1-substituted alkyl-1,2-dihydro-2-pyrazinone derivatives

BACKGROUND OF THE INVENTION
This invention relates to novel 1-substituted alkyl-2-dihydro pyrazine derivatives and 1-substituted alkyl-2-hexahydro quinoxaline derivatives, 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.
Recently, a significant number of compounds having platelet aggregation inhibiting activity have been reported. Of these, the only known compounds having a pyrazine 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).
It is of great importance to discover high quality pharmaceuticals having stronger inhibitory activities for platelet aggregation, in order effectively to treat circulatory and metabolic disorders.
We have found that 1-substituted alkyl-2-dihydro pyrazinone derivatives and 1-substituted alkyl-2-hexahydro quinoxaline derivatives display inhibitory action on platelet aggregation, vasodilation activity and/or anti-lipoperoxide generation, and are expected to have excellent pharmaceutical properties.
SUMMARY OF THE INVENTION
In the present invention, a compound of the formula ##STR3## is provided, wherein R is hydroxyl, halogen, lower alkanoyloxy, R.sub.4 -carbamoyloxy, arylthio, 1-methyltetrazole-5-yl-thio, 1-imidazolyl, morpholino, ##STR4## in which R.sub.4 is lower alkyl or aryl, R.sub.5 is hydrogen, lower alkyl or aryl, R.sub.6 is hydrogen, lower alkyl, hydroxy-lower alkyl, aryl, aryl-lower alkanoyl, arylcarbonyl, arylsulfonyl or thienyl-lower alkanoyl, A and A.sub.1 are lower alkylene, m is an integer of 4-6, n is an integer of 2-3, the above aryl is phenyl or phenyl substituted with C.sub.1-3 alkyl, halogen, nitro or lower alkoxy, R.sub.1 is alkyl, phenyl-lower alkyl optionally having substituent, R.sub.2 and R.sub.3 are each lower alkyl, or together form tetramethylene.
The compound [1] can be provided in salt form. The salts must be pharmacologically acceptable non-toxic salts 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, glutaric, methanesulfonic or toluenesulfonic. Salts of other known acids can be used as well.
DETAILED DESCRIPTION OF THE INVENTION
The compound [1] can be produced by the following processes:
Process A:
A process for production of compound [1] wherein R is hydroxyl, and the compound produced thus has the formula ##STR5## wherein R.sub.1, R.sub.2, R.sub.3 and A are defined as above.
The above compound [1a] can be produced by reacting a compound of the formula ##STR6## where R.sub.1, R.sub.2 and R.sub.3 are defined as above, with a hydroxyalkyl halide of the formula
X--A--OH
where X is halogen and A is defined as above, in an organic solvent.
In the compound [2] above, R.sub.1 is alkyl, optionally substituted phenyl, or optionally substituted phenyl-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 alkoxy. "Optionally substituted phenyl-lower alkyl", as used above, is defined as phenyl or phenyl substituted with C.sub.1-3 lower alkyl, halogen, nitro or lower alkoxy, in which lowere alkyl means methyl, 2-ethyl, 1-ethyl, 3-propyl or 1-propyl. Examples are benzyl, p-chlorobenzyl, 2-phenylethyl and 1-phenylethyl.
In the compound [2] above, R.sub.2 and R.sub.3 are each lower alkyl, or together form tetramethylene. The lower alkyl can be methyl, ethyl or propyl. The compound [2] wherein R.sub.2 and R.sub.3 together form tetramethylene can be designated as 2-hydroxy-3-substituted-hexahydro quinoxaline. Among the class of compounds [2] in which R.sub.2 and R.sub.3 are lower alkyl, i.e. 2-hydroxy-3-substituted-5,6-di(lower alkyl)pyrazine, 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, i.e. 2-hydroxy-3-substituted-hexahydro quinoxaline derivatives, is produced by the process developed by the present inventors, in which an .alpha.-amino acidamide, other than glycine, is reacted with 1,2-cyclohexanedione in an alkaline medium.
The group A in the above hydroxylalkyl halide is defined as above, namely, lower alkylene. Examples of lower alkylene are methylene, ethylene, methylmethylene, propylene, 1-methylethylene, 1,1-dimethylmethylene or 1-ethylmethylene; ethylene is preferred.
The group X in the above hydroxyalkyl halide is halogen, such as chlorine or bromine, and in general chlorine is preferred. The preferred hydroxyalkyl halide is ethylene chlorohydrin.
Reaction of the compound [2] with hydroxyalkyl halide proceeds in an organic solvent such as butanol.
The above reaction is preferably effected in an aqueous alkali solvent such as hydroxy alkali, and preferably, is possible, under heating. Isolation of the product [1a] can be performed by adding water to the reaction mixture and extracting with water-immiscible organic solvent.
Process B:
A process for production of compound [1] wherein R is lower alkanoyloxy (hereinafter designated as compound [1b]):
A compound [1b] can be produced by acylating an above compound [1a] with lower fatty acid or its reactive derivative.
Examples of lower fatty acid are branched or unbranched C.sub.1-6 fatty acids such as acetic acid, propionic acid, butyric acid, isobutyric acid, sec-butyric acid, valeric acid, isovaleric acid and hexanoic acid. Examples of reactive derivatives are known acylating agents for the hydroxyl group, such as acid halide, acid anhydride, mixed anhydride or active ester. The lower fatty acid can itself be acylated in the presence of a condensation reagent such as N,N-dicyclohexyl carbodiimide (DCC).
In the above reactions, co-generated acid can be removed by an acid-binder, for example a known tertiary organic amine such as pyridine or triethylamine.
The product [1b] can be isolated by pouring the reaction mixture into dilute aqueous alkali and extracting with water-immiscible organic solvent.
Process C:
A process for production of compound [1] wherein R is R.sub.4 -carbamoyloxy (hereinafter designated as a compound [1c]):
A compound [1c] can be produced by reacting the above compound [1a] with lower alkyl isocyanate or aryl isocyanate.
"Lower alkyl" in the above lower alkyl carbamoyloxy means branched or unbranched C.sub.1-6 alkyl, and "aryl" in the above aryl carbamoyloxy means phenyl or phenyl substituted with C.sub.1-3 lower alkyl, halogen, nitro or lower alkoxy.
Reaction of the compound [1a] and the isocyanate compound proceeds in an organic solvent such as pyridine. Isolation of the product [1c] can be effected by removing solvent from the reaction mixture and extracting the resultant residue with an inert organic solvent in an aqueous medium, or precipitating the product [1c] by adding solvent such as ether.
Process D:
A process for production of compound [1] wherein R is halogen, and the compound produced thus has the formula ##STR7## wherein X is halogen, and A, R.sub.1, R.sub.2 and R.sub.3 are defined as above.
A compound [1d] can be produced by halogenating the compound [1a] above with halogenating agent.
The said halogenating agent may be any known halogenating agent. More specifically, known chlorination reagents or bromination reagents can be used. Conventional chlorination reagents such as SOCl.sub.2, PCl.sub.5 and POCl.sub.3 can be applied. The halogenation reaction can be effected, in general, in an inert organic solvent such as chloroform. Reaction proceeds at room temperature. Isolation of the product [1d] 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 compound [1d] can be used without purification, as by silica-gel column chromatography, as an intermediate in the synthesis of compounds [1e] and [1f] below.
Process E:
A process for production of compound [1] wherein R is arylthio or 1-methyltetrazole-5-yl-thio (hereinafter designated as compound [1e]):
A compound [1e] can be produced by reacting the above compound [1d] with an alkali metal salt of arylmercaptan or an alkali metal salt of 1-methyl-5-mercaptotetrazole in an organic solvent.
"Aryl" in the above arylthio means phenyl or phenyl substituted with C.sub.1-3 lower alkyl, halogen, nitro or lower alkoxy.
Examples of the above alkali salts of arylmercaptan or 1-methyl-5-mercaptotetrazole are the corresponding sodium and potassium salts.
Reaction of the above compound [1d] and the said alkali metal salt of the mercapto compound proceeds, in general, in an organic solvent such as dimethyl formamide (DMF). Isolation of the product [1e] can be performed by removing the reaction solvent and extracting the residue with water-immiscible organic solvent in the presence of dilute aqueous alkali.
Process F:
A process for production of compound [1] wherein R is a group other than hydroxyl, halogen, lower alkanoyloxy, R.sub.4 -carbamoyloxy, arylthio and 1-methyltetrazole-5-yl-thio (hereinafter designated as compound [1f]):
A compound [1f] can be produced by reacting a compound [1d] with an amine of the formula
R'--H
wherein R' is 1-imidazolyl, morpholino, ##STR8## and R.sub.1, R.sub.2, R.sub.3, R.sub.5, R.sub.6, A, A.sub.1, m and n are defined as above. ##STR9## wherein m is an integer of 4-6, is defined as pyrrolidine, piperidine or hexamethyleneimine ring. R.sub.5 means hydrogen, lower alkyl or aryl. The position of the R.sub.5 group may be any position in the ring hereinabove except at position 1 (nitrogen). The above alkyl means branched or unbranched C.sub.1-6 alkyl. "Aryl" as used above means phenyl or phenyl substituted with C.sub.1-3 lower alkyl, halogen, nitro or lower alkoxy.
The group R.sub.6 in the above ##STR10## is defined as hydrogen, lower alkyl, hydroxy-lower alkyl, aryl, aryl-lower alkanoyl, arylcarbonyl, arylsulfonyl or thienyl-lower alkanoyl. Examples of the above alkyl are branched or unbranched C.sub.1-4 alkyl such as methyl, 2-ethyl, 1-ethyl, propyl, isopropyl and 1-methylethyl. Examples of aryl are phenyl; or phenyl substituted with C.sub.1-3 alkyl, halogen, nitro or lower alkoxy, such as tolyl, xylyl, p(m or o)-nitrophenyl, p(m or o)-fluorophenyl, 2,4(2,3-, 3,4-, 2,5-, 3,5- or 2,6-)-dichlorophenyl, p(m or o)-nitrophenyl, p(m or o)-methoxyphenyl, 2,3(2,4-, 3,4-, 2,5-, 3,5- or 2,6)-dimethoxyphenyl. The above lower alkanoyl is branched or unbranched C.sub.2-4 alkanoyl such as acetyl, propionyl, butyryl, isobutyryl or sec-butyryl.
The ring of the group ##STR11## wherein N is integer of 2-3, is piperazine or homopiperazine. A.sub.1 is lower alkylene such as methylene, ethylene, methylmethylene, propylene, 1-methylethylene or 1-ethylmethylene, and preferred examples are methylene and ethylene. "Aryl" as used above means phenyl or phenyl substituted with C.sub.1-3 lower alkyl, halogen, nitro or lower alkoxy. Examples thereof have been set forth above.
Accordingly, specific examples of the amine (R'--H) are 1-imidazole, morpholine, pyrrolidine, piperidine, 4-methylpiperazine, 4-ethylpiperazine, 4-butylpiperazine, 4-(2-hydroxyethyl)-piperazine, 4-phenyl-piperazine, 4-(o-chlorophenyl)-piperazine, 4-(o-methoxyphenyl)-piperazine, 4 (phenylacetyl)-piperazine, 4-benzoyl-piperazine, 4-(p-chlorobenzoyl)-piperazine, 4-(p-nitrobenzoyl)-piperazine, 4-(p-methoxybenzoyl)-piperazine, 4-(2,3-dimethoxybenzoyl)-piperazine, 4-(2,4-dimethoxybenzoyl)-piperazine, 4-(3,4-dimethoxybenzoyl)-piperazine, 4-(3,4,5-trimethoxybenzoyl)-piperazine, 4-benzenesulfonyl-piperazine, 4-(p-chlorobenzenesulfonyl)-piperazine, 4-(2-thienylacetyl)-piperazine, 4-benzyl-piperazine, 4-(p-methylbenzyl)-piperazine, 4-(p-chlorobenzyl)-piperazine, 4-(m-chlorobenzyl)-piperazine, 4-(o-chlorobenzyl)-piperazine, 4-(2,4-dichlorobenzyl)-piperazine, 4-(p-fluorobenzyl)-piperazine, 4-(p-nitrobenzyl)-piperazine, 4-(p-methoxybenzyl)-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. Reaction of the compound [1d] and the above amine ordinarily proceeds in an inert organic solvent such as benzene, under heating. In the reaction, hydrogen halogenide is generated so that the said reaction proceeds in the presence of acid binder, for example known tertiary organic amines such as triethylamine. The compound [1f] can be isolated by pouring the reaction mixture into dilute aqueous alkali and extracting with water-immiscible organic solvent such as benzene or chloroform.
Process G:
A process for production of compound [1] wherein R is ##STR12## in which R.sub.6 is aryl-lower alkanoyl, arylcarbonyl, arylsulfonyl, or thienyl-lower alkanoyl (hereinafter designated as compound [1g]).
A compound [1g] can be produced by Process F above, but is also produced by means of another method in which a compound of the formula ##STR13## wherein R.sub.1, R.sub.2, R.sub.3 and A have the same meanings hereinbefore, is acylated with an organic acid or a reactive derivative thereof.
The above organic acid is aryl-lower fatty acid, arylcarboxylic acid, arylsulfonic acid or thienyl-lower fatty acid, in which aryl means phenyl or phenyl substituted with C.sub.1-3 alkyl, halogen, nitro or lower alkoxy, and lower fatty acid means a branched or unbranched C.sub.1-4 fatty acid, for example acetic acid, propionic acid, butyric acid, isobutyric acid or sec-butyric acid. Examples of organic acid are phenyl-acetic acid, benzoic acid, p-chlorobenzoic acid, p-nitrobenzoic acid, p-methoxybenzoic acid, 2,3-dimethoxy benzoic acid, 2,4-dimethoxybenzoic acid, 3,4-dimethoxybenzoic acid, 3,4,5-trimethoxybenzoic acid, benzenesulfonic acid, p-toluenesulfonic acid and 2-thienylacetic acid. Examples of reactive derivatives are known acylating agents for the amino group, for example acid halide, acid anhydride, mixed anhydride and activated ester. Also, the organic acid can itself be acylated in the presence of a condensation agent such as DCC. Because acid is co-generated in the reaction, the reaction may proceed in the presence of an acid binder, for example known tertiary organic amines such as pyridine or triethylamine. The acylating reaction proceeds in a conventional organic solvent. The produced compound [1g] can be isolated by pouring the reaction mixture into dilute aqueous alkali and extracting with a water-immiscible organic solvent.
The thus-obtained compound [1] is purified, if required, by column chromatography using silica-gel, activated alumina or adsorption resin with 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 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 Table 1.
TABLE 1__________________________________________________________________________ ##STR14##Compound No. R.sub.1 R.sub.2 R.sub.3 A R__________________________________________________________________________018 Me Me Me CH.sub.2 CH.sub.2 ##STR15##019 Me Me Me CH.sub.2 CH.sub.2 ##STR16##020 Me Me Me CH.sub.2 CH.sub.2 ##STR17##021 Me Me Me CH.sub.2 CH.sub.2 ##STR18##022 Me Me Me CH.sub.2 CH.sub.2 1-imidazolyl023 Me Me Me CH.sub.2 CH.sub.2 ##STR19##024 Me Me Me CH.sub.2 CH.sub.2 ##STR20##025 Me Me Me CH.sub.2 CH.sub.2 ##STR21##026 Me Me Me CH.sub.2 CH.sub.2 OH027 Me Me Me CH.sub.2 CH.sub.2 SPh028 Me Me Me CH.sub.2 CH.sub.2 S(1-methyltetrazole-5-yl)061 Me Me Me CH.sub.2 CH.sub.2 OCOMe062 Me Me Me CH.sub.2 CH.sub.2 OCONHMe063 Me Me Me CH.sub.2 CH.sub.2 OCONHPh064 Me Me Me CH.sub.2 CH.sub.2 OCONHPhCl(p)101 Me Me Me CH.sub.2 CH.sub.2 ##STR22##109 Ph Me Me CH.sub.2 CH.sub.2 OH110 Ph Me Me CH.sub.2 CH.sub.2 ##STR23##111 Ph Me Me CH.sub.2 CH.sub.2 ##STR24##112 CH.sub.2 Ph Me Me CH.sub.2 CH.sub.2 OH113 CH.sub.2 Ph Me Me CH.sub.2 CH.sub.2 ##STR25##114 CH.sub.2 Ph Me Me CH.sub.2 CH.sub.2 ##STR26##115 CH.sub.2 Ph Me Me CH.sub.2 CH.sub.2 ##STR27##116 CH.sub.2 Ph Me Me CH.sub.2 CH.sub.2 ##STR28##117 Pro (CH.sub.2).sub.4 CH.sub.2 CH.sub.2 ##STR29##118 Pro (CH.sub.2).sub.4 CH.sub.2 CH.sub.2 ##STR30##119 Pro (CH.sub.2).sub.4 CH.sub.2 CH.sub.2 ##STR31##120 Pro (CH.sub.2).sub.4 CH.sub.2 CH.sub.2 ##STR32##121 Pro Me Me CH.sub.2 CH.sub.2 ##STR33##122 Pro Me Me CH.sub.2 CH.sub.2 ##STR34##123 iso-Bu Me Me CH.sub.2 CH.sub.2 ##STR35##124 iso-Bu Me Me CH.sub.2 CH.sub.2 ##STR36##125 iso-Bu Me Me CH.sub.2 CH.sub.2 ##STR37##126 iso-Bu Me Me CH.sub.2 CH.sub.2 ##STR38##127 iso-Bu (CH.sub.2).sub.4 CH.sub.2 CH.sub.2 ##STR39##128 iso-Bu (CH.sub.2).sub.4 CH.sub.2 CH.sub.2 ##STR40##129 iso-Bu (CH.sub.2 ).sub.4 CH.sub.2 CH.sub.2 ##STR41##130 Pro Et Et CH.sub.2 CH.sub.2 ##STR42##131 Pro Et Et CH.sub.2 CH.sub.2 ##STR43##132 Pro Et Et CH.sub.2 CH.sub.2 ##STR44##133 Pro Et Et CH.sub.2 CH.sub.2 ##STR45##134 Pro Et Et CH.sub.2 CH.sub.2 ##STR46##141 Bu (CH.sub.2).sub.4 CH.sub.2 CH.sub.2 ##STR47##142 Bu (CH.sub.2).sub.4 CH.sub.2 CH.sub.2 ##STR48##143 Bu (CH.sub.2).sub.4 CH.sub.2 CH.sub.2 ##STR49##144 Bu (CH.sub.2).sub.4 CH.sub.2 CH.sub.2 ##STR50##145 Bu (CH.sub.2).sub.4 CH.sub.2 CH.sub.2 ##STR51##146 Bu (CH.sub.2).sub.4 CH.sub.2 CH.sub.2 ##STR52##147 CH.sub.2 Ph Me Me CH.sub.2 CH.sub.2 OCOMe148 iso-Pro Me Me CH.sub.2 CH.sub.2 ##STR53##149 iso-Pro Me Me CH.sub.2 CH.sub.2 ##STR54##150 iso-Pro Me Me CH.sub.2 CH.sub.2 ##STR55##151 iso-Pro Me Me CH.sub.2 CH.sub.2 ##STR56##152 sec-Bu Me Me CH.sub.2 CH.sub.2 ##STR57##153 sec-Bu Me Me CH.sub.2 CH.sub.2 ##STR58##154 sec-Bu Me Me CH.sub.2 CH.sub.2 ##STR59##155 sec-Bu Me Me CH.sub.2 CH.sub.2 ##STR60##156 Bu Me Me CH.sub.2 CH.sub.2 ##STR61##157 Bu Me Me CH.sub.2 CH.sub.2 ##STR62##158 Bu Me Me CH.sub.2 CH.sub.2 ##STR63##159 iso-Pro Et Et CH.sub.2 CH.sub.2 ##STR64##160 iso-Pro Et Et CH.sub.2 CH.sub.2 ##STR65##161 iso-Pro Et Et CH.sub.2 CH.sub.2 ##STR66##162 iso-Pro Et Et CH.sub.2 CH.sub.2 ##STR67##163 iso-Pro Et Et CH.sub.2 CH.sub.2 ##STR68##164 iso-Pro Et Et CH.sub.2 CH.sub.2 ##STR69##165 iso-Pro Et Et CH.sub.2 CH.sub.2 ##STR70##166 iso-Bu Et Et CH.sub.2 CH.sub.2 ##STR71##167 iso-Bu Et Et CH.sub.2 CH.sub.2 ##STR72##168 iso-Bu Et Et CH.sub.2 CH.sub.2 ##STR73##170 iso-Bu Et Et CH.sub.2 CH.sub.2 ##STR74##171 sec-Bu Et Et CH.sub.2 CH.sub.2 ##STR75##172 sec-Bu Et Et CH.sub.2 CH.sub.2 ##STR76##173 sec-Bu Et Et CH.sub.2 CH.sub.2 ##STR77##174 sec-Bu Et Et CH.sub.2 CH.sub.2 ##STR78##175 sec-Bu Et Et CH.sub.2 CH.sub.2 ##STR79##176 sec-Bu Et Et CH.sub.2 CH.sub.2 ##STR80##177 sec-Bu Et Et CH.sub.2 CH.sub.2 ##STR81##178 Et Et CH.sub.2 CH.sub.2 ##STR82##179 Bu Et Et CH.sub.2 CH.sub.2 ##STR83##180 Bu Et Et CH.sub.2 CH.sub.2 ##STR84##181 Bu Et Et CH.sub.2 CH.sub.2 ##STR85##182 Bu Et Et CH.sub.2 CH.sub.2 ##STR86##183 Bu Et Et CH.sub.2 CH.sub.2 ##STR87##185 Bu Et Et CH.sub.2 CH.sub.2 ##STR88##187 Et Et Et CH.sub.2 CH.sub.2 ##STR89##188 Et Et Et CH.sub.2 CH.sub.2 ##STR90##189 Et Et Et CH.sub.2 CH.sub.2 ##STR91##190 Et Me Me CH.sub.2 CH.sub.2 ##STR92##191 Et Me Me CH.sub.2 CH.sub.2 ##STR93##192 Et Me Me CH.sub.2 CH.sub.2 ##STR94##193 Et Me Me CH.sub.2 CH.sub.2 ##STR95##250 (CH.sub.2).sub.4 CH.sub.3 (CH.sub.2).sub.4 CH.sub.2 CH.sub.2 ##STR96##251 (CH.sub.2).sub.4 CH.sub.3 (CH.sub.2).sub.4 CH.sub.2 CH.sub.2 ##STR97##252 (CH.sub.2).sub.4 CH.sub.3 (CH.sub.2).sub.4 CH.sub.2 CH.sub.2 ##STR98##253 (CH.sub.2).sub.4 CH.sub.3 (CH.sub.2).sub.4 CH.sub.2 CH.sub.2 ##STR99##254 (CH.sub.2).sub.4 CH.sub.3 (CH.sub.2).sub.4 CH.sub.2 CH.sub.2 ##STR100##255 (CH.sub.2).sub.5 CH.sub.3 (CH.sub.2).sub.4 CH.sub.2 CH.sub.2 ##STR101##256 (CH.sub.2).sub.5 CH.sub.3 (CH.sub.2).sub.4 CH.sub.2 CH.sub.2 ##STR102##257 (CH.sub.2).sub.5 CH.sub.3 (CH.sub.2).sub.4 CH.sub.2 CH.sub.2 ##STR103##258 (CH.sub.2).sub.5 CH.sub.3 (CH.sub.2).sub.4 CH.sub.2 CH.sub.2 ##STR104##259 (CH.sub.2).sub.6 CH.sub.3 (CH.sub.2).sub.4 CH.sub.2 CH.sub.2 ##STR105##260 (CH.sub.2).sub.6 CH.sub.3 (CH.sub.2).sub.4 CH.sub.2 CH.sub.2 ##STR106##261 (CH.sub.2).sub.6 CH.sub.3 (CH.sub.2).sub.4 CH.sub.2 CH.sub.2 ##STR107##262 (CH.sub.2).sub.6 CH.sub.3 (CH.sub.2 ).sub.4 CH.sub.2 CH.sub.2 ##STR108##263 (CH.sub.2).sub.6 CH.sub.3 (CH.sub.2).sub.4 CH.sub.2 CH.sub.2 ##STR109##264 (CH.sub.2).sub.6 CH.sub.3 (CH.sub.2).sub.4 CH.sub.2 CH.sub.2 ##STR110##265 (CH.sub.2).sub.7 CH.sub.3 (CH.sub.2).sub.4 CH.sub.2 CH.sub.2 ##STR111##266 (CH.sub.2).sub.7 CH.sub.3 (CH.sub.2).sub.4 CH.sub.2 CH.sub.2 ##STR112##267 (CH.sub.2).sub.7 CH.sub.3 (CH.sub.2).sub.4 CH.sub.2 CH.sub.2 ##STR113##268 (CH.sub.2).sub.7 CH.sub.3 (CH.sub.2).sub.4 CH.sub.2 CH.sub.2 ##STR114##269 (CH.sub.2).sub.7 CH.sub.3 (CH.sub.2).sub.4 CH.sub.2 CH.sub.2 ##STR115##270 (CH.sub.2).sub.7 CH.sub.3 (CH.sub.2).sub.4 CH.sub.2 CH.sub.2 ##STR116##271 (CH.sub.2).sub.8 CH.sub.3 (CH.sub.2).sub.4 CH.sub.2 CH.sub.2 ##STR117##272 (CH.sub.2).sub.8 CH.sub.3 (CH.sub.2).sub.4 CH.sub.2 CH.sub.2 ##STR118##273 (CH.sub.2).sub.8 CH.sub.3 (CH.sub.2).sub.4 CH.sub.2 CH.sub.2 ##STR119##274 (CH.sub.2).sub.8 CH.sub.3 (CH.sub.2).sub.4 CH.sub.2 CH.sub.2 ##STR120##275 (CH.sub.2).sub.8 CH.sub.3 (CH.sub.2).sub.4 CH.sub.2 CH.sub.2 ##STR121##276 (CH.sub.2).sub.11 CH.sub.3 (CH.sub.2).sub.4 CH.sub.2 CH.sub.2 ##STR122##277 (CH.sub.2).sub.11 CH.sub.3 (CH.sub.2).sub.4 CH.sub.2 CH.sub.2 ##STR123##278 (CH.sub.2).sub.11 CH.sub.3 (CH.sub.2).sub.4 CH.sub.2 CH.sub.2 ##STR124##279 (CH.sub.2).sub.11 CH.sub.3 (CH.sub.2).sub.4 CH.sub.2 CH.sub.2 ##STR125##280 (CH.sub.2).sub.13 CH.sub.3 (CH.sub.2).sub.4 CH.sub.2 CH.sub.2 ##STR126##281 (CH.sub.2).sub.13 CH.sub.3 (CH.sub.2).sub.4 CH.sub.2 CH.sub.2 ##STR127##282 (CH.sub.2).sub.13 CH.sub.3 (CH.sub.2).sub.4 CH.sub.2 CH.sub.2 ##STR128##283 (CH.sub.2).sub.15 CH.sub.3 (CH.sub.2).sub.4 CH.sub.2 CH.sub.2 ##STR129##284 (CH.sub.2).sub.15 CH.sub.3 (CH.sub.2).sub.4 CH.sub.2 CH.sub.2 ##STR130##285 (CH.sub.2).sub.15 CH.sub.3 (CH.sub.2).sub.4 CH.sub.2 CH.sub.2 ##STR131##286 (CH.sub.2).sub.15 CH.sub.3 (CH.sub.2).sub.4 CH.sub.2 CH.sub.2 ##STR132##287 Et Me Me CH.sub.2 CH.sub.2 ##STR133##288 Et Me Me CH.sub.2 CH.sub.2 ##STR134##289 Et Me Me CH.sub.2 CH.sub.2 ##STR135##290 Et Me Me CH.sub.2 CH.sub.2 ##STR136##291 CH.sub.2 Ph Et Et CH.sub.2 CH.sub.2 ##STR137##292 CH.sub.2 Ph Et Et CH.sub.2 CH.sub.2 ##STR138##293 CH.sub.2 Ph Et Et CH.sub.2 CH.sub.2 ##STR139##294 CH.sub.2 Ph Et Et CH.sub.2 CH.sub.2 ##STR140##295 CH.sub.2 Ph Et Et CH.sub.2 CH.sub.2 ##STR141##296 CH.sub.2 Ph Et Et CH.sub.2 CH.sub.2 ##STR142##297 CH.sub.2 Ph Et Et CH.sub.2 CH.sub.2 ##STR143##305 (CH.sub.2).sub.5 CH.sub.3 (CH.sub.2).sub.4 CH.sub.2 CH.sub.2 ##STR144##306 (CH.sub.2).sub.5 CH.sub.3 (CH.sub.2).sub.4 CH.sub.2 CH.sub.2 ##STR145##307 (CH.sub.2).sub.5 CH.sub.3 (CH.sub.2).sub.4 CH.sub.2 CH.sub.2 ##STR146##308 (CH.sub.2).sub.5 CH.sub.3 (CH.sub.2).sub.4 CH.sub.2 CH.sub.2 ##STR147##309 (CH.sub.2).sub.5 CH.sub.3 (CH.sub.2).sub.4 CH.sub.2 CH.sub.2 ##STR148##310 (CH.sub.2).sub.5 CH.sub.3 (CH.sub.2).sub.4 CH.sub.2 CH.sub.2 ##STR149##311 (CH.sub.2).sub.5 CH.sub.3 (CH.sub.2).sub.4 CH.sub.2 CH.sub.2 ##STR150##312 (CH.sub.2).sub.5 CH.sub.3 (CH.sub.2).sub.4 CH.sub.2 CH.sub.2 ##STR151##313 (CH.sub.2).sub.5 CH.sub.3 (CH.sub.2).sub.4 CH.sub.2 CH.sub.2 ##STR152##314 (CH.sub.2).sub.6 CH.sub.3 (CH.sub.2).sub.4 CH.sub.2 CH.sub.2 ##STR153##315 (CH.sub.2).sub.6 CH.sub.3 (CH.sub.2).sub.4 CH.sub.2 CH.sub.2 ##STR154##316 (CH.sub.2).sub.6 CH.sub.3 (CH.sub.2).sub.4 CH.sub.2 CH.sub.2 ##STR155##317 (CH.sub.2).sub.6 CH.sub.3 (CH.sub.2).sub.4 CH.sub.2 CH.sub.2 ##STR156##318 (CH.sub.2).sub.6 CH.sub.3 (CH.sub.2).sub.4 CH.sub.2 CH.sub.2 ##STR157##319 (CH.sub.2).sub.6 CH.sub.3 (CH.sub.2).sub.4 CH.sub.2 CH.sub.2 ##STR158##320 (CH.sub.2).sub.6 CH.sub.3 (CH.sub.2).sub.4 CH.sub.2 CH.sub.2 ##STR159##321 (CH.sub.2).sub.7 CH.sub.3 (CH.sub.2).sub.4 CH.sub.2 CH.sub.2 ##STR160##322 (CH.sub.2).sub.7 CH.sub.3 (CH.sub.2).sub.4 CH.sub.2 CH.sub.2 ##STR161##323 (CH.sub.2).sub.7 CH.sub.3 (CH.sub.2).sub.4 CH.sub.2 CH.sub.2 ##STR162##324 (CH.sub.2).sub.7 CH.sub.3 (CH.sub.2).sub.4 CH.sub.2 CH.sub.2 ##STR163##325 (CH.sub.2).sub.7 CH.sub.3 (CH.sub.2).sub.4 CH.sub.2 CH.sub.2 ##STR164##326 (CH.sub.2).sub.7 CH.sub.3 (CH.sub.2).sub.4 CH.sub.2 CH.sub.2 ##STR165##327 (CH.sub.2).sub.7 CH.sub.3 (CH.sub.2).sub.4 CH.sub.2 CH.sub.2 ##STR166##328 (CH.sub.2).sub.8 CH.sub.3 (CH.sub.2).sub.4 CH.sub.2 CH.sub.2 ##STR167##329 (CH.sub.2).sub.8 CH.sub.3 (CH.sub.2).sub.4 CH.sub.2 CH.sub.2 ##STR168##330 (CH.sub.2).sub.8 CH.sub.3 (CH.sub.2).sub.4 CH.sub. 2 CH.sub.2 ##STR169##331 (CH.sub.2).sub.8 CH.sub.3 (CH.sub.2).sub.4 CH.sub.2 CH.sub.2 ##STR170##332 (CH.sub.2).sub.8 CH.sub.3 (CH.sub.2).sub.4 CH.sub.2 CH.sub.2 ##STR171##334 (CH.sub.2).sub.9 CH.sub.3 (CH.sub.2).sub.4 CH.sub.2 CH.sub.2 ##STR172##335 (CH.sub.2).sub.9 CH.sub.3 (CH.sub.2).sub.4 CH.sub.2 CH.sub.2 ##STR173##336 (CH.sub.2).sub.9 CH.sub.3 (CH.sub.2).sub.4 CH.sub.2 CH.sub.2 ##STR174##337 (CH.sub.2).sub.9 CH.sub.3 (CH.sub.2).sub.4 CH.sub.2 CH.sub.2 ##STR175##338 (CH.sub.2).sub.9 CH.sub.3 (CH.sub.2).sub.4 CH.sub.2 CH.sub.2 ##STR176##339 (CH.sub.2).sub.9 CH.sub.3 (CH.sub.2).sub.4 CH.sub.2 CH.sub.2 ##STR177##340 (CH.sub.2).sub.9 CH.sub.3 (CH.sub.2).sub.4 CH.sub.2 CH.sub.2 ##STR178##374 CH.sub.2 Ph Et Et CH.sub.2 CH.sub.2 ##STR179##375 CH.sub.2 Ph Et Et CH.sub.2 CH.sub.2 ##STR180##378 CH.sub.2 Ph Et Et CH.sub.2 CH.sub.2 ##STR181##380 CH.sub.2 Ph Et Et CH.sub.2 CH.sub.2 ##STR182##384 CH.sub.2 PhCl(p) Et Et CH.sub.2 CH.sub.2 ##STR183##385 CH.sub.2 PhCl(p) Et Et CH.sub.2 CH.sub.2 ##STR184##386 CH.sub.2 PhCl(p) Et Et CH.sub.2 CH.sub.2 ##STR185##387 CH.sub.2 PhCl(p) Et Et CH.sub.2 CH.sub.2 ##STR186##454 Et Me Me CH.sub.2 CH.sub.2 ##STR187##455 Et Me Me CH.sub.2 CH.sub.2 ##STR188##456 Et Me Me CH.sub.2 CH.sub.2 ##STR189##457 Et Me Me CH.sub.2 CH.sub.2 ##STR190##458 Et Me Me CH.sub.2 CH.sub.2 ##STR191##459 Et Me Me CH.sub.2 CH.sub.2 ##STR192##460 Et Me Me CH.sub.2 CH.sub.2 ##STR193##461 Et Me Me CH.sub.2 CH.sub.2 ##STR194##462 Et Me Me CH.sub.2 CH.sub.2 ##STR195##463 Et Me Me CH.sub.2 CH.sub.2 ##STR196##464 Et Me Me CH.sub.2 CH.sub.2 ##STR197##465 Et Me Me CH.sub.2 CH.sub.2 ##STR198##467 CH.sub.2 PhCl(p) Et Et CH.sub.2 CH.sub.2 ##STR199##470 CH.sub.2 Ph (CH.sub.2).sub.4 CH.sub.2 CH.sub.2 ##STR200##471 CH.sub.2 Ph (CH.sub.2).sub.4 CH.sub.2 CH.sub.2 ##STR201##472 CH.sub.2 Ph (CH.sub.2).sub.4 CH.sub.2 CH.sub.2 ##STR202##473 CH.sub.2 Ph (CH.sub.2).sub.4 CH.sub.2 CH.sub.2 ##STR203##474 CH.sub.2 Ph (CH.sub.2).sub.4 CH.sub.2 CH.sub.2 ##STR204##475 CH.sub.2 Ph (CH.sub.2).sub.4 CH.sub.2 CH.sub.2 ##STR205##476 CH.sub.2 CH.sub.2 Ph (CH.sub.2).sub.4 CH.sub.2 CH.sub.2 ##STR206##477 CH.sub.2 CH.sub.2 Ph (CH.sub.2).sub.4 CH.sub.2 CH.sub.2 ##STR207##478 CH.sub.2 CH.sub.2 Ph (CH.sub.2).sub.4 CH.sub.2 CH.sub.2 ##STR208##479 CH.sub.2 CH.sub.2 Ph (CH.sub.2).sub.4 CH.sub.2 CH.sub.2 ##STR209##480 CH.sub.2 CH.sub.2 Ph (CH.sub.2).sub.4 CH.sub.2 CH.sub.2 ##STR210##481 Et (CH.sub.2).sub.4 CH.sub.2 CH.sub.2 ##STR211##482 Et (CH.sub.2).sub.4 CH.sub.2 CH.sub.2 ##STR212##483 Et (CH.sub.2).sub.4 CH.sub.2 CH.sub.2 ##STR213##484 Et (CH.sub.2).sub.4 CH.sub.2 CH.sub.2 ##STR214##485 Et (CH.sub.2).sub.4 CH.sub.2 CH.sub.2 ##STR215##486 Et (CH.sub.2).sub.4 CH.sub.2 CH.sub.2 ##STR216##487 (CH.sub.2).sub.13 CH.sub.3 (CH.sub.2).sub.4 CH.sub.2 CH.sub.2 ##STR217##488 (CH.sub.2).sub.13 CH.sub.3 (CH.sub.2).sub.4 CH.sub.2 CH.sub.2 ##STR218##489 (CH.sub.2).sub.13 CH.sub.3 (CH.sub.2).sub.4 CH.sub.2 CH.sub.2 ##STR219##490 (CH.sub.2).sub.13 CH.sub.3 (CH.sub.2).sub.4 CH.sub.2 CH.sub.2 ##STR220##611 Me Me Me CH.sub.2 CH.sub.2 ##STR221##612 Ph Me Me CH.sub.2 CH.sub.2 Cl613 CH.sub.2 Ph Me Me CH.sub.2 CH.sub.2 Cl614 Pro (CH.sub.2).sub.4 CH.sub.2 CH.sub.2 OH615 Pro (CH.sub.2).sub.4 CH.sub.2 CH.sub.2 SPh616 Pro Me Me CH.sub.2 CH.sub.2 OH617 iso-Bu Me Me CH.sub.2 CH.sub.2 OH618 iso-Bu (CH.sub.2).sub.4 CH.sub.2 CH.sub.2 OH619 iso-Bu Me Me CH.sub.2 CH.sub.2 ##STR222##620 Pro Et Et CH.sub.2 CH.sub.2 OH621 Bu (CH.sub.2).sub.4 CH.sub.2 CH.sub.2 OH622 iso-Pro Me Me CH.sub.2 CH.sub.2 OH623 sec-Bu Me Me CH.sub.2 CH.sub.2 OH624 Bu Me Me CH.sub.2 CH.sub.2 OH625 iso-Pro Et Et CH.sub.2 CH.sub.2 OH626 iso-Bu Et Et CH.sub.2 CH.sub.2 OH627 sec-Bu Et Et CH.sub.2 CH.sub.2 OH628 Bu Et Et CH.sub.2 CH.sub.2 OH629 Et Et Et CH.sub.2 CH.sub.2 OH630 Et Me Me CH.sub.2 CH.sub.2 OH631 (CH.sub.2).sub.4 CH.sub.3 (CH.sub.2).sub.4 CH.sub.2 CH.sub.2 OH632 (CH.sub.2).sub.5 CH.sub.3 (CH.sub.2).sub.4 CH.sub.2 CH.sub.2 OH633 (CH.sub.2).sub.6 CH.sub.3 (CH.sub.2).sub.4 CH.sub.2 CH.sub.2 OH634 (CH.sub.2).sub.7 CH.sub.3 (CH.sub.2).sub.4 CH.sub.2 CH.sub.2 OH635 (CH.sub.2).sub.8 CH.sub.3 (CH.sub.2).sub.4 CH.sub.2 CH.sub.2 OH636 (CH.sub.2).sub.9 CH.sub.3 (CH.sub.2).sub.4 CH.sub.2 CH.sub.2 OH637 (CH.sub.2).sub.11 CH.sub.3 (CH.sub.2).sub.4 CH.sub.2 CH.sub.2 OH638 (CH.sub.2).sub.13 CH.sub.3 (CH.sub.2).sub.4 CH.sub.2 CH.sub.2 OH639 (CH.sub.2).sub.15 CH.sub.3 (CH.sub.2).sub.4 CH.sub.2 CH.sub.2 OH640 CH.sub.2 Ph Et Et CH.sub.2 CH.sub.2 OH641 CH.sub.2 PhCl(p) Et Et CH.sub.2 CH.sub.2 OH642 Me Me Me CH.sub.2 CH.sub.2 ##STR223##643 CH.sub.2 Ph (CH.sub.2).sub.4 CH.sub.2 CH.sub.2 OH644 CH.sub.2 Ph (CH.sub.2).sub.4 CH.sub.2 CH.sub.2 Cl645 CH.sub.2 CH.sub.2 Ph (CH.sub.2).sub.4 CH.sub.2 CH.sub.2 OH646 Et (CH.sub.2).sub.4 CH.sub.2 CH.sub.2 OH647 CH.sub.2 PhCl(p) Et Et CH.sub.2 CH.sub.2 Cl__________________________________________________________________________ Me; methyl Et; ethyl Pro; propyl iso-Pro; isopropyl Bu; butyl iso-Bu; isobutyl sec-Bu; secbutyl Ph; benzene ring ##STR224## ##STR225## ##STR226## ##STR227## A letter or number in ( ) indicates the position of the preceding substituent.
The pharmacological acitvity 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 mins. A platelet activation factor (PAF, final concentration 10-50 ng/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 aggrigometer. The results of assays for PAF-induced aggregation are shown in Table 2, and those for collagen-induced aggregation are shown in Table 3, which tables show the strong platelet aggregation inhibitory activity of the compounds [1] of the present invention.
TABLE 2______________________________________Platelet Aggregation Inhibitory Action onPAF-Induced AggregationCompound Concentration InhibitionNo. .mu. M %______________________________________114 500 63115 " 88116 " 76120 " 83126 " 54128 " 83129 " 79132 " 72133 " 63134 " 57142 " 82143 " 87145 " 52146 " 87154 " 54158 " 64160 " 97161 " 93162 " 93163 " 62165 " 92166 " 87168 " 76170 " 80172 " 57173 " 61174 " 96175 " 94176 " 81177 " 79178 " 94179 " 93180 " 90183 " 85185 " 61188 " 86189 " 69191 " 62253 100 93263 " 70306 " 60308 " 40310 " 46313 " 48316 " 49321 " 43323 " 43326 " 51332 " 46386 " 71387 " 41______________________________________
TABLE 3______________________________________Platelet Aggregation Inhibitory Action onCollagen-Induced AggregationCompound Concentration InhibitionNo. .mu. M %______________________________________114 100 50115 " 50251 " 78252 " 42253 " 52255 " 48263 " 73265 " 45287 " 50288 " 72289 " 58292 " 50384 " 76386 " 71467 " 80471 " 81473 " 64474 " 81475 " 81477 " 72______________________________________
2. Vasodilation activity:
A dog, pretreated with morphine (81.5 mg/kg, sc) is anesthetized with urethane (8450 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 with a valve at 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 papaverine is administered intra-arterially. The results are shown in Table 4, where it will be seen that the compounds [1] of the present invention have strong vasodilation activity.
TABLE 4______________________________________Vasodilation Activity VasodilationCompound No. activity %______________________________________023 118024 182025 112114 174115 210116 147119 132120 223122 161124 278125 220126 310128 155129 201131 158132 231133 251134 143142 151143 119144 120146 125149 122150 229151 121153 197157 162158 139160 117161 214162 212165 222166 153168 205170 178171 122174 179175 151176 159177 122178 111179 139180 136181 125183 107185 115188 188189 133191 165193 226254 232287 170288 232297 229______________________________________
3. Antitoxidant activity:
Antitoxidant 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 supernatant solution. The supernatant solution is diluted five-fold 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 mins., 35% perchloric acid (0.2 ml) is added, and the mixture is then 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), whereafter it is heated at 100.degree. C. for 30 mins. and ice-cooled, so as to measure its absorbency at 532 nm. The amount of lipoperoxide thus-generated is expressed as an amount of malondialdehyde. The results are shown in Table 5, where it will be seen that the compounds [1] of the present invention inhibit lipoperoxide generation.
TABLE 5______________________________________Antioxidant Activity Compound Inhibition No. %______________________________________ 115 44 119 41 129 53 132 53 133 51 134 49 142 48 143 53 150 45 154 51 158 44 160 41 161 76 162 47 165 70 168 59 175 49 176 88 177 73 178 67 180 69 183 41 185 63 256 66 258 87 260 62 264 79 267 68 268 77 269 70 270 93 272 83 273 77 274 77 275 80 276 67 277 70 278 87 279 73 280 67 281 77 282 87 283 53 295 55 305 61 306 54 307 50 308 57 309 71 310 79 311 89 312 93 313 89 314 75 315 82 316 86 317 68 318 82 319 89 320 86 321 75 322 79 323 75 324 64 325 92 326 88 327 92 328 72 329 88 330 92 331 88 332 80 334 56 335 80 336 96 337 88 338 80 339 72 340 92 378 52 385 67 386 50 387 77 467 61 472 53 473 58 478 59 479 53 487 72 488 84 489 78 490 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.

EXAMPLES
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 (Merck)
Developer: chloroform-methanol (20:1)
Physical properties of the compounds [1] obtained in the following examples are shown in Table 27.
Example 1
1-(2-hydroxyethyl)-3,5,6-trimethyl-2-oxo-1,2-dihydropyrazine (compound 026)
2-Hydroxy-3,5,6-trimethylpyrazine (13.8 g, 0.1M) and 5N NaOH (100 ml, 0.5M) were added to t-butanol (200 ml). Ethylene chlorohydrin (40.3 g, 0.5M) was added thereto and the mixture was stirred at 60.degree. C. for 2 hours. Water was added to the reaction mixture, which was then extracted 10 times with chloroform (100 ml), and the extract 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) and eluted with chloroform-methanol (300:1) to obtain the product (14.4 g, yield: 79.1%).
Dihydrochloride: m.p.: 140.degree.-144.degree. C.
Examples 2-9
1-(2-substituted ethyl)-3,5,6-trimethyl-2-oxo-1,2-dihydropyrazine
Thionylchloride (0.86 ml, 12 mM) in chloroform (0.5 ml) was added dropwise under ice-cooling to the compound 026 (1.82 g, 10 mM) suspended in chloroform (5 ml) and stirred at room temperature for 3 hours to chlorinate. The reaction mixture was poured into dilute aqueous Na.sub.2 CO.sub.3, extracted three times with chloroform, and the extract dried with anhydrous sodium sulfate and concentrated in vacuo.
The obtained chlorinated compound was dissolved in benzene (60 ml), base (20 mM) and triethylamine (2.8 ml, 20 mM) were added thereto, and the mixture was refluxed. The reaction mixture was washed with dilute aqueous Na.sub.2 CO.sub.3 and the aqueous layer was extracted two times with benzene. The combined benzene layer, which was dried with anhydrous sodium sulfate, was concentrated in vacuo. The residue was chromatographed on a silica-gel (80 g) column residue using an elution solvent of chloroform-methanol to obtain the compounds in Table 6.
Table 6 shows the identify of the base, the reflux time and the ratio of chloroform-methanol mixture used in each of the above examples.
Examples 10-11
1-(2-substituted thioethyl)-3,5,6-trimethyl-2-oxo-1,2-dihydropyrazine
Compound 026 (0.91 g, 5 mM) was chlorinated with thionylchloride according to the same method used in Examples 2-9. The thus-obtained chlorinated compound was dissolved in dimethylformamide (DMF, 10 ml), sodium mercaptan (5 mM) was added, and the mixture was stirred at room temperature for 2 days. DMF was driven off in vacuo. Dilute aqueous K.sub.2 CO.sub.3 solution was added to the residue, whereafter it was extracted with chloroform, dried by adding anhydrous sodium sulfate and concentrated in vacuo. The residue was chromatographed on a silica-gel (C-200, 50 g) column eluted with benzene-ethyl acetate (5:1) to obtain the product in Table 7.
Table 7 shows the particular mercaptans used in the above examples.
Example 12
1,4-bis[2-(3,5,6-trimethyl-2-oxo-1,2-dihydropyrazine-1-yl)ethyl]piperazine (compound 101)
Chloroform (3 ml) in solution with thionylchloride (4.3 ml, 60 mM) was added dropwise under ice-cooling to compound 026 (9.10 g, 50 mM) suspended in chloroform (15 ml). After stirring at room temperature for 3 hours, the reaction mixture was poured into dilute aqueous K.sub.2 CO.sub.3 and extracted with chloroform (200 ml). The chloroform layer was dried with anhydrous magnesium sulfate and concentrated in vacuo. The residue was dissolved in benzene (300 ml), piperazine (2.15 g) and triethylamine (0.8 ml, 50 mM) were added, and the mixture was refluxed for 3 hours. The reaction mixture was washed with dilute aqueous K.sub.2 CO.sub.3 and the aqueous layer was extracted with chloroform. The chloroform layer was dried with anhydrous magnesium sulfate and concentrated in vacuo. The residue was charged on a column of silica-gel (C-200, 180 g), and eluted with chloroform-methanol (100:1) to obtain compound 101 (7.60 g, yield: 73.2%).
Example 13
1-(2-piperazinoethyl)-3,5,6-trimethyl-1,2-dihydropyrazine (compound 642)
Piperazine (17.2 g, 0.2M) and triethylamine (28 ml, 0.2M) were used in the method of Example 12, the other conditions being preserved, to obtain compound 642 (5.52 g, yield: 44.2%) which displayed a lower Rf value relative to compound 101.
Example 14
1-(2-hydroxyethyl)-3-phenyl-5,6-dimethyl-2-oxo-1,2-dihydropyrazine (compound 109)
Ethylene chlorohydrin (20.2 g, 0.25M) was added to a solution of 2-hydroxy-3-phenyl-5,6-dimethyl-pyrazine (10.0 g, 50 mM) and 5N NaOH (50 ml) in t-butanol (150 ml), and stirred at 60.degree. C. for 2.5 hours. Water was added to the reaction mixture, the mixture extracted with chloroform, and the extract dried with anhydrous sodium sulfate and concentrated in vacuo. The residue was charged on a column of silica-gel (C-200, 130 g) packed with chloroform and eluated with chloroform-methaol (100:1) to obtain compound 109 (8.73 g, yield: 71.5%).
Example 15
1-(2-chloroethyl)-3-phenyl-5,6-dimethyl-2-oxo-1,2-dihydropyrazine (compound 612)
Thionylchloride (0.42 ml, 6.0 mM) was added dropwise under ice-cooling to compound 109 (1.22 g, 50 mM) dissolved in chloroform (10 ml), and stirred at room temperature for 3 hours. Chloroform was added to the reaction mixture, whereafter the mixture was washed with dilute aqueous K.sub.2 CO.sub.3 and the resultant aqueous layer extracted with further chloroform. The chloroform layer was combined, dried with anhydrous magnesium sulfate and concentrated in vacuo. The residue was charged on a column of silica-gel (C-200, 25 g), and eluted with chloroform to obtain compound 612 (0.59 g, yield: 42.7%).
Examples 16-17
1-(2-substituted ethyl)-3-phenyl-5,6-dimethyl-2-oxo-1,2-dihydropyrazine
Base (5 mM) and triethylamine (0.70 ml, 5 mM) were added to compound 612 (0.66 g, 2.5 mM) dissolved in benzene (15 ml), and refluxed. The reaction mixture was washed with dilute aqueous K.sub.2 CO.sub.3, and the resultant aqueous layer extracted with benzene. The benzene layer was combined, dried with anhydrous sodium sulfate and concentrated in vacuo. The residue was charged on a column of silica-gel (C-200, 65 g) and eluted with chloroform-methanol to obtain the compounds in Table 8.
Table 8 identifies the base, reflux time and the ratio of the chloroform-methanol mixture used in the above examples.
Example 18
1-(2-hydroxyethyl)-3-benzyl-5,6-dimethyl-2-oxo-1,2-dihydropyrazine (compound 112)
Ethylene chlorohydrin (4.03 g, 50 mM) was added to a solution of 2-hydroxy-3-benzyl-5,6-dimethyl-pyrazine (2.14 g, 10 mM) and 5N NaOH (10 ml) in t-butanol (30 ml), and stirred at 60.degree. C. for 2.5 hours. Water (100 ml) was added to the reaction mixture, and the mixture was extracted three times with chloroform, the extract dried with anhydrous magnesium sulfate and concentrated in vacuo. The residue was charged on a column of silica-gel (C-200, 25 g) and eluted with chloroform-methanol (100:1) to obtain compound 112 (2.22 g, yield: 86.0%).
Example 19
1-(2-chloroethyl)-3-benzyl-5,6-dimethyl-2-oxo-1,2-dihydropyrazine (compound 613)
Thionylchloride (0.42 ml, 6.0 mM) was added dropwise under ice-cooling to a compound 112 (1.29 g, 5 mM) dissolved in chloroform (6 ml), and stirred at room temperature for 5 hours. Chloroform (70 ml) was added to the reaction mixture, which mixture was then washed with dilute aqueous K.sub.2 CO.sub.3, the resulting aqueous layer being twice extracted with further chloroform. The chloroform layer was combined, dried with anhydrous magnesium sulfate and concentrated in vacuo. The residue was charged on a column of silica-gel (C-200, 25 g), packed with chloroform, and eluted with chloroform to obtain compound 613 (1.00 g, yield: 87.5%).
Examples 20-23
1-(2-substituted ethyl)-3-benzyl-5,6-dimethyl-2-oxo 1,2-dihydropyrazine
Base (6.0 mM) and triethylamine (0.84 ml, 6.0 mM) were added to compound 613 (0.83 g, 3.0 mM) dissolved in benzene (15 ml), and refluxed. The reaction mixture was washed with dilute aqueous K.sub.2 CO.sub.3, and the aqueous layer extracted with further benzene. The benzene layer was combined, dried with anhydrous sodium sulfate and concentrated in vacuo. The residue was charged on a column of silica-gel (C-200, 65 g) packed with chloroform and eluted with chloroform-methanol to obtain the compounds of Table 9.
Table 9 identifies the base, reflux time and ratio of chloroform-methanol mixture used in the above examples.
Examples 24-28
1-(2-hydroxyethyl)-3-alkyl-5,6-dimethyl-2-oxo-1,2-dihydropyrazine
Aqueous 5N NaOH (10 ml, 50 mM), t-butanol (30 ml) and ethylene chlorohydrin (50 mM) were added to 2-hydroxy-3-alkyl-5,6-dimethyl-pyrazine (10 mM) and stirred at 60.degree. C. Water was added to the reaction mixture, which mixture was then extracted three times with chloroform, dried with anhydrous magnesium sulfate and concentrated in vacuo. The residue was charged on a column of silica-gel (C-200, 120 g) and eluted with chloroform-methanol to obtain the compounds (hydroxy ethyl form) of Table 10.
Table 10 identifies the specific 2-hydroxy-3-alkyl-5,6-dimethyl-pyrazine, its amount used, reaction time in hours, and ratio of mixture of chloroform-methanol used in each of the above examples.
Examples 29-46
1-(2-substituted ethyl)-3-alkyl-5,6-trimethyl-2-oxo 1,2-dihydropyrazine
Thionylchloride (0.34 ml) was added dropwise under ice-cooling to the hydroxy ethyl form (4 mM) of the compounds obtained in Examples 24-28, and the reaction mixture was dissolved in chloroform (5 ml) and stirred at room temperature for one hour. Chloroform was added to the reaction mixture, which mixture was washed with dilute aqueous K.sub.2 CO.sub.3, and the resultant aqueous layer extracted twice with further chloroform. The chloroform layer was combined, dried with anhydrous magnesium sulfate and concentrated in vacuo. Benzene (30 ml), triethylamine (1.12 ml) and base (8 mM) were added to the residue and the resultant mixture was refluxed. Chloroform (100-120 ml) was added to the reaction mixture and washed with dilute aqueous K.sub.2 CO.sub.3. The aqueous layer was extracted twice with chloroform. The chloroform layer was combined, dried with anhydrous magnesium sulfate and concentrated in vacuo. The residue was charged on a column of silica-gel (C-200, 60 g) and eluted with chloroform-methanol to obtain the compounds shown in Table 11.
Table 11 identifies the starting material (hydroxy ethyl form), base, reflux time and ratio of chloroform-methanol mixture used in the above examples.
Examples 47-49
1-(2-hydroxyethyl)-3-alkyl-5,6-dimethyl-2-oxo-1,2,5,6,7,8-hexahydroquinoxaline
Aqueous 5N NaOH (10 ml, 50 mM), t-butanol (30 ml) and ethylene chlorohydrin (50 mM) were added to 2-hydroxy-3-alkyl-5,6,7,8-tetrahydroquinoxaline (10 mM) and stirred at 60.degree. C. Water was added to the reaction mixture, which mixture was then extracted with chloroform, dried with anhydrous magnesium sulfate and concentrated in vacuo. The residue was charged on a column of silica-gel (C-200) and eluted with chloroform-methanol to obtain the compounds (hydroxy ethyl form) of Table 12.
Table 12 identifies the specific 2-hydroxy-3-alkyl-5,6,7,8-tetrahydroquinoxaline (group R.sub.1), its amount used, reaction time in hours, and ratio of the chloroform-methanol mixture used in the above examples.
Examples 50-62
1-(2-substituted ethyl)-3-alkyl-2-oxo-1,2,5,6,7,8-hexahydroquinoxaline
Thionylchloride (0.34 ml) was added dropwise under ice-cooling to the hydroxy ethyl form (4 mM) of the compounds obtained in Examples 47-49, dissolved in chloroform and stirred at room temperature for one hour. Chloroform was added to the reaction mixture, which mixture was then washed with dilute aqueous K.sub.2 CO.sub.3, and the resultant aqueous layer extracted with chloroform. The chloroform layer was combined, dried with anhydrous magnesium sulfate and concentrated in vacuo. Benzene (30 ml), triethylamine (1.12 ml, 8 mM) and base (8 mM) were added to the reaction mixture, followed by refluxing. Chloroform (100 ml) was added to the reaction mixture, which mixture was then washed with dilute aqueous K.sub.2 CO.sub.3, and the resultant aqueous layer extracted with chloroform. The chloroform layer was combined, dried with anhydrous magnesium sulfate and concentrated in vacuo. The residue was charged on a column of silica-gel (C-200, 70 g) and eluted with chloroform-methanol to obtain the compounds shown in Table 13.
Table 13 identifies the starting material (hydroxy ethyl form), base, reflux time and ratio of chloroform-methanol mixture used in the above examples.
Examples 63-68
1-(2-hydroxyethyl)-3-alkyl-5,6-diethyl-2-oxo-1,2-dihydropyrazine
Aqueous 5N NaOH (10 ml, 50 mM), t-butanol (30 ml) and ethylene chlorohydrin (50 mM) were added to 2-hydroxy-3-alkyl-5,6-diethyl-pyrazine (10 mM) and stirred at 60.degree. C. Water was added to the reaction mixture, which mixture was then extracted with chloroform, dried with anhydrous sodium sulfate and concentrated in vacuo.
The residue was charged on a silica-gel column (C-200) packed with chloroform, and eluted with chloroform-methanol to obtain the compounds in Table 14.
Table 14 identifies the specific 2-hydroxy-3-alkyl-5,6-diethyl-pyrazine (group R.sub.1), its amount used, reaction time in hours, amount of silica-gel and ratio of chloroform-methanol mixture used in each of the above examples.
Examples 69-101
1-(2-substituted ethyl)-3-alkyl-5,6-diethyl-2-oxo-1,2-dihydropyrazine
Thionylchloride (0.34 ml) was added dropwise under ice-cooling to the hydroxy ethyl form (4 mM) of the compounds obtained in Examples 63-68, dissolved in chloroform (5 ml) and stirred at room temperature for one hour. Chloroform was added to the reaction mixture, which mixture was then washed with dilute aqueous K.sub.2 CO.sub.3, and the resultant aqueous layer extracted twice with further chloroform. The chloroform layer was combined, dried with anhydrous magnesium sulfate and concentrated in vacuo. Benzene (30 ml), triethylamine (1.12 ml, 8 mM) and base (8 mM) were added to the residue, followed by refluxing. Chloroform (100 ml) was added to the reaction mixture, and the mixture was washed with dilute aqueous K.sub.2 CO.sub.3. The resultant aqueous layer was extracted with additional chloroform. The chloroform layer was combined, dried with anhydrous magnesium sulfate and concentrated in vacuo. The residue was charged on a column of silica-gel (C-200, 60 g) packed with chloroform, and eluted with chloroform-methanol to obtain the compounds shown in Table 15.
Table 15 identifies the starting material (hydroxy ethyl form), base, reflux time and ratio of chloroform-methanol mixture used in the above examples.
Example 102
1-(2-hydroxyethyl)-3-ethyl-5,6-dimethyl-2-oxo-1,2-dihydropyrazine (compound 630)
Ethylene chlorohydrin (32.21 g, 0.4M) was added to a solution of 2-hydroxy-3-ethyl-5,6-dimethyl-pyrazine (12.16 g, 80 mM) and 5N NaOH (80 ml) in t-butanol (240 ml), and stirred at 60.degree. C. for 3 hours. Dilute aqueous K.sub.2 CO.sub.3 was added to the reaction mixture, the mixture extracted with chloroform, and the resultant aqueous layer extracted twice with further chloroform. The combined chloroform layers were dried with anhydrous magnesium sulfate and concentrated in vacuo. The residue was charged on a column of silica-gel (C-200, 250 g) packed with chloroform and eluted with chloroform-methanol form-methanol (from 200:1 to 50:1) to obtain compound 630 (12.31 g, yield: 78.5%).
Examples 103-110
1-(2-substituted ethyl)-3-ethyl-5,6-dimethyl-2-oxo-1,2-dihydropyrazine
Thionylchloride (0.43 ml) was added dropwise under ice-cooling to compound (0.98 g, 5 mM) dissolved in chloroform (5 ml), and stirred at room temperature for one hour. Chloroform (50 ml) was added to the reaction mixture, the mixture then washed with dilute aqueous K.sub.2 CO.sub.3, and the resultant aqueous layer extracted twice with additional chloroform (50 ml). The chloroform layer was combined, dried with anhydrous magnesium sulfate and concentrated in vacuo. Benzene (30 ml), triethylamine (1.40 ml) and base (10 mM) were added to the residue and refluxed. Chloroform (100 ml) was added to the reaction mixture, which mixture was then washed with dilute aqueous K.sub.2 CO.sub.3. The resultant aqueous layer was extracted twice with chloroform (50 ml). The chloroform layer was combined, dried with anhydrous magnesium sulfate and concentrated in vacuo. The residue was charged on a column of silica-gel (C-200, 70 g) packed with chloroform, and eluted with chloroform-methanol to obtain the compounds shown in Table 16.
Table 16 identifies the base, reflux time and ratio of chloroform-methanol mixture used in the above examples.
Example 111
1-(2-hydroxyethyl)-3-benzyl-5,6-diethyl-2-oxo-1,2-dihydropyrazine (compound 640)
Ethylene chlorohydrin (20.15 g, 0.25M) was added to a solution of 2-hydroxy-3-benzyl-5,6-diethyl-pyrazine (12.10 g, 50 mM) and 5N NaOH (50 ml) in t-butanol (150 ml), and stirred at 60.degree. C. for 3 hours. The t-butanol was distilled off in vacuo, water was added thereto 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, 230 g) packed with chloroform and eluted with chloroform-methanol (100:1) to obtain compound 640 (12.31 g, yield: 58.7%).
Examples 112-122
1-(2-substituted ethyl)-3-benzyl-5,6-dimethyl-2-oxo-1,2-dihydropyrazine
Thionylchloride (0.34 ml) was added dropwise under ice-cooling to compound 640 (1.15 g, 4.0 mM) dissolved in chloroform (5 ml) and stirred at room temperature for one hour. Chloroform (100 ml) was added to the reaction mixture, which mixture was then washed with dilute aqueous K.sub.2 CO.sub.3, and the resultant aqueous layer extracted twice with additional chloroform (30 ml). The chloroform layer was combined, dried with anhydrous sodium sulfate and concentrated in vacuo. Triethylamine (1.12 ml, 8 mM) and base (8 mM) were addd to the residue dissolved in benzene (30 ml), followed by refluxing. The reaction mixture was washed with dilute aqueous K.sub.2 CO.sub.3. The resultant aqueous layer was extracted twice with benzene. The benzene layer was combined, dried with anhydrous sodium sulfate and concentrated in vacuo. The residue was charged on a column of silica-gel (C-200, 60 g) and eluted with chloroform-methanol to obtain the compounds shown in Table 17.
Table 17 identifies the base, reflux time and ratio of chloroform-methanol mixtures used in the above examples.
Example 123
1-(2-hydroxyethyl)-3-p-chlorobenzyl-5,6-dimethyl-2-oxo-1,2-dihydropyrazine (compound 641)
Ethylene chlorohydrin (16.11 g, 0.20M) was added to a solution of 2-hydroxy-3-p-chlorobenzyl-5,6-dimethylpyrazine (11.06 g, 40 mM) in aqueous 5N NaOH (40 ml) and t-butanol (120 ml), and stirred at 60.degree. C. for 3 hours. The t-butanol was distilled off in vacuo. Dilute aqueous K.sub.2 CO.sub.3 was added to the residue, the resulting mixture being extracted three times with chloroform, dried wit anhydrous sodium sulfate and concentrated in vacuo. The residue was charged on a column of silica-gel (C-200, 300 g) packed with chloroform and eluted with chloroform-methanol (100:1) to obtain compound 641 (9.73 g, yield: 75.9%).
Example 124
1-(2-chloroethyl)-3-p-chlorobenzyl-5,6-diethyl-2-oxo-1,2-dihydropyrazine (compound 647)
Thionylchloride (1.20 ml) was added dropwise to compound 641 (4.16 g, 13 mM) dissolved in chloroform (20 ml) under ice-cooling and stirred at room temperature for 1.5 hours. Dilute aqueous K.sub.2 CO.sub.3 was added to the reaction mixture, the resulting mixture being extracted with chloroform, dried with anhydrous sodium sulfate and concentrated in vacuo to obtain compound 647 (4.27 q, yield: 96.9%).
Examples 125-129
1-(2-substituted ethyl)3-p-chlorobenzyl-5,6-diethyl-2-oxo-1,2-dihydropyrazine
Base (6 mM) and triethylamine were added to chloroethyl compound 649 (1.023 g, 3 mM) dissolved in benzene (30 ml), and refluxed. The reaction mixture was poured into dilute aqueous K.sub.2 CO.sub.3, the resultant aqueous layer being washed and extracted with benzene. The benzene layer was combined, dried with anhydrous sodium sulfate and concentrated in vacuo. The residue was charge don a column of silica-gel (C-200, 65 g) packed with chloroform and eluted with chloroform-methanol to obtain the compounds of Table 18.
Table 18 identifies the base, reflux time and ratio of chloroform-methanol mixture used in the above examples.
Examples 130-138
1-(2-hydroxyethyl)-3-alkyl-2-oxo-1,2,5,6,7,8-hexahydroquinoxaline
Ethylene chlorohydrin (4.03 g, 50 mM) was added to a solution of 2-hydroxy-3-alkyl-5,6,7,8-tetrahydro quinoxaline (10 mM) in aqueous 5N NaOH (10 ml, 50 mM) and t-butanol (30 ml), and stirred at 60.degree. C. for 4 hours. Water was added to the reaction mixture, which mixture was then extracted with chloroform, dried with anhydrous sodium sulfate and concentrated in vacuo. The residue was charged on a column of silica-gel (C-200) packed with chloroform and eluted to obtain the compounds (hydroxy ethyl form) of Table 19.
The kind of 2-hydroxy-3-alkyl-5,6,7,8-tetrahydro quinoxaline (group R.sub.1), its amount used, amount of silica gel used in column chromatography and kind of elution solvent are illustrated in Table 19.
Examples 139-214
1-(2-substituted ethyl)-3-alkyl-2-oxo-1,2,3,5,6,7,8-hexahydroquinoxaline
Thionylchloride (1.3 equivalent) was added dropwise under ice-cooling to the hydroxyl ethyl form (3-5 mM) of the compounds obtained in Examples 130-138, dissolved in chloroform (3-5 ml) and stirred at room temperature for one hour. Dilute aqueous K.sub.2 CO.sub.3 was added to the reaction mixture, which mixture was then extracted three times with chloroform (50 ml), dried with anhydrous sodium sulfate, and concentrated in vacuo. Benzene (30 ml), triethylamine (2 eq.) and base (2 eq.) were added to the residue, followed by refluxing. The reaction mixture was poured into dilute aqueous K.sub.2 CO.sub.3, then extracted several times with benzene. The extract was dried with anhydrous sodium sulfate and concentrated in vacuo. The residue was charged on a column of silica-gel (C-200, 60 g) and eluted with chloroform-methanol (200:1) to obtain the compounds shown in Table 20.
The kind of starting material (hydroxy ethyl form), amount thereof used, base and reflux time are shown in Table 20.
Example 215
1-(2-piperazinyl ethyl)-3-ethyl-5,6-dimethyl-2-oxo-1,2-dihydropyrazine
Thionylchloride (6.6 ml) was added dropwise under ice-cooling to compound 630 (13.72 g, 70 mM) dissolved in chloroform (70 ml), and stirred at room temperature for one hour. Dilute aqueous K.sub.2 CO.sub.3 was added to the reaction mixture, which was then extracted with chloroform. The extract was dried with anhydrous magnesium sulfate and concentrated in vacuo. Triethylamine (19.6 ml, 0.14M) and anhydrous piperazine (64.4 g, 0.75M) were added to the residue dissolved in benzene (420 ml), and refluxed for 3 hours. The reaction mixture was washed with dilute aqueous K.sub.2 CO.sub.3. The resultant aqueous layers was extracted with benzene. The benzene layer was combined, dried with anhydrous magnesium sulfate and concentrated in vacuo. The residue was charged on a column of silica-gel (C-200, 375 g) packed with chloroform and eluted with chloroform-methanol (10:1) to obtain compound 454 (13.66 g, yield: 73.9%).
Examples 216-226
1-[2-(4'-arylpiperazinyl)ethyl]-3-ethyl-5,6-dimethyl-2-oxo-1,2-dihydropyrazine
(a) Acid chloride method:
Triethylamine (0.84 ml, 6 mM) was added to compound 454 (0.81 g, 3 mM) dissolved in chloroform (10 ml), and acid chloride (3 mM) was added thereto under ice-cooling. Dilute aqueous K.sub.2 CO.sub.3 was added to the reaction mixture, which mixture was then extracted three times which chloroform. The combined chloroform 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) packed with chloroform and eluted with chloroform-methanol to obtain the compounds shown in Table 21.
(b) Mixed anhydride method:
Triethylamine (0.70 ml) was added to the carboxylic acid (5 mM) dissolved in tetrahydrofuran (10 ml). After pivaloyl chloride (0.61 g, 5 mM) was added dropwise thereto at -5.degree. C. and stirred for 30 mins., a solution of compound 454 (1.06 g, 4 mM) in chloroform was added dropwise. Reaction was continued under gradually increasing temperature, up to room temperature. The reaction mixture was thereafter treated as in method (a) above, to obtain the products shown in Table 21.
Acylation method, acylating agent used, reaction time and ratio of chloroform-methanol mixture are shown in Table 21.
Example 227
1-(2-hydroxyethyl-3-benzyl-2-oxo-1,2,5,6,7,8-hexahydroquinoxaline (compound 643)
Ethylene chlorohydrin (16.10 g, 0.2M) was added to a solution of 2-hydroxy-3-benzyl-5,6,7,8-tetrahydro quinoxaline (9.60 g, 40 mM) in dilute aqueous 5N NaOH (40 ml) and t-butanol (120 ml), and stirred at 60.degree. C. for 3 hours. The t-butanol was distilled off in vacuo. The residue was extracted three times with chloroform, dried with anhydrous sodium sulfate and concentrated in vacuo. The residue was charged on a column of silica-gel (C-200, 220 g) packed with chloroform, and eluted with chloroform-methanol (200:1) to obtain compound 643 (10.90 g, yield: 83.8%).
Example 228
1-(2-chloroethyl)-3-benzyl-2-oxo-1,2,5,6,7,8-hexahydroquinoxaline (compound 644)
Thionylchloride (2.96 ml, 1.3 eq.) was added dropwise under ice-cooling to compound 643 (9.09 g, 32 mM) dissolved in chloroform (30 ml), and stirred at room temperature for 2 hours. Dilute aqueous K.sub.2 CO.sub.3 was added to the reaction mixture, which mixture was then extracted twice with chloroform, dried with anhydrous sodium sulfate and concentrated in vacuo. The residue was charged on a column of silica-gel (C-200, 100 g) packed with chloroform and eluted with chloroform to obtain a compound 644 (7.55 g, yield: 78.0%).
Examples 229-234
1-(2-substituted ethyl)-3-benzyl-2-oxo-1,2,5,6,7,8-hexahydroquinoxaline
Base (7 mM) and triethylamine (0.98 ml) were added to compound 644 (1.05 g, 3.5 mM) dissolved in benzene (30 ml), and refluxed. The reaction mixture was washed with dilute aqueous K.sub.2 CO.sub.3, and the resultant aqueous layer was extracted with benzene. The combined benzene layer was dried with anhydrous sodium sulfate and concentrated in vacuo. The residue was charged on a column of silica-gel (C200, 65 g) packed with chloroform and eluted with chloroform-methanol to obtain the compounds shown in Table 22.
The kind of base, reflux time and ratio of chloroform-methanol mixture are shown in Table 22.
Example 235
1-(2-hydroxyethyl)-3-(2-phenylethyl)-2-oxo-1,2,5,6,7,8-hexahydroquinoxaline (compound 645)
Ethylene chlorohydrin (9.0 g) was added to a solution of 2-hydroxy-3-(2-phenylethyl)-5,6,7,8-tetrahydro quinoxaline (5.59 g, 22 mM) in aqueous 5N NaOH and t-butanol (60 ml), and stirred at 60.degree. C. for 3 hours. The t-butanol was distilled off in vacuo, water was added to the residue, 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, 170 g) packed with chloroform, and eluted with chloroform-methanol (200:1) to obtain compound 645 (6.73 g, yield: 90.9%).
Example 236
1-(2-chloroethyl)-3-(2-phenylethyl)-2-oxo-1,2,5,6,7,8-hexahydroquinoxaline (compound 647)
Thionylchloride (2.05 ml) was added dropwise under ice-cooling to compound 645 (6.49 g, 22.1 mM) dissolved in chloroform (25 ml), and stirred at room temperature for 2 hours. Dilute aqueous K.sub.2 CO.sub.3 was added to the reaction mixture, which mixture was then extracted twice with chloroform. The extract was dried with anhydrous sodium sulfate and concentrated in vacuo to obtain compound 647, which was used without further purification in the following reactions.
Examples 237-241
1-(2-substituted ethyl)-3-(2-phenylethyl)-2-oxo-1,2,5,6,7,8-hexahydroquinoxaline
Base (7 mM) and triethylamine (0.98 ml) were added to compound 647 (1.11 g, 3.5 mM) dissolved in benzene (30 ml), and refluxed. The reaction mixture was washed with dilute aqueous K.sub.2 CO.sub.3, and the resultant aqueous layer was extracted with benzene. The combined benzene layer was dried with anhydrous sodium sulfate and concentrated in vacuo. The residue was charged on a column of silica-gel (C-200), 65 g) packed with chloroform and eluted with chloroform-methanol to obtain the compounds shown in Table 23.
The kind of base, reflux time and ratio of chloroform-methanol mixture are shown in Table 23.
Example 242
1-(2-hydroxyethyl)-3-ethyl-2-oxo-1,2,5,6,7,8-hexahydroquinoxaline (compound 646)
Ethylene chlorohydrin (20.2 g, 0.25M) was added to a solution of 2-hydroxy-3-ethyl-5,6,7,8-tetrahydro quinoxaline (8.90 g, 50 mM) in dilute aqueous 5N NaOH (50 ml) and t-butanol (150 ml), and stirred at 60.degree. C. for 3 hours. The t-butanol was distilled off in vacuo. Water was added to the residue, which residue was then extracted three times with chloroform, dried with anhydrous sodium sulfate and concentrated in vacuo. The residue was charged on a column of silica-gel (C-200, 170 g) packed with chloroform, and eluted with chloroform-methanol (100:1) to obtain compound 646 (9.30 g, yield: 83.8%).
Examples 243-248
1-(2-substituted ethyl)-3-ethyl-2-oxo-1,2,5,6,7,8-hexahydroquinoxaline
Thionylchloride (0.47 ml) was added dropwise under ice-cooling to compound 646 (1.11 g, 5 mM) dissolved in chloroform (4 ml), and stirred at room temperature for one hour. Dilute aqueous K.sub.2 CO.sub.3 was added to the reaction mixture, which mixture was then extracted with chloroform. The extract was dried with anhydrous sodium sulfate and concentrated in vacuo.
Benzene (30 ml), triethylamine (1.4 ml) and base (10 mM) were added to the residue, followed by refluxing. The reaction mixture was poured into dilute aqueous K.sub.2 CO.sub.3 and extracted with benzene. The extract was dried with anhydrous sodium sulfate and concentrated in vacuo. The residue was charged on a column of silica-gel (C-200, 65 g) packed with chloroform and eluted with chloroform-methanol to obtain the compounds shown in Table 24.
The kind of base, reflux time and ratio of chloroform-methanol mixture are shown in Table 24.
Example 249
1-(2-acetoxyethyl)-3,5,6-trimethyl-2-oxo-1,2-dihydropyrazine (compound 061)
Acetic anhydride (2 ml) was added under ice-cooling to compound 026 (0.91 g, 5 mM) dissolved in pyridine (10 ml), and stirred at room temperature for 1.5 hours. The reaction mixture was concentrated in vacuo and dilute aqueous K.sub.2 CO.sub.3 was added thereto, the resultant mixture being 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 (Florisil, 60 g) packed with benzene and eluted with benzene-ethyl acetate (5:1) to obtain compound 061 (0.58 g, yield: 51.8%).
Example 250
1-(2-phenylthioethyl)-3-propyl-2-oxo-1,2,5,6,7,8-hexahydroquinoxaline (compound 615)
Thionylchloride (0.47 ml) was added dropwise under ice-cooling to compound 614 (1.18 g, 5 mM, hydroxy ethyl form) as obtained in Example 47 dissolved in chloroform (5 ml), and stirred at room temperature for one hour. Chloroform was added to the reaction mixture, which mixture was then washed with dilute aqueous K.sub.2 CO.sub.3 and extracted with chloroform. The combined chloroform layer was dried with anhydrous magnesium sulfate and concentrated in vacuo.
Sodium thiophenolate (0.66 g) was added to the residue dissolved in DMF (20 ml), and stirred at room temperature for 2 days. DMF was distilled off in vacuo, dilute aqueous K.sub.2 CO.sub.3 was added to the residue, and the resulting mixture was extracted 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, 50 g) and eluted with benzene-ethyl acetate (5:1) to obtain compound 615 (1.32 g, yield: 80.7%).
Comparative Example 1
2-hydroxy-3-ethyl-5,6,7,8-tetrahydroquinoxaline
1,2-cyclohexanedione (6.72 g, 60 mM) was added all at once to a methanol solution (100 ml) of .alpha.-aminobutylamide (5.1 g, 50 mM) at -30.degree. C., and aqueous 12.5N NaOH (5 ml) was added dropwise thereto. The reaction mixture was stirred at -30.degree. C. for 30 mins., whereafter the cooling was removed and the mixture was stirred at room temperature for 3 hours. Concentrated hydrochloric acid (6.25 ml) was added to the reaction mixture under ice-cooling, and sodium bicarbonate (5 g) was added after 10 mins., the methanol being distilled off in vacuo. The residue was extracted with chloroform, and the extract was washed with water, dried with anhydrous sodium sulfate and concentrated in vacuo. The residue was washed with acetone and recrystallized from acetone to obtain the product as colorless crystals (5.3 g, yield: 60%, m.p.: 152.degree.-153.degree. C.).
NMR (CDCl.sub.3) .delta. (ppm): 1.25 (t, 3H, --CH.sub.2 CH.sub.3), 1.7-1.9 (m, 4H, 6-H.sub.2, 7-H.sub.2), 2.5-2.8 (m, 4H, 5-H.sub.2, 8-H.sub.2), 2.80 (q, 2H, --CH.sub.2 CH.sub.3), 13.06 (br. s, 1H, OH)
Mass (CI): 179 (M.sup.30 +1)
Comparative Example 2
2-hydroxy-3-propyl-5,6,7,8-tetrahydroquinoxaline
1,2-cyclohexanedione (5.4 g, 48 mM) was added all at once to a methanol solution (80 ml) of norvalineamide hydrochloride (6.1 g, 40 mM) at -30.degree. C., and aqueous 12.5N NaOH (8 ml) was added dropwise thereto. The reaction mixture was stirred at -30.degree. C. for 30 mins., cooling was removed, and the mixture stirred to room temperature for 3 hours. Conc. hydrochloric aicd (10 ml) was added to the reaction mixture under ice-cooling, sodium bicarbonate (8 g) was added after 10 mins., the methanol then being distilled off in vacuo. The residue was extracted with chloroform, and the extract washed with water, dried with anhydrous sodium sulfate and concentrated in vacuo. The residue was washed with acetone and recrystallized from acetone to obtain the product as colorless crystals (3.8 g., yield: 50%, m.p.: 131.degree.-133.degree. C.).
NMR (CDCl.sub.3) .delta. (ppm: 1.00 (t, 3H, --CH.sub.2 CH.sub.2 CH.sub.3), 1.55-1.90 (m, 4H, 6-H, --CH.sub.2 CH.sub.2 CH.sub.3, 6-H.sub.2, 7-H.sub.2), 2.67-2.83 (m, 6H, --CH.sub.2 CH.sub.2 CH.sub.3, 5-H.sub.2, 6-H.sub.2), 13.09 (br. s, 1H, OH)
Mass (CI): 193 (M.sup.+ +1)
Comparative Examples 3-13
2-hydroxy-3-alkyl-5,6,7,8-tetrahydroquinoxazline
1,2-cyclohexanedione (6.72 g, 60 mM) was added all at once to a methanol solution (100 ml) of .alpha.-amino acidamide hydrochloride (50 mM) at -30.degree. C., and aqueous 12N NaOH (10 ml) was added dropwise thereto. The reaction mixture was stirred for 30 mins., cooling was removed, and the mixture was stirred at room temperature for 5 hours. Conc. hydrochloric acid (12.5 ml) was added to the reaction mixture under ice-cooling, and sodium bicarbonate (10 g) was added after 10 mins., whereafter the methanol was distilled off in vacuo. The residue was extracted with chloroform, and the extract was washed with water, dried with anhydrous sodium sulfate and concentrated in vacuo. The residue was washed with acetone and recrystallized from acetone to obtain the product shown in Table 25.
The kind of product, yield (weight and %) and physical properties are shown in Table 25.
Comparative Example 14
2-hydroxy-3-benzyl-5,6,7,8-tetrahydroquinoxaline
A methanol (30 ml) solution of 1,2-cyclohexanedione (13.44 g, 0.12M) was added to phenylalanineamide hydrochloride (20.05 g, 0.1M) dissolved in methanol (200 ml) under cooling below -30.degree. C., and aqueous 12.5N NaOH (20 ml) was added dropwise thereto. The reaction mixture was stirred under -30.degree. C. for 30 mins., whereafter cooling was removed and the mixture was stirred at room temperature for 3 hours. Conc. hydrochloric acid (25 ml) was added to the reaction mixture under ice-cooling, and sodium bicarbonate (15 g) was added after 10 mins. stirring, the methanol then being distilled off in vacuo. The residue, to which was added water, was extracted three times with chloroform, and the extract was washed with water, dried with anhydrous magnesium sulfate and concentrated in vacuo. The residue was washed with acetone and recrystallized from acetone to obtain the product (19.7 g, yield: 82.1%).
NMR (CDCl.sub.3, TMS) .delta. (ppm): 1.6-2.0 (m, 4H), 2.4-2.7 (m, 4H), 4.02 (s, 2H), 7.0-7.4 (m, 5H)
Mass (CI): 241 (M.sup.+ +1)
Comparative Example 15
2-hydroxy-3-(phenylethyl)-5,6,7,8-tetrahydroquinoxaline
A methanol (20 ml) solution of 1,2-cyclohexanedione (5.38 g) was added to a methanol suspension (100 ml) of .alpha.-amino-(3-phenyl)-butylamine hydrochloride (8.58 g, 40 mM) at below -30.degree. C., and aqueous 12.5N NaOH (8 ml) was added dropwise thereto. The reaction mixture was stirred at below -30.degree. C. for 30 mins., cooling was removed, and the mixture was stirred at room temperature for 6 hours. Conc. hydrochloric acid (8 ml) was added to the reaction mixture under ice-cooling, and sodium bicarbonate (6.0 g) was added after 10 mins. stirring, the methanol then being distilled off in vacuo. The residue, to which was added water, was extracted three times with chloroform, whereafter the extract was washed with water, dried with anhydrous sodium sulfate and concentrated in vacuo. The residue was washed with acetone and recrystallized from acetone to obtain the product (6.79 g, yield: 66.8%).
NMR (CDCl.sub.3, TMS) .delta. (ppm): 1.6-2.0 (m, 4H), 2.5-2.8 (m, 4H), 3.06 (s, 2H.times.2), 7.1-7.3 (s, 5H), 12.9 (br. s, 1H)
Mass (CI): 225 (M.sup.+ +1)
Comparative Examples 16-23
2-hydroxy-3-alkyl-5,6-diethylpyrazine
.alpha.-amino acidamide (0.20M) and 3,4-hexane (22.8 g, 020M) were added to triethylamine (200 ml), the mixture was stirred at room temperature for 30 mins. and refluxed for 15 hours. Triethylamine was distilled off in vacuo, and the residue was dissolved in chloroform and washed with dilute aqueous K.sub.2 CO.sub.3. The chloroform layer was dried with anhydrous sodium sulfate and concentrated in vacuo. The residue was recrystallized from acetone to obtain the products shown in Table 26.
Product, yield, (weight and %) and physical properties are shown in Table 26.
TABLE 6__________________________________________________________________________1-(2-substituted ethyl)-3,5,6-trimethyl-2-oxo-1,2-dihydropyrazine Starting Heat Elution solventExample Product* Base Material* time (hr) ratio Yield (g) Yield (%)__________________________________________________________________________2 018 ##STR228## 026 1.75h 20:1 1.96 78.53 019 ##STR229## 026 4 40:1 1.61 64.14 020 ##STR230## 026 1.75 20:1 1.70 64.45 021 ##STR231## 026 2 10:1 2.25 76.56 022 1-imidazole 026 2 50:1 1.45 62.47 023 ##STR232## 026 5 100:1 2.42 71.28 024 ##STR233## 026 5 100:1 3.34 86.59 025 ##STR234## 026 5 100:1 3.64 97.2__________________________________________________________________________ *Compound No.
TABLE 7______________________________________1-(2-substituted thioththyl)-3,5,6-trimethy-2-oxo-1,2-dihydropyrazineEx- Starting Yield Yieldample Product* Mercaptane material* (g) (%)______________________________________10 027 HS--Ph 026 1.06 77.411 028 1-methyl-5- 026 1.04 78.8 mercaptotetrazole______________________________________ *Compound No.
TABLE 8__________________________________________________________________________1-(2-substituted ethyl)-3-phenyl-5,6-dimethyl-2-oxo-1,2-dihydropyrazine Starting Heat Elution solventExample Product* Base material* time (hr) ratio Yield (g) Yield (%)__________________________________________________________________________16 110 ##STR235## 612 3 100:1 0.70 89.517 111 ##STR236## 612 3 100:1 0.99 91.0__________________________________________________________________________ *Compound No.
TABLE 9__________________________________________________________________________1-(2-substituted ethyl)-3-benzyl-5,6-dimethyl-2-oxo-1,2-dihydropyrazine Starting Heat Elution solventExample Product* Base material* time (hr) ratio Yield (g) Yield (%)__________________________________________________________________________20 113 ##STR237## 613 3h 100:1 0.78 79.521 114 ##STR238## 613 2 100:1 1.07 85.522 115 ##STR239## 613 3 100:1 0.78 57.723 116 ##STR240## 613 2 100:1 0.96 71.0__________________________________________________________________________ *Compound No.
TABLE 10__________________________________________________________________________1-(2-hydroxyethyl)-3-alkyl-5,6-dimetyl-2-oxo-1,2-dihydropyrazine Reaction ElutionExample Product* Starting material (R.sub.1) time (hr) solvent ratio Yield (g) Yield (%)__________________________________________________________________________24 616 Pro 3.32 g (20 mM) 2 h 100:1 3.42 81.425 622 iso-Pro 4.50 g (27 mM) 2 100:1 4.32 76.226 624 Bu 2.70 g (15 mM) 2 50:1 3.31 98.527 617 iso-Bu 5.40 g (30 mM) 2 50:1 5.12 76.228 623 sec-Bu 4.50 g (25 mM) 2 100:1 4.74 84.6__________________________________________________________________________ *Compound No.
TABLE 11__________________________________________________________________________1-(2-substituted ethyl)-3-alkyl-5,6-dimethyl-2-oxo-1,2-dihydropyrazine Starting Heat ElutionExample Product* Base material* time (hr) solvent ratio Yield (g) Yield (%)__________________________________________________________________________29 121 ##STR241## 616 1.5h 100:1 0.94 67.430 122 ##STR242## 616 2 100:1 1.00 67.931 123 ##STR243## 617 2.5 150:1 0.72 61.432 124 ##STR244## 617 2 150:1 1.41 92.333 125 ##STR245## 617 1.5 150:1 1.58 94.834 126 ##STR246## 617 1.5 150:1 1.27 76.235 619 ##STR247## 617 1.5 150:1 1.16 72.536 148 ##STR248## 622 1.5 200:1 0.94 84.237 149 ##STR249## 622 1.5 200:1 1.42 96.538 150 ##STR250## 622 2 200:1 1.41 87.639 151 ##STR251## 622 2 150:1 1.21 78.440 156 ##STR252## 624 1.5 150:1 0.85 72.541 157 ##STR253## 624 1.5 150:1 1.03 67.442 158 ##STR254## 624 1.5 150:1 1.08 64.843 152 ##STR255## 623 1 150:1 0.49 41.844 153 ##STR256## 623 1.25 150:1 0.64 41.945 154 ##STR257## 623 1.25 150:1 1.05 63.046 155 ##STR258## 623 1.5 150:1 1.12 70.0__________________________________________________________________________ *Compound No.
TABLE 12__________________________________________________________________________1-(2-hydroxyethyl)-3-alkyl-2-oxo-1,2,5,6,7,8-hexahydro quinoxaline Reaction ElutionExample Product* Starting material (R.sub.1) time (hr) solvent ratio Yield (g) Yield (%)__________________________________________________________________________47 614 Pro 6.26 g (32 mM) 1.25 h 50:1 7.15 94.748 621 Bu 5.15 g (25 mM) 2 50:1 6.15 98.449 618 iso-Bu 4.12 g (20 mM) 2 50:1 4.12 82.4__________________________________________________________________________ *Compound No.
TABLE 13__________________________________________________________________________1-(2-substituted ethyl)-3-alkyl-2-oxo-1,2,5,6,7,8-hexahydro quinoxaline Starting Heat ElutionExample Product* Base material* time (hr) solvent ratio Yield (g) Yield (%)__________________________________________________________________________50 118 ##STR259## 614 3h 100:1 1.14 93.551 119 ##STR260## 614 3 100:1 1.21 95.852 120 ##STR261## 614 2.5 100:1 1.57 91.953 117 ##STR262## 614 2.5 50:1 0.70 62.254 127 ##STR263## 618 2.5 200:1 1.07 83.655 128 ##STR264## 618 1 200:1 1.58 96.856 129 ##STR265## 618 1 200:1 1.46 82.557 141 ##STR266## 621 1 200:1 0.76 59.658 142 ##STR267## 621 1 200:1 0.95 58.259 143 ##STR268## 621 2 200:1 1.49 84.260 144 ##STR269## 621 1 200:1 0.86 67.861 145 ##STR270## 621 2 50:1 0.92 63.562 146 ##STR271## 621 1.25 200:1 1.15 67.5__________________________________________________________________________ *Compound No.
TABLE 14__________________________________________________________________________1-(2-hydroxy ethyl )-3-alkyl-5,6-diethyl-2-oxo-1,2-dihydropyrazine Reaction ElutionExample Product* Starting material (R.sub.1) time (hr) solvent ratio Yield (g) Yield (%)__________________________________________________________________________63 620 Pro 7.76 g (40 mM) 5.5 h 50:1 6.89 73.364 625 iso-Pro 9.70 g (50 mM) 5.5 100:1 8.70 73.165 628 Bu 10.40 g (50 mM) 3 100:1 8.53 68.266 626 iso-Bu 5.20 g (25 mM) 3 100:1 5.08 81.367 627 sec-Bu 10.40 g (50 mM) 3 100:1 9.94 79.568 629 Et 4.50 g (25 mM) 2 100:1 4.38 78.2__________________________________________________________________________ *Compound No.
TABLE 15__________________________________________________________________________1-(2-substituted ethyl)-3-alkyl-5,6-diethyl-2-oxo-1,2-dihydropyrazine Starting Heat Elution Sol-Example Product* Base material* time (hr) vent ratio Yield (g) Yield (%)__________________________________________________________________________69 130 ##STR272## 620 3 h 100:1 0.77 62.770 131 ##STR273## 620 1.5 200:1 1.05 66.371 132 ##STR274## 620 1.25 200:1 0.90 52.172 133 ##STR275## 620 1.5 200:1 1.02 59.073 134 ##STR276## 620 1.25 200:1 0.63 36.574 159 ##STR277## 625 1.25 200:1 0.65 52.975 160 ##STR278## 625 1.25 200:1 0.74 46.876 161 ##STR279## 625 1.25 200:1 0.99 57.577 162 ##STR280## 625 1.25 200:1 0.55 33.278 163 ##STR281## 625 1.25 200:1 0.55 45.179 164 ##STR282## 625 1.25 50:1 0.47 33.680 165 ##STR283## 625 1.25 200:1 0.77 44.781 166 ##STR284## 626 1.25 200:1 1.20 70.182 167 ##STR285## 626 1.25 200:1 0.70 54.583 168 ##STR286## 626 1.25 200:1 1.17 65.684 170 ##STR287## 626 1.25 200:1 1.31 79.985 171 ##STR288## 627 1.25 200:1 0.33 25.986 172 ##STR289## 627 2 50:1 0.30 20.687 173 ##STR290## 627 1 200:1 0.68 53.088 174 ##STR291## 627 1 200:1 0.46 28.089 175 ##STR292## 627 1.25 200:1 0.39 22.890 176 ##STR293## 627 1 200:1 0.78 43.691 177 ##STR294## 627 1.25 200:1 0.52 29.192 178 ##STR295## 628 1.25 200:1 1.08 60.893 179 ##STR296## 628 1.25 200:1 0.92 56.194 180 ##STR297## 628 1.25 200:1 1.54 86.795 181 ##STR298## 628 1 200:1 0.90 70.596 182 ##STR299## 628 1.25 200:1 0.98 76.397 183 ##STR300## 628 1.25 200:1 1.28 74.898 185 ##STR301## 628 1.25 200:1 0.78 43.999 187 ##STR302## 629 2 200:1 0.86 77.6100 188 ##STR303## 629 1.25 100:1 0.80 48.1101 189 ##STR304## 629 1.25 100:1 0.79 51.7__________________________________________________________________________ *Compound No.
TABLE 16__________________________________________________________________________1-(2-substituted ethyl)-3-ethyl-5,6-dimethyl-2-oxo-1,2-dihydropyrazine Starting Heat ElutionExample Product* Base material* time (hr) solvent ratio Yield (g) Yield__________________________________________________________________________ (%)103 190 ##STR305## 630 2 200:1 1.03 77.7104 191 ##STR306## 630 2 200:1 1.54 79.3105 192 ##STR307## 630 1.5 200:1 1.23 66.1106 193 ##STR308## 630 2 200:1 1.70 88.5107 287 ##STR309## 630 1 200:1 1.37 77.4108 288 ##STR310## 630 1 200:1 1.42 70.6109 289 ##STR311## 630 1 200:1 1.05 54.4110 290 ##STR312## 630 1.5 200:1 1.39 69.7__________________________________________________________________________ *Compound No.
TABLE 17__________________________________________________________________________1-(2-substituted ethyl)-3-benzyl-5,6-diethyl-2-oxo-1,2-dihydropyrazine Starting Heat Elution solventExample Product* Base material* time (hr) ratio Yield (g) Yield__________________________________________________________________________ (%)112 291 ##STR313## 640 4h 100:1 1.15 81.0113 292 ##STR314## 640 1 100:1 1.15 81.4114 293 ##STR315## 640 3 100:1 1.11 62.5115 294 ##STR316## 640 2 100:1 1.60 83.6116 295 ##STR317## 640 2.5 100:1 0.95 46.3117 296 ##STR318## 640 4 100:1 1.45 78.5118 297 ##STR319## 640 2.5 100:1 0.99 52.2119 374 ##STR320## 640 1 200:1 1.21 70.5120 375 ##STR321## 640 1 200:1 0.99 67.4121 378 ##STR322## 640 1 100:1 1.57 80.3122 380 ##STR323## 640 2 200:1 0.73 42.4__________________________________________________________________________ *Compound No.
TABLE 18__________________________________________________________________________1-(2-substituted ethyl)-3-p-chlorobenzyl-5,6-diethyl-2-oxo-1,2-dihydropyrazine Starting Heat Elution solventExample Product* Base material* time (hr) ratio Yield (g) Yield__________________________________________________________________________ (%)125 384 ##STR324## 641 2 100:1 0.89 76.2126 467 ##STR325## 641 2 100:1 1.10 76.6127 385 ##STR326## 641 2 100:1 1.23 79.9128 386 ##STR327## 641 2 100:1 1.15 75.4129 387 ##STR328## 641 2 100:1 1.03 56.2__________________________________________________________________________ *Compound No.
TABLE 19__________________________________________________________________________1-(2-hydroxyethyl)-3-alkyl-2-oxo-1,2,5,6,7,8-hexahydroquinozalineExample Product* Starting material (R.sub.1) silica-gel Elution solvent Yield (g) Yield (%)__________________________________________________________________________130 631 --(CH.sub.2).sub.4 CH.sub.3 30 mM 150 g chloroform-methanol (200:1) 6.44 81.3131 632 --(CH.sub.2).sub.5 CH.sub.3 20 mM 100 g chloroform-methanol (200:1) 4.66 83.8132 633 --(CH.sub.2).sub.6 CH.sub.3 30 mM 150 g chloroform-methanol (200:1) 8.39 95.8133 634 --(CH.sub.2).sub.7 CH.sub.3 28 mM 150 g chloroform-methanol (200:1) 7.60 89.2134 635 --(CH.sub.2).sub.8 CH.sub.3 40 mM 200 g chloroform-methanol (200:1) 11.00 85.9135 636 --(CH.sub.2).sub.9 CH.sub.3 30 mM 150 g chloroform-methanol (200:1) 8.42 84.0136 637 --(CH.sub.2).sub.11 CH.sub.3 20 mM 100 g benzene-ethyl acetate (5:1 .fwdarw. 3:1) 6.06 84.2137 638 --(CH.sub.2).sub.13 CH.sub.3 15 mM 100 g benzene-ethyl acetate (5:1) 3.86 66.2138 639 --(CH.sub.2).sub.15 CH.sub.3 20 mM 100 g benzene-ethylacetate (5:1 .fwdarw. 3:1) 5.92 70.8__________________________________________________________________________ *Compound No.
TABLE 20__________________________________________________________________________1-(2-substituted ethyl)-3-alkyl-2-oxo-1,2,5,6,7,8-hexahydro quinoxaline HeatExample Product* Starting material* Base time (hr) Yield (g) Yield (%)__________________________________________________________________________139 250 631 1.06 g (4 mM) ##STR329## 1.5 h 1.59 87.1140 251 631 1.06 g (4 mM) ##STR330## 2 1.65 93.8141 252 631 1.32 g (5 mM) ##STR331## 1.5 1.05 63.1142 253 631 1.06 g (4 mM) ##STR332## 2 1.01 65.1143 254 631 1.06 g (4 mM) ##STR333## 1.5 1.35 74.7144 255 632 1.25 g (4.5 mM) ##STR334## 2 1.34 85.8145 256 632 0.95 g (3.5 mM) ##STR335## 2 0.88 53.4146 257 632 0.95 g (3.5 mM) ##STR336## 2 1.50 89.1147 258 632 1.12 g (4 mM) ##STR337## 2 1.44 76.9148 305 632 1.12 g (4 mM) ##STR338## 2 1.38 81.7149 306 632 1.12 g (4 mM) ##STR339## 2 1.32 75.7150 307 632 1.12 g (4 mM) ##STR340## 2 1.49 83.9151 308 632 1.12 g (4 mM) ##STR341## 2 1.73 92.8152 309 632 1.12 g (4 mM) ##STR342## 2.5 1.38 75.6153 310 632 1.12 g (4 mM) ##STR343## 2.5 1.43 79.1154 311 632 1.12 g (4 mM) ##STR344## 2.5 1.44 72.7155 312 632 1.12 g (4 mM) ##STR345## 2 1.49 76.9156 313 632 1.12 g (4 mM) ##STR346## 2 0.81 42.2157 259 633 1.17 g (4 mM) ##STR347## 2 0.94 65.1158 260 633 1.17 g (4 mM) ##STR348## 2 1.03 53.4159 261 633 1.17 g (4 mM) ##STR349## 2 1.50 75.8160 262 633 1.17 g (4 mM) ##STR350## 2 1.28 68.4161 263 633 1.17 g (4 mM) ##STR351## 2 0.85 51.1162 264 633 1.17 g (4 mM) ##STR352## 2 1.42 71.4163 314 633 1.17 g (4 mM) ##STR353## 2 1.50 83.3164 315 633 1.17 g (4 mM) ##STR354## 2 0.44 25.2165 316 633 1.17 g (4 mM) ##STR355## 2 1.70 93.3166 317 633 1.17 g (4 mM) ##STR356## 2 1.30 69.1167 318 633 1.17 g (4 mM) ##STR357## 2.5 1.11 57.6168 319 633 1.17 g (4 mM) ##STR358## 2 1.01 51.1169 320 633 1.17 g (4 mM) ##STR359## 1.5 1.29 63.4170 265 634 1.23 g (4 mM) ##STR360## 2 1.01 67.3171 266 634 0.92 g (3 mM) ##STR361## 2 1.49 99.6172 267 634 0.92 g (3 mM) ##STR362## 2 1.24 83.7173 268 634 0.92 g (3 mM) ##STR363## 2 1.40 91.7174 269 634 0.92 g (3 mM) ##STR364## 2 1.27 87.8175 270 634 1.23 g (4 mM) ##STR365## 2 1.18 59.5176 321 634 1.23 g (4 mM) ##STR366## 2 1.79 96.4177 322 634 1.23 g (4 mM) ##STR367## 2 1.58 87.8178 323 634 1.23 g (4 mM) ##STR368## 3 1.90 99.0179 324 634 1.23 g (4 mM) ##STR369## 2 1.54 79.5180 325 634 1.23 g (4 mM) ##STR370## 2 1.45 69.3181 326 634 1.23 g (4 mM) ##STR371## 2 1.33 65.5182 327 634 1.23 g (4 mM) ##STR372## 2 1.41 68.8183 271 635 1.28 g (4 mM) ##STR373## 2 1.03 66.2184 272 635 0.96 g (3 mM) ##STR374## 2 1.15 74.8185 273 635 0.96 g (3 mM) ##STR375## 2 1.25 84.0186 274 635 0.96 g (3 mM) ##STR376## 2 1.15 73.3187 275 635 0.96 g (3 mM) ##STR377## 2 0.72 47.2188 328 635 0.96 g (3 mM) ##STR378## 2 1.30 90.7189 329 635 0.96 g (3 mM) ##STR379## 2 0.87 55.1190 330 635 0.96 g (3 mM) ##STR380## 2.5 1.08 67.0191 331 635 0.96 g (3 mM) ##STR381## 2 0.61 39.9192 332 635 0.96 g (3 mM) ##STR382## 2 1.04 66.4193 334 636 1.01 g (3 mM) ##STR383## 2 0.96 79.4194 335 636 1.01 g (3 mM) ##STR384## 2 1.28 86.6195 336 636 1.01 g (3 mM) ##STR385## 2 0.91 63.5196 337 636 1.01 g (3 mM) ##STR386## 2.5 1.38 88.1197 338 636 1.01 g (3 mM) ##STR387## 2 1.32 83.6198 339 636 1.01 g (3 mM) ##STR388## 3 1.48 89.5199 340 636 1.01 g (3 mM) ##STR389## 2 1.24200 276 637 1.09 g (3 mM) ##STR390## 2 1.16 89.5201 277 637 1.09 g (3 mM) ##STR391## 2 1.27 76.3202 278 637 1.09 g (3 mM) ##STR392## 2 0.60 36.2203 279 637 1.09 g (3 mM) ##STR393## 2 1.35 79.6204 280 638 1.17 g (3 mM) ##STR394## 2 0.91 66.1205 281 638 1.17 g (3 mM) ##STR395## 2 1.21 69.8206 282 638 1.17 g (3 mM) ##STR396## 2 0.97 55.7207 487 638 1.17 g (3 mM) ##STR397## 2 1.43 87.0208 488 638 1.17 g (3 mM) ##STR398## 3 0.89 48.9209 489 638 1.17 g (3 mM) ##STR399## 3 0.92 51.4210 490 638 1.17 g (3 mM) ##STR400## 2.5 0.98 55.2211 283 639 1.26 g (3 mM) ##STR401## 2 1.22 83.5212 284 639 1.26 g (3 mM) ##STR402## 2 1.52 83.0213 285 639 1.26 g (3 mM) ##STR403## 2 1.77 95.0214 286 639 1.26 g (3 mM) ##STR404## 2 1.76 93.9__________________________________________________________________________ *Compound No.
TABLE 21__________________________________________________________________________1-[ 2-(4'-acylpiperadinyl)ethyl]-3-5,6-dimethyl-2-oxo-1,2-dihydropyrazine Acylation Reaction ElutionExample Product* Method Acylating agent time solvent ratio Yield (g) Yield (5)__________________________________________________________________________216 455 acid chloride ClCO--CH.sub.2 Ph 1 h 100:1 0.93 81.2217 457 acid anhydride 2-thienylchloride 4 100:1 1.35 87.0218 459 acid anhydride HOOC--CH.sub.2 Ph--NO.sub.2 (p) 5 200:1 0.98 57.4219 465 acid chloride CISO.sub.2 --Ph--Cl (p) 1 200:1 1.23 93.5220 456 acid anhydride HOOC--Ph--Cl (p) 2 100:1 1.49 92.5221 458 acid anhydride HOOC--Ph--NO.sub.2 (p) 2 100:1 1.59 96.2222 460 acid chloride HOOC--Ph--OMe (p) 1 100:1 1.07 89.6223 461 acid anhydride HOOC--Ph--OMe.sub.2 (2,3) 2 100:1 1.56 91.1224 462 acid anhydride HOOC--Ph--OMe.sub.2 (2,4) 2 200:1 1.51 88.2225 463 acid anhydride HOOC--Ph--OMe.sub.2 (3,4) 4 100:1 1.55 90.5226 464 acid anhydride HOOC--Ph--OMe.sub.3 (3,4,5) 3 100:1 1.40 99.0__________________________________________________________________________ *Compound No.
TABLE 22__________________________________________________________________________1-(2-substituted ethyl)-3-benzyl-2-oxo-1,2,5,6,7,8-hexahydro quinoxaline Starting Heat Elution solventCompound Product* Base material* time (hr) ratio Yield (g) Yield__________________________________________________________________________ (%)229 470 ##STR405## 643 3h 100:1 0.67 52.6230 471 ##STR406## 643 3 100:1 1.01 62.3231 472 ##STR407## 643 3 200:1 0.82 54.7232 473 ##STR408## 643 3 200:1 1.10 66.0233 474 ##STR409## 643 2.5 100:1 0.93 56.3234 475 ##STR410## 643 2.75 100:1 1.15 71.4__________________________________________________________________________ *Compound No.
TABLE 23__________________________________________________________________________1-(2-substituted ethyl)-3-(2-phenylethyl)-2-oxo-1,2,5,6,7,8-hexahydroquinoxaline Starting Heat Elution solventExample Product* Base material* time (hr) ratio Yield (g) Yield__________________________________________________________________________ (%)237 476 ##STR411## 645 2h 100:1 1.07 83.3238 477 ##STR412## 645 2 100:1 1.35 84.6239 478 ##STR413## 645 2 200:1 1.01 65.2240 479 ##STR414## 645 2.5 100:1 1.41 82.0241 480 ##STR415## 645 2.5 100:1 0.98 57.6__________________________________________________________________________ *Compound No.
TABLE 24__________________________________________________________________________1-(2-substituted ethyl)-3-(2-phenylethyl)-2-oxo-1,2,5,6,7,8-hexahydroquinoxaline Starting Heat ElutionExample Product* Base material* time (hr) solvent ratio Yield (g) Yield__________________________________________________________________________ (%)243 481 ##STR416## 646 2.5 h 100:1 0.98 62.6244 482 ##STR417## 646 2.5 100:1 1.54 74.3245 483 ##STR418## 646 2 100:1 1.67 87.9246 484 ##STR419## 646 2.5 200:1 1.29 70.5247 485 ##STR420## 646 2 100:1 1.25 58.3248 486 ##STR421## 646 3 100:1 1.78 86.8__________________________________________________________________________ *Compound No.
TABLE 25__________________________________________________________________________2-hydroxy-3-alkyl-5,6,7,8-tetrahydro quinoxaline ##STR422##Comp. Yield YieldExa. Product (R.sub.1) (g) (%) NMR (CDCl.sub.3) .delta. (ppm) Mass__________________________________________________________________________3 Bu 7.49 73.0 0.94 (t, 3H,butyl 4-CH.sub.3), 1.24.about.2.00 (m, butyl 2-CH.sub.2, 207 (M.sup.+ + 1) 3-CH.sub.2, quinoxaline 6-H.sub.2, 7-H.sub.2), 2.55.about.2.85 (m, 6H, butyl 1-CH.sub.2, quinoxaline 5-H.sub.2, 8-H.sub.2), 12.99 (br. s, 1H, OH)4 iso-Bu 6.58 64.0 0.96 (d, 6H, isobutyl 2 .times. CH.sub.3), 1.6.about.2.0 (m, 4H, 6-H.sub.2, 7- 207 (M.sup.+ + 1) H.sub.2), 2.0.about.2.4 (isobutyl CH), 2.5.about.2.8 (m, 6H, 5-H.sub.2, 8- H.sub.2)5 (CH.sub.2).sub.4 CH.sub.3 9.03 82.0 0.90 (t, 3H, J .apprxeq. 6.3), 1.2.about.1.5 (m, 4H), 1.5.about.1.9 (m, 221 (M.sup.+ + 1) 6H), 2.5.about.2.9 (m, 6H) 1646 (CH.sub.2).sub.5 CH.sub.3 7.81 66.7 0.88 (t, 3H, J .apprxeq. 7.9), 1.1.about.1.5 (m, 6H), 1.5.about.2.0 (m, 235 (M.sup.+ + 1) 6H), 2.4.about.2.9 (m, 6H)7 (CH.sub.2).sub.5 CH.sub.3 9.33 75.0 0.88 (t, 3H, J .apprxeq. 7.4), 1.1.about.1.5 (m, 8H), 1.5.about.2.0 (m, 249 (M.sup.+ + 1) 6H), 2.5.about.2.9 (m, 6H)8 (CH.sub.2).sub.7 CH.sub.3 11.67 89.1 0.88 (t, 3H, J .apprxeq. 7.5), 1.1.about.1.5 (m, 10H), 1.5.about.2.0 (m, 263 (M.sup.+ + 1) 6H), 2.5.about.2.9 (m, 6H)9 (CH.sub.2).sub.8 CH.sub.3 12.73 92.2 0.88 (t, 3H, J .apprxeq. 6.2), 1.1.about.1.5 (m, 12H), 1.5.about.2.0 (m, 277 (M.sup.+ + 1) 6H), 2.5.about.2.8 (m, 6H) 16410 (CH.sub.2).sub.9 CH.sub.3 10.46 72.4 0.88 (t, 3H, J .apprxeq. 6.0), 1.2.about.2.0 (m, 20H), 2.5.about.2.9 (m, 291 (M.sup.+ + 1) 6H), 12.7 (br. s, 1H)11 (CH.sub.2).sub.11 CH.sub.3 14.00 88.1 0.88 (t, 3H, J .apprxeq. 6), 1.1.about.1.9 (m, 24H), 2.4.about.2.8 (m, 6H) 319 (M.sup.+ + 1) 16412 (CH.sub.2).sub.13 CH.sub.3 16.58 95.8 0.88 (t, 3H, J .apprxeq. 6), 1.1.about.1.9 (m, 28H), 2.4.about.2.8 (m, 6H) 347 (M.sup.+ + 1) 16413 (CH.sub.2).sub.15 CH.sub.3 18.55 99.2 0.88 (t, 3H, J .apprxeq. 6), 1.1.about.1.9 (m, 32H), 2.5.about.2.8 (m, 6H) 375 (M.sup.+ + 1) 164__________________________________________________________________________
TABLE 26__________________________________________________________________________2-hydroxy-3-alkyl-5,6-diethylpyrazine ##STR423##Comp. Yield YieldExa. Product (R.sub.1) (g) (%) NMR (CDCl.sub.3) .delta. (ppm) Mass__________________________________________________________________________16 Et 14.4 40 1.1.about.1.4 (m, 9H), 2.3.about.3.0 (m, 6H), 13.2 (br. s, 1H) 16717 Pro 16.5 43 1.00 (t, 3H), 1.19 (t, 3H), 1.28 (t, 3H), 1.5.about.1.9 (m, 181 2H), 2.47 (q, 2H), 2.54 (q, 2H), 2.76 (q, 2H), 13.1 (br. s, 1H)18 iso-Pro 18.2 47 1.0.about.1.4 (m, 12H), 2.56 (q, 2H), 2.58 (q, 2H), 3.40 195 (sept, 1H), 12.9 (br. s, 1H)19 Bu 17.5 42 0.95 (t, 3H), 1.19 (t, 3H), 1.27 (t, 3H), 1.2.about.1.9 (m, 209 4H), 2.57 (q, 2H .times. 2), 2.73 (t, 3H), 12.9 (br. s, 1H)20 iso-Bu 16.5 40 0.96 (t, 3H), 1.19 (t, 3H), 1.28 (t, 3H), 1.9.about.2.4 (m, 209 H), 2.41 (q, 2H), 2.58 (q, 2H), 2.66 (d, 2H), 13.0 (br. s, 1H)21 sec-Bu 17.5 42 0.88 (t, 3H .times. 2), 1.0.about.1.4 (m, 9H), 1.4.about.2.0 (m, 2H), 209 2.46 (q, 2H), 2.57 (q, 2H), 12.8 (br. s, 1H)22 CH.sub.2 Ph 27.9 57.6 1.19 (t, 3H, J .apprxeq. 7.6), 1.23 (t, 3H, J .apprxeq. 7.6), 2.50 (q, 2H, 243 J .apprxeq. 7.6), 2.53 (q, 2H, J .apprxeq. 7.6), 4.07 (s, 2H), 7.0.about.7.4 (m, 5H), 13.2 (br. s, 1H)23 CH.sub.2 PhCl 27.4 49.6 1.19 (t, 3H, J .apprxeq. 7.7), 1.23 (t, 3H, J .apprxeq. 7.7), 2.53 (q, 2H, 279 (p) J .apprxeq. 7.7), 2.57 (q, 2H, J .apprxeq. 7.7), 4.03 (s, 2H), 7.0.about.7.4 277 (m, 4H), 13.3 (br. s, 1H)__________________________________________________________________________
TABLE 27__________________________________________________________________________Compound Nos. NMR (CDCl.sub.3, TMS) .delta. Mass TLC__________________________________________________________________________018 1.3-1.8(6H,m), 2.30(3H,s), 2.38(3H,s), 2.41(3H,s), 2.5-2.8(6H,m), 4.1-4.3(2H,m) 250(M.sup.+ + 1) 0.25019 2.31(3H,s), 2.34(3H,s), 2.41(3H,s), 2.5-2.7(6H,m), 3.6-3.8(4H,m), 4.0-4.2(2H,m) 252(M.sup.+ + 1) 0.31020 2.29(3Hx2,s), 2.34(3H,s), 2.41(3H,s), 2.3-2.9(10H,m), 4.0-4.2(2H,m) 265(M.sup.+ + 1) 0.10021 2.30(3H,s), 2.34(3H,s), 2.41(3H,s), 2.4-2.7(12H,m), 2.92(1H,s), 2.63(2H,t,J.apprxeq. 295(M.sup.+ + 1) 0.08 5.4), 4.0-4.2(2H,m)022 1.79(3H,s), 2.24(3H,s), 2.45(3H,s), 4.2-4.4(4H,m), 6.7-6.8(1H,m), 7.0-7.1(1H,m) 233(M.sup.+ + 1) 0.30 7.2-7.4(1H,m)023 2.30(3H,s), 2.33(3H,s), 2.41(3H,s), 2.3-2.7(10H,m), 3.54(2H,s), 4.0-4.2(2H,m), 341(M.sup.+ + 1) 0.35 7.30(5H,s)024 2.30(3H,s), 2.33(3H,s), 2.41(3H,s), 2.3-2.7(10H,m), 3.47(2H,s), 4.0-4.2(2H,m), 375 377 0.36 7.24(4H,s) (M.sup.+ + 1)025 2.30(3H,s), 2.34(3H,s), 2.41(3H,s), 2.57(8H,s), 2.5-2.7(2H,m), 3.62(2H,s), 4.0- 375 377 0.36 4.2(2H,m), 7.1-7.5(4H,m) (M.sup.+ + 1)026 2.29(3H,s), 2.35(3H,s), 2.38(3H,s), 3.4(1H,bs), 3.8-4.0(2H,m), 4.1-4.3(2H,s) 183(M.sup.+ + 1) 0.26027 2.21(3H,s), 2.25(3H,s), 2.38(3H,s), 3.1-3.3(2H,m), 4.1-4.3(2H,m), 7.1-7.6(5H,m) 275(M.sup.+ + 1) 0.48028 2.32(3H,s), 2.43(3H,s), 2.46(3H,s), 3.4-3.7(2H,m), 3.95(3H,s), 4.3-4.6(2H,m) 281(M.sup.+ + 1) 0.39061 2.06(3H,s), 2.32(3H,s), 2.34(3H,s), 2.42(3H,s), 4.31(2H,t,J.apprxeq.3.3), 4.33(2H,t,J.apprxeq. 225(M.sup.+ + 1) 0.31 3.3)062 2.31(3Hx2,s), 2.41(3H,s), 2.79(3H,d,J.apprxeq.5.4), 4.1-4.4(4H,m), 4.8-5.0(1H,bm) 240(M.sup.+ + 1) 0.31063 2.21(3H,s), 2.25(3H,s), 2.31(3H,s), 4.1-4.4(4H,m), 4.8-5.0(1H,b), 6.9-7.5(5H,m) 302(M.sup.+ + 1) 0.41064 2.20(3H,s), 2.25(3H,s), 2.31(3H,s), 4.2-4.4(4H,m), 4.8-5.0(1H,b), 7.1-7.5(4H,m) 388(M.sup.+ + 1) 0.42 336101 2.30(3Hx2,s), 2.33(3Hx2,s), 2.58(3Hx2,s), 2.58(8H,s), 2.5-2.7(4H,m), 4.0-4.2( 415(M.sup.+ + 1) 0.13 4H,m)109 2.38(3H,s), 2.41(3H,s), 3.97(2H,t,J.apprxeq.5.2), 4.25(2H,t,J.apprxeq.5.2), 7.2-7.5(3H,m), 8.1- 265(M.sup.+ + 1) 0.34 8.2(2H,m)110 2.42(3Hx2,s), 2.4-2.8(6H,m), 3.6-3.8(4H,m), 4.25(2H,t,J.apprxeq.6. 9), 7.3-7.5(3H,m), 314(M.sup.+ + 1) 0.40 8.1-8.3(2H,m) 227111 2.41(3Hx2,s), 2.3-2.8(10H,m), 3.46(2H,s), 4.23(2H,t,J.apprxeq.6.1) , 7.27(4H,s), 7.2- 441 439 0.40 7.4(2H,m), 8.1-8.3(2H,m) (M.sup.+ + 1)112 2.32(3Hx2,s), 3.90(2H,t,J=5.3), 4.08(2H,s), 4.20(2H,t,J=5.3), 7.1-7.5(5H,m) 258(M.sup.+ + 1) 0.34113 2.31(3Hx2,s), 2.4-2.7(6H,m), 3.5-3.7(4H,m), 4.08(2H,s), 4.0-4.2(2H,m), 7.1-7.5 328(M.sup.+ + 1) 0.35 (5H,m) 241 114114 2.30(3Hx2,s), 2.3-2.7(10H,m), 3.51(2H,s), 4.08(2H,s), 3.9-4.2(2H,m), 7.1-7.4( 417(M.sup.+ + 1) 0.32 10H,m)115 2.30(3Hx2,s), 2.3-2.7(10H,m), 3.45(2H,s), 4.08(2H,s), 3.9-4.2(2H,m), 7.1-7.4( 452(M.sup.+ + 1) 0.35 9H,m) 450 223116 2.31(3Hx2,s), 2.4-2.7(10H,m), 3.62(2H,s), 4.08(2H,s), 4.0-4.2(2H,m), 7.1-7.9( 452(M.sup.+ + 1) 0.38 9H,m) 450 223117 0.99(3H,t,J=7.3), 1.5-2.0(6H,m), 2.0-2.3(2H,m), 2.4-2.8(16H,m), 3.5-3.7(2H,m), 349(M.sup.+ + 1) 0.08 3.9-4.2(2H,m)118 0.99(3H,t,J=7.3), 1.5-2.0(6H,m), 2.4-2.9(12H,m), 3.5-3.8(4H,m), 3.9-4.2(2H,m) 306(M.sup.+ + 1) 0.43 219 214119 0.98(3H,t,J.apprxeq.7.3), 1.7-2.0(6H,m), 2.3-2.9(16H,m), 3.51(2H,s), 3.9-4.2(2H,m), 395(M.sup.+ + 1) 0.40 7.29(5H,s) 189120 0.99(3H,t,J=7.3), 1.7-2.0(6H,m), 2.3-2.9(16H,m), 3.47(2H,s), 3.9-4.2(2H,m), 429(M.sup.+ + 1) 0.38 7.26(4H,s) 431121 0.99(3H,t,J=7.3), 1.5-1.0(2H,m), 2.31(3H,s), 2.33(3H,s), 2.4- 2.8(8H,m), 3.6- 280(M.sup.+ + 1) 0.33 3.8(4H,m), 4.0-4.3(2H,m) 193122 0.98(3H,t,J=7.3), 1.5-1.9(2H,m), 2.30(2Hx3,s), 2.4-2.8(12H,m), 3.51(2H,s), 369(M.sup.+ + 1) 0.22 4.0-4.2(2H,m), 7.29(5H,s) 193123 0.94(3Hx2,d,J=6.6), 1.9-2.4 (1H,m), 2.31(3H,s), 2.33(3H,s), 2.4-2.7(8H,m), 3.6- 294(M.sup.+ + 1) 0.40 3.8(4H,m), 4.0-4.3(2H,m) 207 114 102124 0.93(3Hx2,d,J=6.6), 1.9-2.4(1H,m), 2.17(3H,s), 2.31(3H,s), 2.4-2.7(12H,m), 3.51 383(M.sup.+ + 1) 0.31 (2H,s), 4.0-4.3(2H,m), 7.30(5H,s) 207125 0.93(3Hx2,d,J=6.6), 1.9-2.4(1H,m), 2.31(3Hx2,s), 2.3-2.8(12H,m), 3.46(2H,s), 419(M.sup.+ + 1) 0.29 4.0-4.3(2H,m), 7.26(4H,s) 417 207 125126 0.94(3Hx2,d,J=6.6), 1.9-2.4(1H,m), 2.31(3Hx2,s), 2.3-2.8(12H,m), 3.47(2H,s), 419(M.sup.+ + 1) 0.31 4.0-4.3(2H,m), 7.26(4H,s) 417 207 125127 0.95(3Hx2,d,J=6.6), 1.7-1.9(4H,m), 2.0-2.2(1H,m), 2.5-2.8(12H,m), 3.6-3.8(4H, 320(M.sup.+ + 1) 0.39 m), 4.0-4.2(2H,m) 233 114 102128 0.94(3Hx2,d,J=6.6), 1.6-2.0(4H,m), 2.0-2.4(1H,m), 2.3-2.8(16H,m), 3.51(2H,s), 409(M.sup.+ + 1) 0.38 3.9-4.2(2H,m), 7.29(5H,s) 233 189129 0.94(3H,d,J=6.4), 0.96(3H,d,J=6.4), 1.6-2.0(4H,m), 2.0-2.4(1H,m), 2.3-2.8(16H, 445(M.sup.+ + 1) 0.37 m), 7.45(2H,s), 3.8-4.3(2H,m), 7.26(4H,s) 443 233 125130 0.99(3H,t,J=7.3), 1.21(3H,t,J=7.6), 1.23(2H, t,J=7.6), 1.5-2.0(2H,m), 2.4-2.9 308(M.sup.+ + 1) 0.37 (12H,m), 3.6-3.8(4H,m), 4.0-4.3(2H,m) 221 102131 0.99(3H,t,J=7.2), 1.20(3H,t,J=7.5), 1.4-1.0(2H,m), 2.2-2.8(16H,m), 3.51(2H, 397(M.sup.+ + 1) 0.38 s), 3.8-4.3(2H, m), 7.29(5H,s) 221132 0.99(3H,t,J=7.2), 1.21(3Hx2,t,J=7.6), 1.5-2.0(2H,m), 2.3-2.9(16H,m), 3.48(2H, 433(M.sup.+ + 1) 0.31 s), 3.9-4.3(2H,m), 7.26(4H,s) 431 307 221 125133 0.99(3H,t,J=7.2), 1.20(3Hx2,t,J=7.6), 1.4-2.1(2H,m), 2.3-2.9(16H,m), 3.48(2H, 433(M.sup.+ + 1) 0.28 s), 4.0-4.3(2H,m), 7.1-7.4(4H,m) 431 239 221 125134 0.99(3H,t,J=7.8), 1.20(3H,t,J=7.6), 1.21(3H,t,J.apprxeq.7.6), 1.4-2.1(2H,m), 2.4-2.9( 433(M.sup.+ + 1) 0.32 16H,m), 2.64(2H,s), 4.0-4.3(2H,m), 7.1-7.5(4H,m) 431 221 125141 0.94(3H,t,J=6.4), 1.2-2.0(8H,m), 2.4-2.9(12H,m), 3.6- 3.8(4H,m), 3.9-4.2(2H,m) 320(M.sup.+ + 1) 0.44142 0.93(3H,t,J.apprxeq.6.4), 1.2-2.0(8H,m), 2.3-2.9(16H,m), 3.51(2H,s), 3.9-4.3(2H,m), 409(M.sup.+ + 1) 0.47 7.29(5H,s) 189143 0.93(3H,t,J=6.4), 1.2-2.0(8H,m), 2.3-2.9(16H,m), 3.46(2H,s), 3.9-4.2(2H,m), 445(M.sup.+ + 1) 0.46 7.26(4H,s) 443 225 223 125144 0.93(3H,t,J=6.4), 1.2-2.0(14H,m), 2.4-2.9(12H,m), 318(M.sup.+ + 1) 0.33 223 111145 0.93(3H,t,J=6.4), 1.2-2.0(8H,m), 2.0-2.9(16H,m), 3.61(2H,t,J=5.2), 3.9-4.2(2H,m) 363(M.sup.+ + 1) 0.09 143 125146 0.93(3H,t,J=6.4), 1.2-2.0(8H,m), 2.3-2.9(16H,m), 3.46(2H,s), 3.9-4.2(2H,m), 427(M.sup.+ + 1) 0.42 6.8-7.1(2H,m), 7.1-7.3(2H,m) 207148 1.21(3Hx2,d,J=6.0), 2.32(3Hx2,s), 2.4-2.7(6H,m), 3.42(1H,sept,J=6.9), 3.6-3.8 280(M.sup.+ + 1) 0.40 (2H,m), 3.8-4.4(4H,m) 114149 1.23(3H,d,J=6.9), 1.24(3H,d,J=6.9), 2.30(3H,s), 2.32(3H,s), 2.3-2.7(10H,m), 369(M.sup.+ + 1) 0.39 3.42(1H,sept,J=6.9), 3.52(2H,s), 3.9-4.2(2H,m), 2049(5H,s)150 1.23(3H,d,J=6.9), 1.25(3H,d,J=6.9), 2.30(3H,s), 2.32(3H,s), 2.3-2.7(10H,m), 405(M.sup.+ + 1) 0.38 3.42(1H,sept,J= 6.9), 3.46(2H,s), 3.8-4.3(2H,m), 4036(4H,s) 223151 1.23(3H,d,J=6.9), 1.24(3H,d,J=6.9), 2.30(3H,s), 2.32(3H,s), 2.3-2.7(10H,m), 413(M.sup.+ + 1) 0.39 3.42(1H,sept,J=6.9), 3.47(2H,s), 3.9-4.2(2H,m), 6.8-7.1(2H,m), 7.1-7.3(2H,m)152 0.88(3H,t,J=7.4), 1.11(3H,d,J=6.9), 1.3-2.0(2H,m), 2.32(3Hx2,s), 2.4-2.8(8H,m) 294(M.sup.+ + 1) 0.44 3.0-3.5(1H,m), 3.6-3.8(4H,m), 4.0-4.4(2H,m) 114 102153 0.88(3H,t,J=7.4), 1.17(3H,d,J=6.9), 1.2-2.0(2H,m), 2.30(3H,s), 2.32(3H,s), 383(M.sup.+ + 1) 0.38 2.3-2.7(10H,m), 3.0-3.4(1H,m), 3.51(2H,s), 3.8-4.3(2H,m), 7.29(5H,s) 189154 0.88(3H,t,J=7.4), 1.17(3H,d,J=6.9), 1.2-2.0(2H,m), 2.31(3Hx2,s), 2.3-2.7(10H, 419(M.sup.+ + 1) 0.34 m), 3.0-3.5(1H,m), 3.47(2H,s), 3.8-4.3(2H,m), 7.26(4H,s) 417 223155 0.88(3H,t,J=7.4), 1.17(3H,d,J=6.8), 1.3-2.0(2H,m), 2.31(3Hx2,s), 2.3-2.7(10H, 401(M.sup.+ + 1) 0.36 m), 3.0-3.5(1H,m), 3.47(2H,s), 4.0-4.3(2H,m), 7.1-7.3(2H,m) 207156 0.94(3H,t,J=6.7), 1.2-1.8(4H,m), 2.31(3H,s), 2.33(3H,s), 2.3-2.9(8H,m), 3.6-3.8 294(M.sup.+ + 1) 0.42 (4H,m), 4.0-4.3(2H,m) 207 114 102157 0.93(3H,t,J=6.7), 1.2-1.9(4H,m), 2.30(3H,s), 2.33(3H,s), 2.3-2.9(12H,m), 3.51 383(M.sup.+ + 1) 0.41 (2H,s), 3.9-4.2(2H,m), 7.29(5H,s) 207158 0.93(3H,t,J=6.7), 1.2-1.8(4H,m), 2.30(3H,s), 2.32(3H,s), 2.3-2.9(12H,m), 3.47 419(M.sup.+ + 1) 0.46 (2H,s), 3.9-4.3(2H,m), 7.26(4H,s) 417 207 125159 1.1-1.4(12H,m), 2.4-2.8(10H,m), 3.42(1H,sept,J=6.8), 3.8-4.4(6H,m) 308(M.sup.+ + 1) 0.47 239 113160 1.1-1.4(12H,m), 2.3-2.8(14H,m), 3.41(1H,sept,J=6.9), 3.52(2H,s), 3.8-4.3(2H,m), 396(M.sup.+ + 1) 0.49 7.29(5H,s) 189161 1.1-1.4(12H,m), 2.4-2.8(14H,m), 3.41(1H,sept,J=6.8), 3.48(2H,s), 3.8-4.3(2H,m), 433(M.sup.+ + 1) 0.48 7.26(4H,s) 431 236 223 125162 1.20(3Hx2,t,J=7.3), 1.21(3Hx2,d,J=6.8), 2.4-2.8(14H,m), 3.41(1H,sept,J=6.8), 415(M.sup.+ + 1) 0.43 3.48(2H,s), 3.9-4.3(2H,m), 6.8-7.1(2H,m), 7.1-7.3(2H,m) 207163 1.0-1.7(18H,m), 2.4-2.8(10H,m), 3.42(1H,sept,J=6.8), 3.8-4.3(2H,m) 306(M.sup.+ + 1) 0.44 239 221164 1.1-1.4(12H,m), 2.4-2.8(14H,m), 3.41(1H,sept,J=6.8), 3.48(2H,s), 3.9-4.3(2H,m), 415(M.sup.+ + 1) 0.13 6.8-7.1(2H,m), 7.1-7.3(2H,m) 207165 1.1-1.4(12H,m), 2.4-2.8(14H,m), 3.42(1H,sept,J=6.8), 3.48(2H,s), 3.8-4.3(2H,m), 433(M.sup.+ + 1) 0.40 7.1-7.3(4H,m) 431 223166 0.94(3H,d,J=6.7), 0.95(3H,d,J=6.7), 1.20(3H,t,J=7.4), 1.21(3H,t,J=7.4), 2.4-2.5 429(M.sup.+ + 1) 0.46 (1H,sept,J=6.7), 2.3-2.9(16H,m), 3.48(2H,s), 3.8-4.3(2H,m), 6.8-7.1(2H,m), 7.1- 220 7.4(2H,m) 207167 0.95(3Hx2,d,J=6.4), 1.21(3Hx2,t,J=7.4), 2.0-2.4(1H,m), 2.4-2.8(12H,m), 3.5-3.8 322(M.sup.+ + 1) 0.41 (4H,m), 4.0-4.3(2H,m)168 0.94(3H,d,J=6.7), 0.95(3H,d,J=6.7), 1.20(3H,t,J=7.3), 1.21(3H,t,J=7.3), 2.0-2.5 447(M.sup.+ + 1) 0.44 (1H,m), 2.3-2.9(16H,m), 3.47(2H,s), 3.9-4.3(2H,m), 4456(4H,s) 223170 0.94(3Hx2,d,J=6.7), 1.20(3H,t,J=6.7), 1.21(3H,t,J=6.5), 2.0-2.4(1H,m), 2.3-2.8 411(M.sup.+ + 1) 0.36 (16H,m), 3.51(12H,s), 4.0-4.3(2H,m), 7.29(5H,m) 189171 0.88(3H,t,J=7.4), 1.17(3H,d,J=6.8), 1.22(3Hx2,t,J=7.2), 1.3-2.0(8H,m), 2.4-2.8 320(M.sup.+ + 1) 0.38 (10H,m), 3.0-3.4(1H,m), 4.1-4.3(2H,m) 111172 0.88(3H,t,J=7.3), 1.17(3H,d,J=6.3), 1.21(3Hx2,t,J=7.2), 1.4-2.0(2H,m), 2.3-2.8 365(M.sup.+ + 1) 0.09 (6H,m), 3.1-3.3(1H,m), 3.61(2H,t,J.apprxeq.5.4), 156-4.3(2H,m)173 0.88(3H,t,J=7.5), 1.17(3H,d,J=6.8), 1.21(3Hx2,t,J=7.1), 1.2-1.9(2H,m), 2.4-2.8 322(M.sup.+ + 1) 0.42 (10H,m), 3.1-3.4(1H,m), 3.6-4.0(4H,m), 4.0-4.3(2H,m) 103174 0.87(3H,t,J=7.2), 1.16(3H,d,J=6.8), 1.20(3Hx2,t,J=6.6), 1.3-1.9(2H,m), 2.4-2.8 411(M.sup.+ + 1) 0.43 (14H,m), 3.0-3.4(1H,m), 3.53(2H,s), 4.1-4.3(2H,m), 7.30(5H,s)175 0.87(3H,t,J=7.4), 1.1-1.3(9H,m), 1.3-2.0(2H,m), 2.4-2.7(14H,m), 3.0-3.4(1H,m), 429(M.sup.+ + 1) 0.42 3.47(2H,s), 3.9-4.3(2H,m), 6.8-7.1(2H,m), 7.1-7.3(2H,m) 220176 0.88(3H,t,J=7.6), 1.17(3H,d,J=7.1), 1.21(3Hx2,t,J=7.1), 1.4-2.0(2H,m), 2.3-2.8 447(M.sup.+ + 1) 0.42 (14H,m), 3.0-3.4(1H,m), 3.47(2H,s), 4.0-4.3(2H,m), 4456(4H,s) 223177 0.87(3H,t,J=7.2), 1.17(3H,d,J=6.8), 1.21(3Hx2,t,J=6.9), 1.2-2.0(2H,m), 2.3-2.8 447(M.sup.+ + 1) 0.39 (14H,m), 3.1-3.4(1H,m), 3.48(2H,s), 4.0-4.3(2H,m), 445-7.4(4H,m) 223178 0.93(3H,t,J=6.4), 1.20(3Hx2,t,J=7.4), 1.2-1.9(4H,m), 2.2-2.9(16H,m), 3.63(2H, 447(M.sup.+ + 1) 0.43 s), 3.9-4.3(2H,m), 7.1-7.5(4H,m) 445 223179 0.93(3H,t,J=6.4), 1.20(3Hx2,t,J=7.5), 1.2-1.9(4H,m), 2.2-2.8(16H,m), 3.52(2H, 411(M.sup.+ + 1) 0.46 s), 3.9-4.3(2H,m), 7.29(5H,s) 189180 0.93(3H,t,J=6.4), 1.21(3Hx2,t,J=7.4), 1.2-1.9(4H,m), 2.2-2.9(16H,m), 3.47(2H, 447(M.sup.+ + 1) 0.43 s), 3.9-4.3(2H,m), 7.26(4H,s) 445 223181 0.94(3H,t,J=6.6), 1.20(3H,t,J=7.6), 1.23(3H,t,J=7.6), 1.2-1.9(10H,m), 2.4-2.9 320(M.sup.+ + 1) 0.40 (12H,m), 4.1-4.4(2H,m)182 0.94(3H,t,J=6.6), 1.21(3H,t,J=7.6), 1.23(3H,t,J=7.6), 1.2-1.9(4H,m), 2.4-2.9( 322(M.sup.+ + 1) 0.39 12H,m), 3.6-4.0(4H,m), 3.9-4.3(2H,m) 113183 0.93(3H,t,J=6.6), 1.20(3Hx2,t,J=7.5), 1.2-1.8(4H,m), 2.3-2.9(16H,m), 3.47(2H, 429(M.sup.+ + 1) 0.42 s), 3.9-4.3(2H,m), 6.8-7.1(2H,m), 7.1-7.4(2H,m) 207185 0.94(3H,t,J=6.4), 1.21(3Hx2,t,J=7.4), 1.2-1.8(4H,m), 2.2-2.9(16H,m), 3.48(2H, 447(M.sup.+ + 1) s), 4.0-4.3(2H,m) 445 223187 1.22(3Hx2,t,J=7.3), 1.23(3H,t,J=7.3), 2.4-2.9(12H,m), 3.6-3.8(4H,m), 3.8-4.3( 294(M.sup.+ + 1) 0.39 2H,m), 207188 1.21(3Hx2,t,J=7.3), 1.22(3H,t,J=7.3), 2.3-2.9(16H,m), 3.48(2H,s), 3.8-4.3(2H, 419(M.sup.+ + 1) 0.40 m), 7.26(4H,s) 417 225189 1.21(3Hx2,t,J=7.3), 1.22(3H,t,J=7.3), 2.4-2.9(16H,m), 3.54(2H,s), 3.8-4.3(2H, 383(M.sup.+ + 1) 0.40 m), 7.29(5H,s) 189190 1.23(3H,t,J=7.5), 2.32(3Hx2,s), 2.2-2.7(6H,m), 2.78(2H,q,J=7.5), 3.6-3.8(4H,m), 266(M.sup.+ + 1) 0.56 4.16(2H,t,J=7.2) 179 174191 1.22(3H,t,J=7.5), 2.31(3Hx2,s), 2.3-2.7(10H,m), 2.78(2H,q,J=7.5), 3.46(2H,s), 391(M.sup.+ + 1) 0.49 3.9-4.3 (2H,m), 7.26(4H,s) 389192 1.22(3H,t,J=7.5), 2.31(3H,s), 2.33(3H,s), 2.3-2.7(10H,m), 2.78(2H,q,J=7.5), 373(M.sup.+ + 1) 0.42 3.47(2H,s), 3.9-4.3(2H,m), 6.8-7.3(4H,m) 207 179193 1.22(3H,t,J=7.5), 2.31(3H,s), 2.33(3H,s), 2.3-2.7(10H,m), 2.78(2H,q,J=7.5), 385(M.sup.+ + 1) 0.50 3.45(2H,s), 3.79(3H,s), 3.8-4.2(2H,m), 6.7-6.9(2H,m), 7.1-7.3(2H,m) 219250 0.89(3H,t,J.apprxeq.6.5), 1.1-1.9(10H,m), 2.3-2.8(16H,m), 3.47(2H,s), 3.8-4.2(2H,m), 459(M.sup.+ + 1) 0.36 7.26(4H,s) 457 247 223251 0.89(3H,t,J.apprxeq.6.5), 1.1-1.9(10H,m), 2.3-2.8(16H,m), 3.48(2H,s), 3.8-4.2(2H,s), 441(M.sup.+ + 1) 0.35 6.8-7.3(4H,m) 247 207252 0.89(3H,t,J.apprxeq.6.5), 1.1-1.5(4H,m), 1.5-1.9(6H,m), 2.4-2.8(12H,m), 3.5-3.7(4H,m), 334(M.sup.+ + 1) 0.35 3.8-4.2(2H,m) 114253 0.8-1.0(6H,m), 1.1-1.9(14H,m), 2.2-2.8(18H,m), 3.9-4.1(2H,m) 389(M.sup.+ + 1) 0.29 155 125254 0.89(3H,t,J.apprxeq.6.5), 1.1-1.9(10H,m), 2.3-2.8(16H,m), 3.47(2H,s), 3.80(3H,s), 3.8- 453(M.sup.+ + 1) 0.34 4.2(2H,m), 6.84(2H,d,J=8.6), 7.22(2H,d,J=8.6) 247 219 111255 0.88(3H,t,J.apprxeq.6.3), 1.1-1.9(12H,m), 2.4-2.9(12H,m), 3.6-3.8(4H,m), 3.9-4.2(2H,m) 348(M.sup.+ + 1) 0.51 113256 0.87(3H,t,J.apprxeq.6.3), 1.1-1.9(12H,m), 2.3-2.8(16H,m), 3.47(2H,s), 3.9-4.2(2H,m), 473 471 0.49 7.26(4H,s) (M.sup.+ + 1) 238 236 112257 0.87(3H,t,J.apprxeq.6.3), 1.1-1.9(12H,m), 2.3-2.8(16H,m), 3.59(2H,s), 3.9-4.2(2H,m), 482(M.sup.+ + 1) 0.42 7.50(2H,d,J=8.8), 8.16(2H,d,J=8.8) 347 234 112258 0.87(3H,t,J.apprxeq.6), 1.2-2.0(14H,m), 2.5-2.9(16H,m), 3.60(2H,s), 3.9-4.2(2H,s), 469(M.sup.+ + 1) 0.46 6.8-7.4(4H,m) 235 221259 0.87(3H,t,J=6.5), 1.1-1.9(14H,m), 2.4-2.9(12H,m), 3.4-3.8(4H,m), 3.9-4.2(2H,m) 362(M.sup.+ + 1) 0.41 114260 0.87(3H,t,J.apprxeq.6), 1.1-1.9(14H,m), 2.3-2.9(16H,m), 3.47(2H,s), 3.9-4.2(2H,m), 485 487 0.40 7.26(4H,s) (M.sup.+ + 1) 223261 0.87(3H,t,J.apprxeq.6), 1.1-1.9(14H,m), 2.4-2.8(16H,m), 3.59(2H,s), 3.9-4.2(2H,m), 496(M.sup.+ + 1) 0.46 7.49(2H,d,J.apprxeq.8.8), 8.17(2H,d,J=8.8) 234262 0.87(3H,t,J.apprxeq.6), 1.1-1.9(14H,m), 2.3-2.9(16H,m), 3.49(2H,s), 3.9-4.1(2H,m), 469(M.sup.+ + 1) 0.42 6.8-7.3(4H,m) 275 207263 0.8-1.0(6H,m), 1.1-1.6(12H,m), 1.5-1.9(6H,m), 2.1-2.9(18H,m), 3.9-4.2(2H,m) 417(M.sup.+ + 1) 0.43 155264 0.87(3H,t,J=6), 1.1-2.0(16H,m), 2.5-2.9(16H,m), 3.59(2H,s), 3.9-4.2(2H,m), 498 500 0.45 7.27(4H,s) (M.sup.+ + 1) 250 237265 0.87(3H,t,J.apprxeq.6), 1.1-1.9(16H,m), 2.4-2.9(12H,m), 3.6-3.8(4H,m), 3.9-4.2(2H,m) 376(M.sup.+ + 1) 0.47 114266 0.87(3H,t,J.apprxeq.6), 1.1-1.9(16H,m), 2.3-2.9(16H,m), 3.47(2H,s), 3.9-4.2(2H,m), 499 501 0.43 7.26(4H,s) (M.sup.+ + 1) 289 223267 0.87(3H,t,J.apprxeq.6), 1.1-2.0(16H,m), 2.3-2.9(16H,m), 3.46(2H,s), 3.80(3H,s), 3.9- 495(M.sup.+ + 1) 0.42 4.1(2H,m), 6.84(2H,d,J=8.6), 7.22(2H,d,J=8.6) 232268 0.87(3H,t,J.apprxeq.6), 1.1-2.0(16H,m), 2.3-2.9(16H,m), 3.59(2H,s), 3.8-4.2(2H,m), 7.5 510(M.sup.+ + 1) 0.46 (2H,d,J=8.8), 8.17(2H,d,J=8.8) 234269 0.87(3H,t,J.apprxeq.6), 1.1-2.0(16H,m), 2.3-2.9(16H,m), 3.47(2H,s), 3.9-4.2(2H,m), 6.8 483(M.sup.+ + 1) 0.51 -7.3(4H,m) 289 207270 0.87(3H,t,J.apprxeq.6), 1.1-2.0(18H,m), 2.5-2.9(16H,m), 3.59(2H,s), 3.9-4.1(2H,m), 6.8 497(M.sup.+ + 0.45 -7.3(4H,m) 235 221271 0.87(3H,t,J.apprxeq.6), 1.1-1.9(18H,m), 2.4-2.9(12H,m), 3.6-3.8(4H,m), 3.9-4.2(2H,m) 390(M.sup.+ + 1) 0.48272 0.87(3H,t,J.apprxeq.6), 1.1-1.9(18H,m), 2.3-2.9(16H,m), 3.46(2H,s), 3.9-4.2(2H,m), 513 515 0.51 7.26(4H,s) (M.sup.+ + 1) 223273 0.87(3H,t,J.apprxeq.6), 1.1-1.9(18H,m), 2.4-2.9(16H,m), 3.46(2H,s), 3.9-4.2(2H,m), 6.8 497(M.sup.+ + 1) 0.48 -7.3(4H,m) 207274 0.87(3H,t,J.apprxeq.6), 1.1-1.9(18H,m), 2.3-2.9(16H,m), 3.59(2H,s), 3.9-4.3(2H,m), 524(M.sup.+ + 1) 0.52 7.50(2H,d,J=8.8), 8.17(2H,d,J=8.8) 247 234275 0.87(3H,t,J.apprxeq.6), 1.1-2.0(18H,m), 2.3-2.9(16H,m), 3.47(2H,s), 3.80(3H,s), 3.9- 509(M.sup.+ + 1) 0.43 4.2(2H,m), 6.85(2H,d,J=8.8), 7.23(2H,d,J=8.8) 232 219276 0.87(3H,t,J.apprxeq.6), 1.1-1.9(24H,m), 2.4-2.9(12H,m), 3.6-3.8(4H,m), 3.9-4.2(2H,m) 432(M.sup.+ + 1) 0.45277 0.87(3H,t,J.apprxeq.6), 1.1-2.0(24H,m), 2.3-2.9(16H,m), 3.47(2H,s), 3.9-4.2(2H,m), 555 557 0.44 7.26(4H,s) (M.sup.+ + 1) 345 236 223278 0.87(3H,t,J.apprxeq.6), 1.1-2.0(26H,m), 2.5-2.9(16H,m), 3.59(2H,s), 3.9-4.1(2H,m), 6.8 553(M.sup.+ + 1) 0.46 -7.3(4H,m) 235 221279 0.87(3H,t,J.apprxeq.6), 1.1-2.0(24H,m), 2.3-2.9(16H,m), 3.58(3H,s), 3.9-4.3(2H,m), 566(M.sup.+ + 1) 0.47 7.49(2H,d,J=8.6), 8.17(2H,d,J=8.6) 431 247 112280 0.88(3H,t,J.apprxeq.6), 1.1-1.9(28H,m), 2.4-2.9(12H,m), 3.5-3.7(4H,m), 3.9-4.2(2H,m) 460(M.sup.+ + 1) 0.53 114281 0.88(3H,t,J.apprxeq.6), 1.1-2.0(28H,m), 2.3-2.9(16H,m), 3.45(2H,s), 3.79(3H,s), 3.9- 579(M.sup.+ + 1) 0.44 4.2(2H,m), 6.84(2H,d,J=8.7), 7.22(2H,d,J=8.7) 232 219282 0.88(3H,t,J.apprxeq.6), 1.1-2.0(30H,m), 2.5-2.9(16H,m), 3.59(3H,s), 3.9-4.1(2H,m), 6.8 581(M.sup.+ + 1) 0.50 -7.3(4H,m) 234 221283 0.88(3H,t,J.apprxeq.6), 1.1-1.7(32H,m), 2.4-2.9(12H,m), 3.5-3.7(4H,m), 3.9-4.2(2H,m) 488(M.sup.+ + 1) 0.54 114284 0.88(3H,t,J.apprxeq.6), 1.1-2.0(32H,m), 2.3-2.9(16H,m), 3.46(2H,s), 3.9-4.2(2H,m), 611 613 0.50 7.26(4H,s) (M.sup.+ + 1) 279 236285 0.88(3H,t,J.apprxeq.6), 1.1-2.0(32H,m), 2.3-2.9(16H,m), 3.58(2H,s), 3.9-4.2(2H,m), 622(M.sup.+ + 1) 0.50 7.49(2H,d,J=8.8), 8.19(2H,d,J=8.8) 419 208286 0.88(3H,t,J.apprxeq.6), 1.1-2.0(34H,m), 2.5-2.9(16H,m), 3.59(2H,s), 3.8- 4.1(2H,m), 627 625 0.48 7.26(4H,s) (M.sup.+ + 1) 307 250287 1.23(3H,t,J=7.5), 2.31(3Hx2,s), 2.3-3.0(12H,m), 3.51(2H,s), 3.9-4.3(2H,m), 355(M.sup.+ + 1) 0.49 7.29(5H,s) 179288 1.23(3H,t,J=7.5), 1.6-1.9(2H,m), 2.31(3Hx2,s), 2.4-3.0(12H,m), 3.59(2H,s),3.9 391(M.sup.+ + 1) 0.40 -4.2(2H,m), 7.27(4H,s) 389289 1.23(3H,t,J=7.5), 1.6-1.9(2H,m), 2.31(3Hx2,s), 2.4-3.0(12H,m), 3.60(2H,s), 387(M.sup.+ + 1) 0.39 3.9-4.2(2H,m), 6.8-7.4(4H,m) 225 221 179290 1.23(3H,t,J=7.5), 2.31(3Hx2,s), 2.3-3.0(12H,m), 3.59(2H,s), 3.9-4.3(2H,m), 400(M.sup.+ + 1) 0.44 7.50(2H,d,J=8.7), 8.17(2H,d,J=8.7) 234 179291 1.21(3Hx2,t,J=7.6), 2.4-2.8(10H,m), 3.5-3.7(2H,m), 3.8-4.2(4H,m), 4.09(2H,s), 356 0.36 7.0-7.4(5H,m)292 1.18(3H,t,J=7.6), 1.20(3H,t,J=7.6), 1.3-1.8(6H,m), 2.3-2.8(10H,m), 3.8-4.3(2H, 354 0.40 m), 4.09(2H,s), 7.0-7.5(5H,m)293 1.18(3H,t,J=7.6), 1.20(3H,t,J=7.6), 2.3-2.8(14H,m), 3.50(2H,s), 3.8-4.2(2H,m), 444 0.36 4.08(2H,s), 7.0-7.4(10H,m) 202 189294 1.18(3H,t,J=7.6), 1.20(3H,t,J=7.6), 2.3-2.8(14H,m), 3.45(2H,s) 3.8-4.2(2H,m), 479, 481 0.36 4.08(2H,s), 7.0-7.4(9H,m) 236295 1.19(3H,t,J=7.6), 1.20(3H,t,J=7.6), 2.3-2.8(14H,m), 3.56(2H,s), 4.09(2H,s), 513,515 0.60 3.8- 4.2(2H,m), 7.0-7.4(8H,m) 517 237 219296 1.18(3H,t,J=7.6), 1.20(3H,t,J=7.6), 2.2.2.8(14H,m), 3.45(2H,s), 3.8-4.2(2H,m), 462 0.37 4.08(2H,s), 6.8-7.4(9H,m) 207297 1.18(3H,t,J=7.6), 1.20(3H,t,J=7.6), 2.2-2.7(14H,m), 3.43(2H,s), 3.79(3H,s), 474 0.37 3.8-4.2(2H,m), 4.08(2H,s), 6.83(2H,d,J=8.8), 7.0-7.4(7H,m) 232 219305 0.87(3H,t,J.apprxeq.5.7), 1.2-2.0(12H,m), 2.4-2.9(12H,m), 3.0-3.4(6H,m), 4.0-4.3(2H, 423,422 0.65 m), 7.1-7.3(5H,m) 174306 0.87(3H,t,J.apprxeq.5.7), 1.2-2.0(12H,m), 2.3-2.9(16H,m), 3.51(2H,s), 3.9-4.2(2H,m), 437 0.36 7.29(5H,s) 189307 0.87(3H,t,J.apprxeq.5.7), 1.2-2.0(12H,m), 2.3-2.9(16H,m), 3.46(2H,s), 3.9-4.2(2H,m), 455 0.38 6.8-7.4(14H,m) 207308 0.87(3H,t,J.apprxeq.5.7), 1.2-2.0(12H,m), 2.3-2.9(16H,m), 3.45(2H,s), 3.79(3H,s), 3.9- 467 0.40 4.2(2H,m), 6.84(2H,d,J=8.6), 7.22(2H,d,J=8.6) 219309 0.87(3H,t,J.apprxeq.5.7), 1.2-2.0(12H,m), 2.6-2.9(12H,m), 3.0-3.2(4H,m), 4.0-4.3(2H, 457,459 0.36 m), 6.8-7.4(4H,m) 209310 0.87(3H,t,J.apprxeq.5.7), 1.2-2.0(12H,m), 2.6-2.9(12H,m), 3.0-3.2(4H,m), 3.89(3H,s), 453 0.53 4.0-4.3(2H,m), 7.7-8.1(4H,m) 203311 0.87(3H,t,J.apprxeq.5.6), 1.2-2.0(14H,m), 2.6-3.0(16H,m), 3.72(2H,s), 3.9-4.2(2H,m), 496 0.43 7.51(2H,d,J=8.8), 8.17(2H,d,J=8.8) 301 248312 0.87(3H,t,J.apprxeq.5.6), 1.2-2.0(14H,m), 2.5-3.0(16H,m), 3.59(2H,s), 3.9-4.2(2H,m), 485,487 0.49 7.28(4H,s) 237313 0.87(3H,t,J.apprxeq.5.7), 1.2-2.0(14H,m), 2.6-2.9(16H,m), 3.58(2H,s), 3.80(3H,s), 3.9- 481 0.48 4.2(2H,m), 6.84(2H,d,J=8.8), 7.24(2H,d, J=8.8) 247 233314 0.87(3H,t,J.apprxeq.5.7), 1.1-1.9(14H,m), 2.3-2.9(16H,m), 3.51(2H,s), 3.9-4.1(2H,m), 451 0.48 7.30(5H,s) 189315 0.87(3H,t,J.apprxeq.5.6), 1.1-1.9(14H,m),2.5-2.9(12H,m), 3.1-3.3(4H,m), 4.0-4.2(2H,m), 437 0.60 6.7-8.3(5H,m) 189 175316 0.87(3H,t,J.apprxeq.5.6), 1.1-2.0(14H,m), 2.5-2.9(12H,m), 2.9-3.2(4H,m), 3.86(3H,s), 467 0.65 3.9-4.2(2H,m), 6.7-7.1(4H,m) 203317 0.87(3H,t,J.apprxeq.5.6), 1.1-2.0(14H,m), 2.5-2.9(12H,m), 2.9-3.2(4H,m), 4.0-4.2(2H, 471,473 0.72 m), 6.7-7.4(4H,m) 209318 0.87(3H,t,J.apprxeq.5.6), 1.1-2.0(16H,m), 2.5-2.9(16H,m), 3.59(2H,s), 3.9-4.1(2H,m), 483 0.40 6.8-7.3(4H,m) 221319 0.87(3H,t,J.apprxeq.5.6), 1.2-2.0(16H,m), 2.5-3.0(16H,m), 3.58(2H,s), 3.8(3H,s), 3.9- 495 0.44 4.2(2H,m), 6.84(2H,d,J=8.8), 7.24(2H,d,J=8.8) 246,247320 0.87(3H,t,J.apprxeq.5.6), 1.1-2.0(16H,m), 2.5-2.9(16H,m), 3.72(2H,s), 3.9-4.1(2H,m), 510 0.45 7.51(2H,d,J=8.8), 8.17(2H,d,J=8.8)321 0.87(3H,t,J.apprxeq.5.6), 1.0-2.0(16H,m), 2.3-2.8(16H,m), 3.51(2H,s), 3.9-4.2(2H,m), 465 0.50 7.29(5H,s) 189322 0.87(3H,t,J.apprxeq.6), 1.0-2.0(16H,m), 2.5-2.9(12H,m), 3.0-3.3(4H,m), 4.0-4.2(2H,m), 451 0.55 6.7-7.4(5H,m) 175323 0.87(3H,t,J.apprxeq.6), 1.1-2.0(16H,m), 2.5-2.9(12H,m), 2.9-3.2(4H,m), 3.58(3H,s), 481 0.57 4.0-4.2(2H,m), 6.7-7.1(4H,m) 205324 0.87(3H,t,J.apprxeq.6), 1.0-2.0(16H,m), 2.5-2.9(12H,m), 2.9-3.2(4H,m), 4.0-4.2(2H,m), 485,487 0.52 6.8-7.4(4H,m) 209325 0.87(3H,t,J.apprxeq.5.6), 1.1-2.0(18H,m), 2.5-3.0(16H,m), 3.72(2H,s), 3.9-4.2(2H,m), 523 0.41 7.51(2H,d,J.apprxeq.8.8), 8.17(2H,d,J=8.8) 339 248326 0.87(3H,t,J.apprxeq.6), 1.1-2.2(18H,m), 2.5-3.0(16H,m), 3.58(2H,s), 3.80(3H,s), 3.9- 509 0.41 4.2(2H,m), 6.84(2H,d,J=8.8), 7.24(2H,d,J=8.8) 247 233327 0.87(3H,t,J.apprxeq.6), 1.1-2.2(18H,m), 2.5-3.0(16H,m), 3.59(2H,s), 3.9-4.2(2H,m), 513,515 0.43 7.26(4H,s) 237328 0.87(3H,t,J.apprxeq.6), 1.2-2.2(18H,m), 2.4-2.9(16H,m), 3.51(2H,s), 3.9-4.2(2H,m), 479 0.48 7.29(5H,s) 189329 0.87(3H,t,J.apprxeq.6), 1.1-2.1(20H,m), 2.4-3.0(16H,m), 3.59(2H,s), 3.9-4.2(2H,m), 527,529 0.49 7.26(4H,s) 237330 0.87(3H,t,J.apprxeq.6), 1.1-2.2(20H,m), 2.5-3.0(16H,m), 3.72(2H,s), 3.9-4.2(2H,m), 538 0.51 7.51(2H,d,J.apprxeq.8.8), 8.17(2H,d,J=8.8) 402331 0.87(3H,t,J.apprxeq.6), 1.1-2.2(20H,m), 2.5-3.0(16H,m), 3.60(2H,s), 3.9-4.2(2H,m), 511 0.45 6.8-7.4(4H,m) 220332 0.87(3H,t,J.apprxeq.6), 1.1-2.2(20H,m), 2.5-3.0(16H,m), 3.58(2H,s), 3.80(3H,s), 3.9- 523 0.43 4.2(2H,m), 6.84(2H,d,J=8.4), 7.24(2H,d,J=8.4) 247 233334 0.87(3H,t,J.apprxeq.6), 1.1-2.0(20H,m), 2.3-2.9(12H,m), 3.5-3.8(4H,m), 3.9-4.2(2H,m) 404 0.46 102335 0.87(3H,t,J.apprxeq.6), 1.1-2.2(20H,m), 2.3-2.9(16H,m), 3.51(2H,s), 3.9-4.2(2H,m), 493 0.47 7.29(5H,s) 189336 0.87(3H,t,J.apprxeq.6), 1.0-2.0(20H,m), 2.5-2.9(12H,m), 3.0-3.3(4H,m), 3.9-4.2(2H,m), 479 0.54 6.7-7.4(4H,m) 190 175337 0.87(3H,t,J.apprxeq.6), 1.0-2.0(20H,m), 2.1-2.9(16H,m), 3.45(2H,s), 3.79(3H,s), 3.9- 523 0.47 4.2(2H,m), 6.84(2H,d,J=8.8), 7.12(2H,d,J=8.8) 232 219338 0.87(3H,t,J.apprxeq.6), 1.0-2.2(20H,m), 2.3-2.9(16H,m), 3.9-4.2(2H,m), 7.26(4H,s) 527,529 0.48 235 223339 0.87(3H,t,J.apprxeq.6), 1.0-2.0(22H,m), 2.5-3.0(16H,m), 3.72(2H,s), 3.9-4.2(2H,m), 552 0.49 7.51(2H,d,J=8.8), 8.17(2H,d,J=8.8) 417 248340 0.87(3H,t,J.apprxeq.6), 1.1-2.1(22H,m), 2.5-3.0(16H,m), 3.60(2H,s), 3.9-4.2(2H,m), 541,543 0.48 7.27(4H,s) 251 237374 1.21(3Hx2,t,J=7.6), 1.7-2.0(4H,m), 2.1-3.3(11H,m), 4.10(2H,s), 4.1-4.3(2H,m), 430 0.74 7.1-7.5(10H,m) 134375 0.91(3H,d,J=4.9), 1.19(3H,t,J=7.7), 1.20(3H,t,J=7.7), 1.4-2.3(5H,m), 2.4-3.0 368 0.53 (10H,m), 3.9-4.2(2H,m), 4.09(2H,s), 7.1-7.5(5H,m) 112378 1.19(3H,t,J=7.6), 1.20(3H,t,J=7.6), 2.4-2.7(14H,m), 3.58(2H,s), 4.09(2H,s), 490 0.49 3.8-4.3(2H,m), 7.1-7.5(7H,m), 8.16(2H,d,J=8.8) 247 191380 1.21(3Hx2,t,J.apprxeq.7.6),2.4-3.6(14H,m),4.10(2H,s), 4.0-4.4(2H,m), 6.8-7.5(10H,m) 431 0.63 188,189 175384 1.20(3Hx2,t,J.apprxeq.7.4),2.2-2.8(10H,m), 3.6-4.3(6H,m), 4.04(2H,s), 7.1-7.4(4H,m) 392 0.43 390 114385 1.19(3Hx2,t,J.apprxeq.7.6), 2.2-2.8(14H,m), 3.46(2H,s), 3.8-4.3(2H,m), 4.04(2H,s), 7.1 517 0.48 -7.4(8H,m) 515 513 303 223386 1.19(3Hx2,t,J.apprxeq.7.6), 2.1-2.8(14H,m), 3.46(2H,s), 3.79(3H,s), 3.9-4.2(2H,m), 511 0.42 4.03(2H,s), 6.84(2H,d,J.apprxeq.8.8), 7.1-7.4(6H,m) 509 232 219387 1.19(3H,t,J=7.1), 1.20(3H,t,J=7.1), 2.3-2.8(14H,m), 3.47(2H,s), 4.05(2H,s), 526 0.43 4.1-4.3(2H,m), 7.52(2H,d,J=8.8), 7.26(4H,s), 8.17(2H,d,J=8.8) 524 247454 1.23(3H,t,J.apprxeq.7.4), 2.32(3H,s), 2.33(3H,s), 2.4-3.0(13H,m), 4.0-4.2(2H,m) 265 179455 1.22(3H,t,J.apprxeq.7.4), 2.30(3Hx2,s), 2.2-3.0(8H,m), 3.44(2H,t,J.apprxeq.5), 3.65(2H,t,J.apprxeq.5), 383 3.72(2H,s), 4.0-4.2(2H,m), 7.1-7.4(5H,m) 217 139456 1.22(3H,t,J=7.4), 2.32(3Hx2,s), 2.4-2.9(8H,m), 3.3-3.8(4H,m), 4.0-4.3(2H,m), 405 7.36(4H,s) 403 251 237457 1.23(3H,t,J=7.4), 2.31(3Hx2,s), 2.3-2.9(8H,m), 3.51(2H,t,J.apprxeq .5), 3.65(2H,t,J.apprxeq.5), 389 3.90(2H,s), 4.0-4.2(2H,m), 6.8-7.3(3H,m) 223458 1.22(3H,t,J=7.4), 2.32(3Hx2,s), 2.4-3.0(8H,m), 3.2-3.5(2H,m), 3.5-3.9(2H,m), 414 4.0-4.3(2H,m), 7.56(2H,d,J.apprxeq.8.8), 8.23(2H,d,J=8.8) 262 248459 1.23(3H,t,J=7.4), 2.31(3Hx2,s), 2.4-3.0(8H,m), 3.48(2H,t,J.apprxeq .5), 3.65(2H,t,J=5), 428 3.81(2H,s), 4.0-4.3(2H,m), 7.41(2H,d,J=8.6), 8.19(2H,d,J=8.6) 265460 1.23(3H,t,J=7.4), 2.32(3Hx2,s), 2.4-2.9(8H,m), 3.5-3.7(4H,m), 3.83(3H,s), 4.0- 399 4.3(2H,m), 6.8-7.0(2H,m), 7.3-7.5(2H,m) 247 233461 1.22(3H,t,J=7.4), 2.31(3Hx2,s), 2.2-3.0(8H,m), 3.1-3.4(2H,m), 3.6-3.9(2H,m), 429 3.85(3H,s), 3.88(3H,s), 4.0-4.3(2H,m), 6.7-7.2(3H,m) 277 263 164462 1.22(3H,t,J=7.4), 2.31(3Hx2,s), 2.2-3.0(8H,m), 3.1-3.4(2H,m), 3.6-3.8(2H,m), 429 3.82(3Hx2,s), 4.0-4.3(2H,m), 6.5-6.7(2H,m), 7.0-7.2(1H,m) 277 263 164463 1.23(3H,t,J=7.4), 2.32(3Hx2,s), 2.4-3.0(8H,m), 3.7-3.9(4H,m), 3.90(3H,s), 3.91 429 (3H,s), 4.0-4.3(2H,m), 6.7-7.0(3H,m) 277 263 164464 1.22(3H,t,J=7.4), 2.32(3Hx2,s), 2.4-3.0(8H,m), 3.4-3.8(4H,m), 3.87(3Hx2,s), 459 4.0-4.3(2H,m), 6.61(2H,s) 306 195465 1.17(3H,t,J.apprxeq.7.4), 2.27(3Hx2,s), 2.4-2.9(8H,m), 2.9-3.1(4H,m), 3.9-4.2(2H,m), 441 7.4-7.8(4H,m) 439 287 283467 1.18(3Hx2,t,J.apprxeq.7.4), 2.3-2.8(14H,m), 3.51(2H,s), 3.9-4.2(2H,m), 4.03(2H,s), 7.1 481(M.sup.+ + 1) 0.42 -7.4(9H,m) 479468 1.19(3H,t,J.apprxeq.7.4), 1.20(3H,t,J.apprxeq.7.4), 2.3-2.8(14H,m), 3.58(2H,s), 3.8-4.0(2H,m), 526(M.sup.+ + 1) 4.05(2H,s), 4.1-4.3(2H,m), 7.0-7.5(2H,m), 7.26(4H,s), 8.17(2H,d,J=8.8) 524 247470 1.6-2.0(4H,m), 2.4-2.8(10H,m), 3.5-3.8(4H,m), 3.9-4.2(2H,m), 4.09(2H,s), 7.0- 354(M.sup.+ + 1) 7.5(5H,m) 114471 1.6-2.0(4H,m), 2.3-2.8(14H,m), 3.50(2H,s), 3.9-4.1(2H,m), 4.09(2H,s), 7.1-7.5 443(M.sup.+ + 1) (10H,m) 189472 1.6-2.0(4H,m), 2.5-2.9(1oH,m), 3.0-3.3(4H,m), 3.9-4.2(2H,m), 4.10(2H,s), 6.7- 429(M.sup.+ + 1) 7.5(10H,m) 175473 1.6-2.0(4H,m), 2.3-2.8(14H,m), 3.45(2H,s), 3.9-4.1(2H,m), 4.09(2H,s), 7.1-7.5 479(M.sup.+ + 1) (5H,m), 7.25(4H,s) 477 223474 1.6-2.0(4H,m), 2.3-2.8(14H,m), 3.44(2H,s), 3.79(3H,s), 3.9-4.1(2H,m), 4.09( 473(M.sup.+ + 1) 2H,s), 6.84(2H,d,J.apprxeq.8.8), 7.0-7.5(7H,m) 219475 1.6-2.0(4H,m), 2.3-2.8(14H,m), 3.46(2H,s), 3.9-4.1(2H,m), 4.09(2H,s), 6.8-7.5 461(M.sup.+ + 1) (9H,m) 207476 1.6-1.9(4H,m), 2.4-2.8(14H,m), 2.9-3.2(4H,m), 4.6-4.8(4H,m), 3.9-4.2(2H,m), 368(M.sup.+ + 1) 7.1-7.4(5H,m) 114477 1.6-1.9(4H,m), 2.4-2.8(14H,m), 2.9-3.2(4H,m), 3.52(2H,s), 3.9-4.2(2H,m), 7.1- 457(M.sup.+ + 1) 7.4(10H,m) 189478 1.6-2.0(4H,m), 2.4-2.9(10H,m), 2.9-3.4(8H,m), 4.0-4.2(2H,m), 6.7-7.4(10H,m) 443(M.sup.+ + 1) 175479 1.6-2.0(4H,m), 2.3-2.8(14H,m), 2.9-3.2(4H,m), 3.47(2H,s), 3.9-4.2(2H,m), 7.0- 493(M.sup.+ + 1) 7.4(5H,m), 7.26(4H,s) 491 236 223480 1.6-2.0(4H,m), 2.3-2.8(14H,m), 2.9-3.2(4H,m), 3.45(2H,s), 3.79(3H,s), 3.9-4.2 407(M.sup.+ + 1) (2H,m), 6.92(2H,d,J.apprxeq.8.8), 7.0-7.4(7H,m) 232 219481 1.23(3H,t,J=7.4), 1.6-2.0(4H,m), 2.3-3.0(12H,m), 3.5-3.8(4H,m), 3.9-4.2(2H,m) 292(M.sup.+ + 1)482 1.23(3H,t,J=7.4), 1.6-2.0(4H,m), 2.3-3.0(16H,m), 3.47(2H,s), 3.9-4.2(2H,m), 417(M.sup.+ + 1) 7.27(4H,s) 415 223483 1.23(3H,t,J=7.4), 1.6-2.0(4H,m), 2.4-3.0(16H,m), 3.52(2H,s), 3.9-4.2(2H,m), 381(M.sup.+ + 1) 7.2-7.3(5H,m) 189484 1.24(3H,t,J=7.4), 1.6-2.0(4H,m), 2.6-3.0(12H,m), 3.1-3.3(4H,m), 4.0-4.3(2H,m), 367(M.sup.+ + 1) 6.7-7.4(5H,m) 175485 1.23(3H,t,J=7.4), 1.6-2.0(6H,m), 2.4-3.0(16H,m), 3.59(2H,s), 3.9-4.2(2H,m), 431(M.sup.+ + 1) 7.27(4H,s) 429 237486 1.22(3H,t,J=7.4), 1.6-2.0(4H,m), 2.3-3.0(16H,m), 3.47(2H,s), 3.80(3H,s), 3.9- 411(M.sup.+ + 1) 4.2(2H,m), 6.84(2H,d,J=8.8), 7.23(2H,d,J=8.8) 219487 0.88(3H,t,J.apprxeq.6), 1.1-1.5(20H,m), 1.5-2.0(10H,m), 2.4-2.9(14H,m), 3.51(2H,s), 549(M.sup.+ + 1) 3.9-4.2(2H,m), 7.29(5H,s) 202 121488 0.88(3H,t,J.apprxeq.6), 1.1-1.5(22H,m), 1.5-2.0(10H,m), 2.5-3.0(14H,m), 3.72(2H,s), 608(M.sup.+ + 1) 3.9-4.2(2H,m), 7.51(2H,d,J.apprxeq.8.8), 8.17(2H,d,J=8.8) 473489 0.88(3H,t,J.apprxeq.6), 1.1-1.5(22H,m), 1.5-2.0(10H,m), 2.4-2.9(14H,m), 3.54(2H,s), 599 3.9-4.2(2H,m), 7.27(4H,s) 597490 0.87(3H,t,J.apprxeq.6), 1.1-1.5(22H,m), 1.5-2.0(10H,m), 2.5-3.0(14H,m), 3.59(2H,s), 593(M.sup.+ + 1) 3.80(3H,s), 3.9-4.2(2H,m), 6.84(2H,d,J=8.8), 7.24(2H,d,J=8.8) 246 101611 2.30(3H,s), 2.34(3H,s), 2.4(3H,s), 2.5-3.0(9H,m), 250(M.sup.+ + 1) 0.04612 2.44(3Hx2,s), 3.91(2H,t,J.apprxeq.6.3), 4.43(2H,t,J.apprxeq.6.3), 8.1-8.3(5H,m) 265 263 0.79 (M.sup.+ + 1)613 2.33(3Hx2,s), 3.80(2H,t,J=5.4), 4.09(2H,s), 4.29(2H,t,J=5.4), 7.1-7.5(5H,m) 278 276 (M.sup.+ + 1)614 0.99(3H,t,J=7.3), 1.5-1.9(6H,m), 2.5-2.9(6H,m), 3.38(1H,bs), 3.8-4.0(2H,m), 237(M.sup.+ + 1) 0.34 4.1-4.3(2H,m) 164615 0.99(3H,t,J=7.3), 1.5-2.0(6H,m), 2.3-2.8(6H,m), 3.1-3.4(2H,m), 4.0-4.2(2H,m), 329(M.sup.+ + 1) 7.1-7.6(5H,m) 319616 0.99(3H,t,J=7.2), 1.5-2.0(2H,m), 2.33(3Hx2,s), 2.74(2H,t,J=7.7), 3.8-4.0(2H, 211(M.sup.+ + 1) 0.29 m), 4.1-4.3(2H,m)617 0.94(3Hx2,d,J=6.6), 1.8-2.4(1H,m), 2.33(3Hx3,s), 2.64(2H,d,J=7.1), 3.8-4.0(2H, 225(M.sup.+ + 1) 0.29 m), 4.1-4.3(2H,m)618 0.95(3Hx2,d,J=6.6), 1.6-2.0(4H,m), 2.0-2.4(1H,m), 2.5-2.8(6H,m), 3.8-4.0(2H, 251(M.sup.+ + 1) 0.34 m), 4.1-4.3(2H,m)619 0.93(3Hx2,d,J= 6.4), 2.0-2.4(1H,m), 2.31(2Hx2,s), 2.3-2.7(12H,m), 3.46(2H,s), 401(M.sup.+ + 1) 0.34 3.9-4.3(2H,m), 6.8-7.1(2H,m), 7.1-7.4(2H,m) 207620 1.00(3H,t,J=7.3), 1.21(3Hx2,t,J=7.5), 1.5-1.9(2H,m), 2.4-2.9(6H,m), 3.9-4.0( 239(M.sup.+ + 1) 0.44 2H,m), 4.1-4.3(2H,m)621 0.94(3H,t,J=7.0), 1.2-2.0(8H,m), 2.5-2.9(6H,m), 3.8-4.0(2H,m), 4.0-4.3(2H,m) 251(M.sup.+ + 1) 0.32622 1.20(3Hx2,d,J=6.8), 2.32(3Hx2,s), 3.41(1H,sept,J=6.8), 3.8-4.1(2H,m), 4.1-4.3( 211(M.sup.+ + 1) 0.36 m)623 0.79(3H,t,J=7.3), 1.18*3H,d,J=6.9), 1.3-2.0(3H,t,J=7.4), 1.11(3H,d,J=6.9), 225(M.sup.+ + 1) 0.35 1.3-2.0(2H,m), 2.32(3Hx2,s), 3.22(1H,sept,J=6.9), 3.94(2H,t,J=5.2), 4.26(2H,t,J= 5.2)624 0.93(3H,t,J=6.7), 1.2-2.0(4H,m), 2.33(3Hx2,s), 2.77(2H,t,J=5.6), 3.7-4.0(2H, 225(M.sup.+ + 1) 0.33 m), 4.1-4.3(2H,m)625 1.1-1.4(12H,m), 2.55(2H,t,J=7.6), 2.72(2H,t,J=7.6), 3.41(1H,sept,J=6.9), 3.72 239(M.sup.+ + 1) 0.40 (1H,bs), 3.8-4.1(2H,m), 4.26(2H,t,J=5.1) 195626 0.95(3Hx2,d,J=6.4), 1.21(3Hx2,t,J=7.4), 2.0-2.4(1H,m), 2.4-2.9(6H,m), 3.8-4.0( 253(M.sup.+ + 1) 0.34 2H,m), 4.1-4.3(2H,m) 210627 0.88(3H,t,J=7.5), 1.0-1.4(9H,m), 1.2-2.2(2H,m), 2.4-2.8(4H,m), 3.1-3.4(1H,m), 253(M.sup.+ 0.34 3.8-4.0(2H,m), 4.1-4.3(2H,m)628 0.97(3Hx2,d,J=6.4), 1.21(3Hx2,t,J=7.4), 1.2-1.9(4H,m), 2.4-2.9(6H,m), 3.8-4.0( 253(M.sup.+ + 1) 0.37 2H,m) 210629 1.1-1.4(9H,m), 2.4-2.6(6H,m), 3.93(3H,t,J=5.1), 225(M.sup.+ + 1) 0.33 130630 1.21(3Ht,J=7.5), 2.32(3Hx2,s), 2.77(2H,q,J=7.5), 3.92(2H,t,J=5.0), 4.24(2H,t, 197(M.sup.+ + 1) J=5.0) 153631 0.89(3H,t,J=6.6), 1.2-1.9(10H,m), 2.5-2.9(6H,m), 3.8-4.0(2H,m), 4.0-4.3(3H,m) 265(M.sup.+ + 1) 0.32 239 208632 0.88(3H,t,J=6.6), 1.2-1.9(12H,m), 2.5-2.9(6H,m), 3.8-4.0(2H,m), 4.0-4.3(2H,m) 265(M.sup.+ + 1) 0.33 219 208633 0.87(3H,t,J.apprxeq.6), 1.1-2.0(14H,m), 2.5-2.9(6H,m), 3.8-4.0(2H,m), 4.0-4.3(2H,m) 293(M.sup.+ + 1) 0.34 247 208634 0.87(3H,t,J.apprxeq.6), 1.1-2.0(16H,m), 2.5-2.9(6H,m), 3.8-4.0(2H,m), 4.0-4.3(2H,m) 307(M.sup.+ + 1) 0.38 208635 0.87(3H,t,J.apprxeq.6), 1.1-2.0(18H,m), 2.5-2.9(6H,m), 3.3(1H,bs), 3.8-4.0(2H,m), 4.0- 321(M.sup.+ + 1) 0.39 4.3(2H,m)636 0.87(3H,t,J.apprxeq.6), 1.2-2.0(20H,m), 2.5-2.9(6H,m), 3.3(1H,bs), 3.8-4.0(2H,m), 4.1- 335(M.sup.+ + 1) 0.35 4.3(2H,m) 208637 0.88(3H,t,J.apprxeq.6), 1.1-2.0(24H,m), 2.5-2.9(6H,m), 3.34(1H,bs), 3.8-4.0(2H,m), 363(M.sup.+ + 1) 0.41 4.0-4.3(2H,m)638 0.88(3H,t,J.apprxeq.6), 1.1-2.0(28H,m), 2.5-2.9(6H,m), 3.20(1H,bs), 3.8-4.0(2H,m), 391(M.sup.+ + 1) 0.41 4.0-4.3(2H,m)639 0.88(3H,t,J.apprxeq.6), 1.1-2.0(32H,m), 2.5-2.9(6H,m), 3.25(1H,bs), 3.8-4.0(2H,m), 419(M.sup.+ + 1) 0.46 4.0-4.3(2H,m)640 1.18(3H,t,J=7.6), 1.20(3H,t,J=7.6), 2.58(2H,q,J=7.6), 2.68(2H,q,J=7.6), 3.89( 286(M.sup.+ + 1) 0.31 2H,t,J.apprxeq.6.6), 4.08(2H,s), 4.19(2H,t,J.apprxeq.6), 7.0-7.4(5H,m)641 1.19(3H,t,J.apprxeq.7.7), 1.20(3H,t,J=7.7), 2.58(2H,q,J=7.7), 2.69(2H,q,J=7.7), 3.8- 323 0.26 4.0(2H,m), 4.05(2H,s), 4.21(2H,t,J=5.2), 7.1-7.4(4H,m) 321642 2.30(3H,s), 2.34(3H,s), 2.41(3H,s), 2.5-3.0(8H,m), 250(M.sup.+ + 1) 0.06643 1.6-1.9(4H,m), 2.5-2.8(4H,m), 3.7-4.0(2H,m), 4.09(2H,s), 4.0-4.2(2H,m), 7.0- 255(M.sup.+ + 1) 7.4(5H,m)644 1.6-2.0(4H,m), 2.5-2.8(4H,m), 3.79(2H,t,J.apprxeq.7), 4.10(2H,s), 4.23(2H,t,J.apprxeq.7), 7.0- 305 7.5(5H,m) 303 267 239645 1.6-2.0(4H,m), 2.5-2.8(4H,m), 3.03(2Hx2,s), 3.90(2H,t,J.apprxeq.5) , 4.18(2H,t,J.apprxeq.5), 299 7.0-7.4(5H,m)646 1.22(3H,t,J.apprxeq. 7.3), 1.7-4.0(4H,m), 2.6-2.8(4H,m), 3.78(2H,q,J.apprxeq.7.3), 3.7-4.0(2H, 223 m), 4.0-4.3(2H,m)647 1.19(3H,t,J.apprxeq.7.7), 1.21(3H,t,J.apprxeq.7.7), 2.61(2H,q,J.apprxeq.7.7), 2.74(2H,q,J.apprxeq.7.7), 343- 4.4(4H,m), 7.1-7.5(4H,m) 341 339(M.sup.+ + 1)__________________________________________________________________________

Number	Name	Date	Kind
3935214	Zellner	Jan 1976
4181724	Hall et al.	Jan 1980

Number	Date	Country
0072932	Mar 1983	EPX
0096517	Dec 1983	EPX
59-219269	May 1983	JPX
1600127	Oct 1981	GBX

1-substituted alkyl-1,2-dihydro-2-pyrazinone derivatives

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CPC

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Abstract

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US Referenced Citations (2)

Foreign Referenced Citations (4)

Non-Patent Literature Citations (3)

Entry
Abstracts of Papers 16th Congress of Heterocyclic Chemistry, Osaka, Japan, 1984, No. 1B-08, pp. 65-68.
"Pharmacological Study on Tetramethyl Pyrazine", Chinese Medical Journal, 4(4), Jul. 1978, pp. 319-322.
Derwent for JP 59-212269.