JP2010222351A - Collagen production inhibitor containing n-substituted anthranilic acid derivative or salt of the same - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a treating agent having collagen production inhibitory action and used for preventing or treating diseases associated with excess production of collagen. <P>SOLUTION: A composition comprising an anthranilic acid derivative or a salt of the same is provided. The composition is useful for treatment such as prevention or therapy of diseases associated with excess collagen production. <P>COPYRIGHT: (C)2011,JPO&INPIT

Description

  The present invention relates to a collagen production inhibitor containing an anthranilic acid derivative or a salt thereof.

Fibrosis in which extracellular matrix including collagen is produced is a mechanism of wound healing. However, if the damage is prolonged, it deviates from the normal process and the extracellular matrix is excessively deposited over a wide area, resulting in fibrosis. Although fibrosis is observed in various organs, the origin of extracellular matrix-producing cells is considered to be common, and is endogenous fibroblasts, epithelial cells and fibrocytes that have undergone epithelial-mesenchymal transition (Non-patent Document 1). ). Fibrosis is a disease state with a poor prognosis leading to organ failure due to a combination of damage to the tissue itself due to the causative disease and functional impairment due to the subsequent fibrosis itself.
To date, attempts have been made to suppress the inflammatory response as a treatment for fibrosis, but a sufficient effect has not been obtained. Research on antifibrotic drugs targeting TGF (Transforming growth factor) -β1, VEGF (Vascular Endothelial Growth Factor), PDGF (Platelet-Derived Growth Factor), angiotensin II (angiotensin II), etc. (Non-Patent Document 2).
The only antifibrotic agent is pirfenidone, which is indicated for idiopathic pulmonary fibrosis. The only efficacy observed in clinical trials is the suppression of decreased vital capacity. In addition, side effects such as photosensitivity were observed in 87.9% (Non-patent Document 3). In terms of both efficacy and safety, it is not a sufficient treatment.
The main component of the extracellular matrix that is excessively deposited during fibrosis is collagen. Among them, type I collagen is the most abundant. Therefore, substances that inhibit collagen production are useful for the prevention or treatment of diseases associated with fibrotic lesions.
So far, anthranilic acid derivatives have been reported to have matrix metalloprotease-13 production inhibitory action (Patent Document 1). However, it is not known at all to have a collagen production inhibitory action.

International Publication No. 2006/098308 Pamphlet

Experimental Biology and Medicine, Vol.233, pp.109-122, 2008 Journal of Pathology, Volume 214, 199-210, 2008 Pirrespa Tablets 200mg package insert, 1st edition, created by Shionogi & Co., Ltd.

  A therapeutic agent for preventing or treating a disease having a collagen production inhibitory effect and involving excessive production of collagen is desired.

「式中、Ｒ^１は、水素原子またはカルボキシル保護基を；Ｒ^２は、水素原子またはイミノ保護基を；Ｒ^３は、置換されていてもよいフェニル、シクロアルキルまたは複素環式基を；Ｒ^４は、置換されていてもよいフェニル、シクロアルキル、シクロアルケニルまたは複素環式基を；Ｘ^１は、置換されていてもよいアルキレンもしくはアルケニレン基または結合手を；Ｘ^２は、カルボニル基または一般式−Ｘ^３−Ｘ^４−、−Ｘ^４−Ｘ^３−、−Ｏ−Ｘ^４−もしくは−Ｘ^４−Ｃ（Ｏ）ＮＨ−（但し、各一般式の左側の結合手が、Ｒ^４に結合するものとする。）「式中、Ｘ^３は、硫黄原子、保護されていてもよいイミノ基、スルフィニル基、スルホニル基または結合手を；Ｘ^４は、置換されていてもよいアルキレンもしくはアルケニレン基または結合手を意味する。」で表される基を意味する。」で表されるアントラニル酸誘導体またはその塩が、コラーゲン産生阻害作用を有し、コラーゲンの過剰産生が関与する疾患の予防または治療などの処置に有用であることを見出し、本発明を完成させた。 Under such circumstances, the present inventors conducted extensive studies, and as a result, the general formula [1]

“Wherein R ¹ represents a hydrogen atom or a carboxyl protecting group; R ² represents a hydrogen atom or an imino protecting group; R ³ represents an optionally substituted phenyl, cycloalkyl or heterocyclic group; R ⁴ is an optionally substituted phenyl, cycloalkyl, cycloalkenyl or heterocyclic group; X ¹ is an optionally substituted alkylene or alkenylene group or bond; X ² is a carbonyl group or general wherein ^{-X 3 -X 4 -, - X} 4 -X 3 -, - O-X 4 - or ^-X 4 -C (O) NH- (where the bond on the left side of each general formula, the ^{R 4} . which shall bind) "wherein, X ³ is sulfur atom, an optionally protected imino group, a sulfinyl group, a sulfonyl group or a bond; X ⁴ is optionally substituted alkylene optionally or alkenylene It means a group represented by means a group or a bond. ". The anthranilic acid derivative represented by the above or a salt thereof has a collagen production inhibitory action and has been found useful for treatment such as prevention or treatment of diseases involving excessive production of collagen, and has completed the present invention. .

  Since the anthranilic acid derivative or salt thereof used in the present invention has a collagen production inhibitory action, for example, prevention of diseases involving excessive production of collagen such as pulmonary fibrosis, scleroderma, nephrosclerosis and cirrhosis or It is useful for treatment such as treatment.

Hereinafter, this invention compound is explained in full detail.
In this specification, unless otherwise stated, each term has the following meaning.

A halogen atom means a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.
The alkyl group means, for example, a linear or branched C _1-6 alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, pentyl and isopentyl. .
A cycloalkyl group means, for example, a C _3-8 cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
A cycloalkenyl group means, for example, a C _3-8 cycloalkenyl group such as cyclopropenyl, cyclobutenyl, cyclopentenyl and cyclohexenyl.

The alkoxy group is, for example, linear or branched C _1-6 alkyl such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy and isopentyloxy. Means an oxy group.
The alkylene group means a linear or branched C _1-6 alkylene group such as methylene, ethylene, propylene, butylene and hexylene.
The alkenylene group means a linear or branched C _2-6 alkenylene group such as vinylene, propenylene, 1-butenylene, and 2-butenylene.

  Monocyclic heterocyclic groups include, for example, azetidinyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, piperidyl, piperazinyl, homopiperazinyl, azepanyl, diazepanyl, octahydroazosinyl, imidazolyl, pyrazolyl, pyridyl, tetrahydropyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, Monocyclic nitrogen-containing heterocyclic groups containing only nitrogen atoms as the hetero atoms forming the ring such as tetrazolyl, imidazolinyl, imidazolidinyl, pyrazolinyl and pyrazolidinyl groups; forming the rings such as tetrahydrofuranyl, furanyl and pyranyl groups Monocyclic oxygen-containing heterocyclic group containing only oxygen atom as a hetero atom; monocyclic sulfur-containing heterocyclic group containing only sulfur atom as a hetero atom forming the ring such as thienyl group; oxazolyl, oxadiazo Monocyclic nitrogen-containing / oxygen heterocyclic groups containing only nitrogen and oxygen atoms as the hetero atoms forming the ring, such as ru, isoxazolyl and morpholinyl groups; thiazolyl, isothiazolyl, thiadiazolyl, thiomorpholinyl, 1-oxidethiomol Monocyclic nitrogen-containing / sulfur heterocyclic groups containing only nitrogen and sulfur atoms as hetero atoms forming the ring, such as folinyl and 1,1-dioxidethiomorpholinyl groups; and thioxanyl groups It means a monocyclic oxygen-containing / sulfur heterocyclic group containing only oxygen and sulfur atoms as the hetero atoms forming the ring.

  Bicyclic heterocyclic groups include indolyl, indolinyl, 2-oxoindolinyl, isoindolyl, indolizinyl, benzimidazolyl, benzotriazolyl, indazolyl, quinolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, quinolidinyl, Containing only 1 to 3 nitrogen atoms as hetero atoms forming the ring such as isoquinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, dihydroquinoxalinyl, quinazolinyl, cinnolinyl, quinuclidinyl and 2,3-dihydrobenzopyrrolyl groups Bicyclic nitrogen-containing heterocyclic groups represented by fused or bridged rings; benzofuranyl, isobenzofuranyl, chromenyl, chromanyl, isochromanyl, benzo-1,3-dioxolyl, benzo-1,4-dioxanyl and 2, 3-jihi A bicyclic oxygen-containing heterocyclic group represented by a condensed ring or a bridged ring containing only an oxygen atom as a hetero atom forming the ring, such as a drobenzofuranyl group; benzothienyl and 2,3-dihydrobenzothienyl A bicyclic sulfur-containing heterocyclic group represented by a condensed ring or a bridged ring containing only a sulfur atom as a hetero atom forming the ring such as a group; 10 or more such as benzomorpholinyl and benzomorpholonyl groups A bicyclic nitrogen-containing / oxygen heterocyclic group represented by a condensed ring or a bridged ring containing a nitrogen atom and an oxygen atom as a hetero atom, and a benzothiazolyl and benzothiadiazolyl group, etc. It means a bicyclic nitrogen-containing / sulfur heterocyclic group represented by a condensed ring or a bridged ring containing a nitrogen atom and a sulfur atom as the hetero atoms forming the ring.

  The heterocyclic group includes, for example, a monocyclic heterocyclic group; a bicyclic heterocyclic group; and thianthenyl, xanthenyl, phenoxathinyl, carbazolyl, β-carbolinyl, phenanthridinyl, acridinyl, perimidinyl , Means a tricyclic heterocyclic group such as phenanthrolinyl, phenazinyl, phenothiazinyl and phenoxazinyl.

  The cyclic amino group may be, for example, either a saturated cyclic amino group or an unsaturated cyclic amino group, and one or more hetero atoms such as nitrogen atom, oxygen atom, sulfur atom and carbonyl in the ring. It may contain carbon, and may be monocyclic or bicyclic, and more specifically, aziridin-1-yl, azetidin-1-yl, pyrrolidin-1-yl, Nitrogen atoms 1 such as pyrrolin-1-yl, pyrrol-1-yl, dihydropyridin-1-yl, tetrahydropyridin-1-yl, piperidin-1-yl, dihydroazepin-1-yl and perhydroazepin-1-yl Saturated or unsaturated monocyclic 3 to 7-membered cyclic amino group having 1 group; imidazol-1-yl, imidazolidin-1-yl, imidazolin-1-y , Pyrazolidin-1-yl, piperazin-1-yl, 1,4-dihydropyrazin-1-yl, 1,2-dihydropyrimidin-1-yl, perhydropyrazin-1-yl, homopiperazin-1-yl and the like A saturated or unsaturated monocyclic 3 to 7-membered cyclic amino group having two nitrogen atoms of 1,2,4-triazol-1-yl, 1,2,3-triazol-1-yl, 1, Saturated or unsaturated monocyclic 3 to 7-membered cyclic amino groups having 3 or more nitrogen atoms such as 2-dihydro-1,2,4-triazin-1-yl and perhydro-S-triazin-1-yl Oxazolidine-3-yl, isoxazolidine-2-yl, morpholin-4-yl, thiazolidin-3-yl, isothiazolidin-2-yl, thiomorpholin-4-yl, homothiomol Saturated or unsaturated monocyclic 3 to 7 having 1 to 4 heteroatoms selected from oxygen atoms and sulfur atoms in addition to nitrogen atoms such as phosphorus-4-yl and 1,2,4-thiadiazolin-2-yl Membered cyclic amino group; isoindoline-2-yl, indoline-1-yl, 1H-indazol-1-yl, 1H-indol-1-yl, 1H-benzimidazol-1-yl, purin-7-yl, Saturated or unsaturated 2- or 3-cyclic cyclic amino groups such as tetrahydroquinolin-1-yl and tetrahydroisoquinolin-2-yl; and 5-azaspiro [2.4] heptan-5-yl, 2,8-diazabicyclo [4.3.0] nonan-8-yl, 3-azabicyclo [3.1.0] hexan-3-yl, 2-oxa-5,8-diazabicyclo [4.3.0] nonane Spiro- or bridged-saturated or unsaturated 5- or 8-, diazaspiro [4.4] nonan-2-yl and 7-azabicyclo [2.2.1] heptan-7-yl, etc. Means a 12-membered cyclic amino group.

Amino protecting groups include all groups that can be used as protecting groups for conventional amino groups. W. Greene et al., Protective Groups in Organic Synthesis, 4th edition, pp. 696-868, 2007, John Wiley & Sons, INC.). Specific examples include linear or branched C _2-12 alkanoyl groups such as acetyl, propionyl and isovaleryl, and C _1-6 alkylsulfonyl groups such as methylsulfonyl, ethylsulfonyl and propylsulfonyl. It is done.

The imino protecting group includes all groups that can be used as protecting groups for ordinary imino groups. W. Greene et al., Protective Groups in Organic Synthesis, 4th edition, pp. 696-868, 2007, John Wiley & Sons, INC.). Specific examples include linear or branched C _2-12 alkanoyl groups such as acetyl, propionyl and isovaleryl.

Hydroxyl protecting groups include all groups that can be used as protecting groups for conventional hydroxyl groups. W. Greene et al., Protective Groups in Organic Synthesis 4th Edition, pp. 16-299, 2007, John Wiley & Sons (John Wiley & Sons, INC.). Specifically, for example, linear or branched C _2-12 alkanoyl groups such as acetyl, propionyl and isovaleryl and methoxycarbonyl, ethoxycarbonyl, 1,1-dimethylpropoxycarbonyl, isopropoxycarbonyl, 2- Examples thereof include linear or branched C _1-12 alkyloxycarbonyl groups such as ethylhexyloxycarbonyl, tert-butoxycarbonyl and tert-pentyloxycarbonyl.

The carboxyl protecting group includes all groups that can be used as protecting groups for ordinary carboxyl groups. W. Greene et al., Protective Groups in Organic Synthesis, 4th edition, pp. 533-643, 2007, John Wiley & Sons (John Wiley & Sons, INC.). Specifically, for example, linear or branched C _1- such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, pentyl, isopentyl, hexyl, heptyl and octyl. _{And 12} alkyl groups.

Examples of the salt of the compound represented by the general formula [1] include a conventionally known salt in a basic group such as an amino group or an acidic group such as a phenolic hydroxyl group or a carboxyl group.
Salts in basic groups include, for example, salts with mineral acids such as hydrochloric acid, hydrogen bromide and sulfuric acid; salts with organic carboxylic acids such as tartaric acid, formic acid, acetic acid, citric acid, trichloroacetic acid and trifluoroacetic acid, and methane Examples thereof include salts with sulfonic acids such as sulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, mesitylenesulfonic acid and naphthalenesulfonic acid.
Examples of the salt in the acidic group include salts with alkali metals such as sodium and potassium; salts with alkaline earth metals such as calcium and magnesium; ammonium salts and trimethylamine, triethylamine, tributylamine, pyridine, N, N-dimethyl. Salts with nitrogen-containing organic bases such as aniline, N-methylpiperidine, N-methylmorpholine, diethylamine, dicyclohexylamine, procaine, dibenzylamine, N-benzyl-β-phenethylamine and N, N′-dibenzylethylenediamine, etc. Can be mentioned.
Furthermore, among the above salts, preferred salts of the compound of the general formula [1] include pharmacologically acceptable salts.

The phenyl, cycloalkyl and heterocyclic groups of R ³ are halogen atoms, cyano groups, nitro groups, acetamido groups, carbamoyl groups, optionally protected carboxyl, amino and hydroxyl groups, and optionally substituted alkyls, It may be substituted with one or more groups selected from alkoxy, phenyl, cyclic amino and heterocyclic groups.

The phenyl, cycloalkyl, cycloalkenyl and heterocyclic groups of R ⁴ are halogen atoms, cyano groups, nitro groups, acetamido groups, carbamoyl groups, optionally protected carboxyl, amino and hydroxyl groups and optionally substituted. It may be substituted with one or more groups selected from good alkyl, alkoxy, phenyl, cyclic amino and heterocyclic groups.

The alkylene and alkenylene groups of X ¹ may be substituted with one or more groups selected from halogen atoms and optionally substituted alkyl, alkoxy, phenyl, cyclic amino, and heterocyclic groups.
The alkylene and alkenylene groups of X ⁴ may be substituted with one or more groups selected from halogen atoms and optionally substituted alkyl, alkoxy, phenyl, cyclic amino, and heterocyclic groups.

  Examples of the substituent of the optionally substituted alkyl, alkoxy, phenyl, cyclic amino and heterocyclic group shown above include, for example, a halogen atom, a cyclic amino group, an alkyl group, an alkoxy group, a phenyl group, a heterocyclic group Groups and optionally protected carboxyl, amino and hydroxyl groups and the like.

In the compound of the present invention, preferred compounds include the following compounds.
A compound in which R ¹ is a hydrogen atom is preferable.
A compound in which R ² is a hydrogen atom is preferable.
A compound in which R ³ is optionally substituted phenyl or a bicyclic heterocyclic group is preferred, a compound in which R ³ is optionally substituted is more preferred, and may be substituted with a halogen atom More preferred are compounds that are phenyl groups.
A compound wherein R ⁴ is an optionally substituted phenyl or a bicyclic heterocyclic group is preferred, and a compound which is an optionally substituted bicyclic heterocyclic group is more preferred, and is substituted. More preferred are compounds that may be indolyl groups.
A compound in which X ¹ is a bond is preferable.
A compound in which X ² is an alkylene group or a bond is preferable, and a compound in which X ² is a bond is more preferable.

  Examples of diseases involving excessive production of collagen include pulmonary fibrosis, scleroderma, nephrosclerosis, and cirrhosis. A preferred disease includes pulmonary fibrosis.

  As a typical compound used for this invention, the compound of Table 1 is mentioned, for example.

  The compound used in the present invention can be produced by a method known per se or a combination thereof, or a method described in Patent Document 1.

  When using the compound used for this invention as a pharmaceutical, you may mix suitably formulation adjuvants, such as an excipient | filler normally used for formulation, a carrier, and a diluent. These are tablets, capsules, powders, syrups, granules, pills, suspensions, emulsions, solutions, powder formulations, suppositories, eye drops, nasal drops, ear drops, patches in accordance with conventional methods. It can be administered orally or parenterally in the form of an agent, ointment or injection. In addition, the administration method, the dosage, and the number of administrations can be appropriately selected according to the age, weight and symptoms of the patient. In general, for adults, oral administration or parenteral administration (for example, injection, infusion, administration to the rectal site, etc.), 0.01 to 1000 mg / kg can be divided into 1 to several times a day. Good.

  Next, the usefulness of the compound used in the present invention will be described in the following test examples.

Test Example 1 Type I Collagen α1 Chain mRNA Expression Inhibition Test Human fetal lung fibroblast cell line WI-38 cells are suspended in Dulbecco's modified Eagle's medium containing 10% fetal bovine serum and seeded at 7.5 × 10 ⁴ cells in a 12-well plate. The cells were cultured for 1 day or 1.5 × 10 ⁵ seeded and cultured for 2 days. After the cells became subconfluent, the cells were replaced with Dulbecco's modified Eagle's medium containing 0.4% fetal bovine serum and 50 μg / mL ascorbic acid, and further cultured for 24 hours. Thereafter, a test compound was added, and after 1 hour, TGF-β1 was added to a final concentration of 1 ng / mL. 24 hours after the addition, total RNA was extracted from the cells using an RNA extraction kit (SV Total RNA Isolation System, Promega), and cDNA was synthesized using reverse transcriptase (ReverTra Ace, TOYOBO). The expression level of type I collagen α1 chain mRNA is determined using a real-time PCR device (ABI PRISM 7700 Sequence Detection System, Applied Biosystems) and a real-time PCR premix reagent (SYBR Premix Ex Taq or SYBR Premix Ex Taq II (Perfect Real Time) , TaKaRa) was analyzed by a real-time PCR method. A PCR reaction was performed using the diluted cDNA as a template and a primer specific for the type I collagen α1 chain gene or the GAPDH gene as an internal standard, and the reaction product was measured. In the PCR reaction, incubation was performed at 95 ° C. for 10 seconds, followed by 45 cycles of denaturation at 95 ° C. for 5 seconds and annealing / extension at 60 ° C. for 30 seconds. The expression level of type I collagen α1 chain mRNA was corrected by GAPDH, and expressed as a relative value when the expression level obtained in the absence of the test compound was taken as 100%.
The results are shown in Table 2.

本発明に用いられる化合物は、優れたコラーゲン産生阻害作用を示した。

The compound used in the present invention showed an excellent collagen production inhibitory action.

Test Example 2 Mouse bleomycin-induced pulmonary fibrosis
Ten-week-old male C57BL / 6N mice (Nippon Charles River) were used. Bleomycin (Nippon Kayaku) was dissolved in physiological saline at 1 mg / mL, and 50 μL / mouse was administered intranasally to induce fibrosis. The test compound was suspended in an aqueous 0.5% methylcellulose solution, and 100 mg / kg was orally administered twice a day from 14 to 28 days after induction. The control group was similarly administered with a 0.5% methylcellulose aqueous solution. Lungs were collected after test compound administration and collagen was quantified. The collected lung is homogenized by adding 0.5 mol / L aqueous acetic acid solution containing protease inhibitor cocktail (Roche Diagnostics), and 50 μL of 100 mg / mL pepsin (Sigma) is added to 500 μL of the homogenate overnight. Extracted. The amount of collagen was measured using a kit (Sircol Soluble Collagen assay kit, Biocolor).
The inhibition rate was calculated by the following formula.
Inhibition rate (%) = (1−lung collagen amount in test compound administration group / lung collagen amount in control group) × 100
The amount of lung collagen in the group administered with the compound of Example 9 was 30% or more lower than that in the control group.

  Since the anthranilic acid derivative or salt thereof used in the present invention has a collagen production inhibitory action, for example, prevention of diseases involving excessive production of collagen such as pulmonary fibrosis, scleroderma, nephrosclerosis and cirrhosis or It is useful for treatment such as treatment.

Claims (9)

“Wherein R ¹ represents a hydrogen atom or a carboxyl protecting group; R ² represents a hydrogen atom or an imino protecting group; R ³ represents an optionally substituted phenyl, cycloalkyl or heterocyclic group; R ⁴ is an optionally substituted phenyl, cycloalkyl, cycloalkenyl or heterocyclic group; X ¹ is an optionally substituted alkylene or alkenylene group or bond; X ² is a carbonyl group or general wherein ^{-X 3 -X 4 -, - X} 4 -X 3 -, - O-X 4 - or ^-X 4 -C (O) NH- (where the bond on the left side of each general formula, the ^{R 4} . which shall bind) "wherein, X ³ is sulfur atom, an optionally protected imino group, a sulfinyl group, a sulfonyl group or a bond; X ⁴ is optionally substituted alkylene optionally or alkenylene It means a group represented by means a group or a bond. ". A collagen production inhibitor comprising an anthranilic acid derivative represented by the formula: The collagen production inhibitor according to claim ¹ , wherein R ¹ is a hydrogen atom; R ² is a hydrogen atom; X ¹ is a bond; X ² is an alkylene group or a bond. The collagen production inhibitor according to claim 1 or 2, wherein R ³ is an optionally substituted phenyl or a bicyclic heterocyclic group. The collagen production inhibitor according to any one of claims 1 to 3, wherein R ⁴ is an optionally substituted phenyl or a bicyclic heterocyclic group.

“Wherein R ¹ represents a hydrogen atom or a carboxyl protecting group; R ² represents a hydrogen atom or an imino protecting group; R ³ represents an optionally substituted phenyl, cycloalkyl or heterocyclic group; R ⁴ is an optionally substituted phenyl, cycloalkyl, cycloalkenyl or heterocyclic group; X ¹ is an optionally substituted alkylene or alkenylene group or bond; X ² is a carbonyl group or general wherein ^{-X 3 -X 4 -, - X} 4 -X 3 -, - O-X 4 - or ^-X 4 -C (O) NH- (where the bond on the left side of each general formula, the ^{R 4} . which shall bind) "wherein, X ³ is sulfur atom, an optionally protected imino group, a sulfinyl group, a sulfonyl group or a bond; X ⁴ is optionally substituted alkylene optionally or alkenylene It means a group represented by means a group or a bond. ". ] The therapeutic agent of the disease in which excessive production of the collagen containing the anthranilic acid derivative or its salt represented by this is involved. The treatment agent according to claim 5, wherein R ¹ is a hydrogen atom; R ² is a hydrogen atom; X ¹ is a bond; X ² is an alkylene group or a bond. The treatment agent according to claim 5 or 6, wherein R ³ is an optionally substituted phenyl or a bicyclic heterocyclic group. The therapeutic agent according to any one of claims 5 to 7, wherein R ⁴ is an optionally substituted phenyl or a bicyclic heterocyclic group. The treatment agent according to any one of claims 5 to 8, wherein the disease associated with overproduction of collagen is pulmonary fibrosis, scleroderma, nephrosclerosis, or cirrhosis.