Arylamino pyrimidine compound

TECHNICAL FIELD
This invention relates to a pyrimidine derivative having both of an excellent selective acetylcholinesterase-inhibiting activity and an excellent selective A type monoamine oxidase-inhibiting activity and useful as an antidepressant and an agent for curing senile dementia, and a salt thereof.
BACKGROUND ART
In senile dementia, acetylcholine in a brain is lacking so that an acetylcholinesterase-inhibiting agent has been studied. For example, as an agent for curing dementia, there have been disclosed 1-benzyl-4-[(5,6-dimethoxy-1-indanon)-2-yl]methylpiperidine, etc. in Japanese Provisional Patent Publication No. 79151/1989 and 1-benzyl-4-[2-(4pyrrolidinobenzoyl)ethyl]piperidine, etc. in Japanese Provisional Patent Publication No. 173867/1991 (U.S. Pat. No. 5,177,087). However, senile dementia is generally accompanied with symptoms such as depression, lowering of volition, etc. so that various symptoms of senile dementia cannot be ameliorated sufficiently only by an acetylcholinesterase-inhibiting agent. On the other hand, depression is related to monoamine (noradrenaline, serotonin), and as an antidepressant having an A type monoamine oxidase-inhibiting activity, there has been known, for example, 4-(4-cyanoanilino)-5,6-dihydro-7H-cyclopenta[d]pyrimidine as disclosed in Japanese Provisional Patent Publication No. 203072/1982 (U.S. Pat. No. 4,450,162).
The present inventors have studied for many years in order to develop a medicine having both of a selective acetylcholinesterase-inhibiting activity and a selective A type monoamine oxidase-inhibiting activity and therefore having a further improved curing effect as an agent for curing senile dementia, and consequently found that a pyrimidine derivative having a specific structure with selective inhibiting activities to both enzymes, to accomplish the present invention.
DISCLOSURE OF THE INVENTION
The present invention is a pyrimidine derivative represented by the formula (I): ##STR2##
(wherein R.sup.1 and R.sup.2 each represent a hydrogen atom, a halogen atom, an amino group, a nitro group, an alkyl group, a lower alkoxy group or a lower alkoxycarbonyl group, or R.sup.1 and R.sup.2 are bonded together to form an alkylene group, and said alkyl group and alkylene group may be substituted by a halogen, hydroxy, a lower alkoxy, a lower alkenyloxy, an aryloxy, an aralkyloxy or an acyloxy.
R.sup.3 represents an aralkyl group or a hetero aromatic ring type-alkyl group and the aryl portion of said aralkyl group and the hetero aromatic ring portion of the hetero aromatic ring type-alkyl group may be substituted by a halogen, amino, alkanoylamino, cyano, nitro, hydroxy, a lower alkyl, a lower alkoxy, an aralkyloxy, an alkylenedioxy, a halogeno-lower alkyl or a halogeno-lower alkoxy.
R.sup.4 represents a hydrogen atom or an acyl group.
R.sup.5 represents a hydrogen atom, a hydroxy group or a lower alkoxy group.
A represents ##STR3## where R.sup.6 represents a hydrogen atom, a halogen atom, a lower alkyl group or a lower alkoxy group, X represents --CH=, --CH=CH--(CH.sub.2).sub.p --, --CH.sub.2 -- or --CH.sub.2 CH.sub.2 --(CH.sub.2).sub.p --, Y represents =CH--(CH.sub.2).sub.p --, --CH.sub.2 --(CH.sub.2).sub.p --, a single bond or a double bond and p represents 0 or 1.
Also, . . . represents a single bond or a double bond, and when . . . represents a double bond or X represents --CH=, or Y represents a double bond, R.sup.5 does not exist) and a salt thereof.
The compounds represented by the above formula (I) are roughly classified into compounds represented by the following formula (II) and formula (III): ##STR4##
(wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, X, Y and . . . have the same meanings as defined above)
As the halogen atom of R.sup.1 and R.sup.2, there may be mentioned fluorine, chlorine, bromine and iodine; as the alkyl group, there may be mentioned a C.sub.1-10 straight or branched alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, hexyl, heptyl, octyl, nonyl and decyl; as the lower alkoxy group, there may be mentioned a C.sub.1-4 straight or branched lower alkoxy group such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy and t-butoxy; as the lower alkoxycarbonyl group, there may be mentioned a C.sub.2-5 atkoxycarbonyl group such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl and t-butoxycarbonyl; and as the alkylene group formed by bonding R.sup.1 and R.sup.2 together, there may be mentioned a C.sub.3-6 straight or branched alkylene group such as trimethylene, 1-, 2- or 3-methyltrimethylene, 1,2-dimethyltrimethylene, 2,2-dimethyltrimethylene, 1,3-dimethyltrimethylene, tetramethylene, 1- or 2-methyltetramethylene and 1,2-dimethyltetramethylene.
The above alkyl group and alkylene group may have a substituent(s). As said substituent, there may be mentioned a halogen atom such as fluorine, chlorine, bromine and iodine; a hydroxy group; a C.sub.1-4 straight or branched lower alkoxy group such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy and t-butoxy; a C.sub.3-4 lower alkenyloxy group such as allyloxy and 2-butenyloxy; an aryloxy group such as phenoxy and naphthoxy; an aralkyloxy group such as benzyloxy and phenethyloxy; a C.sub.1-10 aliphatic acyloxy group such as formyloxy, acetyloxy, propionyloxy, butyryloxy, isobutyryloxy, valeryloxy, isovaleryloxy, pivaloyloxy, hexanoyloxy, heptanoyloxy, octanoyloxy, nonanonyloxy and decanoyloxy; an aromatic aliphatic acyloxy group such as phenylacetoxy and cinnamoyloxy; and an aromatic acyloxy group such as benzoyloxy and naphthoyloxy.
As the groups of R.sup.1 and R.sup.2, preferred are a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, a C.sub.1-7 straight or branched alkyl group, a trimethylene group, a tetramethylene group and a 2,2-dimethyltrimethylene group, and as the group having a substituent(s), preferred are a hydroxymethyl group, a fluoromethyl group, a chloromethyl group, a bromomethyl group, a methoxymethyl group, a phenoxymethyl group, a benzyloxymethyl group, an acetoxymethyl group, a propionyloxymethyl group, a benzoyloxymethyl group, a 1- or 2-hydroxyethyl group, a 1- or 2-fluoroethyl group, a 1- or 3-hydroxytrimethylene group, a 1- or 3-fluorotrimethylene group, a 1- or 3-chlorotrimethylene group, a 1- or 3-bromotrimethylene group, a 1- or 3-methoxytrimethylene group, a 1- or 3-phenoxytrimethylene group, a 1- or 3-acetoxytrimethylene group, a 1,3-dihydroxytrimethylene group and a 1,3-difluorotrimethylene group. As the groups of R.sup.1 and R.sup.2, particularly preferred are a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, a trimethylene group, a tetramethylene group and a 2,2-dimethyltrimethylene group, and as the group having a substituent(s), particularly preferred are a hydroxymethyl group, a fluoromethyl group, a methoxymethyl group, an acetoxymethyl group, a 1- or 3-hydroxytrimethylene group, a 1- or 3-fluorotrimethylene group, a 1- or 3-methoxytrimethylene group, a 1- or 3-acetoxytrimethylene group and a 1,3-difluorotrimethylene group. It is particularly preferred that R.sup.1 and R.sup.2 form a trimethylene group or a tetramethylene group in combination, or one is a C.sub.1-4 alkyl group and the other is a hydrogen atom, a chlorine atom or a C.sub.1-4 alkyl group, and most preferred is a compound wherein R.sup.1 and R.sup.2 form a trimethylene group in combination or R.sup.1 is a C.sub.1-4 alkyl group and R.sup.2 is a hydrogen atom or a C.sub.1-4 alkyl group.
As the aralkyl group of R.sup.3, there may be mentioned an aryl C.sub.1-4 alkyl group such as benzyl, phenethyl, sec-phenethyl, phenylpropyl, phenylbutyl, naphthylmethyl and diphenylmethyl; and as the hetero aromatic ring type-alkyl group, there may be mentioned a hetero aromatic ring type-C.sub.1-4 alkyl group such as thienylmethyl, thienylethyl, thienylpropyl, thienylbutyl, furylmethyl, pyridylmethyl, pyrimidinylmethyl, thiazolylmethyl, oxazolylmethyl, imidazolylmethyl, 2-benzothiazolylmethyl, 2-benzoxazolylmethyl and 2-benzoimidazolylmethyl. The aryl portion of the above aralkyl group and the hetero aromatic ring portion of the hetero aromatic ring type-alkyl group may have a substituent(s), and as said substituent, there may be mentioned a halogen atom such as fluorine, chlorine, bromine and iodine; a C.sub.1-4 straight or branched lower alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and t-butyl; a C.sub.1-4 straight or branched lower alkoxy group such as methoxy, ethoxy, propoxy, iso-propoxy, butoxy, isobutoxy, sec-butoxy and t-butoxy; an aralkyloxy group such as benzyloxy, phenethyloxy and naphthylmethoxy; an alkylenedioxy group such as methylenedioxy and ethylenedioxy; an amino group, a C.sub.1-4 alkanoylamino such as formylamino, acetylamino, propionylamino, butyrylamino and isobutyrylamino; a nitro group; a cyano group; a hydroxy group; a C.sub.1-4 halogeno-lower alkyl group such as fluoromethyl, chloromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2-chloroethyl, 2-bromoethyl, 2,2,2-trifluoroethyl, 3-fluoropropyl and 4-fluorobutyl; and a C.sub.1-4 halogeno-lower alkoxy group such as fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2-fluoroethoxy, 2-chloroethoxy, 2-bromoethoxy, 2,2,2-trifluoroethoxy, 3-fluoropropoxy and 4-fluorobutoxy.
As the group of R.sup.3, preferred are a benzyl group, a sec-phenethyl group, a fluorobenzyl group, a methoxybenzyl group, an ethylenedioxybenzyl group, a hydroxybenzyl group, a chlorobenzyl group, a methylbenzyl group, a trifluoromethylbenzyl group, an aminobenzyl group, an acetylaminobenzyl group, a nitrobenzyl group, a cyanobenzyl group, a diphenylmethyl group, a di(4-fluorophenyl)methyl group, a thienylmethyl group, a furylmethyl group, a pyridylmethyl group, a methylpyridylmethyl group and a pyrimidinylmethyl group. As the group of R.sup.3, particularly preferred are a benzyl group, a sec-phenethyl group, a 2-, 3- or 4-fluorobenzyl group, a 2-, 3- or 4-chlorobenzyl group, a 2-, 3- or 4-methoxybenzyl group, a 2-, 3- or 4-cyanobenzyl group, a 2-, 3- or 4-nitrobenzyl group, a 2-thienylmethyl group, a 2-furylmethyl group, a 2-pyridylmethyl group and a 6-methyl-2-pyridylmethyl group.
As the acyl group of R.sup.4, there may be mentioned a C.sub.1-10 aliphatic acyl group such as formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, heptanoyl, octanoyl, nonanoyl and decanoyl; an aromatic aliphatic acyl group such as phenylacetyl and cinnamoyl; and an aromatic acyl group such as benzoyl and naphthoyl.
As the group of R.sup.4, preferred are a hydrogen atom, a formyl group, an acetyl group, a propionyl group, a butyryl group and a pivaloyl group, and particularly preferred are a hydrogen atom and an acetyl group.
As the lower alkoxy group of R.sup.5, the same lower alkoxy group mentioned in R.sup.1 and R.sup.2 may be mentioned.
As the group of R.sup.5, preferred are a hydrogen atom, a hydroxy group, a methoxy group and an ethoxy group, and particularly preferred is a hydrogen atom.
As the halogen atom and the lower alkoxy group of R.sup.6, the same halogen atom and lower alkoxy group mentioned in R.sup.1 and R.sup.2 may be mentioned; and as the lower alkyl group, there may be mentioned a C.sub.1-4 straight or branched alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl and sec-butyl.
As the group of R.sup.6, preferred are a hydrogen atom, a fluorine atom, a chlorine atom, a methyl group and a methoxy group, and particularly preferred are a hydrogen atom, a fluorine atom, a chlorine atom and a methoxy group.
As X in the formula (II), --CH=, --CH.sub.2 --, --CH.sub.2 CH.sub.2 -- and --CH=CH-- are particularly preferred. As Y in the formula (III), --CH.sub.2 -- and =CH-- are particularly preferred. The compound of the formula (II) is preferred for achieving the object of the present invention.
The . . . is preferably a single bond.
The compounds of the formula (I), the formula (II) and the formula (III) may be converted into salts, if necessary. As a pharmaceutically acceptable salt, there may be mentioned a salt of a mineral acid such as hydrochloride, hydrobromide, hydroiodide, sulfate and phosphate; a sulfonate such as methanesulfonate, ethanesulfonate, benzenesulfonate and p-toluenesulfonate; oxalate, maleate, fumarate and tartrate; and an acid addition salt of an organic acid such as citrate. The compounds of the formula (I), the formula (II) and the formula (III) or salts thereof may exist as hydrates.
Examples of the compound of the formula (II) are shown in Table 1 (Compound II), and examples of the compound of the formula (III) are shown in Table 2 (Compound III), respectively.
TABLE 1__________________________________________________________________________(Compound II) ##STR5## ##STR6## ##STR7## ##STR8## ##STR9## ##STR10## ##STR11## ##STR12##__________________________________________________________________________ 1 CH.sub.2 CH.sub.2 CH.sub.2 H H CH.sub.2 ##STR13## benzyl 2 " " " (CH.sub.2).sub.2 " " 3 " " " (CH.sub.2).sub.3 " " 4 " " " CH ##STR14## " 5 " " " CHCH ##STR15## " 6 " " " CHCHCH.sub.2 " " 7 " " " CH.sub.2 " 4-fluoro- benzyl 8 " " " (CH.sub.2).sub.2 " 4-fluoro- benzyl 9 " " " (CH.sub.2).sub.3 " 4-fluoro- benzyl 10 " " " CH ##STR16## 4-fluoro- benzyl 11 " " " CHCH ##STR17## 4-fluoro- benzyl 12 " " " CHCHCH.sub.2 " 4-fluoro- benzyl 13 " " " CH.sub.2 " 3-fluoro- benzyl 14 " " " (CH.sub.2).sub.2 " 3-fluoro- benzyl 15 " " " (CH.sub.2).sub.3 " 3-fluoro- benzyl 16 " " " CH ##STR18## 3-fluoro- benzyl 17 " " " CHCH ##STR19## 3-fluoro- benzyl 18 " " " CHCHCH.sub.2 " 3-fluoro- benzyl 19 CH.sub.2 CH.sub.2 CH.sub.2 H H CH.sub.2 ##STR20## 2-fluoro- benzyl 20 " " " (CH.sub.2).sub.2 " 2-fluoro- benzyl 21 " " " (CH.sub.2).sub.3 " 2-fluoro- benzyl 22 " " " CH ##STR21## 2-fluoro- benzyl 23 " " " CHCH ##STR22## 2-fluoro- benzyl 24 " " " CHCHCH.sub.2 " 2-fluoro- benzyl 25 " " " CH.sub.2 " 4-meth- oxy- benzyl 26 " " " (CH.sub.2).sub.2 " 4-meth- oxy- benzyl 27 " " " (CH.sub.2).sub.3 " 4-meth- oxy- benzyl 28 " " " CH ##STR23## 4-meth- oxy- benzyl 29 " " " CHCH ##STR24## 4-meth- oxy- benzyl 30 " " " CHCHCH.sub.2 " 4-meth- oxy- benzyl 31 " " " CH.sub.2 " 3-meth- oxy- benzyl 32 " " " (CH.sub.2).sub.2 " 3-meth- oxy- benzyl 33 " " " (CH.sub.2).sub.3 " 3-meth- oxy- benzyl 34 " " " CH ##STR25## 3-meth- oxy- benzyl 35 " " " CHCH ##STR26## 3-meth- oxy- benzyl 36 " " " CHCHCH.sub.2 " 3-meth- oxy- benzyl 37 " " " CH.sub.2 " 2-meth- oxy- benzyl 38 CH.sub.2 CH.sub.2 CH.sub.2 H H (CH.sub.2).sub.2 ##STR27## 2-meth- oxy- benzyl 39 " " " (CH.sub.2).sub.3 " 2-meth- oxy- benzyl 40 " " " CH ##STR28## 2-meth- oxy- benzyl 41 " " " CHCH ##STR29## 2-meth- oxy- benzyl 42 " " " CHCHCH.sub.2 " 2-meth- oxy- benzyl 43 " " " CH.sub.2 " 4- hydroxy- benzyl 44 " " " (CH.sub.2).sub.2 " 4- hydroxy- benzyl 45 " " " (CH.sub.2).sub.3 " 4- hydroxy- benzyl 46 " " " CH ##STR30## 4- hydroxy- benzyl 47 " " " CHCH ##STR31## 4- hydroxy- benzyl 48 " " " CHCHCH.sub.2 " 4- hydroxy- benzyl 49 " " " CH.sub.2 " 4-chloro- benzyl 50 " " " (CH.sub.2).sub.2 " 4-chloro- benzyl 51 " " " (CH.sub.2).sub.3 " 4-chloro- benzyl 52 " " " CH ##STR32## 4-chloro- benzyl 53 " " " CHCH ##STR33## 4-chloro- benzyl 54 " " " CHCHCH.sub.2 " 4-chloro- benzyl 55 " " " CH.sub.2 " 3-chloro- benzyl 56 " " " (CH.sub.2).sub.2 " 3-chloro- benzyl 57 CH.sub.2 CH.sub.2 CH.sub.2 H H (CH.sub.2).sub.3 ##STR34## 3-chloro- benzyl 58 " " " CH ##STR35## 3-chloro- benzyl 59 " " " CHCH ##STR36## 3-chloro- benzyl 60 " " " CHCHCH.sub.2 " 3-chloro- benzyl 61 " " " CH.sub.2 " 2-chloro- benzyl 62 " " " (CH.sub.2).sub.2 " 2-chloro- benzyl 63 " " " (CH.sub.2).sub.3 " 2-chloro- benzyl 64 " " " CH ##STR37## 2-chloro- benzyl 65 " " " CHCH ##STR38## 2-chloro- benzyl 66 " " " CHCHCH.sub.2 " 2-chloro- benzyl 67 " " " CH.sub.2 " 4-methyl- benzyl 68 " " " (CH.sub.2).sub.2 " 4-methyl- benzyl 69 " " " (CH.sub.2).sub.3 " 4-methyl- benzyl 70 " " " CH ##STR39## 4-methyl- benzyl 71 " " " CHCH ##STR40## 4-methyl- benzyl 72 " " " CHCHCH.sub.2 " 4-methyl- benzyl 73 " " " CH.sub.2 " 4-nitro- benzyl 74 " " " (CH.sub.2).sub.2 " 4-nitro- benzyl 75 " " " (CH.sub.2).sub.3 " 4-nitro- benzyl 76 CH.sub.2 CH.sub.2 CH.sub.2 H H CH ##STR41## 4-nitro- benzyl 77 " " " CHCH ##STR42## 4-nitro- benzyl 78 " " " CHCHCH.sub.2 " 4-nitro- benzyl 79 " " " CH.sub.2 " 4-tri- fluoro- methyl- benzyl 80 " " " (CH.sub.2).sub.2 " 4-tri- fluoro- methyl- benzyl 81 " " " CH ##STR43## 4-tri- fluoro- methyl- benzyl 82 " " " (CH.sub.2).sub.3 ##STR44## 4-tri- fluoro- methyl- benzyl 83 " " " CHCH " 4-tri- fluoro- methyl- benzyl 84 " " " CHCHCH.sub.2 " 4-tri- fluoro- methyl- benzyl 85 " " " CH.sub.2 " sec-phen- ethyl 86 " " " (CH.sub.2).sub.2 " sec-phen- ethyl 87 " " " (CH.sub.2).sub.3 " sec-phen- ethyl 88 " " " CH ##STR45## sec-phen- ethyl 89 " " " CHCH ##STR46## sec-phen- ethyl 90 " " " CHCHCH.sub.2 " sec-phen- ethyl 91 " " " CH.sub.2 " diphenyl- methyl 92 " " " (CH.sub.2).sub.2 " diphenyl- methyl 93 " " " (CH.sub.2).sub.3 " diphenyl- methyl 94 " " " CH ##STR47## diphenyl- methyl 95 CH.sub.2 CH.sub.2 CH.sub.2 H H CHCH ##STR48## diphenyl- methyl 96 " " " CHCHCH.sub.2 " diphenyl- methyl 97 " " " CH.sub.2 " di(4- fluoro- phenyl)- methyl 98 " " " (CH.sub.2).sub.2 " di(4- fluoro- phenyl)- methyl 99 " " " (CH.sub.2).sub.3 " di(4- fluoro- phenyl)- methyl100 " " " CH ##STR49## di(4- fluoro- phenyl)- methyl101 " " " CHCH ##STR50## di(4- fluoro- phenyl)- methyl102 " " " CHCHCH.sub.2 " di(4- fluoro- phenyl)- methyl103 " " " CH.sub.2 " 2-thienyl- methyl104 " " " (CH.sub.2).sub.2 " 2-thienyl- methyl105 " " " (CH.sub.2).sub.3 " 2-thienyl- methyl106 " " " CH ##STR51## 2-thienyl- methyl107 " " " CHCH ##STR52## 2-thienyl- methyl108 " " " CHCHCH.sub.2 " 2-thienyl- methyl109 " " " CH.sub.2 " 2- pyridyl- methyl110 " " " (CH.sub.2).sub.2 " 2- pyridyl- methyl111 " " " (CH.sub.2).sub.2 " 2- pyridyl- methyl112 " " " CH ##STR53## 2- pyridyl- methyl113 CH.sub.2 CH.sub.2 CH.sub.2 H H CHCH ##STR54## 2- pyridyl- methyl114 " " " CHCHCH.sub.2 " 2- pyridyl- methyl115 " " " CH.sub.2 " 4- pyridyl- methyl116 " " " (CH.sub.2).sub.2 " 4- pyridyl- methyl117 " " " (CH.sub.2).sub.3 " 4- pyridyl- methyl118 " " " CH ##STR55## 4- pyridyl- methyl119 " " " CHCH ##STR56## 4- pyridyl- methyl120 " " " CHCHCH.sub.2 " 4- pyridyl- methyl121 " " " CH.sub.2 " 2-pyr- imidinyl- methyl122 " " " (CH.sub.2).sub.2 " 2-pyr- imidinyl- methyl123 " " " (CH.sub.2).sub.3 " 2-pyr- imidinyl- methyl124 " " " CH ##STR57## 2-pyr- imidinyl- methyl125 " " " CHCH ##STR58## 2-pyr- imidinyl- methyl126 " " " CHCHCH.sub.2 " 2-pyr- imidinyl- methyl127 " " " CH.sub.2 " 4-pyr- imidinyl- methyl128 " " " (CH.sub.2).sub.2 " 4-pyr- imidinyl- methyl129 " " " (CH.sub.2).sub.3 " 4-pyr- imidinyl- methyl130 " " " CH ##STR59## 4-pyr- imidinyl- methyl131 " " " CHCH ##STR60## 4-pyr- imidinyl- methyl132 CH.sub.2 CH.sub.2 CH.sub.2 H H CHCHCH.sub.2 ##STR61## 4-pyr- imidinyl- methyl133 " " " (CH.sub.2).sub.2 " 4-di- fluoro- methoxy- benzyl134 " " " " " 3-di- fluoro- methoxy- benzyl135 " " " " " 2-di- fluoro- methoxy- benzyl136 H H " " (CH.sub.2).sub.2 " benzyl137 " CH.sub.3 " " " " "138 " C.sub.2 H.sub.5 " " " " "139 " C.sub.3 H.sub.7 " " " " "140 " i-C.sub.3 H.sub.7 " " " " "141 " C.sub.4 H.sub.9 " " " " "142 " sec-C.sub.4 H.sub.9 " " " " "143 " C.sub.6 H.sub.13 " " " " "144 " C.sub.8 H.sub.17 " " " " "145 " C.sub.10 H.sub.21 " " " " "146 " Cl " " " " "147 " Br " " " " "148 " OCH.sub.3 " " " " "149 " OC.sub.2 H.sub.5 " " " " "150 CH.sub.3 CH.sub.3 H H (CH.sub.2).sub.2 ##STR62## benzyl151 C.sub.2 H.sub.5 " " " " " "152 C.sub.3 H.sub.7 " " " " " "153 i-C.sub.3 H.sub.7 " " " " " "154 C.sub.4 H.sub.9 " " " " " "155 sec-C.sub.4 H.sub.9 " " " " " "156 i-C.sub.4 H.sub.9 " " " " " "157 C.sub.5 H.sub.11 " " " " " "158 C.sub.7 H.sub.15 " " " " " "159 C.sub.9 H.sub.19 " " " " " "160 Cl " " " " " "161 Br " " " " " "162 Cl " " " CHCH " "163 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 " " (CH.sub.2).sub.2 " "164 CH(CH.sub.3)CH.sub.2 CH.sub.2 " " " " "165 CH.sub.2 CH(CH.sub.3)CH.sub.2 " " " " "166 CH.sub.2 CH.sub.2 CH(CH.sub.3) " " " " "167 CH.sub.2 CH.sub.2 CH(OH) " " " " "168 CH.sub.2 CH.sub.2 CH(OCH.sub.3) " " " " "169 CH.sub.2 CH.sub.2 CH(OC.sub.2 H.sub.5) H H (CH.sub.2).sub.2 ##STR63## benzyl170 CH.sub.2 CH.sub.2 CH(OC.sub.3 H.sub.7) " " " " "171 CH.sub.2 CH.sub.2 CH(OCH.sub.2 CHCH.sub.2) " " " " "172 CH.sub.2 CH.sub.2 CH(OCH.sub.2 C.sub.6 H.sub.5) " " " " "173 CH.sub.2 CH.sub.2 CH(OCH.sub.3) " " CHCH " "174 CH.sub.2 CH.sub.2 CH(OCOH) " " (CH.sub.2).sub.2 " "175 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 " " CHCH " "176 CH.sub.2 CH.sub.2 CH(OCOCH.sub.3) " " (CH.sub.2).sub.2 " "177 CH.sub.2 CH.sub.2 CH(OCOC.sub.2 H.sub.5) " " " " "178 CH.sub.2 CH.sub.2 CH(OCOC.sub.3 H.sub.7) " " " " "179 CH.sub.2 CH.sub.2 CH(OCOC.sub.5 H.sub.11) " " " " "180 CH.sub.2 CH.sub.2 CH(OCOC.sub.9 H.sub.19) " " " " "181 CH.sub.2 CH.sub.2 CH(OCOCH.sub.2 C.sub.6 H.sub.5) " " " " "182 CH.sub.2 CH.sub.2 CH(OCOC.sub.6 H.sub.5) " " " " "183 CH.sub.2 CH.sub.2 CH(F) " " " " "184 CH.sub.2 CH.sub.2 CH(Cl) " " " " "185 CH.sub.2 CH.sub.2 CH(Br) " " " " "186 CH.sub.2 CH.sub.2 C(F).sub.2 " " " " "187 CH(Br)CH.sub.2 CH(Br) " " " " "188 CH.sub.2 CH.sub.2 CH(F) H H CHCH ##STR64## benzyl189 CH.sub.3 H " " (CH.sub.2).sub.2 " "190 " Cl " " " " "191 " Br " " " " "192 " CH.sub.2 OH " " " " "193 " CH.sub.2 OCH.sub.3 " " " " "194 " CH.sub.2 OCOCH.sub.3 " " " " "195 " CH.sub.2 F " " " " "196 " CH.sub.2 Cl " " " " "197 C.sub.2 H.sub.5 H " " " " 2-pyr- imidinyl- methyl198 CH.sub.2 C(CH.sub.3).sub.2 CH.sub.2 " " " " benzyl199 CH.sub.3 CH.sub.3 " " CHCH " "200 C.sub.2 H.sub.5 C.sub.2 H.sub.5 " " " " "201 CH.sub.2 C(CH.sub.3).sub.2 CH.sub.2 " " " " "202 CH.sub.3 H " " " " "203 C.sub.2 H.sub.5 " " " " " "204 C.sub.3 H.sub.7 " " " " " "205 C.sub.2 H.sub.5 " " " (CH.sub.2).sub.2 " "206 C.sub.3 H.sub.7 " " " " " "207 CH.sub.2 CH.sub.2 CH(OC.sub.6 H.sub.5) H H (CH.sub.2).sub.2 ##STR65## benzyl208 CH.sub.2 CH.sub.2 CH(O-1-C.sub.10 H.sub.7 ) " " " " "209 CH.sub.2 CH.sub.2 CH.sub.2 " " CHCH " 3- pyridyl- methyl210 " " " (CH.sub.2).sub.2 " 3- pyridyl- methyl211 " " " CHCH " 2-methyl- benzyl212 " " " (CH.sub.2).sub.2 " 2-methyl- benzyl213 " " " CHCH " 3-methyl- benzyl214 " " " (CH.sub.2).sub.2 " 3-methyl- benzyl215 " " " CH.sub.2 ##STR66## benzyl216 " " " " ##STR67## "217 " " " " ##STR68## "218 " " " (CH.sub.2).sub.2 ##STR69## 4-cyano- benzyl219 CH.sub.3 H " " CH.sub.2 " 2- pyridyl- methyl220 " " " " " " benzyl221 CH.sub.2 CH.sub.2 CH.sub.2 COCH.sub.3 " (CH.sub.2).sub.2 " "222 COOC.sub.2 H.sub.5 H H " " " "223 C.sub.2 H.sub.5 C.sub.2 H.sub.5 " " " " "224 CH.sub.2 CH.sub.2 CH.sub.2 " " " " 1- naphthyl- methyl225 " " " " " 3-cyano- benzyl226 CH.sub.3 H H 2-F CH.sub.2 ##STR70## benzyl227 " " " 3-F " " "228 " " " 3-Cl " " "229 Cl " " H (CH.sub.2).sub.2 " "230 Br " " " " " "231 CH.sub.2 CH.sub.2 CH.sub.2 " " " " 3,4- methyl- ene- dioxy- benzyl232 " " " " " 3-tri- fluoro- methyl- benzyl233 " " " " " 2,3-di- methoxy- benzyl234 CH.sub.3 CH.sub.3 " " CH.sub.2 " benzyl235 CH.sub.2 CH.sub.2 CH.sub.2 " " (CH.sub.2).sub.2 " 3,4- ethylene- dioxy- benzyl236 CH.sub.2 CH.sub.2 CH(OH) " " CH.sub.2 " benzyl237 CH.sub.2 CH.sub.2 CH(OCOCH.sub.3) " " " " "238 CH.sub.2 CH.sub.2 CH.sub.2 " " (CH.sub.2).sub.2 " 6- methyl-2- pyridyl- methyl239 " " " " " 3-benzyl- oxy- benzyl240 NO.sub.2 OCH.sub.3 " " " " benzyl241 NH.sub.2 Cl " " " " "242 CH.sub.2 CH.sub.2 CH.sub.2 H H (CH.sub.2).sub.2 ##STR71## 2-nitro- benzyl243 " " " " " 3-nitro- benzyl244 " " " " " 3-amino- benzyl245 " " 2-OCH.sub.3 CH.sub.2 " benzyl246 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 " " " " "247 CH.sub.2 CH.sub.2 CH.sub.2 " 2-Cl " " "248 CH.sub.3 H " H (CH.sub.2).sub.2 " 2- pyridyl- methyl249 CH.sub.2 CH.sub.2 CH.sub.2 " " " " 2-acetyl- amino- benzyl250 CH.sub.3 H " 2-CH.sub.3 CH.sub.2 " benzyl251 " " " 3-CH.sub.3 " " "252 C.sub.2 H.sub.5 " " H " " "253 C.sub.3 H.sub.7 " " " " " "254 i-C.sub.3 H.sub.7 " " " " " "255 C.sub.4 H.sub.9 " " " " " "256 sec-C.sub.4 H.sub.9 " " " " " "257 i-C.sub.4 H.sub.9 " " " " " "258 CH.sub.3 " " " " " 2-thienyl- methyl259 " " " " " " 3-thienyl- methyl260 " " " " " " 2-furyl- methyl261 CH.sub.3 H H H CH.sub.2 ##STR72## 3-furyl- methyl262 " " " " " " 3- pyridyl- methyl263 " " " " " " 4- pyridyl- methyl264 " " " " " " 2- pyr- imidinyl- methyl265 " " " " " " 4-pyr- imidinyl- methyl266 " " " 3-OCH.sub.2 " " benzyl267 CH.sub.2 CH.sub.2 CH.sub.2 " H " " 3-thienyl- methyl268 " " " " " 3- pyridyl- methyl269 " " " " " 2-furyl- methyl270 " " " " " 3-furyl- methyl271 " " " (CH.sub.2).sub.2 " 4-amino- benzyl272 " " " " " 2-amino- benzyl273 " " " " " 4-acetyl- amino- benzyl274 " " " " " 3-acetyl- amino- benzyl275 CH.sub.3 H COH " CH.sub.2 " benzyl276 " " COC.sub.2 H.sub.5 " " " "277 " " COC.sub.3 H.sub.7 " " " "278 CH.sub.3 H COC.sub.4 H.sub.9 H CH.sub.2 ##STR73## benzyl279 " " COC.sub.6 H.sub.13 " " " "280 " " COC.sub.8 H.sub.27 " " " "281 " " COC.sub.10 H.sub.21 " " " "282 " " H " " ##STR74## "283 " " " " " ##STR75## "284 " " " " " ##STR76## "285 " " " 3-Br " ##STR77## "286 " " " 3-C.sub.2 H.sub.5 " " "287 " " " 3-C.sub.3 H.sub.7 " " "288 " " " 3-OC.sub.2 H.sub.5 " " "289 " " " 3-OC.sub.3 H.sub.7 " " "290 " " " 3-OC.sub.4 H.sub.9 " " "291 " " " H " " 4-ethoxy- benzyl292 " " " " " " 4-butoxy- benzyl293 " " " " " " 4-t-butyl- benzyl294 " " " " " " 4-di- fluoro- methyl- benzyl295 CH.sub.3 H H H CH.sub.2 ##STR78## 4-(2- fluoro- ethoxy)- benzyl296 " " " " " " 4- butyryl- amino- benzyl297 H OC.sub.3 H.sub.7 " " " " benzyl298 " OC.sub.4 H.sub.9 " " " " "299 CH.sub.2 CH.sub.2 CH.sub.2 CH(CH.sub.3) " " " " "300 CH.sub.2 CH.sub.2 CH(OCH.sub.2 CH.sub.2 C.sub.6 H.sub.5) " " " " "301 CH.sub.3 H " " " " phen- ethyl302 " " " " " " diphenyl- methyl303 C.sub.2 H.sub.5 " " 3-OCH.sub.3 " " benzyl304 " " " 3-F " " "305 " " " 3-Cl " " "306 " " " 3-CH.sub.3 " " "307 " " " H " " 2-thienyl- methyl308 C.sub.3 H.sub.7 " " 3-OCH.sub.3 " " benzyl309 " " " 3-F " " "310 " " " 3-Cl " " "311 " " " 3-CH.sub.3 " " "312 " " " H " " 2-thienyl- methyl313 i-C.sub.3 H.sub.7 H H 3-OCH.sub.3 CH.sub.2 ##STR79## benzyl314 " " " 3-F " " "315 " " " 3-Cl " " "316 " " " 3-CH.sub.3 " " "317 CH.sub.3 " " H " " 3-phenyl- propyl318 " " " 3-OCH.sub.3 " " 2-thienyl- methyl319 " " " 3-F " " 2-thienyl- methyl320 " " " 3-Cl " " 2-thienyl- methyl321 " " " 3-CH.sub.3 " " 2-thienyl- methyl322 CH.sub.2 CH.sub.2 CH.sub.2 " " 3-OCH.sub.3 " " 2-thienyl- methyl323 " " " 3-F " " 2-thienyl- methyl324 " " " 3-Cl " " 2-thienyl- methyl325 " " " 3-CH.sub.3 " " 2-thienyl- methyl326 C.sub.2 H.sub.5 " " H " " 3-thienyl- methyl327 CH.sub.3 " " 3-OCH.sub.3 " " 3-thienyl- methyl328 " " " 3-F " " 3-thienyl- methyl329 " " " 3-Cl " " 3-thienyl- methyl330 " " " 3-CH.sub.3 " " 3-thienyl- methyl__________________________________________________________________________
TABLE 2__________________________________________________________________________(Compound III) ##STR80## ##STR81## ##STR82## ##STR83## ##STR84## ##STR85## ##STR86##__________________________________________________________________________ 1 CH.sub.2 CH.sub.2 CH.sub.2 H double bond ##STR87## benzyl 2 " " single bond ##STR88## " 3 " " CH " " 4 " " CH.sub.2 " " 5 " " CHCH.sub.2 " " 6 " " (CH.sub.2).sub.2 " " 7 " " double bond ##STR89## 4-fluorobenzyl 8 " " single bond ##STR90## " 9 " " CH " " 10 " " CH.sub.2 " " 11 " " CHCH.sub.2 " " 12 " " (CH.sub.2).sub.2 " " 13 " " double bond ##STR91## 3-fluorobenzyl 14 " " single bond ##STR92## " 15 " " CH " " 16 " " CH.sub.2 " " 17 " " CHCH.sub.2 " " 18 " " (CH.sub.2).sub.2 " " 19 CH.sub.2 CH.sub.2 CH.sub.2 H double bond ##STR93## 2-fluorobenzyl 20 " " single bond ##STR94## " 21 " " CH " " 22 " " CH.sub.2 " " 23 " " CHCH.sub.2 " " 24 " " (CH.sub.2).sub.2 " " 25 " " double bond ##STR95## 4-methoxybenzyl 26 " " single bond ##STR96## " 27 " " CH.sub.2 " " 28 " " CH.sub.2 " " 29 " " CHCH.sub.2 " " 30 " " (CH.sub.2).sub.2 " " 31 " " double bond ##STR97## 3-methoxybenzyl 32 " " single bond ##STR98## " 33 " " CH " " 34 " " CH.sub.2 " " 35 " " CHCH.sub.2 " " 36 " " (CH.sub.2).sub.2 " " 37 CH.sub.2 CH.sub.2 CH.sub.2 H double bond ##STR99## 4-hydroxybenzyl 38 " " single bond ##STR100## " 39 " " CH " " 40 " " CH.sub.2 " " 41 " " CHCH.sub.2 " " 42 " " (CH.sub.2).sub.2 " " 43 " " double bond ##STR101## 4-chlorobenzyl 44 " " single bond ##STR102## " 45 " " CH " " 46 " " CH.sub.2 " " 47 " " CHCH.sub.2 " " 48 " " (CH.sub.2).sub.2 " " 49 " " double bond ##STR103## 3-chlorobenzyl 50 " " single bond ##STR104## " 51 " " CH " " 52 " " CH.sub.2 " " 53 " " CHCH.sub.2 " " 54 " " (CH.sub.2).sub.2 " " 55 CH.sub.2 CH.sub.2 CH.sub.2 H double bond ##STR105## 2-chlorobenzyl 56 " " single bond ##STR106## " 57 " " CH " " 58 " " CH.sub.2 " " 59 " " CHCH.sub.2 " " 60 " " (CH.sub.2).sub.2 " " 61 " " double bond ##STR107## 4-methylbenzyl 62 " " single bond ##STR108## " 63 " " CH " " 64 " " CH.sub.2 " " 65 " " CHCH.sub.2 " " 66 " " (CH.sub.2).sub.2 " " 67 " " double bond ##STR109## 4-nitrobenzyl 68 " " single bond ##STR110## " 69 " " CH " " 70 " " CH.sub.2 " " 71 " " CHCH.sub.2 " " 72 " " (CH.sub.2).sub.2 " " 73 CH.sub.2 CH.sub.2 CH.sub.2 H double bond ##STR111## 4-trifluoromethylbenzyl 74 " " single bond ##STR112## " 75 " " CH " " 76 " " CH.sub.2 " " 77 " " CHCH.sub.2 " " 78 " " (CH.sub.2).sub.2 " " 79 " " double bond ##STR113## sec-phenethyl 80 " " single bond ##STR114## " 81 " " CH " " 82 " " CH.sub.2 " " 83 " " CHCH.sub.2 " " 84 " " (CH.sub.2).sub.2 " " 85 " " double bond ##STR115## diphenylmethyl 86 " " single bond ##STR116## " 87 " " CH " " 88 " " CH.sub.2 " " 89 " " CHCH.sub.2 " " 90 " " (CH.sub.2).sub.2 " " 91 CH.sub.2 CH.sub.2 CH.sub.2 H double bond ##STR117## di(4-fluorophenyl)methyl 92 " " single bond ##STR118## " 93 " " CH " " 94 " " CH.sub.2 " " 95 " " CHCH.sub.2 " " 96 " " (CH.sub.2).sub.2 " " 97 " " double bond ##STR119## 2-thienylmethyl 98 " " single bond ##STR120## " 99 " " CH " "100 " " CH.sub.2 " "101 " " CHCH.sub.2 " "102 " " (CH.sub.2).sub.2 " "103 " " double bond ##STR121## 2-pyridylmethyl104 " " single bond ##STR122## "105 " " CH " "106 " " CH.sub.2 " "107 " " CHCH.sub.2 " "108 " " (CH.sub.2).sub.2 " "109 CH.sub.2 CH.sub.2 CH.sub.2 H double bond ##STR123## 4-pyridylmethyl110 " " single bond ##STR124## "111 " " CH " "112 " " CH.sub.2 " "113 " " CHCH.sub.2 " "114 " " (CH.sub.2).sub.2 " "115 " " double bond ##STR125## 2-pyrimidinylmethyl116 " " single bond ##STR126## "117 " " CH " "118 " " CH.sub.2 " "119 " " CHCH.sub.2 " "120 " " (CH.sub.2).sub.2 " "121 " " double bond ##STR127## 4-pyrimidinylmethyl122 " " single bond ##STR128## "123 " " CH " "124 " " CH.sub.2 " "125 " " CHCH.sub.2 " "126 " " (CH.sub.2).sub.2 " "127 H H H CH.sub.2 ##STR129## benzyl128 " CH.sub.3 " " " "129 " C.sub.2 H.sub.5 " " " "130 " C.sub.3 H.sub.7 " " " "131 " i-C.sub.3 H.sub.7 " " " "132 " C.sub.4 H.sub.9 " " " "133 " sec-C.sub.4 H.sub.9 " " " "134 " C.sub.6 H.sub.13 " " " "135 " C.sub.8 H.sub.17 " " " "136 " C.sub.10 H.sub.21 " " " "137 " Cl " " " "138 " Br " " " "139 " OCH.sub.3 " " " "140 " OC.sub.2 H.sub.5 " " " "141 CH.sub.3 CH.sub.3 " " " "142 C.sub.2 H.sub.5 " " " " "143 C.sub.3 H.sub.7 " " " " "144 i-C.sub.3 H.sub.7 " " " " "145 C.sub.4 H.sub.9 CH.sub.3 H CH.sub.2 ##STR130## benzyl146 sec-C.sub.4 H.sub.9 " " " " "147 i-C.sub.4 H.sub.9 " " " " "148 C.sub.5 H.sub.11 " " " " "149 C.sub.7 H.sub.15 " " " " "150 C.sub.9 H.sub.19 " " " " "151 Cl CH.sub.3 " " " "152 Br " " " " "153 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 " " " "154 CH(CH.sub.3)CH.sub.2 CH.sub.2 " " " "155 CH.sub.2 CH(CH.sub.3)CH.sub.2 " " " "156 CH.sub.2 CH.sub.2 CH(CH.sub.3) " " " "157 CH.sub.2 CH.sub.2 CH(OH) " " " "158 CH.sub.2 CH.sub.2 CH(OCH.sub.3) " " " "159 CH.sub.2 CH.sub.2 CH(OC.sub.2 H.sub.5) " " " "160 CH.sub.2 CH.sub.2 CH(OC.sub.3 H.sub.7) " " " "161 CH.sub.2 CH.sub.2 CH(OCH.sub.2 CHCH.sub.2) " " " "162 CH.sub.2 CH.sub.2 CH(OCH.sub.2 C.sub.6 H.sub.5) " " " "163 CH.sub.2 CH.sub.2 CH(OCOH) " " " "164 CH.sub.2 CH.sub.2 CH(OCOCH.sub.3) H CH.sub.2 ##STR131## benzyl165 CH.sub.2 CH.sub.2 CH(OCOC.sub.2 H.sub.5) " " " "166 CH.sub.2 CH.sub.2 CH(OCOC.sub.3 H.sub.7) " " " "167 CH.sub.2 CH.sub.2 CH(OCOC.sub.5 H.sub.11) " " " "168 CH.sub.2 CH.sub.2 CH(OCOC.sub.9 H.sub.19) " " " "169 CH.sub.2 CH.sub.2 CH(OCOCH.sub.2 C.sub.6 H.sub.5) " " " "170 CH.sub.2 CH.sub.2 CH(OCOC.sub.6 H.sub.5) " " " "171 CH.sub.2 CH.sub.2 CH(F) " " " "172 CH.sub.2 CH.sub.2 CH(Cl) " " " "173 CH.sub.2 CH.sub.2 CH(Br) " " " "174 CH.sub.2 CH.sub.2 C(F).sub.2 " " " "175 CH(Br)CH.sub.2 CH(Br) " " " "176 CH.sub.3 Cl " " " "177 " Br " " " "178 " CH.sub.2 OH " " " "179 " CH.sub.2 OCH.sub.3 " " " "180 " CH.sub.2 OCOCH.sub.3 " " " "181 " CH.sub.2 F " " " "182 " CH.sub.2 Cl " " " "183 CH.sub.2 CH.sub.2 CH.sub.2 H CH.sub.2 ##STR132## 2-pyrimidinylmethyl184 CH.sub.2 C(CH.sub.3).sub.2 CH.sub.2 " " " benzyl185 CH.sub.2 CH.sub.2 CH(OC.sub.6 H.sub.5) " " " "__________________________________________________________________________
In the formula (II), the compounds (IIa to e) wherein R.sup.4 is a hydrogen atom can be prepared by [Preparation process 1-1], [Preparation process 2-1], [Preparation process 3-1] or [Preparation process 4-1], and in the formula (III), the compounds (IIIa to e) wherein R.sup.4 is a hydrogen atom can be prepared by [Preparation process 1-2], [Preparation process 2-2], [Preparation process 3-2] or [Preparation process 4-2].
On the other hand, in the formula (II), the compound (IIf) wherein R.sup.4 is an acyl group can be prepared by [Preparation process 5-1] and in the formula (III), the compound (IIIf) wherein R.sup.4 is an acyl group can be prepared by [Preparation process 5-2]. ##STR133##
(wherein R.sup.1, R.sup.2, R.sup.3, R.sup.5, R.sup.6, X, Y and . . . have the same meanings as described above and Z represents a halogen atom)
In [Preparation process 1-1] or [Preparation process 1-2], the compound (IIa) or (IIIa) is prepared by reacting the compound (IV) or (VI) with the compound (V) in a 1- to 5-fold molar amount, preferably a 1- to 2-fold molar amount in a solvent in the presence or absence of an acid.
The solvent to be used is not particularly limited so long as it is inert to the above reactions, and may include, for example, alcohols such as methanol, ethanol, propanol, isopropanol, butanol, etc.; aprotic polar solvents such as dimethylformamide, dimethyl sulfoxide, dimethylacetamide, hexamethylphosphoric acid triamide, etc.; halogenated hydrocarbons such as chloroform, carbon tetrachloride, dichloroethane, etc.; esters such as ethyl acetate, etc.; and nitriles such as acetonitrile, etc. Preferred are the aforesaid alcohols, halogenated hydrocarbons and aprotic polar solvents.
As the acid to be used, there may be mentioned, for example, a Br.phi.nsted acid such as hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, propionic acid, methanesulfonic acid, benzenesulfonic acid, p-toluene-sulfonic acid, etc.; and a Lewis acid such as stannous chloride, stannic chloride, zinc chloride, aluminum chloride, titanium tetrachloride, etc., preferably hydrochloric acid, stannous chloride, stannic chloride and zinc chloride. The amount to be used is generally a 0.01- to 10-fold molar amount, preferably a 0.1- to 5-fold molar amount based on the compound (V).
The reaction temperature is 0.degree. to 200.degree. C., preferably the reaction is carried out in the range of 0.degree. to 150.degree. C. The reaction time varies depending on conditions other than those described above, but the reaction is carried out generally for 5 minutes to 24 hours, preferably for 10 minutes to 12 hours.
The compound (IV) is generally used as a free material, but a salt with the Br.phi.nsted acid or a complex with the Lewis acid as mentioned above may be also used. In that case, the reaction can proceed smoothly without further adding the Br.phi.nsted acid or Lewis acid as mentioned above to the reaction system.
Also, when the compound (IV) or (VI) wherein R.sup.5 is a hydroxy group is reacted in the aforesaid alcohol in the presence of an acid, as the formed compound (IIa) or (IIIa), in addition to the compound wherein R.sup.5 is a hydroxy group, a compound (for example, in the reaction in ethanol, a compound wherein R.sub.5 is an ethoxy group) wherein R.sup.5 is an alkoxy group which can be obtained by replacing the hydroxy group with an alcohol of the solvent and a compound having a double bond which is a dehydrated product can be obtained. ##STR134##
(wherein R.sup.1, R.sup.2, R.sup.3, R.sup.6 and p have the same meanings as described above)
In [Preparation process 2-1] or [Preparation process 2-2], the compound (IIb), (IIc), (IIIb) or (IIIc) is prepared by subjecting the compound (VII) or (X) and the compound (VIII) or (IX) in a 1- to 5-fold molar amount, preferably a 1- to 2-fold molar amount to condensation reaction in a solvent in the presence of a base.
The solvent to be used is not particularly limited so long as it is inert to the above reactions, and may include, for example, alcohols such as methanol, ethanol, propanol, isopropanol, butanol, etc.; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, etc.; aprotic polar solvents such as dimethylformamide, dimethyl sulfoxide, dimethylacetamide, etc.; nitriles such as acetonitrile, etc.; and esters such as ethyl acetate, etc. Preferred are the above alcohols, ethers and nitriles.
As the base to be used, there may be mentioned, for example, alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium t-butoxide, etc.; alkyl lithiums such as butyl lithium, t-butyl lithium, etc.; alkali metal hydrides such as sodium hydride, lithium hydride, etc.; alkali metal amides such as sodium amide, etc.; amines such as triethylamine, tributylamine, diisopropylethylamine, pyridine, picoline, luridine, etc.; alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, etc.; and alkali metal carbonates such as sodium carbonate, potassium carbonate, etc. Preferred are the above alkali metal alkoxides, alkyl lithiums, alkali metal hydrides and amines. The amount to be used is generally a 1- to 10-fold molar amount, preferably a 1- to 5-fold molar amount based on the compound (VII) or (X).
The reaction temperature is -70.degree. to 150.degree. C., preferably the reaction is carried out in the range of -50.degree. to 100.degree. C. The reaction time varies depending on conditions other than those described above, but the reaction is carried out generally for 15 minutes to 100 hours, preferably for 30 minutes to 72 hours. ##STR135##
(wherein R.sup.1, R.sup.2, R.sup.3, R.sup.6 and p have the same meanings as described above)
In [Preparation process 3-1] or [Preparation process 3-2], the compound (IId), (IIe), (IIId) or (IIIe) is prepared by subjecting the compound (IIb), (IIc), (IIIb) or (IIIc) to catalytic reduction with a hydrogen gas in a solvent in the presence of a catalyst or to reduction by a reducing agent.
The solvent to be used when catalytic reduction with a hydrogen gas is carried out is not particularly limited so long as it is inert to the above reaction, and may include, for example, alcohols such as methanol, ethanol, propanol, isopropanol, butanol, etc.; ethers such as diethyl ether, tetrahydrofuran, dioxane, etc.; water; and acetic acid. Preferred are the above alcohols. When the compound (IIb), (IIc), (IIIb) or (IIIc) is not easily dissolved in the above solvent, dissolution can be accelerated by a method of mixing these solvents, adding a small amount of hydrochloric acid, etc., whereby the reaction can be accelerated.
As the catalyst to be used, there may be mentioned, for example, a noble metal type catalyst such as platinum oxide, palladium-carbon, platinum-carbon, etc., preferably platinum oxide and palladium-carbon. The amount of the catalyst to be used is generally 0.01 to 50% by weight, preferably 0.1 to 50% by weight based on the compound (IIb), (IIc), (IIIb) or (IIIc).
The hydrogen gas may be passed to the reaction mixture at normal pressure or may be reacted in an autoclave under pressurization up to 100 kg/cm.sup.2. The pressure is preferably normal pressure to 50 kg/cm.sup.2.
The reaction temperature is 0.degree. to 200.degree. C., preferably the reaction is carried out in the range of 0.degree. to 150.degree. C. The reaction time varies depending on conditions other than those described above, but the reaction is carried out generally for 10 minutes to 24 hours, preferably for 15 minutes to 12 hours.
On the other hand, when reduction is carried out by using a reducing agent, as the reducing agent, preferred is a reducing agent used for reduction of an .alpha..beta.-unsaturated ketone, such as metallic lithium-ammonia, triethylsilane-trifluoroacetic acid, triphenyltin hydride, lithium aluminum hydride-cuprous iodide, etc. These reactions can be carried out, for example, under conditions described in "New Experimental Chemistry Lecture" edited by the Japan Chemical Society, vol. 14 (I), p. 5. ##STR136##
(wherein R.sup.1, R.sup.2, R.sup.3, R.sup.5, R.sup.6 X, Y, Z and . . . have the same meanings as described above and R.sup.7 represents a protective group such as a t-butoxycarbonyl group, a benzyloxycarbonyl group, an acetyl group, a trifluoroacetyl group, a benzoyl group, a triphenylmethyl group and a methoxymethyl group)
In [Preparation process 4-1] or [Preparation process 4-2], the compound (IIa) or (IIIa) can be also prepared by reacting the compound (IV') or (VI') having the protective group R.sup.7 with the compound (V) to prepare the compound (II'a) or (III'a), removing the protective group and then carrying out alkylation.
The protective group R.sup.7 may be any protective group generally used as a protective group for an amino group, and there may be mentioned, for example, a protective group such as a t-butoxycarbonyl group, a benzyloxycarbonyl group, an acetyl group, a trifluoroacetyl group, a benzoyl group, a triphenylmethyl group and a methoxymethyl group.
The reactions for obtaining the compound (II'a) from the compounds (IV') and (V) and the compound (III'a) from the compounds (VI') and (V) can be carried out according to the same method as described above in [Preparation process 1-1] and [Preparation process 1-2].
The deprotection reaction for obtaining the compound (XI) from the compound (II'a) or the compound (XIII) from the compound (III'a) can be carried out by suitably selecting from methods described in literature (e.g. T. W. Greene, "Protective Groups in Organic Synthesis" John Wiley & Sons), for example, a method using an acid, an alkali or hydrogen reduction, etc.
In the alkylation reactions for obtaining the compound (IIa) from the compound (XI) and the compound (IIIa) from the compound (XIII), the solvent to be used is not particularly limited so long as it is inert to the above reactions, and may include, for example, ketones such as acetone, methyl ethyl ketone, etc.; ethers such as diethyl ether, tetrahydrofuran, dioxane, etc.; alcohols such as methanol, ethanol, propanol, isopropanol, butanol, etc.; aprotic polar solvents such as dimethylformamide, dimethyl sulfoxide, dimethylacetamide, hexamethylphosphoric acid triamide, etc.; halogenated hydrocarbons such as chloroform, dichloromethane, dichloroethane, etc. and others.
It is generally desired to carry out the above reactions in the presence of a base. As the base, there may be mentioned alkali metal carbonates such as sodium carbonate, potassium carbonate, etc.; and amines such as triethylamine, tributylamine, diisopropylethylamine, pyridine, picoline, etc.
The reaction temperature is 0.degree. to 150.degree. C., preferably the reaction is carried out in the range of 0.degree. to 100.degree. C. The reaction time is generally 15 minutes to 72 hours, preferably the reaction is carried out for 30 minutes to 24 hours. ##STR137##
(wherein R.sup.1, R.sup.2, R.sup.3, R.sup.5, R.sup.6, X, Y, Z and . . . have the same meanings as described above and R.sup.4' represents the same acyl group described in R.sup.4)
In [Preparation process 5-1] or [Preparation process 5-2], the compound (IIf) or (IIIf) is prepared by reacting the compound (IIa) or (IIIa) with the acyl halide (XIV) in a 1- to 5-fold molar amount, preferably a 1- to 2-fold molar amount in the presence of a base.
The solvent to be used is not particularly limited so long as it is inert to the above reactions, and may include, for example, halogenated hydrocarbons such as methylene chloride, chloroform, dichloroethane, etc.; aprotic polar solvents such as dimethylformamide, dimethyl sulfoxide, dimethylacetamide, hexamethylphosphoric acid triamide, etc.; esters such as ethyl acetate, etc.; and nitriles such as acetonitrile, etc. Preferred are halogenated hydrocarbons and aprotic polar solvents.
As the base to be used, there may be mentioned amines such as triethylamine, tributylamine, diisopropylethylamine, pyridine, picoline, lutidine, etc.; alkali metal carbonates such as sodium carbonate, potassium carbonate, etc. and others. Preferred are amines. The amount to be used is generally a 1- to 10-fold molar amount, preferably a 1- to 5-fold molar amount based on the acyl halide.
The reaction temperature is -70.degree. to 150.degree. C., preferably the reaction is carried out in the range of -50.degree. to 100.degree. C. The reaction time varies depending on conditions, but the reaction is carried out generally for 15 minutes to 100 hours, preferably for 30 minutes to 72 hours.
In the compound (II) or (III), when at least one of R.sup.1, R.sup.2 and R.sup.3 has a functional group such as a hydroxy group, an amino group, etc., these can be converted into an acyloxy group, an acylamino group, etc., respectively, according to a known method, for example, by subjecting it to acylation reaction. When it has a nitro group, it can be converted into an amino group by reduction reaction.
The compounds (VIII) and (IX) to be used in the above [Preparation process 2-1] and [Preparation process 2-2] are known compounds or compounds easily prepared from known compounds according to a conventional method.
The compounds (V), (VII) and (X) to be used as starting materials in [Preparation process 1-1], [Preparation process 1-2], [Preparation process 2-1], [Preparation process 2-2], [Preparation process 4-1] and [Preparation process 4-2] can be prepared easily according to known methods (see Japanese Provisional Patent Publication No. 203072/1982 and Japanese Provisional Patent Publication No. 70/1987). The compounds (IV), (VI), (IV') and (VI') to be used as starting materials in [Preparation process 1-1], [Preparation process 1-2], [Preparation process 4-1] and [Preparation process 4-2] can be prepared by [Preparation process 6-1], [Preparation process 6-2], [Preparation process 8-1], [Preparation process 8-2], [Preparation process 9-1] and [Preparation process 9-2] shown below. ##STR138##
(wherein R.sup.3, R.sup.6 and p have the same meanings as described above and R.sup.8 represents a methyl group, an ethyl group or a phenyl group) ##STR139##
(wherein R.sup.3 and p have the same meanings as described above)
The condensation reactions of [Preparation process 6-1] and [Preparation process 6-2] are carried out by the same methods as described above in [Preparation process 2-1] and [Preparation process 2-2], or carried out by a known method known as the Horner-Wadsworth-Emmons reaction (see, for example, M. A. Blanchette et at., Tetrahedron Letters, vol. 25, 2183).
In the reduction reactions of [Preparation process 6-1] and [Preparation process 6-2], partial reduction reactions for obtaining the compound (IVa) from the compound (XVIa), the compound (IVc) from the compound (XVIb), the compound (VIa) from the compound (XVIIIa) and the compound (VIc) from the compound (XVIIIb) are carried out by a method of using stannous chloride, tin, zinc or iron, preferably stannous chloride or tin under acidic conditions or using zinc under neutral or alkaline conditions. As the solvent to be used for these reactions, there may be mentioned, in addition to alcohols such as methanol, ethanol, propanol, etc., acetonitrile, acetic acid, water, etc. Preferred are alcohols, acetic acid and water. These may be used as a mixture. Further, as the acid to be used, there may be mentioned mineral acids such as hydrochloric acid, sulfuric acid and phosphoric acid or organic acids such as acetic acid and propionic acid. Preferred are hydrochloric acid, sulfuric acid and acetic acid. As the alkali, there may be mentioned an alkali metal hydroxide such as sodium hydroxide and potassium hydroxide. The reactions are carried out generally at a temperature of 0.degree. to 200.degree. C., preferably in the range of 0.degree. to 150.degree. C. for 30 minutes to 72 hours, preferably 1 hour to 24 hours.
On the other hand, in the reduction reactions of [Preparation process 6-1] and [Preparation process 6-2], simultaneous reduction reactions of nitro groups and double bonds for obtaining the compound (Ivb) from the compound (XVIa), the compound (IVd) from the compound (XVIb), the compound (VIb) from the compound (XVIIIa) and the compound (VId) from the compound (XVIIIb) are carried out by the same methods as described above in [Preparation process 3-1] and [Preparation process 3-2].
The nitro compounds (XVIa), (XVIb), (XVIIIa) and (XVIIIb) which are intermediates in [Preparation process 6-1] and [Preparation process 6-2] and the compounds (IV') (i.e., IV'a, IV'b, IV'c and IV'd) and the compounds (VI') (i.e., VI'a, VI'b, VI'c and VI'd) which are starting materials in [Preparation process 4-1] and [Preparation process 4-2] can be also prepared by [Preparation process 7-1] and [Preparation process 7-2] shown below. ##STR140##
(wherein R.sup.3, R.sup.6, R.sup.7, Z and p have the same meanings as described above) ##STR141##
(wherein R.sup.3, R.sup.7 and p have the same meanings as described above)
The condensation reactions of [Preparation process 7-1] and [Preparation process 7-2] are carried out by the same methods as described above in [Preparation process 6-1] and [Preparation process 6-2], and the deprotection reactions are carried out in the same manner as in [Preparation process 4-1] and [Preparation process 4-2], by suitably selecting a known method of using an acid, an alkali or hydrogen reduction, etc. Also, the N-alkylation reaction by the compound (XII) is carried out by the same methods as described above in [Preparation process 4-1] and [Preparation process 4-2], and the reduction reactions of the compounds (XVI'a), (XVI'b), (XVIII'a) and (XVIII'b) can be carried out by the same methods as described above in [Preparation process 6-1] and [Preparation process 6-2]. ##STR142##
(wherein R.sup.3, R.sup.6 and p have the same meanings as described above and R.sup.9 represents a protective group such as a t-butoxycarbonyl group, a benzyloxycarbonyl group, an acetyl group, a trifluoroacetyl group and a benzoyl group) ##STR143##
(wherein R.sup.3, R.sup.9 and p have the same meanings as described above)
In [Preparation process 8-1] or [Preparation process 8-2], the compound (XXIIa), (XXIId), (XXIVa) or (XXIVd) is prepared by subjecting the compound (XXI) or (XXIII) with the compound (VIII) or (IX) in a 1- to 5-fold molar amount, preferably a 1- to 2-fold molar amount to condensation reaction in a solvent in the presence of a strong base.
R.sup.9 as the protective group is not particularly limited so long as it is stable under these reaction conditions, and preferred are a t-butoxycarbonyl group, a benzyloxycarbonyl group, an acetyl group, a trifluoroacetyl group, a benzoyl group, etc.
As the solvent to be used, there may be mentioned ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, etc.; aliphatic and aromatic hydrocarbons such as pentane, hexane, cyclohexane, benzene, toluene, etc.; and aprotic polar solvents such as hexamethylphosphoric acid triamide, dimethyl sulfoxide, etc. Also, a mixture of these solvents may be used.
As the strong base to be used, preferred are alkyl lithiums such as n-butyl lithium, t-butyl lithium, etc.; alkali metal amides such as lithium diisopropylamide, lithium ditrimethylsilylamide, sodium amide, etc.; and alkali metal hydrides such as sodium hydride, potassium hydride, etc. The amount to be used is generally a 1- to 5-fold molar amount, preferably a 2- to 3-fold molar amount based on the compound (XXI) or (XXIII).
The reaction temperature is -70.degree. to 100.degree. C., preferably the reaction is carried out in the range of -70.degree. to 50.degree. C.
The dehydration reactions of [Preparation process 8-1] and [Preparation process 8-2] are generally carried out by suitably selecting from various known methods used when an olefin is synthesized from an alcohol. There may be mentioned, for example, a dehydration method under acidic conditions using an inorganic acid such as hydrochloric acid, sulfuric acid, phosphoric acid, etc.; or an organic acid such as p-tolunesulfonic acid, benzenesulfonic acid, etc., or a dehydration method in the coexistence of a dehydrating agent such as thionyl chloride, phosphorus oxychloride, methanesulfonic acid chloride, methanesulfonic anhydride, acetic anhydride, etc. and an organic base such as pyridine, picoline, lutidine, 1,8-diazabicyclo[5.4.0.]-7-undecene, triethylamine, etc. Particularly when the protective group R.sup.9 is unstable under acidic conditions, the latter method is preferred.
In the above dehydration reactions, as in the examples of the compounds (XXIIe) and (XXIIf), and (XXIVe) and (XXIVf), isomers having the double bond at different positions may be produced. These may be separated and used or may be used as a mixture when they are used for the reduction reactions.
The reduction reactions of [Preparation process 8-1] and [Preparation process 8-2] are carried out by the same methods as described above in [Preparation process 3-1] and [Preparation process 3-2].
By deprotecting the above compounds (XXIIa), (XXIIb), (XXIIc), (XXIId), (XXIIe), (XXIIf), (XXIIg), (XXIVa), (XXIVb), (XXIVc), (XXIVd), (XXIVe), (XXIVf) and (XXIVg), the compounds (IVe), (IVa), (IVb), (IVf), (IVc), (IVg), (IVd), (VIe), (VIa), (VIb), (VIf), (VIc), (VIg) and (VId) are prepared, respectively. The deprotection reactions are carried out by the same methods as described above in [Preparation process 4-1] and [Preparation process 4-2]. ##STR144##
(wherein R.sup.3, R.sup.6, R.sup.7, R.sup.9, Z and p have the same meanings as described above) ##STR145##
(wherein R.sup.3, R.sup.6, R.sup.7, R.sup.9, Z and p have the same meanings as described above)
In [Preparation process 9-1] and [Preparation process 9-2], the condensation reactions, dehydration reactions and reduction reactions are carried out by the same methods as described in [Preparation process 8-1] and [Preparation process 8-2].
R.sup.7 and R.sup.9 as protective groups may be different or may be the same. The respective compounds obtained in the respective reactions of [Preparation process 9-1] and [Preparation process 9-2] are supplied to the deprotection reactions, respectively. In this case, by suitably selecting the kinds of the two protective groups R.sup.7 and R.sup.9 or suitably selecting deprotection conditions, either one of R.sup.7 and R.sup.9 can be selectively removed. Also, both of them can be removed simultaneously. The selections of these R.sup.7 and R.sup.9 and deprotection conditions can be carried out by referring to literature, for example, T. W. Greene, "Protective Groups in Organic Synthesis" John Wiley & Sons.
The compounds (XXVa), (XXVIa), (XXVb), (XXVIb), (XXVc), (XXVIc), (XXVd), (XXVId), (XXVe), (XXVIe), (XXVf), (XXVIf), (XXVg), (XXVIg), (XXVIIa), (XXVIIIa), (XXVIIb), (XXVIIIb), (XXVIIc), (XXVIIIc), (XXVIId), (XXVIIId), (XXVIIe), (XXVIIIe), (XXVIIf), (XXVIIIf), (XXVIIg) and (XXVIIIg) thus obtained can be converted into (XXIIa), (IVe), (XXIIb), (IVa), (XXIIc), (IVb), (XXIId), (IVf), (XXIIe), (IVc), (XXIIf), (IVg), (XXIIg), (IVd), (XXIVa), (VIe), (XXIVb), (VIa), (XXIVc), (VIb), (XXIVd), (VIf), (XXIVe), (VIc), (XXIVf), (VIg), (XXIVg) and (VId), respectively, by subjecting to alkylation using the compound (XII) (R.sup.3 -Z) by the same methods as described above in [Preparation process 4-1] and [Preparation process 4-2], respectively.
After completion of the reactions, the desired compounds of the respective reactions can be obtained by treating the reaction mixtures according to a conventional method and further can be purified by using a conventional purification means such as recrystallization, column chromatography, etc., if necessary. The compounds of the formula (I), the formula (II) and the formula (III) of the present invention are converted into desired salts according to a conventional method, if necessary.
In the compounds of the formula (I), the formula (II) and the formula (III) thus prepared, optical isomers or geometric (cis and trans or E and Z) isomers may exist. In that case, by carrying out the above reactions by using starting compounds which are optically resolved or separated as desired, optical isomers or geometric isomers of the corresponding desired compounds can be obtained. Also, by treating a mixture of optical isomers or geometric isomers according to a conventional optical resolution method or separation method, the respective isomers can be obtained.
In the formula (I), the formula (II) and the formula (III), all of optical isomers, geometric isomers and mixtures thereof are represented by the same formulae, but the respective isomers and mixtures thereof are included in the present invention as a matter of course.
BEST MODE FOR PRACTICING THE INVENTION
In the following, the present invention is described in detail by showing Examples, but the scope of the present invention is not limited by these.

EXAMPLE 1
(E)-N-(5,6-dimethylpyrimidin-4-yl)-4-[3-(1-benzyl-piperidin-4-yl)propenoyl]aniline (Compound II-199 in Table 1)
1.27 g of 4-[3-(1-benzylpiperidin-4-yl)propenoyl]-nitrobenzene was added to a mixed solution of 10 ml of acetic acid and 2 ml of hydrochloric acid, and then 1.38 g of stannous chloride was added thereto under ice cooling. The mixture was stirred for 24 hours while further adding 0.69 g of stannous chloride twice during the reaction. The solvent was removed under reduced pressure to obtain a crude product of (E)-4-[3-(1-benzylpiperidin-4-yl)propenoyl]aniline. Then, this was dissolved in 15 ml of ethanol, and to the solution was added 0.67 g of 4-chloro-5,6-dimethylpyrimidine. Subsequently, the mixture was reacted by heating at 60.degree. C. for 30 minutes. The reaction mixture was neutralized by adding a 28% sodium methylate-methanol solution under cooling, solids were removed by filtration, and then the filtrate was consensed under reduced pressure. The obtained residue was applied to silica gel column chromatography to obtain 1.02 g of the title compound as pale yellow powder.
m.p. 188.degree. to 190.degree. C. (decomposed)
Mass; m/z=426 (M.sup.+)
NMR (.delta., CDCl.sub.3); 1.45 to 1.87 (4H, m), 1.96 to 2.13 (2H, m), 2.13 to 2.40 (1H, m), 2.22 (3H, s), 2.49 (3H, s), 2.86 to 3.02 (2H, m), 3.52 (2H, s), 6.62 (1H, s, br), 6.87 (1H, d, J=15.6 Hz), 7.03 (1H, dd, J=15.6 Hz, J=6.5 Hz), 7.18 to 7.43 (5H, m), 7.74 (2H, d, J=8.8 Hz), 7.96 (2H, d, J=8.8 Hz), 8.58 (1H, s)
EXAMPLE 2
N-(5,6-dimethylpyrimidin-4-yl)-4-[3-(1-benzylpiperidin-4-yl)propanoyl]aniline (Compound II-150 in Table 1)
0.82 g of (E)-N-(5,6-dimethylpyrimidin-4-yl)-4-[3-(1-benzylpiperidin-4-yl)propenoyl]aniline obtained in Example 1 was added to a mixed solvent of 30 ml of ethanol and 40 ml of dioxane, and then 0.05 g of platinum oxide was added thereto. The mixture was stirred in a hydrogen stream at room temperature for 3.5 hours. After the catalyst was removed by filtration, the filtrate was condensed under reduced pressure. The obtained residue was applied to silica gel column chromatography to obtain 0.39 g of the title compound as pale yellow powder.
m.p. 168.degree. to 170.degree. C.
Mass; m/z =428 (M.sup.+)
NMR (.delta., CDCl.sub.3); 1.20 to 1.46 (3H, m), 1.60 to 1.85 (4H, m), 1.85 to 2.07 (2H, m), 2.22 (3H, s), 2.49 (3H, s), 2.83 to 3.04 (4H, m), 3.50 (2H, s), 6.60 (1H, s, br), 7.20 to 7.40 (5H, m), 7.72 (2H, d, J=8.8 Hz), 7.96 (2H, d, J=8.8 Hz), 8.58 (1H, s)
EXAMPLE 3
N-(5-chloro-6-methylpyrimidin-4-yl)-4-[3-(1-benzyl-piperidin-4-yl)propanoyl]aniline.multidot.2HCl (2HCl salt of Compound II-160 in Table 1)
0.29 g of N- (5-chloro-6-methylpyrimidin-4-yl) -4- [3- (1-benzylpiperidin-4-yl)propanoyl]aniline obtained in the same manner as in Example 1 was dissolved in a mixed solvent of 10 ml of ethyl acetate and 5 ml of ethanol, and a hydrogen chloride gas-saturated ethyl acetate solution was added to the mixture until the pH became 3. Crystals precipitated were collected by filtration and dried to obtain 0.21 g of the title compound as white powder.
(as 1/2H.sub.2 O adduct)
m.p. 217.degree. to 220.degree. C.
Mass; m/z=448 (M.sup.+)
NMR (.delta., CDCl.sub.3 -DMSO-d.sub.6); 1.70 to 1.90 (7H, m), 2.71 (3H, s), 2.82 to 3.23 (4H, m), 3.34 to 3.42 (2H, m), 4.28 (2H, d, J=4.9 Hz), 7.43 to 7.46 (3H, m), 7.67 to 7.69 (2H, m), 7.83 (2H, d, J=8.8 Hz), 8.00 (2H, d, J=8.8 Hz), 8.71 (1H, s), 10.24 (1H, s), 11.15 (1H, s, br)
In the same manner as in Example 1, Example 2 or Example 3, the following compounds were synthesized.
EXAMPLE 4
(E) -N- (5-chloro-6-methylpyrimidin-4-yl ) -4-[3-(1-benzylpiperidin-4-yl)propenoyl]aniline (Compound II-162 in Table 1)
White powder
m.p. 164.degree. to 166.degree. C.
Mass; m/z=446 (M.sup.+)
NMR (.delta., CDCl.sub.3); 1.49 to 1.70 (2H, m), 1.73 to 1.88 (2H, m), 1.98 to 2.10 (2H, m), 2.18 to 2.36 (1H, m), 2.59 (3H, s), 2.90 to 2.98 (2H, m), 3.52 (2H, s), 6.87 (1H, d, J=15 to 16 Hz), 7.04 (1H, dd, J=15 to 16 Hz, J=6 to 7 Hz), 7.41 (1H, s), 7.79 (2H, d, J=8 to 9 Hz), 7.98 (2H, d, J=8 to Hz), 8.58 (1H, s)
EXAMPLE 5
N-(6-chloropyrimidin-4-yl)-4-[3-(1-benzylpiperidin-4-yl)propanoyl]aniline.multidot.HCl (HCl salt of Compound II-146 in Table 1)
(as 1/2H.sub.2 O adduct)
Pale yellow powder
m.p. 246.degree. to 260.degree. C. (decomposed)
Mass; m/z=434 (M.sup.+)
NMR (.delta., CDCl.sub.3 -DMSO-d.sub.6); 1.40 to 1.72 (4H, m), 1.72 to 2.03 (3H, m), 2.77 to 3.20 (6H, m), 4.22 (2H, d, J=4.9 Hz), 6.95 (1H, s), 7.38 to 7.49 (3H, m), 7.38 to 7.63 (2H, m), 7.83 (2H, d, J=8.8 Hz ), 7.93 (2H, d, J=8.8 Hz ), 8.52 (1H, s ), 10.05 (1H, br), 10.28 (1H, s)
EXAMPLE 6
(E)-N-(5,6-dihydro-7H-cyclopenta[d]pyrimidin-4-yl)-4-[3-(1-benzylpiperidin-4-yl)propenoyl]aniline (Compound II-5 in Table 1)
Pale yellow powder
m.p. 212.degree. to 214.degree. C.
Mass; m/z=438 (M.sup.+)
NMR (.delta., CDCl.sub.3); 1.46 to 1.87 (4H, m), 1.93 to 2.38 (5H, m), 2.78 to 3.06 (6H, m), 3.52 (2H, s), 6.61 (1H, s, br), 6.87 (1H, d, J=15.6 Hz), 7.04 (1H, dd, J=15.6 Hz, J=6.4 Hz), 7.20 to 7.40 (5H, m), 7.77 (2H, d, J=8.8 Hz), 7.96 (2H, d, J=8.8 Hz ), 8.65 (1H, s )
EXAMPLE 7
N-(5,6-dihydro-7H-cyclopenta[d]pyrimidin-4-yl)-4-[3(1-benzylpiperidin-4-yl)propanoyl]aniline (Compound II-2 in Table 1)
Pale yellow powder
m.p. 203.degree. to 205.degree. C.
Mass; m/z=440 (M.sup.+)
NMR (.delta., CDCl.sub.3); 1.23 to 1.41 (3H, m), 1.63 to 1.77 (4H, m), 1.88 to 1.99 (2H, m), 2.14 to 2.26 (2H, m), 2.78 to 3.07 (8H, m), 3.49 (2H, s), 6.49 (1H, s), 7.20 to 7.30 (2H, m), 7.20 to 7.26 (3H, m), 7.76 (2H, d, J=8.8 Hz), 9.96 (2H, d, J=8.8 Hz ), 8.65 (1H, s )
EXAMPLE 8
N-(5,6-dihydro-7H-cyclopenta[d]pyrimidin-4-yl)-4-[3(1-benzylpiperidin-4-yl)propanoyl]aniline. 2HCl (2HCl salt of Compound II-2 in Table 1)
(as H.sub.2 O adduct)
Grayish white crystal
m.p. 198.degree. to 201.degree. C. (decomposed)
Mass; m/z=440 (M.sup.+)
NMR (.delta., CDCl.sub.3 -DMSO-d.sub.6); 1.52 to 2.21 (7H, m), 2.20 to 2.42 (2H, m), 2.68 to 3.55 (10H, m), 4.21 (2H, d, J=4.9 Hz), 7.38 to 7.52 (3H, m), 7.60 to 7.80 (2H, m), 7.80 to 8.03 (4H, m), 8.60 (1H, s), 11.53 to 11.80 (1H, m, br)
EXAMPLE 9
(E)-N-(5,6,7,8-tetrahydroquinazolin-4-yl)-4-[3-(1-benzylpiperidin-4-yl)propenoyl]aniline (Compound II-175 in Table 1)
White crystal
m.p. 171.degree. to 172.degree. C.
Mass (CI); m/z=453 (M.sup.+ +1)
NMR (.delta., CDCl.sub.3); 1.52 to 2.15 (10H, m), 2.18 to 2.36 (1H, m), 2.56 to 2.60 (2H, m), 2.82 to 2.88 (2H, m), 2.92 to 3.13 (2H, m), 3.55 (2H, s), 6.56 (1H, s), 6.87 (1H, d, J=15.6 Hz), 7.04 (1H, dd, J=6.4 Hz, J=15.6 Hz), 7.25 to 7.35 (5H, m), 7.77 (2H, d, J=8.8 Hz), 7.97 (2H, d, J=8.8 Hz), 8.60 (1H, s)
EXAMPLE 10
N-(5,6,7,8-tetrahydroquinazolin-4-yl)-4-[3-(1-benzyl-piperidin-4-yl)propanoyl]aniline (Compound II-163 in Table 1)
(as 3/4H.sub.2 O adduct)
White crystal
m.p. 156.degree. to 157.degree. C.
Mass (CI); m/e=455 (M.sup.+ +1)
NMR (.delta., CDCl.sub.3); 1.22 to 1.44 (3H, m), 1.61 to 1.74 (4H, m), 1.90 to 2.00 (6H, m), 2.52 to 2.58 (2H, m), 2.79 to 2.98 (6H, m), 3.48 (2H, s), 6.52 (1H, s), 7.25 to 7.32 (5H, m), 7.74 (2H, d, J=8.8 Hz), 7.96 (2H, d, J=8.8 Hz), 8.59 (1H, s)
EXAMPLE 11
(E)-N-(7-methoxy-5,6-dihydro-7H-cyclopenta[d]pyrimidin-4-yl)-4-[3-(1-benzylpiperidin-4-yl)propenoyl]aniline (Compound II-173 in Table 1)
(as 1/4H.sub.2 O adduct)
White crystal
m.p. 193.degree. to 195.degree. C. (decomposed)
Mass; m/z=468 (M.sup.+)
NMR (.delta., CDCl.sub.3); 1.50 to 1.82 (4H, m), 2.00 to 2.38 (4H, m), 2.40 to 2.56 (1H, m), 2.64 to 2.80 (1H, m), 2.90 to 3.12 (3H, m), 3.54 (2H, s), 3.58 (3H, s), 4.72 to 4.77 (1H, m), 6.59 (1H, s), 6.87 (1H, d, J=15.6 Hz ), 7.04 (1H, dd, J=6.4 Hz, 15.6 Hz), 7.26 to 7.34 (5H, m), 7.79 (2H, d, J=8.8 Hz ), 7.97 (2H, d, J=8.8 Hz), 8.75 (1H, s)
EXAMPLE 12
N-(7-methoxy-5,6-dihydro-7H-cyclopenta[d]pyrimidin-4-yl)-4-[3-(1-benzylpiperidin-4-yl)propanoyl]aniline (Compound II-168 in Table 1)
(as 1/4H.sub.2 O adduct)
White crystal
m.p. 178.degree. to 180.degree. C.
Mass; m/z=470 (M.sup.+)
NMR (.delta., CDCl.sub.3); 1.19 to 1.45 (3H, m), 1.60 to 1.81 (4H, m), 1.88 to 2.01 (2H, m), 2.07 to 2.24 (1H, m), 2.39 to 2.60 (1H, m), 2.64 to 2.78 (1H, m), 2.85 to 3.02 (5H, m), 3.48 (2H, s), 3.58 (3H, s), 4.71 to 4.76 (1H, m), 6.52 (1H, s), 7.21 to 7.28 (5H, m), 7.76 (2H, d, J=8.8 Hz), 7.96 (2H, d, J=8.8 Hz)
EXAMPLE 13
(E)-N-(7-fluoro-5,6-dihydro-7H-cyclopenta[d]pyrimidin-yl)-4-[3-(1-benzylpiperidin-4-yl)propenoyl]aniline (Compound II-188 in Table 1)
Pale yellow powder
Mass ; m/z=456 (M.sup.+)
NMR (.delta., CDCl.sub.3 -DMSO-d.sub.6); 1.47 to 1.90 (4H, m), 1.96 to 2.16 (2H, m), 1.86 to 2.16 (1H, m), 2.16 to 2.76 (3H, m), 2.76 to 3.23 (4H, m), 3.54 (2H, s), 5.70 to 5.78 and 5.96 to 6.06 (total 1H, each m), 6.89 (1H, d, J=15 to 16 Hz), 7.02 (1H, dd, J=15 to 16 Hz, J=5 to 6 Hz), 7.18 to 7.40 (5H, m), 7.86 to 8.04 (4H, m), 8.46 (1H, s), 8.74 (1H, s)
EXAMPLE 14
N-(7-fluoro-5,6-dihydro-7H-cyclopenta[d]pyrimidin-4yl)-4-[3-(1-benzylpiperidin-4-yl)propanoyl]aniline.multidot.2HCl (2HCl salt of Compound II-183 in Table 1)
(as 1/2H.sub.2 O adduct)
White crystal
m.p. 173.degree. to 175.degree. C.
Mass; m/z=458 (M.sup.+)
NMR (.delta., CDCl.sub.3 -DMSO-d.sub.6); 1.55 to 1.98 (7H, m), 2.16 to 2.80 (2H, m), 2.80 to 3.47 (8H, m), 4.30 (2H, d, J=4.9 Hz), 5.95 to 6.02 and 6.20 to 6.31 (total 1H, each m), 7.36 to 7.53 (3H, m), 7.59 to 7.76 (2H, m), 7.90 to 8.12 (4H, m), 8.88 (1H, s), 10.70 (1H, s), 10.88 (1H, br)
EXAMPLE 15
(E)-N-(5,6-dihydro-7H-cyclopenta[d]pyrimidin-4-yl)-4-{3-[1-(4-methoxybenzyl)piperidin-4-yl]propenoyl}aniline (Compound II-29 in Table 1)
(as 1/2H.sub.2 O adduct)
White powder
m.p. 198.degree. to 199.5.degree. C.
Mass; m/z=468 (M.sup.+)
NMR (.delta., CDCl.sub.3 -DMSO-d.sub.6); 1.50 to 1.68 (2H, m), 1.76 to 1.82 (2H, m), 2.00 to 2.28 (5H, m), 2.88 to 3.04 (6H, m), 3.47 (2H, s), 3.80 (3H, s), 6.80 to 6.95 (3H, m), 7.01 (1H, dd, J=15.1 Hz, J=6.4 Hz), 7.23 (2H, d, J=8.3 Hz), 7.57 (1H, s), 7.84 (2H, d, J=8.8 Hz), 7.94 (2H, d, J=8.8 Hz), 8.61 (1H, s)
EXAMPLE 16
(E)-N-(5,6-diethylpyrimidin-4-yl)-4-[3-(1-benzyl-piperidin-4-yl)propenoyl]aniline (Compound II-200 in Table 1)
Pale yellow powder
Mass (CI); m/z=455 (M++i)
NMR (.delta., CDCl.sub.3); 1.20 to 1.38 (6H, m), 1.46 to 1.88 (4H, m), 1.96 to 2.16 (2H, m), 2.15 to 2.40 (1H, m), 2.60 to 2.84 (4H, m), 2.88 to 3.02 (2H, m), 3.51 (2H, s), 6.71 (1H, s, br), 6.88 (1H, d, J=15 to 16 Hz), 7.04 (1H, dd, J=15 to 16 Hz, J=6 to 7 Hz), 7.20 to 7.45 (5H, m), 7.35 (2H, d, J=8 to 9 Hz), 7.97 (2H, d, J=8 to 9 Hz), 8.64 (1H, s)
EXAMPLE 17
(E)-N-(5,6-dihydro-7H-cyclopenta[d]pyrimidin-4-yl)-4-{3-[1-(4-fluorobenzyl)piperidin-4-yl]propenoyl}aniline (Compound II-11 in Table 1)
(as 1/2H.sub.2 O adduct)
White powder
m.p. 209.degree. to 210.5.degree. C.
Mass; m/z=456 (M.sup.+)
NMR (.delta., CDCl.sub.3); 1.52 to 1.64 (2H, m), 1.80 to 1.84 (2H, m), 2.05 to 2.10 (2H, m), 2.13 to 2.22 (2H, m), 2.23 to 2.31 (1H, m), 2.90 to 3.02 (6H, m), 3.49 (2H, s), 6.90 (1H, d, J=15.1 Hz), 6.92 to 7.03 (3H, m), 7.28 to 7.30 (2H, m), 7.85 (1H, s), 7.88 (2H, d, J=8.8 Hz), 7.94 (2H, d, J=8.8 Hz), 8.60 (1H, s)
EXAMPLE 18
N-(5,6-dihydro-7H-cyclopenta[d]pyrimidin-4-yl)-4-{3-[1-(4-fluorobenzyl)piperidin-4-yl]propanoyl}aniline (Compound II-8 in Table 1)
(as 1/2H.sub.2 O adduct)
Pale yellow powder
m.p. 179.degree. to 181.degree. C.
Mass; m/z=458 (M.sup.+)
NMR (.delta., CDCl.sub.3); 1.29 to 1.45 (3H, m), 1.66 to 1.80 (4H, m), 1.94 to 2.10 (2H, m), 2.15 to 2.26 (2H, m), 2.82 to 3.05 (8H, m), 3.56 (2H, s, br), 6.46 (1H, s), 6.96 to 7.05 (2H, m), 7.25 to 7.36 (2H, m), 7.78 (2H, d, J=8.8 Hz), 7.96 (2H, d, J=8.8 Hz), 8.66 (1H, s)
EXAMPLE 19
(E)-N-(5,6-dihydro-7H-cyclopenta[d]pyrimidin-4-yl)-4-{3-[1-(3-fluorobenzyl)piperidin-4-yl]propenoyl}aniline (Compound II-17 in Table 1)
White powder
m.p. 210.degree. to 211.degree. C.
Mass (CI); m/z=457 (M.sup.+ +1)
NMR (.delta., CDCl.sub.3); 1.51 to 1.85 (4H, m), 2.02 to 2.30 (5H, m), 2.83 to 3.06 (6H, m), 3.52 (2H, s), 6.46 (1H, s), 6.89 (1H, d, J=15.6 Hz), 6.95 to 7.12 (4H, m), 7.23 to 7.35 (1H, m), 7.78 (2H, d, J=8.8 Hz), 7.98 (2H, d, J=8.8 Hz ), 8.66 (1H, s)
EXAMPLE 20
N-(5,6-dihydro-7H-cyclopenta[d]pyrimidin-4-yl)-4-(3-[1-(3-fluorobenzyl)piperidin-4-yl]propanoyl)aniline.multidot.2HCl (2HCl salt of Compound II-14 in Table 1)
(as 3/2H.sub.2 O adduct)
White powder
m.p.>252.degree. C. (decomposed)
Mass (CI); 459 (M.sup.+ +1)
NMR (.delta., CDCl.sub.3); 1.24 to 1.40 (3H, m), 1.54 to 1.77 (4H, m), 1.89 to 2.02 (2H, m), 2.15 to 2.25 (2H, m), 2.82 to 2.91 (4H, m), 2.91 to 3.05 (4H, m), 3.47 (2H, s), 6.45 (1H, s), 6.89 to 6.96 (1H, m), 7.02 to 7.11 (2H, m), 7.22 to 7.28 (1H, m), 7.76 (2H, d, J=8.8 Hz), 7.97 (2H, d, J=8.8 Hz), 8.65 (1H, s)
EXAMPLE 21
4-[1-Oxo-2-(1-benzylpiperidin-4-yl)methyleneindan-5-yl]amino-5,6-dihydro-7H-cyclopenta[d]pyrimidine (Compound III-3 in Table 2)
Under ice cooling, 1.70 g of a 28% sodium methoxide.multidot.methanol solution was added to 1.96 g of 4-(1-oxoindan-5-yl)amino-5,6-dihydro-7H-cyclopenta[d]pyrimidine dissolved in tetrahydrofuran, and then 1.80 g of 1-benzyl-4-formylpiperidine was added dropwise thereto. After the mixture was stirred for 1.5 hours, a saturated saline solution was added to the reaction mixture, and the mixture was extracted with chloroform. The extract was dried over anhydrous sodium sulfate and condensed under reduced pressure. The obtained residue was applied to silica gel column chromatography and then recrystallized from chloroform to obtain 1.35 g of the title compound as pale yellow crystal.
(as 1/2H.sub.2 O adduct)
m.p.>260.degree. C. (decomposed)
Mass; m/z=450 (M.sup.+)
NMR (.delta., CDCl.sub.3); 1.45 to 1.85 (4H, m), 1.96 to 2.46 (5H, m), 2.80 to 3.10 (6H, m), 3.56 (2H, s), 3.70 (2H, s), 6.55 (1H, s), 6.70 (1H, d, J=9.8 Hz), 7.24 to 7.41 (6H, m), 7.82 (1H, d, J=5.3 Hz), 8.18 (1H, s), 8.66 (1H, s)
EXAMPLE 22
4-[1-Oxo-2-(1-benzylpiperidin-4-yl)methylindan-5-yl]amino-5,6-dihydro-7H-cyclopenta[d]pyrimidine (Compound III-4 in Table 2)
0.53 g of platinum oxide was added to 1.35 g of 4-[1-oxo-2-(1-benzylpiperidin-4-yl)methyleneindan-5-yl]amino-5,6-dihydro-7H-cyclopenta[d]pyrimidine dissolved in a mixed solution of 60 ml of tetrahydrofuran, 60 ml of ethanol and 1 ml of acetic acid, and the mixture was stirred under a hydrogen stream at room temperature for 8 hours. After the catalyst was removed by filtration, the filtrate was condensed. The obtained residue was applied to silica gel column chromatography to obtain 1.31 g of the title compound as pale yellow powder.
m.p. 200.degree. to 202.degree. C.
Mass; m/z=452 (M.sup.+)
NMR (.delta., CDCl.sub.3); 1.18 to 2.12 (9H, m), 2.12 to 2.30 (2H, m), 2.62 to 3.08 (8H, m), 3.25 to 3.44 (1H, m), 3.55 (2H, s), 6.49 (1H, s), 7.20 to 7.41 (6H, m), 7.71 (1H, d, J=8.3 Hz), 8.10 (1H, d, J=1 to 2 Hz), 8.66 (1H, s)
EXAMPLE 23
N-(5-ethylpyrimidin-4-yl)-4-[3-(1-benzylpiperidin-4-yl)propanoyl]aniline (Compound II-205 in Table 1)
To 10 ml of ethanol were added 0.23 g of 4-[3-(1-benzylpiperidin-4-yl)propanoyl]aniline and 0.13 g of 4-chloro-5-ethylpyrimidine, and after adding 2 ml of an ethanol solution of hydrochloric acid (containing 0.071 g of hydrochloric acid), the mixture was reacted under reflux for 2 hours. After cooling, a 28% sodium methylate-methanol solution was added to the reaction mixture to make it alkaline, and then the mixture was condensed under reduced pressure. The obtained residue was applied to silica gel column chromatography to obtain 0.18 g of the title compound as pale yellow crystal.
m.p. 136.5.degree. to 138.degree. C.
Mass (CI); m/z=429 (M.sup.+ +1)
NMR (.delta., CDCl.sub.3); 1.24 to 1.43 (3H, m), 1.37 (3H, t, J=7.3 Hz), 1.56 to 1.80 (4H, m), 1.87 to 2.05 (2H, m), 2.61 (2H, q, J=7.3 Hz), 2.81 to 3.00 (4H, m), 3.51 (2H, s), 6.63 (1H, s, br), 7.18 to 7.37 (5H, m), 7.77 (2H, d, J=9.2 Hz), 7.98 (2H, d, J=9.2 Hz), 8.27 (1H, s), 8.71 (1H, s)
EXAMPLE 24
N-(5,6-dihydro-7H-cyclopenta[d]pyrimidin-4-yl)-4-{3-[1-(2-nitrobenzyl)piperidin-4-yl]propanoyl}aniline (Compound II-242 in Table 1)
(1) N-(5,6-dihydro-7H-cyclopenta[d]pyrimidin-4-yl)-4-[3(1-acetylpiperidin-4-yl)propanoyl]aniline
To 80 ml of chloroform were added 4.53 g of 4-[3-(1-acetylpiperidin-4-yl)propanoyl]aniline and 3.83 g of 4-chloro-5,6-dihydro-7H-cyclopenta[d]pyrimidine, and after adding 10 ml of a chloroform solution of hydrochloric acid (containing 0.9 g of hydrochloric acid), the mixture was refluxed under heating for 5 hours. After completion of the reaction, a 28% sodium methoxide was added to the mixture under ice cooling to make it alkaline and then the solvent was removed by distillation under reduced pressure. The obtained residue was applied to silica gel column chromatography to obtain 6.16 g of the title compound as brown powder.
Mass; m/z=392 (M.sup.+)
NMR (.delta., CDCl.sub.3 -DMSO-d.sub.6); 1.00 to 1.27 (2H, m), 1.52 to 1.87 (5H, m), 2.05 (3H, s), 2.03 to 2.23 (2H, m), 2.45 to 2.61 (2H, m), 2.87 to 3.11 (6H, m), 3.76 to 3.89 (1H, m), 4.46 to 4.58 (1H, m), 7.86 to 7.96 (4H, m), 8.51 (1H, s), 8.70 (1H, s)
(2) N-(5,6-dihydro-7H-cyclopenta[d]pyrimidin-4-yl)-4-[3-(piperidin-4-yl)propanoyl]aniline.multidot.2HCl salt
30 ml of conc. hydrochloric acid was added to 6.16 g of N-(5,6-dihydro-7H-cyclopenta[d]pyrimidin-4-yl)-4-[3-(1-acetylpiperidin-4-yl)propanoyl]aniline, and after refluxing under heating for 7 hours, the mixture was condensed under reduced pressure. The obtained residue was washed with methanol to obtain 3.38 g of the title compound as yellow powder.
Mass; m/z=350 (M.sup.+)
NMR (.delta., CD.sub.3 OD); 1.36 to 1.56 (2H, m), 1.64 to 1.83 (3H, m), 1.95 to 2.09 (2H, m), 2.92 to 3.24 (8H, m), 3.35 to 3.46 (2H, m), 7.08 to 7.25 (1H, m), 7.90 (2H, d, J=9.2 Hz), 8.08 (2H, d, J=9.2 Hz), 8.75 (1H, s) (3) N-(5,6-dihydro-7H-cyclopenta[d]pyrimidin-4-yl)-{3-[1(2-nitrobenzyl)piperidin-4-yl]acetyl}aniline
30 ml of acetone, 7.12 g of potassium carbonate and 0.62 g of 2-nitrobenzyl bromide were added to 1.00 g of N-(5,6-dihydro-7H-cyclopenta[d]pyrimidin-4-yl)-4-[3-(piperidin-4-yl]propanoyl]aniline.multidot.2HCl salt, and the mixture was stirred at room temperature for 2 hours and allowed to stand overnight. Then, after separating the solid by filtration and removing the solvent by distillation under reduced pressure, the obtained residue was applied to silica gel column chromatography to obtain 0.72 g of the title compound as white powder.
m.p. 164.degree. to 166.degree. C.
Mass (SIMS); m/z=486 (M.sup.+ +1)
NMR (.delta., CDCl.sub.3); 1.16 to 1.40 (3H, m), 1.52 to 1.77 (4H, m), 1.94 to 2.08 (2H, m), 2.09 to 2.27 (2H, m), 2.72 to 3.06 (8H, m), 3.75 (2H, s), 6.47 (1H, s), 7.32 to 7.43 (1H, m), 7.48 to 7.59 (1H, m), 7.60 to 7.68 (1H, m), 7.76 (2H, d, J=8.5 Hz), 7.74 to 7.83 (1H, m), 7.96 (2H, d, J=9.2 Hz), 8.65 (1H, s)
EXAMPLE 25
N-(5-methylpyrimidin-4-yl)-4-[(1-benzylpiperidin-4-yl)acetyl]aniline (Compound II-220 in Table 1)
To 70 ml of chloroform were added 7.00 g of 4-[(1-benzylpiperidin-4-yl)acetyl]aniline.multidot.2HCl salt and 8.38 g of 4-chloro-5-methylpyrimidine, and after further adding 10 ml of an ethanol solution of hydrochloric acid (containing 1.7 g of hydrochloric acid), the mixture was reacted under reflux for 5 hours. After the reaction, a 28% sodium methylate-methanol solution was added to the reaction mixture to make it alkaline and then the mixture was condensed under reduced pressure. The obtained residue was applied to silica gel column chromatography to obtain 5.30 g of the title compound as pale yellow crystal.
m.p. 211.degree. to 213.degree. C.
Mass; m/z=400 (M.sup.+)
NMR (.delta., CDCl.sub.3); 1.26 to 1.47 (2H, m), 1.63 to 1.80 (3H, m), 1.89 to 2.08 (2H, m), 2.25 (3H, s), 2.76 to 2.93 (4H, m), 3.48 (2H, s), 6.58 (1H, s, br), 7.17 to 7.38 (5H, m), 7.78 (2H, d, J=8.6 Hz), 7.97 (2H, d, J=8.6 Hz), 8.24 (1H, s), 8.70 (1H, s)
EXAMPLE 26
N-(5,6-dihydro-7H-cyclopenta[d]pyrimidin-4-yl)-4-[(1-benzylpiperidin-4-yl)acetyl]aniline (Compound II-1 in Table 1)
(1) N-(5,6-dihydro-7H-cyclopenta[d]pyrimidin-4-yl)-4-[(1-acetylpiperidin-4-yl)acetyl]aniline
To 50 ml of chloroform were added 6.63 g of 4-[(1-acetylpiperidin-4-yl)acetyl]aniline.multidot.trifluoroacetate and 3.01 g of 4-chloro-5,6-dihydro-7H-cyclopenta[d]pyrimidine, and after adding 10 ml of a chloroform solution of hydrochloric acid (containing 0.6 g of hydrochloric acid), the mixture was reacted under reflux for 3 hours. After the reaction, a 28% sodium methylate-methanol solution was added to the reaction mixture under cooling to make it alkaline. After removing solid material, the filtrate was condensed under reduced pressure and the obtained residue was applied to silica gel column chromatography to obtain 6.08 g of the title compound as yellowish white powder.
m.p. 225.degree. to 227.degree. C.
Mass (CI); m/z=379 (M.sup.+ +1)
NMR (.delta., CDCl.sub.3); 1.12 to 1.33 (2H, m), 1.72 to 1.92 (2H, m), 2.04 to 2.35 (3H, m), 2.09 (3H, s), 2.52 to 2.68 (1H, m), 2.68 to 2.93 (4H, m), 2.93 to 3.18 (3H, m), 3.94 to 4.12 (1H, m), 4.55 to 4.70 (1H, m), 6.65 (1H, s, br), 7.79 (2H, d, J=8.8 Hz), 7.89 (2H, d, J=8.8 Hz), 8.65 (1H, s) (2) N- (5,6-dihydro-7H-cyclopenta[d]pyrimidin-4-yl)-4-[(piperidin-4-yl)acetyl]aniline.multidot.2HCl salt
50 ml of conc. hydrochloric acid was added to 6.08 g of N-(5,6-dihydro-7H-cyclopenta[d]pyrimidin-4-yl)-4-[(1-acetylpiperidin-4-yl)acetyl]aniline, and after refluxing the mixture under heating, the solvent was removed by distillation under reduced pressure. The obtained solid was washed with hot-ethanol to obtain 5.13 g of the title compound as yellowish white powder.
Mass (CI); m/z=337 (M.sup.+ +1)
NMR (.delta., CDCl.sub.3 -DMSO-d.sub.6); 1.48 to 1.69 (2H, m), 1.84 to 2.00 (2H, m), 2.10 to 2.35 (3H, m), 2.72 to 3.21 (8H, m), 3.21 to 3.38 (2H, m), 7.92 (2H, d, J=9.2 Hz), 7.99 (2H, d, J=8.6 Hz), 8.84 (1H, s), 10.64 (1H, s)
(3) N-(5,6-dihydro-7H-cyclopenta[d]pyrimidin-4-yl)-4-[(1-benzylpiperidin-4-yl)acetyl]aniline
50 ml of acetone, 1.14 g of potassium carbonate and 0.4 ml of benzyl bromide were added to 1.34 g of N-(5,6-dihydro-7H-cyclopenta[d]pyrimidin-4-yl)-4-[(piperidin-4-yl)acetyl]aniline, and the mixture was stirred at room temperature for 4 hours. After separating the solid by filtration and removing the solvent by distillation under reduced pressure, the obtained residue was applied to silica gel column chromatography to obtain 1.05 g of the title compound as yellowish white powder.
m.p. 212.degree. to 214.degree. C. (decomposed)
Mass; m/z=426 (M.sup.+)
NMR (.delta., CDCl.sub.3); 1.28 to 1.48 (2H, m), 1.67 to 1.80 (2H, m), 1.90 to 2.09 (3H, m), 2.12 to 2.28 (2H, m), 2.79 to 2.90 (6H, m), 2.98 to 3.05 (2H, m), 3.49 (2H, s), 6.42 (1H, s), 7.20 to 7.38 (5H, m), 7.77 (2H, d, J=8.8 Hz), 7.96 (2H, d, J=8.8 Hz), 8.66 (1H, s)
EXAMPLE 27
N-(5-methylpyrimidin-4-yl)-4-{[1-(2-pyridylmethyl)piperidin-4-yl]acetyl}aniline (Compound II-219 in Table 1)
In the same manner as in Example 26-(1), (2) and (3) except for using 4-chloro-5-methylpyrimidine in place of 4-chloro-5,6-dihydro-7H-cyclopenta[d]pyrimidine and using 2-chloromethylpyridine in place of benzyl bromide in Example 26-(1), (2) and (3), the following compounds were obtained, respectively.
(1) N-(5-methylpyrimidin-4-yl)-4-[(1-acetylpiperidin-4yl)acetyl]aniline
Yellowish white solid
Mass (CI); m/z=353 (M.sup.+ +1)
NMR (.delta., CDCl.sub.3); 1.12 to 1.30 (2H, m), 1.73 to 1.93 (3H, m), 2.08 (3H, s), 2.26 (3H, s), 2.52 to 2.67 (1H, m), 2.84 to 2.93 (2H, m), 3.02 to 3.17 (1H, m), 3.73 to 3.86 (1H, m), 4.54 to 4.67 (1H, m), 6.92 (1H, s), 7.82 (2H, d, J=8.6 Hz), 7.97 (2H, d, J=9.2 Hz), 8.24 (1H, s), 8.69 (1H, s)
(2) N- (5-methylpyrimidin-4-yl)-4-[(piperidin-4-yl)acetyl]aniline
Yellowish white solid
Mass (CI); m/z=311 (M.sup.+ +1)
NMR (.delta., CDCl.sub.3); 1.46 to 1.70 (2H, m), 1.82 to 1.98 (3H, m), 2.42 (3H, s), 2.83 to 3.09 (2H, m), 3.02 (2H, d, J=6.7 Hz), 3.21 to 3.38 (2H, m), 7.85 (2H, d, J=8.5 Hz), 8.02 (2H, d, J=8.5 Hz), 8.43 (1H, s), 8.86 (1H, s), 10.36 (1H, s)
(3) N-(5-methylpyrimidin-4-yl)-4-{[1-(2-pyridylmethyl)piperidin-4-yl]acetyl}aniline
White crystal
m.p. 207.degree. to 209.degree. C.
Mass (CI); m/z=402 (M.sup.+ +1)
NMR (.delta., CDCl.sub.3); 1.33 to 1.50 (2H, m), 1.66 to 1.81 (2H, m), 1.81 to 1.94 (1H, m), 2.07 to 2.20 (2H, m), 2.52 (3H, s), 2.86 (2H, d, J=6.7 Hz), 2.78 to 2.95 (2H, m), 3.64 (2H, s), 6.63 (1H, s), 7.11 to 7.20 (1H, m), 7.40 (1H, d, J=7.3 Hz), 7.61 to 7.70 (1H, m), 7.79 (2H, d, J=8.5 Hz), 7.98 (2H, d, J=9.2 Hz), 8.25 (1H, s), 8.55 (1H, d, J=4.8 Hz), 8.70 (1H, s)
EXAMPLE 28
(E)-N-(5,6-dihydro-7H-cyclopenta[d]pyrimidin-4-yl)-4-[4-(1-benzylpiperidin-4-yl)-2-butenoyl]aniline (Compound II-6 in Table 1)
30 ml of ethanol and 0.58 g of 4-chloro-5,6-dihydro-7H-cyclopenta[d]pyrimidine were added to 1.21 g of 4-[4-(1-benzylpiperidin-4-yl)-3-hydroxybutanoyl]aniline.multidot.trifluoroacetate, 1 ml of an ethanol solution of hydrochloric acid (containing 0.29 g of hydrochloric acid) was added thereto and the mixture was stirred under heating at 60.degree. C. for 40 minutes. Then, a saturated sodium hydrogen carbonate aqueous solution was added thereto and the mixture was extracted with chloroform. After drying over anhydrous sodium sulfate, the solvent was removed by distillation under reduced pressure and the obtained residue was applied to silica gel column chromatography to obtain 0.40 g of the title compound as yellow powder.
m.p. 184.degree. to 185.degree. C.
Mass (CI); m/z=453 (M.sup.+ +1)
NMR (.delta., CDCl.sub.3); 1.24 to 1.60 (3H, m), 1.60 to 1.82 (2H, m), 1.88 to 2.05 (2H, m), 2.10 to 2.34 (4H, m), 2.80 to 2.98 (4H, m), 2.98 to 3.08 (2H, m), 3.50 (2H, s), 6.48 (1H, s, br), 6.90 (1H, d, J=16.9 Hz), 6.98 to 7.12 (1H, m), 7.12 to 7.41 (5H, m), 7.78 (2H, d, J=8.8 Hz), 7.97 (2H, d, J=8.8 Hz), 8.66 (1H, s)
EXAMPLE 29
N-(5,6-dihydro-7H-cyclopenta[d]pyrimidin-4-yl)-4-[4-(1-benzylpiperidin-4-yl)butanoyl]aniline (Compound II-3 in Table 1)
30 ml of ethanol and 0.1 g of platinum oxide were added to 0.24 g of (E)-N-(5,6-dihydro-7H-cyclopenta[d]pyrimidin-4-yl)-4-[4-(1-benzylpiperidin-4-yl)-2-butenoyl]aniline, and the mixture was stirred at room temperature under a hydrogen stream for 45 minutes. After removing the solid by filtration, the solvent was removed by distillation and the obtained residue was applied to silica gel column chromatography to obtain 0.19 g of the title compound as white powder.
m.p. 170.degree. to 173.degree. C.
Mass (CI); m/z=455 (M.sup.+ +1)
NMR (.delta., CDCl.sub.3); 1.14 to 1.38 (5H, m), 1.56 to 1.83 (6H, m), 1.83 to 2.01 (2H, m), 2.14 to 2.27 (2H, m), 2.85 to 2.96 (4H, m), 2.96 to 3.06 (2H, m), 3.49 (2H, s), 6.42 (1H, s, br), 7.19 to 7.35 (5H, m), 7.76 (2H, d, J=8.8 Hz), 7.97 (2H, d, J=8.8 Hz), 8.65 (1H, s)
EXAMPLE 30
(a) N-(5,6-dihydro-7H-cyclopenta[d]pyrimidin-4-yl)-4[(1-benzyl-4-hydroxypiperidin-4-yl)acetyl]aniline (Compound II-216 in Table 1),
(b) N-(5,6-dihydro-7H-cyclopenta[d]pyrimidin-4-yl)-4[(1-benzyl-4-ethoxypiperidin-4-yl)acetyl]aniline (Compound II-215 in Table 1) and
(c) N-(5,6-dihydro-7H-cyclopenta[d]pyrimidin-4-yl)-4[(1-benzyl-1,2,5,6-tetrahydropyridin-4-yl)acetyl]aniline (Compound II-217 in Table 1)
30 ml of ethanol and 0.59 g of 4-chloro-5,6-dihydro-7H-cyclopenta[d]pyrimidine were added to 1.04 g of 4-[(1-benzyl-4-hydroxypiperidin-4-yl)acetyl]aniline.multidot.trifluoroacetate, then 1 ml of an ethanol solution of hydrochloric acid (containing 0.29 g of hydrochloric acid) was added to the mixture and the mixture was stirred at 60.degree. C. for 45 minutes. Thereafter, 1 ml of triethylamine and water were added thereto, and the reaction mixture was extracted with chloroform and dried over anhydrous sodium sulfate. After removing the solvent by distillation under reduced pressure, the obtained residue was applied to silica gel column chromatography to obtain 0.60 g, 0.23 g and 0.05 g of the title compounds (a), (b) and (c), respectively.
Compound of (a)
Yellowish white crystal
m.p. 193.degree. to 195.degree. C.
Mass (CI); m/z=443 (M.sup.+ +1)
NMR (.delta., CDCl.sub.3); 1.62 to 1.88 (4H, m), 2.12 to 2.30 (2H, m), 2.42 to 2.58 (2H, m), 2.58 to 2.72 (2H, m), 2.86 (2H, t, J=7.3 Hz), 2.93 to 3.06 (2H, m), 3.08 (2H, s), 3.56 (2H, s), 4.14 (2H, s), 6.49 (1H, s, br), 7.21 to 7.38 (5H, m), 7.79 (2H, d, J=8.6 Hz), 7.95 (2H, d, J=8.6 Hz), 8.66 (1H, s)
Compound of (b)
Yellowish white crystal
m.p. 142.degree. to 143.degree. C.
Mass (CI); m/z=471 (M.sup.+ +1)
NMR (.delta., CDCl.sub.3); 1.13 (3H, t, J=7.7 Hz), 1.74 to 1.95 (4H, m), 2.13 to 2.28 (2H, m), 2.28 to 2.44 (2H, m), 2.54 to 2.70 (2H, m), 2.85 (2H, t, J=7.3 Hz), 3.01 (2H, t, J=7.9 Hz), 3.10 (2H, s), 3.40 to 3.48 (2H, m), 3.51 (2H, s, br), 6.43 (1H, s), 7.18 to 7.38 (5H, m), 7.76 (2H, d, J=8.5 Hz), 7.96 (2H, d, J=9.2 Hz), 8.65 (1H, s)
Compound of (c)
Pale yellow crystal
m.p. 165.degree. to 167.degree. C.
Mass; 424 (M.sup.+)
NMR (.delta., CDCl.sub.3); 2.12 to 2.28 (4H, m), 2.53 to 2.66 (2H, m), 2.78 to 2.91 (2H, m), 2.91 to 3.08 (4H, m), 3.60 (2H, s), 3.61 (2H, s), 5.54 (1H, s, br), 6.47 (1H, s), 7.20 to 7.59 (5H, m), 7.77 (2H, d, J=8.5 Hz), 7.99 (2H, d, J=8.5 Hz), 8.65 (1H, s)
EXAMPLE 31
N-(5,6-dihydro-7H-cyclopenta[d]pyrimidin-4-yl)-4-[(1-benzyl-4-piperidinyliden)acetyl]aniline (Compound II-4 in Table 1)
To a mixed solvent of 40 ml of chloroform and 20 ml of ethanol were added 2.33 g of 4-[(1-benzyl-4-piperidinyliden)acetyl]aniline and 1.63 g of 4-chloro-5,6-dihydro-7H-cyclopenta[d]pyrimidine, and further 6 ml of an ethanol solution of hydrochloric acid (containing 0.4 g of hydrochloric acid) was added to the mixture and the mixture was stirred at 50.degree. to 60.degree. C. for 3.5 hours under heating. Then, under ice cooling, a 28% sodium methylate-methanol solution was added to the mixture to make it alkaline, and then the solvent was removed by distillation under reduced pressure and the obtained residue was applied to silica gel column chromatography to obtain 0.3 g of the title compound as yellowish white powder.
Mass (CI); m/z=425 (M.sup.+ +1)
NMR (.delta., CDCl.sub.3); 2.13 to 2.24 (2H, m), 2.40 to 2.51 (2H, m), 2.51 to 2.65 (4H, m), 2.75 to 2.90 (2H, m), 2.90 to 3.06 (4H, m), 3.54 (2H, s), 6.50 (1H, s), 6.64 (1H, s), 7.18 to 7.43 (5H, m), 7.61 (2H, d, J=9.2 Hz), 7.95 (2H, d, J=8.5 Hz), 8.65 (1H, s)
EXAMPLE 32
N-(5,6-dihydro-7H-cyclopenta[d]pyrimidin-4-yl)-4-{3-[1-(2-thienylmethyl)piperidin-4-yl]propanoyl}aniline.multidot.2HCl
(2HCl salt of Compound II-104 in Table 1)
30 ml of 1,2-dichloroethane and 0.07 ml of triethylsilane were added to 0.20 g of N-(5,6-dihydro-7H-cyclopenta[d]pyrimidin-4-yl)-4-{3-[1-(2-thienylmethyl)piperidin-4-yl]propenoyl}aniline, then 0.35 ml of trifluoroacetic acid was added to the mixture and the mixture was stirred at 50.degree. C. for 3 hours under heating. After the reaction, the solvent was removed by distillation under reduced pressure, a 1N sodium hydroxide aqueous solution was added to the residue and the residue was extracted with chloroform. After drying over anhydrous sodium sulfate, the solvent was removed by distillation under reduced pressure and the obtained residue was applied to silica gel column chromatography to obtain an ocherous solid. The solid was recrystallized form isopropyl alcohol and further treated with hydrochloric acid to obtain 0.05 g of the title compound as white powder.
(as 3/4H.sub.2 O adduct)
m.p. 187.degree. C. (decomposed)
Mass (CI); m/z=447 (M.sup.+ +1)
NMR (.delta., CDCl.sub.3); 1.14 to 1.46 (2H, m), 1.46 to 1.84 (5H, m), 1.88 to 2.12 (2H, m), 2.12 to 2.20 (2H, m), 2.74 to 3.10 (8H, m), 3.70 to 3.85 (2H, m), 6.40 (1H, s), 6.87 to 7.02 (2H, m), 7.16 to 7.20 (6H, m), 7.76 (2H, d, J=9.2 Hz), 7.97 (2H, d, J=8.5 Hz), 8.65 (1H, s)
EXAMPLE 33
N-(7-hydroxy-5,6-dihydro-7H-cyclopenta[d]pyrimidin-4-yl)-4-[3-(1-benzylpiperidin-4-yl)propanoyl]aniline (Compound II-167 in Table 1)
To 15 ml of ethanol were added 0.60 g of 4-[3-(1-benzylpiperidin-4-yl)propanoyl]aniline and 0.51 g of 7-acetoxy-4-chloro-5,6-dihydro-7H-cyclopenta[d]pyrimidine, then 3 ml of an ethanol solution of hydrochloric acid (containing 0.19 g of hydrochloric acid) was added to the mixture and the mixture was reacted under reflux for 30 minutes. After cooling, a 28% sodium methylate-methanol solution was added to the reaction mixture to make it alkaline, and the mixture was condensed under reduced pressure. The obtained residue was applied to silica gel column chromatography to obtain 0.49 g of the title compound as white crystal.
m.p. 189.degree. to 190.degree. C.
Mass; m/z=456 (M.sup.+)
NMR (.delta., CDCl.sub.3 -DMSO-d.sub.6); 1.21 to 1.45 (3H, m), 1.56 to 1.81 (4H, m), 1.86 to 2.11 (3H, m), 2.47 to 3.08 (7H, m), 3.50 (2H, s), 4.83 (1H, br), 5.05 to 5.17 (1H, m), 7.16 to 7.38 (5H, m), 7.87 (2H, d, J=8.8 Hz), 7.94 (2H, d, J=8.8 Hz), 8.16 (1H, s), 8.68 (1H, s)
EXAMPLE 34
N-(7-hydroxy-5,6-dihydro-7H-cyclopenta[d]pyrimidin-4-yl)-4-[(1-benzylpiperidin-4-yl)acetyl]aniline (Compound II-236 in Table 1)
In the same manner as in Example 33 except for using 4-[1-benzylpiperidin-4-yl)acetyl]aniline in place of 4-[3(1-benzylpiperidin-4-yl)propanoyl]aniline, the reaction was carried out to obtain the tile compound as white crystal.
m.p. 174.degree. to 176.degree. C.
Mass; m/z=442 (M.sup.+)
NMR (.delta., CDCl.sub.3 -DMSO-d.sub.6); 1.18 to 1.48 (3H, m), 1.66 to 1.80 (2H, m), 1.88 to 2.13 (4H, m), 2.50 to 2.66 (1H, m), 2.66 to 3.05 (3H, m), 2.85 (2H, d, J=6.7 Hz), 3.49 (2H, s), 5.09 to 5.20 (1H, m), 7.18 to 7.43 (6H, m), 7.85 (2H, d, J=9.2 Hz), 7.95 (2H, d, J=9.2 Hz), 8.69 (1H, s)
EXAMPLE 35
N-(7-acetoxy-5,6-dihydro-7H-cyclopenta[d]pyrimidin-4-yl)-4-[(1-benzylpiperidin-4-yl)acetyl]aniline (Compound II-237 in Table 1)
20 ml of chloroform and 0.65 ml of acetic anhydride were added to 0.35 g of N-(7-hydroxy-5,6-dihydro-7H-cyclopenta[d]pyrimidin-4-yl)-4-[(1-benzylpiperidin-4-yl)acetyl]aniline, and the mixture was refluxed under heating for 4 hours. Then, the solvent was removed by distillation under reduced pressure and the obtained residue was applied to silica gel column chromatography to obtain 0.16 g of the title compound as white crystal.
(as 1/2H.sub.2 O adduct)
m.p. 210.degree. to 212.degree. C.
Mass; m/z=484 (M.sup.+)
NMR (.delta., CDCl.sub.3); 1.29 to 1.47 (3H, m), 1.54 to 1.63 (2H, m), 1.68 to 1.94 (4H, m), 2.15 (3H, s), 2.67 to 3.04 (4H, m), 2.86 (2H, d, J=6.7 Hz), 3.50 (2H, s, br), 6.07 to 6.14 (1H, m), 6.53 (1H, s), 7.19 to 7.34 (5H, m), 7.78 (2H, d, J=9.2 Hz), 7.98 (2H, d, J=8.6 Hz), 8.78 (1H, s)
EXAMPLE 36
N-(5,6-dihydro-7H-cyclopenta[d]pyrimidin-4-yl)-4-{3-[1-(2-aminobenzyl)piperidin-4-yl]propanoyl}aniline (Compound II-272 in Table 1)
To 0.59 g of N- (5,6-dihydro-7H-cyclopenta[d]pyrimidin-4-yl)-4-3-[1-(2-nitrobenzyl)piperidin-4-yl]propanoyl)aniline were added 20 ml of ethanol, 40 ml of methanol, 5 ml of acetic acid and 0.05 g of platinum oxide, and the mixture was stirred at room temperature under a hydrogen stream for 4 hours. Then, after the solid was removed by filtration and the solvent was removed by distillation under reduced pressure, a saturated sodium hydrogen carbonate aqueous solution was added to the residue and the mixture was extracted with chloroform. The solvent was removed by distillation under reduced pressure and the obtained solid was recrystallized from ethanol to obtain 0.32 g of the title compound as pale brown crystal.
Mass; m/z=455 (M.sup.+)
NMR (.delta., CDCl.sub.3); 1.12 to 1.32 (3H, m), 1.56 to 1.77 (4H, m), 1.83 to 1.98 (2H, m), 2.14 to 2.28 (2H, m), 2.79 to 3.07 (8H, m), 3.47 (2H, s), 4.81 (2H, s, br), 6.43 (1H, s, br), 6.62 to 6.68 (2H, m), 6.97 (1H, d, J=6.7 Hz), 7.05 to 7.11 (1H, m), 7.76 (2H, d, J=8.5 Hz), 7.97 (2H, d, J=9.2 Hz), 8.65 (1H, s)
EXAMPLE 37
N- (5,6-dihydro-7H-cyclopenta[d]pyrimidin-4-yl)-4-{3-[1-(2-acetylaminobenzyl)piperidin-4-yl]propanoyl}aniline (Compound II-249 in Table 1)
To 0.17 g of N-(5,6-dihydro-7H-cyclopenta[d]pyrimidin-4-yl)-4-(3-[1-(2-aminobenzyl)piperidin-4-yl]propanoyl)aniline were added 30 ml of chloroform, 1 ml of acetic anhydride and 0.38 g of 4-dimethylaminopyridine, and the mixture was stirred at 50.degree. C. for 10 minutes. Then, the solvent was removed by distillation under reduced pressure and the obtained residue was applied to silica gel column chromatography to obtain 0.06 g of the title compound as white crystal.
m.p. 219.degree. to 221.5.degree. C.
Mass; m/z=497 (M.sup.+)
NMR (.delta., CDCl.sub.3); 1.14 to 1.34 (2H, m), 1.34 to 1.50 (1H, m), 1.66 to 1.89 (4H, m), 1.96 to 2.10 (2H, m), 2.14 (3H, s), 2.11 to 2.28 (2H, m), 2.80 to 3.08 (8H, m), 3.57 (2H, s), 6.44 (1H, s), 6.94 to 7.01 (1H, m), 7.25 (2H, d, J=6.1 Hz), 7.23 to 7.31 (1H, m), 7.78 (2H, d, J=8.5 Hz), 7.97 (2H, d, J=9.2 Hz), 8.27 (1H, d, J=8.6 Hz), 8.65 (1H, s), 11.04 (1H, s)
EXAMPLE 38
N-acetyl-N-(5,6-dihydro-7H-cyclopenta[d]pyrimidin-4yl)-4-[3-(1-benzylpiperidin-4-yl)propanoyl]aniline.multidot.2HCl (2HCl salt of Compound II-221 in Table 1)
To 10 ml of a chloroform solution containing 0.72 g of N-(5,6-dihydro-7H-cyclopenta[d]pyrimidin-4 -yl)-4-[3-(1-benzylpiperidin-4-yl)propanoyl]aniline were added under ice cooling 0.66 g of triethylamine and 0.46 ml of acetyl chloride. After stirring under ice cooling for one hour, a saturated saline solution was added to the mixture and the mixture was extracted with chloroform. The chloroform layer was dried over anhydrous sodium sulfate and condensed under reduced pressure. The obtained residue was applied to silica gel column chromatography to obtain the free material of the title compound. This material was dissolved in ethyl acetate and treated with a hydrogen chloride gas to obtain 0.54 g of the title compound as pale brown crystal.
(as H.sub.2 O adduct)
m.p. 128.degree. to 131.5.degree. C.
Mass (CI); m/z=483 (M.sup.+ +1)
NMR (.delta., CDCl.sub.3); 1.52 to 1.96 (5H, m), 2.00 to 2.38 (4H, m), 2.23 (3H, s), 2.53 to 2.86 (4H, m), 2.93 to 3.12 (2H, m), 3.34 to 3.57 (4H, m), 4.16 (2H, d, J=4.4 Hz), 7.35 (2H, d, J=8.1 Hz), 7.40 to 7.53 (3H, m), 7.57 to 7.70 (2H, m), 8.08 (2H, d, J=8.1 Hz), 8.83 (1H, s), 12.25 (1H, s, br)
EXAMPLES 39 TO 78
In the same manner as in Example 1, 2, 3, 23, 24 or 36, the following compounds were obtained.
______________________________________Exam- Characteristics.ple Compound Physical properties______________________________________39 N-(5,6-dihydro-7H-cyclopenta- (as 3/2H.sub.2 O adduct) [d]pyrimidin-4-yl)-4-{3-[1-(2- White powder fluorobenzyl)piperidin-4-yl]- m.p. 205 to 209.degree. C. propanoyl}aniline.2HCl (2HCl salt (decomposed) of Compound II-20 in Table 1)40 N-(5,6-dihydro-7H-cyclopenta- White powder [d]pyrimidin-4-yl)-4-{3-[1-(4- m.p. 213 to 216.degree. C. chlorobenzyl)piperidin-4-yl]- propanoyl}aniline (Compound II- 50 in Table 1)41 N-(5,6-dihydro-7H-cyclopenta- (as 1/4H.sub.2 O adduct) [d]pyrimidin-4-yl)-4-{3-[1-(3- Yellow crystal chlorobenzyl)piperidin-4-yl]- m.p. 189 to 191.degree. C. propanoyl}aniline.2HCl (2Hcl salt of Compound II-56 in Table 1)42 N-(5,6-dihydro-7H-cyclopenta- (as 1/2H.sub.2 O adduct) [d]pyrimidin-4-yl)-4-{3-[1-(3- Yellowish white methoxybenzyl)piperidin-4-yl]- powder propanoyl}aniline.2HCl (2HCl salt m.p. 186 to 188.degree. C. of Compound II-32 in Table 1)43 N-(5,6-dihydro-7H-cyclopenta- Yellowish white [d]pyrimidin-4-yl)-4-{3-[1-(2- powder methoxybenzyl)piperidin-4-yl]- m.p. 169.5 to 172 propanoyl}aniline (Compound II- .degree.C. 38 in Table 1)44 N-(5,6-dihydro-7H-cyclopenta- (as 1/2H.sub.2 O adduct) [d]pyrimidin-4-yl)-4-{3-[1-(3- Yellowish white benzyloxybenzyl)piperidin-4- powder yl]propanoyl}aniline (Compound m.p. 193 to 195.degree. C. II-239 in Table 1)45 N-(5,6-dihydro-7H-cyclopenta- Yellowish white [d]pyrimidin-4-yl)-4-{3-[1-(4- powder methylbenzyl)piperidin-4-yl]- m.p. 192 to 195.degree. C. propanoyl}aniline.HCl (HCl salt (decomposed) of Compound II-68 in Table 1)46 N-(5,6-dihydro-7H-cyclopenta- (as 1/2H.sub.2 O adduct) [d]pyrimidin-4-yl)-4-{3-[1-(3- White powder methylbenzyl)piperidin-4-yl]- m.p. 116 to 117.5 propanoyl}aniline (Compound II- .degree.C. 214 in Table 1)47 N-(5,6-dihydro-7H-cyclopenta- (as 1/4H.sub.2 O adduct) [d]pyrimidin-4-yl)-4-{3-[1-(4- Yellowish white trifluoromethylbenzyl)piperi- crystal din-4-yl]propanoyl}aniline m.p. 216 to 218.degree. C. (Compound II-80 in Table 1)48 N-(5,6-dihydro-7H-cyclopenta- Yellow crystal [d]pyrimidin-4-yl)-4-{3-[1-(3- m.p. 209 to 211.5 trifluoromethylbenzyl)piperi- .degree.C. din-4-yl]propanoyl}aniline (Compound II-232 in Table 1)49 N-(5,6-dihydro-7H-cyclopenta- White powder [d]pyrimidin-4-yl)-4-{3-[1-(4- m.p. 180 to 182.5 cyanobenzyl)piperidin-4-yl]- .degree.C. propanoyl}aniline (Compound II- 218 in Table 1)50 N-(5,6-dihydro-7H-cyclopenta- White powder [d]pyrimidin-4-yl)-4-{3-[1-(3- m.p. 188 to 190.degree. C. cyanobenzyl)piperidin-4-yl]- (decomposed) propanoyl}aniline (Compound II- 225 in Table 1)51 N-(5,6-dihydro-7H-cyclopenta- White powder [d]pyrimidin-4-yl)-4-{3-[1-(1- m.p. 197 to 199.degree. C. naphthylmethyl)piperidin-4-yl]- propanoyl}aniline (Compound II- 224 in Table 1)52 N-(5,6-dihydro-7H-cyclopenta- Pale yellow crystal [d]pyrimidin-4-yl)-4-{3-[1- m.p. 190 to 193.degree. C. (sec-phenethyl)piperidin-4-yl]- (decomposed) propanoyl}aniline (Compound II- 86 in Table 1)53 N-(5,6-dihydro-7H-cyclopenta- Yellow crystal [d]pyrimidin-4-yl)-4-{3-[1-(2- m.p. 181.5 to 183 pyridylmethyl)piperidin-4-yl]- .degree.C. propanoyl}aniline (Compound II- 110 in Table 1)54 N-(5,6-dihydro-7H-cyclopenta- Pale brown crystal [d]pyrimidin-4-yl)-4-{3-[1-(3- m.p. 167 to 169.degree. C. pyridylmethyl)piperidin-4-yl]- propanoyl}aniline (Compound II- 210 in Table 1)55 N-(5,6-dihydro-7H-cyclopenta- (as 1/4H.sub.2 O adduct) [d]pyrimidin-4-yl)-4-{3-[1-(4- Pale brown crystal pyridylmethyl)piperidin-4-yl]- m.p. 174 to 175.degree. C. propanoyl}aniline (Compound II- 116 in Table 1)56 N-(5,6-dihydro-7H-cyclopenta- Pale yellow crystal [d]pyrimidin-4-yl)-4-{3-[1-(6- m.p. 200 to 201.5 methyl-2-pyridylmethyl)piperi- .degree.C. din-4-yl]propanoyl}aniline (Compound II-238 in Table 1)57 (E)-N-(5,6-dihydro-7H-cyclo- Yellowish white penta[d]pyrimidin-4-yl)-4-{3- crystal [1-(2-thienylmethyl)piperidin- m.p. 199 to 200.degree. C. 4-yl]propenoyl]aniline (Compound II-107 in Table 1)58 N-(5,6-dihydro-7H-cyclopenta- White crystal [d]pyrimidin-4-yl)-4-{3-[1-(3, m.p. 198.5 to 200 4-methylenedioxybenzyl)piperi- .degree.C. din-4-yl]propanoyl}aniline (Compound II-231 in Table 1)59 N-(5,6-dihydro-7H-cyclopenta- Yellowish white [d]pyrimidin-4-yl)-4-{3-[1-(3, crystal 4-ethylenedioxybenzyl)piperi- m.p. 185 to 186.degree. C. din-4-yl]propanoyl}aniline (Compound II-235 in Table 1)60 N-(5,6-dihydro-7H-cyclopenta- White crystal [d]pyrimidin-4-yl)-4-{3-[1-(2, m.p. 179 to 181.degree. C. 3-dimethoxybenzyl)piperidin-4- yl]propanoyl}aniline (Compound II-233 in Table 1)61 N-(6,6-dimethyl-5,6-dihydro-7H- (as 1/2H.sub.2 O adduct) cyclopenta[d]pyrimidin-4-yl)-4- Pale yellow crystal [3-benzylpiperidin-4-yl)- m.p. 225 to 227.degree. C. propanoyl]aniline.2HCl (2HCl salt of Compound II-198 in Table 1)62 N-(pyrimidin-4-yl)-4-[3-(1-ben- Pale yellow crystal zylpiperidin-4-yl)propanoyl]- m.p. 149.5 to 151 aniline (Compound II-136 in .degree.C. Table 1)63 N-(5-methylpyrimidin-4-yl)-4- (1/2H.sub.2 O adduct) [3-(1-benzylpiperidin-4-yl)- White powder propanoyl]aniline.2HCl (2HCl salt m.p. 180 to 184.degree. C. of Compound II-189 in Table 1)64 N-(5,6-diethylpyrimidin-4-yl)- White needle crystal 4-[3-(1-benzylpiperidin-4-yl)- m.p. 137 to 139.degree. C. propanoyl]aniline (Compound II- 223 in Table 1)65 N-(5-butyl-6-methylpyrimidin-4- White powder yl)-4-[3-(1-benzylpiperidin-4- m.p. 149.5 to 151 yl)propanoyl]aniline (Compound .degree.C. II-154 in Table 1)66 N-(5-ethoxycarbonylpyrimidin-4- Pale yellow crystal yl)-4-[3-(1-benzylpiperidin-4- m.p. 117 to 118.5 yl)propanoyl]aniline (Compound .degree.C. II-222 in Table 1)67 N-(6-ethoxypyrimidin-4-yl)-4- Pale yellow crystal [3-(1-benzylpiperidin-4-yl)- m.p. 168 to 170.degree. C. propanoyl]aniline (Compound II- 149 in Table 1)68 N-(6-chloro-5-methylpyrimidin- (as 1/2H.sub.2 O adduct) 4-yl)-4-[3-(1-benzylpiperidin- White needle crystal 4-yl)propanoyl]aniline m.p. 175 to 177.degree. C. (Compound II-190 in Table 1)69 N-(5-chloropyrimidin-4-yl)-4- Pale brown crystal [3-(1-benzylpiperidin-4-yl)- m.p. 142 to 144.degree. C. propanoyl]aniline (Compound II- 229 in Table 1)70 N-(5-bromopyrimidin-4-yl)-4-[3- Pale yellow crystal (1-benzylpiperidin-4-yl)propan- m.p. 151 to 153.degree. C. oyl]aniline (Compound II-230 in Table 1)71 N-(5-nitro-6-methoxypyrimidin- Yellow crystal 4-yl)-4-[3-(1-benzylpiperidin- m.p. 126 to 128.degree. C. 4-yl)propanoyl]aniline (Compound II-240 in Table 1)72 N-(5-methylpyrimidin-4-yl)-4- White crystal {3-[1-(2-pyridylmethyl)piperi- m.p. 142 to 143.degree. C. din-4-yl)propanoyl]aniline (Compound II-248 in Table 1)73 N-(5-amino-6-chloropyrimidin-4- (as 1/4H.sub.2 O adduct) yl)-4-[3-(1-benzylpiperidin-4- Yellowish orange yl)propanoyl]aniline (Compound crystal II-241 in Table 1) m.p. 163 to 165.degree. C.74 N-(5,6-dihydro-7H-cyclopenta- White powder [d]pyrimidin-4-yl)-4-{3-[1-(4- m.p. 200 to 202.degree. C. nitrobenzyl)piperidin-4-yl]- propanoyl}aniline (Compound II- 74 in Table 1)75 N-(5,6-dihydro-7H-cyclopenta- White powder [d]pyrimidin-4-yl)-4-{3-[1-(3- m.p. 184.5 to 186 nitrobenzyl)piperidin-4-yl]- .degree.C. propanoyl}aniline (Compound II- 243 in Table 1)76 N-(5,6-dihydro-7H-cyclopenta- Pale brown powder [d]pyrimidin-4-yl)-4-{3-[1-(4- m.p. 174 to 176.5 aminobenzyl)piperidin-4-yl]- .degree.C. propanoyl}aniline (Compound II- 271 in Table 1)77 N-(5,6-dihydro-7H-cyclopenta- (as 1/2H.sub.2 O adduct) [d]pyrimidin-4-yl)-4-{3-[1-(3- White needle crystal aminobenzyl)piperidin-4-yl]- m.p. 187 to 188.degree. C. propanoyl}aniline (Compound II- 244 in Table 1)78 N-(5,6-dihydro-7H-cyclopenta- White powder [d]pyrimidin-4-yl)-4-{3-[1-(4- NMR (.delta., CD.sub.3 OD); hydroxybenzyl)piperidin-4-yl]- 1.20-1.49 (3H, m), propanoyl}aniline (Compound II- 1.58-1.80 (4H, m), 44 in Table 1) 1.98-2.10 (2H, m), 2.15-2.27 (2H, m), 2.87-3.03 (8H, m), 3.59 (2H, s), 6.86 (2H, d, J=8.4Hz), 7.29 (2H, d, J=8.4 Hz), 7.90 (2H, d, J=8.8Hz), 7.98 (2H, d, J=8.8Hz), 8.51 (1H, s)______________________________________
EXAMPLES 79 TO 91
In the same manner as in Example 3, 25, 26, 27 or 31, the following compounds were obtained.
______________________________________Exam- Characteristics.ple Compound Physical properties______________________________________79 N-(5,6-dimethylpyrimidin-4-yl- White crystal 4-[(1-benzylpiperidin-4-yl)- m.p. 212 to 214.degree. C. acetyl]aniline (Compound II-234 in Table 1)80 N-(5,6-dihydro-7H-cyclopenta- (as 3/2H.sub.2 O adduct) [d]pyrimidin-4-yl)-4-[(1-benz- White crystal ylpiperidin-4-yl)acetyl]-2- m.p. 228 to 232.degree. C. methoxyaniline.2HCl (2HCl salt of Compound II-245 in Table 1)81 N-(5,6,7,8-tetrahydroquinazo- (as H.sub.2 O adduct) lin-4-yl)-4-[(1-benzylpiperi- White crystal din-4-yl)acetyl]-2-methoxy- m.p. 215 to 219.degree. C. aniline.2HCl (2HCl salt of Compound II-246 in Table 1)82 N-(5,6-dihydro-7H-cyclopenta- Pale yellow crystal [d]pyrimidin-4-yl)-4-[(1-benz- m.p. 128 to 130.degree. C. ylpiperidin-4-yl)acetyl]-2- chloroaniline (Compound II-247 in Table 1)83 N-(5,6-dihydro-7H-cyclopenta- Yellow crystal [d]pyrimidin-4-yl)-4-{[1-(4- m.p. 195 to 197.degree. C. fluorobenzyl)-4-piperidinyli- (decomposed) den]acetyl}aniline (Compound II-10 in Table 1)84 N-(5,6-dihydro-7H-cyclopenta- White crystal [d]pyrimidin-4-yl)-4-{[1-(4- m.p. 191 to 193.degree. C. fluorobenzyl)piperidin-4-yl]- acetyl}aniline (Compound II-7 in Table 1)85 N-(5,6-dihydro-7H-cyclopenta- White crystal [d]pyrimidin-4-yl)-4-{[1-(2- m.p. 196 to 197.5 pyridylmethyl)piperidi-4-yl]- .degree.C. acetyl}aniline (Compound II-109 in Table 1)86 N-(5,6-dihydro-7H-cyclopenta- Yellowish white [d]pyrimidin-4-yl)-4-{[1-(2- crystal methoxybenzyl)piperidin-4-yl]- m.p. 168 to 170.degree. C. acetyl}aniline (Compound II-37 in Table 1)87 N-(5,6-dihydro-7H-cyclopenta- White crystal [d]pyrimidin-4-yl)-4-{[1-(2- m.p. 197 to 199.degree. C. thienylmethyl)piperidin-4-yl]- acetyl}aniline (Compund II-103 in Table 1)88 N-(5-methylpyrimidin-4-yl)-4- White crystal {[1-(2-thienylmethyl)piperidin- m.p. 209 to 211.degree. C. 4-yl]acetyl}aniline (Compound II-258 in Table 1)89 N-(5-methylpyrimidin-4-yl)-4- White crystal [(1-phenethylpiperidin-4-yl)- m.p. 193 to 194.degree. C. acetyl]aniline (Compound II-301 in Table 1)90 N-(5-methylpyrimidin-4-yl)-4- White crystal [(1-diphenylmethylpiperidin-4- m.p. 195.5 to 197 yl)acetyl]aniline (Compound II- .degree.C. 302 in Table 1)91 N-(5,6-dihydro-7H-cyclopenta- White crystal [d]pyrimidin-4-yl)-4-{[1-(2- m.p. 207 to 209.degree. C. furylmethyl)piperidin-4-yl]- acetyl}aniline (Compund II-269 in Table 1)92 N-(5-methylpyrimidin-4-yl)-4- Yellowish white {[1-(3-phenylpropyl)piperidin- crystal 4-yl]acetyl}aniline (Compound m.p. 167.5 to 169 II-317 in Table 1) .degree.C.93 N-(5-ethylpyrimidin-4-yl)-4- White crystal [(1-benzylpiperidin-4-yl)- m.p. 169 to 171.degree. C. acetyl]aniline (Compound II-252 in Table 1)94 N-(5-propylpyrimidin-4-yl)-4- Yellow crystal [(1-benzylpiperidin-4-yl)- m.p. 140.5 to 141.5 acetyl]aniline (Compound II-253 .degree.C. in Table 1)95 N-(5-methylpyrimidin-4-yl)-4- White crystal {[1-(3-thienylmethyl)piperidin- m.p. 212 to 214.degree. C. 4-yl]acetyl}aniline (Compound II-259 in Table 1)96 N-(5,6-dihydro-7H-cyclopenta- Yellowish white [d]pyrimidin-4-yl)-4-{[1-(3- crystal thienylmethyl)piperidin-4-yl]- m.p. 193 to 195.degree. C. acetyl}aniline (Compound II-267 in Table 1)97 N-(5-methylpyrimidin-4-yl)-4- Pale brown crystal [(1-benzylpiperidin-4-yl)- m.p. 168 to 170.degree. C. acetyl]-3-methoxyaniline (Compound II-266 in Table 1)______________________________________
Reference Example 1
4-[3-(1-benzylpiperidin-4-yl)propenoyl]nitrobenzene
Under ice cooling, 0.40 g of 64% sodium hydride was added to 3.03 g of diethyl (4-nitrobenzoylmethyl)phosphonate dissolved in 30 ml of tetrahydrofuran. After about 10 minutes, 4.07 g of 4-formyl-1-benzylpiperidine was added to the mixture. The mixture was stirred under ice cooling for 30 minutes and then stirred at room temperature for about 16 hours. After completion of the reaction, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The obtained residue was applied to silica gel column chromatography to obtain 1.99 g of the title compound as pale yellow crystal.
Mass; m/z=350 (M.sup.+)
NMR (.delta., CDCl.sub.3); 1.47 to 1.70 (2H, m), 1.70 to 1.87 (2H, m), 1.97 to 2.16 (2H, m), 2.16 to 2.40 (1H, m), 2.86 to 3.02 (2H, m), 3.53 (2H, m), 6.82 (1H, dd, J=15.6 Hz, J=-1 Hz), 7.09 (1H, dd, J=15.6 Hz, J=6.4 Hz), 7.21 to 7.37 (5H, m), 8.03 (2H, d, J=8.8 Hz), 8.32 (2H, d, J=8.8 Hz)
Reference Example 2
(E)-4-[3-(1-benzylpiperidin-4-yl)propenoyl]aniline
1.27 g of (E)-4-[3-(1-benzylpiperidin-4-yl)propenoyl]nitrobenzene was added to a mixed solution of 10 ml of acetic acid and 2 ml of hydrochloric acid, and then 1.38 g of stannous chloride was added thereto under ice cooling. The mixture was stirred for 24 hours. During the reaction, 0.69 g of stannous chloride was further added twice. After completion of the reaction, the reaction mixture was condensed under reduced pressure to obtain 5.50 g of a crude product of the title compound. This was used without purification for the next reaction.
Mass; m/z=320 (M.sup.+)
TLC Rf value; 0.42 (silica gel produced by Merck Co.; 60F.sub.254, solvent; chloroform/methanol=9/1)
Reference Example 3
4-[3-(1-t-butoxycarbonylpiperidin-4-yl)propenoyl]nitrobenzene
0.28 g of lithium chloride, 0.85 g of diisopropylethylamine and 2.13 g of 4-formyl-l-t-butoxycarbonylpiperidine were added to 2.0 g of diethyl (4-nitrobenzoylmethyl)phosphonate dissolved in 20 ml of acetonitrile, and the mixture was stirred at room temperature for about 3 days. Then, water was added to the reaction mixture, and the mixture was extracted with toluene. The extract was dried over anhydrous sodium sulfate and condensed. The obtained residue was applied to silica gel column chromatography to obtain 1.76 g of the title compound as pale yellow crystal.
Mass (CI); m/z=261 (M.sup.+ -99)
NMR (.delta., CDCl.sub.3); 1.37 to 1.53 (2H, m), 1.47 (9H, s), 1.77 to 1.86 (2H, m), 2.40 to 2.52 (2H, m), 2.74 to 2.87 (2H, m), 4.08 to 4.28 (2H, m), 6.85 (1H, dd, J=1.5 Hz, 15.6 Hz), 7.06 (1H, dd, J=6.4 Hz, 15.1 Hz), 8.05 (2H, d, J=8.8 Hz), 8.32 (2H, d, J=8.8 Hz)
Reference Example 4
(E)-4-[3-(piperidin-4-yl)propenoyl]nitrobenzene
3 ml of trifluoroacetic acid was added to 2.52 g of (E)-4-[3-(1-t-butoxycarbonylpiperidin-4-yl)propenoyl]nitrobenzene dissolved in 20 ml of methylene chloride, and the mixture was stirred at room temperature for 3 hours. Subsequently, 7 ml of trifluoroacetic acid was further added to the mixture, and the mixture was stirred for 3 hours. Then, the solvent was removed by distillation, and a saturated sodium hydrogen carbonate solution was added to the residue. After the mixture was extracted with ethyl acetate, the extract was dried over anhydrous sodium sulfate and condensed. The obtained solid was washed with methylene chloride to obtain 0.7 g of the title compound as pale yellow powder.
Mass (CI); m/z=261 (M.sup.+ +1)
NMR (.delta., CDCl.sub.3 -DMSO-d.sub.6); 1.80 to 2.12 (4H, m), 2.30 to 2.70 (1H, m), 2.89 to 3.08 (2H, m), 3.44 to 3.68 (2H, m), 6.90 (1H, d, J=15 to 16 Hz), 7.04 (1H, dd, J=15 to 16 Hz, J=6 to 7 Hz), 8.06 (2H, d, J=8 to 9 Hz), 8.32 (2H, d, J=8 to 9 Hz)
Reference Example 5
(E)-4-{3-[1-(3-fluorobenzyl)piperidin-4-yl]propenoyl}nitrobenzene
1.11 g of 3-fluorobenzylbromide and 2.53 g of potassium carbonate were added to 3.0 g of (E)-4-[3-(piperidin-4-yl)propenoyl]nitrobenzene dissolved in 30 ml of dimethylformamide at room temperature, and the mixture was stirred for 2 hours. After completion of the reaction, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The obtained residue was applied to silica gel column chromatography to obtain 1.06 g of the title compound as pale yellow crystal.
Mass (CI); m/z=369 (M.sup.+ +1)
NMR (.delta., CDCl.sub.3); 1.46 to 1.88 (4H, m), 2.00 to 2.12 (2H, m), 2.18 to 2.40 (1H, m), 2.84 to 3.50 (2H, m), 3.51 (2H, s), 6.82 (1H, dd, J=-1 Hz, 15.6 Hz), 6.88 to 6.99 (1H, m), 7.03 to 7.14 (3H, m), 7.20 to 7.34 (1H, m), 8.04 (2H, d, J=8.8 Hz), 8.31 (2H, d, J=8.8 Hz)
In the same manner as in Reference example 5, the following compounds were obtained.
Reference Example 6
(E)-4-{3-[1-(4-fluorobenzyl)piperidin-4-yl]propenoyl}-nitrobenzene
Orange powder
Mass (CI); m/z=369 (M.sup.+ +1)
NMR (.delta., CDCl.sub.3); 1.45 to 1.88 (4H, m), 1.92 to 2.16 (2H, m), 2.16 to 2.40 (1H, m), 2.85 to 3.00 (2H, m), 3.47 (2H, s), 6.81 (1H, dd, J=-1 Hz, 15.6 Hz), 6.95 to 7.05 (2H, m), 7.07 (1H, dd, J=6.4 Hz, J=15.6 Hz), 7.24 to 7.31 (2H, m), 8.03 (2H, d, J=8.8 Hz), 8.31 (2H, d, J=8.8 Hz)
Reference Example 7
(E)-4-(3-[1-(4-methoxybenzyl)piperidin-4-yl]propenoyl)nitrobenzene
Brown oily product
Mass; m/z=380 (M.sup.+)
NMR (.delta., CDCl.sub.3); 1.46 to 1.84 (4H, m), 1.97 to 2.10 (2H, m), 2.20 to 2.35 (1H, m), 2.91 to 2.99 (2H, m), 3.46 (2H, s), 3.82 (3H, s), 6.88 to 6.92 (3H, m), 7.10 (1H, dd, J=6 to 7 Hz, 15 to 16 Hz), 7.22 to 7.35 (2H, m), 8.03 (2H, d, J=8 to 9 Hz), 8.32 (2H, d, J=8 to 9 Hz)
Reference Example 8
(E)-4-(3-[1-(4-picolyl)piperidin-4-yl]propenoyl)nitrobenzene
Brown crystal
Mass; m/z=351 (M.sup.+)
NMR (.delta., CDCl.sub.3); 1.55 to 1.66 (2H, m), 1.78 to 1.85 (2H, m), 1.85 to 2.14 (2H, m), 2.25 to 2.37 (1H, m), 2.87 to 2.97 (2H, m), 3.53 (2H, s), 6.83 (1H, d, J=15.6 Hz), 7.08 (1H, dd, J=6.8 Hz, J=15.6 Hz), 7.28 (2H, d, J=5.9 Hz), 8.05 (2H, d, J=8.8 Hz), 8.32 (2H, d, J=8.8 Hz), 8.55 (2H, d, J=5.9 Hz)
Reference Example 9
4-chloro-7-fluoro-5,6-dihydro-7H-cyclopenta[d]pyrimidine
(1) 5.54 g of lithium hydroxide.multidot.hydrate was added to 24.2 g of 7-acetoxy-4-chloro-5,6-dihydro-7H-cyclopenta[d]pyrimidine dissolved in 150 ml of tetrahydrofuran, and the mixture was stirred at room temperature for about 20 hours. After the reaction, water was added to the reaction mixture, and then the mixture was extracted with chloroform. The extract was dried over anhydrous sodium sulfate and then condensed. The obtained residue was applied to silica gel column chromatography to obtain 10.5 g of 4-chloro-7-hydroxy-5,6-dihydro-7H-cyclopenta[d]pyrimidine.
Mass; m/z=170
NMR (.delta., CDCl.sub.3); 2.00 to 2.23 (1H, m), 2.52 to 2.73 (1H, m), 2.79 to 3.02 (1H, m), 3.02 to 3.24 (1H, m), 5.20 (1H, br), 5.30 (1H, t, J=8.0 Hz), 8.90 (1H, s)
(2) Under ice cooling, 3.9 ml of diethylaminosulfite trifluoride (DAST) was added dropwise to 5.00 g of 4-chloro-7-hydroxy-5,6-dihydro-7H-cyclopenta[d]pyrimidine obtained above dissolved in 40 ml of chloroform, and the mixture was stirred at the same temperature for 10 minutes. After the solvent was removed under reduced pressure, water was added to the mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and condensed. The obtained residue was applied to silica gel column chromatography to obtain 3.09 g of the title compound as a yellow oily product.
Mass; m/z=172 (M.sup.+)
NMR (.delta., CDCl.sub.3); 2.23 to 2.77 (2H, m), 2.87 to 3.40 (2H, m), 5.78 to 5.89 and 6.05 to 6.18 (total 1H, each m), 9.01 (1H, s)
Reference Example 10
4-[3-(1-benzylpiperidin-4-yl)propanoyl]aniline
2.00 g of (E)-4-[3-(1-benzylpiperidin-4-yl)propenoyl]nitrobenzene was added to a mixed solvent of 30 ml of ethanol and 5 ml of acetic acid, and then 0.20 g of platinum oxide was added thereto. Thereafter, the mixture was stirred in a hydrogen stream at room temperature for 7.5 hours. After the reaction, the catalyst was removed by filtration, and the filtrate was condensed under reduced pressure. The obtained residue was applied to silica gel column chromatography to obtain 0.69 g of the title compound as pale yellow crystal.
Mass; m/z=322 (M.sup.+)
NMR (.delta., CDCl.sub.3); 1.32 to 1.54 (3H, m), 1.63 to 1.78 (4H, m), 2.14 to 2.25 (2H, m), 2.86 (2H, t, J=7.3 Hz), 3.09 to 3.18 (2H, m), 3.77 (2H, s), 6.63 (2H, d, J=8.8 Hz), 7.28 to 7.37 (5H, m), 7.78 (2H, d, J=8.8 Hz)
Reference Example 11
(E)-4-[3-(1-acetylpiperidin-4-yl) propenoyl]nitrobenzene
In the same manner as in Reference example 3 except for using 4-formyl-l-acetylpiperidine in place of 4-formyl-t-butoxycarbonylpiperidine, the reaction was carried out to obtain the title compound as yellowish orange solid.
Mass; m/z=302 (M.sup.+)
NMR (.delta., CDCl.sub.3); 1.36 to 1.57 (2H, m), 1.83 to 1.99 (2H, m), 2.12 (3H, s), 2.48 to 2.75 (2H, m), 3.10 to 3.25 (1H, m), 3.85 to 3.96 (1H, m), 4.63 to 4.75 (1H, m), 6.86 (1H, d, J=15.9 Hz), 7.06 (1H, dd, J=15.8 Hz, 6.7 Hz), 8.06 (2H, d, J=9.2 Hz), 8.32 (2H, d, J=9.2 Hz)
Reference Example 12
4-[3-(1-acetylpiperidin-4-yl) propanoyl]aniline
To 6.74 g of (E)-4-[3-(1-acetylpiperidin-4-yl)propenoyl]nitrobenzene were added 300 ml of methanol and 0.30 g of platinum oxide, and under a hydrogen stream, the mixture was stirred at room temperature for 3 hours. Then, the solid was removed by filtration, the solvent was removed by distillation under reduced pressure, and the obtained residue was applied to silica gel column chromatography to obtain 4.81 g of the title compound as brownish white powder.
Mass; m/z=274 (M.sup.+)
NMR (.delta., CDCl.sub.3); 1.02 to 1.25 (2H, m), 1.46 to 1.86 (5H, m), 2.08 (3H, s), 2.43 to 2.61 (1H, m), 2.90 (2H, t, J=7.3 Hz), 2.95 to 3.09 (1H, m), 3.70 to 3.86 (1H, m), 4.27(2H, s, br), 4.52 to 4.64 (1H, m), 6.65 (2H, d, J=8.6 Hz), 7.80 (2H, d, J=8.6 Hz)
Reference Example 13
N-acetyl-4-[(1-benzyl-4-hydroxypiperidin-4-yl)acetyl]aniline
A mixed solution comprising 140 ml of a tetrahydrofuran solution containing 10.00 g of 4-acetylaminoacetophenone and 10 ml of hexamethylphosphoric acid triamide (HMPA) was cooled to -60.degree. C. under an argon stream, and then 83 ml of a tetrahydrofuran solution containing 1.5M of lithium diisopropylamide was added dropwise to the mixture. After completion of the dropwise addition, the mixture was stirred at -35.degree. to -30.degree. C. for 20 minutes and cooled again to -60.degree. C. To the mixture was added dropwise 10.68 g of 1-benzyl-4-piperidone, and the temperature of the resulting mixture was gradually raised to room temperature. The reaction mixture was quenched to a saturated ammonium chloride aqueous solution, and 3.62 g of the precipitated title compound was collected by filtration. The filtrate was further extracted with ethyl acetate and condensed, and then the condensate was applied to silica gel column chromatography to obtain 8.28 g of the title compound.
White crystal
Mass (CI); m/z=349 (M.sup.+ +1-H.sub.2 O)
NMR (.delta., CDCl.sub.3); 1.67 to 1.89 (4H, m), 2.22 (3H, s), 2.50 to 2.77 (4H, m), 3.05 (2H, s), 3.62 (2H, s), 4.14 (1H, s), 7.21 to 7.45 (5H, m), 7.66 (2H, d, J=9.2 Hz), 7.87 (2H, d, J=9.2 Hz), 8.07 (1H, s, br)
Reference Example 14
N-acetyl-4-[(1-benzyl-4-piperidinyliden)acetyl]aniline and N-acetyl-4-[(1-benzyl-1,2,5,6-tetrahydropyridin-4-yl)acetyl]aniline
To a chloroform solution containing 11.90 g of N-acetyl-4-[(1-benzyl-4-hydroxypiperidin-4-yl)acetyl]aniline was added 15 ml of pyridine under ice cooling, and then 3.8 ml of thionyl chloride was added dropwise thereto. After completion of the dropwise addition, the mixture was stirred at room temperature for about 6 hours. After completion of the reaction, ice-water was added and then a 1N sodium hydroxide aqueous solution was added to the mixture to make it weak alkaline, then the mixture was extracted with chloroform. The extract was dried over anhydrous sodium sulfate and then condensed. The residue obtained was applied to silica gel column chromatography to obtain 7.11 g of the mixture of the title compounds.
Brown liquid
Mass (CI); m/z=349 (M.sup.+ +1)
NMR (.delta., CDCl.sub.3); 2.20 (3H, s), 2.37 to 2.63, 2.85 to 3.02 and 3.60 (total 8H, each m), 3.53 and 3.56 (total 2H, each s), 5.52 and 6.62 (total 1H, m and s, respectively), 7.18 to 7.39 (5H, m), 7.62 (2H, d, J=8.6 Hz), 7.85 to 8.05 (3H, m)
Reference Example 15
N-acetyl-4-[(1-benzylpiperidin-4-yl)acetyl]aniline
In a mixed solution of 80 ml of ethanol and 30 ml of toluene was dissolved 7.10 g of the mixture of N-acetyl-4[(1-benzyl-4-piperidinyliden)acetyl]aniline and N-acetyl-4[(1-benzyl-1,2,5,6-tetrahydropyridin-4-yl)acetyl]aniline obtained in Reference example 14, and then 0.10 g of platinum oxide was added thereto. The mixture was stirred under a hydrogen stream for 5.5 hours. After the reaction, the catalyst was removed by filtration and condensed under reduced pressure. The residue obtained was applied to silica gel column chromatography to obtain 5.54 g of the title compound.
Pale yellow crystal
Mass (CI); m/z=351 (M.sup.+ +1)
NMR (.delta., CDCl.sub.3); 1.25 to 1.44 (2H, m), 1.63 to 1.77 (2H, m), 1.88 to 2.07 (3H, m), 2.19 (3H, s), 2.76 to 2.92 (4H, m), 3.48 (2H, s), 7.18 to 7.38 (5H, m), 7.62 (2H, d, J=9.2 Hz), 7.89 (2H, d, J=9.2 Hz), 8.13 (1H, s, br)
Reference example 16
4-[(1-benzylpiperidin-4-yl)acetyl]aniline.multidot.2HCl salt
5.54 g of N-acetyl-4-[(1-benzylpiperidin-4-yl)acetyl]aniline was added to a mixed solution of 15 ml of ethanol and 20 ml of conc. hydrochloric acid, and then the mixture was heated under reflux for 4.5 hours. After the reaction, the reaction mixture was condensed under reduced pressure, and the obtained solid was washed with ethanol to obtain 6.20 g of the title compound.
Pale brown crystal
Mass (CI); m/z=309 (M.sup.+ +1)
NMR (.delta., CDCl.sub.3 -DMSO-d.sub.6); 1.68 to 1.97 (4H, m), 2.07 to 2.28 (1H, m), 2.82 to 3.10 (4H, m), 3.29 to 3.43 (2H, m), 4.27 (2H, d, J=5.5 Hz), 7.18 (2H, d, J=8.7 Hz), 7.31 to 7.51 (3H, m), 7.58 to 7.76 (2H, m), 7.87 (2H, d, J=8.7 Hz)
Reference Example 17
N-t-butoxycarbonyl-4-[(1-benzyl-4-hydroxypiperidin-4-yl)acetyl]aniline
30 ml of tetrahydrofuran was added to 2.00 g of N-t-butoxycarbonyl-4-acetylaniline, and 8.8 ml of a 1.7M t-butyl lithium.multidot.pentane solution was added thereto under an argon stream at -78.degree. C. Then, 1.41 g of 1-benzyl-4-piperidone was dissolved in 20 ml of tetrahydrofuran, and the solution was added dropwise. After stirring for 2 hours, a saturated ammonium chloride aqueous solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the obtained residue was applied to silica gel column chromatography to obtain 2.07 g of the title compound as white powder.
Mass (CI); m/z=307 (M.sup.+ -118)
NMR (.delta., CDCl.sub.3); 1.53 (9H, s), 1.60 to 1.75 (2H, m), 1.75 to 1.83 (2H, m), 2.43 to 2.53 (2H, m), 2.56 to 2.65 (2H, m), 3.06 (2H, s), 3.54 (2H, s), 4.10 (1H, s, br), 6.74 (1H, s, br), 7.23 to 7.35 (5H, m), 7.45 (2H, d, J=8.8 Hz), 7.89 (2H, d, J=8.8 Hz)
Reference Example 18
4-[(1-benzyl-4-hydroxypiperidin-4-yl)acetyl]aniline.multidot.trifluoroacetate
30 ml of chloroform was added to 2.07 g of N-t-butoxy-carbonyl-4-[(1-benzyl-4-hydroxypiperidin-4-yl)acetyl]aniline, trifluoroacetic acid was added thereto three times in a total amount of 8 ml, and the mixture was stirred at room temperature. Thereafter, the solvent was removed by distillation under reduced pressure, and the obtained residue was applied to silica gel column chromatography to obtain 1.14 g of the title compound as reddish white powder.
Mass (CI); m/z=325 (M.sup.+ +1)
NMR (.delta., CDCl.sub.3); 1.88 to 1.96 (2H, m), 2.01 to 2.16 (2H, m), 3.03 (2H, s), 3.13 to 3.36 (4H, m), 4.19 (2H, s), 5.01 (2H, br), 6.63 (2H, d, J=8.8 Hz), 7.38 to 7.55 (5H, m), 7.73 (2H, d, J=8.8 Hz), 12.07 (1H, br)
Reference Example 19
(a) N-t-butoxycarbonyl-4-[(1-benzyl-4-piperidinyliden)acetyl]aniline and (b) N-t-butoxycarbonyl-4-[(1-benzyl-1,2,5,6-tetrahydropyridin-4-yl)acetyl]aniline
100 ml of chloroform was added to 14.9 g of N-t-butoxycarbonyl-4-[2-(1-benzyl-4-hydroxypiperidin-4-yl)acetyl]aniline. After 3.1 ml of thionyl chloride was added to the mixture under ice cooling, 11.8 ml of triethylamine was added dropwise thereto. After the mixture was stirred at room temperature for 1 hour, water was added to the reaction mixture, and the mixture was extracted with chloroform. The extract was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. The obtained residue was applied to silica gel column chromatography to obtain the title compounds, respectively.
Compound of (a)
White powder
Mass (CI); m/z=407 (M.sup.+ +1)
NMR (.delta., CDCl.sub.3); 1.57 (9H, s), 2.38 to 2.49 (2H, m), 2.49 to 2.67 (4H, m), 2.86 to 3.00 (2H, m), 3.56 (2H, s), 6.61 (1H, s), 6.66 (1H, s), 7.23 to 7.39 (5H, m), 7.44 (2H, d, J=8.5 Hz), 7.90 (2H, d, J=8.5 Hz)
Compound of (b)
White powder
Mass (CI); m/z=407 (M.sup.+ +1)
NMR (.delta., CDCl.sub.3); 1.52 (9H, s), 2.11 to 2.22 (2H, m), 2.22 to 2.54 (2H, m), 2.95 to 3.04 (2H, m), 3.57 (4H, s), 5.50 to 5.56 (1H, m), 6.76 (1H, s, br), 7.19 to 7.39 (5H, m), 7.43 (2H, d, J=8.8 Hz), 7.92 (2H, d, J=8.8 Hz)
Reference Example 20
4-[(1-benzyl-4-piperidinylidene)acetyl]aniline
4.12 g of N-t-butoxycarbonyl-4-[(1-benzyl-4-piperidinyliden)acetyl]aniline was added to 50 ml of chloroform, and then 10 ml of trifluoroacetic acid was added thereto. The mixture was stirred at room temperature for 4 hours. After the reaction, the reaction mixture was condensed under reduced pressure, and the residue was dissolved in chloroform. Then, the solution was neutralized by adding a 28% sodium methylate.multidot.methanol solution thereto. The residue obtained by condensation under reduced pressure was applied to silica gel column chromatography to obtain 2.33 g of the title compound as bluish green powder.
Mass; m/z=306 (M.sup.+)
NMR (.delta., CDCl.sub.3); 2.29 to 2.69 (2H, m), 2.69 to 3.05 (2H, m), 3.31 to 3.86 (4H, m), 4.22 (2H, s), 6.64 (2H, d, J=8.6 Hz), 6.71 (1H, s), 7.73 (2H, d, J=9.2 Hz)
Reference Example 21
N-t-butoxycarbonyl-4-[(1-acetyl-4-hydroxypiperidin-4-yl)acetyl]aniline
In the same manner as in Reference example 17 except for using 1-acetyl-4-piperidone in place of 1-benzyl-4-piperidone, the reaction was carried out to obtain the title compound as white solid.
Mass (SIMS); 377 (M.sup.+ +1)
NMR (.delta., CDCl.sub.3); 1.37 to 1.62 (2H, m), 1.53 (9H, s ), 1.75 to 1.95 (2H, m), 2.10 (3H, s), 3.06 (2H, s), 3.47 to 3.67 (2H, m), 4.32 to 4.47 (2H, m), 7.07 (1H, s, br), 7.50 (2H, d, J=8.8 Hz ), 7.88 (2H, d, J=8.8 Hz )
Reference Example 22
N-t-butoxycarbonyl-4-[(1-acetyl-4-piperidinyliden)acetyl]aniline and N-t-butoxycarbonyl-4-[(1-acetyl-1,2,5,6-tetrahydropyridin-4-yl) acetyl]aniline
In the same manner as in Reference example 14, the reaction was carried out by using the compound obtained in Reference example 21 to obtain the mixture of the title compounds.
Yellowish white powder
Mass (CI); m/z=359 (M.sup.+ +1)
NMR (.delta., CDCl.sub.3); 1.53 (9H, s), 2.12 and 2.16 (total 3H, each s), 1.98 to 2.30, 2.38 to 2.57, 2.85 to 3.01, 3.38 to 3.82 and 3.82 to 4.13 (total 8H, each m), 5.45 to 5.64 and 7.01 (total 1H, m and s, respectively), 6.75 and 7.01 (total 1H, s, respectively), 7.47 (2H, d, J=8.8 Hz), 7.91 (2H, d, J=8.8 Hz)
Reference Example 23
N-t-butoxycarbonyl-4-[(1-acetylpiperidin-4-yl)acetyl]aniline
In the same manner as in Reference example 15, the reaction was carried out by using the mixture obtained in Reference example 22 to obtain the title compound as white powder.
Mass (CI); m/z=261 (M.sup.+ -99)
NMR (.delta., CDCl.sub.3); 1.11 to 1.32 (2H, m), 1.53 (9H, s), 1.72 to 1.90 (2H, m), 2.08 (3H, s), 2.15 to 2.34 (1H, m), 2.53 to 2.66 (1H, m), 2.82 to 2.90 (2H, m), 3.02 to 3.17 (1H, m), 3.73 to 3.85 (1H, m), 4.57 to 4.68 (1H, m), 6.79 (1H, s, br), 7.46 (2H, d, J=8.8 Hz), 7.90 (2H, d, J=8.8 Hz)
Reference Example 24
4-[(1-acetylpiperidin-4-yl) acetyl]aniline
50 ml of chloroform was added to 6.90 g of N-t-butoxy-carbonyl-[4-(1-acetylpiperidin-4-yl)acetyl]aniline, and trifluoroacetic acid was added to the mixture at room temperature until no foaming occurred. The solvent was removed by distillation under reduced pressure, water was added to the residue, and the mixture was neutralized with sodium hydrogen carbonate and then extracted with chloroform. After the extract was dried over anhydrous sodium sulfate, the solvent was removed by distillation under reduced pressure. The obtained residue was applied to silica gel column chromatography to obtain 3.56 g of the title compound as yellow solid.
Mass (CI); m/z=261 (M.sup.+ +1)
NMR (.delta., CDCl.sub.3); 1.10 to 1.30 (2H, m), 1.68 to 1.91 (2H, m), 2.08 (3H, s), 2.12 to 2.34 (1H, m), 2.48 to 2.68 (1H, m), 2.68 to 2.93 (2H, m), 3.00 to 3.17 (1H, m), 3.72 to 3.85 (1H, m), 4.54 (1H, m), 6.66 (2H, d, J=8.8 Hz), 7.80 (2H, d, J=8.8 Hz)
Reference Example 25
N-t-butoxycarbonyl-4-[4-(1-benzylpiperidin-4-yl)-3-hydroxybutanoyl]aniline
50 ml of tetrahydrofuran was added to 3.80 g of N-t-butoxycarbonyl-4-acetylaniline, and 19.0 ml of a 1.7M t-butyl lithium.multidot.pentane solution was added dropwise thereto under an argon stream at -78.degree. C. Subsequently, a solution of 3.50 g of (1-benzylpiperidin-4-yl)acetaldehyde dissolved in 10 ml of tetrahydrofuran was added to the mixture, and the resulting mixture was stirred until its temperature was returned to room temperature. Then, a saturated ammonium chloride aqueous solution was added to the reaction mixture, the mixture was extracted with ethyl acetate, and the extract was dried over anhydrous sodium sulfate. Then, the solvent was removed by distillation under reduced pressure, and the obtained residue was applied to silica gel column chromatography to obtain 4.57 g of the title compound as white powder.
Mass (CI); m/z=453 (M.sup.+ +1)
NMR (.delta., CDCl.sub.3); 1.15 to 1.42 (4H, m), 1.42 to 1.72 (4H, m), 1.53 (9H, s), 1.72 to 1.86 (1H, m), 1.86 to 2.08 (2H, m), 2.84 to 2.95 (2H, m), 3.50 (2H, s), 4.23 to 4.38 (1H, m), 6.86 (1H, s, br), 7.13 to 7.40 (5H, m), 7.45 (2H, d, J=8.8 Hz), 7.89 (2H, d, J=8.8 Hz)
Reference Example 26
4-[4-(1-benzylpiperidin-4-yl)-3-hydroxybutanoyl]aniline.multidot.trifluoroacetate
50 ml of dichloromethane was added to 4.55 g of N-t-butoxycarbonyl-4-[4-(1-benzylpiperidin-4-yl)-3-hydroxybutanoyl]aniline, and trifluoroacetic acid was added to the mixture at room temperature until no foaming occurred. Then, the solvent was removed by distillation under reduced pressure, and the obtained residue was applied to silica gel column chromatography to obtain 1.21 g of the title compound as white powder.
Mass (CI); m/z=353 (M.sup.+ +1)
NMR (.delta., CDCl.sub.3); 1.22 to 2.08 (7H, m), 2.62 to 2.84 (2H, m), 2.94 (2H, d, J=5.9 Hz), 3.42 to 3.62 (2H, m), 4.20 (3H, m, br), 6.63 (2H, d, J=8.8 Hz), 7.36 to 7.55 (5H, m), 7.73 (2H, d, J=8.8 Hz)
Reference Examples 27 TO 42
In the same manner as in Reference example 5, the following compounds were obtained.
__________________________________________________________________________Refer-enceexample Compound MassNo. (characteristics) (m/z) NMR (.delta., CDCl.sub.3)__________________________________________________________________________27 (E)-4-{3-[1-(2- 368 1.54 to 1.67 (2H, m), 1.77 to 1.86 fluorobenzyl)- (M.sup.+) (2H, m), 2.08 to 2.18 (2H, m), piperidin-4- 2.22 to 2.37 (1H, m), 2.92 to 3.01 yl]propenoyl}- (2H, m), 3.62 (2H, s), 6.82 (1H, nitrobenzene d, J=15.6Hz), 7.00 to 7.17 (3H, (brown liquid) m), 7.21 to 7.30 (1H, m), 7.35 to 7.43 (1H, m), 8.03 (2H, d, J= 8.8Hz), 8.31 (2H, d, J=8.8Hz)28 (E)-4-{3-[1-(3- 384 1.46 to 1.71 (2H, m), 1.75 to 1.89 chlorobenzyl)- (M.sup.+) (2H, m), 2.00 to 2.19 (2H, m), piperidin-4- 2.22 to 2.39 (1H, m), 2.85 to 3.04 yl]propenoyl}- (2H, m), 3.52 (2H, s), 6.83 (1H, nitrobenzene d, J=15Hz), 7.09 (1H, dd, J=15Hz, (brown crystal) 6Hz), 7.15 to 7.41 (4H, m), 8.04 (2H, d, J=9Hz), 8.32 (2H, d, J= 9Hz)29 (E)-4-{3-[1-(3- 381 1.53 to 1.67 (2H, m), 1.75 to 1.85 methoxybenzyl)- (CI) (2H, m), 2.01 to 2.13 (2H, m), piperidin-4- (M.sup.+ +1) 2.24 to 2.37 (1H, m), 2.93 to 3.01 yl]propenoyl}- (2H, m), 3.51 (2H, s), 3.82 (3H, nitrobenzene s), 6.82 (1H, d, J=15.6Hz), 6.80 (yellowish to 6.84 (1H, m), 6.86 to 6.95 (1H, brown crystal) m), 7.08 (1H, dd, J=15.6Hz, 8.7Hz), 7.22 to 7.28 (1H, m), 8.03 (2H, d, J=8.8Hz), 8.31 (2H, d, J=8.8Hz)30 (E)-4-{3-[1-(2- 380 1.52 to 1.70 (2H, m), 1.70 to 1.85 methoxybenzyl)- (M.sup.+) (2H, m), 2.05 to 2.20 (2H, m), piperidin-4- 2.20 to 2.38 (1H, m), 2.94 to 3.06 yl]propenoyl}- (2H, m), 3.59 (2H, s), 3.82 (3H, nitrobenzene s), 6.81 (1H, d, J=15.3Hz), 6.84 (pale yellow to 6.99 (2H, m), 7.08 (1H, dd, J= crystal) 15.3 Hz, 6.7Hz), 7.19 to 7.29 (1H, m), 7.35 (1H, d, J=7.3Hz), 8.03 (2H, d, J=8.5Hz), 8.31 (2H, d, J=8.5Hz)31 (E)-4-{3-[1-(3- 364 1.47 to 1.71 (2H, m), 1.71 to 1.89 methylbenzyl)- (M.sup.+) (2H, m), 1.96 to 2.13 (2H, m), piperidin-4- 2.21 to 2.40 (1H, m), 2.35 (3H, yl]propenoyl}- s), 2.88 to 3.03 (2H, m), 3.49 nitrobenzene (2H, s), 6.82 (1H, d, J=16.9Hz), (yellow crystal) 7.02 to 7.29 (5H, m), 8.03 (2H, d, J=8.8Hz), 8.31 (2H, d, J=8.8Hz)32 (E)-4-{3-[1-(3- 418 1.49 to 1.70 (2H, m), 1.70 to 1.87 trifluoromethyl- (M.sup.+) (2H, m), 2.00 to 2.16 (2H, m), benzyl)piperi- 2.22 to 2.40 (1H, m), 2.85 to 2.97 din-4-yl]pro- (2H, m), 3.57 (2H, s), 6.83 (1H, penoyl}nitro- d, J=15.9Hz), 7.09 (1H, dd, J= benzene (brown 15.9Hz, 6.7Hz), 7.37 to 7.48 (1H, liquid) m), 7.48 to 7.58 (2H, m), 7.60 (1H, s), 8.04 (2H, d, J=9.2Hz), 8.31 (2H, d, J=9.2Hz)33 (E)-4-{3-[1-(4- 375 1.48 to 1.70 (2H, m), 1.75 to 1.87 cyanobenzyl)- (M.sup.+) (2H, m), 2.03 to 2.17 (2H, m), piperidin-4- 2.23 to 2.40 (1H, m), 2.82 to 2.97 yl]propenoyl}- (2H, m), 3.56 (2H, s), 6.83 (1H, nitrobenzene d, J=15.4Hz), 7.08 (1H, dd, (yellow crystal) J=15.4Hz, 6.6Hz), 7.46 (2H, d, J=8.1Hz), 7.61 (2H, d, J=8.1Hz), 8.04 (2H, d, J=8.8Hz), 8.32 (2H, d, 8.8hz)34 (E)-4-{3-[1-(3- 375 1.47 to 1.70 (2H, m), 1.75 to 1.89 cyanobenzyl)- (M.sup.+) (2H, m), 2.02 to 2.18 (2H, m), piperidin-4- 2.22 to 2.44 (1H, m), 2.82 to yl]propenoyl}- 2.96 (2H, m), 3.59 (2H, s), 6.84 nitrobenzene (1H, d, J=15.4Hz), 7.09 (1H, dd, (brown liquid) J=15.4Hz, 6.6Hz), 7.37 to 7.50 (1H, m), 7.50 to 7.62 (2H, m), 7.66 (1H, s), 8.05 (2H, d, J=8.8Hz), 8.32 (2H, d, J=8.8Hz)35 (E)-4-{3-[1-(1- 400 1.46 to 1.66 (2H, m), 1.71 to 1.85 naphthylmethyl)- (M.sup.+) (2H, m), 2.04 to 2.22 (2H, m), piperidin-4- 2.22 to 2.40 (1H, m), 2.93 to 3.07 yl]propenoyl}- (2H, m), 3.91 (2H, s), 6.80 (1H, nitrobenzene d, J=16.3Hz), 7.07 (1H, dd, J= (brown liquid) 16.3Hz, 6.6Hz), 7.37 to 7.55 (4H, m), 7.74 to 7.89 (2H, m), 8.02 (2H, d, J=8.8Hz), 8.30 (3H, d, 8.8Hz)36 (E)-4-{3-[1-(.beta.- 364 1.39 (3H, d, J=6.6Hz), 1.43 to phenethyl)piper- (M.sup.+) 2.13 (6H, m), 2.13 to 2.32 (1H, idin-4-yl]pro- m), 2.81 to 2.93 (1H, m), 3.04 to penoyl}nitro- 3.17 (1H, m), 3.46 (1H, q, J= benzene (reddish 6.6Hz), 6.79 (1H, d, J=15.4Hz), brown liquid) 7.06 (1H, dd, J=15.4Hz, 6.6Hz), 7.17 to 7.39 (5H, m), 8.02 (2H, d, J=8.8Hz), 8.30 (2H, d, J=8.8Hz)37 (E)-4-{3-[1-(3- 352 1.49 to 1.68 (2H, m), 1.74 to 1.88 pyridylmethyl)- (CI) (2H, m), 2.01 to 2.16 (2H, m), piperidiin-4- (M.sup.+ +1) 2.22 to 2.39 (1H, m), 2.83 to 2.99 yl]propenoyl}- (2H, m), 3.54 (2H, s), 6.83 (1H, nitrobenzene d, J=15.9Hz), 7.08 (1H, dd, J=15.9 (reddish brown Hz, 6.7Hz), 7.21 to 7.30 (1H, m), crystal) 7.63 to 7.72 (1H, m), 8.04 (2H, d, J=9.2Hz), 8.31 (2H, d, J=9.2Hz), 8.46 to 8.58 (2H, m)38 (E)-4-{3-[1-(6- 366 1.53 to 1.72 (2H,m), 1.74 to 1.86 methyl-2-pyridyl- (CI) (2H, m), 2.09 to 2.24 (2H, m), methyl)piperidin- (M.sup.+ +1) 2.24 to 2.39 (1H, m), 2.55 (3H, 4-yl]propenoyl}- s), 2.93 to 3.03 (2H, m), 3.65 nitrobenzene (2H, s), 6.83 (1H, d, J=15.3Hz), (yellowish 7.03 (1H, d, J=7.9Hz), 7.09 (1H, brown crystal) dd, J=15.3Hz, 6.7Hz), 7.55 (1H, t, J=7.9Hz), 8.04 (2H, d, J=9.2Hz), 8.31 (2H, d, J=9.2Hz)39 (E)-4-{3-[1-(2- 357 1.54 to 1.66 (2H, m), 1.76 to 1.85 thienylmethyl)- (CI) (2H, m), 2.03 to 2.15 (2H, m), piperidin-4- (M.sup.+ +1) 2.23 to 2.36 (1H, m), 2.96 to 3.04 yl]propenoyl}- (2H, m), 3.75 (2H, s), 6.82 (1H, nitrobenzene d, J=15.6Hz), 6.99 to 7.03 (1H, (yellow crystal) m), 7.03 to 7.06 (1H, m), 7.08 (1H, dd, J=15.6Hz, 6.4Hz), 7.24 (1H, d, J=6.4Hz), 8.02 (2H, d, J=8.8Hz), 8.31 (2H, d, J=8.8Hz)40 (E)-4-{3-[1-(3,4- 394 1.48 to 1.67 (2H, m), 1.74 to 1.87 methylenedioxy- (M.sup.+) (2H, m), 1.96 to 2.11 (2H, m), benzyl)piperi- 2.20 to 2.37 (1H, m), 2.88 to 3.00 din-4-yl]pro- (2H, m), 3.43 (2H, s), 5.94 (2H, penoyl}nitro- s), 6.74 (2H, s), 6.82 (1H, d, benzene (pale J=15.9Hz), 6.85 (1H, s), 7.08 (1H, yellow crystal) dd, J=15.9Hz, 6.7Hz), 8.03 (2H, d, J=9.2Hz), 8.31 (2H, d, J=9.2Hz)41 (E)-4-{3-[1-(3,4- 409 1.49 to 1.72 (2H, m), 1.72 to 1.84 ethylenedioxy- (CI) (2H, m), 1.95 to 2.11 (2H, m), benzyl)piperi- (M.sup.+ +1) 2.20 to 2.36 (1H, m), 2.89 to 2.99 din-4-yl]pro- (2H, m), 3.41 (2H, s), 4.25 (4H, penoyl}nitro- s), 6.81 (1H, d, J=15.3Hz), 6.79 benzene (brown to 6.84 (3H, m), 7.08 (1H, dd, liquid) J=15.3Hz, 6.7Hz), 8.03 (2H, d, J=9.2Hz), 8.31 (2H, d, J=8.8Hz)42 (E)-4-{3-[1-(2,3- 410 1.46 to 1.66 (2H, m), 1.73 to 1.85 dimethoxybenz- (M.sup.+) (2H, m), 2.02 to 2.18 (2H, m), yl)piperidin-4- 2.18 to 2.37 (1H, m), 2.94 to 3.03 yl]propenoyl}- (2H, m), 3.57 (2H, s), 3.83 (3H, nitrobenzene s), 3.87 (3H, s), 6.80 (1H, d, (brown liquid) J=15.9Hz), 6.80 to 6.86 (1H, m), 6.95 to 7.00 (2H, m), 7.07 (1H, dd, J=15.3Hz, 6.7Hz), 8.03 (2H, d, J=9.2Hz), 8.31 (2H, d, J=9.2Hz)__________________________________________________________________________
Reference Examples 43 to 56
In the same manner as in Reference example 10, the following compounds were obtained.
__________________________________________________________________________Refer-enceexample Compound MassNo. (characteristics) (m/z) NMR (.delta., CDCl.sub.3)__________________________________________________________________________43 4-{3-[1-(2- 340 1.19 to 1.40 (3H, m), 1.54 to 1.78 fluorobenzyl)- (M.sup.+) (4H, m), 1.91 to 2.09 (2H, m), piperidin-4- 2.77 to 2.96 (4H, m), 3.57 (2H, yl]propanoyl]- s), 4.09 (2H, s, br), 6.63 (2H, d, aniline (pale J=8.8Hz), 6.95 to 7.13 (2H, m), yellow crystal) 7.16 to 7.29 (1H, m), 7.34 to 7.43 (1H, m), 7.80 (2H, d, J=8.8Hz)44 4-{3-[1-(4- 356 1.23 to 1.42 (3H, m), 1.63 to 1.75 chlorobenzyl)- (M.sup.+) (4H, m), 1.85 to 2.04 (2H, m), piperidin-4- 2.81 to 2.95 (4H, m), 3.39 to 3.54 yl]propanoyl}- (2H, br), 4.09 (2H, br), 6.64 (2H, aniline (white d), 7.23 to 7.33 (4H, m), 7.80 crystal) (2H, d)45 4-{3-[1-(2- 352 (CDCl.sub.3 DMSO-d.sub.6) 1.38 to 1.59 (1H, methoxybenzyl)- (M.sup.+) m), 1.59 to 1.90 (6H, m), 2.38 to piperidin-4- 2.62 (2H, m), 2.86 (2H, t, J= yl]propanoyl}- 7.3Hz), 3.16 to 3.33 (2H, m), 3.85 aniline.HCl (3H, s), 4.01 (2H, s, br), 4.69 salt (yellowish (2H, s, br), 6.64 (2H, d, J= brown crystal) 8.6Hz), 6.90 to 7.03 (2H, m), 7.30 to 7.40 (1H, m), 7.54 to 7.63 (1H, m), 7.74 (2H, d, J=8.6Hz)46 4-{3-[1-(3- 428 1.20 to 1.39 (3H, m), 1.59 to 1.74 benzyloxybenz- (M.sup.+) (4H, m), 1.85 to 2.00 (2H, m), yl)piperidin-4- 2.79 to 3.01 (4H, m), 3.46 (2H, yl]propanoyl}- s), 4.09 (2H, s, br), 5.06 (2H, aniline (brown s), 6.64 (2H, d, J=8.6Hz), 6.82 to liquid) 6.91 (2H, m), 7.18 (1H, s), 7.19 to 7.27 (1H, m), 7.31 to 7.48 (5H, m), 7.80 (2H, d, J=8.6Hz)47 4-{3-[1-(3- 336 1.19 to 1.40 (3H, m), 1.53 to 1.77 methylbenzyl)- (M.sup.+) (4H, m), 1.84 to 2.01 (2H, m), piperidin-4- 2.34 (3H, s), 2.76 to 2.96 (4H, yl]propanoyl}- m), 3.44 (2H, s), 4.11 (2H, s, aniline (yellow br), 6.63 (2H, d, J=8.8Hz), 7.00 crystal) to 7.26 (4H, m), 7.80 (2H, d, J=8.8Hz)48 4-{3-[1-(3-tri- 390 1.17 to 1.42 (3H, m), 1.56 to 1.80 fluorobenzyl)- (M.sup.+) (4H, m), 1.88 to 2.04 (2H, m), piperidin-4- 2.79 to 2.94 (4H, m), 3.51 (2H, yl]propanoyl}- s), 4.12 (2H, s, br), 6.64 (2H, d, aniline (yellow J=8.6Hz), 7.37 to 7.45 (1H, m), crystal) 7.45 to 7.56 (2H, m), 7.57 (1H, s), 7.80 (1H, d, J=8.6Hz)49 4-{3-[1-(4- 347 (CDCl.sub.3 -DMSO-d.sub.6) 1.13 to 1.40 (3H, cyanobenzyl)- (M.sup.+) m), 1.51 to 1.78 (4H, m), 1.87 to piperidin-4- 2.05 (2H, m), 2.69 to 2.92 (4H, yl]propanoyl}- m), 3.52 (2H, s), 4.98 (2H, s, aniline (pale br), 6.63 (2H, d, J=8.8Hz), 7.46 brown crystal) (2H, d, J=8.1Hz), 7.60 (2H, d, J=8.1Hz), 7.74 (2H, d, J=8.8Hz)50 4-{3-[1-(2- 372 (CDCl.sub.3 -DMSO-d.sub.6) 1.28 to 1.50 (1H, naphthylmethyl)- (M.sup.+) m), 1.50 to 1.81 (6H, m), 2.10 to piperidin-4- 2.50 (2H, m), 2.83 (2H, t, J= yl]propanoyl}- 7.3Hz), 2.93 to 3.27 (2H, m), 3.81 aniline.HCl to 4.27 (2H, br), 5.29 (2H, s), salt (yellowish 6.61 (2H, d, J=8.8Hz), 7.40 to brown crystal) 7.59 (4H, m), 7.69 (2H, d, J= 8.8Hz), 7.76 to 7.92 (2H, m), 8.23 to 8.34 (1H, m)51 4-{3-[1-(2- 323 1.20 to 1.45 (3H, m), 1.50 to 1.80 pyridylmethyl)- (M.sup.+) (4H, m), 1.95 to 2.15 (2H, m), piperidin-4- 2.80 to 3.00 (4H, m), 3.64 (2H, yl]propanoyl}- s), 4.09 (2H, s, br), 6.64 (2H, d, aniline (yellow J=8.8Hz), 7.10 to 7.20 (1H, m), crystal) 7.38 to 7.47 (1H, m), 7.60 to 7.69 (1H, m), 7.81 (2H, d, J=8.8Hz), 8.52 to 8.60 (1H, m)52 4-{3-[1-(3- 323 1.13 to 1.40 (3H, m), 1.54 to 1.78 pyridylmethyl)- (M.sup.+) (4H, m), 1.84 to 2.03 (2H, m), piperidin-4- 2.75 to 2.93 (4H, m), 3.48 (2H, yl]propanoyl}- s), 4.19 (2H, s, br), 6.64 (2H, d, aniline (pale J=8.8Hz), 7.19 to 7.30 (1H, m), yellow crystal) 7.62 to 7.71 (1H, m), 7.80 (2H, d J=8.8Hz), 8.45 to 8.58 (2H, m)53 4-{3-[1-(4- 323 1.18 to 1.41 (3H, m), 1.50 to 1.79 pyridylmethyl)- (M.sup.+) (4H, m), 1.89 to 2.07 (2H, m), piperidin-4- 2.73 to 2.93 (4H, m), 3.48 (2H, yl]propanoyl}- s), 4.10 (2H, s, br), 6.64 (2H, d, aniline (pale J=8.8Hz), 7.27 (2H, d, J=5.9Hz), yellow crystal) 7.81 (2H, d, J=8.8Hz), 8.52 (2H, d, J=5.9Hz)54 4-{3-[1-(6- 338 1.26 to 1.46 (3H, m), 1.62 to 1.76 methyl-4-pyrid- (CI) (4H, m), 1.97 to 2.13 (2H, m), ylmethyl)piper- (M.sup.+ +1) 2.54 (3H, s), 2.83 to 2.95 (4H, idin-4-yl]pro- m), 3.61 (2H, s), 4.10 (2H, s, panoyl}aniline br), 6.64 (2H, d, J=9.2Hz), 7.00 (yellow crystal) (1H, d, J=7.3Hz), 7.21 to 7.30 (1H, m), 7.49 to 7.58 (1H, m), 7.81 (2H, d, J=9.2Hz)55 4-{3-[1-(3,4- 380 1.24 to 1.38 (3H, m), 1.61 to 1.74 ethylenedioxy- (M.sup.+) (4H, m), 1.83 to 1.97 (2H, m), benzyl)piperi- 2.81 to 2.93 (4H, m), 3.37 (2H, din-4-yl]pro- s), 4.10 (2H, s, br), 4.24 (4H, panoyl}aniline s), 6.64 (2H, d, J=9.2Hz), 6.78 to (brown liquid) 6.82 (3H, m), 7.80 (2H, d, J= 9.2Hz)56 4-{3-[1-(2,3- 382 1.20 to 1.37 (3H, m), 1.62 to 1.74 dimethoxybenz- (M.sup.+) (4H, m), 1.94 to 2.07 (2H, m), yl)piperidin-4- 2.82 to 2.97 (4H, m), 3.54 (2H, yl]propanoyl}- s), 4.82 (3H, s), 3.86 (3H, s), aniline (brown 4.12, (2H, s, br) 6.64 (2H, d, J= liquid) 8.6Hz), 6.82 (1H, d, J=7.3Hz), 6.94 to 7.05 (2H, m), 7.80 (2H, d, J=8.6Hz)__________________________________________________________________________
Reference Examples 57 to 66
In the same manner as in Reference examples 13, 14, 15 and 16, the following compounds were obtained.
__________________________________________________________________________Refer-enceexample Compound MassNo. (characteristics) (m/z) NMR (.delta., (CDCl.sub.3)__________________________________________________________________________57 N-trifluoroace- 403 2.39 to 2.49 (2H, m), 2.49 to 2.66 tyl-4-[(1-benzyl- (M.sup.+ +1) (4H, m), 2.87 to 3.00 (2H, m), 4-piperidinylid- 3.54 (2H, s), 6.63 (1H, s), 7.17 ene)acetyl]ani- to 7.41 (5H, m), 7.69 (2H, d, line (pale yel- J=8.5Hz), 7.97 (2H, d, J=8.5Hz), low crystal) 8.38 (1H, br)58 N-trifluoroace- 405 1.25 to 1.47 (2H, m), 1.63 to 1.79 tyl-4-[(1-benzyl- (M.sup.+ +1) (2H, m), 1.87 to 2.08 (3H, m), piperidin-4-yl)- 2.76 to 2.94 (4H, m), 3.49 (2H, acetyl]aniline s), 7.18 to 7.37 (5H, m), 7.70 (pale yellow (2H, d, J=9.1Hz), 7.97 (2H, d, crystal) J=9.1Hz)59 N-acetyl-4-[(1- 397 1.56 to 1.90 (4H, m), 2.23 (3H, benzyl-4-hydroxy- (M.sup.+ +1) s), 2.40 to 2.69 (4H, m), 3.09 piperidin-4-yl)- (2H, s), 3.52 (2H, s), 3.96 (3H, acetyl]-2-meth- s), 4.10 (1H, s), 6.93 (1H, d, oxyaniline (pale J=8.5Hz), 7.17 to 7.40 (5H, m), yellow crystal) 7.67 to 7.80 (2H, m), 8.99 (1H, d, J=2.4Hz)60 N-acetyl-4-[(1- 379 2.22 (3H, s), 2.37 to 2.48 (2H, benzyl-4-piperi- (M.sup.+ +1) m), 2.48 to 2.65 (4H, m), 2.88 to dinylidene)ace- 2.99 (2H, m), 3.53 (2H, s), 3.94 tyl]-2-methoxy- (3H, s), 6.65 (1H, s), 6.934 (1H, aniline (yellow d, J=8.5Hz), 7.20 to 7.39 (5H, m), crystal) 7.67 to 7.80 (2H, m), 8.97 (1H, d, J=2.4Hz)61 N-acetyl-4-[(1- 381 1.30 to 1.44 (2H, m), 1.60 to 1.78 benzylpiperidin)- (M.sup.+ +1) (3H, m), 1.93 to 2.06 (2H, m), 4-yl)acetyl]-2- 2.22 (3H, s), 2.79 to 2.91 (4H, methoxyaniline m), 3.49 (2H, s), 3.94 (3H, s), (yellowish 6.92 (1H, d, J=8.8Hz), 7.20 to brown liquid) 7.36 (5H, m), 7.72 (1H, dd, J= 8.8Hz, 2.0Hz), 7.76 (1H, s, br), 8.98 (1H, d, J=2.0Hz)62 4-[(1-benzyl- 339 (CDCl.sub.3 -DMSO-d.sub.6) 1.66 to 1.72 (2H, piperidin-4- (M.sup.+ +1) m), 1.72 to 1.96 (2H, m), 2.09 to yl)acetyl]-2- 2.23 (1H, m), 2.88 to 3.07 (4H, methoxyaniline. m), 3.29 to 3.40 (2H, m), 3.99 2HCl salt (pale (3H, s), 4.27 (2H, d, J=4.9Hz), brown crystal) 7.20 (1H, d, J=8.8Hz), 7.39 to 7.46 (3H, m), 7.60 to 7.72 (2H, m), 7.92 (1H, dd, J=8.8Hz, 2.0Hz), 7.98 (1H, d, J=2.0Hz), 10.82 (1H, br)63 N-acetyl-4-[(1- 382 1.58 to 1.87 (4H, m), 2.82 (3H, benzyl-4-hydroxy- (M.sup.+ s), 2.40 to 2.71 (4H, m), 3.05 piperidin-4-yl)- -18) (2H, s), 3.52 (2H, s), 3.80 (1H, acetyl]-2-chloro- s), 7.20 to 7.36 (5H, m), 7.78 to aniline (pale 7.90 (2H, m), 7.98 (1H, d, brown liquid) J=1.8Hz), 8.56 (1H, d, J=9.1Hz)64 Mixture of N-ace- 383 2.08 to 2.22, 2.40 to 2.65, 2.88 tyl-4-[()1-benzyl- (M.sup.+ +1) to 3.04 and 3.30 to 3.64 (total 4-piperidinyl- 10H), 2.28 (3H, s), 5.33 and 6.60 idene-acetyl]-2- (total 1H), 7.17 to 7.39 (5H, m), chloroaniline and 7.73 to 7.91 (2H, m), 7.96 to 8.03 N-acetyl-4-[(1- (1H, m), 8.49 to 8.57 (1H, m) benzyl-1,2,5,6- tetrahydropyridin- 4-yl)acetyl]-2- chloroaniline (pale brown liquid)65 N-acetyl-4-[(1- 385 1.81 to 2.03 (2H, m), 2.03 to 2.35 benzylpiperi- (M.sup.+ +1) (3H, m), 2.28 (3H, s), 2.59 to din-4-yl)ace- 2.80 (2H, m), 2.88 to 2.99 (2H, tyl]-2-chloro- m), 3.34 to 3.53 (2H, m), 4.14 aniline.HCl (2H, s), 7.40 to 7.50 (3H, m), salt (pale yel- 7.57 to 7.68 (2H, m), 7.77 to 7.88 low crystal) (2H, m), 7.95 (1H, d, J=1.8Hz), 8.55 (1H, d, J=9.1Hz)66 4-[(1-benzyl- 343 (CDCl.sub.3 -DMSO-d.sub.6) 1.82 to 2.00 (2H, piperidin-4- (M.sup.+ +1) m), 2.00 to 2.32 (3H, m), 2.61 to yl)acetyl]-2- 2.90 (2H, m), 2.84 (2H, d, J= chloroaniline. 6.1Hz), 3.33 to 3.53 (2H, m), 4.15 2HCl salt (pale (2H, d, J=4.9Hz), 6.89 (1H, d, brown solid) J=8.6Hz), 7.35 to 7.52 (3H, m), 7.52 to 7.74 (3H, m), 7.83 (1H, d, J=2.4Hz), 12.22 (1H, br)67 N-acetyl-4-[(1- 397 1.61 to 1.78 (4H, m), 2.24 (3H, benzyl-4-hydroxy- (M.sup.+ +1) s), 2.39 to 2.91 (4H, m), 3.08 piperidin-4- (2H, s), 3.53 (2H, s), 3.81 (1H, yl)acetyl]-3- s, br), 3.88 (3H, s), 6.60 (1H, methoxyaniline dd, J=9.2Hz, 2.4Hz), 7.16 to 7.40 (pale yellow (5H, m), 7.80 (1H, d, J=9.2Hz), liquid) 8.43 (1H, d, J=2.4Hz), 11.95 (1H, s, br)68 N-acetyl-4-[(1- 381 1.27 to 1.46 (2H, m), 1.64 to 1.78 benzylpiperidin- (M.sup.+ +1) (2H, m), 1.83 to 2.09 (3H, m), 4-yl)acetyl]-3- 2.23 (3H, s), 2.75 to 2.94 (2H, methoxyaniline m), 2.84 (2H, d, J=6.7Hz), 3.49 (pale yellow (2H, s), 3.87 (3H, s), 6.60 (1H, liquid) dd, J=9.2Hz, 2.4Hz), 7.13 to 7.40 (5H, m), 7.81 (1H, d, J=8.6Hz), 8.42 (1H, d, J=2.4Hz), 12.15 (1H, s, br)69 4-[(1-benzyl- 339 (CDCl.sub.3 -DMSO-d.sub.6) 1.84 to 2.33 (5H, piperidin-4- (M.sup.+ +1) m), 2.74 to 2.98 (2H, m), 2.87 yl)acetyl]-3- (2H, d, J=6.1Hz), 3.31 to 3.50 methoxyaniline. (2H, m), 3.82 (3H, s), 4.21 (2H, 2HCl salt d, J=4.9Hz), 6.38 (1H, dd, J= (reddish brown 9.2Hz, 2.4Hz), 6.52 (1H, d, J= solid) 2.4Hz), 7.28 to 7.52 (3H, m), 7.52 to 7.83 (3H, m), 11.70 (1H, br)__________________________________________________________________________
EFFECTS OF THE INVENTION
The compound having the formula (I) of the present invention has excellent selective inhibiting activities to both of acetylcholinesterase and A type monoamine oxidase, and is extremely useful as an antidepressant and an agent for curing senile dementia.
As an administration form for such purposes, there may be mentioned, for example, oral administration by a tablet, a capsule, a granule, a powder, syrup, etc. or parenteral administration by an intravenous injection, an intramuscular injection, a suppository, etc. The dose varies depending on age, body weight, symptoms, an administration form, an administration time, etc., but it is generally about 1 to 1,000 mg per day in one dose or divided doses to an adult.
Test example 1. Acetylcholinesterase-inhibiting activity
As an enzyme source, a crude synaptosome fraction of a rat cerebrum was used. The crude synaptosome fraction was prepared by homogenizing a rat cerebrum in a 0.32M sucrose solution and, after centrifugal operation, suspending it in a 0.1M phosphate buffer.
The activity of acetylcholinesterase was measured by a partially modified method of the method of Ellman et. al. (Ellman, G. L. et al., Biochem. Pharmacol., 7, 88 (1961)). That is, to the crude synaptosome fraction of the rat cerebrum suitably diluted with a 0.1M phosphate buffer were added each compound to be tested, 5,5'-dithiobis(2-nitrobenzoic acid) (hereinafter referred to as DTNB) and acetylthiocholine as a substrate, and the mixture was incubated at 25.degree. C. for a predetermined time. Subsequently, the amount of yellow anions formed by reaction of acetylthiocholine and DTNB was measured as absorbance at 410 nm to determine the activity of acetylcholinesterase.
Enzyme activity-inhibiting rates were calculated from absorbances in the presence of the compounds to be tested having various concentrations based on absorbances in the absence of the compounds to be tested, with absorbance when reaction was carried out in the absence of the substrate being defined as blank. IC.sub.50 values were calculated by Hill analysis.
Test example 2. Butyrylcholinesterase-inhibiting activity
As an enzyme source, a rat serum was used.
The activity of butyrylcholinesterase was measured by a partially modified method of the above method of Ellman et. al. That is, to the rat serum suitably diluted with a 0.1M phosphate buffer were added each compound to be tested, DTNB and butyrylthiocholine as a substrate, and the mixture was incubated at 25.degree. C. for a predetermined time. Subsequently, the amount of yellow anions formed by reaction of butyrylthiocholine and DTNB was measured as absorbance at 410 nm to determine the activity of butyrylcholinesterase.
Enzyme activity-inhibiting rates were calculated from absorbances in the presence of the compounds to be tested having various concentrations based on absorbances in the absence of the compounds to be tested, with absorbance when reaction was carried out in the absence of the substrate being defined as blank. IC.sub.50 values were calculated by Hill analysis.
Test example 3. A type and B type monoamine oxidase-inhibiting activity
As an enzyme source, a rat cerebrum homogenized in a 0.1M phosphate buffer was used.
The activities of monoamine oxidases were measured by a partially modified method of the method of Da Prada et al. (Da Prada, M. et al., J. Pharmacol. Exp. Ther., 248 (1), 400 (1989)). That is, the rat cerebrum homogenate suitably diluted with a 0.1M phosphate buffer and each compound to be tested were preincubated at 37.degree. C. for 30 minutes. Then, a substrate labeled with .sup.14 C (5-hydroxy-tryptamine (5-HT) having a final concentration of 200 .mu.M was used in measurement of the activity of A type monoamine oxidase, and .beta.-phenylethylamine (.beta.-PEA) having a final concentration of 20 .mu.M was used in measurement of the activity of B type monoamine oxidase) was added to the preincubated mixture, and the mixture was incubated at 37.degree. C. for a predetermined time. After the reaction was terminated by adding hydrochloric acid (final concentration; 1.2M), the reaction mixture and a predetermined amount of an organic solvent (diethyl ether was used in measurement of the activity of A type monoamine oxidase, and heptane was used in measurement of the activity of B type monoamine oxidase) were vigorously stirred so that deaminated metabolites were extracted into the organic layer. After the mixture was separated into two layers by centrifugation, a part of the organic layer was mixed with liquid scintillation cocktail. Radioactivity extracted into the organic layer was measured by a liquid scintillation counter to calculate the enzyme activity.
Inhibiting rates were calculated from enzyme activities in the presence of the compounds to be tested having various concentrations based on enzyme activities in the absence of the compounds to be tested, with absorbance when reaction was carried out in the absence of the homogenate being defined as blank. IC.sub.50 values were calculated by Hill analysis.
The results of Test examples 1 to 3 are shown in Table 3.
TABLE 3__________________________________________________________________________ IC.sub.50 value (M) Inhibition Inhibition Inhibition of Inhibition of of A type of B typeCompound to acetylcholin- butyrylcholin- monoamine monoaminebe tested esterase esterase oxidase oxidase__________________________________________________________________________Compound of 3.3 .times. 10.sup.-9 >10.sup.-5 1.6 .times. 10.sup.-6 >10.sup.-5Example 1Compound of 3.6 .times. 10.sup.-9 >10.sup.-5 8.9 .times. 10.sup.-7 >10.sup.-5Example 2Compound of 3.1 .times. 10.sup.-9 >10.sup.-5 2.2 .times. 10.sup.-7 >10.sup.-5Example 6Compound of 2.0 .times. 10.sup.-9 >10.sup.-5 8.5 .times. 10.sup.-8 >10.sup.-5Example 8Compound of 1.4 .times. 10.sup.-9 >10.sup.-5 1.4 .times. 10.sup.-6 >10.sup.-5Example 9Compound of 1.1 .times. 10.sup.-9 >10.sup.-5 3.2 .times. 10.sup.-7 >10.sup.-5Example 10Compound of 2.0 .times. 10.sup.-8 >10.sup.-5 6.0 .times. 10.sup.-7 >10.sup.-5Example 21Compound of 7.3 .times. 10.sup.-9 >10.sup.-5 8.1 .times. 10.sup.-7 >10.sup.-5Example 22Compound of 2.5 .times. 10.sup.-7 >10.sup.-5 3.4 .times. 10.sup.-7 6.8 .times. 10.sup.-6Example 25Compound of 1.5 .times. 10.sup.-7 >10.sup.-5 5.6 .times. 10.sup.-8 >10.sup.-5Example 26Compound of 1.7 .times. 10.sup.-8 >10.sup.-5 8.5 .times. 10.sup.-8 >10.sup.-5Example 53Compound of 2.7 .times. 10.sup.-7 >10.sup.-5 3.5 .times. 10.sup.-8 >10.sup.-5Example 87Compound of 3.3 .times. 10.sup.-7 >10.sup.-5 2.5 .times. 10.sup.-7 2.1 .times. 10.sup.-6Example 88Compound of 2.0 .times. 10.sup.-7 >10.sup.-5 4.2 .times. 10.sup.-7 7.2 .times. 10.sup.-6Example 93Compound A 7.3 .times. 10.sup.-9 3.9 .times. 10.sup.-6 >10.sup.-5 >10.sup.-5Compound B >10.sup.-5 >10.sup.-5 1.6 .times. 10.sup.-7 >10.sup.-5__________________________________________________________________________ Compound A: 1benzyl-4-[(5,6dimethoxy-1-indanon)-2-yl]methylpiperidine Compound B: 4(4-cyanoanilino)-5,6-dihydro-7H-cyclopenta-[d]pyrimidine

Number	Name	Date
4450162	Kamioka et al.	May 1984
4895841	Sugimoto et al.	Jan 1990
5100901	Sugimoto et al.	Mar 1992
5177087	Goto et al.	Jan 1993

Number	Date	Country
0067630	May 1985	EPX
0378207	Jul 1990	EPX
57-203072	Dec 1982	JPX
3-173867	Jul 1991	JPX

Arylamino pyrimidine compound

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