2-substituted alkoxy-3-substituted-pyrazines

Abstract

A compound of the formula ##STR1## wherein Q is --CO-- or --CH.sub.2 --, R is hydroxyl, lower alkoxy, halogen, --NH-lower alkylene-OH, --NH-lower alkylene-arylthio, --NH-lower alkylene-halogen, ##STR2## is dilower alkylamino, cycloalkylamino, morpholino, ##STR3## in which R.sub.9 is hydrogen, lower alkyl or aryl, R.sub.10 is hydrogen, lower alkyl, hydroxy-lower alkyl, hydroxy-lower alkoxy-lower alkyl or di(aryl)-lower alkyl, m is an integer from 4 to 6, n is 2 or 3, R.sub.1 is alkyl or aryl-lower alkyl, R.sub.2 and R.sub.3 are each lower alkyl, or together form tetramethylene, and R.sub.4 is hydrogen, lower alkyl or aryl, in which aryl is phenyl which is optionally substituted with a group selected from the group consisting of 1-3 halogen, nitro, lower alkyl and lower alkoxy, or a pharmaceutically acceptable salt thereof, inhibits blood platelet aggregation, has vasodilating activity and inhibits lipoperoxide generation.

Description

FIELD OF THE INVENTION

This invention relates to novel 2-substituted alkoxy-3-substituted pyrazines, which are useful as pharmaceuticals for treating circulatory and metabolic disorders. The compounds of the invention are active as platelet aggregation inhibiting, vasodilating and/or anti-lipoperoxide generating agents.

KNOWN PRIOR ART

Recently, a significant number of compounds having platelet aggregation inhibiting activity have been reported. Of these, the only known compounds having a pyrazine or 5,6,7,8-tetrahydro quinoxaline ring as the basic structure are tetramethyl pyrazine (16th Heterocyclic Chemistry Symposium (Osaka), pp. 65-68 (1984)) and 2-higher fatty acid acyloxymethyl pyrazine (Jap. Pat. Unexam. Publ. No. 59-219269). Furthermore, a compound of the formula ##STR4## wherein Z is hydrogen or methyl, is known as an .alpha.-sympathetic nerve blocking agent (Jap. Pat. Exam. Publ. No. 48-21949). These compounds have almost no platelet aggregation inhibiting, vasodilating or antioxidant activity.

OBJECT OF THE INVENTION

It is an object of the invention to provide high quality pharmaceuticals having stronger inhibitory activities for platelet aggregation, in order effectively to treat circulation and metabolic disorders.

SUMMARY OF THE INVENTION

We have found that 2-substituted alkoxy-3-substituted pyrazines display inhibitory action on platelet aggregation, vasodilation activity and/or anti-lipoperoxide generation, and are expected to have excellent pharmaceutical properties.

According to the present invention, a compound of the formula ##STR5## is provided, wherein Q is --CO-- or --CH.sub.2 --, R is hydroxyl, lower alkoxy, halogen, --NH-lower alkylene-OH, --NH-lower alkylene-arylthio, --NH-lower alkylene-halogen, ##STR6## is dilower alkylamino, cycloalkylamino, morpholino, ##STR7## in which R.sub.9 is hydrogen, lower alkyl or aryl, R.sub.10 is hydrogen, lower alkyl, hydroxy-lower alkyl, hydroxy-lower alkoxy-lower alkyl or di(aryl)-lower alkyl, m is an integer from 4 to 6, n is 1 or 2, R.sub.1 is alkyl or aryl-lower alkyl, R.sub.2 and R.sub.3 are each lower alkyl, or together form tetramethylene, and R.sub.4 is hydrogen, lower alkyl or aryl, in which aryl is phenyl which is optionally substituted with a group selected from the group consisting of 1-3 halogen, nitro, lower alkyl and lower alkoxy, or a pharmaceutically acceptable salt thereof.

Compound [1] can be provided in salt form. The salts must be pharmacologically acceptable non-toxic salt thereof. Examples of such salts are salts of an inorganic acid such as hydrochloric, sulfuric, or phosphoric, and salts of an organic acid such as acetic, propionic, butyric, glycolic, gluconic, malic, tartaric, succinic, mandelic, aspartic, glutamic, methanesulfonic or toluenesulfonic. Salts of other known acids can be used as well.

Compound [1] can be produced by the following processes:

Process A

A process for the production of compound [1] wherein Q is --CO-- and R is lower alkoxy (hereinafter designated as compound [1a]):

The above compound [1a] can be produced by reacting a compound of the formula ##STR8## wherein M is alkali metal, and R.sub.1, R.sub.2 and R.sub.3 have the same meanings hereinbefore, with an .alpha.-halogen-carboxylate ester of the formula ##STR9## wherein X is halogen, R.sub.11 is lower alkyl and R.sub.4 has the same meaning hereinbefore, in an organic solvent.

The above compound [3] can be obtained by dissolving a compound of the formula ##STR10## wherein R.sub.1, R.sub.2 and R.sub.3 have the same meanings hereinbefore, in methanol containing alkali metal methylate and distilling off methanol in vacuo.

The above compound [2] can be expressed as a tautomer of a compound of the formula ##STR11## wherein R.sub.1, R.sub.2 and R.sub.3 have the same meanings hereinabove.

In compound [2] above, R.sub.1 is alkyl or aryl-lower alkyl. "Alkyl", as used above, is defined as saturated or unsaturated C.sub.1-20 alkyl, which may be branched or unbranched. Examples are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, isopentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl or hexadecyl, "Optionally substituted phenyl", as used above, is defined as phenyl or phenyl substituted with C.sub.1-3 lower alkyl, halogen, nitro, or lower alkxoy. Aryl-lower alkyl, as used above, is defined as phenyl or phenyl substituted with 1-3 halogen, nitro, lower alkyl or lower alkoxy, in which lower alkyl means C.sub.1-4 alkyl such as methyl, 1-ethyl, 2-ethyl, 3-propyl or 1-propyl. Examples are benzyl, p-chlorobenzyl, 2-phenylethyl and 1-phenylethyl.

In compound [2] above, R.sub.2 and R.sub.3 are each lower alkyl, or together form tetramethylene. The lower alkyl can be C.sub.1-4 alkyl such as methyl, ethyl or propyl. Among the class of compounds [2], some examples have been reported. These compounds can be produced by a process or an improvement thereto as disclosed in J. Am. Chem. Soc., 71:78-81 (1949) and ibid. 74:1580-1583 (1952). Novel derivatives thereof can also be produced according to the methods described in the above references. The compound [2] wherein R.sub.2 and R.sub.3 together form tetramethylene of the formula ##STR12## wherein R.sub.1 has the same meaning hereinabove, hexahydroquinoxaline derivatives, is produced by the process, in which an .alpha.-amino acidamide of the formula ##STR13## wherein R.sub.1 has the same meaning hereinabove, is reacted with 1,2-cyclohexanedione in an alkaline medium.

The reaction of the above .alpha.-amino acidamide or a salt thereof with 1,2-cyclohexanedione proceeds in an organic solvent, for example a lower alcohol such as methanol or ethanol. The condensation reaction proceeds preferably below 0.degree. C. at first; however, as the reaction proceeds, it can be effected at room temperature. The progress of the reaction can be checked by thin layer chromatography (hereinafter TLC) or high performance liquid chromatography (hereinafter HPLC) and is terminated upon reaching maximum production.

Isolation of the product [2'] can be performed by neutralizing the reaction mixture with an acid such as hydrochloric acid or sulfuric acid, thereafter extracting with water immiscible organic solvent such as chloroform under weakly alkaline conditions, and recrystallizing from an organic solvent such as acetone.

The thus-obtained product [2'] can be purified if necessary, by column chromatography using silica-gel, active alumina or an adsorption resin.

The group R.sub.4 in the above .alpha.-halogenocarboxylate ester [4] is defined as hydrogen, lower alkyl or aryl. Examples of lower alkyl are C.sub.1-4 alkyls such as methyl, ethyl or propyl, and that of aryl are phenyl optionally substituted with 1-3 halogen, nitro, lower alkyl or lower alkoxy.

The group R.sub.9 in the above ester [4] is C.sub.1-4 alkyl such as methyl, ethyl or propyl and the group X is halogen, such as chlorine, bromine or iodine.

The reaction of the compound [3] with an .alpha.-halogeno carboxylate ester [4] is in general effected in an organic solvent such as dimethylforamide while heating. Isolation of the product [1a] can be performed by distilling off the reaction solvent and extracting the residue with a water-immiscible organic solvent such as benzene chloroform.

Process B

A process for the production of compound [1] wherein Q is --CO-- and R is hydroxyl (hereinafter compound [1b]):

Compound [1b] can be produced by de-esterifying the above compound [1a] by any known de-esterification procedure. For example, compound [1a] is hydrolyzed by alkali hydroxide such as KOH or NaOH, and in case any unreacted compound [1a] remains, after removing the same by extracting with a water-immiscible organic solvent such as chloroform, the reaction mixture is neutralized with an acid and the precipitated product [1b] is filtered or extracted with a water-immiscible organic solvent.

Process C

A process for the production of compound [1] wherein Q is --CO-- and R is --NH-lower alkylene-OH or ##STR14## (hereinafter compound [1c]):

Compound [1c] can be produced by reacting an amine of the formula

H--R' [5] wherein R' is --NH-lower alkylene-OH or ##STR15## is di-lower alkylamino, cycloalkylamino morpholino, ##STR16## wherein R.sub.9, R.sub.10, aryl, m and n have the same meanings hereinbefore, with a compound [1b] or its reactive derivatives for N-acylation.

In the group R' in the above amine [5] the lower alkylene moiety is defined as straight or branched C.sub.1-4 lower alkylene.

Examples of lower alkylene are methylene, ethylene, methylmethylene, propylene, 1-methylethylene, ethyl-methylene butylene, isobutylene or sec-butylene; C.sub.1-3 is preferred.

Di-lower alkylamino in the above ##STR17## is dialkylamino of C.sub.1-4 alkyl such as dimethylamino, diethylamino or dipropylamino.

The above cycloalkylamino is cycloalkylamino of C.sub.5-8, cycloalkyl such as cyclopentylamino, cyclohexyamino or cycloheptylamino.

The ring ##STR18## in the above ##STR19## wherein m is an integer of 4-6, is defined as pyrrolidine, piperidine or a hexamethyleneimine ring, R.sub.9 means hydrogen, lower alkyl or aryl. "Lower alkyl" means branched or unbranched C.sub.1-4 alkyl. "Aryl" as used above means phenyl or phenyl substituted with 1-3 halogen, nitro, lower alkyl or lower alkoxy.

The group R.sub.10 in the above ##STR20## is defined as hydrogen, lower alkyl, hydroxy-lower alkyl, aryl, hydroxy-lower alkoxy-lower alkyl or di(aryl)-lower alkyl. Examples of the above alkyl are branched or unbranched C.sub.1-4 alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and t-butyl. Examples of the above hydroxy-lower alkyl are hydroxyalkyl of C.sub.1-4 such as hydroxymethyl, 2-hydroxyethyl or 3-hydroxypropyl. Examples of hydroxy-lower alkoxy-lower alkyl are hydroxy alkoxy alkyl comprising alkoxy which is C.sub.1-4 lower alkoxy and alkyl which is C.sub.1-4 lower alkyl, for example hydroxymethoxymethyl, (2-hydroxyethoxy) methyl, 2-(2-hydroxyethoxy) ethyl or 2-(hydroxymethoxy) ethyl. The group "aryl" in the above di-(aryl)-lower alkyl is phenyl optionally substituted with 1-3 halogen, nitro, lower alkyl or lower alkoxy, and the group "lower alkyl" hereinabove is C.sub.1-4 alkyl such as methyl or ethyl. An example of di-(aryl)-lower alkyl is diphenylmethyl.

The ring of the group ##STR21## in the above ##STR22## wherein n is 2 or 3, is piperazine or homopiperazine. A lower alkylene bound to the above ring is defined hereinabove and is branched or unbranched C.sub.1-4 alkylene.

Examples of aryl are phenyl or phenyl substituted with 1-3 halogen, nitro, lower alkyl or lower alkoxy, such as phenyl, tolyl, xylyl, p(m or o)-chlorophenyl, p(m or o)-fluorophenyl, p(m or o)-bromophenyl, 2,4(2,3-, 3,4-, 2,5-, 3,5- or 2,6-)dichlorophenyl, p(m or o)-nitrophenyl, p(m or o)-methoxyphenyl, 2,4(2,3-, 3,4-, 2,5-, 3,5- or 2,6)-dimethoxyphenyl.

Accordingly, specific examples of the amine [5] are dimethylamine, diethylamine, 2-hydroxyethylamine, cyclohexylamine, morpholine, pyrrolidine, piperizine, hexamethyleneimine, 4-methylpiperizine, 4-phenylpiperazine, piperazine, 4-methylpiperazine, 4-ethylpiperazine, 4-propylpiperazine, 4-butylpiperazine, 4-(2-hydroxyethyl)-piperazine, 4-[2-(2-hydroxyethoxy)ethyl]-piperazine, 4-benzylpiperazine, 4-(o-chlorobenzyl)-piperazine, 4-(p-chlorobenzyl)-piperazine, 4-(2,4-dichlorobenzyl)-piperazine, 4-(p-nitrobenzyl)-piperazine, 4-(m-nitrobenzyl)-piperazine, 4-(o-nitrogenzyl)-piperazine, 4-(p-methoxybenzyl)-piperazine, 4-(methylbenzyl)-piperazine, 4-(diphenylmethyl)-piperazine, 4-benzyl-homopiperazine, 4-(p-methylbenzyl)-homopiperazine, 4-(p-chlorobenzyl)-homopiperazine, 4-(p-fluorobenzyl)-homopiperazine, 4-(p-nitrobenzyl)-homopiperazine and 4-(p-methoxybenzyl)-homopiperazine.

The reaction of the above amine [5] and the compound [1b] or its reaction derivative ordinarily proceeds by mixed anhydride method reacting the compound [1b] and amine [5] with pivaloyl chloride in the presence of a tertiary amine such as tetrahydrofuran.

The resulting compound [1f] can be isolated by pouring the reaction mixture into dilute aqueous alkali and extracting with a water-immiscible organic solvent such as benzene or chloroform.

In the above reaction, when piperazine is used as amine [5], a compound [1c], wherein R is ##STR23## in which R.sub.1, R.sub.2, R.sub.3 and R.sub.4 have the same meanings hereinbefore, is produced depending on a ratio of piperazine used.

Process D

A process for the production of the compound [1] wherein Q is --CO-- and R is NH-lower alkylene-halogen (hereinafter compound [1d]):

Compound [1d] can be produced by N-acylating a compound of the formula

X-lower alkylene-NH.sub.2 [6] wherein X is halogen and lower alkyl has the same meaning hereinabove, with compound [1b] or a reactive derivative thereof.

"Lower alkylene" in the above amine [6] means, as defined hereinbefore, branched or unbranched C.sub.1-4 alkylene, such as methylene, ethylene, methylmethylene, propylene, 1-methylethylene, ethylmethylene, butylene, isobutylene or sec-butylene, and --(CH.sub.2).sub.1-3 is preferred.

Examples of the above amine [6] are 2-chloroethylamine and 2-bromoethylamine.

The reaction of the above amine [6] with the compound [1b] or its reactive derivative is performed in the same way as in the process C hereinabove to produce the compound [1d].

Process E

A process for the production of compound [1] wherein Q is --CO-- and R is ##STR24## (hereinafter compound [1e]):

Compound [1e] can be produced by aminating the above compound [1d] with an amino of the formula ##STR25## has the same meaning hereinbefore.

The group ##STR26## in the above amine [7] has the same meaning as ##STR27## as defined in the above amine [5], and the group aryl as defined in the above ##STR28## means phenyl or phenyl substituted with 1-3 halogen, nitro, lower alkyl or lower alkoxy.

Examples of amine [7] are the amine [5] hereinbefore and 4-phenylpiperazine, 4-(o-chlorophenyl)-piperazine, 4-(p-chlorophenyl)-piperazine, 4-(p-methoxyphenyl)-piperazine, 4-(m-methoxyphenyl)-piperazine or 4-(m-methoxyphenyl)-piperazine.

The above amination reaction can be effected in an inert organic solvent such as benzene in the presence of a tertiary organic amine such as triethylamine. Isolation of the product [1d] can be performed by pouring the reaction mixture into dilute aqueous alkali and extracting with a water-immiscible organic solvent such as chloroform.

Process F

A process for the production of compound [1] wherein Q is --CH.sub.2 -- and R is --NH-lower alkylene-arylthio (hereinafter compound [1f]):

The above compound [1f] can be produced by thioetherification of the above compound [1d] with aryl-thiol [8].

Aryl in the above aryl-thiol [8] means phenyl or phenyl substituted with 1-3 halogen, nitro, lower alkyl or lower alkoxy, such as thiophenol.

The above thio-etherification can be effected in a reaction solvent such as dimethylformamide in the presence of an alkali such as potassium carbonate or sodium carbonate. Isolation of the compound [1f] can be performed by removing the reaction solvent and extracting with a water-immiscible organic solvent such as chloroform in a dilute aqueous alkali.

Process G

A process for the production for compound [1] wherein Q is --CH.sub.2 -- and R is hydroxyl (hereinafter compound [1g]):

Compound [1g] can be produced by reducing the above compound [1a] with alkali borohydride in lower alcohol with heating.

Isolation of the product [1g] can be performed by removing the organic solvent from the reaction, adding water to the residue and extracting with a water-immiscible organic solvent such as chloroform.

Process H

A process for the production of compound [1] wherein Q is --CH.sub.2 -- and R is halogen (hereinafter compound [1h]):

Compound [1h] can be produced by halogenating the above compound [1g] with a halogenating agent in a reaction solvent.

The said halogenating agent may be any known halogenating agent. Conventional chlorination reagents such as SOCl.sub.2, PCl.sub.5 and POCl.sub.3 can be used. The halogenation reaction can be effected, in general, in an inert organic solvent such as chloroform. The reaction proceeds at room temperature. Isolation of the product [1h] can be performed by adding a water-immiscible organic solvent such as chloroform, washing with dilute aqueous alkali, dehydrating the organic layer and removing the solvent therefrom.

The resulting compound [1h] can be used without purification, as by silica-gel column chromatography, to derive compound [1j] below from compound [1h].

Process J

A process for production of compound [1] wherein Q is --CH.sub.2 -- and R is ##STR29## (hereinafter compound [1j]):

A compound [1j] can be produced by aminating compound [1h] above with the amine [5] in a reaction solvent with heating.

The above amination reaction can be effected in an organic solvent such as benzene with heating

In the above reaction, co-generated acid can be removed by an acid binder, for example a known tertiary organic amine such as triethylamine.

The product [1j] can be isolated by pouring the reaction mixture into dilute aqueous alkali and extracting with a water-immiscible organic solvent such as benzene or chloroform.

The thus-obtained compound [1] is purified, if required, by column chromatography using silica gel, activated alumina or an adsorption resin with an elution solvent such as chloroform-methanol or benzene-ethyl acetate.

A compound [1] is generally produced in the form of its free base, but it can also be produced in the form of a conventional salt thereof. For example, a hydrochloride can be prepared by dissolving a compound [1] in a lower alcohol such as methanol or ethanol, adding a slight molar excess of hydrochloric acid, and isolating the precipitated material, or if not precipitated, by adding ether therein to precipitate the same. The molar ratio of hydrochloric acid may be different according to the specific compound [1].

Examples of the compound [1] of the present invention are set forth in Tables 1 and 2.

TABLE 1__________________________________________________________________________ ##STR30##Compound No. R.sub.1 R.sub.2 R.sub.3 R.sub.4 Q R__________________________________________________________________________034 Me Me Me H CO OMe035 Me Me Me Me CO OMe036 Me Me Me Ph CO OMe037 Me Me Me H CO OH038 Me Me Me Me CO OH039 Me Me Me Ph CO OH066 Me Me Me H CO ##STR31##067 Me Me Me H CO ##STR32##068 Me Me Me H CO ##STR33##069 Me Me Me H CO NHCH.sub.2 CH.sub.2OH070 Me Me Me H CO ##STR34##071 Me Me Me H CO NHCH.sub.2 CH.sub.2NMe.sub.2072 Me Me Me H CO NHCH.sub.2 CH.sub.2SPh073 Me Me Me H CO ##STR35##074 Me Me Me H CO ##STR36##075 Me Me Me H CO ##STR37##076 Me Me Me H CO ##STR38##103 Me Me Me H CO ##STR39##105 Me Me Me H CO ##STR40##135 Me Me Me H CO ##STR41##136 Me Me Me H CO ##STR42##137 Me Me Me H CO ##STR43##341 Et Me Me Ph CO ##STR44##342 Et Me Me Ph CO ##STR45##343 Et Me Me Ph CO ##STR46##344 Et Me Me Ph CO ##STR47##345 Et Me Me Ph CO ##STR48##346 Et Me Me Ph CO ##STR49##347 Et Me Me Ph CO ##STR50##348 Et Me Me Ph CO ##STR51##376 CH.sub.2 Ph Et Et H CO ##STR52##377 CH.sub.2 Ph Et Et H CO ##STR53##379 " Et Et H CO ##STR54##381 " Et Et H CO ##STR55##382 " Et Et H CO ##STR56##491 Et Me Me H CH.sub.2 ##STR57##492 Et Me Me H CH.sub.2 ##STR58##493 Et Me Me H CH.sub.2 ##STR59##494 Et Me Me H CH.sub.2 ##STR60##495 Et Me Me H CH.sub.2 ##STR61##496 Et Me Me H CH.sub.2 ##STR62##497 Et Me Me H CH.sub.2 ##STR63##498 Et Me Me H CH.sub.2 ##STR64##499 Et Me Me H CH.sub.2 ##STR65##500 Et Me Me H CH.sub.2 ##STR66##501 Et Me Me H CH.sub.2 ##STR67##502 Et Me Me H CH.sub.2 ##STR68##503 Et Me Me H CH.sub.2 ##STR69##504 Et Me Me H CH.sub.2 ##STR70##511 CH.sub.2 Ph Me Me H CH.sub.2 ##STR71##512 " Me Me H CH.sub.2 ##STR72##516 " Me Me H CH.sub.2 ##STR73##536 Me Me Me H CH.sub.2 ##STR74##537 Me Me Me H CH.sub.2 ##STR75##538 Me Me Me H CH.sub.2 ##STR76##539 Me Me Me H CH.sub.2 ##STR77##540 Me Me Me H CH.sub.2 ##STR78##541 Me Me Me H CH.sub.2 ##STR79##544 iso-Pro Me Me H CH.sub.2 ##STR80##546 " Me Me H CH.sub.2 ##STR81##547 " Me Me H CH.sub.2 ##STR82##550 " Et Et H CH.sub.2 ##STR83##551 " Et Et H CH.sub.2 ##STR84##552 iso-Pro Et Et H CH.sub.2 ##STR85##553 " Et Et H CH.sub.2 ##STR86##556 iso-Bu Et Et H CH.sub.2 ##STR87##558 " Et Et H CH.sub.2 ##STR88##648 Me Me Me H CO NHCH.sub.2 CH.sub. 2Br649 Me Me Me H CO NHCH.sub.2 CH.sub.2Cl650 Me Me Me H CO NHCH.sub.2 CH.sub.2C.sub.6 H.sub.11651 Et Me Me Ph CO OMe652 Et Me Me Ph CO OH653 Et Me Me Ph CO NHCH.sub.2 CH.sub.2Cl654 CH.sub.2 Ph Et Et H CO OMe655 " Et Et H CO OH656 " Et Et H CO NHCH.sub.2 CH.sub.2Cl657 " Et Et H CO ##STR89##658 " Et Et H CO ##STR90##662 Et Me Me H CO OMe663 CH.sub.2 Ph Me Me H CO OMe664 iso-Pro Me Me H CO OMe665 " Et Et H CO OMe666 iso-Pro Et Et H CO OMe679 Me Me Me H CH.sub.2 OH680 Et Me Me H CH.sub.2 OH681 CH.sub.2 Ph Me Me H CH.sub.2 OH682 iso-Pro Me Me H CH.sub.2 OH683 " Et Et H CH.sub.2 OH684 iso-Bu Et Et H CH.sub.2 OH697 iso-Pro Me Me H CH.sub.2 ##STR91##810 Me Me Me H CH.sub.2 ##STR92##812 Et Me Me H CH.sub.2 ##STR93##814 iso-Pro Me Me H CH.sub.2 ##STR94##822 Me Me Me H CH.sub.2 ##STR95##825 iso-Pro Me Me H CH.sub.2 ##STR96##826 iso-Pro Et Et H CH.sub.2 ##STR97##834 iso-Pro Me Me H CH.sub.2 ##STR98##842 Me Me Me H CH.sub.2 NEt.sub.2844 Et Me Me H CH.sub.2 NEt.sub.2846 iso-Pro Me Me H CH.sub.2 NEt.sub.2848 iso-Pro Et Et H CH.sub.2 NEt.sub.2__________________________________________________________________________ Me; methyl Et; ethyl Pro; propyl Bu; butyl Ph; benzene ring ( ): position of substituent ##STR99## ##STR100## ##STR101## ##STR102## TABLE 2__________________________________________________________________________ ##STR103##Compound No. R.sub.1 Q R__________________________________________________________________________368 CH.sub.2 Ph CO ##STR104##369 " CO ##STR105##370 " CO ##STR106##371 " CO ##STR107##372 " CO ##STR108##373 " CO ##STR109##517 Bu CH.sub.2 ##STR110##518 Bu CH.sub.2 ##STR111##519 Bu CH.sub.2 ##STR112##520 Bu CH.sub.2 ##STR113##521 Bu CH.sub.2 ##STR114##522 Bu CH.sub.2 ##STR115##559 (CH.sub.2).sub.4 CH.sub.3 CH.sub.2 ##STR116##560 (CH.sub.2).sub.4 CH.sub.3 CH.sub.2 ##STR117##561 " CH.sub.2 ##STR118##562 " CH.sub.2 ##STR119##563 " CH.sub.2 ##STR120##564 (CH.sub.2).sub.5 CH.sub.3 CH.sub.2 ##STR121##565 " CH.sub.2 ##STR122##567 " CH.sub.2 ##STR123##568 " CH.sub.2 ##STR124##569 " CH.sub.2 ##STR125##570 " CH.sub.2 ##STR126##571 (CH.sub.2).sub.6 CH.sub.3 CH.sub.2 ##STR127##572 (CH.sub.2).sub.7 CH.sub.3 CH.sub.2 ##STR128##573 " CH.sub.2 ##STR129##574 " CH.sub.2 ##STR130##575 " CH.sub.2 ##STR131##576 " CH.sub. 2 ##STR132##577 (CH.sub.2).sub.7 CH.sub.3 CH.sub.2 ##STR133##578 " CH.sub.2 ##STR134##579 (CH.sub.2).sub.8 CH.sub.3 CH.sub.2 ##STR135##580 " CH.sub.2 ##STR136##581 " CH.sub.2 ##STR137##582 " CH.sub.2 ##STR138##583 " CH.sub.2 ##STR139##584 " CH.sub.2 ##STR140##585 (CH.sub.2).sub.9 CH.sub.3 CH.sub.2 ##STR141##586 " CH.sub.2 ##STR142##587 " CH.sub.2 ##STR143##588 " CH.sub.2 ##STR144##589 " CH.sub.2 ##STR145##590 " CH.sub.2 ##STR146##591 " CH.sub.2 ##STR147##592 " CH.sub.2 ##STR148##593 (CH.sub.2).sub.9 CH.sub.3 CH.sub.2 ##STR149##594 (CH.sub.2).sub.11 CH.sub.3 CH.sub.2 ##STR150##595 " CH.sub.2 ##STR151##596 " CH.sub.2 ##STR152##597 " CH.sub.2 ##STR153##598 " CH.sub.2 ##STR154##599 " CH.sub.2 ##STR155##600 (CH.sub.2).sub.13 CH.sub.3 CH.sub.2 ##STR156##601 " CH.sub.2 ##STR157##602 " CH.sub.2 ##STR158##603 " CH.sub.2 ##STR159##604 " CH.sub.2 ##STR160##605 " CH.sub.2 ##STR161##606 (CH.sub.2).sub.15 CH.sub.3 CH.sub.2 ##STR162##607 " CH.sub.2 ##STR163##608 " CH.sub.2 ##STR164##609 (CH.sub.2).sub.15 CH.sub.3 CH.sub.2 ##STR165##610 " CH.sub.2 ##STR166##659 CH.sub.2 Ph CO OMe660 " CO OH661 " CO NHCH.sub.2 CH.sub.2Cl667 Bu CO OMe668 (CH.sub.2).sub.4 CH.sub.3 CO OMe669 (CH.sub.2).sub.5 CH.sub.3 CO OMe670 (CH.sub.2).sub.6 CH.sub.3 CO OMe671 (CH.sub.2).sub.7 CH.sub.3 CO OMe672 (CH.sub. 2).sub.8 CH.sub.3 CO OMe673 (CH.sub.2).sub.9 CH.sub.3 CO OMe674 (CH.sub.2).sub.11 CH.sub.3 CO OMe675 (CH.sub.2).sub.13 CH.sub.3 CO OMe676 (CH.sub.2).sub.15 CH.sub.3 CO OMe677 Pro CO OMe678 sec-Bu CO OMe685 Bu CH.sub.2 OH686 (CH.sub.2).sub.4 CH.sub.3 CH.sub.2 OH687 (CH.sub.2).sub.5 CH.sub.3 CH.sub.2 OH688 (CH.sub.2).sub.6 CH.sub.3 CH.sub.2 OH689 (CH.sub.2).sub.7 CH.sub.3 CH.sub.2 OH690 (CH.sub.2).sub.8 CH.sub.3 CH.sub.2 OH691 (CH.sub.2).sub.9 CH.sub.3 CH.sub.2 OH692 (CH.sub.2).sub.11 CH.sub.3 CH.sub.2 OH693 (CH.sub.2).sub.13 CH.sub.3 CH.sub.2 OH694 (CH.sub.2 ).sub.15 CH.sub.3 CH.sub.2 OH695 Pro CH.sub.2 OH696 sec-Bu CH.sub.2 OH817 Bu CH.sub.2 ##STR167##830 (CH.sub.2).sub.7 CH.sub.3 CH.sub.2 ##STR168##837 Bu CH.sub.2 ##STR169##839 (CH.sub.2).sub.7 CH.sub.3 CH.sub.2 ##STR170##850 Bu CH.sub.2 NEt.sub.2851 (CH.sub.2).sub.7 CH.sub.3 CH.sub.2 NEt.sub.2__________________________________________________________________________ Me; methyl Et; ethyl Pro; propyl Bu; butyl Ph; benzene ring ( ): position of substituent ##STR171## ##STR172## ##STR173## ##STR174##

The pharmacological activity of the present compounds [1] is illustrated below All the compounds [1] used in the pharmacological tests were tested in the form of the hydrochloride salt thereof.

1. Platelet aggregation inhibition

Sample solution containing a compound [1] (final concentration 500 or 100 .mu.M) is added to rabbit platelet plasma to which was added 10% by volume of a 3.8% sodium citrate solution, and the mixture is incubated at 37.degree. C. for 3 minutes. A platelet activation factor (PAF, final concentration 10-50 .mu.g/ml) or collagen (final concentration 2.5 .mu.g/ml) is added thereto as an aggregating agent, and platelet aggregation activity is measured with an aggregometer. The results of assays for PAF-induced aggregation are shown in Table 3, and those for collagen-induced aggregation are shown in Table 4, which tables show the strong platelet aggregation inhibitory activity of the compounds [1] of the present invention.

TABLE 3______________________________________Platelet aggregation inhibitory action on PAF-induced aggregation concentration inhibition ratioCompound No. (.mu.M) (%)______________________________________560 100 97561 100 56562 100 45565 100 94567 100 58570 100 40571 100 88573 100 86580 100 94587 100 91588 100 64595 100 85600 100 52067 300 53070 500 48135 500 77136 100 50137 100 76341 100 42342 100 43344 100 44347 100 59348 100 70502 100 81503 100 42504 100 60541 100 44550 100 56551 100 97552 100 78553 100 82556 100 51______________________________________ TABLE 4______________________________________Platelet aggregation inhibitory action oncollagen-induced aggregation concentration inhibition ratiocompound No. (.mu.M) (%)______________________________________573 100 58580 100 80582 100 58585 100 41587 100 79588 100 78547 100 56550 100 85556 100 40______________________________________

2. Vasodilation activity

A dog, pretreated with morphine (1.5 mg/kg, sc) is anesthesized with urethane (450 mg/kg, iv) and .alpha.-chloralose (45 mg/kg, iv), and immobilized in the dosal position. Right femoral arterial blood is introduced into a left femoral artery via a perfusion pump, and Sterling's resistance is connected to the exosomatic circulatory system to perfuse blood to a left back limb at constant pressure. The perfusion pressure is set at a valve slightly higher than that of the average blood pressure of the animal. Sample (100 .mu.g) dissolved in physiological saline solution is administered to a right femoral artery, and changes in blood flow are measured. Vasodilation activity is measured as a relative activity, by defining as 100% the increased rate of blood flow when 30 .mu.g papaverin is administered intraarterially. The results are shown in Table 5, where it will be seen that the compounds [1] of the present invention have strong vasodilation activity.

TABLE 5______________________________________Vasodilation Activitycompound No. vasodilation activity (%)______________________________________075 89135 242136 204137 216______________________________________

3. Antioxidant activity

Antioxidant activity is determined according to the method of Stocks et al. [Clin. Sci. Mol. Med., 47: 215 (1974)]. Rat cerebrum is added to ice-cooled 40 mM phosphate saline buffer solution (PBS) (pH 7.4, 4 ml buffer per 1 g cerebrum), homogenized and centrifuged (1000.times.g, 4.degree. C., 10 min.) to obtain a supernatant solution. The supernatant solution is diluted fivefold with the above ice-cooled PBS solution, and to a 0.9 ml aliquot thereof is added a sample containing a compound [1] (0.1 ml, final concentration 100 .mu.M) dissolved in ethanol. The resultant mixture is incubated at 37.degree. C. for 15 minutes, 35% perchloric acid (0.2 ml) is added, and the mixture is ice-cooled to stop the reaction and centrifuged (1300.times.g, 4.degree. C., 10 min.). 0.5 ml thiobarbituric acid (5 g/lit. of 50% acetic acid) is added to the supernatant solution (1 ml), so as to measure its absorbancy at 532 nm. The amount of lipoperoxide thus generated is expressed as an amount of malondialdehyde. The results are shown in Table 6, where it will be seen that the compounds [1] of the present invention inhibit lipoperoxide generation.

TABLE 6______________________________________Antioxidant activitycompound No. inhibition ratio (%)______________________________________371 49372 64373 49520 83562 65568 61569 81570 65573 56574 71575 79576 85577 71578 88580 77581 71582 82583 82584 65585 62586 68587 65588 65589 74590 74591 59592 85593 73594 58595 70596 73597 76598 88599 70600 61601 67602 64603 76607 52608 55609 61344 48345 54347 51348 62379 50382 83502 69516 75______________________________________

As explained hereinabove, a compound [1] of the present invention or its corresponding salt inhibits platelet aggregation, has-vasodilating activity, and/or inhibits lipoperoxide generation, and is useful in pharmaceutical form for treating circulatory and metabolic disorders.

The following examples are illustrative of the present invention but are not to be construed as limiting.

In the examples, the Rf value of silica-gel thin layer chromatography (TLC) is either specified by or measured using the following carrier and developing solvent:

Carrier: silica gel, Kieselgel 60 F.sub.254 Art 5715 (Merck) Developer: chloroform - methanol (20:1)

Physical properties (NMR, Mass, CI, Rf upon TLC) of the compounds [1] obtained in the following examples are shown in Tables 25-27.

Symbols for chemical structure in Tables 7-19 have the same meanings as in Table 1, and the symbols in Tables 20-24 have the same meanings as in Table 2.

EXAMPLE 1

Methyl (3,5,6-trimethylpyrazine-2-yl oxy) acetate (compound 034)

Metallic sodium (1.29 g, 56 mM) was dissolved in anhydrous methanol (120 ml). 2-hydroxy-3,5,6-trimethylpyrazine (7.74 g, 56 mM) was dissolved therein, and methanol was distilled off in vacuo to obtain sodium 3,5,6-trimethyl-2-pyrazinolate which was suspended in dimethylformamide (150 ml). Methyl chloroacetate (10.85 g, 0.10M) was added thereto and the mixture was stirred at 95.degree.-100.degree. C. for 3 hours. The solvent was removed in vacuo. Dilute aqueous sodium carbonate was added to the residue, which was then extracted twice with chloroform (200 ml), and the extract was dried with anhydrous magnesium sulfate and concentrated in vacuo. The residue was charged on a column of silica gel (Wako Pure Chem. Co., C-200, 170 g) and eluted with benzene and benzene-ethyl acetate (10:1) successively to obtain the product. (8.23 g, yield: 70.0%)

EXAMPLE 2

Methyl .alpha.-(3,5,6-trimethylpyrazine-2-yl oxy) propionate (compound 035)

Methyl .alpha.-chloropropionate (12.25 g, 0.10 mM) was added to sodium 3,5,6-trimethyl-2-pyrazinolate (8.00 g, 50 mM) suspended in dimethylformamide (100 ml) and the mixture was stirred 95.degree.-100.degree. C. for 7 hours. The solvent was distilled off in vacuo. Dilute aqueous sodium carbonate was added to the residue, which was then extracted once with chloroform (200 ml) and twice with chloroform (100 ml), and the extract was dried with anhydrous magnesium sulfate and concentrated in vacuo. The residue was charged on a column of silica gel (Wako Pure Chem. Co., C-200, 160 g) and eluted wtih benzene and benzene-ethyl acetate (10:1) successively to obtain the product. (8.39 g, yield: 74.9%)

EXAMPLE 3

Methyl .alpha.-(3,5,6-trimethylpyrazine-2-yl oxy) phenyl acetate (compound 036)

Methyl .alpha.-bromophenyl acetate (23.0 g, 0.10 mM) was added to sodium 3,5,6-trimethyl-2-pyrazinolate (8.00 g, 50 mM) suspended in dimethylformamide (150 ml) and the mixture was stirred at 100.degree. C. for 5 hours. The reaction mixture was treated in the same way as in Example 2 to obtain the product. (10.97 g, yield: 76.7%)

EXAMPLE 4

(3,5,6-trimethylpyrazine-2-yl oxy) acetate (compound 037)

Aqueous 1N-NaOH (80 ml) was added to compound 034 (8.40 g, 40 mM) and the mixture was stirred for 30 minutes. 1N-HCl (80 ml) was added to the reaction mixture and the precipitated crystals were collected by filtration to obtain a portion of the product. (3.15 g) The filtrate was dried in vacuo and the residue was extracted with hot ethanol, then the extract was dried in vacuo to obtain the remainder of the product. (4.09 g) (Total: 7.24 g, yield: 92.3%)

EXAMPLE 5

.alpha.-(3,5,6-trimethylpyrazine-2-yl oxy) propionate (compound 038)

Aqueous 1N-NaOH (80 ml) was added to compound 035 (7.81 g, 35 mM) and the mixture was stirred for 1 hour. The reaction mixture was extracted with chloroform to remove unreacted compound. 1N-HCl (70 ml) was added to the aqueous layer and the mixture was concentrated in vacuo to precipitate crystals, which were collected by filtration, washed with water completely and dried to obtain the product. (6.66 g, yield: 90.6%)

EXAMPLE 6

.alpha.-(3,5,6-trimethylpyrazine-2-yl oxy) phenyl acetate (compound 039)

Aqueous 1N-NaOH (75 ml) was added to compound 0.36 (10.80 g, 37.7 mM) dissolved in methanol (75 ml) and the mixture was stirred for 1.5 hour. Methanol was distilled off in vacuo and the aqueous layer was washed with chloroform. 1N-HCl (75 ml) was added to the aqueous layer which was extracted with chloroform. The extract was dried with anhydrous magnesium sulfate and concentrated in vacuo to obtain the product as white crystals. (9.89 g, yield: 96.4%

EXAMPLES 7-12

2-(substituted carbonylmethoxy)-3,5,6-trimethylpyrazine

Triethylamine (0.70 ml, 5 mM) was added to compound 037 (0.98 g, 5 mM) dissolved in tetrahydrofuran Pivaloyl chloride (0.16 g, 5 mM) was added dropwise at -5.degree. C. and the mixture was stirred for 30 minutes with ice cooling. A tetrahydrofuran solution of a base (5 mM) was added dropwise to the reaction mixture and the mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated in vacuo and the residue was dried with chloroform, then concentrated in vacuo. The residue was charged on a column of silica gel (C-20, 60 g) and eluted with chloroform and chloroform-methanol (200:1) successively to obtain the compounds in Table 7.

Table 7 identifies the product, yields in weight and percentage, the base and its amount used.

EXAMPLE 13

N-(2-bromoethyl)-3,5,6-trimethylpyrazine-2-yl oxy) acetamide (compound 648)

Triethylamine (7.0 ml, 50 mM) was added to compound 037 (9.80 g, 50 mM) dissolved in tetrahydrofuran (100 ml) and chloroform (100 ml) in solution with bromoethylamine hydrobromide (10.30 g, 50 mM) and triethylamine (7.7 ml, 55 mM) was added dropwise at -5.degree. C., then the mixture was stirred for 4 hours with ice cooling. The reaction mixture was concentrated in vacuo, the residue was dissolved in chloroform and washed with dilute aqueous potassium carbonate. The aqueous layer was extracted with chloroform. The organic layer was combined, dried with anhydrous magnesium sulfate, and concentrated in vacuo. The residue was charged on a column of silica gel (Chlodil, 250 g), and eluted successively with chloroform and chloroform-methanol (500:1) to obtain the product (6.92 g)

EXAMPLE 14

N-(2-chloroethyl)-(3,5,6-trimethylpyrazine-2-yl oxy) acetamide (compound 649)

Triethylamine (3.50 ml, 25 mM) was added to compound 037 (4.90 g, 25 mM) dissolved in tetrahydrofuran (50 ml) and pivaloyl chloride (3.05 g, 25 mM) was added dropwise at -5.degree. C., then the mixture was stirred for 30 mintes. Chloroform (50 ml) in solution with 2-chloroethylamine hydrochloride (2.90 g, 25 mM) and triethylamine (3.9 ml, 28 mM) was added dropwise thereto, then the mixture was stirred for 4 hours while slowly reaching room temperature. The reaction mixture was concentrated in vacuo, the residue was dissolved in chloroform and washed with dilute aqueous potassium carbonate. The aqueous layer was extracted with chloroform. The organic layer was combined, dried with anhydrous magnesium sulfate, and concentrated in vacuo. The residue was charged on a column of silica gel (C-200, 40 g), and eluted successively with chloroform and chloroform-methanol (20:1) to obtain the product (5.66 g, yield: 7.5%)

EXAMPLES 15-21

N-(2-substituted ethyl)-(3,5,6-trimethylpyrazine-2-yl oxy) acetamide:

Benzene (20 ml) in solution with compound 648 (0.91 g, 3.0 mM), triethylamine (0.84 ml) and a base was refluxed. The reaction mixture was washed with dilute aqueous potassium carbonate, and the aqueous layer was extracted with chloroform. The organic layers (benzene and chloroform) was combined, dried with anhydrous magnesium sulfate, and concentrated in vacuo. The residue was charged on a column of silica gel (C-200, 65 g) and eluted successively with chloroform and chloroform-methanol to obtain the compounds in Table 8.

Table 8 shows the reflux time, yield in weight and percentage, the base and its amount used and the ratio of chloroform-methanol mixture used in each of the above examples.

EXAMPLE 22

N-(2-phenylthioethyl)-(3,5,6-trimethylpyrazine-2-yl oxy) acetamide (compound 072)

Thiophenol (0.60 g, 5.4 mM) and potassium carbonate (0.75 g, 5.4 mM) were added to compound 648 (0.91 g, 3.0 mM) dissolved in dimethylformamide (10 ml) and the mixture was stirred for 2 hours at room temperature. The reaction mixture was concentrated in vacuo, the residue was dissolved in chloroform and washed with dilute aqueous potassium carbonate. The aqueous layer was further extracted with chloroform. The combined organic layer was chromatographed by eluting successively with benzene and benzene-ethyl acetate (10:1) to obtain the product (0.35 g, yield: 35.2%)

EXAMPLES 23-25

N-(2-substituted ethyl)-(3,5,6-trimethylpyrazine-2-yl oxy) acetamide

Benzene (25 ml) in solution with compound 649 (0.98 g, 4 mM), triethylamine (1.14 ml) and a base was refluxed. The reaction mixture was washed with dilute aqueous potassium carbonate, and the aqueous layer was further extracted with chloroform. The organic layers (benzene and chloroform) were combined, dried with anhydrous magnesium sulfate, and concentrated in vacuo. The residue was charged on a column of silica gel (C-200, 80 g) and eluted successively with chloroform and chloroform-methanol to obtain the compounds in Table 9.

Table 9 shows the identity of the base and its amount used, the reflux time, the ratio of chloroform-methanol mixture used, the products and the yield in weight and percentage, in each of the above examples.

EXAMPLE 26

Methyl .alpha.-(3-ethyl-5,6-dimethylpyrazine-2-yl oxy) phenyl acetate (compound 651)

A solution (12.5 ml) of 4N-CH.sub.3 ONa/methanol was added to a solution of 2-hydroxy-3-ethyl-5,6-dimenthylpyrazine (7.60 g, 50 mM) in anhydrous methanol (100 ml), and methanol was distilled off in vacuo. The residue was dissolved in dimethylformamide (150 ml). Methyl .alpha.-bromophenyl acetate (11.5 g, 50 mM) was added thereto, and the mixture was stirred at 100.degree. C. for 5 hours. The reaction mixture was concentrated in vacuo. The residue was dissolved in chloroform, and washed with dilute aqueous potassium carbonate. The aqueous layer was further extracted twice with chloroform. The organic layers were combined, dried with anhydrous magnesium sulfate, and concentrated in vacuo. The residue was charged on a column of silica gel (C-200, 170 g) and eluted successively with benzene and benzene-ethyl acetate (50:1) to obtain the product (10.42 g, yield 69.5%)

EXAMPLE 27

.alpha.-(3-ethyl-5,6-dimethylpyrazine-2-yl oxy) phenyl acetate (compound 652):

Aqueous 2N-NaOH (25.7 ml) was added to compound 651 (7.72 g, 25.7 mM) dissolved in methanol (30 ml) and the mixture was stirred for 4.5 hours at room temperature. The reaction mixture, to which 2N-HCl (25.7 ml) was added, was ice cooled to precipitate crystals. The thus-precipitated crystals were collected by filtration, washed with water and dried to obtain the product (6.91 g, yield: 94.0%)

EXAMPLE 28

N-(2-chloroethyl)-.alpha.-(3-ethyl-5,6-dimethylpyrazine-2-yl oxy) phenyl acetamide (compound 653)

Triethylamine (3.7 ml, 26.6 mM) was added to compound 652 (7.50 g, 26.2 mM) dissolved in tetrahydrofuran (44 ml) and pivaloylchloride (3.21 g, 26.3 mM) was added dropwise at -5.degree. C., then the mixture was stirred for 30 minutes. Chloroform (26 ml) in solution with 2-chloroethylamine hydrochloride (3.05 g, 26.3 mM) and triethylamine (3.7 ml) was added dropwise thereto with cooling at 0.degree.-5.degree. C., then the mixture was stirred for 1 hour with ice cooling and for 4 hours at room temperature. Chloroform was added to the reaction mixture and the mixture was washed with dilute aqueous potassium carbonate. The aqueous layer was further extracted twice with chloroform. The organic layer were combined, dried with anhydrous magnesium sulfate, and concentrated in vacuo. The residue was charged on a column of silica gel (C-200, 170 g), and eluted successively with benzene, benzene-ethyl acetate (40:1) and benzene-ethyl acetate (10:1) to obtain the product (6.46 g, yield 70.4%)

EXAMPLES 29-36

N-(2-substituted ethyl)-.alpha.-(3-ethyl-5,6-dimethylpyrazine-2-yl oxy) phenyl acetamide

A base (8.0 mM) was added to benzene (30 ml) in solution with compound 653 (1.39 g, 4.0 mM) and triethylamine (1.12 ml) and the mixture was refluxed overnight. The reaction mixture was washed with dilute aqueous potassium carbonate, and the aqueous layer was further extracted three times with chloroform. The organic layers (benzene and chloroform) were combined, dried with anhydrous magnesium sulfate, and concentrated in vacuo. The residue was charged on a column of silica gel (C-200, 65 g) and eluted successively with chloroform and chloroform-methanol (100:1) to obtain the compounds in Table 10.

Table 10 shows the identity of the base and its amount used, the compounds and their yield in weight and percentage in each of the above examples.

EXAMPLE 37

Methyl (3-benzyl-5,6-diethylpyrazine-2-yl oxy) acetate (compound 654)

A solution of 4N-CH.sub.3 ONa/methanol (10.0 ml, 40 mM) was added to a solution of 2-hydroxy-3-benzyl-5,6-diethylpyrazine (9.68 g, 40 mM) in anhydrous methanol (120 ml), and methanol was distilled off in vacuo. The residue was dissolved in dimethylformamide (150 ml). Methyl chloroacetate (4.34 g, 40 mM) was added thereto, and the mixture was stirred at 100.degree. C. for 5 hours. The reaction mixture was concentrated in vacuo, diluted aqueous potassium carbonate was added to the residue and the aqueous layer was extracted three times with chloroform. The extract was dried with anhydrous magnesium sulfate, and concentrated in vacuo. The residue was charged on a column of silica gel (C-200, 170 g) and eluted successively with benzene and benzene-ethyl acetate (100:1) to obtain the product. (11.41 g, yield: 90.8%)

EXAMPLE 38

(3-benzyl-5,6-diethylpyrazine-2-yl oxy) acetate (compound 655)

Aqueous 2N-NaOH (34 ml) was added to compound 954 (10.68 g, 34.0 mM) dissolved in methanol (34 ml) and the mixture was stirred for 3 hours. 2N-HCl (34 ml) was added to the reaction mixture and the precipitated crystals were collected by filtration, washed completely with water and dried to obtain the product. (8.86 g, yield: 86.9%)

EXAMPLE 39

N-(2-chloroethyl)-(3-benzyl-5,6-diethylpyrazine-2-yl oxy) acetamide (compound 656)

Pivaloyl chloride (3.66 g, 30 mM) was added dropwise at -5.degree. C. to compound 655 (8.62 g, 28.7 mM) and triethylamine (4.2 ml, 30 mM) dissolved in tetrahydrofuran (50 ml), then the mixture was stirred for 30 minutes. Chloroform (30 ml) in solution with 2-fluoroethylamine hydrochloride (3.48 g) and triethylamine (4.2 ml) was added dropwise thereto with cooling at 0.degree. to -5.degree. C. then the mixture was stirred for 1 hour with ice cooling and 4 hours at room temperature. Dilute aqueous potassium carbonate was added to the reaction mixture and the mixture was extracted three times with chloroform. The extract was dried with anhydrous magnesium sulfate, and concentrated in vacuo. The residue was charged on a column of silica gel (C-200, 175 g) and eluted successively with benzene and benzene-ethyl acetate (5:1) to obtain the product. (9.21 g, yield: 88.8%)

EXAMPLES 40-46

N-(2-substituted ethyl)-(3-benzyl-5,6-dimethylpyrazine-2-yl oxy) acetamide

Benzene (30 ml) in solution with compound 656 (1.27 g, 3.5 mM), triethylamine (0.98 ml, 7 mM) and a base (7 mM) was refluxed. Dilute aqueous potassium carbonate was added to the reaction mixture and the mixture was extracted three times with chloroform. The organic layer was dried with anhydrous magnesium sulfate and concentrated in vacuo. The residue was charged on a column of silica gel (C-200, 80 g) and eluted successively with chloroform and chloroform-methanol (100:1) to obtain the compounds in Table 11.

Table 11 shows the identity of the base and its amount used, the reflux time, and the product and yield in weight and percentage in each of the above examples.

EXAMPLES 47-51

Methyl (3,5,6-trialkylpyrazine-2-yl oxy) acetate

Metallic sodium (1.15 g) was dissolved in anhydrous methanol (100 ml). A starting material 2-hydroxy-3,5,6-trialkylpyrazine (50 mM) was dissolved therein, and methanol was distilled off in vacuo to obtain the sodium salt thereof. Dimethylformamide (100 ml) and methyl chloroacetate (5.43 g, 50 mM) were added thereto, then the mixture was extracted three times with chloroform. The extract was dried with anhydrous magnesium sulfate and concentrated in vacuo. The residue was charged on a column of silica gel (C-200) and eluted successively with benzene and benzene-ethyl acetate (20:1) to obtain the compounds in Table 12.

Table 12 shows the identity of the starting compound and its amount used, the reaction time, the amount of silica gel used and the product and yield in weight and percentage in each of the above examples.

EXAMPLES 52-57

2-(2-hydroxyethoxy)-3,5,6-trialkylpyrazine

A starting compound was dissolved in methanol 6-8 equivalents of NaBH4 were added stepwise while refluxing. The reaction mixture was concentrated in vacuo, water was added thereto, then the mixture was extracted three times with chloroform. The extract was dried with anhydrous magnesium sulfate and concentrated in vacuo. The residue was charged on a column of silica gel (C-200) and eluted successively with benzene and benzene-ethyl acetate (10:1) to obtain the compounds in Table 13.

Table 13 shows the identity of the starting compound and its amount used, the amount of NaBH.sub.4 used, the reflux time, the amount of silica gel used and the product and yield in weight and percentage in each of the above examples.

EXAMPLES 58-66

2-(2-substituted ethoxy)-3,5,6-trimethylpyrazine

Thionyl chloride (0.56 ml, 1.3 equivalent) was added dropwise with ice cooling to compound 679 (1.10 g, 6.0 mM) dissolved in chloroform and the mixture was stirred at room temperature for 2.5 hours. Dilute aqueous potassium carbonate was added to the reaction mixture and the mixture was extracted three times with chloroform. The extract, which was dried with anhydrous sodium sulfate, was concentrated in vacuo. Benzene (30 ml), triethylamine (1.68 ml, 12 mM) and a base (12 mM) were added to the residue, and the mixture was refluxed. Dilute aqueous potassium carbonate was added to the reaction mixture, and the mixture was extracted three times with chloroform. The extract was dried with anhydrous magnesium sulfate and concentrated in vacuo. The residue was charged on a column of silica gel (C-200, 75 g) and eluted successively with chloroform and chloroform-methanol (200:1) to obtain the compounds in Table 14.

Table 14 shows the identity of the base and its amount used, the reflux time, and the product and yield in weight and percentage in each of the above examples.

EXAMPLES 67-72

2-(2-substituted ethoxy)-3-isopropyl-5,6-diethylpyrazine

Thionyl chloride (0.47 ml, 1.3 equivalent) was added dropwise with ice cooling to compound 683 (1.19 g, 5.0 mM) dissolved in chloroform (5 ml) and the mixture was stirred at room temperature for 4 hours. Dilute aqueous potassium carbonate was added to the reaction mixture and the mixture was extracted three times with chloroform. The extract, which was dried with anhydrous sodium sulfate, was concentrated in vacuo. Benzene (30 ml), triethylamine (1.40 ml, 10 mM) and a base (10 mM) were added to the residue, and the mixture was refluxed. Dilute aqueous potassium carbonate was added to the reaction mixture, and the mixture was extracted three times with chloroform. The extract was dried with anhydrous magnesium sulfate and concentrated in vacuo. The residue was charged on a column of silica gel (C-200, 75 g) and eluted successively with chloroform and chloroform-methanol (200:1) to obtain the compounds in Table 15.

Table 15 shows the identity of the base and its amount used, the reflux time, and the product and yield in weight and percentage in each of the above examples.

EXAMPLES 73-88

2-(2-substituted ethoxy)-3-ethyl-5,6-dimethylpyrazine

Thionyl chloride (0.43 ml, 1.3 equivalent) was added dropwise with ice cooling to compound 680 (0.98 g, 5.0 mM) dissolved in chloroform (5 ml) and the mixture was stirred at room temperature for 3 hours. Dilute aqueous potassium carbonate was added to the reaction mixture and the mixture was extracted three times with chloroform. The extract, which was dried with anhydrous sodium sulfate, was concentrated in vacuo. Benzene (60 ml), triethylamine (1.40 ml, 10 mM) and a base (10 mM) were added to the residue, and the mixture was refluxed. Dilute aqueous potassium carbonate was added to the reaction mixture, and the mixture was extracted three times with chloroform. The extract was dried with anhydrous magnesium sulfate and concentrated in vacuo. The residue was charged on a column of silica gel (C-200 75 g) and eluted successively with chloroform and chloroform-methanol to obtain the compounds in Table 16.

Table 16 shows the identity of the base and its amount used, the reflux time, the ratio of chloroform-methanol in the column chromatography, and the product and yield in weight and percentage in each of the above examples.

EXAMPLES 89-91

2-(2-substituted ethoxy)-3-benzyl-5,6-dimethylpyrazine:

Thionyl chloride (0.36 ml, 1.3 equivalent) was added dropwise with ice cooling to compound 681 (1.04 g, 4.0 mM) dissolved in chloroform (5 ml) and the mixture was stirred at room temperature for 3 hours. Dilute aqueous potassium carbonate was added to the reaction mixture and the mixture was extracted three times with chloroform. The extract, which was dried with anhydrous sodium sulfate, was concentrated in vacuo. Benzene (30 ml), triethylamine (1.40 ml, 10 mM) and a base (8.0 mM) were added to the residue, and the mixture was refluxed. Dilute aqueous potassium carbonate was added to the reaction mixture, and the mixture was extracted three times with chloroform. The extract was dried with anhydrous magnesium sulfate and concentrated in vacuo. The residue was charged on a column of silica gel (C-200, 75 g) and eluted successively with chloroform and chloroform-methanol to obtain the compounds in Table 17.

Table 17 shows the identity of the base and its amount used, the reflux time, ratio of chloroform-methanol in column chromatography, and the product and yield in weight and percentage in each of the above examples.

EXAMPLES 92-98 2-(2-substituted ethoxy)-3-isopropyl-5,6-dimethylpyrazine

Thionyl chloride (0.47 ml, 1.3 equivalent) was added dropwise with ice cooling to compound 682 (1.05 g, 4.0 mM) dissolved in chloroform (5 ml) and the mixture was stirred at room temperature for 3.5 hours. Dilute aqueous potassium carbonate was added to the reaction mixture and the mixture was extracted three times with chloroform. The extract, which was dried with anhydrous sodium sulfate, was concentrated in vacuo. Benzene (30 ml), triethylamine (1.40 ml, 10 mM) and a base (10 mM) were added to the residue, and the mixture was refluxed. Dilute aqueous potassium carbonate was added to the reaction mixture, and the mixture was extracted three times with chloroform. The extract was dried with anhydrous magnesium sulfate and concentrated in vacuo. The residue was charged on a column of silica gel (C-200, 75 g) and eluted successively with chloroform and chloroform-methanol to obtain the compounds in Table 18.

Table 18 shows the identity of the base and its amount used, the reflux time, the ratio of chloroform-methanol in the column chromatography, and the product and yield in weight and percentage in each of the above examples.

EXAMPLES 99-100

2-(2-substituted ethoxy)-3-isobutyl-5,6-diethylpyrazine:

Thionyl chloride (0.47 ml, 1.3 equivalent) was added dropwise with ice cooling to compound 684 (1.26 g, 5.0 mM) dissolved in chloroform (5 ml) and the mixture was stirred at room temperature for 4 hours. Dilute aqueous potassium carbonate was added to the reaction mixture and the mixture was extracted three times with chloroform. The extract, which was dried with anhydrous sodium sulfate, was concentrated in vacuo. Benzene (30 ml), triethylamine (1.40 ml, 10 mM) and a base (10 mM) were added to the residue, and the mixture was refluxed. Dilute aqueous potassium carbonate was added to the reaction mixture, and the mixture was extracted three times with chloroform. The extract was dried with anhydrous magnesium sulfate and concentrated in vacuo. The residue was charged on a column of silica gel (C-200, 75 g) and eluted successively with chloroform and chloroform-methanol to obtain the compounds in Table 19.

Table 19 shows the identity of the base and its amount used, the reflux time, and the product and yield in weight and percentage in each of the above examples.

Comparative Example 1

2-hydroxy-3-benzyl-5,6,7,8-tetrahydroquinoxaline:

A methanol (30 ml) solution of cyclohexane-1,2-dione (13.44 g, 0.12 M) was added to phenylalanineamide hydrochloride (20.05 g, 0.1 M) dissolved in methanol (200

ml) with cooling below -30.degree. C., and aqueous 12.5 N-NaOH (20 ml) was added dropwise thereto. The reaction mixture was 1 stirred at below -30.degree. C. for 30 minutes and was further stirred at room temperature for 3 hours. Conc. hydrochloric acid (25 ml) was added to the reaction mixture, and sodium bicarbonate (15 g) was added after 10 minutes stirring, the solvent then being distilled off in vacuo. The residue, to which was added water, was extracted three times with chloroform, and the extract was dried with anhydrous magnesium sulfate and concentrated in vacuo. The residue was recrystallized from acetone to obtain the product. (19.7 g, yield: 82.1%)

COMPARATIVE EXAMPLE 2

2-hydroxy-3-(2-phenylethyl)-5,6,7,8-tetrahydroquinoxaline:

A methanol (20 ml) solution of cyclohexane-1,2-dione (5.38 g) was added to o-amino-2-phenylacetic acidamide hydrochloride (8.58 g, 40 mM) dissolved in methanol (100 ml) with cooling below -30.degree. C., and aqueous 12.5 N-NaOH was added dropwise thereto. The reaction mixture was stirred at below -30.degree. C. for 30 minutes, and the mixture was stirred at room temperature for 6 hours. Conc. hydrochloric acid (8 ml) was added to the reaction mixture, and sodium bicarbonate (6.0 g) was added after 10 minutes stirring, the solvent then being distilled off in vacuo. The residue, to which was added water, was extracted three times with chloroform, dried with anhydrous magnesium sulfate and concentrated in vacuo. The residue was recrystallized from acetone to obtain the product. (6.79 g, yield: 66.8%)

COMPARATIVE EXAMPLE 3

2-hydroxy-3-methyl-5,6,7,8-tetrahydroquinoxaline:

A methanol (20 ml) solution of cyclohexane-1,2-dione (6.72 9) was added to alanine (4.4 g, 50 mM) dissolved in methanol (100 ml) with cooling below -30.degree. C., and aqueous 12.5 N-NaOH (5 ml) was added dropwise thereto. The reaction mixture was stirred at below -30.degree. C. for 30 minutes, and the mixture was stirred at room temperature for 3 hours. Conc. hydrochloric acid (8 ml) was added to the reaction mixture, and sodium bicarbonate (5 g) was added after 10 minutes stirring, the solvent then being distilled off in vacuo. The residue, to which was added water, was extracted three times with chloroform, dried with anhydrous magnesium sulfate and concentrated in vacuo. The residue was recrystallized from acetone to obtain the product as pale yellowish crystals. (6.50 g, yield: 79.0%)

COMPARTIVE EXAMPLE 4

2-hydroxy-3-ethyl-5,6,7,8-tetrahydroquinoxaline:

A methanol (20 ml) solution of cyclohexane-1,2-dione (6.72 g, 60 mM) was added to a methanol solution (100 ml) of .alpha.-aminobutylamide (5.1 g, 50 mM) with cooling below -30.degree. C., and aqueous 12.5 N-NaOH (5 ml) was added dropwise thereto. The reaction mixture was stirred at below -30.degree. C. for 30 mins. and the mixture was stirred at room temperature for 3 hours. Conc. hydrochloric acid (6.25 ml) was added to the reaction mixture and sodium bicarbonate (5 g) was added after 10 minutes stirring, the solvent being distilled off in vacuo. The residue, to which was added water, was extracted three times with chloroform, dried with anhydrous magnesium sulfate and concentrated in vacuo. The residue was recrystallized from acetone to obtain the colorless crystals. (5.30 gm, yield: 60.0%)

COMPARATIVE EXAMPLES 5-

2-hydroxy-3-alkyl-5,6,7,8-tetrahydroquinoxaline:

Cyclohexane-1,2-dione (6.72 g, 60 mM) was added a 11 at once to amino acidamine hydrochloride (50 mM) dissolved in methanol (100 ml) with cooling below -30.degree. C., and aqueous 12 N-NaOH (5 ml) was added dropwise thereto. The reaction mixture was stirred for 30 minutes with cooling below -30.degree. C., and the mixture was stirred at room temperature for 5 hours. Conc. hydrochloric acid (12.5 ml) was added to the reaction mixture and sodium bicarbonate (7.5 g) was added after 10 minutes, whereafter the solvent was distilled off in vacuo. The residue, to which was added water, was extracted three times with chloroform, dried with anhydrous sodium sulfate and concentrated in vacuo. The residue was recrystallized from acetone to obtain the products shown in Table 20.

Table 20 shows the identity of the acid amide hydrochloride and its amount used and the product and yield in weight and percentage in each of the above comparative examples.

EXAMPLE 101

Methyl (3-benzyl-5,6,7,8-tetrahydroquinoxaline-2-yl oxy) acetate (compound 656):

2-hydroxy-3-benzyl-5,6,7,8-tetrahydroquinoxaline (12.0 g, 50 mM) was dissolved in a solution of metallic sodium (1.15 g, 50 mM) in anhydrous methanol (200 ml), whereafter methanol was distilled off in vacuo to obtain the sodium salt thereof, which was suspended in dimethylformamide (100 ml). Methyl chloroacetate (5.43 g, 50 mM) was added thereto and the mixture was stirred at 100.degree. C. for 3 hours. The reaction mixture was concentrated in vacuo. Dilute aqueous sodium carbonate was added to the residue, which was then extracted three times with chloroform, and the extract was dried with anhydrous sodium sulfate and concentrated in vacuo. The residue was charge on a column of silica gel (C-200, 180 g) and eluted successively with benzene and benzene-ethyl acetate (10:1) to obtain the product. (14.12 g, yield: 90.5%)

EXAMPLE 102

(3-benzyl-5,6,7,8-tetrahydroquinoxaline-2-yl oxy) acetate (compound 660):

Aqueous 2N-NaOH (30 ml) was added to compound 656 (9.42 g, 30.2 mM) dissolved in methanol (30 ml) and the mixture was stirred for 3 hours at room temperature. 2N-HCl (30 ml) was added to the reaction on mixture with ice cooling and the precipitated crystals were collected by filtration, washed with water and dried to obtain most of the product. (8.10 g) The filtrate was concentrated in vacuo and the residue was extracted with hot ethanol, then the extract was concentrated in vacuo. The residue dissolved in dilute aqueous NaOH, was neutralized with 1 N-HCl and the precipitated crystals were collected by filtration, washed with water, then dried to obtain the remainder of the product. (0.32 g) (Total: 8.42 g, yield: 93.6%)

EXAMPLE 103

N-(2-chloroethyl)-(3-benzyl-5,6,7,8-tetrahydroquinoxaline-2-yl oxy) acetamide (compound 661):

Pivaloyl chloride (3.05 g, 25 mM) was added dropwise at -5.degree. C. to compound 660 (7.45 g, 25 mM) and triethylamine (3.5 ml, 25 mM) dissolved in tetrahydrofuran (45 ml), then the mixture was stirred for 30 minutes. Chloroform (25 ml) in solution with 2-chloroethylamine hydrochloride (2.90 g) and triethylamine (3.5 ml) was added dropwise thereto, then the mixture was stirred for 1 hour with ice cooling and 4 hours at room temperature. Dilute aqueous potassium carbonate was added to the reaction mixture and the mixture was extracted twice with chloroform. The extract was dried with anhydrous sodium sulfate, and concentrated in vacuo. The residue was charged on a column of silica gel (C-200, 175 g) and eluted successively with benzene and benzene-ethyl acetate to obtain the product. (7.142 g, yield: 79.5%)

EXAMPLES 104-109

N-(2-substituted ethyl)-(3-benzyl-5,6,7,8-tetra-hydroquinoxaline-2-yl oxy) acetamide:

Benzene (30 ml) in solution with compound 661(1.08 g, 3.0 mM), triethylamine (0.84 m) and a base (6.0 mM) was refluxed. Dilute aqueous potassium carbonate was added to the reaction mixture, and the aqueous layer was extracted three times with chloroform. The organic layer was dried with anhydrous sodium sulfate, and concentrated in vacuo. The residue was charged on a column of silica gel (C-200, 80 g) and eluted successively with benzene and benzene-ethyl acetate (10:1) to obtain the compounds in Table 21.

Table 21 shows the identity of the base and its amount used, the reflux time, the products and the yield in weight and percentage, in each of the above examples. Examples 110-121

Methyl (3-alkyl-5,6,7,8-tetrahydroquinoxaline-2-yl oxy) acetate:

Metallic sodium (1.15 g) was dissolved in anhydrous methanol (100 ml). 2-hydroxy-3,-alkyl-5,6,7,8-tetrahydroquinoxaline (50 mM) was dissolved therein, and methanol was distilled off in vacuo to obtain the sodium salt. Dimethylformamide (100 ml) and methyl chloroacetate (5.43 g, 50 mM) were added thereto and the mixture was stirred at 100.degree. C. The reaction mixture was concentrated in vacuo, and dilute aqueous sodium carbonate was added to the residue, which was then extracted three times with chloroform, and the extract was dried with anhydrous sodium sulfate and concentrated in vacuo. The residue was charged on a column of silica gel (C-200) and eluted successively with benzene and benzene-ethyl acetate- (20:1) to obtain the compounds in Table 22.

Table 22 shows the identity of the starting compound and its amount used, the reaction time, the amount of silica gel used, the products and the yield in weight and percentage in each of the above examples.

EXAMPLES 122-123

2-(2-hydroxyethoxy)-3-alkyl-5,6,7,8-tetrahydroquinoxaline:

The starting compound was dissolved in methanol. 6-8 equivalents of NaBH4 were added several portionwise while refluxing. The reaction mixture was concentrated in vacuo, water was added thereto, then the mixture was extracted three times with chloroform. The extract was dried with anhydrous sodium sulfate and concentrated in vacuo. The residue was charged on a column of silica gel (C-200) and eluted successively with benzene and benzene-ethyl acetate (10:1) to obtain the compounds in Table 23.

Table 23 shows the identity of the starting compound and its amount used, the amount of methanol used, the amount of NaBH.sub.4 used, the reflux time, the amount of silica gel used and the product and yield in weight and percentage in each of the above examples.

EXAMPLES 134-185

2-(2-substituted ethoxy)-3-alkyl-5,6,7,8-tetrahydroquinoxaline:

Thionyl chloride (1.3 equivalent) was added dropwise with ice cooling to a starting compound 2-(2-hydroxy- ethoxy)-3-alkyl-5,6,7,8-tetrahydroquinoxaline (3-5 mM) dissolved in chloroform and the mixture was stirred at room temperature for 2.5 hours to chlorinate the compound. The reaction mixture was poured into dilute aqueous potassium carbonate and extracted three times with chloroform. The extract, which was dried with anhydrous sodium sulfate, was concentrated in vacuo. Benzene (30 ml), triethylamine (2 equivalents) and a base (2 equivalents) were added to the residue, and the mixture was refluxed. The reaction mixture was poured into dilute aqueous potassium carbonate, and the mixture was extracted three times with chloroform. The extract was dried with anhydrous sodium sulfate and concentrated in vacuo. The residue was charged on a column of silica gel (C-200, 75 g) and eluted successively with chloroform and chloroform-methanol (200:1) to obtain the compounds in Table 24.

Table 24 shows the identity of the starting compound and its amount used, the chlorination reaction time, the base and its amount used, the reflux time, and the product and yield in weight and percentage in each of the above examples.

TABLE 7__________________________________________________________________________2-(substituted carbonylmethoxy)-3,5,6-trimethylpyrazineBase Yield YieldExample name used (g) Product (g) (%)__________________________________________________________________________ ##STR175## 0.50 066 1.12 80.58 ##STR176## 0.43 067 1.10 83.69 ##STR177## 0.66 068 1.23 79.810 H.sub.2 NCH.sub.2 CH.sub.2OH 0.32 069 0.88 73.611 ##STR178## 0.43 070 0.91 82.012 ##STR179## 0.44 075 1.10 83.0__________________________________________________________________________ Product is shown by No. of compound TABLE 8__________________________________________________________________________N-(2-substituted ethyl)-(3,5,6-trimethylpyrazine-2-yloxy)acetamide solventBase reaction ratio Yield YieldExample name used (g) (time) (hr.) product (g) (%)__________________________________________________________________________15 40% HN (CH.sub.3).sub.2 aqueous solution 8.68 1 50:1 071 0.22 27.616 ##STR180## 0.53 (6 mM) 1.5 100:1 073 0.41 44.417 ##STR181## 0.43 (5 mM) 1 20:1 074 0.55 59.918 ##STR182## 0.78 (6 mM) 1.5 50:1 076 0.58 55.019 ##STR183## 3.44 (40 mM) 1.5 10:1 103 0.94 30.020 ##STR184## 0.60 (6 mM) 1 50:1 105 0.27 28.021 H.sub.2 NC.sub.6 H.sub. 11 0.60 (6 mM) 1.5 50:1 650 0.17 17.7__________________________________________________________________________ product is shown by No. of compound TABLE 9__________________________________________________________________________N-(2-substituted ethyl)-(3,5,6-trimethylpyrazine-2-yloxy)acetamide reactionBASE time solvent Yield YieldExample name used (g) (hr.) ratio Product (g) (%)__________________________________________________________________________23 ##STR185## 1.68 (8 mM) 8 100:1 135 0.50 30.524 ##STR186## 1.41 (8 mM) 6 50:1 136 0.43 27.125 ##STR187## 1.68 (8 mM) 8 100:1 137 0.50 30.5__________________________________________________________________________ product is shown by No. of compound TABLE 10__________________________________________________________________________N(2-substituted ethyl)-.alpha. -(3-ethyl-5,6-dimethylpyrazine-2-yloxy)-phenylacetamideBASE Yield YieldExample name used (g) product (g) (%)__________________________________________________________________________29 ##STR188## 0.70 341 0.94 59.030 ##STR189## 1.41 342 1.48 76.031 ##STR190## 1.69 343 1.27 60.932 ##STR191## 1.77 344 1.32 62.033 ##STR192## 1.96 345 0.91 41.034 ##STR193## 1.30 346 1.20 63.435 ##STR194## 1.67 347 1.28 61.536 ##STR195## 1.80 348 1.77 82.6__________________________________________________________________________ product is shown by No. of compound TABLE 11__________________________________________________________________________N-(2-substituted ethyl)-(3-benzyl-5,6-dimethylpyrazine-2-yloxy)-acetamideBASE reaction Yield YieldExample name used (g) (day) product (g) (%)__________________________________________________________________________40 ##STR196## 1.24 2 376 1.54 87.841 ##STR197## 1.48 2 377 1.48 81.542 ##STR198## 1.48 2 379 1.17 62.443 ##STR199## 1.38 1 381 1.29 70.744 ##STR200## 1.58 2 382 1.38 71.845 ##STR201## 0.61 2 657 0.73 50.646 ##STR202## 1.14 1 658 1.15 67.6__________________________________________________________________________ product is shown by No. of compound TABLE 12__________________________________________________________________________methyl(3,5,6-trialkylpyrazine-2-yloxy)-acetatestarting materialR.sub.3 N OH reactionR.sub.2 N R.sub.1 used time silica-gel Yield YieldExample R.sub.1 R.sub.2 R.sub.3 (g) (hr.) (g) product (g) (%)__________________________________________________________________________47 Et Me Me 7.60 2.5 160 662 9.62 85.948 --CH.sub.2 Ph Me Me 10.70 2.5 210 663 12.03 84.149 iso-Pro Me Me 8.3 2.5 160 664 9.92 83.450 " Et Et 9.70 2.5 180 665 12.77 96.051 iso-Bu Et Et 10.40 3 230 666 12.86 91.9__________________________________________________________________________ product is shown by No. of compound TABLE 13__________________________________________________________________________2-(2-hydroxyethoxy)-3,5,6-trialkylpyrazine reactionstarting material methanol NaBH.sub.4 time silica-gel Yield YieldExample name used g (mM) (ml) (g) (hr.) (g) product (g) (%)__________________________________________________________________________52 034 17.00(80.95) 200 18.6 3.0 200 679 12.84 87.253 662 9.62(42.94) 200 9.9 4.0 120 680 7.69 91.354 663 8.75(30.6) 150 9.4 2.5 160 681 7.22 91.555 664 19.67(82.65) 200 25.2 3.0 200 682 15.51 89.456 665 9.18(34.5) 150 10.5 4.0 200 683 7.48 91.157 666 7.32(26.14) 100 8.0 3.5 160 684 5.94 90.1__________________________________________________________________________ product is shown by No. of compound TABLE 14__________________________________________________________________________2-(2-substituted ethoxy)-3,5,6-trimethylpyrazine reactionBASE time Yield YieldExample name used (g) (hr.) product (g) (%)__________________________________________________________________________58 ##STR203## 1.05 2.5 536 0.95 63.159 ##STR204## 1.10 2.5 537 1.03 68.960 ##STR205## 2.02 3.0 538 1.31 64.261 ##STR206## 2.11 2.5 539 1.62 72.162 ##STR207## 1.94 2.0 540 1.59 74.063 ##STR208## 2.25 2.5 541 1.56 66.964 ##STR209## 1.70 5.0 810 1.28 70.065 ##STR210## 3.90 5.0 822 1.56 94.566 HNEt.sub.2 0.88 5.0 842 0.51 35.7__________________________________________________________________________ product is shown by No. of compound TABLE 15__________________________________________________________________________2-(2-substituted ethoxy)-3-isopropyl-5,6-diethylpyrazine reactionBASE time Yield YieldExample name used (g) (hr.) product (g) (%)__________________________________________________________________________67 ##STR211## 0.85 3.0 550 0.83 54.468 ##STR212## 1.42 2.5 551 0.93 51.469 ##STR213## 1.76 3.0 552 1.05 52.870 ##STR214## 2.20 3.0 553 1.01 46.071 ##STR215## 1.30 5.0 826 1.15 66.272 HNEt.sub.2 0.73 6.5 848 0.36 25.2__________________________________________________________________________ product is shown by No. of compound TABLE 16__________________________________________________________________________2-(2-substituted ethoxy)-3-ethyl-5,6-dimethylpyrazineBase reaction solvent Yield YieldExample name used (g) time (hr.) ratio product (g) (%)__________________________________________________________________________73 ##STR216## 0.87 2.5 200:1 491 0.66 49.874 ##STR217## 0.85 2.0 200:1 492 0.79 60.175 ##STR218## 1.00 2.0 200:1 493 0.67 48.476 ##STR219## 1.00 2.0 30:1 494 0.84 44.677 ##STR220## 1.20 2.0 100:1 .fwdarw. 10:1 495 0.73 47.478 ##STR221## 1.74 2.0 50:1 496 1.13 64.279 ##STR222## 1.68 2.0 200:1 497 1.15 65.080 ##STR223## 2.11 2.0 200:1 498 1.10 56.681 ##STR224## 2.06 2.0 200:1 499 1.17 60.982 ##STR225## 1.94 2.0 200:1 500 1.17 62.983 ##STR226## 2.21 2.0 200:1 501 1.40 70.284 ##STR227## 2.35 2.0 200:1 502 0.62 30.085 ##STR228## 2.08 2.0 200:1 503 1.00 51.886 ##STR229## 2.25 2.0 200:1 504 1.14 56.687 ##STR230## 1.42 2.0 200:1 812 0.67 42.088 HNEt.sub.2 0.73 3.0 200:1 844 0.23 18.8__________________________________________________________________________ product is shown by No. of compound TABLE 17__________________________________________________________________________2-(2-substituted ethoxy)-3-benzyl-5,6-dimethylpyrazineBase reaction solvent Yield YieldExample name used (g) time (hr.) ratio product (g) (%)__________________________________________________________________________89 ##STR231## 0.70 2.0 200:1 511 0.57 43.690 ##STR232## 1.04 2.0 200:1 512 1.04 62.591 ##STR233## 1.80 2.0 200:1 516 1.20 64.6__________________________________________________________________________ product is shown by No. of compound TABLE 18__________________________________________________________________________2-(2-substituted ethoxy)-3-isopropyl-5,6-dimethylpyrazine reactionBASE time solvent Yield YieldExample name used (g) (hr.) ratio product (g) (%)__________________________________________________________________________92 ##STR234## 0.87 2.5 200:1 544 0.89 63.893 ##STR235## 2.11 2.5 200:1 546 1.57 80.894 ##STR236## 2.25 2.5 200:1 547 1.42 68.295 ##STR237## 1.43 3.0 200:1 697 0.94 56.396 ##STR238## 1.43 2.0 200:1 814 0.77 46.097 ##STR239## 1.30 2.5 200:1 825 1.24 77.098 ##STR240## 0.85 5.0 200:1 834 1.17 68.399 HNEt.sub.2 0.73 18.0 200:1 846 0.12 11.2__________________________________________________________________________ product is shown by No. of compound TABLE 19__________________________________________________________________________2-(2-substituted ethoxy)-3-isobutyl-5,6-diethylpyrazine reactionBASE time Yield YieldExample name used (g) (hr.) product (g) (%)__________________________________________________________________________ 99 ##STR241## 1.76 3.5 556 0.45 21.9100 ##STR242## 2.20 4.0 558 0.77 33.9__________________________________________________________________________ product is shown by No. of compound TABLE 20______________________________________2-hydroxy-3-alkyl-5,6,7,8-tetrahydroquinoxaline ##STR243## ##STR244## ProductReference amino acidamide Yield Yieldexample HCl used (g) R.sub.1 (g) (%)______________________________________ 5 7.63 Pro 4.75 50.0 6 7.63 iso-Pro 4.95 51.6 7 8.32 Bu 7.49 73.0 8 8.32 iso-Bu 6.58 64.0 9 8.32 sec-Bu 6.58 64.010 9.04 (CH.sub.2).sub.4 CH.sub.3 9.03 82.011 9.74 (CH.sub.2).sub.5 CH.sub.3 7.81 66.712 10.44 (CH.sub.2).sub.6 CH.sub.3 9.33 75.013 11.14 (CH.sub.2).sub.7 CH.sub.3 11.67 89.114 11.83 (CH.sub.2).sub.8 CH.sub.3 10.50 72.415 12.55 (CH.sub.2).sub.9 CH.sub.3 12.73 92.216 13.95 (CH.sub.2 ).sub.11 CH.sub.3 14.00 88.117 15.35 (CH.sub.2).sub.13 CH.sub.3 16.58 95.818 16.75 (CH.sub.2).sub.15 CH.sub.3 18.55 99.2______________________________________ TABLE 21__________________________________________________________________________N-(2-substituted ethyl)-(3-benzyl-5,6,7,8-tetrahydroquinoxaline-2-yloxy)-acetamideBASE reaction ProductExample name used (g) time (day) No. of comp Yield (g) Yield (%)__________________________________________________________________________104 ##STR245## 1.06 1 368 1.00 66.8105 ##STR246## 1.24 4 369 1.38 87.0106 ##STR247## 1.27 2 370 1.07 67.0107 ##STR248## 1.18 3 371 1.36 87.3108 ##STR249## 1.25 3 372 1.21 76.0109 ##STR250## 0.73 2 373 0.73 50.2__________________________________________________________________________ TABLE 22__________________________________________________________________________methyl(3-alkyl-5,6,7,8-tetrahydroquinoxaline-2-yloxy)-acetatestarting compoundN OH reaction ProductN R.sub.1 used time silica-gel No. of Yield YieldExample R.sub.1 (g) (hr.) (g) compound (g) (%)__________________________________________________________________________110 Bu 10.30 3 210 667 11.54 83.2111 --(CH.sub.2).sub.4 CH.sub.3 10.10 3 210 668 11.64 79.7112 --(CH.sub.2).sub.5 CH.sub.3 11.70 2.5 210 669 12.24 80.0113 --(CH.sub.2).sub.6 CH.sub.3 12.40 2.5 210 670 13.35 83.5114 --(CH.sub.2).sub.7 CH.sub.3 13.10 3 200 671 13.02 78.0115 --(CH.sub.2).sub.8 CH.sub.3 13.80 3 240 672 13.71 78.8116 --(CH.sub.2).sub.9 CH.sub.3 14.50 2.5 210 673 13.61 75.2117 --(CH.sub.2).sub.11 CH.sub.3 15.90 3 280 674 16.00 82.1118 --(CH.sub.2).sub.13 CH.sub.3 17.30 3 280 675 16.33 78.1119 --(CH.sub.2).sub.15 CH.sub.3 18.70 2.5 340 676 18.74 84.0120 Pro 9.60 3 220 677 10.29 78.0121 sec-Bu 10.30 2.5 260 678 11.73 84.4__________________________________________________________________________ TABLE 23__________________________________________________________________________2-(2-hydroxyethoxy)-3-alkyl-5,6,7,8-tetrahydroquinoxaline reactionstarting compound methanol NaBH.sub.4 time silica-gel ProductExample No. of comp used g (mM) (ml) (g) (hr.) (g) No. of comp Yield (g) Yield__________________________________________________________________________ (%)122 667 12.40(44.6) 200 10.2 2.5 200 685 10.63 95.3123 668 9.07(31.1) 200 7.2 3.0 200 686 7.12 86.7124 669 9.55(31.2) 200 9.6 2.5 200 687 7.95 91.7125 670 9.70(30.3) 200 9.3 3.0 200 688 8.05 91.0126 671 11.10(33.2) 300 7.8 3.0 250 689 9.31 91.6127 672 9.50(27.3) 250 9.4 3.0 250 690 8.20 93.9128 673 10.80(29.8) 250 9.1 2.5 250 691 9.15 92.0129 674 9.54(24.46) 250 7.5 3.0 200 692 7.94 89.7130 675 9.56(22.9) 250 6.9 3.0 200 693 8.63 96.6131 676 9.17(32.9) 250 6.2 3.0 200 694 7.27 84.6132 677 7.78(29.47) 200 9.0 3.0 200 695 6.60 95.0133 678 7.50(27.0) 200 8.4 2.5 170 696 5.77 85.5__________________________________________________________________________ TABLE 24__________________________________________________________________________2-(2-substituted ethoxy-3-alkyl-5,6,7,8-tetrahydroquinoxalinestarting compound chlorin- reflux productExam- No. of ation BASE time No. of Yield Yieldple comp used g time (hr) name used g (hr.) comp (g) (%)__________________________________________________________________________134 685 1.25 (5 mM) 3.0 ##STR251## 0.87 (10 mM) 2.0 517 1.38 86.5135 685 1.00 (4 mM) 3.0 ##STR252## 1.42 (8 mM) 2.0 518 1.23 75.4136 685 1.00 (4 mM) 3.0 ##STR253## 1.69 (8 mM) 2.0 519 0.89 50.3137 685 1.00 (4 mM) 3.0 ##STR254## 1.80 (8 mM) 2.5 520 1.00 54.8138 686 1.32 (5 mM) 3.5 ##STR255## 0.87 (10 mM) 3.0 559 0.92 55.3139 686 1.32 (5 mM) 3.5 ##STR256## 1.42 (10 mM) 2.5 560 1.01 52.1140 686 1.32 (5 mM) 3.5 ##STR257## 1.76 (10 mM) 3.0 561 1.27 60.2141 686 1.32 (5 mM) 3.5 ##STR258## 2.08 (10 mM) 2.5 562 1.24 54.6142 687 1.39 (5 mM) 3.5 ##STR259## 0.87 (10 mM) 3.0 564 0.99 57.1143 687 1.39 (5 mM) 3.5 ##STR260## 1.42 (10 mM) 3.0 565 1.11 55.2144 687 1.39 (5 mM) 3.5 ##STR261## 1.76 (10 mM) 2.5 567 1.25 57.3145 687 1.39 (5 mM) 3.5 ##STR262## 2.10 (10 mM) 2.5 568 1.62 68.9146 687 1.39 (5 mM) 3.5 ##STR263## 2.08 (10 mM) 2.5 569 1.29 55.4147 688 1.17 (4 mM) 3.0 ##STR264## 1.14 (8 mM) 2.5 571 1.01 60.7148 689 1.53 (5 mM) 3.0 ##STR265## 0.87 (10 mM) 2.0 572 1.06 56.5149 689 1.23 (4 mM) 3.0 ##STR266## 1.14 (8 mM) 2.0 573 0.87 50.6150 689 1.23 (4 mM) 3.0 ##STR267## 1.42 (8 mM) 2.0 574 0.95 52.9151 689 1.23 (4 mM) 3.0 ##STR268## 1.68 (8 mM) 2.0 575 0.65 32.6152 689 1.23 (4 mM) 3.0 ##STR269## 1.67 (8 mM) 2.5 576 0.57 28.7153 690 1.60 (5 mM) 3.5 ##STR270## 0.87 (10 mM) 2.0 579 0.63 32.4154 690 1.28 (4 mM) 3.5 ##STR271## 1.14 (8 mM) 2.5 580 0.54 30.4155 690 1.28 (4 mM) 3.5 ##STR272## 1.41 (8 mM) 2.0 581 0.84 43.9156 690 1.28 (4 mM) 3.5 ##STR273## 1.65 (8 mM) 2.0 582 1.01 47.8157 690 1.28 (4 mM) 3.5 ##STR274## 1.80 (8 mM) 2.5 583 0.78 37.0158 691 1.67 (5 mM) 3.0 ##STR275## 0.87 (10 mM) 2.0 585 0.79 39.2159 691 1.34 (4 mM) 3.0 ##STR276## 0.68 (8 mM) 2.5 586 0.65 40.5160 691 1.34 (4 mM) 3.0 ##STR277## 1.14 (8 mM) 2.5 587 0.77 42.0161 691 1.34 (4 mM) 3.0 ##STR278## 1.04 (8 mM) 2.5 588 0.58 32.5162 691 1.34 (4 mM) 3.0 ##STR279## 1.41 (8 mM) 2.5 589 0.93 47.3163 691 1.34 (4 mM) 3.0 ##STR280## 1.68 (8 mM) 2.5 590 1.07 50.8164 691 1.34 (4 mM) 3.0 ##STR281## 2.01 (8 mM) 2.5 591 1.17 51.5165 691 1.34 (4 mM) 3.0 ##STR282## 1.67 (8 mM) 2.0 592 0.70 33.4166 692 1.09 (3 mM) 4.5 ##STR283## 0.53 (6 mM) 3.0 594 0.64 49.5167 692 1.09 (3 mM) 5.0 ##STR284## 0.86 (6 mM) 2.5 595 0.84 57.6168 692 1.09 (3 mM) 5.0 ##STR285## 1.06 (6 mM) 2.5 596 0.92 59.0169 692 1.09 (3 mM) 5.0 ##STR286## 1.24 (6 mM) 2.5 597 0.93 56.4170 692 1.09 (3 mM) 4.5 ##STR287## 1.25 (6 mM) 2.5 598 0.83 50.1171 693 1.17 (3 mM) 5.0 ##STR288## 0.86 (6 mM) 2.5 600 0.74 48.0172 693 1.17 (3 mM) 5.0 ##STR289## 1.06 (6 mM) 2.5 601 0.84 51.1173 693 1.17 (3 mM) 5.0 ##STR290## 1.17 (6 mM) 2.5 602 0.93 54.8174 693 1.17 (3 mM) 5.0 ##STR291## 1.35 (6 mM) 2.5 603 0.92 51.4175 693 1.17 (3 mM) 5.0 ##STR292## 1.51 (6 mM) 2.5 604 0.65 34.7177 694 1.26 (3 mM) 4.5 ##STR293## 0.86 (6 mM) 2.5 607 0.86 52.9178 694 1.26 (3 mM) 5.0 ##STR294## 1.06 (6 mM) 2.0 608 0.88 50.9179 694 1.26 (3 mM) 4.5 ##STR295## 1.32 (6 mM) 2.5 609 0.95 51.1180 685 1.25 (5 mM) 6.0 ##STR296## 1.42 (10 mM) 5.0 817 1.10 59.0181 689 0.77 (2.5 mM) 5.5 ##STR297## 1.60 (12.3 mM) 5.0 830 0.45 43.1182 685 1.18 (4.7 mM) 6.5 ##STR298## 0.85 (10 mM) 5.0 837 0.89 56.3183 689 0.77 (2.5 mM) 6.0 ##STR299## 0.43 (5 mM) 6.0 839 0.61 65.1184 685 1.25 (5 mM) 5.0 HNEt.sub.2 1.46 (20 mM) 24 850 0.38 25.0185 689 0.77 (2.5 mM) 7.0 HNEt.sub.2 0.73 (10 mM) 24 851 0.47 52.1__________________________________________________________________________ TABLE 25__________________________________________________________________________NMR spectrum, Mass spectrum and Rf-value on silica-gel layerchromatographyComp. No. NMR (CDCl.sub.3, inner standard TMS) ppm MASS Rf__________________________________________________________________________034 2.34(3H, s), 2.40(3H, s), 2.46(3H, s), 3.76(3H, s), 4.89(2H, 211035 1.53(3H, d, J=6.9), 2.28(3H, s), 2.34(3H.times.2, s), 3.65(3H, s), 5.17 225 (1H, q, J=6.9)036 2.36(3H, s), 2.41(3H, s), 2.51(3H, s), 3.70(3H, s), 6.11(1H, 287 7.3-7.6(5H, m)037 2.30(3H, s), 2.35(6H, s), 4.83(2H, s) 197038 1.66(2H, d, J=7.1), 2.32(3H, s), 2.38(3H, s), 2.45(3H, s), 2117 (1H, q, J=7.1)039 2.33(3H, s), 2.35(3H, s), 2.38(3H, s), 6.05(1H, s), 7.3-7.6(5H, 273066 2.32(3H, s), 2.35(3H, s), 2.39(3H, s), 2.46(3H, s), 2.3-2.5(4H, 279, 179067 1.5-1.7(3H.times.2), 2.35(3H, s), 2.39(3H, s), 2.47(3H, s), 263, 179 (4H, m), 4.99(2H, s)068 2.35(3H, s), 2.39(3H, s), 2.46(3H, s), 2.2-2.7(6H, m), 309, 179 (4H, m), 4.99(2H, s)069 2.37(3H, s), 2.41(3H, s), 2.45(3H, s), 3.3-3.6(2H, m), 3.75(2H, 240, 179 J.apprxeq.4.7), 4.84(2H, s), 6.86(1H, bs)070 2.35(3H.times.2, s), 2.40(3H.times. 2, s), 2.47(3H.times.2, s), 3.6(8H, bs), 5.02 443, 180 (4H, s) 179071 2.21(3H.times.2, s), 2.38(3H, s), 2.42(3H, s), 2.47(3H, s), 3.1-3.5(4H, 267 m), 4.83(2H, s), 7.0(1H, bs)072 2.37(3H, s), 2.42(3H, s), 2.48(3H, s), 3.07(2H, t, J.apprxeq.6.1), 3.54 332, 179 (2H, t, J.apprxeq.6.1), 79(2H, s), 6.8(1H, bs), 7.0-7.4(5H, m)073 2.38(3H, s), 2.42(3H, s), 2.51(3H, s), 2.3-2.6(6H, m), 3.42(2H, 309, 240 J.apprxeq.5.7), 3.5-3.8(4H, m), 4.84(2H, s) 179074 1.3-1.7(6H, m), 2.38(3H, s), 2.42(3H, s), 2.50(3H, s), 307, 240 (6H, m), 3.41(2H, sext, J.apprxeq.5.6), 3.76(1H, t, J.apprxeq.5.6), 4.84(2H, s) 179075 2.36(3H, s), 2.40(3H, s), 2.47(3H, s), 3.4-3.8(8H, m), 4.99(2H, 266, 179076 2.42(3H, s), 2.46(3H, s), 2.50(3H, s), 2.3-2.6(12H, m), 3520(2H, q, J.apprxeq.6), 3.62(2H, t, J.apprxeq.5.2), 4.84(2H, s)103 2.38(3H, s), 2.42(3H, s), 2.51(3H, s), 2.3-2.6(6H, m), 308-2.9 (4H, m), 3.41(2H, q, J.apprxeq.5.5), 4.84(2H, s), 7.0(1H, bs)105 2.26(3H, s), 2.38(3H, s), 2.43(3H, s), 2.51(3H, s), 322, 1134H, m), 4.84(2H, s), 7.0(1H, bs)135 2.37(3H, s), 2.43(3H, s), 2.51(3H, s), 2.2-2.6(10H, m), 3.2- 434, 432 (2H, m), 3.42(2H, s), 4.83(2H, s), 7.26(4H, s) 223, 125136 2.26(3H, s), 2.38(3H, s), 2.50(3H, s), 2.2-2.6(10H, m), 398, 304 (2H, m), 3.48(2H, s), 4.83(2H, s), 7.30(5H, s) 189137 2.38(3H, s), 2.44(3H, s), 2.46(3H, s), 2.3-2.6(10H, m), 434, 432 (2H, m), 3.60(2H, s), 4.84(2H, s), 6.9-7.5(4H, m) 223, 125341 1.33(3H, t, J=7.4), 1.74(2H, br. s), 2.35(3H, s), 2.40(3H, s), 399- 2.6(4H, m), 2.92(2H, q, J=7.4), 3.2-3.5(2H, m), 3.5-3.7(4H, m), 6. 44(1H, s), 7.0(1H, br. s), 7.2-7.7(5H, m)342 1.33(3H, t, J=7.4), 1.77(4H, br. s), 2.34(3H, s), 2.40(3H, s), 488, 189 2.6(6H, m), 2.91(2H, q, J=7.4), 3.2-3.5(2H, m), 3.49(2H, s), 6.42 (1H, s), 7.0-7.7(11H, m)343 1.33(3H, t, J=7.4), 1.6(4H, br. s), 2.34(3H, s), 2.40(3H, s), 524, 522 2.8(6H, m), 2.92(2H, q, J=7.4), 3.2-3.5(2H, m), 3.43(2H, s), 2232 (1H, s), 7.26(1H, s), 7.2-7.6(5H, m)344 1.34(3H, t, J=7.4), 1.66(4H, br. s), 2.35(3H, s), 2.40(3H, s), 533, 234 2.6(6H, m), 2.92(2H, q, J=7.4), 3.2-3.5(2H, m), 2.56(2H, s), 6.43 (1H, s), 7.0(1H, br. s), 7.2-7.7(7H, m), 8.18(2H, d, J=8.8)345 1.34(3H, t, J=7.4), 1.90(2H, br. s), 2.34(3H, s), 2.41(3H, s), 560, 558 2.6(8H, m), 2.92(2H, q, J=7.4), 3.2-3.5(2H, m), 3.55(2H, s), 556, 258 (1H, s), 7.0-7.7(9H, m) 256346 1.34(3H, t, J=7.4), 1.73(2H, br. s), 2.35(3H, s), 2.38(3H, s), 474, 330 2.6(6H, m), 2.88(2H, q, J=7.4), 3.0-3.2(2H, m), 3.3-3.5(2H, 175 6.45(1H, s), 6.7-7.7(10H, m)347 1.31(3H, t, J=7.4), 1.6-2.1(4H, m), 2.34(3H, s), 2.40(3H, s), 521, 520 2.8(8H, m), 2.90(2H, q, J=7.4), 3.2-3.5(2H, m), 3.54(2H, s), 2213 (1H, s), 6.8-7.7(10H, m)348 1.31(3H, t, J=7.4), 1.6-2.1(2H, m), 2.34(3H, s), 2.40(3H, s), 538, 536 2.8(12H, m), 3.1-3.5(2H, m), 3.54(2H, s), 6.43(1H, s), 239, 237 s), 7.2-7.6(5H, m)376 1.23(3H.times.2, t, J.apprxeq.7.6), 1.4-2.2(8H, m), 2.2-3.6(10H, m), 4.21(4H, 487, 174 0.44 s), 4.83(2H, s), 6.51(1H, br. s), 7.0-7.4(10H, m)377 1.22(3H, t, J.apprxeq.7.6), 1.26(3H, t, J=7.6), 1.6-2.0(2H, m), 2.2-2.5 520, 207 0.38 (8H, m), 2.69(2H, q, J.apprxeq.7.6), 2.77(2H, q, J.apprxeq.7.6), 3.1-3.6(2H, m), 3.36(2H, s), 4.18(2H, s), 4.81(2H, s), 6.4(1H, br. s), 6.8-7.4(9H, m)379 1.22(3H, t, J.apprxeq.7.6), 1.26(3H, t, J=7.6), 1.6-2.0(2H, m), 2.2-3.0 538, 536 0.40 (14H, m), 3.0-3.6(2H, m), 3.36(2H, s), 4.18(2H, s), 4.81(2H, 225, 223 6.4(1H, br. s), 7.0-7.4(9H, m)381 1.23(2H.times.2, t, J.apprxeq.7.6), 1.6-1.8(2H, m), 2.2-3.0(14H, m), 3.0-3.5 524, 522 0.62 (2H, m), 4.19(2H, s), 4.84(2H, s), 6.51(1H, br. s), 6.8-7.4(9H, m)382 1.22(3H, t, J.apprxeq.7.6), 1.25(3H.times.2, t, J.apprxeq.7.6), 1.4-2.0(2H, m), 2.2- 552, 550 0.37 3.0(14H, m), 3.0-3.4(2H, m), 3.50(2H, s), 4.07(2H, s), 343, 237 s), 6.4(1H, br. s), 7.0-7.4(9H, m)491 1.23(3H, t, J.apprxeq.7.6), 2.32(3H.times.2), 2.3-3.0(8H, m), 3.6-3.8(4H, m), 266, 114 0.33 4.0-4.3(2H, m)492 1.23(3H, t, J.apprxeq.7.4), 1.3-2.0(6H, m), 2.31(3H, s), 2.33(2H, s), 2.5- 264, 179 0.28 3.0(8H, m), 4.2-4.5(2H, m)493 0.9-1.2(3H, m), 1.23(3H, t, J.apprxeq.7.4), 1.3-2.0(5H, m), 2.31(3H, s), 278, 111 0.29 2.33(3H, s), 2.5-3.0(8H, m), 4.2-4.5(2H, m)494 1.23(3H, t, J.apprxeq.7.4), 2.30(3H.times.2, s), 2.31(3H, s), 2.3-3.0(12H, m), 279, 113 0.15 4.0-4.3(2H, m)495 1.22(3H, t, J.apprxeq.7.4), 2.31(3H.times.2, s), 2.3-3.0(14H, m), 3.62(2H, t, 309, 143 0.06 J=5.4), 4.0-4.3(2H, m)496 1.23(3H, t, J.apprxeq.7.4), 2.31(3H.times.2, s), 2.3-3.0(14H, m), 3.5-3.8(6H, 353, 187 0.11 m), 4.0-4.3(3H, m)497 1.22(3H, t, J.apprxeq.7.4), 2.31(3H.times.2, s), 2.3-3.0(12H, m), 3.52(2H, s), 355, 189 0.38 4.0-4.3(2H, m), 7.30(5H, s)498 1.22(3H, t, J.apprxeq.7.4), 2.31(3H.times.2, s), 2.3-3.0(12H, m), 3.48(2H, s), 391, 389 0.36 4.0-4.3(2H, m), 7.29(4H, s) 223499 1.22(3H, t, J.apprxeq.7.4), 2.31(3H.times.2, s), 2.3-3.0(12H, m), 3.46(2H, s), 385, 219 0.33 3.79(3H, s), 4.0-4.3(2H, m), 6.84(2H, d, J=8.6), 7.22(2H, d, J= 8.6)500 1.22(3H, t, J.apprxeq.7.4), 2.31(3H.times.2, s), 2.3-3.0(12H, m), 3.47(2H, s), 373, 207 0.35 4.0-4.3(2H, m), 6.8-7.4(4H, m)501 1.22(3H, t, J.apprxeq.7.4), 2.31(3H, s), 2.33(3H, s), 2.3-3.0(12H, m), 400, 234 0.39 3.59(2H, s), 4.0-4.2(2H, m), 7.50(2H, d, J=8.8), 8.17(2H, d, J= 8.8)502 1.23(3H, t, J.apprxeq.7.4), 1.6-2.0(2H, m), 2.31(3H, s), 2.33(3H, s), 2.5- 414, 248 0.28 3.0(12H, m), 3.72(2H, s), 4.0-4.3(2H, m), 7.51(2H, d, J.apprxeq.8.8), 8.19(2H, d, J.apprxeq.8.8)503 1.23(3H, t, J.apprxeq.7.4), 1.6-2.0(2H, m), 2.31(3H.times.2, s), 2.5-3.0(12H, 387 0.20 m), 3.60(2H, s), 4.0-4.3(2H, m), 6.8-7.4(4H, m)504 1.22(3H, t, J.apprxeq.7.4), 1.6-2.0(2H, m), 2.31(3H.times.2, s), 2.5-3.0(12H, 405, 403 0.23 m), 7.27(4H, s) 237511 2.31(3H.times.2, s), 2.4-2.7(6H, m), 3.6-3.8(4H, m), 4.0-4.3(2H, s), 328, 114 0.41 7.1-7.5(5H, m)512 2.30(3H.times.2, s), 2.3-2.7(10H, m), 3.51(2H, s), 4.0-4.2(2H, 417, 202 0.37 4.08(2H, s), 7.1-7.5(10H, m) 189516 1.6-2.0(2H, m), 2.30(3H.times.2, s), 2.5-3.0(10H, m), 3.58(2H, 467, 465 0.24 3.9-4.2(2H, m), 4.08(2H, s), 7.1-7.5(10H, m) 251, 237536 2.30(3H, s), 2.34(3H, s), 2.41(3H, s), 2.4-2.7(6H, m), 252, 101 0.30 (4H, m), 4.0-4.3(2H, m)537 1.2-1.8(6H, m), 2.30(3H, s), 2.36(3H, s), 2.41(3H, s), 250, 111 0.20 (6H, m), 4.1-4.3(2H, m)538 2.29(3H, s), 2.32(3H, s), 2.40(3H, s), 2.3-2.8(10H, m), 341, 189 0.27 s), 4.0-4.3(2H, m), 7.30(5H, s)539 2.30(3H, s), 2.32(3H, s), 2.41(3H, s), 2.3-2.8(10H, m), 377, 375 0.27 s), 4.0-4.3(2H, m), 7.26(4H, s) 223540 2.30(3H, s), 2.33(3H, s), 2.41(3H, s), 2.4-2.8(10H, m), 359, 220 0.20 s), 4.0-4.3(2H, m), 6.8-7.4(4H, m) 207541 1.6-2.0(2H, m), 2.30(3H, s), 2.32(3H, s), 2.41(3H, s), 391, 389 0.17 (10H, m), 3.60(2H, s), 4.0-4.3(2H, m), 7.26(4H, s) 237, 165544 1.20(3H.times.2, d, J=6.8), 2.32(3H.times.2, s), 2.4-2.8(6H, m), 3.42(1H, 280, 114 0.33 sept, J=6.8), 3.5-3.8(4H, m), 4.0-4.3(2H, m)546 1.20(3H.times.2, d, J=6.8), 2.30(3H.times.2, s), 2.2-2.8(10H, m), 3.42(1H, 405, 403 0.33 sept, J=6.8), 3.47(2H, s), 3.9-4.2(2H, m), 7.27(4H, s)547 1.20(3H.times.2, d, J=6.8), 1.6-2.0(2H, m), 2.30(3H.times.2, s), 2.5-3.0 419, 417 0.23 (10H, m), 3.42(1H, sept, J=6.8), 3.60(2H, s), 3.9-4.2(2H, 237 7.27(4H, s)550 1.0-1.3(12H, m), 1.3-1.8(6H, m), 2.3-2.8(10H, m), 3.42(1H, 306, 112 0.30 J=6.8), 4.0-4.3(2H, m)551 0.91(3H, t, J.apprxeq.6), 1.20(3H.times.2, d, J=6.8), 1.21(3H.times.2, d, J=7.6), 363, 155 0.25 1.2-1.6(4H, m), 2.3-2.8(16H, m), 3.42(1H, sept, J=6.8), 4.0-4.2(2H, m)552 1.20(3H.times.2, d, J=6.8), 1.21(3H.times.2, d, J=7.6), 2.3-2.8(14H, m), 397, 189 0.35 3.42(1H, sept, J=6.8), 3.51(2H, s), 4.0-4.2(2H, m), 7.30(5H, s)553 1.20(3H.times.2, d, J=6.8), 1.21(3H.times.2, d, J=7.6), 1.6-2.0(2H, m), 2.4- 441, 233 0.21 3.0(14H, m), 3.42(1H, sept, J=6.8), 3.59(2H, s), 3.80(3H, s), 3.9- 4.2(2H, m), 6.84(2H, d, J=8.8), 7.24(2H, d, J=8.8)556 0.94(3H.times.2, d, J=6.7), 1.20(3H, t, J=7.6), 1.21(3H, t, J=7.6), 2.0- 411, 189 0.32 2.4(1H, m), 2.4-3.0(16H, m), 3.53(2H, s), 4.0-4.3(2H, m), 7.30 (5H, s)558 0.94(3H.times.2, d, J=6.7), 1.20(3H, t, J=7.6), 1.21(3H, t, 455, 246 0.17 1.6-2.0(2H, m), 2.0-2.4(1H, m), 2.4-3.0(16H, m), 3.60(2H, s), 1210 (3H, s), 3.9-4.2(2H, m), 6.84(2H, d, J=8.6), 7.25(2H, d, J=8.6)648 2.32(3H, s), 2.35(3H.times.2, s), 3.3-3.5(2H, m), 4.2-4.4(2H, m), 4.99 304, 302 (2H, s), 8.0(1H, br. s) 222, 179649 2.38(3H, s), 2.43(3H, s), 2.48(3H, s), 3.6-3.8(4H, m), 260, 258 s), 6.8(1H, br. s)650 0.7-2.0(10H, m), 2.1-2.5(1H, m), 2.37(3H, s), 2.42(3H, s), 3218 (3H, s), 2.81(2H, t, J=5.8), 3.2-3.5(3H, m), 4.84(2H, s), 7.1 (1H, br. s)651 1.29(3H, t, J.apprxeq.7), 2.36(3H, s), 2.41(3H, s), 2.87(2H, q, J.apprxeq.7), 3.69 301, 121 (3H, s), 6.14(1H, s), 7.3-7.7(5H, m)652 1.22(3H, t, J.apprxeq.7.6), 2.31(3H, s), 2.37(3H, s), 2.83(2H, q, J.apprxeq.7.6), 287 5.65(1H, br. s), 6.14(1H, s), 7.2-7.6(5H, m)653 1.22(3H/2, t, J.apprxeq.7.4), 1.27(3H/2, t, J.apprxeq.7.4), 2.72(1H, q, J=7.4), 364, 362 2.80(1H, q, J.apprxeq.7.4), 3.2-3.5(4H, m), 4.17(2H, s), 4.81(2H, s), 6.9 241, 146 (1H, br. s), 7.0-7.4(5H, m)654 1.19(3H, t, J=5.7), 1.23(3H, t, J=5.7), 2.65(2H, q, J=5.7), 3153 (2H, q, J=5.7), 3.73(3H, s), 4.16(2H, s), 4.85(2H, s), 7.0-7.5(5H, m)655 1.19(3H, t, J=7.6), 1.21(3H, t, J=7.6), 2.65(2H, q, J=7.6), 3015 (2H, q, J=7.6), 4.16(2H, s), 4.88(2H, s), 6.98(1H, br. s), 7.0-7.4 (5H, m)656 1.22(3H, t, J=7.4), 1.27(3H, t, J=7.4), 2.72(2H, q, J=7.4), 364, 362 (2H, q, J=7.4), 3.2-3.5(4H, m), 4.17(2H, s), 4.81(2H, s), 241, 146 br. s), 7.0-7.4(5H, m)657 1.23(3H, t, J.apprxeq.7.6), 1.26(3H, t, J.apprxeq.7.6), 1.6.1.8(2H, m), 2.34 413, 102 0.50 (2H.times.2, J.apprxeq.4.7), 2.70(2H, q, J.apprxeq.7.6), 2.78(2H, q, J.apprxeq.7.6), 3.0-3.4 (2H, m), 3.4-3.6(4H, m), 4.18(2H, s), 4.83(2H, s), 6.31(1H, br. s), 7.0-7.4(5H, m)658 1.23(3H, t, J=7.6), 1.4-2.0(2H, m), 2.2-3.6(10H, m), 4.21(2H, 487, 174 0.44 4.83(2H, s), 6.51(1H, br. s), 70.-7.4(10H, m)662 1.23(3H, t, J.apprxeq.7.6), 2.39(3H.times.2, s), 2.83(2H, q, J.apprxeq.7.4), 3.75(3H, s) 225 4.88(2H, s)663 2.33(3H, s), 2.41(3H, s), 3.73(3H, s), 4.15(2H, s), 4.87(2H, 287 7.0-7.4(5H, m)664 1.27(3H.times.2, d, J=6.8), 2.32(3H, s), 2.40(3H, s), 3.34(1H, sept, J= 239 6.8), 3.75(3H, s), 4.90(2H, s)665 1.23(3H, t, J=7.6), 1.24(3H, t, J=7.6), 1.28(3H.times.2, d, 267.8), 0.89 2.65(2H, q, J=7.6), 2.73(2H, q, J=7.6), 3.34(1H, sept, J=6.8), 3.74(3H, s), 4.87(2H, s)666 0.94(3H.times.2, d, J=6.7), 1.20(3H, t, J.apprxeq.7.3), 1.21(3H, t, J.apprxeq.7.3), 2.18 281 0.68 (1H, sept, J=7.3), 2.5-2.9(6H, m), 3.74(3H, s), 4.86(2H, s)679 2.38(3H, s), 2.41(3H.times.2, s), 3.64(1H, t, J.apprxeq.5.5), 3.8-4.1(3H, m), 183 0.59 4.4-4.6(2H, m)680 1.23(3H, t, J.apprxeq.7.4), 2.32(3H.times.2, s), 2.78(2H, q, J.apprxeq.7.4), 3.8-4.1 197 0.64 (3H, m), 4.4-4.6(2H, m)681 2.38(3H, s), 2.45(3H, s), 2.6-2.8(1H, br. m), 3.7-3.9(2H, m), 2591 0.91 (2H, s), 4.3-4.5(2H, m), 7.1-7.4(5H, m)682 1.24(3H.times.2, d, J.apprxeq.6.8), 2.37(3H, s), 2.42(3H, s), 3.29(1H, sept, J.apprxeq. 211 0.57 6.8), 3.6-4.0(2H, m), 4.3-4.5(2H, m)683 1.1-1.4(12H, m), 2.70(2H, q, J=7.6), 3.30(1H, sept, J=6.8), 239- 0.63 4.1(3H, m), 4.4-4.6(2H, m)684 0.93(3H.times.2, d, J.apprxeq.6.7), 1.20(3H, t, J.apprxeq.7.3), 1.26(3H, t, J.apprxeq.7.3), 253 0.71 2.13(1H, sept, J.apprxeq.7.3), 2.6-2.9(6H, m), 3.67(1H, t, J.apprxeq.5.3), 3.8- 4.1(3H, m), 4.4-4.6(2H, m)697 0.91(3H, t, J.apprxeq.6), 1.20(3H.times.2, d, J=6.8), 1.2-1.6(4H, m), 2.2-2.8 345 0.18 (12H, m), 2.31(3H.times.2, q), 3.43(1H, sept, J=6.8), 4.0-4.3(2H, m)810 0.91(3H, t), 1.1-1.6(4H, m), 2.30(3H, s), 2.34(3H, s), 3071(3H, 0.26 s), 4.15(2H, t), 2.3-2.7(12H, m)812 0.91(3H, t), 1.23(3H, t), 1.1-1.6(4H, m), 2.31(6H, s), 321-2.9 0.19 (14H, m), 4.14(2H, t)814 0.91(3H, t), 1.20(6H, t), 1.1-1.7(4H, m), 2.31(6H, s), 335-2.9 0.22 (12H, m), 3.42(1H, sept), 4.14(2H, t)822 2.30(3H, s), 2.33(3H, s), 2.41(3H, s), 2.3-2.7(12H, m), 2952(2H, 0.02 t), 4.15(3H, t)825 1.20(6H, d), 2.31(6H, s), 2.1-2.9(12H, m), 3.42(1H, sept), 3232 0.06 (2H, t), 4.14(2H, t)826 1.21(6H, d), 1.21(6H, t), 2.0-2.9(12H, m), 3.42(1H, sept), 3512 0.04 (2H, t), 4.13(2H, t)834 1.20(6H, d), 1.3-1.8(6H, m), 2.31(3H, s), 2.34(3H, s), 278-2.7 0.22 (6H, m), 3.42(1H, sept), 4.21(2H, t)842 1.04(6H, t), 2.30(3H, s), 2.35(3H, s), 2.41(3H, s), 238-2.8(6H, 0.63 m), 4.11(2H, t)844 1.04(6H, t), 1.23(3H, t), 2.31(3H, s), 2.34(3H, s), 252-2.9(8H, 0.46 m), 4.11(2H, t)846 1.09(6H, t), 1.20(6H, d), 2.31(3H, s), 2.34(3H, s), 266-2.9(6H, 0.63 m), 3.43(1H, sept), 4.14(2H, t)848 0.99-1.27(18H, m), 2.4-2.9(10H, m), 3.44(1H, sept), 4.13(2H, 294 0.27__________________________________________________________________________ TABLE 26__________________________________________________________________________physical properties of 2-hydroxy-3-substituted-5,6,7,8-tetrahydroquinoxakine ##STR300##R.sub.1 NMR (CDCl.sub.3 , inner standard TMS) .delta. ppm MASS__________________________________________________________________________Me 1.78-1.84 (4H, m), 2.42 (3H, s), 2.66 (4H, m), 13.05 (1H, br, 165Et 1.25 (3H, t), 1.7-1.9 (4H, m), 2.5-2.8 (4H, m), 2.80 (2H, q), 13.06 (1H, 179 br, s)Pro 1.00 (4H, t), 1.55 (6H, m), 2.67-2.83 (6H, m), 13.09 (1H, br, 193iso-Pro 1.24 (3H.times.2, d.times.2, J=6.8), 1.7-2.0 (4H, m), 2.5-2.8 (4H, m), 3.41 (1H, 193 sept, J=6.8), 12.9 (1H, br, s)Bu 0.94 (3H, t), 1.24-2.00 (8H, m), 2.55-2.85 (6H, m), 12.99 (1H, br, s) 207iso-Bu 0.96 (3H.times.2, d), 1.6-2.0 (4H, m), 2.0-2.4 (1H, m), 2.5-2.8 (6H, m) 207sec-Bu 0.96 (3H.times.2, d.times.2, J=6.7), 1.6-2.2 (5H, m), 2.5-2.8 (6H, m) 207(CH.sub.2).sub.4 CH.sub.3 0.90 (3H, t, J=6.3), 1.2-1.5 (4H, m), 1.5-1.9 (6H, m), 2.5-2.9 (6H, m) 221, 164(CH.sub.2).sub.5 CH.sub.3 0.88 (3H, t, J=7.9), 1.1-1.5 (6H, m), 1.5-2.0 (6H, m), 2.4-2.9 (6H, m) 235(CH.sub.2).sub.6 CH.sub.3 0.88 (3H, t, J.apprxeq.7.4), 1.1-1.5 (8H, m), 1.5-2.0 (6H, m), 2.5-2.9 (6H, m) 249, 164(CH.sub.2).sub.7 CH.sub.3 0.88 (3H, t, J=7.5), 1.1-1.5 (10H, m), 1.5-2.0 (6H, m), 2.5-2.9 (6H, m) 263(CH.sub.2).sub.8 CH.sub.3 0.88 (3H, t, J=6.2), 1.1-1.5 (12H, m), 1.5-2.0 (6H, m), 2.5-2.8 (6H, m) 277, 164(CH.sub.2).sub.9 CH.sub.3 0.88 (3H, t, J.apprxeq.6), 1.2-2.0 (20H, m), 2.5-2.9 (6H, m), 12.7(1H, br, s) 291(CH.sub.2).sub.11 CH.sub.3 0.88 (3H, t, J.apprxeq.6), 1.1-1.9 (24H, m), 2.4-2.8 (6H, 319, 164(CH.sub.2).sub.13 CH.sub.3 0.88 (3H, t, J.apprxeq.6), 1.1-1.9 (28H, m), 2.5-2.8 (6H, 347, 164(CH.sub.2).sub.15 CH.sub.3 0.88 (3H, t, J.apprxeq.6), 1.1-1.9 (32H, m), 2.5-2.8 (6H, 375, 164CH.sub.2 Ph 1.6-2.0 (4H, m), 2.4-2.7 (4H, m), 4.02 (2H, s), 7.0-7.4 (4H, 241CH.sub.2 CH.sub.2 Ph 1.6-2.0 (4H, m), 2.5-2.8 (4H, m), 3.06 (2H.times.2, s), 7.1-7.3 (5H, s), 12.9 255 (1H, br, s)__________________________________________________________________________ TABLE 27__________________________________________________________________________physical properties of a compound of the present inventionComp. No. NMR (CDCl.sub.3, inner standard TMS) .delta. ppm MASS Rf__________________________________________________________________________368 1.7-2.0 (4H, m), 2.2-3.0 (14H, m), 3.0-3.6 (2H, m), 3.40 (2H, s), 4.17 500, 189 0.45 (2H, s), 4.79 (2H, s), 6.4 (1H, br, s), 7.0-7.4 (10H, m)369 1.6-2.0 (4H, m), 2.1-3.0 (14H, m), 3.0-3.6 (2H, m), 3.34 (2H, s), 3.79 530, 219 0.43 (3H, s), 4.17 (2H, s), 4.79 (2H, s), 6.4 (1H, br, s), 6.7-7.4 (9H, m)370 1.6-2.0 (4H, m), 2.1-3.0 (14H, m), 3.0-3.6 (2H, m), 3.35 (2H, s), 4.18 535, 533 0.4 (2H, s), 4.79 (2H, s), 6.3 (1H, br, s), 7.0-7.4 (9H, 223371 1.6-2.0 (4H, m), 2.3-3.0 (10H, m), 3.0-3.4 (6H, m), 4.19 (2H, s), 4.82 522, 520 0.48 (2H, s), 6.4 (1H, br, s), 6.7-7.4 (9H, m) 209372 1.5-2.1 (6H, m), 2.3-3.0 (14H, m), 3.0-3.4 (2H, m), 3.51 (2H, s), 4.17 532, 221 0.38 (2H, s), 4.79 (2H, s), 6.3 (1H, br, s), 6.9-7.4 (9H, m)373 1.6-2.1 (2H, m), 2.2-3.0 (10H, m), 3.0-3.4 (4H, m), 4.15 (2H, s), 4.81 486, 342 0.49 (2H, s), 6.3 (1H, br, s), 6.6-7.4 (10H, m) 175517 0.93 (3H, t, J.apprxeq.6.6), 1.2-2.0 (8H, m), 2.4-3.0 (12H, m), 3.6-3.8 (4H, 320, 102 0.42 m), 3.9-4.2 (2H, m)518 0.93 (3H, t, J.apprxeq.6.6), 1.2-2.0 (8H, m), 2.4-3.0 (16H, m), 3.53 (2H, s), 409, 189 0.41 3.9-4.2 (2H, m), 7.30 (5H, s)519 0.93 (3H, t, J.apprxeq.6.6), 1.2-2.0 (8H, m), 2.4-3.0 (16H, m), 3.47 (2H, s), 445, 443 0.43 3.9-4.2 (2H, m), 7.27 (4H, s) 227520 0.93 (3H, t, J.apprxeq.6.6), 1.2-2.0 (10H, m), 2.4-3.0 (16H, m), 3.60 (2H, s), 459, 457 0.29 3.9-4.2 (2H, m), 7.27 (4H, s) 237521 0.93 (3H, t, J.apprxeq.6.6), 1.2-2.0 (8H, m), 2.4-3.0 (12H, m), 3.0-3.3 (4H, 395, 175 0.61 m), 4.0-4.3 (2H, m), 6.7-7.4 (5H, m)522 0.93 (3H, t, J.apprxeq.6.6), 1.2-2.0 (8H, m), 2.5-3.0 (12H, m), 3.2-3.2 (4H, 425, 205 0.69 m), 3.86 (3H, s), 4.0-4.3 (2H, m), 6.7-7.1 (4H, m)559 0.89 (3H, t, J.apprxeq.6), 1.2-2.0 (10H, m), 2.4-2.9 (12H, m), 3.6-3.8 (4H, 334, 102 0.44 m), 3.9-4.2 (2H, m)560 0.89 (3H, t, J.apprxeq.6), 0.91 (3H, t, J.apprxeq.6), 1.2-2.0 (14H, m), 2.2-2.9 (18H, 389, 155 0.24 m), 3.9-4.2 (2H, m)561 0.89 (3H, t, J.apprxeq.6), 1.1-2.0 (10H, m), 2.4-2.9 (16H, m), 3.53 (2H, s), 423, 189 0.31 3.9-4.2 (2H, m), 7.30 (5H, s)562 0.89 (3H, t, J.apprxeq.6), 1.1-2.0 (12H, m), 2.4-2.9 (16H, m), 3.61 (2H, s), 455, 234 0.19 3.9-4.2 (2H, m), 6.8-8.4 (4H, m) 221563 0.89 (3H, t, J.apprxeq.6), 1.2-2.0 (10H, m), 2.5-2.9 (12H, m), 3.0-3.2 (4H, m), 3.86 (3H, s), 4.0-4.3 (2H, m), 6.7-7.1 (4H, m)564 0.87 (3H, t, J.apprxeq.6), 1.1-2.0 (12H, m), 2.4-2.9 (12H, m), 3.6-3.8 (4H, 348, 101 0.32 m), 3.9-4.2 (2H, m)565 0.87 (3H, t, J.apprxeq.6), 0.91 (3H, t, J.apprxeq.6), 1.1-2.0 (16H, m), 2.1-2.9 (18H, 403, 155 0.20 m), 3.9-4.2 (2H, m)567 0.87 (3H, t, J.apprxeq.6), 1.1-2.0 (12H, m), 2.3-2.9 (16H, m), 3.52 (2H, s), 437, 189 0.28 2.9-4.2 (2H, m), 7.30 (5H, s)568 0.87 (3H, t, J.apprxeq.6), 1.1-2.0 (12H, m), 2.4-2.9 (16H, m), 3.52 (2H, s), 473, 471 0.31 3.9-4.2 (2H, m), 7.30 (4H, s) 236, 223569 0.87 (3H, t, J.apprxeq.6), 1.1-2.0 (14H, m), 2.4-3.0 (16H, m), 3.60 (2H, s), 469, 234 0.20 3.9-4.2 (2H, m), 6.8-7.4 (4H, m) 221570 0.87 (3H, t, J.apprxeq.6), 1.1-2.0 (12H, m), 2.5-3.0 (12H, m), 2.9-3.2 (4H, 453, 218 0.53 3.86 (3H, s), 4.0-4.3 (2H, m), 6.7-7.1 (4H, m) 205571 0.7-1.0 (6H, m), 1.1-2.0 (18H, m), 2.2-2.9 (18H, m), 3.9-4.2 (2H, m) 417, 155 0.33572 0.87 (3H, t, J.apprxeq.6), 1.1-2.0 (16H, m), 2.4-2.9 (12H, m), 3.6-3.8 (4H, 376 0.58 m), 3.9-4.2 (2H, m)573 0.7-1.0 (6H, m), 1.1-2.0 (20H, m), 2.2-2.9 (18H, m), 3.9-4.2 (2H, m) 431, 155 0.27574 0.87 (3H, t, J.apprxeq.6), 1.1-2.0 (16H, m), 2.4-2.9 (16H, m), 3.53 (2H, s), 465, 189 0.52 3.9-4.2 (2H, m), 7.30 (5H, s)575 0.87 (3H, t, J.apprxeq.6), 1.1-2.0 (16H, m), 2.3-2.9 (16H, m), 3.9-4.2 (2H, 501, 499 0.43 m), 7.26 (4H, s) 223576 0.87 (3H, t, J.apprxeq.6), 1.1-2.0 (18H, m), 2.5-2.9 (16H, m), 3.59 (2H, s), 497, 235 0.24 3.9-4.2 (2H, m), 6.8-7.4 (4H, m) 221577 0.88 (3H, t, J.apprxeq.6), 1.1-2.0 (16H, m), 2.5-2.9 (12H, m), 3.0-3.3 (4H, 450, 189 0.67 m), 4.0-4.3 (2H, m), 6.7-7.4 (5H, m) 175578 0.87 (3H, t, J.apprxeq.6), 1.1-2.0 (16H, m), 2.5-2.9 (12H, m), 3.0-3.2 (4H, 480, 218 0.55 m), 3.77 (3H, s), 4.0-4.2 (2H, m), 6.86 (4H, s) 205579 0.87 (3H, t, J.apprxeq.6), 1.0-2.0 (18H, m), 2.4-2.9 (12H, m), 3.5-3.8 (4H, 390, 102 0.39 m), 3.9-4.2 (2H, m)580 0.87 (3H, t, J.apprxeq.6), 0.91 (3H, t, J.apprxeq.6), 1.0-2.0 (22H, m), 2.3-2.9 (18H, 445, 155 0.29 m), 3.9-4.2 (2H, m)581 0.87 (3H, t, J.apprxeq.6), 1.0-2.0 (18H, m), 2.4-2.9 (16H, m), 3.52 (2H, s), 479, 202 0.32 3.9-4.2 (2H, m) 189582 0.87 (3H, t, J.apprxeq.6), 1.0-2.0 (18H, m), 2.3-2.9 (16H, m), 3.47 (2H, s), 509, 232 0.28 3.80 (3H, s), 3.9-4.2 (2H, m), 6.84 (2H, d, J=8.8), 7.23 (2H, d, J=8.8) 219583 0.87 (3H, t, J.apprxeq.6), 1.0-2.0 (20H, m), 2.4-3.0 (16H, m), 3.59 (2H, s), 529, 527 0.39 3.9-4.2 (2H, m), 7.26 (4H, s) 250, 237584 0.87 (3H t, J.apprxeq.6), 1.0-2.0 (18H, m), 2.4-2.9 (12H, m), 3.0-3.2 (4H, 501, 499 0.46 m), 3.9-4.2 (2H, m), 6.7-7.3 (4H, m) 222, 209585 0.87 (3H, t, J.apprxeq.6), 1.0-2.0 (20H, m), 2.4-2.9 (12H, m), 3.5-3.8 (4H, 404, 113 0.37 m), 3.9-4.2 (2H, m) 102586 0.87 (3H, t, J.apprxeq.6), 1.0-2.0 (26H, m), 2.4-2.9 (12H, m), 4.0-4.3 (4H, 402, 112 0.29 m)587 0.87 (3H, t, J.apprxeq.6), 0.91 (3H, t, J.apprxeq.6), 1.0-2.0 (24H, m), 2.2-2.9 (18H, 459, 155 0.26 m), 3.9-4.2 (2H, m) 125588 0.87 (3H, t, J.apprxeq.6), 1.0-2.0 (20H, m), 2.3-2.9 (18H, m), 3.62 (2H, t, 447, 156 0.12 J.apprxeq.6), 3.9-4.2 (2H, m) 143, 125589 0.87 (3H, t, J.apprxeq.6), 1.0-2.0 (20H, m), 2.4-2.9 (16H, m), 3.52 (2H, s), 493, 202 0.37 3.9-4.2 (2H, m), 7.30 (5H, s) 189590 0.87 (3H, t, J.apprxeq.6), 1.0-2.0 (20H, m), 2.3-2.9 (16H, m), 3.52 (2H, s), 529, 527 0.41 3.9-4.2 (2H, m), 7.26 (4H, s) 236, 223 125591 0.87 (3H, t, J.apprxeq.6), 1.0-2.0 (20H, m), 2.3-2.9 (16H, m), 3.8-4.2 (2H, 569, 278 0.66 m), 4.22 (1H, s), 7.0-7.6 (10H, m) 167592 0.87 (3H, t, J.apprxeq.6), 1.0-2.0 (22H, m), 2.4-3.0 (16H, m), 3.60 (2H, s), 525, 234 0.27 3.9-4.2 (2H, m), 6.8-7.4 (4H, m) 221593 0.87 (3H, t, J.apprxeq.6), 1.0-2.0 (20H, m), 2.4-2.9 (12H, m), 2.9-3.2 (4H, 509, 218 0.60 m), 3.77 (4H, s), 3.9-4.2 (2H, m), 6.6-7.0 (4H, m) 205594 0.88 (3H, t, J.apprxeq.6), 1.0-2.0 (24H, m), 2.4-3.0 (12H, m), 3.6-3.8 (4H, 432, 101 0.34 m), 3.9-4.2 (2H, m)595 0.88 (3H, t, J.apprxeq.6), 0.91 (3H, t, J.apprxeq.6), 1.0-2.0 (28H, m), 2.2-3.0 (18H, 487, 155 0.16 m), 3.9-4.2 (2H, m)596 0.88 (3H, t, J.apprxeq.6), 1.0-2.0 (24H, m), 2.3-2.9 (16H, m), 3.53 (2H, s), 521, 202 0.21 3.9-4.2 (2H, m), 7.30 (5H, s) 179597 0.88 (3H, t, J.apprxeq.6), 1.0-2.0 (24H, m), 2.4-2.9 (16H, m), 3.47 (2H, s), 551, 232 0.21 3.79 (3H, s), 3.9-4.2 (2H, m), 6.84 (2H, d, J.apprxeq.8.6), 7.22 (2H, d, J=8.6) 219598 0.88 (3H, t, J.apprxeq.6), 1.0-2.0 (26H, m), 2.4-3.0 (16H, m), 3.9-4.2 (2H, 553, 234 0.15 m), 6.8-7.4 (4H, m) 221599 0.88 (3H, t, J.apprxeq.6), 1.0-2.0 (24H, m), 2.5-2.9 (12H, m), 2.9-3.2 (4H, 537, 208 0.43 m), 3.86 (3H, s), 3.9-4.1 (2H, m), 6.7-7.1 (2H, m) 205600 0.88 (3H, t, J.apprxeq.6), 0.91 (3H, t, J.apprxeq.6), 1.0-2.0 (32H, m), 2.2-2.9 (18H, 515, 155 0.22 m), 3.9-4.2 (2H, m)601 0.88 (3H, t, J.apprxeq. 6), 1.0-2.0 (28H, m), 2.4-2.9 (16H, m), 3.51 (2H, s), 549, 202 0.36 3.9-4.2 (2H, m), 7.29 (5H, s) 189602 0.88 (3H, t, J.apprxeq.6), 1.0-2.0 (28H, m), 2.3-2.9 (16H, m), 3.47 (2H, s), 567, 549 0.37 3.9-4.2 (2H, m), 6.8-7.4 (4H, m) 220, 207603 0.88 (3H, t, J.apprxeq.6), 1.0-2.0 (30H, m), 2.4-3.0 (16H, m), 3.60 (2H, s), 599, 597 0.30 3.9-4.2 (2H, m), 7.27 (4H, s) 250604 0.88 (3H, t, J.apprxeq.6), 1.0-2.0 (28H, m), 2.3-2.9 (16H, m), 3.9-4.2 (2H, 625, 228 0.71 m), 4.23 (1H, s), 7.0-7.5 (10H, m) 167605 0.88 (3H, t, J.apprxeq.6), 1.0-2.0 (28H, m), 2.5-3.0 (12H, m), 2.9-3.2 (4H, 571, 569 0.71 m), 4.0-4.3 (2H, m), 6.8-7.4 (4H, m) 222, 209606 0.88 (3H, t, J.apprxeq.6), 1.0-2.0 (28H, m), 2.4-2.9 (12H, m), 3.5-3.8 (4H, 488, 113 0.47 m), 3.9-4.2 (2H, m)607 0.88 (3H, t, J.apprxeq.6), 0.91 (3H, t, J.apprxeq.6), 1.0-2.0 (36H, m), 2.1-2.8 (18H, 543, 168 0.26 m), 3.9-4.2 (2H, m) 155608 0.88 (3H, t, J.apprxeq.6), 1.0-2.0 (32H, m), 2.3-2.9 (16H, m), 3.51 (2H, s), 578, 202 0.35 3.9-4.2 (2H, m), 7.29 (5H, s)609 0.88 (3H, t, J.apprxeq.6), 1.0-2.0 (34H, m), 2.5-2.9 (16H, m), 3.62 (2H, s), 621, 246 0.25 3.80 (3H, s), 3.9-4.2 (2H, m), 6.84 (2H, d, J=8.6), 7.26 (2H, d, J=8.6) 121610 0.88 (3H, t, J.apprxeq.6), 1.0-2.0 (32H, m), 2.4-2.9 (12H, m), 2.9-3.2 (4H, 592, 218 0.45 m), 3.76 (3H, s), 3.9-4.2 (2H, m), 6.6-7.0 (4H, m)659 1.7-1.9 (4H, m), 2.6-2.9 (4H, m), 3.73 (3H, s), 4.16 (2H, s), 4.86 (2H, 313 s), 7.0-7.4 (5H, m)660 1.7-1.9 (4H, m), 2.6-3.0 (4H, m), 4.16 (2H, s), 4.87 (2H, s), 7.0-7.5 299 (5H, m)661 1.7-1.9 (4H, m), 2.6-2.9 (4H, m), 3.2-3.5 (4H, m), 4.17 (2H, s), 4.85 362, 360 (2H, s), 7.0-7.5 (5H, m)667 0.94 (3H, t, J.apprxeq.7.4), 1.2-2.0 (8H, m), 2.6-3.0 (6H, m), 3.75 (3H, s), 279 0.89 4.88 (2H, s)668 0.89 (3H, t, J.apprxeq.6), 1.2-2.0 (10H, m), 2.6-3.0 (6H, m), 3.75 (3H, s), 293 0.90 4.89 (2H, s)669 0.88 (3H, t, J.apprxeq.6), 1.2-2.0 (12H, m), 2.6-3.0 (6H, m), 3.75 (3H, s), 307 0.92 4.88 (2H, s)670 0.88 (3H, t, J.apprxeq.6), 1.2-2.0 (14H, m), 2.6-3.0 (6H, m), 3.75 (3H, s), 321 0.93 4.89 (2H, s)671 0.87 (3H, t, J.apprxeq.6), 1.2-2.0 (16H, m), 2.6-3.0 (6H, m), 3.75 (3H, s), 335 0.93 4.88 (2H, s)672 0.87 (3H, t, J.apprxeq.6), 1.1-2.0 (18H, m), 2.6-3.0 (6H, m), 3.75 (3H, s), 349 0.93 4.88 (2H, s)673 0.87 (3H, t, J.apprxeq.6), 1.1-2.0 (20H, m), 2.6-3.0 (6H, m), 3.75 (3H, s), 363 0.94 4.88 (2H, s)674 0.87 (3H, t, J.apprxeq.6), 1.1-2.0 (24H, m), 2.6-3.0 (6H, m), 3.75 (3H, s), 391 0.94 4.88 (2H, s)675 0.88 (3H, t, J.apprxeq.6), 1.0-2.0 (28H, m), 2.6-3.0 (6H, m), 3.75 (3H, s), 419 0.94 4.88 (2H, s)676 0.88 (3H, t, J.apprxeq.6), 1.0-2.0 (32H, m), 2.6-3.0 (6H, m), 3.75 (3H, s), 447 0.95 4.88 (2H, s)677 0.99 (3H, t, J=7.3), 1.5-2.0 (6H, m), 3.75 (3H, s), 3.89 (2H, 265 0.86678 0.86 (3H, t, J=7.4), 1.25 (2H, d, J=7.8), 1.6-2.0 (6H, m), 2.792.9 0.88 (4H, m), 2.9-3.3 (1H, m), 3.74 (3H, s), 4.88 (2H, s)685 0.93 (3H, t, J.apprxeq.6.7), 1.1-2.0 (8H, m), 2.6-3.0 (6H, m), 3.6-4.1 (3H, 251 0.66 m), 4.4-4.6 (2H, m)686 0.89 (3H, t, J.apprxeq.6), 1.2-2.0 (10H, m), 2.6-3.0 (6H, m), 3.7 (1H, br, s), 265 0.67 3.8-4.1 (2H, m), 4.4-4.6 (2H, m)687 0.88 (3H, t, J.apprxeq.6), 1.0-2.0 (12H, m), 2.6-3.0 (6H, m), 3.7 (1H, br, s), 279 0.67 3.8-4.1 (2H, m), 4.3-4.6 (2H, m)688 0.88 (3H, t, J.apprxeq.6), 1.2-2.0 (14H, m), 2.6-3.0 (6H, m), 3.7 (1H, br, s), 293 0.67 3.8-4.1 (2H, m), 4.4-4.6 (2H, m)689 0.88 (3H, t, J.apprxeq.6), 1.1-2.0 (16H, m), 2.6-3.0 (6H, m), 3.7 (1H, br, s), 307 0.69 3.8-4.1 (2H, m), 4.4-4.6 (2H, m)690 0.87 (3H, t, J.apprxeq.6), 1.0-2.0 (18H, m), 2.6-3.0 (6H, m), 3.7 (1H, br, s), 321 0.70 3.8-4.1 (2H, m), 4.4-4.6 (2H, m)691 0.88 (3H, t, J.apprxeq.6), 1.1-2.0 (20H, m), 2.6-3.0 (6H, m), 3.7-4.1 (3H, m), 335 0.72 4.4-4.6 (2H, m)692 0.88 (3H, t, J.apprxeq.6), 1.0-2.0 (24H, m), 2.6-3.0 (6H, m), 3.7-4.1 (3H, m), 363 0.78 4.4-4.6 (2H, m)693 0.88 (3H, t, J.apprxeq.6), 1.0-2.0 (28H, m), 2.5-3.0 (6H, m), 3.7-4.1 (3H, m), 391 0.81 4.4-4.6 (2H, m)694 0.88 (3H, t, J.apprxeq.6), 1.0-2.0 (32H, m), 2.6-3.0 (6H, m), 3.7-4.1 (3H, m), 419 0.81 4.3-4.6 (2H, m)695 0.97 (3H, t, J=7.3), 1.5-2.0 (6H, m), 2.6-3.0 (6H, m), 3.7 (1H, br, s), 237 0.54 3.8-4.1 (2H, m), 4.4-4.6 (2H, m)696 0.84 (3H, t, J=7.4), 1.21 (3H, d, J.apprxeq.7), 1.2-2.0 (6H, m), 2.6-2.9 (6H, 251 0.65 m), 2.8-3.3 (1H, m), 3.8-4.1 (3H, m), 4.3-4.5 (2H, m)817 0.91 (3H, t), 0.93 (3H, t), 1.1-1.9 (12H, m), 2.0-3.0 (18H, m), 4.08 375 0.22 (2H, t)830 0.87 (3H, t), 1.1-1.5 (10H, m), 1.5-2.0 (6H, m), 2.4-2.9 (18H, 419 0.23 3.63 (2H, t), 4.09 (2H, t)837 0.93 (3H, t), 1.0-2.0 (14H, m), 2.0-3.0 (12H, m), 4.11 (3H, 318 0.28839 0.87 (3H, t), 1.1-2.0 (22H, m), 2.4-2.9 (12H, m), 4.12 (2H, 274 0.30850 0.93 (3H, t), 1.06 (6H, t), 1.1-2.0 (8H, m), 2.4-3.0 (12H, m), 3068 0.69 (2H, t)851 0.87 (3H, t), 1.04 (6H, t), 1.2-1.5 (10H, m), 1.5-2.0 (6H, m), 2.5-3.0 362 0.19 (12H, m), 4.06 (2H, t)__________________________________________________________________________

Claims

1. A compound of the formula ##STR301## wherein R is hydroxyl, lower alkoxy, --NH--lower alkylene--OH, --NH--lower alkylene-arylthio, ##STR302## is di-lower alkylamino, morpholino, ##STR303## in which R.sub.9 is hydrogen, lower alkyl or aryl, R.sub.10 is hydrogen, lower alkyl, hydroxy-lower alkyl or hydroxy-lower alkoxy-lower alkyl, m is an integer from 4 to 6, n is 2 or 3, R.sub.1 is alkyl or aryl-lower alkyl, R.sub.2 and R.sub.3 are each lower alkyl, and R.sub.4 is hydrogen, lower alkyl or aryl, in which aryl is phenyl which is optionally substituted with a group selected from the group consisting of 1-3 halogen, nitro, lower alkyl and lower alkoxy, or a pharmaceutically acceptable salt thereof.

2. A compound of the formula ##STR304## wherein R is hydroxyl or ##STR305## is di-lower alkylamino, morpholino, ##STR306## in which R.sub.9 is hydrogen, lower alkyl or aryl, R.sub.10 is hydrogen, lower alkyl, hydroxy-lower alkyl or hydroxy-lower alkoxy-lower alkyl, m is an integer from 4 to 6, n is 2 or 3, R.sub.1 is alkyl or aryl-lower alkyl, R.sub.2 and R.sub.3 are each lower alkyl, and R.sub.4 is hydrogen, lower alkyl or aryl, in which aryl is phenyl which is optionally substituted with a group selected from the group consisting of 1-3 halogen, nitro, lower alkyl and lower alkoxy, or a pharmaceutically acceptable salt thereof.