JP2003335670A - Adhesion-preventing agent - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To obtain a safe and effective adhesion-preventing agent without side effects to enhance the quality of daily life of a patient by preventing adhesion after operation. <P>SOLUTION: This adhesion-preventing agent contains an N-substituted benzothiophenesulfonamide derivative having a specific structure or a pharmaceutically acceptable salt thereof as an active ingredient. <P>COPYRIGHT: (C)2004,JPO

Description

DETAILED DESCRIPTION OF THE INVENTION [0001] The present invention relates to a novel chymase inhibitor
Derivation of N-substituted benzothiophene sulfonamides as harmful agents
Adhesion containing the body and its pharmaceutically acceptable salts as active ingredients
Related to inhibitors. [0002] 2. Description of the Related Art Tissue adhesion in mammals including humans
Are gastroenterology, cardiology, orthopedics, gynecology, ophthalmology, etc.
May occur after surgery in the hospital and cause pain to the postoperative patient
In addition, it has a profound effect on prognosis. For example,
In the case of laparotomy, the organs inside the abdominal cavity after surgery, namely the abdominal wall, intestine
A phenomenon in which the tubes and the like adhere to each other occurs, which may cause intestinal obstruction.
In some cases, reoperation is necessary. In gynecology area
Develops postoperative adhesions in patients who have had infections or pelvic surgery
However, oviduct obstruction can cause infertility. heart
Adhesion limits reoperation in surgery
Bleeding in some cases or during reoperation may be a problem. Ophthalmic territory
In the area, if organic adhesion or postoperative adhesion occurs, intraocular pressure
Quality of visi, including trawl failure
On becomes difficult to maintain. [0003] As a method of preventing adhesions after surgery, various drugs and special features are used.
Attempts have been made to use special membranes. Drugs to prevent adhesions
Examples of the agent include a high-molecular-weight polysaccharide having a wound covering effect, for example,
Sodium alginate, sodium chondroitin sulfate
Dextran and sodium hyaluronate
Dexame as an anti-adhesion agent after fallopian tube surgery
Carbohydrates such as tazone and triamcinolone acetonide
Coid is used. Gelatin is used as a film
Film or sponge used (Zel film, Zelfo
(Registered trademark)), a polytetrafluoroethylene
(Gore-Tex®), carboxymethyl
Hyaluronic acid sheet modified with cellulose etc.
Lafilm (registered trademark)). But,
At present, none of these drugs is effective enough
It is. On the other hand, chymase is present in mast cell granules.
Is a type of serine protease that activates mast cells.
Secreted by granules, long in heart, blood vessels, skin, etc.
Exerts enzymatic activity during anagen and participates in various biological reactions
It is known. Chymase is used in hearts and blood vessels, etc.
Production of Ngiotensin II (hereinafter referred to as Ang II)
It is said to be involved in
70% to 80% of the amount of Ang II produced in blood vessels and chymase
(Non-Patent Document 2)
Therefore, chymase inhibitors can cause abnormal enhancement of Ang II production
As a preventive / therapeutic agent for cardiac and cardiovascular diseases
Have been. Chymase also promotes mast cell degranulation
Activation, interleukin-1β activation, matrix
Has various actions such as activation of taroprotease
In various inflammatory allergic diseases,
Has been suggested to play a new role.
You. Recently, a chymase inhibitor, pepti
Suc-Val-Pro-Phe^P(OPh)_TwoBut ha
Suppresses the adhesion of organs after uterine scraping with the Muster adhesion model
(Non-Patent Document 3) and a Canine Trabeculectomy Model
Reported that the adhesion of the filtration bleb was suppressed by non-patent document 4.
It has been tell. In addition, chymase which is a quinazoline derivative
Inhibitors improve extracellular matrix metabolism abnormalities after surgery
Can be used to prevent the adhesion of
1). [0005] [Non-Patent Document 1] "Circulation Research (Ci
rculation Research) ", (USA)
Association (American Heart Association),
1990, Vol. 66, p. 883 [Non-Patent Document 2] "The Journal of Biology
Cal chemistry (The Journal of biological chem
istry) "(US), American Society
O Biochemistry and Molecular Ba
Iology (American Society for Biochemistry and M
olecular Biology), 1990, vol. 265, p. 2
2348 [Non-Patent Document 3] "European Journal of
Pharmacology (European journal of pharmacolog
y) ", (Netherlands), Elsevier Science (Elsev)
ier Scince), 2002, Vol. 435, p. 265 [Non-Patent Document 4] Journal of the Japanese Ophthalmology Society, 2002, No. 1
06 (extra number), p. 131 [Patent Document 1] International Publication No. 01/62292 Pamphlet
Pit [0006] SUMMARY OF THE INVENTION The present invention relates to post-operative healing.
To prevent wear and enhance the quality of life for patients,
To provide a safe and effective anti-adhesion agent
With the goal. [0007] Means for Solving the Problems The present inventors have achieved the above object.
As a result of intensive studies to achieve
Derivation of N-substituted benzothiophene sulfonamides as harmful agents
The body or its pharmaceutically acceptable salt is induced after surgery
To prevent adhesions, and completed the present invention.
Was. That is, the present invention provides a compound represented by the general formula (I): [0008] Embedded image [Wherein, R¹Is a hydrogen atom, a halogen atom or
Represents a lower alkyl group, R^TwoRepresents a lower alkyl group, R^Threeas well as
R^FourMay be different from each other, and
Alkoxycarbonyl group, lower alkylsulfonyl group,
Nzoyl group, C 1-4 acyl group, lower alkoxy
Group, lower alkoxycarbonylmethylthioacetyl group,
Nitro group, -CONHR⁶(Where R⁶Is a hydrogen atom, lower
Alkoxycarbonylmethyl group, carboxymethyl group or
Is -CH (CH_TwoOH) COOR⁷(Where R⁷Is hydrogen field
Represents a lower alkyl group or a lower alkyl group)), [0010] Embedded image A group represented by the formula:⁷Is as defined above
is there), Embedded image A group represented by the formula (wherein R⁸And R⁹Each
Hydrogen atom, lower alkyl group, lower
Lower alkylsulfanyl group, lower alkylsulfinyl
Group, lower alkylsulfonyl group or lower alkoxycar
Bonyl group), hydroxy lower alkyl group, cyano
Group or [0013] Embedded image (A represents an oxygen atom, a sulfur atom or NH,
The dotted line indicates a single bond or a double bond)
Heterocyclic group (however, a hydrogen atom on the ring is a halogen atom
Lower alkyl group which may be substituted, lower alkoxy
Group, hydroxy lower alkyl group, lower alkoxycarbo
It may be substituted with a phenyl group or a carboxyl group. )
(Where R^ThreeAnd R^FourIs not a hydrogen atom at the same time
No). R^FiveRepresents a hydrogen atom, a lower alkoxy group or a lower
N-substituted benzothiophene represented by the following formula:
A sulfonamide derivative or a pharmaceutically acceptable salt thereof.
An anti-adhesion agent characterized by containing it as an active ingredient
It is about. The N-substituted base represented by the general formula (I) of the present invention
Nzothiophene sulfonamide derivatives or pharmaceutically acceptable
Acceptable salts have potent inhibitory activity against chymase
New chymase inhibitor
Was found to be useful as an anti-adhesion agent. [0016] DETAILED DESCRIPTION OF THE INVENTION¹Examples of the halogen atom are
For example, a fluorine, chlorine, bromine or iodine atom
And a fluorine atom or a chlorine atom is preferred.
No. R¹, R^Two, R^Five, R⁷, R⁸And R⁹Lower alkyl group
Are, for example, methyl, ethyl, propyl,
Isopropyl, butyl, isobutyl, sec-butyl
And a tert-butyl group.
Or an ethyl group is preferred. R^Three, R^Four, R⁸And R⁹Lower alkoxyca
Examples of the rubonyl group include a methoxycarbonyl group and
Toxoxycarbonyl group, propoxycarbonyl group, isop
Ropoxycarbonyl group, butoxycarbonyl group, isobu
Toxoxycarbonyl group, sec-butoxycarbonyl group or
Is a tert-butoxycarbonyl group, and among them,
Also methoxycarbonyl group, ethoxycarbonyl group, iso
Propoxycarbonyl group or tert-butoxycarbo
Nyl groups are preferred. R^Three, R^Four, R⁸And R⁹Low-grade archi
As a rusulfonyl group, for example, a methanesulfonyl group,
Ethanesulfonyl group, propanesulfonyl group, isopro
Pansulfonyl group, butanesulfonyl group, isobutane
Ruphonyl group, sec-butanesulfonyl group or tert
-Butanesulfonyl group;
A phonyl group or an ethanesulfonyl group is preferred. R^ThreeAnd R^FourAn acyl group having 1 to 4 carbon atoms
For example, formyl group, acetyl group, propionyl
Group, butyryl group or isobutyryl group.
Also, an acetyl group is preferable. R^Three, R^FourAnd R^FiveLow grade al
As the oxy group, for example, a methoxy group, an ethoxy group,
Loxy, isopropoxy, butoxy, isobut
Xy group, sec-butoxy group or tert-butoxy group
And among them, a methoxy group or an ethoxy group is preferred.
New R^ThreeAnd R^FourLower alkoxycarbonylmethylthio
Oacetyl groups include, for example, methoxycarbonylmethyl
Luthioacetyl group, ethoxycarbonylmethylthioacet
A tyl group, a propoxycarbonylmethylthioacetyl group,
Isopropoxycarbonylmethylthioacetyl group, buto
Xycarbonylmethylthioacetyl group, isobutoxyca
Rubonylmethylthioacetyl group, sec-butoxy
Bonylmethylthioacetyl group or tert-butoxyca
Rubonylmethylthioacetyl group.
Ethoxycarbonylmethylthioacetyl group or ethoxyca
A rubonylmethylthioacetyl group is preferred. R^ThreeAnd R^FourIs -CONHR⁶If it is,
R⁶Examples of the lower alkoxycarbonylmethyl group include
For example, methoxycarbonylmethyl group, ethoxycarbonyl
Methyl group, propoxycarbonylmethyl group, isopropo
Xycarbonylmethyl group, butoxycarbonylmethyl
Group, isobutoxycarbonylmethyl group, sec-butoxy
Cicarbonylmethyl group or tert-butoxycarboni
A methoxycarbonyl group.
Tyl group, ethoxycarbonylmethyl group or isopropoxy
A cyclocarbonylmethyl group is preferred. R^ThreeAnd R^FourThe hydro
Examples of the xy lower alkyl group include hydroxymethyl
Group, hydroxyethyl group, hydroxypropyl group, hydr
C1-C4 linear or branched such as loxybutyl group
Of these, a hydroxymethyl group or
A droxyethyl group is preferred. R⁸And R⁹Low-grade archi
Examples of the nylsulfanyl group include methylsulfanyl
Group, ethylsulfanyl group, propylsulfanyl
Group having 1 to 4 carbon atoms such as butylsulfanyl group
Or branched ones, among which methylsulfa
A nyl group or an ethylsulfanyl group is preferred. R⁸as well as
R⁹Examples of the lower alkylsulfinyl group include
Tansulfinyl group, ethanesulfinyl group, propane
1 to 1 carbon atoms such as a sulfinyl group and a butanesulfinyl group
Four straight-chain or branched ones are mentioned.
Tansulfinyl or ethanesulfinyl is preferred
No. [0020] Embedded image The group represented by the following is, for example, a vinyl group,
Methylsulfanylvinyl group, methanesulfinylvinyl
Or 2-methanesulfinyl-2-methylsulfa
Nylvinyl groups are preferred. [0022] Embedded image A hydrogen atom on the ring which may be substituted
Lower alkoxy groups, hydroxy lower alkyl groups and lower
The meaning of the alkoxycarbonyl group is the same as described above. Ma
A lower alkyl optionally substituted with a halogen atom
The group, in addition to the lower alkyl group, a fluorine atom,
Lower alkyl substituted with chlorine, bromine or iodine
Alkyl group, chloromethyl group, bromomethyl group,
Chloromethyl group, 1-chloroethyl group and the like.
You. A lower group which may be substituted by a halogen atom
Alkyl group, lower alkoxy group, hydroxy lower alkyl
Group, lower alkoxycarbonyl group or carboxyl group
May be different from each other on the heterocyclic ring.
Can be exchanged. [0025] Embedded image (A represents an oxygen atom, a sulfur atom or NH,
The dotted line indicates a single bond or a double bond)
A heterocyclic group is, for example, [0027] Embedded image Is mentioned. A hydrogen atom on the ring is replaced by a halogen atom.
Lower alkyl group, lower alkoxy group,
Droxy lower alkyl group, lower alkoxycarbonyl group
Or may be substituted with a carboxyl group, [0029] Embedded image (A represents an oxygen atom, a sulfur atom or NH,
The dotted line indicates a single bond or a double bond)
Specific examples of the heterocyclic group include [0031] Embedded image Preferably, these substituents are R^FourWhen
Is preferably substituted. At this time,
R^ThreeIs a methanesulfonyl group, and R^FiveIs a hydrogen atom
Is more preferable. Examples of specific compounds include methyl
4- (5-chloro-3-methylbenzo [b] thiof
2-Sulfonylamino) -3-methanesulfonyl
Benzoate, methyl 4- (5-chloro-3-methyl
Benzo [b] thiophen-2-sulfonylamino) -3
-Methanesulfonyl benzoate sodium salt, isop
Ropyl 4- (5-chloro-3-methylbenzo [b] thi
Ofen-2-sulfonylamino) -3-methanesulfo
Nylbenzoate, 5-chloro-3-methylbenzo
[B] Thiophene-2-sulfonic acid (4-acetyl-2)
-Methanesulfonylphenyl) amide, 5-chloro-3
-Methylbenzo [b] thiophene-2-sulfonic acid (4
-Benzoyl-2-methanesulfonylphenyl) amido
, Ethyl 4- (5-chloro-3-methylbenzo
[B] Thiophene-2-sulfonylamino) -3-meta
Sulphonylbenzoate, tert-butyl 4-
(5-chloro-3-methylbenzo [b] thiophene-2
-Sulfonylamino) -3-methanesulfonylbenzoe
, Methyl 4- (5-chloro-3-methylbenzo)
[B] thiophen-2-sulfonylamino) -3-eta
Sulfonylbenzoate, methyl 4- (5-chloro-
3-methylbenzo [b] thiophen-2-sulfonylua
Mino) -5-methanesulfonyl-2-methylbenzoate
G, dimethyl 4- (5-chloro-3-methylbenzo)
[B] Thiophene-2-sulfonylamino) isophthale
, Methyl 4- (5-chloro-3-methylbenzo)
[B] thiophen-2-sulfonylamino) -3-methoate
Xybenzoate, methyl 4- (5-chloro-3-meth
Tylbenzo [b] thiophen-2-sulfonylamino)
-3-nitrobenzoate, ethyl 4- (5-chloro
-3-Methylbenzo [b] thiophen-2-sulfonyl
Amino) benzoate, 5-chloro-3-methylbenzo
[B] Thiophene-2-sulfonic acid (2,4-dimethane
Sulfonylphenyl) amide, 5-chloro-3-methyl
Benzo [b] thiophene-2-sulfonic acid (4-acetyl
2-nitrophenyl) amide, 5-chloro-3-meth
Tylbenzo [b] thiophene-2-sulfonic acid (4-h
Droxymethyl-2-methanesulfonylphenyl) amido
, 5-chloro-3-methylbenzo [b] thiophene-
2-sulfonic acid (4-benzoylphenyl) amide, 5
-Chloro-3-methylbenzo [b] thiophen-2-s
Sulfonic acid (2-methanesulfonylphenyl) amide,
Tyl 4- (5-fluoro-3-methylbenzo [b] thi
Ofen-2-sulfonylamino) -3-methanesulfo
Nylbenzoate, methyl 4- (5-methyl-3-meth
Tylbenzo [b] thiophen-2-sulfonylamino)
-3-methanesulfonylbenzoate, 5-fluoro-
3-methylbenzo [b] thiophene-2-sulfonic acid
(4-acetyl-2-methanesulfonylphenyl) amido
De, methyl 4- (3-methylbenzo [b] thiophene
-2-sulfonylamino) -3-methanesulfonylben
Zoate, 2- [4- (5-chloro-3-methylbenzo)
[B] Thiophene-2-sulfonylamino) -3-meta
Nsulfonylphenyl] oxazole-4-carboxylic acid
Methyl ester, 2- [4- (5-fluoro-3-methyl
Rubenzo [b] thiophen-2-sulfonylamino)-
3-methanesulfonylphenyl] oxazole-4-ca
Rubonic acid methyl ester, 2- [4- (5-chloro-3
-Methylbenzo [b] thiophen-2-sulfonylami
No) -3-Methanesulfonylphenyl] oxazole-
4-carboxylic acid, 2- [4- (5-fluoro-3-methyl)
Rubenzo [b] thiophen-2-sulfonylamino)-
3-methanesulfonylphenyl] oxazole-4-ca
Rubonic acid, 2- [4- (5-chloro-3-methylbenzo)
[B] Thiophene-2-sulfonylamino) -3-meta
Nsulfonylphenyl] oxazole-4-carboxylic acid
Disodium salt, 2- [4- (5-fluoro-3-methyl
Rubenzo [b] thiophen-2-sulfonylamino)-
3-methanesulfonylphenyl] oxazole-4-ca
Disodium rubonate, 5-fluoro-N- (2-meth
Tansulfonyl-4-oxazol-5-ylphenyi
L) -3-Methylbenzo [b] thiophen-2-sulfo
Amide, 2- [4- (5-fluoro-3-methylben
Zo [b] thiophen-2-sulfonylamino) -3-meth
Tansulfonylphenyl] thiazole-4-carboxylic
Acid, 2- [4- (5-fluoro-3-methylbenzo)
[B] Thiophene-2-sulfonylamino) -3-meta
Sulfonylphenyl] thiazole-4-carboxylic acid
Tyl ester, 5-fluoro-N- [4- (4-hydro
(Xymethylthiazol-2-yl) -2-methanesulfo
Nylphenyl] -3-methylbenzo [b] thiophene-
2-sulfonamide, 5-fluoro-N- [2-methane
Sulfonyl-4- (4-methylthiazol-2-yl)
Phenyl] -3-methylbenzo [b] thiophen-2-
Sulfonamide, 5-fluoro-N- [2-methanesulfur
Honyl-4- (2-methylthiazol-4-yl) fe
Nil] -3-methylbenzo [b] thiophen-2-sul
Honamide, 5-fluoro-N- [2-methanesulfoni
4- (5-methylthiazol-2-yl) phenyl
3-Methylbenzo [b] thiophen-2-sulfo
Amide, 5-fluoro-N- [2-methanesulfonyl
-4- (5-methoxy-4-methylthiazol-2-i
L) phenyl] -3-methylbenzo [b] thiophene-
2-sulfonamide, 5-fluoro-N- [2-methane
Sulfonyl-4- (4,5-dimethylthiazole-2-
Yl) phenyl] -3-methylbenzo [b] thiophene
-2-sulfonamide, 5-fluoro-N- [4- (4
-Hydroxymethyloxazol-2-yl) -2-me
Tansulfonylphenyl] -3-methylbenzo [b] thi
Offen-2-sulfonamide, 5-fluoro-N-
[2-methanesulfonyl-4- (4-methyloxazo
Ru-2-yl) phenyl] -3-methylbenzo [b] thi
Offen-2-sulfonamide, 5-fluoro-N-
[2-Methanesulfonyl-4- (5-methoxy-4-me
Tyloxazol-2-yl) phenyl] -3-methyl
Benzo [b] thiophene-2-sulfonamide, 5-f
Fluoro-N- [2-methanesulfonyl-4- (4,5-
Dimethyloxazol-2-yl) phenyl] -3-me
Tylbenzo [b] thiophene-2-sulfonamide, 5
-Fluoro-N- [2-methanesulfonyl-4- (5-
Methyloxazol-2-yl) phenyl] -3-methyi
Rubenzo [b] thiophene-2-sulfonamide, 5-
Fluoro-N- [2-methanesulfonyl-4-((E)
-2-methanesulfinyl-2-methylsulfanyl-
Vinyl) phenyl] -3-methylbenzo [b] thiophene
2-sulfonamide. Next, the N-substituted benzothiophene of the present invention
Preparation of a rufonamide derivative or a pharmaceutically acceptable salt thereof
The manufacturing method will be described. Compounds of general formula (I) according to the invention
Is manufactured by the manufacturing method described by the reaction formula shown below.
can do. [0035] Embedded image That is, the compound represented by the compound (III)
Mining dioxane, tetrahydrofuran (hereinafter THF)
), Acetone, dimethylformamide (hereinafter D)
MF), dimethyl sulfoxide (hereinafter, DMSO)
Abbreviated), chloroform, pyridine, etc. or a mixture thereof
In a solvent, the temperature ranges from -10 ° C to the boiling point of the solvent.
Lium amide, lithium amide, sodium hydride, charcoal
Acid potassium, potassium tert-butoxide, triethyl
Ruamine, ethyldiisopropylamine, pyridine,
1,8-diazabicyclo [5.4.0] undec-7
-Sulfo in the presence of a base such as -ene (hereinafter abbreviated as DBU).
Manufactured by reacting with nyl chloride (II)
be able to. In addition, R of the compound of the general formula (I)^ThreeIs low
Primary alkylsulfonyl group, R^FiveIs a hydrogen atom, and R
^FourBut, [0037] Embedded image Wherein A is the same as in the general formula (I)
Righteous, R^TenAnd R¹¹May be different
And may be substituted with a hydrogen atom or a halogen atom.
Lower alkyl group, lower alkoxy group, hydroxy lower alkyl
Kill group, lower alkoxycarbonyl group or carboxyl
Represents a group).
Can also be. In this case, R¹¹Is a substituent other than a hydrogen atom
In the case of the compound having, the compound of the general formula (I)
Manufactured by the manufacturing method described in the reaction formula
Can also be. [0039] Embedded image That is, a method known in the literature (J. Med.
Chem. , 40, 2017 (1997)).
A compound represented by compound (IV) synthesized from chlorobenzoic acid
Min (wherein, R¹²And R¹³Represents a lower alkyl group)
Dioxane, THF, acetone, DMF, DMSO,
In loroform, pyridine or the like or a mixed solvent thereof, -1
Sodium amyloid in the range of 0 ° C to the boiling point of the solvent.
, Lithium amide, sodium hydride, potassium carbonate
, Potassium tert-butoxide, triethylamido
, Ethyldiisopropylamine, pyridine, DBU, etc.
With sulfonyl chloride (II) in the presence of a base
To give compound (V) (Step B),
The compound (VI) is obtained by the dissolution (Step C). Next, the compound
(VI) and an amine represented by the general formula (VII) (R¹⁴Is hydrogen
An atom or lower alkyl group^FifteenIs a lower alkyl group or
Lower alkoxy group) is triethylamine, ethyl
In the presence of a base such as diisopropylamine or DBU, N,
N'-dicyclohexylcarbodiimide (hereinafter referred to as DCC
Abbreviated), 1-ethyl-3- (3-dimethylaminopro
Condensing agents such as pillcarbodiimide (hereinafter abbreviated as EDC)
To obtain a compound (VIII) (Step D).
Using phosphorus oxychloride or diphosphorus pentasulfide, compound (I)
a) (Step E)
You. Further, R¹¹For compounds where is a hydrogen atom
In this case, the compound of the general formula (I) is represented by the following reaction formula.
It can also be manufactured by the manufacturing method described. [0042] Embedded image That is, compound (VI) and serine ester
Hydrochloride, cysteine ester hydrochloride or S-trityl
Cysteine ester etc.
In the presence of bases such as isopropylamine and DBU,
Compound (IX) obtained by reacting with a condensing agent (in the formula,
R¹⁶Is a hydroxy optionally having a protecting group such as a trityl group
Represents a methyl group or a mercaptomethyl group;¹⁷Is low
An alkyl group) can be prepared by a method known in the literature (Tetrah
edron. Letters. , 33, 907 (199
2). Org. Chem. , 38, 26 (197
3). Org. Chem. , 58, 4494 (19
93), Org. Lett. , 2,1165 (200
0), Tetrahedron. Letters. , 4
2,4171 (2001)).
(Steps F and G). Further reduction of the ester group
By converting to a hydroxymethyl group, the compound (I)
c) can be produced (step H). Also, compounds
Compound (Id) is obtained by halogenating (Ic).
(R¹⁸Represents a halogen atom)
(Step I), and further reduction of a halogen atom of the compound (Id)
Compound (Ie) by converting to a methyl group
Can be produced (Step J). The compound (I
Compound (If) is obtained by ester hydrolysis of b).
Can be produced (step K). [0044] Embedded image Further, R of the compound of the general formula (I)^ThreeBut low
Alkylsulfonyl group, R^FiveIs a hydrogen atom, and R^FourBut, [0046] Embedded image If (R¹⁹And R²⁰Are different
May be substituted with a hydrogen atom or a halogen atom
Lower alkyl group, lower alkoxy group,
A xy lower alkyl group, a lower alkoxycarbonyl group or
A carboxyl group) is a compound of the general formula (I)
Is manufactured by the manufacturing method described by the reaction formula shown below.
You can also. [0048] Embedded image That is, compound (XI) (wherein R¹²Is
From the same meaning as described above, a method known in the literature (JP-A-200
0-256262), compound (XII) (wherein R
^{twenty one}Represents a halogen atom) (step L). More
Ring closure with oacetamide or formamide
To produce compound (Ig) (step
M). In addition, R of the compound of the general formula (I)^ThreeIs low-grade alk
Rusulfonyl group, R^FiveIs a hydrogen atom, and R^FourBut, [0050] Embedded image In the case of, it is explained by the following reaction formula.
It can be manufactured by the manufacturing method described below. [0052] Embedded image That is, compound (V) (wherein R¹²Is before
As defined above), followed by oxidation
Compound (XIV) converted to an aldehyde group by
(Steps N and O), a method known from the literature (Bull. Che.
m. Soc. Jpn. , 52, 2013 (1979))
(Ih) can be produced (step
P). The thus obtained general formula (I)
Compounds can be used for recrystallization, column chromatography, etc.
It can be isolated and purified by appropriate means. General of the invention
The compound of formula (I) is prepared by a conventional method using a pharmaceutically acceptable acid.
Or salts with bases, hydrochlorides, hydrobromic acid depending on the compound
Inorganic such as salt, hydroiodide, sulfate, nitrate and phosphate
Acid salts, acetates, trifluoroacetates, oxalates,
Fumarate, maleate, tartrate, mesylate,
Salts with organic acids such as silates, sodium salts, potassium salts
Alkaline earths such as calcium salts and salts with alkali metals
It can lead to salts with similar metals. The compound of the general formula (I) includes an asymmetric carbon atom
May be present. In the present invention
Is the isolated form of these various isomers and
A mixture of sexes is included. Also, a compound of the general formula (I)
Include hydrates and various solvates. General formula (I)
Include all of their crystalline forms. General
The compound of formula (I) or a pharmaceutically acceptable salt thereof is
It can be administered orally or parenterally. For administration
Dosage form is a pharmaceutically acceptable excipient
Agent, binder, buffer, thickener, stabilizer, emulsifier, dispersion
Agents, suspending agents, preservatives, etc. can be added
It can be formulated by a method. As the preparation for oral administration, for example, tablets (sugars)
(Including coated tablets and film-coated tablets), pills, granules
Preparations, powders, capsules (including soft capsules), liquids
Preparations, syrups, emulsions, suspensions and the like. This sutra
Oral preparations are commonly used additives in the pharmaceutical field
And can be produced according to a known method.
Such additives include, for example, lactose, mannitol
Excipients, such as anhydrous calcium hydrogen phosphate, hydroxy
Propyl cellulose, methyl cellulose, polyvinyl
Binders such as loridone, starch, carboxymethylcell
Disintegrators such as loin, magnesium stearate, talc
And the like. Parenterally, injections, rectal preparations,
It can be administered as a local administration agent or the like. As an injection
Examples thereof include a sterile solution or suspension. this
These injections are, for example, compounds of the formula (I) or pharmaceuticals thereof.
Dissolvable or suspended in the Japan Pharmacopoeia water for injection.
It is manufactured by If necessary, such as sodium chloride
Tonicity agent, sodium hydrogen phosphate, sodium hydrogen phosphate
And a solubilizing agent such as a buffer. Also,
Dissolving (powder-filled, freeze-dried) injection for use
In this case, excipients such as mannitol and lactose
It can be added and produced in a usual manner. Examples of the rectal preparations include suppositories and the like.
You. Suppositories include, for example, compounds of general formula (I) or
Soluble salts in bases such as cocoa butter and macrogol
After dissolving or suspending, it is manufactured by pouring into a mold and molding.
Also, put the liquid or cream in a container for injection and administer rectally
It can also be a formulation. Formulation for topical administration is liquid, eye drops
Preparations, creams, ointments, gel preparations, sprays, powders, etc.
No. The solution is a compound of the formula (I) or a drug thereof
Add a biologically acceptable salt to the water and add stabilizers,
It is manufactured by adding a thickener, dispersant, suspending agent, etc. as necessary.
Can be Gelatin, here
Sodium luronate, high molecular weight dextran, alginic acid
Using sodium, sodium chondroitin sulfate, etc.
Can be Eye drops are buffer, pH adjuster, isotonic
It can be produced by adding a preservative in addition to the agent. K
Reams and ointments may be formulated with an aqueous or oily base such as water,
Animal paraffin, vegetable oil (peanut oil, castor oil, etc.),
It can be manufactured using macrogol or the like. gel
Preparations can be prepared using known methods, such as gelatin, pectin,
Genan, agar, tragacanth, alginate, cellulose
Ether (methyl cellulose, sodium
Acetylcellulose), pectin derivatives, polyacryle
Sheet, polymethacrylate, polyvinyl alcohol and
And polyvinylpyrrolidone.
Wear. The spray is a compound of general formula (I) or a drug thereof.
After dissolving or suspending a physiologically acceptable salt in water or the like,
It can be manufactured in a play container. Powder
In such a case, the compound of the general formula (I) or a pharmaceutically acceptable compound thereof is
The salt can be used as it is,
It can be manufactured by mixing with an agent. Also, the general formula
A compound of (I) or a pharmaceutically acceptable salt thereof,
Make a solution on a sheet of tin sponge, hyaluronic acid, etc.
Can also be administered
Can also be administered. Compounds of general formula (I) or pharmaceutically acceptable
The daily adult dosage of acceptable salt is based on the oral dose.
In this case, about 10 μg to 1 g is appropriate and about 100 μg
g to 100 mg are preferred. When administering as injection
Is administered 1/10 to 1/2 of the oral dose
Just do it. In addition, in the case of local administration directly to the surgical site,
One ng to 1 g may be administered. These doses are
Increase or decrease appropriately according to the condition of surgery, weight, age, etc. of the elderly
Is possible. A compound of general formula (I) or
Acceptable salt toxicity is low, against 6-week-old male rats
3 days after oral administration (single, 300 mg / kg)
There are no notable toxicological findings, and the safety of these compounds is
It is determined to be high. [0060] EXAMPLES The present invention will be described below with reference to Examples and Test Examples.
As will be described in more detail, the present invention is limited by these.
It is not something to be done. Reference Example 1 [4- (5-fluoro-3-
Methylbenzo [b] thiophen-2-sulfonylami
No) -3-Methanesulfonyl] benzoic acid Dissolve 24.8 g of compound 17 in 500 mL of methanol
Then, 50 mL of 1 mol / L sodium hydroxide was added. Addition
After stirring under heat reflux for 3 hours, the solvent was distilled off under reduced pressure to obtain a residue.
Water was added to the residue and washed with ether. 2mol / L in aqueous layer
Add hydrochloric acid and extract with ethyl acetate.
After washing with water, it was dried over anhydrous sodium sulfate. Solvent
The residue obtained by evaporation under reduced pressure was washed with ether to give a colorless powder.
To give 14.3 g of the title compound. Melting point: 290 ° C¹ H-NMR (CDCl_Three): Δ 2.66 (3H, s), 3.05 (3H, s), 6.76
(1H, dd, J = 2.0,8.6Hz), 7.45 (1H, dd, J = 2.0,8.6Hz), 7.
75 (1H, dd, J = 4.6,9.0Hz), 7.82 (1H, d, J = 8.8Hz), 8.17
(1H, dd, J = 2.0,8.8Hz), 8.49 (1H, d, J = 2.0Hz). IR ν_max(KBr): 3239,2925,1687,1609,1501,1442,142
1,1400,1356,1287,1161 cm^-1. Reference Example 2 (2S) -2- [4- (5-
Fluoro-3-methylbenzo [b] thiophen-2-s
Ruphonylamino) -3-methanesulfonylphenylcar
Boxyamide] propionic acid methyl ester 3.78 g of L-alanine methyl ester hydrochloride was added to dichloromethane.
Suspended in 100 mL of dichloromethane, and triethylamine at 0 ° C.
3.8 mL was added. Here, the compound 10.0 of Reference Example 1 was added.
g of dichloromethane suspension was added. At the same temperature
After stirring for 5 minutes, 5.19 g of EDC hydrochloride was added, and the mixture was brought to room temperature.
And stirred for 19 hours. Stop the reaction with 1 mol / L hydrochloric acid
After that, the dichloromethane layer was separated, and the solvent was distilled off under reduced pressure.
Ethyl acetate-THF mixed solution (1:
1) was added thereto, and the mixture was washed successively with water and a saturated saline solution.
It was dried with gnesium. The solvent was obtained by evaporation under reduced pressure.
The residue was washed with methanol to give the title compound as a colorless powder.
9.22 g of the product were obtained. Melting point: 162-163 ° C¹ H-NMR (CDCl_Three): Δ 1.49 (3H, d, J = 7.3Hz), 2.69 (3
H, s), 3.07 (3H, s), 3.79 (3H, s), 4.74 (1H, dq, J
= 7.3,7.3Hz), 6.96 (1H, d, J = 7.3Hz), 7.28 (1H, ddd, J
= 2.4,8.6,8.8Hz), 7.47 (1H, dd, J = 2.4,9.2Hz), 7.77
(1H, dd, J = 4.7,8.8Hz), 7.81 (1H, d, J = 8.7Hz), 7.89
(1H, dd, J = 2.0,8.7Hz), 8.25 (1H, d, J = 2.0Hz), 9.71
(1H, s). IR ν_max(KBr): 3323,3222,3068,3003,2924,1737,163
6,1607,1496,1306,1165,924 cm^-1. Reference Example 3 4- (5-fluoro-3-meth
Tylbenzo [b] thiophen-2-sulfonylamino)
-3-Methanesulfonylbenzaldehyde Dissolve 830 mg of compound 75 in 25 mL of ethyl acetate,
4.15 g of neutral manganese dioxide is added and stirred at room temperature for 5 hours
did. Dilute the reaction solution with ethyl acetate and filter through celite.
To remove manganese dioxide. Evaporation of the solvent, colorless powder
As a result, 696 mg of the title compound was obtained. Melting point: 167-170 ° C¹ H-NMR (CDCl_Three): Δ 2.70 (3H, s), 3.10 (3H, s),
7.31 (1H, ddd, J = 2.4, 8.7, 9.0Hz), 7.48 (1H, dd, J =
2.4, 9.0Hz), 7.78 (1H, dd J = 4.5, 9.0Hz), 7.96 (1
H, d, J = 8.7Hz), 8.06 (1H, dd, J = 2.1, 8.7Hz), 8.36
(1H, d, J = 2.1Hz), 9.90 (1H, s), 9.92 (1H, s). IR ν_max(KBr): 3260,1694,1602,1496,1308,1164,91
2 cm^-1. [Production Example 1] Methyl 4- (5-chloro-
3-methylbenzo [b] thiophen-2-sulfonylua
Mino) -3-methanesulfonylbenzoate (compound
Synthesis of 1) Methyl 4-amino-3-methanesulfonylbenzoate
985 mg of THF mixed with 20 mL of THF and 3 mL of DMF
Dissolve in solvent and add sodium hydride (oil, 60
%) 170 mg was added. After stirring at the same temperature for 20 minutes,
5-chloro-2-chlorosulfonyl-3-methyl at C
Add 1.28 g of benzo [b] thiophene and add 1 at room temperature.
Stirred for hours. In addition, at room temperature, sodium hydride (oil
150%) and stirred at the same temperature for 2 hours.
Was. After confirming the disappearance of the raw materials, saturated ammonium chloride was added at 0 ° C.
After stopping the reaction by adding water, the mixture was extracted with ethyl acetate,
After washing the organic layer with saturated saline, anhydrous sodium sulfate was used.
Dried. After evaporation of the solvent, silica gel chromatography
(Ethyl acetate: hexane = 3: 1), colorless powder
As a result, 911 mg of the title compound was obtained. Melting point: 179-181 ° C¹ H-NMR (CDCl_Three): Δ 2.70 (3H, s), 3.06 (3H, s), 3.90
(3H, s), 7.48 (1H, dd, J = 2.1,8.6Hz), 7.74 (1H, d, J = 8.
6Hz), 7.89 (1H, d, J = 2.1Hz), 7.86 (1H, d, J = 8.8Hz), 8.
19 (1H, dd, J = 2.0,8.8Hz), 8.50 (1H, d, J = 2.0Hz), 9.84
(1H, s). IR ν_max(KBr): 3217,1720,1608,1504,1442,1392,130
8,1165,1119 cm^-1. [Production Example 2] Ethyl 4- (5-chloro-
3-methylbenzo [b] thiophen-2-sulfonylua
Mino) -3-methanesulfonylbenzoate (compound
Synthesis of 2) Ethyl 4-amino-3-methane as in Production Example 1
As a colorless powder from 559 mg of sulfonyl benzoate
529 mg of the title compound were obtained. Melting point: 167-169 ° C¹ H-NMR (CDCl_Three): Δ 1.36 (3H, t, J = 7.1Hz), 2.70 (3H,
s), 3.06 (3H, s), 4.36 (2H, q, J = 7.1Hz), 7.47 (1H, dd,
J = 2.0,8.8Hz), 7.74 (1H, d, J = 8.8Hz), 7.78 (1H, d, J = 2.
0Hz), 7.86 (1H, d, J = 8.8Hz), 8.19 (1H, dd, J = 2.0,8.8H
z), 8.50 (1H, d, J = 2.0Hz), 9.83 (1H, brs). IR ν_max(KBr): 3224,2985,1716,1608,1500,1358,130
0,1142 cm^-1. [Production Example 3] tert-butyl 4- (5
-Chloro-3-methylbenzo [b] thiophen-2-s
Ruphonylamino) -3-methanesulfonylbenzoate
Synthesis of (Compound 3) Tert-Butyl 4-amino-
Colorless from 128 mg of 3-methanesulfonylbenzoate
148 mg of the title compound were obtained as a powder. Melting point: 236-238 ℃¹ H-NMR (CDCl_Three): Δ 1.54 (9H, s), 2.52 (3H, s), 3.28
(3H, s), 7.55-7.80 (4H, m), 8.00 (1H, s), 8.25-8.30
(1H, m). IR ν_max(KBr): 3467,2974,2327,1705,1662,1597,147
7,1396,1296,1130,1099cm^-1. [Production Example 4] Methyl 4- (5-chloro-
3-methylbenzo [b] thiophen-2-sulfonylua
Mino) -3-ethanesulfonyl benzoate (compound
Synthesis of 4) Methyl 4-amino-3-ethane as in Production Example 1
76 mg of sulfonyl benzoate as a colorless powder
80 mg of the title compound were obtained. Melting point: 172-173 ° C¹ H-NMR (CDCl_Three): Δ 1.27 (3H, t, J = 7.3Hz), 2.74 (3H,
s), 3.24 (2H, q, J = 7.3 Hz), 3.77 (3H, s), 7.20-7.31 (2
H, m), 7.43-7.56 (3H, m), 8.31 (1H, s). IR ν_max(KBr): 3482,3217,2931,1709,1597,1481,143
9,1284,1126 cm^-1. [Production Example 5] Methyl 4- (5-chloro-
3-methylbenzo [b] thiophen-2-sulfonylua
Mino) -5-methanesulfonyl-2-methylbenzoate
Synthesis of compound (compound 5) Methyl 4-amino-5-methanesulfonyl-2-methyl
Dissolve 135mg of lubenzoate in THF (10mL)
And sodium hydride (oil, 60%) 22m at room temperature
g was added. After stirring at the same temperature for 20 minutes,
Loro-2-chlorosulfonyl-3-methylbenzo [b]
After adding thiophene (130 mg) and stirring at room temperature for 1 hour,
The mixture was refluxed for 5 hours. DMF (1 mL), hydrogenation
22 mg sodium (oil, 60%) and 5-chloro-
2-chlorosulfonyl-3-methylbenzo [b] thiof
The mixture was heated under reflux for 2.5 hours. Raw material consumption
After confirming the loss, add saturated aqueous ammonium chloride at 0 ° C.
After terminating the reaction, extraction with ethyl acetate was performed to saturate the organic layer.
After washing with a saline solution, the extract was dried over anhydrous sodium sulfate.
After evaporating the solvent, silica gel chromatography (ethyl acetate)
Hexane = 3: 2) and purified as a colorless powder.
102 mg of the title compound were obtained. Melting point: 205-207 ° C¹ H-NMR (CDCl_Three): Δ 2.65 (3H, s), 2.71 (3H, s), 3.04
(3H, s), 3.87 (3H, s), 7.49 (1H, dd, J = 2.0,8.6Hz), 7.
68 (1H, s), 7.77 (1H, d, J = 8.6Hz), 7.80 (1H, d, J = 2.0H)
z), 8.42 (1H, s), 9.73 (1H, s). IR ν_max(KBr): 3259,1728,1604,1554,1504,1439,138
5,1354,1300,1257,1157,1092 cm^-1. Production Example 6 Dimethyl 4- (5-chloro)
-3-Methylbenzo [b] thiophen-2-sulfonyl
Synthesis of amino) isophthalate (compound 6) 115 mg of dimethyl 4-aminoisophthalate was added to TH
F8mL dissolved in sodium hydride (oil, 60%)
22 mg was added, and the mixture was stirred at room temperature for 20 minutes.
5-chloro-2-chlorosulfonyl-3-methylben
130 mg of zo [b] thiophene was added, and the mixture was added at room temperature for 30 minutes
While stirring. Further sodium hydride (oil, 60%)
26 mg was added, and the mixture was heated under reflux for 6 hours. Confirmed disappearance of raw materials
Then, the reaction was quenched by adding saturated aqueous ammonium chloride at 0 ° C.
After stopping, extraction was performed with ethyl acetate, and the organic layer was washed with saturated saline.
And then dried over anhydrous sodium sulfate. Solvent evaporation
Followed by silica gel chromatography (ethyl acetate:
Purified by Sun = 1: 1), as pale yellow amorphous
62 mg of the title compound were obtained.¹ H-NMR (CDCl_Three): Δ 2.64 (3H, s), 3.88 (3H, s), 3.95
(3H, s), 7.44 (1H, dd, J = 2.0,8.8Hz), 7.71 (1H, d, J = 8.
8Hz), 7.74 (1H, d, J = 2.0Hz), 7.86 (1H, d, J = 8.8Hz), 8.
11 (1H, dd, J = 2.0,8.8Hz), 8.63 (1H, d, J = 2.0Hz). IR ν_max(KBr): 3440,3140,2954,1724,1693,1608,150
0,1439,1331,1246,1165,1119 cm^-1. [Production Example 7] Methyl 4- (5-chloro-
3-methylbenzo [b] thiophen-2-sulfonylua
Synthesis of Mino) -3-methoxybenzoate (Compound 7) Methyl 4-amino-3-methoxybenzoate 120
mg and 5-chloro-2-chlorosulfonyl-3-methyl
Lubenzo [b] thiophene 150 mg in pyridine 4 mL
And stirred at room temperature for 14 hours. Confirmed disappearance of raw materials
Thereafter, the reaction was stopped by adding water at 0 ° C., and then ethyl acetate was added.
, And the organic layer is washed with a saturated saline solution.
Dry with thorium. After evaporation of the solvent, silica gel chromatography
For chromatography (chloroform: methanol = 9: 1)
The title compound 110m as a colorless amorphous
g was obtained.¹ H-NMR (CDCl_Three): Δ 2.55 (3H, s), 3.79 (3H, s), 3.86
(3H, s), 7.42 (1H, dd, J = 2.0,8.6Hz), 7.45 (1H, dd, J =
2.0,8.6 Hz), 7.61 (1H, d, J = 2.0Hz), 7.62 (1H, d, J = 8.6
Hz), 7.68 (1H, d, J = 8.6Hz), 7.71 (1H, d, J = 2.0Hz). IR ν_max(KBr): 3248,2951,1716,1601,1512,1439,135
0,1284,1242,1161,1115cm^-1. [Production Example 8] Methyl 4- (5-chloro-
3-methylbenzo [b] thiophen-2-sulfonylua
Synthesis of Mino) -3-nitrobenzoate (Compound 8) Methyl 4-amino-3-nitro was prepared in the same manner as in Production Example 6.
Title compound as yellow powder from benzoate 122mg
146 mg were obtained. Melting point: 164-165 ° C¹ H-NMR (CDCl_Three): Δ 2,47 (3H, s), 3.84 (3H, s), 7.56
(1H, d, J = 8.6Hz), 7.57 (1H, brd, J = 8.6Hz), 8.01 (1H,
d, J = 1.8Hz), 8.06 (1H, d, J = 8.6Hz), 8.07 (1H, brd, J = 8.
6Hz), 8.25 (1H, d, J = 1.8Hz). IR ν_max(KBr): 3442,3237,3060,2949,1732,1621,153
5,1507,1440,1356,1297,1164,1106 cm^-1. [Production Example 9] 5-chloro-3-methylben
Zo [b] thiophene-2-sulfonic acid (2,4-dimeta
Synthesis of Nsulfonylphenyl) amide (Compound 9) In the same manner as in Production Example 6, 2,4-dimethanesulfonylani
The title compound (368m) as a colorless powder from 200mg of phosphorus
g was obtained. Melting point: 176-178 ° C¹ H-NMR (DMSO-d₆): Δ 2,65 (3H, s), 3.00 (3H, s), 3.
07 (3H, s), 7.44 (1H, dd, J = 1.8,8.6Hz), 7.71 (1H, d, J =
8.6Hz), 7.76 (1H, d, J = 1.8Hz), 7.92 (1H, d, J = 8.8Hz),
8.04 (1H, dd, J = 1.8,8.8Hz), 8.34 (1H, d, J = 1.8Hz). IR ν_max(KBr): 3236,3020,1593,1489,1392,1354,130
4,1157 cm^-1. [Production Example 10] 5-chloro-3-methylbe
Nzo [b] thiophene-2-sulfonic acid (4-acetyl
Synthesis of -2-nitrophenyl) amide (Compound 10) In the same manner as in Production Example 6, 4-acetyl-2-nitroanili
96 mg of the title compound was obtained as a colorless powder in 59 mg.
Was. Melting point: 130-131 ° C¹ H-NMR (CDCl_Three): Δ 2.58 (3H, s), 2.69 (3H, s), 7.46
(1H, dd, J = 2.0,8.6Hz), 7.73 (1H, d, J = 8.6Hz), 7.78 (1
H, d, J = 2.0Hz), 8.05 (1H, d, J = 8.8Hz), 8.16 (1H, dd, J =
1.8,8.8 Hz), 8.74 (1H, d, J = 1.8Hz). IR ν_max(KBr): 3745,3479,3363,3262,3089,2927,285
8,1689,1620,1531,1419,1354,1115,1080 cm^-1. [Production Example 11] 5-chloro-3-methylbe
Nzo [b] thiophene-2-sulfonic acid (4-acetyl
-2-methanesulfonylphenyl) amide (compound 1
Synthesis of 1) 4-amino-3-methanesulfonylacetophenone 24
1mg in a mixed solvent of THF20mL and DMF5mL
Dissolve and at -78 ° C sodium hydride (oil, 60
%) 136 mg were added. After stirring at the same temperature for 20 minutes,
At 78 ° C, 5-chloro-2-chlorosulfonyl-3-me
Add 350 mg of tylbenzo [b] thiophene and gradually
The mixture was heated and stirred at -10 ° C for 1 hour. Confirmed disappearance of raw materials
Then, the reaction was quenched by adding saturated aqueous ammonium chloride at 0 ° C.
After stopping, extraction was performed with ethyl acetate, and the organic layer was washed with saturated saline.
And then dried over anhydrous sodium sulfate. Solvent evaporation
Followed by silica gel chromatography (ethyl acetate:
Sun = 1: 1) to give the title compound as a colorless powder
427 mg were obtained. Melting point: 207-209 ℃¹ H-NMR (CDCl_Three): Δ 2.56 (3H, s), 2.69 (3H, s), 3.07
(3H, s), 7.46 (1H, dd, J = 1.9,8.7Hz), 7.72-7.79 (2H,
m), 7.86 (1H, d, J = 8.6Hz), 8.10 (1H, d, J = 8.6Hz), 8.40
(1H, d, J = 1.9Hz). IR ν_max(KBr): 3456,3236,3086,3005,2924,2854,167
0,1593,1489,1389,1354,1308,1261,1165,1130,1053 cm
^-1. [Production Example 12] 5-chloro-3-methylbe
Benzo [b] thiophene-2-sulfonic acid (4-benzoyi)
2-methanesulfonylphenyl) amide (compound 1
Synthesis of 2) In the same manner as in Production Example 11, 4-amino-3-methanesulfo
Titled as colorless powder from 94 mg of Nylbenzophenone
68 mg of the compound were obtained. Melting point: 144-146 ° C¹ H-NMR (CDCl_Three): Δ 2.70 (3H, s), 3.08 (3H, s), 7.45-
7.50 (3H, m), 7.58-7.62 (2H, m), 7.68-7.71 (4H, m),
7.85 (1H, d, J = 8.6Hz), 7.97 (1H, d, J = 8.6Hz), 8.31 (1
H, brs). IR ν_max(KBr): 3456,3248,3001,2927,2858,2256,170
9,1655,1597,1496,1450,1389,1350,1308,1161,1130,108
4 cm^-1. [Production Example 13] 5-chloro-3-methyl
Benzo [b] thiophene-2-sulfonic acid (4-hydro
Xymethyl-2-methanesulfonylphenyl) amide
Synthesis of (Compound 13) 305 mg of the compound of Production Example 1 in 10 mL of toluene
And cooled to -78 ° C.
2.2m toluene solution of isobutylaluminum hydride
L was added. After stirring at the same temperature for 20 minutes, gradually to 0 ° C
The mixture was heated and stirred for 1 hour. The reaction was stopped by adding water to the reaction solution.
After stopping, dilute with ethyl acetate and add sodium tartrate
And saturated aqueous potassium solution, and stirred at room temperature for 30 minutes.
Was. Extract with ethyl acetate, wash the organic layer with saturated saline
Then, it was dried over anhydrous sodium sulfate. After evaporation of the solvent,
Ricagel chromatography (ethyl acetate: hexane =
1: 1) to give the title compound 230 as a colorless powder.
mg was obtained. Melting point: 183-184 ° C¹ H-NMR (CDCl_Three): Δ 1.83 (1H, brs), 2.69 (3H, s), 2.9
7 (3H, s), 4.69 (2H, d, J = 5.7Hz), 7.47 (1H, dd, J = 2.1,
8.7Hz), 7.57 (1H, dd, J = 2.1,8.7Hz), 7.74 (1H, d, J = 9.3
Hz), 7.78 (1H, d, J = 9.3Hz), 7.79 (1H, d, J = 2.1Hz), 7.8
6 (1H, d, J = 2.1Hz), 9.49 (1H, brs). IR ν_max(KBr): 3563,3236,1612,1500,1392,1277,1142
cm^-1. [Production Example 14] Ethyl 4- (5-chloro)
-3-Methylbenzo [b] thiophen-2-sulfonyl
Synthesis of amino) benzoate (compound 14) 60 mg of 4-aminobenzoic acid ethyl ester in pyridine
Dissolve in 3 mL, and add 5-chloro-2-chlorosulfur at 0 ° C.
Phonyl-3-methylbenzo [b] thiophene 123 mg
Was added and stirred at room temperature for 2 hours. After confirming the disappearance of raw materials, 2
mol / L hydrochloric acid was added, and the mixture was extracted with ether.
After washing with brine, drying over anhydrous magnesium sulfate
Was. The solvent was distilled off under reduced pressure.
Column chromatography (ethyl acetate: hexane =
1: 3) to give the title compound 80 as a pale pink powder.
mg was obtained. Melting point: 224-226 ° C¹ H-NMR (DMSO-d₆): Δ 1.26 (3H, t, J = 7.1Hz), 2.50 (3
H, s), 4.23 (2H, q, J = 7.1Hz), 7.27 (2H, d, J = 8.8Hz), 7.
57 (1H, dd, J = 2.0,8.6Hz), 7.84 (2H, d, J = 8.8Hz), 8.01
(1H, d, J = 2.0Hz), 8.05 (1H, d, J = 8.6Hz). IR ν_max(KBr): 3213,1696,1608,1511,1347,1288,115
9 cm^-1 _. [Production Example 15] 5-chloro-3-methylbe
Benzo [b] thiophene-2-sulfonic acid (4-benzoyi)
Synthesis of (Ruphenyl) amide (Compound 15) In the same manner as in Production Example 14, 4-benzoylaniline 126
187 mg of the title compound was obtained as a colorless powder from the resulting compound. Melting point: 198-200 ° C¹ H-NMR (CDCl_Three): Δ 2.56 (3H, s), 7.22-7.26 (2H,
m), 7.44-7.48 (3H, m), 7.55-7.60 (1H, m), 7.70-7.76
(6H, m). IR ν_max(KBr): 3213,2927,1724,1639,1589,1508,145
0,1408,1288,1234,1149cm^-1 _. [Production Example 16] 5-chloro-3-methylbe
Nzo [b] thiophene-2-sulfonic acid (2-methanes
Synthesis of Ruphonylphenyl) amide (Compound 16) 2-methanesulfonylaniline in the same manner as in Production Example 14
From 100 mg, 52 mg of the title compound was obtained as a colorless powder.
Was. Melting point: 191-193 ℃¹ H-NMR (CDCl_Three): Δ 2.68 (3H, s), 3.00 (3H, s), 7.24-
7.29 (1H, m), 7.35 (1H, s), 7.74-7.80 (2H, m), 7.46
(1H, dd, J = 1.8,8.6Hz), 7.74-7.80 (1H, m), 7.85 (1H, d
d, J = 1.5,7.9Hz). IR ν_max(KBr): 3467,3371,3228,3016,2927,2858,171
2,1624,1566,1485,1408,1288,1134,1026 cm^-1. [Production Example 17] Methyl 4- (5-fluoro)
B-3-Methylbenzo [b] thiophen-2-sulfoni
Ruamino) -3-methanesulfonylbenzoate (compound
Synthesis of compound 17) Methyl 4-amino-3-methanesulfonylbenzoate
Was dissolved in 300 mL of THF.
6.10 g of sodium iodide (oil, 60%) was added.
After stirring at the same temperature for 40 minutes, 5-fluoro-2-
Chlorosulfonyl-3-methylbenzo [b] thiophene
16.0 g was added, and the mixture was stirred at room temperature for 3 hours. Raw material disappearance
After confirming, the reaction was stopped by adding 2 mol / L hydrochloric acid at 0 ° C.
After stopping, the mixture was extracted with ethyl acetate.
After washing with aqueous sodium hydrogen chloride solution and saturated saline, anhydrous sodium sulfate
Dry with thorium. After evaporating the solvent, the residue was ethyl acetate
The solution is treated with activated carbon and recrystallized (vinegar).
(Ethyl acetate / ether) as a colorless powder
24.8 g of the compound were obtained. Melting point: 202-204 ° C¹ H-NMR (CDCl_Three): Δ 2.69 (3H, s), 3.06 (3H, s), 3.90
(3H, s), 7.28 (1H, ddd, J = 2.6,8.7,8.9Hz), 7.46 (1H, d
d, J = 2.6,9.2Hz), 7.76 (1H, dd, J = 4.7,8.9Hz), 7.87 (1
H, d, J = 8.8Hz), 8.19 (1H, dd, J = 2.0,8.8Hz), 8.50 (1H,
d, J = 2.0Hz), 9.83 (1H, s). IR ν_max(KBr): 3182,1724,1604,1504,1442,1396,134
6,1303,1157 cm^-1. [Production Example 18] Methyl 4- (5-methyl)
-3-methylbenzo [b] thiophen-2-sulfonylua
Mino) -3-methanesulfonylbenzoate (compound 1
8) Synthesis Methyl 4-amino-3-methanesulfonylbenzoate
183 mg of THF was dissolved in 8.0 mL of THF.
96 mg of sodium iodide (oil, 60%) were added. same
After stirring at room temperature for 20 minutes, 5-methyl-2-chloro
Losulfonyl-3-methylbenzo [b] thiophene 25
0 mg was added, and the mixture was stirred at room temperature for 6 hours. Confirm the disappearance of raw materials
After confirmation, the reaction was stopped by adding 1 mol / L hydrochloric acid at 0 ° C.
After that, the mixture was extracted with chloroform, and the organic layer was extracted with saturated saline.
After washing, it was dried with anhydrous sodium sulfate. Solvent evaporation
Followed by silica gel column chromatography (ethyl acetate
/ Hexane = 3/1 to 1/1) and purified as a colorless powder.
This gave 181 mg of the title compound. Melting point: 179-181 ° C¹ H-NMR (CDCl_Three): Δ 2.48 (3H, s), 2.70 (3H, s), 3.02
(3H, s), 3.89 (3H, s), 7.35 (1H, dd, J = 2.2,8.8Hz), 7.
60 (1H, d, J = 2.2Hz), 7.69 (1H, d, J = 8.8Hz), 7.88 (1H,
d, J = 8.8Hz), 8.18 (1H, dd, J = 1.8,8.8Hz), 8.50 (1H, d, J
= 1.8Hz). IR ν_max(KBr): 3460, 3178,3016,2927,2861,1724,160
4,1500,1439,1396,1300,1130,1061 cm^-1. [Production Example 19] 5-Fluoro-3-methyl
Benzo [b] thiophene-2-sulfonic acid (4-acetyl
-2-methanesulfonylphenyl) amide (compound 1
Synthesis of 9) (4-amino-3-methanesulfonyl) acetophenone
6.30 g was mixed with 168 mL of THF and 42 mL of DMF.
Dissolve in a mixed solvent and add sodium hydride (oil
(State, 60%). Stir at the same temperature for 10 minutes
After stirring, 2-chlorosulfonyl-5-fluoro-
8.60 g of 3-methylbenzo [b] thiophene was added,
The mixture was stirred at the same temperature for 4 hours. After confirming the disappearance of raw materials, at the same temperature
The reaction was stopped by adding 1 mol / L hydrochloric acid, and then concentrated hydrochloric acid was added.
PH 1 and extract with chloroform to saturate the organic layer
After washing with brine, the extract was dried over anhydrous sodium sulfate. Dissolution
After distilling off the solvent, the residue was diluted with chloroform and the solution was
After the treatment with activated carbon, the solvent is distilled off.
And 10.9 g of the title compound was obtained as a colorless powder.
Obtained. Melting point: 174-175 ° C¹ H-NMR (CDCl_Three): Δ 2.56 (3H, s), 2.69 (3H, s), 3.08
(3H, s), 7.29 (1H, ddd, J = 2.5,8.8,8.8Hz), 7.47 (1H, d
d, J = 2.5,8.8Hz), 7.77 (1H, dd, J = 4.6,8.8Hz), 7.84 (1
H, d, J = 8.6Hz), 8.12 (1H, dd, J = 2.2,8.6Hz), 8.42 (1H,
d, J = 2.2Hz), 9.83 (1H, brs). IR ν_max(KBr): 3243,3092,3006,2925,1672,1599,144
3,1392,1262,1130,1056,1029 cm^-1. [Production Example 20] Methyl 4- (3-methyl)
Benzo [b] thiophen-2-sulfonylamino) -3-
Synthesis of methanesulfonyl benzoate (compound 20) 640mg of 5% palladium / carbon in 30mL of methanol
And 30 mL of dioxane in a mixed solvent.
The mixture was stirred for 10 minutes. Compound 1 under argon atmosphere
  330 mg was added, and the mixture was stirred under a hydrogen atmosphere at 5 atm for 3 days.
Stirred. After confirming the disappearance of the raw materials, the reaction solution was filtered, and silica gel was removed.
Column chromatography (ethyl acetate / hexane =
2/1) to give 70m of the title compound as a colorless powder.
g was obtained. Melting point: 170-172 ° C¹ H-NMR (CDCl_Three): Δ 2.75 (3H, s), 3.04 (3H, s), 3.90
(3H, s), 7.49 (1H, dd, J = 7.1,7.7Hz), 7.51 (1H, dd, J =
7.1,7.7Hz), 7.83 (2H, d, J = 7.7Hz), 7.89 (1H, d, J = 8.8H
z), 8.20 (1H, dd, J = 2.0,8.8Hz), 8.51 (1H, d, J = 2.0H
z), 9.82 (1H, s). IR ν_max(KBr): 3209,1720,1604,1500,1442,1392,135
0,1308,1165,1122 cm^-1. [Production Example 21] (2S) -2- [4- (5
-Fluoro-3-methylbenzo [b] thiophen-2-
Sulfonylamino) -3-methanesulfonyl] benzoi
Methyl ruamino-3-hydroxy-propionate (compound
Synthesis of compound 21) The compound of Reference Example 1 (14.3 g) was mixed with chloroform (450 m).
L-serine methyl ester hydrochloride at room temperature
After adding 7.54 g and 9.30 g of EDC hydrochloride, 0 ° C.
6.80 mL of triethylamine was added thereto. At the same temperature
After stirring for 2 hours, 2 mol / L hydrochloric acid was added at 0 ° C for reaction.
And then extract with chloroform to saturate the organic layer
After washing with brine, the extract was dried over anhydrous sodium sulfate. Dissolution
After distilling off the solvent, the residue is subjected to silica gel chromatography (acetic acid).
Ethyl) to yield the title compound as a colorless amorphous
12.9 g of the product were obtained.¹ H-NMR (CDCl_Three): Δ 2.71 (3H, s), 3.07 (3H, s), 3.81
(3H, s), 4.00 (1H, dd, J = 4.2,11.4Hz), 4.15 (1H, dd, J =
5.4,11.4Hz), 4.85 (1H, dd, J = 4.2,5.4Hz), 7.33 (1H, d
d, J = 2.1,8.6Hz), 7.48 (1H, dd, J = 2.1,8.6Hz), 7.79 (1
H, dd, J = 4.6,8.6Hz), 7.87 (1H, d, J = 8.8Hz), 8.00 (1H, d
d, J = 2.1,8.8Hz), 8.32 (1H, d, J = 2.1Hz), 9.76 (1H, s). IR ν_max(KBr): 3401,1735,1655,1606,1510,1491,144
0,1353,1308,1164,1136cm^-1. [Production Example 22] 2- [4- (5-fluoro)
-3-Methylbenzo [b] thiophen-2-sulfonyl
Amino) -3-methanesulfonylphenyl] -4,5-
Methyl dihydro-oxazole-4-carboxylate
Synthesis of Compound (Compound 22) Dissolve 12.9 g of compound 21 in 180 mL of THF,
Burgess reagent (J. Org. Chem., 38)
Vol. 26, 1973, J. Mol. Org. Chem. , 5
8, p. 4494, 1993).
Stirred at 0 ° C. for 2 hours. After confirming that the raw materials have disappeared, the solvent is distilled off.
Water, add water and extract with ethyl acetate.
After washing with brine, it was dried over anhydrous sodium sulfate. solvent
After evaporation, the residue was chromatographed on silica gel (acetic acid
Purified by chill: hexane = 9: 1) to give colorless amorpha
As a result, 9.92 g of the title compound was obtained.¹ H-NMR (CDCl_Three): Δ 2.68 (3H, s), 3.02 (3H, s), 3.81
(3H, s), 4.60 (1H, dd, J = 9.0,10.6Hz), 4.69 (1H, dd, J
= 7.9,9.0Hz), 4.93 (1H, dd, J = 7.9,10.6Hz), 7.29 (1H, d
dd, J = 2.1,8.8,8.8Hz), 7.46 (1H, dd, J = 2.1,8.8Hz), 7.7
6 (1H, dd, J = 4.6,8.8Hz), 7.87 (1H, d, J = 8.8Hz), 8.15
(1H, dd, J = 2.1,8.8Hz), 8.43 (1H, d, J = 2.1Hz), 9.81 (1
H, s). IR ν_max(KBr): 3226,1737,1647,1608,1498,1441,139
5,1355,1308,1248,1211,1164 cm^-1. [Production Example 23] 2- [4- (5-fluoro)
-3-Methylbenzo [b] thiophen-2-sulfonyl
Amino) -3-methanesulfonylphenyl] oxazo
Synthesis of methyl 4-carboxylate (Compound 23)
Success Compound 22 1.10 g in dichloromethane (40 mL)
In bromotrichloromethane at -20 ° C.
mg was added. Further, 700 mg of DBU was dropped at the same temperature.
After stirring at the same temperature for 5 minutes, the temperature was raised to 0 ° C. for 3.5 hours.
Stirred. After confirming the disappearance of the raw materials,
The reaction was stopped by adding an aqueous solution of thorium, and then ethyl acetate was added.
, And the organic layer is washed with a saturated saline solution.
It was dried with gnesium. After distilling off the solvent,
Matography (ethyl acetate: methanol = 20: 1)
To obtain 597 mg of the title compound as a colorless powder.
Was. Melting point: 290-292 ° C¹ H-NMR (CDCl_Three): Δ 2.70 (3H, s), 3.06 (3H, s), 3.95
(3H, s), 7.30 (1H, ddd, J = 2.4,8.7,8.7Hz), 7.47 (1H, d
d, J = 2.4,9.0Hz), 7.77 (1H, dd, J = 4.8,9.0Hz), 7.94 (1
H, d, J = 9.0Hz), 8.27 (1H, s), 8.28 (1H, dd, J = 2.1,9.0H)
z), 8.57 (1H, d, J = 2.1Hz), 9.78 (1H, s). IR ν_max(KBr): 3243,1720,1618,1590,1518,1485,144
0,1355,1320,1303,1259,1162,1136 cm^-1. [Production Example 24] 2- [4- (5-fluoro)
-3-Methylbenzo [b] thiophen-2-sulfonyl
Amino) -3-methanesulfonylphenyl] oxazo
Synthesis of l-4-carboxylic acid (compound 24) Dissolve 7.85 g of compound 23 in 150 mL of methanol
And a 10% aqueous sodium hydroxide solution (15 mL) at room temperature.
Then, 15 mL of water and water were added, and the mixture was stirred for 15 minutes. Precipitated crystals
Was dissolved by adding 90 mL of water, and
Stirred for hours. After distilling off the solvent, 1 mol / L salt was added to the residue.
After adding 45 mL of acid, the precipitated crystals were collected by filtration and washed with water.
Then, add 100 mL of DMF to the obtained crude crystals and heat to reflux.
did. After hot filtration, add 70 mL of ethanol and reconstitute
Crystallized. The obtained crystals are collected by filtration and alternately added with ethanol and water.
And dried over diphosphorus pentoxide under reduced pressure to give a colorless powder.
As a result, 5.78 g of the title compound was obtained. Melting point: 289-291 ° C¹ H-NMR (DMSO-d₆): Δ 2.55 (3H, s), 3.41 (3H, s), 7.
44 (1H, ddd, J = 1.8,8.7,9.0Hz), 7.64 (1H, d, J = 8.4Hz),
7.79 (1H, dd, J = 1.8,9.9Hz), 8.08 (1H, dd, J = 4.8,8.7H
z), 8.19 (1H, dd, J = 1.8,8.4Hz), 8.41 (1H, d, J = 1.8H
z), 8.84 (1H, s). IR ν_max(KBr): 3232,1717,1690,1616,1487,1440,135
5,1313,1161,1140 cm^-1. [Production Example 25] 2- [4- (5-chloro-
3-methylbenzo [b] thiophen-2-sulfonylua
Mino) -3-methanesulfonylphenyl] oxazole
Synthesis of -4-carboxylic acid methyl ester (compound 25) Dissolve 495 mg of copper dibromide in dichloromethane (10 mL)
And add 310 mg of hexamethyltetramine at room temperature.
I got it. At 0 ° C, 337 mg of DBU was added dropwise, and the same temperature was maintained for 5 minutes.
After stirring for 30 minutes, 300 mg of compound 47 was added at 0 ° C.
The mixture was stirred at room temperature for 3 hours. After confirming that the raw materials have disappeared, add vinegar to the reaction mixture.
After adding ethyl acetate, the organic layer is washed with saturated aqueous ammonium chloride.
1: 1 mixture of solution and 25% aqueous ammonia, saturated
After washing with aqueous sodium hydrogen carbonate solution and saturated saline, anhydrous
It was dried over magnesium sulfate. After distilling off the solvent,
Chromatography (chloroform: methanol = 1
0: 1) to give the title compound 110 as a colorless powder.
mg was obtained. Melting point: 237-239 ° C¹ H-NMR (CDCl_Three): Δ 2.70 (3H, s), 3.05 (3H, s), 3.95
(3H, s), 7.47 (1H, dd, J = 2.1,8.7Hz), 7.74 (1H, d, J = 8.
7 Hz), 7.79 (1H, d, J = 2.1Hz), 7.93 (1H, d, J = 9.0Hz),
8.27 (1H, s), 8.28 (1H, dd, J = 2.1,9.0Hz), 8.56 (1H, d,
J = 2.1Hz), 9.72 (1H, brs). IR ν_max(KBr): 3231,1744,1486,1317,1136 cm^-1. [Production Example 26] 2- [4- (5-chloro-
3-methylbenzo [b] thiophen-2-sulfonylua
Mino) -3-methanesulfonylphenyl] oxazole
Synthesis of -4-carboxylic acid (compound 26) From compound 25 (70 mg) in the same manner as in Production Example 24
68 mg of the title compound were obtained as a colorless powder. Melting point: 296-298 ℃¹ H-NMR (DMSO-d₆): Δ 2.58 (3H, s), 3.37 (3H, s), 7.
55 (1H, dd, J = 2.1,8.7Hz), 7.62 (1H, d, J = 8.7Hz), 8.01
(1H, d, J = 2.1Hz), 8.09 (1H, d, J = 8.4Hz), 8.12 (1H, dd,
J = 2.1,8.4Hz), 8.40 (1H, d, J = 2.1Hz), 8.83 (1H, s). IR ν_max(KBr): 3221,2924,1701,1485,1311,1153 cm
^-1. [Production Example 27] 2- [4- (5-fluoro)
-3-Methylbenzo [b] thiophen-2-sulfonyl
Amino) -3-methanesulfonylphenyl] oxazo
Combination of disodium 4-carboxylate (compound 27)
Success Dissolve 290 mg of compound 23 in 30 mL of methanol
Then, 77 mg of sodium methoxide was added. At room temperature
After stirring for 8 hours, ether was added and the precipitated crystals were collected by filtration.
Thereafter, the residue was washed with ether to give the title compound 300 as a colorless powder.
mg was obtained. Melting point: 341-343 ° C¹ H-NMR (DMSO-d₆): Δ 2.49 (3H, s), 3.42 (3H, s), 7.
26 (1H, dd, J = 2.4,8.8,9.0Hz), 7.40 (1H, dd, J = 9.0,9.0
Hz), 7.56 (1H, dd, J = 2.4,8.9Hz), 7.89 (1H, dd, J = 2.2,
9.0Hz), 7.95 (1H, d, J = 9.0Hz), 8.19 (1H, d, J = 2.2Hz). IR ν_max(KBr): 3490,1609,1570,1523,1470,1441,140
0,1302,1280,1119 cm^-1. Hereinafter, the compounds of Production Examples 28 to 49 in the same manner as in Production Example 1
28-49 were synthesized. [0091] [Table 1][0092] [Table 2][Production Example 50] 2- [4- (5-chloro-
3-methylbenzo [b] thiophen-2-sulfonylua
Mino) -3-methoxybenzoylamino] acetic acid (compound
Synthesis of 50) 104 mg of the compound of Production Example 37 in 25 mL of ethanol
Dissolve, 1 mol / L sodium hydroxide aqueous solution at room temperature
After adding 1 mL, the mixture was stirred at the same temperature for 15 hours. Raw material consumption
After confirming the loss, the solvent was distilled off and extracted with ether.
ol / L hydrochloric acid, and extracted with ethyl acetate.
After washing with saturated saline, it was dried over anhydrous sodium sulfate.
Was. After distilling off the solvent, the obtained powder was washed with ether,
97 mg of the title compound were obtained as a yellow powder. Melting point: 282-285 ℃¹ H-NMR (CDCl_Three/ CD_ThreeOD): δ 2.50 (3H, s), 3.82 (2H,
s), 3.84 (3H, s), 7.10-7.15 (2H, m), 7.20-7.35 (2H,
m), 7.60-7.70 (2H, m). IR ν_max(KBr): 3394,2974,1604,1554,1493,1412,128
4,1230,1130 cm^-1 _. [Production Example 51] Methyl 4- (5-chloro)
-3-Methylbenzo [b] thiophen-2-sulfonyl
Amino) -3-methanesulfonylbenzoate sodium
Synthesis of salt (compound 51) Dissolve 115 mg of the compound of Preparation Example 1 in THF (8 mL)
And sodium hydride (oil, 60%) 15m at room temperature
g was added. After stirring at the same temperature for 1.5 hours, the solvent was distilled off.
The obtained powder was washed with ether and the title was a colorless powder.
61 mg of the compound were obtained. Melting point:> 300 ° C¹ H-NMR (DMSO-d₆): Δ 2.51 (3H, s), 3.37 (3H, s), 3.7
2 (3H, s), 7.39 (1H, d, J = 2.1,8.8Hz), 7.40 (1H, dd, J =
1.8,8.5Hz), 7.68 (1H, dd, J = 1.8,8.8Hz), 7.80 (1H, d, J
= 1.8Hz), 7.93 (1H, d, J = 8.5Hz), 8.23 (1H, d, J = 1.8H
z). IR ν_max(KBr): 3448,1705,1597,1481,1442,1292,113
4, 1103 cm^-1. Ester hydrolysis of the compounds of Production Examples 43, 44 and 46
After that, it was converted into a sodium salt under the same conditions as in Production Example 51,
Compounds 52 and 53 of Production Examples 52, 53 and 54, respectively
And 54 were synthesized. [0095] [Table 3]Hereinafter, the equipment data of each production example is shown. [0097] [Table 4] [0098] [Table 5][0099] [Table 6][0100] [Table 7][0101] [Table 8][0102] [Table 9] [Production Example 55] 5-Fluoro-N- [2-
Methanesulfonyl-4- (5-methoxy-4-methylthio
Azol-2-yl) phenyl] -3-methylbenzo
[B] Thiophene-2-sulfonamide (compound 55)
Synthesis of Under an argon atmosphere, 2-methanesulfonyl-4- (5-
Methoxy-4-methylthiazol-2-yl) aniline
41 mg of THF (3 mL) -dimethylacetamide (3
mL) of the mixed solution. This is cooled to -25 ° C,
Add 15 mg of sodium hydride (oil, 60%),
For 10 minutes. Further, 2-chlorosulfonyl
-5-fluoro-3-methylbenzo [b] thiophene 4
After adding 4 mg and stirring at the same temperature for 2 hours, 1 mol / L hydrochloric acid was added.
To stop the reaction. After returning the reaction solution to room temperature,
The mixture was extracted with chilled toluene (2: 1).
Washing was sequentially performed with a saline solution. Organic layer is dried with anhydrous sodium sulfate
After drying with a solvent, the residue obtained by evaporating the solvent under reduced pressure is removed.
Silica gel chromatography (ethyl acetate: hexane
= 1: 1) to give the title compound 5 as a pale yellow powder.
1 mg was obtained. Melting point: 216-217 ° C¹ H-NMR (CDCl_Three): Δ 2.29 (3H, s), 2.68 (3H, s), 2.
99 (3H, s), 3.93 (3H, s), 7.27 (1H, ddd, J = 2.6,8.
6,8.8Hz), 7.46 (1H, dd, J = 2.6,9.2Hz), 7.75 (1H, dd, J
= 4.7,8.8Hz), 7.82 (1H, d, J = 8.7Hz), 7.96 (1H, dd, J =
2.1,8.7Hz), 8.25 (1H, d, J = 2.1Hz), 9.57 (1H, s). IR ν_max(KBr): 3202,2989,2910,1604,1558,1501,144
1,1349,1298,1253,1156,1133,926 cm^-1. [Production Example 56] 5-Fluoro-N- [2-
Methanesulfonyl-4- (5-methoxy-4-methylo
Xazol-2-yl) phenyl] -3-methylbenzo
[B] Thiophene-2-sulfonamide (compound 56)
Synthesis of 5.28 g of the compound of Reference Example 2 in 26 mL of phosphorus oxychloride
Was added and heated under reflux for 3 hours. Bring the reaction to room temperature and add ice
And extracted with chloroform. Organic layer is saturated with water
Wash sequentially with brine and dry over anhydrous sodium sulfate.
Was. The residue obtained by distilling off the solvent under reduced pressure was silica gel
Purified by chromatography (chloroform), colorless powder
As a result, 2.02 g of the title compound was obtained. Melting point: 232-233 ° C¹ H-NMR (DMSO-d₆): Δ2.02 (3H, s), 2.57 (3H, s),
3.32 (3H, s), 3.96 (3H, s), 7.46 (1H, ddd, J = 2.5,
9.0,9.0Hz), 7.54 (1H, d, J = 8.4Hz), 7.81 (1H, dd, J =
2.5,9.9Hz), 8.06 (1H, dd, J = 1.9,8.4Hz), 8.10 (1H, d
d, J = 4.9,9.0Hz), 8.26 (1H, d, J = 1.9Hz). IR ν_max(KBr): 3253,3083,3000,2922,1665,1491,144
2,1393,1354,1308,1169,1131 cm^-1. [Production Example 57] 5-Fluoro-N- [2-
Methanesulfonyl-4- (5-methylthiazole-2-
Yl) phenyl] -3-methylbenzo [b] thiophene
Synthesis of -2-sulfonamide (compound 57) 4- (5-fluoro-3-methylbenzo [b] thiophene
N-2-yl) sulfonamido-3-methanesulfonyl
-N- (2-oxopropyl) benzamide 150 mg
135 mg of diphosphorus pentasulfide in 5 mL of 1,4-dioxane solution
Was added and the mixture was heated under reflux for 4.5 hours. Add water to the reaction mixture
The reaction was stopped, and the mixture was extracted with ethyl acetate. The organic layer is saturated with water
Wash sequentially with Japanese saline and dry over anhydrous sodium sulfate
did. The residue obtained by distilling off the solvent under reduced pressure was
Chromatography (hexane: ethyl acetate 2: 1 to 1:
Purify in 1) to give the title compound 115 as amorphous
mg was obtained.¹ H-NMR (CDCl_Three): 2.51 (3H, s), 2.69 (3H, s), 3.02 (3
H, s), 7.27 (1H, ddd, J = 2.4,8.6,8.9Hz), 7.47 (1H, dd, J
= 2.4,9.2Hz), 7.50 (1H, s), 7.76 (1H, dd, J = 4.8,8.9H
z), 7.86 (1H, d, J = 8.8Hz), 8.05 (1H, dd, J = 2.1,8.8Hz),
 8.35 (1H, d, J = 2.1Hz), 9.64 (1H, s). IR ν_max(KBr): 3240,3010,2926,1607,1499,1353,130
2,1160,994 cm^-1. Hereinafter, Production Example 5 is performed in the same manner as Production Example 56 and Production Example 57.
Compounds 8 to 62 were synthesized. [0106] [Table 10] [Production Example 63] 5-Fluoro-N- [4-
(4-hydroxymethylthiazol-2-yl) -2-
Methanesulfonylphenyl] -3-methylbenzo [b]
Synthesis of Thiophene-2-sulfonamide (Compound 63) 298 mg of lithium aluminum hydride in THF suspension
Dissolve 4.52 g of compound 69 in 226 mL at 5 ° C.
452 mL of the THF solution was added dropwise and stirred at room temperature for 6 hours.
Was. Further, 298 mg of lithium aluminum hydride was added.
Then, the mixture was stirred at room temperature for 14 hours. After confirming the disappearance of raw materials, 1
Stop the reaction by adding 10 mL of water at 0 ° C and stir for 30 minutes
did. The solvent was distilled off under reduced pressure, and the residue obtained was chloroform.
And the organic layer is added to 1 mol / L sulfuric acid, water, and saturated saline.
And dried over anhydrous sodium sulfate. solvent
Was distilled off under reduced pressure, and the residue obtained was purified by silica gel chromatography.
And purified with acetic acid (ethyl acetate: hexane = 1: 1)
Was. 140 mL of chloroform and hexane were added to the obtained crystals.
28 mL was added and the mixture was heated under reflux. Refilter after hot filtration
The crystals obtained in the above were collected by filtration and dried under reduced pressure to give a pale yellow powder.
As a result, 2.58 g of the title compound was obtained. Melting point: 209-210 ° C¹ H-NMR (CDCl_Three): Δ 2.69 (3H, s), 3.04 (3H, s), 4.80
(2H, s), 7.22 (1H, s), 7.27 (1H, ddd, J = 2.4,8.6,8.8H
z), 7.47 (1H, dd, J = 2.4,9.2Hz), 7.76 (1H, dd, J = 4.7,8.
8Hz), 7.88 (1H, d, J = 8.8Hz), 8.09 (1H, dd, J = 2.2,8.8H
z), 8.42 (1H, d, J = 2.2Hz), 9.65 (1H, s). IR ν_max(KBr): 3423,3237,3114,3026,2930,1605,150
9,1445,1354,1294,1152,1135 cm^-1. [Production Example 64] N- [4- (4-chlorometh
Tiltthiazol-2-yl) -2-methanesulfonyl
Enyl] -5-fluoro-3-methylbenzo [b] thio
Synthesis of phen-2-sulfonamide (Compound 64) 159 mg of Compound 63 was suspended in 20 mL of chloroform.
Was. Add 47 μL of thionyl chloride at 0 ° C.,
Stir for 1 hour. Add 1 mL of thionyl chloride and add 1 hour
Heated to reflux. Add 2 mL of triethylamine at 0 ° C
After stirring for 3 hours, the reaction was stopped with 1 mol / L hydrochloric acid.
Stopped. Extract with ethyl acetate, then sequentially with water and saturated saline
Next, it was washed and dried over anhydrous sodium sulfate. Reduce solvent
The residue obtained by distillation under reduced pressure is subjected to silica gel chromatography.
-Purified with (chloroform) as light brown powder
104 mg of the compound were obtained. Melting point: 190-191 ° C¹ H-NMR (CDCl_Three): Δ 2.69 (3H, s), 3.04 (3H, s), 4.7
0 (2H, s), 7.28 (1H, ddd, J = 2.5,8.6,8.8Hz), 7.34 (1
H, s), 7.47 (1H, dd, J = 2.5,9.2Hz), 7.76 (1H, dd, J = 4.
7,8.8Hz), 7.89 (1H, d, J = 8.8Hz), 8.11 (1H, dd, J =
2.2, 8.8Hz), 8.41 (1H, d, J = 2.2Hz), 9.66 (1H, s). IR ν_max(KBr): 3236,3098,3027,2927,1607,1507,145
7,1354,1306,1156,1137,912 cm^-1. [Production Example 65] 5-Fluoro-N- [2-
Methanesulfonyl-4- (4-methylthiazole-2-
Yl) phenyl] -3-methylbenzo [b] thiophene
Synthesis of -2-sulfonamide (compound 65) Compound 64 (64 mg) was dissolved in acetone (10 mL) and iodinated.
After adding 180 mg of sodium and heating under reflux for 24 hours,
Add 180 mg of sodium iodide and heat for 19 hours
Shed. After evaporating the solvent under reduced pressure, the residue was dissolved in ethyl acetate.
Water, 5% sodium thiosulfate aqueous solution, water, saturated salt
Washed sequentially with water and dried over anhydrous sodium sulfate.
The solvent was distilled off under reduced pressure to obtain 5-fluoro-N- [4-
(4-Iodomethylthiazol-2-yl) -2-meta
Nsulfonylphenyl] -3-methylbenzo [b] thio
Phen-2-sulfonamide was added to toluene (5 mL)
Dissolve in a mixed solution of methylsulfoxide (0.5 mL),
Tributyltin hydride 45μL and 1.06mol / L
Add 13 μL of hexane solution of triethylboron to room temperature
And stirred for 6 hours. Furthermore, tributyltin hydride 24μ
L, and the mixture was stirred at room temperature for 3 hours.
The reaction was stopped by adding an aqueous solution of ammonium. In ethyl acetate
After extraction, the organic layer was washed successively with water and saturated saline. Nothing
After drying over sodium sulfate, the solvent is removed by evaporation under reduced pressure.
Silica gel chromatography (hexane to
Purified with hexane: ethyl acetate = 3: 1) to give a colorless powder.
This gave 29 mg of the title compound. Melting point: 199-200 ° C¹ H-NMR (CDCl_Three): Δ 2.48 (3H, s), 2.69 (3H, s), 3.0
3 (3H, s), 6.91 (1H, s), 7.27 (1H, ddd, J = 2.4,8.6,8.
8Hz), 7.46 (1H, dd, J = 2.4,9.2Hz), 7.75 (1H, dd, J = 4.
7,8.8Hz), 7.87 (1H, d, J = 8.7Hz), 8.09 (1H, dd, J = 2.
1,8.7Hz), 8.40 (1H, d, J = 2.1Hz), 9.65 (1H, s). IR ν_max(KBr): 3243,3105,3028,2925,1607,1508,144
2,1355,1308,1162,1135,913 cm^-1. Hereinafter, Production Examples 66 to 68 are performed in the same manner as Production Examples 63 to 65.
Compounds 66 to 68 were synthesized. [0110] [Table 11] [Production Example 69] 2- [4- (5-fluoro)
-3-Methylbenzo [b] thiophen-2-sulfonyl
Amino) -3-methanesulfonylphenyl] thiazole
Synthesis of -4-carboxylic acid methyl ester (compound 69) 11.06 g of compound 74 in 204 mL of dichloromethane
Dissolve and add 2.4 mL of bromotrichloromethane at 0 ° C for 5 minutes.
It was added dropwise over a period of minutes. After stirring at the same temperature for 20 minutes, D
7.6 mL of BU was added dropwise over 15 minutes. 5 o'clock at room temperature
After stirring for 1 hour, the reaction was stopped with 1 mol / L hydrochloric acid.
The organic layer was separated, washed with water and saturated saline, and then dried.
It was dried over sodium sulfate. The solvent was removed by evaporation under reduced pressure.
The residue obtained is chromatographed on silica gel (chloroform
9.18 g of the title compound as a colorless powder
I got Melting point: 241-242 ° C¹ H-NMR (DMSO-d₆): Δ 2.61 (3H, s), 3.38 (3H, s),
3.87 (3H, s), 7,47 (1H, ddd, J = 2.5,9.0,9.0Hz), 7.60
(1H, d, J = 8.6Hz), 7.83 (1H, dd, J = 2.5,9.9Hz), 8.11
(1H, dd, J = 4.7,9.0Hz), 8.22 (1H, dd, J = 2.1, 8.6Hz),
 8.44 (1H, d, J = 2.1Hz), 8.63 (1H, s). IR ν_max(KBr): 3193,3113,3021,3003,2923,1730,160
6,1509,1392,1359,1295,1225,1162,1131,988,918 cm^-1. [Production Example 70] 2- [4- (5-fluoro)
-3-Methylbenzo [b] thiophen-2-sulfonyl
Amino) -3-methanesulfonylphenyl] thiazole
Synthesis of -4-carboxylic acid (compound 70) Compound 954 mg was dissolved in 45 mL of methanol, and 1
4.0 mL of mol / L sodium hydroxide was added. heating
After stirring for 20 minutes under reflux, the solvent was distilled off under reduced pressure to obtain a residue.
The residue was extracted with ether-water (1: 1). 2m in water layer
ol / L hydrochloric acid was added, and the precipitated crystals were washed with ether.
746 mg of the title compound were obtained as a colorless powder. Melting point: 257-258 ℃¹ H-NMR (DMSO-d₆): Δ 2.59 (3H, s), 3.36 (3H, s),
7.45 (1H, ddd, J = 2.3,8.8,8.8Hz), 7.57 (1H, d, J = 8.5H
z), 7.81 (1H, dd, J = 2.3,9.9Hz), 8.09 (1H, dd, J = 5.0,8.
8Hz), 8.18 (1H, dd, J = 2.0,8.5Hz), 8.42 (1H, d, J = 2.0H
z), 8.51 (1H, s). IR ν_max(KBr): 3448,3233,3104,3027,2924,1711,160
7,1516,1461,1352,1306,1217,1153,1137 cm^-1. [Production Example 71] 5-Fluoro-N- [2-
Methanesulfonyl-4- (2-methylthiazole-4-
Yl) phenyl] -3-methylbenzo [b] thiophene
Synthesis of -2-sulfonamide (Compound 71) Dissolve 200 mg of compound 19 in 4.0 mL of chloroform
And benzyltrimethylammonium tribromide 1
94 mg was added, and the mixture was stirred at room temperature for 1 hour. Water to the reaction solution
After the reaction was stopped in addition, the solvent was distilled off once and 1 mol / mol
After adding L hydrochloric acid to adjust the pH to 2-3, extract with ethyl acetate.
The organic layer was washed with saturated saline, and then dried over anhydrous sodium sulfate.
And dried in a vacuum. The residue obtained by evaporating the solvent under reduced
After washing with ethanol, N- (4-bromoamine) was obtained as a colorless solid.
Cetyl-2-methanesulfonylphenyl) -5-fluoro
B-3-Methylbenzo [b] thiophen-2-sulfone
201 mg of the amide were obtained. The N- thus obtained
(4-bromoacetyl-2-methanesulfonylphenyi
L) -5-Fluoro-3-methylbenzo [b] thiophene
2-Sulfonamide (150 mg) was treated with dioxane (1.5
mL) -ethanol (1.5 mL).
Sodium hydrogen oxyoxide 53mg, thioacetamide 26mg
Next, the mixture was stirred under reflux with heating for 2 hours. Add water to the reaction solution
After stopping the reaction, the solvent was distilled off under reduced pressure.
Adjust to pH 2-3 by adding L hydrochloric acid and extract with ethyl acetate
The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate.
And dried. The residue obtained by evaporating the solvent under reduced pressure
Purify by gel column chromatography to obtain pale yellow crystals.
61 mg of the title compound were obtained. Melting point: 217-220 ° C¹ H-NMR (CDCl_Three): Δ 2.68 (3H, s), 2.75 (3H, s),
2.99 (3H, s) 7.27 (1H, ddd, J = 2.4, 8.7, 9.0Hz), 7.3
3 (1H, s), 7.45 (1H, dd, J = 2.4, 9.3Hz), 7.75 (1H,
dd J = 4.5, 9.0Hz), 7.84 (1H, d, J = 8.7Hz), 8.06 (1
H, dd, J = 2.1, 8.7Hz), 8.35 (1H, d, J = 2.1Hz), 9.55
(1H, s). IR ν_max(KBr): 3237,1604,1514,1352,1296,1163,89
9 cm^-1. [Production Example 72] 5-Fluoro-N- [2-
Methanesulfonyl-4-((E) -2-methanesulfi
Nyl-2-methylsulfanylvinyl) phenyl] -3
-Methylbenzo [b] thiophene-2-sulfonamide
Synthesis of (Compound 72) 135 mg of the compound of Reference Example 3 was added to THF2 under an argon atmosphere.
Dissolve in mL and add methylmethylsulfinylmethyls
196mg of sulfide, 40% Triton B in methanol
862 μL of the solution was added in sequence, and the mixture was stirred for 16 hours under reflux.
Was. The reaction was stopped by adding 1 mol / L hydrochloric acid to the reaction solution.
After that, dilute with ethyl acetate and wash sequentially with water and saturated saline
Then, it was dried over anhydrous sodium sulfate. The solvent is distilled off under reduced pressure
Residue obtained by silica gel column chromatography
-(Ethyl acetate: hexane = 1: 1), colorless
105 mg of the amorphous title compound were obtained.¹ H-NMR (CDCl_Three): Δ 2.32 (3H, s), 2.70 (3H, s),
2.76 (3H, s), 3.04 (3H, s), 7.28 (1H, ddd, J = 2.4, 9.0,
 9.3Hz), 7.48 (1H, dd, J = 2.4, 9.3Hz), 7.52 (1H, s),
  7.78 (1H, dd J = 4.8, 9.0Hz), 7.83 (1H, d, J = 8.7H
z), 8.02 (1H, dd, J = 2.1, 8.7Hz), 8.46 (1H, d, J = 2.1
Hz), 9.65 (1H, s). IR ν_max(KBr): 3446, 3225, 1604, 1492, 1303, 11
63, 1133, 924 cm^-1. Below, the equipment data of each production example is shown. [0115] [Table 12][Production Example 73] 5-Fluoro-N- [2-
Methanesulfonyl-4- (oxazol-2-yl) phenyl
Enyl] -3-methylbenzo [b] thiophen-2-ice
Synthesis of Rufonamide (Compound 73) 902 mg of the compound 24 was melted by open flame. The obtained mosquito
The ramel-like substance is subjected to silica gel chromatography (chloro
Form) and then recrystallized (ethyl acetate-hexa
To give the title compound 30 as pale yellow crystals.
6 mg were obtained. Melting point: 207-208 ° C¹ H-NMR (CDCl_Three): Δ 2.69 (3H, s), 3.03 (3H, s), 7.23 (1
H, s), 7.27 (1H, ddd, J = 2.6,8.8,8.8Hz), 7.46 (1H, dd, J =
2.6,9.2Hz), 7.71 (1H, s), 7.76 (1H, d, J = 4.8,8.8Hz),
7.91 (1H, d, J = 8.7Hz), 8.21 (1H, dd, J = 2.1,8.7Hz), 8.50
(1H, d, J = 2.1Hz), 9.70 (1H, s). IR ν_max(KBr): 3237,3140,3020,2925,1615,1519,148
1,1354,1303,1163, 1139,912,650 cm^-1. [Production Example 74] (4R) -2- [4- (5
-Fluoro-3-methylbenzo [b] thiophen-2-
Sulfonylamino) -3-methanesulfonylphenyl]
Thiazoline-4-carboxylic acid methyl ester (Compound 7
Synthesis of 4) (2R) -2- [4- (5-fluoro-3-methylben
Zo [b] thiophen-2-sulfonylamino) -3-meth
Tansulfonylphenylcarboxamide] -3-tri
31.04 g of methyl thiothiopropionate was added to di
Dissolved in 1500 mL of chloromethane. Cool to 0 ° C
Then, add 19.8 mL of hexamethylphosphoramide, and add
Further, 12.9 mL of titanium tetrachloride in dichloromethane (435)
mL) solution was added dropwise (Tetrahedron. Let
ters. , 42, 4171 (2001)). At room temperature
After stirring for 21 hours, water was added to stop the reaction. solvent
Was distilled off under reduced pressure, and the residue obtained was redissolved in ethyl acetate.
Then, the resultant was washed with water and saturated saline in this order. Anhydrous sodium sulfate
The residue obtained by evaporating the solvent under reduced pressure
To silica gel chromatography (chloroform)
Purification and recrystallization from chloroform-hexane
Gives 11.09 g of the title compound as a colorless powder
Was. Melting point: 170-171 ° C¹ H-NMR (CDCl_Three): Δ 2.68 (3H, s), 3.03 (3H, s),
3.66 (1H, dd, J = 9.1,11.5Hz), 3.73 (1H, dd, J = 9.1,1
1.5Hz), 3.82 (3H, s), 5.25 (1H, t, J = 9.1Hz), 7.28
(1H, dd, J = 2.5,8.7,8.9Hz), 7.46 (1H, dd, J = 2.5, 9.
2Hz), 7.76 (1H, dd, J = 4.7,8.9Hz), 7.85 (1H, d, J = 8.6
Hz), 8.01 (1H, dd, J = 2.0,8.6Hz), 8.31 (1H, d, J = 2.0
Hz), 9.76 (1H, s). IR ν_max(KBr): 3186,3029,3000,2954,2920,1744,160
6,1498,1357,1293,1225,1163,1131,989,927 cm^-1. [Production Example 75] 5-Fluoro-N- (4-
Hydroxymethyl-2-methanesulfonylphenyl)-
3-methylbenzo [b] thiophene-2-sulfonami
Synthesis of Compound (Compound 75) Dissolve 2.08 g of compound 17 in 120 mL of toluene,
After cooling to −30 ° C., 1.01 mol / L diisobutylamine
Add 22.5 mL of toluene solution of luminium hydride
Was. Stir at the same temperature for 5 hours, add water to the reaction solution,
After stopping, dilute with ethyl acetate and add saturated sodium tartrate
Aqueous potassium solution and stirred at room temperature for 30 minutes.
Was. Extract with ethyl acetate, wash the organic layer with saturated saline
Then, it was dried over anhydrous sodium sulfate. The solvent is distilled off under reduced pressure
The residue obtained by silica gel chromatography (vinegar
Ethyl acid: hexane = 1: 1) to give a colorless powder
This gave 1.38 g of the title compound. Melting point: 120-121 ° C¹ H-NMR (CDCl_Three): Δ 2.68 (3H, s), 2.96 (3H, s), 4.68
(2H, s), 7.26 (1H, ddd, J = 2.4,8.7,9.0Hz), 7.46 (1H, dd,
J = 2.4,9.0Hz), 7.57 (1H, dd, J = 1.8,8.4Hz), 7.75 (1H,
dd, J = 4.5,8.7Hz), 7.77 (1H, d, J = 8.4Hz), 7.86 (1H, d, J
= 1.8Hz), 9.48 (1H, s). IR ν_max(KBr): 3504,3221,1608,1497,1347,1296,11
50,926 cm^-1. [Example 1] Sarquimase or human chimer
Measurement of enzyme inhibitory activity Sarquimase is prepared by the human heart chymase purification method (J. Bio
l. Chem. , 265, 22348 (1990))
Purified from the rhesus monkey heart according to
The gene encoding human chymase (FEBS.L
et. , 412, 86 (1997))
Use from silkworms infected with the urovirus
Was. Chymase activity was determined by a method known in the literature (Miyazaki et al .;
20, p. 207, 1997). You
That is, free His-Leu produced with Ang II
With o-phthalaldehyde (hereinafter abbreviated as OPT)
To obtain a fluorescent derivative, and the amount is determined using a fluorometer.
It was measured by weighing. First, each test compound 3.6 μm
The mol was weighed into a test tube and dissolved in 3 mL of DMSO.
This DMSO solution was added to 0.01% Triton X-100 and
20 mmol / containing 0.5 mol / L potassium chloride
1,000 times dilution with L Tris-HCl buffer (pH 8.0)
Then 1.2 × 10^-6mol / L solution and buffer
1.2 × 10^-6from mol / L to 1.2
× 10^-9Test sample solutions up to mol / L were prepared. each
Enzyme solution in 500 μL of test sample solution or buffer
Add 50 μL of the solution, and incubate at 37 ° C for 10 minutes.
After the addition, 0.1 mmol / L AngI solution 5
The reaction was started by adding 0 μL. AngI is human angi
Otensin I (manufactured by SIGMA) was used. Used for reaction
The enzyme solution hydrolyzes about 60% of the substrate under these conditions.
And add a buffer containing no enzyme.
It was checked. After incubation at 37 ° C for 120 minutes, 1
The reaction was stopped by adding 900 μL of 5% trichloroacetic acid.
Was. Thereafter, the reaction solution is kept at 4 ° C. and 3,000 rpm for 10 minutes.
2 mL / L sodium hydroxide is added to 1 mL of the supernatant obtained by centrifugation.
2 mL of methanol and 1 mL of methanol were added. Here in 1mL
1.2 mg of N-acetyl-L-cysteine and 1 mg of OPT
Derivatization reaction by adding 100 μL of methanol solution containing
After leaving for exactly 1 hour at room temperature, the excitation wavelength
The fluorescence intensity at 304 nm and a fluorescence wavelength of 502 nm was measured. Measurement
The determination was repeated twice for each sample and for the blind test.
The fluorescence intensity obtained by subtracting the average value of
Was. The enzyme reaction was performed using a buffer instead of the test sample solution.
The reaction was used as a control, and the chymase activity
The inhibition rate of the test sample was determined based on the chymase activity of the control.
The difference in activity when added is determined by the control chymase activity.
To determine the inhibition rate. In addition, 50% inhibition from each inhibition rate
Concentration (hereinafter, IC₅₀Value). Representativeization
Compound IC₅₀The values are shown in Table 13. [0120] [Table 13][Example 2] Using a hamster adhesion model
Consideration Five-week-old female hamsters (10 per group) were injected into the abdominal cavity.
By administration of sodium barbital (50mg / kg)
After anesthesia and midline abdominal incision, the uterus was scraped with a cotton swab. That
Thereafter, a physiological saline solution of the test compound (compound 24:10)^-Fourmo
1 / L) 1 mL was dropped into the abdominal cavity, and the incision was sutured. one
On the other hand, as a control, only physiological saline was dropped, and the same treatment was performed.
Placed. Four weeks after surgery, the animals were sacrificed and the abdominal cavity was exposed.
And examined the adhesions. Adhesion is determined by the following five-step scoring system.
Data analysis was performed using the Mann-Whitney U test.
Was performed using Adhesion score 0: No adhesion 1: Very weak adhesion (adhesion that can be easily peeled off in the form of a film) 2: Limited adhesion (strong adhesion that is difficult to peel off at only one location) 3: Extensive adhesions (strong adhesions that are difficult to peel off at several places) 4: Very strong adhesion (very strong adhesion that cannot be peeled off) As a result, while the average score of the control group was 2.0,
And the average score of the group to which the test compound (Compound 24) was administered.
A was 0.9, which significantly suppressed post-operative adhesions (p
<0.05). [Example 3] In a rat cecal abrasion model
Examination by Six-week-old SD rats were pentobarbital (70 mg /
kg, intramuscular injection) Under anesthesia, midline incision of lower abdomen and cecum external
Pulled out. Two serosas of caecum (about 2 cm ²Each)
After rubbing with a cotton swab 100 times until petechiae occur,
100 μL of ethanol was added dropwise. The cecum into the abdominal cavity again
After storing, phosphoric acid of test compound (compound 24 or 70)
2 mL of buffered saline (PBS, pH 7.4) solution
It was dropped into the cavity and the incision was sutured. Test compound solution concentration
The degree is 10 each^-5mol / L, and the control group was PBS
Only, and treated similarly (each group 11 or 12).
One). One week after the operation, the animal was sacrificed, reopened, and cecum
The state of adhesion is indicated by the strength of the adhesion and the adhesion area as indices.
Evaluation was based on the wearing score. Score values are divided into the following five levels
Was. In addition, the adhesion area (%) is the total area of the part where the adhesion was made.
Was determined as a percentage of the area of the rubbing site. Adhesion score 0: No adhesion 1: Partially localized (less than 25% adhesion area)
Possible adhesions 2: Easy to peel over a wide area (adhesion area 25% or more)
Noble adhesion Or limited to part (adhesion area less than 25%)
adhesion 3: Healing that is difficult to peel over a wide area (adhesion area 25% or more)
Wear 4: Non-peelable adhesion or adhesion with serosa damage at the time of peeling As a result, the adhesion score distribution indicates severe adhesion.
The sum of scores 3 and 4 was 63.6% in the control group,
Compound Example 24 and 10 of Compound Example 70^-5mol / L solution
In the administration group, it decreased to 41.7% and 33.3%, respectively.
Adhesion due to compound administration was suppressed. [Example 4] Using an adhesion model after canine eye surgery
Study The beagle dog was anesthetized and the conjunctiva of both eyes was removed under a stereoscopic microscope.
mm × 5 mm was peeled off. At this time, the Tenon's capsule remains on the conjunctival side.
And did not leave it on the scleral side. Test compound (compound
70) Incision of sponge immersed in physiological saline solution for 3 minutes
After placing in place, one stitch of 10-0 nylon thread was sutured.
The concentration of each test compound solution was 10^{− 4}mol / L
The control group was treated similarly with physiological saline (each group).
6). 7 days after surgery, animals are killed and eyeballs are removed and healed
Evaluated wearing. Evaluation cuts the sutured thread during model production
After that, the conjunctiva is pulled with tweezers to heal the adhesion
It was done with a wearing score. Score values shall be in the following five stages,
The analysis of the data used the Mann-Whittonny U test. Adhesion score 0: No adhesion 1: Very weak adhesion (adhesion that can be easily peeled off in the form of a film) 2: Limited adhesion (strong adhesion that is difficult to peel off at only one location) 3: Extensive adhesions (strong adhesions that are difficult to peel off at several places) 4: Very strong adhesion (very strong adhesion that cannot be peeled off) As a result, the average score of the control group was 3.67.
In contrast, the average score of the test compound (compound 70) group was 2.
67, which significantly inhibited post-operative adhesions (p <0.0
Five). [Formulation Example 1] Production of tablets Compound 24 (5 g) was treated with lactose (125 g), corn
Mix with 40g of pun and 20g of microcrystalline cellulose,
6 g of xypropylcellulose in 10% ethanol solution
And kneaded and granulated, and passed through a screen with a diameter of 8 mm
Extruded to prepare granules, dried and dried
4 g of cesium is added and compression-molded to give compound 2 in one tablet.
A tablet weighing 200 mg containing 5 mg of 4 was prepared. [Formulation Example 2] Production of injection or liquid preparation Injection of 50 mg of compound 24 and 900 mg of sodium chloride
After dissolving using 90 mL of water, 0.1 mmol / L water
Adjust pH to 7 with sodium oxide and use water for injection
And the total amount was 100 mL. After aseptically filtering this solution, 2
Fill a glass ampoule with each mL and add Compound 2 to one tube.
An injection (solution) containing 1 mg of No. 4 was produced. [Formulation Example 3] Production of suppository Witepsol H-15 is heated and melted, and the compound
24 to a concentration of 10 mg / mL and mix well.
Was. Inject 2mL each into plastic suppository container
Chilled, containing 20 mg of compound 24 in one
An agent was manufactured. [Formulation Example 4] Production of eye drops 50 mg of compound 24, sodium dihydrogen phosphate dihydrate
0.1g, sodium chloride 0.9g and benzal chloride
Dissolve 5 mg of conium in 80 mL of purified water, and add 0.1 mol /
L sodium hydroxide aqueous solution was added to adjust the pH to 7.0,
Purified water was added to make the total volume 100 mL. This liquid is sterile filtered
After filling, add 5mL each to polypropylene ophthalmic container
To produce an eye drop having a concentration of Compound 24 of 0.05%.
did. [0127] According to the present invention, an excellent anti-adhesion agent is provided.
can do.

──────────────────────────────────────────────────の Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) C07D 333/62 C07D 333/62 409/12 409/12 413/12 413/12 F-term (Reference) 4C063 AA01 BB07 CC94 DD03 DD52 EE01 4C086 AA01 AA02 BB03 BC07 BC69 GA04 GA07 GA09 MA01 MA04 NA14 ZC20

Claims (1)

Claims: 1. A compound represented by the general formula (I): [Wherein, R ¹ is a hydrogen atom, a halogen atom or a lower alkyl group, R ² is a lower alkyl group, R ³ and R ⁴ may be different from each other, and may be a hydrogen atom, a lower alkoxycarbonyl group, a lower alkylsulfonyl. Group, benzoyl group,
An acyl group having 1 to 4 carbon atoms, a lower alkoxy group, a lower alkoxycarbonylmethylthioacetyl group, a nitro group,-
CONHR ⁶ (wherein R ⁶ is a hydrogen atom, a lower alkoxycarbonylmethyl group, a carboxymethyl group or —CH (C
H ₂ OH) COOR ⁷ (wherein R ⁷ represents a hydrogen atom or a lower alkyl group); (Wherein R ⁷ has the same meaning as described above); (Wherein R ⁸ and R ⁹ may be different from each other and represent a hydrogen atom, a lower alkyl group, a lower alkylsulfanyl group, a lower alkylsulfinyl group, a lower alkylsulfonyl group or a lower alkoxycarbonyl group) ), Hydroxy lower alkyl group, cyano group or (A represents an oxygen atom, a sulfur atom or NH, and a dotted line portion represents a single bond or a double bond) (however, a hydrogen atom on the ring is substituted with a halogen atom) Which may be substituted with a lower alkyl group, a lower alkoxy group, a hydroxy lower alkyl group, a lower alkoxycarbonyl group or a carboxyl group, wherein R ³ and R ⁴ are not hydrogen atoms at the same time. R ⁵ represents a hydrogen atom, a lower alkoxy group or a lower alkyl group], or an N-substituted benzothiophene sulfonamide derivative represented by the following formula or a pharmaceutically acceptable salt thereof as an active ingredient: .