# Patent

## Title
Amide compounds and medications containing the same technical field

## Abstract

The present invention provides to a novel compound having an ACAT inhibiting activity.
The present invention relates to compounds represented by formula (I) 




    
    
        wherein represents an optionally substituted divalent residue such as benzene, pyridine, cyclohexane or naphthalene, or a group,
        Het represents a 5- to 8-membered, substituted or unsubstituted heterocyclic group containing at least one heteroatom selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom, such as a monocyclic group, a polycyclic group or a group of a fused ring,
        X represents —NH—, an oxygen atom or a sulfur atom,
        Y represents —NR4—, an oxygen atom, a sulfur atom, a sulfoxide or a sulfone,
        Z represents a single bond or —NR5—,
        R4 represents a hydrogen atom, a lower alkyl group, an aryl group or an optionally substituted silyl lower alkyl group,
        R5 represents a hydrogen atom, a lower alkyl group, an aryl group or an optionally substituted silyl lower alkyl group, and
        n is integer of from 1 to 15,

or salts or solvates thereof, and a pharmaceutical composition containing at one of these compounds.

## Background
This application is a continuation of Ser. No. 09/358,083 filed Jul. 21, 1999, now abandoned.


TECHNICAL FIELD
The present invention relates to novel amide compounds and medications containing the same. More specifically, the present invention relates to compounds represented by the the formula (I) 




    
    
        wherein 




        represents an optionally substituted divalent residue such as benzene, pyridine, cyclohexane or naphthalene, or a group, 




        Het represents a 5- to 8-membered, substituted or unsubstituted heterocyclic group containing at least one heteroatom selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom, such as a monocyclic group, a polycyclic group or a group of a fused ring,
        X represents —NH—, an oxygen atom or a sulfur atom,
        Y represents —NR4—, an oxygen atom, a sulfur atom, a sulfoxide or a sulfone,
        Z represents a single bond or —NR5—,
        R4 represents a hydrogen atom, a lower alkyl group, an aryl group or an optionally substituted silyl lower alkyl group,
        R5 represents a hydrogen atom, a lower alkyl group, an aryl group or an optionally substituted silyl lower alkyl group, and n is an integer of from 1 to 15,

or salts or solvates thereof, and a pharmaceutical composition containing these compounds.

    
    


Specifically, the present invention relates to compounds represented by the the formula (IA) 




    
    
        wherein 




        represents an optionally substituted divalent residue such as benzen or pyridine,
        Py represents an optionally substituted pyridyl or pyrimidyl group,
        Y represents —NR4—, an oxygen atom, a sulfur atom, a sulfoxide or a sulfone,
        Z represents a single bond or —NR5—,
        R4 represents a hydrogen atom, a lower alkyl group, an aryl group or an optionally substituted silyl lower alkyl group,
        R5 represents a hydrogen atom, a lower alkyl group, an aryl group or an optionally substituted silyl lower alkyl group, and
        n is an integer of from 1 to 15,

or salts or solvates thereof, and a pharmaceutical composition containing these compounds.

    
    


More specifically, the present invention relates to compounds represented by the formula (II) 




    
    
        wherein
        X represents —NH—, an oxygen atom or a sulfur atom, Y represents —NR4—, an oxygen atom, a sulfur atom, a sulfoxide or a sulfone,
        Z represents a single bond or —NR5—,
        R4 represents a hydrogen atom, a lower alkyl group, an aryl group or an optionally substituted silyl lower alkyl group,
        R5 represents a hydrogen atom, a lower alkyl group, an aryl group or an optionally substituted silyl lower alkyl group,
        Py represents an optionally substituted pyridyl or pyrimidyl group, and
        n is an integer of from 1 to 15,

or salts or solvates thereof, and a pharmaceutical composition containing these compounds.

    
    


BACKGROUND ART
In recent years, hyperlipemia and arteriosclerosis derived therefrom have been rapidly increased with the change to western eating habits with high-calory and high-cholesterol foods bused on the higher level of life and with the advance of age of the population, and this has been one of social problems. The conventional pharmacotherapy of hyperlipemia and arteriosclerosis has mainly put stress on the decrease in blood lipid that causes these diseases, and the lesion of the arteriosclerosis itself has not been treated as a target. Acyl coenzyme A cholesterol acyltransferase (ACAT) is an enzyme that catalyzes synthesis from cholesterol to cholesterol ester, and plays a vital role in metabolism of cholesterol and absorption thereof in digestive organs. Inhibition of the ACAT enzyme that catalyzes esterification of free cholesterol in epithelial cells of the small intestine results in inhibition of absorption of cholesterol from the intestine, and inhibition of synthesis of cholesterol ester in the liver based on the ACAT inhibition results in suppression of secretion of VLDL from the liver to the blood. These results are considered to lead to an activity of decreasing blood cholesterol. Most of conventional ACAT inhibitors have been expected to exhibit an activity of decreasing blood cholesterol as an antihyperlipemic agent by acting on the ACAT enzymes in the small intestine and the liver.
For example, as an ACAT inhibitor, the specification of U.S. Pat. No. 4,716,175 describes 2,2-dimethyl-N-(2,4,6-trimethoxyphenyl)dodecanamide, and European Patent No. 372,445 describes N′-(2,4-difluorophenyl)-N-[5-(4,5-diphenyl-1H-imidazol-2-ylthio)pentyl]-N-heptylurea. However, most of the conventional ACAT inhibitors have put stress on an activity of decreasing blood cholesterol as an antihyperlipemic agent, and the administration thereof at a high dose for exhibiting its activity has often caused side effects such as intestinal bleeding, intestinal disorders, diarrhea, hepatopathy and the like at the stage of a clinical test, making difficult the clinical development thereof.
The arteriosclerosis is inherently a characteristic lesion such as intima hypertrophy and lipidosis of the blood vessel. According to the recent studies, suppression of foamation of macrophages that play a main role in formation of the arteriosclerosis lesion has been expected to lead to regression of the arteriosclerosis lesion itself. Foam cells derived from macrophages (cholesterol ester is stored in cells as fat droplets) have been observed in the gruel arteriosclerosis lesion, and the foamation of macrophages is deemed to deeply participate in the progression of the lesion. Further, it has been reported that the ACAT activity in the blood vessel wall in the arteriosclerosis lesion site is increased and cholesterol ester is stored in the blood vessel wall (refer to Gillease, J. et al., Exp. Mole. Pathol., 44, 329-339 (1986)).
The inhibition of esterification of cholesterol with an ACAT inhibitor results in formation of free cholesterol in cells, and this free cholesterol is removed with high-density lipoprotein (HDL), transferred to the liver (inversely transferred with HDL), and metabolized. Accordingly, suppression of storage of cholesterol ester in the lesion site is expected. As a result, it is considered to provide a direct anti-arteriosclerotic activity. There is a report that ACAT includes two types, a type present in the small intestine and a type present in the blood vessel wall [Kinunen M. et al., Biochemistry, 27, 7344-7350 (1988)]. However, many of the past researches on the ACAT inhibitor have been conducted using an enzyme of a type present in the small intestine and the liver [Tomoda Elichi et al., J. Antibiotics, 47, 148-153 (1994)].
The present inventors considered that medications which selectively inhibit an ACAT enzyme of a type present in the blood vessel wall can be those for treating arteriosclerosis that give less side effects, and have conducted synthesis and researches of such inhibitors.
The present inventors continued studies for achieving this object, and found in advance that compounds represented by the formula (IV) 




    
    
        wherein 




        represents an optionally substituted divalent residue such as benzene, pyridine, cyclohexane or naphthalene or a group, 




        Ar represents an optionally substituted aryl group
        X represents —NH—, an oxygen atom or a sulfur atom,
        Y represents —NR4—, an oxygen atom, a sulfur atom, a sulfoxide or a sulfone,
        Z represents a single bond or —NR5—,
        R4 represents a hydrogen atom, a lower alkyl group, an aryl group or an optionally substituted silyl lower alkyl group,
        R5 represents a hydrogen atom a lower alkyl group, an aryl group or an optionally substituted silyl lower alkyl group, and
        n is an integer of from 0 to 15,

or salts or solvates thereof, and compounds represented by the formula (V) 




        wherein 




        represents an optionally substituted divalent residue such as benzene, pyridine, cyclohexane or naphthalene, or a group, 




        Ar represents an optionally substituted aryl group,
        X represents —NH—, an oxygen atom or a sulfur atom,
        Y represents —NR4—, an oxygen atom, a sulfur atom, a sulfoxide or a sulfone,
        Z represents a single bond or —NR5—,
        R4 represents a hydrogen atom, a lower alkyl group, an aryl group or an optionally substituted silyl lower alkyl group,
        R5 represents a hydrogen atom, a lower alkyl group, an aryl group or an optionally substituted silyl lower alkyl group,
        l is an integer of from 0 to 15,
        m is an integer of 2 or 3, and
        n is integer of from 0 to 3,

or salts or solvates thereof have an excellent ACAT inhibitory activity, and they applied the same for patents (Japanese Patent Application Nos. 88,660/1997, 90,146/1997 and 149,892/1997).

    
    


Further, as compounds similar to the compounds represented by the formula (I), 3-(benzothiazol-2-ylthio)-N-(phenyl)propanamide is disclosed in J. Chem. Eng. Data, 27, 207 (1982), and 3-(benzoxazol-2-ylthio)-N-(phenyl)propanamide in Fungitsidy, Ed. Melnikov, N. N. Izd. Fan Uzb. SSR: Tashkent, USSR. 82-88 (1980). However, these compounds are not only those in which an amide moiety is a phenyl group, but also these documents are totally devoid of the description that the compounds have an ACAT inhibitory activity.
Thus, the present inventors found that the compounds represented by the formula (IV) or (V) have an organ-selective ACAT inhibitory activity and an intracellular cholesterol transfer inhibitory activity, and that these are useful as an antihyperlipemic agent having an activity of decreasing blood cholesterol and as an agent for preventing and treating arteriosclerosis having a macrophage foamation inhibitory activity.
However, the compounds represented by these formulas (IV) and (V) did not necessarily have a sufficient activity, nor was the organ-selectivity satisfactory.
Under these circumstances, the present inventors have conducted further investigations to develop an ACAT inhibitor having a superior ACAT inhibitory activity, and have consequently found that the compounds represented by the formula (I) are useful ACAT inhibitors which conquer the above-mentioned defects. This finding has led to the completion of the present invention.
DISCLOSURE OF INVENTION
The present invention is to provide compounds represented by the formula (I) 




    
    
        wherein 




        represents an optionally substituted divalent residue such as benzene, pyridine, cyclohexane or naphthalene, or a group 




        Met represents a 5- to 8-membered, substituted or unsubstituted heterocyclic group containing at least one heteroatom selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom, such as a monocyclic group, a polycyclic group or a group of a fused ring.
        X represents —NH—, an oxygen atom or a sulfur atom,
        Y represents —NR4—, an oxygen atom, a sulfur atom, a sulfoxide or a sulfone,
        Z represents a single bond or —NR5—,
        R4 represents a hydrogen atom, a lower alkyl group, an aryl group or an optionally substituted silyl lower alkyl group,
        R5 represents a hydrogen atom, a lower alkyl group, an aryl group or an optionally substituted silyl lower alkyl group, and
        n is an integer of from 1 to 15,

or salts or solvates thereof.

    
    


Further, the present invention is to provide a pharmaceutical composition containing at least one type selected from the compounds represented by the formula (I), and the salts and the solvates thereof in a therapeutically effective amount, and a pharmaceutically acceptable carrier.
Still further, the present invention is to provide an ACAT inhibitor, an intracellular cholesterol transfer inhibitor, a blood cholesterol depressant or a macrophage foamation suppressant containing at least one type selected from the compounds represented by the formula (I), and the salts and the solvates thereof in a therapeutically effective amount, and a pharmaceutically acceptable carrier. That is, the present invention is to provide a medication for treating or preventing diseases such as hyprlipemia, arteriosclerosis, cervical and cerebral arteriosclerosis, cerebrovascular accidents, ischemic heart disease, coronary arteriosclerosis, nephrosclerosis, arteriosclerotic nephrosclerosis, arteriolonephrosclerosis, malignant nephrosclerosis, ischemic intestinal disease, acute occlusion of mesenteric vessel, chronic mesenteric angina, ischemic colitis, aortic aneurysm and arteriosclerosis obliterans (ASO), this medication containing at least one type selected from the compounds represented by the formula (I), and the salts and the solvates thereof, and a pharmaceutically acceptable carrier, as well as a therapeutic method using the same.
BEST MODE FOR CARRYING OUT THE INVENTION
As preferable examples of the compounds represented by the the formula (IA) 




    
    
        wherein 




        represents an optionally substituted divalent residue such as benzen or pyridine.
        Py represents an optionally substituted pyridyl or pyrimidyl group,
        X represents —NH—, an oxygen atom or a sulfur atom,
        Y represents —NR4—, an oxygen atom, a sulfur atom, a sulfoxide or a sulfone,
        Z represents a single bond or —NR5—,
        R4 represents a hydrogen atom, a lower alkyl group, an aryl group or an optionally substituted silyl lower alkyl group,
        R5 represents a hydrogen atom, a lower alkyl group, an aryl group or an optionally substituted silyl lower alkyl group, and
        n is an integer of from 1 to 15,

or salts or solvates thereof, and a pharmaceutical composition containing these compounds can be mentioned.

    
    


As more preferable examples of the compounds represented by the formula (I) in the present invention, the compounds represented by the formula (II) 




    
    
        wherein Py represents an optionally substituted pyridyl or pyrimidyl group, and the other substituents are the same as described in the above-mentioned the formula (I), and the salts or the solvates thereof can be mentioned.
    
    


As further preferable examples of the compounds represented by the formula (I) in the present invention, the compounds represented by the formula (III) 




    
    
        wherein
        W represents ═CH— or ═N—, and
        R1, R2 and R3 are the same or different, and each represents a hydrogen atom, a lower alkyl group, a lower alkoxy group, a halogen atom, a hydroxyl group, a phosphate group, a sulfonamide group, a lower alkylthio group or an optionally substituted amino group, or two of R1, R2 and R3 together form an alkylenedioxide group.
    
    


The substituent Het of the compounds represented by the formula (I) in the present invention is a 5- to 8-membered, substituted or unsubstituted heterocyclic group containing at least one heteroatom selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom. This cyclic group may be a monocyclic group, a polycyclic group in which the heterocyclic groups are bound to each other or bound to a carbon ring such as a 6-membered aromatic ring either directly or through a carbon chain, or a group of a fused ring in which the heterocyclic groups are fused to each other or to a carbon ring such as a 6-membered aromatic ring. Among these heterocyclic groups, a 5- to 8-membered heterocyclic group, preferably a 5- or 6-membered heterocyclic group, containing one or two nitrogen atoms is preferable. Preferable examples of the substituent Het include a substituted or unsubstituted pyridyl group, a substituted or unsubstituted pyrimidyl group, a substituted or unsubstituted indolyl group, and a substituted or unsubstituted quinolyl group. A substituted or unsubstituted pyridyl group, and a substituted or unsubstituted pyrimidyl group are further preferable.
These heterocyclic groups may be unsubstituted, but have preferably one or more substituents. The substituent of these heterocyclic groups is not particularly limited unless the ACAT inhibitory activity of the present invention is impaired. Preferable examples thereof include an amino group substituted with a lower alkyl group, a lower alkoxy group, a lower alkylthio group, a lower alkylcarbonyl group, a halogen atom, an amino group or a lower alkyl group; a substituted or unsubstituted aryl group such as a phenyl group or a naphthyl group; and a substituted or unsubstituted aralkyl group such as a benzyl group or a phenetyl group. Further, two substituents may be bound to form an alkylenedioxy group such as a methylenedioxy group.
As the lower alkyl group, a linear or branched alkyl group having from 1 to 10 carbon atoms, preferably from 1 to 6 carbon atoms is preferable. Especially preferable examples thereof include methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, n-pentyl and n-hexyl groups.
As the lower alkyl group in the lower alkoxy group, the lower alkylthio group and the lower alkylcarbonyl group, the above-mentioned linear or branched alkyl group having from 1 to 10 carbon atoms, preferably from 1 to 6 carbon atoms is preferable. Examples thereof include methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, tert-butoxy, n-pentyloxy, n-hexyloxy, methylthio, ethylthio, n-propylthio, iso-propylthio, n-butylthio, iso-butylthio, tert-butylthio, n-pentylthio, n-hexylthio, methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, iso-propylcarbonyl, n-butylcarbonyl, iso-butylcarbonyl, tert-butylcarbonyl, n-pentylcarbonyl and n-hexylcarbonyl groups.
Preferable examples of the halogen atom include fluorine, chlorine, bromine and iodine atoms.
As the aryl group, an aryl group having from 6 to 20 carbon atoms, preferably from 6 to 10 carbon atoms is mentioned. This aryl group may be unsubstituted or substituted with the above-mentioned lower alkyl group, lower alkoxy group, lower alkylthio group, lower alkylcarbonyl group, halogen atom, amino group or amino group substituted with the lower alkyl group. Preferable examples of the aryl group include phenyl, naphthyl, 2-methoxyphenyl and 4-methylthiophenyl groups.
The aralkyl group is an aralkyl group having from 7 to 20 carbon atoms, preferably from 7 to 12 carbon atoms. This aralkyl group may be unsubstituted or substituted with the above-mentioned lower alkyl group, lower alkoxy group, lower alkylthio group, lower alkylcarbonyl group, halogen atom, amino group or amino group substituted with the lower alkyl group. Preferable examples of the aralkyl group include benzyl, phenetyl and 4-methylbenzyl groups.
Examples of the substituent in the substituted amino group include the above-mentioned lower alkyl, lower alkylcarbonyl, aryl and aralkyl groups, and the number of the substituent in the amino group may be 1 or 2. Preferable examples of the substituted amino group include methylamino, ethylamino, dimethylamino, diethylamino, acetylamino and benzylamino groups.
The alkylene group of the alkylenedioxy group is a linear or branched alkylene group having from 1 to 10 carbon atoms, preferably from 1 to 5 carbon atoms. Preferable examples thereof include methylenedioxy and ethylenedioxy groups.
As the preferable Het group, a group represented by the formula (VI) is mentioned. 




    
    
        wherein W, R1, R2 and R3 are as defined above.
    
    


Preferable examples of the Het group include

    
    
        2-methylthio-3-pyridyl,
        2-ethylthio-3-pyridyl,
        2-(iso-propylthio)-3-pyridyl,
        2-methoxy-3-pyridyl,
        2-chloro-3-pyridyl,
        2-methylthio-4-methyl-3-pyridyl,
        2-ethylthio-4-methyl-3-pyridyl,
        2-(iso-propylthio)-4-methyl-3-pyridyl,
        2-methoxy-4-methyl-3-pyridyl,
        2,6-bis(methylthio)-3-pyridyl,
        2,6-bis(ethylthio)-3-pyridyl,
        2,6-bis(iso-propylthio)-3-pyridyl,
        2-methylthio-6-methoxy-3-pyridyl,
        2-ethylthio-6-methoxy-3-pyridyl,
        2-(iso-propylthio)-6-methoxy-3-pyridyl,
        2-methylthio-6-methyl-3-pyridyl,
        2-ethylthio-6-methyl-3-pyridyl,
        2-(iso-propylthio)-6-methyl-3-pyridyl
        2,6-dimethoxy-3-pyridyl,
        2-methoxy-6-methyl-3-pyridyl,
        2-methyl-6-methylthio-3-pyridyl,
        2-methyl-6-ethylthio-3-pyridyl,
        2-methyl-6-(iso-propylthio)-3-pyridyl,
        2-methyl-6-methoxy-3-pyridyl,
        2,6-dimehtyl-3-pyridyl,
        2,6-diethyl-3-pyridyl,
        2,4-bismethylthio-6-methyl-3-pyridyl,
        2,4-bisethylthio-6-methyl-3-pyridyl,
        2,4-bis(iso-propylthio)-6-methyl-3-pyridyl,
        2,4-dimethoxy-6-methyl-3-pyridyl,
        2,4,6-trimethyl-3-pyridyl,
        4-ethyl-2,6-dimethyl-3-pyridyl,
        2,4-dichloro-6-methyl-3-pyridyl,
        4,6-bis(methylthio)-5-pyrimidyl,
        4,6-bis(ethylthio)-5-pyrimidyl,
        4,6-bis(iso-propylthio)-5-pyrimidyl,
        4,6-dimethoxy-5-pyrimidyl,
        4,6-dichloro-2-methyl-5-pyrimidyl,
        4,6-bis(dimethylamino)-5-pyrimidyl,
        4,6-bismethylthio-2-methyl-5-pyrimidyl,
        2,4,6-trimethoxy-5-pyrimidyl
        4-methyl-6-methyltio-3-pyridyl,
        5-methylthio-2-pyridyl,
        2,4,6-tris(methylthio)-5-pyrimidyl groups and so on.
    
    


The substituent 




in the compounds represented by the the formula (I) in the present invention is a divalent group adjacent the azole ring which is formed with two carbon atoms constituting the azole ring. It is preferably an optionally substituted divalent group such as benzene, pyridine, cyclohexane or naphthalene, or a group as follows. 




An optionally substituted divalent residue such as benzen or pyridine is preferable. These divalent groups may have a substituent. Examples of the substituent include the above-mentioned lower alkyl group, lower alkoxy group, lower alkylsulfonyl group lower alkylthio group, lower alkylcarbonyl group, halogen atom, amino group, amino group substituted with the lower alkyl group, substituted or unsubstituted aryl group such as the phenyl group or the naphthyl group, and substituted or unsubstituted aralkyl group such as the benzyl group or the phenetyl group. Further, the two substituents may be bound to form an alkylenedioxy group such as a methylenedioxy group.
The substituent X in the compounds represented by the formula (I) in the present invention represents —NH—, an oxygen atom or a sulfur atom, and forms, together with the above-mentioned substituent, an azole ring such as imidazole, oxazole or thiazole.
Further, the substituent Y in the compounds represented by the formula (I) of the present invention represents —NR4—, an oxygen atom, a sulfur atom, a sulfoxide or a sulfone, and the substituent R4 of the nitrogen atom represents a hydrogen atom, a lower alkyl group, an aryl group or an optionally substituted silyl lower alkyl group. The lower alkyl group or the aryl group as the substituent R4 is as mentioned above. Examples thereof include methyl, ethyl and phenyl groups. The lower alkyl group of the optionally substituted silyl lower alkyl group as the substituent R4 may be the above-mentioned group. Examples of the substituent of the silyl lower alkyl group include the above-mentioned lower alkyl, aryl and aralkyl groups. Preferable examples thereof include trimethylsilylmethyl and dimethylphenylsilylmethyl groups.
As the substituent Y, a sulfur atom is preferable.
The substituent Z in the compounds represented by the formula (I) of the present invention represents a single bond or —NR5—, and the substituent R5 of the nitrogen atom represents a hydrogen atom, a lower alkyl group, an aryl group or an optionally substituted silyl lower alkyl group. Examples of these substituents are the above-mentioned groups.
The number n of recurring units in the compounds represented by the formula (I) in the present invention is an integer of from 1 to 15, preferably an integer of from 1 to 9. As the recurring unit, a methylene group is mentioned in the formula (I). The methylene group may have a substituent or one or more methylene units may be substituted with a heteroatom such as a nitrogen atom, an oxygen atom or a sulfur atom unless the ACAT inhibitory activity of the present invention is impaired.
The substituents X, Y, Z and the recurring unit in the compounds represented by the formula (II) in the present invention are the above-mentioned ones. The substituent Py represents an optionally substituted pyridyl or pyrimidyl group. The substituent of the pyridyl or pyrimidyl group is not particularly limited unless the ACAT inhibitory activity of the present invention is impaired. The group represented by the formula (VI) is preferable.
The substituents X, Y, Z and the recurring unit in the compounds represented by the formula (III) in the present invention are the above-mentioned ones. The substituent W represents a carbon atom or a nitrogen atom, and forms a pyridine or pyrimidine ring. Further, the substituents R1, R2 and R3 are the same or different, and each represents a hydrogen atom, a lower alkyl group, a lower alkoxy group, a halogen atom, a hydroxyl group, a phosphate group, a sulfonamide group, a lower alkylthio group or an optionally substituted amino group, or two of R1, R2 and R3 together form an alkylenedioxy group. Of these groups, the lower alkyl group, the lower alkoxy group, the halogen atom, the lower alkylthio group, the optionally substituted amino group and the alkylenedioxy group are the above-mentioned ones. Preferable examples of R1, R2 and R3 include methyl, ethyl, iso-propyl, methoxy, ethoxy and iso-propoxy groups, chlorine, and methylthio, ethylthio, iso-propylthio and dimethylamino groups. The site of the pyridine ring or the pyrimidine ring bound to the adjacent nitrogen atom is not particularly limited either unless the ACAT inhibitory activity of the present invention is impaired.
The salts of the compounds represented by the formula (I), (II) or (III) in the present invention are not particularly limited unless the ACAT inhibitory activity of the present invention is impaired. Acid addition salts or base addition salts can be used as required. Preferable examples of the acid addition salts include inorganic acid salts such as a hydrochloride, a sulfate, a nitrate and a phosphate; and organic acid salts such as a methanesulfonate, a maleate, a fumarate and a citrate.
Further, the solvates of the compounds represented by the formula (I), (II) or (III) in the present invention are products to which solvents used in the production, the purification or the like, such as water, alcohol and the like are added, and are not particularly limited unless they have an adverse effect on the ACAT inhibitory activity. As the solvates, hydrides are preferable.
A process for producing the compounds of the present invention is described below.
Compounds (I) can be produced by various known processes, and the process is not particularly limited. For example, compounds (I) can be produced according to the following reaction steps.

    1. Process for producing compounds of the formula (I) when the substituent Z is a single bond:


A carboxylic acid represented by the formula (VII) or its reactive derivative, for example, an acid halide, is reacted with a heterocyclic amine represented by the formula (VIII) according to the following reaction formulae 




 

wherein R6 represents a leaving group, and R7 represents a reactive derivative residue of a hydroxyl group or a carboxylate group, to form an amide derivative represented by the formula (IX). When the resulting compound of the formula (IX) is reacted with an azole derivative represented by the formula (X), a desired compound (I′) in which the substituent Z in the formula (I) is a single bond can be produced.

An ordinary method used in peptide synthesis can be applied to the reaction between compounds (VII) and (VIII). Examples of the leaving group R6 in the formula (VII) include halogen atoms such as chlorine and bromine atoms. Preferable examples of the reactive derivative residue R7 include acid anhydride residues with mesylic acid, tosylic acid, acetic acid, pivaloylic acid and the like. This reaction is described more specifically below. The desired compound can be obtained by reacting both of the compounds in a solvent in the presence of a condensation agent. As the condensation agent, for example, 1-(3′-dimethylaminopropyl)-3-ethylcarbodiimide (WSC) and 1,3-dicyclohexylcarbodiimide (DCC) may be used singly, and a combination of 1-hydroxybenzotriazole (HOBt) and N-hydroxysuccinimide (HOSU) is also available. The solvent is not particularly limited. For example, dimethylformamide, methylene chloride, chloroform, tetrahydrofuran and toluene can be used either singly or in combination. The reaction conditions vary depending on a starting material to be used. Generally, the reaction is conducted at from 0 to 100° C., preferably at a temperature close to room temperature, for from 1 to 30 hours, preferably for from 10 to 20 hours. In this manner, the reaction is completed. Further, when a carbonyl halide having a high reactivity is used as compound (VII), for example, compounds (VII) and (VIII) can be reacted in the presence of a base, for example, triethylamine, 4-dimethylaminopyridine or N-methylmorpholine in a usual manner.
With respect to starting compounds (VII) and (VIII), for example, compound (VII) can be produced by a method in which a haloalkyl alcohol is oxidized into a carboxylic acid with a Jones' reagent or the like, and compound (VIII) by a method in which a nitrated heterocyclic compound is subjected to a reduction reaction such as a catalytic reduction or the like to obtain a corresponding amino heterocyclic compound, respectively.
The reaction between compounds (IX) and (X) obtained by the above-mentioned methods can be conducted in a solvent in the presence or absence of a base. As the solvent, the above-mentioned various types can be used. The base includes inorganic bases, for example, alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkali metal carbonates such as sodium carbonate and potassium carbonate, and alkali metal hydrogencarbonates such as sodium hydrogencarbonate and potassium hydrogencarbonate; and organic bases such as pyridine, triethylamine, N,N-diisopropylethylamine, N-methylmorpholine and N,N-dimethylaniline.
Further, with respect to the desired compound represented by the formula (I′), according to the reaction shown by the following formula 




    
    
        wherein R6 represents a leaving group, and R7 represents a reactive derivative residue of a hydroxyl group or a carboxylate group, an azole derivative represented by the formula (X) is reacted with a free carboxylic acid or an inactive substance of a carboxylic acid as the compound represented by the formula (VII) to obtain a carboxylic acid derivative represented by the formula (XI). When the resulting compound represented by the formula (XI) or its reactive derivative, for example, an acid halide, is reacted with a heterocyclic amine derivative represented by the formula (VIII), the desired compound (I′) in which the substituent Z in the formula (I) is a single bond can be produced.
    
    


The reaction between compounds (X) and (VII) can be conducted according to the second step of the above-mentioned reaction formula. The reaction in which potassium hydroxide is used as a base and ethanol as a solvent respectively is especially preferable. The reaction between the resulting compounds (XI) and (VIII) can be conducted according to the first step of the above-mentioned reaction formula.

    2. Process for producing compounds of the formula (I) when the substituent Z is —NH—:


The compound represented by the formula (I) in which Z is —NH— can be produced by various processes. It is preferable to produce the same by the process shown by the following reaction formula. 




    
    
        wherein R8 represents a leaving group.
    
    


The isocyanate derivative represented by the formula (XII) is reacted with the heterocyclic amine represented by the formula (VIII) to obtain an urea derivative represented by the formula (XIII). The resulting urea derivative is reacted with compound (X) to form desired compound (I′′) in which the substituent Z in the formula (I) is —NH—.
With respect to the reaction between compounds (XII) and (VIII) in the first step of this reaction formula, compound (XII) is reacted with compound (VIII) in an amount of from 1 to 2 equivalents in a solvent to obtain compound (XIII). At this time, the solvent is not particularly limited. Preferable examples thereof include methylene chloride, chloroform, ether, tetrahydrofuran, toluene, xylene and dimethylformamide. The reaction proceeds in a boiling point of a solvent used from 0° C. for a reaction time of from 1 to 24 hours.
The isocyanate derivative represented by the formula (XII) is a known compound, and it can be produced by, for example, a method in which the above-mentioned carboxylic acid as compound (VII) is reacted with diphenylphospholyl azide in the presence of a base (method of Shioiri et al.), a method via an acid azide by reacting the acid halide of compound (VII) with sodium azide.
The reaction between compounds (XIII) and (X) can be conducted according to the second step of the above-mentioned reaction formula.
Further, when the substituent Z in the formula (I) is —NR5— (wherein R5 represents the above-mentioned groups except a hydrogen atom), the compound can be produced by replacing a nitrogen atom with the substituent R5 at an appropriate stage.
The intermediate and the desired compound obtained in each of the above-mentioned reactions can be isolated and purified by a purification method which is ordinarily used in the synthetic organic chemistry, such as filtration, extraction, washing, drying, concentration, recrystallization and various chromatographies. Further, each intermediate is subjected to the subsequent step without any purification unless any trouble is caused, which is well known to those skilled in the art.
The resulting compounds (I) can be formed into salts of the present invention in a usual manner.
Further, compounds (I) can be formed into solvates with solvents such as a reaction solvent, a recrystallization solvent and the like, especially hydrides in a usual manner, which is well known to those skilled in the art.
The compounds represented by the formula (I), (II) or (III), which are obtained by the process of the present invention are shown in Tables 1 to 63 below.













TABLE 1





Compound No.





X
Y
Z
n
Het





















 1





O
S
*
1
2-methylthio-3-pyridyl


 2
′′
O
S
*
2
2-methylthio-3-pyridyl


 3
′′
O
S
*
3
2-methylthio-3-pyridyl


 4
′′
O
S
*
4
2-methylthio-3-pyridyl


 5
′′
O
S
*
5
2-methylthio-3-pyridyl


 6
′′
O
S
*
6
2-methylthio-3-pyridyl


 7
′′
O
S
*
7
2-methylthio-3-pyridyl


 8
′′
O
S
*
8
2-methylthio-3-pyridyl


 9
′′
O
S
*
9
2-methylthio-3-pyridyl


10
′′
O
S
*
14
2-methylthio-3-pyridyl


11
′′
S
S
*
1
2-methylthio-3-pyridyl


12
′′
S
S
*
2
2-methylthio-3-pyridyl


13
′′
S
S
*
3
2-methylthio-3-pyridyl


14
′′
S
S
*
4
2-methylthio-3-pyridyl


15
′′
S
S
*
5
2-methylthio-3-pyridyl


16
′′
S
S
*
6
2-methylthio-3-pyridyl


17
′′
S
S
*
7
2-methylthio-3-pyridyl


18
′′
S
S
*
8
2-methylthio-3-pyridyl


19
′′
S
S
*
9
2-methylthio-3-pyridyl


20
′′
S
S
*
14
2-methylthio-3-pyridyl





*: Single Bond 






 














TABLE 2





Compound No.





X
Y
Z
n
Het





















21





NH
S
*
1
2-methylthio-3- pyridyl


22
′′
NH
S
*
2
2-methylthio-3-








pyridyl


23
′′
NH
S
*
3
2-methylthio-3-








pyridyl


24
′′
NH
S
*
4
2-methylthio-3-








pyridyl


25
′′
NH
S
*
5
2-methylthio-3-








pyridyl


26
′′
NH
S
*
6
2-methylthio-3-








pyridyl


27
′′
NH
S
*
7
2-methylthio-3-








pyridyl


28
′′
NH
S
*
8
2-methylthio-3-








pyridyl


29
′′
NH
S
*
9
2-methylthio-3-








pyridyl


30
′′
NH
S
*
14
2-methylthio-3-








pyridyl


31
′′
O
S
*
1
2-ethylthio-3-








pyridyl


32
′′
O
S
*
2
2-ethylthio-3-








pyridyl


33
′′
O
S
*
3
2-ethylthio-3-








pyridyl


34
′′
O
S
*
4
2-ethylthio-3-








pyridyl


35
′′
O
S
*
5
2-ethylthio-3-








pyridyl


36
′′
O
S
*
6
2-ethylthio-3-








pyridyl


37
′′
O
S
*
7
2-ethylthio-3-








pyridyl


38
′′
O
S
*
8
2-ethylthio-3-








pyridyl


39
′′
O
S
*
9
2-ethylthio-3-








pyridyl


40
′′
O
S
*
14
2-ethylthio-3-








pyridyl





*: Single Bond 






 














TABLE 3





Compound No.





X
Y
Z
n
Het





















41





S
S
*
1
2-ethylthio-3- pyridyl


42
′′
S
S
*
2
2-ethylthio-3-








pyridyl


43
′′
S
S
*
3
2-ethylthio-3-








pyridyl


44
′′
S
S
*
4
2-ethylthio-3-








pyridyl


45
′′
S
S
*
5
2-ethylthio-3-








pyridyl


46
′′
S
S
*
6
2-ethylthio-3-








pyridyl


47
′′
S
S
*
7
2-ethylthio-3-








pyridyl


48
′′
S
S
*
8
2-ethylthio-3-








pyridyl


49
′′
S
S
*
9
2-ethylthio-3-








pyridyl


50
′′
S
S
*
14
2-ethylthio-3-








pyridyl


51
′′
NH
S
*
1
2-ethylthio-3-








pyridyl


52
′′
NH
S
*
2
2-ethylthio-3-








pyridyl


53
′′
NH
S
*
3
2-ethylthio-3-








pyridyl


54
′′
NH
S
*
4
2-ethylthio-3-








pyridyl


55
′′
NH
S
*
5
2-ethylthio-3-








pyridyl


56
′′
NH
S
*
6
2-ethylthio-3-








pyridyl


57
′′
NH
S
*
7
2-ethylthio-3-








pyridyl


58
′′
NH
S
*
8
2-ethylthio-3-








pyridyl


59
′′
NH
S
*
9
2-ethylthio-3-








pyridyl


60
′′
NH
S
*
14
2-ethylthio-3-








pyridyl





*: Single Bond 






 














TABLE 4





Compound No.





X
Y
Z
n
Het





















61





O
S
*
1
2-(iso-propylthio)-3- pyridyl


62
′′
O
S
*
2
2-(iso-propylthio)-3-








pyridyl


63
′′
O
S
*
3
2-(iso-propylthio)-3-








pyridyl


64
′′
O
S
*
4
2-(iso-propylthio)-3-








pyridyl


65
′′
O
S
*
5
2-(iso-propylthio)-3-








pyridyl


66
′′
O
S
*
6
2-(iso-propylthio)-3-








pyridyl


67
′′
O
S
*
7
2-(iso-propylthio)-3-








pyridyl


68
′′
O
S
*
8
2-(iso-propylthio)-3-








pyridyl


69
′′
O
S
*
9
2-(iso-propylthio)-3-








pyridyl


70
′′
O
S
*
14
2-(iso-propylthio)-3-








pyridyl


71
′′
S
S
*
1
2-(iso-propylthio)-3-








pyridyl


72
′′
S
S
*
2
2-(iso-propylthio)-3-








pyridyl


73
′′
S
S
*
3
2-(iso-propylthio)-3-








pyridyl


74
′′
S
S
*
4
2-(iso-propylthio)-3-








pyridyl


75
′′
S
S
*
5
2-(iso-propylthio)-3-








pyridyl


76
′′
S
S
*
6
2-(iso-propylthio)-3-








pyridyl


77
′′
S
S
*
7
2-(iso-propylthio)-3-








pyridyl


78
′′
S
S
*
8
2-(iso-propylthio)-3-








pyridyl


79
′′
S
S
*
9
2-(iso-propylthio)-3-








pyridyl


80
′′
S
S
*
14
2-(iso-propylthio)-3-








pyridyl





*: Single Bond 






 














TABLE 5





Compound No.





X
Y
Z
n
Het





















 81





NH
S
*
1
2-(iso-propylthio)-3- pyridyl


 82
′′
NH
S
*
2
2-(iso-propylthio)-3-








pyridyl


 83
′′
NH
S
*
3
2-(iso-propylthio)-3-








pyridyl


 84
′′
NH
S
*
4
2-(iso-propylthio)-3-








pyridyl


 85
′′
NH
S
*
5
2-(iso-propylthio)-3-








pyridyl


 86
′′
NH
S
*
6
2-(iso-propylthio)-3-








pyridyl


 87
′′
NH
S
*
7
2-(iso-propylthio)-3-








pyridyl


 88
′′
NH
S
*
8
2-(iso-propylthio)-3-








pyridyl


 89
′′
NH
S
*
9
2-(iso-propylthio)-3-








pyridyl


 90
′′
NH
S
*
14
2-(iso-propylthio)-3-








pyridyl


 91
′′
O
S
*
1
2-methoxy-3-pyridyl


 92
′′
O
S
*
2
2-methoxy-3-pyridyl


 93
′′
O
S
*
3
2-methoxy-3-pyridyl


 94
′′
O
S
*
4
2-methoxy-3-pyridyl


 95
′′
O
S
*
5
2-methoxy-3-pyridyl


 96
′′
O
S
*
6
2-methoxy-3-pyridyl


 97
′′
O
S
*
7
2-methoxy-3-pyridyl


 98
′′
O
S
*
8
2-methoxy-3-pyridyl


 99
′′
O
S
*
9
2-methoxy-3-pyridyl


100
′′
O
S
*
14
2-methoxy-3-pyridyl





*: Single Bond 






 














TABLE 6





Compound No.





X
Y
Z
n
Het





















101





S
S
*
1
2-methoxy-3-pyridyl


102
′′
S
S
*
2
2-methoxy-3-pyridyl


103
′′
S
S
*
3
2-methoxy-3-pyridyl


104
′′
S
S
*
4
2-methoxy-3-pyridyl


105
′′
S
S
*
5
2-methoxy-3-pyridyl


106
′′
S
S
*
6
2-methoxy-3-pyridyl


107
′′
S
S
*
7
2-methoxy-3-pyridyl


108
′′
S
S
*
8
2-methoxy-3-pyridyl


109
′′
S
S
*
9
2-methoxy-3-pyridyl


110
′′
S
S
*
14
2-methoxy-3-pyridyl


111
′′
NH
S
*
1
2-methoxy-3-pyridyl


112
′′
NH
S
*
2
2-methoxy-3-pyridyl


113
′′
NH
S
*
3
2-methoxy-3-pyridyl


114
′′
NH
S
*
4
2-methoxy-3-pyridyl


115
′′
NH
S
*
5
2-methoxy-3-pyridyl


116
′′
NH
S
*
6
2-methoxy-3-pyridyl


117
′′
NH
S
*
7
2-methoxy-3-pyridyl


118
′′
NH
S
*
8
2-methoxy-3-pyridyl


119
′′
NH
S
*
9
2-methoxy-3-pyridyl


120
′′
NH
S
*
14
2-methoxy-3-pyridyl





*: Single Bond 






 














TABLE 7





Compound No.





X
Y
Z
n
Het





















121





O
S
*
1
2-chloro-3-pyridyl


122
′′
O
S
*
2
2-chloro-3-pyridyl


123
′′
O
S
*
3
2-chloro-3-pyridyl


124
′′
O
S
*
4
2-chloro-3-pyridyl


125
′′
O
S
*
5
2-chloro-3-pyridyl


126
′′
O
S
*
6
2-chloro-3-pyridyl


127
′′
O
S
*
7
2-chloro-3-pyridyl


128
′′
O
S
*
8
2-chloro-3-pyridyl


129
′′
O
S
*
9
2-chloro-3-pyridyl


130
′′
O
S
*
14
2-chloro-3-pyridyl


131
′′
S
S
*
1
2-chloro-3-pyridyl


132
′′
S
S
*
2
2-chloro-3-pyridyl


133
′′
S
S
*
3
2-chloro-3-pyridyl


134
′′
S
S
*
4
2-chloro-3-pyridyl


135
′′
S
S
*
5
2-chloro-3-pyridyl


136
′′
S
S
*
6
2-chloro-3-pyridyl


137
′′
S
S
*
7
2-chloro-3-pyridyl


138
′′
S
S
*
8
2-chloro-3-pyridyl


139
′′
S
S
*
9
2-chloro-3-pyridyl


140
′′
S
S
*
14
2-chloro-3-pyridyl





*: Single Bond 






 














TABLE 8





Compound No.





X
Y
Z
n
Het





















141





NH
S
*
1
2-chloro-3-pyridyl


142
′′
NH
S
*
2
2-chloro-3-pyridyl


143
′′
NH
S
*
3
2-chloro-3-pyridyl


144
′′
NH
S
*
4
2-chloro-3-pyridyl


145
′′
NH
S
*
5
2-chloro-3-pyridyl


146
′′
NH
S
*
6
2-chloro-3-pyridyl


147
′′
NH
S
*
7
2-chloro-3-pyridyl


148
′′
NH
S
*
8
2-chloro-3-pyridyl


149
′′
NH
S
*
9
2-chloro-3-pyridyl


150
′′
NH
S
*
14
2-chloro-3-pyridyl


151
′′
O
S
*
1
2-methylthio-4-








methyl-3-pyridyl


152
′′
O
S
*
2
2-methylthio-4-








methyl-3-pyridyl


153
′′
O
S
*
3
2-methylthio-4-








methyl-3-pyridyl


154
′′
O
S
*
4
2-methylthio-4-








methyl-3-pyridyl


155
′′
O
S
*
5
2-methylthio-4-








methyl-3-pyridyl


156
′′
O
S
*
6
2-methylthio-4-








methyl-3-pyridyl


157
′′
O
S
*
7
2-methylthio-4-








methyl-3-pyridyl


158
′′
O
S
*
8
2-methylthio-4-








methyl-3-pyridyl


159
′′
O
S
*
9
2-methylthio-4-








methyl-3-pyridyl


160
′′
O
S
*
14
2-methylthio-4-








methyl-3-pyridyl





*: Single Bond 






 














TABLE 9





Compound No.





X
Y
Z
n
Het





















161





S
S
*
1
2-methylthio-4- methyl-3-pyridyl


162
′′
S
S
*
2
2-methylthio-4-








methyl-3-pyridyl


163
′′
S
S
*
3
2-methylthio-4-








methyl-3-pyridyl


164
′′
S
S
*
4
2-methylthio-4-








methyl-3-pyridyl


165
′′
S
S
*
5
2-methylthio-4-








methyl-3-pyridyl


166
′′
S
S
*
6
2-methylthio-4-








methyl-3-pyridyl


167
′′
S
S
*
7
2-methylthio-4-








methyl-3-pyridyl


168
′′
S
S
*
8
2-methylthio-4-








methyl-3-pyridyl


169
′′
S
S
*
9
2-methylthio-4-








methyl-3-pyridyl


170
′′
S
S
*
14
2-methylthio-4-








methyl-3-pyridyl


171
′′
NH
S
*
1
2-methylthio-4-








methyl-3-pyridyl


172
′′
NH
S
*
2
2-methylthio-4-








methyl-3-pyridyl


173
′′
NH
S
*
3
2-methylthio-4-








methyl-3-pyridyl


174
′′
NH
S
*
4
2-methylthio-4-








methyl-3-pyridyl


175
′′
NH
S
*
5
2-methylthio-4-








methyl-3-pyridyl


176
′′
NH
S
*
6
2-methylthio-4-








methyl-3-pyridyl


177
′′
NH
S
*
7
2-methylthio-4-








methyl-3-pyridyl


178
′′
NH
S
*
8
2-methylthio-4-








methyl-3-pyridyl


179
′′
NH
S
*
9
2-methylthio-4-








methyl-3-pyridyl


180
′′
NH
S
*
14
2-methylthio-4-








methyl-3-pyridyl





*: Single Bond 






 














TABLE 10





Compound No.





X
Y
Z
n
Het





















181





O
S
*
1
2-ethylthio-4-methyl- 3-pyridyl


182
′′
O
S
*
2
2-ethylthio-4-methyl-








3-pyridyl


183
′′
O
S
*
3
2-ethylthio-4-methyl-








3-pyridyl


184
′′
O
S
*
4
2-ethylthio-4-methyl-








3-pyridyl


185
′′
O
S
*
5
2-ethylthio-4-methyl-








3-pyridyl


186
′′
O
S
*
6
2-ethylthio-4-methyl-








3-pyridyl


187
′′
O
S
*
7
2-ethylthio-4-methyl-








3-pyridyl


188
′′
O
S
*
8
2-ethylthio-4-methyl-








3-pyridyl


189
′′
O
S
*
9
2-ethylthio-4-methyl-








3-pyridyl


190
′′
O
S
*
14
2-ethylthio-4-methyl-








3-pyridyl


191
′′
S
S
*
1
2-ethylthio-4-methyl-








3-pyridyl


192
′′
S
S
*
2
2-ethylthio-4-methyl-








3-pyridyl


193
′′
S
S
*
3
2-ethylthio-4-methyl-








3-pyridyl


194
′′
S
S
*
4
2-ethylthio-4-methyl-








3-pyridyl


195
′′
S
S
*
5
2-ethylthio-4-methyl-








3-pyridyl


196
′′
S
S
*
6
2-ethylthio-4-methyl-








3-pyridyl


197
′′
S
S
*
7
2-ethylthio-4-methyl-








3-pyridyl


198
′′
S
S
*
8
2-ethylthio-4-methyl-








3-pyridyl


199
′′
S
S
*
9
2-ethylthio-4-methyl-








3-pyridyl


200
′′
S
S
*
14
2-ethylthio-4-methyl-








3-pyridyl





*: Single Bond 






 














TABLE 11





Compound No.





X
Y
Z
n
Het





















201





NH
S
*
1
2-ethylthio-4- methyl-3-pyridyl


202
′′
NH
S
*
2
2-ethylthio-4-








methyl-3-pyridyl


203
′′
NH
S
*
3
2-ethylthio-4-








methyl-3-pyridyl


204
′′
NH
S
*
4
2-ethylthio-4-








methyl-3-pyridyl


205
′′
NH
S
*
5
2-ethylthio-4-








methyl-3-pyridyl


206
′′
NH
S
*
6
2-ethylthio-4-








methyl-3-pyridyl


207
′′
NH
S
*
7
2-ethylthio-4-








methyl-3-pyridyl


208
′′
NH
S
*
8
2-ethylthio-4-








methyl-3-pyridyl


209
′′
NH
S
*
9
2-ethylthio-4-








methyl-3-pyridyl


210
′′
NH
S
*
14
2-ethylthio-4-








methyl-3-pyridyl


211
′′
O
S
*
1
2-(iso-propylthio)-4-








methyl-3-pyridyl


212
′′
O
S
*
2
2-(iso-propylthio)-4-








methyl-3-pyridyl


213
′′
O
S
*
3
2-(iso-propylthio)-4-








methyl-3-pyridyl


214
′′
O
S
*
4
2-(iso-propylthio)-4-








methyl-3-pyridyl


215
′′
O
S
*
5
2-(iso-propylthio)-4-








methyl-3-pyridyl


216
′′
O
S
*
6
2-(iso-propylthio)-4-








methyl-3-pyridyl


217
′′
O
S
*
7
2-(iso-propylthio)-4-








methyl-3-pyridyl


218
′′
O
S
*
8
2-(iso-propylthio)-4-








methyl-3-pyridyl


219
′′
O
S
*
9
2-(iso-propylthio)-4-








methyl-3-pyridyl


220
′′
O
S
*
14
2-(iso-propylthio)-4-








methyl-3-pyridyl





*: Single Bond 






 














TABLE 12





Compound No.





X
Y
Z
n
Het





















221





S
S
*
1
2-(iso-propylthio)-4- methyl-3-pyridyl


222
′′
S
S
*
2
2-(iso-propylthio)-4-








methyl-3-pyridyl


223
′′
S
S
*
3
2-(iso-propylthio)-4-








methyl-3-pyridyl


224
′′
S
S
*
4
2-(iso-propylthio)-4-








methyl-3-pyridyl


225
′′
S
S
*
5
2-(iso-propylthio)-4-








methyl-3-pyridyl


226
′′
S
S
*
6
2-(iso-propylthio)-4-








methyl-3-pyridyl


227
′′
S
S
*
7
2-(iso-propylthio)-4-








methyl-3-pyridyl


228
′′
S
S
*
8
2-(iso-propylthio)-4-








methyl-3-pyridyl


229
′′
S
S
*
9
2-(iso-propylthio)-4-








methyl-3-pyridyl


230
′′
S
S
*
14
2-(iso-propylthio)-4-








methyl-3-pyridyl


231
′′
NH
S
*
1
2-(iso-propylthio)-4-








methyl-3-pyridyl


232
′′
NH
S
*
2
2-(iso-propylthio)-4-








methyl-3-pyridyl


233
′′
NH
S
*
3
2-(iso-propylthio)-4-








methyl-3-pyridyl


234
′′
NH
S
*
4
2-(iso-propylthio)-4-








methyl-3-pyridyl


235
′′
NH
S
*
5
2-(iso-propylthio)-4-








methyl-3-pyridyl


236
′′
NH
S
*
6
2-(iso-propylthio)-4-








methyl-3-pyridyl


237
′′
NH
S
*
7
2-(iso-propylthio)-4-








methyl-3-pyridyl


238
′′
NH
S
*
8
2-(iso-propylthio)-4-








methyl-3-pyridyl


239
′′
NH
S
*
9
2-(iso-propylthio)-4-








methyl-3-pyridyl


240
′′
NH
S
*
14
2-(iso-propylthio)-4-








methyl-3-pyridyl





*: Single Bond 






 














TABLE 13





Compound No.





X
Y
Z
n
Het





















241





O
S
*
1
2-methoxy-4-methyl- 3-pyridyl


242
′′
O
S
*
2
2-methoxy-4-methyl-








3-pyridyl


243
′′
O
S
*
3
2-methoxy-4-methyl-








3-pyridyl


244
′′
O
S
*
4
2-methoxy-4-methyl-








3-pyridyl


245
′′
O
S
*
5
2-methoxy-4-methyl-








3-pyridyl


246
′′
O
S
*
6
2-methoxy-4-methyl-








3-pyridyl


247
′′
O
S
*
7
2-methoxy-4-methyl-








3-pyridyl


248
′′
O
S
*
8
2-methoxy-4-methyl-








3-pyridyl


249
′′
O
S
*
9
2-methoxy-4-methyl-








3-pyridyl


250
′′
O
S
*
14
2-methoxy-4-methyl-








3-pyridyl


251
′′
S
S
*
1
2-methoxy-4-methyl-








3-pyridyl


252
′′
S
S
*
2
2-methoxy-4-methyl-








3-pyridyl


253
′′
S
S
*
3
2-methoxy-4-methyl-








3-pyridyl


254
′′
S
S
*
4
2-methoxy-4-methyl-








3-pyridyl


255
′′
S
S
*
5
2-methoxy-4-methyl-








3-pyridyl


256
′′
S
S
*
6
2-methoxy-4-methyl-








3-pyridyl


257
′′
S
S
*
7
2-methoxy-4-methyl-








3-pyridyl


258
′′
S
S
*
8
2-methoxy-4-methyl-








3-pyridyl


259
′′
S
S
*
9
2-methoxy-4-methyl-








3-pyridyl


260
′′
S
S
*
14
2-methoxy-4-methyl-








3-pyridyl





*: Single Bond 






 














TABLE 14





Compound No.





X
Y
Z
n
Het





















261





NH
S
*
1
2-methoxy-4- methyl-3-pyridyl


262
′′
NH
S
*
2
2-methoxy-4-








methyl-3-pyridyl


263
′′
NH
S
*
3
2-methoxy-4-








methyl-3-pyridyl


264
′′
NH
S
*
4
2-methoxy-4-








methyl-3-pyridyl


265
′′
NH
S
*
5
2-methoxy-4-








methyl-3-pyridyl


266
′′
NH
S
*
6
2-methoxy-4-








methyl-3-pyridyl


267
′′
NH
S
*
7
2-methoxy-4-








methyl-3-pyridyl


268
′′
NH
S
*
8
2-methoxy-4-








methyl-3-pyridyl


269
′′
NH
S
*
9
2-methoxy-4-








methyl-3-pyridyl


270
′′
NH
S
*
14
2-methoxy-4-








methyl-3-pyridyl


271
′′
O
S
*
1
2,6-bismethylthio-3-








pyridyl


272
′′
O
S
*
2
2,6-bismethylthio-3-








pyridyl


273
′′
O
S
*
3
2,6-bismethylthio-3-








pyridyl


274
′′
O
S
*
4
2,6-bismethylthio-3-








pyridyl


275
′′
O
S
*
5
2,6-bismethylthio-3-








pyridyl


276
′′
O
S
*
6
2,6-bismethylthio-3-








pyridyl


277
′′
O
S
*
7
2,6-bismethylthio-3-








pyridyl


278
′′
O
S
*
8
2,6-bismethylthio-3-








pyridyl


279
′′
O
S
*
9
2,6-bismethylthio-3-








pyridyl


280
′′
O
S
*
14
2,6-bismethylthio-3-








pyridyl





*: Single Bond 






 














TABLE 15





Compound No.





X
Y
Z
n
Het





















281





S
S
*
1
2,6-bismethylthio-3- pyridyl


282
′′
S
S
*
2
2,6-bismethylthio-3-








pyridyl


283
′′
S
S
*
3
2,6-bismethylthio-3-








pyridyl


284
′′
S
S
*
4
2,6-bismethylthio-3-








pyridyl


285
′′
S
S
*
5
2,6-bismethylthio-3-








pyridyl


286
′′
S
S
*
6
2,6-bismethylthio-3-








pyridyl


287
′′
S
S
*
7
2,6-bismethylthio-3-








pyridyl


288
′′
S
S
*
8
2,6-bismethylthio-3-








pyridyl


289
′′
S
S
*
9
2,6-bismethylthio-3-








pyridyl


290
′′
S
S
*
14
2,6-bismethylthio-3-








pyridyl


291
′′
NH
S
*
1
2,6-bismethylthio-3-








pyridyl


292
′′
NH
S
*
2
2,6-bismethylthio-3-








pyridyl


293
′′
NH
S
*
3
2,6-bismethylthio-3-








pyridyl


294
′′
NH
S
*
4
2,6-bismethylthio-3-








pyridyl


295
′′
NH
S
*
5
2,6-bismethylthio-3-








pyridyl


296
′′
NH
S
*
6
2,6-bismethylthio-3-








pyridyl


297
′′
NH
S
*
7
2,6-bismethylthio-3-








pyridyl


298
′′
NH
S
*
8
2,6-bismethylthio-3-








pyridyl


299
′′
NH
S
*
9
2,6-bismethylthio-3-








pyridyl


300
′′
NH
S
*
14
2,6-bismethylthio-3-








pyridyl





*: Single Bond 






 














TABLE 16





Compound No.





X
Y
Z
n
Het





















301





O
S
*
1
2,6-bisethylthio-3- pyridyl


302
′′
O
S
*
2
2,6-bisethylthio-3-








pyridyl


303
′′
O
S
*
3
2,6-bisethylthio-3-








pyridyl


304
′′
O
S
*
4
2,6-bisethylthio-3-








pyridyl


305
′′
O
S
*
5
2,6-bisethylthio-3-








pyridyl


306
′′
O
S
*
6
2,6-bisethylthio-3-








pyridyl


307
′′
O
S
*
7
2,6-bisethylthio-3-








pyridyl


308
′′
O
S
*
8
2,6-bisethylthio-3-








pyridyl


309
′′
O
S
*
9
2,6-bisethylthio-3-








pyridyl


310
′′
O
S
*
14
2,6-bisethylthio-3-








pyridyl


311
′′
S
S
*
1
2,6-bisethylthio-3-








pyridyl


312
′′
S
S
*
2
2,6-bisethylthio-3-








pyridyl


313
′′
S
S
*
3
2,6-bisethylthio-3-








pyridyl


314
′′
S
S
*
4
2,6-bisethylthio-3-








pyridyl


315
′′
S
S
*
5
2,6-bisethylthio-3-








pyridyl


316
′′
S
S
*
6
2,6-bisethylthio-3-








pyridyl


317
′′
S
S
*
7
2,6-bisethylthio-3-








pyridyl


318
′′
S
S
*
8
2,6-bisethylthio-3-








pyridyl


319
′′
S
S
*
9
2,6-bisethylthio-3-








pyridyl


320
′′
S
S
*
14
2,6-bisethylthio-3-








pyridyl





*: Single Bond 






 














TABLE 17





Compound No.





X
Y
Z
n
Het





















321





NH
S
*
1
2,6-bisethylthio-3- pyridyl


322
′′
NH
S
*
2
2,6-bisethylthio-3-








pyridyl


323
′′
NH
S
*
3
2,6-bisethylthio-3-








pyridyl


324
′′
NH
S
*
4
2,6-bisethylthio-3-








pyridyl


325
′′
NH
S
*
5
2,6-bisethylthio-3-








pyridyl


326
′′
NH
S
*
6
2,6-bisethylthio-3-








pyridyl


327
′′
NH
S
*
7
2,6-bisethylthio-3-








pyridyl


328
′′
NH
S
*
8
2,6-bisethylthio-3-








pyridyl


329
′′
NH
S
*
9
2,6-bisethylthio-3-








pyridyl


330
′′
NH
S
*
14
2,6-bisethylthio-3-








pyridyl


331
′′
O
S
*
1
2,6-bis(iso-propyl-








thio)-3-pyridyl


332
′′
O
S
*
2
2,6-bis(iso-propyl-








thio)-3-pyridyl


333
′′
O
S
*
3
2,6-bis(iso-propyl-








thio)-3-pyridyl


334
′′
O
S
*
4
2,6-bis(iso-propyl-








thio)-3-pyridyl


335
′′
O
S
*
5
2,6-bis(iso-propyl-








thio)-3-pyridyl


336
′′
O
S
*
6
2,6-bis(iso-propyl-








thio)-3-pyridyl


337
′′
O
S
*
7
2,6-bis(iso-propyl-








thio)-3-pyridyl


338
′′
O
S
*
8
2,6-bis(iso-propyl-








thio)-3-pyridyl


339
′′
O
S
*
9
2,6-bis(iso-propyl-








thio)-3-pyridyl


340
′′
O
S
*
14
2,6-bis(iso-propyl-








thio)-3-pyridyl





*: Single Bond 






 














TABLE 18





Compound No.





X
Y
Z
n
Het





















341





S
S
*
1
2,6-bis(iso-propyl- thio)-3-pyridyl


342
′′
S
S
*
2
2,6-bis(iso-propyl-








thio)-3-pyridyl


343
′′
S
S
*
3
2,6-bis(iso-propyl-








thio)-3-pyridyl


344
′′
S
S
*
4
2,6-bis(iso-propyl-








thio)-3-pyridyl


345
′′
S
S
*
5
2,6-bis(iso-propyl-








thio)-3-pyridyl


346
′′
S
S
*
6
2,6-bis(iso-propyl-








thio)-3-pyridyl


347
′′
S
S
*
7
2,6-bis(iso-propyl-








thio)-3-pyridyl


348
′′
S
S
*
8
2,6-bis(iso-propyl-








thio)-3-pyridyl


349
′′
S
S
*
9
2,6-bis(iso-propyl-








thio)-3-pyridyl


350
′′
S
S
*
14
2,6-bis(iso-propyl-








thio)-3-pyridyl


351
′′
NH
S
*
1
2,6-bis(iso-propyl-








thio)-3-pyridyl


352
′′
NH
S
*
2
2,6-bis(iso-propyl-








thio)-3-pyridyl


353
′′
NH
S
*
3
2,6-bis(iso-propyl-








thio)-3-pyridyl


354
′′
NH
S
*
4
2,6-bis(iso-propyl-








thio)-3-pyridyl


355
′′
NH
S
*
5
2,6-bis(iso-propyl-








thio)-3-pyridyl


356
′′
NH
S
*
6
2,6-bis(iso-propyl-








thio)-3-pyridyl


357
′′
NH
S
*
7
2,6-bis(iso-propyl-








thio)-3-pyridyl


358
′′
NH
S
*
8
2,6-bis(iso-propyl-








thio)-3-pyridyl


359
′′
NH
S
*
9
2,6-bis(iso-propyl-








thio)-3-pyridyl


360
′′
NH
S
*
14
2,6-bis(iso-propyl-








thio)-3-pyridyl





*: Single Bond 






 














TABLE 19





Compound No.





X
Y
Z
n
Het





















361





O
S
*
1
2-methylthio-6- methoxy-3-pyridyl


362
′′
O
S
*
2
2-methylthio-6-








methoxy-3-pyridyl


363
′′
O
S
*
3
2-methylthio-6-








methoxy-3-pyridyl


364
′′
O
S
*
4
2-methylthio-6-








methoxy-3-pyridyl


365
′′
O
S
*
5
2-methylthio-6-








methoxy-3-pyridyl


366
′′
O
S
*
6
2-methylthio-6-








methoxy-3-pyridyl


367
′′
O
S
*
7
2-methylthio-6-








methoxy-3-pyridyl


368
′′
O
S
*
8
2-methylthio-6-








methoxy-3-pyridyl


369
′′
O
S
*
9
2-methylthio-6-








methoxy-3-pyridyl


370
′′
O
S
*
14
2-methylthio-6-








methoxy-3-pyridyl


371
′′
S
S
*
1
2-methylthio-6-








methoxy-3-pyridyl


372
′′
S
S
*
2
2-methylthio-6-








methoxy-3-pyridyl


373
′′
S
S
*
3
2-methylthio-6-








methoxy-3-pyridyl


374
′′
S
S
*
4
2-methylthio-6-








methoxy-3-pyridyl


375
′′
S
S
*
5
2-methylthio-6-








methoxy-3-pyridyl


376
′′
S
S
*
6
2-methylthio-6-








methoxy-3-pyridyl


377
′′
S
S
*
7
2-methylthio-6-








methoxy-3-pyridyl


378
′′
S
S
*
8
2-methylthio-6-








methoxy-3-pyridyl


379
′′
S
S
*
9
2-methylthio-6-








methoxy-3-pyridyl


380
′′
S
S
*
14
2-methylthio-6-








methoxy-3-pyridyl





*: Single Bond 






 














TABLE 20





Compound No.





X
Y
Z
n
Het





















381





NH
S
*
1
2-methylthio-6- methoxy-3-pyridyl


382
′′
NH
S
*
2
2-methylthio-6-








methoxy-3-pyridyl


383
′′
NH
S
*
3
2-methylthio-6-








methoxy-3-pyridyl


384
′′
NH
S
*
4
2-methylthio-6-








methoxy-3-pyridyl


385
′′
NH
S
*
5
2-methylthio-6-








methoxy-3-pyridyl


386
′′
NH
S
*
6
2-methylthio-6-








methoxy-3-pyridyl


387
′′
NH
S
*
7
2-methylthio-6-








methoxy-3-pyridyl


388
′′
NH
S
*
8
2-methylthio-6-








methoxy-3-pyridyl


389
′′
NH
S
*
9
2-methylthio-6-








methoxy-3-pyridyl


390
′′
NH
S
*
14
2-methylthio-6-








methoxy-3-pyridyl


391
′′
O
S
*
1
2-ethylthio-6-








methoxy-3-pyridyl


392
′′
O
S
*
2
2-ethylthio-6-








methoxy-3-pyridyl


393
′′
O
S
*
3
2-ethylthio-6-








methoxy-3-pyridyl


394
′′
O
S
*
4
2-ethylthio-6-








methoxy-3-pyridyl


395
′′
O
S
*
5
2-ethylthio-6-








methoxy-3-pyridyl


396
′′
O
S
*
6
2-ethylthio-6-








methoxy-3-pyridyl


397
′′
O
S
*
7
2-ethylthio-6-








methoxy-3-pyridyl


398
′′
O
S
*
8
2-ethylthio-6-








methoxy-3-pyridyl


399
′′
O
S
*
9
2-ethylthio-6-








methoxy-3-pyridyl


400
′′
O
S
*
14
2-ethylthio-6-








methoxy-3-pyridyl





*: Single Bond 






 














TABLE 21





Compound No.





X
Y
Z
n
Het





















401





S
S
*
1
2-ethylthio-6- methoxy-3-pyridyl


402
′′
S
S
*
2
2-ethylthio-6-








methoxy-3-pyridyl


403
′′
S
S
*
3
2-ethylthio-6-








methoxy-3-pyridyl


404
′′
S
S
*
4
2-ethylthio-6-








methoxy-3-pyridyl


405
′′
S
S
*
5
2-ethylthio-6-








methoxy-3-pyridyl


406
′′
S
S
*
6
2-ethylthio-6-








methoxy-3-pyridyl


407
′′
S
S
*
7
2-ethylthio-6-








methoxy-3-pyridyl


408
′′
S
S
*
8
2-ethylthio-6-








methoxy-3-pyridyl


409
′′
S
S
*
9
2-ethylthio-6-








methoxy-3-pyridyl


410
′′
S
S
*
14
2-ethylthio-6-








methoxy-3-pyridyl


411
′′
NH
S
*
1
2-ethylthio-6-








methoxy-3-pyridyl


412
′′
NH
S
*
2
2-ethylthio-6-








methoxy-3-pyridyl


413
′′
NH
S
*
3
2-ethylthio-6-








methoxy-3-pyridyl


414
′′
NH
S
*
4
2-ethylthio-6-








methoxy-3-pyridyl


415
′′
NH
S
*
5
2-ethylthio-6-








methoxy-3-pyridyl


416
′′
NH
S
*
6
2-ethylthio-6-








methoxy-3-pyridyl


417
′′
NH
S
*
7
2-ethylthio-6-








methoxy-3-pyridyl


418
′′
NH
S
*
8
2-ethylthio-6-








methoxy-3-pyridyl


419
′′
NH
S
*
9
2-ethylthio-6-








methoxy-3-pyridyl


420
′′
NH
S
*
14
2-ethylthio-6-








methoxy-3-pyridyl





*: Single Bond 






 














TABLE 22





Compound No.





X
Y
Z
n
Het





















421





O
S
*
1
2-(iso-propylthio)-6- methoxy-3-pyridyl


422
′′
O
S
*
2
2-(iso-propylthio)-6-








methoxy-3-pyridyl


423
′′
O
S
*
3
2-(iso-propylthio)-6-








methoxy-3-pyridyl


424
′′
O
S
*
4
2-(iso-propylthio)-6-








methoxy-3-pyridyl


425
′′
O
S
*
5
2-(iso-propylthio)-6-








methoxy-3-pyridyl


426
′′
O
S
*
6
2-(iso-propylthio)-6-








methoxy-3-pyridyl


427
′′
O
S
*
7
2-(iso-propylthio)-6-








methoxy-3-pyridyl


428
′′
O
S
*
8
2-(iso-propylthio)-6-








methoxy-3-pyridyl


429
′′
O
S
*
9
2-(iso-propylthio)-6-








methoxy-3-pyridyl


430
′′
O
S
*
14
2-(iso-propylthio)-6-








methoxy-3-pyridyl


431
′′
S
S
*
1
2-(iso-propylthio)-6-








methoxy-3-pyridyl


432
′′
S
S
*
2
2-(iso-propylthio)-6-








methoxy-3-pyridyl


433
′′
S
S
*
3
2-(iso-propylthio)-6-








methoxy-3-pyridyl


434
′′
S
S
*
4
2-(iso-propylthio)-6-








methoxy-3-pyridyl


435
′′
S
S
*
5
2-(iso-propylthio)-6-








methoxy-3-pyridyl


436
′′
S
S
*
6
2-(iso-propylthio)-6-








methoxy-3-pyridyl


437
′′
S
S
*
7
2-(iso-propylthio)-6-








methoxy-3-pyridyl


438
′′
S
S
*
8
2-(iso-propylthio)-6-








methoxy-3-pyridyl


439
′′
S
S
*
9
2-(iso-propylthio)-6-








methoxy-3-pyridyl


440
′′
S
S
*
14
2-(iso-propylthio)-6-








methoxy-3-pyridyl





*: Single Bond 






 














TABLE 23





Compound No.





X
Y
Z
n
Het





















441





NH
S
*
1
2-(iso-propylthio)-6- methoxy-3-pyridyl


442
′′
NH
S
*
2
2-(iso-propylthio)-6-








methoxy-3-pyridyl


443
′′
NH
S
*
3
2-(iso-propylthio)-6-








methoxy-3-pyridyl


444
′′
NH
S
*
4
2-(iso-propylthio)-6-








methoxy-3-pyridyl


445
′′
NH
S
*
5
2-(iso-propylthio)-6-








methoxy-3-pyridyl


446
′′
NH
S
*
6
2-(iso-propylthio)-6-








methoxy-3-pyridyl


447
′′
NH
S
*
7
2-(iso-propylthio)-6-








methoxy-3-pyridyl


448
′′
NH
S
*
8
2-(iso-propylthio)-6-








methoxy-3-pyridyl


449
′′
NH
S
*
9
2-(iso-propylthio)-6-








methoxy-3-pyridyl


450
′′
NH
S
*
14
2-(iso-propylthio)-6-








methoxy-3-pyridyl


451
′′
O
S
*
1
2-methylthio-6-








methyl-3-pyridyl


452
′′
O
S
*
2
2-methylthio-6-








methyl-3-pyridyl


453
′′
O
S
*
3
2-methylthio-6-








methyl-3-pyridyl


454
′′
O
S
*
4
2-methylthio-6-








methyl-3-pyridyl


455
′′
O
S
*
5
2-methylthio-6-








methyl-3-pyridyl


456
′′
O
S
*
6
2-methylthio-6-








methyl-3-pyridyl


457
′′
O
S
*
7
2-methylthio-6-








methyl-3-pyridyl


458
′′
O
S
*
8
2-methylthio-6-








methyl-3-pyridyl


459
′′
O
S
*
9
2-methylthio-6-








methyl-3-pyridyl


460
′′
O
S
*
14
2-methylthio-6-








methyl-3-pyridyl





*: Single Bond 






 














TABLE 24





Compound No.





X
Y
Z
n
Het





















461





S
S
*
1
2-methylthio-6- methyl-3-pyridyl


462
′′
S
S
*
2
2-methylthio-6-








methyl-3-pyridyl


463
′′
S
S
*
3
2-methylthio-6-








methyl-3-pyridyl


464
′′
S
S
*
4
2-methylthio-6-








methyl-3-pyridyl


465
′′
S
S
*
5
2-methylthio-6-








methyl-3-pyridyl


466
′′
S
S
*
6
2-methylthio-6-








methyl-3-pyridyl


467
′′
S
S
*
7
2-methylthio-6-








methyl-3-pyridyl


468
′′
S
S
*
8
2-methylthio-6-








methyl-3-pyridyl


469
′′
S
S
*
9
2-methylthio-6-








methyl-3-pyridyl


470
′′
S
S
*
14
2-methylthio-6-








methyl-3-pyridyl


471
′′
NH
S
*
1
2-methylthio-6-








methyl-3-pyridyl


472
′′
NH
S
*
2
2-methylthio-6-








methyl-3-pyridyl


473
′′
NH
S
*
3
2-methylthio-6-








methyl-3-pyridyl


474
′′
NH
S
*
4
2-methylthio-6-








methyl-3-pyridyl


475
′′
NH
S
*
5
2-methylthio-6-








methyl-3-pyridyl


476
′′
NH
S
*
6
2-methylthio-6-








methyl-3-pyridyl


477
′′
NH
S
*
7
2-methylthio-6-








methyl-3-pyridyl


478
′′
NH
S
*
8
2-methylthio-6-








methyl-3-pyridyl


479
′′
NH
S
*
9
2-methylthio-6-








methyl-3-pyridyl


480
′′
NH
S
*
14
2-methylthio-6-








methyl-3-pyridyl





*: Single Bond 






 














TABLE 25





Compound No.





X
Y
Z
n
Het





















481





O
S
*
1
2-ethylthio-6-methyl- 3-pyridyl


482
′′
O
S
*
2
2-ethylthio-6-methyl-








3-pyridyl


483
′′
O
S
*
3
2-ethylthio-6-methyl-








3-pyridyl


484
′′
O
S
*
4
2-ethylthio-6-methyl-








3-pyridyl


485
′′
O
S
*
5
2-ethylthio-6-methyl-








3-pyridyl


486
′′
O
S
*
6
2-ethylthio-6-methyl-








3-pyridyl


487
′′
O
S
*
7
2-ethylthio-6-methyl-








3-pyridyl


488
′′
O
S
*
8
2-ethylthio-6-methyl-








3-pyridyl


489
′′
O
S
*
9
2-ethylthio-6-methyl-








3-pyridyl


490
′′
O
S
*
14
2-ethylthio-6-methyl-








3-pyridyl


491
′′
S
S
*
1
2-ethylthio-6-methyl-








3-pyridyl


492
′′
S
S
*
2
2-ethylthio-6-methyl-








3-pyridyl


493
′′
S
S
*
3
2-ethylthio-6-methyl-








3-pyridyl


494
′′
S
S
*
4
2-ethylthio-6-methyl-








3-pyridyl


495
′′
S
S
*
5
2-ethylthio-6-methyl-








3-pyridyl


496
′′
S
S
*
6
2-ethylthio-6-methyl-








3-pyridyl


497
′′
S
S
*
7
2-ethylthio-6-methyl-








3-pyridyl


498
′′
S
S
*
8
2-ethylthio-6-methyl-








3-pyridyl


499
′′
S
S
*
9
2-ethylthio-6-methyl-








3-pyridyl


500
′′
S
S
*
14
2-ethylthio-6-methyl-








3-pyridyl





*: Single Bond 






 














TABLE 26





Compound No.





X
Y
Z
n
Het





















501





NH
S
*
1
2-ethylthio-6- methyl-3-pyridyl


502
′′
NH
S
*
2
2-ethylthio-6-








methyl-3-pyridyl


503
′′
NH
S
*
3
2-ethylthio-6-








methyl-3-pyridyl


504
′′
NH
S
*
4
2-ethylthio-6-








methyl-3-pyridyl


505
′′
NH
S
*
5
2-ethylthio-6-








methyl-3-pyridyl


506
′′
NH
S
*
6
2-ethylthio-6-








methyl-3-pyridyl


507
′′
NH
S
*
7
2-ethylthio-6-








methyl-3-pyridyl


508
′′
NH
S
*
8
2-ethylthio-6-








methyl-3-pyridyl


509
′′
NH
S
*
9
2-ethylthio-6-








methyl-3-pyridyl


510
′′
NH
S
*
14
2-ethylthio-6-








methyl-3-pyridyl


511
′′
O
S
*
1
2-(iso-propylthio)-6-








methyl-3-pyridyl


512
′′
O
S
*
2
2-(iso-propylthio)-6-








methyl-3-pyridyl


513
′′
O
S
*
3
2-(iso-propylthio)-6-








methyl-3-pyridyl


514
′′
O
S
*
4
2-(iso-propylthio)-6-








methyl-3-pyridyl


515
′′
O
S
*
5
2-(iso-propylthio)-6-








methyl-3-pyridyl


516
′′
O
S
*
6
2-(iso-propylthio)-6-








methyl-3-pyridyl


517
′′
O
S
*
7
2-(iso-propylthio)-6-








methyl-3-pyridyl


518
′′
O
S
*
8
2-(iso-propylthio)-6-








methyl-3-pyridyl


519
′′
O
S
*
9
2-(iso-propylthio)-6-








methyl-3-pyridyl


520
′′
O
S
*
14
2-(iso-propylthio)-6-








methyl-3-pyridyl





*: Single Bond 






 














TABLE 27





Compound No.





X
Y
Z
n
Het





















521





S
S
*
1
2-(iso-propylthio)- 6-methyl-3-pyridyl


522
′′
S
S
*
2
2-(iso-propylthio)-








6-methyl-3-pyridyl


523
′′
S
S
*
3
2-(iso-propylthio)-








6-methyl-3-pyridyl


524
′′
S
S
*
4
2-(iso-propylthio)-








6-methyl-3-pyridyl


525
′′
S
S
*
5
2-(iso-propylthio)-








6-methyl-3-pyridyl


526
′′
S
S
*
6
2-(iso-propylthio)-








6-methyl-3-pyridyl


527
′′
S
S
*
7
2-(iso-propylthio)-








6-methyl-3-pyridyl


528
′′
S
S
*
8
2-(iso-propylthio)-








6-methyl-3-pyridyl


529
′′
S
S
*
9
2-(iso-propylthio)-








6-methyl-3-pyridyl


530
′′
S
S
*
14
2-(iso-propylthio)-








6-methyl-3-pyridyl


531
′′
NH
S
*
1
2-(iso-propylthio)-








6-methyl-3-pyridyl


532
′′
NH
S
*
2
2-(iso-propylthio)-








6-methyl-3-pyridyl


533
′′
NH
S
*
3
2-(iso-propylthio)-








6-methyl-3-pyridyl


534
′′
NH
S
*
4
2-(iso-propylthio)-








6-methyl-3-pyridyl


535
′′
NH
S
*
5
2-(iso-propylthio)-








6-methyl-3-pyridyl


536
′′
NH
S
*
6
2-(iso-propylthio)-








6-methyl-3-pyridyl


537
′′
NH
S
*
7
2-(iso-propylthio)-








6-methyl-3-pyridyl


538
′′
NH
S
*
8
2-(iso-propylthio)-








6-methyl-3-pyridyl


539
′′
NH
S
*
9
2-(iso-propylthio)-








6-methyl-3-pyridyl


540
′′
NH
S
*
14
2-(iso-propylthio)-








6-methyl-3-pyridyl





*: Single Bond 






 














TABLE 28





Compound No.





X
Y
Z
n
Het





















541





O
S
*
1
2,6-dimethoxyl-3- pyridyl


542
′′
O
S
*
2
2,6-dimethoxyl-3-








pyridyl


543
′′
O
S
*
3
2,6-dimethoxyl-3-








pyridyl


544
′′
O
S
*
4
2,6-dimethoxyl-3-








pyridyl


545
′′
O
S
*
5
2,6-dimethoxyl-3-








pyridyl


546
′′
O
S
*
6
2,6-dimethoxyl-3-








pyridyl


547
′′
O
S
*
7
2,6-dimethoxyl-3-








pyridyl


548
′′
O
S
*
8
2,6-dimethoxyl-3-








pyridyl


549
′′
O
S
*
9
2,6-dimethoxyl-3-








pyridyl


550
′′
O
S
*
14
2,6-dimethoxyl-3-








pyridyl


551
′′
S
S
*
1
2,6-dimethoxyl-3-








pyridyl


552
′′
S
S
*
2
2,6-dimethoxyl-3-








pyridyl


553
′′
S
S
*
3
2,6-dimethoxyl-3-








pyridyl


554
′′
S
S
*
4
2,6-dimethoxyl-3-








pyridyl


555
′′
S
S
*
5
2,6-dimethoxyl-3-








pyridyl


556
′′
S
S
*
6
2,6-dimethoxyl-3-








pyridyl


557
′′
S
S
*
7
2,6-dimethoxyl-3-








pyridyl


558
′′
S
S
*
8
2,6-dimethoxyl-3-








pyridyl


559
′′
S
S
*
9
2,6-dimethoxyl-3-








pyridyl


560
′′
S
S
*
14
2,6-dimethoxyl-3-








pyridyl





*: Single Bond 






 














TABLE 29





Compound No.





X
Y
Z
n
Het





















561





NH
S
*
1
2,6-dimethoxyl-3- pyridyl


562
′′
NH
S
*
2
2,6-dimethoxyl-3-








pyridyl


563
′′
NH
S
*
3
2,6-dimethoxyl-3-








pyridyl


564
′′
NH
S
*
4
2,6-dimethoxyl-3-








pyridyl


565
′′
NH
S
*
5
2,6-dimethoxyl-3-








pyridyl


566
′′
NH
S
*
6
2,6-dimethoxyl-3-








pyridyl


567
′′
NH
S
*
7
2,6-dimethoxyl-3-








pyridyl


568
′′
NH
S
*
8
2,6-dimethoxyl-3-








pyridyl


569
′′
NH
S
*
9
2,6-dimethoxyl-3-








pyridyl


570
′′
NH
S
*
14
2,6-dimethoxyl-3-








pyridyl


571
′′
O
S
*
1
2-methoxy-6-








methyl-3-pyridyl


572
′′
O
S
*
2
2-methoxy-6-








methyl-3-pyridyl


573
′′
O
S
*
3
2-methoxy-6-








methyl-3-pyridyl


574
′′
O
S
*
4
2-methoxy-6-








methyl-3-pyridyl


575
′′
O
S
*
5
2-methoxy-6-








methyl-3-pyridyl


576
′′
O
S
*
6
2-methoxy-6-








methyl-3-pyridyl


577
′′
O
S
*
7
2-methoxy-6-








methyl-3-pyridyl


578
′′
O
S
*
8
2-methoxy-6-








methyl-3-pyridyl


579
′′
O
S
*
9
2-methoxy-6-








methyl-3-pyridyl


580
′′
O
S
*
14
2-methoxy-6-








methyl-3-pyridyl





*: Single Bond 






 














TABLE 30





Compound No.





X
Y
Z
n
Het





















581





S
S
*
1
2-methoxy-6- methyl-3-pyridyl


582
′′
S
S
*
2
2-methoxy-6-








methyl-3-pyridyl


583
′′
S
S
*
3
2-methoxy-6-








methyl-3-pyridyl


584
′′
S
S
*
4
2-methoxy-6-








methyl-3-pyridyl


585
′′
S
S
*
5
2-methoxy-6-








methyl-3-pyridyl


586
′′
S
S
*
6
2-methoxy-6-








methyl-3-pyridyl


587
′′
S
S
*
7
2-methoxy-6-








methyl-3-pyridyl


588
′′
S
S
*
8
2-methoxy-6-








methyl-3-pyridyl


589
′′
S
S
*
9
2-methoxy-6-








methyl-3-pyridyl


590
′′
S
S
*
14
2-methoxy-6-








methyl-3-pyridyl


591
′′
NH
S
*
1
2-methoxy-6-








methyl-3-pyridyl


592
′′
NH
S
*
2
2-methoxy-6-








methyl-3-pyridyl


593
′′
NH
S
*
3
2-methoxy-6-








methyl-3-pyridyl


594
′′
NH
S
*
4
2-methoxy-6-








methyl-3-pyridyl


595
′′
NH
S
*
5
2-methoxy-6-








methyl-3-pyridyl


596
′′
NH
S
*
6
2-methoxy-6-








methyl-3-pyridyl


597
′′
NH
S
*
7
2-methoxy-6-








methyl-3-pyridyl


598
′′
NH
S
*
8
2-methoxy-6-








methyl-3-pyridyl


599
′′
NH
S
*
9
2-methoxy-6-








methyl-3-pyridyl


600
′′
NH
S
*
14
2-methoxy-6-








methyl-3-pyridyl





*: Single Bond 






 














TABLE 31





Compound No.





X
Y
Z
n
Het





















601





O
S
*
1
2-methyl-6-methyl- thio-3-pyridyl


602
′′
O
S
*
2
2-methyl-6-methyl-








thio-3-pyridyl


603
′′
O
S
*
3
2-methyl-6-methyl-








thio-3-pyridyl


604
′′
O
S
*
4
2-methyl-6-methyl-








thio-3-pyridyl


605
′′
O
S
*
5
2-methyl-6-methyl-








thio-3-pyridyl


606
′′
O
S
*
6
2-methyl-6-methyl-








thio-3-pyridyl


607
′′
O
S
*
7
2-methyl-6-methyl-








thio-3-pyridyl


608
′′
O
S
*
8
2-methyl-6-methyl-








thio-3-pyridyl


609
′′
O
S
*
9
2-methyl-6-methyl-








thio-3-pyridyl


610
′′
O
S
*
14
2-methyl-6-methyl-








thio-3-pyridyl


611
′′
S
S
*
1
2-methyl-6-methyl-








thio-3-pyridyl


612
′′
S
S
*
2
2-methyl-6-methyl-








thio-3-pyridyl


613
′′
S
S
*
3
2-methyl-6-methyl-








thio-3-pyridyl


614
′′
S
S
*
4
2-methyl-6-methyl-








thio-3-pyridyl


615
′′
S
S
*
5
2-methyl-6-methyl-








thio-3-pyridyl


616
′′
S
S
*
6
2-methyl-6-methyl-








thio-3-pyridyl


617
′′
S
S
*
7
2-methyl-6-methyl-








thio-3-pyridyl


618
′′
S
S
*
8
2-methyl-6-methyl-








thio-3-pyridyl


619
′′
S
S
*
9
2-methyl-6-methyl-








thio-3-pyridyl


620
′′
S
S
*
14
2-methyl-6-methyl-








thio-3-pyridyl





*: Single Bond 






 














TABLE 32





Compound No.





X
Y
Z
n
Het





















621





NH
S
*
1
2-methyl-6-methyl- thio-3-pyridyl


622
′′
NH
S
*
2
2-methyl-6-methyl-








thio-3-pyridyl


623
′′
NH
S
*
3
2-methyl-6-methyl-








thio-3-pyridyl


624
′′
NH
S
*
4
2-methyl-6-methyl-








thio-3-pyridyl


625
′′
NH
S
*
5
2-methyl-6-methyl-








thio-3-pyridyl


626
′′
NH
S
*
6
2-methyl-6-methyl-








thio-3-pyridyl


627
′′
NH
S
*
7
2-methyl-6-methyl-








thio-3-pyridyl


628
′′
NH
S
*
8
2-methyl-6-methyl-








thio-3-pyridyl


629
′′
NH
S
*
9
2-methyl-6-methyl-








thio-3-pyridyl


630
′′
NH
S
*
14
2-methyl-6-methyl-








thio-3-pyridyl


631
′′
O
S
*
1
2-methyl-6-ethyl-








thio-3-pyridyl


632
′′
O
S
*
2
2-methyl-6-ethyl-








thio-3-pyridyl


633
′′
O
S
*
3
2-methyl-6-ethyl-








thio-3-pyridyl


634
′′
O
S
*
4
2-methyl-6-ethyl-








thio-3-pyridyl


635
′′
O
S
*
5
2-methyl-6-ethyl-








thio-3-pyridyl


636
′′
O
S
*
6
2-methyl-6-ethyl-








thio-3-pyridyl


637
′′
O
S
*
7
2-methyl-6-ethyl-








thio-3-pyridyl


638
′′
O
S
*
8
2-methyl-6-ethyl-








thio-3-pyridyl


639
′′
O
S
*
9
2-methyl-6-ethyl-








thio-3-pyridyl


640
′′
O
S
*
14
2-methyl-6-ethyl-








thio-3-pyridyl





*: Single Bond 






 














TABLE 33





Compound No.





X
Y
Z
n
Het





















641





S
S
*
1
2-methyl-6-ethy- thio-3-pyridyl


642
′′
S
S
*
2
2-methyl-6-ethy-








thio-3-pyridyl


643
′′
S
S
*
3
2-methyl-6-ethy-








thio-3-pyridyl


644
′′
S
S
*
4
2-methyl-6-ethy-








thio-3-pyridyl


645
′′
S
S
*
5
2-methyl-6-ethy-








thio-3-pyridyl


646
′′
S
S
*
6
2-methyl-6-ethy-








thio-3-pyridyl


647
′′
S
S
*
7
2-methyl-6-ethy-








thio-3-pyridyl


648
′′
S
S
*
8
2-methyl-6-ethy-








thio-3-pyridyl


649
′′
S
S
*
9
2-methyl-6-ethy-








thio-3-pyridyl


650
′′
S
S
*
14
2-methyl-6-ethy-








thio-3-pyridyl


651
′′
NH
S
*
1
2-methyl-6-ethy-








thio-3-pyridyl


652
′′
NH
S
*
2
2-methyl-6-ethy-








thio-3-pyridyl


653
′′
NH
S
*
3
2-methyl-6-ethy-








thio-3-pyridyl


654
′′
NH
S
*
4
2-methyl-6-ethy-








thio-3-pyridyl


655
′′
NH
S
*
5
2-methyl-6-ethy-








thio-3-pyridyl


656
′′
NH
S
*
6
2-methyl-6-ethy-








thio-3-pyridyl


657
′′
NH
S
*
7
2-methyl-6-ethy-








thio-3-pyridyl


658
′′
NH
S
*
8
2-methyl-6-ethy-








thio-3-pyridyl


659
′′
NH
S
*
9
2-methyl-6-ethy-








thio-3-pyridyl


660
′′
NH
S
*
14
2-methyl-6-ethy-








thio-3-pyridyl





*: Single Bond 






 














TABLE 34





Compound No.





X
Y
Z
n
Het





















661





O
S
*
1
2-methyl-6-(iso- propylthio)-3-pyridyl


662
′′
O
S
*
2
2-methyl-6-(iso-








propylthio)-3-pyridyl


663
′′
O
S
*
3
2-methyl-6-(iso-








propylthio)-3-pyridyl


664
′′
O
S
*
4
2-methyl-6-(iso-








propylthio)-3-pyridyl


665
′′
O
S
*
5
2-methyl-6-(iso-








propylthio)-3-pyridyl


666
′′
O
S
*
6
2-methyl-6-(iso-








propylthio)-3-pyridyl


667
′′
O
S
*
7
2-methyl-6-(iso-








propylthio)-3-pyridyl


668
′′
O
S
*
8
2-methyl-6-(iso-








propylthio)-3-pyridyl


669
′′
O
S
*
9
2-methyl-6-(iso-








propylthio)-3-pyridyl


670
′′
O
S
*
14
2-methyl-6-(iso-








propylthio)-3-pyridyl


671
′′
S
S
*
1
2-methyl-6-(iso-








propylthio)-3-pyridyl


672
′′
S
S
*
2
2-methyl-6-(iso-








propylthio)-3-pyridyl


673
′′
S
S
*
3
2-methyl-6-(iso-








propylthio)-3-pyridyl


674
′′
S
S
*
4
2-methyl-6-(iso-








propylthio)-3-pyridyl


675
′′
S
S
*
5
2-methyl-6-(iso-








propylthio)-3-pyridyl


676
′′
S
S
*
6
2-methyl-6-(iso-








propylthio)-3-pyridyl


677
′′
S
S
*
7
2-methyl-6-(iso-








propylthio)-3-pyridyl


678
′′
S
S
*
8
2-methyl-6-(iso-








propylthio)-3-pyridyl


679
′′
S
S
*
9
2-methyl-6-(iso-








propylthio)-3-pyridyl


680
′′
S
S
*
14
2-methyl-6-(iso-








propylthio)-3-pyridyl





*: Single Bond 






 














TABLE 35





Compound No.





X
Y
Z
n
Het





















681





NH
S
*
1
2-methyl-6-(iso- propylthio)-3- pyridyl


682
′′
NH
S
*
2
2-methyl-6-(iso-








propylthio)-3-








pyridyl


683
′′
NH
S
*
3
2-methyl-6-(iso-








propylthio)-3-








pyridyl


684
′′
NH
S
*
4
2-methyl-6-(iso-








propylthio)-3-








pyridyl


685
′′
NH
S
*
5
2-methyl-6-(iso-








propylthio)-3-








pyridyl


686
′′
NH
S
*
6
2-methyl-6-(iso-








propylthio)-3-








pyridyl


687
′′
NH
S
*
7
2-methyl-6-(iso-








propylthio)-3-








pyridyl


688
′′
NH
S
*
8
2-methyl-6-(iso-








propylthio)-3-








pyridyl


689
′′
NH
S
*
9
2-methyl-6-(iso-








propylthio)-3-








pyridyl


690
′′
NH
S
*
14
2-methyl-6-(iso-








propylthio)-3-








pyridyl


691
′′
O
S
*
1
2-methyl-6-








mehoxy-3-pyridyl


692
′′
O
S
*
2
2-methyl-6-








mehoxy-3-pyridyl


693
′′
O
S
*
3
2-methyl-6-








mehoxy-3-pyridyl


694
′′
O
S
*
4
2-methyl-6-








mehoxy-3-pyridyl


695
′′
O
S
*
5
2-methyl-6-








mehoxy-3-pyridyl


696
′′
O
S
*
6
2-methyl-6-








mehoxy-3-pyridyl


697
′′
O
S
*
7
2-methyl-6-








mehoxy-3-pyridyl


698
′′
O
S
*
8
2-methyl-6-








mehoxy-3-pyridyl


699
′′
O
S
*
9
2-methyl-6-








mehoxy-3-pyridyl


700
′′
O
S
*
14
2-methyl-6-








mehoxy-3-pyridyl





*: Single Bond 






 














TABLE 36





Compound No.





X
Y
Z
n
Het





















701





S
S
*
1
2-methyl-6- mehoxy-3-pyridyl


702
′′
S
S
*
2
2-methyl-6-








mehoxy-3-pyridyl


703
′′
S
S
*
3
2-methyl-6-








mehoxy-3-pyridyl


704
′′
S
S
*
4
2-methyl-6-








mehoxy-3-pyridyl


705
′′
S
S
*
5
2-methyl-6-








mehoxy-3-pyridyl


706
′′
S
S
*
6
2-methyl-6-








mehoxy-3-pyridyl


707
′′
S
S
*
7
2-methyl-6-








mehoxy-3-pyridyl


708
′′
S
S
*
8
2-methyl-6-








mehoxy-3-pyridyl


709
′′
S
S
*
9
2-methyl-6-








mehoxy-3-pyridyl


710
′′
S
S
*
14
2-methyl-6-








mehoxy-3-pyridyl


711
′′
NH
S
*
1
2-methyl-6-








mehoxy-3-pyridyl


712
′′
NH
S
*
2
2-methyl-6-








mehoxy-3-pyridyl


713
′′
NH
S
*
3
2-methyl-6-








mehoxy-3-pyridyl


714
′′
NH
S
*
4
2-methyl-6-








mehoxy-3-pyridyl


715
′′
NH
S
*
5
2-methyl-6-








mehoxy-3-pyridyl


716
′′
NH
S
*
6
2-methyl-6-








mehoxy-3-pyridyl


717
′′
NH
S
*
7
2-methyl-6-








mehoxy-3-pyridyl


718
′′
NH
S
*
8
2-methyl-6-








mehoxy-3-pyridyl


719
′′
NH
S
*
9
2-methyl-6-








mehoxy-3-pyridyl


720
′′
NH
S
*
14
2-methyl-6-








mehoxy-3-pyridyl





*: Single Bond 






 














TABLE 37





Compound No.





X
Y
Z
n
Het





















721





O
S
*
1
2,6-dimethyl-3-pyridyl


722
′′
O
S
*
2
2,6-dimethyl-3-pyridyl


723
′′
O
S
*
3
2,6-dimethyl-3-pyridyl


724
′′
O
S
*
4
2,6-dimethyl-3-pyridyl


725
′′
O
S
*
5
2,6-dimethyl-3-pyridyl


726
′′
O
S
*
6
2,6-dimethyl-3-pyridyl


727
′′
O
S
*
7
2,6-dimethyl-3-pyridyl


728
′′
O
S
*
8
2,6-dimethyl-3-pyridyl


729
′′
O
S
*
9
2,6-dimethyl-3-pyridyl


730
′′
O
S
*
14
2,6-dimethyl-3-pyridyl


731
′′
S
S
*
1
2,6-dimethyl-3-pyridyl


732
′′
S
S
*
2
2,6-dimethyl-3-pyridyl


733
′′
S
S
*
3
2,6-dimethyl-3-pyridyl


734
′′
S
S
*
4
2,6-dimethyl-3-pyridyl


735
′′
S
S
*
5
2,6-dimethyl-3-pyridyl


736
′′
S
S
*
6
2,6-dimethyl-3-pyridyl


737
′′
S
S
*
7
2,6-dimethyl-3-pyridyl


738
′′
S
S
*
8
2,6-dimethyl-3-pyridyl


739
′′
S
S
*
9
2,6-dimethyl-3-pyridyl


740
′′
S
S
*
14
2,6-dimethyl-3-pyridyl





*: Single Bond 






 














TABLE 38





Compound No.





X
Y
Z
n
Het





















741





NH
S
*
1
2,6-dimethyl-3- pyridyl


742
′′
NH
S
*
2
2,6-dimethyl-3-








pyridyl


743
′′
NH
S
*
3
2,6-dimethyl-3-








pyridyl


744
′′
NH
S
*
4
2,6-dimethyl-3-








pyridyl


745
′′
NH
S
*
5
2,6-dimethyl-3-








pyridyl


746
′′
NH
S
*
6
2,6-dimethyl-3-








pyridyl


747
′′
NH
S
*
7
2,6-dimethyl-3-








pyridyl


748
′′
NH
S
*
8
2,6-dimethyl-3-








pyridyl


749
′′
NH
S
*
9
2,6-dimethyl-3-








pyridyl


750
′′
NH
S
*
14
2,6-dimethyl-3-








pyridyl


751
′′
O
S
*
1
2,6-dimethyl-3-








pyridyl


752
′′
O
S
*
2
2,6-dimethyl-3-








pyridyl


753
′′
O
S
*
3
2,6-dimethyl-3-








pyridyl


754
′′
O
S
*
4
2,6-dimethyl-3-








pyridyl


755
′′
O
S
*
5
2,6-dimethyl-3-








pyridyl


756
′′
O
S
*
6
2,6-dimethyl-3-








pyridyl


757
′′
O
S
*
7
2,6-dimethyl-3-








pyridyl


758
′′
O
S
*
8
2,6-dimethyl-3-








pyridyl


759
′′
O
S
*
9
2,6-dimethyl-3-








pyridyl


760
′′
O
S
*
14
2,6-dimethyl-3-








pyridyl





*: Single Bond 






 














TABLE 39





Compound No.





X
Y
Z
n
Het





















761





S
S
*
1
2,6-diethyl-3- pyridyl


762
′′
S
S
*
2
2,6-diethyl-3-








pyridyl


763
′′
S
S
*
3
2,6-diethyl-3-








pyridyl


764
′′
S
S
*
4
2,6-diethyl-3-








pyridyl


765
′′
S
S
*
5
2,6-diethyl-3-








pyridyl


766
′′
S
S
*
6
2,6-diethyl-3-








pyridyl


767
′′
S
S
*
7
2,6-diethyl-3-








pyridyl


768
′′
S
S
*
8
2,6-diethyl-3-








pyridyl


769
′′
S
S
*
9
2,6-diethyl-3-








pyridyl


770
′′
S
S
*
14
2,6-diethyl-3-








pyridyl


771
′′
NH
S
*
1
2,6-diethyl-3-








pyridyl


772
′′
NH
S
*
2
2,6-diethyl-3-








pyridyl


773
′′
NH
S
*
3
2,6-diethyl-3-








pyridyl


774
′′
NH
S
*
4
2,6-diethyl-3-








pyridyl


775
′′
NH
S
*
5
2,6-diethyl-3-








pyridyl


776
′′
NH
S
*
6
2,6-diethyl-3-








pyridyl


777
′′
NH
S
*
7
2,6-diethyl-3-








pyridyl


778
′′
NH
S
*
8
2,6-diethyl-3-








pyridyl


779
′′
NH
S
*
9
2,6-diethyl-3-








pyridyl


780
′′
NH
S
*
14
2,6-diethyl-3-








pyridyl





*: Single Bond 






 














TABLE 40





Compound No.





X
Y
Z
n
Het





















781





O
S
*
1
2,4-bismethylthio- 6-methyl-3-pyridyl


782
′′
O
S
*
2
2,4-bismethylthio-








6-methyl-3-pyridyl


783
′′
O
S
*
3
2,4-bismethylthio-








6-methyl-3-pyridyl


784
′′
O
S
*
4
2,4-bismethylthio-








6-methyl-3-pyridyl


785
′′
O
S
*
5
2,4-bismethylthio-








6-methyl-3-pyridyl


786
′′
O
S
*
6
2,4-bismethylthio-








6-methyl-3-pyridyl


787
′′
O
S
*
7
2,4-bismethylthio-








6-methyl-3-pyridyl


788
′′
O
S
*
8
2,4-bismethylthio-








6-methyl-3-pyridyl


789
′′
O
S
*
9
2,4-bismethylthio-








6-methyl-3-pyridyl


790
′′
O
S
*
14
2,4-bismethylthio-








6-methyl-3-pyridyl


791
′′
S
S
*
1
2,4-bismethylthio-








6-methyl-3-pyridyl


792
′′
S
S
*
2
2,4-bismethylthio-








6-methyl-3-pyridyl


793
′′
S
S
*
3
2,4-bismethylthio-








6-methyl-3-pyridyl


794
′′
S
S
*
4
2,4-bismethylthio-








6-methyl-3-pyridyl


795
′′
S
S
*
5
2,4-bismethylthio-








6-methyl-3-pyridyl


796
′′
S
S
*
6
2,4-bismethylthio-








6-methyl-3-pyridyl


797
′′
S
S
*
7
2,4-bismethylthio-








6-methyl-3-pyridyl


798
′′
S
S
*
8
2,4-bismethylthio-








6-methyl-3-pyridyl


799
′′
S
S
*
9
2,4-bismethylthio-








6-methyl-3-pyridyl


800
′′
S
S
*
14
2,4-bismethylthio-








6-methyl-3-pyridyl





*: Single Bond 






 














TABLE 41





Compound No.





X
Y
Z
n
Het





















801





NH
S
*
1
2,4-bismethylthio- 6-methyl-3-pyridyl


802
′′
NH
S
*
2
2,4-bismethylthio-








6-methyl-3-pyridyl


803
′′
NH
S
*
3
2,4-bismethylthio-








6-methyl-3-pyridyl


804
′′
NH
S
*
4
2,4-bismethylthio-








6-methyl-3-pyridyl


805
′′
NH
S
*
5
2,4-bismethylthio-








6-methyl-3-pyridyl


806
′′
NH
S
*
6
2,4-bismethylthio-








6-methyl-3-pyridyl


807
′′
NH
S
*
7
2,4-bismethylthio-








6-methyl-3-pyridyl


808
′′
NH
S
*
8
2,4-bismethylthio-








6-methyl-3-pyridyl


809
′′
NH
S
*
9
2,4-bismethylthio-








6-methyl-3-pyridyl


810
′′
NH
S
*
14
2,4-bismethylthio-








6-methyl-3-pyridyl


811
′′
O
S
*
1
2,4-bisethylthio-6-








methyl-3-pyridyl


812
′′
O
S
*
2
2,4-bisethylthio-6-








methyl-3-pyridyl


813
′′
O
S
*
3
2,4-bisethylthio-6-








methyl-3-pyridyl


814
′′
O
S
*
4
2,4-bisethylthio-6-








methyl-3-pyridyl


815
′′
O
S
*
5
2,4-bisethylthio-6-








methyl-3-pyridyl


816
′′
O
S
*
6
2,4-bisethylthio-6-








methyl-3-pyridyl


817
′′
O
S
*
7
2,4-bisethylthio-6-








methyl-3-pyridyl


818
′′
O
S
*
8
2,4-bisethylthio-6-








methyl-3-pyridyl


819
′′
O
S
*
9
2,4-bisethylthio-6-








methyl-3-pyridyl


820
′′
O
S
*
14
2,4-bisethylthio-6-








methyl-3-pyridyl





*: Single Bond 






 














TABLE 42





Compound No.





X
Y
Z
n
Het





















821





S
S
*
1
2,4-bisethylthio-6- methyl-3-pyridyl


822
′′
S
S
*
2
2,4-bisethylthio-6-








methyl-3-pyridyl


823
′′
S
S
*
3
2,4-bisethylthio-6-








methyl-3-pyridyl


824
′′
S
S
*
4
2,4-bisethylthio-6-








methyl-3-pyridyl


825
′′
S
S
*
5
2,4-bisethylthio-6-








methyl-3-pyridyl


826
′′
S
S
*
6
2,4-bisethylthio-6-








methyl-3-pyridyl


827
′′
S
S
*
7
2,4-bisethylthio-6-








methyl-3-pyridyl


828
′′
S
S
*
8
2,4-bisethylthio-6-








methyl-3-pyridyl


829
′′
S
S
*
9
2,4-bisethylthio-6-








methyl-3-pyridyl


830
′′
S
S
*
14
2,4-bisethylthio-6-








methyl-3-pyridyl


831
′′
NH
S
*
1
2,4-bisethylthio-6-








methyl-3-pyridyl


832
′′
NH
S
*
2
2,4-bisethylthio-6-








methyl-3-pyridyl


833
′′
NH
S
*
3
2,4-bisethylthio-6-








methyl-3-pyridyl


834
′′
NH
S
*
4
2,4-bisethylthio-6-








methyl-3-pyridyl


835
′′
NH
S
*
5
2,4-bisethylthio-6-








methyl-3-pyridyl


836
′′
NH
S
*
6
2,4-bisethylthio-6-








methyl-3-pyridyl


837
′′
NH
S
*
7
2,4-bisethylthio-6-








methyl-3-pyridyl


838
′′
NH
S
*
8
2,4-bisethylthio-6-








methyl-3-pyridyl


839
′′
NH
S
*
9
2,4-bisethylthio-6-








methyl-3-pyridyl


840
′′
NH
S
*
14
2,4-bisethylthio-6-








methyl-3-pyridyl





*: Single Bond 






 














TABLE 43





Compound No.





X
Y
Z
n
Het





















841





O
S
*
1
2,4-bis(iso-propyl- thio)-6-methyl-3- pyridyl


842
′′
O
S
*
2
2,4-bis(iso-propyl-








thio)-6-methyl-3-








pyridyl


843
′′
O
S
*
3
2,4-bis(iso-propyl-








thio)-6-methyl-3-








pyridyl


844
′′
O
S
*
4
2,4-bis(iso-propyl-








thio)-6-methyl-3-








pyridyl


845
′′
O
S
*
5
2,4-bis(iso-propyl-








thio)-6-methyl-3-








pyridyl


846
′′
O
S
*
6
2,4-bis(iso-propyl-








thio)-6-methyl-3-








pyridyl


847
′′
O
S
*
7
2,4-bis(iso-propyl-








thio)-6-methyl-3-








pyridyl


848
′′
O
S
*
8
2,4-bis(iso-propyl-








thio)-6-methyl-3-








pyridyl


849
′′
O
S
*
9
2,4-bis(iso-propyl-








thio)-6-methyl-3-








pyridyl


850
′′
O
S
*
14
2,4-bis(iso-propyl-








thio)-6-methyl-3-








pyridyl


851
′′
S
S
*
1
2,4-bis(iso-propyl-








thio)-6-methyl-3-








pyridyl


852
′′
S
S
*
2
2,4-bis(iso-propyl-








thio)-6-methyl-3-








pyridyl


853
′′
S
S
*
3
2,4-bis(iso-propyl-








thio)-6-methyl-3-








pyridyl


854
′′
S
S
*
4
2,4-bis(iso-propyl-








thio)-6-methyl-3-








pyridyl


855
′′
S
S
*
5
2,4-bis(iso-propyl-








thio)-6-methyl-3-








pyridyl


856
′′
S
S
*
6
2,4-bis(iso-propyl-








thio)-6-methyl-3-








pyridyl


857
′′
S
S
*
7
2,4-bis(iso-propyl-








thio)-6-methyl-3-








pyridyl


858
′′
S
S
*
8
2,4-bis(iso-propyl-








thio)-6-methyl-3-








pyridyl


859
′′
S
S
*
9
2,4-bis(iso-propyl-








thio)-6-methyl-3-








pyridyl


860
′′
S
S
*
14
2,4-bis(iso-propyl-








thio)-6-methyl-3-








pyridyl





*: Single Bond 






 














TABLE 44





Compound No.





X
Y
Z
n
Het





















861





NH
S
*
1
2,4-bis(iso-propyl- thio)-6-methyl-3- pyridyl


862
′′
NH
S
*
2
2,4-bis(iso-propyl-








thio)-6-methyl-3-








pyridyl


863
′′
NH
S
*
3
2,4-bis(iso-propyl-








thio)-6-methyl-3-








pyridyl


864
′′
NH
S
*
4
2,4-bis(iso-propyl-








thio)-6-methyl-3-








pyridyl


865
′′
NH
S
*
5
2,4-bis(iso-propyl-








thio)-6-methyl-3-








pyridyl


866
′′
NH
S
*
6
2,4-bis(iso-propyl-








thio)-6-methyl-3-








pyridyl


867
′′
NH
S
*
7
2,4-bis(iso-propyl-








thio)-6-methyl-3-








pyridyl


868
′′
NH
S
*
8
2,4-bis(iso-propyl-








thio)-6-methyl-3-








pyridyl


869
′′
NH
S
*
9
2,4-bis(iso-propyl-








thio)-6-methyl-3-








pyridyl


870
′′
NH
S
*
14
2,4-bis(iso-propyl-








thio)-6-methyl-3-








pyridyl


871
′′
O
S
*
1
2,4-dimethoxy-6-








methyl-3-pyridyl


872
′′
O
S
*
2
2,4-dimethoxy-6-








methyl-3-pyridyl


873
′′
O
S
*
3
2,4-dimethoxy-6-








methyl-3-pyridyl


874
′′
O
S
*
4
2,4-dimethoxy-6-








methyl-3-pyridyl


875
′′
O
S
*
5
2,4-dimethoxy-6-








methyl-3-pyridyl


876
′′
O
S
*
6
2,4-dimethoxy-6-








methyl-3-pyridyl


877
′′
O
S
*
7
2,4-dimethoxy-6-








methyl-3-pyridyl


878
′′
O
S
*
8
2,4-dimethoxy-6-








methyl-3-pyridyl


879
′′
O
S
*
9
2,4-dimethoxy-6-








methyl-3-pyridyl


880
′′
O
S
*
14
2,4-dimethoxy-6-








methyl-3-pyridyl





*: Single Bond 






 














TABLE 45





Compound No.





X
Y
Z
n
Het





















881





S
S
*
1
2,4-dimethoxy-6- methyl-3-pyridyl


882
′′
S
S
*
2
2,4-dimethoxy-6-








methyl-3-pyridyl


883
′′
S
S
*
3
2,4-dimethoxy-6-








methyl-3-pyridyl


884
′′
S
S
*
4
2,4-dimethoxy-6-








methyl-3-pyridyl


885
′′
S
S
*
5
2,4-dimethoxy-6-








methyl-3-pyridyl


886
′′
S
S
*
6
2,4-dimethoxy-6-








methyl-3-pyridyl


887
′′
S
S
*
7
2,4-dimethoxy-6-








methyl-3-pyridyl


888
′′
S
S
*
8
2,4-dimethoxy-6-








methyl-3-pyridyl


889
′′
S
S
*
9
2,4-dimethoxy-6-








methyl-3-pyridyl


890
′′
S
S
*
14
2,4-dimethoxy-6-








methyl-3-pyridyl


891
′′
NH
S
*
1
2,4-dimethoxy-6-








methyl-3-pyridyl


892
′′
NH
S
*
2
2,4-dimethoxy-6-








methyl-3-pyridyl


893
′′
NH
S
*
3
2,4-dimethoxy-6-








methyl-3-pyridyl


894
′′
NH
S
*
4
2,4-dimethoxy-6-








methyl-3-pyridyl


895
′′
NH
S
*
5
2,4-dimethoxy-6-








methyl-3-pyridyl


896
′′
NH
S
*
6
2,4-dimethoxy-6-








methyl-3-pyridyl


897
′′
NH
S
*
7
2,4-dimethoxy-6-








methyl-3-pyridyl


898
′′
NH
S
*
8
2,4-dimethoxy-6-








methyl-3-pyridyl


899
′′
NH
S
*
9
2,4-dimethoxy-6-








methyl-3-pyridyl


900
′′
NH
S
*
14
2,4-dimethoxy-6-








methyl-3-pyridyl





*: Single Bond 






 














TABLE 46





Compound No.





X
Y
Z
n
Het





















901





O
S
*
1
2,4,6-trimethyl-3-pyridyl


902
′′
O
S
*
2
2,4,6-trimethyl-3-pyridyl


903
′′
O
S
*
3
2,4,6-trimethyl-3-pyridyl


904
′′
O
S
*
4
2,4,6-trimethyl-3-pyridyl


905
′′
O
S
*
5
2,4,6-trimethyl-3-pyridyl


906
′′
O
S
*
6
2,4,6-trimethyl-3-pyridyl


907
′′
O
S
*
7
2,4,6-trimethyl-3-pyridyl


908
′′
O
S
*
8
2,4,6-trimethyl-3-pyridyl


909
′′
O
S
*
9
2,4,6-trimethyl-3-pyridyl


910
′′
O
S
*
14
2,4,6-trimethyl-3-pyridyl


911
′′
S
S
*
1
2,4,6-trimethyl-3-pyridyl


912
′′
S
S
*
2
2,4,6-trimethyl-3-pyridyl


913
′′
S
S
*
3
2,4,6-trimethyl-3-pyridyl


914
′′
S
S
*
4
2,4,6-trimethyl-3-pyridyl


915
′′
S
S
*
5
2,4,6-trimethyl-3-pyridyl


916
′′
S
S
*
6
2,4,6-trimethyl-3-pyridyl


917
′′
S
S
*
7
2,4,6-trimethyl-3-pyridyl


918
′′
S
S
*
8
2,4,6-trimethyl-3-pyridyl


919
′′
S
S
*
9
2,4,6-trimethyl-3-pyridyl


920
′′
S
S
*
14
2,4,6-trimethyl-3-pyridyl





*Single Bond 






 














TABLE 47





Compound No.





X
Y
Z
n
Het





















921





NH
S
*
1
2,4,6-trimethyl-3-pyridyl


922
′′
NH
S
*
2
2,4,6-trimethyl-3-pyridyl


923
′′
NH
S
*
3
2,4,6-trimethyl-3-pyridyl


924
′′
NH
S
*
4
2,4,6-trimethyl-3-pyridyl


925
′′
NH
S
*
5
2,4,6-trimethyl-3-pyridyl


926
′′
NH
S
*
6
2,4,6-trimethyl-3-pyridyl


927
′′
NH
S
*
7
2,4,6-trimethyl-3-pyridyl


928
′′
NH
S
*
8
2,4,6-trimethyl-3-pyridyl


929
′′
NH
S
*
9
2,4,6-trimethyl-3-pyridyl


930
′′
NH
S
*
14
2,4,6-trimethyl-3-pyridyl


931
′′
O
S
*
1
4-ethyl-2,6-dimethyl-3-pyridyl


932
′′
O
S
*
2
4-ethyl-2,6-dimethyl-3-pyridyl


933
′′
O
S
*
3
4-ethyl-2,6-dimethyl-3-pyridyl


934
′′
O
S
*
4
4-ethyl-2,6-dimethyl-3-pyridyl


935
′′
O
S
*
5
4-ethyl-2,6-dimethyl-3-pyridyl


936
′′
O
S
*
6
4-ethyl-2,6-dimethyl-3-pyridyl


937
′′
O
S
*
7
4-ethyl-2,6-dimethyl-3-pyridyl


938
′′
O
S
*
8
4-ethyl-2,6-dimethyl-3-pyridyl


939
′′
O
S
*
9
4-ethyl-2,6-dimethyl-3-pyridyl


940
′′
O
S
*
14
4-ethyl-2,6-dimethyl-3-pyridyl





*Single Bond 






 














TABLE 48





Compound No.





X
Y
Z
n
Het





















941





S
S
*
1
4-ethyl-2,6-dimethyl-3-pyridyl


942
′′
S
S
*
2
4-ethyl-2,6-dimethyl-3-pyridyl


943
′′
S
S
*
3
4-ethyl-2,6-dimethyl-3-pyridyl


944
′′
S
S
*
4
4-ethyl-2,6-dimethyl-3-pyridyl


945
′′
S
S
*
5
4-ethyl-2,6-dimethyl-3-pyridyl


946
′′
S
S
*
6
4-ethyl-2,6-dimethyl-3-pyridyl


947
′′
S
S
*
7
4-ethyl-2,6-dimethyl-3-pyridyl


948
′′
S
S
*
8
4-ethyl-2,6-dimethyl-3-pyridyl


949
′′
S
S
*
9
4-ethyl-2,6-dimethyl-3-pyridyl


950
′′
S
S
*
14
4-ethyl-2,6-dimethyl-3-pyridyl


951
′′
NH
S
*
1
4-ethyl-2,6-dimethyl-3-pyridyl


952
′′
NH
S
*
2
4-ethyl-2,6-dimethyl-3-pyridyl


953
′′
NH
S
*
3
4-ethyl-2,6-dimethyl-3-pyridyl


954
′′
NH
S
*
4
4-ethyl-2,6-dimethyl-3-pyridyl


955
′′
NH
S
*
5
4-ethyl-2,6-dimethyl-3-pyridyl


956
′′
NH
S
*
6
4-ethyl-2,6-dimethyl-3-pyridyl


957
′′
NH
S
*
7
4-ethyl-2,6-dimethyl-3-pyridyl


958
′′
NH
S
*
8
4-ethyl-2,6-dimethyl-3-pyridyl


959
′′
NH
S
*
9
4-ethyl-2,6-dimethyl-3-pyridyl


960
′′
NH
S
*
14
4-ethyl-2,6-dimethyl-3-pyridyl





*Single Bond 






 














TABLE 49





Compound No.





X
Y
Z
n
Het





















961





O
S
*
1
2,4-dichloro-6-methyl-3-pyridyl


962
′′
O
S
*
2
2,4-dichloro-6-methyl-3-pyridyl


963
′′
O
S
*
3
2,4-dichloro-6-methyl-3-pyridyl


964
′′
O
S
*
4
2,4-dichloro-6-methyl-3-pyridyl


965
′′
O
S
*
5
2,4-dichloro-6-methyl-3-pyridyl


966
′′
O
S
*
6
2,4-dichloro-6-methyl-3-pyridyl


967
′′
O
S
*
7
2,4-dichloro-6-methyl-3-pyridyl


968
′′
O
S
*
8
2,4-dichloro-6-methyl-3-pyridyl


969
′′
O
S
*
9
2,4-dichloro-6-methyl-3-pyridyl


970
′′
O
S
*
14
2,4-dichloro-6-methyl-3-pyridyl


971
′′
S
S
*
1
2,4-dichloro-6-methyl-3-pyridyl


972
′′
S
S
*
2
2,4-dichloro-6-methyl-3-pyridyl


973
′′
S
S
*
3
2,4-dichloro-6-methyl-3-pyridyl


974
′′
S
S
*
4
2,4-dichloro-6-methyl-3-pyridyl


975
′′
S
S
*
5
2,4-dichloro-6-methyl-3-pyridyl


976
′′
S
S
*
6
2,4-dichloro-6-methyl-3-pyridyl


977
′′
S
S
*
7
2,4-dichloro-6-methyl-3-pyridyl


978
′′
S
S
*
8
2,4-dichloro-6-methyl-3-pyridyl


979
′′
S
S
*
9
2,4-dichloro-6-methyl-3-pyridyl


980
′′
S
S
*
14
2,4-dichloro-6-methyl-3-pyridyl





*Single Bond 






 














TABLE 50





Compound No.





X
Y
Z
n
Het





















981





NH
S
*
1
2,4-dichloro-6-methyl-3-pyridyl


982
′′
NH
S
*
2
2,4-dichloro-6-methyl-3-pyridyl


983
′′
NH
S
*
3
2,4-dichloro-6-methyl-3-pyridyl


984
′′
NH
S
*
4
2,4-dichloro-6-methyl-3-pyridyl


985
′′
NH
S
*
5
2,4-dichloro-6-methyl-3-pyridyl


986
′′
NH
S
*
6
2,4-dichloro-6-methyl-3-pyridyl


987
′′
NH
S
*
7
2,4-dichloro-6-methyl-3-pyridyl


988
′′
NH
S
*
8
2,4-dichloro-6-methyl-3-pyridyl


989
′′
NH
S
*
9
2,4-dichloro-6-methyl-3-pyridyl


990
′′
NH
S
*
14
2,4-dichloro-6-methyl-3-pyridyl


991
′′
O
S
*
1
4,6-bismethylthio-5-pyrimidyl


992
′′
O
S
*
2
4,6-bismethylthio-5-pyrimidyl


993
′′
O
S
*
3
4,6-bismethylthio-5-pyrimidyl


994
′′
O
S
*
4
4,6-bismethylthio-5-pyrimidyl


995
′′
O
S
*
5
4,6-bismethylthio-5-pyrimidyl


996
′′
O
S
*
6
4,6-bismethylthio-5-pyrimidyl


997
′′
O
S
*
7
4,6-bismethylthio-5-pyrimidyl


998
′′
O
S
*
8
4,6-bismethylthio-5-pyrimidyl


999
′′
O
S
*
9
4,6-bismethylthio-5-pyrimidyl


1000 
′′
O
S
*
14
4,6-bismethylthio-5-pyrimidyl





*Single Bond 






 














TABLE 51





Compound No.





X
Y
Z
n
Het





















1001





S
S
*
1
4,6-bismethylthio-5-pyrimidyl


1002
′′
S
S
*
2
4,6-bismethylthio-5-pyrimidyl


1003
′′
S
S
*
3
4,6-bismethylthio-5-pyrimidyl


1004
′′
S
S
*
4
4,6-bismethylthio-5-pyrimidyl


1005
′′
S
S
*
5
4,6-bismethylthio-5-pyrimidyl


1006
′′
S
S
*
6
4,6-bismethylthio-5-pyrimidyl


1007
′′
S
S
*
7
4,6-bismethylthio-5-pyrimidyl


1008
′′
S
S
*
8
4,6-bismethylthio-5-pyrimidyl


1009
′′
S
S
*
9
4,6-bismethylthio-5-pyrimidyl


1010
′′
S
S
*
14
4,6-bismethylthio-5-pyrimidyl


1011
′′
NH
S
*
1
4,6-bismethylthio-5-pyrimidyl


1012
′′
NH
S
*
2
4,6-bismethylthio-5-pyrimidyl


1013
′′
NH
S
*
3
4,6-bismethylthio-5-pyrimidyl


1014
′′
NH
S
*
4
4,6-bismethylthio-5-pyrimidyl


1015
′′
NH
S
*
5
4,6-bismethylthio-5-pyrimidyl


1016
′′
NH
S
*
6
4,6-bismethylthio-5-pyrimidyl


1017
′′
NH
S
*
7
4,6-bismethylthio-5-pyrimidyl


1018
′′
NH
S
*
8
4,6-bismethylthio-5-pyrimidyl


1019
′′
NH
S
*
9
4,6-bismethylthio-5-pyrimidyl


1020
′′
NH
S
*
14
4,6-bismethylthio-5-pyrimidyl





*Single Bond 






 














TABLE 52





Compound No.





X
Y
Z
n
Het





















1021





O
S
*
1
4,6-bisethylthio-5-pyrimidyl


1022
′′
O
S
*
2
4,6-bisethylthio-5-pyrimidyl


1023
′′
O
S
*
3
4,6-bisethylthio-5-pyrimidyl


1024
′′
O
S
*
4
4,6-bisethylthio-5-pyrimidyl


1025
′′
O
S
*
5
4,6-bisethylthio-5-pyrimidyl


1026
′′
O
S
*
6
4,6-bisethylthio-5-pyrimidyl


1027
′′
O
S
*
7
4,6-bisethylthio-5-pyrimidyl


1028
′′
O
S
*
8
4,6-bisethylthio-5-pyrimidyl


1029
′′
O
S
*
9
4,6-bisethylthio-5-pyrimidyl


1030
′′
O
S
*
14
4,6-bisethylthio-5-pyrimidyl


1031
′′
S
S
*
1
4,6-bisethylthio-5-pyrimidyl


1032
′′
S
S
*
2
4,6-bisethylthio-5-pyrimidyl


1033
′′
S
S
*
3
4,6-bisethylthio-5-pyrimidyl


1034
′′
S
S
*
4
4,6-bisethylthio-5-pyrimidyl


1035
′′
S
S
*
5
4,6-bisethylthio-5-pyrimidyl


1036
′′
S
S
*
6
4,6-bisethylthio-5-pyrimidyl


1037
′′
S
S
*
7
4,6-bisethylthio-5-pyrimidyl


1038
′′
S
S
*
8
4,6-bisethylthio-5-pyrimidyl


1039
′′
S
S
*
9
4,6-bisethylthio-5-pyrimidyl


1040
′′
S
S
*
14
4,6-bisethylthio-5-pyrimidyl





*Single Bond 






 














TABLE 53





Compound No.





X
Y
Z
n
Het





















1041





NH
S
*
1
4,6-bisethylthio-5-pyrimidyl


1042
′′
NH
S
*
2
4,6-bisethylthio-5-pyrimidyl


1043
′′
NH
S
*
3
4,6-bisethylthio-5-pyrimidyl


1044
′′
NH
S
*
4
4,6-bisethylthio-5-pyrimidyl


1045
′′
NH
S
*
5
4,6-bisethylthio-5-pyrimidyl


1046
′′
NH
S
*
6
4,6-bisethylthio-5-pyrimidyl


1047
′′
NH
S
*
7
4,6-bisethylthio-5-pyrimidyl


1048
′′
NH
S
*
8
4,6-bisethylthio-5-pyrimidyl


1049
′′
NH
S
*
9
4,6-bisethylthio-5-pyrimidyl


1050
′′
NH
S
*
14
4,6-bisethylthio-5-pyrimidyl


1051
′′
O
S
*
1
4,6-bis(iso-propylthio)-5-pyrimidyl


1052
′′
O
S
*
2
4,6-bis(iso-propylthio)-5-pyrimidyl


1053
′′
O
S
*
3
4,6-bis(iso-propylthio)-5-pyrimidyl


1054
′′
O
S
*
4
4,6-bis(iso-propylthio)-5-pyrimidyl


1055
′′
O
S
*
5
4,6-bis(iso-propylthio)-5-pyrimidyl


1056
′′
O
S
*
6
4,6-bis(iso-propylthio)-5-pyrimidyl


1057
′′
O
S
*
7
4,6-bis(iso-propylthio)-5-pyrimidyl


1058
′′
O
S
*
8
4,6-bis(iso-propylthio)-5-pyrimidyl


1059
′′
O
S
*
9
4,6-bis(iso-propylthio)-5-pyrimidyl


1060
′′
O
S
*
14
4,6-bis(iso-propylthio)-5-pyrimidyl





*Single Bond 






 














TABLE 54





Compound No.





X
Y
Z
n
Het





















1061





S
S
*
1
4,6-bis(iso-propylthio)-5-pyrimidyl


1062
′′
S
S
*
2
4,6-bis(iso-propylthio)-5-pyrimidyl


1063
′′
S
S
*
3
4,6-bis(iso-propylthio)-5-pyrimidyl


1064
′′
S
S
*
4
4,6-bis(iso-propylthio)-5-pyrimidyl


1065
′′
S
S
*
5
4,6-bis(iso-propylthio)-5-pyrimidyl


1066
′′
S
S
*
6
4,6-bis(iso-propylthio)-5-pyrimidyl


1067
′′
S
S
*
7
4,6-bis(iso-propylthio)-5-pyrimidyl


1068
′′
S
S
*
8
4,6-bis(iso-propylthio)-5-pyrimidyl


1069
′′
S
S
*
9
4,6-bis(iso-propylthio)-5-pyrimidyl


1070
′′
S
S
*
14
4,6-bis(iso-propylthio)-5-pyrimidyl


1071
′′
NH
S
*
1
4,6-bis(iso-propylthio)-5-pyrimidyl


1072
′′
NH
S
*
2
4,6-bis(iso-propylthio)-5-pyrimidyl


1073
′′
NH
S
*
3
4,6-bis(iso-propylthio)-5-pyrimidyl


1074
′′
NH
S
*
4
4,6-bis(iso-propylthio)-5-pyrimidyl


1075
′′
NH
S
*
5
4,6-bis(iso-propylthio)-5-pyrimidyl


1076
′′
NH
S
*
6
4,6-bis(iso-propylthio)-5-pyrimidyl


1077
′′
NH
S
*
7
4,6-bis(iso-propylthio)-5-pyrimidyl


1078
′′
NH
S
*
8
4,6-bis(iso-propylthio)-5-pyrimidyl


1079
′′
NH
S
*
9
4,6-bis(iso-propylthio)-5-pyrimidyl


1080
′′
NH
S
*
14
4,6-bis(iso-propylthio)-5-pyrimidyl





*Single Bond 






 














TABLE 55





Compound No.





X
Y
Z
n
Het





















1081





O
S
*
1
4,6-dimethoxy-5-pyrimidyl


1082
′′
O
S
*
2
4,6-dimethoxy-5-pyrimidyl


1083
′′
O
S
*
3
4,6-dimethoxy-5-pyrimidyl


1084
′′
O
S
*
4
4,6-dimethoxy-5-pyrimidyl


1085
′′
O
S
*
5
4,6-dimethoxy-5-pyrimidyl


1086
′′
O
S
*
6
4,6-dimethoxy-5-pyrimidyl


1087
′′
O
S
*
7
4,6-dimethoxy-5-pyrimidyl


1088
′′
O
S
*
8
4,6-dimethoxy-5-pyrimidyl


1089
′′
O
S
*
9
4,6-dimethoxy-5-pyrimidyl


1090
′′
O
S
*
14
4,6-dimethoxy-5-pyrimidyl


1091
′′
S
S
*
1
4,6-dimethoxy-5-pyrimidyl


1092
′′
S
S
*
2
4,6-dimethoxy-5-pyrimidyl


1093
′′
S
S
*
3
4,6-dimethoxy-5-pyrimidyl


1094
′′
S
S
*
4
4,6-dimethoxy-5-pyrimidyl


1095
′′
S
S
*
5
4,6-dimethoxy-5-pyrimidyl


1096
′′
S
S
*
6
4,6-dimethoxy-5-pyrimidyl


1097
′′
S
S
*
7
4,6-dimethoxy-5-pyrimidyl


1098
′′
S
S
*
8
4,6-dimethoxy-5-pyrimidyl


1099
′′
S
S
*
9
4,6-dimethoxy-5-pyrimidyl


1100
′′
S
S
*
14
4,6-dimethoxy-5-pyrimidyl





*Single Bond 






 














TABLE 56





Compound No.





X
Y
Z
n
Het





















1101





NH
S
*
1
4,6-dichloro-2-methyl-5-pyrimidyl


1102
′′
NH
S
*
2
4,6-dichloro-2-methyl-5-pyrimidyl


1103
′′
NH
S
*
3
4,6-dichloro-2-methyl-5-pyrimidyl


1104
′′
NH
S
*
4
4,6-dichloro-2-methyl-5-pyrimidyl


1105
′′
NH
S
*
5
4,6-dichloro-2-methyl-5-pyrimidyl


1106
′′
NH
S
*
6
4,6-dichloro-2-methyl-5-pyrimidyl


1107
′′
NH
S
*
7
4,6-dichloro-2-methyl-5-pyrimidyl


1108
′′
NH
S
*
8
4,6-dichloro-2-methyl-5-pyrimidyl


1109
′′
NH
S
*
9
4,6-dichloro-2-methyl-5-pyrimidyl


1110
′′
NH
S
*
14
4,6-dichloro-2-methyl-5-pyrimidyl


1111
′′
O
S
*
1
4,6-bis(dimethylamino)-5-pyrimidyl


1112
′′
O
S
*
2
4,6-bis(dimethylamino)-5-pyrimidyl


1113
′′
O
S
*
3
4,6-bis(dimethylamino)-5-pyrimidyl


1114
′′
O
S
*
4
4,6-bis(dimethylamino)-5-pyrimidyl


1115
′′
O
S
*
5
4,6-bis(dimethylamino)-5-pyrimidyl


1116
′′
O
S
*
6
4,6-bis(dimethylamino)-5-pyrimidyl


1117
′′
O
S
*
7
4,6-bis(dimethylamino)-5-pyrimidyl


1118
′′
O
S
*
8
4,6-bis(dimethylamino)-5-pyrimidyl


1119
′′
O
S
*
9
4,6-bis(dimethylamino)-5-pyrimidyl


1120
′′
O
S
*
14
4,6-bis(dimethylamino)-5-pyrimidyl





*Single Bond 






 














TABLE 57





Compound No.





X
Y
Z
n
Het





















1121





S
S
*
1
4,6-bis(dimethylamino)-5-pyrimidyl


1122
′′
S
S
*
2
4,6-bis(dimethylamino)-5-pyrimidyl


1123
′′
S
S
*
3
4,6-bis(dimethylamino)-5-pyrimidyl


1124
′′
S
S
*
4
4,6-bis(dimethylamino)-5-pyrimidyl


1125
′′
S
S
*
5
4,6-bis(dimethylamino)-5-pyrimidyl


1126
′′
S
S
*
6
4,6-bis(dimethylamino)-5-pyrimidyl


1127
′′
S
S
*
7
4,6-bis(dimethylamino)-5-pyrimidyl


1128
′′
S
S
*
8
4,6-bis(dimethylamino)-5-pyrimidyl


1129
′′
S
S
*
9
4,6-bis(dimethylamino)-5-pyrimidyl


1130
′′
S
S
*
14
4,6-bis(dimethylamino)-5-pyrimidyl


1131
′′
NH
S
*
1
4,6-bis(dimethylamino)-5-pyrimidyl


1132
′′
NH
S
*
2
4,6-bis(dimethylamino)-5-pyrimidyl


1133
′′
NH
S
*
3
4,6-bis(dimethylamino)-5-pyrimidyl


1134
′′
NH
S
*
4
4,6-bis(dimethylamino)-5-pyrimidyl


1135
′′
NH
S
*
5
4,6-bis(dimethylamino)-5-pyrimidyl


1136
′′
NH
S
*
6
4,6-bis(dimethylamino)-5-pyrimidyl


1137
′′
NH
S
*
7
4,6-bis(dimethylamino)-5-pyrimidyl


1138
′′
NH
S
*
8
4,6-bis(dimethylamino)-5-pyrimidyl


1139
′′
NH
S
*
9
4,6-bis(dimethylamino)-5-pyrimidyl


1140
′′
NH
S
*
14
4,6-bis(dimethylamino)-5-pyrimidyl





*Single Bond 






 














TABLE 58





Compound No.





X
Y
Z
n
Het





















1141





O
S
*
1
4,6-bismethylthio-2-methyl-5-pyrimidyl


1142
′′
O
S
*
2
4,6-bismethylthio-2-methyl-5-pyrimidyl


1143
′′
O
S
*
3
4,6-bismethylthio-2-methyl-5-pyrimidyl


1144
′′
O
S
*
4
4,6-bismethylthio-2-methyl-5-pyrimidyl


1145
′′
O
S
*
5
4,6-bismethylthio-2-methyl-5-pyrimidyl


1146
′′
O
S
*
6
4,6-bismethylthio-2-methyl-5-pyrimidyl


1147
′′
O
S
*
7
4,6-bismethylthio-2-methyl-5-pyrimidyl


1148
′′
O
S
*
8
4,6-bismethylthio-2-methyl-5-pyrimidyl


1149
′′
O
S
*
9
4,6-bismethylthio-2-methyl-5-pyrimidyl


1150
′′
O
S
*
14
4,6-bismethylthio-2-methyl-5-pyrimidyl


1151
′′
S
S
*
1
4,6-bismethylthio-2-methyl-5-pyrimidyl


1152
′′
S
S
*
2
4,6-bismethylthio-2-methyl-5-pyrimidyl


1153
′′
S
S
*
3
4,6-bismethylthio-2-methyl-5-pyrimidyl


1154
′′
S
S
*
4
4,6-bismethylthio-2-methyl-5-pyrimidyl


1155
′′
S
S
*
5
4,6-bismethylthio-2-methyl-5-pyrimidyl


1156
′′
S
S
*
6
4,6-bismethylthio-2-methyl-5-pyrimidyl


1157
′′
S
S
*
7
4,6-bismethylthio-2-methyl-5-pyrimidyl


1158
′′
S
S
*
8
4,6-bismethylthio-2-methyl-5-pyrimidyl


1159
′′
S
S
*
9
4,6-bismethylthio-2-methyl-5-pyrimidyl


1160
′′
S
S
*
14
4,6-bismethylthio-2-methyl-5-pyrimidyl





*Single Bond 






 














TABLE 59





Compound No.





X
Y
Z
n
Het





















1161





NH
S
*
1
4,6-bismethylthio-2-methyl-5-pyrimidyl


1162
′′
NH
S
*
2
4,6-bismethylthio-2-methyl-5-pyrimidyl


1163
′′
NH
S
*
3
4,6-bismethylthio-2-methyl-5-pyrimidyl


1164
′′
NH
S
*
4
4,6-bismethylthio-2-methyl-5-pyrimidyl


1165
′′
NH
S
*
5
4,6-bismethylthio-2-methyl-5-pyrimidyl


1166
′′
NH
S
*
6
4,6-bismethylthio-2-methyl-5-pyrimidyl


1167
′′
NH
S
*
7
4,6-bismethylthio-2-methyl-5-pyrimidyl


1168
′′
NH
S
*
8
4,6-bismethylthio-2-methyl-5-pyrimidyl


1169
′′
NH
S
*
9
4,6-bismethylthio-2-methyl-5-pyrimidyl


1170
′′
NH
S
*
14
4,6-bismethylthio-2-methyl-5-pyrimidyl


1171
′′
O
S
*
1
2,4,6-trimethoxy-5-pyrimidyl


1172
′′
O
S
*
2
2,4,6-trimethoxy-5-pyrimidyl


1173
′′
O
S
*
3
2,4,6-trimethoxy-5-pyrimidyl


1174
′′
O
S
*
4
2,4,6-trimethoxy-5-pyrimidyl


1175
′′
O
S
*
5
2,4,6-trimethoxy-5-pyrimidyl


1176
′′
O
S
*
6
2,4,6-trimethoxy-5-pyrimidyl


1177
′′
O
S
*
7
2,4,6-trimethoxy-5-pyrimidyl


1178
′′
O
S
*
8
2,4,6-trimethoxy-5-pyrimidyl


1179
′′
O
S
*
9
2,4,6-trimethoxy-5-pyrimidyl


1180
′′
O
S
*
14
2,4,6-trimethoxy-5-pyrimidyl





*Single Bond 






 














TABLE 60





Compound No.





X
Y
Z
n
Het





















1181





S
S
*
1
2,4,6-trimethoxy-5-pyrimidyl


1182
′′
S
S
*
2
2,4,6-trimethoxy-5-pyrimidyl


1183
′′
S
S
*
3
2,4,6-trimethoxy-5-pyrimidyl


1184
′′
S
S
*
4
2,4,6-trimethoxy-5-pyrimidyl


1185
′′
S
S
*
5
2,4,6-trimethoxy-5-pyrimidyl


1186
′′
S
S
*
6
2,4,6-trimethoxy-5-pyrimidyl


1187
′′
S
S
*
7
2,4,6-trimethoxy-5-pyrimidyl


1188
′′
S
S
*
8
2,4,6-trimethoxy-5-pyrimidyl


1189
′′
S
S
*
9
2,4,6-trimethoxy-5-pyrimidyl


1190
′′
S
S
*
14
2,4,6-trimethoxy-5-pyrimidyl


1191
′′
NH
S
*
1
2,4,6-trimethoxy-5-pyrimidyl


1192
′′
NH
S
*
2
2,4,6-trimethoxy-5-pyrimidyl


1193
′′
NH
S
*
3
2,4,6-trimethoxy-5-pyrimidyl


1194
′′
NH
S
*
4
2,4,6-trimethoxy-5-pyrimidyl


1195
′′
NH
S
*
5
2,4,6-trimethoxy-5-pyrimidyl


1196
′′
NH
S
*
6
2,4,6-trimethoxy-5-pyrimidyl


1197
′′
NH
S
*
7
2,4,6-trimethoxy-5-pyrimidyl


1198
′′
NH
S
*
8
2,4,6-trimethoxy-5-pyrimidyl


1199
′′
NH
S
*
9
2,4,6-trimethoxy-5-pyrimidyl


1200
′′
NH
S
*
14
2,4,6-trimethoxy-5-pyrimidyl





*Single Bond 






 














TABLE 61





Compound No.





X
Y
Z
n
Het







1201





O
SO
*
5
2-methylthio-3-pyridyl


1202
′′
O
SO2
*
5
2-methylthio-3-pyridyl


1203
′′
O
NH
*
5
2-methylthio-3-pyridyl


1204
′′
S
SO
*
5
2-methylthio-3-pyridyl


1205
′′
S
SO2
*
5
2-methylthio-3-pyridyl


1206
′′
S
NH
*
5
2-methylthio-3-pyridyl


1207
′′
NH
SO
*
5
2-methylthio-3-pyridyl


1208
′′
NH
SO2
*
5
2-methylthio-3-pyridyl


1209
′′
NH
NH
*
5
2-methylthio-3-pyridyl


1210
′′
O
SO
NH
6
2-methylthio-3-pyridyl


1211
′′
O
SO2
NH
6
2-methylthio-3-pyridyl


1212
′′
O
NH
NH
6
2-methylthio-3-pyridyl


1213
′′
S
SO
NH
6
2-methylthio-3-pyridyl


1214
′′
S
SO2
NH
6
2-methylthio-3-pyridyl


1215
′′
S
NH
NH
6
2-methylthio-3-pyridyl


1216
′′
NH
SO
NH
6
2-methylthio-3-pyridyl


1217
′′
NH
SO2
NH
6
2-methylthio-3-pyridyl


1218
′′
NH
NH
NH
6
2-methylthio-3-pyridyl





*Single Bond 






 














TABLE 62





Compound No.





X
Y
Z
n
Het







1219





O
SO
*
5
2,4-bismethylthio-6-methyl-3-pyridyl


1220
′′
O
SO2
*
5
2,4-bismethylthio-6-methyl-3-pyridyl


1221
′′
O
NH
*
5
2,4-bismethylthio-6-methyl-3-pyridyl


1222
′′
S
SO
*
5
2,4-bismethylthio-6-methyl-3-pyridyl


1223
′′
S
SO2
*
5
2,4-bismethylthio-6-methyl-3-pyridyl


1224
′′
S
NH
*
5
2,4-bismethylthio-6-methyl-3-pyridyl


1225
′′
NH
SO
*
5
2,4-bismethylthio-6-methyl-3-pyridyl


1226
′′
NH
SO2
*
5
2,4-bismethylthio-6-methyl-3-pyridyl


1227
′′
NH
NH
*
5
2,4-bismethylthio-6-methyl-3-pyridyl


1228
′′
O
SO
NH
6
2,4-bismethylthio-6-methyl-3-pyridyl


1229
′′
O
SO2
NH
6
2,4-bismethylthio-6-methyl-3-pyridyl


1230
′′
O
NH
NH
6
2,4-bismethylthio-6-methyl-3-pyridyl


1231
′′
S
SO
NH
6
2,4-bismethylthio-6-methyl-3-pyridyl


1232
′′
S
SO2
NH
6
2,4-bismethylthio-6-methyl-3-pyridyl


1233
′′
S
NH
NH
6
2,4-bismethylthio-6-methyl-3-pyridyl


1234
′′
NH
SO
NH
6
2,4-bismethylthio-6-methyl-3-pyridyl


1235
′′
NH
SO2
NH
6
2,4-bismethylthio-6-methyl-3-pyridyl


1236
′′
NH
NH
NH
6
2,4-bismethylthio-6-methyl-3-pyridyl





*Single Bond 






 














TABLE 63





Compound No.





X
Y
Z
n
Het







1237





O
S
Single Bond
5







1238





O
S
Single Bond
5







1239





O
S
Single Bond
8







1240





O
S
Single Bond
8







1241





O
S
Single Bond
5







1242





O
S
Single Bond
5







1243





O
S
Single Bond
8







1244





O
S
Single Bond
8







1245





S
S
Single Bond
1







1246





NH
S
Single Bond
1














 














TABLE 64





Compound No.





X
Y
Z
n
Het





















1247





O
S
Single Bond
1







1248





O
S
Single Bond
2







1249





O
S
Single Bond
3







1250





O
S
Single Bond
4







1251





O
S
Single Bond
5







1252





O
S
Single Bond
6







1253





O
S
Single Bond
7







1254





O
S
Single Bond
8







1255





O
S
Single Bond
9







1256





O
S
Single Bond
14














 














TABLE 65





Compound No.





X
Y
Z
n
Het





















1257





O
S
Single Bond
1







1258





O
S
Single Bond
2







1259





O
S
Single Bond
3







1260





O
S
Single Bond
4







1261





O
S
Single Bond
5







1262





O
S
Single Bond
6







1263





O
S
Single Bond
7







1264





O
S
Single Bond
8







1265





O
S
Single Bond
9







1266





O
S
Single Bond
14














 














TABLE 66





Compound No.





X
Y
Z
n
Het





















1267





O
S
Single Bond
1







1268





O
S
Single Bond
2







1269





O
S
Single Bond
3







1270





O
S
Single Bond
4







1271





O
S
Single Bond
5







1272





O
S
Single Bond
6







1273





O
S
Single Bond
7







1274





O
S
Single Bond
8







1275





O
S
Single Bond
9







1276





O
S
Single Bond
14














 














TABLE 67





Compound No.





X
Y
Z
n
Het





















1277





O
S
Single Bond
1







1278





O
S
Single Bond
2







1279





O
S
Single Bond
3







1280





O
S
Single Bond
4







1281





O
S
Single Bond
5







1282





O
S
Single Bond
6







1283





O
S
Single Bond
7







1284





O
S
Single Bond
8







1285





O
S
Single Bond
9







1286





O
S
Single Bond
14














 














TABLE 68





Compound No.





X
Y
Z
n
Het





















1287





O
S
Single Bond
1







1288





O
S
Single Bond
2







1289





O
S
Single Bond
3







1290





O
S
Single Bond
4







1291





O
S
Single Bond
5







1292





O
S
Single Bond
6







1293





O
S
Single Bond
7







1294





O
S
Single Bond
8







1295





O
S
Single Bond
9







1296





O
S
Single Bond
14














 














TABLE 69





Compound No.





X
Y
Z
n
Het





















1297





O
S
Single Bond
1







1298





O
S
Single Bond
2







1299





O
S
Single Bond
3







1300





O
S
Single Bond
4







1301





O
S
Single Bond
5







1302





O
S
Single Bond
6







1303





O
S
Single Bond
7







1304





O
S
Single Bond
8







1305





O
S
Single Bond
9







1306





O
S
Single Bond
14














 














TABLE 70





Compound No.





X
Y
Z
n
Het





















1307





O
S
Single Bond
1







1308





O
S
Single Bond
2







1309





O
S
Single Bond
3







1310





O
S
Single Bond
4







1311





O
S
Single Bond
5







1312





O
S
Single Bond
6







1313





O
S
Single Bond
7







1314





O
S
Single Bond
8







1315





O
S
Single Bond
9







1316





O
S
Single Bond
14



























TABLE 71





Compound No.





X
Y
Z
n
Het





















1317





O
S
Single Bond
1







1318





O
S
Single Bond
2







1319





O
S
Single Bond
3







1320





O
S
Single Bond
4







1321





O
S
Single Bond
5







1322





O
S
Single Bond
6







1323





O
S
Single Bond
7







1324





O
S
Single Bond
8







1325





O
S
Single Bond
9







1326





O
S
Single Bond
14














 














TABLE 72





Compound No.





X
Y
Z
n
Het





















1327





O
S
Single Bond
1







1328





O
S
Single Bond
2







1329





O
S
Single Bond
3







1330





O
S
Single Bond
4







1331





O
S
Single Bond
5







1332





O
S
Single Bond
6







1333





O
S
Single Bond
7







1334





O
S
Single Bond
8







1335





O
S
Single Bond
9







1336





O
S
Single Bond
14














 














TABLE 73





Compound No.





X
Y
Z
n
Het





















1337





O
S
*
1
4-methyl-6-methylthio-3-pyridyl


1338
′′
O
S
*
2
4-methyl-6-methylthio-3-pyridyl


1339
′′
O
S
*
3
4-methyl-6-methylthio-3-pyridyl


1340
′′
O
S
*
4
4-methyl-6-methylthio-3-pyridyl


1341
′′
O
S
*
5
4-methyl-6-methylthio-3-pyridyl


1342
′′
O
S
*
6
4-methyl-6-methylthio-3-pyridyl


1343
′′
O
S
*
7
4-methyl-6-methylthio-3-pyridyl


1344
′′
O
S
*
8
4-methyl-6-methylthio-3-pyridyl


1345
′′
O
S
*
9
4-methyl-6-methylthio-3-pyridyl


1346
′′
O
S
*
14
4-methyl-6-methylthio-3-pyridyl


1347
′′
S
S
*
1
4-methyl-6-methylthio-3-pyridyl


1348
′′
S
S
*
2
4-methyl-6-methylthio-3-pyridyl


1349
′′
S
S
*
3
4-methyl-6-methylthio-3-pyridyl


1350
′′
S
S
*
4
4-methyl-6-methylthio-3-pyridyl


1351
′′
S
S
*
5
4-methyl-6-methylthio-3-pyridyl


1352
′′
S
S
*
6
4-methyl-6-methylthio-3-pyridyl


1353
′′
S
S
*
7
4-methyl-6-methylthio-3-pyridyl


1354
′′
S
S
*
8
4-methyl-6-methylthio-3-pyridyl


1355
′′
S
S
*
9
4-methyl-6-methylthio-3-pyridyl


1356
′′
S
S
*
14
4-methyl-6-methylthio-3-pyridyl





* = Single Bond 






 














TABLE 74





Compound No.





X
Y
Z
n
Het





















1357





NH
S
*
1
4-methyl-6-methylthio-3-pyridyl


1358
′′
NH
S
*
2
4-methyl-6-methylthio-3-pyridyl


1359
′′
NH
S
*
3
4-methyl-6-methylthio-3-pyridyl


1360
′′
NH
S
*
4
4-methyl-6-methylthio-3-pyridyl


1361
′′
NH
S
*
5
4-methyl-6-methylthio-3-pyridyl


1362
′′
NH
S
*
6
4-methyl-6-methylthio-3-pyridyl


1363
′′
NH
S
*
7
4-methyl-6-methylthio-3-pyridyl


1364
′′
NH
S
*
8
4-methyl-6-methylthio-3-pyridyl


1365
′′
NH
S
*
9
4-methyl-6-methylthio-3-pyridyl


1366
′′
NH
S
*
14
4-methyl-6-methylthio-3-pyridyl


1367
′′
O
S
*
1
5-methylthio-2-pyridyl


1368
′′
O
S
*
2
5-methylthio-2-pyridyl


1369
′′
O
S
*
3
5-methylthio-2-pyridyl


1370
′′
O
S
*
4
5-methylthio-2-pyridyl


1371
′′
O
S
*
5
5-methylthio-2-pyridyl


1372
′′
O
S
*
6
5-methylthio-2-pyridyl


1373
′′
O
S
*
7
5-methylthio-2-pyridyl


1374
′′
O
S
*
8
5-methylthio-2-pyridyl


1375
′′
O
S
*
9
5-methylthio-2-pyridyl


1376
′′
O
S
*
14
5-methylthio-2-pyridyl





* = Single Bond 






 














TABLE 75





Com-








pound


No.





X
Y
Z
n
Het





















1377





S
S
*
1
5-methylthio-2-pyridyl


1378
′′
S
S
*
2
5-methylthio-2-pyridyl


1379
′′
S
S
*
3
5-methylthio-2-pyridyl


1380
′′
S
S
*
4
5-methylthio-2-pyridyl


1381
′′
S
S
*
5
5-methylthio-2-pyridyl


1382
′′
S
S
*
6
5-methylthio-2-pyridyl


1383
′′
S
S
*
7
5-methylthio-2-pyridyl


1384
′′
S
S
*
8
5-methylthio-2-pyridyl


1385
′′
S
S
*
9
5-methylthio-2-pyridyl


1386
′′
S
S
*
14
5-methylthio-2-pyridyl


1387
′′
NH
S
*
1
5-methylthio-2-pyridyl


1388
′′
NH
S
*
2
5-methylthio-2-pyridyl


1389
′′
NH
S
*
3
5-methylthio-2-pyridyl


1390
′′
NH
S
*
4
5-methylthio-2-pyridyl


1391
′′
NH
S
*
5
5-methylthio-2-pyridyl


1392
′′
NH
S
*
6
5-methylthio-2-pyridyl


1393
′′
NH
S
*
7
5-methylthio-2-pyridyl


1394
′′
NH
S
*
8
5-methylthio-2-pyridyl


1395
′′
NH
S
*
9
5-methylthio-2-pyridyl


1396
′′
NH
S
*
14
5-methylthio-2-pyridyl





* = Single Bond 






 














TABLE 76





Compound No.





X
Y
Z
n
Het





















1397





O
S
*
1
2,4,6-trismethylthio-5-pyrimidyl


1398
′′
O
S
*
2
2,4,6-trismethylthio-5-pyrimidyl


1399
′′
O
S
*
3
2,4,6-trismethylthio-5-pyrimidyl


1400
′′
O
S
*
4
2,4,6-trismethylthio-5-pyrimidyl


1401
′′
O
S
*
5
2,4,6-trismethylthio-5-pyrimidyl


1402
′′
O
S
*
6
2,4,6-trismethylthio-5-pyrimidyl


1403
′′
O
S
*
7
2,4,6-trismethylthio-5-pyrimidyl


1404
′′
O
S
*
8
2,4,6-trismethylthio-5-pyrimidyl


1405
′′
O
S
*
9
2,4,6-trismethylthio-5-pyrimidyl


1406
′′
O
S
*
14
2,4,6-trismethylthio-5-pyrimidyl


1407
′′
S
S
*
1
2,4,6-trismethylthio-5-pyrimidyl


1408
′′
S
S
*
2
2,4,6-trismethylthio-5-pyrimidyl


1409
′′
S
S
*
3
2,4,6-trismethylthio-5-pyrimidyl


1410
′′
S
S
*
4
2,4,6-trismethylthio-5-pyrimidyl


1411
′′
S
S
*
5
2,4,6-trismethylthio-5-pyrimidyl


1412
′′
S
S
*
6
2,4,6-trismethylthio-5-pyrimidyl


1413
′′
S
S
*
7
2,4,6-trismethylthio-5-pyrimidyl


1414
′′
S
S
*
8
2,4,6-trismethylthio-5-pyrimidyl


1415
′′
S
S
*
9
2,4,6-trismethylthio-5-pyrimidyl


1416
′′
S
S
*
14
2,4,6-trismethylthio-5-pyrimidyl





*Single Bond 






 














TABLE 77





Compound No.





X
Y
Z
n
Het





















1417





NH
S
*
1
2,4,6-trismethylthio-5-pyrimidyl


1418
′′
NH
S
*
2
2,4,6-trismethylthio-5-pyrimidyl


1419
′′
NH
S
*
3
2,4,6-trismethylthio-5-pyrimidyl


1420
′′
NH
S
*
4
2,4,6-trismethylthio-5-pyrimidyl


1421
′′
NH
S
*
5
2,4,6-trismethylthio-5-pyrimidyl


1422
′′
NH
S
*
6
2,4,6-trismethylthio-5-pyrimidyl


1423
′′
NH
S
*
7
2,4,6-trismethylthio-5-pyrimidyl


1424
′′
NH
S
*
8
2,4,6-trismethylthio-5-pyrimidyl


1425
′′
NH
S
*
9
2,4,6-trismethylthio-5-pyrimidyl


1426
′′
NH
S
*
14
2,4,6-trismethylthio-5-pyrimidyl





*Single Bond 






 














TABLE 78





Compound No.





X
Y
Z
n
Het







1427





O
S
Single Bond
1







1428





O
S
Single Bond
1














 

The compounds represented by the formula (I) in the present invention has an ACAT inhibitory activity and/or an intracellular cholesterol transfer inhibitory activity, and is useful in the medical field as medications for treating hyperlipemia or arteriosclerosis. Especially, the compounds of the present invention exhibit an activity of selectively inhibiting an ACAT enzyme which is present in the blood vessel wall. Accordingly, it is expected to have a less side effect than a non-selective ACAT inhibitor, and is preferable as an active ingredient of a drug.
The pharmaceutical composition of the present invention contains the compounds represented by the formula (I) or acid addition salts or solvates thereof as active ingredients. It comprises at least one type of the active ingredients in a therapeutically effective amount, and a pharmaceutically acceptable carrier.
The pharmaceutical composition of the present invention contains the compounds represented by the formula (I), or the acid addition salts or the solvates thereof as active ingredients. At least one type of the active ingredients is used singly, or can be shaped into an administrable preparation such as a tablet, a capsule, a granule, a powder, an injection or a suppository using a pharmaceutically acceptable carrier well-known to those skilled in the art, such as a excipient, a binder, a support or a diluent. These preparations can be produced by a known method. For example, an orally administrable preparation can be produced by mixing the compound represented by the formula (I) with an excipient such as starch, mannitol or lactose, a binder such as carboxymethylcellulose sodium or hydroxypropyl cellulose, a disintegrant such as crystalline cellulose or carboxymethyl cellulose calcium, a lubricant such as talc or magnesium stearate, and a fluidity improving agent such as light silicic anhydride, which are combined as required.
The pharmaceutical composition of the present invention can be administered either orally or parenterally.
The dose of the pharmaceutical composition of the present invention varies depending on the weight, the age, the sex, the progression of disease and the like of patients. Generally, it is preferably administered to an adult person at a dose of from 1 to 100 mg, preferably from 5 to 200 mg a day, from one to three times a day.
The ACAT inhibitory activity of the compounds represented by the formula (I) in the present invention was tested in the following Experiment Examples.
Experiment Example 1
(ACAT Inhibitory Activity)
A microsome was prepared from the breast aorta of a rabbit which had been fed with 1% cholesterol food for 8 weeks in a usual manner, and suspended in a 0.15 M phosphate buffer solution (pH 7.4) to form an enzyme solution. An enzyme solution derived from the small intestine was prepared from the small intestine of a rabbit that had eaten a normal food.
The ACAT inhibitory activity was measured by modifying the method of J. G. Heider (J. Lipid Res., 24, 1127-1134, 1983). That is, 2 μl of a test compound dissolved in dimethyl sulfoxide (DMSO) were added to 88 μl of a 0.15 M phosphate buffer solution (pH 7.4)containing 14C-Oleoyl-CoA (40 μM, 60,000 dpm) and bovine serum albumin (2.4 mg/ml), and the mixture was incubated at 37° C. for 5 minutes.
To this solution were added 10 μl of the enzyme solution, and the mixture was reacted at 37° C. for 5 minutes (for 3 minutes in the case of the small intestine). Then, 3 ml of a chloroform/methanol (2/1) mixture and 0.5 ml of 0.04 N hydrochloric acid were added thereto to stop the reaction. The lipid was then extracted. The solvent layer was concentrated to dryness, and dissolved in hexane. The solution was spotted on a TLC plate (supplied by Merck Co.). The elution was conducted with a hexane:ether:acetic acid (75:25:1) mixture.
The radioactivity of the resulting cholesterol ester fraction was measured using BAS 2000 (supplied by Fuji Photo Film Co., Ltd.). An IC50 value was obtained from the calculation in contrast with a control containing only DMSO. The results are shown in Table 79.










TABLE 79





Test Compound
Enzyme from A*
Enzyme from B*
IC50 (B*)/


No.
IC50 (μM)
IC50 (μM)
IC50 (A*)


















795
0.028
0.016
0.6


811
0.014
0.38
27.1


815
0.014
0.017
1.2


818
0.0056
0.016
2.9


831
0.63
0.61
1.0


Control 1
0.43
0.87
1.9


Control 2
0.047
0.13
2.8


Control 3
0.034
0.056
1.7


Control 4
0.026
0.037
1.4


Control 5
0.01
0.065
6.5


Control 6
0.11
0.51
4.6





A*: the blood vessel wall 


B*: the small intestine 






 

Experiment Example 2
(ACAT Inhibitory Activity (Anti-foamation Activity) in J744 Cells and HepG2 Cells)
J774 cells or HepG2 cells were spread on a 24-well plate. The cells were incubated in a 5% CO2 incubator at 37° C. for 24 hours using DMEM in the case of the J774 cells and a MEM culture solution in the case of the HepG2 cells (both containing 10% fetal calf serum).
The medium was replaced with 0.5 ml of each culture solution containing 10 μg/ml of 25-OH cholesterol and a test piece, and the cells were further incubated for 18 hours.
The medium was removed, and the residue was washed twice with PBS, then extracted with 1.5 ml of a hexane:isopropanol (3:2) mixture, and concentrated to dryness. The extract was dissolved in 0.2 ml of isopropanol containing 10% Triton X-100. Total cholesterol (TC) and free cholesterol (FC) were measured using Cholesterol E Test Wako (supplied by Wako Pure Chemical Industries, Ltd.) and Free Cholesterol E Test Wako (supplied by Wako Pure Chemical Industries, Ltd.).
The cell extract residue was solubilized in 0.25 ml of 2N NaOH at 37° C. for 30 minutes, and the protein amount was measured using BCA Protein Assay Reagent (Pierce).
The amount of cholesterol based on the protein was calculated from the difference between TC and FC, and an IC50 value was obtained from the calculation in contrast with the control results are shown in Table 80.










TABLE 80





Test Compound
Enzyme (1774)
Enzyme (HepG2)
IC50 (HepG2)/


No.
IC50 (μM)
IC50 (μM)
IC50 (1774)


















 795
0.050
0.35
7.0


 797
0.0036
0.029
8.1


 811
0.050
1.8
36.0


 815
0.12
2.6
21.7


 818
0.062
0.063
1.0


 831
0.057
5.4
94.7


1253
0.0041
0.0044
1.1


1282
0.0032
0.0062
1.9


1292
0.0027
0.030
11.1


1294
0.0042
0.0024
0.6


1302
0.0021
0.015
7.1


Control 1
0.56
5.3
9.5


Control 2
0.58
1.1
1.9


Control 3
0.32
1.3
4.3


Control 4
0.12
0.75
6.3


Control 5
1.9
1.6
0.8


Control 6
0.28
9.1
32.8









 

As control compounds, the following control compounds (1) to (6) were subjected to the same test, and the results are also shown in Tables 64 and 65. Control Compounds (1) to (6) are as follows.
Control compound (1):
5-[2-(2-(4-fluorophenyl)ethyl)-3-(1-methyl-1H-imidazol-2-yl)-2H-1-benzopyran-6-yl]oxy-2,2-dimethyl-N-(2,6-diisopropylphenyl)pentanamide (WO 92/09582)
Control compound (2):
(+)-(S)-2-[5-(3,5-dimethylpyrazol-1-yl)pentasulfinyl]-4,5-diphenylimidazole (EP 523941)
Control compound (3):
N-(2,2,5,5-tetramethyl-1,3-dioxan-4-ylcarbonyl)-β-alanine 2 (S)-[N′-(2,2-dimethylpropyl)-N′-nonylureido]-1(S)-cyclohexyl ester (EP 421441)
Control compound (4):
[5-(4,5-diphenyl-1H-imidazol-2-ylthio)pentyl]-N-heptyl-2-benzoxazolamie (WO 93/23392)
Control compound (5):
6-(benzoxazol-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide (compound of Japanese Patent Application No. 88,660/1997)
Control compound (6):
2-[4-[2-(benzimidazol-2-ylthio)ethyl]piperazin-1-yl]-N-(2,6-diisopropylphenyl)acetamide (compound of Japanese Patent Application No. 149,892/1997)


EXAMPLES
The present invention is illustrated more specifically by referring to the following Examples. However, the present invention is not limited to these Examples.
Example 1 (Compound No. 5 in Table)
Production of 6-(benzoxazol-2-ylthio)-N-(2-methylthio-3-pyridyl)hexanamide:
A methanol (50 ml) solution of 2-chloro-3-nitropyridine (4.30 g, 27.1 mmol) was added dropwise to a methanol (30 ml) solution of sodium thiomethoxide (2.10 g, 28.5 mmol) while being cooled with ice, and the mixed solution was stirred for 17 hours. Water was then added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, and dried over sodium sulfate. Subsequently, the solvent was distilled off, and the resulting crystals were recrystallized from a mixture of an ethyl acetate-hexane mixture to obtain 2.93 g (yield 64%) of 2-methylthio-3-nitropyridine as a yellow needle crystal.
This nitropyridine (851 mg, 5.0 mmol) was dissolved in a mixed solvent of acetic acid (35 ml) and conc. hydrochloric acid (1.4 ml), and zinc (3.92 g, 60 mmol) was added thereto in small portions while being cooled with ice. After the mixture was stirred for 30 minutes, the reaction mixture was filtered, and the filtrate was neutralized with an aqueous solution of sodium hydrogencarbonate, and extracted with methylene chloride. The organic layer was washed with water and then with a saturated aqueous solution of sodium chloride, and dried over sodium sulfate. Subsequently, the solvent was distilled off to obtain 600 mg (yield 86%) of 3-amino-2-methylthiopyridine as a pale yellow oil.
Triethylamine (520 mg, 5.14 mmol) was added to a THF (7 ml) solution of this aminopyridine (600 mg, 4.28 mmol). Subsequently, 6-bromohexanoyl chloride (1.10 g, 5.14 mmol) was slowly added dropwise thereto while being cooled with ice, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with water, and extracted with ethyl acetate. The organic layer was washed with water and then with a saturated aqueous solution of sodium chloride, and dried over sodium sulfate. Thereafter, the solvent was distilled off, and the resulting crude product was purified through silica gel chromatography (silica gel 125 g, eluent-hexane:ethyl acetate=6:1→3:1→2:1) to obtain 1.08 g (yield 79%) of 6-bromo-N-(2-methylthio-3-pyridyl)hexanamide as a colorless needle crystal (melting point: 66 to 67° C.).
To a DMF (2 ml) solution of this amide (159 mg, 0.5 mmol) and 2-mercaptobenzoxazole (83 mg, 0.55 mmol) were added 18-crown-6 (13 mg, 0.05 mmol) and potassium carbonate (83 mg, 0.6 mmol), and the mixture was stirred at 80° C. for 3 hours. The reaction mixture was diluted with water, and extracted with ethyl acetate. The organic layer was washed with water and then with a saturated aqueous solution of sodium chloride, and dried over sodium sulfate. Subsequently, the solvent was distilled off, and the resulting crude product was purified through silica gel chromatography silica gel 20 g, eluent-hexane:ethyl acetate=5:2→2:1) to obtain 156 g (yield 81%) of a desired compound as a colorless needle crystal.
Melting point: 127-128° C.
IR (KBr) cm−1: 3447, 3265, 1654, 1522, 1508.
1H-NMR (CDCl3) δ: 1.58-1.65 (2H, m), 1.83 (2H, quint, J=7.4 Hz), 1.92 (2H, quint, J=7.4 Hz), 2.46 (2H, t, J=7.4 Hz), 2.62 (3H, s), 3.34 (2H, t, J=7.4 Hz), 7.06 (1H, dd, J=8.1, 4.6 Hz), 7.21-7.30 (3H, m), 7.44 (1H, m), 7.59 (1H, m), 8.26 (1H, d, J=4.6 Hz), 8.28 (1H, d, J=8.1 Hz).
EIMS m/z (relative intensity): 387 (M+), 165 (100).
Elemental analysis: as C19H21N3O2S2; calculated: C, 58.89; H, 5.46; N, 10.84; S, 16.55. found: C, 58.92; H, 5.43; N, 10.78; S, 16.55.
Example 2 (Compound No. 8 in Table)
Production of 9-(benzoxazol-2-ylthio)-N-(2-methylthio-3-pyridyl)nonanamide:
The reaction and the treatment were conducted in the same manner as in Example 1 except that 9-bromononanoyl chloride was used instead of 6-bromohexanoyl chloride to obtain 9-bromo-N-(2-methylthio-3-pyridyl)nonanamide.
To a DMF (5 ml) solution of this amide (90 mg, 0.25 mmol) and 2-mercaptobenzoxazole (38 mg, 0.25 mmol) were added potassium carbonate (42 mg, 0.30 mmol) and 18-crown-6 (7 mg, 0.03 mmol), and the mixture was stirred at 80° C. for 3 hours. The reaction mixture was allowed to cool, and then extracted with ethyl acetate. The organic layer was washed with water and then with a saturated aqueous solution of sodium chloride, and dried over sodium sulfate. Subsequently, the solvent was distilled off, and the resulting residue was recrystallized from a mixture of ethyl acetate-hexane to obtain 83 mg (yield 77%) of the desired compound as a colorless powdery crystal.
Melting point: 84-85° C.
IR (KBr) cm−1: 3465, 3276, 2926, 1664, 1505.
1H-NMR (CDCl3) δ: 1.35-1.53 (8H, m), 1.72-1.77 (2H, m), 1.80-1.87 (2H, m), 2.42 (2H, t, J=7.3 Hz). 2.63 (3H, s), 3.31 (2H, t, J=7.4 Hz), 7.06 (1H, dd, J=8.0, 4.7 Hz), 7.21-7.30 (3H, m), 7.43 (1H, dd, J=7.0, 0.6 Hz), 7.59 (1H, dd, J=7.6, 0.6 Hz), 8.25 (1H, d, J=4.7 Hz), 8.31 (1H, d, J=7.8 Hz).
EIMS m/z (relative intensity): 429 (M+), 297 (100).
Elemental analysis: as C22H27N3O2S2; calculated: C, 61.51; H, 6.33; N, 9.78; S, 14.93. found: C, 61.51; H, 6.28; N, 9.64; S, 14.99.
Example 3 (Compound No. 15 in Table)
Production of 6-(benzothiazol-2-ylthio)-N-(2-methylthio-3-pyridyl)hexanamide:
The reaction and the treatment were conducted in the same manner as in Example 1 except that 2-mercaptobenzothiazole was used instead of 2-mercaptobenzoxazole to obtain the desired compound as a colorless needle crystal.
Melting point: 118-119° C.
IR (KBr) cm−1: 3429, 3265, 1654, 1522, 1508.
1H-NMR (CDCl3) δ: 1.57-1.65 (2H, m), 1.83 (2H, quint, J=7.4 Hz), 1.91 (2H, quint, J=7.4 Hz), 2.46 (2H, t, J=7.4 Hz), 2.61 (3H, s), 3.38 (2H, t, J=7.4 Hz), 7.06 (1H, dd, J=8.1, 4.9 Hz), 7.25 (1H, br s), 7.29 (1H, m), 7.41 (1H, m), 7.75 (1H, m), 7.86 (1H, m), 8.25 (1H, d, J=4.9 Hz), 8.29 (1H, d, J=8.1 Hz).
EIMS m/z (relative intensity): 403 (M+), 223 (100).
Elemental analysis: as C18H21N3OS3; calculated: C, 56.55; H, 5.24N, 10.41; S, 23.83. found: C, 56.69; H, 5.30; N, 10.24; S, 23.77.
Example 4 (Compound No. 18 in Table)
Production of 9-(benzothiazol-2-ylthio)-N-(2-methylthio-3-pyridyl)nonanamide:
The reaction and the treatment were conducted in the same manner as in Example 2 except that 2-mercaptobenzothiazole was used instead of 2-mercaptobenzoxazole to obtain the desired compound as a colorless needle crystal.
Melting point: 107-108° C.
IR (KBr) cm−1: 3448, 3256, 2923, 1656, 1525.
1H-NMR (d6-DMSO) δ: 1.24-1.34 (6H, m), 1,36-1.43 (2H, m), 1.54-1.59 (2H, m), 1.69-1.77 (2H, m), 2.26 (2H, t, J=7.4 Hz), 2.40 (3H, s), 3.28 (2H, t, J=7.2 Hz), 7.01 (1H, dd, J=7.8, 4.6 Hz), 7.26 (1H, dt, J=8.1, 1.2 Hz), 7.36 (1H, dt, J=7.3, 1.2 Hz), 7.58 (1H, dd, J=7.8, 1.5 Hz), 7.74 (1H, d, J=8.1 Hz), 7.85 (1H, dd, J=7.3, 1.2 Hz), 8.21 (1H, dd, J=4.6, 1.5 Hz), 8.73 (1H, br s).
EIMS m/z (relative intensity): 445 (M+), 297 (100).
Elemental analysis: as C22H27N3OS3; calculated: C, 59.29; H, 6.11; N, 9.43; S, 21.58. found: C, 59.12; H, 6.02; N, 9.25; S, 21.62.
Example 5 (Compound No. 25 in Table)
Production of 6-(benzimidazol-2-ylthio)-N-(2-methylthio-3-pyridyl)hexanamide:
The reaction and the treatment were conducted in the same manner as in Example 1 except that 2-mercaptobenzimidazole was used instead of 2-mercaptobenzoxazole to obtain the desired compound as a pale yellow needle crystal.
Melting point: 121-123° C.
IR (KBr) cm−1: 3386, 3276, 1658, 1511, 1398.
1H-NMR (CDCl3) δ: 1.52-1.60 (2H, m), 1.74-1.86 (4H, m), 2.42 (2H, t, J=7.2 Hz), 2.60 (3H, s), 3.32 (2H, t, J=7.2 Hz), 7.05 (1H, dd, J=8.1, 4.9 Hz), 7.18-7.19 (2H, m), 7.32 (1H, br s), 7.36 (1H, br s), 7.66 (1H, br s), 8.23-8.26 (2H, m), 9.84 (1H, br s).
EIMS m/z (relative intensity): 386 (M+), 205 (100).
Elemental analysis: as C19H22N4OS2; calculated: C, 59.04; H, 5.74; N, 14.49; S, 16.59. found: C, 59.06; H, 5.76; N, 14.35; S, 16.57.
Example 6 (Compound No. 28 in Table)
Production of 9-(benzimidazol-2-ylthio)-N-(2-methylthio-3-pyridyl)nonanamide:
The reaction and the treatment were conducted in the same manner as in Example 2 except that 2-mercaptobenzimidazole was used instead of 2-mercaptobenzoxazole to obtain the desired compound as a colorless powdery crystal.
IR (KBr) cm−1: 3260, 2929, 2851, 1664, 1519, 1394.
1H-NMR (CDCl3) δ: 1.31-1.47 (6H, m), 1.57-1.61 (2H, m), 1.69-1.79 (4H, m), 2.42 (2H, t, J=7.2 Hz), 2.63 (3H, s), 3.32 (2H, t, J=7.4 Hz), 7.06 (1H, dd, J=8.1, 4.6 Hz), 7.18-7.23 (4H, m), 7.67 (1H, br s), 8.26 (1H, d, J=4.6 Hz), 8.30 (1H, d, J=7.8 Hz), 9.31 (1H, br s).
EIMS m/z (relative intensity): 428 (M+), 164 (100).
Example 7 (Compound No. 158 in Table)
Production of 9-(benzoxazol-2-ylthio)-N-(4-methyl-2-methylthio-3-pyridyl)nonanamide:
The reaction and the treatment were conducted in the same manner as in Example 1 except that 2-chloro-4-methyl-3-nitropyridine was used instead of 2-chloro-3-nitropyridine to obtain 4-methyl-2-methylthio-3-nitropyridine. This nitropyridine (474 mg, 2.57 mmol) was dissolved in a mixed solvent of acetic acid (18 ml) and conc. hydrochloric acid (0.7 ml), and zinc (2.02 g, 30.88 mmol) was added thereto in small portions while being cooled with ice. After the mixture was stirred for 30 minutes, the reaction mixture was filtered, and the filtrate was neutralized with an aqueous solution of sodium hydrogencarbonate, and extracted with methylene chloride. The organic layer was washed with water and then with a saturated aqueous solution of sodium chloride, and dried over sodium sulfate. Subsequently, the solvent was distilled off to obtain 307 mg (yield 77%) of 3-amino-4-methyl-2-methylthiopyridine as a colorless crystal.
Triethylamine (302 mg, 2.99 mmol) was added to a chloroform (4 ml) solution of this aminopyridine (307 mg, 1.99 mmol), and a chloroform (4 ml) solution of 9-bromononanyl chloride (2.99 mmol) was then slowly added thereto dropwise while being cooled with ice. The mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with water, and extracted with ethyl acetate. The organic layer was washed with water and then with a saturated aqueous solution of sodium chloride, and dried over sodium sulfate. Thereafter, the solvent was distilled off, and the resulting crude product was purified through silica gel chromatography (silica gel 125 g, eluent-hexane:ethyl acetate=3:1→2:1) to obtain 261 mg (yield 35%) of 9-bromo-N-(4-methyl-2-methylthio-3-pyridyl)nonanamide as a colorless powdery crystal (melting point: 77 to 78° C.). To a DMF (5 ml) solution of this amide (114 mg, 0.31 mmol) and 2-mercaptobenzoxazole (46 mg, 0.31 mmol) were added 18-crown-6 (8 mg, 0.03 mmol) and potassium carbonate (51 mg, 0.37 mmol), and the mixture was stirred at 80° C. for 2 hours. The reaction mixture was diluted with water, and then extracted with ethyl acetate. The organic layer was washed with water and then with a saturated aqueous solution of sodium chloride, and dried over sodium sulfate. Subsequently, the solvent was distilled off, and the resulting crude product was purified through preparative thin-layer chromatography (eluent-chloroform:methanol=20:1) to obtain 89 mg (yield 66%) of the desired compound as a colorless powdery crystal.
Melting point 91-92° C.
IR (KBr) cm−1: 3433, 3268, 2924, 1518, 1496. 1H-NMR (CDCl3) δ: 1.36-1.53 (8H, m), 1.74-1.88 (4H, m), 2.21 (3H, s), 2.43 (2H, t, J=7.6 Hz), 2.53 (3H, s), 3.32 (2H, t, J=7.3 Hz), 6.63 (1H, br s), 6.90 (1H, d, J=5.1 Hz), 7.22-7.30 (1H, m), 7.43 (1H, dd, J=7.2, 1.4 Hz), 7.60 (1H, dd, J=7.6, 1.4 Hz), 8.24 (1H, d, J=4.9 Hz).
EIMS m/z (relative intensity); 443 (M+, 100).
Elemental analysis: as C23H29N3O2S2; calculated: C, 62.27; H, 6.59; N, 9.47; S, 14.45. found: C, 62.34; H, 6.58; N, 9.33; S, 14.44.
Example 8 (Compound No. 168 in Table)
Production of 9-(benzothiazol-2-ylthio)-N-(4-methyl-2-methylthio-3-pyridyl)nonanamide:
The reaction and the treatment were conducted in the same manner as in Example 7 except that 2-mercaptobenzothiazole was used instead of 2-mercaptobenzoxazole to obtain the desired compound as a colorless powdery crystal.
Melting point: 88-90° C.
IR (KBr) cm−1: 3449, 3271, 2925, 1657, 1425, 997.
1H-NMR (CDCl3) δ: 1.37-1.53 (8H, m), 1.73-1.87 (4H, m), 2.21 (3H, s), 2.43 (2H, t, J=7.6 Hz), 2.53 (3H, s), 3.35 (2H, t, J=7.3 Hz), 6.62 (1H, br s), 6.90 (1H, d, J=5.1 Hz), 7.23-7.31 (1H, m), 7.39-7.43 (1H, m), 7.75 (1H, dd, J=8.1, 0.5 Hz), 7.86 (1H, dd, J=8.1, 0.5 Hz), 8.24 (1H, d, J=5.1 Hz).
Elemental analysis: as C23H29N3OS3; calculated: C, 60.10; H, 6.36N, 9.14. found: C, 59.99; H, 6.36; N, 9.00.
Example 9 (Compound No. 275 in Table)
Production of 6-(benzoxazol-2-ylthio)-N-[2,6-bis(methylthio)-3-pyridyl]hexanamide:
The reaction and the treatment were conducted in the same manner as in Example 1 except that 2,6-dichloro-3-nitropyridine was used instead of 2-chloro-3-nitropyridine. This nitropyridine (800 mg, 3.70 mmol) was dissolved in a mixed solvent of acetic acid (100 ml) and conc. hydrochloric acid (5.6 ml), and zinc (2.90 g, 44.39 mmol) was added thereto in small portions while being cooled with ice. After the mixture was stirred for 30 minutes, the reaction mixture was filtered, and the filtrate was neutralized with an aqueous solution of sodium hydrogencarbonate, and extracted with methylene chloride. The organic layer was washed with water and then with a saturated aqueous solution of sodium chloride, and dried over sodium sulfate. Subsequently, the solvent was distilled off, and the resulting crude product was purified through silica gel chromatography (eluent:hexane:ethyl acetate=4:1) to obtain 301 mg (yield 44%) of 3-amino-2,6-bis(methylthio)pyridine as a pale yellow powdery crystal.
Triethylamine (196 mg, 1.94 mmol) was added to a THF (3 ml) solution of this aminopyridine (301 mg, 1.62 mmol), and a THF (1 ml) solution of 6-bromohexanoyl chloride (345 mg, 1.62 mmol) was then slowly added thereto dropwise while being cooled with ice, and the mixture was stirred at 0° C. for 3 hours. The reaction mixture was diluted with water, and extracted with ethyl acetate. The organic layer was washed with water and then with a saturated aqueous solution of sodium chloride, and dried over magnesium sulfate. Subsequently, the solvent was distilled off, and the resulting crude product was purified through silica gel chromatography (eluent-hexane:ethyl acetate=4:1) to obtain 453 mg (yield 77%) of 6-bromo-N-[2,6-bis(methylthio)-3-pyridyl]hexanamide as a colorless powdery crystal (melting point: 117 to 119° C.). To a DMF (4 ml) solution of this amide (100 mg, 0.28 mmol) and 2-mercaptobenzoxazole (42 mg, 0.28 mmol) were added 18-crown-6 (7 mg, 0.03 mmol) and potassium carbonate (46 mg, 0.33 mmol), and the mixture was stirred at 80° C. for 3 hours. The reaction mixture was diluted with water, and then extracted with ethyl acetate. The organic layer was washed with water and then with a saturated aqueous solution of sodium chloride, and dried over magnesium sulfate. Subsequently, the solvent was distilled off, and the resulting crude product was recrystallized from a mixture of ethyl acetate and hexane to obtain 83 mg (yield 70%) of the desired compound as a colorless powdery crystal.
Melting point: 125-126° C.
IR (KBr) cm−1: 3436, 3253, 2937, 1653, 1519, 1505.
1H-NMR (CDCl3) δ: 1.57-1.65 (2H, m), 1.78-1.86 (2H, m), 1.88-1.95 (2H, m), 2.44 (2H, t, J=7.4 Hz), 2.57 (3H, s), 2.62 (3H, s), 3.33 (2H, t, J=7.3 Hz), 6.93 (1H, d, J=8.4 Hz), 7.02 (1H, br s), 7.21-7.30 (2H, m), 7.43 (1H, dd, J=7.4, 1.7 Hz), 7.59 (1H, dd, J=7.4, 1.7 Hz), 8.01 (1H, d, J=8.4 Hz),
Elemental analysis: as C20H23N3O2S3; calculated: C, 55.40; H, 5.35; N, 9.69. found: C, 55.53; H, 5.38; N, 9.68.
Example 10 (Compound No. 455 in Table)
Production of 6-(benzoxazol-2-ylthio)-N-(6-methyl-2-methylthio-3-pyridyl)hexanamide:
The reaction and the treatment were conducted in the same manner as in Example 1 except that 2-chloro-6-methyl-3-nitropyridine was used instead of 2-chloro-3-nitropyridine to obtain 6-methyl-2-methylthio-3-nitropyridine. This nitropyridine (921 mg, 5.0 mmol) was dissolved in a mixed solvent of acetic acid (40 ml) and conc. hydrochloric acid (1.75 ml), and zinc (3.81 g, 60 mmol) was added thereto in small portions while being cooled with ice. After the mixture was stirred for 30 minutes, the reaction mixture was filtered, and the filtrate was neutralized with an aqueous solution of sodium hydrogencarbonate, and extracted with methylene chloride. The organic layer was washed with water and then with a saturated aqueous solution of sodium chloride, and dried over sodium sulfate. Subsequently, the solvent was distilled off to obtain 685 mg (yield 88%) of 3-amino-6-methyl-2-methylthiopyridine as a yellow oil.
Triethylamine (475 mg, 4.7 mmol) was added to a chloroform (10 ml) solution of this aminopyridine (601 mg, 3.9 mmol), and 6-bromohexanoyl chloride (944 mg, 4.29 mmol) was then slowly added thereto dropwise while being cooled with ice, and the mixture was stirred at room temperature for 12 hours. The reaction mixture was diluted with water, and extracted with methylene chloride. The organic layer was washed with water and then with a saturated aqueous solution of sodium chloride, and dried over magnesium sulfate. Subsequently, the solvent was distilled off, and the resulting crude product was purified through silica gel chromatography (silica gel 50 g, eluent-hexane:ethyl acetate=10:1→5:1) to obtain 773 mg (yield 59%) of 6-bromo-N-(6-methyl-2-methylthio-3-pyridyl)hexanamide as a colorless crystal (melting point: 98 to 99° C.). To a DMF (2 ml) solution of this amide (133 mg, 0.4 mmol) and 2-mercaptobenzoxazole (67 mg, 0.44 mmol) were added 18-crown-6 (11 mg, 0.04 mmol) and potassium carbonate (67 mg, 0.44 mmol), and the mixture was stirred at 80° C. for 90 minutes. The reaction mixture was diluted with water, and extracted with ethyl acetate. The organic layer was washed with water and then with a saturated aqueous solution of sodium chloride, and dried over sodium sulfate. Subsequently, the solvent was distilled off, and the resulting crude product was purified through silica gel chromatography (silica gel 20 g, eluent-hexane:acetone=5:1→5:3) to obtain 125 mg (yield 78%) of the desired compound as a colorless needle crystal.
Melting point: 140-141° C.
IR (KBr) cm−1: 3437, 3267, 1654, 1528, 1506.
1H-NMR (CDCl3) δ: 1.57-1.65 (2H, m), 1.82 (2H, quint, J=7.4 Hz), 1.91 (2H, quint, J=7.4 Hz), 2.44 (2H, t, J=7.4 Hz), 2.48 (3H, s), 2.60 (3H, s), 3.33 (2H, t, J=7.4 Hz), 6.90 (1H, d, J=8.1 Hz), 7.21-7.30 (2H, m), 7.43 (1H, m), 7.59 (1H, m), 8.13 (1H, d, J=8.1 Hz).
EIMS m/z (relative intensity): 401 (M+), 203 (100).
Elemental analysis: as C20H23N3O2S2; calculated: C, 59.82; H, 5.77; N, 10.46. found: C, 59.90; H, 5.84; N, 10.32.
Example 11 (Compound No. 458 in Table)
Production of 9-(benzoxazol-2-ylthio)-N-(6-methyl-2-methylthio-3-pyridyl)nonanamide:
Triethylamine (607 mg, 6.0 mmol) was added to a chloroform (10 ml) solution of 3-amino-6-methyl-2-methylthiopyridine (685 mg, 4.44 mmol), and a chloroform (3 ml) solution of 9-bromononanyl chloride (1,281 mg, 5 mmol) was then slowly added thereto dropwise while being cooled with ice. The mixture was stirred at room temperature for 17 hours. The reaction mixture was diluted with water, and then extracted with ethyl acetate. The organic layer was washed with water and then with a saturated aqueous solution of sodium chloride, and dried over sodium sulfate. Subsequently, the solvent was distilled off, and the resulting crude product was purified through silica gel chromatography (silica gel 75 g, eluent-hexane:ethyl acetate=10:1→4:1) to obtain 433 mg (yield 27%) of 9-bromo-N-(6-methyl-2-methylthio-3-pyridyl)nonanamide as a colorless crystal (melting point: 80 to 82° C.).
To a DMF (1.5 ml) solution of this amide (131 mg, 0.35 mmol) and 2-mercaptobenzoxazole (58 mg, 0.385 mmol) were added 18-crown-6 (9 mg, 0.035 mmol) and potassium carbonate (58 mg, 0.42 mmol), and the mixture was stirred at 80° C. for 3 hours. The reaction mixture was diluted with water, and then extracted with ethyl acetate. The organic layer was washed with water and then with a saturated aqueous solution of sodium chloride, and dried over sodium sulfate. Subsequently, the solvent was distilled off, and the resulting crude product was purified through silica gel chromatography (silica gel 30 g, eluent-hexane:ethyl acetate=4:1→3:1) to obtain 123 mg (yield 79%) of the desired compound as a colorless needle crystal.
Melting point: 99-100° C.
IR (KBr) cm−1: 3421, 3235, 2924, 1655, 1528, 1497, 1455.
1H-NMR (CDCl3) δ: 1.32-1.42 (6H, m), 1.43-1.51 (2H, m), 1.70-1.78 (2H, m), 1.83 (2H, quint, J=7.4 Hz), 2.40 (2H, t, J=7.4 Hz), 2.48 (3H, s), 2.61 (3H, s), 3.31 (2H, t, J=7.4 Hz), 6.90 (1H, d, J=8.1 Hz), 7.21-7.30 (3H, m), 7.43 (1H, m), 7.60 (1H, m), 8.15 (1H, d, J=8.1 Hz).
EIMS m/z (relative intensity): 443 (M+), 311 (100).
Example 12 (Compound No. 465 in Table)
Production of 6-(benzothiazol-2-ylthio)-N-(6-methyl-2-methylthio-3-pyridyl)hexanamide:
The reaction and the treatment were conducted in the same manner as in Example 10 except that 2-mercaptobenzothiazole was used instead of 2-mercaptobenzoxazole to obtain the desired compound as a colorless needle crystal.
Melting point: 122-123° C.
IR (KBr) cm−1: 3438, 3290, 1656, 1515, 1431.
1H-NMR (CDCl3) δ: 1.57-1.65 (2H, m), 1.82 (2H, quint, J=7.4 Hz), 1.90 (2H, quint, J=7.4 Hz), 2.44 (2H, t, J=7.4 Hz), 2.48 (3H, s), 2.60 (3H, s), 3.37 (2H, t, J=7.4 Hz), 6.90 (1H, d, J=8.3 Hz), 7.22(1H, br s) 7.29 (1H, m), 7.41 (1H, m), 7.75 (1H, m), 7.86 (1H, m), 8.13 (1H, J=8.3 Hz).
EIMS m/z (relative intensity): 417 (M+), 168 (100).
Elemental analysis: as C20H23N3OS3; calculated: C, 57.52; H, 5.55; N, 10.06. found: C, 57.65; H, 5.63; N, 9.97.
Example 13 (Compound No. 468 in Table)
Production of 9-(benzothiazol-2-ylthio)-N-(6-methyl-2-methylthio-3-pyridyl)nonanamide:
The reaction and the treatment were conducted in the same manner as in Example 11 except that 2-mercaptobenzothiazole was used instead of 2-mercaptobenzoxazole to obtain the desired compound as a colorless needle crystal.
Melting point: 104-105° C.
IR (KBr) cm−1: 3280, 2924, 1662, 1527, 1428.
1H-NMR (CDCl3) δ: 1.32-1.41 (6H, m), 1.43-1.51 (2H, m), 1.70-1.77 (2H, m), 1.82 (2H, quint, J=7.4 Hz), 2.40 (2H, t, J=7.4 Hz), 2.48 (3H, s), 2.61 (3H, s), 3.34 (2H, t, J=7.4 Hz), 6.90 (1H, d, J=8.1 Hz), 7.22 (1H, br s) 7.29 (1H, m), 7.41 (1H, m), 7.76 (1H, m), 7.86 (1H, m), 8.15 (1H, d, J=8.1 Hz),
EIMS m/z (relative intensity): 459 (M+), 293 (100).
Elemental analysis: as C23H29N3OS3; calculated: C, 60.10; H, 6.36; N, 9.14. found: C, 60.17; H, 6.40; N, 9.11.
Example 14 (Compound No. 475 in Table)
Production of 6-(benzimidazol-2-ylthio)-N-(6-methyl-2-methylthio-3-pyridyl)hexanamide:
The reaction and the treatment were conducted in the same manner as in Example 10 except that 2-mercaptobenzimidazole was used instead of 2-mercaptobenzoxazole to obtain the desired compound as a colorless crystal.
Melting point: 138-140° C.
IR (KBr) cm−1: 3385, 3244, 1668, 1509, 1440.
1H-NMR (CDCl3) δ: 1.53-1.61 (2H, m), 1.78 (2H, quint, J=7.6 Hz), 1.82 (2H, quint, J=7.6 Hz), 2.41 (2H, t, J=7.6 Hz), 2.48 (3H, s), 2.59 (3H, s), 3.31 (2H, t, J=7.6 Hz), 6.88 (1H, d, J=8.3 Hz), 7.16-7.23 (2H, m), 7.31-7.32 (2H, m), 7.67 (1H, m), 8.08 (1H, d, J=8.3 Hz), 9.72 (1H, br s).
EIMS m/z (relative intensity): 400 (M+), 164 (100).
Elemental analysis: as C20H24N4OS2; calculated: C, 59.97; H, 6.04; N, 13.99. found: C, 60.08; H, 6.08; N, 13.94.
Example 15 (Compound No. 478 in Table)
Production of 9-(benzimidazol-2-ylthio)-N-(6-methyl-2-methylthio-3-pyridyl)nonanamide:
The reaction and the treatment were conducted in the same manner as in Example 11 except that 2-mercaptobenzimidazole was used instead of 2-mercaptobenzoxazole to obtain the desired compound as a colorless needle crystal.
Melting point: 73-75° C.
IR (KBr) cm−1: 3254, 2926, 1663, 1515, 1438.
1H-NMR (CDCl3) δ: 1.27-1.43 (8H, m), 1.68-1.78 (4H, m), 2.40 (2H, t, J=7.4 Hz), 2.48 (3H, s), 2.60 (3H, s), 3.31 (2H, t, J=7.4 Hz), 6.89 (1H, d, J=8.1 Hz), 7.17-7.20 (2H, m), 7.31-7.33 (2H, m), 7.67 (1H, m), 8.13 (1H, d, J=8.1 Hz), 9.69 (1H, br s).
Example 16 (Compound No. 781 in Table)
Production of 2-(benzoxazol-2-ylthio)-N-[2,4-bis(methylthio)-6-methyl-3-pyridyl]acetamide:
Triethylamine (274 mg, 2.71 mmol) was added to a chloroform (10 ml) solution of 3-amino-2,4-bis(methylthio)-6-methylpyridine (492 mg, 2.46 mmol), and bromoacetyl bromide (521 mg, 2.58 mmol) was then slowly added thereto dropwise while being cooled with ice. The mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with water, and then extracted with methylene chloride. The organic layer was washed with 1N hydrochloric acid, water, an aqueous solution of sodium hydrogencarbonate, water and a saturated aqueous solution of sodium chloride in this order, and dried over sodium sulfate. Subsequently, the solvent was distilled off, and the resulting crude product was purified through silica gel chromatography (silica gel 25 g, eluent-hexane:acetone=7:1→5:1→3:1) to obtain 100 mg (yield 13%) of 2-bromo-N-[2,4-bis(methylthio)-6-methyl-3-pyridyl]acetamide as a colorless crystal (melting point: 171 to 172° C.).
Potassium carbonate (46 mg, 0.33 mmol) was added to an acetonitrile (5 ml) solution of this amide (96 mg, 0.3 mmol) and 2-mercaptobenzoxazole (45 mg, 0.3 mmol), and the mixture was stirred at room temperature for 90 minutes. The reaction mixture was diluted with water, and then extracted with ethyl acetate. The organic layer was washed with water and then with a saturated aqueous solution of sodium chloride, and dried over sodium sulfate. Subsequently, the solvent was distilled off, and the resulting crude product was purified through silica gel chromatography (silica gel 10 g, eluent-hexane:acetone=5:2) to obtain 88 mg (yield 75%) of the desired compound as a colorless crystal.
Melting point: 203-205° C.
IR (KBr) cm−1: 3437, 3238, 1669, 1509, 1454.
1H-NMR (CDCl3) δ: 2.31 (3H, s), 2.41 (3H, s), 2.46 (3H, s), 4.10 (2H, s), 6.61 (1H, s), 7.28-7.33 (2H, m), 7.49 (1H, m), 7.60 (1H, m), 8.77 (1H, br s).
EIMS m/z (relative intensity): 391 (M+), 227 (100).
Elemental analysis: as C17H17N3O2S3; calculated: C, 52.15; H, 4.38; N, 10.73. found: C, 52.14; H, 4.44; N, 10.57.
Example 17 (Compound No. 783 in Table)
Production of 4-(benzoxazol-2-ylthio)-N-[2,4-bis(methylthio)-6-methyl-3-pyridyl]butanamide:
Triethylamine (206 mg, 2.04 mmol) was added to a THF (6 ml) solution of 3-amino-2,4-bis(methylthio)-6-methylpyridine (341 mg, 1.70 mmol), and 4-bromobutanoyl chloride (379 mg, 2.04 mmol) was then slowly added thereto dropwise while being cooled with ice. The mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with water, and then extracted with ethyl acetate. The organic layer was washed with water and then with a saturated aqueous solution of sodium chloride, and dried over sodium sulfate. Subsequently, the solvent was distilled off, and the resulting crude product was purified through silica gel chromatography (silica gel 75 g, eluent-hexane:acetone=5:1→3:1) to obtain 390 mg (yield 66%) of 4-bromo-N-[2,4-bis(methylthio)-6-methyl-3-pyridyl]butanamide as a colorless crystal (melting point: 139 to 140° C.).
To a DMF (2 ml) solution of this amide (105 mg, 0.3 mmol) and 2-mercaptobenzoxazole (50 mg, 0.33 mmol) were added 18-crown-6 (8 mg, 0.03 mmol) and potassium carbonate (50 mg, 0.36 mmol), and the mixture was stirred at 80° C. for 3 hours. The reaction mixture was diluted with water, and then extracted with ethyl acetate. The organic layer was washed with water and then with a saturated aqueous solution of sodium chloride, and dried over sodium sulfate. Subsequently, the solvent was distilled off, and the resulting crude product was purified through preparative thin-layer chromatography (eluent-hexane:ethyl acetate=3:2, eluted twice) to obtain 67 mg (yield 53%) of the desired compound as a colorless needle crystal.
Melting point: 149-150° C.
IR (KBr) cm−1: 3437, 3248, 1667, 1503, 1455.
1H-NMR (d6-DMSO) δ: 2.13 (2H, quint, J=7.2 Hz), 2.37 (3H, s), 2.38 (3H, s), 2.44 (3H, s), 2.49 (2H, t, J=7.2 Hz), 3.43 (2H, t, J=7.2 Hz), 6.88 (1H, s), 7.30-7.37 (2H, m), 7.64-7.68 (2H, m), 9.45 (1H, br s).
EIMS m/z (relative intensity): 419 (M+, 100).
Elemental analysis: as C19H21N3O2S3; calculated: C, 54.39; H, 5.04; N, 10.01. found: C, 54.58; H, 5.08; N, 9.98.
Example 18 (Compound No. 785 in Table)
Production of 6-(benzoxazol-2-ylthio)-N-[2,4-bis(methylthio)-6-methyl-3-pyridyl]hexanamide:
The reaction and the treatment were conducted in the same manner as in Example 17 except that 6-bromohexanoyl chloride was used instead of 4-bromobutanoyl chloride to obtain the desired compound as a colorless powdery crystal.
Melting point: 120-121° C.
IR (KBr) cm−1: 3433, 3235, 1662, 1502, 1455.
1H-NMR (d6-DMSO) δ: 1.44-1.54 (2H, m), 1.58-1.68 (2H, m), 1.72-1.82 (2H, m), 2.18-2.27 (2H, m), 2.32 (3H, s), 2.34 (3H, s), 2.37 (3H, s), 3.27 (2H, t, J=7.2 Hz), 6.78 (1H, s), 7.19-7.26 (2H, m), 7.47-7.53 (2H, m), 8.74 (1H, br s).
EIMS m/z (relative intensity): 446 (M+−1), 200 (100).
Elemental analysis: as C21H25N3O2S3; calculated: C, 56.35; H, 5.63; N, 9.39; S, 21.49. found: C, 56.42; H, 5.62; N, 9.26; S, 21.39.
Example 19 (Compound No. 788 in Table)
Production of 9-(benzoxazol-2-ylthio)-N-[2,4-bis(methylthio)-6-methyl-3-pyridyl]nonanamide:
The reaction and the treatment were conducted in the same manner as in Example 17 except that 9-bromononanoyl chloride was used instead of 4-bromobutanoyl chloride to obtain the desired compound as a colorless powdery crystal.
Melting point; 123-124° C.
IR (KBr) cm−1: 3461, 3246, 1671, 1504, 1454.
1H-NMR (d6-DMSO) δ: 1.26-1.46 (8H, m), 1.53-1.63 (2H, m), 1.72-1.83 (2H, m), 2.24 (2H, t, J=7.3 Hz), 2.37 (3H, s), 2.38 (3H, s), 2.43 (3H, s), 3.31-3.41 (2H, m), 6.86 (1H, s), 7.27-7.34 (2H, m), 7.58-7.66 (2H, m), 9.26 (1H, br s).
EIMS m/z (relative intensity): 489 (M+, 100).
Elemental analysis: as C24H31N3O2S3; calculated: C, 58.86; H, 6.38; N, 8.58; S, 19.64. found: C, 58.94; H, 6.37; N, 8.44, S, 19.55.
Example 20 (Compound No. 793 in Table)
Production of 4-(benzothiazol-2-ylthio)-N-[2,4-bis(methylthio)-6-methyl-3-pyridyl]butanamide:
The reaction and the treatment were conducted in the same manner as in Example 17 except that 2-mercaptobenzothiazole was used instead of 2-mercaptobenzoxazole to obtain the desired compound as a colorless crystal.
Melting point: 131-133° C.
IR (KBr) cm−1: 3435, 3250, 1665, 1509, 1428.
1H-NMR (d6-DMSO) δ: 2.11 (2H, quint, J=7.2 Hz), 2.37 (3H, s), 2.38 (3H, s), 2.44 (3H, s), 2.49 (2H, t, J=7.2 Hz), 3.46 (2H, t, J=7.2 Hz), 6.88 (1H, s), 7.37 (1H, m), 7.47 (1H, m), 7.87 (1H, m), 8.02 (1H, m), 9.45 (1H, s).
EIMS m/z (relative intensity): 435 (M+), 168 (100).
Elemental analysis: as C19H21N3OS4; calculated: C, 52.39; H, 4.86; N, 9.65. found: C, 52.39; H, 4.84; N, 9.56.
Example 21 (Compound No. 795 in Table)
Production of 6-(benzothiazol-2-ylthio)-N-[2,4-bis(methylthio)-6-methyl-3-pyridyl]hexanamide:
The reaction and the treatment were conducted in the same manner as in Example 18 except that 2-mercaptobenzothiazole was used instead of 2-mercaptobenzoxazole to obtain the desired compound as a pale yellow crystal.
Melting point: 123-125° C.
IR (KBr) cm−1: 3433, 3258, 2923, 1661, 1429.
1H-NMR (d6-DMSO) δ: 1.49-1.58 (6H, m), 1.67 (2H, quint, J=7.2 Hz), 1.83 (2H, quint, J=7.2 Hz), 2.29 (2H, t, J=7.2 Hz), 2.38 (3H, s), 2.39 (3H, s), 2.45 (3H, s), 3.38 (2H, t, J=7.2 Hz), 6.68 (1H, s), 7.36 (1H, td, J=8.0, 1.0 Hz), 7.46 (1H, td, J=8.0, 1.0 Hz), 7.86 (1H, dd, J=8.0, 1.0 Hz), 8.01 (1H, br d, J=8.0 Hz), 9.31 (1H, s).
EIMS m/z (relative intensity): 463 (M+), 201 (100).
Elemental analysis: as C21H25N3OS4; calculated: C, 54.40; H, 5.43; N, 9.06; S, 27.66. found: C, 54.42, H, 5.45; N, 8.79; S, 27.68.
Example 22 (Compound No. 798 in Table)
Production of 9-(benzothiazol-2-ylthio)-N-[2,4-bis(methylthio)-6-methyl-3-pyridyl]nonanamide:
The reaction and the treatment were conducted in the same manner as in Example 19 except that 2-mercaptobenzothiazole was used instead of 2-mercaptobenzoxazole to obtain the desired compound as a colorless powdery crystal.
Melting point: 126-127° C.
IR (KBr) cm−1: 3440, 3252, 2924, 1661, 1430.
1H-NMR (d6-DMSO) δ: 1.31-1.52 (8H, m), 1.59-1.68 (2H, m), 1.77-1.85 (2H, m), 2.23-2.33 (2H, m), 2.40 (3H, s), 2.42 (3H, s), 2.45 (3H, s), 3.36 (2H, t, J=7.2 Hz), 6.86 (1H, s), 7.34 (1H, dt, J=7.8, 1.2 Hz), 7.44 (1H, dt, J=7.8, 1.2 Hz), 7.83 (1H, d, J=8.3 Hz). 7.93 (1H, dt, J=7.8, 0.6 Hz), 8.78 (1H, br s).
EIMS m/z (relative intensity): 504 (M+−1), 200 (100).
Elemental analysis: as C24H31N3OS4; calculated: C, 57.00; H, 6.18; N, 8.31; S, 25.36. found: C, 57.08; H, 6.17; N, 8.15; S, 25.41.
Example 23 (Compound No. 803 in Table)
Production of 4-(benzimidazol-2-ylthio)-N-[2,4-bis(methylthio)-6-methyl-3-pyridyl]butanamide:
The reaction and the treatment were conducted in the same manner as in Example 17 except that 2-mercaptobenzimidazole was used instead of 2-mercaptobenzoxazole to obtain the desired compound as a pale yellow needle crystal.
Melting point: 177-179° C.
IR (KBr) cm−1: 3421, 3147, 1659, 1645, 1438.
1H-NMR (d6-DMSO) δ: 2.06 (2H, quint, J=7.2 Hz), 2.38 (3H, s), 2.39 (3H, s), 2.44 (3H, s), 2.46 (2H, t, J=7.2 Hz), 3.36 (2H, t, J=7.2 Hz), 6.88 (1H, s), 7.09-7.13 (2H, m), 7.34-7.52 (2H, m), 9.48 (1H, s), 12.54 (1H, br s).
EIMS m/z (relative intensity): 418 (M+), 150 (100).
Example 24 (Compound No. 805 in Table)
Production of 6-(benzimidazol-2-ylthio)-N-[2,4-bis(methylthio)-6-methyl-3-pyridyl]hexanamide:
The reaction and the treatment were conducted in the same manner as in Example 18 except that 2-mercaptobenzimidazole was used instead of 2-mercaptobenzoxazole to obtain the desired compound as a colorless crystal.
Melting point: 139-141° C.
IR (KBr) cm−1: 3433, 3244, 2924, 1659, 1437.
1H-NMR (d6-DMSO) δ: 1.47-1.56 (2H, m), 1.65 (2H, quint, J=7.2 Hz), 1.76 (2H, quint, J=7.2 Hz), 2.28 (2H, t, J=7.2 Hz), 2.38 (3H, s), 2.39 (3H, s), 2.44 (3H, s), 3.29 (2H, t, J=7.2 Hz), 6.68 (1H, s), 7.08-7.13 (2H, m), 7.36 (1H, m), 7.50 (1H, m), 9.30 (1H, s), 12.50 (1H, br s).
EIMS m/z (relative intensity): 446 (M+), 200 (100).
Example 25 (Compound No. 808 in Table)
Production of 9-(benzimidazol-2-ylthio)-N-[2,4-bis(methylthio)-6-methyl-3-pyridyl]nonanamide:
The reaction and the treatment were conducted in the same manner as in Example 19 except that 2-mercaptobenzimidazole was used instead of 2-mercaptobenzoxazole to obtain the desired compound as a colorless powdery crystal.
IR (KBr) cm−1: 3146, 2925, 2854, 1660, 1523, 1437.
1H-NMR (d6-DMSO) δ: 1.25-1.44 (8H, m), 1.53-1.61 (2H, m), 1.65-1.74 (2H, m), 2.24 (2H, t, J=7.3 Hz), 2.37 (3H, s), 2.38 (3H, s), 2.43 (3H, s), 3.26 (2H, t, J=7.1 Hz), 6.86 (1H, s), 7.07-7.12 (2H, m), 7.32-7.37 (1H, m), 7.46-7.54 (1H, m), 9.26 (1H, s).
EIMS m/z (relative intensity): 488 (M+), 150 (100).
Example 26 (Compound No. 811 in Table)
Production of 2-(benzoxazol-2-ylthio)-N-[2,4-bis(ethylthio)-6-methyl-3-pyridyl]acetamide:
Ethanethiol (1.55 g, 25 mmol) was added dropwise to an ethanol (50 ml) solution of sodium ethoxide (1.27 g, 25 mmol) while being cooled with ice, and the mixture was stirred for 30 minutes. While being cooled with ice, a DMF (40 ml) solution of 2,4-dichloro-6-methyl-3-nitropyridine (2.1 g, 10 mmol) was slowly added thereto dropwise. After the mixture was stirred for 2 hours, the reaction mixture was extracted with ethyl acetate. The organic layer was washed with water and then with a saturated aqueous solution of sodium chloride, and dried over sodium sulfate. Subsequently, the solvent was distilled off to obtain 2.45 g (yield 95%) of 2,4-bis(ethylthio)-6-methyl-3-nitropyridine as a yellow needle crystal.
This nitropyridine (775 mg, 3 mmol) was dissolved in a mixed solvent of acetic acid (30 ml) and conc. hydrochloric acid (1.5 ml), and zinc (4 g, 60 mmol) was added thereto in small portions while being cooled with ice. After the mixture was stirred for 10 minutes, the reaction mixture was filtered, and the filtrate was neutralized with a sodium hydroxide aqueous solution, and extracted with ethyl acetate. The organic layer was washed with water and then with a saturated aqueous solution of sodium chloride, and dried over sodium sulfate. Subsequently, the solvent was distilled off to obtain 590 mg (yield 86%) of 3-amino-2,6-bis(ethylthio)-6-methylpyridine as a yellow oil. Triethylamine (304 mg, 3 mmol) was added to a THF (10 ml) solution of this aminopyridine (590 mg, 2.6 mmol), and bromoacetyl bromide (606 mg, 3 mmol) was then slowly added thereto dropwise while being cooled with ice. The mixture was stirred at room temperature for 1 hour. The reaction mixture was filtered, and the filtrate was concentrated. Then, the residue was purified through silica gel chromatography (silica gel 60 g, eluent-hexane:acetone=10:1→5:1) to obtain 410 mg (yield 45%) of 2-bromo-N-[2,4-bis(ethylthio)-6-methyl-3-pyridyl]acetamide as a light brown needle crystal. Potassium carbonate (46 mg, 0.33 mmol) was added to an acetonitrile (3 ml) solution of this amide (105 mg, 0.3 mmol) and 2-mercaptobenzoxazole (45 mg, 0.3 mmol), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was extracted with ethyl acetate. The organic layer was washed with water and then with a saturated aqueous solution of sodium chloride, and dried over magnesium sulfate. Subsequently, the solvent was distilled off, and the resulting crude product was purified through preparative thin-layer chromatography (eluent-hexane:ethyl acetate=3:1) to obtain 70 mg (yield 56%) of the desired compound as a colorless needle crystal.
Melting point: 143-145° C.
IR (KBr) cm−1: 3429, 3224, 1673, 1509, 1454.
1H-NMR (CDCl3) δ: 1.17 (3H, t, J=7.3 Hz), 1.20 (3H, t, J=7.5 Hz), 2.43 (3H, s), 2.81 (2H, q, J=7.3 Hz), 3.04 (2H, q, J=7.5 Hz), 4.11 (2H, s), 6.63 (1H, s), 7.25-7.33 (2H, m), 7.48 (1H, m), 7.61 (1H, m), 8.63 (1H, br s).
EIMS m/z (relative intensity): 419 (M+), 268 (100).
Elemental analysis: as C19H21N3O2S3; calculated: C, 54.39; H, 5.04; N, 10.01. found: C, 54.39; H, 5.05; N, 10.00.
Example 27 (Compound No. 815 in Table)
Production of 6-(benzoxazol-2-ylthio)-N-[2,4-bis(ethylthio)-6-methyl-3-pyridyl]hexanamide:
The reaction and the treatment were conducted in the same manner as in Example 26 except that 6-bromohexanoyl chloride was used instead of bromoacetyl bromide to obtain 6-bromo-N-[2,4-bis(ethylthio)-6-methyl-3-pyridyl]hexanamide. To a DMF (2 ml) solution of this amide (122 mg, 0.3 mmol) and 2-mercaptobenzoxazole (45 mg, 0.3 mmol) were added potassium carbonate (46 mg, 0.33 mmol) and 18-crown-6 (8 mg, 0.03 mmol), and the mixture was stirred at 80° C. for 1.5 hours. The reaction mixture was allowed to cool, and then extracted with ethyl acetate. The organic layer was washed with water and then with a saturated aqueous solution of sodium chloride, and dried over sodium sulfate. Subsequently, the solvent was distilled off, and the resulting residue was purified through preparative thin-layer chromatography (eluent-hexane:acetone=5:2) to obtain 65 mg (yield 46%) of the desired compound as a light brown needle crystal.
Melting point: 100-103° C.
IR (KBr) cm−1: 3233, 2928, 1668, 1504, 1455.
1H-NMR (d6-DMSO) δ: 1.26 (3H, t, J=7.3 Hz), 1.27 (3H, t, J=7.3 Hz), 1.58 (2H, m), 1.70 (2H, m), 1.85 (2H, m), 2.32 (2H, m), 2.43 (3H, s), 2.94 (2H, q, J=7.3 Hz), 3.07 (2H, q, J=7.3 Hz), 3.35 (2H, t, J=7.3 Hz), 6.89 (1H, s), 7.26-7.34 (2H, m), 7.54-7.62 (2H, m), 8.77 (1H, br s).
EIMS m/z (relative intensity); 475 (M+, 100).
Elemental analysis: as C23H29N3O2S3; calculated: C, 58.08; H, 6.14; N, 8.83; S, 20.22. found: C, 58.07; H, 6.13; N, 8.66; S, 20.27.
Example 28 (Compound No. 818 in Table)
Production of 9-(benzoxazol-2-ylthio)-N-[2,4-bis(ethylthio)-6-methyl-3-pyridyl]nonanamide:
The reaction and the treatment were conducted in the same manner as in Example 27 except that 9-bromononanoyl chloride was used instead of 6-bromohexanoyl bromide to obtain the desired compound as a colorless needle crystal.
Melting point: 84-87° C.
IR (KBr) cm−1: 3252, 2923, 1665, 1501, 1455.
1H-NMR (d6-DMSO) δ: 1.26 (3H, t, J=7.3 Hz), 1.27 (3H, t, J=7.3 Hz), 1.28-1.52 (8H, m), 1.63 (2H, m), 1.82 (2H, quint, J=7.2 Hz), 2.26 (2H, m), 2.43 (3H, s), 2.94 (2H, q, J=7.3 Hz), 3.07 (2H, q, J=7.3 Hz), 3.34 (2H, t, J=7.2 Hz), 6.88 (1H, s), 7.26-7.34 (2H, m), 7.54-7.62 (2H, m), 8.72 (1H, br s).
EIMS m/z (relative intensity): 517 (M+), 367 (100).
Elemental analysis: as C26H35N3O2S3; calculated: C, 60.31; H, 6.81; N, 8.12. found: C, 60.52; H, 6.85; N, 7.85.
Example 29 (Compound No. 821 in Table)
Production of 2-(benzothiazol-2-ylthio)-N-[2,4-bis(ethylthio)-6-methyl-3-pyridyl]acetamide;
The reaction and the treatment were conducted in the same manner as in Example 26 except that 2-mercaptobenzothiazole was used instead of 2-mercaptobenzoxazole to obtain the desired compound as a colorless needle crystal.
Melting point: 119-120° C.
IR (KBr) cm−1: 3453, 3254, 1672, 1510, 1428.
1H-NMR (CDCl3) δ: 1.20 (3H, t, J=7.4 Hz), 1.22 (3H, t, J=7.4 Hz), 2.42 (3H, s), 2.82 (2H, q, J=7.4 Hz), 3.06 (2H, q, J=7.4 Hz), 4.18 (2H, s), 6.63 (1H, s), 7.33 (1H, m), 7.42 (1H, m), 7.77 (1H, m), 7.91 (1H, m), 8.95 (1H, br s).
EIMS m/z (relative intensity): 435 (M+), 148 (100).
Elemental analysis: as C19H21N3OS4; calculated: C, 52.39; H, 4.86; N, 9.65. found: C, 52.40; H, 4.86; N, 9.53.
Example 30 (Compound No. 825 in Table)
Production of 6-(benzothiazol-2-ylthio)-N-[2,4-bis(ethylthio)-6-methyl-3-pyridyl]hexanamide:
The reaction and the treatment were conducted in the same manner as in Example 27 except that 2-mercaptobenzothiazole was used instead of 2-mercaptobenzoxazole to obtain the desired compound as a colorless needle crystal.
Melting point: 81-83° C.
IR (KBr) cm−1: 3150, 2927, 1647, 1524, 1428.
1H-NMR (d6-DMSO) δ: 1.25 (3H, t, J=7.3 Hz), 1.26 (3H, t, J=7.3 Hz), 1.57 (2H, m), 1.69 (2H, m), 1.84 (2H, m), 2.29 (2H, m), 2.42 (3H, s), 2.93 (2H, q, J=7.3 Hz), 3.05 (2H, q, J=7.3 Hz), 3.36 (2H, t, J=7.3 Hz), 6.87 (1H, s), 7.33 (1H, m), 7.43 (1H, m), 7.82 (1H, m), 7.92 (1H, m), 8.77 (1H, br s).
EIMS m/z (relative intensity): 491 (M+), 168 (100).
Elemental analysis: as C23H29N3OS4; calculated: C, 56.18; H, 5.94; N, 8.55; S, 26.08. found: C, 56.19; H, 5.91; N, 8.43; S, 26.06.
Example 31 (Compound No. 828 in Table)
Production of 9-(benzothiazol-2-ylthio)-N-[2,4-bis(ethylthio)-6-methyl-3-pyridyl]nonanamide:
The reaction and the treatment were conducted in the same manner as in Example 28 except that 2-mercaptobenzothiazole was used instead of 2-mercaptobenzoxazole to obtain the desired compound as a colorless needle crystal.
Melting point: 88-92° C.
IR (KBr) cm−1: 3433, 3241, 2928, 1668, 1510.
1H-NMR (d6-DMSO) δ: 1.25 (3H, t, J=7.3 Hz), 1.26 (3H, t, J=7.3 Hz), 1.28-1.54 (8H, m), 1.62 (2H, m), 1.80 (2H, quint, J=7.2 Hz), 2.24 (2H, m), 2.42 (3H, s), 2.93 (2H, q, J=7.3 Hz), 3.05 (2H, q, J=7.3 Hz), 3.35 (2H, t, J=7.2 Hz), 6.87 (1H, s), 7.33 (1H, m), 7.43 (1H, m), 7.81 (1H, m), 7.92 (1H, m), 8.72 (1H, br s).
Example 32 (Compound No. 831 in Table)
Production of 2-(benzimidazol-2-ylthio)-N-[2,4-bis(ethylthio)-6-methyl-3-pyridyl]acetamide:
The reaction and the treatment were conducted in the same manner as in Example 26 except that 2-mercaptobenzimidazole was used instead of 2-mercaptobenzoxazole to obtain the desired compound as a colorless needle crystal.
Melting point: 182-183° C.
IR (KBr) cm−1: 3148, 2928, 1674, 1524, 1412.
1H-NMR (d6-DMSO) δ: 1.21 (3H, t, J=7.3 Hz), 1.21 (3H, t, J=7.3 Hz), 2.41 (3H, s), 2.90 (2H, q, J=7.3 Hz), 3.03 (2H, q, J=7.3 Hz), 4.15 (2H, br s), 6.87 (1H, s), 7.08-7.12 (2H, m), 7.39-7.44 (2H, m).
EIMS m/z (relative intensity): 418 (M+), 357 (100).
Elemental analysis: as C19H22N4OS3; calculated: C, 54.52; H, 5.30; N, 13.38. found: C, 54.44; H, 5.30; N, 13.16.
Example 33 Compound No. 835 in Table)
Production of 6-(benzimidazol-2-ylthio)-N-[2,4-bis(ethylthio)-6-methyl-3-pyridyl]hexanamide:
The reaction and the treatment were conducted in the same manner as in Example 27 except that 2-mercaptobenzimidazole was used instead of 2-mercaptobenzoxazole to obtain the desired compound as a colorless needle crystal.
Melting point: 139-142° C.
IR (KBr) cm−1: 3433, 3143, 2928, 1660, 1510.
1H-NMR (CDCl3) δ: 1.25 (3H, t, J=7.3 Hz), 1.26 (3H, t, J=7.3 Hz), 1.54 (2H, m), 1.68 (2H, m), 1.77 (2H, m), 2.28 (2H, m), 2.42 (3H, s), 2.92 (2H, q, J=7.3 Hz), 3.05 (2H, q, J=7.3 Hz), 3.27 (2H, t, J=7.2 Hz), 6.87 (1H, s), 7.05-7.11 (2H, m), 7.27-7.52 (2H, m), 8.75 (1H, br s), 12.05 (1H, br s).
Example 34 (Compound No. 838 in Table)
Production of 9-(benzimidazol-2-ylthio)-N-[2,4-bis(ethylthio)-6-methyl-3-pyridyl]nonanamide:
The reaction and the treatment were conducted in the same manner as in Example 28 except that 2-mercaptobenzimidazole was used instead of 2-mercaptobenzoxazole to obtain the desired compound as a colorless needle crystal.
Melting point: 76-78° C.
IR (KBr) cm−1: 3104, 2928, 2854, 1658, 1526.
1H-NMR (d6-DMSO) δ: 1.25 (3H, t, J=7.3 Hz), 1.26 (3H, t, J=7.3 Hz), 1.28-1.49 (8H, m), 1.61 (2H, m), 1.73 (2H, quint, J=7.2 Hz), 2.24 (2H, m), 2.42 (3H, s), 2.92 (2H, q, J=7.3 Hz), 3.05 (2H, q, J=7.3 Hz), 3.26 (2H, t, J=7.2 Hz), 6.87 (1H, s), 7.05-7.10 (2H, m), 7.24-7.54 (2H, m), 8.71 (1H, br s), 12.05 (1H, br s).
Example 35 (Compound No. 841 in Table)
Production of 2-(benzoxazol-2-ylthio)-N-[2,4-bis(isopropylthio)-6-methyl-3-pyridyl]acetamide:
To a 2-propanol (50 ml) solution of sodium isopropoxide (2.05 g, 25 mmol) was added dropwise 2-propanethiol (1.90, 25 mmol) while being cooled with ice, and the mixtrue was stirred for 30 minutes. While being cooled with ice, a DMF (40 ml) solution of 2,4-dichloro-6-methyl-3-nitropyridine (2.07 g, 10 mmol) was slowly added thereto dropwise. After the mixture was stirred for 2 hours, the reaction mixture was extracted with ethyl acetate. The organic layer was washed with water and then with a saturated aqueous solution of sodium chloride, and dried over sodium sulfate. Subsequently, the solvent was distilled off to obtain 2.77 g (yield 97%) of 2,4-bis(isopropylthio)-6-methyl-3-nitropyridine as a yellow needle crystal.
This nitropyridine (1.08 g, 3.77 mmol) was dissolved in a mixed solvent of acetic acid (35 ml) and conc. hydrochloric acid (1.6 ml), and zinc (2.96 g, 45.25 mmol) was added thereto in small portions while being cooled with ice. After the mixture was stirred for 1 hour, the reaction mixture was filtered, and the filtrate was neutralized with an aqueous solution of sodium hydrogencarbonate, and extracted with chloroform. The organic layer was washed with water and then with a saturated aqueous solution of sodium chloride, and dried over sodium sulfate. Subsequently, the solvent was distilled off, and the resulting residue was purified through silica gel column chromatography (eluent-hexane:ethyl acetate=30:1→10:1) to obtain 774 mg (yield 80%) of 3-amino-2,4-bis(isopropylthio)-6-methylpyridine as a yellow oil. Triethylamine (336 mg, 3.32 mmol) was added to a THF (10 ml) solution of this aminopyridine (774 mg, 3.02 mmol), and bromoacetyl bromide (732 mg, 3.62 mmol) was then slowly added thereto dropwise while being cooled with ice, and the mixture was stirred for 17 hours. The reaction mixture was filtered, and the filtrate was concentrated. Then, the residue was purified through silica gel chromatography (eluent-hexane:ethyl acetate=10:1) to obtain 595 mg (yield 52%) of 2-bromo-N-[2,4-bis(isopropylthio)-6-methyl-3-pyridyl]acetamide as a colorless powdery crystal, sodium hydrogencarbonate (29 mg, 0.35 mmol) was added to an acetonitrile (5 ml) solution of this amide (132 mg, 0.35 mmol) and 2-mercaptobenzoxazole (53 mg, 0.35 mmol), and the mixture was stirred at room temperature for 28 hours. The reaction mixture was extracted with ethyl acetate. The organic layer was washed with water and then with a saturated aqueous solution of sodium chloride, and dried over magnesium sulfate. Subsequently, the solvent was distilled off, and the resulting crude product was purified through preparative thin-layer chromatography (eluent-hexane:benzen=6:1) to obtain 69 mg (yield 44%) of the desired compound as a colorless powdery crystal.
Melting point: 151-152° C.
IR (KBr) cm−1: 3404, 2967, 1743, 1637, 1360.
1H-NMR (CDCl3) δ: 1.37-1.40 (12H, m), 2.52 (3H, s), 3.58 (1H, sept, J=6.8 Hz), 4.06 (2H, s), 4.11 (1H, sept, J=6.8 Hz), 6.01 (1H, s). 6.81-6.86 (2H, m), 6.92 (1H, dd, J=8.1, 1.3 Hz), 7.00-7.07 (2H, m).
Example 36 (Compound No. 845 in Table)
Production of 6-(benzoxazol-2-ylthio)-N-[2,4-bis(isopropylthio)-6-methyl-3-pyridyl]hexanamide:
The reaction and the treatment were conducted in the same manner as in Example 35 except that 6-bromohexanoyl chloride was used instead of bromoacetyl bromide to obtain 6-bromo-N-[2,4-bis(isopropylthio)-6-methyl-3-pyridyl]hexanamide. To a DMF (4 ml) solution of this amide (100 mg, 0.23 mmol) and 2-mercaptobenzoxazole (35 mg, 0.23 mmol) were added potassium carbonate (38 mg, 0.28 mmol) and 18-crown-6 (6 mg, 0.02 mmol), and the mixture was stirred at 80° C. for 2.5 hours. The reaction mixture was allowed to cool, and then extracted with ethyl acetate. The organic layer was washed with water and then with a saturated aqueous solution of sodium chloride, and dried over sodium sulfate. Subsequently, the solvent was distilled off, and the resulting residue was purified through preparative thin-layer chromatography (eluent-hexane:ethyl acetate=3:1) to obtain 92 mg (yield 79%) of the desired compound as a colorless powdery crystal.
Melting point: 98-100° C.
IR (KBr) cm−1: 3135, 2961, 1648, 1498, 1454, 1133.
1H-NMR (d6-DMSO) δ: 1.32 (6H, d, J=6.8 Hz), 1.35 (6H, d, J=6.8 Hz), 1.55-1.64 (2H, m), 1.65-1.75 (2H, m), 1.82-1.92 (2H, m), 2.23-2.36 (2H, m), 2.46 (3H, s), 3.38 (2H, t, J=7.1 Hz), 3.59 (1H, sept, J=6.8 Hz), 3.93 (1H, sept, J=6.8 Hz), 6.96 (1H, s), 7.29-7.37 (2H, m), 7.57-7.64 (2H, m), 8.95 (1H, br s).
Example 37 (Compound No. 1237 in Table)
Production of 6-(oxazolo[4,5-b]pyridin-2-ylthio)-N-[2,4-bis(methylthio)-6-methyl-3-pyridyl]hexanamide:
To a DMF (4 ml) solution of 6-bromo-N-[2,4-bis(methylthio)-6-methyl-3-pyridyl]hexanamide (100 mg, 0.27 mmol) and 2-mercaptoxazolo[4,5-b]pyridine (40 mg, 0.27 mmol) were added 18-crown-6 (7 mg, 0.03 mmol) and potassium carbonate (40 mg, 0.29 mmol), and the mixture was stirred at 80° C. for 4 hours. The reaction mixture was diluted with water, and then extracted with ethyl acetate. The organic layer was washed with water and then with a saturated aqueous solution of sodium chloride, and dried over magnesium sulfate. Subsequently, the solvent was distilled off, and the resulting crude product was purified through preparative thin-layer chromatography (eluent-hexane:acetone=2:1) to obtain 85 mg (yield 72%) of the desired compound as a colorless powdery crystal.
Melting point: 132-133° C.
IR (KBr) cm−1: 3435, 3243, 2923, 1655, 1493, 1404.
1H-NMR (d6-DMSO) δ: 1.53-1.63 (2H, m), 1.65-1.76 (2H, m), 1.83-1.93 (2H, m), 2.27-2.35 (2H, m), 2.40 (3H, s), 2.42 (3H, s), 2.45 (3H, s), 3.40 (2H, t, J=7.3 Hz), 6.86 (1H, s), 7.30 (1H, dd, J=8.1, 4.9 Hz), 7.97 (1H, dd, J=8.1, 1.3 HZ), 8.42 (1H, dd, J=4.9, 1.3 HZ), 8.83 (1H, br s).
EIMS m/z (relative intensity): 447 (M+−1), 400 (100).
Elemental analysis: as C20H24N4O2S3; calculated: C, 53.55; H, 5.39; N, 12.59; S, 21.44. found: C, 53.72; H, 5.39; N, 12.41; S, 21.51.
Example 38 (Compound No. 1238 in Table)
Production of 6-(7-methoxycarbonylbenzoxazol-2-ylthio)-N-[2,4-bis(methylthio)-6-methyl-3-pyridyl]hexanamide:
The reaction and the treatment were conducted in the same manner as in Example 37 except that 7-methoxycarbonyl-2-mercaptobenzoxazole was used instead of 2-mercaptoxazolo[4,5-b]pyridine to obtain the desired compound as a colorless powdery crystal.
Melting point: 141-142° C.
IR (KBr) cm−1: 3425, 3236, 2923, 1726, 1667, 1509.
1H-NMR (d6-DMSO) δ: 1.54-1.63 (2H, m), 1.67-1.76 (2H, m), 1.84-1.93 (2H, m), 2.28-2.35 (2H, m), 2.40 (3H, s), 2.42 (3H, s), 2.45 (3H, s), 3.39 (2H, t, J=7.1 Hz), 3.95 (3H, s), 6.86 (1H, s), 7.44 (1H, t, J=7.8 Hz), 7.81 (1H, dd, J=7.8, 1.2 Hz), 7.85 (1H, dd, J=7.8, 1.2 Hz), 8.82 (1H, br s).
EIMS m/z (relative intensity): 504 (M+−1), 167 (100).
Elemental analysis: as C23H27N3O4S3; calculated: C, 54.63; H, 5.38; N, 8.31; S, 19.02. found: C, 54.70; H, 5.37; N, 8.27; S, 19.15.
Example 39 (Compound No. 1240 in Table)
Production of 9-(7-methoxycarbonylbenzoxazol-2-ylthio)-N-[2,4-bis(methylthio)-6-methyl-3-pyridyl]nonanamide:
To a DMF (4 ml) solution of 9-bromo-N-[2,4-bis(methylthio)-6-methyl-3-pyridyl]nonanamide (90 mg, 0.22 mmol) and 7-methoxycarbonyl-2-mercaptobenzoxazole (45 mg, 0.22 mmol) were added 18-crown-6 (6 mg, 0.02 mmol) and potassium carbonate (36 mg, 0.26 mmol), and the mixture was stirred at 80° C. for 4 hours. The reaction mixture was diluted with water, and then extracted with ethyl acetate. The organic layer was washed with water and then with a saturated aqueous solution of sodium chloride, and dried over magnesium sulfate. Subsequently, the solvent was distilled off, and the resulting crude product was recrystallized from a mixture of ethyl acetate and hexane to obtain 84 mg (yield 72%) of the desired compound as a colorless powdery crystal.
Melting point: 126-128° C.
IR (KBr) cm−1: 3231, 2924, 1720, 1657, 1508, 1297.
1H-NMR (d6-DMSO) δ: 1.27-1.47 (8H, m), 1.54-1.62 (2H, m), 1.74-1.85 (2H, m), 2.24 (2H, t, J=7.3 Hz), 2.37 (3H, s), 2.38 (3H, s), 2.43 (3H, s), 3.31-3.41 (2H, m), 3.91 (3H, s), 6.86 (1H, s), 7.45 (1H, t, J=7.8 Hz), 7.81 (1H, dd, J=7.8, 1.0 Hz), 7.91 (1H, dd, J=7.8, 1.0 Hz), 9.26 (1H, s).
EIMS m/z (relative intensity), 546 (M+−1), 500 (100).
Elemental analysis: as C26H33N3O4S3; calculated: C, 57.01; H, 6.07; N, 7.67; S, 17.56. found: C, 57.10; H, 5.95; N, 7.67; S, 17.60.
Examples 40 (Compound No. 151 in Table)
Production of 2-(benzoxazol-2-ylthio)-N-(4-methyl-2-methylthio-3-pyridyl)acetamide:
The reaction and the treatment were conducted in the same manner as in Example 16 except that 3-amino-4-methyl-2-methylthiopyridine was used instead of 3-amino-2,4-bis(methylthio)-6-methylpyridine to obtain the desired compound as a colorless needle crystal.
Melting point: 146-148° C.
IR (KBr) cm−1: 3437, 3245, 1671, 1659, 1507, 1454.
1H-NMR (CDCl3) δ: 2.17 (3H, s), 2.42 (3H, s), 4.11 (2H, s), 6.87 (1H, d, J=4.9 Hz), 7.28-7.34 (2H, m), 7.50 (1H, m), 7.61 (1H, m), 8.23 (1H, d, J=4.9 Hz), 8.88 (1H, br s).
EIMS m/z (relative intensity): 345 (M+, 100).
Elemental analysis: as C16H15N3O2S3; calculated: C, 55.63; H, 4.38; N, 12.16; S, 18.56. found: C, 55.66; H, 4.46, N, 12.02; S, 18.55.
Example 41 (Compound No. 155 in Table)
Production of 6-(benzoxazol-2-ylthio)-N-(4-methyl-2-methylthio-3-pyridyl)hexanamide:
The reaction and the treatment were conducted in the same manner as in Example 18 except that 3-amino-4-methyl-2-methylthiopyridine was used instead of 3-amino-2,4-bis(methylthio)-6-methylpyridine to obtain the desired compound as a colorless needle crystal.
Melting point: 122-124° C.
IR (KBr) cm−1: 3437, 3245, 1660, 1521, 1507, 1133.
1-NMR (d6-DMSO) δ: 1.49-1.56 (2H, m), 1.68 (2H, quint, J=7.4 Hz), 1.84 (2H, quint, J=7.4 Hz), 2.09 (3H, s), 2.33 (2H, t, J=7.4 Hz), 2.40 (3H, s), 3.36 (2H, t, J=7.4 Hz), 7.02 (1H, d, J=4.9 Hz), 7.29-7.36 (2H, m), 7.61-7.66 (2H, m), 8.24 (1H, d, J=4.9 Hz), 9.40 (1H, br s).
EIMS m/z (relative intensity): 401 (M+, 100).
Elemental analysis: as C20H23N3O2S2; calculated: C, 59.82; H, 5.77; N, 10.46; S, 15.97. found: C, 59.93; H, 5.89; N, 10.34; S, 15.99.
Example 42 (Compound No. 365 in Table)
Production of 6-(benzoxasole-2-ylthio)-N-(6-methoxy-2-methylthio-3-pyridyl)hexanamide:
A methanol (100 ml) solution of 2-chloro-6-methoxy-3-nitropyridine (2.0 g, 10.4 mmol) was added dropwise to a methanol (20 ml) solution of sodium thiomethoxide (805 mg, 10.9 mmol) while being cooled with ice, and the temperature thereof was raised to the room temperature and the mixed solution was stirred for 17 hours and the precipitated crystal was filtered to obtain 1.26 g (yield 59%) of 6-methoxy-2-methylthio-3-nitropyridine as a yellow powdery crystal.
This nitropyridine (400 mg, 2.0 mmol) was dissolved in a mixed solvent of acetic acid (20 ml) and conc. hydrochloric acid (0.5 ml), and zinc (1.57 g, 24.0 mmol) was added thereto in small portions while being cooled with ice for 5 minutes. After the mixture was stirred for 40 minutes at the room temperature, the reaction mixture was filtered, and the filtrate was neutralized with an aqueous solution of sodium hydrogencarbonate, and extracted with methylene chloride. The organic layer was washed with water and then with a saturated aqueous solution of sodium chloride, and dried over sodium sulfate. Thereafter, the solvent was distilled off, and the resulting crude product was purified through silica gel chromatography (eluent-hexane:ethyl acetate=6:1→4:1) to obtain 264 mg (yield 78%) of 3-amino-6-methoxy-2-methylthiopyridine as a pale brown powdery crystal.
And then the reaction and the treatment were conducted in the same manner as in Example 18 except that 3-amino-6-methoxy-2-methylthiopyridine was used instead of 3-amino-2,4-bis(methylthio)-6-methylpyridine to obtain the desired compound as a colorless powdery crystal.
Melting point: 102-104° C.
IR (KBr) cm−1: 3430, 3224, 2940, 1652, 1591.
1H-NMR (CDCl3) δ: 1.61 (2H, quint, J=7.4 Hz), 1.82 (2H, quint, J=7.4 Hz). 1.92 (2H, quint, J=7.4 Hz), 2.42 (2H, t, J=7.4 Hz), 2.59 (3H, s), 3.34 (2H, t, J=7.4 Hz), 3.94 (3H, s), 6.47 (1H, d, J=8.5 Hz), 6.91 (1H, br s), 7.23 (1H, td, J=7.7, 1.5 Hz), 7.27 (1H, td, J=7.7, 1.5 Hz), 7.43 (1H, dd, J=7.7, 1.5 Hz), 7.58 (1H, dd, J=7.7, 1.5 Hz), 7.93 (1H, d, J=8.5 Hz).
EIMS m/z (relative intensity): 417 (M+), 171 (100).
Example 43 (Compound No. 451 in Table)
Production of 2-(benzoxazol-2-ylthio)-N-(6-methylthio-3-pyridyl)acetamide:
The reaction and the treatment were conducted in the same manner as in Example 16 except that 3-amino-6-methyl-2-methylthiopyridine was used instead of 3-amino-2,4-bis(methylthio)-6-methylpyridine to obtain the desired compound as a colorless needle crystal.
Melting point: 180-181° C.
IR (KBr) cm−1: 3437, 3254, 1661, 1534, 1509, 1135.
1H-NMR (CDCl3) δ: 2.46 (3H, s), 2.50 (3H, s), 4.10 (2H, s), 6.87 (2H, d, J=8.1 Hz), 7.26-7.34 (2H, m), 7.48 (1H, m), 7.62 (1H, m), 8.12 (2H, d, J=8.1 Hz), 9.27 (1H, br s).
EIMS m/z (relative intensity): 345 (M+), 298 (100).
Elemental analysis: as C16H15N3O2S2; calculated: C, 55.63; H, 4.38; N, 12.16; S, 18.56. found: C, 55.62; H, 4.40; N, 12.10; S, 18.50.
Example 44 (Compound No. 461 in Table)
Production of 2-(benzothiazol-2-ylthio)-N-(6-methyl-2-methylthio-3-pyridyl)acetamide:
The reaction and the treatment were conducted in the same manner as in Example 43 except that 2-mercaptobenzothiazole was used instead of 2-mercaptobenzoxazole to obtain the desired compound as a colorless needle crystal.
Melting Point: 175-176° C.
IR (KBr) cm−1: 3437, 3248, 1656, 1532, 1430.
1H-NMR (CDCl3) δ: 2.45 (3H, s), 2.47 (3H, s), 4.18 (2H, s), 6.87 (1H, d, J=8.1 Hz), 7.34 (1H, m), 7.44 (1H, m), 7.77 (1H, m), 8,01 (1H, m), 8.07 (1H, d, J=8.1 Hz), 9.31 (1H, br s).
EIMS m/z (relative intensity): 361 (M+), 210 (100).
Elemental analysis: as C16H15N3OS2; calculated: C, 53.16; H, 4.18; N, 11.62; S, 26.61. found: C, 53.23; H, 4.25; N, 11.55; S, 26.67.
Example 45 (Compound No. 471 in Table)
Production of 2-(benzimidazol-2-ylthio)-N-(6-methyl-2-methylthio-3-pyridyl)acetamide:
The reaction and the treatment were conducted in the same manner as in Example 43 except that 2-2-mercaptobenzimidazole was used instead of 2-mercaptobenzoxazole to obtain the desired compound as a colorless needle crystal.
Melting point: 192-193° C. (d.)
IR (KBr) cm−1: 3420, 3249, 1667, 1550, 1438, 744.
1H-NMR (CDCl3) δ: 2.45 (3H, s), 2.50 (3H, s), 4.08 (2H, s), 6.84 (1H, d, J=8.1 Hz), 7.19-7.25 (2H, m), 7.35 (1H, m), 7.73 (1H, m), 8.00 (1H, d, J=8.1 Hz), 9.95 (1H, br s), 10.00 (1H, br s).
EIMS m/z (relative intensity): 344 (M+), 118 (100).
Elemental analysis: as C16H16N4OS2; calculated: C, 55.79; H, 4.68; N, 16.27; S, 18.62. found: C, 55.80; H, 4.68; N, 16.16; S, 18.65.
Example 46 (Compound No. 784 in Table)
Production of 5-(benzoxazol-2-ylthio)-N-(2,4-bis(methylthio)-6-methyl-3-pyridyl)pentanamide:
The reaction and the treatment were conducted in the same manner as in Example 17 except that 5-bromopentanoic acid chloride was used instead of 4-bromobutanoyl chloride to obtain the desired compound as a colorless needles crystal.
Melting point: 147-150° C.
IR (KBr) cm−1: 3230, 1664, 1501, 1455, 1136.
1H-NMR (d6-DMSO) δ: 1.72-1.96 (4H, m), 2.36 (3H, s), 2.26-2.42 (2H, m), 2.39 (3H, s), 2.43 (3H, s), 3.36 (2H, t, J=7.2 Hz), 6.83 (1H, s), 7.23-7.33 (2H, m), 7.52-7.59 (2H, m), 8.74 (1H, br s).
EIMS m/z (relative intensity): 433 (M+), 201 (100).
Example 47 (Compound No. 786 in Table)
Production of 7-(benzoxazol-2-ylthio)-N-[2,4-bis(methylthio)-6-methyl-3-pyridyl]heptanamide:
The reaction and the treatment were conducted in the same manner as in Example 17 except that 7-bromoheptanonyl chloride was used instead of 4-bromobutanoyl chloride to obtain the desired compound as a colorless powdery crystal.
Melting point: 137-139° C.
IR (KBr) cm−1: 3437, 3242, 2922, 2857, 1660, 1500, 1455, 1132.
1H-NMR (d6-DMSO) δ: 1.41-1.54 (4H, m), 1.60-1.70 (2H, m), 1.81 (2H, quint, J=7.1 Hz), 2.26-2.32 (2H, m), 2.38 (3H, s), 2.40 (3H, s), 2.43 (3H, s), 3.33 (2H, t, J=7.1 Hz), 6.81 (1H, s), 7.27 (1H, td, J=7.6, 1.7 Hz), 7.30 (1H, td, J=7.6, 1.7 Hz), 7.54-7.60 (2H, m), 8.79 (1H, br s).
EIMS m/z (relative intensity): 461 (M+), 200 (100).
Example 48 (Compound No. 787 in Table)
Production of 8-(benzoxazol-2-ylthio)-N-[2,4-bis(methylthio)-6-methyl-3-pyridyl]octanamide:
The reaction and the treatment were conducted in the same manner as in Example 17 except that 8-bromooctanoyl chloride was used instead of 4-bromobutanonyl chloride to obtain the desired compound as a colorless prism crystal.
Melting point: 119-122° C.
IR (KBr) cm−1: 3435, 3248, 2923, 2856, 1660, 1501, 1454, 1131.
1H-NMR (d6-DMSO) δ: 1.33-1.52 (6H, m), 1.58-1.69 (2H, m), 1.81 (2H, quint, J=7.1 Hz), 2.26-2.32 (2H, m), 2.38 (3H, s), 2.41 (3H, s), 2.44 (3H, s), 3.33 (2H, t, J=7.1 Hz), 6.84 (1H, s), 7.27 (1H, td, J=7.6, 1.7 Hz), 7.30 (1H, td, J=7.6, 1.7 Hz), 7.54-7.60 (2H, m), 8.77 (1H, br s).
EIMS m/z (relative intensity): 475 (M+), 200 (100).
Example 49 (Compound No. 791 in Table)
Production of 2-(benzothiazol-2-ylthio)-N-[2,4-bis(methylthio)-6-methyl-3-pyridyl)acetamide:
An acetonitrile solution (6 ml) of 2-bromo-N-[2,4-bis(methylthio)-3-pyridyl]acetamide (64 mg, 0.2 mmol) was added to an acetonitrile solution (1 ml) of sodium hydrogencarbonate (17 mg, 0.2 mmol) and 2-mercaptobenzothiazole (34 mg, 0.2 mmol), and the mixed solution was stirred for 48 hours at the room temperature. And the solution of reaction mixture was concentrated under reduced pressure, and the residue was extraxted with ethyl acetate after dilluting with water. The organic layer was washed with water and then with a saturated aqueous solution of sodium chloride, and dried over sodium sulfate. Thereafter, the solvent was distilled off, and the resulting crude product was purified through preparative thin layer chromatography (eluent-chloroform:methanol=20:1) to obtain 46 mg (yield 33%) as a colorless needle crystal.
Melting point: 178-179° C.
IR (KBr) cm−1: 3437, 3246, 1665, 1564, 1497, 1430.
1H-NMR (CDCl3) δ: 2.33 (3H, s), 2.44 (3H, s), 2.46 (3H, s), 4.17 (2H, s), 6.61 (1H, s), 7.33 (1H, m), 7.43 (1H, m), 7.78 (1H, m), 7.90 (1H, m), 9.11 (1H, br s).
EIMS m/z (relative intensity): 407 (M+), 209 (100).
Elemental analysis: as C17H17N3OS4; calculated: C, 50.10; H, 4.20; N, 10.31; S, 31.46. found: C, 50.18; H, 4.29; N, 10.23; S, 31.49.
Example 50 (Compound No. 794 in Table)
Production of 5-(benzothiazol-2-ylthio)-N-[2,4-bis(methylthio)-6-methyl-3-pyridyl)pentanamide:
The reaction and the treatment were conducted in the same manner as in Example 46 except that 2-mercaptobenzothiazole was used instead of 2-mercaptobenzoxazole to obtain the desired compound as a colorless needle crystal.
Melting point: 121-123° C.
IR (KBr) cm−1: 3437, 3240, 2923, 1664, 1515, 1456, 1428, 995.
1H-NMR (d6-DMSO) δ: 1.78-1.87 (2H, m), 1.88-1.96 (2H, m), 2.30-2.40 (2H, m), 2.38 (3H, s), 2.41 (3H, s), 2.45 (3H, s), 3.41 (2H, t, J=7.1 Hz), 6.85 (1H, s), 7.34 (1H, t, J=7.6 Hz), 7.45 (1H, t, J=7.6 Hz), 7.84 (1H, d, J=7.6 Hz), 7.94 (1H, d, J=7.6 Hz), 8.87 (1H, br s).
EIMS m/z (relative intensity): 449 (M+), 201 (100).
Example 51
Compound No. 796 in Table
Production of 7-(benzothiazol-2-ylthio)-N-[2,4-bis(methylthio)-6-methyl-3-pyridyl)heptamamide:
The reaction and the treatment were conducted in the same manner as in Example 47 except that 2-mercaptobenzothiazole was used instead of 2-mercaptobenzoxazole to obtain the desired compound as a colorless needle crystal.
Melting point: 129-130° C.
IR (KBr) cm−1: 3436, 3245, 2922, 1661, 1506, 1428.
1H-NMR (d6-DMSO) δ: 1.44-1.54 (4H, m), 1.62-1.71 (2H, m), 1.83 (2H, quint, J=7.2 Hz), 2.13-2.33 (2H, m), 2.39 (3H, s), 2.42 (3H, s), 2.45 (3H, s), 3.37 (2H, t, J=7.2 Hz), 6.86 (1H, s), 7.34 (1H, td, J=7.8, 1.2 Hz), 7.45 (1H, td, J=7.8, 1.2 Hz), 7.84 (1H, dd, J=7.8, 1.2 Hz), 7.94 (1H, dd, J=7.8, 1.2 Hz), 8.81 (1H, br s).
EIMS m/z (relative intensity): 477 (M+), 200 (100).
Elemental analysis: as C22H27N3OS4; calculated: C, 55.31; H, 5.70; N, 8.80. found: C, 55.41; H, 5.71; N, 8.64.
Example 52
Compound No. 797 in Table
Production of 8-(benzthiazol-2-ylthio)-N-[2,4-bis(methylthio)-6-methyl-3-pyridyl)octanamide:
The reaction and the treatment were conducted in the same manner as in Example 48 except that 2-mercaptobenzothiazole was used instead of 2-mercaptobenzoxazole to obtain the desired compound as a colorless needle crystal.
Melting point: 104-108° C.
IR (KBr) cm−1: 3242, 2925, 1665, 1508, 1459, 1428.
1H-NMR (d6-DMSO) δ: 1.30-1.51 (6H, m), 1.55-1.69 (2H, m), 1.81 (2H, quint, J=7.1 Hz), 2.23-2.29 (2H, m), 2.38 (3H, s), 2.41 (3H, s), 2.44 (3H, s), 3.35 (2H, t, J=7.2 Hz), 6.83 (1H, s), 7.32 (1H, m), 7.43 (1H, m), 7.81 (1H, m), 7.91 (1H, m), 8.76 (1H, br s).
EIMS m/z (relative intensity): 491 (M+), 200 (100).
Example 53
Compound No. 801 in Table
Production of 2-(benzimidazol-2-ylthio)-N-[2,4-bis(methylthio)-6-methyl-3-pyridyl)pentanamide:
The reaction and the treatment were conducted in the same manner as in Example 49 except that 2-mercaptobenzimidazole was used instead of 2-mercaptobenothiazole to obtain the desired compound as a colorless needle crystal.
Melting point: 235-237° C. (d.)
IR (KBr) cm−1: 3429, 3243, 2978, 2923, 1661, 1505, 1439.
1H-NMR (CDCl3) δ: 2.35 (3H, s), 2.46 (3H, s), 2.47 (3H, s), 4.03 (2H, s), 6.63 (1H, s), 7.21 (1H, t, J=6.1 Hz), 7.22 (1H, t, J=6.1 Hz), 7.43-7.60 (2H, m), 9.43 (1H, br s).
EIMS m/z (relative intensity): 390 (M+), 344 (100).
Example 54
Compound No. 804 in Table
Production of 5-(benzimidazol-2-ylthio)-N-[2,4-bis(methylthio)-6-methyl-3-pyridyl]pentanamide:
The reaction and the treatment were conducted in the same manner as in Example 46 except that 2-mercaptobenzimdazole was used instead of 2-mercaptobenoxazole to obtain the desired compound as a colorless needle crystal.
Melting point: 176-177° C.
1H-NMR (d6-DMSO) δ: 1.74-1.84 (4H, m), 2.26-2.35 (2H, m), 2.36 (3H, s), 2.39 (3H, s), 2.43 (3H, s), 3.26-3.36 (2H, m), 6.84 (1H, s), 7.04-7.13 (2H, m), 7.34-7.45 (2H, m), 8.84 (1H, br s), 12.06 (1H, br s).
EIMS m/z (relative intensity): 432 (M+), 200 (100).
Example 55
Compound No. 806 in Table
Production of 7-(benzimidazol-2-ylthio)-N-[2,4-bis(methylthio)-6-methyl-3-pyridyl]heptanamide:
The reaction and the treatment were conducted in the same manner as in Example 47 except that 2-mercaptobenzimidazole was used instead of 2-mercaptobenzoxazole to obtain the desired compound as a colorless prism crystal.
Melting point: 189-192° C.
IR (KBr) cm−1: 3139, 2925, 2854, 1668, 1561, 1523, 1435, 1401.
1H-NMR (d6-DMSO) δ: 1.39-1.52 (4H, m), 1.56-1.70 (2H, m), 1.75 (2H, quint, J=7.1 Hz), 2.28-2.34 (2H, m), 2.38 (3H, s), 2.40 (3H, s), 2.43 (3H, s), 3.27 (2H, t, J=7.1 Hz), 6.84 (1H, s), 7.07 (1H, t, J=7.1 Hz), 7.08 (1H, t, J=7.1 Hz), 7.32 (1H, d, J=7.1 Hz), 7.46 (1H, d, J=7.1 Hz), 8.79 (1H, br s).
EIMS m/z (relative intensity): 460 (M+), 150 (100).
Example 56
Compound No. 807 in Table
Production of 8-(benzimidazol-2-ylthio)-N-[2,4-bis(methylthio)-6-methyl-3-pyridyl]octanamide:
The reaction and the treatment were conducted in the same manner as in Example 48 except that 2-mercaptobenzimidazole was used instead of 2-mercaptobenzoxazole to obtain the desired compound as a colorless crystal.
Melting point: 186-187° C.
IR (KBr) cm−1: 3430, 3222, 2925, 1661, 1564, 1522, 1437, 808. 1H-NMR (d6-DMSO) δ: 1.35-1.43 (4H, m), 1.47 (2H, quint, J=7.2 Hz), 1.60-1.68 (2H, m), 1.76 (2H, quint, J=7.2 Hz), 2.23-2.32 (2H, m), 2.40 (3H, s), 2.42 (3H, s), 2.45 (3H, s), 3.28 (2H, t, J=7.2 Hz), 6.89 (1H, s), 7.09 (1H, t, J=5.9 Hz), 7.09 (1H, t, J=5.9 Hz), 7.40 (1H, d, J=5.9 Hz), 7.41 (1H, d, J=5.9 Hz), 8.80 (1H, br s), 12.09 (1H, br s).
EIMS m/z (relative intensity): 474 (M+), 150 (100).
Example 57
Compound No. 813 in Table
Production of 4-(benzoxazol-2-ylthio)-N-[2,4-bis(ethylthio)-6-methyl-3-pyridyl]butanamide:
The reaction and the treatment were conducted in the same manner as in Example 27 except that 4-bromobutanoyl chloride was used instead of 6-bromohexanoyl chloride to obtain the desired compound as a colorless crystal.
Melting point: 123-125° C.
IR (KBr) cm−1: 3436, 3239, 2974, 2929, 1656, 1502, 1454, 1130.
1H-NMR (d6-DMSO) δ: 1.23-1.28 (6H, m), 2.12-2.19 (2H, m), 2.43 (3H, s), 2.48-2.50 (2H, m), 2.93 (2H, q, J=7.1 Hz), 3.06 (2H, q, J=7.1 Hz), 3.41-3.48 (2H, m), 6.89 (3H, s), 7.29-7.34 (2H, m), 7.56-7.62 (2H, m), 8.96 (1H, br s).
EIMS m/z (relative intensity): 447 (M+), 227 (100).
Example 58
Compound No. 814 in Table
Production of 5-(benzoxazol-2-ylthio)-N-[2,4-bis(ethylthio)-6-methyl-3-pyridyl]pentanamide:
The reaction and the treatment were conducted in the same manner as in Example 27 except that 5-bromopentanoyl chloride was used instead of 6-bromohexanoyl chloride to obtain the desired compound as a colorless needle crystal.
Melting point: 122-123° C.
1H-NMR (d6-DMSO) δ: 1.25 (3H, t, J=7.3 Hz), 1.26 (3H, t, J=7.3 Hz), 1.76-1.87 (2H, m), 1.87-1.97 (2H, m), 2.29-2.40 (2H, m), 2.43 (3H, s), 2.92 (2H, q, J=7.3 Hz), 3.05 (2H, q, J=7.3 Hz), 3.38 (2H, t, J=7.2 Hz), 6.88 (1H, s), 7.26-7.35 (2H, m), 7.55-7.60 (2H, m), 8.82 (1H, br s).
EIMS m/z (relative intensity): 461 (M+), 227 (100).
Example 59 (Compound No. 816 in Table)
Production of 7-(benzoxazol-2-ylthio)-N-[2,4-bis(ethylthio)-6-methyl-3-pyridyl]heptanamide:
The reaction and the treatment were conducted in the same manner as in Example 27 except that 7-bromoheptanoyl chloride was used instead of 6-bromohexanoyl chloride to obtain the desired compound as a colorless needle crystal.
Melting point: 103-105° C.
IR (KBr) cm−1: 3247, 1663, 1501, 1455.
1H-NMR (d6-DMSO) δ: 1.24 (3H, t, J=7.3 Hz), 1.25 (3H, t, J=7.3 Hz), 1.38-1.54 (4H, m), 1.57-1.72 (2H, m), 1.73-1.89 (2H, m), 2.19-2.32 (2H, m), 2.41 (3H, s), 2.92 (2H, q, J=7.3 Hz), 3.05 (2H, q, J=7.3 Hz), 3.33 (2H, t, J=7.1 Hz), 6.86 (1H, s), 7.24-7.32 (2H, m), 7.52-7.60 (2H, m), 8.65 (1H, br s).
EIMS m/z (relative intensity): 489 (M+), 228 (100).
Example 60 (Compound No. 817 in Table)
Production of 8-(benzoxazol-2-ylthio)-N-[2,4-bis(ethylthio)-6-methyl-3-pyridyl]octanamide:
The reaction and the treatment were conducted in the same manner as in Example 27 except that 8-bromooctanoyl chloride was used instead of 6-bromohexanoyl chloride to obtain the desired compound as a colorless needle crystal.
Melting point: 82-84° C.
IR (KBr) cm−1: 3449, 3245, 2932, 1669, 1500, 1455, 1132.
1H-NMR (d6-DMSO) δ: 1.26 (3H, t, J=7.3 Hz), 1.27 (3H, t, J=7.3 Hz), 1.37-1.42 (4H, m), 1.48 (2H, quint, J=7.2 Hz), 1.60-1.67 (2H, m), 1.82 (2H, quint, J=7.2 Hz), 2.24-2.30 (2H, m), 2.43 (3H, s), 2.94 (2H, q, J=7.3 Hz), 3.07 (2H, q, J=7.3 Hz), 3.34 (2H, t, J=7.2 Hz), 6.88 (1H, s), 7.27-7.33 (2H, m), 7.56-7.61 (2H, m), 8.73 (1H, br s).
EIMS m/z (relative intensity): 503 (M+), 229 (100).
Example 61 (Compound No. 823 in Table)
Production of 4-(benzothiazol-2-ylthio)-N-[2,4-bis(ethylthio)-6-methyl-3-pyridyl]butanamide:
The reaction and the treatment were conducted in the same manner as in Example 57 except that 2-mercaptobenzothiazole was used instead of 2-mercaptobenzoxazole to obtain the desired compound as a colorless powdery crystal.
Melting point: 119-120° C.
1H-NMR (d6-DMSO) δ: 1.25 (3H, t, J=7.4 Hz), 1.26 (3H, t, J=7.4 Hz). 2.07-2.23 (2H, m), 2.43 (3H, s), 2.45-2.55 (2H, m,), 2.93 (2H, q, J=7.4 Hz), 3.06 (2H, q, J=7.4 Hz), 3.41-3.54 (2H, m), 6.89 (1H, s), 7.35 (1H, t, J=8.1 Hz), 7.45 (1H, t, J=8.1 Hz), 7.83 (1H, d, J=8.1 Hz). 7.94 (1H, d, J=8.1 Hz), 8.95 (1H, br s).
EIMS m/z (relative intensity): 463 (M+), 229 (100).
Example 62 (Compound No. 824 in Table)
Production of 5-(benzothiazol-2-ylthio)-N-[2,4-bis(ethylthio)-6-methyl-3-pyridyl]pentanamide:
The reaction and the treatment were conducted in the same manner as in Example 58 except that 2-mercaptobenzothiazole was used instead of 2-mercaptobenzoxazole to obtain the desired compound as a colorless needle crystal.
Melting point: 102-104° C.
1H-NMR (d6-DMSO) δ: 1.25 (3H, t, J=7.3 Hz), 1.26 (3H, t, J=7.3 Hz), 1.77-1.88 (2H, m), 1.88-2.00 (2H, m), 2.29-2.41 (2H, m), 2.43 (3H, s), 2.93 (2H, q, J=7.3 Hz), 3.06 (2H, q, J=7.3 Hz), 3.41 (2H, t, J=7.0 Hz), 6.89 (1H, s), 7.35 (1H, ddd, J=8.2, 7.2, 1.2 Hz), 7.45 (1H, ddd, J=8.2, 7.2, 1.2 Hz), 7.84 (1H, dd, J=8.2, 1.2 Hz), 7.94 (1H, dd, J=8.2, 1.2 Hz), 8.84 (1H, br s).
EIMS m/z (relative intensity): 477 (M+), 229 (100).
Example 63 (Compound No. 826 in Table)
Production of 7-(benzothiazol-2-ylthio)-N-[2,4-bis(ethylthio)-6-methyl-3-pyridyl]heptanamide:
The reaction and the treatment were conducted in the same manner as in Example 59 except that 2-mercaptobenzothiazole was used instead of 2-mercaptobenzoxazole to obtain the desired compound as a colorless needle crystal.
Melting Point: 114-116° C.
IR (KBr) cm−1: 3245, 1665, 1536, 1509, 1426.
1H-NMR (d6-DMSO) δ: 1.24 (3H, t, J=7.3 Hz), 1.25 (3H, t, J=7.3 Hz), 1.39-1.56 (4H, m), 1.58-1.71 (2H, m), 1.75-1.88 (2H, m), 2.19-2.31 (2H, m), 2.42 (3H, s), 2.92 (2H, q, J=7.3 Hz), 3.05 (2H, q, J=7.3 Hz), 3.35 (2H, t, J=7.2 Hz), 6.86 (1H, s), 7.32 (1H, td, J=7.6, 1.2 Hz), 7.42 (1H, td, J=7.6, 1.2 Hz), 7.81 (1H, dd, J=7.6, 1.2 Hz), 7.91 (1H, dd, J=7.6, 1.2 Hz), 8.67 (1H, br s).
EIMS m/z (relative intensity): 505 (M+), 227 (100).
Example 64 (Compound No. 827 in Table)
Production of 8-(benzothiazol-2-ylthio)-N-[2,4-bis(ethylthio)-6-methyl-3-pyridyl]octanamide:
The reaction and the treatment were conducted in the same manner as in Example 60 except that 2-mercaptobenzothiazole was used instead of 2-mercaptobenzoxazole to obtain the desired compound as a colorless needle crystal.
Melting point: 94-96° C.
IR (KBr) cm−1: 3433, 3243, 2929, 1669, 1511, 1428.
1H-NMR (d6-DMSO) δ: 1.26 (3H, t, J=7.3 Hz), 1.27 (3H, t, J=7.3 Hz). 1.37-1.43 (4H, m), 1.45-1.52 (2H, m), 1.57-1.68 (2H, m), 1.82 (2H, quint, J=7.2 Hz), 2.20-2.32 (2H, m), 2.43 (3H, s), 2.94 (2H, q, J=7.3 Hz), 3.07 (2H, q, J=7.3 Hz), 3.37 (2H, t, J=7.2 Hz), 6.88 (1H, s), 7.34 (1H, td, J=7.6, 1.1 Hz), 7.44 (1H, td, J=7.6, 1.1 Hz), 7.83 (1H, dd, J=7.6, 1.1 Hz), 7.93 (1H, dd, J=7.6, 1.1 Hz), 8.73 (1H, br s).
EIMS m/z (relative intensity): 519 (M+), 227 (100).
Example 65 (Compound No. 833 in Table)
Production of 4-(benzimidazol-2-ylthio)-N-[2,4-bis(ethylthio)-6-methyl-3-pyridyl]butanamide:
The reaction and the treatment were conducted in the same manner as in Example 57 except that 2-mercaptobenzimidazole was used instead of 2-mercaptobenzoxazole to obtain the desired compound as a pale-yellow powdery crystal.
Melting point: 160-161° C.
1H-NMR (d6-DMSO) δ: 1.25 (3H, t, J=7.3 Hz), 1.26 (3H, t, J=7.3 Hz), 2.27-2.37 (2H, m), 2.44 (3H, s), 2.48-2.50 (2H, m), 2.93 (2H, q, J=7.3 Hz), 3.06 (2H, q, J=7.3 Hz), 3.34-3.46 (2H, m), 6.89 (1H, s), 7.05-7.14 (2H, m), 7.33 (1H, m), 7.46 (1H, m), 8.95 (1H, br s).
EIMS m/z (relative intensity): 446 (M+), 195 (100).
Example 66 (Compound No. 834 in Table)
Production of 5-(benzimidazol-2-ylthio)-N-[2,4-bis(ethylthio)-6-methyl-3-pyridyl]pentanamide:
The reaction and the treatment were conducted in the same manner as in Example 58 except that 2-mercaptobenzimidazole was used instead of 2-mercaptobenzoxazole to obtain the desired compound as a colorless needle crystal.
Melting point: 163-165° C.
1H-NMR (d6-DMSO) δ: 1.23 (3H, t, J=7.3 Hz), 1.24 (3H, t, J=7.3 Hz), 1.74-1.88 (4H, m), 2.27-2.38 (2H, m), 2.41 (3H, s), 2.90 (2H, q, J=7.3 Hz), 3.03 (2H, q, J=7.3 Hz), 3.26-3.34 (2H, m), 6.86 (1H, s), 7.04-7.11 (2H, m), 7.32 (1H, m), 7.46 (1H, m), 8.79 (1H, br s).
EIMS m/z (relative intensity): 460 (M+), 195 (100).
Example 67 (Compound No. 836 in Table)
Production of 7-(benzimidazol-2-ylthio)-N-[2,4-bis(ethylthio)-6-methyl-3-pyridyl]heptanamide:
The reaction and the treatment were conducted in the same manner as in Example 59 except that 2-mercaptobenzimidazole was used instead of 2-mercaptobenzoxazole to obtain the desired compound as a colorless needle crystal.
Melting point: 151-156° C.
IR (KBr) cm−1: 3136, 3106, 1656, 1518, 1438, 1401, 1337, 1268.
1H-NMR (d6-DMSO) δ: 1.24 (3H, t, J=7.3 Hz), 1.25 (3H, t, J=7.3 Hz). 1.36-1.54 (4H, m), 1.55-1.82 (4H, m), 2.15-2.32 (2H, m), 2.41 (3H, s), 2.92 (2H, q, J=7.3 Hz), 3.05 (2H, q, J=7.3 Hz), 3.26 (2H, t, J=7.3 Hz), 6.86 (1H, s), 7.03-7.11 (2H, m), 7.34-7.44 (2H, m), 8.67 (1H, br s).
EIMS m/z (relative intensity): 488 (M+), 151 (100).
Example 68 (Compound No. 837 in Table)
Production of 8-(benzimidazol-2-ylthio)-N-[2,4-bis(ethylthio)-6-methyl-3-pyridyl]octanamide:
The reaction and the treatment were conducted in the same manner as in Example 60 except that 2-mercaptobenzoimidazole was used instead of 2-mercaptobenzoxazole to obtain the desired compound as a colorless crystal.
Melting point: 166-168° C.
IR (KBr) cm−1: 3427, 3147, 2928, 1660, 1560, 1526, 1437.
1H-NMR (d6-DMSO) δ: 1.26 (3H, t, J=7.3 Hz), 1.27 (3H, t, J=7.3 Hz), 1.36-1.41 (4H, m), 1.47 (2H, quint, J=7.2 Hz), 1.60-1.67 (2H, m), 1.75 (2H, quint, J=7.2 Hz), 2.22-2.32 (2H, m), 2.43 (3H, s), 2.94 (2H, q, J=7.3 Hz), 3.07 (2H, q, J=7.3 Hz,), 3.28 (2H, t, J=7.2 Hz), 6.85 (1H, s), 7.08 (1H, t, J=5.9 Hz), 7.09 (1H, t, J=5.9 Hz), 7.40 (1H, d, J=5.9 Hz), 7.41 (1H, d, J=5.9 Hz), 8.73 (1H, br s).
EIMS m/z (relative intensity): 502 (M+), 151 (100).
Example 69 (Compound No. 843 in Table)
Production of 4-(benzoxazol-2-ylthio)-N-[2,4-bis(isopropylthio)-6-methyl-3-pyridyl]butanamide:
The reaction and the treatment were conducted in the same manner as in Example 36 except that 4-bromobutanoyl chloride was used instead of 6-bromohexanoyl chloride to obtain the desired compound as a colorless needle crystal.
Melting point: 128-129° C.
IR (KBr) cm−1: 3448, 3235, 2962, 1683, 1657, 1555, 1515, 1500, 1456, 1131.
1H-NMR (d6-DMSO) δ: 1.27 (6H, d, J=6.6 Hz), 1.30 (6H, d, J=6.8 Hz). 2.10-2.17 (2H, m), 2.42 (3H, s), 2.47-2.50 (2H, m), 3.39-3.47 (2H, m), 3.55 (1H, sept, J=6.6 Hz), 3.89 (1H, sept, J=6.8 Hz), 6.92 (1H, s), 7.28 (1H, td, J=7.3, 1.7 Hz), 7.30 (1H, td, J=7.3, 1.7 Hz), 7.56 (1H, dd, J=7.3, 1.7 Hz), 7.58 (1H, dd, J=7.3, 1.7 Hz), 8.90 (1H, br s).
EIMS m/z (relative intensity): 475 (M+), 207 (100).
Example 70 (Compound No. 844 in Table)
Production of 5-(benzoxazol-2-ylthio)-N-[2,4-bis(isopropylthio)-6-methyl-3-pyridyl]pentanamide:
The reaction and the treatment were conducted in the same manner as in Example 36 except that 5-bromopentanoyl chloride was used instead of 6-bromohexanoyl chloride to obtain the desired compound as a colorless prism crystal.
Melting point: 129-130° C.
IR (KBr) cm−1: 3448, 3215, 3167, 2965, 1654, 1555, 1525, 1500, 1454, 1128.
1H-NMR (d6-DMSO) δ: 1.27 (6H, d, J=6.8 Hz), 1.30 (6H, d, J=6.8 Hz), 1.75-1.85 (2H, m), 1.86-1.96 (2H, m), 2.26-2.40 (2H, m), 2.42 (3H, s), 3.37 (2H, t, J=7.1 Hz), 3.54 (1H, sept, J=6.8 Hz), 3.88 (1H, sept, J=6.8 Hz), 6.91 (1H, s), 7.27 (1H, td, J=7.6, 1.7 Hz), 7.30 (1H, td, J=7.6, 1.7 Hz), 7.55 (1H, dd, J=7.6, 1.7 Hz), 7.58 (1H, dd, J=7.6, 1.7 Hz), 8.75 (1H, br s).
EIMS m/z (relative intensity): 489 (M+), 221 (100).
Example 71 (Compound No. 846 in Table)
Production of 7-(benzoxazol-2-ylthio)-N-[2,4-bis(isopropylthio)-6-methyl-3-pyridyl]heptanamide:
The reaction and the treatment were conducted in the same manner as in Example 36 except that 7-bromoheptanoyl chloride was used instead of 6-bromohexanoyl chloride to obtain the desired compound as a colorless needle crystal.
Melting point: 76-78° C.
IR (KBr) cm−1: 3436, 3265, 2929, 1663, 1503, 1455.
1H-NMR (d6-DMSO) δ: 1.29 (6H, d, J=6.8 Hz), 1.32 (6H, d, J=6.8 Hz), 1.43-1.54 (4H, m), 1.65 (2H, quint, J=7.2 Hz), 1.83 (2H, quint, J=7.2 Hz), 2.20-2.33 (2H, m), 2.43 (3H, s), 3.35 (2H, t, J=7.2 Hz), 3.56 (1H, sept, J=6.8 Hz), 3.90 (1H, sept, J=6.8 Hz), 6.93 (1H, s), 7.27-7.34 (2H, m), 7.56-7.61 (2H, m), 8.72 (1H, br s).
EIMS m/z (relative intensity): 517 (M+), 249 (100).
Example 72 (Compound No. 847 in Table)
Production of 8-(benzoxazol-2-ylthio)-N-[2,4-bis(isopropylthio)-6-methyl-3-pyridyl]octanamide:
The reaction and the treatment were conducted in the same manner as in Example 36 except that 8-bromooctanoyl chloride was used instead of 6-bromohexanoyl chloride to obtain the desired compound as a colorless oil.
IR (KBr) cm−1: 3241, 1664, 1559, 1526, 1501, 1454.
1H-NMR (d6-DMSO) δ: 1.29 (6H, d, J=6.8 Hz), 1.31 (6H, d, J=6.8 Hz), 1.34-1.54 (6H, m), 1.55-1.69 (2H, m), 1.73-1.89 (2H, m), 2.15-2.28 (2H, m), 2.42 (3H, s), 3.27 (2H, t, J=7.3 Hz), 3.54 (1H, sept, J=6.8 Hz), 3.89 (1H, sept, J=6.8 Hz), 6.90 (1H, s), 7.24-7.32 (2H, m), 7.51-7.60 (2H, m), 8.59 (1H, br s).
EIMS m/z (relative intensity): 531 (M+), 263 (100).
Example 73 (Compound No. 848 in Table)
Production of 9-(benzoxazol-2-ylthio)-N-[2,4-bis(isopropylthio)-6-methyl-3-pyridyl]nonanamide:
The reaction and the treatment were conducted in the same manner as in Example 36 except that 9-bromononanoyl chloride was used instead of 6-bromohexanoyl chloride to obtain the desired compound as a pale yellow oil.
IR (Cap) cm−1: 3243, 2962, 2927, 1668, 1558, 1505, 1455, 1130.
1H-NMR (d6-DMSO) δ: 1.28 (6H, d, J=6.8 Hz) 1.31 (6H, d, J=6.8 Hz), 1.28-1.50 (8H, m), 1.55-1.65 (2H, m), 1.80 (2H, quint, J=7.3 Hz), 2.17-2.27 (2H, m), 2.42 (3H, s), 3.32 (2H, t, J=7.3 Hz), 3.55 (1H, sept, J=6.8 Hz), 3.89 (1H, sept, J=6.8 Hz), 6.91 (1H, s), 7.27 (1H, td, J=7.3, 1.7 Hz), 7.30 (1H, td, J=7.3, 1.7 Hz), 7.54-7.60 (2H, m), 8.65 (1H, br s).
EIMS m/z (relative intensity): 545 (M+), 277 (100).
Example 74 (Compound No. 851 in Table)
Production of 2-(benzothiazol-2-ylthio)-N-[2,4-bis(isopropylthio)-6-methyl-3-pyridyl]acetamide:
The reaction and the treatment were conducted in the same manner as in Example 49 except that 2-bromo-N-[2,4-bis(isopropylthio)-6-methyl-3-pyridyl]acetamide was used instead of 2-bromo-N-2,4-bis(methylthio)-6-methyl-3-pyridyl]acetamide to obtain the desired compound as a colorless needle crystal.
Melting point: 117-118° C.
IR (KBr) cm−1: 3431, 3179, 2967, 1660, 1559, 1526, 1428.
1H-NMR (CDCl3) δ: 1.19 (6H, d, J=6.7 Hz), 1.21 (6H, d, J=6.7 Hz), 2.41 (3H, s), 3.39 (1H, sept, J=6.7 Hz), 3.92 (1H, sept, J=6.7 Hz), 4.18 (2H, s), 6.68 (1H, s), 7.32 (1H, td, J=7.7, 1.2 Hz), 7.41 (1H, td, J=7.7, 1.2 Hz), 7.77 (1H, d, J=7.7 Hz), 7.91 (1H, d, J=7.7 Hz), 8.80 (1H, br s).
EIMS m/z (relative intensity): 463 (M+), 180 (100).
Elemental Analysis: as C21H25N3OS4; Calculated: C, 54.39; H, 5.43; N, 9.06; S, 27.66. Found: C, 54.28; H, 5.45; N, 8.93; S, 27.73.
Example 75 (Compound No. 853 in Table)
Production of 4-(benzothiazol-2-ylthio)-N-[2,4-bis(isopropylthio)-6-methyl-3-pyridyl]butanamide:
The reaction and the treatment were conducted in the same manner as in Example 69 except that 2-mercaptobenzothiazole was used instead of 2-mercaptobenzoxazole to obtain the desired compound as a colorless powdery crystal.
Melting point: 116-117° C.
IR (KBr) cm−1: 3450, 3257, 2962, 1667, 1557, 1510, 1457, 1429, 987.
1H-NMR (d6-DMSO) δ: 1.27 (6H, d, J=6.8 Hz), 1.30 (6H, d, J=6.8 Hz), 2.08-2.17 (2H, m), 2.42 (3H, s), 2.43-2.47 (2H, m), 3.45 (2H, t, J=7.1 Hz), 3.55 (1H, sept, J=6.8 Hz), 3.89 (1H, sept, J=6.8 Hz), 6.92 (1H, s), 7.33 (1H, t, J=7.8 Hz), 7.43 (1H, t, J=7.8 Hz), 7.81 (1H, d, J=7.8 Hz), 7.92 (1H, d, J=7.8 Hz), 8.90 (1H, br s).
EIMS m/z (relative intensity): 491 (M+), 69 (100).
Example 76 (Compound(No. 854 in Table)
Production of 5-(benzothiazol-2-ylthio)-N-[2,4-bis(isopropylthio)-6-methyl-3-pyridyl]pentanamide:
The reaction and the treatment were conducted in the same manner as in Example 70 except that 2-mercaptobenzothiazole was used instead of 2-mercaptobenzoxazole to obtain the desired compound as a colorless powdery crystal.
Melting point: 107-109° C.
IR (KBr) cm−1: 3441, 3215, 2963, 1656, 1557, 1523, 1460, 1429, 996.
1H-NMR (d6-DMSO) δ: 1.27 (6H, d, J=6.8 Hz), 1.30 (6H, d, J=6.8 Hz), 1.76-1.85 (2H, m), 1.86-1.96 (2H, m), 2.26-2.40 (2H, m), 2.42 (3H, s), 3.39 (2H, t, J=7.1 Hz), 3.54 (1H, sept, J=6.8 Hz), 3.89 (1H, sept, J=6.8 Hz), 6.91 (1H, s), 7.33 (1H, td, J=8.1, 1.2 Hz), 7.43 (1H, td, J=8.1, 1.2 Hz), 7.82 (1H, dd, J=8.1, 1.2 Hz), 7.92 (1H, dd, J=8.1, 1.2 Hz), 8.75 (1H, br s).
EIMS m/z (relative intensity): 505 (M+), 221 (100).
Example 77 (Compound No. 855 in Table)
Production of 6-(benzothiazol-2-ylthio)-N-[2,4-bis(isopropylthio)-6-methyl-3-pyridyl]hexanamide:
The reaction and the treatment were conducted in the same manner as in Example 36 except that 2-mercaptobenzothiazole was used instead of 2-mercaptobenzoxazole to obtain the desired compound as a colorless crystal.
Melting point: 84-86° C.
IR (KBr) cm−1: 3436, 3212, 2961, 2925, 1655, 1555, 1522, 1428.
1H-NMR (d6-DMSO) δ: 1.30 (6H, d, J=6.6 Hz), 1.33 (6H, d, J=6.8 Hz), 1.54-1.62 (2H, m), 1.65-1.73 (2H, m), 1.85 (2H, quint, J=7.0 Hz), 2.22-2.33 (2H, m), 2.43 (3H, s), 3.38 (2H, t, J=7.0 Hz), 3.57 (1H, sept, J=6.6 Hz), 3.91 (1H, sept, J=6.8 Hz), 6.93 (1H, s), 7.34 (1H, t, J=7.8 Hz), 7.44 (1H, t, J=7.8 Hz), 7.83 (1H, d, J=7.8 Hz), 7.93 (1H, d, J=7.8 Hz), 8.73 (1H, br s).
EIMS m/z (relative intensity): 519 (M+), 235 (100).
Example 78 (Compound No. 856 in Table)
Production of 7-(benzothiazol-2-ylthio)-N-[2,4-bis(isopropylthio)-6-methyl-3-pyridyl]heptanamide:
The reaction and the treatment were conducted in the same manner as in Example 71 except that 2-mercaptobenzothiazole was used instead of 2-mercaptobenzoxazole to obtain the desired compound as a colorless crystal.
Melting point: 74-76° C.
IR (KBr) cm−1: 3436, 3200, 3158, 2961, 2928, 1654, 1525, 1427.
1H-NMR (d6-DMSO) δ: 1.29 (6H, d, J=6.6 Hz), 1.32 (6H, d, J=6.8 Hz), 1.43-1.55 (4H, m), 1.65 (2H, quint, J=7.2 Hz), 1.83 (2H, quint, J=7.2 Hz), 2.22-2.33 (2H, m), 2.43 (3H, s), 3.37 (2H, t, J=7.2 Hz), 3.56 (1H, sept, J=6.6 Hz), 3.90 (1H, sept, J=6.8 Hz), 6.93 (1H, s), 7.34 (1H, td, J=7.7, 1.2 Hz), 7.44 (1H, td, J=7.7, 1.2 Hz), 7.83 (1H, dd, J=7.7, 1.2 Hz), 7.94 (1H, dd, J=7.7, 1.2 Hz), 8.68 (1H, br s).
EIMS m/z (relative intensity): 533 (M+), 249 (100).
Example 79 (Compound No. 857 in Table)
Production of 8-(benzothiazol-2-ylthio)-N-[2,4-bis(isopropylthio)-6-methyl-3-pyridyl]octanamide:
The reaction and the treatment were conducted in the same manner as in Example 72 except that 2-mercaptobenzothiazole was used instead of 2-mercaptobenzoxazole to obtain the desired compound as a colorless neddle crystal.
Melting point: 107-108° C.
IR (KBr) cm−1: 3239, 1664, 1559, 1526, 1456, 1428.
1H-NMR (d6-DMSO) δ: 1.29 (6H, d, J=6.8 Hz), 1.31 (6H, d, J=6.8 Hz), 1.34-1.54 (6H, m), 1.55-1.70 (2H, m), 1.73-1.88 (2H, m), 2.15-2.29 (2H, m), 2.42 (3H, s), 3.35 (2H, t, J=7.3 Hz), 3.54 (1H, sept, J=6.8 Hz), 3.89 (1H, sept, J=6.8 Hz), 6.90 (1H, s), 7.31 (1H, t, J=7.8 Hz), 7.42 (1H, t, J=7.8 Hz), 7.81 (1H, d, J=7.8 Hz), 7.90 (1H, d, J=7.8 Hz), 8.59 (1H, br s).
EIMS m/z (relative intensity): 547 (M+), 263 (100).
Example 80 (Compound No. 858 in Table)
Production of 9-(benzothiazol-2-ylthio)-N-[2,4-bis(isopropylthio)-6-methyl-3-pyridyl]nonanamide:
The reaction and the treatment were conducted in the same manner as in Example 73 except that 2-mercaptobenzothiazole was used instead of 2-mercaptobenzoxazole to obtain the desired compound as a pale yellow oil.
IR (Cap) cm−1: 3243, 2962, 2927, 1668, 1559, 1526, 1456.
1H-NMR (d6-DMSO) δ: 1.28 (6H, d, J=6.8 Hz), 1.31 (6H, d, J=6.8 Hz), 1.28-1.50 (8H, m), 1.55-1.65 (2H, m), 1.80 (2H, quint, J=7.0 Hz), 2.17-2.27 (2H, m), 2.42 (3H, s), 3.34 (2H, t, J=7.0 Hz), 3.55 (1H, sept, J=6.8 Hz), 3.89 (1H, sept, J=6.8 Hz), 6.91 (1H, s), 7.32 (1H, td, J=7.1, 1.2 Hz), 7.43 (1H, td, J=7.1, 1.2 Hz), 7.81 (1H, dd, J=7.1, 1.2 Hz), 7.91 (1H, dd, J=7.1, 1.2 Hz), 8.65 (1H, br s).
EIMS m/z (relative intensity): 561 (M+), 277 (100).
Example 81 (Compound No. 861 in Table)
Production of 2-(benzimidazol-2-ylthio)-N-[2,4-bis(isopropylthio)-6-methyl-3-pyridyl]acetamide:
The reaction and the treatment were conducted in the same manner as in Example 53 except that 2-bromo-N-[2,4-bis(isopropylthio)-6-methylpyridyl]acetamide was used instead of 2-bromo-N-[2,4-bis(methylthio)-6-methylpyridyl]acetamide to obtain the desired compound as a colorless needle crystal.
Melting point: 223-224° C.
IR (KBr) cm−1: 3437, 3138, 3106, 2960, 1668, 1534, 1414.
1H-NMR (CDCl3) δ: 1.22 (6H, d, J=6.8 Hz), 1.25 (6H, d, J=6.8 Hz), 2.42 (3H, s), 3.41 (3H, sept, J=6.8 Hz), 3.95 (1H, sept, J=6.8 Hz), 4.05 (2H, H), 6.69 (1H, s), 7.18 (1H, t, J=6.1 Hz), 7.19 (1H, t, J=6.1 Hz), 7.34 (5H, br s), 7.62 (1H, br s), 9.33 (1H, br s), 10.61 (1H, br s).
EIMS m/z (relative intensity): 446 (M+), 371 (100).
Elemental analysis: as C21H26N4OS3; calculated: C, 56.47; H, 5.87; N, 12.54. found: C, 56.42; H, 5.87; N, 12.56.
Example 82 (Compound No. 863 in Table)
Production of 4-(benzomidazol-2-ylthio)-N-[2,4-bis(isopropylthio)-6-methyl-3-pyridyl]butanamide:
The reaction and the treatment were conducted in the same manner as in Example 69 except that 2-mercaptobenzimidazole was used instead of 2-mercaptobenzoxazole to obtain the desired compound as a pale-yellow powdery crystal.
Melting point: 209-211° C.
IR (KBr) cm−1: 3480, 3196, 2963, 1664, 1557, 1529, 1428.
1H-NMR (d6-DMSO) δ: 1.25 (6H, d, J=6.8 Hz), 1.28 (6H, d, J=6.8 Hz). 2.04 (2H, quint, J=7.1 Hz), 2.43 (3H, s), 2.44 (2H, t, J=7.1 Hz), 3.36 (2H, t, J=7.1 Hz). 3.61 (1H, sept, J=6.8 Hz), 3.86 (1H, sept, J=6.8 Hz), 6.96 (1H, s), 7.09 (1H, dd, J=7.3, 5.4 Hz), 7.12 (1H, dd, J=7.3, 5.4 Hz), 7.35 (1H, m), 7.49 (1H, m), 9.38 (1H, s), 12.53 (1H, s).
EIMS m/z (relative intensity): 474 (M+), 207 (100).
Example 83 (Compound No. 864 in Table)
Production of 5-(benzimidazol-2-ylthio)-N-[2,4-bis(isopropylthio)-6-methyl-3-pyridyl]pentanamide:
The reaction and the treatment were conducted in the same manner as in Example 70 except that 2-mercaptobenimidazole was used instead of 2-mercaptobenzoxazole to obtain the desired compound as a colorless powdery crystal.
Melting point: 175-176° C.
IR (KBr) cm−1: 3447, 3195, 2965, 1663, 1557, 1526, 1428, 1400.
1H-NMR (d6-DMSO) δ: 1.28 (6H, d, J=6.8 Hz), 1.30 (6H, d, J=6.8 Hz), 1.75-1.90 (4H, m), 2.26-2.38 (2H, m), 2.42 (3H, s), 3.30 (2H, t, J=7.1 Hz), 3.54 (1H, sept, J=6.8 Hz), 3.88 (1H, sept, J=6.8 Hz), 6.91 (1H, s), 7.07 (1H, t, J=6.1 Hz), 7.08 (1H, t, J=6.1 Hz), 7.32 (1H, d, J=6.1 Hz), 7.46 (1H, d, J=6.1 Hz), 8.72 (1H, br s).
EIMS m/z (relative intensity): 488 (M+), 221 (100).
Example 84 (Compound No. 865 in Table)
Production of 6-(benzimidazol-2-ylthio)-N-[2,4-bis(isopropylthio)-6-methyl-3-pyridyl]hexanamide:
The reaction and the treatment were conducted in the same manner as in Example 36 except that 2-mercaptobenzimidazole was used instead of 2-mercaptobenzoxazole to obtain the desired compound as a colorless powdery crystal.
Melting point: 175-176° C.
1H-NMR (d6-DMSO) δ: 1.30 (6H, d, J=6.7 Hz), 1.32 (6H, d, J=6.7 Hz), 1.47-1.61 (2H, m), 1.62-1.72 (2H, m), 1.73-1.84 (2H, m), 2.18-2.35 (2H, m), 2.43 (3H, s), 3.21-3.33 (2H, m), 3.55 (1H, sept, J=6.7 Hz), 3.90 (1H, sept, J=6.7 Hz), 6.92 (1H, s), 7.03-7.12 (2H, m), 7.33 (1H, m), 7.47 (1H, m), 8.75 (1H, br s), 12.05 (1H, br s).
EIMS m/z (relative intensity): 502 (M+), 235 (100).
Example 85 (Compound No. 866 in Table)
Production of 7-(benzoimidazol-2-ylthio)-N-[2,4-bis(isopropylthio)-6-methyl-3-pyridyl]heptanamide:
The reaction and the treatment were conducted in the same manner as in Example 71 except that 2-mercaptobenzoimidazole was used instead of 2-mercaptobenzoxazole to obtain the desired compound as a pale-yellow needle crystal.
Melting point: 118-121° C.
IR (KBr) cm−1: 3393, 3219, 2963, 2928, 1663, 1559, 1526, 1439.
1H-NMR (d6-DMSO) δ: 1.29 (6H, d, J=6.6 Hz), 1.32 (6H, d, J=6.8 Hz), 1.41-1.53 (4H, m), 1.64 (2H, quint, J=7.2 Hz), 1.76 (2H, quint, J=7.2 Hz), 2.18-2.33 (2H, m), 2.43 (3H, s), 3.28 (2H, t, J=7.2 Hz), 3.56 (1H, sept, J=6.6 Hz), 3.90 (1H, sept, J=6.8 Hz), 6.93 (1H, s), 7.08 (1H, t, J=5.9 Hz), 7.09 (1H, t, J=5.9 Hz), 7.40 (1H, d, J=5.9 Hz), 7.41 (1H, d, J=5.9 Hz), 8.86 (1H, br s).
EIMS m/z (relative intensity): 516 (M+), 399 (100).
Example 86 (Compound No. 867 in Table)
Production of 8-(benzimidazol-2-ylthio)-N-[2,4-bis(isopropylthio)-6-methyl-3-pyridyl]octanamide:
The reaction and the treatment were conducted in the same manner as in Example 72 except that 2-mercaptobenzimidazole was used instead of 2-mercaptobenzoxazole to obtain the desired compound as a colorless powdery crystal.
Melting point: 170-171° C.
IR (KBr) cm−1: 3158, 2963, 2930, 1665, 1559, 1526, 1508, 1429.
1H-NMR (d6-DMSO) δ: 1.28 (6H, d, J=6.8 Hz), 1.31 (6H, d, J=6.8 Hz) 1.32-1.50 (6H, m), 1.56-1.66 (2H, m), 1.74 (2H, quint, J=7.3 Hz), 2.17-2.27 (2H, m), 2.42 (3H, s), 3.26 (2H, t, J=7.3 Hz), 3.54 (1H, sept, J=6.8 Hz), 3.89 (1H, sept, J=6.8 Hz), 6.91 (1H, s), 7.05-7.10 (2H, m), 7.32 (1H, m), 7.45 (1H, m), 8.65 (1H, br s).
EIMS m/z (relative intensity): 530 (M+), 413 (100).
Example 87 (Compound No. 868 in Table)
Production of 9-(benzimidazol-2-ylthio)-N-[2,4-bis(isopropylthio)-6-methyl-3-pyridyl]nonanamide:
The reaction and the treatment were conducted in the same manner as in Example 73 except that 2-mercaptobenzimidazole was used instead of 2-mercaptobenzoxazole to obtain the desired compound as a pale brown powdery crystal.
Melting point: 112-114° C.
IR (KBr) cm−1: 3435, 3185, 2927, 1660, 1558, 1526, 1437.
1H-NMR (d6-DMSO) δ: 1.28 (6H, d, J=6.8 Hz) 1.31 (6H, d, J=6.8 Hz), 1.28-1.48 (8H, m), 1.52-1.65 (2H, m), 1.73 (2H, quint, J=7.1 Hz), 2.18-2.28 (2H, m), 2.42 (3H, s), 3.25 (2H, t, J=7.1 Hz), 3.55 (1H, sept, J=6.8 Hz), 3.89 (1H, sept, J=6.8 Hz), 6.91 (1H, s), 7.07 (1H, t, J=6.1 Hz), 7.08 (1H, t, J=6.1 Hz), 7.32 (1H, d, J=6.1 Hz), 7.46 (1H, d, J=6.1 Hz), 8.80 (1H, br s), 12.05 (1H, br s).
EIMS m/z (relative intensity): 544 (M+), 151 (100).
Example 88 (Compound No. 1145 in Table)
Production of 6-(benzoxazole-2-ylthio)-N-[2-methyl-4,6-bis(methylthio)-5-pyrimidyl)hexanamide:
4,6-Dihydroxy-2-methylpyrimidine (1.0 g, 7.9 mmol) was added gradualy to ice-cooled fuming nitric acid (3 ml) stirring. The mixture was stirred for 2 hours cooling with ice and for 1 hour at the room temperature, and then the precipitated crystal was filtered and dried to obtain 207 mg (yield 15%) of 4,6-dihydroxy-2-methyl-5-nitropyrimidine.
This nitropyrimidine (205 mg, 1.2 mmol) was dissolved in phosphoryl chloride (1 ml) and diethylaniline (0.3 ml, 1.9 mmol) was added thereto, and the mixture was stirred for 1 hour at 100° C. and for 1 hour at 120° C. The reaction solution was added to ice and then extracted with ethyl acetate. The organic layer was washed with water and then with a saturated aqueous solution of sodium chloride, and dried over magnesium sulfate. Thereafter, the solvent was distilled off, and the resulting crude product was purified through silica gel chromatography (eluent-hexane:ethyl acetate=20:1) to obtain 194 mg (yield 77%) of 4,6-dichloro-2-methyl-5-nitropyrimidine as a colorless needle crystal.
And then a methanol (10 mml) solution of 4,6-dichloro-2-methyl-5-nitropyrimidine (1.0 g, 4.81 mmol) was added dropwise to a methanol (10 ml) solution of sodium thiomethoxide (780 mg, 10.6 mmol) while being cooled with ice, and after the mixture was stirred for 1 hour while being cooled with ice, water added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with water and then with a saturated aqueous solution of sodium chloride, and dried over magnesium sulfate. Thereafter, the solvent was distilled off, and the resulting crude product was recrystalized with ethyl acetate-hexan to obtain 609 mg (yield 55%) of 4,6-bis(methylthio)-2-methyl-5-nitropyrimidine.
Potassium carbonate (119 mg, 0.865 mmol) and pratinum dioxide (40 mg, 0.18 mmol) were added to ethanol (100 ml) solution of this nitropyrimidine (100 mg, 0.43 mmol) and stirred in hydrogen. After 1.5 hours, the reaction mixture was filtered, the filtrate was distilled off, and the resulting crude product was purified through silica gel chromatography (eluent-hexane:ethyl acetate 6:1) to obtain 66 mg (yield 76%) of 5-amino-4,6-bis(methylthio)-2-methylpyrimidine.
And then the reaction and the treatment were conducted in the same manner as in Example 18 except that 5-amino-4,6-bis(methylthio)-2-methylthiopyrimidine was used instead of 3-amino-2,4-bis(methylthio)-6-methylpyridine to obtain the desired compound as a colorless powdery crystal.
Melting point: 148-151° C.
IR (KBr) cm−1: 3440, 3245, 2929, 1660, 1530.
1H-NMR (CDCl3) δ: 1.43-1.55 (2H, m), 1.57-1.69 (2H, m), 1.72-1.84 (2H, m), 2.14-2.29 (2H, m), 2.38 (6H, s), 2.48 (3H, m), 3.28 (2H, t, J=7.3 Hz), 7.21 (1H, td, J=7.4, 1.7 Hz), 7.24 (1H, td, J=7.4, 1.7 Hz), 7.49 (1H, dd, J=7.4 Hz), 7.51 (1H, dd, J=7.4, 1.7 Hz), 8.91 (1H, br s).
EIMS m/z (relative intensity): 448 (M+, 100).
Example 89 (Compound No. 1247 in Table)
Production of 2-(7-trifluoromethylbenzoxazol-2-ylthio)-N-[2,4-bis(methylthio)-6-methyl-3-pyridyl]acetamide:
The reaction and the treatment were conducted in the same manner as in Example 49 except that 2-mercapto-7-trifluoromethylbenzoxazole was used instead of 2-mercaptobenzoxazole to obtain the desired compound as a colorless needle crystal.
Melting point: 207-209° C.
IR (KBr) cm−1: 3435, 3235, 1673, 1509, 1433, 1329, 1130.
1H-NMR (CDCl3) δ: 2.32 (3H, s), 2.41 (3H, s), 2.48 (3H, s), 4.14 (2H, s), 6.81 (1H, s), 7.41 (1H, t, J=7.8 Hz), 7.52 (1H, d, J=7.8 Hz), 7.79 (1H, d, J=7.8 Hz), 8.46 (1H, br s).
EIMS m/z (relative intensity): 459 (M+), 227 (100).
Elemental analysis: as C18H16F3N3O2S3; Calculated: C, 47.05; H, 3.51; N, 9.14. Found: C, 46.84; H, 3.66; N, 9.03.
Example 90 (Compound No. 1250 in Table)
Production of 5-(7-trifluoromethylbenzoxazol-2-ylthio)-N-[2,4-bis(methylthio)-6-methyl-3-pyridyl]pentanamide:
The reaction and the treatment were conducted in the same manner as in Example 46 except that 2-mercapto-7-trifluoromethylbenzoxazole was used instead of 2-mercaptobenzoxazole to obtain the desired compound as a colorless crystal.
Melting point: 179-180° C.
1H-NMR (d6-DMSO) δ: 1.75-1.87 (2H, m), 1.87-2.00 (2H, m), 2.37 (3H, s), 2.39 (3H, s), 2.30-2.39 (2H, m), 2.43 (3H, s), 3.36-3.46 (2H, m), 6.84 (1H, s), 7.50 (1H, t, J=7.9 Hz), 7.59 (1H, d, J=7.9 Hz). 7.89 (1H, d, J=7.9 Hz), 8.85 (1H, br s).
EIMS m/z (relative intensity): 501 (M+), 200 (100).
Example 91 (Compound No. 1252 in Table)
Production of 7-(7-trifluoromethylbenzoxazol-2-ylthio)-N-[2,4-bis(methylthio)-6-methyl-3-pyridyl]heptanamide:
The reaction and the treatment were conducted in the same manner as in Example 47 except that 2-mercapto-7-trifluoromethylbenzoxazole was used instead of 2-mercaptobenzoxazole to obtain the desired compound as a colorless needle crystal.
Melting point: 129-131° C.
IR (KBr) cm−1: 3247, 1662, 1505, 1435, 1337, 1128.
1H-NMR (d6-DMSO) δ: 1.40-1.55 (4H, m), 1.60-1.71 (2H, m), 1.80-1.89 (2H, m), 2.20-2.34 (2H, m), 2.38 (3H, s), 2.40 (3H, s), 2.44 (3H, s), 3.37 (2H, t, J=7.1 Hz), 6.84 (1H, s), 7.49 (1H, t, J=7.8 Hz), 7.58 (1H, d, J=7.8 Hz), 7.88 (1H, d, J=7.8 Hz), 8.78 (1H, br s).
EIMS m/z (relative intensity): 529 (M+), 200 (100).
Example 92 (Compound No. 1253 in Table)
Production of 8-(7-trifluoromethylbenzoxazol-2-ylthio)-N-[2,4-bis(methylthio)-6-methyl-3-pyridyl]octanamide:
The reaction and the treatment were conducted in the same manner as in Example 48 except that 2-mercapto-7-trifluoromethylbenzoxazole was used instead of 2-mercaptobenzoxazole to obtain the desired compound as a colorless powdery crystal.
Melting point: 115-116° C.
1H-NMR (d6-DMSO) δ: 1.40-1.54 (6H, m), 1.56-1.72 (2H, m), 1.85 (2H, quint, J=7.0 Hz), 2.18-2.36 (2H, m), 2.40 (3H, s), 2.43 (3H, s), 2.46 (3H, s), 3.38 (2H, t, J=7.3 Hz), 6.86 (1H, s), 7.51 (1H, t, J=7.5 Hz), 7.60 (1H, d, J=7.5 Hz), 7.90 (1H, d, J=7.5 Hz), 8.16 (1H, br s).
EIMS m/z (relative intensity): 543 (M+), 200 (100).
Example 93 (Compound No. 1260 in Table)
Production of 5-(5-chloro-7-isopropyl-4-methylbenzoxazol-2-ylthio)-N-[2,4-bis(methylthio)-6-methyl-3-pyridyl]pentanamide:
The reaction and the treatment were conducted in the same manner as in Example 46 except that 5-chloro-7-isopropyl-2-mercapto-4-metylbenzoxazole was used instead of 2-mercaptobenzoxazole to obtain the desired compound as a colorless needle crystal.
Melting point: 155-156° C.
1H-NMR (d6-DMSO) δ: 1.31 (6H, d, J=7.1 Hz), 1.72-1.85 (2H, m), 1.85-1.98 (2H, m), 2.36 (3H, s), 2.39 (3H, s), 2.32-2.40 (2H, m), 2.43 (3H, s), 2.46 (3H, s), 3.22 (1H, sept, J=7.1 Hz), 3.31-3.42 (2H, m), 6.84 (1H, s), 7.13 (1H, s), 8.73 (1H, br s).
EIMS m/z (relative intensity): 525 (M+: 37 Cl), 523 (M30 : 35Cl), 200 (100).
Example 94 (Compound No. 1262 in Table)
Production of 7-(5-chloro-7-isopropyl-4-methylbenzoxazol-2-ylthio)-N-[2,4-bis(methylthio)-6-methyl-3-pyridyl]heptanamide:
The reaction and the treatment were conducted in the same manner as in Example 47 except that 5-chloro-7-isopropyl-2-mercapto-4-metylbenzoxazole was used instead of 2-mercaptobenzoxazole to obtain the desired compound as a colorless prism crystal.
Melting point: 129-131° C.
IR (KBr) cm−1: 3413, 3241, 2964, 2924, 1655, 1567, 1505, 1490, 1435, 1149.
1H-NMR (d6-DMSO) δ: 1.31 (6H, d, J=7.1 Hz), 1.40-1.55 (4H, m), 1.56-1.70 (2H, m), 1.83 (2H, quint, J=7.1 Hz), 2.30 (2H, t, J=7.1 Hz), 2.38 (3H, s), 2.40 (3H, s), 2.41 (3H, s), 2.46 (3H, s), 3.21 (1H, sept, J=7.1 Hz), 3.34 (2H, t, J=7.1 Hz), 6.84 (1H, s), 7.14 (1H, s), 8.51 (1H, br s).
EIMS m/z (relative intensity): 553 (M+: 37Cl) 551 (M+: 35Cl), 200 (100).
Example 95 (Compound No. 1260 in Table)
Production of 8-(5-chloro-7-isopropyl-4-methylbenzoxazol-2-ylthio)-N-[2,4-bis(methylthio)-6-methyl-3-pyridyl]octanamide:
The reaction and the treatment were conducted in the same manner as in Example 48 except that 5-chloro-7-isopropyl-2-mercapto-4-methylbenzoxazole was used instead of 2-mercaptobenzoxazole to obtain the desired compound as a colorless needle crystal.
Melting point: 128-131° C.
IR (KBr) cm−1: 3423, 3231, 2929, 1662, 1504, 1489.
1H-NMR (d6-DMSO) δ: 1.32 (6H, d, J=7.0 Hz), 1.38-1.43 (4H, m), 1.49 (2H, quint, J=7.2 Hz), 1.60-1.69 (2H, m), 1.84 (2H, quint, J=7.2 Hz), 2.23-2.33 (2H, m), 2.40 (3H, s), 2.42 (3H, s), 2.45 (3H, s), 2.47 (3H, s), 3.23 (1H, sept, J=7.0 Hz), 3.35 (1H, t, J=7.2 Hz), 6.86 (1H, s), 7.15 (1H, s), 8.78 (1H, br s).
EIMS m/z (relative intensity): 567 (M+; 37Cl), 565 (M+; 35Cl), 200 (100).
Example 96 (Compound No. 1267 in Table)
Production of 2-(7-trifluoromethylbenzoxazol-2-ylthio)-N-[2,4-bis(ethylthio)-6-methyl-3-pyridyl]acetamide:
The reaction and the treatment were conducted in the same manner as in Example 89 except that 3-amino-2,4-bis(ethylthio)-6-methylpyridine was used instead of 3-amino-2,4-bis(methylthio)-6-methylpyridine to obtain the desired compound as a colorless prism crystal.
Melting point: 182-183° C.
IR (KBr) cm−1: 3435, 3244, 1663, 1508, 1432, 1332.
1H-NMR (CDCl3) δ: 1.16 (3H, t, J=7.4 Hz), 1.20 (3H, t, J=7.4 Hz), 2.42 (3H, s), 2.81 (2H, q, J=7.4 Hz), 3.03 (2H, q, J=7.4 Hz), 4.14 (2H, s), 6.63 (1H, s), 7.40 (1H, t, J=7.8 Hz), 7.52 (1H, d, J=7.8 Hz), 7.68 (1H, d, J=7.8 Hz), 8.34 (1H, br s).
EIMS m/z (relative intensity): 487 (M+), 235 (100).
Elemental Analysis: C20H20F3N3O2S3; Calculated: C, 49.27; H, 4.13; N, 8.62; F, 11.69. Found: C, 49.41; H, 4.20; N, 8.62; F, 11.59.
Example 97 (Compound No. 1269 in Table)
Production of 4-(7-trifluoromethylbenzoxazol-2-ylthio)-N-[2,4-bis(ethylthio)-6-methyl-3-pyridyl]butanamide:
The reaction and the treatment were conducted in the same manner as in Example 57 except that 2-mercapto-7-trifluoromethylbenzoxazole was used instead of 2-mercaptobenzoxazole to obtain the desired compound as a colorless powdery crystal.
Melting point: 148-150° C.
IR (KBr) cm−1: 3439, 3256, 2975, 2929, 1656, 1509, 1433, 1332, 1125.
1H-NMR (d6-DMSO) δ: 1.23 (3H, t, J=7.3 Hz), 1.24 (3H, t, J=7.3 Hz), 2.04-2.22 (2H, m), 2.42 (3H, s), 2.47-2.48 (2H, m), 2.92 (2H, q, J=7.3 Hz), 3.04 (2H, q, J=7.3 Hz), 3.42-3.51 (2H, m), 6.87 (1H, s), 7.51 (1H, t, J=7.8 Hz) 7.59 (1H, d, J=7.8 Hz), 7.89 (1H, d, J=7.8 Hz), 8.95 (1H, br s).
EIMS m/z (relative intensity): 515 (M+), 227 (100).
Example 98 (Compound No. 1270 in Table)
Production of 5-(7-trifluoromethylbenzoxazol-2-ylthio)-N-[2,4-bis(ethylthio)-6-methyl-3-pyridyl]pentanamide:
The reaction and the treatment were conducted in the same manner as in Example 58 except that 2-mercapto-7-trifluoromethylbenzoxazole was used instead of 2-mercaptobenzoxazole to obtain the desired compound as a colorless powdery crystal.
Melting point: 155-156° C.
1H-NMR (d6-DMSO) δ: 1.20-1.30 (6H, m), 1.73-2.05 (4H, m), 2.30-2.41 (2H, m), 2.42 (3H, s), 2.85-3.00 (2H, m), 3.01-3.09 (2H, m), 3.37-3.48 (2H, m), 6.88 (1H, s), 7.51 (1H, t, J=7.5 Hz), 7.60 (1H, d, J=7.5 Hz), 7.90 (1H, d, J=7.5 Hz), 8.75 (1H, br s).
EIMS m/z (relative intensity): 529 (M+), 227 (100).
Example 99 (Compound No. 1272 in Table)
Production of 7-(7-trifluoromethylbenzoxazol-2-ylthio)-N-[2,4-bis(ethylthio)-6-methyl-3-pyridyl]heptanamide:
The reaction and the treatment were conducted in the same manner as in Example 59 except that 2-mercapto-7-trifluoromethylbenzoxazole was used instead of 2-mercaptobenzoxazole to obtain the desired compound as a colorless needle crystal.
Melting point: 127-128° C.
IR (KBr) cm−1: 3448, 1659, 1506, 1336, 1128, 1116.
1H-NMR (d6-DMSO) δ: 1.24 (3H, t, J=7.3 Hz), 1.25 (3H, t, J=7.3 Hz), 1.39-1.56 (4H, m), 1.56-1.72 (2H, m), 1.78-1.91 (2H, m), 2.19-2.33 (2H, m), 2.42 (3H, s), 2.92 (2H, q, J=7.3 Hz), 3.05 (2H, q, J=7.33 Hz), 3.37 (2H, t, J=7.2 Hz), 6.86 (1H, s), 7.49 (1H, t, J=7.9 Hz), 7.58 (1H, d, J=7.9 Hz), 7.88 (1H, d, J=7.9 Hz), 8.67 (1H, br s).
EIMS m/z (relative intensity): 557 (M+), 227 (100).
Example 100 (Compound No. 1273 in Table)
Production of 8-(7-trifluoromethylbenzoxazol-2-ylthio)-N-[2,4-bis(ethylthio)-6-methyl-3-pyridyl]octanamide:
The reaction and the treatment were conducted in the same manner as in Example 60 except that 2-mercapto-7-trifluoromethylbenzoxazole was used instead of 2-mercaptobenzoxazole to obtain the desired compound as a colorless crystal.
Melting point: 99-100° C.
IR (KBr) cm−1: 3425, 3245, 2923, 1655, 1509, 1433, 1332, 1125.
1H-NMR (d6-DMSO) δ: 1.26 (3H, t, J=7.3 Hz), 1.27 (3H, t, J=7.3 Hz), 1.38-1.43 (4H, m), 1.49 (2H, quint, J=7.2 Hz), 1.60-1.68 (2H, m), 1.85 (2H, quint, J=7.2 Hz), 2.20-2.30 (2H, m), 2.43 (3H, s), 2.94 (2H, q, J=7.3 Hz), 3.06 (2H, q, J=7.3 Hz), 3.38 (2H, t, J=7.2 Hz), 6.88 (1H, s), 7.51 (1H, t, J=7.8 Hz), 7.60 (1H, d, J=7.8 Hz), 7.90 (1H, d, J=7.8 Hz), 8.73 (1H, br s).
EIMS m/z (relative intensity): 571 (M+), 227 (100).
Example 101 (Compound No. 1274 in Table)
Production of 9-(7-trifluoromethylbenzoxazol-2-ylthio)-N-[2,4-bis(ethylthio)-6-methyl-3-pyridyl]nonanamide:
The reaction and the treatment were conducted in the same manner as in Example 28 except that 2-mercapto-7-trifluoromethylbenzoxazole was used instead of 2-mercaptobenzoxazole t o obtain the desired compound as a colorless powdery crystal.
Melting point: 115-116° C.
1H-NMR (d6-DMSO) δ: 1.26 (3H, t, J=7.2 Hz), 1.27 (3H, t, J=7.2 Hz), 1.31-1.55 (8H, m), 1.57-1.69 (2H, m), 1.84 (2H, quint, J=6.9 Hz), 2.18-2.34 (2H, m), 2.43 (3H, s), 2.94 (2H, q, J=7.2 Hz), 3.06 (2H, q, J=7.2 Hz), 3.37 (2H, t, J=7.3 Hz), 6.88 (1H, s), 7.51 (1H, t, J=8.4 Hz), 7.61 (1H, d, J=8.4 Hz), 7.90 (1H, d, J=8.4 Hz), 8.73 (1H, br s).
EIMS m/z (relative intensity): 585 (M+) 227 (100).
Example 102 (Compound No. 1279 in Table)
Production of 4-(5-chloro-7-isopropyl-4-methylbenzoxazol-2-ylthio)-N-[2,4-bis(ethylthio)-6-methyl-3-pyridyl]butanamide:
The reaction and the treatment were conducted in the same manner as in Example 57 except that 5-chloro-7-isopropyl-2-mercapto-4-methylbenzoxazole was used instead of 2-mercaptobenzoxazole to obtain the desired compound as a colorless needle crystal.
Melting point: 122-123° C.
IR (KBr) cm−1: 3258, 1665, 1502, 1145.
1H-NMR (d6-DMSO) δ: 1.23 (3H, t, J=7.3 Hz), 1.24 (3H, t, J=7.3 Hz), 1.31 (6H, d, J=6.8 Hz), 2.15 (2H, t, J=7.0 Hz), 2.42 (3H, s), 2.46 (3H, s), 2.47-2.50 (2H, m), 2.92 (2H, q, J=7.3 Hz), 3.04 (2H, q, J=7.3 Hz), 3.22 (1H, sept, J=6.8 Hz), 3.43 (2H, t, J=7.0 Hz), 6.87 (1H, s), 7.14 (1H, s), 8.83 (1H, br s).
EIMS m/z (relative intensity): 559 (M+: 37Cl), 557 (M+: 35Cl), 227 (100).
Example 103 (Compound No. 1280 in Table)
Production of 5-(5-chloro-7-isopropyl-4-methylbenzoxazol-2-ylthio)-N-[2,4-bis(ethylthio)-6-methyl-3-pyridyl]pentanamide:
The reaction and the treatment were conducted in the same manner as in Example 58 except that 5-chloro-7-isopropyl-2-mercapto-4-methylbenzoxazole was used instead of 2-mercaptobenzoxazole to obtain the desired compound as a colorless powdery crystal.
Melting point: 141-142° C.
1H-NMR (d6-DMSO) δ: 1.25 (3H, t, J=7.4 Hz), 1.26 (3H, t, J=7.4 Hz), 1.32 (6H, d, J=6.9 Hz), 1.75-1.86 (2H, m), 1.87-2.00 (2H, m), 2.30-2.40 (2H, m), 2.43 (3H, s), 2.45-2.52 (3H, s), 2.92 (2H, q, J=7.4 Hz), 3.04 (2H, q, J=7.4 Hz), 3.23 (1H, sept, J=6.9 Hz), 3.33-3.43 (2H, m), 6.88 (1H, s), 7.15 (1H, s), 8.82 (1H, br s).
EIMS m/z (relative intensity): 553 (M+; 37Cl), 551 (M+; 35Cl), 227 (100).
Example 104 (Compound No. 1282 in Table)
Production of 7-(5-chloro-7-isopropyl-4-methylbenzoxazol-2-ylthio)-N-[2,4-bis(ethylthio)-6-methyl-3-pyridyl]heptanamide:
The reaction and the treatment were conducted in the same manner as in Example 59 except that 5-chloro-7-isopropyl-2-mercapto-4-methylbenzoxazole was used instead of 2-mercaptobenzoxazole to obtain the desired compound as a colorless prism crystal.
Melting point: 117-120° C.
IR (KBr) cm−1: 3320, 1668, 1506, 1482, 1150.
1H-NMR (d6-DMSO) δ: 1.24 (3H, t, J=7.3 Hz), 1.25 (3H, t, J=7.3 Hz), 1.31 (6H, d, J=6.8 Hz), 1.39-1.57 (4H, m), 1.57-1.71 (2H, m), 1.77-1.89 (2H, m), 2.19-2.30 (2H, m), 2.42 (3H, s), 2.46 (3H, s), 2.92 (2H, q, J=7.3 Hz), 3.05 (2H, q, J=7.3 Hz), 3.21 (1H, sept, J=6.8 Hz), 3.33 (2H, t, J=7.2 Hz), 6.86 (1H, s), 7.13 (1H, s), 8.66 (1H, br s).
EIMS m/z (relative intensity): 581 (M+: 37Cl), 579 (M+: 35Cl), 227 (100).
Example 105 (Compound No. 1283 in Table)
Production of 8-(5-chloro-7-isopropyl-4-methylbenzoxazol-2-ylthio)-N-[2,4-bis(ethylthio)-6-methyl-3-pyridyl]octanamide:
The reaction and the treatment were conducted in the same manner as in Example 60 except that 5-chloro-7-isopropyl-2-mercapto-4-methylbenzoxazole was used instead of 2-mercaptobenzoxazole to obtain the desired compound as a colorless needle crystal.
Melting point: 82-84° C.
IR (KBr) cm−1: 3435, 3259, 2929, 1655, 1504, 1490.
1H-NMR (d6-DMSO) δ: 1.26 (3H, t, J=7.3 Hz), 1.27 (3H, t, J=7.3 Hz), 1.32 (6H, d, J=6.8 Hz), 1.39-1.43 (4H, m), 1.49 (2H, quint, J=7.2 Hz), 1.60-1.68 (2H, m), 1.84 (2H, quint, J=7.2 Hz), 2.22-2.32 (2H, m), 2.43 (3H, s), 2.47 (3H, s), 2.94 (2H, q, J=7.3 Hz), 3.06 (2H, q, J=7.3 Hz), 3.22 (1H, sept, J=6.8 Hz), 3.35 (2H, t, J=7.2 Hz), 6.88 (1H, s), 7.15 (1H, s), 8.73 (1H, br s).
EIMS m/z (relative intensity): 595 (M+; 37Cl), 593 (M+; 35Cl),
Example 106 (Compound No. 1284 in Table)
Production of 9-(5-chloro-7-isopropyl-4-methylbenzoxazol-2-ylthio)-N-[2,4-bis(ethylthio)-6-methyl-3-pyridyl]nonanamide:
The reaction and the treatment were conducted in the same manner as in Example 28 except that 5-chloro-7-isopropyl-2-mercapto-4-methylbenzoxazole was used instead of 2-mercaptobenzoxazole to obtain the desired compound as a colorless powdery crystal.
Melting point: 93-94° C.
1H-NMR (d6-DMSO) δ: 1.27 (3H, t, J=7.3 Hz), 1.28 (3H, t, J=7.3 Hz), 1.32 (6H, d, J=7.0 Hz), 1.29-1.55 (8H, m), 1.56-1.69 (2H, m), 1.83 (2H, quint, J=6.9 Hz), 2.07-2.17 (2H, m), 2.43 (3H, s), 2.45-2.49 (3H, m), 2.94 (2H, q, J=7.3 Hz), 3.07 (2H, q, J=7.3 Hz), 3.22 (1H, sept, J=7.0 Hz), 3.34 (2H, t, J=7.3 Hz), 6.88 (1H, s), 7.15 (1H, s), 8.73 (1H, br s).
EIMS m/z (relative intensity): 609 (M+; 37Cl), 607 (M+; 35Cl), 229 (100).
Example 107 (Compound No. 1287 in Table)
Production of 2-(7-triffluoromethylbenzoxazol-2-ylthio)-N-[2,4-bis(isopropylthio)-6-methyl-3-pyridyl]acetamide:
The reaction and the treatment were conducted in the same manner as in Example 89 except that 2-bromo-N-[2,4-bis(isopropylthio)-6-methylpyridyl]amide was used instead of 2-bromo-[2,4-bis(methylthio)-6-methylpyridyl]acetamide to obtain the desired compound as a colorless needle crystal.
Melting point: 121-122° C.
IR (KBr) cm−1: 3426, 3210, 2967, 1655, 1507, 1431, 1329.
1H-NMR (CDCl3) δ: 1.17 (6H, d, J=6.8 Hz), 1.19 (6H, d, J=6.8 Hz), 2.42 (3H, s), 3.39 (1H, sept, J=6.8 Hz), 3.90 (1H, sept, J=6.8 Hz), 4.13 (2H, s), 6.68 (1H, s), 7.41 (1H, t, J=7.9 Hz), 7.52 (1H, d, J=7.9 Hz), 7.80 (1H, d, J=7.9 Hz), 8.30 (1H, br s).
EIMS m/z (relative intensity): 515 (M+), 181 (100).
Elemental analysis: as C22H24F3N3O2S3; Calculated: C, 51.25; H, 4.69; N, 8.15; F, 11.05. Found: C, 51.28; H, 4.73; N, 8.07; F, 11.02.
Example 108 (Compound No. 1289 in Table)
Production of 4-(7-trifluoromethylbenzoxazol-2-ylthio)-N-[2,4-bis(isopropylthio)-6-methyl-3-pyridyl]butanamide:
The reaction and the treatment were conducted in the same manner as in Example 69 except that 2-mercapto-7-trifluoromethylbenzoxazole was used instead of 2-mercaptobenzoxazole to obtain the desired compound as a colorless prism crystal.
Melting point: 135-136° C.
IR (KBr) cm−1: 3446, 3255, 2968, 1660, 1559, 1531, 1504, 1491, 1433, 1139.
1H-NMR (d6-DMSO) δ: 1.27 (6H, d, J=6.8 Hz), 1.29 (6H, d, J=6.8 Hz), 2.13-2.21 (2H, m), 2.42 (3H, s), 2.47-2.50 (2H, m), 3.44-3.50 (2H, m), 3.55 (1H, sept, J=6.8 Hz), 3.88 (1H, sept, J=6.8 Hz), 6.92 (1H, s), 7.51 (1H, t, J=7.8 Hz), 7.59 (1H, d, J=7.8 Hz), 7.88 (1H, d, J=7.8 Hz), 8.91 (1H, br s).
EIMS m/z (relative intensity): 543 (M+), 207 (100).
Example 109 (Compound No. 1290 in Table)
Production of 5-(7-trifluoromethylbenzoxazol-2-ylthio)-N-[2,4-bis(isopropylthio)-6-methyl-3-pyridyl]pentanamide:
The reaction and the treatment were conducted in the same manner as in Example 70 except that 2-mercapto-7-trifluoromethylbenzoxazole was used instead of 2-mercaptobenzoxazole to obtain the desired compound as a colorless needle crystal.
Melting point: 118-120° C.
IR (KBr) cm−1: 3208, 3163, 1663, 1506, 1431, 1328, 1139.
1H-NMR (d6-DMSO) δ: 1.27 (6H, d, J=6.8 Hz), 1.30 (6H, d, J=6.8 Hz), 1.73-1.87 (2H, m), 1.87-2.01 (2H, m), 2.23-2.38 (2H, m), 2.41 (3H, s), 3.41 (2H, t, J=7.0 Hz), 3.54 (1H, sept, J=6.8 Hz), 3.88 (1H, sept, J=6.8 Hz), 6.91 (1H, s), 7.49 (1H, t, J=7.9 Hz), 7.58 (1H, d, J=7.9 Hz), 7.88 (1H, d, J=7.9 Hz), 8.67 (1H, br s).
EIMS m/z (relative intensity): 557 (M+), 221 (100).
Example 110 (Compound No. 1291 in Table)
Production of 6-(7-trifluoromethylbenzoxazol-2-ylthio)-N-[2,4-bis(isopropylthio)-6-methyl-3-pyridyl]hexanamide:
The reaction and the treatment were conducted in the same manner as in Example 36 except that 2-mercapto-7-trifluoromethylbenzoxazole was used instead of 2-mercaptobenzoxazole to obtain the desired compound as a colorless needle crystal.
Melting point: 102-103° C.
IR (KBr) cm−1: 3136, 1648, 1507, 1431, 1332, 1129.
1H-NMR (d6-DMSO) δ: 1.28 (6H, d, J=6.8 Hz), 1.31 (6H, d, J=6.8 Hz), 1.49-1.76 (4H, m), 1.77-1.94 (2H, m), 2.19-2.32 (2H, m), 2.42 (3H, s), 3.38 (2H, t, J=7.3 Hz), 3.55 (1H, sept, J=6.8 Hz), 3.89 (1H, sept, J=6.8 Hz), 6.91 (1H, s), 7.49 (1H, t, J=7.8 Hz), 7.58 (1H, d, J=7.8 Hz), 7.87 (1H, d, J=7.8 Hz), 8.62 (1H, br s).
EIMS m/z (relative intensity): 571 (M+), 235 (100).
Example 111 (Compound No. 1292 in Table)
Production of 7-(7-trifluoromethylbenzoxazol-2-ylthio)-N-[2,4-bis(isopropylthio)-6-methyl-3-pyridyl]heptanamide:
The reaction and the treatment were conducted in the same manner as in Example 71 except that 2-mercapto-7-trifluoromethylbenzoxazole was used instead of 2-mercaptobenzothiazole to obtain the desired compound as a colorless crystal.
Melting point: 76-78° C.
IR (KBr) cm−1: 3423, 3268, 2931, 1660, 1506, 1433, 1334.
1H-NMR (d6-DMSO) δ: 1.29 (6H, d, J=6.8 Hz), 1.31 (6H, d, J=6.8 Hz), 1.43-1.54 (4H, m), 1.61-1.69 (2H, m), 1.86 (2H, quint, J=7.2 Hz), 2.18-2.32 (2H, m), 2.43 (3H, s), 3.39 (2H, t, J=7.2 Hz), 3.56 (1H, sept, J=6.8 Hz), 3.90 (1H, sept, J=6.8 Hz), 6.93 (1H, s), 7.51 (1H, dd, J=8.1, 7.8 Hz), 7.60 (1H, d, J=7.8 Hz). 7.90 (1H, d, J=8.1 Hz), 8.68 (1H, br s).
EIMS m/z (relative intensity): 585 (M+), 249 (100).
Example 112 (Compound No. 1293 in Table)
Production of 8-(7-trifluoromethylbenzoxazol-2-ylthio)-N-[2,4-bis(isopropylthio)-6-methyl-3-pyridyl]octanamide:
The reaction and the treatment were conducted in the same manner as in Example 72 except that 2-mercapto-7-trifluoromethylbenzoxazole was used instead of 2-mercaptobenzoxazole to obtain the desired compound as a pale yellow oil.
IR (Cap) cm−1: 3246, 2964, 2930, 1664, 1559, 1506, 1432.
1H-NMR (d6-DMSO) δ: 1.28 (6H, d, J=6.8 Hz), 1.30 (6H, d, J=6.8 Hz), 1.32-1.50 (6H, m), 1.56-1.66 (2H, m), 1.83 (2H, quint, J=7.1 Hz), 2.17-2.27 (2H, m), 2.42 (3H, s), 3.36 (2H, t, J=7.1 Hz), 3.55 (1H, sept, J=6.8 Hz), 3.89 (1H, sept, J=6.8 Hz), 6.91 (1H, s), 7.50 (1H, t, J=7.8 Hz), 7.59 (1H, d, J=7.8 Hz), 7.88 (1H, d, J=7.8 Hz), 8.65 (1H, br s).
EIMS m/z (relative intensity): 599 (M+), 263 (100)
Example 113 (Compound No. 1294 in Table)
Production of 9-(7-trifluoromethylbenzoxazol-2-ylthio)-N-[2,4-bis(isopropylthio)-6-methyl-3-pyridyl]nonanamide:
The reaction and the treatment were conducted in the same manner as in Example 73 except that 2-mercapto-7-trifluoromethylbenzoxazole was used instead of 2-mercaptobenzoxazole to obtain the desired compound as a pale-yellow powdery crystal.
Melting point: 97-98° C.
IR (KBr) cm−1: 3446, 3266, 2928, 1661, 1560, 1506, 1335, 1127.
1H-NMR (d6-DMSO) δ: 1.28 (6H, d, J=6.6 Hz), 1.30 (6H, d, J=6.8 Hz) 1.28-1.51 (8H, m), 1.55-1.64 (2H, m), 1.83 (2H, quint, J=7.3 Hz), 2.20-2.30 (2H, m), 2.42 (3H, s), 3.36 (2H, t, J=7.3 Hz), 3.55 (1H, sept, J=6.6 Hz), 3.89 (1H, sept, J=6.8 Hz), 6.91 (1H, s), 7.50 (1H, t, J=7.8 Hz), 7.59 (1H, d, J=7.8 Hz), 7.89 (1H, d, J=7.8 Hz), 8.71 (1H, br s).
EIMS m/z (relative intensity): 613 (M+), 277 (100).
Example 114 (Compound No. 1299 in Table)
Production of 4-(5-chloro-7-isopropyl-4-methylbenzoxazol-2-ylthio)-N-[2,4-bis(isopropylthio)-6-methyl-3-pyridyl]butanamide:
The reaction and the treatment were conducted in the same manner as in Example 69 except that 5-chloro-2-mercapto-4-methylbenzoxazole was used instead of 2-mercaptobenzoxazole to obtain the desired compound as a colorless needle crystal.
Melting point: 141-143° C.
1H-NMR (d6-DMSO) δ: 1.27 (6H, d, J=6.8 Hz), 1.29 (6H, d, J=6.8 Hz), 1.31 (6H, d, J=6.8 Hz), 2.03-2.21 (2H, m), 2.42 (3H, s), 2.43-2.50 (5H, m), 3.22 (1H, sept, J=6.8 Hz), 3.38-3.48 (2H, m), 3.55 (1H, sept, J=6.8 Hz), 3.88 (1H, sept, J=6.8 Hz), 6.92 (1H, s), 7.14 (1H, s), 8.87 (1H, br s).
EIMS m/z (relative intensity): 567 (M+: 37Cl), 565 (M+: 35Cl), 207 (100).
Example 115 (Compound No. 1300 in Table)
Production of 5-(5-chloro-7-isopropyl-4-methylbenzoxazol-2-ylthio)-N-[2,4-bis(isopropylthio)-6-methyl-3-pyridyl]pentanamide:
The reaction and the treatment were conducted in the same manner as in Example 70 except that 5-chloro-7-isopropyl-2-mercapto-4-methylbenzoxazole was used instead of 2-mercaptobenzoxazole to obtain the desired compound as a colorless needle crystal.
Melting point: 143-145° C.
IR (KBr) cm−1: 3231, 2924, 1720, 1657, 1508, 1297.
1H-NMR (d6-DMSO) δ: 1.27 (6H, d, J=6.8 Hz), 1.29 (6H, d, J=6.8 Hz), 1.31 (6H, d, J=6.8 Hz), 1.73-1.85 (2H, m), 1.85-1.98 (2H, m), 2.25-2.37 (2H, m), 2.41 (3H, s), 2.43-2.50 (3H, s), 3.21 (1H, sept, J=6.8 Hz), 3.37 (2H, t, J=7.2 Hz), 3.54 (1H, sept, J=6.8 Hz), 3.88 (1H, sept, J=6.8 Hz), 6.92 (1H, s), 7.14 (1H, s), 8.76 (1H, br s).
EIMS m/z (relative intensity): 581 (M+: 37Cl), 579 (M+: 35Cl, 100).
Example 116 (Compound No. 1301 in Table)
Production of 6-(5-chloro-7-isopropyl-4-methylbenzoxazol-2-ylthio)-N-[2,4-bis(isopropylthio)-6-methyl-3-pyridyl]hexanamide:
The reaction and the treatment were conducted in the same manner as in Example 36 except that 5-chloro-7-isopropyl-2-mercapto-4-methylbenzoxazole was used instead of 2-mercaptobenzoxazole to obtain the desired compound as a colorless needle crystal.
Melting point: 99-101° C.
IR (KBr) cm−1: 3413, 3224, 2964, 1663, 1506, 1148.
1H-NMR (d6-DMSO) δ: 1.29 (6H, d, J=6.8 Hz), 1.32 (12H, d, J=6.8 Hz), 1.54-1.62 (2H, m), 1.70 (2H, quint, J=7.1 Hz), 1.87 (2H, quint, J=7.1 Hz), 2.22-2.33 (2H, m). 2.43 (3H, s), 2.48 (3H, s), 3.23 (1H, sept, J=6.8 Hz), 3.36 (2H, t, J=7.1 Hz), 3.57 (1H, sept, J=6.8 Hz), 3.90 (1H, sept, J=6.8 Hz), 6.93 (1H, s), 7.15 (1H, s), 8.72 (1H, br s).
EIMS m/z (relative intensity): 595 (M+; 37Cl), 593 (M+; 35Cl), 518 (100).
Example 117 (Compound No. 1302 in Table)
Production of 7-(5-chloro-7-isopropyl-4-methylbenzoxazol-2-ylthio)-N-[2,4-bis(isopropylthio)-6-methyl-3-pyridyl]heptanamide:
The reaction and the treatment were conducted in the same manner as in Example 71 except that 5-chloro-7-isopropyl-2-mercapto-4-methylbenzoxazole was used instead of 2-mercaptobenzoxazole to obtain the desired compound as a colorless needle crystal.
Melting point: 91-93° C.
IR (KBr) cm−1: 3436, 3213, 3169, 2962, 2929, 1666, 1505, 1152.
1H-NMR (d6-DMSO) δ: 1.29 (6H, d, J=6.8 Hz), 1.31 (6H, d, J=6.8 Hz), 1.31 (6H, d, J=6.8 Hz), 1.40-1.52 (4H, m), 1.60-1.68 (2H, m), 1.85 (2H, quint, J=7.1 Hz), 2.17-2.32 (2H, m), 2.43 (3H, s), 2.47 (3H, s), 3.22 (1H, sept, J=6.8 Hz), 3.35 (2H, t, J=7.1 Hz), 3.56 (1H, sept, J=6.8 Hz), 3.90 (1H, sept, J=6.8 Hz), 6.93 (1H, s), 7.15 (1H, s), 8.67 (1H, br s).
EIMS m/z (relative intensity): 609 (M+; 37Cl), 607 (M+; 35Cl), 532 (100).
Example 118 (Compound No. 1303 in Table)
Production of 8-(5-chloro-7-isopropyl-4-methylbenzoxazol-2-ylthio)-N-[2,4-bis(isopropylthio)-6-methyl-3-pyridyl]octanamide:
The reaction and the treatment were conducted in the same manner as in Example 72 except that 5-chloro-7-isopropyl-2-mercapto-4-methylbenzoxazole was used instead of 2-mercaptobenzoxazole to obtain the desired compound as a pale yellow oil.
IR (Cap) cm−1: 3242, 2964, 2928, 1668, 1559, 1506, 1148.
1H-NMR (d6-DMSO) δ: 1.28 (6H, d, J=6.6 Hz), 1.31 (12H, d, J=6.8 Hz), 1.32-1.50 (6H, m), 1.57-1.67 (2H, m), 1.82 (2H, quint, J=7.1 Hz), 2.17-2.27 (2H, m), 2.42 (3H, s), 2.46 (3H, s), 3.21 (1H, sept, J=6.8 Hz), 3.33 (2H, t, J=7.1 Hz), 3.55 (1H, sept, J=6.6 Hz), 3.89 (1H, sept, J=6.8 Hz), 6.91 (1H, s), 7.14 (1H, s), 8.65 (1H, br s).
EIMS m/z (relative intensity): 623 (M+: 37Cl), 621 (M+: 35Cl), 546 (100).
Example 119 (Compound No. 1304 in Table)
Production of 9-(5-chloro-7-isopropyl-4-methylbenzoxazol-2-ylthio)-N-[2,4-bis(isopropylthio)-6-methyl-3-pyridyl]nonanamide:
The reaction and the treatment were conducted in the same manner as in Example 73 except that 5-chloro-7-isopropyl-2-mercapto-4-methylbenzoxazole was used instead of 2-mercaptobenzoxazole to obtain the desired compound as a pale yellow oil.
IR (Cap) cm−1: 3249, 2961, 2926, 1667, 1563, 1505.
1H-NMR (d6-DMSO) δ: 1.28 (6H, d, J=6.8 Hz), 1.30 (12H, d, J=7.1 Hz), 1.28-1.50 (8H, m), 1.55-1.65 (2H, m), 1.81 (2H, quint, J=7.1 Hz), 2.17-2.27 (2H, m), 2.41 (3H, s), 2.46 (3H, s), 3.21 (1H, sept, J=7.1 Hz), 3.32 (2H, t, J=7.1 Hz), 3.54 (1H, sept, J=6.8 Hz), 3.89 (1H, sept, J=7.1 Hz), 6.91 (1H, s), 7.14 (1H, s), 8.65 (1H, br s).
EIMS m/z (relative intensity): 637 (M+: 37Cl), 635 (M+: 35Cl), 560 (100).
Example 120 (Compound No. 1317 in Table)
Production of 2-(7-methansulfonylbenzoxazol-2-ylthio)-N-[2,4-bis(ethylthio)-6-methyl-3-pyridyl]acetamide:
The reaction and the treatment were conducted in the same manner as in Example 96 except that 2-mercapto-7-methansulfonylbenzoxazole was used instead of 2-mercapto-7-trifluoromethylbenzoxazole to obtain the desired compound as a colorless needle crystal.
Melting point: 159-162° C.
IR (KBr) cm−1: 3449, 3271, 2966, 2928, 1678, 1508, 1315, 1118.
1H-NMR (CDCl3) δ: 1.14 (3H, t, J=7.3 Hz), 1.20 (3H, t, J=7.3 Hz), 2.43 (3H, s), 2.82 (2H, q, J=7.3 Hz), 3.01 (2H, q, J=7.3 Hz), 3.27 (2H, s), 4.15 (2H, s), 6.63 (1H, s), 7.49 (1H, t, J=7.9 Hz), 7.83 (1H, dd, J=7.9, 1.2 Hz), 7.90 (1H, dd, J=7.9, 1.2 Hz), 8.17 (1H, br s).
EIMS m/z (relative intensity): 497 (M+), 311 (100).
Elemental analysis: as C20H23N3O4S4; Calculated: C, 48.27; H, 4.66; N, 8.44; S, 25.77. Found: C, 48.36; H, 4.66; N, 8.31; S, 25.76.
Example 121 (Compound No. 1327 in Table)
Production of 2-(7-methansulfonylbenzoxazol-2-ylthio)-N-[2,4-bis(isopropylthio)-6-methyl-3-pyridyl]acetamide:
The reaction and the treatment were conducted in the same manner as in Example 74 except that 2-mercapto-7-methansulfonylbenzoxazole was used instead of 2-mercaptobenzothiazole to obtain the desired compound as a pale yellow amorphous.
IR (KBr) cm−1: 3435, 3337, 2965, 2926, 1695, 1506, 1424, 1319, 1117.
1H-NMR (CDCl3) δ: 1.16 (6H, d, J=6.8 Hz), 1.21 (6H, d, J=6.8 Hz), 2.42 (3H, s), 3.26 (3H, s), 3.40 (1H, sept, J=6.8 Hz), 3.90 (1H, sept, J=6.8 Hz), 4.15 (2H, s), 6.68 (1H, s), 7.49 (1H, t, J=7.9 Hz), 7.83 (1H, dd, J=7.9, 1.0 Hz), 7.90 (1H, dd, J=7.9, 1.0 Hz), 8.11 (1H, br s).
EIMS m/z (relative intensity): 525 (M+), 339 (100).
Example 122 (Compound No. 1341 in Table)
Production of 6-(benzoxasole-2-ylthio)-N-(4-methyl-2-(methylthio)-5-pyridyl)hexanamide:
A methanol (8 mml) solution of 2-dichloro-4-methyl-5-nitropyrimidine (2.0 g, 10.4 mmol) was added dropwise to a methanol (8 ml) solution of sodium thiomethoxide (436 mg, 5.9 mmol) while being cooled with ice, and after the mixture was stirred for 15 hours while raising its temperature to the room temperature, water added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with water and then with a saturated aqueous solution of sodium chloride, and dried over sodium sulfate. Thereafter, the solvent was distilled off, and the resulting crude product was recrystalized with ethyl acetate-hexan to obtain 1.02 g (yield 98%) of 4-methyl-2-methylthio-5-nitropyridine as a pale-yellow needle crystal.
This nitropyridine (497 mg, 2.7 mmol) was dissolved in a mixed solvent of acetic acid (15 ml) and conc. hydrochloric acid (0.5 ml), and zinc (2.12 g, 32.4 mmol) was added thereto in small portions while being cooled with ice for 5 minutes. After the mixture was stirred for 30 minutes at the room temperature, the reaction mixture was filtered, and the filtrate was neutralized with an aqueous solution of sodium hydrogencarbonate, and extracted with methylene chloride. The organic layer was washed with water and then with a saturated aqueous solution of sodium chloride, and dried over sodium sulfate. Thereafter, the solvent was distilled off, and the resulting crude product was purified through silica gel chromatography (eluent-hexane:ethyl acetate=1:1) to obtain 352 mg (yield 85%) of 5-amino-4-methyl-2-methylthiopyridine as a pale-yellow powdery crystal.
And then the reaction and the treatment were conducted in the same manner as in Example 18 except that 5-amino-4-methyl-2-methylthiopyridine was used instead of 3-amino-2,4-bis(methylthio)-6-methylpyridine to obtain the desired compound as a colorless powdery crystal.
Melting point: 125-127° C.
IR (KBr) cm−1: 3433, 3284, 2930, 1654, 1598.
1H-NMR (CDCl3) δ: 1.61 (2H, quint, J=7.4 Hz), 1.83 (2H, quint, J=7.4 Hz), 1.92 (2H, quint, J=7.4 Hz), 2.19 (3H, s), 2.43 (2H, t, J=7.4 Hz), 2.54 (3H, s), 3.33 (2H, t, J=7.4 Hz), 6.92 (1H, br s), 7.03 (1H, s), 7.24 (1H, td, J=7.7, 1.7 Hz), 7.28 (1H, td, J=7.7, 1.7 Hz), 7.43 (1H, dd, J=7.7, 1.7 Hz), 7.57 (1H, dd, J=7.7, 1.7 Hz), 8.57 (1H, s).
EIMS m/z (relative intensity): 401 (M+), 69 (100).
Example 123 (Compound No. 1371 in Table)
Production of 6-(benzoxasole-2-ylthio)-N-(5-methylthio-2-pyridyl)hexanamide:
After conc. sulfuric acid (50 ml) was cooled with ice, 30% aqueous solution of hydrogen peroxide (25 ml) was dropped thereto stirring, and then conc. sulfuric acid (50 ml) solution of 2-amino-5-chloropyridine (5.0 g, 38.9 mmol) was dropped thereto further and stirred for 48 hours at the room temperature. The reaction mixture was added into ice and filtered. The residue was recrystallized with ethanol to obtain 4.38 g (yield 71%) of 5-chloro-2-nitoropyriine as a colorless powdery crystal.
A methanol (40 mml) solution of 5-chloro-2-nitropyridine (2.0 g, 12.6 mmol) was added dropwise to a methanol (20 ml) solution of sodium thiomethoxide (1.02 g, 13.9 mmol) while being cooled with ice, and after the mixture was stirred for 13 hours while raising its temperature to the room temperature, water added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with water and then with a saturated aqueous solution of sodium chloride, and dried over magnesium sulfate. Thereafter, the solvent was distilled off, and the resulting crude product was recrystalized with ethyl acetate-hexane to obtain 972 mg (yield 45%) of 5-methylthio-2-nitropyridine.
This nitropyridine (300 mg, 1.8 mmol) was dissolved in a mixed solvent of acetic acid (7 ml) and conc. hydrochloric acid (0.5 ml), and zinc (692 g, 10.6 mmol) was added thereto in small portions while being cooled with ice for 5 minutes. After the mixture was stirred for 30 minutes at the room temperature, the reaction mixture was filtered, and the filtrate was neutralized with an aqueous solution of sodium hydrogencarbonate, and extracted with methylene chloride. The organic layer was washed with water and then with a saturated aqueous solution of sodium chloride, and dried over sodium sulfate. Thereafter, the solvent was distilled off, and the resulting crude product was purified through silica gel chromatography (eluent-hexane:ethyl acetate=1:1→chloroform:methanol=20:1) to obtain 158 mg (yield 64%) of 2-amino-5-methylthiopyridine as a pale-yellow powdery crystal.
And then the reaction and the treatment were conducted in the same manner as in Example 18 except that 2-amino-5-methylthiopyridine was used instead of 3-amino-2,4-bis(methylthio)-6-methylpyridine to obtain the desired compound as a colorless powdery crystal.
Melting point: 83-85° C.
IR (KBr) cm−1: 3246, 2930, 1684, 1576, 1522.
1H-NMR (CDCl3) δ: 1.59 (2H, quint, J=7.4 Hz), 1.81 (2H, quint, J=7.4 Hz), 1.90 (2H, quint, J=7.4 Hz), 2.42 (2H, t, J=7.4 Hz), 2.48 (3H, s), 3.32 (2H, t, J=7.4 Hz), 7.23 (1H, td, J=7.4, 1.4 Hz), 7.28 (1H, td, J=7.4, 1.4 Hz), 7.43 (1H, dd, J=7.4, 1.4 Hz), 7.59 (1H, dd, J=7.4, 1.4 Hz), 7.64 (1H, dd, J=8.6, 2.5 Hz), 7.82 (1H, br s), 8.15 (1H, d, J=8.6 Hz), 8.18 (1H, d, J=2.5 Hz).
EIMS m/z (relative intensity): 387 (M+, 100).
Example 124 (Compound No. 1401 in Table)
Production of 6-(benzoxazol-2-ylthio)-N-[2,4,6-tris(methylthio)-5-pyrimidyl]hexanamide:
The reaction and the treatment were conducted in the same manner as in Example 88 except that 4,6-dihydroxy-2-methylthiopyrimidine was used instead of 4,6-dihydroxy-2-methylpyrimidine to obtain the desired compound as a colorless powdery crystal.
Melting point: 149-153° C.
IR (KBr) cm−1: 3448, 3247, 2926, 1667, 1496.
1H-NMR (CDCl3) δ: 1.46-1.62 (2H, m), 1.63-1.76 (2H, m), 1.77-1.91 (2H, m), 2.20-2.36 (2H, m), 2.46 (9H, s), 3.36 (2H, t, J=7.1 Hz), 7.22-7.35 (2H, m), 7.51-7.62 (2H, m), 9.02 (1H, br s).
EIMS m/z (relative intensity): 480 (M+, 100).
Example 125 (Compound No. 1427 in Table)
Production of 2-(7-methoxycarbonylbenzoxazol-2-ylthio)-N-[2,4-bis(ethylthio)-6-methyl-3-pyridyl]acetamide:
The reaction and the treatment were conducted in the same manner as in Example 26 except that 2-mercapto-7-methoxycarbonylbenzoxazole was used instead of 2-mercaptobenzoxasole to obtain the desired compound as a colorless needle crystal.
Melting point: 168-169° C.
IR (KBr) cm−1: 3433, 3257, 1727, 1677, 1513, 1297, 1120.
1H-NMR (CDCl3) δ: 1.16 (3H, t, J=7.4 Hz), 1.19 (3H, t, J=7.4 Hz), 2.42 (3H, s), 2.80 (2H, q, J=7.4 Hz), 3.03 (2H, q, J=7.4 Hz), 4.00 (3H, s), 4.12 (2H, s), 6.63 (1H, s), 7.38 (1H, dd, J=8.1, 7.8 Hz), 7.80 (1H, dd, J=8.1, 1.2 Hz), 7.92 (1H, dd, J=7.8, 1.2 Hz), 8.48 (1H, br s).
EIMS m/z (relative intensity): 477 (M+), 323 (100).
Elemental analysis: as C21H23N3O4S3; Calculated: C, 52.81; H, 4.85; N, 8.80; S, 20.14. Found: C, 52.90; H, 4.91; N, 8.73; S, 20.12.
Example 126 (Compound No. 1428 in Table)
Production of 2-(oxazolo[4,5-b]pyridine-2-ylthio)-N-[2,4-bis(ethylthio)-6-methyl-3-pyridyl]acetamide:
The reaction and the treatment were conducted in the same manner as in Example 49 except that 2-mercaptoxazolo[4,5-b]pyridine was used instead of 2-mercaptobenzoxasole to obtain the desired compound as a colorless crystal.
IR (KBr) cm−1: 3460, 3167, 2972, 1685, 1561.
1H-NMR (CDCl3) δ: 1.14 (3H, t, J=7.4 Hz), 1.21 (3H, t, J=7.4 Hz), 2.42 (3H, s), 2.82 (2H, q, J=7.4 Hz), 3.02 (2H, q, J=7.4 Hz), 4.16 (2H, s), 6.62 (1H, s), 7.25 (1H, dd, J=8.3, 5.1 Hz), 7.78 (1H, dd, J=8.3, 1.2 Hz), 8.40 (1H, br s), 8.49 (1H, dd, J=5.1, 1.2 Hz).
EIMS m/z (relative intensity): 420 (M+, 100).
Example 127 (Compound No. 1257 in Table)
Production of 2-(5-chloro-7-isopropyl-4-methylbenzoxazol-2-ylthio)-N-[2,4-bis(methylthio)-6-methyl-3-pyridyl]acetamide:
The reaction and the treatment were conducted in the same manner as in Example 49 except that 5-chloro-7-isopropyl-2-mercapto-4-methylbenzoxazole was used instead of 2-mercaptobenzothiazole to obtain the desired compound as a colorless powdery crystal.
EIMS m/z (relative intensity): 481 (M+), 210 (100).
Example 128 (Compound No. 1277 in Table)
Production of 2-(5-chloro-7-isopropyl-4-methylbenzoxazol-2-ylthio)-N-[2,4-bis(ethylthio)-6-methyl-3-pyridyl]acetamide:
The reaction and the treatment were conducted in the same manner as in Example 127 except that 3-amino-2,4-bis(isopropylthio)-6-methylpyridine was used instead of 3-amino-2,4-bis(methylthio)-6-methylpyridine to obtain the desired compound as a colorless powdery crystal.
EIMS m/s (relative intensity): 511 (M+; 37Cl), 509 (M+; 35Cl), 235 (100).
Example 129 (Compound No. 1297 in Table)
Production of 2-(5-chloro-7-isopropyl-4-methylbenzoxazol-2-ylthio)-N-[2,4-bis(isopropylthio)-6-methyl-3-pyridyl]acetamide:
The reaction and the treatment were conducted in the same manner as in Example 127 except that 3-amino-2,4-bis(isopropylthio)-6-methylpyridine was used instead of 3-amino-2,4-bis(methylthio)-6-methylpyridine to obtain the desired compound as a colorless powdery crystal.
EIMS m/z (relative intensity): 539 (M+; 37Cl), 537 (M+; 35Cl), 223 (100).

## Claims

1. Compounds represented by the formula (I) 



wherein 




represents an optionally substituted divalent residue of benzene, cyclohexane or naphthalene, or a group: 




Het represents a 2,4-disubstituted-6-alkyl-pyridin-3-yl, wherein each substituent is a lower alkyloxy group having between 1 and 6 carbon atoms or a lower alkylthio group having between 1 and 6 carbon atoms; 
X represents an oxygen atom; 
Y represents —NR4—, an oxygen atom, a sulfur atom, a sulfoxide or a sulfone; 
Z represents a single bond; 
R4 represents a hydrogen atom, a lower alkyl group, an aryl group or an optionally substituted silyl lower alkyl group; and 
n is an integer of from 2 to 15, or salts or solvates thereof.

2. The compounds according to claim 1, which are represented by the formula (IA) 



wherein 




represents an optionally substituted divalent residue of; 
Py represents a 2,4-disubstituted-6-alkyl-pyridin-3-yl, wherein each substituent is a lower alkyloxy group having between 1 and 6 carbon atoms or a lower alkylthio group having between 1 and 6 carbon atoms; 
X represents an oxygen atom; 
Y represents —NR4—, an oxygen atom, a sulfur atom, a sulfoxide or a sulfone; 
Z represents a single bond; 
R4 represents a hydrogen atom, a lower alkyl group, an aryl group or an optionally substituted silyl lower alkyl group; and 
n is an integer of from 2 to 15; 
or salts or solvates thereof.

3. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and at least one compound selected from the compounds represented by the formula (I) 



wherein 




represents an optionally substituted divalent residue of benzene, cyclohexane or naphthalene, or a group: 




Het represents a 2,4-disubstituted-6-alkyl-pyridin-3-yl, wherein each substituent is a lower alkyloxy group having between 1 and 6 carbon atoms or a lower alkylthio group having between 1 and 6 carbon atoms; 
X represents an oxygen atom; 
Y represents —NR—, an oxygen atom, a sulfur atom, a sulfoxide or a sulfone; 
Z represents a single bond; 
R4 represents a hydrogen atom, a lower alkyl group, an aryl group or an optionally substituted silyl lower alkyl group; and 
n is an integer of from 2 to 15, or salts or solvates thereof.

4. The pharmaceutical composition according to claim 3, which is a remedy or a medication for preventing hyperlipemia, arteriosclerosis, cerebrovascular accidents, ischemic heart disease, ischemic intestinal disease or aortic aneurysm.

5. A method for treating hyperlipemia, arteriosclerosis, cerebrovascular accidents, ischemic heart disease, ischemic intestinal disease or aortic aneurysm by administering to a patient in need of such treatment a compound of the formula (I′) 



wherein 




represents an optionally substituted divalent residue of benzene, cyclohexane or naphthalene, or a group: 




Het represents substituted or unsubstituted pyridyl group; 
X represents an oxygen atom; 
Y represents —NR4—, an oxygen atom, a sulfur atom, a sulfoxide or a sulfone; 
Z represents a single bond; 
R4 represents a hydrogen atom, a lower alkyl group, an aryl group or an optionally substituted silyl lower alkyl group; and 
n is an integer of from 1 to 15; 
or salts or solvates thereof.

6. The method of claim 5 wherein a compound of formula (I′A) is administered 



wherein 




represents an optionally substituted divalent residue of benzene; 
Py represents an optionally substituted pyridyl or pyrimidinyl group; 
X represents an oxygen atom; 
Y represents —NR4—, an oxygen atom, a sulfur atom, a sulfoxide or a sulfone; 
Z represents a single bond; 
R4 represents a hydrogen atom, a lower alkyl group, an aryl group or an optionally substituted silyl lower alkyl group; 
n is an integer of from 1 to 15, 
or salts or solvates thereof.

7. The method of claim 5 wherein a compound of formula (III′) is administered 



wherein, W represents ═CH—, 
X represents an oxygen atom; 
Y represents —NR4— an oxygen atom, a sulfur atom, a sulfoxide or a sulfone; 
Z represents a single bond; 
R1, R2, and R3 are the same or different, and each represents a hydrogen atom, a lower alkyl group, a lower alkoxy group, a halogen atom, a hydroxyl group, a phosphate group, a sulfonamide group, a lower alkylthio group or an optionally substituted amino group, or two of R1, R2, and R3, together form an alkylenedioxide group; 
R4 represents a hydrogen atom, a lower alkyl group, an aryl group or an optionally substituted silyl lower alkyl group; and 
n is an integer of from 1 to 15; 
or salts or solvates thereof.

8. A method claim 5 wherein a compound represented by formula (I) is administered, 



wherein 




represents an optionally substituted divalent residue of benzene; 
Het represents a substituted or unsubstituted pyridyl group; 
X is an oxygen atom; 
Y is a sulfur atom; 
Z is a single bond; 
n is 1; 
or salts or solvates thereof.

9. The compound of claim 1, wherein the Het represents a 2,4-di(alkylthio)-6-methyl-pyridin-3-yl, wherein each alkylthio group has between 1 and 6 carbon atoms.

10. The compound of claim 2, wherein the Py represents a 2,4-di(alkylthio)-6-methyl-pyridin-3-yl, wherein each alkylthio group has between 1 and 6 carbon atoms.

11. The pharmaceutical composition of claim 3, wherein the Het represents a 2,4-di(alkylthio)-6-methyl-pyridin-3-yl, wherein each alkylthio group has between 1 and 6 carbon atoms.

12. The method of claim 5, wherein Het represents a 2,4-disubstituted-6-alkyl-pyridin-3-yl, wherein each substituent is a lower alkyloxy group having between 1 and 6 carbon atoms or a lower alkylthio group having between 1 and 6 carbon atoms.

13. The method of claim 8, wherein Py represents a 2,4-disubstituted-6-alkyl-pyridin-3-yl, wherein each substituent is a lower alkyloxy group having between 1 and 6 carbon atoms or a lower alkylthio group having between 1 and 6 carbon atoms.

14. The method of claim 8, wherein Het represents a 2,4-disubstituted-6-alkyl-pyridin-3-yl, wherein each substituent is a lower alkyloxy group having between 1 and 6 carbon atoms or a lower alkylthio group having between 1 and 6 carbon atoms.