WO2000020385A1 - Dithiol derivatives - Google Patents

Abstract

Novel glutathione reductase activity intensifiers, which are compounds having general formula (I) and pharmacologically acceptable salts, thioesters, and other derivatives thereof, wherein m is 0 or 1; n is 2 when m is 0, and n is 1 when m is 1; k is an integer of 0 to 12; R1 is hydrogen, one member selected from substituents α, etc.; A is a group having -N(R2)CO-, -CON(R2)CO-, or -CON(R2)SO2- (R2 is hydrogen, alkyl, etc.), etc; and B is a single bond, -N(R5)- (R5 is hydrogen, alkyl, etc.), etc. [Substituents α] optionally substituted aryls, optionally substituted heterocyclic groups [Substituents β] alkyls, halogenated lower alkyls, etc. [Substituents η] lower alkoxys, hydroxy, etc.

Description

 Description Dithiol derivative

[Technical field]

 The present invention relates to a dithiol derivative having an excellent activity of enhancing daltathione reductase activity, a method for producing the same, and use thereof.

[Background technology]

 Glutathione is widely found in tissues of living organisms, is a major intracellular reducing agent, and plays an important role in redox reduction. In particular, reduced daltathione (GSH) plays an important role in various cell defense and repair mechanisms, depending on the thiol group present in the molecule. Glutathione peroxidase is an enzyme that catalyzes the reaction in which peroxides (such as hydrogen peroxide and lipid peroxide) are reduced by GSH, and is an important enzyme in the antioxidant mechanism. On the other hand, daltathione reductase is an enzyme that reduces oxidized glutathione (oxidized daltathione: GSSG) in the presence of NADPH to regenerate it into GSH.

Antioxidant mechanisms, including these compounds and enzymes, protect cells from the harmful effects of pro-oxidants (eg, the above peroxides and free radicals). Oxidative stress occurs when the balance between pro-oxidants and antioxidant mechanisms predominates [J. Appl. Physiol. 1996 Nov., 81 (5), pp. 2199-2202]. Its oxidative stress is involved in various diseases, such as ischemic heart disease; cataract; idiopathic pulmonary fibrosis, adult respiratory distress syndrome, emphysema, asthma, and bronchopulmonary hypoplasia Lung diseases such as interstitial pulmonary fibrosis; chronic renal failure; peripheral nerves and central nervous system such as Parkinson's disease, schizophrenia, Alzheimer's disease, epilepsy, amyotrophic lateral sclerosis, cerebral ischemia Nervous system diseases including: gastric ulcer; diabetes mellitus; necrosis and apoptosis of hepatocytes such as ethanol-induced liver damage; viral diseases such as influenza, hepatitis B, HIV; and colorectal cancer. Yes [J.Appl.Phvsiol. 1996 Nov., 81 (5), pp. 2199-2202; Free Radical Biology & Medicine, Vol. 21 No. 6, 845-853 (199 (5 years); Free Radical Biology & Medicine, Vol. 20 No. 7 Gut, Vol. 34, pp. 25-931 (1996); Gastoroenterology, 112, 855-863 (1997).

1G 1-165 (1996); Lancet, 338, pp. 215-216 (1991); Diabetologia, 39, 357-363 (1996); Eur. Cancer., 1996 Jan, 32A (1), 30-38; Am. J. Med., 1 991 Sep 30. 91 (3c), 95s- 105s; Alcohol. Clin. Exp. Res., 1996 Dec, 20 (9 Suppl), 340Λ-346Α; Free Radical Biology & Medicine, Vol.21 No.5, pp.641-649 (19%); Pharmacol.Toxicol., 1997 Apr, 80 (4), pp.159-166; Cell. Mol. Biol. (Noisy-le- grancl), 1996 Feb, 42 (1), pp. 17-26; Prostaglandins. Leukot. Essent. Fatty Acids,

1996 Aug, 55 (1-2), pages 33-43; FASEB J., 1995 Sep, 9 (12), 1173-1182]. In addition, in addition to these, Down syndrome, nephritis, optic inflammation, dermatitis, exertion, rheumatism, various birth defects (eg, Duchenne Nudism Trophy, Becker's Trophy, Du-Bin-Johnson Syndrome, favism, etc.) Dianemia, carcinogenesis and metastasis, sepsis, vascular hyperpermeability, leukocyte adhesion, retinopathy of prematurity, eyeball disease, drugs (anticancer agents such as platinum complex, antibiotics, antiparasitic agents, paraquat, Oxidative stress is also considered to be one of the inducers of toxic effects and radiation damage caused by carbon tetrachloride and halothane (superoxide dismutase and active enzyme regulator, written by Yoshihiko Oyanagi). WO 94/12527 also states that compounds that promote the synthesis of endogenous GSH may contain glutathione deficiencies, such as those associated with oxidative tissue damage, especially those associated with excessive free radical damage. It is disclosed that it is suitable for the treatment of various diseases caused by, for example, excessive drinking of alcohol, xenobiotics, radiation damage, intracellular oxidation state caused by liver disease, drugs and chemicals. Poisoning, heavy metal poisoning, physiological aging of the brain (e.g., brain decline caused by a decrease in glutathione levels due to changes in defense mechanisms against oxidants, such as loss of memory and learning abilities) Parkinson's disease) and acute and chronic neurodegenerative diseases (acute medical conditions include acute ischemic conditions, especially cerebral seizures, hypoglycemia, and epileptic seizures; Is a Jo, amyotrophic lateral sclerosis, Alzheimer's disease, Hanchin tons chorea), dysfunction, in particular cancer immunotherapy immune system, infertility, in particular male infertility are mentioned. Furthermore, It is disclosed that the compound is also suitable for organ reperfusion following an ischemic condition, which is the main cause of free radicals.

 Further, JP-A-64-265615 discloses that a compound that increases daltathione concentration is useful for the treatment and prevention of various diseases including cataract, liver disease and kidney disease. ing.

 By the way, dihydrolipoic acid (compound of the following structural formula A) is known as a compound having two thiol groups in the molecule and exerting an antioxidant action in vivo, like the compound of the present invention. However, no effect of dihydrolipoic acid on glutathione reductase has been reported. On the other hand, the compound of the present invention has a structure different from that of dihydrolipoic acid, and has a daltathione reductase enhancing action in ^.

 'COOH

 '-I I Compound A

 SH SH

[Disclosure of the Invention]

 The present inventors have conducted intensive studies on the synthesis of pharmacological agents and prophylactic and therapeutic agents for diseases caused by oxidative stress. As a result, dithiol derivatives showed excellent daltathione reductase activity enhancing activity and peroxidation. The present inventors have found that they have an object erasing effect and have low irritation to eyes, and have completed the present invention.

 Another object of the present invention is to use a dithiol derivative for producing a drug (particularly, daltathione reductase activity enhancer) and a pharmaceutical (particularly, daltathione reductase activity enhancer) containing a dithiol derivative as an active ingredient. An object of the present invention is to provide a method for preventing or treating a disease caused by oxidative stress, which comprises administering a pharmacologically effective amount of a dithiol derivative. The present invention

(1) A compound having the following general formula (I), a pharmacologically acceptable salt thereof, thioester or other derivative thereof:

 {Where,

 m represents 0 or 1, when m is 0, n represents 2, when m is 1, n represents 1,

 k represents 0 or an integer of 1 to 12,

R ¹ is a hydrogen atom, a group selected from substituent group α, or

It may be substituted with 1 to 3 substituents selected from Substituent group α and Substituent group y. 1 to 12 carbon atoms which may have an oxygen atom and / or a sulfur atom interposed Represents an alkyl group of

A is a single bond, an oxygen atom, a carbonyl group, or one N (R ² ) CO—,

— N; (R ² ) CS-, one N (R ² ) S 0 ₂ —, -C ON (R ² ) N (R ³ ) CO-, -CON (R2) CO-, one CON (R ² ) CS -, -CON (R ²⁾ S_〇 _{2 -, - O - CO -} , -ON (R 2) CO -, -O (R 2) S 0 2 -,

One O—CON (R ² ) N (R ³ ) CO-, One O—CON (R ² ) CO-,

-O- CON (R ² ) S 0 ₂ —, one CO—O—, one CO—CO—,

— CO-CON (R ² ) N (R ³ ) CO-, -CO- CON (R2) CO-,

-CO-CON (R ² ) S 0 _2- , one N (R ² ) O-, --N (R ² ) CO CO-, one N (R2) N (R3) CO-, one N (R ² ) N (R3) S 0 _2- ,

One N (R2) CON (R3) N ⁴ ) CO-,-N (R ² ) CON (R ³ ) CO-, One N (R2) CON (R3) S 0 ₂ — or

— N (R2) CON (R3) S 0 ₂ N (R4) CO— wherein R ² , R3 and R4 are the same or different and are a hydrogen atom, an alkyl group having 1 to 12 carbon atoms, An aralkyl group, an aralkyl group in which an aryl moiety is substituted with one to three groups selected from a substituent group, or one group selected from a substituent group α. ] A group having

Β is a single bond or —N (R5) — or — N (RN (R5) — [wherein, R ⁵ and R ⁶ are the same or different, and a hydrogen atom, an alkyl group having 1 to 12 carbon atoms, an aralkyl group, and an aryl moiety are substituted with 1 to 3 groups selected from a substituent group | 3 been Ararukiru group, shows one group selected from Ashiru group or substituent group alpha, further, R ⁵ is 5-7 membered ring of the double ring together with the nitrogen atom to which R ¹ and they are attached May be formed. ]

Furthermore, Α is one N (R ² ) CO—, one N (R ² ) CS—,

- CON (R2) N (R3 ) CO -, - CON (R 2) CO -,

One CON (R ² ) CS-, One O— CO,-ON (R ² ) CO-,

-O-CON (R ² ) N-(R ³ ) CO-,-O-CON (R ² ) CO-,

One CO-CON (R ² ) N (R3) CO-, One CO— CON (R ² ) CO-,

- N '; (R2) N (R3) CO -, one ^{N (R 2) CO (R3} ) N (R 4) CO -, or one ^{N (R 2) CON (R} 3) CO - [ wherein, R ² , R 3 and are the same as defined above], and when B is a single bond, R ¹ has, in addition to the definition described above, a group OR?

(In the formula, R ⁷ is selected from a lower alkyl group, a lower alkenyl group, an aralkyl group, an aralkyl group substituted with 1 to 3 groups selected from the substituent group i3 or a substituent group α. Represents one group to be obtained.)

Α, — CON (R ² ) S 0 _2- , — ON (R ² ) S 0 _2- ,

One O-CON (R ² ) S 0 _2- , One CO-CO-, One CO — CON (R ² ) S 0 _2- , One N (R2) COCO —,-N (R ² ) N (R ³ ) S 0 ₂ -, or one ^{N (R 2) CON (R} 3) S 0 2 - [ wherein, R2 and R3 are as defined above. And B is a single bond, and A is not an oxygen atom, one CO—O— or one N (R ² ) O—, and B is —N (R5) — Wherein R5 is as defined above. In the formula, R ¹ may be, in addition to the above definition, a hydroxyl group or a group OR? (Wherein, R? Has the same meaning as described above.).

 However,

 When A is an oxygen atom, B is a single bond or one N (R5) — wherein R5 has the same meaning as defined above. ]

A is one CO—O— or one N (R ² ) O—, wherein R 2 has the same meaning as described above. ] B is a single bond; and

 When k-force; 4 is shown, ABR1 does not show a carboxyl group. )

 [Substituent fresh α]

Aryl group, heterocyclic group, substituent group | aryl group substituted with 1 to 3 groups selected from | 3, heterocyclic group substituted with 1 to 3 groups selected from substituent group / 3 Ring group

 [Substituent groups | 3]

A lower alkyl group, a halogenated lower alkyl group, a lower alkoxy group, a lower alkylthio group, a hydroxyl group, a carboxyl group, a nitrogen atom-substituted rubamoyl group, a lower alkoxycarbonyl group, a halogen atom, a nitro group, and an amine residue Group, sulfo group, sulfamoyl group, cyano group, hydroxy lower alkyl group

 [Substituent group γ]

A lower alkoxy group, a lower alkylthio group, a hydroxyl group, a nitroxy group, a carboxyl group, a lower alkoxycarbonyl group, a halogen atom, a sulfo group, a sulfamoyl group, an amine residue, and a nitrogen atom which may be substituted with a nitrogen atom.

 Of these, preferred compounds include

(2) General formula (I), following general formula (I ') _:

To CH ₂ ) _k -A-I B— R ¹

HS SH C)

A compound that is

 (3) k force; a compound which is 0 or an integer of 1 to 8,

 (4) a compound whose k force is an integer of 2 to 6,

 (5) a compound having a k force of 4 or 5,

 (6) Rl force heterocyclic group, heterocyclic group substituted with 1 to 3 groups selected from substituent groups, 1 to 3 substituent groups selected from substituent group α and substituent group γ A compound which is an alkyl group having 1 to 12 carbon atoms, a hydroxyl group or an alkoxy group having 1 to 5 carbon atoms which may be substituted with

(7) Rl force ';, a heterocyclic group, a heterocyclic group substituted with 1 to 3 groups selected from substituent group i3, or 1 selected from substituent group α and substituent group 7 With 3 to 3 substituents A compound which is an alkyl group having 1 to 12 carbon atoms which may be replaced by an oxygen atom and a hydrogen atom or a sulfur atom,

 (8) a compound wherein Rl is a hydroxyl group or an alkoxy group having 1 to 5 carbon atoms,

(9) R ¹ force; heterocyclic group; heterocyclic group substituted by 1 to 3 groups selected from substituent group | 3; alkyl group having 1 to 5 carbon atoms; 3 to 8 carbon atoms A compound having 1 to 5 carbon atoms, a carboxyalkyl group having 2 to 7 carbon atoms, a hydroxyalkyl group having 2 to 5 carbon atoms, a heterocyclic group or an alkoxy group having 1 to 5 carbon atoms,

(1 0) A is a carbonyl group, or the formula ^{- CON (R 2) S 0} 2 -, one N (R ²⁾ CO-, one N: (R2) CS-, one CON (R ²⁾ CO-, one N (R ²⁾ COCO- or single _{N, (R2) S 0 2} "[ wherein, R ² is a hydrogen atom, a 1 to 1 2 alkyl group or Njiru group carbon atoms.] group having A compound that is

(11) A force; a carbonyl group, or a compound of the formula CON (R ² ) S 0 ₂ —,

— N '(R ² ) CO-, N (R ² ) CS, -CON (R ² ) CO-,

-N (R2) CO CO- or single N (R2) S0 ₂ - [wherein, R2 is 1 or hydrogen atom or a carbon atoms is 1 2 alkyl group. A compound having the group

(1 2) A force; carbonyl group, One CONHS C - one CONCH ₃ S 0 ₂ -,

— NHCO—, —NHC S—, — CONHCO—, one NHCOCO— or

-NH S 0 ₂ -, compound,

(1 3) B is a single bond or a formula one N (R5) - or single N (R6) N (R5) - [ wherein, R ⁵ and R ⁶ are the same or different and represent a hydrogen atom, or 1 carbon atoms Shows 12 alkyl groups or benzyl groups. A compound having the group

(14) B is a single bond or a formula — N (R ⁵ ) — or one N (RN (R5) — [wherein, R ⁵ and are the same or different and are each a hydrogen atom or 1 to 12 carbon atoms. A group having the formula:

(15) B force; a compound that is a single bond, one NH—, one NCH ₃ — or one NHNCH3—, or a pharmaceutically acceptable salt, thiol ester or other derivative thereof. .

Furthermore, the above (2), (3) to (5), (6) to (9), (10) to (12) Further, a compound satisfying any combination of requirements arbitrarily selected from the groups (13) to (15) is also suitable.

 Particularly preferred compounds include

 • 1 1 (5,7-dimercaptoheptyl) 1 3— (2—hydroxyxethyl) perea, • [3— (5,7-dimercaptoheptyl) ureide] methyl acetate,

 • 3 — (6,8-dimercaptootanoylamino) methyl propionate, • N— (6,8-dimercaptooctanoyl) methanesulfonamide

Alternatively, a pharmacologically acceptable salt, thiol ester or other derivative thereof can be mentioned.

 Further, the medicament (particularly, daltathione reductase activity enhancer) of the present invention is a compound according to any one of (1) to (15), a pharmacologically acceptable salt thereof, and a thiol ester. Or other derivatives are contained as an active ingredient.

In the above general formula (I),

 In the definition of [substituent group α], “aryl group” of “aryl group” and “aryl group substituted with 1 to 3 groups selected from substituent group 3” is the number of carbon atoms It represents 6 to 14 aromatic hydrocarbon groups, and examples thereof include groups such as phenyl, indul, naphthyl, phenanthrenyl and anthracenyl. Preferably it is phenyl.

 The “aryl group” may be condensed with a cycloalkyl group having 3 to 10 carbon atoms, and examples thereof include a group such as 2-indanyl.

 In the definition of [Substituent group H], the “heterocyclic group” in “heterocyclic group” and “heterocyclic group substituted by 1 to 3 groups selected from substituent group / 3” refers to sulfur A 5- to 7-membered saturated or unsaturated heterocyclic group (preferably, an aromatic heterocyclic group) containing 1 to 3 atoms, oxygen atoms or 1 and 3 nitrogen atoms.

Examples of the “saturated heterocyclic group” include, for example, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, dithiolanyl, thiadiazolidinyl, oxaziazolidinyl, dithiazolin Ridininole, piperidyl, piperazur, morpholinyl, thiomorpholinyl, dioxanyl, homopiperazinyl and the like. Preferably, it contains at least one nitrogen atom, such as pyrrolidinyl, thiazolidinyl, imidazolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, and further contains one sulfur atom, oxygen atom or nitrogen atom. And a 5- or 7-membered saturated heterocyclic group.

 The above “saturated heterocyclic group” may be substituted with an oxo group and / or a thioxo group. Examples of such a group include piperidonyl, pyrrolidonyl, thiazolidonyl, dioxothiazolidinyl. Thioxodithiazolidinyl, dioxoimidazolidinyl, dioxoxazolidinyl and the like.

 Further, the above “saturated heterocyclic group” may be condensed with another cyclic group, and examples of such a group include benzodioxanyl, indolinyl, isoindrinyl, benzoxazinyl Benzothiazolidinyl, benzothiazinyl, chromanyl, 6-acetoxy 2,5,7,8-tetramethylchroman-12-yl, isoindole-11,3-dione-12-yl .

 As the "aromatic heterocyclic group", preferably, furyl, phenyl, pyrrolyl, azepinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxaziazolyl, triazolyl, tetrazolyl, thiadiazolyl Examples thereof include groups such as vilanyl, pyridyl, pyridazinyl, pyrimidinyl, and pyrazur, and are preferably a 5- to 7-membered aromatic containing at least one nitrogen atom and optionally containing an oxygen atom or a sulfur atom. Represents a heterocyclic group, for example, pyrrolyl, azepinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyrimidinyl Alkenyl, mention may be made of groups such as Pirajuru, more preferably, pyridyl, Imidazoriru, Okisazoriru a Birajiniru and thiazol 'Le.

The “aromatic heterocyclic group” may be condensed with another cyclic group, and examples thereof include indolyl, benzofuryl, benzothenyl, benzoxazolyl, and benzoimidazo. Examples include groups such as ril, isoquinolyl, quinolyl, and quinoxalyl. Further, the above “aromatic heterocyclic group” may be substituted with an oxo group and / or a thioxo group. Examples of such a group include pyridonyl, oxazolonyl, villazolonyl, isoxazolonyl, and thioxodithiazolyl. And the like.

In the definition of R ² , R ³ , R R5 and R ⁶ , “an alkyl group having 1 to 12 carbon atoms” and, in the definition of R ¹ , “1 to 3 substituents selected from a substituent group γ `` An alkyl group having 1 to 12 carbon atoms '' in `` an alkyl group having 1 to 12 carbon atoms which may be substituted with a substituent and which may be interposed with an oxygen atom and a sulfur or sulfur atom '' Is a straight or branched chain alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butynole, pentyl, 2-pentyl, 3-pentynole, 2-methylbutyl, 3-Methylbutyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, hexyl, 2-hexyl, 3-hexynole, 2-methylpentyl, 3-methinolepentyl, 4- 1,2-Dimethylbutyl, 1,3-Dimethylbutyl, 2,2-Dimethylbutyl, 2,3-Dimethylbutynole, 3,3-Dimethynolebutyl, 1,3-Dimethynolebutynole 1,2—trimethylpropinole, 1,2,2—trimethinolepropyl, heptyl, 2—heptinole, 3—heptyl, 4 heptyl, 3,3—dimethylpentyl, octinole, 2-methinole Petinole, 2-ethylethylhexyl, 1,1,3,3-tetramethynolebutynole, nonyl, 2-noel, 3-noninole, 4-noninole, 5-noninole, 2-methylinoleoctyl, 3-methyloctyl, 4-methylinole Octyl, 5-methylinoleoctinole, 6-methinoleoctyl, 7-methyloctyl, 8-methylinoleoctinole, 6,6-dimethylheptyl, decyl, 2-decyl, 3-decyl 1, 4-decyl, 5-decyl, 2-methinolenoninole, 3-methinolenoninole, 4-methinolenoninole, 6,6-undedecyl, 2-indecyl, 3-indecyl, 4-indecyl, 5-

6-Pindecyl, 2-Methyldecyl, 3—Methyldecyl, 4-Methyldecyl, 5-Methyldecyl, 6-Methylenodecinole, 7—Methylenodecinole, 8—Methylenodecinole, 9-Methyldecyl, 7 —Echinolenoninole, Dodecyl, 2 Dodecyl, 3 1 Dodecyl. 4 1 Do Decyl, 5-dodecyl, 6-dodecyl, 2-methylindenoline, 3-methylindenoline, 4-methylinodecinole, 5-methylinodecinole, 6-methylinodecinore, 6-methodinodecinole, 7-methylinodecyl, 8-methylindenyl, 9-methylinodecinole, 10-methylindyl and the like. Preferably, it is a straight-chain or branched-chain alkyl having 1 to 6 carbon atoms, more preferably, a straight-chain or branched-chain alkyl having 1 to 4 carbon atoms, still more preferably. Is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl.

In the definition of R ¹ , `` alkyl having from 1 to 3 carbon atoms which may be substituted with 1 to 3 substituents selected from substituent group Y and may be interposed with an oxygen atom and / or a sulfur atom Examples of the group in which an oxygen atom and / or a sulfur atom are interposed among the groups include, for example, a group in which the above “alkyl group” is substituted with one “alkoxy group” or “alkylthio group”. (Here, “alkoxy group” and “'alkylthio group” mean the same groups as those defined in the substituent group and the substituent group γ.) Examples of such a group include: For example, substituted with an alkoxyalkyl group having 2 to 10 carbon atoms, an alkylthioalkyl group having 2 to 10 carbon atoms, an alkyl group having 1 to 5 carbon atoms substituted with a benzyloxy group, and a benzylthio group An alkyl group having 1 to 5 carbon atoms (here, a benzyloxy group and a benzyl moiety of the benzyloxy group may be substituted with 1 to 3 groups selected from a substituent group β). I can do it. Preferably, methoxymethyl, methoxyxetil, ethoxy methinole, methinolethiomethinole, methinorethy ethinole, ethinolethy methinole, benzinole xymethyl, benzinoleoxyethyl, benzylthiomethyl, 4-methoxybenzinole thiomethyl.

In the definition of R ² , R ³ , RRR ⁶ and R ⁷ , “aralkyl group” and “aralkyl group in which the aryl moiety is substituted with 1 to 3 groups selected from substituent group | 3” “Aralkyl group” means benzyl, 1-phenylethyl, 2-phenylethyl, α-naphthylmethyl, / 3-naphthinolemethinole, dipheninolemethinole, triphenylenomethyl, α-naphthyldiph It represents a "lower alkyl group" substituted with one to three aryl groups such as enylmethyl and 9-anthrinolemethyl. Preferably, benzyl, 1 One feninole etinole, 2 — huenii.

In the definition of R ² RKR ⁴ , R 5 and R ⁶ , the term “acyl group” refers to, for example, formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, vivaloyl, relinole, isolelinole, octanoienole, Nonylcarbonyl, decylcarbonyl, 3-methylnonylcarbonyl, 8-methylnonylcarbonyl, 3-ethyloctylcarbonyl, 3,7-dimethyloctylcarbonyl, pendecylcarbonyl, dodecylcarbonyl, tridecylcarbonyl, tetradecylcarbonyl, Pentadecinolecanoleboninole, hexadecylcarbonyl, 1-methinolepentadecinolecanoleboninole, 14-methylpentadecylcarbonyl, 13,13-dimethyltetradecylcarbonyl, heptadecylcarbonyl, 15 — Methylhexadecyl 1 to 30 carbon atoms such as carbonyl, octadecinolecarbonyl, 1-methylheptadecylcarboninole, nonadecinolecarbinole, aicosylcarbonyl, and henicosylcarboel (preferably, 1 to 21, more preferably 1 to 8 and most preferably 1 to 5) phenolic olenocarbonyl groups, chloroacetinole, dichloroacetinole, trichloroacetinole, trifluoroacetyl Halogenated alkylcarbonyl groups such as methoxyacetyl, lower alkoxyalkylcarbonyl groups such as methoxyacetyl, acryloyl, propionyl, methacryloyl, crotonyl, arylcanolebonyl, isocrotoninole, (E) -2-methyl-2-butenyl An “aliphatic acyl group” such as an unsaturated alkylcarbonyl group such as Nore, α-naphthyl,] 3-arylphtalyl groups such as naphthoyl, 2-bromobenzoinole, 4-halogene-like arylene groups such as benzoinole, rubonyl group, 2,4 6-trimethylbenzoy Lower alkylated aryl carbonyl groups such as 4-toluoyl, 3,5-dimethinole-1-hydroxybenzoyl, 3,5-di-tert-butyl-1-hydroxybenzoyl Such as a hydroxylated benzyl group, a lower alkoxylated arylcarbonyl group such as 4-anisyl, a 4-nitrobenzoyl group, and a 2-nitrobenzoyl group such as a 2-nitrobenzoyl group; — Lower alkoxycarbonylated arylcarbonyl groups such as (methoxycarbonyl) benzoyl, arylated aryloxy groups such as 4-phenylbenzoyl "Aromatic Ashiru group" such as a ball two Le group; main butoxycarbonyl, et butoxycarbonyl, Provo Lower alkoxycarbonyl groups such as xycarbonyl, butoxycarbonyl, s-butoxycarbonyl, tert-butoxycarbonyl, and isobutoxycarbonyl, 2,2,2-trichloromouth ethoxycanoleboninole, 2-trimethinole Lower alkoxylity substituted by halogen or tri-lower alkylsilyl group such as silinoleto ethoxy canolebonyl “alkoxycarbonyl group” such as norebonyl group; benzinolecarbonyl, 4-methoxybenzinolecarbonyl, 3,4-dimene The aryl ring is substituted with one or two lower anolexoxy or nitro groups, such as methoxybenzylcarbonyl, 2-nitrobenzylcarbonyl, 4-nitrobenzylcarbonyl; "Aralkylcarbonyl group";': methanesulfonyl, ethanesulfoninole , 1-"lower anolesulfonole group", such as prononsulfonyl; halogenated "lower alkenosulfonyl groups, such as chloromethanesulfoninole, triphenylenole methanesnolephonyl ^ pentafluoroethanesulfonyl" And "arylsulfonyl groups" such as benzenesulfoninole and p-toluenesulfonyl. Of these, “aliphatic acyl group”, “aromatic acyl group”, “alkoxycarbonyl group” and “lower alkane sulfonyl group” are preferable, and alkylcarbonyl group and lower alkoxy group are more preferable. It is carbonyl.

Examples of the “5- to 7-membered heterocyclic group” formed by R ¹ and R 5 together with the nitrogen atom to which they are bonded include pyrrolidino, 3-thiazolidinyl, piperidino, piperazino, morpholino, thiomorpholino, A 5- to 7-membered heterocyclic group containing at least one nitrogen atom, such as homopiperazino, imidazolidinyl and imidazolyl, and which may further contain one sulfur atom, oxygen atom or nitrogen atom. Can be. Further, the “5- to 7-membered heterocyclic group” may be substituted with an oxo group and / or 1 to 3 groups selected from substituent group i3, and is condensed with another cyclic group. It may be ringed. Such groups include, for example, N-methylbiperazino, Nt-butoxycarbylbiperazino, 1-indolinyl, 2-carboxy-1 monoindolinyl, 2-methoxycarbone-1,1-indolinolinole, 3,4-dimethinole Examples include indoline-1,5-dione-11-yl and isoindole-1,3-dione-1-yl. R ⁷ and “lower alkyl group” in the definition of [substituent group ii], “lower alkyl group” in “halogenated lower alkyl group” in the definition of [substituent group i3], and [lower alkyl group] in [substituent group β] The “lower alkyl group” of the “hydroxy lower alkyl group” in the definition means a linear or branched alkyl group having 1 to 6 carbon atoms, for example, methyl, ethyl, η-propyl, isopropyl, η- Butyl, isobutyl, s-butynole, tert-butynole, n-pentynole, isopentynole, 2-methinolebutynole, neopentynole, 1-ethynole propynole, n-hexynole, isohexynole, 4-methylpentynole, 3-methylpentynole —Methinolepentinole, 1-methinolepentinole, 3, 3 —dimethinoleb'tinole, 2,2-dimethylbutyl, 1,1 —dime Examples thereof include butylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, and 2-ethylbutyl. Preferably, it is a straight-chain or branched-chain alkyl having 1 to 4 carbon atoms, and more preferably, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl. Preferably, it is methyl.

“Lower alkenyl group” in the definition of R ⁷ includes vinyl, aryl, methallyl, 1-propenyl, isopropylidinole, 1-buteninole, 2-butenyl, 3-buteninol, 1

—Pentenole, 2-pentenole, 3 —pentenole, 4-pentenole, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4 —hexenyl Indicates 6 straight or branched alkenyl. Preferably, it is an alkenyl group having 2 to 4 carbon atoms, such as butyl, aryl, methallyl, 1-propenyl, isopropyl, butenyl, and more preferably aryl, 2-butenyl.

The “halogenated lower alkyl group” in the definition of the “substituent group” refers to a group substituted by a halogen atom such as the above “lower alkyl group”, a fluorine atom, a chlorine atom, a bromine atom and an iodine atom. Examples of such groups include, for example, chloromethinole, dichloromethinole, trichloromethinole, trifrenoleolomethinole, 2-chloroethynole, 2-funoleolechinole, · 2-bromoethynole, 2-odoethynole, 2,2,2—trichloroethinole, 2,2,2—trinoleolochinole, 3—clopropinole, 3-fluoropropyl, 3-bromopropinole, 3-bromopropyl, 3,3,3-tri Krolov. Lopinore, 3,3,3—Trifunoleo Mouth Propinore, 4-Chlorobutinole, 4-Funole O-butyl, 4-bromobutyl and 4-monobutyl.

 [Substituted-group / 5] and [lower alkoxy group] in the definition of [S substituent group γ], and [lower alkoxycarbonyl group] in the definition of [substituent group] 3] and [substituent group γ] The term "lower alkoxy group" in "means a group wherein the above" lower alkyl group "is bonded to an oxygen atom, for example, methoxy, ethoxy, η-propoxy, isopropoxy, η-butoxy, isobutoxy, s-butoxy, tert-butoxy, n-pentyloxy, isopentinoleoxy, 2-methynolebutoxy, 1-ethynolepropoxy, n-hexynoleoxy, 4-methylpentyloxy, 3-methylpentyloxy, 2-methylpentyloxy , 3,3-dimethylbutoxy, 2,2-dimethylbutoxy, 1,1-dimethylbutoxy, 1,2-dimethylbutoxy, 1,3-dimethylbutoxy, A linear or branched alkoxy group having 1 to 6 carbon atoms such as 2,3-dimethylbutoxy or 2-ethylbutoxy; preferably a linear or branched alkoxy group having 1 to 4 carbon atoms; And more preferably methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, and most preferably methoxy.

 The “lower alkylthio group” in the definition of [substituent group | 3] and [substituent group γ] refers to a group in which the above “lower alkyl group” is bonded to a sulfur atom, for example, methylthio, ethylthio, η— Propylthio, isopropylthio, η-butylthio, isobutylthio, s-butinorethio, tert, -peptinorethio, n-pentinorethio, isopentinorethio, 2-methylbutylthio, .1 -ethylpropylthio, n-hexylthio, 4 -Methynole pentylthio, 3-methylpentylthio, 2-methylpentylthio, 3,3-dimethylbutylthio, 2,2-dimethylbutylthio, 1,1-dimethylbutylthio, 1,2-dimethylbutylthio, 1,3— Linear or branched having 1 to 6 carbon atoms, such as dimethylbutylthio, 2,3-dimethylbutylthio, or 2-ethylbutylthio Represents a chain alkylthio group, preferably a straight-chain or branched-chain alkylthio group having 1 to 4 carbon atoms, and more preferably methylthio, ethylthio, propylthio, isopropylthio, butyrthio, tertbutylthio. Most preferably, it is methylthio.

The “halogen atom” in the definition of [substituent group / 3] and [substituent group "y"] represents a fluorine atom, a chlorine atom, a bromine atom and an iodine atom. In the definitions of [Substituent group / 3] and [Substituent group γ], the term "amine residue" refers to an amino group; methylamino, ethylamino, isopropylamino, butylamino, dimethylamino, getylamino, diisopropylamino, dibutylamino. An amino group substituted by one or two "lower alkyl groups" such as "cyclopentylamino, cyclohexylamino, dicyclopentylamino, dicyclohexylamino" and "a cycloalkyl group having 5 to 7 carbon atoms" 1 or 2 substituted amino groups; Saturated cyclic amine residues having a nitrogen atom in the ring, such as pyrrolidino, piperidino, piperazino, Ν-methylbiperazino, morpholino, thiomorpholino; anilino, benzylamino, Ν-tylanilino 、, such as Ν-methylbenzylamino, nitrogen The aryl atom may be substituted by "lower alkyl ¾". An aryl or aralkylamino group; a nitrogen atom such as pyridyl amiso, Ν-methylpyri.dilamino, Ν-ethylpyridylamino may be substituted by "lower alkyl". Examples thereof include an amine residue bonded by a nitrogen atom such as an optionally substituted heteroarylamino group, and an amino group; a “lower alkyl group”; an amino group substituted by 1 or 2 amino acids; A saturated cyclic amine residue having a nitrogen atom in the ring, such as pyrrolidino, piperidino, piperazino, p-methylbiperazino, morpholino, and thiomorpholino; and anilino, benzylamino, p-methylanilino, p-methyl. Even if the nitrogen atom is replaced by a “lower alkyl group” such as benzylamino, aryl or arylalkyl No group.

 In the definitions of [substituent group | 3] and [substituent group γ], the term "a rubamoyl group optionally substituted with a nitrogen atom" refers to a group in which the above "amine residue" is bonded to a carbonyl group, and And a carbamoyl group in which a nitrogen atom is substituted with the above-mentioned “acyl group” or aminosulfonyl. Examples of such a group include methanesulfonylaminocarbonyl and aminomethanesulfonyl.

 “Hydroxy lower alkyl group” in the definition of [substituent group | 3] refers to a group in which the above “lower alkyl group” is substituted by a hydroxyl group. Examples of such a group include hydroxymethyl and hydroxy. Droxityl, hydroxypropyl and hydroxybutyl can be mentioned.

"Pharmacologically acceptable salt thereof" means that the compound (I) of the present invention has an amino group and an imine group. By reacting with an acid when it has a basic group such as a phenyl group, or by reacting with a base when it has an acidic group such as a carboxy group and / or an imido group. Since it can be made into a salt, the salt is shown.

 The salt based on a basic group is preferably a hydrohalide such as hydrofluoride, hydrochloride, hydrobromide, hydroiodide, nitrate, perchlorate, carbonate Inorganic salts such as salts, sulfates and phosphates; lower alkane sulfonates such as methanesulfonate, trifluoromethanesulfonate and ethanesulfonate, benzenesulfonate, p-toluenesulfonic acid Salts such as arylsulfonate, acetic acid, malic acid, fumarate, succinate, citrate, ascorbate, tartrate, oxalate, maleate, lactate, dalconate, benzoate Organic acid salts such as acid salts; and amino acid salts such as glycine salts, lysine salts, arginine salts, orditin salts, glutamate salts, and aspartate salts.

 On the other hand, the salt based on an acidic group is preferably an alkali metal salt such as a sodium salt, a potassium salt, or a lithium salt, an alkaline earth metal salt such as a barium salt or a magnesium salt, or a calcium salt. Metal salts such as aluminum salts, iron salts, etc .; inorganic salts such as ammonium salts, t-octylamine salts, dibenzylamine salts, morpholine salts, dalcosamine salts, phenyldaricin alkyl ester salts, ethylenediamine salts, and N-methylglucamine salts. , Guanidine salt, methylamine salt, dimethylamine salt, getylamine salt, triethylamine salt, diisopropylamine salt, cyclohexylamine salt, dicyclohexylamine salt, N, Ν'-dibenzylethylenediamine salt, chloroprocaine salt, propower Yin salt, Jetanoamine salt, Ν Amine salts such as organic salts such as benzylphenethylamine salt, piperazine salt, tetramethylammonium salt, and tris (hydroxymethyl) aminomethane salt; and glycine, lysine and arginine salts And amino acid salts such as orditin salt, glutamate and aspartate.

In the present invention, the term “thiol ester or other derivative” refers to a compound in which one or two thiol groups of the compound of the general formula (I) of the present invention are protected by a “thiol group-protecting group”. means. Examples of the “thiol protecting group” include, for example, 1 to 1 such as Jill, phenetinole, 1-pheninolepropyl, α-naphthinolemethyl, | 3-naphthinolemethyl, diphenylmethyl, tripheninolemethinole, α-naphthinolespheninolemethinole, 9-anthrylmethyl Lower alkyl group substituted with 3 aryl groups, 4-methylbenzyl, 2,4,6—trimethylbenzinole, 3,4,5—trimethinolebenzyl, 4-methoxybenzyl Λ ^, 4-meh Toxifeninoresifeninolemethinole, 2-nitrobenzinole, 4-nitrobenzinole, 4-chlorobenzinole, 4-bromobenzinole, 4-cyanobenzyl, lower alkyl such as piperonyl, lower alkoxy, nitro, An aralkyl such as a lower alkyl group substituted with one to three aryl groups in which the aryl ring is substituted with a halogen or cyano group; Groups: formyl, acetyl, propionyl, butyryl, isobutylinole, pentanoinole, pinocleinole, nocinole, nonocarbonyl, nonylcarbinole, decylcarbonyl, 3-methylnonylcarbonyl , 8 monomethylnonylcarbonyl, 3-ethyloctylcarbonyl, 3,7-dimethyloctylcarbonyl, pendecylcarbonyl, dodecylcarbonyl, tridecinole carbonyl, tetradecylcarbonyl, pentadecylcarbonel, hexadecylcarbonyl, 1 1-methylpentadecylcarbonyl, 14-methylpentadecylcarbonyl, 13-, 13-dimethyltetradecylcarbonyl, heptadecylcarbonyl, 15-methylhexadecylcarbonyl, octadecylcarbonyl, 1-methylhexyl Alkanoyl groups such as tadecyl carbonyl, nonadecyl canolebonyl, eicosyl carbonyl, henicosyl canolebonyl, halogenated alkylcarbonyl groups such as chloroacetyl, dichloroacetyl, trichloro acetyl, trifluoroacetyl, methoxy acetyl And lower alkylalkylcarbonyl groups, acryloyl, arylcanolevonyl, propioloyl, methacryloyl, crotonyl, isocrotonyl, and unsaturated alkylcarbonyl groups such as (Ε) -2-methyl-2-butenoyl. Aliphatic acyl group ”; Benzoyl, α-naphthyl, j3-naphthoyl-like arylcarbonyl group, 2'-bromobenzoinole, 4-chlorobenzoylene-like arylcarbonyl group , 2, 4, 6-trimethylbenzoyl, lower alkylated arylcarbonyl groups such as 4-toluoyl, lower alkoxylated arylcarbonyl groups such as 4-anisyl, 412trobenzyl, 2-trobenzoyl Such as a nitrated arylcarbonyl group such as a lower alkoxycarbonylated arylcarbonyl group such as 2- (methoxycarbonyl) benzoyl, and an arylated arylcarbonyl group such as 4-phenylbenzoyl; Lower-group alkoxycarbonyl groups such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, s-butoxycarbonyl, tert-butoxycarbonyl, and isobutoxycarbonyl; 2,2,2-trichloromouth ethoxycarbonyl "Alkoxycarbonyl group" such as lower alkoxycarbonyl group substituted by halogen or tri-lower alkylsilyl group such as 2-, trimethylsilylethoxycarbonyl; '; benzyloxycanoleboninole, 4-methoxypentinoleoxy 1 to 2 lower alkoxy or 2 tol groups, such as canoleboninole, 3,4,1; ^ methoxybenzyl carbonyl, 2-nitrobenzyl carboxy, 4,1 benzyloxycarbonyl An “aralkyloxycarbonyl group” in which the aryl ring may be substituted; benzylcarbonyl, phenacinole, 4-methoxybenzylcarbonyl, 3,4-dimethoxybenzylcarbinole, 2-d An aralkylcarbonyl group in which the aryl ring may be substituted with one or two lower alkoxy or ditro groups such as trobenzinolecanoleboninole and 412 trobenzylcarbonyl; "And the like. Preferred are an "aralkyl group", an "aliphatic acyl group", an "aromatic acyl group", an "alkoxycarbonyl group" and an "aralkyloxycarbonyl group". It is methoxybenzyl, triphenylmethyl, acetinole, benzoyl, 4-nitrobenzoyl, tert-butoxycarbonyl, benzyloxycarbonyl or 4-nitro-2-benzyloxycarbonyl.

 Furthermore, when the compound (I) of the present invention is left in the air, it may absorb water and may become adsorbed water or form a hydrate, and such salts are also included in the present invention. Is done.

 The compound (I) of the present invention has an asymmetric carbon in the molecule, and there are stereoisomers each of which is R-coordinate and S-coordination. Both are included in the present invention.

Examples of the dithiol derivative of the present invention include the following compounds qd- (oooia)--HN-oo-oz

^ d ■ (ooo) ■ z -HN- -oo- 6ΐ

^ d Doo) -f -HN- -oo- ■ 8ΐ

 -HN- ■ 00 "LI cHOOOH) -HN- ■ oo- V 91

¾d- (OOOH) -S -HN-oo-ST qd-OH -HN-oo-n

^ d ■ olΛ ■ z -HN- -oo- ετ

^ d ■ o -ψ -HN "-oo- Zl

^ d ■ o 'Z -HN- -oo- Π

 -HN- -oo- 01

• HN- -oo- 6

-HN- -oo- V 8

-HN- -oo- P L

-HN- -oo- f 9

• HN- -oo- s

-HN- -oo--

• HN- -oo- {:

^ d -HN "-oo- V z

H ■ HN- -o-I a.

 V Ά

(■ I) HS SH

u_g_ _V _ »(3 _H0 )-

. §-

OZ

ZZfS0 / 66df / 13d

IZ

Zhi S0 / 66dI7 丄 :) dl S8C0l / 00 ΟΛ \

9Ζ

H S0 / 66df / i:> d S8C0i / 00 O

203 4 -coo- i¾ fcfc A.

 Flat polo port 2-CN-Ph

204 4 -coo- flat '"Π mouth π 4-CN-Ph

205 4 -COO- Single bond 2- (HOCH ₂ ) -Ph

206 4 -COO- Single bond 4- (HOCH ₂ ) -Ph

207 4 -COO- Single bond Me

208 4 -COO- Single bond Et

209 4 -COO- Single bond Pr

 210 4 -coo- Single bond i-Pr

211 4 -coo- Single bond Bu

21; 24 -coo- single bond HOOCCH _2-

213 4 -coo- Single bond HOOC- (CH ₂ ) 2-

214 4 -coo- Single bond Me-CH (COOMe)-

215 4 -coo- Single bond 1-HOOC-i-Bu

216 4 -coo- Single bond l-HOOC-i-Pn

217 4 -coo- Single bond

 218 4 ■ COO- Single bond

 219 4 -COO- Single bond Position 3

220 4 -coo- Single bond Position 4

221 4 -coo- early bout mouth 5

222 4 -coo- Single bond Position 6

223 4 -coo- Single bond Place 7

224 4 -coo- Single bond

 225 4 -coo- Single bond Position 9

226 4 .-coo- single bond 10

227 4 -coo- half / ΐ mouth mouth position 11

228 4 -coo- Single bond Placement 12

6Z

Zhi S0 / 66df / 丄 :) d S8 £ 0Z / 00 OW -( ^Θ ΜΟΟΟ) ΗΟ " ^Θ Μ -OOHNOO- OSS

-0) ΌΟΟΗ ^ ¾South -OOHNOO- 6LZ

-(HOOO) HO- ^ M -OOHNOO- • P SLZ

½ΟΟΟΟ ^θ ΙΜ -OOHNOO- LIZ

-1HOOOOH ^ 'South -O0HNO3- 9LZ

 ¾ 南 ■ OOHNOO-LZ

 -OOHNO ^ ■ PLZ South -OOHNOO- P Z

¾3 -OOHNOO- V ZLZ

O Μ 'South ■ OOHNOO-ILZ

¾H OOH)-Minami-OOHNOO-OLZ

Hd- ( ^s HOOH) -S ¾tooth o ^ HNO ^-V 6dZ

-OOHNOO- P S9Z 导 ¾ * -OOHNOO "L9Z qd- (s ⁵ o N) • OOHNOO-99Z d- (S ^? 0 ² HN) '-S -OOHNOO- dZ qd- (s ^s OH)--OOHNOO -V nz qd- (S ^s OH) -S South South -OOHNOO- P

 ■ OOHNOO- P zdz

-OOHNOO- P

 'South ■ OOHNOO- V 09? ¾South -OOHNOO- P 6 2 ¾ * ■ OOHNOO- Ψ S Z

 -O HNOO- L Z 导 ¾ * -OOHNOO- V 99 S

■ OOHNOD-Z

08

Zhi S0 / 66df / 丄 :) d S8C0Z / 00 OW qd-siAHP's "OOHNOO-908

 'South -00 (3V) N00- 90S M Rain 雨 00 (3V) N00-'

 ^ d ■ 00 (^ V) N03- εοε

H -00 (3V) N00- Minami -OOHNOO- f τοε

^ ¾South ■ OOHNOO- οοε zi a 'South ■ OOHNOO- mz South • ΟΟΗΝΟ · f 86δ oi a ^ ¾South -OOHNOO- L6Z

6 a ^ 'South -OOHNOO- dGZ sm ^' • OOHNOO6Ζ

L B 导 ¾ ■ OOHNOO- V V6Z 导 'South • 00 plate 00 · 26Ζ

9 »^ ¾ Tooth ■ OOHNOO-V 7 Z S 导 ¾South ■ OOHNOO" IGZ ε¾ ^ 'South -O HNOO- ΰ ζ

ZM 导 ■ OOHNOO "Ψ 6SZ ΐ B ¾ 南-OOHNOO-P 88?

H ^C OS¾0 ^S HO Ma-OOHNOO-V LSZ

Minami -OOHNOO- 98?

'South ■ OOHNOO-SZ ud-t-ooo ⁹ wT 导 ¾South -o ^ HNO ^ ■ z ud- ト ΟΟΟΗ-ΐ ^^ South ■ OOHNOO- V

 J OOOH 导 ¾ * ■ OOHNOO-V ZSZ ηΗ · ϊ-ΟΟΟΗ-Τ ^ ¾South -O0HNO0 ■ V

12

Zh S0 / 66di7 丄 :) d S8 £ 0Z / 00 O 307 4 -CON (Ac) CO- Single bond 3,4-diMe-Ph

308 4 -CON (Ac) CO- Single bond 2- (CF ₃ ) -Ph

309 4 -CON (Ac) CO- Single bond 4- (CF ₃ ) -Ph

310 4 -CON (Ac) CO- Single bond 2-MeO-Ph

311 4 -CON (Ac) CO- Single bond 4-MeO-Ph

312 4 -CON (Ac) CO- Single bond 2-EtO-Ph

313 4 -CON (Ac) CO- Single bond 4-EtO-Ph

314 4 -CON (Ac) CO- Single bond 2-HO-Ph

315 4 -CON (Ac) CO- Single bond 4-HO-Ph

31G 4 -CON (Ac) CO- Single bond 2- (HOOC) -Ph

317 4 -CON (Ac) CO- Single bond 4- (HOOC) -Ph

318 4 -CON (Ac) CO- Single bond 2- (MeOOC) -Ph

319 4 -CON (Ac) CO- Single bond 4- (MeOOC) -Ph

320 4 -CO (Ac) CO- Single bond 2- (EtOOC) -Ph

321 4 -CON (Ac) CO- Single bond 4- (EtOOC) -Ph

322 4 -CON (Ac) CO- Single bond 2- (t-BuOOC) -Ph

323 4 -CON (Ac) CO- Single bond 4- (t-BuOOC) -Ph

324 4 -CON (Ac) CO- Single bond 2-Cl-Ph

325 4 -CON (Ac) CO- Single bond 4-Cl-Ph

326 4 -CON (Ac) CO- Single bond 2-Br-Ph

327 4 -CON (Ac) CO- Single bond 4-Br-Ph

328 4 -CON (Ac) CO- Single bond 2-I-Ph

329 4 -CON (Ac) CO- Single bond 4-I-Ph

330 4. -CON (Ac) CO- single bond 2-N0 ₂ -Ph

331 4 -CON (Ac) CO- Flat small mouth 4-N0 ₂ -Ph

332 4 -CON (Ac) CO-

Kou 'Shimoguchi 2-NH ₂ -Ph

-HN- -OOHNOO- 0

■ HN- ■ OOHNOO- f 6017, -HN- ■ OOHNOO "80 ^

¾J- (S ^ 01HN) -S -HN- ■ OOHNOO "

qc [-(s ^s OH) -HN- "OOHNOO" Hata

Hd- (S ^g OH) -S ■ HN- -OOHNOO "SO qd- N- -HN- -O0HNO0-

-HN- • O0HNO0 'P

 "HN- ■ OOHNOO" V

 -HN "-OOHNOO" 10

-HN "■ OOHNOO" 00

^{-HN- -OOHNOO- G68 qd- j a [•} HN- -OOHNOO- 868

 -HN "-OOHNOO- L6

Md-lO- ⁷ -HN-OOHNOO-968

• HN- -OOHNOO "V

Μ- (0ΟΟ ^η 9-ϊ)-^ -HN- OOHNOO- V62

-HN--OOHNOO-¾68

Ϊ 000ϊ3) HN- -OOHNOO- P? 68 d- (ooo a) -s -HN--OOHNOO "Τ68

¾ [-(οοο)-■ HN- ■ OOHNOO "V 068

¾-tooo ⁹ w) -s • HN--OOHNOD · G88 d- (OOOH) "^ -HN- ■ OOHNOD-

Md- (OOOH)-^ -HN- -O0HNO0-

4d-OH -HN- ■ OOHNOD-V 988

¾-ΟΗ2 -HN- -O ^ HNO0 ■

38

Ζ ひ S0 / 66dm d S8 € 0r / 00 O

98

ί ひ S0 / 66dm d (S8eOZ / 00 O 437 4 -CONHCO- -NH- s-BuO

438 4-CONHCO--NH- t-BuO

439 4 -CONHCO- Fuku-HxO

440 4-CO HCO--NH- PhO

441 4 -CO HCO- -NH- BnO

442 4 -CONHCO- -NH-

443 4 -CONHCO- -NH- Place 2

444 4-CONHCO--NH- Place 3

445 4 -CONHCO- -NH-

446 4 -CONHCO- -NH-

447 4 -CONHCO- -NH- 6

448 4 -CONHCO- -NH- Place 7

449 4-CO HCO--NH- Place 8

450 4 -CONHCO- -NH- Place 9

451 4 -CONHCO- -NH- Place 10

452 4 -CONHCO- -NH- Place 11

453 4 -CONHCO- -NH- Place 12

454 4 -CONHCO- -NH- 3-Py

455 4 -CONHCO- -NH- 4-Py

456 4 -CONHSO2- Single bond H

457 -CONHSO2- single bond Ph

458 4 -CONHS0 ₂ -Single bond 2-Me-P

459 4 -CONHSO2- Single bond 4-Me-Ph

460 4--CONHSO2- Single bond 2,4-diMe-Ph

461 4 -CONHSO-Single bond 3,4-diMe-Ph

462 4 -CONHSO2- Single bond 2- (CF ₃ ) -Ph

i66

in

 00 o

 〇〇H 〇§o 8 ooffi

 〇0 00

 〇ΐ 〇ΐ (

osffiN0 30 ε

α c ^ -ΟΟΗΝ- f 9

¾d- (〇oo ⁿ 8--• ΟΟΗΝ- f 8 ^ 9

'South "OOHN" ■ f zfd ¾ "OOHN" 9 d' (OOOia) -2 ¾South -OOHN- 09

v¾South -OOHN- 689

¾d- (OOO ^a IM) -S -OOHN- 889

^ d ■ (DOon)-South -OOHN- L2d

¾- (OOOH) -S ^ ¾South -OOHN- 989 qd-OH -OOHN- S89 d-OH-S 导 ¾South -OOHN- Hd

 ^ ¾South ■ OOHN-889

^ d ■ o -z ^ -OOHN- P Z2d

 "OOHN- f 189 South -OOHN- 089 导 -OOHN- GS9 s South -OOHN- SZd ¾ * -OOHN- LZd

¾ί-3] Α [? Ρ 'S ■ ODH-dZd

 -OOHN- Zd

-OOHN- fZ9 a α tooth -OOHN- £ ZD

H 导 ¾ * -O HN- ZZd d- -ΗΝ--^ OSHNOO- IZd

• ΗΝ--^ OSHNOO- OZd si a -ΗΝ- • ^ OSHNOD- V 619 n

Z HI S0 / 66df / on :) d S8 € 0Z / 00 OW

ZH S0 / 66di7 丄 :) d S8 £ 0Z / 00 O -ΗΝ "-OOHN" f S69

 "ΗΝ" ■ OOHN- '

 H "ΗΝ-OOHN" ψ g69

 'South ■ OOHN "V 269 ¾ ^ ■ 00 HN-169

Zl Jin00HN-069

Π g or -O HN- 689

01 a -Ό0ΗΝ- 889

6 S -OOHN- p ISd

8 a V 'South -O HN- 989

L S -OOHN- S89

9 8 v¾South -OOHN "^ 89 g SOOHN- 889 p a ^ ¾" O0HN-289

 ¾yoshi ■ OOHN "189 z ¾ ■ OOHN-

I a -OOHN- f

 -OOHN "SLd o ^ a South South -OOHN" p LLd

0 ⁹ MOOHN- 9Ld

v¾South • OOHN- L9

"Η- ^θ Μ-ζ-0ΟΟΗ-ΐ ^ ¾South -OOHN" V LB ud-ί-ΟΟΟΗ-τ ^ ¾South -O0HN- ^, Ld

"Η-ϊ-οοοΗ-τ South -O0HN- Ψ ZL9

-(9ΜΟΟ0) Η0- ^θ导 ¾OOHN-U9

9

ZZj7S0 / 66 <If lDd S8 £ 0Z / 00 OAV qd ^ ON- ■ HN- ■ OOHN- ZZL

 -HN- -03HN- f IZL

■ HN- -Ο0ΗΝ · OZL

^ d ■ l ■ z -HN- -OOHN "GIL

^ d ^^ ■ f ■ HN- -OOHN- SIL

^ d ■ ^ -z ■ HN "-ODHN- LIL

■ HN- -O0HN- IL

• HN- ■ OOHN- 91L

-HN- -OOHN- m d- (ooo ⁿ e-^)-sHN- -OOHN- f 21L

¾Ηοοο ■ HN- -OOHN- ZIL qd- (ooo-sHN- ■ OOHN- UL qd- (Doo ³ )--HN- -O0HN- OIL

^ d DOo) -z -HN- -OOHN- f GOL

Md-OOOH) "! ⁷ -HN- ■ 03HN- SOL d- (OOOH) -S -HN" -OOHN- LOL

■ HN- -OOHN- P dOL

-HN- -OOHN- f 90L

-HN- -OOHN- WL

• HN- ■ OOHN-0L

-HN- -OOHN- ZOL

• HN "-OOHN- P 10 L

■ HN- ■ OOHN- 00L

• HN- ■ OOHN- V 669

■ HN- ■ OOHN- V 8G9

-HN- -OOHN- V L6d

L

Z ^ S0 / 66df / lDd 58εθΓ / 00 OM <K71> one

A -NHCO- -NH- CH CH9SOQH

4 -NH CO- -Thigh -OH

4 -NHCO--H- MeO

4 -NHCO- -NH- EtO

4 -NHCO- -NH- PrO

4 -NHCO- -NH-

4 -NHCO- -NH- BuO

4 -NHCO- -NH- i-BuO

4 -NHCO- -NH- s-BuO

4 -NHCO- -NH- t-BuO

4 -NHCO- -NH- HxO

4 -NHCO- -NH- P O

4 -NHCO- -NH- BnO

4 -NHCO- -NH-

O

 4 -NHCO- -NH-

4 -NHCO- -NH-

4 -NHCO- -NH-

4 -NHCO- -NH-

4 -NHCO- -NH- 6

4 -NHCO- -NH- Place 7

4 -NHCO- -NH-

4 -NHCO- -NH-

4 -NHCO- -NH- Place 10

4.-NHCO- -NH-

4 -NHCO- -NH- Place 12

4 -NHCO- -NH- 3-Py -9HN- "OOHN" 008

 -9 Marauder- "OOHN" 66Z-

- ⁹顧-. ■ O0HN- f 86A nd- \ Dz - 3 noodles ^{- -OOHN- V LGL d- (ooo n} e ^) - ^ -S顧- ■ O0HN- 96Z-

¾d- (ooo ⁿ a-^)-s-9 麵--OOHN- V S6A

 -3 customers--OOHN- V6L d- (ooo ^ a) -s-9 customers--OOHN- 26L

 -S Marauder- ■ OOHN- ZSL

-S marauder- "OOHN- V 16L d- (OOOH)-^-3 customers- -OOHN- 06Z,

Hci- (OOOH) -S-3 customers--OOHN "68A

 -s 麵-■ OOHN- 88L

• 3 Marauders- ■ OOHN- L2L

-3 marauders.- OOHN-dSL

• 9 麵--OOHN- S8

-s marauder- • OOHN- VSL

-3 麵-■ OOHN- V SL rT-(^ TO)-^ 麵--OOHN- ZSL

• 9 Customer- -OOHN- Ϊ8

-S customer--OOHN- OSL

-9 麵--00 HN- 6LL

-3 Marauder- ■ OOHN- SLL

-S Customer--001- IN-LLL

¾d-S Band- ■ OOHN "V dLL

■ HN- -OOHN- V LL

OS

Zh S0 / 66JI7 丄 :) d S8 £ 0Z / 00 O

6 a -ΘPicture- ■ Ο0ΗΝ- Z S

8 - ⁹顧- -00ΗΝ- p IS8

 -9 customers-00HN- 0S8

-ΘReview- ■ 00HN- G ^ 8 sa-Reo- -00ΗΝ- 8 8 a -3 麵-■ 00HN- V LPS ε a -9Review- -00ΗΝ- 9 ^ 8 za -3 Marauder- ■ Ο0ΗΝ- S 8

- 9-screen ^{- -00ΗΝ "8 o u a -} 9 strokes - -00ΗΝ- fS o ^ d -9讀-" OOHN "ΖΨ8

0 ^X H -9 noodles - -00HN- 8 on -9 noodles ^{- ■ 00HN- 0 ^ 8 o n} a- s • 9顧^{- ■ 00HN- 688 o n a- -} ? 9顧- -O0HN- 888 o ⁿ a-3 customer--00HN- L2S o3 麵--00HN- 9έ8

• 9 continued- • 00HN- S88 o¾ • 3 麵-■ Ο0ΗΝ · ^ 88

0 • 3 麵--0DI-IN- 888

HO -S Customer- -O0HN- Z S

-3 difficult--00HN- ΐΒ'8 ng-ew-S OO ^Q MT-3 customers--00HN- 088 na-9M-s-oooH-i -s 麵--00HN- V GZS ud-i-D00 ⁹ WI • 9 麵--00ΗΝ · SZS ud10 OOOH-I-, Ν- -00HN- V LZS

Z

ZZfS0 / 66dT / 13d seeoz / oo OW 853 4 -NHCO- -NMe-

854 4 -NHCO- -NMe- g ll

85 4 -NHCO- -NMe-

8Γ) 6 4 -NHCO- -NMe- 3-Py

857 4 -NHCO- -NMe- 4-Py

858 4 -NHCO- -NHNH- H

859 4 -NHCO- -NHNH- Me

860 4 -NHCO- -NHNH- Et

861 4 -NHCO- -NHNMe- Me

8f? 2 4 -NHCO- -NHNMe- Et

863 4 -NHCO- -NHNMe- Pr

864 4 -NHCONHNHCO- -NH- H

865 4 -NHCONHNHCO- -NH- Ph

866 4 -NHCONHNHCO- -NH- 2-Me-Ph

867 4 -NHCONHNHCO--丽-4-Me-Ph

868 4 -NHCONHNHCO- -NH- 2,4-diMe-Ph

869 4 -NHCONHNHCO- -NH- 3,4-diMe-Ph

870 4 -NHCONHNHCO- -NH- 2- (CF ₃ ) -Ph

871 4 -NHCONHNHCO- -NH- 4- (CF ₃ ) -Ph

872 4 -NHCONHNHCO- -NH- 2-MeO-Ph

873 4 -NHCONHNHCO- -NH- 4-MeO-Ph

874 4 -NHCONHNHCO- -NH- 2-EtO-Ph

875 4 -NHCONHNHCO- -NH- 4-EtO-Ph

876 4 .-NHCONHNHCO- -NH- 2-HO-Ph

877 4 -NHCONHNHCO- -NH- 4-HO-Ph

878 4 -NHCONHNHCO- -NH- 2- (HOOC) -Ph 879 4 -NHCONHNHCO- -NH- 4- (HOOC) -Ph

880 4 -NHCONHNHCO- -NH- 2- (MeOOC) -Ph

881 4 -NHCONHNHCO- -NH- 4- (MeOOC) -Ph

882 4 -NHCO HNHCO- -NH- 2- (EtOOC) -Ph

883 4-HCONHNHCO--NH- 4- (EtOOC) -Ph

884 4 -NHCONHNHCO- -NH- 2- (t-BuOOC) -Ph

885 4 -NHCONHNHCO- -NH- 4- (t-BuOOC) -Ph

88G 4 -NHCONHNHCO- -NH- 2-Cl-Ph

887 4 -NHCONHNHCO- -NH- 4-Cl-Ph

888 4 -NHCONHNHCO- -NH- 2-Br-Ph

889 4 -NHCONHNHCO- -NH- 4-Br-Ph

890 4 -NHCONHNHCO- -NH- 2-I-Ph

891 4 -NHCONHNHCO- -NH- 4-I-P

_{892 4 -NHCONHNHCO- -NH- 2-N0 2} -Ph

_{893 4 -NHCONHNHCO- -NH- 4-N0 2} -Ph

894 4 -NHCONHNHCO- -NH- 2-NH ₂ -Ph

895 4 -NHCONHNHCO- -NH- 4-NH ₂ -Ph

_{896 4 -NHCONHNHCO- -NH- 2- (H0 3} S) -Ph

_{897 4 -NHCONHNHCO- -NH- 4- (H0 3} S) -Ph

_{898 4 -NHCONHNHCO- -NH- 2- (NH 2} 0 2 S) -Ph

_{899 4 -NHCONHNHCO- -NH- 4- (NH 2} 0 2 S) -Ph

900 4 -NHCONHNHCO- -NH- 2-CN-Ph

901 4 -NHCONHNHCO- -NH- 4-CN-Ph

902 4 .-NHCONHNHCO- -NH- 2- (HOCH ₂ ) -Ph

903 4 -NHCONHNHCO- -NH- 4- (HOCH ₂ ) -Ph

904 4 -NHCONHNHCO- -NH- Me 905 4 -NHCONHNHCO- -NH- Et

 906 4 -NHCONHNHCO- -NH- Pr

 907 4 -NHCONHNHCO- -NH- i-Pr

908 4 -NHCONHNHCO- -NH- Bu

 909 4 -NHCONHNHCO- -NH- HOOCCHj-

910 4-NHCO HNHCO--NH- MeOOCCH _2-

911 4-HCO H HCO- -NH- Me-CH (COOH)-

912 4 -NHCONHNHCO- -NH- HOOC- (CH ₂ ) _2-

913 4 -NHCONHNHCO- -NH- Me-CH (COOMe)-

914 4 -NHCONHNHCO- -NH-1 -HOOC-i-Bu

915 4 -NHCONHNHCO- -NH- 1-MeOOC Small Bu

916 4 -NHCONHNHCO- -NH-1 -HOOC-i-Pn

917 4 -NHCONHNHCO- -NH-1 -MeOOC-i-Pn

918 4 Measure ICONHNHCO- -NH- l-HOOC-2-Me-Bu

919 4 -NHCONHNHCO- -NH- l-MeOOC-2-Me-Bu

920 4 -NHCONHNHCO- -NH- CH ₂ CH ₂ S0 ₃ H

921 4 -NHCONHNHCO- -NH- OH

 922 4 -NHCONHNHCO- -NH- MeO

923 4 -NHCONHNHCO- -NH- EtO

 924 4 -NHCONHNHCO- '-NH- PrO

 925 4 -NHCONHNHCO- -NH- i-PrO

926 4 -NHCONHNHCO- -NH- BuO

927 4 -NHCONHNHCO- -NH- i-BuO

928 4 .-NHCONHNHCO- -NH- s-BuO

929 4 -NHCONHNHCO- -NH- t-BuO

930 4 -NHCONHNHCO- ■ NH- HxO J-Π OJ

W ni KT.-Oo ■ Π M Π WM-

Hd F l M J ^ JTL

 -7a

 \ J 1 oc ^ 7S

--, Π Τ Μ Μ Π Π ΗΛΤ-tIr -0TAT-7 Ma JriJM Jr J l U U nd. Ma tJirl Nl rll \ L

 u α, ^ Y

 i v -Π Μ1 NT nJ v ^ UT NMT-

-ODHNFT-TMODHNF- u

 J q

7T M JL J b ττ H i

 -UNJ--Π KT T- M Π H NT-a direct -t JNT- J tl J JHL U U 1 f oi o-Π U iJ U t M TJ N MT Π ^ J UHL 1 N> Tί-rllN -Ο UT Γ-1T M r TUll NT UiJ rl I MN. * Uoo y -T rJll Mv--U Jrt NT TJ i N> Ti T iJ "NT-ooO o * ¾ -T NT--T- T NT Τ-Τ ΜΠ ^ ΤΚΤ- I) p wealth rllM -Π Τ ~ Γ NT Τ-Τ \ Τ m Τ no-no?

 ) g ¾ η

 g ¾ -HN- -OOHNHNOOHN- p ¾G im -HN- -OOHNHNOOHN- V 8¾G

0 ^U 9 -HN- -O0HNHNO0HN- V Z2G

0¾d -HN-OOHNHNOOHN-IC6

99

rZt'S0 / 66Jf / I3d S8C0Z / 00 O 957 4 -NH CONHCO- <rfc A

 Flat pp mouth 2-EtO-Ph

958 4 -NHCONHCO- Single bond 4-EtO-Ph

959 4 -NHCONHCO- single bond 2-HO-Ph

960 A -NH CONHCO- Single bond 4-HO-Ph

961 A -NHCONHCO- Single bond 2- (HOOC) -Ph

962 A -NHCONHCO- Single bond 4- (HOOC) -Ph

963 4 -NHCONHCO- Single bond 2- (MeOOC) -Ph

964 4 -NHCONHCO- Mouth Mouth 4- (MeOOC) -Ph

965 A -NHCONHCO- tp port .2- (EtOOC) -Ph

9 (3 Γ 4 -NHCONHCO- single bond 4- (E OOC) -Ph

967 4 -NHCONHCO- Single bond 2- (t-BuOOC) -Ph

968 A -NHCONHCO- Single bond 4- (t-BuOOC) -Ph

969 4 -NHCONHCO- Single bond 2-Cl-Ph

970 4 -NHCONHCO- Single bond 4-Cl-Ph

971 4-NHCO HCO-Single bond 2-Br-Ph

972 4-HCO HCO- Single bond 4-Br-Ph

973 4 -NHCONHCO- Single bond 2-I-Ph

97 4 -NHCONHCO- Single bond 4-I-Ph

975 4 -NHCONHCO- single bond _2-N0 2 -Ph

976 4 -NHCONHCO- single bond 4-N0 ₂ -Ph

977 4 -NHCONHCO- Single bond 2-NH ₂ -Ph

978 4 -NHCONHCO- Single bond 4-NH ₂ -Ph

979 4 -NHCONHCO- Flat b Π 2- (H0 ₃ S) -Ph

980 4 - -NHCONHCO- single bond 4- (H0 ₃ S) -Ph

981 4 -NHCONHCO- single bond _{2- (NH 2 0 2 S)} -Ph

982 4 -NHCONHCO- single bond _{4- (NH 2 0 2 S)} -Ph ■ OOHNOOHN '8001

0 ^J dT 'South -OOHNOOHN' Ζ, ΟΟΐ

 ^ ¾South -OOHNOOHN "'9001

■ OOHNOOHN- 900 T o -OOHNOOHN- 1/00 T 导 'South ■ OOHNOOHN- εοοτ η9- ^θ Μ-ζ · οοο ⁹ ΐΑ [-τ -OOHNOOHN- ΐ nQ- ⁹ lA [-S-000H-I -ΐθθΐ ud small ΟΟΟ ^θ ΙΑ [-Ι ■ OOHNOOHN "p οοοι ud-T OOH-T ^ South ■ OOHNOOHN" 666 n8 0009 ΐ

-(9WOO0) H0-9W South South -OOHNOOHN- 966

^-ί (^ Η) "Γ) ΩΠΗ -OOHNOOHN- 966

■ (Η000) Η0 " ^Θ 1Λ [导 ¾ * -O HNOOHN" 1 / 6G

 ¾ * -OOHNOOHN "p 866

-^ HO OOH ¾OK -OOHNOOHN- t 266

 ¾South ■ OOHNOOHN- 166 导 ¾ * -OOHNOOHN- P 06G v¾South "OOHNOOHN" p 686

^ ¾ -OOHNOOHN- 886 ¾ -OOHNOOHN "L86

Hd- ^ HOOH)-^ ¾South -OOHNOOHN- \ 986 qd- ( ^s H OH) -S ¾South -ODHNOOHN- ¾86

Md-NO-l'OOHNOOHN- V 1 ^ 86

 -OOHNOOHN- £ '86

89

rifS0 / 66df / X3d S8 € 0Z / 00 OAV 1009 4 -NIICONHCO- Single bond i-BuO

1010 4 -NH CONHCO- Single bond s-BuO

1011 4 -NH CONH CO- early; f¾guchi t-BuO

1012 4 -NHCONHCO- Single bond HxO

1013 4 -NHCONHCO- Single bond PhO

1014 A -NH CONHCO- Single bond BnO

1015 4 -NHCONHCO- single bond 1

1016 4 -NHCONHCO- Single bond Position 2

1017 4 -NHCONHCO- Table B Location 3

10L8 4 -NHCONHCO- Single bond 4

1019 4-NHCONHCO-Single bond 5

_{Έ Γ}

 1020 4 -NHCONHCO- single bond

 1021 4 -NHCONHCO- single bond

 1022 4 -NHCONHCO- single bond

 1023 4 -NHCONHCO- single bond

 1024 4 -NHCONHCO- ^-^ p 'Position 10

1025 4 -NHCONHCO- single bond

 1026 4 -NHCONHCO- Single bond Position 12

1027 4 -NHCONHCO- Single bond 3-Py

1028 4 -NHCONHCO- Single bond 4-Py

1029 4 -NHCONHS0 ₂ -Single bond H

1030 4 -NHCONHS0 ₂ -Single bond Ph

1031 4 -NHCONHSOj- Single bond 2-Me-Ph

1032 4- '-NHCONHSO2- single bond 4-Me-Ph

1033 4 -NHCONHSO2- Single bond 2,4-diMe-Ph

1034 4 -NHCONHSO2- Single bond 3,4-diMe-Ph

1139 4 -NHCO- Pyr

1140 4 -NHCO- Pipri

1141 4 -NHCO- Pipra

1142 4 -NH CO- Mor

1143 4 -NHCO- Thmor

1144 4 -NHCO- -NH-Pyr

1145 4 -NHCO- -NH-Pipri

1146 4 -NHCO- -NH-Pipra

1147 A -NHCO- -NH-Mor

1148 A -NHCO- -NH-Thmor

1149 4-CONHCO-Pyr

1150 4 -CONHCO- Pipri

1151 4 -CONHCO- Pipra

1152 4 -CONHCO- Mor

1153 4 -CONHCO- Thmor

1154 4 -CONHCO- -NH-Pyr

1155 4 -CONHCO- -NH-Pipri

1156 4 -CONHCO- -NH-Pipra

1157 4 -CONHCO- -NH-Mor

1158 4 -CONHCO- -NH-Thmor

1159 4 -CONHSO2- Pyr

1160 4 -CONHSO2- Pipri

1161 4 -CONHSO2- Pipra

1162 4--CONHSO2- Mor

1163 4 -CONHSO2- Thmor

1164 4 -CONHSO2- -NH-Pyr

 Φ

 〇H 4

 C〇〇N: HS

 NH c〇s〇Nn

 NHPi c〇〇Nisi-

NHPi COONHJS- L

L T L

 99

ZZ ^ S0 / 66clf / XDd S8 £ 0Z / 00 O W 00/2 85

 67

1217 4 -CO- -NMe- Pr

 1218 4 -CO- -NMe- i-Pr

1 21!) A -CO- -NMe- Bu

1220 4 ■ co- -NMe- HOOCCH _2-

1221 4 -co- -NMe- MeOOCCH ₂ -

1222 4 -co---NMe- Me-CH (COOH)-

1223 4 -co- -NMe- HOOC- (CH ₂ ) _2-

1224 4 -co- -NMe- Me-CH (COOMe)-

1225 4 -co- -NMe- 1-HOOC-i-Bu

1226 4 -co- -NMe- 1-MeOOC-i-Bu

1227 4 -co- -NMe-1-HOOC-i-Pn

1228 4 -co- -NMe-1-MeOOC-i-Pn

1229 4 -co- -NMe- l-HOOC-2-Me-Bu

1230 4 -co- -NMe- l-MeOOC-2-Me-Bu

1231 4 -co- -NMe- CH2CH2SO3H

1232 4 -co- -NMe- OH

 1233 4 -co- -NMe- MeO

1234 4 -co- -NMe- EtO

 1235 4 -co- -NMe- PrO

 1236 4 -co- -NMe- i-PrO

1237 4 -co- -NMe- BuO

1238 4 -co- -NMe- i-BuO

1239 4 -co- -NMe- s-BuO

1240 4 .-co- -NMe- t-BuO

1241 4 -co- -NMe- HxO

1242 4 -co- -NMe- PhO 1243 4 -CO- -NMe- BnO

1244 4 -CO- -NMe-

1245 4 -CO- -NMe-

1246 4 -CO- -NMe-

1247 4 -CO- -NMe-

1248 4 -CO- -NMe-

1249 4 -CO- -NMe-

1250 4 -CO- -NMe-

1251 4 -CO- -NMe-

12.4 -co--Marauder e-place 9

1253 4 -co- -NMe-

1254 4 -co- -NMe-

1255 4 -co- -NMe-

1256 4 -co- -NMe- 3-Py

1257 4 -co- -NMe- 4-Py

1258 4 -co- T iad

1259 4 -CO- -NH-Thiad

1260 4 -NHCO- Thiad

1261 4 -NHCO- -NH-Thiad

1262 4 -CONHCO- Thiad

1263 4 -CONHCO- -NH-Thiad

1264 4 -CONHS0 ₂ -Thiad

1265 4 -CONHS0 ₂ --NH-Thiad

1266 4 .-NHCS- -NH- H

1267 4 -NHCS- -NH- Me

1268 4 -NHCS- -NH- Et

OL

seeor / oo OM

Pon

ζ ひ 50/66 <117 丄:) <1 S8C0Z / 00 OAV

ZL

S8 £ 0 00 OAV

PL

Zhi S0 / 66dr / 丄 :) d S8C0Z / 00 ΟΛ

L

9L

ZZPSQ / 66dT / lDd seeor / oo OM

1503 5 -coo- Single bond 2-CN-Ph

1504 5 -coo- Single bond 4-CN-Ph

1505 5 -coo- Single bond 2- (HOCH ₂ ) -Ph

1506 5 -coo- Single bond 4- (HOCH ₂ ) -Ph

1507 5 -coo- Single bond Me

1508 5 -coo- Single bond Et

1509 5 -coo- Single bond Pr

1510 Γ) -coo- Hiraguchi a ι-Pr

1511 5 -coo- Single bond Bu

1512 5 -coo- Single bond HOOCCH _2-

1513 5 -coo- Single bond HOOC- (CH ₂ ) _2-

1514 5 -coo- Single bond Me-CH (COOMe)-

1515 5 -coo- Single bond l-HOOC-i-Bu

1516 5 -coo- Single bond 1-HOOC-i-Pn

1517 5 -coo- Single bond 1

1518 5 -coo- Single bond Position 2

1519 5 -coo- Single bond Position 3

1520 5 -coo- Single bond 4

1521 5 -coo- Single bond Place 5

1522 .5 -coo- single bond 6

1523 5 -coo- ψ- ϊί ^ Oral 7

1524 5 -coo- Single bond Position 8

1525 5 -coo- Single bond Position 9

1526 5.-coo- single bond 10

1527 5 -coo- Single bond Placement 11

1528 5 -coo- Single bond Placement 12

6L

ZZfS0 / 66df / X3d s8eor / oo ΟΛ \ ' ^Λ \ -ί¾ OJHNOO s 089T

H ⁶ HOrOOOH UJ UN J

 o

UJrlNUJ

 f ~

 UJrlNUJ LL, J L

° H0DOOH v UJrlNUJ

 t r

 UJrlNUJ 、, j V Ma ¥ ¾ UJrlNUJ ゝ

 a. , O P

 J i JM J

V Fu UJHNUJ ZL ^ L

Q (JJHNUJ

 J- ^ HOOH)-^ Ma UJHNUJ OL ^ L

^ I- ^ HOOH)-^ Ma ΐ? Rain-M-d.NlJ V-^ U NJO f,

 a *

 .Q J O a

V Teru OU sri 0

 > i \ JvJ i / << i "n

 UJrlNUJ L ctHS ^ OH)-^ Ma Rain

¾d- (S ^£ OH) -S OJHNOJ rt

 l

 ¾ΗΗΝ-OJHNOJ

d- ^J HN-S South U JiiNUJ v Rain U ϋΗ υ J

 Ma O 0 T na 1 V V 1 q Q OCOT

^ ¾South -Ο0ΗΝΟ0- (j * -ΟΟΗΝΟΟ-9

 -OOHNOO- (J 9Ϊ

08

Hi S0 / 66dfAL d S8 £ O recitation O 1581 5 -CONHCO- Single bond 1-HOOC- i-Bu

1582 5 -CONHCO- Single bond 1-MeOOC small Bu

1583 5 -CONHCO- Single bond 1-HOOC-i-Pn

1584 5 -CONHCO- Single bond 1-MeOOC-i-Pn

1585 5 -CONHCO- Single bond l-HOOC-2-Me-Bu

1586 5-CONHCO-Single bond l-MeOOC-2-Me-Bu

1587 5 -CONHCO- Single bond CH ₂ CH ₂ S0 ₃ H

1588 5-CO HCO-single bond 1

1589 5-CONHCO-Single / Place 2

1590 5 -CONHCO- Single bond 3

1591 5 -CONHCO- Single bond Position 4

1592 5 -CONHCO- Single bond 5

1593 Γ) -CONHCO- Single bond 6

1594 5 -CONHCO- Single bond 7

1595 5 -CONHCO- single bond

 1596 5 -CONHCO- Single bond Position 9

1597 5 -CONHCO- Place 10

1598 5 -CONHCO- Single bond Position 11

1599 5 -CONHCO- Single bond Position 12

1600 5 -CONHCO- Single bond 3-Py

1601 5 -CONHCO- Single bond 4-Py

1602 5 -CON (Ac) CO- Single bond H

 1603 5 -CON (Ac) CO- Single bond Ph

 1604 5 -CON (Ac) CO- Single bond 2-Me-Ph

1605 5 -CON (Ac) CO- Single bond 4-Me-Ph

1606 5 -CON (Ac) CO- Single bond 2,4-diMe-Ph

S8

ZZPS0 / 66dT / LOd S8 £ 0Z / 00 OAV 1711 5 -CONHCO- -NH- 2- (HOCH ₂ ) -Ph

17125 -CONHCO- -NH- 4- (HOCH ₂ ) -Ph

1713 5 -CONHCO- -NH- Me

 1714 5-CONHCO--NH- Et

 1715 5 -CONHCO- -NH- Pr

 1716 5 -CONHCO- -NH- i-Pr

1717 5 -CONHCO- -NH- Bu

1718 5 -CONHCO- -NH- HOOCCH _2-

1719 5 -CONHCO- -NH- MeOOCCH _2-

1720 5 -CONHCO- -NH- Me-CH (COOH)-

1721 5 -CONHCO- -NH- HOOC- (CH ₂ ) _2-

1722 5 -CONHCO- -NH- Me-CH (COOMe)-

1723 5 -CONHCO- -NH- 1-HOOC-i-Bu

1724 5 -CONHCO- -NH- 1-MeOOC-i-Bu

1725 5 -CONHCO- -NH- 1-HOOC-i-Pn

1726 5 -CONHCO- -NH- 1-MeOOC-i-Pn

1727 5 -CONHCO- -NH- l-HOOC-2-Me-Bu

1728 5 -CONHCO- -NH- l-MeOOC-2-Me-Bu

1729 5 -CONHCO- -NH- CH ₂ CH ₂ S0 ₃ H

1730 5 -CONHCO- -NH- HO

 1731 5 -CONHCO- -NH- MeO

1732 5 -CONHCO- -NH- EtO

 1733 5 -CONHCO- -NH- PrO

 1734 5 .-CONHCO- -NH- i-PrO

1735 5 -CONHCO- -NH- BuO

1736 5 -CONHCO- -NH- i-BuO

rZfS0 / 66df / XDd S8 £ 0Z / 00 OAV

t

^ 6

HI S0 / 66cU7JL:> d S8 € 0r / 00 OAV a 齿

^{- J (¾0) -0OOH ■ OOHN-} S 0L61

"(ΗΟΟΟ) ΗΟ-ΘΜ South -OOHN- S 6961

½00009W V ■ OOHN- '8961 a. *

 -¾OOOOH -OOHN- 9 961 na ^^ South -OOHN- 9 9961

¾ * ■ OOHN- ' ⁽ J96I

 -OOHN- ΐ

OOHN- S 896T South -OOHN- 9 S9GT qd- (tooH)-^ ¾ -OOHN- 9 Τ96ΐ

Hd- ( ^? HOOH) -2 O HN- 9 09GI qd-ND ¾ -OOHN- S G96T

-OOHN- 9 8961 d- (S ^s O¾)-^ ¾South -OOHN- SZ, S6T d- (S ^ O ^s HN) "Z ¾ * OOHN- 9 9 ⁽ J6I qd- (s ^s OH tooth- OOHN- 9 gs6i qd- (sk) H) -s South South OOHN- (J

 ¾South -OOHN-S 8S6Is South -OOHN- 9? set

^ ¾South -OOHN-

^ d ■ ^l OR-z 导 ¾ south -O HN- 9

 nd-i- Minami -OOHN- S 6 6l

^ d-l ■ z ^ ¾South -OOHN-9

qd- ^j g -OOHN-

^ ά ■ ^ -z ^ 亩 -OOHN- S 9 ^ 61 a-io-t ⁷ ¾ 亩 -OOHN- 9 ΰΐ'βΐ

96

Zhi S0 / 66df / i:> d

86

ZZfS0 / 66 «ir / lDd S8C0Z / 00 Ο / Λ ■ HN- -OOHN-S m OS zi m -HN- -OOHN-S 2L0Z

IT a ■ HN- -OOHN- • s ZLQZ ox a -HN- -OOHN- s I LQZ

6 SHN- -OOHN- (J 0

8H ■ HN- -OOHN- 690S

LH ■ HN- • OOHN- 2 890S

9 a -HN- -OOHN- S L90Z

 -HN- -O0HN- S 9902 v m -HN-O0HN- S S90S

■ HN- ■ OOHN- Sza -HN- -OOHN- 9 ε 爾-喜 -HN- ■ OOHN- S zdoz

 -HN- -OOHN- S 190S

■ HN- ■ OOHN- s OdOZ

O ^x H -HN- -OOHN- (JGZ

 -HN- -OOHN- s4bz

■ HN "-OOHN- s L 0Z o ⁿ aT ■ HN" -OOHN- 9 9S0S o ⁿ e -HN- -OOHN- S SS02 ow -HN- -ODHN- (J 0Z

 -HN- ■ OOHN-

-HN- -OOHN- S Z 0Z

-HN "• OOHN- 1902

HO -HN "-OOHN- S OSOS

H ^c OS¾0¾0 -HN- -OOHN- y 6V0Z

66

ί ひ S0 / 66dfALOd S8 £ 0r / 00 OW -9MN- ■ O0HN- 9 001 s

 , N--OOHN- 660S

-s picture- ■ ΟΟΗΝ · S 8G0S

M-10-2-9 customers-OOHN- S L60Z

 -s Customer--OOHN- 2 960S

-3 strokes--O0HN- S 60Z

-Animation--O0HN- 9 60S

^ d DOo) -z-9 strokes--OOHN- 9 60Z

 -9 customers-O0HN- Z60Z

-S 麵--OOHN- 9 1602 qd- (OOOH)--3 continued--ODHN- 9 060? D- (OOOH) -S -9

 -S customer--O0HN- Q 8802 nd-on-z-9 麵-OOHN- S LS0Z 麵--OOHN- 9 980?

-9 customer--O0HN- 9 S802

-S customer-■ O0HN- 9 mz

-9 strokes--O0HN- S 2S0Z

-3 麵--OOHN- 2 2802

-3 strokes-OOHN- 9 180S

-Θ Θ--ODHN- 080S

-3 customers--OOHN- GL0Z

-s 麵--OOHN- S SL0Z

-3 Customer-OOHN "(J LLQZ

^ d-3 strokes--OOHN "S dLOZ

 -HN- -00 HN- 9 (J

00 ΐ

IZfrS0 / 66clf / lDd S8 £ 0Z / 00 OM

TOT

ZZfS0 / 66df / XDd SSZOZ / 00 OW 6 翟 • 3 brain- -OOHN- S

 sa 9 marauder--OOHN- S

AS-S marauder--OOHN- S 0 1Z dm-9 customers--OOHN- 9 Gnz

9 翟 -9 Marauder- ■ OOHN- S Ki-9 Marauder- -OOHN- tnz

8 S - 9 wicked person - -OOHN- S dnz zm -9 noodles - ■ OOHN- 9 nz l Hee -Θ續- -OOHN- S mz o ^u e -3顧- -OOHN- 9 nz o ^ d - 3 wicked person -■ OOHN- 9 znz

0 ^X H - 3 Yuzuru - -OOHN- S mz ow • 3 flame ^{- -OOHN- S OPIZ o n es -} S wicked person - -OOHN- 681 so ⁿ ai -Θ noodles ^{-? ■ OOHN- S 881 o n} a • 3Kan- -OOHN- ΰ ίΐ, ΙΖ o-3 customers-OOHN- (J 981?

-9 Customer--OOI-IN- (J

 -sread- -OOHN- (J mz

-3 sect- • OOHN- S

 HO -3 Marauder- • OOHN- 9 Z21Z

H ^s OS¾O ^z HO-3 Marauders--ODHN- 1 1Z

 -3 marauders- ■ OOHN- ΟΫ, ΙΖ na-Qw-s-oooH-i9 marauders- -ΟΟΗΝ · (J GZdZ

 -3 Marauders-• OOI- IN · S SZIZ ud-x-OOOH-I-匪 Marauders--OOHN- S LZIZ

SOT

ZZfrS0 / 66ir / X3d S8 £ 0Z / 00 O

■ HN- ΟΗΝΗΝΟΟΗΝ "S ozz qd- (tooH)--HN- • O0HNHNO0HN- S mzz

^ d ■ (RDOU) ■ Z -HN- ■ OOHNHNOOHN- ■ S ZQZZ

■ HN- ■ O0HNHNO0HN- 9 wzz

■ HN- ■ OOHNHNOOHN- S 00

-HN- -OOHNHNOOHN- S 66TS

-HN- ■ OOHNHNODHN- 9 86IS

■ HN- ■ OOHNHNOOHN- ⁽ J qd- (S ^e 0H) "3 -HN- -O0HNHNO0HN- 9 96IS

■ HN- ■ OOHNHNOOHN- 9

 -HN-OOHNHNOOHN- 9 VGIZ

-HN- OOHNHNOOHN- 9 8613

^ d ■ ^l O! ί ■ z -HN "-O0HNHNO0HN- S ζο, ιζ

^ d ■ l'ψ HN- -OOHNHNOOHN- S Ϊ6Ϊ3

^ d ■ ι ■ z ■ HN- ■ OOHNHNOOHN- 9 061 S

 -HN- -OOHNHNOOHN- 9 68TS

^ d ■ ^ ■ z -HN- -OOHNHNOOHN- S 881 S

^ d ■ D · ψ • HN- ■ OOHNHNOOHN- S LSIZ

Hd-10-2 -HN- -OOHNHNOOHN- (j 98 ΐ 2

¾Κ ΟΟ ^η 3 '-HN- ■ OOHNHNOOHN- ¾8ΐζ

Hd- (ooo ⁿ e-'4) -s -HN- -OOHNHNOOHN- SIZ

 -HN- -OOHNHNOOHN-

¾- (ooo ^ a) -s -HN- -OOHNHNOOHN- Q

-HN- OOHNHNOOHN- T8TS d- (000 ⁹ W) -S -HN- -OOHNHNOOHN- S

 Md- (OOOH)-^ ■ HN- ■ OOHNHNOOHN "6L \ Z

lifS0 / 66df / IDd S8 £ 0Z / 00 OAV

-_

Θ-

¾ South -ΟΟΗΝΟΟΗΝ- S

 ^ ¾ -ΟΟΗΝΟΟΗΝ- S qd-to)-3 south -ODHNOOHN- '(' S

 ^ ¾SouthΟΟ0ΗΝΟ0ΗΝ-9

- ⁹ Sir - 's α. -ΟΟΗΝΟΟΗΝ- S

 导 • OOHNOOHN "Q α -OOHNOOHN-

^ 'South -OOHNOOHN- S

 'South -OOHNO HN- 9

 H 导 'South ■ OOHNOOHN-9

 -ΗΝ- ΟΗΝΗΝΟΟΗΝ-

■ ΗΝ- -ΟΟΗΝΗΝΟΟΗΝ · 9

Zlki -ΗΝ- • OOHNHNOOHN- S π S ■ ΗΝ- ■ OOHNHNOOHN- 92 2fZZ

01 m -ΗΝ- ΟΗΝΗΝΟΟΗΝ- (J znz

 -ΗΝ- ■ OOHNHNOOHN "S wzz sm -ΗΝ- -ΟΟΗΝΗΝΟΟΗΝ- (J O ZZ

L ■ ΗΝ- • OOHNHNOOHN · S G ZZ

9 m -ΗΝ- • Ο ΗΝΗΝΟΟΗΝ

I a -ΗΝ- ■ OOHNHNOOHN "ΰ

 -ΗΝ- • ΟΟΗΝΗΝΟΟΗΝ- (J Z ZZ

O d ■ ΗΝ- • OOHNHNOOHN · (j \ ZZ

901

J: hi S0 / 66df / 丄 :) d S8 € 0I / 00 O 2257 5 -NHCONHCO- fast bond 2-EtO-Ph

2258 5 -NHCONHCO- Early 4-EtO-Ph

2259 Γ) -NHCONHCO- fast bond 2-HO-Ph

2260 5 -NHCONHCO- fast bond 4-HO-Ph

2261 5 -NHCONHCO- Single bond 2- (HOOC) -Pn

2262 5 -NHCONHCO- Compound 4- (HOOC) -Ph

2263 5 -NHCONHCO- fast bond 2- (MeOOC) -Ph

2264 5 -NHCONHCO- Early) 4- (MeOOC) -Ph

2265 5 -NHCONHCO- Hayago 2- (EtOOC) -Pn

22B6 5 -NHCONHCO- fast bond 4- (EtOOC) -Ph

22G7 5 -NHCONHCO- fast bond 2- (t-BuOOC) -Ph

2268 5 -NHCONHCO- bond 4- (t-BuOOC) -Ph

2269 5 -NHCONHCO- Single 2-Cl-Ph

2270 5 -NHCONHCO- Single bond 4-Cl-Ph

2271 5 -NHCONHCO- Table? 2-Br-Ph

2272 5 -NHCONHCO- early 'g combined 4-Br-Ph

2273 5 -NHCONHCO- bond 2-I-Ph

2274 5 -NHCONHCO- Single bond 4-I-Ph

2275 5 -NHCONHCO- fast binding

 2276 5 -NHCONHCO- Single bond 4-NU2- h

2277 5 -NHCONHCO- 'Single bond 2-H2-Ph

2278 5 -NHCONHCO- 早 合 4-J rl2- n

2279 5 -NHCONHCO- Single bond 2- (H0 ₃ S) -Ph

2280 f) .- NHCONHCO- single bond 4- (HOgS) -Ph

2281 5 - NHCONHCO - Single _{/ 2- (NH 2 0 2 S} ) -Ph

2282 5 -NHCONHCO- single bond _{4- (NH 2 0 2 S)} -Ph o ⁿ e ¾South -OOHNOOHN "S 808S

 tn w meal -OOHNOOHN- S 导 ¾South ■ OOHNOOHN- • 9 908S o¾ 导 'South -OOHNOOHN- S 308?

0, -OOHNOOHN- e OSS

H OS¾0¾0 ^ 'South -OOHNOOHN- s

Ma T¾> s¾ -OOHNOOHN- 9 2082

导 ¾South -OOHNOOHN- 9

«D- t-000 ⁹ -T South South -OOHNOOHN- 0082

«D-ΐ ΟΟΗ-ΐ ■ OOHNOOHN" s n30 ooosw-τ ^ 'South -OOHNOOHN- s S6ZZ ne-ΐ-οοοΗ-ΐ 导 ¾ * ■ OOHNOOHN- s LGZZ

■ (9WOO0) H0-9W ■ OOHNOOHN-s d6ZZ

- ⁵ (¾0) -000H -OOHNOOHN-

-(HOO.) H0- • OOHNOOHN- (J βΖΖ

-OOHNOOHN- (J 6ZZ

■ tooooH 导 ¾ * • OOHNOOHN- s ΖβΖΖ ne ¾South • OOHNOOHN-s

 -O ^ HNOOHN- s 062?

■ OOHNOOHN-s

 -OOHNOOHN- 9

 -OOHNOOHN- ΰ qd- (too 'South -OOHNOOHN- 9

^ d ^l HDOU) -Z-OOHNOOHN "S

 • OOHNOOHN- (J South-OOHNOOH-(J

801

Ζ ひ S0 / 66dfAL:><I S8C0Z / 00 OW ^ 'South-^ OSHNOOHN- S 2Z 导'-^ OSHNOOHN "S 8883 导 ¾South-^ OSHNOOHN- SZZ

^ South-^ OSHNOOHN- 9 Ma-^ OSHNOOHN- 022Z

H ¾South-^ OSHNOOHN- S GZ Z

 -O0HNO0HN- 9

 -OOHNOOHN- S LZ Z ζι SOOHNOOHN- 9

U S Ma ΐ¾ South -OOHNOOHN- 9 Z Z

01 S -OOHNOOHN-

6 M ¾ -OOHNOOHN- 9 2Z £ Z

8S 导 ¾ * ■ OOHNOOH-9 ZZ £ Z

L m -OOHNO ^ HN- 9 's

9 a ¾South -OOHNOOHN- 0Z Z m South ■ OOHNOOHN- 9

 ¾South ■ OOHNODHN- 9 8 res

? 23导¾ south • OOHNOOI Flèches LUIZ zm -OOHNOOHN- (J 918 im -OOHNOOHN- (J o u a导¾ south - OOHNOOHN "S

 ^ -O0HNO0HN- 9 SI S3

O ^x H ^ ¾ -OOHNOOI Flèches S Z1 Z on 'South • OOHNOOHN- 9: zo ⁿ e- ^s导¾ ■ OOHNOOHN- S 0l £ Z o n ei ^ ¾ south -OOHNOOHN- S 6082

601

Zhi S0 / 66di7 丄 :) d S8C0Z / 00 OM

so / 66df / l: £ 8§ /; one

o4d 5 -Silver- -INMe- xinU o44 α -Shift U- -l lVie- η ί.) -Silver- -i \ Me- ft.

Z b ί) -Shi- "\ TTVyT ft.

 ί) -Shiri- -J Me- Na 4AO

 0 -shi U- -IN Μβ- place 5 ί) -shi U- -IN M β-area o

/ X

 u • 1 \ IV t3-la i t i-ίΜΡ-place 8

 -D- 1 1V1 ti Place Q tj o ϋ-I 1V1 tJ-[E! .U

 0 -NMe- 11

0-then-NMe-place 12

Δ Ό 0 • Li-NMe-3-Py

ΔΟ i 0-n shi o- -NMe- 4-Py

 0-then Thiad

0 NH-Thiad

0 -ΓΝ Thiad

 ΔΟΌ -IN r NH-Thiad

 0 Π I Τ n Ο Thiad ουο 0 IN ϋ NH-Thiad

Ζ0θ4 0 Thiad

2565 5 -co thigh so ₂ -NH-Thiad

2566 5--NHCS- -NH- H

2567 5 -NHCS- -NH- Me

2568 5 -NHCS- -NH- Et

^{- Z HOOOHN 2 OSN 2 H -HN-} -oo- 9 H000HN s 0SN s H ■ HN- ■ oo-

-¾000HN ^ 0S ⁹ W -HN- -00HN-

■ ¾000HN ^J 0S ⁹ W -HN- -00HN- f

-¾0O0HN ^z OS9IA [-HN- ■ oo- 9

-¾000HN ^z 0S ⁹ W -HN- ■ oo-mz

■ ¾0 ( ^δ Ηθ) ΗΟ¾0ΟΗ -HN- -O0HN- 90

^{■ ¾0 (ε Η0) Η0¾0ΟΗ ■} HN- -OOHN- 6892

-¾0 ( ^ε Η0) Η0 ⁵ Η00ΗHN- -oo- S 889S

^{-¾0 (ε Η0) Η0¾00Η • HN-} • oo- L2 Z

 OOHN- (j 92dZ

^ ¾South -OOHN- 2893 ζι m 'South ■ o- S V dZ π S ¾South -o- S 29Z

Οΐ 喜 导 ¾ 南 -o- Z ^ dZ em 导 -o- Q sm ¾ * -o- S 0 9Z

L m 导 ¾ South -o- 9 6ZdZ

9 a ¾South -o- SZdZ s m M o- (J LZdZ a M m -o- DZ9Z ε 翟 导 'South-0_

 zm -o- S zdz l 葚 导 -o- ('' 2Ζ Ζ

 -O- (J ZZdZ Ma -o- (J

IZl

Zhi S0 / 66dfAL d S8C0Z / 00 OM

o n o Single bond Me

 Ω Π A

 D / 4 4 -shi u- 1-Indn

 lb l 5-Shiri-1-Indn

 Zb ih 4 -J Jr 丄 shi)-1-Indn

 2677 5 -N l Shiri-1-Indn

 2678 4 -S--(Jd (JU)) -l-lndn

 2679 0 -Silver-2- (HOOC) -l-Indn

 2680 A -ΜΗ ΓΟ- 2- (HOOC) -Undn

 Γ) -NHCO- 2- (HOOC) -l-Indn

2682 4 Single bond 3,4-diMe-2,5-diox-l-Imdd

2683 5 simple 3,4-diMe-2,5-diox-l-Imdd

2684 4 -CONHS0 ₂ -Single bond CF _{3 In the} above table, `` Ph '' indicates a phenyl group, `` Me '' indicates a methyl group, `` Et '' indicates an ethyl group, and `` Pr '' indicates a propyl group. "I-Pr" represents an isopropyl group, ": Buj represents a butyl group," i-BuJ represents an isobutyl group, "3-: 8 ^ represents an s-butyl group, and" t- “Bu” indicates a tert-butyl group, “Pn” indicates a pentyl group, “i-Pn_l indicates an isopentyl group,“ Hx ”indicates a hexyl group,“ Bn ”indicates a benzyl group, and“ Boc ” ”Represents a tert-butoxycarbonyl group,“ Pyr ”represents a pyrrolidino group,“ PipriJ represents a piperidino group, “Pipra” represents a piperazino group, “MorJ represents a morpholino group, and“ ThmorJ Represents a thiomorpholino group, “Thiad” represents a 3-thiazolidinyl group, “Ac” represents an acetyl group, and “Py” represents a pyridyl group. “Indn” represents an indanyl group, “ri, 3-diox-IInd” represents an isoindole-13-dione-12-yl group, and “3,4-diMe-2,5-dio x- "Imdd" represents a 34-dimethyl-imidazoline_2,5-dione-11-yl group. Further, in the above table, each of the units 1 to 12 represents the following groups.

Place 2

Place 3

Place 6

Among these compounds, preferred compounds include the compounds of Compound Nos. 1 to 83, the compounds of Compound Nos. 23 to 62, the compounds of Compound Nos. 676-1863, and the compound No. 1 11 2 to 11 6 9 compounds, compound number 12 24 compound, compound numbers 12 58 to 13 8 3 compounds, compound number 15 52 to 19 21 compound, 19 Compounds of 62 to 2163, Compound No. 24 29 to 2614, Compound of Compound No. 2657, Compound of Compound No. 2665, Compound of Compound No. 2667 Compound No. 2669 can be mentioned. More preferred compounds include compounds of compound numbers 2 to 80, compounds of compound numbers 2771 to 539, compounds of compound numbers 6776 to 863, and compound numbers of 111 to 12] Compound No. 8, Compound No. 1222, Compound No. 125 8 to 1280, Compound No. 1962 to 1993, Compound No. 2470 to 26 14, compound No. 26657, compound No. 2665, compound No. 2667, and compound No. 2669. ·

 More preferred compounds include the compounds of Compound Nos. 41 to 80, the compounds of Compound Nos. 271 to 2886, the compounds of Compound Nos. 4557 to 539, and the compound Nos. 733 to 750. Compound No., Compound Nos. 815 to 863, Compound Nos. 1129 to 1: 148, Compound No. 1224, Compound Nos. 1258 to 1

Compound No. 280, Compound No. 1962-2993, Compound No. Compound No. 247-0-257, Compound No. 266, Compound No. 266, Compound No. The compound of compound No. 266, the compound of compound No. 266, and the compound of compound of No. 266 can be exemplified.

 More preferred compounds include the compounds of Compound Nos. 46 to 71, the compounds of Compound Nos. 271 to 2886, the compounds of Compound Nos. 457 to 539, and the compound Nos. 733 to 7500. Compound, compound No. 815, compound No. 820, compound No. 861, compound No. 1134 to 1148, compound No. 1224, compound No. Compounds of 1258 to 1280, Compound of Compound No. 1502, Compounds of Compound No. 2566 to 2578, Compounds of Compound No. 2657, Compound No. 2 The compound of the compound of compound No. 666, the compound of compound No. 266, and the compound of compound No. 266 can be mentioned.

 More preferred compounds include the compounds of compound numbers 46 to 50, the compound of compound number 71, the compound of compound number 271, the compound of compound number 496, and the compound number 5

Compound No. 39, Compound No. 733, Compound No. 738 to Compound 742, Compound No. 815, Compound No. 820, Compound No. 861 , Compound No. 1 1 3 5 Compound, Compound No. 1 1 4 5 Compound, Compound No. 1 2 Compound No. 24, Compound No. 1 258, Compound No. 1 260, Compound No. 1 275, Compound No. 1 276, Compound No. 280 Compound, Compound No. 1963, Compound No. 1993, Compound No. 2470, Compound No. 2502, Compound No. 2567, Compound No. 2657 The compound of No. 266, the compound of No. 266, and the compound of No. 266 can be mentioned.

 Particularly preferred compounds include compound No. 49, compound No. 271, compound No. 496, compound No. 539, compound No. 733, compound No. 7 39 Compound, Compound No. 7400 to Compound 742, Compound No. 820 Compound, Compound No. 861 Compound, Compound No. 1 135 Compound, Compound No. 1 222 Compound, compound of compound 1,258, compound of compound number 1,260, compound of compound number 1,275, compound of compound number 1,963, compound of compound number 2,470, compound number 2,520 Of the compound of the compound number 2567, the compound of the compound number 2657, the compound of the compound number 2665, the compound of the compound number 2667, and the compound of the compound number 2669. Can be mentioned.

 The most preferred compounds include

 • 1- (5,7-dimercaptoheptyl) 1-3- (2—Hydroxitytyl) perea (Compound No. 26663),

 • [3— (5,7-dimercapdoheptyl) ureido] methyl acetate (Compound No. 7

3 9),

 • 3- (6,8-dimercaptooctanoylamino) methyl propionate (Compound No. 47), and

 • N— (6,8—dimercaptooctanoyl) methanesulfonamide (compound number

4 9 6),

Can be mentioned. [Embodiment of the invention]

The dithiol derivative of the present invention can be produced by the method described below. You.

 [Method A]

R ¹

HS—

 In the above formula,

 R k, m and n are as defined above,

A ¹ is, in the definition of “A”, one CO—O— and —N (R ² ) O—, wherein R ² is': and has the same meaning as described above. ] Represents a group other than

B1 is one N (R ⁵ ) one or —N (R ⁶ ) N (R ⁵ ) — wherein R ⁵ and R ⁶ are as defined above. ].

 Y represents a leaving group.

 The term "leaving group" is not particularly limited as long as it is a group which usually leaves as a nucleophilic residue, but is preferably a halogen atom such as chlorine, bromine or iodine; Trihalogenomethyl group; lower alkenyl sulfonyloxy groups such as methanesulfonyloxy and ethanesulfonyloxy; lower alkenyl sulfonyl groups such as trifluoromethanesulfoninoleoxy and pentafluoroethanesulfonyloxy And an aryl group such as benzenesulfonyloxy, p-toluenesulfonyloxy, p-toluenebenzenesulfonyloxy, and more preferably a halogen atom.

 Sep A1 is a step of producing a dithiol derivative (I-a) by reacting compound (II) with compound (III) in a solvent in the presence of a base.

The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. Examples thereof include aromatic hydrocarbons such as benzene, toluene and xylene; methylene chloride, and Halogenated hydrocarbons such as form, carbon tetrachloride, dichloroethane, dichlorobenzene, and 'dichlorobenzene'; such as dimethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether Ethers: acetone, methyl Ketones such as rutile ketone, methyl isobutyl ketone, isophorone, cyclohexanone: nitriles such as acetonitrile, propionitrile, isobutyronitrile; formamide, N, N dimethylformamide, N, N Examples include amides such as dimethylacetamide, N-methyl-2-pyrrolidone, N-methylpyrrolidinone, hexamethylphosphotriamide; sulfoxides such as dimethylsulfoxide; and sulfones such as sulfolane. Preferred are ketones, ethers and amides, and more preferred are acetone, tetrahydrofuran, N, N dimethylformamide and N, N dimethylacetamide.

 The base to be used is not particularly limited as long as it is used as a base in a usual reaction, but is preferably an alkali metal such as sodium carbonate, potassium carbonate, lithium carbonate or cesium carbonate. Metal carbonates; Alkali metal bicarbonates such as sodium bicarbonate, hydrogen bicarbonate, lithium bicarbonate; Alkali metals such as lithium hydride, hydrogen hydride, hydrogen hydride Metal hydrides; alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, barium hydroxide, and lithium hydroxide; alkali metal hydroxides such as sodium fluoride and lithium fluoride Inorganic bases such as metal fluorides; sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, potassium t-butoxide, lithium metal Alkali metal alkoxides such as tium methoxide can be mentioned. More preferably, they are alkali metal carbonates, alkali metal hydrides, and alkali metal alkoxides, and even more preferably, they are carbon dioxide rim, sodium hydride, and potassium t-butoxide.

 The reaction temperature is 20. C. to 100.degree. C., preferably 0.degree. To 50.degree.

 The reaction time varies depending mainly on the reaction temperature, the starting compound, the reaction reagent or the type of the solvent used, but is usually from 10 minutes to 24 hours, preferably from 30 minutes to 12 hours. is there.

[Law B]

Method B is based on the general formula (I): A is an oxygen atom, one N (R ² ) CO—, one N (R ² ) S 0 ₂ —,

— ON (R2) CO-, -ON (R ² ) S 0 _2- , 1 N (R ² ) N (R ³ ) CO-, -N (R2) N (R3) S 0 _2- , 1 N ( R ² ) CON (R ³ ) N (R ⁴ ) CO-, — N (R2) CON (R3) CO— or one N (R ² ) CON (R ³ ) S 0 ₂ — where R ² ,

R ³ and R ⁴ are as defined above. ] It is a method of manufacturing the compound which is.

HS— _(CH2)

 In the above formula,

 B, Rl, Y, k, m and n are as defined above,

A ² : is an oxygen atom, one N (R ² ) CO—, — N (R2) S 0 ₂ —, one ON (R ² ) CO—, one ON (R ² ) S 0 _2- , — N (R ^{2) N (R 3) CO} -,

N '(R ² ) N (R3) S 0 _2- , — N (R ² ) CON (R ³ ) N (R ⁴ ) CO-,

— N (R ² ) CON (R3) CO— or one N (R ^) CON (R ³ ) S〇 ₂ — where R ² ,

R ³ and R ⁴ are as defined above. ].

 Step B 1 is a step of reacting compound (IV) with compound (V) in a solvent in the presence of a base to produce a dithiol derivative (I-b). Achieved by performing the reaction according to

[Method C]

 Method C is based on the general formula (I):

A is — N (R ² ) CO-,-N (R ² ) S 0 ₂ —,

-CON (R ² ) N (R3) CO-, -CON (R ² ) CO—,

One CON (R ² ) S 0 ₂ —, One O—CO—, -ON (R ² ) CO—,

One _{ON (R2) S 0 2 -} , -O- CON (R2) N (R 3) CO -,

— O— CON (R ² ) CO-, -O-CON (R ² ) S 0 ₂ —,

-CO-CON (R ² ) N (R ³ ) CO—, -CO-CON (R ² ) CO—,

-CO- CON (R ² ) S 0 ₂ —, one N (R2) CO-CO-, One N (R ² ) N (R ³ ) CO-, one N (R ² ) N (R3) S 0 ₂ ,

— N (R2) CON (R3) N (R4) CO—, —N (R ² ) CO (R ³ ) CO— or one N (R2) C ON (R3) S 0 ₂ — where R2, R3 and R are as defined above. ]

 This is a method for producing a compound in which B is a single bond.

(CHA—D ¹ -H (CH ₂ ) _k — D ¹ -E ¹ -FT

_HS — _{(CH2) n} -γ,, — _r1 _! Ί ^ £ HS- (CH ₂ ) _n-

(CH ₂ ) _n

⁽ ? ^{H2) m} (V „)

 SH (VI) SH (l-c)

 Ri, k, m and n are as defined above,

D ¹ : is an oxygen atom, one N (R ² ) —, one CON (R2) —, one ON (R ² ) one, —O—CON (R ² ) —, — N (R ² ) N (R ³ ) one or —N (R ² ) C ON (R ³ ) one, wherein R ² and R ³ have the same meaning as described above. ]

E ¹ represents a carbonyl group, a sulfonyl group or a group COCO-,

 Y ′ represents a leaving group in the definition of Y; an imidazolyl group; or an active ester residue such as an acyloxy group such as acetoxy or an alkoxyoxy group such as methoxyacetoxy.

 Step C1 is a step of producing a dithiol derivative (Ic) by acylating or sulfonylating compound (VI) with compound (VII) in a solvent in the presence of a base in a solvent.

The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. Examples thereof include aromatic hydrocarbons such as benzene, toluene, and xylene; methylene chloride, and chlorine. Halogenated hydrocarbons such as mouth form, carbon tetrachloride, dichloroethane, and ku mouth benzene, dichlorobenzene; ethers such as getyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; acetone, Ketones such as methylethyl ketone, methyl isobutyl ketone, isophorone and cyclohexanone: diacetones such as acetonitrile, propionitrile and isobutyronitrile Tolyls; amides such as formamide, N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-12-pyrrolidone, N-methylpyrrolidinone, hexamethyl phosphorotriamide be able to. Preferred are aromatic hydrocarbons, halogenated hydrocarbons, ethers, and amides, and more preferred are halogenated hydrocarbons, ethers, and amides.

 The base to be used is not particularly limited as long as it is used as a base in a usual reaction, but is preferably N-methylmorpholine, triethylamine, tripropylamine, tributylamine, diisopropylethylamine. , N-methyldicyclohexylamine, N-methylbiperidine, pyridine, 4-pyrrolidinopyridine, picoline, 4- (N, N-dimethylamino) pyridine, 2,6-di (t-butyl) ': 1-4-methylpyridine , Quinoline, N, N-dimethylaniline, N, N-diethylaniline, 1,5-diazabicyclo [4.3.0] nona-5-ene (DBN), 1,4 diazabicyclo [2.2.2. 2] Organic bases such as octane (DAB CO), 1,8-diazabicyclo [5.4.0] pendant-7-ene (DBU), and more preferably A Ruamin and diisopropyl E chill § Min.

 The reaction is carried out at a temperature of from 120 ° C. to 100 ° C., preferably 0 °. From 80 to 80.

 The reaction time varies depending mainly on the reaction temperature, the starting compound, the reaction reagent and the type of the solvent used, but is usually 5 minutes to 2 days, preferably 20 minutes to 1 day.

When reacting with the compound (VII) in which E ¹ represents a carbonyl group, a compound having the general formula HOOC-Rl (wherein R ¹ has the same meaning as described above) is used, It is also achieved by reacting with a "condensing agent" in a solvent in the presence or absence of a base.

 The 'condensing agent' used is

(1) Combinations of the following bases with phosphoric esters such as getyl phosphoryl cyanide and diphenyl phosphoryl azide; (2) carbodiimides such as 1,3-dicyclohexylcarbodiimide, 1,3-diisopropylcarbodiimide, and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide; the carbodiimides A combination of carbodiimides and N-hydroxy such as N-hydroxysuccinimide, 1-hydroxybenzozotriazole, N-hydroxy-5-norbornene-12,3-dicarboxymid; Combinations of hydroxys;

 (3) Combination of 2,2 'dipyridyl disulfide, 2,2'-disulfides such as dibenzothiazolyl disulfide and phosphines such as triphenylphosphine and tributylphosphine;

 (4) N, Ν'—disuccinimidyl-carbonate, G2-pyridyl-carbonate, S, S'-bis (1-phenyl-1-H-tetrazol-5-yl) Carbonates, such as dithioforce monocarbonate;

 (5) Phosphinic chlorides such as N, N'-bis (2-oxo-l-oxazolidinyl) phosphinic chloride;

 (6) N, N'-disuccinimidyl oxalate, N, Ν 'diphthalimidio doxalate, Ν, Ν'-bis (5-norbornene-1,2,3-dicarboximidyl) oxalate, 1, 1'-bis (benzotriazolyl) oxalate, 1,1'-bis (6-benzobenzotriazolyl) oxalate, 1, 1'-bis (6-trifluoromethylbenzotriazolyl) oxalate Oxalates, such as

(7) a combination of the phosphine and azodicarboxylate such as 1,1 ′-(azodicarbonyl) dipiperidine or an azodicarboxylic acid amide such as 1,1 ′-(azodicarbonyl) dipiperidine;

 (8) 2-ethyl-5-phenylisoxazolyum 3'-sulfonate-like lower alkyl-5-arylisoxazolyum 3'-sulfonates;

(9) Diheteroaryldiselenides such as di-2-pyridyldiselenide;

(10) arylsulfonyl triazolides, such as ρ-'but-mouth benzenesulfonyltriazolide;

(1 1) 2—Chloro 1-like 1-Methylpyridinium iodide 2-Halo 1 Lower alkylpyridinium halides; ..

(1 2) 1,] '-Imidazole diimidazole, N, N' Imidazoles such as carbonyldiimidazole;

 (1 3) 3-Ethyl-1-chloro-benzothiazolide benzothiazolone fluorenoborolate 3-lower alkyl-2-halogen-benzothiazolide fluoroborate;

(14) 3-lower alkyl-benzothiazole-2-seones such as 3-methyl-benzothiazonoure 2-cellone;

 (15) Phosphates such as phenyl dichlorophosphate and polyphosphate esters;

 (16) halogenosulfonyl isocyanates such as chlorosulfonyl isocyanate;

 (17) halogenosilanes such as trimethylsilinochloride and triethylsilyl chloride;

 (18) A combination of a lower alkanesulfonyl halide such as methanesulfoyluclide and a base described below;

 (19) N, N, N ', N'-N, N, Ν', N'-tetra-lower-alkylhalogenoformimidum chlorides, such as tetramethyl lactoformamide chloride;

(20) A combination of a lower alkyloxycarbol halide such as ethyl chlorocarbonate with the following bases;

Among them, the above (1), (2), (7), (12) and (20) are preferable.

The solvent to be used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, but is preferably aliphatic hydrocarbons such as hexane and heptane; benzene and toluene. Aromatic hydrocarbons such as methylene chloride, xylenes; halogenated hydrocarbons such as methylene chloride, chlorophonolem, tetrachlorosilane, dichloroethane, benzene, dichlorobenzene; ethyl formate, ethyl acetate, propyl acetate, acetic acid Esters such as butyl and getyl carbonate; getyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxetane, diethylene glycol Ethers such as dimethyl ether; nitriles such as acetonitrile and isobutyronitrile; formamide, N, N-dimethylformamide, N, N-dimethylacetamide, and N-methinole 2- Amides such as pyrrolidone, N-methinolepyrrolidinone, and hexamethylphosphorotriamide can be mentioned.

 The base used is not particularly limited as long as it is used as a base in a usual reaction, but is preferably N-methylmorpholine, triethylamine, tributylamine, diisopropylethylamine, dicyclohexynoleamine. , N-methylpiperidine, pyridine, 4-pyrrolidinopyridine, picoline, 4- (N, N-dimethylamino) pyridine, 2,6-di (tert-butyl) -14-methylpyridine, quinoline, N And organic salts such as N, N-dimethylaniline and N, N-getylaniline.

 In addition, forty-one (N, N-dimethylamino) pyridine and four-pyrrolidinopyridine can be used in combination with other bases in a catalytic amount, and in order to carry out the reaction effectively, a molecular sieve is used. Quaternary ammonium salts such as benzyltriethylammonium chloride, tetrabutylammonium chloride, crown ethers such as dibenzo-18-crown-16, Acid scavengers such as, 4-dihydro-1H-pyrido [1,2-a] pyrimidin-2-one can also be added.

 The reaction temperature is from -20 ° C to 80 ° C, preferably from 0 ° C to room temperature.

 The reaction time varies depending mainly on the reaction temperature, the starting compound, the reaction reagent or the type of the solvent used, but is usually from 10 minutes to 3 days, preferably from 30 minutes to 1 day.

[Method D]

 Method D is based on the general formula (I):

A is a carbonyl group, one ^{CON (R 2) N (R3} ) CO-, one ^{CON (R 2) CO-, -CON} (R 2) S 0 2 -, one CO-〇 one, -CO-CON ( R ² ) N (R ³ ) C〇 — CO— CON (R ² ) CO— or one CO— CON (R ² ) S 0 ₂ — [where R ² and

R ³ has the same meaning as described above. ] It is a method of manufacturing the compound which is.

HS- (CH ₂ )

 In the above formula,

 B, Rl, Y ', k, m and n are as defined above,

D ² represents a carbonyl group or one CO—CO—,

E2 is an oxygen ^{atom, -. N (R 2)} N (R3) CO-, one N (R ²⁾ CO- or one _{N (R2) S 0 2 -} [ wherein, R2 and R3 are the same Show meaning. ]

 S_¾ ep D 1 is a step of producing a dithiol derivative (I-d) by acylating compound (IX) with compound (VIII) in a solvent in the presence of a base, according to the above-mentioned tep C 1 Achieved by performing the reaction.

 The dithiol derivative (I-d) has the following general formula (V I I '):

 (In the formula, D2, k, m and n have the same meanings as described above.)

And compound (IX), in a solvent, in the presence or absence of a base, by reacting with the above-mentioned "condensing agent".

The solvent used is not particularly limited as long as it does not hinder the reaction and dissolves the starting material to some extent. Preferably, aliphatic solvents such as hexane and heptane; benzene, toluene, Aromatic hydrocarbons such as xylenes; Halogenated hydrocarbons such as methylene chloride, black form, tetrachloride, dichloroethane, black benzene, dichlorobenzene; ethyl formate, ethyl acetate, propyl acetate, acetic acid Esters such as butyl and getyl carbonate; ethers such as getyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxetane, diethylene glycol dimethyl ether; acetonitril and isobbutyro Nitrile Nitriles such as; formamide, N, N-dimethylformamide, N, N-dimethylacetamide, N-.methyl-2-pyrrolidone, N-methylpyrrolidinone, and amides such as hexamethylphosphorotriamide And the like.

 The base to be used is not particularly limited as long as it is used as a base in a usual reaction, but is preferably N-methylmorpholine, triethylamine, tributylamine, diisopropylethylamine, dicyclohexylamine. , N-methylpiperidine, pyridine, 4-pyrrolidinopyridine, picoline, 4- (N, N-dimethylamino) pyridine, 2,6-di (tert-butyl) 14-methylpyridine, quinoline, N, N— Organic bases such as dimethylaniline and N, N-jetylaniline can be mentioned.

 In addition, ', 4- (N, N-dimethylamino) pyridine and 4-pyrrolidinopyridine may be used in combination with other bases in a catalytic amount, and in order to make the reaction proceed effectively, Dehydrating agents such as sieves; quaternary ammonium salts such as benzyltriethylammonium chloride; tetrabutylammonium chloride; crown ethers such as dibenzo-18-crown-16 , And acid scavengers such as 3,4-dihydro-1H-pyrido [1,2-a] pyrimidin-2-one can also be added.

The reaction is carried out at a temperature of from 20 C to 80 C, preferably from 0 ^& C to room temperature.

 The reaction time varies depending mainly on the reaction temperature, the starting compound, the reaction reagent or the type of the solvent used, but is usually from 10 minutes to 3 days, preferably from 30 minutes to 1 day.

[Method E]

 Method E is based on the general formula (I):

A is one N ′ (R ² ) CO—, wherein R 2 represents a hydrogen atom,

B is one N (R5) — or one N (R5) N (R6) — wherein R5 and R6 have the same meaning as described above. ] It is a method of manufacturing the compound which is. (CH ₂ ) _k — COOH (CH ₂ ) _k — NCO HS- (CH ₂ ) _n -Step E 1 HS- (CH ₂ ) _n-

(CH ₂ ) _r ^ (CH ₂ ) _m

 (X) i, (

SH SH B -R

Where:

 BkRKk, m and n have the same meaning as described above.

 Step E 1 is an azide compound produced in a solvent, in the presence or absence of a catalyst, from a carboxyl group of the compound (X) to produce an acid azide compound, which is then heated to give an isocyanate ester. (XI).

 The solvent used for the azidation is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. Preferably, aromatic solvents such as benzene, toluene, and xylene; Halogenated hydrocarbons such as methylene chloride and chloroform; ethers such as getyl ether, tetrahydrofuran, dioxane, and dimethoxyethane; or nitriles such as acetonitrile; formamide; Amides such as N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-1-pyrrolidone, N-methylpyrrolidinone, hexamethylphosphorotriamide And more preferably aromatic hydrocarbons, halogenated hydrocarbons and ethers.

 The reagent to be used is not particularly limited as long as it is usually used for azidation, but is preferably a diarylphosphorus azide derivative such as diphenyl folic acid azide; trimethylsilinoleazide, Trialkylsilyl azides such as triethylsilyl azide or alkali metal azides such as sodium azide, potassium azide and lithium azide can be mentioned. It is a phosphate azide derivative.

The catalysts used include trimethylsilinolate triflate, triethylsilinolate Trialkylsilino retrates such as reflate, Lewis acid such as trifluorobolanaterate, aluminum chloride, zinc chloride; N-methylmorpholine, triethylamine, tributylamine, diisopropylethylamine, dicyclohexylamine , N-methylbiperidine, pyridine, 4-pyrrolidinopyridine, picolin, 4- (N, N-dimethylamino) pyridine, 2,6-di (tert-butyl) 4-methylpyridine, quinoline, N, N-dimethylaniline, Organic bases such as N, N-Jetylaniline can be mentioned.

 The reaction temperature is from 20 ° C to 180 ° C, preferably from 50 ° C to 150 ° C. The reaction time varies depending on the reaction temperature, the starting compound, the reagent or the type of the solvent used, but is usually from 10 minutes to 24 hours, preferably from 30 minutes to 8 hours. It is.

 Step E 2 is a process for producing a dithiol derivative (I e) by reacting the isocyanate (X I) with the conjugate (X I I) in a solvent.

 The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. Examples thereof include aromatic hydrocarbons such as benzene, toluene and xylene; methylene chloride, and chlorine. Halogenated hydrocarbons such as mouth form, carbon tetrachloride, dichloroethane, ku mouth benzene, dic mouth benzene; ethers such as getyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether Ketones such as acetone, methylethylenoketone, methylisobutynoletone, isophorone and cyclohexanone: nitriles such as acetonitrile, propionitrile and isobutyronitrile; formamide, N, N dimethylform Amides such as amide, N, N dimethylacetamide, N-methyl-2-pyrrolidone, N-methylpyrrolidinone, hexamethyl phosphorotriamide; sulfoxides such as dimethyl sulfoxide; sulfones such as sulfolane be able to. Preferably, they are aromatic hydrocarbons, halogenated hydrocarbons, ethers, nitriles, amides, and more preferably, aromatic hydrocarbons, ethers, nitriles. And amides.

The reaction temperature is between 20 ° C. and 100 ° C .; preferably between 0 ° C. and 80 ° C. It is.

 The reaction time varies depending mainly on the reaction temperature, the starting compound, the reaction reagent or the type of the solvent used, but is usually from 5 minutes to 2 days, preferably from 10 minutes to 1 day.

In addition, the isocyanate (XI) and the general formula: H—D3—B—R ¹ (wherein, .B and Rl have the same meanings as described above, and D3 represents one N (R3) N ( R CO-, one N (R3) CO- or _{- N (R3) S 0 2} -. [ which. wherein, R ³ and R ^4, which as defined above] a} and shows the, in this process By reacting according to the above, in the general formula (I), A is one N (R ² ) CON (R3) N (R ⁴ ) CO—,

— N (R ² ) CON (R ³ ) CO— or _N (R ² ) CON (R ³ ) S 0 ₂ — wherein R ² represents a hydrogen atom, and R ³ and R ⁴ are as defined above. Show the same significance. ] Can be produced,

The isocyanic ester (XI) is reacted with a compound having the general formula: HOR? (Wherein R? Has the same meaning as described above) according to this step, whereby the above-mentioned general formula is obtained. In (I), A is one N (R2) CO— (where R2 represents a hydrogen atom), B is a single bond, and R ¹ is a group OR? Has the same meaning as described above.)

Further, in the general formula (I), a compound in which R ² , RK RR ⁵ and Z or R ⁶ represent a hydrogen atom, and a compound represented by the formula Y—R ⁸ (Y is as defined above, R ⁸ is RK RK R ⁴ and RG represent a group other than a hydrogen atom.), Or react with alcohols according to the above-mentioned [Method A] By performing alkylation using a combination of carbodiimides such as above, a hydrogen atom of an amino, amide or imido group can be substituted with a group R8. By this method, for example, after synthesizing the dithiol derivative of the present invention by the above [Method E], the hydrogen atom of the amide group of the compound can be replaced with another group. -'

[Method F] Method F is based on the general formula (I):

A force one O-CO, one N (R ² ) CO—, — N (R ² ) CS-,

One ^{CON (R 2) CO -,} GON (R 2) CS -, one ^{ON (R 2) CO -,} - O- CON (R 2) CO-, one ^{N (R 2) N (R} 3) CO- Or

I N (R ² ) CON (R ³ ) CO— wherein R 2 and R ³ are as defined above. ]

 B is a single bond or —N (R5 ′) — wherein R5 ′ represents a group other than hydrogen in the definition of R5. ]

 This is a method for producing a compound in which R is a group other than hydrogen.

 Where:

D ¹ , k, m and n are as defined above,

 E3 is a single bond or —N (R5 ′) — wherein R5 ′ is as defined above. G represents an oxygen atom or a sulfur atom,

R ¹ ′ represents a group other than hydrogen in the definition of R ¹ .

 Step F1 is a step of producing a dithiol derivative (If) by reacting an isocyanate or an isothiocyanate (XIII) with a compound (VI).

 This step is performed according to the aforementioned Step E2.

In addition, instead of isocyanate or isothiocyanate (XIII), a general formula: G 2 CN—R9 [wherein, G has the same meaning as described above, and R9 represents trimethylsilyl, triethylsilyl, isopropyldimethyl Cyril, t-butyl dimethyl Tri-lower alkylsilyl groups such as luciryl, methyldiisopropylsilyl, methyldi-tert-butylsilyl, triisopropylsilyl, diphenylmethylsilyl, diphenylbutylsilyl, diphenylisopropylsilyl, phenyldiisopropylsilyl It represents a "silyl group" such as a tri-lower alkylsilyl group substituted with one or two aryl groups. To produce a compound of formula (I-I ') in which Ε3 is a single bond and R ¹ ' is a hydrogen atom.

[Method G]

(CH ₂ ) _k — Α-BR ¹ (CH ₂ ) _k -ABR ¹

R ^a S- (C ₂ ) _n -f One Step GI HS- (CH ₂ ) _n-

(CH ₂ ) _m (CH ₂ ) _m

Rb ( ^XIV > ^{(l) wherein} A, B, Rl, k, m and n have the same meanings as above,

R ^a and R ^b are the same or different and each represent a thiol-protecting group, or together represent a single bond or a carboxy group.

The “thiol group-protecting group” represented by R ^a and R ^b is not particularly limited as long as it is generally used as a thiol-protecting group.

1 to 3 such as benzyl, phenethyl, 1-phenylenopropinole, α-naphthylmethyl, / 3-naphthinole methinole, dipheninolemethinole, trifeninolemethyl, α-naphthyldiphenylmethyl, 9-anthrylmethyl Lower alkyl groups substituted with four aryl groups, 4-methylbenzyl, 2,4,6—trimethylbenzyl, 3,4,5—trimethylbenzyl, 4-methoxybenzyl, 4-methoxybenzyl Lower alkyls such as methoxyphenyldiphenylmethyl, 2-nitrobenzene, 4-212benzene, 4-chlorobenzene, 4-bromobenzole, 4-cyanobenzyl, and piperonyl An aralkyl group such as a lower alkyl group substituted with one to three aryl groups in which the aryl ring is substituted with a lower alkoxy, a nitrogen, a halogen, a cyano group; Mill, acetyl, propionyl, butyrinole, isobutylinole, pentanoy ^ \ bivaloyl, norelli リ \ isonokurarenore, octanoinole, nonylcarbonyl, decylcarbonyl, 3-methylnonylcarboninole, 8-methylnonylcarbonyl, 3-methylonylcarbonyl Butylcarbonyl, 3,7-dimension Cyloctylcarbonyl, pentadecylcarbonyl, dodecylcarbonyl, tridecylcarbonyl, tetradecylcarbonyl, pentadecylcarbonyl, hexadecyl canoleboninole, 1-methylpentadecylcarbonyl, 14-methylpentadecylcarbonyl, 13, 13 —Dimethyltetradecylcarbonyl, heptadecylcarboel, 1 5 —Methylhexadecinolecarbonyl, octadecylcanolebonyl, 1 —Methylhepta. Tadecylcarbonyl, nonadecylcarbonyl, eicosylcarbonyl, Henikosylcanolevonyl Lower alcohols such as phenolic phenols, chloroacetylinoles, chloroacetylinoles, trichloroacetonoles, trichloroacetones, trichloroenoacetyls, etc. "Aliphatic acyl group" such as an unsaturated alkylcarbonyl group such as a xyalkylcarbonyl group, acryloyl, arylcarbonyl, propioloyl, methacryloyl, crotonolyl, isocrotonyl, (E) -2-methyl-2-butenoyl, etc. Benzoyl, α-naphthoyl,] 3-naphthoyl-like arylene carbonyl group, 2-bromobromozinole, 4-chlorobenzoyl halide carbonyl group such as benzoinole, 2,4,6 —Lower alkylated arylcarbonyl groups such as trimethylbenzoyl, 4-tonoleyl oil, lower alkoxylated arylcarbonyl groups such as 4-anisole, 412trobenzoyl, and 2-nitrobenzoyl Aryloxycarbonyl such as benzyl, 2- (methoxycarbonyl) benzoyl "Aromatic acyl groups" such as lower alkoxycarbonylated arylcarbonyl groups, arylarylcarbonyl groups such as 4-phenylbenzyl, etc .; methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl A lower alkoxycarbonyl group such as s-butoxycarbonyl, tert-butoxycarbonyl, isobutoxycarbonyl, a halogen or tri-lower group such as 2,2,2-trichloromouth ethoxycarbonyl, 2-trimethylsilylethoxycarbonyl; “Alkoxycarbinole groups” such as lower alkoxycarbonyl groups substituted with a rusilsilyl group; benzyloxycarbonyl, 4-methoxybenzinoleoxycanolebonyl, 3,4-dimethoxybenzyloxycarbonyl, 2-2 Trovensiloxy The aryl group may be substituted with one or two lower alkoxy or dinitro groups such as carbonyl, 4-12 trobenzyloxycarbonyl, etc. 1 to 2 such as benzylcarbonyl, phenacyl, 4-methoxybenzylcarbonyl, 3,4-dimethybenzylbenzylcutaneboninole, 2-ditrobendinolecanoleboninole, 412-nitrobenzylcarbonyl And an "arsyl group" such as an "aralkylcarbonyl group" in which the aryl ring may be E-substituted by one or two lower alkoxy groups. Preferably, they are an "aralkyl group", an "aliphatic acyl group", an "aromatic acyl group", an "alkoxycarbonyl group" and an "aralkyloxycarbonyl group".

 Step G1 is a step of producing the dithiol derivative (I) of the present invention by removing the Ra group and the Rb group of the compound (XIV).

(a): When R a and _R l> are the above “aralkyl group”, the reaction can be removed by treating with an acid in the presence or absence of a solvent.

 The acid used is not particularly limited as long as it does not inhibit the reaction, as long as it is generally used as an acid. Preferably, inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, and hydrobromic acid are used. Acids, organic acids such as acetic acid, trifluoroacetic acid, and trifluoromethanesulfonic acid, and Lewis acids such as B-bromocatechol borane can be mentioned. More preferably, it is an inorganic acid or an organic acid, and particularly preferably, hydrochloric acid or trifluoromethanesulfonic acid.

 The solvent to be used is not particularly limited as long as it is used in a usual hydrolysis reaction. Water; methanol, ethanol, n-prono. An organic solvent such as alcohols such as ethanol, ethers such as tetrahydrofuran and dioxane, or a mixed solvent of water and the above-mentioned organic solvent is preferable.

 The reaction temperature and reaction time vary depending on the starting material, the solvent and the acid or base used, and are not particularly limited. However, in order to suppress a side reaction, the reaction temperature is usually from −10 to 150 ° C. C for 1 to 10 hours.

 (b) When the R 3 and R b forces are the above-mentioned `` acyl group '', and when R 3 and Rb are linked to form a carbonyl group, the reaction is carried out in the presence of an aqueous solvent. Underneath, it can be removed by treating with an acid or a base.

The acid to be used is not particularly limited as long as it does not inhibit the reaction, and is not particularly limited as long as it does not hinder the reaction. Mention may be made of inorganic acids or Lewis acids such as B-bromocatechol borane. More preferably, it is an inorganic acid, particularly preferably hydrochloric acid.

 The base used is not particularly limited as long as it does not affect the other parts of the compound, but is preferably a metal alkoxide such as sodium methoxide, sodium carbonate, or potassium carbonate. Alkali metal carbonates such as lithium carbonate, sodium hydroxide, potassium hydroxide, alkali metal hydroxides such as lithium hydroxide or ammonia water, ammonia such as concentrated ammonia-methanol Is used. The solvent to be used is not particularly limited as long as it is used in a usual hydrolysis reaction. Water; alcohols such as methanol, ethanol, n-propanol, tetrahydrofuran, dioxane Preferred are organic solvents such as ethers or mixed solvents of water and the above-mentioned organic solvents.

 The reaction temperature and the reaction time vary depending on the starting material, the solvent and the acid or base used, and are not particularly limited. However, in order to suppress a side reaction, the reaction temperature is usually from 10 ° C to 150 ° C. For 1 to 10 hours.

 (c) When R a and R b together form a single bond, the reaction is achieved by reducing compound (XIV) with a reducing agent in a solvent.

 The solvent used is not particularly limited as long as it does not hinder the reaction and dissolves the starting material to some extent. For example, aromatic hydrocarbons such as benzene, toluene, and xylene; methylene chloride, Halogenated hydrocarbons such as porcine form, carbon tetrachloride, dichloroethane, phenol benzene, chlorobenzene, etc .; Ethers; alcohols such as methanol and ethanol; water; and mixed solvents thereof. Preferred are halogenated hydrocarbons, ethers and alcohols, and more preferred are ethers and alcohols.

The reducing agent used in the reaction is not particularly limited as long as it can cleave a disulfide bond, but is preferably a hydride such as sodium borohydride or lithium borohydride. Boron Al lithium metal; lithium aluminum hydride, hydrogenation Aluminum hydride compounds such as aluminum lithium trioxide; tellurium sodium hydride; hydrides such as organoaluminum hydride reducing agents such as disobutylaluminum hydride and di (methoxhetoxy) aluminum sodium dihydride; Examples thereof include a halide reagent, more preferably an alkali metal borohydride, and most preferably sodium borohydride.

 The reaction is carried out at a temperature ranging from 178 C to the boiling point of the solvent, preferably from 120 C to 5 () C.

 The reaction time varies depending mainly on the reaction temperature, the starting compound, the reaction reagent or the type of the solvent used, but is usually from 5 minutes to 24 hours, preferably from 10 minutes to 10 hours. . After completion of each of the above reactions, the target compound is collected from the reaction mixture according to a conventional method. For example, the reaction mixture is appropriately neutralized, and if there is any insoluble matter, it is removed by filtration. Then, an immiscible organic solvent such as water and ethyl acetate is added. Is obtained by separating an organic layer containing, drying with anhydrous sodium sulfate, anhydrous magnesium sulfate and the like, and distilling off the solvent.

 If necessary, the obtained target compound can be obtained by a conventional method, for example, recrystallization, reprecipitation, or a method usually used for separation and purification of organic compounds, for example, silica gel, alumina, magnesium gel-based gel system. Adsorption column chromatography using a carrier such as Florisil; Sephadex LH-20 (Pharmacia), Amberlite XAD-11 (Rohm and Haas), Diaion HP-20 A method using a synthetic adsorbent such as distribution column chromatography using a carrier (manufactured by Mitsubishi Kasei Co., Ltd.), a method using ion-exchange chromatography, or normal and reversed phases using silica gel or alkylated silica gel. Combine appropriate column chromatography methods (preferably high performance liquid chromatography) and elute with a suitable eluent. Can be separated and refined.

The starting materials in the above-mentioned methods A to G are known compounds or compounds synthesized by known methods from known compounds. For example, starting materials in Method A, Method C and Method F An amino derivative [the following general formula (I-1h)] can be produced according to the following "Method H".

 [Method H]

(CH ₂ ) _k -NH ₂

Step H3 HS- (CH ₂ ) _n-

(CH ₂

 (l-h)

 In the SH formula,

R ^a , RK k, m and n are as defined above.

 StepHII is a process for producing a phthalimid derivative (XVII) by performing a Mitsunobu reaction of the compound (XV) with phthalimid (XVI).

The reagent used for the Mitsunobu reaction is not particularly limited as long as it can be used for the Mitsunobu reaction, but is preferably azodicarboxylate such as dimethyl azodicarboxylate, ethyl azodicarboxylate, and diisopropyl azodicarboxylate. Lower alkyls or azo compounds such as azodicarbonyls such as 1,1 '-(azodicarbonyl) dipiperidine and triarylphosphines such as triphenylphosphine or tri-lower alkylphosphines such as tri-n-butylphosphine and the like. And more preferably a combination of di-lower alkyl azodicarboxylate and triarylphosphine, and most preferably a combination of dimethyl azodicarboxylate and triphenylphosphine. The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, but is preferably an aromatic hydrocarbon such as benzene, toluene, or xylene; methylene chloride; Halogenated hydrocarbons such as chloroform, carbon tetrachloride, dichloroethane, octabenzene, and benzene; esters such as ethyl formate, ethyl acetate, propyl acetate, butyl acetate, and getyl carbonate; Ethers such as mono-ter, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxetane, and methylenglycol dimethyl ether; nitriles such as acetonitrile and isobutyronitrile; formamide, N, N-dimethinoformamide; N, N-dimethylacetamide, N-meth Amides such as tyl-1-pyrrolidone, N-methylpyrrolidinone, and hexamethylphosphorotriamide; sulfoxides such as dimethyl sulfoxide and sulfolane; and aromatic hydrocarbons are preferable. And ethers.

 The reaction is carried out at a temperature of from 20 ° C. to 100 ° C., preferably from 0 ° C. to 50 ° C.

 The reaction time mainly depends on the reaction temperature, the starting compound, the reaction reagent or the type of the solvent used; it is usually from 10 minutes to 3 days, preferably from 30 minutes to 12 hours. is there.

 Step H2 is a process for producing an amino derivative (XVIII) by reacting a phthalimidine derivative (XVII) with n-butylamine or hydrazine in a solvent. This is achieved by reacting the amide derivative (XVII) with n-butylamine for 6 hours at room temperature.

Step H3 is a step of producing a dithiol derivative (I-Ih) by removing the ^Ra group and the ^Rb group, and is achieved by performing a reaction according to Step Ste1 described above.

Further, the compound (XIV) as a starting material in the “method G” may be a known compound or a known compound (for example, α_lipoic acid or the like). It can be easily synthesized according to “Method F” and “Method H”. Since the dithiol derivative of the present invention has an excellent glutathione reductase activity-enhancing activity, daltathione reductase activity enhancers containing those compounds or pharmacologically acceptable salts thereof are useful for treating diseases caused by oxidative stress. Can be used as a prophylactic or therapeutic agent. “Diseases caused by oxidative stress” include: alcohol ingestion, xenobiotics or radiation damage; oxidative state in cells caused by liver disease; drugs and chemicals (eg, anticancer drugs such as platinum complexes, antibiotics). Poisoning with substances, antiparasitic agents, paraquat, carbon tetrachloride, halothane); poisoning with heavy metals; cerebral and neurodegenerative disorders (cerebral ischemia, cerebral attack, hypoglycemia, epilepsy, amyotrophic lateral cord) Nervous system diseases such as sclerosis, Alzheimer's disease, Parkinson's disease, Huntington's chorea); dysfunction of the immune system, especially immunotherapy of cancer; infertility, especially male infertility; ischemic heart disease; cataract; premature infant Ocular diseases such as retinopathy and eyeball disease; idiopathic pulmonary fibrosis, adult respiratory distress syndrome, emphysema, asthma, bronchopulmonary hypoplasia, interstitium Chronic renal failure; gastric ulcer; carcinogenesis and cancer metastasis such as colorectal cancer; diabetes; necrosis and apoptosis of hepatocytes such as ethanol-induced liver damage; influenza, B Viral diseases such as hepatitis hepatitis, HIV; Fanco 12 anemia, sepsis, increased vascular permeability, blood or vascular abnormalities such as blood cell adhesion; Down's syndrome, Duchenne's trophy, Becker's trophy, Dubin's Johnson syndrome, Inflammatory diseases such as nephritis, knee inflammation, dermatitis, exertion, and rheumatism; or dithiol derivatives of the present invention or pharmacologically thereof. Acceptable salts include, inter alia, radiation damage, intracellular oxidation states caused by liver disease, poisoning by anticancer drugs such as platinum complexes (ie, Side effects), diseases of the nervous system, cataract, diabetes, necrosis and apoptosis of liver cells, viral diseases, effective against a disease or pathological conditions such as inflammatory diseases.

 Among the above-mentioned "preventive or therapeutic agents for diseases caused by oxidative stress", there are diseases that do not completely return to the normal state once they occur, but are referred to as "therapeutic agents" for such diseases. Means a medicament for preventing or slowing the progress of the condition.

Further, the dithiol derivative of the present invention or a pharmacologically acceptable salt thereof may be used as a prophylactic or therapeutic agent for the above-mentioned diseases specifically described as “disease caused by oxidative stress”. It can be used in combination with known drugs.

Pharmaceuticals that are effective against alcohol overdose, xenobiotics or radiation-induced disorders include, for example, cyanamide, disulfiram, adenine, and cysteine; pharmaceuticals that are effective against intracellular oxidation caused by liver disease Examples thereof include aminoethyl sulfonic acid, protoporphyrinininatridium, diisopropylamine dichloroacetate, and the like; drugs and chemicals (eg, anticancer drugs such as platinum complex, antibiotics, and antiparasitics). Drugs that are effective against poisoning with drugs, paraquat, carbon tetrachloride, and halothane) or poisoning with heavy metals include, for example, glutathione, dimercaprol, edetate, and the like. Cerebral ischemia, cerebral attack, hypoglycemia, epilepsy, amyotrophic lateral sclerosis, Pharmaceuticals effective for nervous system diseases such as Alzheimer's disease, Parkinson's disease, and Nuntington's chorea include, for example, phenocanol norepital, phenytoin, bromocriptine mesylate, snorepiride, sodium norphate sodium, Haloperidol, levodopa 'carbidopa, idebenone, aniracetam, and the like are known; dysfunction of the immune system, particularly as a drug effective for immunotherapy of cancer, for example, cyclophosphamide, interferon-1α, interferon Known drugs that are effective for infertility, especially male infertility, include sildenafil; and drugs that are effective for ischemic heart disease include, for example, digitoxin. And digoxin are known; effective for ophthalmic diseases such as cataract, retinopathy of prematurity, and eyeball disease Examples of known drugs include pirenoxin; idiopathic pulmonary fibrosis, adult respiratory distress syndrome, pulmonary air, asthma, broncho-pulmonary hypoplasia, interstitial pulmonary fibrosis Drugs effective for lung diseases such as, for example, theophylline, ketotifen fumarate, epinastine hydrochloride, pranlukast, suplatast tosilate; drugs effective for chronic renal failure include, for example, furosemide, ethac Phosphoric acid, bumetanide, etc. are known; effective drugs for gastric ulcers include, for example, teprenone, leninomin, pentametholium, pranotol, famotidine, latitidine hydrochloride, lansoprazole, etc. Pharmaceuticals for suppressing canceration and metastasis of cancer such as colorectal cancer include, for example, Marimastat (B B—25 16), AG 334, etc. are known; effective drugs for diabetes include, for example, Epales Tutu, voglibose, acarbose, insulin, glibenclamide, torodaritazone, etc. are known; pharmaceuticals effective for hepatocyte necrosis and apoptosis such as ethanol-induced liver injury include, for example, aminoethyl Sulfonic acid, protoporphyrinin sodium, dicyclopropylacetate dicyclopropylacetate and the like are known; effective drugs for viral diseases such as influenza, hepatitis B, and HIV include, for example, acyclovir , Zidovudine, interferon-1α, interferon-1β, interferon-1γ, etc. are known; effective drugs for abnormal blood or blood vessels such as funco- 12 anemia, sepsis, increased vascular permeability, blood cell adhesion, etc. For example, erythropoietin preparations and the like are known; nephritis, Pharmaceuticals that are effective against inflammatory diseases such as inflammation, dermatitis, exercise, and rheumatism include fenipentol, mesilic acid powermostat, indomethacin, loxoprofen sodium, and diclofenac sodium. I have. The dosage form of the dithiol derivative of the present invention or a pharmacologically acceptable salt thereof is, for example, oral administration such as tablets, capsules, granules, powders or syrups, or parenteral administration such as injections or suppositories. Can be given. These preparations are manufactured by known methods using additives such as excipients, lubricants, binders, disintegrants, stabilizers, flavoring agents, and diluents.

 Examples of the excipient include sugar derivatives such as lactose, sucrose, glucose, mannite, and sonorebit; starch derivatives such as corn starch, potato starch, Hi-starch, dextrin, and carboxymethyl starch; and crystals. Cellulose derivatives such as cellulose, low-substituted hydroxypropynolecellulose, hydroxypropylmethinoresel cellulose, carboxymethylcellulose, carboxymethylcellulose calcium, internally crosslinked carboxymethylcellulose sodium; arabiagom; dextran; Organic excipients such as pullulan; and

Inorganic substances such as' silicic anhydride ',' synthetic aluminum silicate, silicate derivatives such as magnesium metasilicate aluminate; phosphates such as calcium phosphate; carbonates such as calcium carbonate; sulfates such as calcium sulfate; System excipients. Lubricants include, for example, metal stearate such as stearic acid, calcium stearate and magnesium stearate; talc; colloid sily; veegum, waxes such as gay 'I; boric acid: adipic acid; sodium sulfate Sulfates such as glycol; glycol; fumaric acid; sodium benzoate; DL-leucine; sodium salts of fatty acids; lauryl sulfates such as sodium lauryl sulfate and magnesium lauryl sulfate; silicic anhydride, silicic acid hydrate And the above-mentioned starch derivatives.

 Examples of the binder include polybutylpyrrolidone, macrogol, and the same compounds as the above-mentioned excipients.

 Examples of the disintegrant include compounds similar to the above-mentioned excipients and chemically modified starch / cellulose such as croscarmellose sodium, carboxymethyl starch sodium, and crosslinked polybutylpyrrolidone.

 Examples of the stabilizer include paraoxybenzoic acid esters such as methylparaben and propylparaben; alcohols such as chlorobutanol, benzyl alcohol and phenylethyl alcohol; benzanolone chloride; phenols such as phenolol and cresol. And sorbic acid.

 Examples of the flavoring agent include commonly used sweeteners, acidulants, flavors and the like. Furthermore, the dithiol derivative of the present invention or a pharmacologically acceptable salt thereof has low irritation to the eyes, and thus can be locally administered to the eyes. Dosage forms suitable for topical administration to the eye include solutions, suspensions, gels, ointments and solid inserts.

 The formulation of these compositions for topical administration has a lower limit of 0.001% (preferably 0.01%) and an upper limit of 10% (preferably 5%). , A dithiol derivative or a pharmaceutically acceptable salt thereof.

Pharmaceutical preparations containing the active compositions are conveniently mixed with non-toxic inorganic or organic pharmaceutical carriers. Can be

 Typical pharmaceutically acceptable carriers are, for example, water, mixtures of water with water-miscible solvents such as lower alkanols or arral knols, vegetable oils, polyalkylene glycols, petroleum based Jelly, ethylcell mouth, ethylethyl oleate, carboxymethylcellulose, polybutylpyrrolidone, isopropyl myristate, and other acceptable carriers that are conveniently used. Pharmaceutical preparations may also contain non-toxic auxiliary substances such as emulsifiers, preservatives, wetting agents, excipients, etc., for example, polyethylene glycols 200, 300, 400 and 600, carbowax 100 0, 150, 400, 600: 00 and 100, 000, p—Methyl hydroxybenzoate, p—P—Hydroxybenzoate, such as propyl hydroxybenzoate, Antibacterial agents such as quaternary ammonium compounds (eg, benzene tonium chloride, benzalkonium chloride), phenylmercury salts, which are known to be pasteurized and are non-toxic to use, thimerosal, 'Methyl and propyl parabens, benzyl alcohol, feninole ethanol, salt, buffer components such as sodium borate, sodium acetate, dalconic acid buffer, and sorbitan monolaurate, tri Tanoruamin, polyoxyethylene sono les Bitanmono / Ku Noremichireto, Jiokuchirunatori um sulfosuccinates, Monochio glycerol, Chio sorbitol, Ru can also include such Echirenjiamin tetraacetate.

 In addition, suitable ophthalmic excipients can be used as the carrier medium for the purposes of the present invention, including the usual phosphate buffered excipient systems (eg, sodium phosphate buffer, potassium phosphate). Buffer), isotonic boric acid excipient, isotonic saline excipient, isotonic sodium borate excipient and the like.

The pharmaceutical preparation can also be in the form of a solid insert that remains almost intact after administration of the drug, or a biodisintegrable insert that dissolves in tears or otherwise disintegrates. In the present invention, the dose of the dithiol derivative or a pharmacologically acceptable salt thereof varies depending on symptoms, age, administration method, and the like. Per day, 0.1 mg (preferably l mg) as the lower limit and 1000 mg (preferably 5000 mg) as the upper limit may be administered in one or several divided doses, depending on the symptoms. desirable. In the case of intravenous administration, the lower limit is 0.01 mg (preferably 0.1 mg) and the upper limit is 500 mg (preferably 2000 mg) per day for adults. It is desirable to administer it once or several times according to the symptoms. For topical administration to the eye, a lower limit of 0.001 mg (preferably 0.0 lmg) and an upper limit of 500 mg (preferably 200 mg) once daily for adults Alternatively, it is desirable to administer the drug in several divided doses according to the symptoms.

[Best Mode for Carrying Out the Invention]

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

 [Example]

 [Example 1]

 11- (5,7-dimercaptoheptyl) 13- (2-Hydroxitytyl) perrea (Exemplary Compound No. 2 66 3)

 {3- [4- (1,2-Dithiolan-1-yl) butyl] ureide} In a solution of 500 mg of methyl acetate in 10 ml of anhydrous tetrahydrofuran, 193 mg of sodium borohydride and anhydrous 0.49 g of methanol was added under ice-cooling, and the mixture was stirred at room temperature for 5 hours. The solvent was distilled off from the reaction mixture under reduced pressure, and the residue was neutralized with 2N-hydrochloric acid and extracted with ethyl acetate. The extract was washed with saturated saline and dried over anhydrous sodium sulfate. Ethyl acetate was distilled off from the extract to obtain 0.25 g of the target compound as white crystals having a melting point of 35 to 38 C. .

[Example 2]

 [3— (5V7—dimercaptoheptyl) ureide 1 Methyl acetate (Exemplary Compound No. 739)

{3- [4- (1,2-dithiolan-1-yl) butyl] peridot} Methyl acetate To a solution of 500 mg of anhydrous tetrahydrofuran (10 ml) was added sodium borohydride (129 mg) and anhydrous methanol (327 mg), and the mixture was stirred at room temperature for 5 hours. The solvent was distilled off from the reaction mixture under reduced pressure, the residue was neutralized with 2N-hydrochloric acid, and extracted with ethyl acetate. The extract was washed with saturated saline and dried over anhydrous sodium sulfate. Ethyl acetate was distilled off from the extract, and the residue was subjected to silica gel column chromatography (ethyl acetate: n-hexane = 3: 1, 1: 0) to obtain R f = 0.29 (silica gel thin layer). 0.111 g of a colorless oily compound having the following formula: mouth chromatography; ethyl acetate: n-hexane = 3: 1) was obtained.

[Example 3]

 3 → (6,8-dimercaptooctanoylamino) methyl propionate (Example Compound No. 47)

 3- (5- (1,2-dithiolan-1-yl) pentanoylamino] methyl propionate 500 mg of anhydrous tetrahydrofuran 10 ml solution of sodium borohydride 12 9 mg And 327 mg of anhydrous methanol were added under ice-cooling, followed by stirring at room temperature for 3 hours and 30 minutes. The solvent was distilled off from the reaction mixture under reduced pressure, the residue was neutralized with 2N-hydrochloric acid, and extracted with ethyl acetate. The extract was washed with saturated saline and dried over anhydrous sodium sulfate. Ethyl acetate was distilled off from the extract, and the residue was subjected to reverse phase preparative column chromatography (acetonitrile: water = 3: 17, 1: 3, 3: 7, 2: 3). Acetonitrile was distilled off from the obtained eluate and extracted with ethyl acetate. The extract was washed with saturated saline and dried over anhydrous sodium sulfate. Ethyl acetate was distilled off from the extract to obtain 351 mg of the target compound as a pale yellow oil having R f = 0.57 (silica gel thin-layer chromatography; ethyl acetate).

[Example 4]

 N— (6,8 dimercaptooctanoyl) methanesulfonamide (Exemplary Compound No. 496)

N— [5— (1,2-dithiolan-1-yl) pentanoyl] methanesulfone To a solution of 50 Omg of the medium in 10 ml of anhydrous tetrahydrofuran, 102 mg of sodium borohydride and 173 mg of anhydrous methanol were added under ice-cooling, followed by stirring at room temperature for 2 hours. The solvent was distilled off from the reaction mixture under reduced pressure, and the residue was neutralized with 2N-hydrochloric acid and extracted with ethyl acetate. The extract was washed with a saturated saline solution and dried over anhydrous sodium sulfate. Ethyl acetate was distilled off from the extract to obtain 0.53 g of the target compound as white crystals having a melting point of 65-66C.

[Reference example]

 [Reference Example 1]

 N— [4- (1,2-dithiolan-1-yl) butyl] —N '— (2-hydroxy ^^ tyl) ゥ rea

 DL-α-lipoic acid 1.0 g, anhydrous toluene 20 m and triethylamine 0.74 m'1, diphenylphosphoryl azide 1.15 m 1, and 2-hydroxy-11-ethylethylamine 0. The reaction was carried out according to Example 46 using 29 ml. The solvent was distilled off from the reaction mixture under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline and dried over anhydrous sodium sulfate. Ethyl acetate was distilled off from the extract, and the residue was subjected to silica gel gel column chromatography (ethyl acetate: ethanolni 39: 1, 19: 1). The solvent was distilled off from the solution, and the residue was recrystallized from methanol to obtain 352 mg of the target compound as yellow crystals having a melting point of 50-65C.

[Reference Example 2]

 3— [4— (1,2-dithiolan-1-yl) butyl] ureidomethyl acetate

To a solution of 500 mg of DL-α-lipoic acid in 10 ml of anhydrous toluene, add 0.73 ml of triethylamine and 0.56 ml of diphenylphosphoric acid, and place the mixture in an oil bath at 80 ° C for 1 hour. The mixture was stirred for 30 minutes. The solvent was distilled off from the reaction mixture under reduced pressure, anhydrous N, N-dimethylformamide 1 Om1 was added to the residue, and L-glycine methyl ester hydrochloride (30 lmg) was added under ice-cooling. Stir for 1 hour. After leaving overnight at room temperature, the solvent was distilled off from the reaction mixture under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. Extract Was washed with saturated saline and dried over anhydrous sodium sulfate. Ethyl acetate was distilled off from the extract, and the residue was subjected to silica gel column chromatography (ethyl acetate: n hexane = 2: 1 → 1: 0), followed by reversed-phase preparative column chromatography. It was applied to the graph (acetonitrile: water = 3: 17—3: 7 → 3: 2). Cetonitrile was distilled off from the obtained eluate, and the residue was extracted with ethyl acetate. The extract was washed with saturated saline, and dried over anhydrous sodium sulfate. Ethyl acetate was distilled off from the extract, and the residue was dissolved in dioxane and freeze-dried to obtain 3336 mg of the target compound as a pale yellow amorphous having a melting point of 62-64 ° C.

[Reference Example 3]

 [5- (1,2-dithiolan-1-yl) pentanoylamino] methyl acetate

 To a solution of 500 mg of D L-α-lipoic acid in 10 ml of anhydrous N, N-dimethylformamide was added 42 mg of N, Ν'-carborodiimidazole, followed by stirring at room temperature for 2 hours. After 0.36 ml of triethylamine was added dropwise to this reaction solution, 301 mg of glycine methyl ester hydrochloride was added, and the mixture was stirred at room temperature for 1 hour. After standing at room temperature for 2 days, the solvent was distilled off from the reaction mixture under reduced pressure, water was added to the obtained residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline and dried over anhydrous sodium sulfate. Ethyl acetate was distilled off from the extract, and the residue was subjected to silica gel column chromatography (ethyl acetate: n-hexane = 3: 1 → 1: 0), and then reversed-phase preparative column chromatography (acetonitrile). : Water = 1: 4 → 3: 7-1 .: 1), acetonitrile was distilled off from the eluate, and the residue was extracted with ethyl acetate. The extract was washed with saturated saline and dried over anhydrous sodium sulfate. Ethyl acetate was distilled off from the extract, and the residue was dissolved in dioxane and lyophilized to give an R f value of 0.26 (silica gel thin-layer chromatography; ethyl acetate: n> xane = 3: 1). There was obtained 32 Omg of the target compound as a yellow oil.

[Reference Example 4]

N—— [5 _- _ (1, — 2-dithiolan-1-yl) pentanoyl] methanesulfone (a) 0.88 g of sodium hydride (55% in mineral oil) was washed with hexane, and 20 ml of dimethylformamide and 1.96 g of methanesulfonamide were added at room temperature. After sonication for a while, the mixture was left overnight at room temperature (reaction solution (A)). Separately, 2.06 g of D, L-α-lipoic acid was dissolved in 20 ml of dimethylformamide, and N, N ^1- carbonyldiimidazole ¹ was dissolved under ice-cooling. .63 g was added and left at room temperature overnight. This reaction solution was added dropwise to the above reaction solution (A) at room temperature, and the mixture was stirred for 7 hours. Further, the mixture was heated at 130 C for 3 hours, allowed to cool, and poured into ice water. Dilute hydrochloric acid was added thereto to adjust the pH to 5, followed by extraction with ethyl acetate. The extract was washed three times with a saturated saline solution, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate: hexane = 4: 11: 0) to give a melting point of 87 ° C to 88 ° C. 0.12 g of the desired compound was obtained.

 (b) Dissolve 2.5 g of D, L-α-lipoic acid in 500 ml of anhydrous N, N-dimethylformamide and add Ν, Ν'-carbonyldiimidazole 21 under ice-cooling.

_{57 g} was added, and the mixture was stirred at room temperature for 2 hours and 30 minutes. To this reaction mixture, under ice cooling, 12.65 g of methanesulfonamide and 5.80 g of sodium hydride (55% in mineral oil) were added, and the mixture was stirred at room temperature for 4 hours. Furthermore, it was left overnight at room temperature. The solvent was distilled off from the reaction mixture under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate: n-xane = 1: 1: 12: 13: 1) to give the target compound having a melting point of 85 C to 88 C. g was obtained.

[Formulation example]

 A preparation containing a dithiol derivative or a pharmacologically acceptable salt thereof can be produced, for example, by the following method.

Formulation Example 1. Powder A powder is obtained by mixing 5 g of the compound of Example 2, lactose 895 g and corn 00 g with a blender. Formulation Example 2. Granule

 After mixing 5 g of the compound of Example 2, lactose 865 g and 100 g of low-substituted hydroxypropylcellulose, 300 g of a 10% aqueous solution of hydroxypropylcellulose was added and kneaded. I do. This is granulated using an extruder and dried to obtain granules. Formulation example 3. Capsule

 After mixing 5 g of the compound of Example 3, lactose 115 g, corn starch 58 g and magnesium stearate 2 g using a V-type mixer, '18 Omg was added to the capsule No. 3 in units of 18 mg. Upon filling, a capsule is obtained. Formulation Example 4. Tablet

 5 g of the compound of Example 4, lactose 90 g, Tomoroko. After mixing 34 g of microcrystalline cellulose, 20 g of crystalline cellulose and 1 g of maternal stearate with a blender, the mixture is compressed with a tablet machine to give tablets. Formulation Example 5. Eye drops

 Compound of Example 4 0 2 g

 Ninadium phosphate 0 16 g

 Phosphate sodium 0 7 2 8 g

 Sodium chloride 0 400 g

 p—Methyl hydroxybenzoate 0 0 2 6 g

 p—Propyl hydroxybenzoate 0 0 1 4 g

 Sterile purified water

 -Sodium hydroxide

 Total volume, .100 ml

Prepare the ophthalmic solution in the usual manner by adjusting the pH to 7.0. Formulation Example 6. Eye drops

 Compound of Example 4 0 2 g

 Ninadium phosphate 0 16 g

 Sodium phosphate 0 7 2 8 g

 Sodium chloride 0 400 g

 p—Methyl hydroxybenzoate 0 0 2 6 g

 p—Propyl hydroxybenzoate 0 0 1 4 g

 Sterile purified water

 Ascorbic acid

 Sodium hydroxide

 Total volume 100 ml

 An eye drop is prepared at a pH of 7.0 by a conventional method.

[Test example]

Test example 1. Measurement of on-reductase activity

 (a) Lens organ culture

 Six- to eight-week-old male SD rats (Japan SLC) were asphyxiated to death by carbon dioxide inhalation, and the binocular eyes were enucleated. The sclera at the back of the eyeball was incised, the vitreous and iris ciliary body were removed, and the lens was removed.

 Each lens thus obtained was immersed in 3 ml of the following culture solution in a 6-well tissue culture plate (FALCON) and cultured. The cultivation was carried out for 72 hours in a carbon dioxide incubator maintained at 37% at a humidity of 100% in the presence of 5% carbon dioxide (in air).

Examples of culture media for control, media © beam 1 9 9 (Me di um 1 9 9 containing penicillin (20 units / ^/ 1 ₁ 11) and Sutorebutomaishi emissions (20 mu g / m 1), formic Bukosha Manufactured).

 As a culture solution for the test, a culture solution obtained by further adding a test compound to the above culture solution was used. The cultured lens was frozen and stored until it was used for the test.

 (b) Measurement of daltathione reductase activity

After homogenizing the frozen rat lens in 2 ml of distilled water, it was subjected to centrifugation (10,000 g, 20 minutes), and the obtained supernatant was used as an enzyme specimen. A solution containing 1 mM oxidized glutathione (GSSG) and AD Ο Ο μΜ NAD PH Add 400 μl of the enzyme sample to 0.6 ml of the phosphate buffer, react at 25 ° C for 6 minutes, and measure the absorbance ( ₃₄₀ nm: OD34 _{() M} ) of the reaction solution. did. The difference (Δ◦D _m ) between ⁰ D Mm before the reaction and OD _34ϋηιη after the reaction was used as an index of GR activity. The dithiol derivative of the present invention exhibited an excellent glutathione reductase activity enhancing action. Test Example 2. Anti-cataract test (1)

 Male SD male rats (6 weeks of age) were euthanized by inhaling carbon dioxide and the lens was removed from the eyeball. The excised lens was placed in Medium 199 (Medium 199, Gibco) containing the test compound (0.05 mg / ml) and 5 mM hydrogen peroxide at 37 C. The cells were cultured for 24 hours. As a control test, excised lenses were used in normal culture medium (Medium 199, Gibco) or medium 199 containing 5 mM hydrogen peroxide (Medium 199, Gibco). The cells were cultured at 37 ° C for 24 hours.

 After culturing for 24 hours, the lens was washed with physiological saline, the surface water was removed on a filter paper, placed on a slide glass, and the opacity of the lens was observed under a microscope. The dithiol derivative of the present invention suppressed turbidity of the lens due to hydrogen peroxide, and exhibited an excellent anticataract effect. Test Example 3. Anti-cataract test (2)

 Male C57BL / 6 mice (body weight: about 20 g) were divided into 5 groups of 9 mice each, which were designated as group A, group B, fresh C, group D, and group E, respectively.

 All mice were given an intraperitoneal dose of 20 mg / kg | 3-naphthoflavone, and 72 and 76 hours after that, 45 mg / kg acetaminophen was intraperitoneally administered. Caused cataracts.

One hour before administration of] -naphthoflavone, the test compound 'was administered intraperitoneally with the compound of Example 4 to the mice of Group B at 5 O mg Z kg, and 10 mg of the compound of Example 4 was intraperitoneally administered intraperitoneally. The compound was orally administered at 50 mg Z kg, and the mice of Group E were orally administered the compound of Example 4 at 100 mg / kg.

 The mice were observed for opacities in both eyes at hourly intervals for 8 hours from the first administration of acetominophen. This observation was performed under conditions in which the pupil of the mouse was dilated by the mydriatic agent.

 The opacity of each eye was evaluated as “ten”, “ten”, “soil”, and “one”, and two points, one point, 0.5 point and zero point, respectively, and the total of each group Points were calculated. .

 The results are shown in the table below.

 By administering the dithiol derivative of the present invention intraperitoneally or orally, the opacity of the lens caused by acetaminophen was suppressed.

 In addition to the methods described in Test Examples 2 and 3, the effect on cataract was determined by the method of Rasvan et al. [WBRathburn el, al., Invest. Ophthalmol. Vis. I Sci., 37, 923-9 29 (1996)].

[Possibility of industrial use]

 Since the dithiol derivative of the present invention has an excellent glutathione reductase activity enhancing action, it is useful as a medicament, and in particular, can be used as a preventive or therapeutic agent for diseases caused by oxidative stress.

Claims

The scope of the claims

1. A compound having the following general formula (1), a pharmacologically acceptable salt thereof, a thiol ester or other derivative:

(CH ₂ ) _k — A-BR ¹ (CH ₂ ) _m

(Where

 m, 0 or 1; when m is 0, n represents 2; when m is 1, n represents 1;

 k represents 0 or an integer of 1 to 12,

R ¹ is a hydrogen atom, a group selected from substituent group α, or

It may be substituted with 1 to 3 substituents selected from the substituent group α and the substituent group γ, and may have 1 to 12 carbon atoms which may be interposed with an oxygen atom and a Ζ or sulfur atom. Represents a alkyl group,

Α represents a single bond, an oxygen atom, a carbonyl group, or one N (R ² ) CO—,

-N (R2) CS-,-N (R ² ) S 0 _2- , one C ON (R ² ) N (R ³ ) CO-, -CON (R ² ) CO-, one CON N (R ² ) CS-,-CON (R ² ) S 0 ₂ -,-O-CO-, -ON (R ² ) CO-, -ON (R ² ) S 0 _2- ,

-O- CON (R ² ) N (R3) CO-, O-CON (R ² ) CO-,

One ^{O - CON (R 2) S} 0 2 -, one CO - O -, one CO - CO -,

-CO-CON (R ² ) N (R ³ ) CO-, -CO- CON (R ² ) CO-,

-CO-CON (R ² ) S 0 _2- , 1 N (R ² ) O-, — N (R ² ) CO CO—, 1 N (R2) N (R3) CO, 1 N (R ² ) N (R3) S 0 _2- ,

One N (R2) CON (R3) N ⁴ ) CO-, One N (R2) CON (R3) CO-,

-N (R2) CON (R3) S 0 ₂ — or

— N (R2) CON (R3) S 0 ₂ N (R4) CO— wherein R ² , R ³ and R ⁴ are the same or different and are a hydrogen atom, an alkyl having 1 to 12 carbon atoms Ki, Aralki An aryl group, an aryl group, or one group selected from the substituent group α in which the aryl group and the aryl portion are substituted with one to three groups selected from the substituent group i3. ] A group having

Β is a single bond or one N (R ⁵ ) one, or —N (R6) N (R5) — wherein R 5 and R 6 are the same or different, and each represents a hydrogen atom, 1 to 12 carbon atoms. An aralkyl group, an aralkyl group, or one group selected from an aralkyl group, an acyl group or a substituent group α in which the aryl moiety is substituted with 1 to 3 groups selected from the substituent group / 3. In addition, R5 may form a 5- to 7-membered heterocyclic ring together with Rl and the nitrogen atom to which they are bonded. ]

In addition, A force; one N (R ² ) CO—, one N (R ² ) CS—,

-CON (R ² ) N (R ³ ) CO-, -C ON (R ² ) CO-,

-CON (R ² ) CS-, —O— CO-, ON (R ² ) CO—,

—O CON (R ² ) N (R ³ ) CO-, —O— CO N (R ² ) CO-,

One CO-CON (R ² ) N (R ³ ) CO-, One CO-CON (R ² ) CO-,

One N (R ² ) N (R3) CO—, one N (R ² ) CON (R ^) N (R ⁴ ) CO—, or -N (R2) CON (R3) CO— [where R2, R3 and R4 have the same meaning as described above. And when B is a single bond, R ¹ is, in addition to the above definition, a group OR? (Where R ⁷ is a lower alkyl group, a lower alkenyl group, an aralkyl group, an aryl group) Part represents an aralkyl group substituted with one to three groups selected from the substituent group / 3 or one group selected from the substituent group _α .)

Α 力 CON (R ² ) S 0 _2- , -ON (R ² ) S 0 _2- ,

One O— C ON (R ² ) S 0 _2- , — CO-CO-, One CO— CON (R ² ) S 0 _2- , -N (R2) CO CO—, -N (R2) N (R3 ) S 0 ₂ —, or

- N (R2) CON (R3 ) S 0 2 - [ wherein, R2 and R3 are as defined above. And B is a single bond, and A is not an oxygen atom, one CO—O— or one N (R2) ′, and B is —N (R5) − [Wherein, R5 has the same meaning as described above. In the formula, R ¹ may be a hydroxyl group or a group OR ⁷ (wherein R ⁷ has the same meaning as described above) in addition to the above definition. However,

When A is an oxygen atom, B is a single bond or one N (R ⁵ ) 1 [wherein, R ⁵ has the same meaning as described above. ]

A is —CO—O— or 1 N (R ² ) O—, wherein R ² is as defined above. ] B is a single bond;

When k-force; 4 is shown, the group --AB R ¹ does not show a carboxyl group. }

[Substituent ¾ _α ]

Aryl group, heterocyclic group, aryl group substituted with 1 to 3 groups selected from 3), substituted group substituted with 1 to 3 groups selected from 3) Heterocyclic group

 [鹭 Exchange group /

A lower alkyl group, a halogenated lower alkyl group, a lower alkoxy group, a lower alkylthio group, a hydroxyl group, a carboxyl group, a nitrogen atom-substituted rubamoyl group, a lower alkoxycarbonyl group, a halogen atom, a nitro group, and an amine residue Group, sulfo group, sulfamoyl group, cyano group, hydroxy lower alkyl group

 [Substituent group γ]

A lower alkoxy group, a lower alkylthio group, a hydroxyl group, a nitroxy group, a carboxyl group, a lower alkoxycarbonyl group, a halogen atom, a sulfo group, a sulfamoyl group, an amine residue, and a nitrogen atom which may be substituted with a nitrogen atom.

2. In claim 1, the general formula (I) and the following general formula (1 '):

Or a pharmaceutically acceptable salt, thiol ester or other derivative thereof.

3. In Claims 1 or 2,

A compound in which k is 0 or an integer of 1 ′ to 8, a pharmacologically acceptable salt thereof, thiol ester or other derivative.

4. In Claims 1 or 2,

a compound in which k is an integer of 2 to 6, a pharmacologically acceptable salt thereof, a thiol ester, or another derivative thereof.

5. In Claims 1 or 2,

A compound in which k is 4 or 5, a pharmacologically acceptable salt thereof, a thiol ester or another derivative thereof.

6. In any one of claims 1 to 5,

R ¹ is a heterocyclic group, a heterocyclic group substituted with 1 to 3 groups selected from a substituent group, a substituent group α, and 1 to 3 substituents selected from a substituent group γ. A compound which may be substituted and which is an alkyl group having 1 to 12 carbon atoms, a hydroxyl group or an alkoxy group having 1 to 5 carbon atoms, which may be interposed with an oxygen atom and / or a sulfur atom, A physiologically acceptable salt, thiol ester or other derivative.

7. In any one of claims 1 to 5,

R ¹ heterocyclic group, heterocyclic group substituted with 1 to 3 groups selected from substituent group / 3, or 1 to 3 selected from substituent group γ and substituent group γ A compound which may be substituted with a substituent and is an alkyl group having 1 to 12 carbon atoms which may be interposed with an oxygen atom and / or a sulfur atom, a pharmacologically acceptable salt thereof, a thiol ester or other Derivatives.

8. In any one of claims 1 to 5,

R ¹ force A compound having a hydroxyl group or an alkoxy group having 1 to 5 carbon atoms, a pharmacologically acceptable salt, a thiol ester or other derivative thereof.

9. In any one of claims 1 to 5,

R ¹ force heterocyclic group, heterocyclic group substituted with 1 to 3 groups selected from substituent group / 3 Group, alkyl group having 1 to 5 carbon atoms, alkoxycarbonyl group having 3 to 8 carbon atoms, carboxyalkyl group having 2 to 7 carbon atoms, hydroxyalkyl group having 2 to 5 carbon atoms, heterocyclic group or Compounds having an alkoxy group having 1 to 5 carbon atoms, pharmacologically acceptable salts, thiol esters or other derivatives thereof.

10. In any one selected from the first term to paragraph 9 claims, A is a carbonyl group, or the formula _{^{-CON (R 2) S0 2 -}} , -N (R 2) CO-, one N (R2) CS-, -CON ( R 2) CO-, one N (R ²⁾ COCO- or single _{N: (R2) S 0 2} - [ wherein, R ² is a hydrogen atom, 1 to carbon atoms 12 alkyl groups or benzyl groups. ], A pharmacologically acceptable salt thereof, a thiol ester or other derivative thereof.

In 1 1. 'according any one of a range selected from paragraphs 1 through 9 wherein the, A is a carbonyl group, or the formula _{^{- CON (R 2) S0 2}} -, one N (R ²⁾ CO- , -N (R2) CS—, -CON (R ² ) CO—, one N (R ² ) COCO— or one N (R2) S 0 _2- [wherein, R ² is a hydrogen atom or carbon atom 1 From 1 to 12 alkyl groups. ], A pharmacologically acceptable salt thereof, thiol ester or other derivative thereof.

1 2. In any one selected from the first term to paragraph 9 claims, A force carbonyl group, One CONHSC - one CONCH ₃ S0 ₂ -, One NHCO-, - NHC S-, One CONHCO —, — A compound that is NHCOCO— or one NHS〇 ₂ —, or a pharmaceutically acceptable salt, thiol ester or other derivative thereof.

1 3. In any one of claims 1 to 12, B is a single bond or a formula — N (R5) — or one N (R6) N (R5) — [Formula among, R5及beauty R ⁶ represents a hydrogen atom, C 1 to 1 2 alkyl group or a benzyl group carbon same or different. ], A pharmacologically acceptable salt thereof, Stele or other derivatives.

1 4. In any one of the claims from paragraphs 1 to 12, B is a single bond or a group represented by the formula —N (R5) — or — N (RN (R ⁵ ) , R ⁵ and R 6 are the same or different and represent a hydrogen atom or an alkyl group having 1 to 12 carbon atoms.], A pharmacologically acceptable salt thereof, a thiol ester or other Derivatives.

1 5. In any one selected from the first term to the first two terms claims, B is a single bond, One NH-, - NCH ₃ -, or single NHNCH ₃ - those compounds, the drug management Salts, thiol esters or other derivatives that are acceptable.

1 6. In Claim 1,

 • 1- (5,7-dimercaptoheptyl) 1- 3 _ (2-hydroxyshetyl) ゥ rea, • [3 -— (5,7-dimercaptoheptyl) ureide〗 methyl acetate,

 • 3- (6,8-dimercaptooctanoylamino) methyl propionate,

• N— (6,8—dimercaptooctanoyl) methanesulfonamide

Or a pharmacologically acceptable salt, thiol ester or other derivative thereof.

1 7. The compound according to any one of claims 1 to 16 or a pharmacologically acceptable salt, thiol ester or other derivative thereof as an active ingredient Medicine.

1 8. The compound according to any one of claims 1 to 16 or a pharmacologically acceptable salt, thiol ester or other derivative thereof as an active ingredient 'Daltathione reductase activity enhancer.

1 9. Used as a preventive or therapeutic agent for diseases caused by oxidative stress. 18. The medicament according to claim 17,

20. The medicament according to claim 17, which is used as an agent for preventing or treating radiation damage.

21. The medicament according to claim 17, which is used as a prophylactic or therapeutic agent for poisoning by an anticancer agent.

22. The medicament according to claim 17, which is used as a prophylactic or therapeutic agent for cataract.

23. The medicament according to claim 17, which is used as a prophylactic or therapeutic agent for diabetes.

24. The compound according to any one of claims 1 to 16, a pharmacologically acceptable salt thereof, a thiol ester or another derivative thereof for the manufacture of a medicament. use.

25. Administer a pharmacologically effective amount of the compound according to any one of claims 1 to 16, a pharmacologically acceptable salt, thiol ester or other derivative thereof. A method for preventing or treating a disease caused by oxidative stress.