WO2000055129A1 - Dithiocarbonimidate derivatives - Google Patents

Abstract

Dithiocarbonimidate derivatives of general formula (1), prodrugs thereof, or pharmaceutically acceptable salts of both, useful as organ or tissue fibroplasia inhibitors and other drugs wherein R1 is alkyl, alkenyl, alkynyl, or cycloalkyl; E is C¿1?-C5 alkylene, C3-C5 alkenylene, or C3-C5 alkynylene; A is nitrogenous heteroaryl or a group represented by general formula (2) (wherein R?2¿ is hydrogen or a substituent; and R3 is hydroxyl, alkoxy, alkenyloxy, alkynyloxy, or -NR4R5); and Ar is aryl or heteroaryl.

Description

 Description Dithio-imidone derivative Technical field

 The present invention relates to dithio-imidone imidate derivatives. The dithio-imidone derivative is useful as an agent for suppressing fibrosis of an organ or tissue.冃 fe

 Fibrosis of an organ or tissue is caused by excessive accumulation of extracellular matrix in the organ as a repair or defense mechanism when the organ or the like is invaded or damaged for some reason. The extracellular matrix refers to a substance that surrounds the cells of a tissue, and mainly includes fibrous proteins such as collagen and elastin, complex carbohydrates such as proteoglycan, and glycoproteins such as fibronectin and laminin. If the degree of damage to the organs due to invasion or damage is minor, no repair scar remains and the organs recover to normal. However, when the degree of damage to the organ or the like due to invasion or damage is large or persistent, fibrosis of the repair scar impairs the original function of the organ or the like, and further causes new fibrosis. If a vicious cycle is formed, such as the formation of a disease, ultimately organ failure will occur, and in the worst case, death will occur.

It is becoming clear that TGF- / 3 (Transforming Growth Factor- / 3) plays an important role in the accumulation of extracellular matrix. When TGF-3 is administered to normal animals, fibrosis occurs in various tissues (International Review of Experimental Pathology, 34B: 43-67, 1993), and transgenic mice highly expressing TGF-3. However, it has been reported that tissue fibrosis is observed (Pro Nat 1. Acad. Sci. USA, 92: 2572-2576, 1995; Laboratory Investigation, 74: 991-1003, 1995). The following three mechanisms have been reported as mechanisms of tissue fibrosis by TGF_i3. These two or three mechanisms result in extracellular matrix formation. It is believed to accumulate.

 ① Acts on cells, fibronectin (Journal of Biological Chemistry, 262: 6443-6446, 1987), collagen (Pro Natl. Acad. Sci. USA, 85: 1105-1)

108, 1988) and proteoglycans (Journal of Biological Chemistry, 263: 3039-3045, 1988).

 ② By reducing the expression of extracellular matrix-degrading enzymes (Journal of Biological Chemistry, 263: 16999-17005, 1988), and by strongly promoting the expression of inhibitors of extracellular matrix-degrading enzymes (Cancer Research, 49 : 2533-2553, 1989), which inhibits the degradation of extracellular matrix.

③ Proliferate cells that produce extracellular matrix (American journal of Physiology, 264: F199-F205, 1993).

 Therefore, inhibition of TGF-3 is considered to be an effective means for inhibiting the accumulation of extracellular matrix, and fibrosis occurs when an antiserum of TGF- ^ is actually administered to a fibrosis model animal. Has been reported to be reduced (Nature, 346: 371-374, 1990).

 JP-A-7-304731 and JP-A-8-73324 describe that a specific dithiocarbonimidate derivative having an oxime structure is useful as an insecticide, acaricide and the like. ing. Disclosure of the invention

 An object of the present invention is to provide a compound useful as an agent for suppressing fibrosis of an organ or tissue. The present inventors have conducted intensive studies and have found that dithiocarbonimidate derivatives can suppress fibrosis of an organ-tissue, thereby completing the present invention.

 That is, the present invention is as follows.

[1] Equation 1

[In the formula, R ¹ represents an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, or an optionally substituted cycloalkyl.

E is optionally substituted C, represents a -C ₅ alkylene, optionally substituted C ₃ be -C ₅ al Keniren or optionally substituted C ₃ ~ C ₅ alkynylene.

A represents a substituted or unsubstituted monocyclic nitrogen-containing heteroaryl having a nitrogen atom at the 2- or 3-position, an optionally substituted bicyclic nitrogen-containing heteroaryl, or a compound represented by the formula:

(In the formula, R ² represents a hydrogen atom or a substituent.

R ³ represents a hydroxyl group, an optionally substituted alkoxy, an optionally substituted alkenyloxy, an optionally substituted alkynyloxy or —NR ⁴ R ⁵ .

R ⁴ and are independently a hydrogen atom, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted aryl or a substituted Represents a heterogeneous that may be done. R ⁴ and R ⁵ may be taken together with a nitrogen atom to represent a nitrogen-containing heterocyclic group which may be substituted with NR ⁴ R ⁵ . ).

 Ar represents an optionally substituted aryl or an optionally substituted heteroaryl. ]

Or a prodrug thereof, or a pharmaceutically acceptable salt thereof.

[2] Formula:

[Wherein, R ¹ R ² , R ³ , E and Ar have the same meanings as in the above [1].

]

The dithiocarbonimidate derivative or prodrug thereof according to [1], or a pharmaceutically acceptable salt thereof.

 [3] Formula:

[Wherein, R ^] , R ² , R ³ , E and Ar are as defined in the above [1]. [2] The dithiocarbonimidate derivative or prodrug thereof according to [2], or a pharmaceutically acceptable salt thereof.

[4] R ³ force A hydroxyl group, an optionally substituted alkoxy or —NHR ⁶ (R ⁶ represents an optionally substituted alkyl, an optionally substituted alkenyl or an optionally substituted alkynyl) [ 2] or [3], a dithiocarbonimide derivative or a prodrug thereof, or a pharmaceutically acceptable salt thereof.

[5] R ² is a hydrogen atom, a halogen atom, an optionally substituted alkyl, an optionally substituted alkoxy, an optionally substituted alkenyl, an optionally substituted alkynyl, a cyano, an optionally substituted aryl , Optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted aryloxy, substituted Optionally substituted heteroaryloxy, optionally substituted alkoxycarbonyl, hydroxyl group, optionally substituted alkanoyl, optionally substituted amino, carboxyl, optionally substituted rubamoyl, optionally substituted A dithiocarbonimidate derivative or a prodrug thereof according to any one of [2] to [4], which is a good sulfamoyl, an optionally substituted alkylthio, an optionally substituted alkanoylamino, or nitro; Pharmaceutically acceptable salts.

[6] R ² is a hydrogen atom or a halogen atom. [5] The dithiophenone diimidate derivative or a prodrug thereof, or a pharmaceutically acceptable [7] A in which A may be substituted. The dithiocarbonimidate derivative or prodrug thereof according to [1], which is a sex nitrogen-containing heteroaryl, or a pharmaceutically acceptable salt thereof.

[8] is E force substituted is optionally C i~C ₃ alkylene or substituted are also good not C ₃ -C ₄ 7 Luque two Ren also [1] Jichio force one carbon according to any one of to [7] An imidate derivative or a prodrug thereof, or a pharmaceutically acceptable dish thereof.

 [9] E force The dithiocarbonimidate derivative or prodrug thereof according to [8], which is methylene which may be substituted, or a pharmaceutically acceptable salt thereof.

 [10] A medicament comprising the dithio-imidone imidate derivative according to any one of [1] to [9], a prodrug thereof, or a pharmaceutically acceptable salt thereof.

 [11] The medicament according to [10], which is an inhibitor of organ or tissue fibrosis.

 [12] The medicament according to [10], which is a TGF- / 3 inhibitor.

 [13] The medicament according to [10], which is a therapeutic agent for diabetic nephropathy.

 [1] The medicament according to [10], which is a therapeutic agent for glomerulonephritis.

[15] The medicament according to [10], which is a therapeutic agent for liver cirrhosis. [16] The medicament according to [10], which is a therapeutic agent for pulmonary fibrosis.

"Alkyl" includes, for example, linear or branched C] -C ,. Alkyl, etc., specifically, methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, pentyl, 1-methylbutyl, 2-methylbutyl, 1-ethylpropyl, hexyl, Heptyl, 1-methylpentyl, 2-methylpentyl, 1.1-ethylpentyl, octyl, decyl and the like.

“Alkoxy” includes, for example, straight-chain or branched C 1, -C,. Alkoxy, etc., and specifically, methoxy, ethoxy, propoxy, 1-methylethoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy, pentyloxy, 1-methylbutoxy, 2-methylbutoxy, 1-ethyl Examples include propoxy, hexyloxy, 1-methylpentyloxy, 2-methylpentyloxy, 1-ethylbutoxy, octyloxy, decyloxy and the like.

“Alkoxycarbonyl” includes, for example, carbonyl substituted with “alkoxy”.

“Alkenyl” includes, for example, C ₂ -C, straight-chain or branched. Examples thereof include alkenyl and the like, and specific examples include vinyl, 1-propenyl, 2-propenyl, 3-pentenyl, 4-hexenyl, 3-octenyl, 5-decenyl and the like.

The “alkenyloxy” includes, for example, straight-chain or branched-chain. ,. Examples thereof include alkenyloxy and the like, and specific examples include 2-provenyloxy, 3-pentenyloxy, 4-hexenyloxy, 3-octenyloxy, and 5-decenyloxy. As the "alkynyl", for example 0 ₂ ～〇 straight or branched chain,. Examples thereof include alkynyl and the like, and specific examples include ethynyl, 1-bromovinyl, 2-propynyl, 3-butynyl, 5-hexynyl, 6-butynyl, and 2-decynyl. As “alkynyloxy”, for example, straight-chain or branched C ₂ -C,. Alkynyloxy and the like, specifically, 2-propynyloxy, 3-butynyloxy, 5-hexynyloxy, 6-octinyloxy, 2-decynyloxy and the like. "Cycloalkyl", for example, C ₃ ~ C _¾ cycloalkyl and the like, concrete cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl to cyclo, Shikurookuchiru and the like.

The "Arukanoiru", for example, C] ~ C _{1 0} Arukanoiru such straight or branched chain, and specific examples thereof include formyl, Asechiru, propionyl, Puchiriru, iso butyryl, valeryl, isovaleryl, Pibaroiru, 2- butyryl , Hexanoyl, octanoyl, decanoyl and the like.

Substitution in "substituted alkyl", "substituted alkoxy", "substituted alkenyl", "substituted alkenyloxy", "substituted alkynyl", "substituted alkynyloxy", "substituted cycloalkyl", "substituted alkanol" and "substituted alkoxycarbonyl" Examples of the group include alkoxy, cycloalkyl, aryl, heteroaryl, aryloxy, heteroaryloxy, halogen atom, cyano, hydroxyl, alkanol, alkoxycarbonyl, optionally substituted amino, alkanoylamino, carboxyl, And optionally substituted sulfamoyl, and optionally substituted sulfamoyl. These may be independently substituted one or more times. Substituted alkoxy in R ^3, a substituted Arukeniruokishi and substituted Arukiniruoki sheet substituents, and substituted alkyl for R ⁴ and R ^5, preferred examples of the substituent of the substituted alkenyl and substituted alkynyl, for example, hydroxyl, Arukanoiru, alkoxycarbonyl , Carboxyl, optionally substituted sorbamoyl, and optionally substituted sulfamoyl.

Preferred examples of the substituent of the substituted alkyl, substituted alkenyl, substituted alkynyl and substituted cycloalkyl in R] include a halogen atom, alkoxy, cycloalkyl, aryl and heteroaryl.

The ".! ~ Ji et alkylene", preferably C] -C ₃ alkylene and the like, specifically, methylene, ethylene, trimethylene, as "C ₃ -C ₅ alkenylene" which Echiriden the like, preferably include C ₃ -C ₄ 7 Luque two lens, specifically, (E) - 2-propenylene, (Z) - 2-propenylene, (E) - 3- butenylene or the like can be mentioned Can be

As the “C ₃ -C ₅ alkynylene”, specifically, 2-propynylene, 2-butynylene, 3-butylinylene and the like can be mentioned.

“Substituted c, to c ₅ alkylene”, “substituted c _{3 to} c ₅ alkenylene” and “substituted c

₃ Examples of the substituent of to c ₅ alkynylene ", for example, an optionally substituted alkyl, alkenyl which may be substituted, an optionally substituted alkynyl, halogen atom, shea § Bruno, carboxyl, may force be substituted Lubamoyl and the like. Preferred substituents include alkyl which may be substituted, alkenyl which may be substituted, alkynyl which may be substituted, a halogen atom, carboxyl and carbamoyl. I can do it. Preferred examples of the substituent include methyl, ethyl, propyl, trifluoromethyl, vinyl, ethynyl, a fluorine atom, and carbamoyl.

As the "Ariru", for example c ₆ ~c,. And phenyl, 1-naphthyl, 2-naphthyl and the like.

Examples of the “heteroaryl” include a monocyclic or bicyclic 5- or 6-membered heteroaryl containing 1 to 3 atoms independently selected from the group consisting of a nitrogen atom, a sulfur atom and an oxygen atom. Is mentioned. Specifically, the 5-membered heteroaryl is independently from the group consisting of a nitrogen atom such as pyrrolyl, phenyl, furyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl and triazolyl, a sulfur atom and an oxygen atom. 1 or 2 independently selected from the group consisting of nitrogen, sulfur and oxygen, such as monocyclic 5-membered heteroaryl, benzothiazolyl, and indolyl containing one or two atoms selected from And two-membered 5-membered heteroaryl containing 10 atoms. Specific examples of the 6-membered heteroaryl include 1 to 3 atoms independently selected from the group consisting of a nitrogen atom, a sulfur atom, and an oxygen atom such as pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, and triazinyl. A monocyclic 6-membered heteroaryl, including nitrogen atom such as quinazolyl, a sulfur atom and an oxygen atom. And ring heteroaryl.

“Aryloxy” and “heteroaryloxy” include, for example, oxy substituted with “aryl” and oxy substituted with “heteroaryl”, respectively.

The “nitrogen-containing heterocyclic group” includes, for example, one or two atoms selected from the group consisting of a nitrogen atom, a sulfur atom and an oxygen atom, which contain one nitrogen atom. And a monocyclic 3- to 7-membered nitrogen-containing heterocyclic group which may contain a child. Preferably, it is a monocyclic 5- or 6-membered ring containing one nitrogen atom and optionally containing one or two atoms independently and arbitrarily selected from the group consisting of a nitrogen atom, a sulfur atom and an oxygen atom. And a ring-containing saturated nitrogen-containing heterocyclic group. Specific examples include a 5-membered saturated nitrogen-containing heterocyclic group such as pyrrolyl, and a monocyclic 6-membered saturated nitrogen-containing heterocyclic group such as morpholyl and piperazinyl.

Examples of the substituent in “substituted aryl”, “substituted heteroaryl”, “substituted aryloxy”, “substituted heteroaryloxy” and “substituted nitrogen-containing heterocyclic group” and the substituent in R ² include, for example, , Halogen atom, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkenyl, optionally substituted alkynyl, cyano, aryl, heteroaryl, optionally substituted cycloalkyl, aryl Monooxy, heteroaryloxy, optionally substituted alkoxycarbonyl, hydroxyl, optionally substituted alkanol, optionally substituted amino, carboxyl, optionally substituted rubamoyl, optionally substituted sulfamoyl , An optionally substituted alkylthio, an optionally substituted alkano Lumino, nitro and the like may be mentioned, and these may be independently substituted one or more times. Preferred substituents include, for example, alkyl which may be substituted, alkenyl which may be substituted, alkynyl which may be substituted, cycloalkyl which may be substituted, alkoxy which may be substituted, aryloxy, and hetero. Aryloxy and the like.

“Alkylthio” includes, for example, thio substituted with “alkyl”.

The “alkanoylamino” includes, for example, an amino substituted with “alkanoyl”. Substituents in "substituted amino", "substituent rubamoyl", "substituted sulfamoyl", "substituted alkylthio" and "substituted alkanoylamino" are, for example, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl. And these may be independently substituted one or two times.

Examples of the “halogen atom” include a fluorine atom, a chlorine atom, a bromine atom, an iodine atom and the like. Preferred examples include a fluorine atom, a chlorine atom and a bromine atom.

As the “monocyclic nitrogen-containing heteroaryl having a nitrogen atom at the 2- or 3-position”, for example, a monocyclic 5- or 6-membered ring containing at least one nitrogen atom at the 2- or 3-position and containing And nitrogen heteroaryl. Specific examples include a monocyclic 6-membered nitrogen-containing heteroaryl such as 3-pyridyl, 3-pyridazinyl and 2-virazinyl, and a monocyclic 5-membered nitrogen-containing heteroaryl such as imidazolyl. Can be

Examples of the “bicyclic nitrogen-containing heteroaryl” include a bicyclic 5-membered or 6-membered nitrogen-containing heteroaryl. Specifically, 2-ring 6-membered nitrogen-containing heteroaryl such as 2-quinolyl, 3-quinolyl, 6-quinolyl, 2-quinoxalinyl, 3-cinnolinyl, 1-isoquinolyl, 4- ^ T-soquinolyl, 5-membered nitrogen-containing heteroaryl in which a benzene ring such as benzimidazolyl is condensed; monocyclic nitrogen-containing heteroaryl having a nitrogen atom at the 2- or 3-position and bicyclic nitrogen-containing When the “heteroaryl” has a substituent, examples of the substituent include the same substituents as those described above for R ² .

As a “prodrug”, the enzymatically or chemically hydrolyzed Those capable of producing a dithio-imidone diimidate derivative. When the dithiocarbonimide derivative of the formula 1 is, for example, a compound having a carboxyl group, a compound having a substituted or unsubstituted alkoxycarbonyl group in the carbonyl group may be mentioned. Is a C alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl or the like, or an alkoxy group substituted at the 1-position such as 1-methoxymethoxycarbonyl, 1-ethoxymethoxycarbonyl, 1-ethoxyethoxycarbonyl, 1-pivaloyloxymethoxycarbonyl, etc. C, c

₆ Compounds that have become alkoxycarbonyl groups and the like. Further, for example, in the case of a compound having an amino group, a compound in which the amino group is an alkanoylamino group, an alkoxycarbonylamino group substituted at the 1-position with an alkoxy group, or a hydroxylamino group, etc. No.

As the “pharmaceutically acceptable salt”, when the dithiocarbonimidate derivative of the formula 1 has a basic group, for example, inorganic salts such as hydrochloride, hydrogen bromide, sulfate, phosphate, nitrate, etc. Acid, and acetate, propionate, succinate, lactate, malate, tartrate, citrate, maleate, fumarate, methanesulfonate, p-toluenesulfonate, Organic salts such as benzenesulfonate and ascorbate are exemplified. In addition, when the dithiocarbonimidate derivative of the formula 1 has an acidic group, it may be used as an inorganic base salt such as a sodium salt, a calcium salt, a potassium salt, or an organic base salt such as a triethylammonium salt or a lysine salt. can do.

In addition, the present invention also includes dithiol-monoimidate derivatives or prodrugs of the formula 1, or hydrates of pharmaceutically acceptable salts thereof, and solvates such as ethanol solvates and the like. The dithiocarbonimidate derivative or prodrug of Formula 1 or a pharmaceutically acceptable salt thereof can be used as a medicament. Furthermore, it is useful, for example, as a therapeutic agent for the following diseases involving fibrosis of various organs or tissues. Diabetic nephropathy

 Glomerulonephritis

 Tubular interstitial nephritis

 Hereditary kidney disease

 Diabetic retinopathy

 Type I diabetes

 Cirrhosis

 Pulmonary fibrosis

 Arteriosclerosis

 Myocardial fibrosis

 Restenosis after PTCA

 Chronic Teng Flame

 Myelofibrosis

 Scar after surgery

 Organ adhesions after surgery

 Burn scar

 Keloid ゃ hypertrophic scar

 Rheumatoid arthritis

 Uterine fibroid

 Prostatic hypertrophy

 Alzheimer's disease Adult respiratory distress syndrome The dithio-bibonimidate derivative of formula 1 can be produced, for example, according to the following production method.

Manufacturing method 1 The dithiocarbonimidate derivative of the formula 11 can be produced by the following method.

[Wherein, RR ² , R ³ , E and Ar are as defined in the above [1].

R ⁷ represents an optionally substituted alkyl.

 Z represents a trialkyl ammonium or an alkali metal.

X and Y independently represent a leaving group. The dithiocarbamate derivative of the formula 5 can be produced by reacting the dithiocarbamate salt of the formula 2 or the salt of dithiocapribonimidate of the formula 3 with the compound of the formula 4. Examples of the leaving group include halogen atoms such as iodine, bromine and chlorine, and sulfonyl groups such as a methanesulfonyl group and a P-toluenesulfonyl group. The amount of the compound of the formula 2 or 3 is, for example, 0.5 to 2 equivalents relative to the compound of the formula 4. Quantity. Examples of the reaction solvent include aromatic hydrocarbons such as benzene, toluene, and xylene; acetyl ether; tetrahydrofuran (THF); ethers such as 1,4-dioxane; and N, N dimethylformamide (DMF). Amides, ketones such as acetone and methyl ethyl ketone and the like can be used. The reaction temperature is, for example, in the range of 20 to 130 ° C, and preferably in the range of 0 to 30 ° C. The dithiocarbamate of the formula 2 or the salt of the dithiocarbonimidate of the formula 3 can be produced, for example, by the method described in JP-A-8-73424. The compound of formula 4 can be produced by a conventional method.For example, the ability to halogenate the corresponding alcohol compound with a halogenating agent such as thionyl chloride or p-toluenesulfonyl chloride, methanesulfonyl It can be produced by sulfonylation using a sulfonylating agent such as cloride. Further, for example, it can also be produced by halogenating a corresponding compound having an alkyl group using a halogenating agent such as N-promosuccinimide. The dithiocarbonimidate derivative of the formula (2) can be produced by reacting the dithiocarbamate derivative of the formula (5) with the compound of the formula (6) in the presence of a base. The amount of the compound of the formula 6 used is, for example, 1 to 2 equivalents to the dithiocarbamate derivative of the formula 5. Examples of the base include alkali metal carbonates such as potassium carbonate and sodium carbonate, and alkali metal hydrides such as sodium hydride. The amount of the base used is, for example, 1 to 3 equivalents. Examples of the reaction solvent include aromatic hydrocarbons such as benzene, toluene, and xylene, ethers such as dimethyl ether, THF, 1,4-dioxane, amides such as DMF, acetone, and methyl ethyl ketone. And the like. As the reaction temperature, For example, the range is 120 to 130 ° C, preferably the range is 0 to 30 ° C. The dithiocarbonimidate derivative of the formula 7 is represented by one COOR ^{7 wherein} R ⁷ represents an optionally substituted alkyl. ), A dithio-imidone derivative having a corresponding lipoxyl group can be produced. Examples of the method of hydrolysis or hydrogenolysis include, for example, the method described in New Experimental Chemistry Course 14-II, 931 (1977) (Maruzen). The dithiocarbonimidite derivative having a carboxyl group obtained here can be amidated or esterified to produce a dithiocarbonimidide derivative of the formula 1-1. Examples of the amidation method include ordinary methods, for example, the formula: HNR ⁴ R ⁵ [wherein R ⁴ and R ⁵ have the same meanings as in the above [1]. ] Can be carried out by condensation with an amine represented by the formula: As a specific condensation method, for example, the method described in the fourth edition of Experimental Chemistry Course 22-IV, 138 (1992) can be used. As the esterification method, a usual method can be used. Further, in the above-mentioned production method, a dithiocarbonimidate derivative of the formula 11-11 can be produced from a raw material having an amide or an ester having a target structure from the beginning. The dithio-biimidate derivative of the formula 1-2 can be produced by the following method.

 twenty three

 70 7-2

 [Wherein, RE and Ar are as defined in the above [1].

 W represents a substituted or unsubstituted monocyclic nitrogen-containing heteroaryl having a nitrogen atom at the 2- or 3-position, or a bicyclic nitrogen-containing heteroaryl which may be substituted.

X, Y and Z are as defined above. The dithiocarbamate derivative of formula 10 can be prepared by reacting a dithiocarbamate salt of formula 2 or a salt of dithiocarbonimidate of formula 3 with a compound of formula 9. The conditions for this reaction are the same as those for the production of the dithiocarbonimide derivative of Formula 11-11. The dithiocarbamate of the formula 2 or the salt of dithiocarbonimidate of the formula 3 can be produced, for example, by the method described in JP-A-8-73424. The compound of formula 9 can be prepared by a conventional method.For example, the corresponding alcohol compound is halogenated using a halogenating agent such as thionyl chloride, or p-toluenesulfonyl chloride, methanesulfonyl Sulfonylating agents such as And can be produced by sulfonylation using Further, for example, it can also be produced by halogenating a corresponding compound having an alkyl group using a halogenating agent such as N-promosuccinimide. The dithiocarbonimidate derivative of the formula 1-2 can be produced by reacting the dithiocarbamate derivative of the formula 10 with the compound of the formula 6 in the presence of a base. The conditions for this reaction are the same as those for the production of the dithiocarbonimidate derivative of Formula 11-11. Manufacturing method 2

[式中、 R ¹ R ²、 Eおよび A rは前記 [ 1 ] と同義である。 r

[Wherein, R ¹ R ² , E and Ar are as defined in the above [1].

R ⁷ represents an optionally substituted alkyl.

W, X, Y and Z are as defined above. The dithiocarbonimide derivative of the formula 7 or 12 is produced by reacting the compound of the formula 4 or 9 with the dithiocarbamate derivative of the formula 8, respectively, in the same manner as in the production method 1. You can also. In addition, prodrugs and pharmaceutically acceptable salts can be produced according to known methods. The dithiocarbonimidate derivative or prodrug of Formula 1 or a pharmaceutically acceptable salt thereof can be used as a medicament by oral or parenteral (for example, intravenous, subcutaneous or intramuscular injection, transdermal, transdermal It can be administered rectally, transdermally, or nasally. Examples of the composition for oral administration include tablets, capsules, pills, granules, powders, solutions, suspensions, and the like. Examples of the composition for parenteral administration include: Aqueous injections, oils, ointments, creams, lotions, aerosols, suppositories, patches and the like can be mentioned. These formulations can be prepared using conventional techniques. For example, it can be produced by mixing the active ingredient of the present invention with a pharmaceutically acceptable ordinary carrier, excipient, binder, stabilizer, buffer, solubilizing agent, isotonic agent and the like. it can. The dose and frequency of administration vary depending on the patient's symptoms, history, age, weight, dosage form, etc.For example, when administered orally to an adult (body weight 60 kg), it is usually 1 to 3000 mg / day, preferably 5 to 30 mg / day. The dosage can be adjusted appropriately in the range of 1000 mg, and can be administered once or in several divided doses. 【Example】

 Hereinafter, the present invention will be described in more detail with reference to Examples, but the present invention is not limited thereto.

Example 1

 S—Methyl S ′ — 2-Methoxycarboxytriphenylmethyl N—p—Trilldithio

 1) Triethylammonium N-p-Trilldithiolbamate

 Carbon disulfide (15.73 g, 147 t ol) was added to a solution of p-toluidine (15.73 g, 147 t ol) and triethylamine (30.7 ml, 220 t ol) in dimethyl ether (200 ml) at room temperature, and the mixture was heated for 30 minutes. Refluxed. After allowing to cool, the precipitate was collected by filtration, washed with getyl ether, and dried under reduced pressure to obtain triethylammonium N-p-tolyldithiol bamate (38.3 g, 72%) as a yellow powder.

Ή-NMR (270 gun _{z, CDC1 3) δ 1 ·} 39 (9H, t, J = 7.3Hz), 2.30 (3H, s), 3.27 (6H, q, J = 7.3H z), 7.12 (2H, d, J = 8.6Hz), 7.46 (2H, d, J = 8.6Hz)

2) Methyl-2-bromomethylbenzoic acid

o-Methyl toluate (7.51 g, 50 t ol) and N-succinimide bromide (8.90 g, 2,2'-Azobisisobutyronitrile (1.64 g, 10 mmol) was added to a solution of 50 ml of carbon tetrachloride (100 ml), and the mixture was heated under reflux for 1 hour. After allowing to cool, filtration was performed, and the filtrate was concentrated to obtain a crude product of methyl-2-bromomethylbenzoic acid.

_{NMR (270 MHz, CDC1 3)} δ 3.80 (3H, s), 4.82 (2H, s), 7.27 (3H, m), 7.83 (1H, dm, J = 8.6Hz)

3) S-2-methoxycarbonylphenylmethyl N-p-tolyldithiolbamate

The product of methyl-2-bromomethylbenzoic acid was dissolved in THF (100 ml) without purification, and triethylammonium Np-tolyldithiolbamate (12.8 _g , 45 tol) was added. Stirred for 10 hours. The reaction mixture diluted Mr water with acetic acid Echiru sequentially washed with saturated brine, dried over Mg S0 _4, the solvent was distilled off, hexane fart and the obtained residue over Jefferies chill ether (1: 2) The crystals were collected by filtration and filtered to obtain S-2-methoxycarbonylphenyl Np-tolyldithiolbamate as colorless prism crystals.

E - field _{R (270 MHz, CDC1 3)} δ 2.34 (3H, s), 3.90 (3H, s), 4.97 (2H, s), 7.17 (2H, dm, J = 7.9Hz), 7.30 (lH, br ), 7.34 (1H, td, J = 7.6 and 1.3 Hz), 7.47 (1H, td, 7.6 and 1.7 Hz), 7.69 (111, (1, 7.9 and 1.3), 7.94 (1H, dd, 7.9 And 1.3 Hz), 8.83 (lH, br.)

4) S-methyl S '— 2-methoxycarbonylphenylmethyl N-p-tolyldithiocarbonimide

S- 2-methoxycarbonylphenyl N-p-Torirujichio force Rubameto (33. Lg, lOOmmol) at room temperature in DMF (300 ml) solution of methyl iodide (28.4g = 12.5ml, 200m mol) and K ₂ C0 ₃ (13.8 g, 100 t ol) and stirred at the same temperature for 6 hours. The reaction mixture was Jechirue one ether diluted, washed with water and brine, dried over Mg S0 _4, the solvent was evaporated and the obtained oil was purified by silica gel column chromatography (torr 5: 1) to give S-methyl as a colorless oil

S′—2-Methoxycarbonylphenylmethyl N—p—tolyldithiocarbonimidate (34.5 g, 100%) was obtained.

_{- NMR (270 MHz, CDC1 3} ) δ 2.32 (3H, s), 2.43 (3H, s), 3.90 (3H, s), 4.74 (2H, s), 6.74 (2H, dm, J = 8.3Hz), 7.11 (2H, dm, J = 8.3Hz), 7.32 (1H, td, J = 7.6 and 1.3Hz), 7.44 (1H, td, J = 7.6 and 1.3Hz), 7.57 (lH, br), 7.95 (1H, d, J = 7.6Hz) Example 2

 S-Methyl S '1 2-Carboxyphenylmethyl N-p-Tolyldithio-Bonimidate

S_Methyl S '— 2-Methoxycarbonylphenylmethyl N-p-tolyl dithioamide (23.5 g, 68 marl 01) was dissolved in THF (200 ml) and methanol (100 ml), and the mixture was dissolved at room temperature. A 2N aqueous solution of sodium hydroxide (68 ml, 136 t ol) was added, and the mixture was stirred at 45 ° C for 3 hours. After cooling, add 1N-HC1 to the reaction mixture to adjust the pH to 1-2, extract twice with ethyl acetate, combine the organic layers, wash with saturated saline, dry magnesium sulfate, and remove the solvent. The purified solid was purified by silica gel column chromatography (toluene / ethyl acetate = 1: 1) to give S-methyl S'—2-carboxyphenylmethyl N-p-tolyldithio-force—bonimidate (18.4 g) as colorless prisms , 82%).

Ή - NMR (270 MHz, CDC1 3) δ 2.31 (3H, s), 2.46 (3H, s), 4.70 (2H, s), 6.70 (2H, dm, J = 8.3Hz), 7.10 (2H, d, J = 8.3Hz), 7.36 (1H, td, J = 7.6 and 1.3Hz), 7.50 (1H, td, J = 7.6 and I.3Hz), 7.62 (lH, br), 7.98 (1H, d, J = 7.8Hz) W

 twenty three

Example 3

 S—Ethyl S ′ — 2-Methoxycarbonylfue, N—p—thiocarbonimidate

In the same manner as in Example 1-4, except that methyl iodide was used with iodine thiol as a colorless oily substance, as S-ethyl S'—2-methoxycarbonylphenylmethyl N-p-tolyldithio. One bonimide (95% yield) was obtained.

Ή-NMR (270 MHz, CDC1 3) δ 1.25 (3H, br. T, J = 7.3Hz), 2.30 (3H, s), 3.01 (2H, q, J = 7 • 3Hz), 4.63 (2H, s ), 6.65 (2H, br.d, J = 7.9Hz), 7.09 (2H, dm, J = 7.9Hz), 7.35 (lH, td, J = 7.6 and 1.3Hz), 7.49 (1H, td, J = 7.6 and 1.6Hz), 7.60 (1H, br.), 7.91 (lH, br.d, J = 7.6Hz)

 S-Ethyl S '2-monocarboxyphenylmethyl N-p-tolyldithio

—Honymit

S—ェチル S' — 2—メトキシカルボニルフエニルメチル N— p—トリル ジチォ力一ボンイミデートより実施例 2と同様な方法で S—ェチル S' — 2— カルボキシルフェニルメチル N— p—トリルジチォ力一ボンイミデートを製造 した（収率 98%)。

S-Ethyl S '— 2-Methoxycarbonylphenylmethyl N-p-tolyl dithioamide imidate S-ethyl S' — 2-carboxylphenylmethyl N-p-tolyldithioamide imidate Was produced (98% yield).

E - negation _{R (270 MHz, CDC1 3)} δ 1.25 (3H, m), 2.32 (3H, s), 2.99 (2H, m), 3.91 (3H, s), 4.73 (2H, s), 6.75 (2H , dm, J = 8.3Hz), 7.12 (2H, dm, J = 8.3Hz), 7.32 (1H, td, J = 7.6 and 1.3Hz), 7.44 (, 1 (1, 7.6 ぉ 1.61 ^) , 7.56 (1H, br.), 7.95 (1H, br.d, J = 7.6Hz)

 S—Ethyl S ′ — 2-Methylaminocarbonylphenylmethyl N—p—Tolyldithio

A solution of S-ethyl S '— 2 carboxyphenylmethyl N-p-tolyldithiocarbonimidate (345 mg, l.Ommol) and methylamine (135 mg, 2.0 mmol) in DMF (3.0 ml) at room temperature was added. Aminopropyl) 1-3-ethylcarbodiimid (383 mg, 2.0 ramol 1-hydroxybenztriazole (20 mg, 0.15 ol) and triethylamine (202 mg, 2.0 mmol) were sequentially added, and the mixture was stirred at the same temperature for 5 hours. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate and 1 N—HCU: and dried over magnesium sulfate to obtain a white solid, which was washed with n-hexane. As a result, S-ethyl S '— 2-methylaminocarbonyl phenylmethyl N-p-tolyldithio-potimimidone (253 mg, 70) was obtained as white crystals. Obtained.

E - noodles _{R (270 MHz, CDC1 3)} δ 1.25 (. 3H, br t, J = 7.3Hz), 2.31 (3H, s), 2.89 (3H, d, J = 5

.0Hz), 3.01 (2H, q, J = 7.3Hz), 4.48 (2H, s), 6.64 (2H, dm, J = 7.9Hz), 7.30-7.60 (4H, m) The compound of (

実施例 し¹ L²

Example ¹ L ²

 6 -Me -H

 7 -Me -CI

 8 -Me -OMe

 9 -iPr -Me

10-(CH ₂ ) ₇ Me -Me

11 -CH ₂ Ph -Me

e -Me

13 -Me 14

e -Me

Example 3

実施例 し L 4

Example L 4

20 (CH ₂ ) ₆ Me -OMe

21-CH ₂ Ph -OMe

24 OMe -〇_Me 25 C_〇_NH ₂ ■ OMe 26 -Et -N

The ¹ H-NMR data of the compounds of Examples 6 to 26 are shown below.

Example 6

Ή-NMR (270 MHz, CDC1 3) δ 2.46 (3H, s), 4.73 (3H, s), 6.82 (2H, dm, J = 7.9Hz), 7.0 9 (1H, t, J = 7.9Hz), 7.38 (1H, td, J = 7.6 and 1.3Hz), 7.52 (1H, td, J = 7.3 and 1.3Hz), 7.63 (lH, br.), 7.98 (1H, d, J = 7.6Hz)

Example 7

Ή-NMR (270 MHz, CDC1 3) 8 2.47 (3H, s), 4.73 (2H, s), 6.74 (2H, dm, J = 8.3Hz), 7.2 6 (2H, dm, J = 8.3Hz), 7.38 (1H, td, J = 7.6 and 1.3Hz), 7.52 (1H, td, J = 7.3 and 1.3Hz), 7.61 (lH, br), 7.98 (1H , d, J = 7.6Hz)

Example 8

Ή-NMR (270 MHz, CDC1 3) δ 2.46 (3H, s), 3.78 (lH, s), 4.66 (2H, s), 6.73 (2H, br.d, J = 8.3Hz), 6.84 (2H, dm, J = 8.3Hz), 7.37 (1H, td, J = 7.6 and 1.3Hz), 7.51 (lH, td, J = 7.6 and 1.3Hz), 7.62 (lH, br.), 7.96 (lH, br. )

Example 9

E - negation _{R (270 MHz, CDC1 3)} δ 1.27 (6H, d, J = 5.6Hz), 2.31 (3H, s), 3.68 (lH, m), 4.72 (2H, s), 6.71 (2H, br .d, J = 7.9Hz), 7.10 (2H, dm, J = 7.9Hz), 7.35 (1H, t, J = 7.6Hz), 7.49 (1H, td, J = 7.6 and 1.3Hz), 7.52 (1H, br.), 8.03 (lH, br.)

Example 10

Ή-NMR (270 MHz, CDC1 3) δ 0.86 (3H, t, J = 6.9Hz), 1.24 (10H, ra), 1.57 (2H, m), 2.3 l (3H, s), 2.96 (2H, m ), 4.68 (2H, s), 6.68 (2H, dm, J = 7.9Hz), 7.10 (2H, dm, J = 7.9Hz), 7.35 (lH, td, J = 7.6 and 1.3Hz), 7.49 (1H , Td, J = 7.6 and 1.5 Hz), 7.52 (lH, br.), 8.03 (lH, br.d, J = 7.6 Hz)

Example 1 1

Ή-NMR (270 MHz, CDC1 3) 8 2.29 (3H, s), 4.23 (1H, br.), 4.68 (2H, s), 6.66 (2H, br .d, J = 7.9Hz), 7.08 (2H , dm, J = 7.9 Hz), 7.25 (5H, m), 7.37 (1H, t, J = 7.6Hz), 7.49 (1H, t, J = 7.3Hz), 7.56 (lH, br.), 8.99 ( (1H, br.d, J = 7.3Hz)

Example 1 2

E - negation _{R (270 MHz, CDC1 3)} δ 0.22 (2H, m), 0.53 (2H, m), 0.97 (lH, m), 2.31 (3H, s), 2.96 (2H, m), 4.71 (2H , S), 6.72 (2H, dm, J = 8.2Hz), 7.11 (2H, dm, J = 7.9Hz), 7.36 (1H, td, J = 7.6 and 1.2Hz), 7.50 (, 1 [1,] = 7.6 ぉ 1.4 ^), 7.60 (1H, br.), 8.01 (1H, br.d, J = 7.6Hz)

Example 13

• H-NMR (270 MHz, CDC1 3) δ 1.54-1.84 (6H, m), 2.09 (2H, m), 2.30 (3H, s), 3.77 (1H, m), 4.64 (2H, s), 6.65 (2H, dm, J = 8.OHz), 7.09 (2H, dm, J = 8.OHz), 7.36 (1H, td, J = 7 .6 and 1.2 Hz), 7.50 (river, 1 (1, _< ] = 7.6 and 1.4), 7.62 (1H, br.), 7.92 (1H, br. D,

(J = 7.6Hz)

Example 14

Ή-NMR (270 MHz, CDC1 3) 5 2.30 (3H, s), 3.21 (2H, m), 3.35 (3H, s), 3.55 (2H, m), 4.72 (2H, s), 6.71 (2H, dm, J = 8.0Hz), 7.10 (2H, dm, J = 8.0Hz), 7.36 (1H, td, J = 7.6 and 1.2Hz), 7.51 (1 1) = 7.6 ぉ 1.4 ^), 7.58 (1H, br.), 8, 01 (1H, br. D, J = 7.6 Hz)

Example 15

Ή-NMR (270 MHz, CDC1 3) 5 2.46 (3H, s), 3.91 (3H, s), 4.77 (2H, s), 6.85 (2H, dm, J = 7.6Hz), 7.12 (lH, t, J = 7.6Hz), 7.36 (3H, m), 7.47 (1H, td, J = 7.6 and 1.3Hz), 7.57 (lH, br.), 7.96 (1H, d, J = 7.6Hz)

Example 16

Ή-NMR (270 MHz, CDC1 3) 8 2.45 (3H, s), 3.90 (3H, s), 4.73C2H, s), 6.78 (2H, dm, J = 8.6Hz), 7,26 (2H, dm , J = 8.6 Hz), 7.34 (1H, td, J = 7.6 and 1.3 Hz), 7.46 (1H, td, J = 7.6 and 1.6), 7.54 (lH, br.), 7.96 (1H, d, (J = 7.3Hz)

Example 17

Ή-NMR (270 MHz, CDC1 3) δ 2.43 (3H, s), 3.79 (3H, s), 3.91 (3H, s), 4.74 (2H, s), 6.82 (4H, ra), 7.33 (1H, td, J = 7.6 and 1.3Hz), 7.45 (1H, td, J = 7.6 and 1.3Hz), 7.60 (lH, br.), 7.96 (lH, d, J = 7.6Hz)

Example 18

Ή-NMR (270 MHz, CDC1 3) δ 2.48 (3H, s), 3.90 (3H, s), 4.76 (2H, s), 7.20 (2H, m), 7.35 (1H, td, J = 7.6 and 1.3 Hz), 7.47 (1H, td, J = 7.6 and 1.3Hz), 7.54 (1H, br.), 7.97 (1H, br.d, J = 7.6Hz), 8.16 (1H, d, J = 1.6Hz) ), 8.32 (1H, dd, J = 5.6 and 1.6Hz)

Ή-NMR (270 MHz, CDCl ^) 5 1.25 (6H, br.), 2.29 (3H, s), 3.68 (lH, m), 3.87 (3H, s), 4.70 (2H, s), 6.72 (2H , br.d, J = 7.9Hz), 7.12 (2H, br.d, J = 7.9Hz), 7.28 (1H, t, J = 7 • 6Hz), 7.40 (1H, t, J = 7.6), 7.53 (1H, br.), 7.91 (1H, br.d, J = 7.6Hz) Example 20

'Η- NMR (270 MHz, CDC1 3) δ 0.87 (3H, t, J = 6.9Hz), 1.21 (10H, m), 1.52 (2H, m), 2.3 2 (3H, s), 2.96 (2H, m), 3.90 (3H, s), 4.73 (2H, s), 6.74 (2H, dm, J = 8.0Hz), 7.11 (2H, dm, J = 8.0Hz), 7.32 (1H, td, J = 7.6Hz) And 1.3Hz), 7.44 (1H, td, J = 7.6 and 1.5Hz), 7.56 (lH, br.), 7.94 (1Η, br.d,

Example 2 1

Ή-NMR (270 MHz, CDC1 3) δ 2.30 (3H, s), 3.88 (3H, s), 4.21 (2H, br.), 4.73 (2H, br.), 6.72 (2H, dm, J = 7.9 Hz), 7.09 (2H, dm, J = 7.9Hz), 7.25 (5H, m), 7.32 (1H, t, J = 7.6Hz), 7.43 (lH, t, J = 7.6Hz), 7.54 (1H, br.), 7.93 (1H, br.d, J = 7.6Hz)

Example 22

Ή-NMR (270 MHz, CDC1 3) δ 0.21 (2H, m), 0.53 (2H, m), 0.98 (lH, m), 2.32 (3H, s), 2.95 (2H, m), 3.90 (3H, s), 4.73 (2H, br.), 6.76 (2H, dm, J = 8.1Hz), 7.12 (2H, dm, J = 8.1Hz), 7.32 (lH, td, J = 7.6 and 1.3Hz), 7.44 (1H, td, J = 7.6 and 1.5Hz), 7.56 (1H, br.), 7.94 (lH, br.d, J = 7.6Hz)

Example 23

'H-NMR (270 MHz, CDC1 3) δ 1.43-1.80 (6H, m), 2.06 (2H, m), 2.32 (3H, s), 3.77 (1H, m), 3.90 (3H, s), 4.73 (2H, s), 6.74 (2H, dm, J = 8.1Hz), 7.11 (2H, dm, J = 8.1Hz), 7.31 (lH, td, J = 7.6 and 1.3Hz), 7.44 (1H, td, J = 7.6 and 1.5Hz), 7.56 (1H, br.), 7.94 (lH, br.d, J = 7.6Hz)

Example 24

Ή-NMR (270 MHz, CDC1 3) δ 2.31 (3H, s), 3.21 (2H, m), 3.32 (3H, s), 3.55 (2H, s), 3.90 (3H, s), 4.73 (2H, s), 6.74 (2H, dm, J = 8.2Hz), 7.11 (2H, dm, J = 8.2Hz), 7.29 (1H, td, J = 7.6 and 1.3Hz), 7.44 (lH, td, J = 7.6Hz) And 1.4Hz), 7.54 (1H, br.), 7.94 (1H, br.d, J = 7.6Hz)

Example 25

Ή - (. 2H, br) (. LH, br) NMR (270 MHz, CDC1 3) 8 2.31 (3H, s), 3.70, 3.88 (3H, s), 4.71 (2H, s), 5.51, 6.75 ( 2H, dm, J = 8.2Hz), 6.95 (1H, br.), 7.11 (2H, dm, J = 8.2Hz), 7 .33 (lH, m), 7.44 (2H, m), 7.94 (1H, br. D, J = 7.6Hz)

Example 26

Ή-NMR (270 MHz, CDC1 3) δ 1.28 (3H, br.), 1.50-2.03 (4H, m), 2.30 (3H, s), 2.83- 3.32 (4H, m), 3.61 (2H, br) , 4.42 (2H, s), 6.71 (2H, dm, J = 8.2Hz), 7.08 (2H, br.d, J = 8.2Hz), 7.22-7.68 (4H, m) Compounds can be produced.

Example HPLC retention time (min) MS (M + H ⁺ )

、COOH

, COOH

Example HPLC retention time (min) MS (M + H ⁺ )

HPLC conditions

 Column YMC Comb i Screen ODS-A (50 x 4.6 thigh I.DS-5 mM, 120 A) Detection wavelength 220 nm

 Flow rate 3.5 ml I min

 Solvent B 40% 0.5min; from 40% B to 99% B 3.7min; B 99% 0

.5mm (Solution A: 0.05% trifluoroacetic acid / water, Solution B: 0.035% trifluoroacetic acid / acetonitrile)

 MS condition

 Mass spectrometer: PE Sciex API150EX

 Measurement range: Mw 200-700

 Positive Mode, Electrospray method (ESI method) Example 45

 S—Methyl S ′ — 3— (0-Methoxycarbonylphenyl) -1-2-propene-1-yl N—p—Tolyldithio

 1) 3-(o-Methoxycarbonylphenyl) propenoic acid

 Under a nitrogen stream, a solution of methyl 2-bromobenzoic acid (1.50 g, 5.72 mmol) in toluene (5.0 ml) was mixed with acrylic acid (0.80 ml, 11.7 ol), tributylamine (2.80 m 1, 11.8 mmol), Palladium acetate (70 mg, 0.312 bandol) and tree 0-tolylphosphine (190 mg, 0.624 mmol) were added, and the mixture was stirred at 110 ° C for 2 hours. After returning to room temperature, 2N aqueous hydrochloric acid (2.0 ml) was added, and the mixture was cooled with ice. The precipitated solid was collected by filtration to give the title compound (862 mg, 73%).

Ή-NMR (270 MHz, CDC1 3) δ 8.57 (d, 1H, J = 15.8 Hz), 7.98 (dd, 1H, J = 1.4, 7.6 Hz), 7.64 (dd, 1H, J = 1.4, 7.6 Hz) , 7.56 (ddd, 1H, J = 1.4, 7.6, 7.6 Hz), 7.47 (dd, 1H, J = 1.4, 7.6, 7.6 Hz), 6.33 (d, 1H, J = 15.8 Hz), 3.95 (s, 3H)

2) 3— (o-Methoxycarbonylphenyl) propene

To a suspension of 3- (o-methoxycarbonylphenyl) propenoic acid (750 mg, 3.64 mmol) in THF (7.0 ml) was added triethylamine (0.56 ml, 4.02 mmol) under a nitrogen stream. The mixture was cooled to 0 ° C, and ethyl chloroformate (0.38 ml, 3.99 mmol) was added dropwise, followed by stirring for 30 minutes. The solid was filtered to remove the solid, and water (2.0 ml) was added. Cool to 0 ° C and water Sodium borohydride (292 mg, 7.71 awake ol) was added and stirred for 1 hour. 1N aqueous hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate and water, and dried over magnesium sulfate. The solvent was distilled off, and the residue was purified by a silica gel column (hexane I-ethyl acetate = 1: 1) to obtain the title compound (481 mg, 69%).

Ή-NMR (270 MHz, CDC1 3) δ 7.89 (dd, 1H, J = 1.3, 7.8 Hz), 7.57 (dd, 1H, J = 1.3, 7.8 Hz), 7.48 (ddd, 1H, J = 1.3, 7.8 , 7.8 Hz), 7.39 (d, 1H, J = 15.8 Hz), 7.31 (ddd, 1H, J = 1.3, 7.8, 7.8 Hz), 6.27 (dt, 1H, J = 15.8, 5.7 Hz), 4.35 (d, 2H, J = 5.7 Hz), 3.90 (s, 3H) 3) S—3— (o-methoxycarbonylphenyl) -12-propene-1-yl N—p—tolyldithiocarbamate G

 Under a stream of nitrogen, a solution of 3- (o-methoxycarbonylphenyl) propene-1-ol (212 mg, 1.10 mraol) in methylene chloride (5.0 ml) was added to carbon tetrabromide (380 mg, 1.15 rnmol), Triphenylphosphine (300 mg, 1.14 mmol) was added, and the mixture was stirred at room temperature for 10 minutes. The solvent was distilled off, and the residue was purified by a silica gel column (hexane I-ethyl acetate = 10: 1) to obtain a Libromo compound (366 mg). After dissolving in THF (10 ml), the compound of Example 11 (310 mg, 1.09 mmol) was added, and the mixture was stirred at room temperature for 2 hours. Water was added, extracted with ethyl acetate, and dried over magnesium sulfate. The solvent was distilled off, and the residue was purified with a silica gel column (hexane I-ethyl acetate = 8: 1) to obtain the title compound (224 mg, 57%).

] _{H- NMR (270 MHz, CDC1 3} ) δ 8.80 (brs, 1Η), 7.86 (dd, 1Η, J = 1.2, 7.6 Hz), 7.53 (d, 1H, J 7,6 Hz), 7.18-7.47 ( m, 7H), 6.20 (dt, 1H, J = 15.8, 7.3 Hz), 4.18 (dd, 2H, J = 1.2, 7.3 Hz), 3.88 (s, 3H), 2.36 (s, 3H) 4) S_ Methyl S '— 3— (o-Methoxycarbonylphenyl) 1-2-Proben-1-yl N—p—Tolyldithiocarbonimidate

Under a stream of nitrogen, S—3— (o-methoxycarbonylphenyl) -1-propene To a DMF solution (2.5 ml) of 1-ylN-p-tolyldithiolrubamate (196 mg, 0.547 mmol) was added potassium carbonate (79.4 mg, 0.547 thigh ol) and methyl iodide (60 μ 1, 0.964 ol). The mixture was stirred at room temperature for 1 hour. Water and a 5% aqueous solution of potassium hydrogen sulfate were added, extracted three times with ethyl acetate-toluene, washed with water and a saturated saline solution, and dried over magnesium sulfate. The solvent was distilled off, and the residue was purified by a silica gel column (hexane / ethyl acetate = 10: 1) to obtain the title compound (176 mg, 87%).

Ή-NMR (270 MHz, CDC1 3) δ 7.87 (dd, 1H, J = 1.0, 7.9 Hz), 7.26-7.55 (m, 4H), 7.12 (d, 2H, J = 8.1 Hz),, 6.78 (d , 2H, J = 8.1 Hz), 6.18 (br, 1H), 3.93 (brs, 2H), 3.88 (s, 3H), 2.50 (s, 3H), 2.32 (s, 3H)

 S—Methyl S ′ — 3— (o-carboxyphenyl) -1-2-propene—1—yl N— p—tolyldithio

 To a solution of the compound of Example 45 (66.5 mg, 0.179 mmol) in THF (0.4 ml) -methanol (0.4 ml) was added a 2N aqueous sodium hydroxide solution (200 ^ 1, 0.400 mmol) under a nitrogen stream. The mixture was stirred at room temperature for 1 hour and at 0 ° C for 1 hour. The mixture was acidified with 1N hydrochloric acid, extracted with ethyl acetate, and dried over magnesium sulfate. The solvent was distilled off, and the residue was purified by a silica gel column (hexane I-ethyl acetate = 1: 1) to give the title compound (52.1 mg, 81%).

Ή-丽_{R (270 MHz, CDC1 3)} δ 8.03 (d, 1H, J = 7.3 Hz), 7.47-7.59 (m, 3H), 7.3 5 (ddd, 1H, J = 1.7, 7.3, 7.3 Hz), 7.12 (d, 2H, J = 8.1 Hz),, 6.79 (d, 2H, J = 8.1 Hz), 6.20 (br, 1H), 3.96 (brs, 2H), 2.51 (s, 3H), 2.31 (s , 3H) Example 47

 S—Methyl S ′ — 3— (o-Methoxycarbonylphenyl) propane— 1 —yl N—p—Tolyldithio

1) 3-(o-Methoxycarbonylphenyl) propane-1-ol Under a stream of nitrogen, to a solution of 3- (ο-methoxycarbonylphenyl) propene-1-ol (230 mg, 1.20 bandol) in methanol (5.0 ml) was added 10% palladium-carbon (39.9 mg). The mixture was replaced with hydrogen and stirred for 1 hour. After filtration through celite, the solvent was distilled off to obtain the title compound (198 _mg , 85%).

_{Ή- MR (270 MHz, CDC1 3} ) δ 7.88 (dd, 1H, J = 1.4, 7.7 Hz), 7.44 (ddd, 1H, J = 1.4, 7.7, 7.7 Hz), 7.23-7.30 (m, 2H), 3.90 (s, 3H), 3.62 (t, 2H, J = 5.9 Hz), 3.06 (t, 2H, J = 7.4 Hz), 2.26 (brs, 1H), 1.91 (tt, 2H, J = 5.9, 7.4 Hz) 2) S— 3— (o-methoxycarbonylphenyl) propane-1-yl N—p

 Example 4 In the same manner as in 5-3, the title compound (18.9 mg, 11%) was obtained from 3- (o-methoxycarbonylphenyl) butanol-1-ol (95.7 mg, 0.493 t). .

Ή-NMR (270 MHz, CDC1 3) δ 8.71 (brs, 1H), 7.88 (dd, 1H, J = 1.5, 7.8 Hz), 7.42 (ddd, 1H, J = 1.5, 7,8, 7.8 Hz), 7.11-7.33 (m, 6H), 3.87 (s, 3H), 3.34 (t, 2H, J = 7.4 Hz), 3.06 (t, 2H, J = 7.8 Hz), 2.36 (s, 3H), 2.02 (tt, 2H, J = 7.4, 7.8 Hz) 3) S-Methyl S'-3-(o-Methoxycarbonylphenyl) propane-1- 1-yl N-p-tolyldithiocarbonimidate

 Example 4 In the same manner as in 5-4, the title compound (18.4 mg, S--3- (o-methoxycarbonylphenyl) propane-1-yl N-p-tolyldithio-potambamate (18.7 mg, 0.0520 mmol) was obtained in the same manner as in 5-4. 95%).

Ή-NMR (270 MHz, CDC1 3) δ 7.88 (dd, 1H, J = 1.4, 7.7 Hz), 7.42 (ddd, 1H, J = 1.4, 7.7, 7.7 Hz), 7.23-7.28 (m, 2H), 7.11 (d, 2H, J = 8.1 Hz), 6.76 (d, 2H, J = 8.1 Hz), 3.87 (s, 3H), 3.02-3.08 (m, 4H), 2.48 (s, 3H), 2.32 ( s, 3H), 2.00 (m, 2H) Example 4 8

 S—Methyl S ′ — 3— (o-carboxyphenyl) propane 1 1 —yl—N—p-tolyldithio

 In the same manner as in Example 46, the title compound (.O mg, quant.) Was obtained from the compound of Example 47 (17.0 mg, 0.0455 nunol).

Ή-NMR (270 MHz, CDC1 3) δ 8.04 (dd, 1H, J = 1.4, 7.9 Hz), 7.48 (ddd, 1H, J = 1.4, 7.9, 7.9 Hz), 7.26-7.33 (m, 2H), 7.11 (d, 2H, J = 7.8 Hz), 6.76 (d, 2H, J = 7.8 Hz), 3.13 (m, 4H), 2.48 (s, 3H), 2.30 (s, 3H), 2.00-2.08 (m , 2H) Example 4 9

 S _methyl S '-3-(3-pyridyl) — 2-propene — 1 —yl _N— p—

 1) 3-(3 -pyridyl) 1-2-propene-1 all

 Triethylamine (1.05 ml, 7.53 mmol) was added to a THF solution (10 ml) of 3-pyridylacrylic acid (1.00 g, 6.70 mmol) under a nitrogen stream. The mixture was cooled to 0 ° C, and ethyl chloroformate (0.70 ml, 7.35 mmol) was added dropwise, followed by stirring for 30 minutes. The solid was removed by filtration, and water (4.0 ml) was added. The mixture was cooled to 0 ° C, sodium borohydride (530 mg, 14.0 mmol) was added, and the mixture was stirred for 1 hour. Water was added, extracted with ethyl acetate, and dried over magnesium sulfate. The solvent was distilled off and the residue was dissolved in methanol (10 ml) and heated under reflux for 4 hours. The solvent was distilled off, and the residue was purified by a silica gel column (hexane I: ethyl acetate = 1: 1 → 0: 1) to obtain the title compound (480 mg, 53%).

_{- NMR (270 MHz, CDC1 3} ) δ 8.59 (d, 1H, J = 1.9 Hz), 8.46 (dd, 1H, J = 1.9, 4.6 Hz), 7.70 (ddd, 1H, J = 1.9, 1.9, 7.8 Hz ), 7.25 (dd, 1H, J = 4.6, 7.8 Hz), 6.62 (d, 1H, J = 16.1 Hz), 6.44 (dt, 1H, J = 16.1, 5.2 Hz), 4.36 ( d, 2H, J = 5.2 Hz), 2.47 (brs, 1H)

2) S-3- (3-pyridyl) —2-propene-1-yl N—p—tolyldithiocarbamate

Under a nitrogen stream, a solution of 3- (3-pyridyl) -2-propen-1-ol (136 _mg , 1.00 ol) in methylene chloride (5.0 ml) was mixed with carbon tetrabromide (350 mg, 1.05 ol). ) And trifenylphosphine (270 mg, 1.03 minol) were added, and the mixture was stirred at room temperature for 10 minutes. Further, the compound of Example 1-1 (620 mg, 2.18 mmol) was added and left overnight. Water was added, extracted with ethyl acetate, and dried over magnesium sulfate. The solvent was distilled off, and the residue was purified by a silica gel column (hexane I ethyl acetate = 3: 1 → 2: 1 → 1: 1) to obtain the title compound (95.5 mg, 32%).

Ή-NMR (270 MHz, CDC1 3) δ 8.88 (brs, 1H), 8.56 (d, 1H, J = 1.8 Hz), 8.46 (dd, 1H, J = 1.8, 4.9 Hz), 7.67 (ddd, 1H, J = 1.8, 1.8, 7.9 Hz), 7.19-7.30 (m, 5H), 6.60 (d, 1H, J = 15.8 Hz), 6.36 (dt, 1H, J = 15.8, 7.3 Hz), 4.17 (d, 2H, J = 7.3 Hz), 2.37 (s, 3H)

3) S—Methyl S ′ — 3— (3-Pyridyl) — 2-Propene-1 —yl N— P—Tolyldithio

 Example 4 In the same manner as in 5-4, the title compound (15.5 mg, 24) was obtained from S-3- (3-pyridyl) -2-propene-1-ylN-p-tolyldithiolbamate (62.0 rag, 0.206 mmol). %).

Ή-NMR (270 MHz, CDC1 3) δ 8.57 (d, 1H, J = 1.8 Hz), 8.47 (dd, 1H, J = 1.8, 4.9 Hz), 7.67 (ddd, 1H, J = 1.8, 1.8, 7.9 Hz), 7.23 (dd, 1H, J = 4.9, 7.9 Hz), 7.13 (d, 2H, J = 8.4 Hz), 6.77 (d, 2H, J = 8.4 Hz), 6.58 (d, 1H, J = 15.8 Hz), 6.37 (br, 1H), 3.92 (brs, 2H), 2.50 (s, 3H), 2.33 (s, 3H) Example 50 S-methyl S '_ 6-quinolylmethyl N-p-tolyldithio

 1) 6-Hydroxymethylquinoline

 Example 4 In the same manner as in 9-11, the title compound (483 mg, 75%) was obtained from 6-quinoline carboxylic acid (700 mg, 4.04 mol).

Ή-NMR (270 MHz, CDC1 3) δ 8.89 (dd, 1H, J = 1.8, 4.3 Hz), 8.15 (dd, 1H, J = 1.8, 8.2 Hz), 8.09 (d, 1H, J = 8.7 Hz) , 7.81 (s, 1H), 7.71 (d, 1H, J = 8.7 Hz), 7.41 (dd, 1H, J = 4.3, 8.2 Hz), 4.91 (d, 2H, J = 5.0 Hz), 2.15 (brt, (1H, J = 5.0 Hz)

2) S_ 6—Quinolylmethyl N_p—Tolyldithiolbamate

 Under a nitrogen stream, a solution of 6-hydroxymethylquinoline (174 mg, 1.09 mmol) in methylene chloride (5.0 ml) was ice-cooled. Carbon tetrabromide (370 mg, 1.16 mmol), triphenyl phosphine (300 mg, 1.14 mmol) ) Was added and stirred for 5 minutes. Further, the compound of Example 1-1 (330 mg, 1.16 t ol) was added, and the mixture was stirred on ice for 2 hours. The solvent was distilled off, and the residue was purified by a silica gel column (hexane I-ethyl acetate = 1: 1) to give the title compound (259 mg, 73%).

Ή-NMR (270 MHz, CDC1 3) δ 9.02 (brs, 1H), 8.88 (dd, 1H, J = 1.9, 4.2 Hz), 8.10 (dd, 1H, J = 1.9, 8.4 Hz), 8.03 (d, 1H, J = 8.7 Hz), 7.81 (s, 1H), 7.69 (d, 1H, J = 8.7 Hz), 7.38 (dd, 1H, J = 4.2, 8.4 Hz), 7.30 (m, 2H), 7.18 (d, 2H, J = 8.3 Hz), 4.75 (s, 2H), 2.34 (s, 3H)

3) S_methyl S '— 6-quinolylmethyl N-p-tolyldithiocarbonate

In a nitrogen stream, potassium carbonate (102 mg, 0.738 mmol) was prepared in a DMF solution (4.0 ml) of S-6-quinolylmethyl N-p-tolyldithiolbamate (220 mg, 0.678 mmol), and 1.61N methyl iodide was prepared. (420 ^ 1, 0.676 mmol) Then, the mixture was stirred at room temperature for 2 hours. Water was added, extracted three times with ethyl acetate-toluene, washed with water, and dried over magnesium sulfate. The solvent was distilled off, and the residue was purified by a silica gel column (hexane I-ethyl acetate = 2: 1) to obtain the title compound— (202 mg, 88%).

Ή-NMR (270 MHz, CDC1 3) δ 8.89 (dd, 1H, J = 1.7, 4.3 Hz), 8.11 (dd, 1H, J = 1.7, 8.4 Hz), 8.06 (d, 1H, J = 8.9 Hz) , 7.80 (brs, 1H), 7.73 (br, 1H), 7.39 (dd, 1H, J = 4.3, 8.4 Hz), 7.12 (d, 2H, J = 8.3 Hz), 6.76 (d, 2H, J = 8.3) Hz), 4.49 (brs, 2H), 2.47 (brs, 3H), 2.32 (s, 3H)

Example 5 1

 ,

S—Methyl S′—2-Quinolylmethyl N—p—Tolyldithiol

 1) 2-Hydroxymethylquinoline

 Example 4 In the same manner as in 91-11, the title compound (1.57 g, 74%) was obtained from quinaldic acid (2.00 g, 13.4 mmol).

Ή-NMR (270 MHz, CDC1 3) δ 8.15 (d, 1H, J = 8.4 Hz), 8.08 (d, 1H, J = 7.9 H z), 7.83 (d, 1H, J = 7.9 Hz), 7.73 ( dd, 1H, J = 7.9, 7.9 Hz), 7.55 (dd, 1H, J = 7.9, 7.9 Hz), 7.29 (d, 1H, J = 8.4 Hz), 4.93 (d, 2H, J = 4.6 Hz) , 4.46 (t, 1H, J = 4.6 Hz)

2) S—2-quinolylmethyl N—p—tolyldithiolbamate

 In the same manner as in Example 50-2, the title compound (439 mg, 72%) was obtained from 2-hydroxymethylquinoline (300 mg, 1.88 tmol).

Ή-NMR (270 MHz, CDC1 3) δ 12.54 (brs, 1H), 8.22 (d, 1H, J = 8.3 Hz), 7.92 (d, 1H, J = 8.0 Hz), 7.85 (d, 1H, J = 8.0 Hz), 7.73 (dd, 1H, J = 8.0, 8.0 Hz), 7.53-7.59 (m, 3H), 7.45 (d, 1H, J = 8.3 Hz), 7.21-7.26 (m, 2H), 4.55 (brs, 2H), 2.38 (s, 3H) 3) S-methyl S '— 2-quinolylmethyl N-p-tolyldithiocarbonate

In the same manner as in Example 50-3, the title compound (195 mg, 60%) was obtained from S-2-quinolylmethyl N_p-tolyldithiocarbamate (314 _mg , 0.968 mraol).

Ή-NMR (270 MHz, CDC1 3) δ 8.10 (d, rivers, J = 8.9 Hz), 8.06 (d, 1H, J = 8.0 H z), 7.79 (d, 1H, J = 8.0 Hz), 7.70 ( dd, 1H, J = 8.0, 8.0 Hz), 7.49-7.58 (m, 2H), 7.13 (d, 2H, J = 8.4 Hz), 6.78 (d, 2H, J = 8.4 Hz), 4.66 (brs, 2H ), 2.49 (s, 3H), 2.32 (s, 3H)

 S-Methyl-1-3-quinolylmethyl N-p-tri _ ^] / dithiocarbonimide

 1) 3-Hydroxymethylquinoline

 Example 4 In the same manner as in 91-11, the title compound (178 mg, 19%) was obtained from 3-quinolinecarboxylic acid (1.00 g, 5.77 ol).

Ή-NMR (270 MHz, CDC1 3) δ 8.85 (d, 1H, J = 2.1 Hz), 8.13 (d, 1H, J = 2.1 H z), 8.09 (d, 1H, J = 7.8 Hz), 7.80 ( d, 1H, J = 7.8 Hz), 7.69 (dd, 1H, J = 7.8, 7.8 Hz), 7.54 (dd, 1H, J = 7.8, 7.8 Hz), 4.91 (s, 2H), 2.97 (brs, 1 H)

2) S—3-quinolylmethyl N—p—tolyldithiolbamate

 In the same manner as in Example 50-2, the title compound (172 mg, 54%) was obtained from 3-hydroxymethylquinoline (157 mg, 0.986 ol).

'Η - NMR (270 MHz, CDC1 3) δ 8.90 (d, 1H, J = 2.3 Hz), 8.16 (d, 1H, J = 2.3 H z), 8.07 (d, 1H, J = 7.9 Hz), 7.78 (d, 1H, J = 7.9 Hz), 7.68 (dd, 1H, J = 7.9, 7.9 Hz), 7.53 (dd, 1H, J = 7.9, 7.9 Hz), 7.26 (m, 2H), 7.19 (d, 2H, J = 8.3 Hz), 4.74 (s, 2H), 2.35 (s, 3H)

3) S-methyl S '— 3-quinolylmethyl N-p-tolyldithiocarbonate

In the same manner as in Example 50-3, the title compound (111 mg, 97%) was obtained from S-3-quinolylmethyl N-p-tolyldithiocarbamate (110 _mg , 0.339 mmol)-丽 R (270 MHz) _{, CDC1 3) δ 8.92 (brs} , 1H), 8.14 (brs, 1H), 8.09 (d, 1H, J = 7.8 Hz), 7.78 (d, 1H, J = 7.8 Hz), 7.70 (dd, 1H, J = 7.8, 7.8 Hz), 7.55 (dd, 1H, J = 7.8, 7.8 Hz), 7.13 (d, 2H, J = 8.3 Hz), 6.75 (d, 2H, J = 8.3 Hz), 4.47 (brs, 2H ), 2.46 (brs, 3H), 2.32 (s, 3H)

 S-methyl S '— 3— (p-chloro-o-methoxycarbonylphenyl) propane-1-yl N—p-tolyldithio

 For the manufacturing method and the like, see Example 54 in the next section. Example 54

S—Methyl S ′ — 3— (p-Chloro-o-methoxycarbonylphenyl) propene 1-yl N—p-tolyldithio

 1) 3— (p-chloro-o-methoxycarbonylphenyl) propenoic acid

Acrylic acid (0.82 ml, 12.0 mmol) and tributylamine (2.85 ml, 12.0 mmol) were added to a toluene solution (5.0 ml) of methyl 2-bromo-5-chlorobenzoic acid (1.50 g, 6.01 mmol) under a nitrogen stream. , Palladium acetate (70 mg, 0.312 ol) and tri_0-tolylphosphine (190 mg, 0.624 mmol) were added, and the mixture was stirred at 110 ° C for 2 hours. The temperature was returned to room temperature, 2N aqueous hydrochloric acid (3.0 ml) was added, and the mixture was cooled with ice. The precipitated solid is collected by filtration. And gave the title compound (1.06 g, 73%).

Ή - NMR (270 MHz, CDC1 3) δ 8.51 (d, 1H, J = 15.8 Hz), 7.97 (d, 1H, J = 1.8 Hz), 7.58 (d, 1H, J = 8.3 Hz), 7.53 (dd , 1H, J = 1.8, 8.3 Hz), 6.32 (d, 1H, J = 15.8 Hz), 3.96 (s, 3H)

2) S-Methyl S'-3-(p-Chloro-o-methoxycarbonylphenyl) propane-1-yl N-p-tolyldithio-one and S-methyl S'-3- (p- Chloro-o-methoxycarbonylphenyl) 1-2-propene 1-yl N-p-tolyldithio

 To a solution of 3- (p-chloro-o-methoxycarbonylphenyl) propenoic acid (917 mg, 3.81 mmol) in THF (8.0 ml) under ice-cooling under ice-cooling, triethylamine (0.58 ml, 4.16 mmol), chloroform Ethyl acid (0.40 ml, 4.20 mmol) was added and stirred for 1 hour. The solid was filtered to remove the solid, and water (2.0 ml) was added. The mixture was cooled to 0 ° C, sodium borohydride (310 mg, 8.19 mmol) was added, and the mixture was stirred for 1 hour. 1N hydrochloric acid was added, extracted with ethyl acetate, washed with water, and dried over magnesium sulfate. The solvent was distilled off, and the residue was purified by a silica gel column (hexane I-ethyl acetate = 1: 1) to give 3- (p-chloro-o-methoxycarbonisolephenyl) propene (1- and 3-). A 1.2: 1.0 mixture (470 mg, 54%) of (p-chloro-o-methoxycarbonylphenyl) propane-1-1-ol was obtained.

Under a nitrogen stream, to a methylene chloride solution (5.0 ml) of this mixture (220 mg, 0.971 mmol) were added carbon tetrabromide (330 mg, 0.995 mmol) and triphenylphosphine (263 mg, 1.00 mmol) under ice-cooling. The mixture was stirred at room temperature for 5 minutes. The solvent was distilled off, and the residue was purified with a silica gel column (hexane I-ethyl acetate = 10: 1) to obtain a rib-end product. The compound was dissolved in methylene chloride (5.0 ml), the compound of Example 11 (280 mg, 0.984 mmol) was added, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off, and the residue was purified with a silica gel column (hexane I ethyl acetate = 8: 1) to give the coupled product S-3_ (p-chloro-1 0-methoxycarbonylphenyl) 1-2-propene-1. 1-yl N— p— There was obtained a mixture (230 mg, 60%) of tolyldithiolbamate and S-3- (p-chloro-o-methoxycarbonylphenyl) propane-1-ylN-p-tolyldithiolbamate.

Under a nitrogen stream, the mixture (230 mg, 0.587 s Awakening ol) in DM F solution (4.0 ml) of potassium carbonate (85.0 ra _g, 0.615 negation ol), while handling Methyl iodide (70μ 1, 1.12 mmol), The mixture was stirred at room temperature for 1 hour. Water and a 5% aqueous solution of potassium hydrogen sulfate were added, extracted three times with ethyl acetate-toluene, washed with water, and dried over magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel column (hexane I ethyl acetate = 25: 1 → 20: 1 → 15: 1) to obtain s-methyl S '— 3— (p-chloro-mono-methoxycarbonyl). Phenyl) propane-1-yl N-p-tolyldithio-butimidate (64.1 mg, 27%), S-methyl S '— 3— (p-chloro-o-methoxycarbonylphenyl) propene-1-yl N — P-Tolyldithio-imidone (26.0 mg, 11%) and a mixture thereof (100 mg, 42%) were obtained.

 S-Methyl S '— 3— (p-chloro-o-methoxycarbonylphenyl) propane— 1 —yl N— p—tolyldithio-potimimidone (Example 53)

Ή-NMR (270 MHz, CDC1 3) δ 7.86 (d, 1H, J = 2.3 Hz), 7.48 (d, 1H, J = 8.6 H z), 7.41 (dd, 1H, J = 2.3, 8.6 Hz), 7.34 (d, 1H, J = 15.8 Hz), 7.12 (d, 2H, J-8.2 Hz), 6.78 (d, 2H, J = 8.2 Hz), 6.17 (br, 1H), 3.90 (brs, 2H) , 3.88 (s, 3H), 2.50 (s, 3H), 2.32 (s, 3H)

S-Methyl S '— 3— (p-chloro-o-methoxycarbonylphenyl) propene 1-yl N— p _ tolyldithiocarbonimide (Example 54) Ή-丽 R ( _{270 MHz, CDC1 3) δ 7.87} (d, 1H, J 2.3 Hz), 7.38 (dd, 1H, J = 2.3, 8.2 Hz), 7.18 (brd, 1H, J = 8.2 Hz), 7.12 (d, 2H, J = 8.1 Hz), 6.75 (d, 2H, J = 8.1 Hz), 3.87 (s, 3H), 3.01 (m, 4H), 2.48 (s, 3H), 2.32 (s, 3H), 1.97 (m, 2H) Example 5 5 S—Methyl S ′ — 3— (p-Chloro-o-carboxyphenyl) 1-2-Probel-1-yl N—p—Tolyldithiocarbonimidate

 To a solution of the compound of Example 53 (18.2 mg, 0.0446 ol) in THF (0.2 ml) and methanol (0.2 ml) was added a 2N aqueous sodium hydroxide solution (40 μ1, 0.080 mmol) under a nitrogen stream, and the mixture was heated at 45 ° C. For 1 hour. The reaction solution was transferred to a 5% aqueous sodium hydrogen sulfate solution, extracted with ethyl acetate, and dried over magnesium sulfate. The solvent was distilled off, and the residue was purified by a silica gel column (hexane I-ethyl acetate = 3: 1 → 1: 1) to give the title compound (15.3 nig, 87%).

Ή-NMR (270 MHz, CDC1 3) δ 8.00 (d, 1H, J = 2.3 Hz), 7.44 (dd, 1H, J = 2.3, 8.3 Hz), 7.22 (d, 1H, J = 8.3 Hz), 7.11 (d, 2H, J = 8.1 Hz), 6.75 (d, 2H, J = 8.1 Hz), 3.08 (m, 4H), 2.48 (s, 3H), 2.31 (s, 3H), 2.00 (m, 2H) Example 56

 S—Methyl S ′ — 3— (p-Chloro-o-carboxyphenyl) propane-1-yl N— p—Tolyldithiocarbonimidate

 In the same manner as in Example 55, the title compound (39.6 ing, 89%) was obtained from the compound of Example 54 (46.4 mg, 0.114 mmol).

Ή-NMR (270 MHz, CDC1 3) δ 8.00 (d, 1H, J = 2.6 Hz), 7.40-7.53 (m, 3H), 7.1 2 (d, 2H, J = 8.2 Hz), 6.78 (d, 2H , J = 8.2 Hz), 6.19 (br, 1H), 3.93 (brs, 2H), 2.50 (s, 3H), 2.31 (s, 3H)

 S_Methyl S '— 3— (o-Methylaminocarbonylphenyl) — 2-Proben-1-yl N—p—Tolyldithio-

In a nitrogen stream, WSCI hydrochloride (23.0 mg, 0.120 mmol) was added to a DMF solution (1.0 ml) of the compound of Example 45-4 (39.8 _mg , 0.111 tmol) and 1-hydroxybenzotriazole (16.5 mg, 0.122 mmol). ), Triethylamine (40μ1, 0.287 mmol), methyl Lamine hydrochloride (8.80 mg, 0.130 ol) was added, and the mixture was stirred at room temperature for 1.5 hours, and left for 2 days. Water was added, extracted with ethyl acetate-toluene, washed with water, and dried over magnesium sulfate. The solvent was distilled off, and the residue was purified by a silica gel column (hexane I-ethyl acetate: = 3 _: ] → 2 _: 1 → 1: 1) to obtain the title compound (41.4 mg, quant.).

-丽_{R (270 MHz, CDC1 3)} δ 7.51 (d, 1H, J = 7.6 Hz), 7.34-7.45 (m, 2H), 7.2 6 (dd 1H, J = 7.6, 7.6 Hz), 7.12 (d, 2H, J = 8.2 Hz), 6.92 (d, 1H, J = 15.8 Hz), 6.77 (d, 2H, J = 8.2 Hz), 6.26 (br, 1H), 5.76 (brs, 1H), 3.89 ( br s, 2H), 2.93 (d, 3H, J = 4. GHz), 2.49 (s, 3H), 2.32 (s, 3H)

 S-Methyl S '-3 ^ (o-dimethylaminocarbonylphenyl) -1-2-propene-1-yl N-p-tolyldithio

 In the same manner as in Example 57, the title compound (32.1 mg, 86%) was obtained from the compound of Example 45-5 (34.9 mg, 0.0976 mmol) and dimethylamine hydrochloride.

JH-NMR (270 MHz, CDC1 3) δ 7.50 (d, 1Η, J = 6.9 Hz), 7.18-7.36 (m, 3H), 7.1 3 (d, 2H, J = 8.1 Hz), 6.78 (d, 2H , J = 8.1 Hz), 6.57 (d, 1H, J = 15.8 Hz), 6.28 (br, 1H), 3.87 (brs, 2H), 3.10 (s, 3H), 2.74 (s, 3H), 2.49 (s , 3H) '2.32 (s, 3H) Example 5 9

 S—Methyl S ′ — 3— (o—Lubamoylphenyl) 1—2-propene—1—yl N— p—Tolyldithio 1—

 In the same manner as in Example 57, the compound of Example 45-4 (40.7 mg, 0.114 ol) and the title compound of ammonium chloride (14.1 mg, 35%) were obtained.

Ή-NMR (270 MHz, CDC1 3) δ 7.50-7.57 (m, 2H), 7.41 (ddd, 1H, J = 1.4, 7.5, 7.5 Hz), 7.29 (ddd, 1H, J = 1.4, 7.5, 7.5 Hz ), 7.12 (d, 2H, J = 8.1 Hz), 7.03 (d, 1H, J = 15.5 Hz), 6.77 (d, 2H, J = 8.1 Hz), 6.25 (br, 1H), 5.79

(br, 2H), 3.90 (brs, 2H), 2.49 (s, 3H), 2.32 (s, 3H)

 S-Methyl S '— (4-Methoxy-2-phenyl) methyl N-p-Tolyldithiocarbonimide

 1) 3-Methyl 6-Methylbenzonitrile

NaCN (4.75 g) was added all at once with vigorous stirring to a suspension of CuCl (3.69 g) in water (10 ml). A large exotherm occurred and the suspension became a clear, pale gray solution. Stirring was continued for 10 minutes and the solution was cooled, forming a gray precipitate. 2 Aminokuro port toluene hydrochloride (5.31 g, 29.8 thigh ol) was suspended in 6 N hydrochloric acid cooled with ice (10 ml) and the solution reaction of water (6 ml) of NaN0 ₂ (2.16 g) in Re this The solution was dropped so that the temperature did not exceed 5 degrees. After completion of the dropwise addition, the mixture was stirred at 5 degrees for 10 minutes, and the pH was adjusted to 7 by adding solid sodium carbonate. At this time, the solution became a pale yellow suspension. Water (10 ml) and toluene (20 ml) were added to the previously prepared suspension of CuCl / NaCN, cooled to 0 ° C, and vigorously stirred. To this, a solution of diazonium salt cooled by a pipe was added dropwise so that the reaction temperature did not exceed 5 ° C. At this time, a reddish brown precipitate was formed from the reaction solution. After completion of the dropwise addition, stirring was continued at 5 ° C for 30 minutes and at room temperature for 2 hours. The mixture was warmed once to 50 ° C., cooled again to room temperature, and extracted three times with 1: 1 toluene monoethyl acetate (100 ml). The organic layers were combined, dried over magnesium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (50: 1 ethyl hexane monoacetate) to obtain the title compound (2.25 g) in a yield of 50%.

'Eta -丽_{R (270 MHz, CDC1 3)} δ 7.57 (d, 1 H, J = 2.3), 7.45 (dd, 1 H, J = 8.3, 2.3 Hz), 7.26 (d, 1 H, J = 8.3 Hz), 2.52 (s, 3 H).

2) 3-—Mouth—6-Methylbenzoic acid

Ethylene glycol of 3-chloro-6-methylbenzonitrile (1.0 g, 6.62 thigh ol) To a solution of sodium hydroxide (10 ml) was added solid sodium hydroxide (1.06 g) and water (about 5 drops). The solution was stirred at 200 ° C. for 2 hours and then cooled to room temperature. The solution was ice-cooled and acidified with concentrated hydrochloric acid to pH 1. The formed gray solid was collected by filtration, washed with a large amount of water, and dried under reduced pressure to obtain the title compound (1.05 g) in a yield of 93%.

匪 -band R (270 MHz, DMS0-d ₆ ) δ 13.13 (brs, 1 H), 7.78 (d, 1 H, J = 2.3 Hz), 7.51 (dd, 1 H, J = 8.2, 2.3 Hz) ), 7.34 (d, 1 H, J = 8.2 Hz), 2.49 (s, 3 H).

3) Methyl 3-chloro-6-methylbenzoic acid

A suspension of 3-chloro-6-methylbenzoic acid (1.05 g, 6.16 ol) in IN HCl / MeOH (30 ml) was heated under reflux for 4 hours, cooled to room temperature, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (50: 1 hexane-ethyl acetate) to give the title compound (968 _mg ) as a colorless oil in a yield of 85%.

Ή-NMR (270 MHz, CDC1 3) δ 7.89 (d, 1 H, J = 2.3 Hz), 7.36 (dd, 1 H, J = 2. 3, 8.3 Hz), 7.17 (d, 1 H, J = 8.3 Hz), 3.90 (s, 3 H), 2.56 (s, 3 H).

4) S-Methyl S '— (4-Chloro-2-methoxycarbonylphenyl) methyl N-p-Tolyldithio-imidone

 The title compound was obtained from methyl 3-chloro-6-methylbenzoic acid in the same manner as in Example 1.

Ή-NMR (270 MHz, CDC1 3) δ 7.94 (d, 1 H, J = 2.0 Hz), 7.53 (d, 1 H, J = 8.2 Hz), 7.40 (dd, 1 H, J = 2.0, 8.2 Hz ), 7.12 (d, 2 H, J = 7.9), 6.73 (d, 2 H, J = 7.9 Hz), 4.69 (brs, 2 H), 3..91 (s, 3 H), 2.43 (brs, 3H), 2.32 (s, 3H).

S-Methyl S '-(4-chloro-2-carboxyphenyl) methyl N-p-tolyldithio-bonimidate In the same manner as in Example 2, the title compound was obtained from S-methyl S '-(4-chloro-2-methoxycarbonylphenyl) methyl N-p-tolyldithiocarbonimidate.

Ή-NMR (270 MHz, DMS0-d ₆ ) 8 7.78 (brs, 1 H), 7.40 (d, 1 H, J = 8.2 Hz), 7.33 (dd, 1 H, J = 2.0, 8.2 Hz) , 7.11 (d, 2 H, J = 7.9 Hz). 6.69 (d, 2 H, J = 7.9 Hz), 4.77 (s, 2 H) 2.41 (brs, 3 H), 2.26 (s, 3 H). Example 6 2

 S-Methyl S '— (2-chloro-6-methoxycarbonylphenyl) methyl N-p-tolyldithiocarbonimide

 1) 3-chloro-2-methylbenzonitrile

 As in Example 60-1, the title compound (2.26 g) was obtained as a red oil from 49-amino-6-chloro-toluene (4.28 g, 30.2 bandol) in a yield of 49% as a red oil.

Ή-NMR (270 MHz, CDC1 3) δ 7.57 (d, 1 H, J = 8.9 Hz), 7.53 (d, 1 H, J = 7.6 Hz), 7.23 (dd, 1 H, J = 7.6, 8.9 Hz ), 2.60 (s, 3 H).

2) 3-chloro-2-methylbenzoic acid

 The title compound (978 mg) was obtained as a gray solid in 86% yield from 3-chloro-2-methylbenzonitrile (1.01 g, 6.65 mol) in the same manner as in Example 60-2.

-NMR (270 MHz, DMSO- d ₆ ) δ 13.15 (brs, 1 H), 7.68 (dd, 1 H, J = 7.6, 1.0 Hz), 7.61 (dd, 1 H, J = 7.9, 1.0 Hz), 7.30 (t, 1 H, J = 7.9 Hz), 2.52 (s, 3 H).

3) Methyl 3-methyl-2-methylbenzoic acid

 As in Example 60-3, the title compound (1054 mg) was obtained as a colorless oil in 100% yield from 3-chloro-2-methylbenzoic acid (978 rag, 5.72 thigh ol).

_{Ή- MR (270 MHz, CDC1 3} ) δ 7.70 (dd, 1 H, J = 1.3, 7.9 Hz), 7.50 (dd, 1 H, J = 1.3, 7.9 Hz), 7.17 (t, 1 H, J = 7.9 hz), 3.90 (s, 3 H), 2.60 (s, 3 H)

4) S-methyl S '— (2-chloro-6-methoxycarbonylphenyl) methyl N-p-tolyldithiocarbonimide

The title compound was obtained from methyl 3-chloro-2-methylbenzoic acid in the same manner as in Example 1.

Ή-NMR (270 MHz, CDC1 ;!) Δ 7.72 (dd, 1 H, J = 1.3, 7.9 Hz), 7.54 (d, 1 H, J = 7.90 Hz), 7.26 (t, 1 H, J = 7.9 Hz), 7.10 (d. 2 H, J = 8.2 Hz), 6.75 (d, 2 H, J = 8.2 Hz), 4.87 (s, 2 H), 3.78 (s, 3 H), 2.45 (s, 3 H), 2.31 (s, 3H).

 S-Methyl S '— (2-chloro-6-carboxyphenyl) methyl N-p-tolyldithiocarbonimide

In the same manner as in Example 2, the title compound was obtained from S-methyl S '-(2-chloro-6-methoxycarbonylphenyl) methyl N-p-tolyldithiocarbonimidate.

Ή-NMR (270 MHz, DMS0-d ₆ ) δ 7.77 (dd, 1 H, J = 7.9, 1.3 Hz), 7.69 (d, 1 H, J = 7.9 Hz), 7.43 (t, 1 H, J = 7.9 Hz), 7.11 (d, 2 H, J = 7.9 Hz), 6.70 (d, 2 H, J = 7.9 Hz), 4.84 (s, 2 H), 2.44 (s, 3 H), 2.25 (s, 3H). Example 64

S—Methyl S ′ — (3-Methoxy-2-ethoxycarbonylphenyl) methyl N—p—Trinoresitio force—The title compound was prepared from ethyl 2-methoxy-6-methylbenzoic acid in the same manner as in Example 1. Obtained. Ή-NMR (270 MHz, CDC1 3) δ 7.29 (t, 1 H, J = 7.9 Hz), 6.95 - 7.15 (m, 3 H), 6.85 (d, 1 H, J = 7.9 Hz), 6.76 (d , 2 H, J = 7.9 Hz), 4.40 (q, 2 H, J = 7.3 Hz), 4.35 (brs, 2 H), 3.82 (s, 3 H), 2.45 (s, 3 H), 2.31 (s , 3 H), 1.38 (t, 3 H, J = 7.3 Hz).

S-Methyl S '-(3-Methoxy-2-carboxyphenyl) methyl N- _P- Tolyldithiocarbonimide

In the same manner as in Example 2, the title compound was obtained from S-methyl S '-(3-methoxy-2-ethoxycarbonylphenyl) methyl N-p-tolyldithiocarbonimidate.

 Ή-NMR (270 MHz, CDC 13) δ 7.28 (brd, 1 H, J = 7.9 Hz), 7.19 (brt, 1 H, J = 7.9 Hz), 7.07 (d, 2 H, J = 7.9 Hz), 6.82 (brd, 1 H, J = 7.9 Hz), 6.65 (d

, 2 H, J = 7.9 Hz), 4.45 (brs, 2 H), 3.84 (brs, 3 H), 2.39 (s, 3 H), 2.30 (s, 3 H).

 S-Methyl S '-(4-Trifluoromethyl-2-methoxycarbonylphenyl) Methyl N-p-Tolyldithio

 1) 2-Methyl-5-trifluoromethylbenzonitrile

 The title compound (2.11 g) was obtained using 2-methyl-5-trifluoromethylaniline (5.0 g) in the same manner as in Example 61-11.

 ΉReview R (270 MHz, CDC 13) δ 7.86 (s, 1 H), 7.74 (d, 1 H, J = 7.9 Hz), 7.48 (d, 1 H, 7.9 Hz), 2.63 (s, 3 H) .

2) Methyl 2-methyl-5-trifluoromethylbenzoic acid

In the same manner as in Example 60-2 and Example 60-3, 2-methyl-5-trifluoromethyl The title compound (835 mg) was obtained using tylbenzonitrile (1.02 g).

 Ή-NMR (270 MHz, CDC13) δ 8.18 (s, 1 H), 7.65 (dd, 1 H, J = 7.9, 1.7 Hz),

7.38 (d, 1 H, J = 7.9 Hz), 3.93 (s, 3 H), 2.67 (s, 3 H). 3) S—Methyl S ′ — (4-Trifluoromethyl—2-Methoxycarbonyl Phenyl) methyl N-p-tolyldithiocarbonimidate

 The title compound was obtained from methyl 2-methyl-5-trifluoromethylbenzoic acid in the same manner as in Example 1.

 NMR-NMR (270 MHz, CDC13) δ 8.22 (s, 1 H), 7.7-7.9 (m, 2 H), 7.13 (d, 2 H, J = 7.9 Hz), 6.73 (d, 2 H, J = 7.9 Hz), 4.77 (s, 2 H), 3.93 (s, 3 H), 2.43 (s, 3 H), 2.33 (s, 3 H).

 S-methyl S '-(4-trifluoromethyl-2-carboxyphenyl) methyl N-p-tolyldithiocarbonimide

 In the same manner as in Example 2, the title compound was obtained from S-methyl S '-(4-trifluoromethyl-12-methoxycarbonylphenyl) methyl N-p-tolyldithiocarbonimidate.

Ή-NMR (270 MHz, DMS0-d ₆ ) δ 8.14 (brs, 1 H), 7.62 (m, 2 H), 7.11 (d, 2 H, J = 7.9 Hz), 6.69 (d, 2 H, J = 7.9 Hz), 4.88 (brs, 2 H), 2.50 (brs, 3 H),

2.39 (s, 3 H). Example 68

 S-methyl S '― (2,4-dichloro-1-6-methoxycarbonylphenyl) tyl N- p-tolyldithio

 1) 4—Black mouth 2—Edo 6—Nitrotonoreen

Stir well in concentrated sulfuric acid (35 ml) at 0 ° C with N-dossuccinimide (13.77 g ) Was added. After stirring at 0 ° C for 40 minutes, a solution of 4-chloro-2-nitrotoluene (7.00 g, 40.8 diol) in concentrated sulfuric acid (50 ml) was slowly added, and added dropwise so that the reaction temperature did not exceed 5 ° C. . After completion of the dropwise addition, the reaction mixture was slowly returned to room temperature, poured into crushed ice, and extracted five times with ethyl acetate (150 ml). The organic layers were combined, dried over magnesium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (hexane) to obtain the title compound (10.21 g) as a pale yellow solid in a yield of 84%.

Ή-NMR (270 MHz, CDC1 3) δ 8.06 (d, 1 H, J = 2.0 Hz), 7.76 (d, 1 H, J = 2.0 Hz), 2.56 (s, 3 H).

2) Methyl 5-chloro-2-methyl-3-nitrobenzoic acid

 4-Chloro-2-aldehyde 6-nitrotoluene (200 mg, 0.67 ml), lime carbonate (372 mg), palladium acetate (1.5 mg) in a 2: 1 mixture of DMF and water (2.7 ml) And saturated with carbon monoxide. The mixture was stirred at room temperature for 4.5 hours under an atmosphere of 1 atm of carbon monoxide. During this time, the solution turned black. Water (10 ml) was added to the mixture, and the mixture was washed twice with ethyl acetate (10 ml). The aqueous layer was acidified and extracted twice with ethyl acetate (15 ml). The organic layers were combined, dried over magnesium sulfate, and concentrated under reduced pressure. IN HCl / MeOH (10 ml) was added to the residue, and the mixture was refluxed under heating for 2.5 hours, cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (20: 1 hexanemonoacetate) to give the title compound (92 mg) as a pale yellow oil in a yield of 60%.

One _{NMR (270 MHz, CDC1 3)} δ 7.99 (d, 1 H, J = 2.3 Hz), 7.85 (d, 1 H, J = 2.3

Hz), 3.95 (s, 3 H), 2.59 (s, 3 H).

3) Methyl 5-methyl-2-methyl-3-aminoaminobenzoic acid

To a solution of methyl 5-chloro-2-methyl-3-nitrobenzoic acid (587 mg) in methanol (20 ml) at 0 ° C was added a 20% aqueous solution of titanium trichloride (12.23 g), and the mixture was stirred at room temperature for 2 hours. did. The reaction mixture was extracted five times with a 1: 1 mixture of ethyl acetate and toluene (20 ml). did. The aqueous layer was concentrated under reduced pressure, made alkaline with aqueous ammonia, and extracted three times with ethyl acetate (60 ml). The combined organic layers were dried over magnesium sulfate and concentrated under reduced pressure to give the title compound (332 mg) as a pale yellow oil in a yield of 65%.

Ή-NMR (270 MHz, CDC1 3) δ 7.20 (d, 1 H, J = 2.3 Hz), 6.80 (d, 1 H, J = 2.3 Hz), 3.88 (s, 3 H), 2.30 (s, 3 H).

4) Methyl 3, 5-dichloro-2-methylbenzoic acid

 Methyl 5-chloro-2-methyl-3-aminobenzoic acid (332 mg, 1.66 mmol) was dissolved in acetonitrile, and tetrafluoroboronic acid (0.323 ml) was added dropwise thereto. The mixture was cooled to 0 ° C, and t-butyl nitrite (223 mg) was added dropwise thereto. The reaction mixture was stirred at 0 degrees for 30 minutes and cooled to 120 degrees. This was added to a stirred suspension of cuprous chloride (8.24 g) and cupric chloride (13.4 g) in water (50 ral) at 0 ° C. After the addition was completed, the temperature was returned to room temperature and stirring was continued for another 2.5 hours. Was. A 5% aqueous sodium bicarbonate solution was added to the reaction mixture, and the mixture was extracted four times with ethyl acetate (100 ml). The organic layers were combined, washed with saturated saline, dried over magnesium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (50: 1 ethyl hexane monoacetate) to give the title compound (283 mg) as colorless crystals in 78% yield.

■ H-NMR (270 MHz, CDC1 3) δ 7.70 (d, 1 H, J = 2.3 Hz), 7.52 (d, 1 H, J = 2.3 Hz), 3.91 (s, 3 H), 2.56 (s, 3 H).

5) S-Methyl S '-(2,4-dichloro mouth-6-Methoxycarbonylphenyl) methyl N-p-tolyldithio-imidone

 The title compound was obtained from methyl 3,5-dichloro-2-methylbenzoic acid in the same manner as in Example 1.

Ή-NMR (270 MHz, CDC1 3) δ 7.70 (brd, 1 H, J = 2.0 Hz), 7.55 (s, 1 H), 7.11 (d, 2 H, J = 7.9 Hz), 6.72 (d, 2 H, J = 7.9 Hz), 4.82 (brs, 3H), 2.43 (brs, 3H), 2.31 (s, 3H). Example 6 9

 S-methyl S '-(2,4-dichloro-6-carboxyphenyl) methyl N-p-tolyldithiocarbonimide

 Similarly to Example 2, the title compound was obtained from S-methyl S '-(2,4-dichloro-6-methoxycarbonylcarbonyl) methyl N-p-tolyldithio-butimidate.

Ή-NMR (270 MHz, DMS0-d ₆ ) δ 7.59 (s, 1 H), 7.51 (s, 1 H), 7.10 (d, 2 H, J = 7.6 Hz), 6.70 (d, 2 H, J = 7,6 Hz), 4.90 (s, 2H), 2.43 (brs, 3H), 2.2

4 (s, 3 H). Example 70

 5-Methyl ^ S '-1-isoquinolylmethyl N-p-tolyldithio-one

 The title compound was obtained from 1-methylisoquinoline in the same manner as in Example 1.

] H-NMR (270 MHz, CDC1 3) δ 8.47 (d, 1 Η, J = 5.6 Hz), 8.33 (br, 1 H), 7.83 (d, 1 H, J = 7.9 Hz), 7.70 (d, 1 H, J = 7.9 Hz), 7.55-7.65 (m, 2 H), 7.57 (d, 1 H, J = 5.6 Hz), 7.13 (brd, 2 H), 6.82 (d, 2 H, J = 7.9 Hz), 5.07 (brs, 2 H), 2.50 (s, 3 H), 2.32 (s, 3 H).

 S—Methyl S′—4-Isoquinolylmethyl N—p—Tolyldithio

 The title compound was obtained from 4-methylisoquinoline in the same manner as in Example 1.

Ή-NMR (270 MHz, CDC1 3) δ 9.18 (s, 1 H), 8.58 (brs, 1 H), 8.0 - 8.15 (m, 1 H), 8.00 (d, 1 H, J = 7.6 Hz), 7.77 (t, 1 H, J = 7.3 Hz), 7.64 (t, 1 H, J = 7.3 Hz), 7.12 (brd, 2 H), 6.83 (brd, 2 H), 4.76 (brs, 2 H), 2.45 (brs , 3H), 2.32 (s, 3H).

 S—Methyl S ′ — 3— (2-Methoxycarbonyl) quinolylmethyl N—p—Tolyldithio

 The title compound was obtained from 3-methyl-2-methoxycarbonylquinoline in the same manner as in Example 1.

Ή-NMR (270 MHz, CDC1 3) δ 8.41 (brs, 1H), 8.22 (d, 1 H, J = 8.3 Hz), 7.81 (d, 1 H, J = 8.3 Hz), 7.75 (brdd, 1 H , J = 6.9, 1.6 Hz), 7.63 (brt, 1 H, J = 6.9 Hz), 7.11 (d, 1 H, J = 8.3 Hz), 6.69 (d, 2 H, J = 8.3 Hz), Example 7 3 4.81 (brs, 2H), 4.05 (s, 3H), 2.42 (s, 3H), 2.32 (s, 3H).

S—Methyl-1- (2-carboxy) quinolylmethyl N— _P —Tolyldithiocarbonimidate

In the same manner as in Example 2, the title compound was obtained from S-methyl S'-3- (2-methoxycarbonyl) quinolylmethyl N-p-tolyldithiocarbonimide. 'Η-NMR (270 MHz, DMSO- d ₆ ) δ 8.28 (brs, 1 H), 7.86 (d, 1 H, J = 7.9 Hz), 7.66 (brt, 1 H, J = 6.6 Hz), 7.53 (brt, 1 H, J = 6.9 Hz), 7.12 (d, 2 H, J = 7.9 Hz), 6.70 (d, 2 H, J = 7.9 Hz), 4.80 (brs, 2 H), 2.42 (s , 3H), 2.26 (s, 3H).

 S—Methyl S ′ — 3— (2-Lubamoyl) quinolylmethyl N—p—Tolyl dithiocarbonimidate

As in Example 59, the title compound was obtained from S-methyl S'—3- (2-carboxy) quinolylmethyl N—p-tolyldithiocarbonimidate and ammonia. Was.

Ή-NMR (270 MHz, DMS0-d ₆ ) 8 8.47 (s, 1 H), 8.28 (brs, 1 H), 8.07 (d, 1 H, J = 8.6 Hz), 8.00 (d, 1 H, J = 8.3 Hz), 7,83 (brt, 1 H, J = 6.9 Hz), 7.75

(brs, 1 H), 7.70 (brt, 1 H, J = 6.9 Hz), 7.11 (d, 2 H, J = 8.3 Hz), 6.67 (d, 2 H, J = 8.3 Hz), 4.88 (s, 2H), 2.43 (s, 3H), 2.26 (s, 3H).

Example 7 5

 S—Methyl S ′ — 3— (2-Methylaminocarbonyl) quinolylmethyl N—P—Tolyldithiocarbonimidate

 As in Example 57, the title compound was obtained from S-methyl S'-3- (2-carboxy) quinolylmethyl N-p-tolyldithiocarbonimidate and methylamine hydrochloride.

-NMR (270 MHz, DMS0-d ₆ ) δ 8.84 (brs, 1 H), 8.47 (s, 1 H), 8.07 (d, 1 H, J = 8.3 Hz), 8.00 (d, 1 H, J = 7.6 Hz), 7.84 (brt, 1 H, J = 6.9 Hz), 7.70 (brt, 1 H, J = 7.4 Hz), 7.11 (d, 2 H, J = 7.9 Hz), 6.67 (d, 2 H, J-7.9 Hz), 4.87 (s, 2H), 2.86 and 2.84 (two brs, 3H), 2.42 (s, 3H), 2.26 (s, 3H).

S—Methyl S ′ — 3-— (2-Dimethylaminocarbonyl) quinolylmethyl N — P—Tolyldithiocarbonimide

 In the same manner as in Example 58, the title compound was obtained from S-methyl S'-3- (2-carboxy) quinolylmethyl N-p-tolyldithiocarbonimidate and dimethylamine (aqueous solution).

NMR-NMR (270 MHz, DMS0_d ₆ ) δ 8.47 (s, 1 H), 8.00 (brd, 2 H, J = 8.8 Hz), 7.81 (brt, 1 H, J = 8.3 Hz), 7.67 (brt , 1 H, J = 7.3 Hz), 7.11 (d, 2 H, J = 7.9 Hz), 6.67 (d, 2 H, J = 7.9 Hz), 4.50 (brs, 2 H), 3.04 (brs, 3 H ) 2.7 6 (brs, 3 H), 2.47 (s, 3 H), 2.25 (s, 3 H)

The structural formulas of Examples 45 to 76 are described below.

Example Example Example

CI C0₂ e

CI C0 ₂ e

試験例 1 Example Example Example Example

Test example 1

Evaluation using rat Thy-1 nephritis model

 The anti-fibrotic effect of the compound of Example 2 was evaluated using a rat Thy-1 nephritis model, which is a kidney fibrosis model.

Male Wistar rats (Charles River Japan Co., Ltd.) were purchased at the age of 3 weeks, and after preliminary breeding, they were subjected to the experiment when they weighed about 100 g. The animals were housed in a controlled room at a temperature of 23 ± 2, a humidity of 55 ± 101 and an illumination time of 8:00 to 20:00. Solid feed CE-2 (CLEA Japan) was freely available, and drinking water was freely available through filtered tap water. Anti thy 1 monochrome one monoclonal antibody (0X- 7: Biosource international, Inc.) was diluted with saline so that 100 g / ml, was re administered by tail vein at a rate of 50.mu. _beta 200 g (body weight). Thereafter, the animals were divided into a vehicle administration group (n = 8) and a test compound administration group (n = 8) based on the body weight as an index. From the day of the administration of the anti-Thy-1 monoclonal antibody, a suspension of the test compound was prepared so that the concentration of the test compound became 7.5 _mg / m 1% arabia gum. 00g body weight: 150 mg / kg / day). 1% gum arabic was similarly administered to the vehicle administration group.

After daily administration for 7 days, the rat kidney was perfused and fixed with phosphate buffered formalin and then excised to prepare a PAS (Periodic Acid Schiff) -stained specimen (one per animal). Under a microscope, six fields of view (magnification: X100) were photographed at random and the degree of PAS positive (the degree of extracellular matrix accumulation) of all glomeruli (about 50-70) in these fields was determined as follows. The score was calculated based on the standard, and the average value was used as the fibrosis score of the individual (Jpn. J. Nephrol. 38: 202-212, 1996). Wilcoxon's rank sum test was performed for the fibrosis score.

 Score 0: PAS positive area is almost equal to normal glomerulus

 Score 1: PAS positive area is less than 50% in the glomerulus

Score 2: PAS positive area is 50-75 in the glomerulus Score 3: PAS-positive area is 75% or more in the glomerulus. Table 1 shows the results. The values indicate the mean standard deviation of 8 animals in each group. These test results show that the dithiocarbonimidate derivative suppresses the accumulation of extracellular matrix in the kidney and improves the fibrosis score.

table 1

 Administration group Fibrosis score Vehicle administration group 1.80 Sat 0.38

Test compound administration group 1.26 persons 0.21 ^s氺: P <0.01 Test Example 2

 Effect of TGF-3 on extracellular matrix production

 The effect of the compound of Example 2 on proteodalican production when TGF-3 was added to fibroblasts was evaluated.

NRK-49F cells (rat fibroblasts) were cultured in Dulbecco's Modified Eagle Medium (DMEM: GIBCO) containing 10% pup serum and used for experiments. Cells were seeded in a 96-well plate at a ratio of 2.5 × 10 ⁴ cells / 100 μ 1 / wel 1 and the next day, 3 ng / ral TGF-β (Nacalai Tesque, Inc.), 0.5 MCi / well [ ³⁵ S] -Na ₂ S0 _{4. The} medium was replaced with a DMEM medium containing the test compound. After culturing for 24 hours, add Command W Chin sulfate A, MgS0 _4, Na Acetate, while handling Ethanol, the radioactivity in the resulting precipitate was measured with 1205 Betaplate (Pharmacia, Inc.). The TGF-3 inhibition rate was calculated by the following formula.

 TGF- / 3 inhibition rate (%) = {1-(a-b) / (c-d)} X 100

 a: Radioactivity of TGF-3 added, compound added we 11

b: Radioactivity of we11 without TGF- / 3 added, compound added c: Radioactivity of we11 with TGF- / 3 added and no compound added

 d: Radioactivity of we11 without TGF-3 added and no compound added The results are shown in Table 2. The results showed that the dithiocarbonimidate derivative antagonized the action of TGF- ^ and inhibited fibroblast production of puliotheoglycan.

Table 2

Compound Compound concentration (^ M) TGF-3 inhibition rate (%) Compound of Example 2 5 13

 1 0 37

 25 6 6

 50 7 0

 1 00 82

Test example 3

 Effect of TGF-3 on extracellular matrix production

 The effect of the compounds of Examples 52 and 55 on proteodalican production when TGF- / 3 was added to fibroblasts was evaluated.

NRK-49F cells (rat fibroblasts) were cultured in Dulbeccois Modified Eagle Medium (DMEM: GIBCO) containing 10 sera and used for experiments. Cells were seeded at a ratio of 2.5 × 10 ⁴ cells / 100 μ 1 / wel 1 on a 96-well plate, and the next day, 3 ng / ml TGF- (Nacalai Tesque, Inc.), OS ^ Ci / well [ ³⁵ S] -Na ₂ S0 _{4. The} medium was replaced with a DMEM medium containing the test compound. After 24 hours, the culture supernatant was collected and subjected to SDS-PAGE according to a conventional method. The gel after electrophoresis was dried with a gel dryer, exposed to an imaging plate, and analyzed with BAS2000 (Fuji Film Co., Ltd.). Determine the radioactivity of electrophoresed proteodalican Then, the TGF- ^ inhibition rate was calculated by the following formula.

 TGF-3 inhibition rate = (① ー ②) X100Z (① ー ③)

 ①: Radioactivity when TGF-3 is added and test compound is not added

②: TGF- / 3, radioactivity when test compound is added

③: TGF-3, radioactivity without test compound added The results are shown in Table 3. These results indicate that dithiocarbonimidate derivatives antagonize the action of TGF-3 and suppress the production of proteoglycans by fibroblasts.

Table 3

Compound Compound concentration (^ M) TGF- ^ inhibition rate (%) Compound 3 52 of Example 52

 1 0 7 3

Compound of Example 5 5 3 4 1

 1 0 57

Industrial applicability

 INDUSTRIAL APPLICABILITY According to the present invention, a dithiobibonimidate derivative useful as a medicament such as an organ or tissue fibrosis inhibitor can be provided.

Claims

 Expression One meter blue

[Wherein, R ¹ represents an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, or an optionally substituted cycloalkyl. E represents optionally substituted C i Cs alkylene, an optionally substituted C ₃ be -C ₅ al Keniren or optionally substituted C ₃ ~ C ₅ alkynylene.  Enclosure A represents a substituted or unsubstituted monocyclic nitrogen-containing heteroaryl having a nitrogen atom at the 2- or 3-position, an optionally substituted bicyclic nitrogen-containing heteroaryl, or a compound represented by the formula:

(In the formula, R ² represents a hydrogen atom or a substituent. R ³ represents a hydroxyl group, an optionally substituted alkoxy, an optionally substituted alkenyloxy, an optionally substituted alkynyloxy or 1 NR ⁴ R ⁵ . R ⁴ and R ⁵ are independently a hydrogen atom, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted Represents a aryl or an optionally substituted heteroaryl. R ⁴ and R ⁵ together with a nitrogen atom may represent a nitrogen-containing heterocyclic group which may be substituted by one NR ⁴ R ⁵ . ).  Ar represents an optionally substituted aryl or an optionally substituted heteroaryl. ] A dithiocarbonimidate derivative or a prodrug thereof represented by Their pharmaceutically acceptable salts. 2. Formula:

[Wherein, RR ² , R ³ , E, and Ar have the same meanings as in claim 1. ] The dithiocarbonimidate derivative or prodrug thereof according to claim 1, which is represented by the formula: or a pharmaceutically acceptable salt thereof. 3 expressions

[Wherein, IV, R ² , R ³ , E and Ar have the same meanings as in claim 1. ] 3. The dithiocarbonimidate derivative or prodrug thereof according to claim 2, which is represented by the formula: or a pharmaceutically acceptable salt thereof. 4. R ^{3 is a} hydroxyl group, an optionally substituted alkoxy or —NHR ⁶ (where R ⁶ represents an optionally substituted alkyl, an optionally substituted alkenyl or an optionally substituted alkynyl). Dichocarbon imidate according to item 2 or 3 A derivative or a prodrug thereof, or a pharmaceutically acceptable salt thereof. 5. R ² is a hydrogen atom, a halogen atom, an optionally substituted alkyl, an optionally substituted alkoxy, an optionally substituted alkenyl, an optionally substituted alkynyl , Cyano, aryl which may be substituted, heteroaryl which may be substituted, cycloalkyl which may be substituted, aryloxy which may be substituted, heteroaryloxy which may be substituted, alkoxycarbonyl which may be substituted , Hydroxyl group, optionally substituted alkanoyl, optionally substituted amino, carboxyl, optionally substituted rubamoyl, optionally substituted sulfamoyl, optionally substituted alkylthio, optionally substituted alkanoyl 5. The dithioamide derivative or prodrug thereof according to any one of claims 2 to 4, which is mino or nitro, or a pharmaceutically acceptable salt thereof. 6. The dithioimide derivative or prodrug thereof according to claim 5, wherein R ² is a hydrogen atom or a halogen atom, or a pharmaceutically acceptable dish thereof.  7. The dithiocarbonimidate derivative or prodrug thereof according to claim 1, wherein Α is an optionally substituted bicyclic nitrogen-containing heteroaryl, or a pharmaceutically acceptable salt thereof. 8. E force optionally substituted C, ~ C ₃ alkylene or Jichio force one Bonimide one preparative derivative according to any one of claims 1 to 7, which is optionally substituted C ₃ ~ 〇 ₄ Aruke two even Len or its Prodrugs or their pharmaceutically acceptable salts. 9. The dithioforce dibonimidate derivative according to claim 8, which is a methylene which may be substituted, or a prodrug thereof, or a pharmaceutically acceptable salt thereof. 10. A medicament comprising the dithiobibonimidate derivative according to any one of claims 1 to 9, or a prodrug thereof, or a pharmaceutically acceptable salt thereof. 1 1. The medicament according to claim 10, which is an inhibitor of organ or tissue fibrosis.  12. The medicament according to claim 10, which is a TGF-3 inhibitor. 13. The medicament according to claim 10, which is a therapeutic agent for diabetic nephropathy.  14. The medicament according to claim 10, which is a therapeutic agent for glomerulonephritis. 15. The medicament according to claim 10, which is a therapeutic agent for liver cirrhosis.  16. The medicament according to claim 10, which is a therapeutic agent for pulmonary fibrosis.