JP2003292482A - Method for producing acylsulfonamide - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method for producing an acylsulfonamide in good yield. <P>SOLUTION: The method for producing the acylsulfonamide represented by R<SP>1</SP>-CONHSO<SB>2</SB>-R<SP>2</SP>[wherein, X denotes a chlorine atom, a bromine atom, an iodine atom, an -OCO-OR<SP>3</SP>or an -OCO-R<SP>3</SP>; R<SP>1</SP>and R<SP>2</SP>denote each independently an alkyl which may be substituted, an aryl which may be substituted or a heteroaryl which may be substituted; and R<SP>3</SP>denotes an alkyl or R<SP>1</SP>] is carried out as follows. R<SP>1</SP>-COX is reacted with R<SP>2</SP>-SO<SB>2</SB>NH<SB>2</SB>in the presence of a potassium base. <P>COPYRIGHT: (C)2004,JPO

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a method for producing an acylsulfonamide in a high yield, and a pyrrole derivative having a TGF-β inhibitory action and useful as an organ or tissue fibrosis inhibitor or the like, or a pharmaceutical thereof. The present invention relates to a method for producing an acceptable salt.

[0002]

The following methods are known for the production of acylsulfonamide. First, a dehydration ring closure reaction of a compound having a sulfonamide group and a carboxyl group in the molecule has been reported. In this method, a base is not required, and although the dehydration agent (carbonyldiimidazole, ethyl chloroformate, thionyl chloride) is used to proceed the ring closure reaction by activating the carboxyl group,
It seems to be unique to the intramolecular reaction. (Non-patent document 1) Also, an addition reaction to a mixed acid anhydride using a cyclic sulfonamide, bornane-10,2-sultam, has been reported. Butyllithium, lithium chloride and sodium hydride are used as bases there. However, since cyclic sulfonamide is used, it is unclear whether similar reaction conditions can be applied to acyclic sulfonamide.
(Non-patent documents 2, 3, 4) Further, a method of reacting methanesulfonamide as it is and a method of using a sodium salt of butanesulfonamide are described. However, the yield is 16% and
38%, which is far from satisfactory. (Non-patent document 5)

On the other hand, inhibiting TGF-β is a useful means for inhibiting the accumulation of extracellular matrix. It has been reported that administration of TGF-β antiserum to fibrosis model animals actually reduces fibrosis. (Non-patent document 6)

[0004]

[Non-Patent Document 1] Tetrahedron, 49 (43), 9801-9814 (199)
3)

[Non-Patent Document 2] Tetrahedron: Asymmetry, 8 (10), 168.
5-1691 (1997)

[Non-Patent Document 3] J. Org. Chem., 60 , 2271-2273 (1995).

[Non-Patent Document 4] Eur. J. Org. Chem., 2000 , 83-90.

[Non-Patent Document 5] J. Chem. Soc. Perkin Trans. I, 198 .
9 , 1815

[Non-Patent Document 6] Nature, 346: 371-374, (1990).

[0005]

The problems to be solved by the present invention are to provide a method for producing acylsul that is advantageous, to have a TGF-β inhibitory action, to obtain a good yield of organ amide, and to use it industrially or It is intended to provide a method for producing a pyrrole derivative or a pharmaceutically acceptable salt thereof, which is useful as an agent for suppressing fibrosis of tissues.

[0006]

The present invention is as follows. ^[1] R 1 -COX and ^R _{2 -SO} 2 NH 2 and potassium presence of a base, by reacting ^R 1 -CONHS
Method for producing acylsulfonamide represented by O ₂ -R ^2. [In the formula, X represents a chlorine atom, a bromine atom, an iodine atom,
Imidazolyl, -OCO-OR ³ or -OCO-R ³
Represents R ¹ and R ² independently represent an organic group. R
³ represents alkyl or R ¹ . [2] The acylsulfonamide according to [1], wherein R ¹ and R ² are independently alkyl which may be substituted, aryl which may be substituted or heteroaryl which may be substituted. Production method. [3] The method for producing an acylsulfonamide according to [1] or [2], wherein the potassium base is potassium t-butoxy. [4] The method for producing an acylsulfonamide according to any one of [1] to [3], wherein X is isopropoxycarbonyloxy, isobutoxycarbonyloxy, sec-butoxycarbonyloxy, t-butoxycarbonyloxy or pivaloyloxy. [5] The method for producing an acylsulfonamide according to any one of [1] to [4], which comprises reacting with an ether solvent in a range of about -80 ° C to about 30 ° C.

[6] Formula 2: And a R ⁷ —SO ₂ NH ₂ compound in the presence of a potassium base to give a pharmaceutically acceptable salt, if necessary. And a method for producing a pharmaceutically acceptable salt thereof. [In the formula, X has the same meaning as described above. R ⁴ represents a halogen atom, cyano, optionally substituted alkoxy or optionally substituted alkyl. R ⁵ represents an optionally substituted alkoxy, an optionally substituted alkyl or a halogen atom. R ⁶ represents a hydrogen atom or methyl. R ⁷ is an optionally substituted alkyl,
Represents optionally substituted aryl or optionally substituted heteroaryl. [7] The pyrrole derivative of the formula 1 has the formula G: [6] The pyrrole derivative according to [6] or a pharmaceutically acceptable salt thereof.

[8] A process for producing a pyrrole derivative of formula 1 or a pharmaceutically acceptable salt thereof according to the following steps. [In the formula, R ⁴ , R ⁵ , R ⁶ , R ⁷ and X have the same meanings as described above. R ⁸ represents alkyl. ] Step I : magnesium halide of pyrrole and R
^The benzoyl halide substituted with ⁵ is reacted. Step II : Reaction with an allyl halide in the presence of a base. Step III : If necessary, Vilsmeier reaction is carried out to introduce formyl. Step IV : Reduce formyl, if necessary. Step V : A compound represented by the following formula is reacted in the presence of a palladium catalyst. [Y represents an iodine atom, trifluoromethanesulfonyloxy, a bromine atom or a chlorine atom. ] Step VI : It hydrolyzes and a carboxyl group is activated. Step VII : The compound (1) is produced by the method according to any one of [1] to [5], and if necessary, converted into a pharmaceutically acceptable salt.

[9] A method for producing a pyrrole derivative of the formula G or a pharmaceutically acceptable salt thereof by the following steps. Step I : The magnesium halide salt of pyrrole is reacted with anisoyl chloride. Step II : Compound A is reacted with an allyl halide in the presence of a base. Step III : Compound B is subjected to Vilsmeier reaction to introduce formyl. Step IV : Formyl of compound C is reduced. Step V : Compound D is reacted with a compound of the following formula in the presence of a palladium catalyst. [R ⁸ and Y are as defined above. Step VI : Hydrolyze the ester of compound E. Step VII : Compound G is activated by activating the carboxyl group and then by the method according to any one of [1] to [5].
To prepare a pharmaceutically acceptable salt, if necessary.

In the present invention, the "organic group" means, unless it shows reactivity in the production reaction of acylsulfonamide,
Any organic group is included. Specifically, examples thereof include alkyl which may be substituted, aryl which may be substituted, and heteroaryl which may be substituted. Examples of the “alkyl” include straight chain or branched chain C ₁ -C ₆ alkyl, specifically methyl,
Ethyl, propyl, 2-propyl, 2-methyl-1-propyl, butyl, 2-butyl, t-butyl, pentyl, 3-methyl
-2-Butyl, 2-methyl-2-butyl, hexyl and the like can be mentioned. Preferably, a straight chain or branched chain C ₁ -C ₄ alkyl is mentioned. The substituent of “substituted alkyl” includes
For example, hydroxyl group, alkanoyloxy, halogen atom,
Cyano, alkanoyl, alkoxy, alkoxycarbonyl, carboxy, amino optionally substituted with alkyl, amino optionally substituted with alkoxyalkyl,
Examples thereof include cyclic amino, aryl, monocyclic heteroaryl, carbamoyl which may be alkyl substituted, cyclic aminocarbonyl, sulfamoyl which may be alkyl substituted, cyclic aminosulfonyl and azide. A plurality of (for example, 2 or 3) substituents can be present, in which case the substituents can be the same or different.

Examples of the "alkoxy" include straight chain or branched chain C ₁ -C ₆ alkoxy, and specifically, methoxy, ethoxy, propyloxy, 2-propyloxy, 2-methyl-2-. Examples include propyloxy, butoxy, pentyloxy, hexyloxy and the like. Preferable one is linear or branched C ₁ -C ₄ alkoxy. As the substituent of “substituted alkoxy”, for example,
Hydroxyl group, alkanoyloxy, halogen atom, cyano,
Alkanoyl, alkoxy, alkoxycarbonyl, carboxy, amino optionally substituted with alkyl, amino optionally substituted with alkoxyalkyl, cyclic amino, monocyclic heteroaryl, carbamoyl optionally substituted with alkyl, cyclic aminocarbonyl, Examples thereof include alkyl-substituted sulfamoyl, cyclic aminosulfonyl, and azide. A plurality of substituents (for example,
2 or 3) may be present, in which case they may be the same or different substituents.

Examples of the "aryl" include C ₆ -C
₁₀ aryl is mentioned, and specifically, phenyl, 1-naphthyl, 2-naphthyl and the like can be mentioned. Preferred is phenyl. Examples of the “heteroaryl” include monocyclic or bicyclic heteroaryl containing 1 to 3 heteroatoms arbitrarily selected from the group consisting of nitrogen atom, oxygen atom and sulfur atom. Specifically, monocyclic 5-membered heteroaryl such as thiophene, furan, pyrrole, imidazole, pyrazole, thiazole, oxazole, isothiazole and isoxazole, and monocyclic 6-membered such as pyridine, pyrimidine, pyrazine, pyridazine and triazine. Heteroaryl, indole, isoindole, indolizine, indazole, purine, 4-H-quinolidine, quinoline, isoquinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, benzthiazole, benzoxazole, benzisothiazole, benzisoxazole, benzofuran, benzo Bicyclic heteroaryl such as thiophene and the like can be mentioned. Examples of the “monocyclic heteroaryl” include monocyclic heteroaryl among heteroaryl. Examples of the substituent in the “substituted aryl” and the “substituted heteroaryl” include the followings. Multiple substituents
There may be (eg 2 or 3) present, in which case they may be the same or different substituents. Optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkenyl, optionally substituted alkynyl, alkenyloxy, hydroxyl group, alkanoyl, alkanoyloxy, halogen atom, alkylsulfonyl, alkyl substitution Optionally substituted amino, cyclic amino, optionally substituted carbamoyl, cyclic aminocarbonyl, optionally substituted sulfamoyl, cyclic amino sulfone, cyano, methylenedioxy, heteroaryl, 1,3-dioxane -2-
Ill etc.

Examples of the "alkanoyl" include linear or branched C ₁ -C ₆ alkanoyl, and specific examples thereof include formyl, acetyl, propanoyl, butanoyl, isobutanoyl, pentanoyl and hexenoyl. Preferably, a linear or branched C ₂ -C
₅ alkanoyl can be mentioned. Examples of the “alkenyl” include straight chain or branched chain C ₂ -C ₆ alkenyl, and specifically, vinyl, allyl, isopropenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3- Hexenyl and the like can be mentioned. Preferably, it includes _C 2 -C ₄ alkenyl straight or branched chain. As the substituent in the "substituted alkenyl", for example, alkoxy, alkoxycarbonyl, alkanoyl, hydroxyl group, alkanoyloxy, halogen atom, cyano, carbamoyl which may be alkyl substituted, cyclic aminocarbonyl, carboxy, which may be alkyl substituted. Amino, cyclic amino, sulfamoyl optionally substituted with alkyl,
Cyclic amino sulfonyl etc. are mentioned. Multiple substituents
There may be (eg 2 or 3) present, in which case they may be the same or different substituents. “Alkenyloxy” includes, for example, straight chain or branched chain C ₃
—C ₆ alkenyloxy may be mentioned, and specifically, allyloxy, 3-butenyloxy, 2-butenyloxy and the like may be mentioned. Preferably, _C 3 -C ₄ straight or branched chain
Alkenyloxy is mentioned.

Examples of "alkynyl" include straight chain or branched chain C ₂ -C ₆ alkynyl, and specifically, ethynyl, 2-propynyl, 1-propynyl, 3-butynyl, 2-butynyl, Examples include 2-pentynyl and 3-hexynyl. Preferred is a straight chain or branched chain C ₂ -C ₄ alkynyl. As the substituent in the "substituted alkynyl", for example, alkoxy, alkoxycarbonyl, alkanoyl, hydroxyl group, alkanoyloxy, halogen atom, cyano, optionally substituted carbamoyl, cyclic aminocarbonyl, carboxy, optionally substituted with alkyl. Amino, cyclic amino, sulfamoyl optionally substituted with alkyl, cyclic aminosulfonyl and the like can be mentioned. A plurality of (for example, 2 or 3) substituents can be present, in which case the substituents can be the same or different. Examples of the “alkynyloxy” include linear or branched C ₃ -C ₆ alkynyloxy, and specific examples thereof include allyloxy, 3-butynyloxy, 2-butynyloxy, 3-pentynyloxy and the like. . Preferably, a linear or branched C ₃
-C ₄ alkynyloxy and the like.

The "halogen atom" is a fluorine atom,
Examples thereof include chlorine atom and bromine atom. Preferable examples include chlorine atom, bromine atom, iodine atom and the like.
In "optionally alkyl-substituted amino", "optionally alkoxyalkyl-substituted amino", "optionally alkyl-substituted carbamoyl" and "optionally alkyl-substituted sulfamoyl", alkyl or alkoxyalkyl When is substituted, 1 or 2 identical or different alkyl or alkoxyalkyl can be substituted. Examples of the "cyclic amino" include 5- to 7-membered cyclic amino which may contain an oxygen atom, a sulfur atom or a nitrogen atom as a ring-constituting atom, and the cyclic amino may be further substituted with alkyl, hydroxyl group or the like. Good. Specific examples include pyrrolidino, piperidino, piperazinyl, 4-methylpiperazinyl, morpholino, thiomorpholino, 4-hydroxypiperidino and the like. A particularly preferred cyclic amino is morpholino.

"-OCO-OR ³ " represented by X is, for example, isopropoxycarbonyloxy, isobutoxycarbonyloxy, sec-butoxycarbonyloxy, t-butoxycarbonyloxy, phenoxycarbonyloxy, benzyloxycarbonyloxy, Methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy, butoxycarbonyloxy,
2,2,2-trichloroethoxycarbonyloxy, hexyloxycarbonyloxy, 2-ethylhexyloxycarbonyloxy and the like can be mentioned, preferably isopropoxycarbonyloxy, isobutoxycarbonyloxy, sec-butoxycarbonyloxy, t-butoxycarbonyloxy. Is mentioned. The "--OCO-R ^3", for example include pivaloyloxy, isobutyryloxy, 2-ethyl butyryloxy, 2-phenyl-butyryl-oxy, 2-ethylhexanoyloxy, cyclopentane carbonyloxy, cyclohexane carbonyloxy etc. And preferably pivaloyloxy. Preferred examples of the “substituted alkoxy” and “substituted alkyl” for R ⁴ and R ⁵ of the present pyrrole derivative include the following. Preferable substituents of "substituted alkyl" include halogen atom, alkoxy, morpholino, hydroxyl group and the like. Preferable substituents of "substituted alkoxy" include halogen atom, alkoxy, morpholino, hydroxyl group and the like, and particularly preferable substituted alkoxy includes 2-morpholinoethoxy and the like. The substitution position of R ⁴ is preferably the para position with respect to the bonding position with the propenylene group. The substitution position of R ⁵ is preferably a para position with respect to the bonding position with the carbonyl group.

As the "pharmaceutically acceptable salt", when the pyrrole derivative of the present invention or a pharmaceutically acceptable salt thereof has an acidic group, for example, an alkali metal salt such as sodium salt, potassium salt, etc., a calcium salt. , Alkaline earth metal salts such as magnesium salts, inorganic metal salts such as zinc salts, triethylamine, triethanolamine, trihydroxymethylaminomethane, organic base salts such as amino acids, and the like. When the pyrrole derivative of the present invention or a pharmaceutically acceptable salt thereof has a basic group, for example, hydrochlorides, hydrobromides, sulfates, phosphates, inorganic acid salts such as nitrates, and acetates, Propionate, succinate, lactate, malate, tartrate, citrate, maleate, fumarate, methanesulfonate, p-toluenesulfonate, benzenesulfonate, ascorbate And the like.

[0018]Method for producing acyl sulfonamide R¹-COX and R^Two-SO_TwoNH_TwoAnd potassium base
By reacting in the presence of R,¹-CONHSO_Two
-R^TwoAcylsulfonamide represented by
It can be manufactured by an industrially advantageous method. The present invention
One of the features is that it uses potassium base.
It If potassium base is used, sodium base,
Side reaction compared with the method using thium base, DBU, etc.
Production of acyl sulfonamide with high yield
It This will be further described in the comparative example below.
Here, examples of the potassium base include alkoxy potassium
Um (t-butoxy potassium, ethoxy potassium, etc.)
Lithium halide, potassium carbonate, potassium hydrogen carbonate, water
Examples thereof include potassium oxide, and a preferable example is t-butoxy.
Examples include citric acid. R^Two-SO_TwoNH_TwoUse of
As the amount, for example, R¹-1-2 equivalent to COX,
Preferably 1.1 to 1.5 equivalents can be used
It R^Two-SO_TwoNH _TwoIs R¹More valuable than COX
Then, on the contrary, R¹-COX is R^Two-SO_TwoNH_TwoLess than
It can also be used in excess. Potassium base is R^Two-S
O_TwoNH_TwoIt is preferable to use approximately equivalent to Reaction melting
As a medium, for example, an ether solvent (tetrahydrofuran
(THF), dimethoxyethane, diethyl ether, etc.)
Aromatic hydrocarbon solvents (benzene, toluene, chloroben
Zen, etc.), amide solvents (N, N-dimethylformamide (D
MF), N, N-dimethylacetamide, etc.), mixed solutions of these
Media, etc., preferably ether solvents, etc.
Preferable examples include THF. As the reaction temperature, for example,
For example, the range of about −80 ° C. to about 30 ° C. is included, and preferably
The range of about -50 ° C to about 0 ° C is included. In particular, R¹−
If mixed acid anhydride is used as COX, the two
In order to increase the selectivity of the reaction of carbonyl with
Perform at a lower temperature as long as the reaction progress is satisfactory.
Is desirable. Satisfies both reaction selectivity and reaction completion
Therefore, for example, the reaction is performed at a low temperature in the initial stage,
It is also preferable to gradually raise the reaction temperature after the reaction progresses.
Yes. In this reaction, the highly reactive functional group is a protecting group.
It is desirable to protect it. Also, as mentioned above,
In a tellurium solvent, the reaction may occur at low temperatures, such as in the range of about -50 ℃ to about 0 ℃
By controlling the reaction, side reactions can be suppressed and the acyl sulphate can be produced in good yield.
Hongamide can be produced.

R ¹ -COX can be easily produced from the corresponding carboxylic acid by a conventional method. For example, in the case of deriving a mixed acid anhydride, as the reagent, for example, an alkyl halide formate (isopropyl chloroformate, sec-butyl chloroformate, t-butyl chloroformate, etc.) is used,
As a base, an organic amine (trialkylamine, pyridine, N-methylmorpholine, etc.) and the like can be coexistent for production.

The pyrrole derivative of formula 1 or a pharmaceutically acceptable form thereof
Method for producing contained salt The pyrrole derivative of formula 1 or a pharmaceutically acceptable salt thereof can be produced from the compound of formula 2 according to the method for producing acylsulfonamide. The compound of formula 2 can be manufactured as follows. [In the formula, R ⁴ , R ⁵ , R ⁶ , R ⁸ and X are as defined above. This production method makes it possible to produce a pyrrole derivative of the formula 1 or a pharmaceutically acceptable salt thereof from pyrrole in a short step.

(1) Preparation of 2-aroylpyrrole By reacting a magnesium halide salt of pyrrole with an optionally substituted benzoyl halide,
2-Aroylpyrrole can be produced. The magnesium halide salt of pyrrole can be obtained, for example, by reacting pyrrole with a Grignard reagent.
Examples of the Grignard reagent include alkyl magnesium halides (methyl magnesium chloride, bromide or iodide, ethyl magnesium chloride, bromide or iodide, propyl magnesium chloride, bromide or iodide, etc.) and the like. As the reaction solvent when the Grignard reagent is allowed to act on the pyrrole, for example, ether solvents (tetradrofuran (THF), diethyl ether, etc.), aromatic hydrocarbon solvents (benzene, toluene, chlorobenzene, etc.), hydrocarbon solvents (Hexane, heptane), these mixed solvents, etc. are mentioned. The reaction temperature is, for example,
The boiling point of the solvent may be in the range of 0 ° C to 20 ° C.
To 50 ° C. This reaction can also be carried out subsequent to the preparation of the Grignard reagent with magnesium and an alkyl halide. In order to completely react the optionally substituted benzoyl halide and increase the yield, the magnesium halide salt of pyrrole is not sufficient in equivalent amount, and it is necessary to use it in excess. Therefore, the amount of the magnesium halide salt of pyrrole to be used is 1.7 to 10 equivalents, preferably 1.8 to 3 equivalents, relative to the optionally substituted benzoyl halide. As the reaction solvent, for example, ether solvent (tetradrofuran (THF), diethyl ether, etc.), aromatic hydrocarbon solvent (benzene, toluene, chlorobenzene, etc.), hydrocarbon solvent (hexane, heptane), a mixture thereof A solvent etc. are mentioned. Examples of the reaction temperature include a range of room temperature to the boiling point of the solvent, and preferably 30 ° C.
The range is from 60 ° C to 60 ° C. This reaction can also be carried out subsequent to the preparation of the magnesium halide salt of pyrrole. Magnesium halide salt of pyrrole and A
By the reaction of r-COX, an aroyl group can be regioselectively introduced at the 2-position of pyrrole with high yield.

(2) Allylation 2-Aroylpyrrole can be N-allylated by reacting allyl halide in the presence of a base.
Examples of the base include alkoxyalkali (t-butoxypotassium, etc.), alkali carbonate (potassium carbonate, sodium carbonate, sodium hydrogencarbonate, etc.), alkali hydride (sodium hydride, lithium hydride, etc.), and preferred examples are t- Examples include butoxy potassium and the like. Examples of the reaction solvent include ether solvents (tetradofuran (THF), diethyl ether, etc.), amide solvents (N, N-dimethylformamide (DM
F), N, N-dimethylacetamide, etc.), ketone solvents (acetone, 2-butanone, etc.), mixed solvents thereof, and the like. The reaction temperature may be in the range of 40 ° C to 60 ° C.

(3) When R is methyl, methyl can be introduced by reacting the methylated allylpyrrole with Vilsmeier reagent to introduce formyl, and then reducing formyl. The reaction with Vilsmeier reagent can be carried out in the same manner as in, for example, Org. Synth. Coll. Vol. IV, 831. In the reduction of formyl, it is necessary to reduce only formyl without reacting with carbonyl and double bond. The reduction reaction can be carried out by using a trialkylsilane (t-butyldimethylsilane, triethylsilane, etc.) or the like in the presence of an acid such as trifluoroacetic acid or methanesulfonic acid. Examples of the reaction solvent include halogenated hydrocarbon solvents (methylene chloride, chloroform, 1,2-dichloroethane, etc.), aromatic hydrocarbon solvents (benzene, toluene, chlorobenzene, etc.), and mixed solvents thereof.

(4) Condensation methylation of benzene ring In the presence of a palladium catalyst, the compound of the formula: [R ⁴ , R ⁸ and Y are as defined above. ] It can carry out by making the compound represented by these react. Examples of the palladium catalyst include a divalent palladium catalyst (palladium acetate and the like), a zero-valent palladium catalyst (Pd (dba) _{2 and the} like) and the like. In this reaction, it is desirable to allow a base to coexist, and examples of the base include alkali carbonates (sodium hydrogen carbonate, sodium carbonate, potassium carbonate, etc.), trialkylamines (triethylamine, etc.), alkali acetates (sodium acetate, potassium acetate, etc.), Examples thereof include alkali phosphates (sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, etc.). Furthermore, the reaction is promoted by adding a phosphine ligand (PPh ₃ or the like), a phase transfer catalyst (benzyl triethylammonium chloride or the like), a silver salt (silver carbonate or the like), or the like.
Examples of the reaction solvent include nitrile solvents (acetonitrile, propionitrile, etc.), amide solvents (N, N-dimethylformamide (DMF), N, N-dimethylacetamide, etc.), ether solvents (tetrahydrofuran (THF ), Diethyl ether, etc.), aromatic hydrocarbon solvents (benzene,
Toluene, chlorobenzene, etc.), a mixed solvent thereof, and the like. Examples of the reaction temperature include room temperature to the boiling point of the solvent. In the present reaction, preferable examples of Y include iodine atom, trifluoromethanesulfonyloxy and bromine atom, and particularly preferable iodine atom and trifluoromethanesulfonyloxy.

(5) Hydrolysis and Activation of Carboxylic Acids Condensates are hydrolyzed according to a conventional method, and then the corresponding carboxylic acid is converted to a halide, carbonyldiimidazole is reacted, or a mixed acid anhydride is used. Can be implemented.

In each of the above reactions, the functional group can be protected if necessary. Protecting groups and their protection,
Deprotection conditions are, for example, TW Greene and PGM Wut
s, "Protecting Groups in Organic Synthesis", 1991,
Those described in John Wiley & Sons and the like can be mentioned.

The pyrrole derivative of the formula 1 and pharmaceutically acceptable salts thereof have TGF-β inhibitory activity and are useful as fibrosis inhibitors for organs or tissues. Specifically, it is useful as a therapeutic agent for the following diseases associated with fibrosis of organs or tissues.・ Kidney disease Diabetic nephropathy, glomerulonephritis, renal tubular interstitial nephritis, hereditary renal disease / respiratory disease Interstitial pneumonia, chronic obstructive pulmonary disease, asthma / digestive disease Cirrhosis, chronic pancreatitis, scirrhous gastric cancer・ Cardiovascular disease myocardial fibrosis, restenosis after PTCA, arteriosclerosis / bone / joint disease myelofibrosis, rheumatoid arthritis / skin disease scars after surgery, burn scars, keloids, hypertrophic scars, atopic dermatitis, Scleroderma / Obstetrical disease Uterine fibroids / urological diseases Prostatic hypertrophy / other diseases Alzheimer's disease, sclerosing peritonitis, diabetic retinopathy, I
Type diabetes mellitus, organ adhesion after surgery

The present invention also includes solvates such as hydrates and ethanol solvates of the pyrrole derivative of formula 1 and its pharmaceutically acceptable salts. When the present pyrrole derivative and the like have optical isomers, geometric isomers, and tautomers, the present invention includes each of these isomers and mixtures thereof.

The pyrrole derivative of formula 1 and its pharmaceutically acceptable salts can be administered orally or parenterally. Examples of the dosage form for oral administration include tablets, pills, granules, powders, capsules, cachets, solutions, suspensions, emulsions, syrups and the like.
Dosage forms for parenteral administration include injections (for intravenous administration, intramuscular administration, etc.), transdermal agents (creams, ointments, lotions, patches, matrices, etc.), Examples include nasal agents, rectal agents (suppositories, etc.) and the like. These formulations can be manufactured according to a conventional method. For oral solid preparations such as tablets, for example, the present pyrrole derivative, etc., an excipient (lactose, D-mannitol, sucrose, corn starch, cellulose, calcium hydrogen phosphate, etc.), a disintegrant (carmellose calcium, low substitution Degree hydroxypropyl cellulose, croscarmellose sodium, sodium carboxymethyl starch, sodium carboxymethyl cellulose, sodium starch glycolate, etc.), binder (polyvinylpyrrolidone, polyvinyl alcohol, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, etc.), lubricant Tablets, granules, powders, capsules and the like can be prepared by a conventional method by mixing with a lubricant (magnesium stearate, talc, magnesium stearate, etc.), a flavoring agent, a stabilizer, a coloring agent and the like. Oral liquid preparations include, for example, the present pyrrole derivative and the like added to water to give coloring agents, flavors, stabilizers, sweeteners, solubilizers,
A thickener and the like can be added as needed to produce the composition. Examples of the thickener include pharmaceutically acceptable natural or synthetic gums, resins, methyl cellulose, sodium carboxymethyl cellulose, known suspending agents, and the like. The injection includes, for example, the present pyrrole derivative,
It is dissolved or suspended in a physiologically acceptable carrier such as water, physiological saline, oil or glucose aqueous solution, and a pH adjusting agent, a buffer, a stabilizer, a solubilizing agent, an emulsifying agent, etc. are added as an auxiliary agent if necessary. It can be manufactured by adding it.

The dose and frequency of administration of the present pyrrole derivative and the like vary depending on the disease, age, body weight, administration form and the like. For example, when orally administered, it is usually about 1 to about 500 mg, preferably about 3 to about 300 mg per day for an adult (60 kg).
Particularly preferably, about 5 to about 100 mg can be administered once or in several divided doses. When administered as an injection,
About 0.1 to about 300 mg, preferably about 1 to about 100 mg, for an adult (60 kg) can be administered once or in several divided doses or continuously.

[0031]

The present invention will be described in more detail with reference to examples, but the present invention is not limited thereto. Example 1

Preparation of Compound A A mixture of magnesium (4.12 g, 170 mmol) and THF (20 mL) was cooled to 10 ° C. and ethyl bromide (20.1 g, 185 mmol) in THF was added.
(60 mL) solution was added dropwise at an internal temperature of 20 to 25 ° C. 30 ℃ mixture
The temperature was raised to 1, the mixture was stirred for 1 hour, and pyrrole (10.3 g, 154 mmol) was added.
Toluene (80 mL) solution of was added dropwise at 30 to 35 ° C. Solution
The mixture was stirred for 0.5 hour, heated to 40 ° C., and a toluene (20 mL) solution of anisoyl chloride (13.2 g, 77.1 mmol) was added dropwise to the solution at 40 to 45 ° C., and further stirred for 0.5 hour. Aqueous ammonium chloride solution and toluene were added and stirred, the organic layer was separated and concentrated. The residue is 2-propanol / water (1: 2)
Recrystallization from Compound A gave Compound A (13.7 g, 88%). ¹ H NMR (CDCl ₃ , 400 MHz) δ9.54 (brs, 1H), 7.94 (d, 2H,
J = 8.9Hz), 7.12 (dt, 1H, J = 1.3, 2.7Hz), 6.93 (d, 2H,
J = 8.9Hz), 6.89 (ddd, 1H, J = 3.8, 2.4, 1.3Hz), 6.34 (d
t, 1H, J = 3.8, 2.7Hz), 3.89 (s, 3H).

Preparation of Compound C Under a stream of nitrogen, potassium t-butoxide (61.3 g, 546 mmol) was added.
In THF (400 g) solution, compound A (100 g, 497 mmol) in THF (2
00 g) solution was added dropwise and the temperature was raised to 45 ° C. Stir for 15 minutes,
A solution of allyl bromide (90.2 g, 746 mmol) in THF (200 g) was added dropwise. Stir at the same temperature for 2 hours, dilute with toluene (800 g) and water.
Washed with (800 g). The toluene layer was concentrated to obtain a toluene solution of compound B. DMF (84.8 g, 1.16 mol) was cooled to 15 ° C, and phosphorus oxychloride (133.6 g, 871 mmol) was added at an internal temperature of 2
It was added dropwise so as not to exceed 0 ° C. Stir for 20 minutes and remove with THF (62.
7 g, 871 mmol) was added, and a solution of compound B (70 g, 260 mmol) in toluene (140 g) was added dropwise so that the internal temperature did not exceed 20 ° C. The mixture was stirred at room temperature for 5 hours, washed with sodium acetate (35
A solution of 7 g, 4.35 mol) in water (714 g) was added dropwise while the internal temperature was rising, and after completion of the addition, the mixture was stirred overnight at room temperature. Compound C
Seed crystals of (100 mg, 371 μmol) were added, and the mixture was stirred for 3 hours. The crystals were collected by filtration, washed with water and toluene and dried. The oil layer of the filtrate was washed with water and concentrated, and the resulting crystals were collected by filtration, washed with cold toluene and dried. Compound C (5
0.6 g, 67%) was obtained. ¹ H NMR (Compound B: CDCl ₃ , 400 MHz) δ7.84 (d, 2H, J =
8.9Hz), 6.98 (dd, 1H, J = 2.5 and 1.7Hz), 6.94 (d, 2H,
J = 8.9Hz), 6.73 (dd, 1H, J = 4.0 and 1.7Hz), 6.19 (dd, 1
H, J = 4.0 and 2.5Hz), 6.07 (ddt, 1H, J = 17.1, 10.2 an
d 5.7Hz), 5.16 (dq, 1H, J = 10.2 and 1.1Hz), 5.06 (dq,
1H, J = 17.1 and 1.1Hz), 5.03 (dt, 2H, J = 5.7 and 1.1
Hz), 3.88 (s, 3H). ¹ H NMR (Compound C: CDCl ₃ , 400 MHz) δ9.81 (s, 1H),
7.85 (d, 2H, J = 8.9Hz), 7.58 (d, 1H, J = 2.3Hz), 7.16 (d,
1H, J = 2.3Hz), 6.97 (d, 2H, J = 8.9Hz), 6.06 (ddt, 1H,
J = 17.1, 10.2 and 5.7Hz), 5.26 (dq, 1H, J = 10.2 and
1.1Hz), 5.16 (dq, 1H, J = 17.1 and 1.1Hz), 5.05 (dt, 2
H, J = 5.7 and 1.1Hz), 3.89 (s, 3H).

Preparation of Compound D Compound C (10.0 g, 37.1 mmol) was dissolved in methylene chloride (212 g) and trifluoroacetic acid (212 g, 1.86 mol), and the mixture was dissolved at 0 ° C.
Cooled to. Add t-butyldimethylsilane (21.
6 g, 186 mmol) was added, and the mixture was stirred at the same temperature for 6 hours. The reaction solution was diluted with toluene (470 g) and poured into a 3N sodium hydroxide aqueous solution. The oil layer was separated, treated with activated carbon and filtered, and the solution was concentrated to give compound D (8.42 g, 89%). ¹ H NMR (CDCl ₃ , 400 MHz) δ7.81 (d, 2H, J = 8.9Hz), 6.
94 (d, 2H, J = 8.9Hz), 6.77 (br, 1H), 6.54 (brd, 1H, J =
1.4Hz), 6.05 (ddt, 1H, J = 10.0, 15.0 and 5.8Hz), 5.1
4 (dq, 1H, J = 10.0 and 1.1Hz), 5.07 (dq, 1H, J = 15.0 a
nd 1.1Hz), 4.97 (dt, 2H, J = 5.8 and 1.1Hz), 3.87 (s,
3H), 2.08 (brs, 3H).

Preparation of Compound E Methyl 5-chloro-2-iodobenzoate (146 m
g, 0.492 mmol), compound D (128 mg, 0.501 mmol), sodium hydrogen carbonate (86.0 mg, 1.01 mmol), benzyltriethylammonium chloride (120 mg, 0.527 mmol), acetonitrile (1.0 ml), palladium acetate (5.7 mg,
0.0254 mmol) was added and the mixture was heated to 50 ° C. and stirred for 16 hours. Water was added to the reaction solution, extracted with toluene, and the organic layer was washed with 10
% Aqueous sodium thiosulfate solution, and dried over magnesium sulfate. The compound E was obtained by filtering and distilling a solvent off (207 mg). ¹ H NMR (CDCl ₃ , 400 MHz) δ7.85 (d, 1 H, J = 2.3 H
z), 7.83 (d, 2 H, J = 8.9 Hz), 7.48 (d, 1 H, J = 8.
5 Hz), 7.39 (dd, 1 H, J = 2.3, 8.5 Hz), 7.21 (d, 1
H, J = 15.8 Hz), 6.94 (d, 2 H, J = 8.9 Hz), 6.85
(d, 1 H, J = 1.1 Hz), 6.57 (d, 1 H, J = 1.1 Hz),
6.34 (dt, 1 H, J = 15.8, 6.1 Hz), 5.14 (d, 2 H, J
= 6.1 Hz), 3.88 (s, 3 H), 3.87 (s, 3 H), 2.09 (s,
3 H)

Preparation of Compound F Under a nitrogen stream, Compound E (400 mg, 0.944 mmol) in THF (2.0 mg
1N aqueous sodium hydroxide solution (1.0 ml, 1.0 mmol) was added to a mixed solution of (ml) and methanol (2.0 ml), and the mixture was stirred at 50 ° C for 1 hr. The solvent was distilled off, and toluene (3.5 ml) and water (2.5 m
l) was added and the mixture was stirred at 0 ° C. for 4 hours to obtain a sodium salt of compound F.
(258 mg). ¹ H NMR (DMSO-d ₆ , 400 MHz) δ 7.76 (d, 2 H, J = 8.8
Hz), 7.47 (d, 1 H, J = 16.0 Hz), 7.40 (d, 1 H, J =
8.3 Hz), 7.39 (d, 1 H, J = 2.4 Hz), 7.12 (dd, 1 H,
J = 2.4, 8.3 Hz), 7.08 (d, 1 H, J = 1.2 Hz), 7.03
(d, 2 H, J = 8.8 Hz), 6.47 (d, 1 H, J = 1.2 Hz), 6.
22 (dt, 1 H, J = 16.0, 6.4 Hz), 5.01 (d, 2 H, J =
6.4 Hz), 3.84 (s, 3 H), 2.03 (s, 3 H) 1N hydrochloric acid was added to the Na salt of compound F and extracted with ethyl acetate,
The solvent was distilled off (226 mg). Compound F (122 mg) was obtained by recrystallizing from acetonitrile (5.0 ml). ¹ H NMR (CDCl ₃ , 400 MHz) δ7.97 (d, 1 H, J = 2.2 H
z), 7.83 (d, 2 H, J = 8.9 Hz), 7.50 (d, 1 H, J = 8.
5 Hz), 7.44 (dd, 1 H, J = 2.2, 8.5 Hz), 7.28 (d, 1
H, J = 15.5 Hz), 6.93 (d, 2 H, J = 8.9 Hz), 6.86
(d, 1 H, J = 1.1 Hz), 6.58 (d, 1 H, J = 1.1 Hz),
6.35 (dt, 1 H, J = 15.5, 6.0 Hz), 5.15 (d, 2 H, J
= 6.0 Hz), 3.85 (s, 3 H), 2.09 (s, 3 H)

Production of Compound G Isopropyl chloroformate (92
Compound F (3.0 μl) was added to THF solution (3.0 ml) of 0 μl, 8.08 mmol).
0 g, 7.32 mmol) and N-methylmorpholine (845 μl, 7.69
THF solution (8.0 ml) of (mmol) was added dropwise, and the mixture was stirred at 0 ° C for 30 minutes. The salt was removed by filtration and washed with THF (5.0 ml) to obtain a THF solution of the mixed acid anhydride of compound F. ¹ H NMR (CDCl ₃ , 400 MHz) δ7.93 (d, 1 H, J = 2.2 H
z), 7.83 (d, 2 H, J = 8.8 Hz), 7.53 (d, 1 H, J = 8.
5 Hz), 7.47 (dd, 1 H, J = 2.2, 8.5 Hz), 7.27 (d, 1
H, J = 15.8 Hz), 6.94 (d, 2 H, J = 8.8 Hz), 6.85
(d, 1 H, J = 1.2 Hz), 6.56 (d, 1 H, J = 1.2 Hz),
6.40 (dt, 1 H, J = 15.8, 6.2 Hz), 5.12 (d, 2 H, J
= 6.2 Hz), 5.08 (sep, 1 H, J = 6.3 Hz), 3.87 (s, 3
H), 2.08 (s, 3 H), 1.41 (d, 6 H, J = 6.3 Hz) Under nitrogen stream, potassium t-butoxide (1.07 g, 9.54 mmol)
Solution of methanesulfonamide (910 mg,
9.57 mmol) was added and the mixture was stirred at room temperature for 1 hour. Then -10 ℃
After cooling to 0 ° C., a THF solution of the mixed acid anhydride of compound F was slowly added dropwise, and the mixture was stirred at −10 ° C. for 8 hours. 1N hydrochloric acid (32.9 g)
Was added, extracted with ethyl acetate (30 ml), and dried over magnesium sulfate. The solvent was distilled off and the precipitated solid (3.65 g) was recrystallized from isopropyl alcohol (70 ml) to give compound G (3.00 g, 84%). ¹ H NMR (CDCl ₃ , 400 MHz) δ 8.67 (brs, 1 H), 7.80
(d, 2 H, J = 8.8 Hz), 7.54 (d, 1 H, J = 2.1 Hz), 7.
46 (d, 1 H, J = 8.4 Hz), 7.41 (dd, 1 H, J = 2.1, 8.
4 Hz), 6.94 (d, 2 H, J = 8.8 Hz), 6.85 (d, 1 H, J
= 1.5 Hz), 6.67 (d, 1 H, J = 15.8 Hz), 6.58 (d, 1
H, J = 1.5 Hz), 6.41 (dt, 1 H, J = 15.8, 5.5 Hz),
5.09 (d, 2 H, J = 5.5 Hz), 3.87 (s, 3 H), 3.35 (s,
3 H), 2.09 (s, 3 H)

Similar to Example 1, the following Examples 2 to 2
Ten compounds can be prepared. Their structures are shown in the table below, followed by the spectral data of the compounds.

Example 2 ¹ H NMR (CDCl ₃ , 400 MHz) δ8.79 (brs, 1H), 7.69 (d, 2H,
J = 8.0Hz), 7.52 (d, 1H, J = 2.1Hz), 7.44 (d, 1H, J = 8.4
Hz), 7.39 (dd, 1H, J = 2.1, 8.4Hz), 7.23 (d, 2H, J = 8.0
Hz), 7.06 (dd, 1H, J = 1.6, 2.5Hz), 6.78 (dd, 1H, J = 1.
6, 4.0Hz), 6.70 (d, 1H, J = 15.6Hz), 6.40 (dt, 1H, J = 1
5.6, 5.4Hz), 6.23 (dd, 1H, J = 2.5, 4.0Hz), 5.16 (d, 2
H, J = 5.4 Hz), 3.33 (s, 3H), 2.41 (s, 3H) Example 3 ¹ H NMR (CDCl ₃ , 400 MHz) δ7.80 (d, 2H, J = 8.7 Hz), 7.5
1 (d, 1H, J = 2.2Hz), 7.43 (d, 1H, J = 8.5Hz), 7.34 (dd,
1H, J = 8.5 and 2.2Hz), 7.05 (dd, 1H, J = 1.7 and 2.5H
z), 6.93 (d, 2H, J = 8.7Hz), 6.75 (dd, 1H, J = 1.7 and
4.0Hz), 6.73 (brd, 1H, J = 15.8Hz), 6.38 (dt, 1H, J = 1
5.8 and 6.0Hz), 6.22 (dd, 1H, J = 2.5 and 4.0Hz), 5.13
(dd, 2H, J = 1.4 and 6.0Hz), 3.86 (s, 3H), 3.30 (brs,
3H). Example 4 ¹ H NMR (CDCl ₃ , 400 MHz) δ 7.73 (d, 2H, J = 8.7 Hz), 7.6
0 (d, 1H, J = 2.2Hz), 7.53 (d, 1H, J = 8.5Hz), 7.35 (dd,
1H, J = 8.5 and 2.2Hz), 7.24 (dd, 1H, J = 1.7 and 2.5H
z), 7.04 (brd, 1H, J = 15.8Hz), 6.88 (d, 2H, J = 8.7Hz),
6.77 (dd, 1H, J = 1.7 and 4.0Hz), 6.39 (dt, 1H, J = 15.
8 and 6.0Hz), 6.25 (dd, 1H, J = 2.5 and 4.0Hz), 5.17 (d
d, 2H, J = 1.4 and 6.0Hz), 3.13 (brs, 3H). Example ^{5 1 H NMR (DMSO-d} 6, 400MHz) δ7.76 (d, 2H, J = 8.8Hz),
7.47-7.49 (m, 2H), 7.25 (dd, 1H, J = 2.4, 8.4Hz), 7.
11 (d, 1H, J = 15.9Hz), 7.10 (d, 1H, J = 1.3Hz), 7.02 (d,
2H, J = 8.8Hz), 6.46 (d, 1H, J = 1.3Hz), 6.29 (dt, 1H, J
= 15.9, 5.8Hz), 5.05 (d, 2H, J = 5.8Hz), 3.83 (s, 3H),
2.82 (s, 3H), 2.02 (s, 3H)

Example 6 ¹ H NMR (DMSO-d ₆ , 400 MHz) δ 7.65 (d, 2H, J = 8.1 Hz),
7.49 (d, 1H, J = 8.5Hz), 7.48 (d, 1H, J = 2.5Hz), 7.29 (d,
2H, J = 8.1Hz), 7.26 (dd, 1H, J = 2.5, 8.5Hz), 7.13 (d,
1H, J = 1.4Hz), 7.10 (d, 1H, J = 15.9Hz), 6.46 (d, 1H, J
= 1.4Hz), 6.30 (dt, 1H, J = 15.9, 5.8Hz), 5.07 (d, 2H,
J = 5.8Hz), 2.83 (s, 3H), 2.38 (s, 3H), 2.01 (s, 3H) Example 7 ¹ H NMR (DMSO-d ₆ , 400MHz) δ 12.31 (brs, 1H), 10.14
(s, 1H), 7.64-7.67 (m, 3H), 7.54 (d, 1H, J = 2.2Hz),
7.47 (dd, 1H, J = 2.2, 8.4Hz), 7.05 (d, 1H, J = 1.4Hz),
6.83 (d, 2H, J = 8.6Hz), 6.48 (d, 1H, J = 1.4Hz), 6.48
-6.51 (m, 2H), 5.08 (d, 2H, J = 3.0 Hz), 3.27 (s, 3H),
2.03 (s, 3H) Example 8 ¹ H NMR (CDCl ₃ , 400 MHz) δ8.39 (brs, 1H), 7.80 (d, 2)
H, J = 7.7Hz), 7.55 (s, 1H), 7.36-7.44 (m, 2H), 6.93
(d, 2H, J = 7.7Hz), 6.85 (s, 1H), 6.70-6.74 (m, 1H),
6.57 (s, 1H), 6.40-6.43 (m, 1H), 5.08 (br, 2H), 3.
86 (s, 3H), 3.53 (br, 2H), 2.09 (s, 3H), 1.41 (t, 3H,
J = 7.4Hz) Example 9 ¹ H NMR (DMSO-d ₆ , 400 MHz) δ 12.73 (brs, 1H), 7.95-
7.97 (m, 2H), 7.75 (d, 2H, J = 8.8Hz), 7.55-7.60 (m, 5
H), 7.48 (d, 1H, J = 2.3Hz), 7.39-7.41 (m, 1H), 7.03
(d, 2H, J = 8.8Hz), 6.99 (d, 1H, J = 1.3Hz), 6.48 (d, 1
H, J = 1.3Hz), 6.32-6.36 (m, 1H), 4.94 (d, 2H, J = 4.7H
z), 3.84 (s, 3H), 2.03 (s, 3H) Example 10 ¹ H NMR (CDCl ₃ , 400MHz) δ7.78 (d, 2H, J = 8.7Hz), 7.4
8 (brs, 1H), 7.42 (d, 1H, J = 8.5Hz), 7.35 (brd, 1H, J =
8.5Hz), 7.05 (dd, 1H, J = 1.7 and 2.5Hz), 6.92 (d, 2H,
J = 8.7Hz), 6.76 (dd, 1H, J = 1.7 and 4.0Hz), 6.64 (br
d, 1H, J = 15.8Hz), 6.39 (dt, 1H, J = 15.8 and 6.0Hz),
6.23 (dd, 1H, J = 2.5 and 4.0Hz), 5.13 (brd, 2H, J = 6.0
Hz), 4.10 (brt, 2H, J = 5.0Hz), 3.96 (brt, 2H, J = 5.0H
z), 3.30 (brs, 3H).

Comparative Example 1 Preparation of Compound G Using Sodium Base Isopropyl chloroformate (46
Compound E (1.5 μl) was added to a THF solution (1.5 ml) of 0 μl, 4.04 mmol).
0 g, 3.66 mmol) and N-methylmorpholine (423 μl, 3.85
THF (4.0 ml) was added dropwise and the mixture was stirred at 0 ° C for 30 minutes.
By removing the salt by filtration and washing with THF (2.5 ml),
A THF solution of a mixed acid anhydride of compound F was obtained. 60% sodium hydride (194 mg, 4.85 mmol) in a stream of nitrogen, THF
(5.0 ml), methanesulfonamide (461 mg, 4.85 mmol)
Was added and the mixture was stirred at 65 ° C. for 1 hour. Then cool to -10 ℃,
A THF solution of a mixed acid anhydride of compound F was slowly added dropwise,
The mixture was stirred at 10 ° C for 28.5 hours, then at 0 ° C for 4 hours, and at room temperature for 12 hours. 1N hydrochloric acid was added, the mixture was extracted with ethyl acetate and dried over magnesium sulfate. The solvent was distilled off and the precipitated solid was recrystallized from isopropyl alcohol to obtain Compound G (1.39 g, 78%).

Comparative Example 2 Comparison of Reaction Rates with Potassium Base and Sodium Base In the reaction using the sodium salt of methanesulfonamide (Comparative Example 1) and the reaction using the potassium salt (Production of Compound G of Example 1), HP of reaction progress at -10 ℃
The result measured by LC is shown in FIG. HPLC conditions are column: SUMIPAX ODS A-212, solvent: 0.1% TFA water / MeCN =
30/70, flow rate: 1.0 ml / min, detection method: UV 254 nm, and the area percentage of compound G was illustrated by the elapsed time. As can be seen from this, the reaction is slow when the sodium salt is used, and the reaction does not seem to be completed at -10 ° C.
In Comparative Example 1, the temperature was raised to room temperature in order to complete the reaction. However, the temperature rise caused an attack on the other carbonyl group of the mixed acid anhydride to produce the carboxylic acid of the compound F as a by-product, thereby increasing the reaction selectivity. falling. When the potassium salt was used for the reaction at room temperature, 10% or more of the compound F was by-produced.

Comparative Example 3 Reaction Using DBU Under a nitrogen stream, the compound (44.6 mg) obtained in Reference Example 1 below was used .
Carbonyldiimidazole (26.0 mg) in DMF solution (0.7 mL)
Was added, and the mixture was stirred at room temperature for 2 hours. Subsequently, methanesulfonamide (15.5 mg) and DBU (30 μL) were added, and the mixture was stirred at 90 ° C. for 2 hours. The mixture was returned to room temperature, 5% aqueous potassium hydrogen sulfate solution was added, and the mixture was extracted with ethyl acetate / toluene. The organic layer was washed with a 5% aqueous potassium hydrogen sulfate solution and then dried over magnesium sulfate. The solvent was distilled off and the silica gel column (hexane /
Example 2 by purifying with ethyl acetate = 1/1 → 0/1)
The same compound (30.5 mg, 57%) was obtained.

Reference Example 1 (1) Methyl 2-bromo-5-chlorobenzoate (6.30
g), tri-o-tolylphosphine (P (o-tol) ₃ ) (770
mg), tri-n-butylamine (9.38g) and acrylic acid (3.64
To a solution of g) in toluene (20 mL) was added palladium acetate (284 mg) under a nitrogen stream, and the mixture was heated at 110 ° C for 3 hours. The mixture was washed with 1N HCl, dried, filtered, concentrated and the residue was purified by silica gel column chromatography. Fractions containing the target compound were collected, dissolved in ethyl acetate, and extracted with saturated aqueous sodium hydrogen carbonate. The aqueous layer was acidified with hydrochloric acid and extracted with ethyl acetate, the organic layer was dried, filtered and concentrated to give 2-
(4-Chloro-2-methoxycarbonylphenyl) acrylic acid was obtained (4.0 g, 66%). ¹ H NMR (CDCl ₃ , 400MHz) δ8.51 (d, 1H, J = 15.9Hz), 7.9
8 (d, 1H, J = 1.9Hz), 7.58 (d, 1H, J = 8.4Hz), 7.53 (dd,
1H, J = 8.4 and 1.9Hz), 6.31 (d, 1H, J = 15.9Hz), 3.95
(s, 3H). (2) Compound (1.40g) of (1) and triethylamine (70
To a solution of 5 mg) in THF (20 mL), a solution of ethyl chloroformate (694 mg) in THF (10 mL) was added dropwise at 0 ° C under a nitrogen stream.
After stirring for 30 minutes, the insoluble matter was filtered off to obtain a mixed acid anhydride solution. Sodium borohydride (212 mg) in THF (10 m
To a mixed solution of L) and water (5 mL), 93% of the mixed acid anhydride solution prepared above was added dropwise at 0 ° C. under a nitrogen stream. Further sodium borohydride (210 mg) was added to the solution.
3N HCl was added to the reaction solution, and the mixture was extracted with diethyl ether. The extract was washed with saturated aqueous sodium hydrogen carbonate, dried, filtered, and concentrated to give 3- (4-chloro-2-methoxycarbonylphenyl) propenol (880 mg, 70% containing about 15% saturated product). ¹ H NMR (CDCl ₃ , 400MHz) δ7.88 (d, 1H, J = 2.2Hz), 7.50
(d, 1H, J = 8.5Hz), 7.44 (dd, 1H, J = 8.5 and 2.2Hz),
7.35 (brd, 1H, J = 15.9Hz), 6.26 (dt, 1H, J = 15.9 and
5.6Hz), 4.36 (brd, 2H, J = 5.6Hz), 3.91 (s, 3H). (3) Compound (870) of (2) and triphenylphosphine (PPh ₃ ) (1.01g) of methylene chloride ( 20 mL) solution, 0
N-Bromosuccinimide (683 mg) was added portionwise at <RTIgt; After stirring for 10 minutes, the reaction solution was concentrated, and the residue was purified by silica gel column chromatography to obtain bromide.
(942 mg, 85%). To a suspension of 60% NaH (167 mg) in THF (5 mL) was added dropwise a solution of (1H-pyrrol-2-yl) (4-methylphenyl) ketone (774 mg) in THF (15 mL). This solution was heated to 55 ° C and the above bromide (930mg) in THF (20m2) was added.
L) was slowly added dropwise to the solution. After stirring for 2 hours, 3 NH
Cl was added and the mixture was extracted with diethyl ether, and the extract was dried, filtered and concentrated. The residue was purified by silica gel column chromatography to obtain a mixture of the methyl ester of the title compound and (1H-pyrrol-2-yl) (4-methylphenyl) ketone (1.4 g molar ratio about 3: 7). This is THF
(7 mL) and methanol (7 mL) mixed solution,
OH water (7 mL) was added, and the mixture was stirred under a nitrogen stream at 40 ° C for 15 minutes. The organic solvent was distilled off and washed with ether. The ether layer was extracted twice with 1N aqueous NaOH, the combined aqueous layers were washed with hexane and acidified with hydrochloric acid. This was extracted with ethyl acetate, dried, treated with activated carbon, filtered, and concentrated to give the title compound (320 mg, 60%). 1N for the title compound (596mg)
Aqueous NaOH (1.52 mL) and THF (2 mL) were added and sonicated. The mixture was concentrated with toluene and the residue was washed with diethyl ether and dried to give the sodium salt of the title compound (520mg, 83%). ¹ H NMR (DMSO-d ₆ , 400MHz) δ 7.67 (d, 2H, J = 8.1Hz), 7.
46 (brd, 1H, J = 16.2Hz), 7.40 (brd, 1H, J = 8.5Hz), 7.3
9 (brs, 1H), 7.33 (dd, 1H, J = 1.7 and 2.4Hz), 7.31 (d,
2H, J = 8.1Hz), 7.13 (brdd, 1H, J = 8.4 and 2.3Hz), 6.6
5 (dd, 1H, J = 1.7 and 4.0Hz), 6.25 (dt, 1H, J = 16.2 an
d 6.4Hz), 6.20 (dd, 1H, J = 2.4 and 4.0Hz), 5.10 (brd,
1H, J = 6.4Hz), 2.38 (s, 3H).

[0045]

INDUSTRIAL APPLICABILITY According to the present invention, an acylsulfonamide having a high yield and industrially advantageous production method are provided, and it has a TGF-β inhibitory action, and is useful as a fibrosis inhibitor for organs or tissues. A method for producing the pyrrole derivative or a pharmaceutically acceptable salt thereof can be provided.

[Brief description of drawings]

FIG. 1 shows the progress of the reaction at −10 ° C. measured by HPLC in the reaction using sodium salt of methanesulfonamide (Comparative Example 1) and the reaction using potassium salt (Production of Compound G of Example 1). The result. The horizontal axis represents time, and for example, 4:48 represents 4 hours and 48 minutes.

   ─────────────────────────────────────────────────── ─── Continued front page    (72) Inventor Hume, William Youwan             3-1,98-1 Kasugade, Konohana-ku, Osaka             Tomo Pharmaceutical Co., Ltd. (72) Inventor Ryu Nagata             3-1,98-1 Kasugade, Konohana-ku, Osaka             Tomo Pharmaceutical Co., Ltd. F-term (reference) 4C069 AC07 CC20                 4C086 AA03 BC05 MA01 MA04 NA14                       ZB26 ZC20

Claims (9)

[Claims] 1. A R ¹ -COX and ^R _{2 -SO} 2 NH 2 and potassium presence of a base, by reacting ^R 1 -CO
Method for producing acylsulfonamide represented by NHSO ₂ -R ^2. [In the formula, X is a chlorine atom, a bromine atom, an iodine atom, imidazolyl, -OCO-OR ³ or -OCO-.
Represents R ³ . R ¹ and R ² independently represent an organic group. R ³ represents alkyl or R ¹ . ] 2. The acyl sulfonamide according to claim 1, wherein R ¹ and R ² are independently an optionally substituted alkyl, an optionally substituted aryl or an optionally substituted heteroaryl. Manufacturing method. 3. The method for producing an acyl sulfonamide according to claim 1 or 2, wherein the potassium base is potassium t-butoxy. 4. X is isopropoxycarbonyloxy,
The method for producing an acyl sulfonamide according to any one of claims 1 to 3, which is isobutoxycarbonyloxy, sec-butoxycarbonyloxy, t-butoxycarbonyloxy or pivaloyloxy. 5. An ethereal solvent at about −80 ° C. to about 30 ° C.
The method for producing an acylsulfonamide according to any one of claims 1 to 4, wherein the reaction is performed within the range. 6. Formula 2: And a R ⁷ —SO ₂ NH ₂ compound in the presence of a potassium base to give a pharmaceutically acceptable salt, if necessary. And a method for producing a pharmaceutically acceptable salt thereof. [In the formula, X has the same meaning as in claim 1. R ⁴ represents a halogen atom, cyano, optionally substituted alkoxy or optionally substituted alkyl. R ⁵ represents an optionally substituted alkoxy, an optionally substituted alkyl or a halogen atom. R
⁶ represents a hydrogen atom or methyl. R ⁷ represents optionally substituted alkyl, optionally substituted aryl or optionally substituted heteroaryl. ] 7. The pyrrole derivative of formula 1 has the formula: The pyrrole derivative according to claim 6 or a pharmaceutically acceptable salt thereof. 8. A method for producing a pyrrole derivative of formula 1 or a pharmaceutically acceptable salt thereof according to the following steps. [In the formula, R ⁴ , R ⁵ , R ⁶ , R ⁷ and X have the same meanings as in claims 1 and 6. R ⁸ represents alkyl. ] Step I : magnesium halide of pyrrole and R
^The benzoyl halide substituted with ⁵ is reacted. Step II : Reaction with an allyl halide in the presence of a base. Step III : If necessary, Vilsmeier reaction is carried out to introduce formyl. Step IV : Reduce formyl, if necessary. Step V : A compound represented by the following formula is reacted in the presence of a palladium catalyst. [Y represents an iodine atom, trifluoromethanesulfonyloxy, a bromine atom or a chlorine atom. ] Step VI : It hydrolyzes and a carboxyl group is activated. Step VII : The compound (1) is produced by the method according to any one of claims 1 to 5, and a pharmaceutically acceptable salt is produced if necessary. 9. A method for producing a pyrrole derivative of formula G or a pharmaceutically acceptable salt thereof according to the following steps. Step I : The magnesium halide salt of pyrrole is reacted with anisoyl chloride. Step II : Compound A is reacted with an allyl halide in the presence of a base. Step III : Compound B is subjected to Vilsmeier reaction to introduce formyl. Step IV : Formyl of compound C is reduced. Step V : Compound D is reacted with a compound of the following formula in the presence of a palladium catalyst. [R ⁸ and Y have the same meaning as in claim 8. Step VI : Hydrolyze the ester of compound E. Step VII : The carboxyl group is activated, and then the compound G is produced by the method according to any one of claims 1 to 5, and a pharmaceutically acceptable salt is produced if necessary.