbonate, and then extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off, the residue was purified by silica gel column chromatography, and N-[(1-ethyl-1H-pyrazol-4-yl) methyl] -N- (4-isopropylphenyl) -2- (morpholine-4- Ilmethyl) -4,5,6,7-tetrahydrobenzo [b] thiophene-4-carboxamide 0.6 g was obtained as a colorless oil.

¹ H-NMR (DMSO-d ₆ ) δ: 1.19 (6H, d, J = 6.9 Hz), 1.30 (3H, t, J = 7.2 Hz), 1.34-1.43 ( 1H, m), 1.70-1.82 (2H, m), 1.90-2.00 (1H, m), 2.36 (4H, brs), 2.58-2.64 (2H, m), 2.90 (1H, sept, J = 6.9 Hz), 3.40 (1H, t, J = 5.1 Hz), 3.52-3.58 (6H, m), 4.06 ( 2H, q, J = 7.2 Hz), 4.63 (2H, s), 6.48 (1H, s), 7.15 (2H, d, J = 8.1 Hz), 7.20 (1H, s), 7.30 (2H, d, J = 8.1 Hz), 7.49 (1H, s).
MS (ESI) m / z: 507 [M + H] ⁺

Example 18

N-[(1-ethyl-1H-pyrazol-4-yl) methyl] -2-formyl-N- (4-isopropylphenyl) -4,5,6,7-tetrahydrobenzo [b] thiophene-4-carboxamide 0.65 g, 0.18 g of 2,2,2-trifluoroethylamine was used as a starting material, and the reaction was carried out in the same manner as in Example 17 to obtain N-[(1-ethyl-1H-pyrazol-4-yl) methyl ] -N- (4-Isopropylphenyl) -2-[(2,2,2-trifluoroethylamino) methyl] -4,5,6,7-tetrahydrobenzo [b] thiophene-4-carboxamide 0.61 g Was obtained as a colorless oil.

¹ H-NMR (DMSO-d ₆ ) δ: 1.19 (6H, d, J = 6.9 Hz), 1.30 (3H, t, J = 7.2 Hz), 1.40-1.48 ( 1H, m), 1.78-1.82 (2H, m), 1.94-2.00 (1H, m), 2.57-2.68 (2H, m), 2.88-2. 97 (2H, m), 3.17-3.26 (2H, m), 3.38-3.42 (1H, m), 3.84 (2H, d, J = 6.3 Hz), 4. 06 (2H, q, J = 7.2 Hz), 4.60-4.72 (2H, m), 6.52 (1H, s), 7.15 (2H, d, J = 8.1 Hz), 7.20 (1H, s), 7.29 (2H, d, J = 8.1 Hz), 7.49 (1H, s)

Example 19

N-[(1-ethyl-1H-pyrazol-4-yl) methyl] -2-formyl-N- (4-isopropylphenyl) -4,5,6,7-tetrahydrobenzo [b] thiophene-4-carboxamide 0.65 g and 0.18 g of N-methylpiperazine were used as starting materials and reacted in the same manner as in Example 17 to give N-[(1-ethyl-1H-pyrazol-4-yl) methyl] -N- ( 4-Isopropylphenyl) -2-[(4-methylpiperazin-1-yl) methyl] -4,5,6,7-tetrahydrobenzo [b] thiophene-4-carboxamide was obtained as a colorless oil.

¹ H-NMR (DMSO-d ₆ ) δ: 1.19 (6H, d, J = 6.9 Hz), 1.31 (3H, t, J = 7.2 Hz), 1.34-1.43 ( 1H, m), 1.74-1.82 (2H, m), 1.90-2.00 (1H, m), 2.14 (3H, s), 2.20-2.42 (8H, m), 2.58-2.64 (2H, m), 2.90 (1H, sept, J = 6.9 Hz), 3.51 (2H, s), 4.06 (2H, q, J = 7.2 Hz), 4.63 (2H, s), 6.47 (1 H, s), 7.15 (2 H, d, J = 8.1 Hz), 7.20 (1 H, s), 7.30 (2H, d, J = 8.1 Hz), 7.49 (1H, s).
MS (ESI) m / z: 520 [M + H] ⁺

Example 20

N-[(1-ethyl-1H-pyrazol-4-yl) methyl] -2-formyl-N- (4-isopropylphenyl) -4,5,6,7-tetrahydrobenzo [b] thiophene-4-carboxamide 0.65 g and 0.13 g of pyrrolidine were used as starting materials and reacted in the same manner as in Example 17 to give N-[(1-ethyl-1H-pyrazol-4-yl) methyl] -N- (4-isopropyl 0.61 g of phenyl) -2- (pyrrolidin-1-ylmethyl) -4,5,6,7-tetrahydrobenzo [b] thiophene-4-carboxamide was obtained as a colorless oil.

¹ H-NMR (DMSO-d ₆ ) δ: 1.19 (6H, d, J = 6.9 Hz), 1.30 (3H, t, J = 7.2 Hz), 1.34-1.43 ( 1H, m), 1.72-1.80 (6H, m), 1.91-1.98 (1H, m), 2.43-2.47 (4H, m), 2.55-2. 60 (2H, m), 2.90 (1 H, sept, J = 6.9 Hz), 3.36-3.40 (1 H, m), 3.59 (1 H, d, J = 13.8 Hz), 3.66 (1H, d, J = 13.8 Hz), 4.63 (2H, s), 6.45 (1H, s), 7.15 (2H, d, J = 8.1 Hz), 7. 20 (1H, s), 7.30 (2H, d, J = 8.1 Hz), 7.49 (1H, s).
MS (ESI) m / z: 491 [M + H] ⁺

Example 21

N-[(1-ethyl-1H-pyrazol-4-yl) methyl] -2-formyl-N- (4-isopropylphenyl) -4,5,6,7-tetrahydrobenzo [b] thiophene-4-carboxamide The reaction was carried out in the same manner as in Preparation Example 39 using 1.86 g as a starting material, whereby N-[(1-ethyl-1H-pyrazol-4-yl) methyl] -2-hydroxymethyl-N- (4-isopropyl Phenyl) -4,5,6,7-tetrahydrobenzo [b] thiophene-4-carboxamide 1.81 g was obtained as a colorless oil.

¹ H-NMR (DMSO-d ₆ ) δ: 1.19 (6H, d, J = 6.9 Hz), 1.30 (3H, t, J = 7.2 Hz), 1.35 to 1.43 ( 1H, m), 1.77-1.83 (2H, m), 1.93-1.98 (1H, m), 2.58-2.63 (2H, m), 2.90 (1H, sept, J = 6.9 Hz), 3.34-3.41 (1H, m), 4.06 (2H, q, J = 7.2 Hz), 4.49 (2H, d, J = 5.4 Hz) ), 4.61 (1H, d, J = 14.7 Hz), 4.68 (1H, d, J = 14.7 Hz), 5.32 (1H, t, J = 5.4 Hz), 6.50. (1H, s), 7.15 (2H, d, J = 8.1 Hz), 7.20 (1H, s), 7.30 (2H, d, J = 8.1 Hz), 7.49 (1H , S)

Example 22

N-[(1-ethyl-1H-pyrazol-4-yl) methyl] -2-hydroxymethyl-N- (4-isopropylphenyl) -4,5,6,7-tetrahydrobenzo [b] thiophene-4- Carboxamide (1.81 g) was dissolved in dichloromethane (10 mL), thionyl chloride (0.36 mL) was added, and the mixture was stirred at room temperature for 3 hr. The solvent was distilled off under reduced pressure, 15 mL of methanol was added to the residue, and further 1.5 mL of 4.85 M sodium methoxide / methanol solution was added with stirring at room temperature. The reaction solution was neutralized with saturated aqueous ammonium chloride, and then extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off, the residue was purified by silica gel column chromatography, the resulting solid was washed with diisopropyl ether, and N-[(1-ethyl-1H-pyrazol-4-yl) methyl] -N- (4 -Isopropylphenyl) -2-methoxymethyl-4,5,6,7-tetrahydrobenzo [b] thiophene-4-carboxamide 0.87 g was obtained as white crystals.

¹ H-NMR (DMSO-d ₆ ) δ: 1.19 (6H, d, J = 6.9 Hz), 1.30 (3H, t, J = 7.2 Hz), 1.37-1.43 ( 1H, m), 1.75-1.81 (2H, m), 1.92-1.96 (1H, m), 2.60-2.67 (2H, m), 2.90 (1H, sept, J = 6.9 Hz), 3.24 (3H, s), 3.39-3.44 (1H, m), 4.06 (2H, q, J = 7.2 Hz), 4.44 ( 2H, s), 4.60 (1H, d, J = 14.7 Hz), 4.68 (1H, d, J = 14.7 Hz), 6.59 (1H, s), 7.16 (2H, d, J = 8.1 Hz), 7.20 (1H, s), 7.30 (2H, d, J = 8.1 Hz), 7.49 (1H, s)

Example 23

Starting materials were 0.2 g of 1,3-dimethyl-4,5,6,7-tetrahydrobenzo [c] thiophene-4-carboxylic acid and 0.35 g of (4-dimethylaminophenylmethyl) (4-isopropylphenyl) amine. By reacting in the same manner as in Example 1, 1,3-dimethyl-N- (4-dimethylaminophenylmethyl) -N- (4-isopropylphenyl) -4,5,6,7-tetrahydrobenzo [C] 0.3 g of thiophene-4-carboxamide was obtained as a brown oil.

¹ H-NMR (DMSO-d ₆ ) δ: 1.19 (6H, d, J = 6.9 Hz), 1.30-1.40 (1H, m), 1.68-1.85 (3H, m), 2.13 (3H, s), 2.34-2.40 (2H, m), 2.83-2.91 (1H, m), 2.85 (6H, s), 3.37. -3.99 (1H, m), 4.67 (1H, d, J = 14.4 Hz), 4.74 (1H, d, J = 14.4 Hz), 6.62 (2H, d, J = 8.7 Hz), 6.97 (2H, d, J = 8.7 Hz), 7.09 (2H, d, J = 8.4 Hz), 7.29 (2H, d, J = 8.4 Hz).
MS (ESI) m / z: 461 [M + H] ⁺

Example 24

Starting with 0.42 g of 2-methyl-5,6,7,8-tetrahydro-4H-cyclohepta [b] thiophene-4-carboxylic acid and 0.54 g of (4-dimethylaminophenylmethyl) (4-isopropylphenyl) amine N- (4-dimethylaminophenylmethyl) -N- (4-isopropylphenyl) -2-methyl-5,6,7,8-tetrahydro-4H was prepared by reacting as a raw material in the same manner as in Example 1. -0.13 g of cyclohepta [b] thiophene-4-carboxamide was obtained as a pale yellow oil.

¹ H-NMR (DMSO-d ₆ ) δ: 1.17 (6H, d, J = 6.9 Hz), 1.35-1.70 (5H, m), 1.90-2.00 (1H, m), 2.28 (3H, s), 2.29-2.38 (1H, m), 2.77-2.90 (1H, m), 2.85 (6H, s), 3.48. -3.51 (1H, m), 4.72 (2H, s), 6.33 (1H, s), 6.63 (2H, d, J = 8.4 Hz), 6.94 (2H, d , J = 8.4 Hz), 6.98 (2H, d, J = 8.4 Hz), 7.22 (2H, d, J = 8.4 Hz).
MS (ESI) m / z: 461 [M + H] ⁺

Example 25

2-methyl-5,6,7,8-tetrahydro-4H-cyclohepta [b] thiophene-4-carboxylic acid 0.27 g, N- (4-dimethylamino-5-trifluoromethylphenyl) -N-[( 6-Methylpyridin-3-yl) methyl] amine is used as a starting material, and the reaction is carried out in the same manner as in Example 1 to give N- (4-dimethylamino-3-trifluoromethylphenyl) -N- 0.42 g of [(6-methylpyridin-3-yl) methyl] -2-methyl-5,6,7,8-tetrahydro-4H-cyclohepta [b] thiophene-4-carboxamide was obtained as a yellow oil.

¹ H-NMR (DMSO-d ₆ ) δ: 1.42-1.69 (5H, m), 1.87-1.95 (1H, m), 2.28 (3H, s), 2.29 -2.38 (1H, m), 2.42 (3H, s), 2.66 (6H, s), 2.73-2.80 (1H, m), 3.46-3.49 (1H M), 4.83 (1H, d, J = 14.7 Hz), 4.90 (1 H, d, J = 8.4 Hz), 6.28 (1 H, s), 7.19-7.54. (5H, m), 8.23 (1H, d, J = 2.0 Hz).
MS (ESI) m / z: 502 [M + H] ⁺

Example 26

0.42 g of 2-methyl-5,6,7,8-tetrahydro-4H-cyclohepta [b] thiophene-4-carboxylic acid, N-[(1-ethyl-1H-pyrazol-4-yl) methyl] -N By using 0.62 g of-(4-dimethylamino-3-trifluoromethylphenyl) amine as a starting material and reacting in the same manner as in Example 1, N- (4-dimethylamino-3-trifluoromethylphenyl) 0.47 g of -N-[(1-ethyl-1H-pyrazol-4-yl) methyl] -2-methyl-5,6,7,8-tetrahydro-4H-cyclohepta [b] thiophene-4-carboxamide is yellow Obtained as an oil.

¹ H-NMR (DMSO-d ₆ ) δ: 1.29 (3H, t, J = 7.2 Hz), 1.38-1.68 (5H, m), 1.87-1.98 (1H, m), 2.27 (3H, s), 2.28-2.37 (1H, m), 2.60-2.80 (2H, m), 2.67 (6H, s), 3.37. -3.41 (1H, m), 4.06 (2H, q, J = 7.2 Hz), 4.61 (1H, d, J = 14.7 Hz), 4.73 (1H, d, J = 14.7 Hz), 6.27 (1 H, s), 7.17 (1 H, brs), 7.22 (1 H, s), 7.33 (1 H, d, J = 8.7 Hz), 7.43 (1H, d, J = 8.7 Hz), 7.54 (1H, s).
MS (ESI) m / z: 505 [M + H] ⁺

Example 27

Starting from 0.32 g of 2-methyl-5,6-dihydro-4H-cyclopenta [b] thiophene-4-carboxylic acid and 0.47 g of (4-dimethylaminophenylmethyl) (4-isopropylphenyl) amine By reacting in the same manner as in Example 1, N- (4-dimethylaminophenylmethyl) -N- (4-isopropylphenyl) -2-methyl-5,6-dihydro-4H-cyclopenta [b] thiophene-4 -0.33 g of carboxamide was obtained as a yellow oil.

¹ H-NMR (DMSO-d ₆ ) δ: 1.17 (6H, d, J = 6.9 Hz), 2.28-2.36 (1H, m), 2.38 (3H, s), 2 .52-2.65 (2H, m), 2.78-2.92 (2H, m), 2.85 (6H, s), 3.69 (1H, t, J = 6.9 Hz), 4 .68 (1H, d, J = 14.4 Hz), 4.77 (1H, d, J = 14.4 Hz), 6.45 (1H, s), 6.63 (2H, d, J = 8. 4 Hz), 6.97 (2H, d, J = 8.4 Hz), 7.09 (2H, d, J = 8.1 Hz), 7.27 (2H, d, J = 8.1 Hz).
MS (ESI) m / z: 433 [M + H] ⁺

Example 28

0.23 g of 1,3-dimethyl-5,6,7,8-tetrahydro-4H-cyclohepta [c] thiophene-4-carboxylic acid and (1-ethyl-1H-pyrazol-4-ylmethyl) (6-isopropylpyridine 1,3-Dimethyl-N-[(1-ethyl-1H-pyrazol-4-yl) methyl] was prepared by reacting in the same manner as in Example 1 using 0.21 g of -3-yl) amine as a starting material. 0.1 g of -N- (6-isopropylpyridin-3-yl) -5,6,7,8-tetrahydro-4H-cyclohepta [c] thiophene-4-carboxamide was obtained as a pale yellow oil.

¹ H-NMR (DMSO-d ₆ ) δ: 1.14-1.25 (2H, m), 1.22 (6H, d, J = 6.9 Hz), 1.28 (3H, t, J = 7.2 Hz), 1.67-1.80 (4H, m), 1.75 (3H, s), 2.18 (3H, s), 2.53-2.58 (1H, m), 2 79-2.87 (1H, m), 3.03 (1H, sept, J = 6.9 Hz), 3.67 (1H, brs), 4.04 (2H, q, J = 7.2 Hz) , 4.52 (1H, d, J = 14.4 Hz), 4.69 (1H, d, J = 14.4 Hz), 7.17 (1H, s), 7.31 (1H, d, J = 8.4 Hz), 7.49-7.53 (2 H, m), 8.27 (1 H, d, J = 1.8 Hz)
MS (ESI) m / z: 451 [M + H]

Example 29

1,3-Dimethyl-5,6,7,8-tetrahydro-4H-cyclohepta [c] thiophene-4-carboxylic acid 0.2 g and N- (4-methoxyphenyl) -1-ethyl-1H-pyrazole-4 -By using 0.21 g of carboxamide as a starting material and reacting in the same manner as in Example 1, 1,3-dimethyl-N-[(1-ethyl-1H-pyrazol-4-yl) methyl] -N- ( 4-methoxyphenyl) -5,6,7,8-tetrahydro-4H-cyclohepta [c] thiophene-4-carboxamide 0.34 g was obtained as a pale yellow oil.

¹ H-NMR (DMSO-d ₆ ) δ: 1.07-1.21 (2H, m), 1.29 (3H, t, J = 7.2 Hz), 1.64-1.82 (4H, m), 1.83 (3H, s), 1.99 (3H, s), 2.59-2.63 (1H, m), 2.91-2.97 (1H, m), 3.77. (3H, s), 3.75-3.79 (1H, m), 4.02 (2H, q, J = 7.2 Hz), 4.48 (1H, d, J = 14.7 Hz), 4 .61 (1H, d, J = 14.7 Hz), 6.97 (2H, d, J = 8.7 Hz), 7.00 (2H, d, J = 8.7 Hz), 7.15 (1H, s), 8.46 (1H, s)
MS (ESI) m / z: 438 [M + H]

Example 30

0.23 g of 1,3-dimethyl-5,6,7,8-tetrahydro-4H-cyclohepta [c] thiophene-4-carboxylic acid and [(6-dimethylaminopyridin-3-yl) methyl] (4-isopropyl 1,4-Dimethyl-N-[(6-dimethylaminopyridin-3-yl) methyl] -N- (4) was prepared by subjecting 0.24 g of phenyl) amine as a starting material to the reaction treatment in the same manner as in Example 1. -Isopropylphenyl) -5,6,7,8-tetrahydro-4H-cyclohepta [c] thiophene-4-carboxamide was obtained as white crystals.

¹ H-NMR (DMSO-d ₆ ) δ: 1.14-1.32 (2H, m), 1.20 (6H, d, J = 6.9 Hz), 1.68-1.82 (4H, m), 1.97 (3H, s), 2.19 (3H, s), 2.56-2.63 (1H, m), 2.86-2.97 (1H, m), 2.97. (6H, s), 3.79 (1H, brs), 4.51 (1H, d, J = 14.4 Hz), 4.76 (1H, d, J = 14.4 Hz), 6.57 (1H , D, J = 8.7 Hz), 7.07 (1H, d, J = 8.7 Hz), 7.28-7.33 (3H, m), 7.76 (1H, d, J = 2. 1Hz)
MS (ESI) m / z: 476 [M + H]

  The excellent pharmacological effect of the compound of the general formula (1) is proved by a series of tests shown below.

Test Example 1: C5a Receptor Binding Test C5a and C5a receptor binding inhibitory action of the test compounds were performed using human cell lines U-937 (human histolytic lymphoma line) and [ ¹²⁵ I] -human C5a (Amersham Pharmacia Biotech) was evaluated by a receptor binding test in which it was reacted in a multiscreen (MILLIPORE). First, U937 cells were stimulated with 1 mM dibutylyl cyclic AMP (dcAMP, sigma) for 2 days to express the C5a receptor (dcAMP-U937 cells), and binding buffer (50 mM HEPES, 1 mM CaCl ₂ , 5 mM MgCl ₂ , 0.5 % Bovine albumin (BSA, Sigma), 0.02% NaN ₃ (pH 7.2)) and stored at −80 ° C. For binding studies, 50 μL of dcAMP-U937 cell suspension thawed just prior to execution, 25 μL of Binding Buffer or test compound solution and 25 μL of [ ¹²⁵ I] -C5a solution (final concentration 200 pM) are added to each well of the multiscreen. And started. In order to calculate nonspecific binding, unlabeled C5a (final concentration 20 nM) was added instead of the test compound solution. After incubating at 4 ° C. for 2 hours, unbound components were removed by repeating suction filtration and adding 300 μL of binding buffer four times. After the multiscreen was dried, the radioactivity on the filter was measured with a gamma counter.

  Calculation of C5a binding inhibition rate (% inhibition) of test compound is as follows: the count value when no test compound is added is Total, the count value when non-labeled C5a is added is Non, and the count value when test compound is added is Test It was performed by the following formula.

% Inhibition = (Test-Non) / (Total-Non) × 100
Furthermore, the concentration (IC ₅₀ value) of the test compound that inhibits the binding of [ ¹²⁵ I] -human C5a by 50% was calculated by a two-point interpolation method. In this evaluation system, the IC ₅₀ value of the compound of Example 11 was 33 nmol / L.

Test Example 2: Effect of C5a-stimulated neutrophils on increase in intracellular Ca ²⁺ concentration A neutrophil fraction was collected from human peripheral venous blood using Lympholyte-poly (Cedarlane), and 1% Fetal bovine serum ( FBS) was added to Hank's Balanced Salt Solution (HBSS, GIBCO BRL). Next, Fura 2-AM (Dojindo Laboratories) with a final concentration of 5 μM was added to the neutrophil fraction (5 × 10 ⁶ cells / mL) and incubated at 37 ° C. for 40 minutes. The cells were washed by centrifugation and then suspended at a concentration of 1 × 10 ⁶ cells / mL. The intracellular Ca ²⁺ concentration was measured using a fluorescence spectrophotometer (CAF-110, JASCO), and the fluorescence intensity at 500 nm when excited at 340 nm and 380 nm (the former was the Ex340 value and the latter was the Ex380 value) The ratio (Ex340 value / Ex380 value) was calculated. First, 450 μL of a neutrophil suspension (1 × 10 ⁶ cells / mL) was dispensed into a cuvette containing a stir bar 5 minutes before the measurement and heated to 37 ° C. Subsequently, 50 μL of the test compound solution was added immediately after the measurement was started by setting the CAF-110 set at 37 ° C. About 45 seconds later, 5 μL of recombinant human C5a (final concentration 100 pmol / L) was added, and measurement was continued for about 1 minute. Subsequently, a final concentration of 0.2% Triton X-100 was added to lyse the cells, and the sb2 value as the Ex340 value and the Rmax value as the Ex340 value / Ex380 value at that time were measured. Next, EGTA having a final concentration of 3 mmol / L was added, and the sf2 value as the Ex340 value and the Rmin value as the Ex340 / Ex380 value at that time were measured. From these measurement results, the intracellular Ca ²⁺ concentration was calculated by the following formula.

The calculation of the inhibition rate (% inhibition) of the increase in intracellular Ca ²⁺ concentration in C5a-stimulated neutrophils by the test compound was performed by calculating the peak value of the increase in intracellular Ca ²⁺ concentration induced by C5a when no test compound was added. The peak value of the intracellular Ca ²⁺ concentration when the test compound is not added and when C5a is not stimulated is Min, and the peak value of the intracellular Ca ²⁺ concentration increase induced by C5a when the test compound is added is the test. It was done by the formula.

% Inhibition = (Test-Min) / (Max-Min) × 100
Furthermore, the concentration (IC ₅₀ value) of the test compound that inhibits the increase in intracellular Ca ²⁺ concentration in C5a-stimulated neutrophils by 50% was calculated by a 2-point interpolation method. The IC ₅₀ value of the compound of Example 24 was 120 nmol / L.

Test Example 3: Effect of C5a-stimulated neutrophils on reactive oxygen species production A neutrophil fraction was fractionated from human peripheral venous blood using Lympholyte-poly (Cedarlane), and 1% Fetal bovine serum (FBS) and The suspension was suspended in Hank's Balanced Salt Solution (HBSS, GIBCO BRL) to which 1 mmol / L luminol (Wako Pure Chemical Industries) was added. For the measurement of active oxygen, a luminometer (MicroLumat, Bertoled) corresponding to a 96-well plate was used. That is, 1 × 10 ⁵ cells / 150 μL of a neutrophil suspension and 25 μL of a test compound solution were added to a well, set in a MicroLumat set at 37 ° C., and left for about 5 minutes. Subsequently, 25 μL of C5a (final concentration: 3 nmol / L) was added, and luminescence generated by the reaction between luminol and active oxygen species was measured over time for 15 minutes. The calculation of the inhibition rate (% inhibition) of reactive oxygen species production in C5a-stimulated neutrophils by the test compound is Max, the peak value of reactive oxygen species production induced by C5a when no test compound is added, The peak value of reactive oxygen species production when C5a was not stimulated was Min, and the peak value of reactive oxygen species production induced by C5a when the test compound was added was Test.

% Inhibition = (Test-Min) / (Max-Min) × 100
Furthermore, the concentration (IC ₅₀ value) of a test compound that inhibits 50% of reactive oxygen species production in C5a-stimulated neutrophils was calculated by a two-point interpolation method. The IC ₅₀ value of the compound of Example 11 was 4.6 nmol / L.

  From these results, it was found that the compound of the present invention has C5a receptor antagonism. Therefore, the compound of the present invention is mediated by a preventive and / or therapeutic agent for C5a-related diseases, an anti-inflammatory agent, and a C5a receptor. It is considered useful as a preventive and / or therapeutic agent for infectious diseases caused by invading bacteria and viruses.

Claims (16)

General formula (1)

[Wherein, R ¹ , R ² and R ³ are the same or different and each has a hydrogen atom, an alkyl which may have a substituent, an alkenyl which may have a substituent, or a substituent. Alkynyl which may have a substituent, cycloalkyl which may have a substituent, alkoxy which may have a substituent, acyl which may have a substituent, acyloxy which may have a substituent, Halogen atom, hydroxyl group, nitro, cyano, mercapto, optionally substituted alkylthio, optionally substituted alkylsulfonyl, amino, optionally substituted alkylamino, substituent Dialkylamino which may have a substituent, cyclic amino which may have a substituent, carbamoyl, alkoxycarbonyl which may have a substituent, carboxyl, sulfamoyl or Shows the mill,
a, b, c, d and e all represent carbon atoms, or any one or two of a, b, c, d and e represent nitrogen atoms and the rest represent carbon atoms,
A represents a hydrogen atom, an optionally substituted cycloalkyl, an optionally substituted aryl, an optionally substituted heteroaryl, or an optionally substituted cyclic. Indicates amino,

Is the following formula

(Wherein R ⁴ and R ⁵ are the same or different, and each may have a hydrogen atom, an optionally substituted alkyl, an optionally substituted alkenyl, or an optionally substituted group. Alkynyl, cycloalkyl which may have a substituent, alkoxy which may have a substituent, acyl which may have a substituent, acyloxy which may have a substituent, a halogen atom, Hydroxyl group, nitro, cyano, mercapto, optionally substituted alkylthio, optionally substituted alkylsulfonyl, amino, optionally substituted alkylamino, substituted Dialkylamino which may have a substituent, cyclic amino which may have a substituent, carbamoyl, alkoxycarbonyl which may have a substituent, carboxyl, sulfamoyl or formyl Indicates bicyclic sulfur-containing heterocyclic ring group selected from the group consisting of indicating),
X represents an oxygen atom or a sulfur atom,
Y represents methylene or alkylene which may have a substituent,
Z represents methylene or alkylene which may have a bond or a substituent. Or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof. R ¹ , R ² and R ^{3 in the} general formula (1) are the same or different and each has 1 to 3 carbon atoms substituted with a hydrogen atom, alkyl having 2 to 4 carbon atoms, methoxy, halogen atom, or halogen atom The amide derivative according to claim 1, which is alkyl, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof. The amide derivative according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, or a ring thereof, wherein the ring composed of a, b, c, d, e and carbon atom in the general formula (1) is phenyl or pyridyl. Hydrates or solvates. The amide derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein A in the general formula (1) is an optionally substituted phenyl or an optionally substituted heteroaryl. Or a hydrate or solvate thereof. Of general formula (1)

The amide derivative according to claims 1 to 4, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof.

Or

R ⁴ and R ^{5 in} the general formula (1) are the same or different and each has a hydrogen atom, an optionally substituted alkyl, a halogen atom, an optionally substituted alkoxy, or a substituted group. The amide derivative according to claim 1, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof. X of general formula (1) is an oxygen atom, The amide derivative of Claims 1-6, its pharmaceutically acceptable salt, those hydrates, or a solvate. Formula (1) of -Y- is _{- (CH 2) -, -} (CH 2) 2 -, - (CH 2) 3 - and is acceptable amide derivative or a pharmaceutically according to claim 1 to 7 Or a hydrate or solvate thereof. Z of general formula (1) is methylene, The amide derivative of Claims 1-8, its pharmaceutically acceptable salt, those hydrates, or a solvate. N- (4-dimethylaminophenylmethyl) -N- (4-isopropylphenyl) -4,5,6,7-tetrahydrobenzo [b] thiophene-4-carboxamide,
N- (4-dimethylaminophenylmethyl) -N- (4-isopropylphenyl) -2-methyl-4,5,6,7-tetrahydrobenzo [b] thiophene-4-carboxamide;
N- (4-dimethylaminophenylmethyl) -N- (4-isopropylphenyl) -3-methyl-4,5,6,7-tetrahydrobenzo [b] thiophene-4-carboxamide;
1,3-dimethyl-N- (4-dimethylaminophenylmethyl) -N- (4-isopropylphenyl) -4,5,6,7-tetrahydrobenzo [c] thiophene-4-carboxamide,
Or N- (4-dimethylaminophenylmethyl) -N- (4-isopropylphenyl) -2-methyl-5,6,7,8-tetrahydro-4H-cyclohepta [b] thiophene-4-carboxamide or a pharmaceutical thereof Acceptable salts or hydrates or solvates thereof. A pharmaceutical composition comprising the amide derivative according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, and a pharmaceutically acceptable additive. A prophylactic and / or therapeutic drug for a disease involving C5a, comprising the amide derivative according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof. Diseases involving C5a are autoimmune diseases, sepsis, adult respiratory distress syndrome, allergic diseases, atherosclerosis, myocardial infarction, cerebral infarction, psoriasis, Alzheimer's disease or ischemia reperfusion or trauma, burns, surgical invasion, etc. The prophylactic and / or therapeutic agent according to claim 12, which is an organ damage caused by leukocyte activation caused by the disease. The anti-inflammatory drug containing the amide derivative in any one of Claims 1-10, its pharmaceutically acceptable salt, or those hydrates or solvates. A C5a receptor antagonist comprising the amide derivative according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof. The C5a receptor antagonist according to claim 15, which is a prophylactic and / or therapeutic agent for infections caused by bacteria or viruses that enter via the C5a receptor.