AU597628B2 - Hydroquinoline compounds, compositions containing same and process for preparing same - Google Patents

Hydroquinoline compounds, compositions containing same and process for preparing same Download PDF

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AU597628B2
AU597628B2 AU70749/87A AU7074987A AU597628B2 AU 597628 B2 AU597628 B2 AU 597628B2 AU 70749/87 A AU70749/87 A AU 70749/87A AU 7074987 A AU7074987 A AU 7074987A AU 597628 B2 AU597628 B2 AU 597628B2
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group
compound
formula
pharmaceutically acceptable
acceptable salt
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Masatoshi Chihiro
Seiji Morita
Minoru Uchida
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/0803—Compounds with Si-C or Si-Si linkages
    • C07F7/081—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te
    • C07F7/0812—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te comprising a heterocyclic ring

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  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Description

7 COMMONWEALTH OF AUSTRALIA ~2~3a 11,, PATENTS ACT 1952 COMPLETE SPECIFICATION FOR OFFICE USE Form Short Title: Int, Cl: Application Number: Lodged: 70 7-9/ 7 Complete Specification-Lodged: Accepted: Lapsed: Published: Priority: Related At: o Related Art: This document contains the aniendiunts made under Sectioni 49 and is correct for printiig.
TO BE COMPLETED BY APPLICANT Name of Applicant: 'Address of Applicant: Actual Inventor: Address for Service Address for Service: YOSHINARI HIGUCHI 582-9, Akishino-cho, Nara-shi, Nara, 631 JAPAN Minoru uchida Seiji Morita and Masatoshi Chihiro GRIFFITH HASSEL FRAZER 71 YORK STREET SYDNEY NSW 2000
AUSTRALIA
Complete Specification for the invention entitled: HYDROQUINOLINE COMPOUNDS, COMPOSITIONS CONTAINING SAME AND PROCESS FOR PREPARING SAME The following statement is a full description of this invention, including the best method of performing it known to me/us: 5142A: rk
:I
r i n.
i~dh~. -i 0000 00 o0 010 o o a 0 0 1 S 15 o S00 0 1 5 0 4 a 1 *20
'*I
1i-.
HYDROQUINOLINE COMPOUNDS, COMPOSITIONS CONTAINING SAME AND PROCESSES FOR PREPARING SAME FIELD OF THE INVENTION This invention relates to new hydroquinoline compounds and pharmaceutically acceptable salts thereof which are useful as anti-ulcer agents, processes for preparing the same, and pharmaceutical compositions containing the hydroquinoline compounds or salts thereof.
BACKGROUND OF THE INVENTION Various hydroquinoline compounds are known which have gastric acid secretion inhibitory activity as described in European Patent Publication Nos. 0,174,717 and 0,176,308.
However, the hydroquinoline compounds of this invention are structurally different from the conventional hydroquinoline compounds.
SUMMARY OF THE INVENTION One object of this invention is to provide hydroquinoline compounds having an anti-ulcer activity.
Another object of this invention is to provide a pharmaceutical composition containing the hydroquinoline compound in a therapeutically effective amount.
A further object of this invention is to provide a -f i i cl 2 process for preparing the hydroquinoline compounds and pharmaceutically acceptable salts thereof.
As a result of extensive research this invention has been accomplished which, in one aspect, provides a hydroquinoline compound of the following formula and pharmaceutically acceptable salts thereof:
(R
3 )n Ro o(R)m (1) 0 N S A R2 oOO H (0)s o 0 wherein A is a lower alkylene group; R is a hydrogen atom, a lower alkyl group which may have 1 to 3 halogen :15 atoms, a lower alkoxy group which may have 1 to 3 halogen atoms, a halogen atom, a lower alkanoyl group, a lower alkoxycarbonyl group or a cycloalkylcarbonyl group; R is a hydrogen atom, a lower alkyl group which may have 1 to 3 halogen atoms, an amino-lower alkyl group which may have a 20 lower alkyl group, a lower alkenyl group, a lower alkynyl group which may have a tri-lower alkylsilyl group, a phenyl-lower alkyl gro'up which may have 1 to 3 groups selected from the group consisting of a halogen atom and an amino group which may have a lower alkyl group as a substituent on the phenyl ring thereof, a lower alkanoyl t~~YuI, 3 group or a cycloalkyl-lower alkyl group; R 3 is a hydrogen atom, a lower alkyl group which may have 1 to 3 halogen atoms, a lower alkoxy group, a halogen atom, an oxo group, a hydroxy groul, a lower alkenyloxy group, a lower alkylenedioxy group, a phenyl group, a hydroxyimino group, a lower alkylimino group, a lower alkylidene group, a hydroxysubstituted lower alkyl group, a carboxy group, a lower alkoxycarbonyl group, a lower alkanoyloxy-lower alkyl group, a lower alkoxy-lower alkoxy group or a group of the 10 formula:
R
(wherein B is a lower alkylene group or a carbonyl group; p is an integer of 0 or 1; R and R 5 are, the same or t different, a hydrogen atom, a lower alkyl group which nay have 1 to 3 groups selected from the group consisting of a halogen atom and a lower alkoxy group, a hydroxy- :,20 substituted lower alkyl group, a cycloalkyl group, a cycloalkyl-lower alkyl group, a cycloalkylcarbonyl group, a lower alkenyl group, a lower alkanoyl group which may have 1 to 3 halogen atoms, or a phenyl lower alkyl group which may have a lower alkoxy group as a substiuent on the phenyl ring thereof; and R 4 and R 5 together with the r S- 4bonding nitrogen atom may form a saturated 5- or 6menbered heterocyclic group which may contain hetero atom(s) consisting of an oxygen atom, a sulfur atom and a nitro gen atom); m and n are integers of 1 to 3; is an integer of 0 or 1 and the bond between the 3- and 4positions of the quinoline skeleton is a single bond or a double bond; provided that the oxo group for R 3 is not substituted at the 2-position of the quinoline skeleton.
'at.
oa.' In another aspect, this invention provides an anti- 10 ulcer composition containing the compound of the formula or a pharmaceutically acceptable salt thereof in an .9 otherapeutically effective amount.
In a further aspect, this invention provides a proa cess for preparing the compounds of the formula and pharmaceutically acceptable salts thereof.
}The hydroquinoline derivatives represented by the above formula of this invention has an anti-ulcer action and is useful as a drug for the treatment of gastroa a as "0 intestinal ulcers such as gastric ulcer and duodenal ul- S 20 cer.
hydrochloric acid production at the gastric mucosa is regulated by many pharmacological factors, and the biochemical mechanism of [H I ion production finally is the rate-determining step. The ATPase that has a nature of being activated by H and K in gastric wall C, 5 cells has been found in recent years to control the acid production. This enzyme exists specifically in gastric wall cells and plays the role of a proton pump key enzyme.
An inhibitor of this enzyme can be a useful for acid secretion suppressant. The compounds of this invention particularly have both acid secretion suppressing action and cytoprotective action, suppresses ulcer factors in both respects of aggressive factors and protective factors and, moreover, is characterized by low toxicity and a long 0 duration of acid secretion suppressing action.
m a 4 o 4 4 4e D 444 "I 1 .4 a .4 4444p .0 4 a4 44\ !o 4 4 tlU 6 9 4 444, 4 4 44 4.L 44 4 DETAILED DESCRIPTION OF THE INVENTION The groups given in terms'of symbols in the above general formula are respectively described in more 15 detail in the following.
The term "lower alkylene" as used herein refers to a straight or branched chain alkylene group having 1 to 6 carbon atoms, such as methylene, ethylene, trimethylene, S methylmethylene, ethylmethylene, 2-methyltrimethylene, '20 2,2-dimethyltrimethylene, 1-methyltrimethylene, tetramethylene, pentamethylene, hexamethylene and the like.
The term "lower alkyl" as used herein refers to a straight or branched chain alkyl group having 1 to 6 carbon atoms,. such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl and the like.
6- The term "lower alkoxy" as used herein refers to a straight or branched chain alkoxy group having 1 to 6 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, pentyloxy, hexyloxy and the like.
The term "halogen atom" as used herein refers to fluorine, chlorine, bromine and iodine.
The term "lower alkyl group which may have 1 to 3 halogen atoms" as used herein refers to, in addition to o o 0 the above-mentioned alkyl group having 1 to 6 carbon 10 atoms, a straight or branched chain alkyl group having 1 to 6 carbon atoms which may have 1 to 3 halogen atoms, such Sas iodomethyl, trifluoromethyl, 2,2-difluoroethyl, 1,1- S. dichloroethyl, dichloromethyl, trichloromethyl, tribromomethyl, 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl, 2fluoroethyl, 2-chloroethyl, 1-fluoroethyl, 1,2-dichloroethyl, 3,3,3-trichloropropyl, 3-fluoropropyl, 4-chlorot ft butyl, 3-chloro-2-methylethyl and the like.
The term "lower alkoxy group which may have 1 to 3 Dd'.o halogen atoms" as used herein refers to, in addition to o 20 the above-mentioned alkoxy group having 1 to 6 carbon atoms, a straight or branched chain alkoxy group having 1 to 6 carbon atoms which may have 1 to 3 halogen atoms, such as iodomethoxy, trifluoromethoxy, 2,2-difluoroethoxy, 1,1-dichloroethoxy, trichloromethoxy, dichloromethoxy, tribromomethoxy, 2,2,2-trifluoroethoxy, 2,2,2-trichloro- -7ethoxy, 2-fluoroethoxy, 2-chloroethoxy, 1-fluoroethoxy, 1, 2-dichloroethoxy, 3, 34 -trichloropropoxy, 3-f luoropropoxy, 4-chlorobutoxy, 3-chloro-2-rnethylethoxv and the like.
The term "lower alkanoyl" as used herein refers to a straight or branched chain alkanoyl group having I. to 6 carbon atoms such as formyl, acetyl, propi.onyl, butyryl, isobutyryl, pentanoyl, hexanoyl and the like.
The term "lower alkoxycarbonyl" as used herein refers to a straight or branched chain alkoxycarbonyl group V 0 A 2having 1 to 6 carbon atomc, such as methoxycarbonyl, ethoxyoarbonyll propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl and the like.
The term "cycloalky" as p,.sed herein refers to a cylkylgroup having 3 to 8 carbon atoms such as cyclopropy,, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like.
tot. The term t"cvcloalkylcarbonvyl" as used herein refers to a cycloalkylcarbonyl group having 3 to 8 carbon atoms such as cyclopropylcarbonyl, cyclobutylcarbonyl, cycloportylcarbonylo cyclohexylcarbony-", cycloheptylcarbonyl, cyclooctylcarbonyl and the lik~e.
The termi "amino-lowor a2lkyl. group which ,aay have a lower alkyl group" as used herein refers to a straight or -8 branched chain alk~yl group having 1 to 6 carbon atoms substituted with an amino group which may have 1 to 2 straight or branched chain aklyl groups having 1 to 6 carbon atoms, such as aminomethyl, 2-arinoethyl, 1-aminoethyl, 3-arinopropyl, 4-aininobutyl, 1, 1-direthyl- 2-aminoethyl, 5-aminopentyl, 6-aninohexyl, 2-methyl- 3- aminopropyl, methylaminomethy., 2-ethylaminoethyl, 1-propylaminoethyl, 3- (n-butylamino) propyl, 4-pentylaminobutyl, 0. 1 4. 1, 1-dimethyl-2-pentylarninoethyl, 5-hexylaminopentyl, 2diinethylaxninoethyl, 6-diethylaninoh~xyl, 2-rnethyl-3- *Votdiethylaminopropyl, dipropylaminonethyl, 2-dipentylam~noethyl, 1-dihexylaninoethyl, 3- (N-n ethyl-N-propyl amino) propyl, 4- (N-methyl-N-tertiary-butylanino) buty2,, 2- (Nethyl-N-pentyl amino) ethyl and the like.
The term "lower alkenyl" as used herein refers to a straight or branched chain aJlkeny3I group having 2 to 6 carbon atcrns such as vinyl, a2llyl, 2-butenylt 3-butenyl, 1-methylallylt 2-pentenyl, 2-hexeny! and the like.
J~ The term "lower alkynyl" as used herein refers to a straight or branched chain aJlkynyJ. group having 2 to 6 carbon atoms such as ethynyl, 2-propyny]l, 2-butynyl, 3butynyl, 1-methyl-2-propynyl, 2-pentynylt 2-hexynyl and the like.
The term "lower alkynyl group which may aav tt 2$ lower alkylsilyl group" as used herein refers to, in addition to the above-mentioned lower alkynyl group having 2 to 6 carbon atoms, a straight or branched chain alkynyl group having 2 to 6 carbon atoms which may have a tri- (straight or branched chain alkyl)silyl group whose alkyl moieties have 1 to 5 carbon atomse such as trimethylsilylethynyl, 3-trimiathylsilyl--2-propynyl, 4-triethylsilyl-3butynyl, 4--tripropylsilyl-3-butynyl, 3-tributylsilyl-1methyl-2-propynyl, 5-tripentylsilyl-4--pentynyl, 6trihexylsilyL- 5-hexyny', 3-diethylmethylsilyl-2-propynyL, 3-dimethylpropylsilyil-2-propynyl and the like.
The term "amino group which may have a lower alkyl group" as used herein 2:efers to an amino group which may have 1 to, 2 of straight or branched chain alkyl groups having I. to.6 carbon atoms, such as amino, methylamino,, 1 0715 ethylainino, propylamino, n-butylamino, pentylamino, 11exylamino, dimethylamino, diethylamino, dipropylamino, dipentyiLaminQ, dihexylamino, N-methyl-N-propylamino, N-xnethyl-N-teritary-butylaninot N-ethyl--N-pentylamino and 4 4 the like.
20 The term "phenyl-lower alkyl"' as used herein refers to a phenylalkyl gioup with a straight or branched chain alkyl group having 1 to 6 carbon atoms in the alkyl moiety such as benzyl, 2-phenylethyl, 1-phenylethyl, 3-.phenylpropylt 4-phenylbutyl, 1, l-dimethyl-2-phenylethyl, 5-phenylpentyl, 6-phenylhexyl, 2-niethyl-3-phenylpropyl and 10 the like.
Therefore, the term "phenyl-lower alkyl group which may have 1 to 3 groups selected from the group consisting of a halogen atom and an amino group which may have a lower alkyl group as a substituent on the phenyl ring thereof" as used herein ref,"-rs to, in addition to the above-mentioned pheriyl-lower alkyl group, a phenylalkyl group which have a straight or branched chain alkyl group having 1 to 6 carbon atoms, and which may have 1 to 3 groups selected from the groups consisting of a halogen atom and an amino group which may have 1 to 2 of a t straight or branched chain alkyl group having 1 to 6 carbon atoms as substituents on the phenyl ring thereof, such as 4-chlorobenzyl, 3-fluorobenzyl, 2-bromobenzyl, Q,*A54-iodobenzyl, 2- (2--fluorophenyl) ethyl, 1-(3-bromophenyl)- 4 0* ethyl, 3-(4-chlorophenyl)propyl, 4-(2,3-dichlorophenyl)butyl, 5-(2,3,4-trichlorophenyl)penthyl, 6-13,4dibromophenyl) hexyl, 4-aminobenzyl, 3-methylaminobenzyl, 2-ethylaminobenzyl, 2- (2-propylaminophenyl) ethyl, 3- (3bVttylr3minophenyl)propyl, 4-(4-pentylaminophenyJ~butyl, (24-hexylaminoJphenyl) pentyl, 6- (4-dimethylaminophenyl) hexyl, 4-dimethylaminobenzyl, 3-diethylaminobenzyl, 2-dipropylaminobenzyl, 2- (N-methyl-N--butylamino)phenyl] ethyl,, 1- 3- (N-ethyl1-N--pentyl amino) phenyl I ethyl, 3 2- (N-methyl-N--hexyl amino) phenyl11propyl, 2-f luoro-4- 1 11 Itaf 4 91 99 9 *9*1 9 4*9* 9* 44 4 *4~ 4*4* 4 444 4* 44 9 4*~ dimethylaminobenzyl, 2 ,4-diaminobenzyl, 2 ,4 ,6-triaminobenzyl and the like.
The term "cycloalkyl-lower alkyl" as used herein refers to a cycloalkylalkyl group which have 3 to 8 carbon atoms in the cycloalkyl moiety and a straight or branched chain alkyl group having 1 to 6 carbon atoms in the alkyl m oiety, such as cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, cyclooctylmethyl, 2-cyclopropylethyl, 1-cyclobutylethyl, 10 3-cyclopentylpropyl, 4-cyclohexylbutyl, pentyl, 6-cyclooctyihexyl, 1 ,1-dimethl1-2-cyclohex,,ylethyl, 1-cyc:lohexylethyl, 2-cyclopropylethyl, 3-cyclohexyipropyl and the like.
The term "lower alkenyloxy" as used herein refers to a straight or branched chain alkenyloxy group having 2 to 6 carbon atoms such as vinyloxy, al .yJloxy, 2-butenyloxy, 3-Ybutenyloxy, trimethylallyloxy, 2-pentenyloxy, 2-hexenyloxy and the like.
The term "lower alkylenedioxy" as used herein refers to an alkylenedioxy group having I. to 4 carbon atoms such as methylenedioxy, ethylenedioxy, trimethylenedioxy, tetramethylenedioxy and the like.
The term "lower alkylirnino"l ks used herein refers to a straight or branched chain alkylimino group having 1 to 6 carbon atoms such as methyliniino, ethylimino, propylw4 go 404 44,44 4*
~PA
~4A~ 11 imino, isopropylimino, butylimino, isobutylimino, pentylimino, hexylimino and the like.
The term "lower alkylidene" as 7.sed herein ref,-:s to a straight or branched chain alkylidene group havi,,g 1 to 6 carbon atoms such as methylene, ethylidene, propylidene, isopropylidene, butylidene, isobutylidene, pentylidene, hexylidene and the like.
The term "hydroxy-coubstituted lower alkyl" as used herein refers to a hydr oxy- substituted alkyl group having 4:10 a straight or branched chain alkyl group of 1 to 6 carbon atoms in the alkyl moiety such as hydroxymethyl, 2hydroxyethyl, 1 -hydroxcyethyl, 3-hydroxypropyl, 4-hydroxy- 0 P butyl, 1, 1-dimethyl-2-hbydroxyethyl, 6-hydroxyhexyl, 2-methyl1-3-hydroxypropyl and the like.
term "lower alka~noyloxy lower alkyl"' as used 4 hereiri refers to an, alkanoyloxyalkyl group which have a straight or branched chain, alkanoyloxy group having 1 to 6 cairbon atoms in the alkanoyloxy moiety and a straiqht or branched chain alkyl group having 1 to 6 carbon atoms in the alkyl moiety such as fo: nyloxymethyl, acetyloxcymethyl, 1-acetyloxyethyl, 2-acetyloxyethyl, 3-prcipionyloxypropyl, 4-butyryloxybutyl, 5-pentanoyloxypentyl, 6-hexanoyloxyhexyl, 1, 1-dixethyl-2-acetyloxyethyl, 2-methyl-3--acetyloxypropyl and the like.
The term "lower alkoxy-lower alkoxy" as used herein -13refers to an alkoxyalkoxy group which have a straight or branched chain a2koxy group having 1 to 6 carbon atoms in the alkoxy moieties such as methoxymethoxy, 2-methoxyethoxy, 1-ethoxyethoxy, 3-propoxypropoxy, 4-butoxybutoxy, 5-pentyloxypentyloxy, 6-hexyloxyhexyloxy, 1,1-dimethyl-2methoxyethoxy, 2-methyl-3-methoxypropoxy and the like.
The term "lower alkyl group which may have 1 to 3 groups selected from the group consisting of a halogen atom and a lower alkoxy group" as used herein refers to, in addition to the above-mentioned lower alkyl group which sho may have 1 to 3 halogen atoms, a straight or branched chain alkyl group having 1to 6 carbon atoms which may have 1 to 3 groups selected from the group consisting of a halogen atom and a straight or branched chain alkoxy group 15 having 1 to 6 carbon atoms, such as methoxymethyl, 2-methoxyethyl, 1-ethoxyethyl, 3-propoxypropyl, 4-buthoxybuthyl, 5-pentyloxypentyl, 6-hexyloxyhexyl, 1,1-dimethyl- 2-methoxyethyl, 2-methyl-3-methoxypropyl, 2,2,2-trifluoro- I-ethoxyethyl, 2,2-dichloro-l-methoxy-ethyl and the like.
The term "lower alkanoyl group which may have 1 to 3 halogen atoms" as used herein refers to, in addition to the above-mentioned lower alkanoyl group, a straight or branched chain alkanoyl group having 1 to 6 carbon atoms which may have 1 to 3 halogen atom, such as 2-iodoacetyl, 2,2,2-trifluoroacetyl, 2,2-dichloroacetyl, 2,2,2-trichloro- 14 acetyl, 2,2,2-tribromoacetyl, 2-fluoropropionyl, 3-fluoropropionyl, 3-chloropropionyl, 2,2-dichloropropionyl, 2,3-dichloropropionyl, 3,3-difluoropropionyl, 3,3,3-trifluoropropionyl, 3,3,3-trichloropropionyl, 2,2,3-trichlorobutyryl, 2-fluorobutyryl, 5-chloropentanoyl, 6-chlorohexanoyl and the like.
The term "phenyl-lower alkyl group which may have a lower alkoxy group as a substituent on the phenyl ring Sthereof" as used herein refers to, in addition to the 10 above-mentioned phenyl-lower alkyl group, a phenylalkyl group which have a straight or branched chain alkyl group having 1 to 6 carbon atoms in the alkyl moiety, and which .4 may have 1 to 3 of a straight or branched chain alkoxy group having 1 to 6 carbon atoms as substituents on the phenyl ring thereofsuch as 3-methoxybenzyl, 2-ethoxybenzyl, 2-(2-propoxyphenyl)ethyl, 3-(3-butoxyphenyl) propyl, 4-(4-pentyloxyphenyl)butyl, 5-(2-hexyloxyphenyl)pentyl, 6-(2,6-dimethoxyphenyl)hexyl, 2,3-dimethoxybenzyl, 3,4-dimethoxybenzyl, 2-(3,4-dimethoxyphenyl)ethyl, 3,4,5trimethoxybenzyl and the like.
The term "saturated 5--or 6-membered heterocyclic group formed by R and R 5 together with the binding nitrogen atom, and optionally containing hetero atom(s) consisting of an oxygen atom, a sulfur atom and a nitrogen atom" as used herein refers to pyrrolidinyl, 15 piperazinyl, piperidino, morpholino, thiomorpholino and the like.
In the formula group R can also substitute at the 1-position of the benzimidazole ring and, when it substitutes at the 1-position thereof, the hydrogen atom is not at the 1-position.
The compounds of this invention can be produced by various procedures such as, for example, those shown in the following reaction schemes: [Reaction Scheme-i]
(R
3 )n IN (3) (Rl)m 3 i 15 N 2- A R 2 15 _X1 X 31X ,0 H
./R
3 )n
N
(la) R 1 2 R3 wherein, R R R A, m, n and the bond between the 3- and 4-positions of the quinoline skeleton have the same meanings as defined above, and X 1 and X 2 are respectively a 16 0 *go mercapto group, a halogen atom, a lower alkanesulfonyloxy group, an arylsulfonyloxy group or an aralkylsulfonyloxy group, provided that when X 1is a mercapto group, X 2is a halogen atom, a lower alkanesulfonyloxy group, an arylsulfonyloxy group or an aralkylsulfonyloxy group and, when X 2is a mercapto group, X Iis a halogen atom, a lower alkanesulfonyloxy group, an arylsulfonyloxy group or an aralkylsulfonyloxy group.
In the formblas and the halogen atom represented by X n/rX2has the same meaning as defined above; examples of the lower alkanesulfonyloxy group include methanesulfonyloxy, ethanesulfonyloxy, isopropanesulfonyloxy, propane'sulfonyloxy, butanesulfonyloxy, tert-but~nesulfonyloxy, pentanesulfonyloxy, hexanesulfonyloxy and the like; examples of the arylsulfonyloxy group include a substituted or unsubstituted arylsulfonyloxy group such as phenylsulfonyloxy, 4-methyiphenylsulfonyloxy, 2-methylphenylsulfonyloxy, 4-nitrophenylsulfonyloxy, 4-nethoxyphenylsulfonyloxy, 3-chlorophenylsulfonyloxy, a-naphthylsulfonyloxy and the Like, and examples of the aralkylgtlfonyloxy gr'oup includIe a substituted or unsubstito-ted aralkylsullonyloxy group such as benzylsulfonyloxy, 2-phenylethylsulfonyloxy, 4-phenylbutyJlsulfonyloxy, 4-methy2.benzylsulfornyloxy, 2-methylbenzylsulfonyloxy, 4-nitrobenzylsuifonyloxy, 4-inethoxy-
I
4 goUU OV 00 0004
A
CC~C~
I
i ii 17 o 0 a boo a8 0040 ('000 0900 00 00 0 04 0000P 0 81 000 04o 40 0 00 benzylsulfonyloxy, 3-chlorobenzylsulfonyloxy, a-naphthylmethylsulfonyloxy and the like.
The reaction between the compound of the formula (2) and the compound of the formula can be carried out in a suitable solvent in the presence of a basic compound.
Any solvent which does not adversely influence the reaction can be used. Examples of the solvent include water; alcohols such as methanol, ethanol, isopropanol, etc.; aromatic hydrocarbons such as benzene, toluene, xylene, 10 etc.; ethers such as diethyl ether, tetrahydrofuran, dioxane, monoglyme, diglyme, etc.; ketones such as acetone, etc.; esters such as methyl acetate, ethyl acetate, etc.; aprotic polar solvents such as N,N-dimethyl firmamide (DM) dimethylsulfoxide (DMSO), hexamethyl phos- 15 phoric triamide (HMPA), etc.; or a mixed solvent thereof.
Examples of the basic compound which can be used include inorganic bases such as sodium hydride, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogencarbonate, potassium hydrogen- 20 carbonate, silver carbonate, etcz.; alkali metals such as sodium, potassium, etc.; alcoholates such as sodium methylate, sodium ethylate, etc.; and organic, bases such as triethylamine, pyridine, N,N-dimethylaminopyridine, N-methylmorpholine, 1,5-diazabicyclo[4.3.0]nonene-5
(DBN),
1,8-diazabicyclo[5.4.01undecen-7(DBU) 1,4-diazabicyclo- 0 04 4 ea o* t
I
-YE,
18 octane (DABC), etc. The reaction proceeds advantageously with the addition of a crown ether such as 18-crown-6(i.e. ,4,7,10,13,16-hexaoxacyclooctadecane)I 15-cro-vn-5 e. 1, 4,7, 10, 13-pentaoxacyclopentadecane), 12-crown-4(i.e. 1,4,7,le-tetraoxacyclododecane) and so on.
0000 0 00 00 0 0~00 10 Op o 0 0 0110 01100 0 0 0000 00 o 1.
0 0110 00 0 Q p 000 0 ~0 p pp pp pp 1. 'I 0 0 0 OaA
II
00 ~l 0# 4, The reaction is carried out usually at 0 0 C to 1501C, preferably at about 0 0 C to 100 0 C, and completed in about 1 to 24 hours. In the above reaction, the suitable amount of the compound of the formula to be used is usually at least eguimolar amount, preferably equimolar to 2 mols, of the compound of the formula per mol of the compound of the formula 7! i 19 [Reaction Scheme-2] W3 n N
N
Z A R 2
A
H (la) (R3l)n
I
H 0 t t H 0 (Ib) 0 e a oo1 weren 1
R
2 3 wherein R R R A, m, n and the bond between the 3- and 4-positions of the quinoline skeleton have the same meanings as defined above.
The oxidation reaction of the compound of the formula 9 °o can be carried out in a suitable solvent in the 04 90 presence of an oxidizing agent. As for the solvent, any 'solvent which does not adversely influence the reaction i can be used. Examples Of the solvent include water; organic acids such as formic acid, acetic acid, trifluoroacetic acid, etc.; alcohols such as methanol, ethanol, isopropanol, etc.; and halogenated hydrocarbons such as 20 chloroform, dichloromethane, dichloroethane and so on.
Any oxidizing agent that usually oxidize a sulfide group to a sulfoxide group can be used. Examples of the oxidizing agent include peroxy acids such as performic acid, peracetic acid, triluo'operacetic acid, perbenzoic acid, m-chloroperbenzoic acid, o-carboxyperbenzoic acid, etc.; hydrogen peroxide; chromates such as chromic acid, sodium chromate, potassium chromate, etc.; permanganates such as 0 permanganic acid, sodium permanganate, potassium permanga- S 10 nate, etc.; iodates such as metasodium periodate, etc.; o and selenic compounds such as selenium dioxide, etc. The S suitable amount of the oxidizing agent to be used is at least equimolar amount, preferably equimolar to 1.5 mols, I of the oxidizing agent per mol of the compound of the .i formula The reaction is carried out usually at i 0 -70°C to 40 0 C, preferably at about -70 0 C to room temperature, and completed in about 5 minutes to 3 hours.
S LiL I i
I
i i -r UY C 21 [Reaction Scheme-31
S
(R )m (1 R (R)m N(i) H 2
NCNH
2 (4) X3a H (R)n (3a) (2a) 3 bq A 2 S- A R 2
H
a( a) wbeeSin RI, fl, R A, n and the bond between the 3- and S00 -45 4-position of the quinoline skeleton have the same mean- S40 ings as defined above, and X 3 a and X3b ,the same or 0 Oa different, represent a halogen atOm respectively.
The halgen atom represented by Xa nd X3b has the absence of a solvent. EXampN es of the solvent which can be used include alcohols such as methano ethanoi, propanl, etstc; others such as diethyl ethae, tetrahydrofuran, dioXnae, ethyleneglycol monogethyl eot, eetc.; aomatic L^ 22hydrocarbons such as benzene, toluene, xylene, etc.; ketones such as acetone, methylethylketone, etc.; and DMF, DMSO, HMPA, etc. I. the above reaction, the suitable amount of thiourea to be used is usually at least 1 mol amount, preferably 1 to 2 mols, of thiourea per mol of the compound of the formula The reaction usually is carried out at room temperature to 200 0
C,
preferably room temperature to about 150 0 C, and completed in about 1 to 5 hours.
S
1 0 The reaction between the intermediate obtained in the above-mentioned reaction and the compound of the formula (3a) can be carried out usually in the presence of a condensing agent. In the above reaction, a basic compound Susually is used as the condensing agent. Various known o 15 basic compounds can be used. Examples of the basic <o compound include inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hyrdogencarbonate, potassium hydrogen- "t carbonate, silver carbonate and the like; alkali metals such as sodium, potassium and the like; alcoholates such as sodium methylate, sodium ethylate and the like; and organic bases such as triethylamine, pyridine, N,Ndimethylaniline, N-methylmorpholine, 4 -dimethylaminopyridine, DBN, DBU, DABCO and the like. The reaction can be carried out in the absence or presence of a solvent. Any S- 23inert solvent which does not adversely influence the reaction can be used. Examples of the solvent include water; alcohols such as methanol, ethanol, propanol, butanol, ethyleneglycol, etc.; ethers such as diethyl ether, tetrahydrofuran, dioxane, monoglyme, diglyme, etc.; ketones such as acetone, methylethylketone, etc.; aromatic hydrocarbons such as benzene, toluene, xylene, etc.; esters such as methyl acetate, ethyl acetate, etc.; aprotic polar solvents such as DMF, DMSO, HMPA, etc.; or a to** 10 mixed solvent thereof. The reaction is carried out OfO« advantageously in the p esence of a metal iodide such as Sso&ium iodide, potassium iodide and the like, The ratio of the compound of the formula (3a) to the compound of the o* formula (2a) in the above-mentir-ied process is not limited 15 particularly but can be varied widely. The suitable amount of the compound of the formula (3a) is usually 0 0.5 to 5 mols, preferably 0.5 to 2 mols, of the compound of the formula (3a) per mol of the compound *b of the formula The reaction temperature 2 0 also is not limited particularly, but is usually 0 C to about 200 0 C, preferably OC to 160 0 C. The reaction is completed usually in about 1 to 30 hours.
IL
WV
F
2 24 [Reaction Scheme-4]
(R
1 )m NH+ NH 2 (Rm HOOC-S-A
R
2 (6) p t i0 (R)n (Rl)m R I N..S A R2 (lc) i R1 2 3 wherein R R R A, m, n and the bond between the 3- and 4-positions of the quinoline skeleton have the same meanings as defined above.
The reaction between the compound of the formula and the compound of the formula can be carried out in the presence of a suitable acid in the absence or presence of a suitable solvent.
Examples of the solvent which can be used include the solvents used in the reaction between the compound of the formula (3a) and the compound formed in the reaction be-
I
S- 25 tween the compound of the formula (2a) and the compound of the formula in the above-mentioned Reaction Scheme-3.
Examples of the acid which can be used include mineral acids such as hydrochloric acid, sulfuric acid, hydrc .romic acid and the like; and organic acids such as benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid and the like.
The suitable amount of the compound of the formula (6) to be used is usually at least equimolar, preferably equimolar to 1.5 mols, of the compound of the formu3a (6) per mol of the compound of the formula The reaction usually is carried out at room temperature to 150 0
C,
preferably about 50 0 C to 120 0 C, and completed in about minutes to 5 hours.
[Reaction 3
(R
1 )m (R n 6 v S-R H R O R (A)q R2 (7) (8 3 In (R )m S- CH2~ R 2 H O (Id) 26wherein R, R, R m, n and the bond between the 3- and 4positions of the quinoline skeleton have the same meanings as defined above, A' is a lower alkylene group and q is an 6 7 integer of 0 or 1, R and R represent a halogen atom or a group: -CH 2 -M (wherein, M is an alkali metal), provided that when R 6 is a group: -CH 2
R
7 is a halogen atom, and when R is a halogen atom, R 7 is a group: -CH 2 and the group does not exceed 6 in carbon number.
OC The alkali metals represented by M in the abovementioned scheme, for example, are sodium, potassium, lithium, etc.
tThe compound of this invention represented by the formula (Id) can be obtained by allowing the compound of I the formula to react with the compound of the formula in a suitable solvent.
Examples of the solvent which can be used include aromatic hydrocarbons such' as benzene, toluene, xylene and the like; ethers such as diethyl ether, tetrahydrofuran, dioxane, monoglyme, diglyme and the like; or a mixed solvent thereof.
The suitable amount of the compound of the formula to be used is usually at least equimolar, preferably equimolar to 1.5 mols, of the compound of the formula (8) per mol of the compound of the formula The reaction is carried out usually at room temperature to 150°C, f 27 preferably room temperature to about 120 0 C, and completed in about 1 to 5 hours.
[Reaction Scheme-6] n
N
r-S- A H H (0)
R
2
X
3 9 O° R3)n S(R!)m P1 N r rN^ A R2 i oH (0)k; 0 f) e R 1 3 0 wherein R R A, m, n and the bond between the 3- and 4- 0 positions of the quinoline skeleton have the same meanings 2' 2 as dafined above, R represents R excluding hydrogen atom, and X 3 represents a halogen atom.
The reaction between the compound of the formula (le) and the compound of the formula can be carried out in the presence of a basic compound in a suitable 4i~,.
2 28 solvent. Examples of the basic compound which can be used include sodium hydride, potassium hydride, sodium, potassium, sodium amide, potassium amide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, alkyl lithiums such as n-butyllithium, etc.; DBN, DBU, DABCO, etc. Examples of the solvent which can be used include ethers such as diethyl ether, tetraeg9 hydrofuran, dioxane, ethyleneglycol monomethyl ether, "o 10 diethyleneglycol dimethyl ether, etc.; aromatic hydrocarbons such as benzene, toluene, xylene, chlorobenzene, etc.; DMF, DMSO, HMPA, aqueous ammonia, etc. or a mixed solvent thereof.
o 0 0 0o *u 4 00 4 The amount of the compound of the formula is not limited particularly, and usually is at least equimolar, preferably equimolar to 2 mols, of the compound of the formula per mol of the compound of the formula (le).
The reaction is carried out usually at -40 0 C to about 150 0 C, preferably at -40°C to about 1000C, and generally completed in 30 minutes to about 24 hours. In this reaction, the compound of the formula sometimes reacts with the alkylene group at the a-position from the group or with the imidazole ring at 1- or 3-position. These compounds, however, can be easily separated.
29 [Reaction Scheme-7] (R 3a)n (R )m N A R 2 H (0)1 g) 1 Reduction 0 10 (R 3 b)n
*(R
1 )m N a1 t fS A R 2 H (0) (lh) S00 1 2 wherein R R 2 k, m, n, A and the bond between the 3- and a 0 4-positions of the quinoline skeleton have the same meanings as defined above, R 3a is an oxo group and R 3 is a hydroxy group.
The compound of the formula (1h) can be obtained by subjecting the compound of the formula (Ig) to a reduction reaction. The reduction reaction of the compound of the formula (ig) is carried out in a suitable solvent in the presence of a hydride reducing agent. Example of the reducing agent which can be used include sodium I P ii -Icll-- i C 30 borohydride, lithium aluminum hydride, diborane, etc. In the above reaction, the suitable amount of the reducing agent to be used is at least equimolar, preferably equimolar to 10 mQls, of the reducing agent per mol of the compound of the formula Examples of the solvent which can be used include water, lower alcohols such as methanol, ethanol, isopropanol, etc.; and ethers such as tetrahydrofuran, diethyl ether, diglyme, etc. The reaction is carried out usually at -60 0 C to 50 0 C, preferably 1 0 to about room temperature and completed in about °Oe minutes to 5 hours. An anhydrous solvent of diethyl ether, tetrahydrofuran, diglyme and the like is used desirably when lithium aluminum hydride or diborane is used as the reducing agent.
1 P "5 [Reaction Scheme-8] R3 a S1i) (R 1 )m3b 8 H (0)s 5 1i) I 8 R Ma(O)
R
N
0 (ij) 31 1 2 3 a 3b wherein R, R, R a R, m, A and the bond between the 3and 4-positions of the quinoline skeleton have the same 8 meanings as defined above, R 8 is a lower alkyl group, and Ma is lithium or MgX 3 where X represents a halogen atom.
(R
3 b 1
R
8 means that R3b and R 8 are attached to the same position of the quinoline skeleton as follows:
R
3 b 8 R R *10O 4 The compound of the formula (lj) can be prepared by allowing the compound of the formula (li) to react with the compound of the formula (10) in a suitable solvent.
.0 The reaction is carried out usually at -60°C to preferably at about -30°C to room temperatue, and completed in about 10 minutes to 5 hours.
In the above reaction, the suitable amount of the compound of the formula (10) which is used is at least 444 ,o equimolar, preferably equimolar to 3 mols, of the compound of the formula (10) per mol of the compound of the formula (li).
Examples of the solvent which can be used include ethers such as tetrahydrofuran, diethyl ether, diglyme and the like.
The compound of the formula (li) ,where the carbonyl 1 32 group is converted to a lower alkylenedioxy group ,can be prepared by allowing the carbonyl group of the quinoline skeleton to react with a lower alkyleneglycol such as ethyleneglycol, trimethyleneglycol, etc. in the presence of a mineral acid such as hydrochloric acid, sulfuric acid, hydrobromic acid, etc., an organic acid such as p-toluenesulfonic acid and in a suitable solvent.
Examples of the solvent which can be used include Q ethers such as diethyl ether, dioxane, tetrahydrofuran, monoglyme, diglyme and the like; alcohols such as methanol, ethanol, isopropanol and the like; aromatic hydrocarbons such as benzene, toluene, xylene and the like; aliphatic hydrocarbons such as n-hexane, heptane, I cyclohexane, ligroin and the like; amines such as pyridine, .O.15 N,N-dimethylaniline and the like; halogenated hydrocarbons such as chloroform, dichloromethane, carbon tetrachloride and the like; aprotic polar solvents such as DMF, DMSO, HMPA and the like; or a mixed solvent thereof. The 'o 0 reaction is carried out usually at room temperature to S 20 170 0 C, preferably at room temperature to about 150°C, and Scompleted in about 1 to 7 hours.
The lower alkylenedioxy group-substituted compound obtained in the above reaction can be led to the carbonyl group-substituted compound by subjecting the former to a hydrolysis reaction. The hydrolysis reaction is carried I i :ii i II 1 u 33
E
(1 1
I
i out usually at room temperature to 150 0 C, preferably at room temperature to 100 0 C, and completed in about 1 to 24 hours, in the presence of a mineral acid such as hydrogen halides hydrochloric acid, hydrobromic acid, etc.), sulfuric acid, phosphoric acid and the like, and in water or in a mixed solvent of water and lower alcohols such as methanol, ethanol, propanol and the like.
I t to
II
I I I I 2 [Reaction Scheme-91 K-S A R' H 1(R)
((R
1 44R 4 R'or 21).
HO~AR m .44 L O 1 0 4# 4 CO(R )m 0 R4 R (1) 3Cn A R 2 (0s) NA 0 0 C
NHF
9 )n
R
NN
H (O)j (1 o)
RIOX
3 c 1R 1
"OH
(17 (14) 1 N 14 )n 9 Mr N R I N'R 10)nr yN s (N
\RO-
R'2 y 7- H Wn S-A R (lv) H :(Oj
:CHO
(I P) 1 -Reduction (ip) H 12
CHO
13)=0 (16) (12) -1 R9 R9 (RI)m N 12 N -A R IH N
R
Rz (lx) H (O)i 'lw) c f~ *2
I
36 (R3a)n (R)m N ~N>S-A R2 H to)) (I g) ,O 44, 4,q 4,4 4 O4,44 qa 44,1 4, 4,4 (R 'N Nl i p e o -S -A R 2 (OXl (1 q)
/OH
\R
1 1 4 4,4 :(Rl 4041 1 'I 4, -A ',4N 4 H (0)1 (in) 4r 0 I Hydrolysis 24 (1 Z) Wherein 1, R R 3a, m, n, A and the bond between the 3and 4-positions of the quinoline skelton have the saile meanings as defined above, X 3 represents a hydroxy group
I
I
37 i:' i t
I
:r i ii I I j :.i j 4 or a halogen atom, and R and R 5 represent, the same or different, a hydrogen atom, a lower alkyl group which may have 1 to 3 groups selected from the group consisting of a halogen atom and a lower alkoxy group, a hydroxysubstitute lower alkyl group, a cycloalkyl group, a cycloalkyl lower alkyl group, a 1l"'er alkenyl group or a phenyl-lower alkyl group which may have a lower alkoxy t group, and R and R 5 together with the bonding nitrogen atom may form a saturated 5- or 6-membered heterocyclic 10 group which may conatin hetero atom(s) consisting of an oxygen atom, a sulfur atom and a nitrogen atom R 9 and R 10 represent a lower alkyl group which may have 1 to 3 groups selected from the group consisting of a halogen atom and a i lower alkox' group, a hydroxy-substituted lower alkyl group, a cycloalkyl group, a cycloalkyl lower alkyl group, a lower alkenyl group or a phenyl lower alkyl group which may have a lower alkoxy group, R12 and R 13 represent a t hydrogen atomn or a lower alkyl group, R 14 represents a cycloalkylcarbonyl group or a lower aIka'noyl group, R 1 20 represents a lower alkanoyl.group, R 3c represents a hydroxyimino group, R 3d represents the group:
SNR
R5 NR4 Wherein R 4 and R 5 have the same meanings as defined above, while R 4 a represents a lower alkyl group which
M
51 -38may have 1 to 3 groups selected from the group consisting of a halogen atom and a lower alkoxy group, a hydroxy-substituted lower alkyl group, a cycloalkyl group, a cycloalkyl lower alkyl group, a lower a kenyl group or a phenyl-lower alkyl group which may have a lower alkoxy group, and 3e 11 11 R represents the group: -R wherein R is a lower alkyl group.
The reaction between the compound of the formula (Ig) and the compound of the formula (11) can be carried out in a suitable inert solvent and in the presence or absence of a basic compound. Examples cf the basic compound which a "o can be used in the reaction include inorganic basic Scompounds such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, etc.; lower alkanoic acid alkali metal salts such as sodium acetate, etc.; and organic bases such as piperidine, pyridine, triethylamine, DBN, DBU, DABCO, etc. Any inert solvent 4 6 which does not adversely influence the reaction can be 20 Used, for example, water, lower alcohols such as methanol, ethanol, isopropanol, etc.; ethers such as dioxane, tetrahydrofuran, diethyl ether ethyleneglycol monomethyl ether, etc.; aromatic hydrocarbons such as benzene, toluene, xylene, etc.; halogenated hydrocarbons such as dichloromethane, dichloroethane chloroform, carbon -a 1 39 tetrachloride, etc.; aprotic polar solvents such as DMF, DMSO, HMPA, etc.; or a mixed solvent thereof. The suitable amount of hydroxylamine (11) is usually at least equimolar, preferably equimolar to 5 mols, of hydroxylamine (11) per mol of the compound of the formula (ig), The reaction temperature usually is desirable to be room temperature to 200°C, preferably 50 0 C to 150°C, and the reaction is generally completed in about 1 to 10 hours.
The method using a hydride reducing agent can be applied to the reduction of the compound of the formula praferably, the reduction can be carried out by subjecting to a catalytic hydrogenation in a suitable oo So 0solvent in the presence of a catalyst. Examples of the solvent which can be used include water; acetic acid; I l5 alcohols such as methanol, ethanol, isopropanol, etc.; hydrocarbons such as hexane, cyclohexane, etc.; ethers such as diethyleneglycol dimethyl ether, dioxane, tetrahydrofuran, diethyl ether, etc.; esters such as ethyl acetate, methyl acetate, etc., aprotic polar solvents such as DMF, etc,; or a mixed solvent thereof. Examples of the S catalyst which can be used include palladium, palladium black, palladium carbon, platinum, platinum oxide, copper chromite, Raney nickel, etc. In the above reaction, the amount of the catalyst is generally 0.02 to 1 time of the catalyst per the amount of the compound of the formula -C 7 I~-rCII~ 40 The reaction temperature is usually about -20°C to 100 0 C, preferably about 0 C to 70 0 C and the hydrogen pressure is usually 1 to 10 atmospheric pressure. The reaction is completed generally in about 0.5 to 20 hours.
Examples of the hydride reducing agent used in the reaction include lithium aluminum hydride, sodium borohydride, diborane, etc. The amount of the reducing agent to be used is usually at least equimolar, preferably equimolar to 10 mols, of the reducing agent per mol of the compound of the formula The suitable solvent such as water, lower alcohols, e.g. methanol, ethanol, isopropanol, etc.; ethers, e.g. tetrahydrofuran, diethyl C"C" ether, diglyme, etc.; and acetic acid is usually used in so this reducing reaction, the reaction usually is carried out at about 0°C to 200OC, preferably 0 0 C to 170 0 C, and 00o1oo completed in about 10 minutes to 10 hours. An anhydrous solvent of diethyl ether, tetrahydrofuran, diglyme and the like is used desirably when lithium aluminum hydride or i *t diborane is used as the reducing agent.
20 The reaction between the compound of the formula (Ig) I and the compound of the formula (18) is carried out without solvents or in a suitable solvent in'the presence or absence of a dehydrating agent. Examples of the solvent which can be used include alcohols such as methanol, ethanol, isopropanol, etc.; aromatic L. 4 j 41 hydrocarbons such as benzene, toluene, xylene, etc.; and aprotic polar solvents such as DMF, dimethyl acetamide, N-methylpyrrolidone, etc. Examples of the dehydrating agent include drying agents such as molecular sieves and the like used for the dehydration of ordinary solvents; mineral acids such as hydrochloric acid, sulfuric acid, boron trifluoride and the like; and organic acids such as p-toluenesulfonic acid and the like. The reaction is carried out usually at room temperature to 250°C, preferably at about 50 0 C to 200 0 C, and generally completed in about 1 to 48 hours. The amount of the compound of the formula (18) to be used is not limited particularly but it Sis usually at least equimolar, preferably large excess, of I the compound of the formula (18) per mol of the compound of the formula The dehydrating agent is used in Slarge excess amount when the drying agent is employed, or i in catalytic amount when the acid is employed. The i compound of the formula (lm) thus obtained may be used, without isolation, in the next reduction reaction.
Various methods are applicable to the reduction reaction of the compound of the formula For example, the reduction method employing a hydride reducing agent is used suitably. Examples of the hydride reducing agent which can be'used include sodium aluminum hydride, sodium borohydride, diborane, etc. Usually, the amount of the S- "42 hydride reducing agent is at least equimolar, preferably equimolar to 10 mols, of the hydride reducin-, agent per mol of the compound of the formula The reduction reaction is conducted in a suitable solvent, for example, water, lower alcohols such as methanol, ethanol, isopropanol, etc.; and ethers such as tetrahydrofuran, diethyl ether, diglyme, etc., and carried out usually at about -60 0 C to 50 0 C, preferably at -30°C to room temperature and completed in about 10 minutes to 5 hours. When lithium aluminum hydride or diborane is used as the reducing agent, an anhydrous solvent of diethyl ether, tetrahydrofuran, diglyme and the like is used desirably.
The reaction that converts the compound of the formula (Ig) to the compound of the formula (Iq) is called
S.
1 5 Witting Reaction, and the compound of the formula (lq) canr o0 be obtained by allowing the compound of the formula (Ig) *to react with Witting reagents represented, for example, by the following formulas: S o
R
1 6 S" IR C 11 2 (R 1 90) 2
P-CH
2
R
11 R' X3- 16 17 18 19 wherein R R 7 R and R represent respectively a lower alkyl group or a phenyl group, and R 1 1 and X 3 have the same meanings as defined above.
r 43 The reaction is conducted in a solvent in the presence of a basic compound. Examples of the basic compound which can be used include inorganic bases such as sodium, potassium, sodium hydride, sodium amide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogencarbonate, etc.; metal alcoholates such as sodium methylate, sodium ethylate, etc.; lithium salts such as methyllithium, n-butyllithium, phenyllithium, etc.; and organic bases such as pyridine, piperidine, quinoline, triethylamine, N,N-dimethylaniline, etc. Any solvent which does not adversely influence the reaction can be used. Examples of the solvent include Sethers such as diethyl ether, dioxane, tetrahydrofuran, monoglyme, diglyme and the like; aromatic hydrocarbons such as benzene, toluene, xylene and the like; aliphatic o- hydrocarbons such as n-hexane, pentane, heptane, cyclohexane and the like; amines such as pyridine, N,Ndimethylaniline and the like; and aprotic polar solvents such as DMF, DMSO, HMPA and the like. The reaction is i "20 carried out usually at -30°C to 150°C, preferably at about -20 0 C to 120OC. The reaction generally is completed in about 0.5 to 15 hours. The suitable amount of Witting reagent is at least equimolar, preferably equimolar to mols, of the Witting reagent per mol of the compound of the formula (1g).
r LI 44 The reaction between the compound of the formula (1I) and the compound of the formula (13) or the reaction between the compound of the formula (lo) and the compound of the formula (17) is carried out in the presence or absence of a dehydrohalogenation agent in a suitable solvent. A basic compound usually is used as the dehydrohalogenation agent. Examples of the basic compound include organic bases such as triethylamine, trimethylamine, pyridine, dimethylaniline, N-methylmorpholine, 4-dimethylaminopyridine, DBN, DBU, DABCO and the like; and inorganic bases such as potassium carbonate, sodium carbonate, potassium hydrogencarbonate, sodium hydrogencarbonate, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride, silver carbonate, alkali metal a alcoholates, e.g. sodium methylate, sodium ethylate and the like.
4o4 In case excess amounts of the compound of the formula S(1) or (o10) is employed, it can be used as the dehydro- Shalogenation agent.
i 20 Examples of the solvent which can be used include halogenated hydrocarbons such as methylene chloride, chloroform, dichlorethane, etc.; aromatic hydrocarbons such as benzene, toluene, xylene, etc.; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dimethoxyethane, etc.; esters such as methyl acetate, ethyl acetate, etc.; aprotic polar solvents such as DMF, DMSO, HMPA, etc.; water; alcohols such as methanol, ethanol, propanol, butanol, 3-methoxy-l-butanol, ethylcellosolve, methylcellosolve, etc.; pyridine, acetone, acetonitrile, etc., or a mixed solvent of more than two kinds thereof. The ratio of the compound of the formula (1t) or (lo) to the compound of the formula (13) or (17) is not limited particularly but can be selected from a wide range. Usually, the latter is used in at least equimolar, preferably equimolar to 5 mols, amount per mol of the former. The reaction usually is carried out at about to 180°C, preferably at about 0OC to 150°C and is generally completed in 5 minutes to 30 hours.
In the reaction between the compound of the formula .15 (It) and the compound of the formula the compound of j fthe formula (13) may react with the alkylene group at the a-position from the group of the compound of the 4 formula or with the imidazole ring at the 1- or 3-posl- 4 2 S l tion, or when R of the compound of the formula is a i 20 hydrogen atom, may react at the 1-position of the hydroquinoline ring, and a group: -N(R )2 may be formed by reacting 2 moles of the compound of the formula (13) with the amino group of the compound of the formula (19).
These compounds, however, can be separated easily.
Likewise, in the reaction between the compound of the r 46 formula (lo) and the compound of the formula (17), the compound of the formula 1 7),may react with the alkylene group at the a-position from the group of the compound of the formula (lo) or with the imidazole ring at the 1- or 3- position or when R 2 of the compound of the formula (lo) is a hydrogen atom, reacts at the 1-position of the hydroquinoline ring.
These compounds, however, can be separated easily.
The reaction between the compound of the formula (1k) or (1r) and the compound of the formula (12) is carried out without solvents or in a suitable solvent in the presence of a reducing agent. Exampls of the solvent which can be used include water; alcohols such as 'a' 0 methanol, ethanol, isopropanol, etc.; acetic acid; ethers such as dioxane, diethyl ether, diglyme, tetrahydrofuran, etc.; and aromatic hydrocarbons such as benzene, toluene, xylene, etc. Examples of the reduction process include a process employing formic acid, a hydride reducing agent such as sodium borohydride, sodium cyanoborohydride, 20 lithium aluminum hydride, etc.; a catalytic reducing o *r process employing a catalytic reducing catalyst such as palladium black, palladium carbon, platinum oxide, ato platinum black, Raney nickel; and so on. When formic acid is used as the reducing agent, the suitable reaction temperature usually is room temperature to 200 0 C, preferably
L
I I- I -e 47 V4 about 50 0 C to 150 0 C, and the reaction is completed in about 1 to 10 hours. The formic acid is used desirably in a large excess amount as compared with the amount of the compound of the formula or (Ir).
When the hydride reducing agent is employed, the suitable reaction temperature usually is -30°C to 100 0 C, preferably about 0 C to 700C, and the reaction is completed in about minutes to 12 hours. The amount of the reducing agent is usually equimolar to 20 mols, preferably 1 to 5 mols, of the reducing agent per mol of the compound of the formula or Particularly, when lithium aluminum hydride is used as the reducing agent, it is desirable that ethers such as diethyl ether, dioxane, tetrahydrofuran, diglyme, and the like; aromatic hydrocarbons such as benzene, toluene, xylene and the like are used as solvents.
When the catalytic reducing catalyst is employed, it is desirable that the reaction is carried out usually under hydrogen atmosphere of ordinary pressure to atmospheric pressure, preferably ordinary pressure to atmospheric pressure, and usually at -30 0 C to 100°C, preferably at 0 C to 60°C. The reaction is completed usually in 1 to 12 hours. The amount of the catalyst to the compound of the formula (1t) or (ir) is usually 0.1 to 40 by weight, preferably 1 to 20 by weight. The 4o, 4r rC ta 44 4 1 44( *4 4.E 48 amount of the compound of the formula (12) is usually at least equimolar, preferably equimolar to large excess, of the compound of the formula (12) per mol of the compound of the formula (It) or (ir).
The reaction between the compound of the formula (i) and the compound of the formula (15) can be carried out under the conditions similar to those of the reaction between the compound of the formula (1k) and the compound of the formula (13) or the reaction between the compound of the formula (1o) and the compound of the formula (17).
The reaction between the compound of the formula (1t) So or (lo) and the compound of the formula (14) is an u" a ordinary amide-forming reaction, to which the conditions for known amide-forming reaction can be readily applied.
0r o Examples of the amide-forming reaction include; the mixed acid anhydride method, wherein the carboxylic acid of the formula (14) is reacted with an alkyl halocarboxylic acid to form a mixed acid anhydride, 44 which is then reacted with the compound of the formula (ii) or the active ester method, wherein the carboxylic acid of the formula (14) is converted into an active ester such as p-nitrophenyl ester, N-hydroxysuccinimide ester, l-hydroxybenzotriazole ester, etc., which is then reacted 49 with the compound of the formula (UZ) or (lo), the carbodiimide method, wherein the compound of the formula or (lo) is condensed with the carboxylic acid of the formula (14) in the presence of an activating agent such as dicyclohexylcarbodiimide, carbonyl diimidazole, etc., and other methods, wherein the carboxylic acid of the formula (14) is converted into a carboxylic acid anhydride with a dehydrating agent such as acetic anhydride, etc., followed by reacting the product with the compound of the formula or the ester of carboxylic acid of the formula (14) and a lower alcohol is reacted with the Q compound of the formula or (lo) at elevated temperature and pressure; and an acid halide of carboxylic acid of the formula i.e. a carboxylic halide, is reacted N with the compound of the formula (1A) or (lo).
The mixed acid anhydride used in the mixed acid anhydride method can be prepared in accordance with
"I
l conventional Schotten-Baumann reaction and subjected, usually without isolation, to reaction with the compound t of the formula (It) or (1o) to give the compound of the formula (It) or The Schotten-BaUmann reaction is carried out in the presence of a basic compound. Any conventional basic compounds commonly used in Schotten- Baumann reaction can be used. Examples of the basic 50 compound include organic bases such as triethylamine, trimethylamine, pyridine, dimethylaniline, N-methylmorpholine, DBN, DBU, DABCO, etc.; inorganic bases such as potassium carbonate, sodium carbonate, potassium hydrogencarbonate, sodium hydrogencarbonate. The reaction is carried out at -20 0 C to 100 0 C, preferably o0C to 50 0 C, in minutes to 10 hours, preferably 5 minutes to 2 hours.
The reaction between the resulting mixed acid anhydride and the compound of the formula (li) or (19) is carried out at -20 0 C to 150 0 C, preferably 10 0 C to 50°C, in minutes to 10 hours, preferably 5 minutes to 5 hours. The mixed acid anhydride method generally is carried out in a a "solvent. Any solvents conventionally used in the mixed acid anhydride method can be used. Examples of the o' A 5 solvent iznclude halogenated hydrocarbons such as methylene o chloride, chloroform, dichloroethane, etc.; aromatic hydrocarbons such as benzene, toluene, xylene, etc.; ethers such as diethyl ether, tetrahydrofuran, dimethoxyethane, etc.; esters such as methyl acetate, 4 yl 20 acetate, etc.; and ar:otic polar waovents such as DMF, DMSO, HMPA, etc. Ex. nPl.ef of th, ;Akyl halocarboxylate F which can be used in .the mixed acid anhydride method irclude methyl chloroformate, methyl bromoformate, ethyl chloroformate, ethyl bromoformate, isobutyl chloroformate, etc. The carboxylic acid of the formula (14) the alkyl r -51halocarboxylate, and the compound of the formula (1k) or (lo) aro usually used in an equimolar amount each.
However, the alkyl halocarboxylate and the carboxylic acid c" the formula (14) may be used in 1 to 1.5 mols amounts per mol of the compound of the formula (1I) or (1o).
When the method of allowing the compound of the formula (1t) or (lo) to react with the halide of the carboxylic acid of the formula (14) is employed, the reaction is carried out in the presence or absence of a basic compound in a suitable solvent. As for the basic compound, various known basic compounds can be used.
Examples of the basic compound *incl.de sodium hydroxide, potassium hydroxide, sodium hya ide, potassium hydride, etc. in addition to those used in the above-mentioned 415 Schotten-Baumann reaction. Examples of the solvent which o 0 can be used include alcohols such as methanol, ethanol, propanol, butanol, 3-methoxy-l-butanol, ethylcellosolve, e *methylcellosolve, etc.; pyridine, acetone, etc. in additi-nl to those used in the above-mentioned Schotten-Baumann S 20 reaction. Proportion of the compound of the formula or (o1) to the carboxylic acid halide is not limited particularly but can be varied appropriately.
The suitable amount of the latter is usually about 0.1 4 to 10 mols, preferably 0.4 to 5 mols, of the latter per mol of the former. The reaction is proceeded at 20 C to IV -52- 180'C, preferably at 0°C to 150°C, and generally completed in 5 minutes to 30 hours.
The reaction between the compound of the formula (1k) or (lo) and glyoxal (16) is carried ouit in a suitable solvent. As for the solvent, all of the solvents used in the above-mentioned reaction between the compound of the formula (Ig) and the compound of the formula (18) can be used. The reaction is carried out usually at 0°C to 100 0 preferably at about 0°C to 70°C, and completed in about 1 to 5 hours. The intermediate thus obtained may be used, without isolation, in the next reduction reaction.
The reduction reaction can be carried out under the condio' tions similar to those of the reduction reaction that forms the compound of the formula (lh) from the compound of the o 15 formula (1g) in the above-mentioned Reaction Scheme-7.
Io The reaction between the compound of the formula (lo) and the compound of the formula (12) can be carried out 4 aa Under' the conditions similar to those of the reaction between 0 the compound of the formula (it) or (Ir) and the 20 compound of the formula (12) mentioned before.
The reaction that converts the compound of the S formula (iq) to the compound of the formula (ly) can be carried out in the presence of a hydroboration reagent in a suitable solvent. Examples of the hydroboration reagent which can be used include various types of borane r 53 derivatives such as borane-tetrahydrofurane complex, borane-dimethylsulfide complex, thexylborane, monochloroborane, dichloroborane, disamylborane, dicyclohexylborane, diisopinocampheylborane, 9-borabicyclo[3.3.1]nonane, 3,5-dimethylborinane, catecholborane. Examples of the solvent which can be used include ethers such as tetrahydrofuran, diethyl ether, dioxane and the like. In the above reaction, the suitable amount of the hydroboration reagent is equimolar to 10 mols, preferably equimolar to mols, of the hydroboration reagent per mol of the compound I of the formula The reaction is carried out usually e at 0 C to 100°C, preferably at about room temperature to and completed in about 1 to 5 hours. The desired J *compounds of the formula (ly) can be obtained by oxidizing I 444415 the resulting intermediate with hydrogen peroxide. The S o reaction is carried out usually in 1 to 5 hours at 0 C to 100 0 C, preferably at room temperature to 80 0 C, in a basic aqufous solution such as sodium hydroxide aqueous soluj 4I tion and the like. The suitable amount of the hydrogen 2* 0 peroxide to be used is usually in a large excess.
SThe reactions of the compound of the formula (ly) S with the compounds of the formulas (19) and (20) can be carried out respectively under the conditions similar to those of the reaction between the compound of the formula (1k) and the compound of the formula (14) and the 54 reaction between the compound of the formula and the comopund of the formula The hydrolysis reactin of the compound of the formula (lz) is carried out usually at room temperature to 150 0
C,
preferably at room temperature to 100 0 C, in the presence of an acidic compound or a basic compound in a solvent and completed in about 1 to 24 hours. Examples of the acidic compound include mineral acid such as hydrogen halide hydrochloric acid, hydrobromic acid, etc.]; sulfuric aci, phosphoric acid, etc. Examples of the basic compound include alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, etc.; and alkali metal carbonates such as sodium carbonate, potassium carbonate, So etc.; alkali metal hydrogencarbonates such as sodium e0a hydrogencarbonate, potassium hydrogencarbonate and so on.
S\ Examples of the solvent include water or a mixed solvent of water and a lower alcohol such as methanol, ethanol, ao propanol, etc.
a In the compounds of the formulas (la) to (lz) in the above-mentioned Reaction Schemes 1 to 9, when R 2 or R Sis a lower alkynyl group having a tri-lower alkylsilyl group, R or R in the compounds of the formulas (la) to (1z) can be converted to a lower alkynyl group by a desilylation reaction.
The desilylation reaction is carried out in a r: suitable solvent and in the presence of a tetraammonium halide such as tetrabutylammonium fluoride, etc.; fluorine compounds such as hydrofluoric acid, pyridinium hydrofluoride, tetrabutylammonium fluoride, etc.; mineral acids such as hydrochloric acid, hydrobromic acid, etc.; organic acids such as acetic acid, etc.; and inorganic bases such as potassium carbonate, sodium hydroxide, potassium hydroxide, etc. The reaction is carried out usually at 0 C to 50 0 C, preferably at about -20 0 C to room temperature and completed in about 10 minutes to 5 hours.
Examples of the solvent which can be used include ethers such as tetrahydrofuran, diethyl ether, dioxane and the like.
In the above reaction, the suitable amount of the desilylating agent is a large excess amount to the starting materials.
The carbonyl group of the compounds of the formulas S4 S (It) and (iv) can be converted to a -CH 2 group by i subjecting the compounds to a reduction reaction.
The reduction reaction is carried out in a suitable solvent in the presence of a hydride reducing agent.
Examples of the reducing agent which can be used include sodium borohydride, lithium aluminum hydride, diborane, etc. In the above reaction, the suitable amount of the reducing agent to be used is at least equimolar, -r I~ i 56 preferably equimolar to 3 mols, of the reducing agent per mol of the starting materials. As for the solvent, there can be used, for example, water, lower alcohols such as methanol, ethanol, isopropanol, etc.; and ethers such as tetrahydrofuran, diethyl ether, diglyme, etc. The reaction is carried out sually at -60°C to 100°C, preferably at about -30 0 C to 80°C and completed in about 10 minutes to 5 hours. Use of anhydrous solvent of diethyl ether, tetrahydrofuran and diglyme is desirable when lithium aluminum hydride or diborane is used as the reducing agent.
The compound of the formula which is used as the starting material in Reaction Scheme-1 partially includes a new compound which is produced, for example, by the processes of the following Reaction Schemes 10 and 11: a o
Q
2 57 [Reaction Schere-lO] (R3)n (FR3 W28) 3)n
RX
2 3a 02 i rCH 2 CH-Xa
CH-OR
21 R 2 2 1) 3 R20 (22) 320(23)
(R
3 )n (R )n ReducR -COOH(29) N Reductdion CHOH CH Rc 2O R$H
(R
3 (24) R2- COOH (29) R2X, 3 b 9 CH CH 2 R2 2 Reduction 2 0 0H i (R )n (R 3 )n (27) (R n
OHC
2
R
22 (Rk2In 3 AO H
OH
(26) (30)
N
C CH 2
R
22 I 0 ~(R 3 )n
(R
3 )n R 20 x e, (3c) CH&-j 2 22 CHR 2
R
20
X
3 a 3a (3b) (3d) rT it
I
i i I 2 58 10 0 4 9 0 S0 a ra o a i 4 2' 3 3a 3b Wherein R R X X 3 n and the bond between the 3- and 4- positions of the quinoline skeleton have the 20 22 same meanings as defined above, R and R represent respectively a hydrogen atom or a lower alkyl group, R 21 represents a lower alkanoyl group, and Y represents a hydrogen atom or alkali metals such as sodium, potassium and the like.
The halogenation reaction that forms the compound of the formula (22) from the compound of the formula (,21) is carried out by treating the compound of the formula (21) with a halogenating agent in a suitable solvent.
Examples of the halogenating agent which can be used include halogen molecules such as chlorine, bromine, eto. N-halogenosuccinimides such as N-bromosuccinimide, N-chlorosuccinimide, etc.; sulfinyl chloride; and copper halides such as copper chloride, copper bromide, etc.
Examples of the solvent which can be used include halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride, etc.; ethers such as diethyl ether, tetrahydrofuran, dioxane, etc.; acetic acid, etc.
The suitable amount of the halogenating agent is equimolar to excess, preferably equimolar to 1.2 mnols, of the halogenating agent per mol of the compoun r -f the formula (21).
r 59 The reaction is usually proceeded at about 0 C to the boiling point of the solvent, preferably at room temperature to 100°C and completed generally in about 1 to 10 hours. radical reaction initiators such as peroxidos for example, benzoyl peroxide, hydrogen peroxide, etc. may be used in this reaction.
The, reaction between the compound of the formula (22) and the compound of the formula (28) is carried out in. the presence or absence of a basic compound in a suitable solvent.
The reaction is carried out usually at room temperature to 200°C, preferably at room temperature to 150°C, and completed in about 1 to 15 hours.
Examples of the solvent which can be used in the above reaction include lower alcohols such as methanol, Sethanol, isopropanol, etc.; ethers such as diethyl ether, tetrahydrofuran, dioxane, ethyleneglycol monomethyl ether, diethyleneglycol dimethyl ether, etc.; aromatic hydrocarbons such as benze, toluenet xylene, etc.; a t4 ketones such as acetone, methylethylketone, etc.; and S* polar solvents such as DMF, DMSO, HMPA, acetic anhydride, etc.
Examples of the b.Lc compound which can be used include inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium s[ 60 carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, silver carbonate, etc.; alkali metals such as sodium, potassium, etc.; sodium amide; sodium hydride; alkali metal alcoholates such as sodium methylate, sodium ethylate, potassium ethylate, etc.; and organic bases such as triethylamine, tripropylamine, pyridine, quinoline, N,N-dimethylaniline, N-methylmorpholine, etc.
The suitable amount of the compound of the formula i (28) is at least equimolar, preferably equimolar to 5 mols, of the compound of the formula (28) per mol of the t compound of the formula (22).
The hydrolysis reaction that produces the compound of the formula (24) from the compound of formula (23) can be carriee out under conditions similar to those of the hydrolysis reaction of the compound of the formula (lz) in the above-mentiored Ieaction Scheme-9.
The redtction reaction which converts the compound of the formula (24) to the compound of the formula 2 is usually carried out by means of a catalytic reduction in the presence of a suitable reducing catalyst Examples of the reducing catalyst which can be used s include conventional catalytic reducing catalysts such as platinum, platinum oxide, palladium black, palladium carbon Raney nickel and the like. The amount of the reducing catalyst to the compound of the tfrmula (24) is 61 usually in the range of about 0.2 to 0.5 time per weight of the compound of the formula The catalytic reduction is carried out, in a solvent, for example, water, methanol, ethanol, isopropanol, diethyl ether, tetrahydrofuran and dioxane under the hydrogen atmosphere 2 2 of 1 to 10 kg/cm preferably 1 to 5 kg/cm at -30°C to the boiling point of the solvent, preferably at about 0°C to 70 0 C while a well stirring.
The reduction process employing a hydride reducing agent, for example, is suitably applied to the reduction of the compound of the formula (24) in the presence of the compound of the formula Xn the above reaction, examples of the hydride reducing agent which can be used include diborane; aluminum hydride metal salts such as sodium aluminum hydride, etc.; alkyl aluminum such as '40 lithium tri-tert-butoxyaluminum hydride, diisobutylaluminum hydride, etc.; and boron compounds such as sodium borohydride, (11l-daimethyl-l-diisopropylmethyl) borohydride, sodium cyanoborohydride, etc. The suitable S 20 amount of the reducing agent is at least about equimolar, preferably about equimolar to 5 mols, of the reducing agent per mol of the compound of the formula The reduction reaction, for example, is carried out in a suitable solvent, for example, ethers such as diethyl ether, tetrahydrofuran, diglyme, etc. aliphatic 62hydrocarbons such as n-hexane, n-octane, etc.; and aromatic hydrocarbons such as benze.ie, toluene, xylene, etc., usually at about -750C to 500C, preferably at 0 C to room temperature, and completed in about minutes to 10 hours. When the boron compound is used as the reducing agent, water, alcohols such as methanol, ethanol, isopropanol, and the like or the compound of the formula (29) may be used as the solvents in addition to the above-mentioned solvents. When aluminum hydride metal salts etc. are used as the reducing agents, use of anhydrous solvents of diethyl ether, tetras.«O hydrofuran and diglyme is desirable.
In the above reaction, the compound of the formula (29) is used usually in large excess amounts as compared with the compound of the formula (24).
o The reduction reaction which converts the compound Sof the formula (23) to the compound of the formula (27) S can be carrie'd out in the presence of an organic acid of the formula (29) such as formic acid, acetic acid, I ,20 pr cpio acid under the conditions similar to those of Sthe above-mentioned reduction reaction which converts Sthe compound of the formula (24) to the compound of the formula In this reaction, the organic acid is used preferably in large excess amounts.
The reaction between the compound of the formula 63 and the compound of the formula can be carried out, for example, under the conditions similar to those of the reaction between the compound of the formula (le) and the compound of the formula in Reaction Scheme-6.
Any of the conventional reaction conditions for halogenation of hydroxy group can be applied to the halogenation reaction of the compounds of the formulas (30) and The halogenation reaction, for example, is carried out by the reaction of the compound of the formula (30) or (27) with a halogenating agent in a suitable inert solvent or without solvents.
Examples of the halogenating agent which can be used a, include hydrogen halide such as hydrochloric acid, o "i hydrobromic acid, etc.; N,N-diethyl-l,2,2-trichloro- '0 15 vinylamide, phosphorus pentachloride, phosphorus pentabromide, phosphorus oxychloride, thionylchloridc, etc. As for the inert solvent, examples of the inert S*"4 solvent which can be used include ethers such as dioxane, tetrahydrofuran, etc.; and halogenated hydrocarbons such as chloroform, methylene chloride, carbon tetrachloride, etc. The amount of the halogenat- 1 ,ing agent is at least equimolar, usually in excess, of the halogenating agent per mol of the compound of the formula (30) or The reaction is carried out usually at 0°C to 150°C, preferably at 0°C to 64 1 -64- OU 4
CC
D 1.5 C C *4r~ 4 t' completed in about 10 minutes to 6 hours.
In the reduction reactions which convert the compound of the formula (23) to the compound of the formula the compound of the formula (24) to the compound of the formula and the compound of the formula (24) to the compound of the formula a mixture of the compound with the quinoline skeleton reduced at the 3- and 4-positions and the compound with the quinoline skeleton reduced at the 1- and 2-position only may be formed. These compounds, however, can be separated readily. In the above reduction reaction, the compounds with the quinoline skeleton reduced at the 1- and 2-positions only may be also formed preferrentially. In this case t the compounds with the quinoline skeleton reduced at the 3and 4-positions can be obtained by reducing them under the same conditions respectively. Furthermore, depending on the reduction conditions, the compounds with the quinoline skeleton reduced at the 3- and 4positions may be formed preferentially.
~i 9u ~x 6- [Reaction Scheme-11]
(R
3 )n 12 5'2 R23OH (32L
-COOH
1) Reduction Reducton Reduction (33) n (R )n
N
(A')-CH
2
X
3 (3e) (A')q-CH 2
OH
(34 .4r 4,4 *4 .4 44L b: I, 4 *4
I
wherein R 2 R n, q, X and the bond between the 3- and 4-positions of the quinoline skeleton have the same meaning as defined above, and R 2 3 represents a lower alkyl group, provided that the group -(A')qCH 2 does not exceed 6 in carbon number.
The esterification reaction between the compound of the formula (31) and the compound of the formula (32) can be carried out under conditions of conventional esterification reactions, for example, 1) a process carried out in a suitable solvent in the presence of a -66 dehydrating agent, 2) a process carried out in a suitable solvent in the presence of an acid or a basic compound, etc.
Examples of the solvent which can be used in above process 1) include halogenated hydrocarbons such as dichloromethane, chloroform, dichloroethane, carbon tetrachloride, etc.; aromatic hydrocarbons such as benzene, toluene, xylene, etc.; ethers such as diethyl ether, tetrahydrofuran, dioxane, ethyleneglycol monomethyl ether, dimethoxyethane, etc.; and aprotic polar solvents such as DMF, DMSO, HMPA, etc. Examples O' of the dehydrating agent which can be used include "o dicyclohexylcarbodiimide, carbonyl diimidazole, etc.
The suitable amount of the alcohol of the formula (32) is at least equimolar, preferably equimolar to 1.5 mols, Soof the alcohol of the formula (32) per mol of the compound of the formula The suitable amount of OP the dehydrating agent is at least equimolar, preferably equimolar to 1.5 mols,of the dehydrating agent per mol 0 420 of the compound of the formula The reaction is Scarried out usually at room temperature to 150 0
C,
*lot preferably at 50 0 C to 100C,rand completed in about 1 to ,i 10 hours.
Examples of the acid which can be used in above process 2) include inorganic acids such as hydrogen chloride, sulfuric acid, phosphoric acid, polyphosphoric I 1 l~c 67acid, boron trifluoride, perchloric acid, etc.; organic acids such as trifluoroacetic acid, trifluoromethanesulfonic acid, naphthalenesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, ethanesulfonic acid, etc.; acid anhydrides such as trichloromethanesulfonic acid anhydride, thifluoromethane sulfonic acid anhydride, etc.; thionyl chloride, acetone dimethyl acetal, etc. Furthermore, an acid ion-exchange resin can be also used.
Examples of the basic compound which can be used include inorganic bases such as sodium hydroxide, pctassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, silver carbonate, etc.; and alcoholates such as sodium methylate, S*,o sodium ethylate, etc. Though the reaction can be carried out without solvents it can be carried out advantageously using the solvent shown in the above-mentioned process 1).
Moreover, the Veaction proceeds advantageously using a drying agent, for example, anhydrous calcium chloride, ona AI anhydrous copper sulfate, anhydrous calcium sulfate and phosphorus pentoxide. The suitable amount of the alcohol of the formula (32) to the compound of the formula (31) is usually in large excess when the reaction is conducted without solvents, and 1 to 5 mols, preferably 1 to 2 mols, of the alcohol of the formula (32) per mol of the compound of the formula (31) is used suitably when the reaction
L
68 o 1
C
QUO
is conducted in the presence of the solvent. The reaction is carried out usually at -20 0 C to 200°C, preferably at about 0 0 C to 150OCrand completed in about 1 to 20 hours.
The reduction reaction of the compound of the formula (31) or (33) can be carried out under the conditions similar to those of the reduction reaction which forms the compound of the formula (lh) from the compound of the formula (ig) in the above-mentioned Reaction Scheme-7.
The halogenation reaction of the compound of the formula (34) is carried out under the conditions similar to those of the halogenation reaction of the compounds of the formula (30) or in Reaction The carboxylic acid of the formula (31) which is the starting material in the Reaction Scheme-11 and its homocarboxylic acid compound can be produced by the process shown in the following Reaction Scheme-12 00 3 04 1 41 ItX rr
A
69 [Reaction Scheme-121 (A')q-X 3 M bCN(36)- 3 C0OR 24
OH,
2 -CO24(38)
(A")-CN
(37) SHydrolysis
(R)
N
R2
Q
24 (A -C CCOOR 24 (39)
CONH
(31) Hydrolysis (R 3 )n t 4 4 )qCH 2 000OH (31 a) _I C I i i i- r ^LI -r 70 2 3 3 wherein R R n, q, X and the bond between the 3- and 4-positions of the quinoline skeleton have the same meanings as defined above, R 24 represents a lower alkyl group, and M represents a metal.
The reaction between the compound of the formula and the compound of the formula (36) can be carried out in a suitable solvent. M CN of the formula (36) includes, for example, cyanides such as potassium cyanide,, sodium cyanide, silver cyanide, copper cyanide, calcium cyanide and the like. Example of the solvent which can be used in the reaction include water, alcohols such as methanol, ethanol, isopropanol and the like; and a mixed solvent thereof. The suitable amount of the o compound of the formula (36) is at least equimolar, preferably equimolar to 1.5 mols, of the compound of the formula (36) per mol of the compound of the formula I° The reaction is carried out usually at room temperature to 150°C, preferably at about 50 0 C to 120 0
C,
and completed in about 30 minutes to 10 hours.
The hydrolysis reaction of the compound of the a formula (37) is carried out in the presence of a hydrolytic catalyst in a suitable solvent or without solvents. Examples of the hydrolytic catalyst include mineral acids such as hydrogen halides [e.g.
hydrochloric acid, hydrobromic acid, etc.], sulfuric c 71 acid, phosphoric acid, etc.; alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, etc.; alkali metal carbonates or alkali metal hydrogencarbonates Luch as sodium carbonate, potassium carbonate and sodium hydrogencarbonate, etc. Examples of the solvent which can be used in the above reaction include water, alcohols such as methanol, ethanol, and the like; or a mixed solvent thereof. The reaction is carried out usually at 0 C to 150°C, preferably at room temperature to 100°C,and completed in about 1 to 24 hours.
The reaction between the compound of the formula and the compound of the formula (38) is carried out in a suitable solvent, in the presence of a basic compound and usually at room temperature to 2 0 0 0
C,
preferably at 60 0 C to 120°C, and completed in about 1 to 24 hours. Examples of the solvent which can be used include ethers such as dioxane, tetrahydrofuran, ethyleneglycol dimethyl ether, diethyl ether, etc.; aromatic Shydrocarbons such as benzene, toluene, xylene, etc.; 20 lower alcohols such as methanol, ethanol, isopropanol, etc.; and polar solvents such as dimethyl formamide, dimethylsulfoxide, etc. Examples of the basic compound which can be used in the above reaction include inorganic bases such as calcium carbonate, sodium carbonate, potassium carbonate, sodium hydrogencarbonate, sodium I ill S- 72 hydroxide, potassium hydroxide, sodium amide, sodium hydride, potassium hydride, sodium methylate, sodium ethylate and the like; and amines such as triethylamine, tripropylamine, pyridine, quinoline and the like. The reaction proceeds advantageously by the using of alkali metal iodides such as potassium iodide, sodium iodide, etc. The amount of the compound of the formula (38) is usually equimolar to large excess, preferably equimolar to 5 mols and more preferably equimolar to 1.2 mols, of the compound of the formula (38) per mol of the compound of the formula The hydrolysis reaction of the compound of the formula (39) is carried out under the conditions similar to those of the hydrolysis reaction of the 15 compound of the formula (37) above.
Some compounds of the formula (34) in Reaction Scheme-11 can be produced, for example, by the processes of the following Reaction Schemes-13 to 19.
4j #4 1 0 'i 0 4 4 l t 2 73 [Reaction Scheme-13] R 25 N NO XOaCH2COX 3 b (41) or (X 'CH 2
CO
2 O(42) R
ON
X~aCH 2 C ~2 11 0 (43) (44) Hydrolysis 4 4 4* 4 oe 44 o v.>9 o o *4 44 444 #4 4 4 4 4 (45)
R
23
OH(
Reduction (46)
IR
2
N
-IOH
2 C R1 2 R 23O0( (47) (8 (48) 74 23 3a 3b wherein R4 R 3
X
a X and the bond between the 3- and 4-positions of the quinoline skeleton have the same meanings as defined above, R 25 represents a hydrogen atom, a lower alkoxy group, a lower alkyl group, a halogen atom, a hydroxy group, a lower alkenyloxy group, a hydroxy-substituted lower alkyl group, group of the formula
I
(wherein 4 and 5 have the same meanings as defined 26 above) or a phenyl group, and represents an aromatic amine.
The reaction between the compound of the formula 5 (40) and the compound of the formula (41) or the compound of the formula (42) is generally called Friedel-Crafts reaction and is usually carried out 4 in a suitable solvent in the presence of a Lewis acid.
2 i '2 As for the solvent, the solvent which is used S S conventionally in this type reaction can be used advantageously, and examples of the solvent include carbon disulfide, nitrobenzene, chlurobenzene, dichloromethane, dichloroethane, trichloroethane, carbon tetrachloride, etc. As for the Lewis acid, conventional 75 Lewis acid, for example, aluminum chloride, zinc chloride, iron chloride, tin chloride, boron tribromide, boron trifluoride, concentrated sulfuric acid, etc. can be used i, the reaction. The amount of the Lewis acid to be used is not limited and can be varied widely, usually 2 to 6 mols, preferably 3 to 4 mols, of the Lewis acid per mol of the compound of the formula (40) are used. The amount of the compound of the formula (41) or (42) is usually at least equimolar, preferably equimolar to 3 mols, of the compound of the formula (41) or (42) per mol of the compound of the formula The reaction temperature is usually about room temperature to 120°C, preferably 40°C to 70 0 C and the reaction time, which varies depending on the materials, catalyst, reaction 15 temperature, etc., is usually about 30 minutes to 24 hours.
In this reaction, when R 2 of the compound of the formula (40) is hydrogen atom, a halogen atom or a lower alkyl group, the compound substituted with the side chain X 3 a CH 2 CO at the 6-position of the carbostylyl skeleton also forms simultaneously. The Scompound however, can be separated readily.
The reaction between the compound 0o the ormula- (43) and the compound of the formula (44) iu aried out in a suitable solvent or without so" for 76 the solvent, any inert solvent which does not affect adversely on the reaction can be used.
Examples of the solvent include halogenated hydrocarbons such as chloroform, methylene chloride, dichloroethane, carbon tetrachloride, etc.; ethers such as diethyl ether, tetrahydrofuran, dioxane, dimethoxyethane, etc.; alcohols such as methanol, ethanol, isopropanol, butanol, etc.; esters such as methyl acetate, ethyl acetate, etc.; aprotic polar solvents such as DMF, DMSO, HMPA, etc.; acetonitrile, etc.
Examples of the aromatic amine of the formula (44) include pyridine, quinoline, etc. The amount of the aromatic amine of the formula (44) is at least equimolar, preferably in large excess, of the aromatic amine of the formula (44) per mol of the compound of the formula oo The reaction temperature is at 50°C to 200°C, o ;preferably 70°C to 150°C and the reaction is completed in about 3 to 10 hours.
The hydrolysis reac'ion which forms the compound of the formula (46) from the resulting compound of the $1 S. formula (45) is carried out in water in the presence of an inorganic base such as sodium hydroxide and potassium hydroxide at room temperature to 150°C in about 1 to 10 hours.
o 0 The esterification reaction between the compound 4| -I I 77 of the formula (46) and the compound of the formula (32) is carried out in the presence of a basic compound in a solvent or without solvents. Examples of the solvent which can be used in the reaction include halogenated hydrocarbons such as methylene chloride, chloroform, dichloroethane, etc.; aromatic hydrocarbons suich as benzene, toluene, xylene, etc.; ethers such as diethyl ether, tetrahydrofuran, dioxane, dimethoxyethane, etc.; and aprotic polar solvents such as DMF, DMSO, HMPA, etc. Examples of the basic catalyst which can be used include organic bases such as triethylamine, trimethylamine, pyridine, dimethylaniline, N-methylmorpholine, 4-dimethylaminopyridine, DBN, DBU, DABCO and "the like; and inorganic bases such as potassium '4 1 carbonate, sodium carbonate, potassium hydrogencarbonate, 1 sodium hydrogencarbonate and the like. In the above *reaction, the suitable amount of the basic compound is at least equimolar, preferably 1 to 1.5 mols, of the basic compound per mol of the compound of the formula 0 The suitable amount of the compound of the formula (32) is usually at least equimolar, preferably in large excess, of the compound of the formula (32) per mol of the compound of the formula The reaction temperature is usually at room temperature to (50 0 C, preferably at about 50°C to 100 0 °Cand the i-r i i i I-~---LlaUIII(CI~-- 78 #94 09 94 4 a 041 94 """15 .4 49 4 4944 94 4 94 94 44 #4 a 0 reaction generally is completed in 30 minutes to 10 hours.
The reaction between the compound of the formula and the compound of the formula (32) can be carried out in the presence of a basic compound in a solvent or without solvents.
Examples of the solvent which can be used in the reaction include halogenated hydrocarbons such as dichloromethane, chloroform, dichloroethane, etc.; aromatic hydrocarbons such as benzene, toluene, xylene, etc.; ethers such as diethyl ether, tetrahydrofuran, dioxane, dimethoxyethane, etc.; and aprotic polar solvents such as DMF, DMSO, HMPA, etc.
Examples of the basic compound which can be used include organic bases such as triethylamine, trimethylamine, pyridine, N,N-dimethylaniline, N-methylmorpholine, 4-dimethylaminopyridine, DBN, DBU, DABCO and the like; and inorganic bases such as potassium carbonate, sodium carbonate, sodium hydrogencarbon&te, potassium hydrogencarbonate and the like.
The suitable amount of the compound of the formula (32) is at least equimolar, preferably in large excess, of the compound of the formula (32) per mol of the compound of the formula The suitable amount of the basic compound is at least equimolar, preferably in equimolar to 1.5 mols, of the basic compound per mol of 4* 944 0 04i 442 '4 1- i I i I 79 the compound of the formula The reaction is carried out usually at room temperature to 1500C, preferably at about 50 0 C to 100 0 C,and generally completed in about minutes to 10 hours.
The reduction reaction of the compound of the formula (47) can be, carried out under the conditions similar to those of the reduction reaction of the compound of the formula (33) mentioned before. In this reaction, lithium aluminum hydride is preferably used as the 0 reducing agent.
[Reaction Scheme-14] Halogenation 3 I HO-CH 2 R HO-HR 2 "dO (49)
S/R
27 M (52)
R
2 7 (51) 2 3 wherein R 2 X M and the bond between the 3- and 4positions of the quinoline skeleton have the same 25 meanings as defined above, and R 27 represents a lower 5 -7 2 ~e c 80
I
U
i
U*
alkoxy group.
The halogenation reaction of the compound of the formula except for the use of 2,4,4,6-tetrabromoas the halogenating agent, can be carried out under the conditions similar to those of the halogenation reaction of the compound of the formula (21) mentioned before.
The reaction between the compound of the formula and the compound of the formula (52) can be carried out in a suitable solvent in the presence or absence of a basic compound.
Examples of the solvent and the basic compound which can be used include the solvent and the basic compound used in the reaction between the compound of 15 the formula and the compound of the formula in Reaction Scheme-1.
The reaction is carried out usually at 0 C to 150 0
C,
preferably at about 0°C to 100 0 C,and completed in about 1 to 24 hours. The suitable amount of the compound of the formula (52) is usually at least equimolar, preferably equimolar to 1.5 mols, of the compound of the formula (52) per mol of the compound of the formula The reaction can proceed advantageously with the addition of.copper halides such as copper iodide, etc.; copper powder, etc.
17 81 [Reaction
OHCOCT,
2 (54) '0 'N NH 2 N' O (53) (55)
H
I
OH
2
=CHCOOR
28 (56) 0 N O Hydrolysis 0 'N N0 'ii na
(CH
2 2 000H 38 SCyclization 0 Redu (59)
(CH
2 2
COOR~
(57) Lctiaon 0 4* I i t 'j(6
R
29
OH
NN
H
OH
(62) 25 )H (6 4) 82 0 R 8 ml (10 (59) R 8,OH 4
'NN
H
OH (6 0) I R' R 8 OR 29 N N Oz'O (68)\
'OH
(67) ,OR 2 9 (69) -I i i L Ci- ~1~-71 r 83 wherein R 8
X
3 and M a have the same meanings as 28 defined above, R represents a lower alkyl group, and 29 R represents a lower alkyl group, a lower alkenyl group or a lower alkoxy lower alkyl group.
The reaction between the compound of the formula (53) and phosgene (54) is carried out in a suitable solvent or without solvents in the presence of a basic compound.
The reaction is carried out usually at room temperature to 150 0 C, preferably at room temperature to 100°C, and completed in about 0.5 to 10 hours.
Examples of the solvent which can be used in the reaction include lower alcohols such as methanol, a o ethanol, isopropanol, etc.; ethers such as diethyl ether, tetrahydrofuran, dioxane, ethyleneglycol monomethyl ether, diethyleneglycol dimethyl ether, etc.; aromatic hydrocarbons such as benzene, toluene, xylene, etc.; ketones such as acetone, methylethylketone, etc.; anr aprotic polar solvents such as DMF, DMSO, HMPA, etc, Examples of the basic compound which can be used inelude inorganic bases sach as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, silver carbonate, etc.; alkali metals such as sodium, potassium, etc.; sodium amide; sodium hydride; alkali metal i. r- 84 alcoholates such as sodium methylate, sodium ethylat;, potassium ethylate, etc.; and organic bases such as triethylamine, tripropylamine, pyridine, quinoline, N,N-dimetihylaniline, N-methylmorpholine, etc.
The suitable amount of phosgene (54) is at least equimolar, preferably equimolar to 5 mols, of phosgene (54) per mol of the compound of the formula (53).
The reaction between the compound of the formula and the compound of the formula (56) is carried out in a suitable solvent in the presence of a basic compound. The reaction is conducted usually at room temperature to 150 0 C, preferably room temperature to 100Cr and completed in about 1 to 10 hours. Examples of the basic compound and solvent which can be used in o' 15 the reaction include the basic compound and solvent illustrated in the above-mentioned reaction between the ro compound of the formula (53)and phosgene (54).
The rectbion that hydrolyzes the compound of the formula (57) and converts it tcv the compound of the formula (58) can be carried out under the conditions similar to those of the above-mentioned hydrolysis reaction that forms the compound of the formula (24) from the compound of the formula (23) in Reaction 425 The cyclization reaction of the compound of the formula (58) can be carried out in accordance with various conventional cyclization methods, for exanple, a cyclization process by heating; a cyclization process using an acid such, as phosphorus oxychloride, phosphorus pentacchloride, phosphorus trichloride, thionyl chloride, concentrated sulfuric acid, polyphosphoric acid and the like; etc. When the heating cyclization process is employed, hydrocarbons and ethers having high-boiling poiht such as tetralin, diphenyl ether, diethyleneglycol dimethyl ether are used, and the heating conditions of 100 0 C to 250 0 C, preferably 150 0 C to 200°C, can be usually applied. When the cyclization process using I ,o the acid is employed, the amount of the acid is usually equimolar to large excess, preferably 3 to 20 mols, of the acid per mol of the compound of the formula (58), and the. reaction is carried out usually at room temperature to 150 0 C for about 0.1 to 6 hours. In the cyclizatin pr4ocess using the acid, the reaction is carried out withcit solvents or in a suitable solvent, for example, ethers such as diethyl ether, dioxane, tetrahydrofuran, monoglyme, diglyme, etc.; aliphatic hydrocarbons such as n-hexane, heptane, ligroin, etc.; halogenated hydrocarbons such as chloroform, methylene chloride, carbon tetrachloride, etc.; aprotic polar solvents such as DMF, DMSO, HIIPA, etc.; and acid 86 anhydrides such as acetic anhydride, etc.
The reduction reaction which converts the compound of the formula (59) to the compound of the formula (61) can be carried u,t under tne conditions similar to those of the above-mentioned reduction reaction that forms the compound of the formula (lh) from the compound of the formula (1g) in Reaction Scheme-7.
The reaction between the compound of the formula (61) or (66) and the compound of the formula (65) can be carried out in a suitable solvent in the presence of a basic compound.
Examples of the solvent which can be used in the reaction include the ethers, alcohols, aromatic hydrocarbons, aliphatic hydrocarbons, amines, halogenated hydrocarbons, aprotic polar solvents or a mixed solvent thereof etc. illustrated in the reaction between the carbonyl group of the quinoline skeleton in the compound of the formula (li) and the lower alkyleneglycols in Reaction Scheme-8.
Examples of the basic compound which can be used include inorganic bases such as sodium, potassium, magnesium, sodium hydride, sodium amide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogencarbonate, etc.; metal alcoholates such as sodium methylate, sodium ethylate, etc.;
I
i 87 and organic bases such as pyridine, piperidine, quinoline, triethylamine, N,N-dimethylaniline, etc.
The reaction temperature is usually -30 0 C to 120 0
C,
preferably C(out 0 0 C to 100 0 C,and the reaction generally is completed in about 0.1 to 15 hours. The suitable amount of the compound of the formula (65) is usually at least equimolar, preferably equimolar to 3 mols, of the compound of the formula (65) per mol of the compounds of the formula (61) or (66).
The reaction which converts the compounds of the formulas (68) and (63) to the compounds of the formulas (67) (69) and (64) .o 0 a respectively can be carried out under the conditions B similar to those of the hydrolysis reaction that forms 15 the compound of the formula (24) from the compound of o 4a the formula (23) in Reaction a 4 The reaction between the compounds of the formula (59) or (60) and the compound of the formula (10) can 0 be carried out under the conditions similar to those of the reaction between the compound of the formula (li) C and the compound of the formula (10) in Reaction Scheme-8.
The compounds of the formulas (67) and C69) can be led to compounds, where the hydrogen atoms at the 1-position of the quinoline skeleton of the compound of the formulas (67) and (69) 88 are substituted with R 2
(R
2 has the same meaning as defined above) respectively, by allowing them to react with the compound of the formula under the conditions similar to those of the reaction between the compound of the formula (25) and the compound of the formula in Reaction The compounds of the formulas (59) and (60) can be converted to the compounds having a lower alkylenedioxy group at the carbonyl group of the compounds of the formulas (59) and (60) respectively by subjecting them to the reaction conducted Under the substantially same conditions as those of the above-mentioned reaction that converts the carbonyl group of the compound of the formula (li) to the lower alkylenedioxy group in Reaction 0-15 Scheme-8.
The lower alkylenedioxy group-substituted compound in the above reaction can be converted to a compound i substituted with a carbonyl group by subjecting the compound to a nyurolysis reaction under the same conditions as in the above-mentioned hydrolysis reaction that converts the lower alkylenedioxy group of the compound of the formula (li) to the carbonyl group in Reaction Scheme-8.
-89- [Reaction Scheme-16] 0 0 OH 3 iReduction fi 5 R R 2 212 2 d2 R R7 OH ROR 30
OR
30 (72) (73)
SOR
29
OR
29 lO R29__ _2 N N iIN
OR
30
OH
(74) .o wherein R 30 represents a silyl group having 1 to 3 2 29 3 a an ~3b of lower alkyl groups, an R R 2 9 X and 1 have the same meanings as defined above.
The reaction between the compound of the formula and the compound of the formula (71) can be carried out in the presence of .a basic compound in a suitable solvent- As for the basic compound, there can be used, for example, inorganic bases such as sodium hydride, potassium hydride, sodium, potassium, sodium amide., potassiu amide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogenicarbonate, potassium hydrogencarbonate, etc.; alkyl lithiums such n-butyl lithium, etc.; and organic bases such as triethylamine, pyridine, N,N-dimethylaminopyridine, imidazole, N-methylmorpholine, DBN, DBU, DABCO, etc.
Examples of the solvent which can be used include all of the solvents shown in the above-mentioned reaction between the compound of the formula (25) and the compound of the formula in Reaction The reaction is conducted usually at 0 C to 100'C, preferably at 0°Cto 80°C,and completed in about minutes to 20 hou-s.
The suitable amount of the compound of the formula (71) is at least equimolar, preferably equimolar to 0$ o{ o 2 mols, of the compound of the formula (71) per mol of the compound of the formula '"15 The reduction reaction of the compound of the formula (72) can be carried out under the conditions 4 similar to those of the reduction reaction of the compound of the formula (ig) in Reaction Scheme--7 SThe reaction between the compound of the formula (73) and the compound of the formula (65) can be carried out under the conditions similar to those of the reaction between the compound of the formula (61) and the compound of the formula (65) in Reaction The reaction dhich leads the compound of the formula (74) to the compound of the formula (75) can be ~T a 91 carried out under the conditions similar to those of the above-mentioned desilylation reaction which is conducted when R 2 is a lower alkynyl group possessing a tri-loweralkylsilyl group in the compounds of the formulas (la) to (ld) 4 8 I t 0 -92- [Reaction Scheme-17] 0 NOH NH 2 I N H20H (11) I Reduction I N N N~ N N N 0000 0 (59)(76) (77)
HNR
R (1
R-
0> 0>0O (81) (83) t Reduction NN
N
(82) (84) 1 5 2 0 r H d oy i 0 N) -93
NH
2
NHCH
2
CH
2 OH
N
NIN CHONH 1 r~ R 6 (77)NH1 (91) eduction R 1 4 H(14) 91) or (R' 4 2 N
O
R 9 x 3c
NHR
9
R
1 2
R
1 3 R 1 2 CH 12) 0 1 14NH4 OH (14) /R 9 NCHO N\R14
CHO
N
N,
(8)1 2 /R9R N 0 0 (7 N/9/1 C2H0 C \R9 94 4' 5' 9 10 11 12 13 14 wherein R R R R R R R R R and X 3 c have the same meanings as defined above.
The reaction between the compound of the formula (59) and hydroxylamine (11) can be carried out under the conditions similar to those of the reaction between the compound of the formula (Ig) and hydroxylamine (11) in Reaction Scheme-9.
The reduction reaction of the compound of the formula (76) can be carried out under the conditions similar to those of the reduction reaction of the compound of the formula (1k) in Reaction Scheme-9.
The reaction between the compound of the formula n (59) and the compound of the formula (18) can be carried G..F out under the conditions similar to those of the reaction between the compound of the formula (1g) and the compound of the formula (18) in Reaction Scheme-9.
The compound of the formula (81) obtained in this reaction is subjected to the next reduction reaction without isolation.
The reduction reaction of the compound of the 4. tI formula (81) can be carried out under the conditions similar to those of the reduction reaction of the t*r" compound of the formula (1m) in Reaction Scheme 9.
SThe reaction between the compound of the formula (78) or (79) and the compound of the formula (12) 95 can be carried out under the conditions similar to those of the reaction between the compound of the formula or (Ir) and the compound of the formula (12) in Reaction Scheme-9.
The reaction between the compound of the formula (77) and the compound of the formula and the reaction between the compound of the formula (79) and the compound of the formula (17) can be carried out under the conditions similar to those of the reaction between the compound of the formula (1A) and the compound of the formula 1 3 and the reaction between the compound of the formula (lo) and the compound of o o the formula (17) in Reaction Scheme-9. In the reaction ,between the compound of the formula (77) and the compound of the formula 2 mols of the compound of 9 3 l the formula (13) may react with the compound of the formula (77) to form the compound having group: -N(R )2.
The resulting compound, however, can be separated readily.
The reaction that leads the compound of the formula (59) to the compound of the formula (83) can be carried out under the conditions similar to those of the Witting Reaction that leads the compound of the formula (1g) to the compound of the formula (ig) in Reaction Scheme-9.
S O.o The reaction between the compound of the formula and the compound of the formula (15) can be carried T I "II~" 96 0 0 8 04g 0 0 00 00 0 000 00 15 0 0 o *a o o 0 84
'WL
S tt out under the conditions similar to those of the reaction between the compound of the formula (1t) and the compound of the formula (13) or the reaction between the compound of the formula (lo) and the compound of the formula (17) in Reaction Scheme-9.
The reaction between the compound of the formula (77) or (79) and the compound of the formula (14) can be carried out under the conditions similar to those of the reaction between the compound of the formula (1) or (lo) and the compound of the formula (14) in Reaction Scheme-9.
The reaction between the compound of the formula (77) or (79) and glyoxal (16) and the subsequent reduction reaction can be carried out under the conditions similar to those of the reaction between the compound of the formula (19) or (1o) and glyoxal (16) and the subsequent reduction reaction in Reaction Scheme-9.
The reaction which leads the compound of the formula (83) to the compound of the formula (84) can be carried out under the conditions similar to -those of the reaction that leads the compound of the formula (lq) to the compound of the formula (ly) in Reaction Scheme-9.
The reaction between the compound of the formula (84) and the compound of the formula (19) can be carried 97 0 0 0 415 00co 090 09 0002 out under the conditions similar to those of the reaction between the compound of the formula (77) and the compound of the formula (15) mentioned before.
The reaction between the compound of the formula (84) and the compound of the formula (20) can be carried out under the conditions similar to those of the reaction between the compound of the formula (77) and the compound of the formula (13) mentioned before.
The hydrolysis reaction of the compound of the formula (85) can be carried out under the conditions similar to those of the hydrolysis reaction of the compound of the formula (lz) in Reaction Scheme-9.
The compounds of the formulas (82), (87) (88) and (84) can be led to respectively corresponding compounds having the following partial structure
NJ
H
OH
by subjecting them to the reaction which is carried out under the conditions similar to those of the reaction which leads the compound of the formula (59) to the compound of the formula (60) in Reaction The carbonyl group of the compounds of the formulas (89) and (90) can be led to -CH 2 -group by subjecting
B
i 4 t I0 44 'r 2 0 4 l a 98 the compounds of the formulas (89) and (90) to the reduction reaction carried out under the same manner as that of the reduction reaction of the compound of the formulas (It) and (lv) in Reaction Scheme-9.
41 When one of R or R is a hydrogen atom and the 4a 4a other is group R 4a (wherein R 4 has the same meaning as defined above) in the formula the compound of the following formula (81a):
NR
4 a N (81a) 00 a (wherein R 4 a has the same meaning as defined above) can also be obtained by the reaction between the compound of the formula (59) and the compound of the formula (18).
G Oa The above mentioned compound can be let to the compound of the following formula (82a): N' HR 4a (82a) (wherein R4ahas the same meaning as defined above) in the same way as the reduction reaction of the compound of the formula (81).
II-
99 [Reaction Scherne-18]
I
I
I
,OH (11)
\R/
PN
OH
(94) Reduction (92) i Reduction
NH
2
N'N
OH
(93) Hydrolysis
R
1 5 0 R 1 1
N
OH
('107) 100 4*4 *4 44 4
III,
4444 44 4' 4 444 4441 I I 444~
NH
2
N
OH
NHR
1 4
R
1 "O C H Ol
NHCH
2
CH
2 0H 1(14 Reduction C' N' 2 2) N OH (15) RXc
R
2 C12
OH
(12)
R
1 qoOH OH2 98 HO(96) (99)'C 10 2
C
2 O (12) H\1 NNNR9
W
1 0
NN
O H O OH 3 (104 20100 (92) (17)
/R
9 ,13=
/R
N15 Redutio RN(1)o N /H\R1 3 R C\1 R 40HI H\1 5:6N'NN No 2 2 0 OH on= OH3C(14 10 (10)(03 -101 wherein R 2
R
4
R
5 R 9 R 0 R R 1 2 R 1 3
R
14
R
15 and X 3c have the same meanings as defined above.
The reaction between the compound of the formula and the compound of the formula (11) can be carried out under the conditions similar to those of the reaction between the compound of the formula (ig) and the compound of the formula (11) in Reaction Scheme-9.
The reduction reaction which leads the compound of the formula (92) to the compound of the formula (93) can be carried out under the conditions similar to those of the reduction reaction which leads the compound of the formula (1k) to the compound of the formula (1k) in Reaction Scheme-9.
The reaction between the compound of the formula (70) and the compound of the formula (18) can be carried out under the conditions similar to those of the reaction between the compound of the formula (1g) and the compound of the formula (10) in Reaction Scheme-9.
The reduction reaction which leads the coinpoUrd of the formula (94) to the compound of the formula (95) can be carried out under the conditions similar to those of .re-duction reaction, which leads the. compound of the formula (1m) to the compound of the formula (1n) ip Reaction Scheme-9.
The reaction between the compounds of the formula -102 (99) or (96) and the compound of the formula (12) can be carried out under the conditions simila- to those of the reaction between the compounds of the formula (1i) or (Ir) and the compound of the formula (12) in Reaction Scheme-9.
The reaction between the compounds of the formula (93) or (96) and the compound of the formula (16) and the subsequent reduction reaction can be carried out under the conditions similar to those of the reaction between the compounds of the formula or (lo) and the compound of the formula (16) and the subsequent reduction reaction in Reaction Scheme-9.
The reaction between the compounds of the formula :i ;S (93) or (96) and the compound of the formula (14) can V" 15 be carried out under the conditions similar to those of °the reaction between the compounds of the formula (1) or (lo) and the compound of the formula (14) in Reaction Scheme-9.
+o o The reaction between the compounds of the formula 20 (93) or (96) and the compound of the formula (15) can be j carried out under the conditions similar to those of the reaction between the compound of the formula (1t) and the compound of the formula (13) or the reaction between the compound of the formula (lo) and the compound of the formula (17) in Reaction Scheme-9.
LZI~~_ -103 The reaction between the compound of the formula (93) and the compound of the formula and the reaction between the compound of the formula (96) and the compound of the formula (17) can be carried out under the conditions similar to those under which the reaction between the compound of the formula (19) and the compound of the formula (13 and the reaction between the compound of the formula (io) and the compound of the formula (17) in Reaction hem--9 are carried out.
2 In the above reaction, when R 2 of the compounds of the formulas (93) and (96) are a hydrogen atom,.the reaction between the 1-position of the hydroquinoline ring and the compound of the formula (13) may occur. The resulting compound, however, can be separated readily. In the reaction between the compound of the formula (93) and o the compound of the formula 2 mols of the compound of the fo/mula (13) may react with the compound of the formula (93) to fo. the compound having groupi -N(R 9 2 However, the resulting compound can be separated readily.
The reaction which leads the compound of the formula to the compound of the formula (105) can be carried out under the conditions simila, to those of the reaction which leads the compound of the formula (1g) to the ocm- -pound of the formula (lq) in Reaction Scheme-9.
The roaction which leads the compound of the formoia 104 (105) to the compound of the formula (106) can be carried out under the conditions similar to those of the reaction which leads the compound of the formula (lq) to the compound of the formula (ly) in Reaction Scheme-9.
E The reaction between the compound of the formula (106) and the compound of the formula (19) or (20) can be carried out under the con,'-ions simi-lar to those of the reaction between the compound of the formula (84) and the compound of the formula (19) or (20) in Reaction Scheme-17.
The hydrolysis reaction of the compound of the formula (107) can be carried out under the conditions similar to those of the hydrolysis reaction of the compound of the j formula (lz) in Reaction Scheme-9.
Tho compounds of the formulas (70) (93) (99), (94) (105) (106) and (107) if necessary, may be allowed to react respectively with the compound of the I formula (71) under the conditions similar to those cf the 1| .reacLion between the compound of the forTmula (70) and the compound of the formula (71) in Reaction Scheme-16 to convert the 8-position of the hydroquinoline ring thereof to -CH 2
OR
3 0
(R
3 0 has the same meanina as defined above), followed by subjecting them respectively to the reactions shown in Reaction Scheme-18, and to the reaction which carried out under the conditions similar to those of the
II
41 _1 i 105 reaction which leads the compound of the formula (74) to the compound of the formula (75) to convert the 8-position of the hydroquinoline ring thereof to
-CH
2 0H group.
In the compound of the formula when one of 4' 5 1' R or R is a hydrogen atom and the other is group: R4a (R4a has the same meaning as defined above), the compound of the following formula: 0
NR
4 a (94a) a /OH I 0 9 (wherein R and R 4 a have the same meanings as defined above) can also be obtained by the reaction between the compound of the formula (70) and the compound of the Sformula (18).
The above-mentioned compound can be led to the 20 compound the following formula: I N
H
R
4 a
R
2
OH
106 2 4a (wherein R 2 and R a have the same meanings as defined above), in the same manner as that of reduction reaction which leads the compound of the formula (94) to the compound of the formula [Reaction Scheme-19]
R
31 X (108) Reduction (72) (109) a
B
de 4e 4 44 00 00 o, QOo
OR
30 011) (112) 00 0 08 044 a 0 a 44 4\ 4 wherein R 31 represents a lower alkyl group which may have 1 to 3 halogen atoms, a phenyl group, a hydroxy-substituted lower alkyl group, a lower alkanoyloxy lower alkyl group, and R 2 R 3 0
X
3 and X3b have the same meanings as defined above.
The reaction between the compound of the formula (72) and the compound of the formula (108) can be carried
I
J
-107 out in a suitable solvent in the presence of a basic compound. Examples of the solvent and basic compound which can be used include all of the solvents, and basic compounds used in the reaction between the compound of the formula (70) and the compound of the formula (71) in Reaction Scheme-16.
The suitable amount of the compound of the formula (108) is at least equimolar, preferably equimolar to 2 mols, of the compound of the formula (108) per mol of the compound of the formula (72).
The reduction reaction of the compound of the formula (109) can be carried out under the conditions Do aO v 1 similar to those of the reduction reaction of the compound of the formula (1g) in Reaction Scheme-7.
15 The reaction between the compound of the formula (110) and the compound of the formula (65) can be carried out under the conditions similar to those of the reaction between the compound of the formula (73) and the compound o of the formula (65) in the Reaction Scheme-16.
The reaction which leads the compound of the formula (111) to the compound of the formula (112) can be carried out under the conditions similar to those of the reaction Swhich leads the compound of the formula (74)'to the compound of the formula (75) in Reaction Scheme-16.
In the compound of the formula and the starting I -108 compounds shown in Reaction Schemes 10 to 12, when the group R is a lower alkoxycarbonyl group, the group R 3 can be led to a hydroxymethyl group by subjecting the compounds having the group R to the reduction reaction which can be carried out under the conditions similar to those of the reduction reaction which forms the compound _f the formula (1h) from the compound of the formula (ig) in Reaction Scheme-7.
3 When the group R is a lower alkoxycarbonyl group, the group R can also be led to a carboxy group by subject- 3 ing the compounds having the group R to the hydrolysis reaction. The hydrolysis reaction can be carried out under the conditions similar to those of the hydrolysis ,so reaction of the compound of the formula (1z).
t15 Furthermore, when the group R is a carboxy group, 3 the group R can be led to a lower alkoxycarbonyl group 3 by subjecting the compound having the group R to cono ventional esterification reaction. The esterification SI: reaction can be carried out under the conditions similar 20 to those of the reaction between the compound of the formula (31) and the compound of the formula (32) in Reaction Scheme-11.
3 When the group R is a carboxy group, the group
R
3 can be led to the amidb group represented by the following formula: i It ii i 109
R
4
-CON\R
\R
4' 5' (wherein R and R have the same meanings as defined above) by subjecting the compound having the group R to the reaction with an amine represented by the following formula: 41 5' (wherein R and R have the same meanings as defined above). This reaction can be carried out in the same 6 manner as that of the reaction which obtains the com- .0 pound of the formula (It) from the compound of the o 15 formula (1l) in Reaction Scheme-9.
0 o When the group R denotes the group of the formula:
/R
4 4 -CON 4 20 (wherein R 4 and R 5 have the same meanings as defined a *3 above), the group R can be led to the group of the formula: 4 110 -i S-110
V
(wherein R 4 and R 5 have the same meanings as defined above) by subjecting the compounds having the group R to the reduction reaction carried out in the same manner as that of the reduction reaction of the compounds of the formulas (It) and (Iv) in Reaction Scheme-9. In the above reaction, when the groups 4 5 R and R denote a cycloalkylcarbonyl group or a lower alkanoyl group, they may be reduced simultaneously to form the cycloalkyl lower alkyl group or the lower alkyl group.
In Reaction Schemes 10 to 14, 16, 18 and 19, when 2 2' the group R or R of each starting compound is a lower alkynyl group possessing a tri-lower alkylsilyl 2 2' group, the group R or R can be led to the lower S 15 alkynyl group by subjecting the compounds havina the I R2 2' group R or R to the desilylation reaction under the conditions similar to those of the de.silylation o reaction of the compounds of the formulas (la) to (ld).
Among the compounds represented by the formula 20 according to the present invention, compounds having acidic groups can be easily converted to salts by reacting them with a pharmaceutically acceptable basic compound. The basic compound is exemplified by metal hydroxides 'l.ch as sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, etc., -e n; 111 alkali metal carbonates or alkali metal hydrogen carbonates such as sodium carbonate, sodium hydrogen carbonate, and alkali metal alcoholates such as sodium methylate, potassium ethylate, etc. While among the compounds represented by the formula compounds having basic groups can be easily converted to salts by permitting a pharmaceutically acceptable acid to act thereon. The acid is exemplified by inorganic acids such as sulfuric acid, nitric acid, hydrochloric acid, hydrobromic acid, etc., and organic acids such as acetic acid, p-toluenesulfonic acid, ethanesulfonic acid, oxalic acid, maleic acid, succinic acid, benzoic acid, etc.
I The compound of the invention naturally includes q 015 stereoisomers and optical isomers.
oI .The thus-produced compound of this invention can be isolated and purified from the reaction system S. without difficulty by conventional means of separation.
Employable as the conventional means of separation are, 20 for instance, distillation, recrystallization, column chromatography preparative thin layer chromatography and solvent extraction.
The compounds of this invention are useful as anti-ulcer agents and are used usually in the form of ordinary pharmaceutical preparations. Commoly 112 used diluents or excipients such as fillers, extenders,, binders, wetting agents, disintegrants, surfactants and lubricants are employed in the formulation of the preparations. Various dosage forms of the therapeutic agents can be selected according to the purpose of the therapy. Typical dosage forms which can be used are tablets, pills, powders, liquid preparations, suspensions, emulsions, granules, capsules, suppositories, and injectable preparations (solutions, suspensions, etc.).
In molding a pharmaceutical composition into a tablet form, a wide range of carriers known in the art can be used. Examples ofsuitable carriers include excipients such as lactose, white sugar, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose and silicic acid, binders such as water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethyl cellulose, shellac, methyl cellulose, 4 20 potassium phosphate and polyvinyl pyrrolidone, disintetrants such as dried starch, sodium alginate, agar powder, laminaria powder, sodium hydrogen- 44 carbonate, calcium carbonate, polyoxyethylenesorbitan fatty acid esters, sodium laurylsulfate, stearic acid monoglyceride, starch, and lactose, disintegration -T i lle 3~i-I 113 inhibitors such as white sugar, stearin, cacao butter and hydrogenated oils, absorption promoters such as quaternary ammonium bases and sodium laurylsulfate, humectants such as glycerol and starch, adsorbents such as starch, lactose, kaolin, bentonite and colloidal silicic acid, and lubricants such as purified talc, stearic acid salts, boric acid powder, polyethylene glycol.
The tablets, if desired, can be coated, and made into sugar-coated tablets, gelatin-coated tablets, enteric-coated tablets, film-coated tablets, or tablets comprising two or more layers.
In molding the pharmaceutical composition into pills, a wide variety of conventional carriers known in the art can be used. Examples of suitable carriers are excipients such as glucose, lactose, starch, cacao butter, hardened vegetable oils, kaolin and talc, binders such as gum arabic powder, tragacanth powder, gelatin, and ethanol, and disintegrants such as laminaria and agar.
In molding the pharmaceutical composition into a suppository form, a wide variety of carriers known in the art can be used. Examples of suitable carriers include polyethylene glycol, cacao butter, higher alcohols, esters of higher alcohols, gelatin, and
V
14 114 semisynthetic glycerides.
When the pharmaceutical composition is formulated into an injectable preparation, the resulting solution and suspension are preferably sterilized, and are isotonic with respect to the blood. In formulating the pharmaceutical composition into the form of a solution or suspension, all diluents customarily used in the art can be used. Examples of suitable diluents are water, ethyl alcohol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, and polyoxyethylenesorbitan fatty acid esters. Sodium chloride, glucose or glycerol may be incrpoporated into a pharmaceutical composition, in an amount sufficient to prepare isotonic solutions. The pharmaceutical 15 composition may further contain ordinary dissolving 4 aids, buffers, painalleviating agents, and optionally coloring agents, preservatives, perfumes, flavors, sweeteners, and other drugs.
0 4 The amount of the compound of this invention as an active ingredient to be incorporated into an antiulcer preparation is not particularly limited, and can vary over a wide range. A suitable effective amount of the compound of this invention is usually about 1 to about 70% by weight, preferably 5 to by weight, based on the entire composition.
I _115 The administration method of. the anti-ulcer preparation using the compound of the invention is not particularly limited and can be adequately selected according to the form of the preparation, age and sex of the patient, and symptom of disease.
For example, the tablets, pills, liquid preparations, suspensions, emulsions, glanules, and capsules are orally admiiiistered. The injectable preparations are intravenously administered either alone or together with ordinary auxiliary agents such as glucose and amino acids. Furthermore, as required, the injectable preparations can singly be administered intramuscularly, intracutaneously, subcutaneously, or intraperitoneally.
The suppository is administered intrarectally.
The dosage of the unti-ulcer preparation containing the compound of this invention is suitably selected according to the purpose of use, age and sex of the patient, and the symptoms of disease, etc. Usually, a preferred dosage of the compound of this invention is 0.6 to 50 mg/kg body weight per day. it is advantageous that the active ingredient is contained in a single unit dose form in an amount of 10 to 1000 mg.
116 Hereinafter, this invention will be described in greater detail with reference to Reference Examples, Examples and Pharmaceuical Examples.
Example t Reference Example 1 8-Methylguinoline (4.02 q) was di9 1 solved In carbon tetrachloride (40 ml), and N-bromosc'cinimide (5.98 g) and benzoyl! peroxide (0.15 g) were added to the solution, and the mixture was heated and refluxed for 3 hours. After filterinj off the insoluble matter, the filtrate was 0 0 concentrated. The resultant residue was recrysta'.ied from ligroin to give 8-bromomethyJJquinoline (3.60 g), 0 000~ ~Pale. brown needle crystals mp: 809C~ Reference Example 2 0 8-Bromoinethyiquinoline (1.11 g) and sodium acetate 0 0(0,82 g) were sua.,,pended and dissolved in e joothyL g:o-ramidee and heate4 for 2 houro at 80 50 0 C. After oorole tion of the .j eaci,.on, dimetQ formarnide was distilled of f, and the re'Zewas extra.-b'ed with a mixed solvent of ethyl aoetate-toluene (3 1) The solvent was distilled of f to give 8-acetoxymethylqUinoline. (0,86 g).
Reference Example. 3 To a solution of 8-acetoxymethylquinoline (12.07 g) 117
!I
in methanol (80 ml) was added an 30% aqueous solution of sodium hydroxide, and the mixture was heated and refluxed for 1.5 hours. After distilling off the methanol, the resulting residue was extracted with chloroform. After drying over anhydrous magnesium sulfate, the solvent was distilled off, The residue was recrystallized from ethyl acetate-n-hexane to give 8-hydroxymathylquinoline (9.21 g).
Pale yellow needle crystals rp: 74 75 C Reference Example 4 Sodium cyanoborohydride (8.80 g) was suspended in tetrahydrofuran (50 ml) an !ormic acid (50 ml) was added to the suspension under ice-u:ooling. After purging the vessel with argon, 8-acetxymethylquinlione (5,65 g) was added thereto, and the mixture was stirred for 3 hours at room temperature. After distilling off tetrahydrofuran, water was added to the residue, and sodium hydroxide was added ,o the mixture under ice-cooling to adjust to alkalinic. The mixture was extracted with chloroform and dried over anhydrous magnesium sulfate, and the solvent was distilled off, The resulting residue was purified by silica gel column chromatography [eluent: n-hexane-ethyl acetate (4 to give 8-hydroxymethyl-l-ethyl-1, 2,3, ,,-tetrahydro- 118 01: 0, 0 0 o 0 P 00 4( 4C
C)
4 0 0u 0 *0 quinoline (2.93 g) Yellow oil NMR(CDC3) 6: 1.27 (3H, t, J 7.5 Hz), 1.66 2.00 (2H, 2.85 (2H, q, J 7.5 Hz), 3.00 3.20 4.00 (1H, 4.75 (2H, 6.93 (3H, s) Reference Example 1-Methyl-8-hydroxymethyl-1,2,3,4-tetrahydroquinoline (0.89 g) was dissolved in dichloromethane (30 ml), and thionyl chloride (1.09 ml) was added thereto, and the mixture was stirred for 2 hours at 45 0 C. After distilling off the solvent, n-hexane was added to the residue, and the solvent was distilled off under reduced pressure to give 1-methyl-8-chloromethyl-1,2,3,4-tetrahydroquinoline (1.1 g), Reference Example 6 To 8-hydroxymethyl-1,2,3,4-tetrahydroquinoline (8.03 g) and sodium hydride (60% in c1l) (1.97 g) was added tetrahydrofurah (100 ml) under ice-cooling and argon at-mosphere, and the mixture was stirred for 2 hours at to 75 CQ. ,At -70 0 C, n-butyllithium (20 ml) was added to the reaction mixture by use of a syringe, and 30 minutes after addition, a solution of methyl iodide (6.98 g) in tetrahydrofuran (30 ml) was added thereto, and The mixture was stirred for 20 hours at room temperature. After
A
i i 119 distilling off tetrahydrofuran, the resulting residue was extracted with chloroform, and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the resulting residue was purified by silica gel column chromatography [eluent: n-hexane-ethyl acetate (4 to give l-methyl-8-hydroxymethyl-1,2,3,4-tetrahydroquinoline (5.00 g).
Yellow oil NMR(CDC3)6: 1.70 2.10 (2H, 2.77 (3H, 2.80 (2H, t, J 6 Hz) 3.00 3.20 (2H, 4.80 (2H, s), I g 5.20 (1H, 6.97 (3H, s) Reference Example 7 1 To a solution of ethyl magnesium bromide prepared o 15 from magnesium (12.2 g) and ethyl bromide (55 g) in tetrahydrofuran (75 ml) was added dropwise a solution of propargyl alcohol (14 g) in tetrahydrofuran (75 ml) at o 0°C. After stirring the mixture for 1.5 hours at the same temperature, trimethylsilyl chloride (55 g) was added dropwise to this solution in 1 hour. The mixture was stirred for 1 hour at 50°C, and for 24 hours at room temperature. To the reaction mixture was added a saturatt ed aqueous solution of ammonium chloride and the mixture was extracted with diethyl ether. After distilling off the solvent, the resulting residue was dissolved in a 1 120 solution of ethanol-water (10 3) containing 1% of hydrochloric acid and stirred for 1 hour. The mixture was extracted with diethyl ether and dried, the solvent was distilled off. The resulting residue was distilled under reduced pressure to give 3-trimethylsilylprop-2-yn-l-ol (12 g).
Colorless oil bp: 77." 78 0 C (12 mmHg) Reference Example 8 To a solution of triphenylphosphine dibromide which was prepared from bromine (19.2 g) and triphenylphosphine 94 S (48 in dimethyl formamide (200 ml), was 6o added a solution of 3-trimethylsilylprop-2-yn-l-ol (10.3 g) in dimethyl formamide (40 ml) at 0°C, and the mixture S 15 was stirred for 3 hours at the same temperature and then for 12 hours at 20 0 C. After extracting the reaction mixture with petroleum ether, the extract was washed with o, a saturated aqueous solution of sodium hydrogencarbonate and dried over anhydrous magnesium sulfate, then the S 20 solvent was distilled off. The resulting residue was distilled under reduced pressure to give 3-bromo-ltrimethylsilylprop-l-yne (5.35 g).
Colorless oil bp: 44 45°C (2 mmHg) .i*1 121 Reference Example 9 8-Hydroxymeth1.quinoline (1.0 g) was dissolved in methanol (30 ml). Platinum oxide (0.25 g) was added thereto and the mixture was subjected to catalytic reduction at 3.5 kg/cm 2 40°C. After completion of the catalytic reduction, the catalyst was filtered off and the filtrate was concentrated under reduced pressure. The resulting residue was recrystallized from ethyl acetate-nhexane to give 8-hydroxymethyl-1,2,3,4-tetrahydroquinoline (1.0 Yellow needle crystals mp: 67 68 0
C
1 Reference Example SIn a manner analogous to Reference Example 9, the i compound mentioned below was obtained using appropriate S0 starting materials.
.i 15 4-Methyl-8-hydroxymethyl-1,2,3,4-tetrahydroquinoline
NMR(CDCZ
3 )6: o 1.27 (3H, d, J 7 Hz) 1.43 2.20 (2H, 2.77 3.07 (1H, 3.17 3.50 (2H, 4.57 (2H, s), I{ 6.53 (1H, t, J 8 Hz), 6.85 (1H, d, J 8 Hz), 7.02 (1H, d, J 8 Hz) In a manner analogous to Reference Example 4, the compound obtained in Reference Example 6 and those mentioned below were obtained using appropriate starting materials.
R
3
HOH
2 C 2 L a 4.4 .4 448 .4 84 8 4 .44 44 .4.4 .4 o 8~ Reference Cr t az fr Melting point Examples R 2
R
3 (recrystallization (OC) 11 n-C 4
H
9 H NMR 1 12 CH 3 4 CH 3 NMR 2 13 C 2
H
5 i 6 Br Pale yellow powder10 6 (n-hexane-ethyl acetate) 10 14 C 2
H
5 6- OCH 3 NMR 3
CH
3 5 OCH 3 NMR 4
J~.
4 123 1) NMR (CDC Z 3 6: 0. 97 (3H, t, J 7 7Hz), 1. 13 2. 00 (6H, in), 2. 67 3. 00 (4H, in) 3 3.00 3 .23 (2H, mn) 4. 77 (2H, s) 6.97 (3H, brs) 2) NMR (CDC k 3 6: 1. 33 (2H, d, J =8 Hz), 1 .43 27 (2H, mn), 2. 67 3. 23 (3H, mn) 2 2.77 (3H, s) 4 4.83 (2H, s) 6 .93 7.37 M,1 in) 3) NMR(CDCY, 3 )6: 1. 23 (3H, t, J =8 Hz) 63 2. 00 (2Hf in) ,2.60 -3 .27 (6H, mn), 3.73 (3H s) 4. 73 (2H, s) 6 .47 (1H, d, J =2 Hz) 6. 57 d, J 2 Hz1) 4) NMR (CDC k 6: 1. 70 2. 00 (2H, in), 2 .50 2 2.80 (2H, in) 2. 74 (3H, s) ,2.90 3.20 (2H, n) 3.78 (3H, s) ,4.73 (2Hi, s) 46 (lH f d) 98 (1H, d) In a manner analogous to Reference 8xarnple 6, the compounds obtainea in Reference Examples 4, and 11 to and those mentioned below were obtained using appropriate starting materials.
HOH
2 C 2 Kq~
A
%bA*- 0 0~~ 000~ 0 4 *00 co. a ceo C 0 e o0 0 o a e *00 0 0 0 0 a
COO
Co~ CC C C.
0 00 Re~ference R 2
R
3 NMR (CDC2.g)6: Examples 1.57-2.OO(2H,m), 2.73(2H,t,J=7Hz), 2.9O-3.l3(2Hm), 16 CH 2
CH=CH
2 H 3.42(2H,d,J=GHz), 4.63(21{,s), 5.03-5.40(2H,n) 5.67-6.17(1H,n), 6.710-7.20(3H,nO 0.17C9H,s), 1.67-2.07(2H,m), 2.80(2H,t,J=7Hz), 17 CH 2 -C C-Si(CH3) 3 H 3.13 3.37(2H,m), 3.72(2H,s), 4.73(2H,S), 6. 77-7 .12 (3H ,m) is-H 1.63-2.07(2H,M), 2.73-3.07(4{,M), 4.07(2H,s), 18 C 2 ~4.82(2H,s), 6.9O-7.6O(8H,m) 19 COCH 3
H
125 Reference Example Sodium cyanoborohydride (7.9 g) was dissolved in tetrahydrofuran (50 ml). After adding and dissolving 8-hydroxymethyl-4-methylquinoline (3.5 g) in the solution, formic acid (50 ml) was added dropwise thereto with stirring under ice-cooling in nitrogen stream. The mixture was stirred for 5 hours at room temperature. After completion of the reaction, water was added to the reaction mixture and the mixture was concentrated under reduced pressure. The resulting residue was adjusted to alkalinic with a sodium hydroxide aquenous solution and extracted with chloroform. After drying the extract over anhydrous magnesium sulfate, chloroform was distilled off.
The resulting residue was purified by silica gel column 15 chromatography [eluent: dichloromethane-methanol(200 0 0o n ~o then 1,4-dimethyl-8-hydroxymethyl-1,2-dihydroquinolieine (0.9 g) was obtained.
NMR(CDC.Z
3 oil 2.08 (3H, d, J i.5 Ha), 2.58 (3H, 3.50 3.70 (2H, 4.78 (2H, 5.50 5.70 (1H, 6.90 7.30 (3H, m) Reference Example 21 1,4-Dimethy-hydrthyl-8-hydroxymethy2-dihydroquinoline (0.9 g) was dissolved in dichloromethane (30 ml). To this solution was added dropwise thionylchloride (0.6 g) with 126 stirring under ice-cooling, and the mixture was stirred for 30 minutes. After completion of the reaction, dichloromethane was distilled off under reduced pressure, and n-hexane was added to the residue. The mixture was concentrated under reduced pressure to give 1,4-dimethyl-8chloromethyl-1,2-dihydroquinoline (0.8 g).
Reference Example 22 To a mixture of 2-hydroxymethylaniline (25 g), triethylamine (32 ml) and tetrahydrofuran (250 ml) was introduced phosgene generated from trichloromethyl chloroformate (12.2 ml) and active carbon,at room temperature with stirring. After stirring for 1 hour at room temperature, the reaction mixture was filtered off and the filtrate was concentrated. The resulting residue was o:t 15 recrystallized from diethyl ether-n-hexane to give 4H-1,2oo° dihydro-2-oxo-[3,1] benooxazine (22.3 g).
0 r UWhite needle crystals 00o0 ao mp: 120 1210C Reference Example 23 To a solution of 4H-1,2-dihydro-2-oxo-[3,31benzoxazine (13 g) in tetrahydrofuran (250 ml) was gradurally 0 o* added sodium hydride (4.2 g) at room temperature 0 with stirring. Then the mixture was stirred for 1 hour at 0 C. After distilling off the solvent, methyl acrylate (10 ml) was added to the residue and the Mixture was 127 heated for 3 hours at 50°C. The reaction mixture was concentrated and extracted with diethyl ether, and the extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled to give a crude methyl 3-(4H-1,2-dihydro-2-oxo-[3,1]benzoxazin-lyl)propionate.
NMR(CDCk 3 6: 2.80 (2H, t, J 8 Hz), 3.70 (3H, 0) 4.20 (2H, t, J 8 Hz), 5.20 (2H, 6.96 7.48 (4H, m) The above compound was used in the next reaction without purification.
To a solution of methyl 3-( 4 H-1,2-dihydro-2-oxo- [3,1]benzoxazin-1-yl)propionate obtained above in methanol (60 ml) was added a saturated aqueous solution of 015 sodium carbonate (10 ml) and the mixture was refluxed for 6 hours. The reaction mixture was washed with diethyl *ether, the water layer was adjusted to acidic with aqueous solution of concentrated hydrochloric acid. The mixture was extracted with diethyl ether, and the solvent I 20 was distilled off to givi 3-(4H-1,2-dihydio-2-oxo-[3,1] benzoxazin-1-yl)propionic acid (20 g).
d NMR(CDC k 3 6: 2.86 (2H, t, J 7 H2), 4.22 (2H, t, J 7 Hz), 5.30 (21, 6.93 7.50 (4H, m) Reference Example 24 7' -T -I i 128 The polyphosphoric acid prepared from phosphorus pentoxide (50 g) and phosphoric acid (50 ml) was heated to 100°C, and 3-(4H-1,2-dihydro-2-oxo-[3,1]benzoxazin-1-yl) propionic acid (20 g) was added thereto. The mixture was heated with stirring at 100 0 C for 4 hours. Then water was added to the reaction mixture and the mixture was extracted with dichloromethane. After the extract was dried over anhydrous sodium sulfate and concentrated, the residue was purified by silica gel column chromatography (eluent: dichloromethane) and recrystallized from ethyl acetate-n-hexane to give 6,7-dihydro-3,7-dioxo-lH,3H,5Hpyrido[3,2,1-ij] benzoxazine (5.1 g).
White needle crystals mp: 130 131C o l 0 6 1 5 Regarding 1H,3H,5H-pyridol3,2,1-ij 1benzoxazine derivatives obtained above and hereinafter, the substitua. tion position number of the skeleton was defined as below E according to the Chemical Abstract, vol. 102, p. 612, 1985.
2 0 t In 129 Reference Example A solution of 6,7-dihydro-3," -dioxo-1H,3H,5H-pyrido [3,2,1-ij][3,1b'enzox.azine (2 ethylene glycol (2.2 ml) and p-toluenesulfonic acid (catalytic amount) in toluene ml) was refluxed by use of Dean-Stark apparatus for 3 hours. After washing the reaction mixture with a saturated aqueous solution of sodium hydrocarbonate, the mixture was dried over anhydrous magrnesium sulfate. The solvent was distilled off tQ give 6,7-dihydro-3-oxo-7,7ethylenedioxy-1H,3H,5H-pyrido[3, ,1-ij] [3,lbenzoxazine (2.1 g).
NMR(CDCZ
3 6 2.08 2.17 (2H, 4.00 4.12 (2H, 4.12 4.30 (4Hi 7.03 7.50 (3H, m) S( 15 Reference Example 26 S" 6,7-Dihydro-3-oxo-7,7-ethylenedioxy-lH,3,5H-pyrido- 13,2,1-ij [3,11benzoxazine (4 g) was dissolved in a mixture of 10% aqueous solution of sodium hydroxide and Smethanol (1 10 v/v, 90 mll and the solution was refluxed for 2 hours, sequntially the solvent was distilled off and the resulting residue was extracted with dichoro- L L methane. The extract was washed with water and dried.
After distilling off the solvent, the resulting residue.
was recrystallized from n-hexane-ethyl acetate to give a 25 8-hydroxymethyl-4,4-ethylenedioXy-1 ,2,3,4-tetrahydro- *P a i a- "9 130 quinoline (2.6 g).
Pale yellow plate crystals mp: 140 141'C Reference Example 27 To a solution of 8-hydroxymethyl-4,4-ethylenedioxy- 1,2,3,4-tetrahydroquinoline (2.5 g) in tetrahydrofuran ml) was added n-butyllithium (14.5 to 17% solution in n-hexane) (10 ml) at -40 0 C and stirred for 30 minutes.
Then methyl iodide (1.9 g) was added to the reaction mixture and the mixture was stirred for 3 hours at -301 to -100C and for 30 minutes at -5OC. After distilling off the solvent, n-hexane-ethyl acetate Was added to the resulting residue and the insoluble matter was filtered off. The filtrate was concentrated to give 8-hydroxy- .*t5 methyl-4 4-ethylenedioxy-1-methyl-1,2,3,4-tetrahydro- 0 0* quinoline (1.9 g).
*060 000 4 NMR(CDk) 6: t 2.00 2.13 (2H, 2.83 (3H, 3.27 3.35 (2H, 4.05 4.30 (4H, m) 4.80 (2H, 7.03 (11, t, 3 6 Hz), 7.18 (1H, dd, J 1.6 Hz), 7.39 (11, dd, J 1.6 Hz) Reference Example 28 To a solution of 6,7-dihydro-3,7-dioxo-1H,3H,5Hpyrido[3,2,1-ijl 3,1benzoxazine (1 g) in methanol (20 ml) was added sodium borohydride (186 mg) by portions at room -131 temperature and the mixture was stirred for 30 minutes at the same temperature. After distilling off the solvent, the resulting residue was extracted with dichloromethane.
The extract was washed with water and dried, and the solvent was distilled off to give 6,7-dihydro-3-oxo-7hydroxy-lH,3H,5H-pyrido[3,2,1-ij] [3,1]benzoxazine (0.9 g).
NMR(CDk 3 )6: 2.03 2.18 (2H, m) 3.80 4.00 (1H, m) 4.00 4.20 (1H, 4.84 (1H, q, J 5 Hz), 5.21 (2H, 7.06 (2H, d, J 5 Hz), 7.38 (1H, t, J 5 Hz) Reference Example 29 To a solution of 6,7-dihydro-3-oxo-7-hydroxy-lH,3H,5Hpyrido[3,2,l-ij] [3,1]benzoxazine (4.3 g) in dimethyl o15 formamide (50 ml) was added sodium hydride 941 mg)
SAD
at room temperature and the mixture was stirred for minutes. To this mixture was added a solution of methyl 4 8*A iodide (3.4 g) in dimethyl formamide (5 ml) and the Smixture was stirred for 1 hour at the same temperature.
Sequentially the reaction mixture was extracted with a mixed solvent of benzene-ethyl acetate (1 The Sextract was washed with water and dried, the solvent was distilled off and the resulting residue vas purified by silica gel column chromatography (eluent: dichloromethane) 23 to give 6,7-dihydro-3-oxo-7-methoxy-lH,3H,5H-pyrido- -132- [3,?,1-ijl[3,1]benzoxazine (4.3 g).
NMR(CDYZ
3 1. 85 2 .08 (1H, m) 2. 15 2 .31 (1Hi, m) 3 342 (3H, s) 3. 70 87 (lH, m) 4. 02 4. 18 (1Hi, m) 4. 29 (1HI, t, J =4 Hz) 5.20 (2H, s) 6.96 7.12 (211, in), 7.22 7.32 (1H, m) Reference Example 6, 7-Dihydro-3-oxo-7-methoxy-lH, 3H, 51li-pyrido [3 ,2,1iji [3,1]benzoxazine (4.3 g) was dissolved in a mixture of 10% aqueous solution of sodium hydroxide and methanol (1 v/v, 55 ml) and the mixture was refluxed for 2 hours.
After distilling off the solvent, the resulting residue was extracted with dichloromethane. The extract was washed with water and dried, the solvent was removed. The resultant residue was purified by silica gel column A Achromatography [eluent: n-hexane-ethyl acetate (4 :1 to give 8-hydroxymethyl-4-methoxy-1,2,3,4-tetrahydroqcuinoline (2.4 g).
6 i
NMR(CDZ
3 6: 420 1.65 -1.88 (1H, m) 2.01 -2.18 (1H, m) 2.92 (1H, brs), 3.16 -3.50 (2H, in) 3.33 (3H, 4.20 (1H, t, J =3 Hz) 4.37 (1H, d, J =13 *Hz) 4.44 (1Hl, d, J ~.13 Hz) ,4.95 (1H, brs) 6.55 (1H, t, J 7 Hz), 6.91 (lHr dd, J =2.7 Hz) 7.06 (111, dd, J =2.7 Hz)
A<I
iQsr rmn~---31-r 133 Reference Example 31 In a manner analogous to Reference Example 27, the compound mentioned below was obtained using appropriate starting materials.
8-hydroxymethyl-4-methoxy-l-ethyl-1,2,3,4-tetrahydroquinoline
NMR(CDA
3 )6: 1.25 (3H, t, J 7 Hz), 1.93 2.05 (2H, 2.96 (2H, q, J 7 Hz), 3.11 3.25 (2H, m) 3.42 (3H, s), 4.28 (1H, t, J 5 Hz), 4.51 (1H, brs), 4.69 (1H, d, J 13 Hz), 4.79 (1H, d, J 13 Hz), 6.98 (1H, t, J 7 Hz) 7.16 (1H, dd, J 2.7 Hz), 7.22 (1H, dd, J 2.7 Hz) Reference Example 32 15 8-Hydroxymethyl-l-ethyl-4-oxo-l, 2,3,4-tetrahydroo quinoline (1.44 g) was dissolved in dimethyl formamide (2 a° ml). Imidazole (1.57 g) and t-butyl dimethylsilyl chloride (1.16 g) were added to the solution and the mix- I'o ture was stirred overnight at room temperature. Water was 20 added to the reaction mixture and the mixture was Sextracted with ethyl acetate-toluene. After the extract t was dried over anhydrous magnesium sulfate, the solvent was distilled off. The resulting residue was purified by silica gel column chromatography [eluent: n-hexane-ethyl acetate (3 to give 4-oxo-8-t-butyldimethylsilyloxy- V% t
I
I 134 methyl-l-ethyl-1,2,3,4-tetrahydroquinoline (2.18 g), Yellow oil Reference Example 33 4-oxo-8-t-butyldimethylsilyloxymethyl-l-ethyl- 1,2,3,4-tetrahydroquinoline (2.17 g) was dissolved in methanol (20 ml). To this solution was added sodium borohydride (0.26 g) at room temperature, and the mixture was stirred for 10 minutes. Water was added to the reaction mixture and the solvent was distilled off to give 8-t-butyldimethylsilyloxymethyl-4-hydroxy-1-ethyl-1,2,3,4tetrahydroquinoline (2.30 g).
Reference Example 34 8-t-butyldimethylsilyloxymethyl-4-hydroxy-l-ethyl- 1,2,3,4-tetrahydroquinoline (2.19 g) was dissolved in dimethyl formamide (15 ml), followed by addition of sodium o hydride (60% in oil, 0.33 and allyl bromide (0.99 g) 4, was added thereto under ice-cooling. The mixture was stirred for 2.5 hours at the same temperature. Further- 1 more sodium hydride (60% in oil, 0.16 g) and allyl bromide (0.48 g) were added to the reaction mixture and the mix- S tuze was stirred overnight at room temperature. Water was S added to the reaction mixture. The mixture was extracted with ethyl acetate-toluene and dried over anhydrous magnesium sulfate, and the solvent was distilled off. The resulting residue was purified by silica gel column 4* 4 ti 135 chromatography [eluent: n-hexane-ethyl acetate (6 to give 8-t-butyldimethylsilyloxymethyl-4-allyloxy-lethyl-1,2,3,4-tetrahydroquinoline (1.83 g).
Yellow oil Reference Example 8-t-Butyldimethylsilyloxymethyl-4-allyloxy-l-ethyl- 1,2,3,4-tetrahydroquinoline (1.81 g) was dissolved in tetrahydrofuran (20 ml), and to this solution was added dropwise 1M tetrabutylammonium fluoride-tetrahydrofuran solution (6 ml) under ice-cooling. The mixture was stirred for 1 hour at the same temperature. Water was added to the reaction mixture and after distilling off tetrahydrofuran, the residue was extracted with dichloromethane. The extract was dried over anhydrous magnesium o 15 sulfate and distilled off then 8-hydroxymethyl-4allyloxybooe l-ethyl-l,2,3,4-tetrahydroquinoline (1.30 g) was obtained.
a" Yellow oil 0 S, Reference Example 36 Sa, 6,7-Dihydro-3,7-dioxo-lH,3H,5H-pyrido3,2,l-ij [3,11 benzoxazine (5 hydroxylamine hydrochloride (2.1 g) and S sodium acetate (7.5 g) were dissolved in a mixed solvent of ethanol-water (5 1) (90 ml) and the mixture was refluxed for 2 hours. After completion of the reaction, the solvent was distilled off and the resulting residue was poured into water. Crystals which precipitated were -136 collected by filtration and dried to give 6,7-dihydro-3oxo-7-hydroxyimino--1H,3H,5H-pyrido[3,2,l-ij] [3,1]benzoxazine. The compound was dissolved in acetic acid (150 ml) and platinum oxide (250 mg) was added thereto. The mixture was subjected to catalytic reduction at 50'C and 4 atmospheres, After completion of the catalytic reduction, catalyst was filtered off and the filtrate was concentrated to give 6,7-dihydro-3-oxo-7-amino--lH,3H,5H-pyrido 1[3,2,1-ij] [3,1]benzoxazine (5 g).
Yellow oilI NMR (CDC 3 6: 2.13 2.32 (2H, in), 3.78 4.13 (2H, mn), 4.35 o 11,br) 70 7.13 (2H, in), 7.36 -7.45 (1H, n Reference Example 37 a a 15 6,7-Dihydro-3-oxo-7-arnino-lH,3H,5H-pyrido[3,2,1-ij]- 0 Q,O (3,2.Ibenzoxazine (5 q) was dissolved in~ a mixed solution of formic acid (10 ml) and 37% aqueous solution of formajlin (10 ml) ,and stirred fo,- 5 hours at 100 0 C. The, residue, obtained by removing the solvent, was extracted with dichloroinethane. The extract wa8s washed with a saturated agueoias solution of sodium hydrogencarbonate and dried over anhydrous mnagnesium sulfate, and the solvo.nt was distilled off to give 6,7-dihydro--3-oxo-7-dimethylaiino-lH,31H,5H-pyriao[3,2,4-ij] r3,llbenzoxazine (4.8 g).
Red viscous oil 137 NMR(CDCk 3 6: 1.94 2.11 (2H, 2.29 (6H, 3.53 (1H, t, J 6 Hz), 3.59 3.76 (1H, 4.07 4.25 (1H, 5.17 (2H, 6.95 7.05 (2H, 7.34 7.46 (1H, m) Reference Example 38 To a solution of 4-oxo-l-ethyl-8-hydroxymethyl- 1,2,3,4-tetrahydroquinoline (3.80 g) in methanol (40 ml), molecular sieve 3A (4 cyclopropylamine (11.42 g) and p-toluenesulfonic acid (catalytic amount) were added and the mixture was stirred for 8 hours at 65 0 C. After icecooling the reaction mixture, molecular sieve 3A was :o filtered off, then sodium borohydride (1.05 g) was added thereto, and the mixture was stirred for 1 hour at room I I",5 temperature. A small amount of water was added to the reaction mixture, and methanol was distilled off. The residue was extracted with d(chloromethane and dried over i i j anhydrous magnesium sulfate. The solvent was distilled Soff and the resulting residue was purified by silica gel column chromatography [eluent: n-hexane-ethyl acetate to give 4-cyclopropylamino-8-hydroxymethyl- 1-ethyl- JA 1,2,3,4-tetrahydroquinoline (3.69 g).
Pale yellow oil
NMR(CDC
3 6: 0.33 0.56(4H, 1.26 (3H, t, J 7.5 Hz), 1.85 j 138 2.15 (2H, 2.15 2.30 (1H, 2.93 (2H, q, J 3.00 3.30 (2H, m) 3.85 (1H, t, J 5.3 Hz) 4.74 (2H, dd, J 13.5Hz) 6.95 (1H, t, J 7.3 Hz), 7.09 (1H, dd, J=7.3 Hz) 7.24 (1H, dd, J=7.3 Hz) Reference Example 39 Acetic anhydride (0.5 ml) and formic acid (0.25 ml) were stirred for 1 hour at 60°C, and to this mixture 4cyclopropylamino-8-hydroxymethyl-l-ethyl-1,2,3,4-tetrahydroquinoline (0.37 g) was added under ice-cooling and the mixture was stirred overnight at room temperature.
The reaction mixture was adjusted to alkalinic with aqueous solution of sodium hydroxide under ice-cooling, tit 'stirred for 0.5 hour, sequentially extracted with dichloromethane. The extract was dried over anhydrous magnesium sulfate. The residue, obtained by distilling off the solvent, was purified by silica gel column chromatography [eluent: dichloromethane-methanol (75:1)] to give 4- (N-formyl-N-cyclopropylamino) -8-hydroxymethyl- 1-ethyl-,2,3,4-tetrahydroquinoline (0.35 g).
Colorless oil NMR(CDC Z 3)6: 0.45 0.85 (4H, 1.29 (3H, t, J 7.5 Hz), 1.75 2.10 (IH, m) 2.30 2.70 (2H, 2.80 3.45 (4H, 4.77 (2H, dd, J 13.5 Hz) 4.82 (IH, br.), 5.64 J 8.5 Hz) 6.85 7.20 (3H, m) 8.50 r 139 (1H, s) Reference Example To a solution of 4-(N-formyl-N-cyclopropylamino)-8hydroxymethyl-l-ethyl-1,2,3,4-tet7tahydroquinoline (0.34 g) in tetrahydrofuran (10 ml), lithium aluminum hydride (0.10 g) was added under ice-cooling and the mixture was refluxed gently for 1.5 hours. A saturated aqueous solution of Rochelle salt was added to the reaction mixture under ice-cooling, followed by addition of diethyl ether, the mixture was stirred for 1 hour at room temperature.
After filtering off the precipitates, the organic layer was 1 I 'dried over anhydrous magnesium sulfate. The solvent was distilled off to give 4-(N-methyl-N-cyclopropylamino)-8o hydroxymethyl-l-ethyl-1,2,3,4-tetrahydroquinoline (0.30 g).
White powder: o Reference Example 41 j To a solution of 6,7-dihydro-3,7-dioxo-lH,3H,5Hpyrido[3,2, -ij] [3,1]benzoxazine (6.10 g) in methanol (100 ml) were added molecular sieve 3A (12 p-toluenesulfonic acid (catalytic amount) and allylamine (50 ml), and the mixture was refluxed overnight. After cooling the reaction mixture, molecular sieve 3A was filtered off and sodium borohydride (1.70 g) was added to the filtrate under ice-cooling, then the mixture was stirred for 1 hour T ii-- Mtpc
W
r~c~ 140 0 09 *000 0*so 00u at room temperature. To the reaction mixture was added a small amount o. water, and methanol was distilled off.
The residue was extracted with dichloromethane and dried over anhydrous magnesium sulfate. After distilling off the solvent, the resulting residue was purified by silica gel column chromatography [eluent: n-hexane-ethyl acetate (3:1)1 to give 6,7-dihydro-3-oxo-7-allylamino-lH,3H,5Hpyrido[3,2,1-ij][3,1]benzoxazine (5.89 g) Yellow oil NMR(CIDCk 3 )6: 1.90 2.10 (2H, 3.25 3.45 (2H, 3.75 3.90 (2H, m) 4.00 4.15 (1H, m) 5.10 5.35 (2i, 5.19 (2H, 5.85 '6.05 (IH, m) 6,95 7.10 (2H, 7.20 7.30 m) Reference Example 42 6,7-Dihydro-3-oxo-7-allylamino-IH,3H,5H-pyrido[3,2,1ij][3,1]benzoxazine (5.86 g) was dissolved in a solution of formic acid (7 ml) and 35% formalin (7 mi), and the solution was stirred for 2 hours at 90 0 C. Formic acid and formalin were distilled off under reduced pressUre, and to this mixture were added ice water and dichoromethane, and the mixture was adjusted to alkalinic with sodium carbonate. The mixture was extracted with diahioromethane, dried over anhydrous magnesium sulfate, and distilled off to give 6,7-dihydro-3-oxo-7-(N-methy-N- 4 0* 00 *D 0 0 -4 141 allylaiino)-1H 3H,5H-pyrido[3,2,l-ij][3,libenzoxazine (5.90 g).
Orange colored oil NMR (CDCZ 3 )6: 1.80 2.20 (2H, 2.24 (3HI 3.00 3.25 (2HI, 3.50 3.60 (1H, 3.80 3.90 (1H, 4.25 4.35 (1H, 5.10 5.30 (2H, 5.19 (2H, 5.80 6.00 (1I 6.90 7.10 (2H, 7.56 (1H, dd, J 6.5 Hz) Reference Example 43 To a solution of 6,7-dihydro-3-oxo-7-(N-ethyl-Nallylamiro) -1H,3H,5H-pyrido[3,2,1-ijl benzoxazine (5.89 g) in methanol (80 i) was added 15% aqueous solution of sodium hydroxide (20 ml) and the mixture was oo 1 refluxed for 6 hours. Aftor distiling off methanol and extracting with dichloromethane, the extract was dried :00 over anhydrous magnesium sulfate. The solvent was 000 di.sti2 ed off to give 4- (N-methyl-N-allylamiino) -8-hydroxy- 00 methyl-i 12 4:-terahydroquin oine (4.i83; g).r NMR (CDCL 3 )6: 1.70 (1H, 1.93 (2H, q 7.0 Hz), 2.24 (3H, 2.95 3.55 (481, 3.89 (1H, t, J 7.0 Hz), 4.59 (2H, dd, J 13.6 Hz), 4.80 (lii 5.0 5.25 (2H, mi) 5.75 6.00 (1H1, 6.60 (1H, tr a 7.5 Hz), 6.91 (1H, ddI J- 7.5 H1z), 7.42 (1 H, dd, J
:I
142 Hz) Reference Example 44 To a suspension of methyltriphenyl phosphonium bromide (11.85 g) in tetrahydrofuran (100 ml) ii-butyl lit-hium (10.2 ml) was added dropwise with stirring in nitrogen flow at -40 0 C. The temperature was raised to -201C over 30 minutes, a solution of 8-(t-butyldimethylsilyloxymethyl)-4-oxo-l-ethyl-L2,3, 4-tetrahydroguinoline (3.8 g) in tetrahydrofuran '100 ml) was added dropwise thereto. The temperature was raised gradually to the room temperature, the mixture was stirred for 2.5 hours. Water was added to the reaction mixture, and the mixture was 4 extracted with dichioromethane and dried, then the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-liexane-ethyl acetate to give 8-(tbutyldimethylsilyloxyzethy2)-4-methylene-1-ethyl-l,2,3,4- 4OP tetrahydroquinoli ne 4 g) p. Reference Example To a solution of 8-(t-butyldimethyllyloyMethyt)-- 4-methylene-1-ethyl-l,2,,3,4-tetrahydrouinolie (2.04 q) in tetrahydrofuran 50 ml), lOM soluition (3.2 m) of borane-dimethylsulfide complex in tetrBaydtt 4fUrar was added dropwise with stirring undk-!E ite-lihqi, A -tar stirring the mixture for 2 hours, at n r tFI
'K
143 0 0Q 00) o oo 0000 0no 00~ 0 0 water was added to the reaction mixture, and furthermore 3N aqueous solution of sodium hydroxide (10 ml) and hydrogen peroxide (10 ml) were added thereto. After stirring for 2 hours at room temperature, the reaction mixture was subjected to salting-out and extracted with dichloromethane. After the extract was dried, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography [eluent: n-hexane-ethyl acetate to give 8- (t--butyldi'nethylsilyloxymethyl) -4-hydroxymethyl-l-ethyl- 1,2,3,4-tetrahydroquinoline (1.98 g).
Reference Example 46 To a solution of 8-(t-butyldimethylsilyloxymethyl)- 1 4-hydroxymethyl-l-ethyl-l,2,3,4-tetrahydroquinoline (1.98 15 g) in pyridine (5 ml) acetic anhydride was added dropwise with stirring under ice-cooling and the mixture was itirred for 2 hours at room temperature. Pyridine was distilled off under reduced pressure, and the resultant S residue was extracted with dichloromethane. After washing with a saturated aqueous solution of copper sulfate and with water In this order, the mixture was dried and the solvent was distilled off under reduced pressure to give 8-t-butyldimethylsilyloxymethyl-4--acetyloxymethethy -ethyl- 1,2,3,4-tetrahydroquinoline (2.23 g).
Reference Example 47 00F so O 00 00ea 0 04 C4 0 ~6- -144 To a solution of 8-(t-butyldimethylsilyloxymethyl)- 4-oxo-l-ethyl,-1,2,3,4-tetrahydroquinoline (3.1 g) in tetrahydrofuran (30 ml), sodium hydride 0.48 g) and methyl iodide (0.8 ml) were added under ice-cooling, and the mixture was stirred for 1 hour. Moreover sodium hydride 0.48 g) and methyl iodide (0.8 ml) were added to the reaction mixture and the mixture was stirred for 1.,5 nours under ice-cooling. After tetrahydrofuran was distilled off, the residue was extracted with ethyl acetate and the extract was dried over anhydrous magnesium sulfate, then the solvent was distilled off. The residue 9 was purified by silica gel column chromatography [eluent: n-hexane-ethyl acetate to give 3-(t-butyldimethylsilyloxymethyl)-4-oxo-3,3-dimethyl-1-ethyl-1,2,3,4tetrahydroquinoline (2.27 g).
Red colored oil Reference Example 48 To a solution of 8-(t-butyldimethylsilyloxymethyl)- 4-oxo-3,3-dimethyl-l-ethyl-1,2,3,4-tetrahydroquinoline S 20 (2.27 g) in tetrahydrofuran (30 ml), 1M solution (7 ml) of tetrabutylammonium fluoride in tetrahydrofuran was added dropwise and the mixture was stirred for 45 minutes under ice-cooling. Water was added to the reaction mixture, and tetrahydrofuran was distilled off.' The residue was extracted with dichloromethane and dried over anhydrous -145 magnesium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography [eluent: n-hexane-ethyl acetate to give 8-hydroxymethyl-4-oxo-3,3-dimethyl-l-ethyl-1,2,3,4-tetrahydroquinoline (1.55 g).
Yellow oil Reference Example 49 To a solution of 8-(t-butyldimethylsilyloxymethyl)- 4-oxo-3,3-dimethyl-l-ethyl-1,2,3,4-tetrahydroquinoline (1.60 g) in methanol (20 ml) was added sodium borohydride 9o< (0.30 g) and the mixture was stirred for 30 minutes.
Methanol was distilled off and the resulting residue was extracted with dichloromethane. After drying the extract over anhydrous magnesium sulfate, the solvent was r o15 distilled off. The resulting crude 8-(t-butyldimethylsilyloxymethyl)-4-hydroxy-3,3-dimethyl-l-ethyl-1,2,3,4-tetrahydroquinoline was dissolved in dimethyl formamide ml), followed by addition of s(<ium hydride 0.24 g), oo methyl iodide (0.85 g) was added thereto. The mixture was stirred overnight at room temperature. The reaction mixture was extracted with ethyl acetate-toluene and dried o B over anhydrous magnesium sulfate, and the solvent was distilled off. The resulting residue was purified by silica gel column chromatography [eluent: n-hexane-ethyl acetate to give 8-(t-butyldimethylsilyloxymethyl)- -146 4-methoxy-3 ,3-dirnethyl-1-ethyl-1 2 ,3 ,4-tetr-ahydroquinoline 40 g).
Colorless oil Reference Example To a solution of 8-(t-butyldimethylsilyloxymethyl)- 4-methoxy-3 ,3 -dinethyl- 1-ethyl- 1, 2,3, 4-tetrahydroguinoline (1.40 g) in tetrahy-drofuran (20 ml), 1M solution (4.2 ml) of tetrabutylarrtonium fluoride in tetrahydrofuran was added dropwise, under ice-cooling. After the mixtute. was stirred for 45 minutes, tetrahydrofuran was distilled off and the resid~ue was extracted with dichloromethane. The extract was ried over anhydrous magnesium sulfate and the solvent was distilled off. The resulting residue was purified by silica gel column chromatography [eluent: 15 n-hexane-ethyl acetate to give 8-hydroxymethyl-4cu methoxy-3 -dimethyl-I -ethyl-1, ,2,3 ,4-tetrahydroquinoline (0.75 g).
Colorless oil II CI Il- C~ 147 Example 1 A rolution of 5-methoxy-2-mercaptobenzimidazole(0.9 g) sodium hydride (60% in oil, 0.20 g) and 18-crown-6(i.e.
1,4,7,10,13,16-hexaoxacyclooctadecane) (50 mg) in dimethyl formamide (15 ml) was stirred for 20 minutes at room temperature. To the mixture was added a solution of 1methyl-8-chloromethyl-, 2, 3 ,4-tetrahydroquinoline hydrochloride (1,1 g) in dimethyl formamide (15 ml) and the solution was stirred for 20 hours at room temperature.
Dimethyl formamide was distilled off, and chloroform, aqueous solution of sodium hydroxide and water were added o to the resulting residue. The mixture was stirred for 2 hours and extracted with chloroform. After drying over Sanhydrous magnesium sulfate, the solvent was distilled off. The resultant residue was purified by silica gel column chromatography [eluent: n-hexane-ethyl acetate to give 8-(5-methoxy-2-benzimidazolyl)thiomethyl- 1-methyl-1,2,3,4-tetrahydroquinoline (0.80 g)
NMR(CDCZ
3 6: 1.60-2.00 (2H, 2.70 (2H, t, J 7 Hz), 2,73 (3H, 2.83-3.23 (2H, m) 3,73 (3H, 4.30 (2H, 6.67-7.40 (6H, 12.50 (1H, br.) O 4 In a manner analogous to Example 1, the compounds shown in the table below were obtained using appropriate *1 148 starting materials.
in the column of "bond between the 3- and 4-positions of the quinoline skeleton" in the table, the symbol means a single bond and means a double bond.
NN
-AR
2 4~A 0 0 0 U, 0 0 0~' 0 0
I
O 01
II
9 0
S
G S 4 S S S SO S S 4
S
094 a a -~bond between the 3- and 4- Crystal form etn on Example Rl m A R 2
R
3 n positions of (recrystallization 0 C) pin 'N.the quinoline solvent) (C skeleton 2 H CH2IC2H H sColorless needle crystals 153-153.5 2 H CH 2
C
2
H
5 H 1(ethyl acetate-n-hexane) 3 5-CaH 3 1 CHZ C 2
H,
5 H 1s NMR 1) 4 5-OCH 3 1 CH 2 C 2
H
5 H 1 S NMA 2 57-F 1 Ca 2
C
2
H
5 H 1 Yellow powder 125-126 (diethyl ether-n-hexane) 6 5-F,6-F 2 CH 2
C
2 HS H 1s NMR 3 7 5-F 25HIs NR4 2 CH 2 CH M 4 8 50OC 2
H
5 .2 CE 2
C
2
H.
5 H 1 s NMR) 6-F 9 5-C. 1 CH 2
C
2
H
5 H 1 sNR6 S-COCH3 CE 2
C
2 HS Hf 1 S NMR 7 11 S-CF 3 1 CH 2
C
2
H
5 H 1 s NM~R 8 12 4-CH 3 1 CH 2
C
2 HS s NMR 9 13 4-Ca 3 1 2 CH 2
C
2 HS HI1f NMR 10
O)
6-CH 3 14 5-CH 3 2CH 2
C
2
H
5 H 1 Pale yellow powder 153-156 3 ___(diel'hyl ether-n-hexane) 15 H 1 CH 2 H 1Colo3.less needle crystals1412 RIC2CH 3 Hs(ethyl acetate-n-hexane) 1412 -Ir-mr la I i rC, t
IC
0 *a a a a aO aao Q a" aC a a a a a a a aa aa o a 0 a a a bond between the 3- and 4- Crystal form melting point Example Ri m A RR n positions of (recrystallization (OC) No- the quinoline solvent) skeleton Yellow needle crystals (ethyl acetate-n-hexane) Colorless needle crystals 150-152.5 17_ I CH2 CH3(ethyl acetate-n-hexane) 18 5-Ck 1 CH 2
CH
3 H 1 s NMRI 19 4-CH 3 1 C11 2
CR
3 H 1 s NMR 1 2 13) 6-OC1 s NMR 14) 21 H CH 2
CH
2
CH=CH
2 H 1 s NMR 22 5-OCH3 1 CM 2
CH
2
CR=CH
2 H 1 s NMR 15 16) 23 5-F 1 CH 2
CH
2
C=CH
2 H 1 s NMR 24 H 1 CH 2 n-C 4
R
9 H 1 s NMR1 7 5-Ca 3 1 C n-C4 H I s NMR I 19) 26 S-OCR 3 1 CH 2 n-C 4 HS H 1 s NMR White powder 27 H 1 :CH 2
CR
2 CHCH H 1 s (dichloromethane- 122.0-122.5 diethyl ether) Yellow powder 28 5-CR 3 1 C 2
CH
2 CECH 1 s (dichloromethane 114.0-115.0 -diethyl etheri 29 H 1 CH 2 Cl 2 1 White powder 172.5-1,73.5 (ethyl acetate) 1- w a
I-_
4j uu no 6 0 0 0* C C 4 6r 664 0 6 6) 0 4 '6 06I I i Example No.bond between the 3- and 4positions of the quinoline skeleton Crystal form (recrystallizatirn solvent) Meltng point
(OC)
5-CU 3 1 CU 2 I CU 2 H White powder 169.5-170.0 (ethyl acetate) 20) 31 H 1 CU 2
CU
3 4-CH3 1 s 0R 5-F 21) 32 S-C 2 CU 2 C'1 3 4-CH 3 1 s NMR 6-OCH3 33 H 1 C 2
C
2 HS 6-Br 1 s NMR 22 4-CH 3 2 H sJR23) 6-CU 2CU 2
CU
3 H M White powder H L 2 C4C~i H 1 s (dichloromethane 140.5-141.5 A 3(C)3 -diethyl ether) Pale brown powder 36 5-CH 3 1 CH 2
CU
2 CSi H 1 s (dichloromethane 146.0-148.0 (CU)0 -diethyl ether) 37 5-COCH 3 1 CU 2 CH3 H 1 s NMR 2 4 :5-F 38 6-OCH3 2 CU 2
C
2
U
5 6-Br 1 s NMR 39 HPale brown powder 142-143 (ethyl acetate-n-hexane) 26) 5-C 2 CH 2
C
2
H
5 6-OCH 3 1 s NMR 6-OCH -1-27) 41 5-CO 2 CH3 1 CU 2
CU
3 H 1 s NMR 42 2 2 CH2 CH3 H 1 s NMR 2 8 r i bond betw een xa the 3- and Crystal form Meltin RAxa 2ple R-3 n positions of (recrystallization the quinoline solvent) skeleton White powder 43 2 CH 2
CH
3 H 1 s (ethyl acetate-diethyl 112-114 6-CH3,CH 6-CH3ether-n-hexane) 29) 424 2 C-CH H 1 s NMR C5I F C 2
H
5 6-OCR 3 1 sBrown powder 160.0-162.0 (ethyl acetate-n-hexane) 4 -F 46 2 CH 2 C2CH--'CH 2 H 1 s NMR 6-OC3_ 1 47 4-CR 3 1 CH 2
CHZCH=CR
2 H 1 s NMR 31 48 C3 C C32) 4 8 2 C-i~~t2/IiZ2CH= CH2 H 1 I s NMR i 9 4 9-a a *40 *a a a C -4 a4 ,I19 4 994 9 9 4~ 4 9 a 9 o 9, 9 94 991 9 9 9 99 bond between the 3- and 4- Crystal form Na ml n positions of (reciystallization Mtgo No.lRRthe quinoline scilvent) (OC) skeleton Colorless needle crystals 143-145 3 1 (diethyl ether) 5-F 33) 2 CHZ CH2CH=CH2 H 1 s NMR 6-OC 2 5 2 CMRCC 2 51 5-9 1 CH 2
CH
2
CH=CH
2 H 1 s NMR 52 5-COCH 3 1 CR 2
CH
2
CH=CH
2 H 1 s NMR 53 H 1 CH2 CH2aH White powder 168-169 (n-hexane-ethyl ac.:tate) White powder 54 5-CH 3 1 CH 2 CH2Z /F H 1 s (dichloromethane 171-171.5 -diethyl ether) White powder 2 C>CH 2 1 H 1 s (dichloromethane 143-144 -diethyl ether) 56 5-OCH 3 1 CH 2
CH
2 CECH H 1 s NMR 3 6 5-F 37) 57 1CH2 CH2CECH H s NMR 6-OCH 3 38) 58 H 1 CH 2
CH
2
C=CH
2 4-CH 3 1 s NMR 59 5-F2CH 3 Colorless needle crystals 165-165.5 6-OCH3 (ethyl acetate) L Ob. nfi
L
crr s r *r a 0 a 0 0 0 0I 000 0 0~ 0 0 a a 0 0 00r a 4 0 00 0 4 P bond between the 3- and 4- Crystal form Melting point n positions of (recrystallization No- the guinoline solvent) (OC) skeleton H 1 CR 2 -CH I H 1 s NMR 3 9 61 5-F 2 Cq 2 -CHZ- H 6-OCH 3 White powder 62 H I CH 2
CH
2
CF
3 H 1 S Whiceowoet 168-169 (aichloromethane) White powder 63 5-CH3, 1 CH2 CH 2 CF3 H 1 s (dichioromethane 158-159 diethyl ether) White powder 64 6-OCH3 2 CH 2
CH
2
CF
3 H 1 s (dichloromethane 133-134 diethyl ether) H 1 CR 2
CZH
5 4-CR 3 1l White powder 135.5-136.5 (diethyl ether) 5-F 411- 66 5-OCH 2 CH 2
C
2 5 4-CR 3 t s NXR 42) 67 5-COCH 3 1 CR 2 CH 5 4-CH3 1 s NMR 68 H 1 CR 2 I CH 2
CH=CR
2 3-CH 3 1 Colorless needle crystals 151.5-152 (diethyl ether) 69 5-CR 3 1 CH CH 2
CH=CH
2 3-CR 3 1Colorless needle crystals 64-67 (diethyl ether-n-hexane) O3 I 12 C3CColorless needle crystals 70-72 -C-H 3 (diethyl ether) I _I z~' S .00 0* 0 0 S a a a S Qoe 0 000 0 4 a 4 0 0 C 4 0 0 ,0a o C 0 4 bond between I~apethe 3- and. 4- Crystal form.Mlig on Exmpe R~ ostinsof (recrystallization 0 c)n pin N .the qinoline solvent) No.. skeleton CE I H~c=CH 3-E 3 Colorless needle czcvstals 72-75 71 H C2 HC1 -H (diethyl ether-n-hexape) 4) 73: H 1 CR2 C nc=CH I4-CR 3 1 s ND4R 4 74 ~Colorless needle crystals13-5 74 H I CH? C 2
H.
5 3-CH 3 1(ethyl acetate-n-hexane)1315 -F 2 CR 2
C
2 HS 3-CR 3 1 s NMR 6-OCR 3 76 5-C 3 1 'C 2
C
3 4-C 3 1d NM46) '77' 5--OCR 3 1 CR 2
CR
3 4-CR 3 1 d Nmi47) 48) 8 5-F C 2
E
3 4-CR 3 1 d NMR 6-4OCH 3 *2 79 E ~1 ICH 2
C
2
R
5 4-CR 3 1 d NMR 9 80 5-F 2 CE 2
C
2
E
5 4-CE 3 1 d 6-OCH 3 81 H 1 CR 2
CH
3 4-CE 3 251 ,CEq3 White powder 82 H 1CE 2 CH2 a"2N N CH I (diethyl ether)15-4 0 0 0s r- 0 0~ 0 0 00 0 0 0 1 o 0 0 00 0000 p00 00 0 0 0 00 bond between Example 1 the 3- and 4- Crystal form melting point R m A R 2 n positions of (recrystallization NO the quinoline s eC) skeleton slvent) Yellow powder 135-136 83 ;H I CH2 -CH3 4-0 1 xae) 13 (ethyl acetate-n-hexane) White powder 84 R I CH2 CH3 4-OH 1 s 144.5-145 (ethyl acetate-n-hexane) 4-OH Yellow powder R 1 CHZ CH3 4-CH 3 2 s (dichloronethane 156-157 -_diethyl ether) 4-OH 52) 86 H 1 CU 2
CU
3 2 s NMR 4-Cq~r 87 H 1 CH 2
C
2
_H
5 4-OCH 3 1 s Pale yellow powder 136-137 1_ (ethyl acetate-n-hexane) LL i I L .h et *I 4 4 4 I i*L 4 0~ 4 44 4 4 0 4 A 4r r rci 4 r^P A I k I bond between Example m A the 3- and 4- CrystalMelting point n positions of recrystalization No. the quinoline solvent) skeleton
'I
White powder 88 H 1 CH 2
C
2 ii 5 4-0 1 s (dichiorormethane 162-163 diethyl ether) White powder 89 5-Gil 3 1 Js (dichloromethane 157.5-158.5 diethyl ether) N White powder q QGi G 2 5 1 :I s Cadichloomethane 158-159 diethyl ether) 91 H 1 GH 2
G
2 il 5 4-OCi 3 s Pale yellow powder l-6-137 1 Cethyl acetate-n-hexane) 92 5-Ga 3 1 Gi 2
G
2
H
5 4-OGH 3 s INM53) 3 1 CH 2
G
2
H
5 4-OH 3 1 s NMR 5 4 631-OH fI354 P6-94 H 2Gi 2
G
2
H
5 4-OCH 3 1 s NMR 55 5-O H5 G 2
H
5 4- 56 6-F OCH 3 s NMR J i ~4 8;a i .4e a *4* 4 C 0 0* *44 4 44* 4 4 44e 4 e 4 4; 44 4 444a o 4 4 444t 44 4; 4 4; 4 4 *4 1 Example No.
R
2 bond between the 3- and 4positions oE the quinoline skeleton Crystal form (recrystallization solvent) Melting point 0
C)
57) 96 5-COCH 3 1 CR 2
CZH
5 4-OCR 3 1 s NMR Yellow powder 97 11 1 CH 2
C
2
H
5 4-N(CH 3 2 1 s (dichloromethane 150-151.5 diethyl ether) 98 6-OCR 2 JCH 2
C
2
H
5 4-N(CH 3 2 1 s NMR Yellow powder 144-145 I (ethyl acetate) Colorless columns 201-202 100 H 1 CR 2
C
2
R
5 4=NO 1 a(methanol) 101 H 1 CR 2
C
2
H
5 4-OCH 2
CH=CR
2 1 s NIR 5 9 White powder 102 H 1 CH 2
C
2 5 4=CH 2 1 s (dichioromethane 148-149 diethyl ether) 103 H l ,R 11'1 White powder 193-194 C1 (methanol) LL- i 4 4 *L 4 4* 1
L
bond between th e 3- and 4 Crystal form melting point Example ml A R 2
R
3 n positions of (recrystallization 0
C)
No. the quinoline slet skaletpn solvent) 104 H 1 C 2
C
2
H
5 3-CO 2
CH
3 White powder 137-139 (ethyl acetate-n-hexane) 105 H 1 CU 2
C
2
H
5 3-CH 2 0H 1White powder 175-177 ___1___(ethanol) 1CH3 White powder 111-113 1CH3 (ethyl acetate-n-hexane) 107 H il CH 2
C
2
H
5 4-N 1 s 61) 108 5-0,CH3 1 CH 2
C
2
H
5 3-CO 2
CH
3 1 s NMR 109 5-OCH 3 1 CU 2
C
2
H
5 3-CH 2 0H 1 White powder 169-171 I _(ethyl acetate-n-hexane) 110 5-CH3 1 CU 2
C
2
H
5 4-OCH 2
CH=CH
2 1 s NMR 6 2 63) 111 5-CCH3 I CEI C 2
H
5 4-OCU 2
CH=CH
2 1 s NMR Yellow powder 128-130 112 H 1 CH 2
C
2
H
5 4=0 1 's (dichloromethane (decomposi- I_ I_ I I I I- diethyl ether) tion) L4_ i L S 1 4 0~ 4,4 0 044 4 40 0s 44 p, 0 4 a 4 4 44 4 o 4 0 444 04 4 4r 4 4 *L a 4 4 E pO1 a between Example RAR 3- and 4- Crystal form melting point n positions of (recrystallization No. the quinoline (OC) skeleton solvent) 64) 113 H 1 CHZ C 2 HS 4-OH 1 s NMR 5-F :5 114 6-C 2 CH 2
C
2
H
5 3-CH 2 0H 1 s NMR 65 6-OCH3 115 5-CR 3 1 CH 2
C
2
H
5 3-CH20H 1 s NMR 66 0 116 11 1 CHZ CH 2
CH=CH
2 4-OCR 3 1 s NMR 6 7 5-CCH 3 117 H 1 CR 2
C
2
R
5 3,3-diCH 3 3 s NMR 68 4=0 118 5 2 CH 2
CH
2
CR=CR
2 4-NC 1 s White powder 144-145 6-OCH 3
C
R
3 (ethyl acetate-n-hexane)
,CR
3 Pale yellow powder 119 H 1 CR 2
CR
2 CH=CHZ 4 -N CR 3 1 s (eyl ote a 131-132 CH1 (ethyl acetate-n-hexane) 120 I ICH2 C2H5 4=NCH3 I s NMR69 I ii *Oa a ~oa a a a a 0 S 4 0 a a 0 4 0 0 00* 0 0 0 040 *V.
a o a a 8 Example No.
121 122 123 124 125 126 127 128 129 Hi
H
6-OCR 3 5-F 6-OCH 3 5-F 6-OCR 3 5-F 6-OCH 3 5-F 6-OCR 3 5-F 6-OCH 3 5-F 6-OCH 3 6-OCH 3 1 2 2 2 2 2 2 A
R
CE!
2
C
2
H
5
CR
2
C
2
H
5
CR
2
C
2
HS
CH2 H
CE!
2
C
2
HS
CR
2
C
2
HS
CR
2
C
2
H
5
CE!
2
C
2
H
5 CH!I C 2
H
5
CH
2 I C 2
H
5 bond between 3the 3- and 4- Crystal form n 3 positions of (recrystallization the quinoline slet skeleton slet 4-N 1-1CH 3 1 s NMR 70
NCH
2
CH
2
CH
3 s NMR 71
COCH
3 1- s NMR72 4-N CF 3 1 s NMR 73
CH
2
CH=CH
2 4-N I-C 1 s N~MR74 4 1 s NMR 7 4-NOjj I s NMR 76 1-1CH3 77) 4 -IN C2H= 1 NMR 78
COCH
3 4NCR 2
CH=CH
2 NM79 1 S
NNR
7 9 3 Melting point
(OC)
4 4 i I rre, c r f
D
.e r bond between Example the 3- and 4 Crystal formpoint n positions of (recrystallization
(C)
the quinoline solvent) skeleton 5-F CH 2
CH=CH
2 Colorless needles 1 131 2; Cu 2
C
2
H
5 4-N 1 s 146-147 6-OCH 3
IC
2
H
5 (ethyl acetate-n-hexane)
~CH
3 132 H 1 CH 2
C
2
H
5 3-CH 2 N 1 s White powder 152-154 0C 3 (ethyl acetate-n-hexane) White powder 181.5-182.5 133 H 1 CH 2
C
2
H
5 3-CO 2 H 1 (ethanol) (decomposition) 134 H 1 R 2
C
2
H
5 -CON 0 1White powder13.-95 134 H 1 I: CH2 i C2HS 3-CON 0 1 :I i s I(ethyl acetate-ethanol) 135 5-F 2 CH 2
C
2
H
5 3-CO 2
CH
3 1 s NMR 80 16 5-F NM 81 136 6-C 2 CH 2
C
2 HS 3-CO 2 H s NMR 8 137 5-F 2 CH2 C2H5 3-CONc 1 s NMR 8 2) 6-OC 3 2C 5-F 0OCH 3 83) 138 2 CH 2
C
2
R
5 1 s NMR 6-OCH35 3-CNH (CH2) 2 -O CH 3 139 H 1 CH 2
C
2
H
5 3-COND3 1 s NMR 84 ,a1F3White powder 140 5-CH 3 1 CR 2
C
2 HS 4-N 1 s (1/4 hydrate) 132-133 I CH 2 CH=CH2 (diethyl ether) -L 4Q 4t1 44 4 r C 4 0 4 4 4r 4* osr 1 i :-ii- 7 T- Example No.
bond between the 3- and 4positions of the quinoline skeleton Crystal form (recrystallization solvent) Melting point 0 c) 141 5-GOGH 3 I CR 2
C
25 4-N1 1 s NMR 8 5 "CH CH=CR 5-F /CHI 3 86) 142 6-O 2 CR 2 CiHS 4-N 1 s NMR 6-OCH3
CR
2
CH=CR
2 143 5-CR 3 1 CH 2
C
2 HS 4-NH- I s NMR 8 7 1 144 5-F 2 CH2 CH 2
CH=CH
2 4-OCR 3 1 s NMR88) 6-OC__ 145 5-CH3 1 CH 2
CH
2
CH=CH
2 4-OCH 3 1 S NMR 89 146 5-COCH 3 1 ICH 2 C2H 5 4-OCH 2
OCH
3 1 's NM 9 0 16 5-COC3
NR
147 5-F 2 CR 2
C
2
R
5 4-CH20H 1 s NMR 9 1 3
ICH
3 Yellow powder 148 5-COCH 3 1 CH2 C 2
H
5 4-N. 1 s (1/4 hydrate) 167.5-168.5 (ethyl acetate-n-hexane) 5-F CR 92) 149 6-OC 3 2 CH2 C2H51 s NMR 6-OCH3 150 S F 2 CR 2
C
2
H
5 4-N 1 s NMR 93 6-OCH3 N_ COCF_ r. -i -I i *co 4 n a 4 r 4 ItO C II 4 kt*L C1I'L 49) 4 4b4~ 4 C 4 4~ 9 4 4? 4 4 #4 a 4 4 09* bond between the 3-and 4 Melting point Examei A R,3 r positions of (recrystallization (CC) No. the quinoline solvent) (C :skeleton
/FCH
3 94) 151 6-OCH3 2 CR 2
C
2 fl 5 1 s NMR 152 H 1 CR 2
C
2
H
5 4-CF 3 1 d NMR 95 0 96) 153 5- 2CH C2HI 1 s NMR 6-OCH 3 4-CHoccH 3 4-OCH3 3 s M 97) 154 5-CH 3 1 CH 2
C
2
H
5 4-OCR 3 S NMR 9 7 155 5-CO-K 1 CHR 2
C
2
CH=CH
2 4-N 1 s NMR 1< NCH 98 ,CH3 1CR 3 C1 H H C 99) 156; 5!-COCR 3 1 )CR 2
CR
2
CHCH
2 4a-N 1 s NMR 4, ~c i 1 165 1) NMR(CDC 3 )6: 1.30 (3H, t, J 7.5 Hz), 1.66 2.10 (2H, 2.08 (3H, 2.73 (2H, t, J 7 Hz), 2.97 (2H, q, J Hz), 3.10 3.34 (2H, 4.25 (2H, 6.80 7.50 (6H, m) 2) NMR(CDCt 3 )6: 1.42 (3H, t, J 7.5 Hz), 2.83 (2H, t, J 7 Hz), 3.08 (2H, q, J 7.5 Hz), 3.23 3.50 (2H, 3.83 (3H, 4.27 (2H, 6.66 7.50 (6H, m) 3) NMR(CDCZ 3 )6: 1.42 (3H, t, J 7.5 Hz), 1.83 2.30 (2H, 2.50 3.00 (2H, 3.10 (2H, q, J 7.5 Hz), 3.23 3.43 (2H, 4.25 (2H, 6.67- 7.60 (5H, 13.17 (1H, br.) 15 4) NMR(CDC9 3 )6: S" 1.33 (3H, t, J 7.5 Hz), 1.66 2.10 (2H, in), 2.77 o (2H, t, J 7 Hz), 3.00 (2H, q, J 7.5 Hz), 3.00 3.33 (2H, 3.83 (3H11, 4.30 (2H, 6.66 7.40 13.00 (1H, br.) 4 4 *20 5) NMR(CDCZ 3 )6: h 1.40 (3H, t, J 7 Hz), 1.43 (3H, t, J 7 Hz), 1.66- 2.13 (2H, 2.85 (2H, t, J 7 Hz), 3.07 (2H, q, J 7 Hz), 3.20 3.50 (2H, 3.50 (2H, q, J 7 Hz), 4,26 (2H, 6.50 7.50 (5H, m) 6) NMR(CDCZ 3 )6: -166- 1.38 (3H, t, J 7.5 Hz), 1.66 2.10 (2H, 2.50 3.00 (2H, 3.05 (2H, q, J 7.5 Hz) 3.10 3.40 (2H, m) 4.25 (2H, s) 6.67 7.63 (6H, m) 12.17 (1H, br.) 7) NMR(CDC93) 6: 1.40 (3H, t, J 7.5 Hz), 1.70 2.20 (2H, 2.63 (3H, 2. ,3 (2H, t, J 7 Hz), 3.07 (2H, q, J Hz), 3.10 3.20 (2H, 4.30 (2H, 6.80 7.20 2 (6H, m) 8) NMR(CDCZ 3 )6: 1.42 (3H, t, J 7 Hz), 1.66 2.20 (2H, 2.80 (2H, t, J 6 Hz), 3.03 (2H, q, J 7 Hz), 3.20 3.50 (2H, 4.28 (2H, 6.70 7.50 (6H, m) 9) NMR(CDC 3 )6: a l *4 S 15 1.35 (3H, t, J 7.5 Hz), 1.66 2.10 (2H, 2.55 I (3H, 2.77 (2H, t, J 7 H2), 3.00 (2H, q, J a c Hz), 3.00 3.20 (2H, 4.25 (2H, 6.67- 7.50 (6H, 12.80 (1H, br.) ,10) NMR(CDCk 3 6: 1.37 (3H, t, J 7.5 Hz), 1.67 2.10 (2H, 2.40 (3H, 2.50 (3H, 2.80 (2H, t, J 7 Hz), 3.03 j(2H, q, J 7.5 Hz), 3.10 3.50 (2H, 4.23 (2H, 6.70 7.43 (5H, 12.50 (1H, br.) S, 11) NMR(CDCY3) 6: 1.70 2.30 (2H, 2.83 (2H, t, J 7 Hz), 2.90 (3H, 4t
A
167 3.20 3.40 (2H, 4.36 (2H, 6.80 7.80 (6H, -3.10 (1H, br.) 12) NMR(CDCL 3 )6: 1.50 2.10 (2H, 2.53 (3H, 2.30- 2.80 (2H, 2.73 (3H, 2.83 3.30 (2H, m) 4.30 (2H, s) 6.70 7.33 (6H, m) 13) NMR(CDCk 3 6: 1.73 2.13 (2H, 2.80 (2H, t, J 6 Hz), 2.83 (3H, s) 3.10 3.33 (2H, 3.83 (3H, 4.33 (2H, s) 6.80 7.33 (5H, m) 11.50 (1H, br.) 14) NMR(CDC.
3 6: 1.67 2.07 (2Hi, 2.60 2.93 (2H, 3.07 3.37 (2H, 3.57 (2H, d, J 6 Hz), 4.33 (2H, 5.07 5.63 (2H, 5.77 6.33 (1H, 6.73 7.63 (7H, m) o 15 15) NMR(CDCZ 3 )6: S1.73 2.10 (2H, 2.83 (2H, t, J 8 Hz), 3.13 3.40 (2H, m) 3.60 (2H, d, J 6 Hz) 3.80 (3H, s) o 0 4.30 (2H, s) 5.17 5.57 (2H, 5.77 6.40 (1H, 6.57 7.50 (6H, m) Vt 20 16) NMR(CDCZ 3 )6: a t 1.70 2.13 (2H, m) 2.82 (2H, t, J 7 Hz), 3.20 j, 3.43 (2H, 3.63 (2H, d, J 6 Hz) 4.30 (2H, s), 4r 5.20 5.60 (2H, 5.83- 6.43 (1H, 6.70 7.67 (6H11, m) 17) NMR(CDCZ 3 )6: a 168 0.95 (3H, t, J 6 Hz), 1.13 1.63 (2H, 1.63 2.17 (4H, 2.67 3.18 (4H, 3.18 3.50 (2H, 4.30 (2H, 6.80 7.83 (7H, m) 18) NMR(CDCk 3 6: 0.93 (3H, t, J 7 Hz), 1.13 1.60 (2H, 1.60 2.13 (4H, in), 2.43 (3H, s) 2.63 3.13 (4H, 3.13 3.43 (2H, 4.30 (2H, 6.87 7.67 (6H, m) 19) NMR(CDC 3 0.93 (3H, t, J 7 Hz), 1.13 1.60 (2H, 1.60 2.17 (4H, 2.63 3.13 (4H, 3.13 3.43 (2H, 3.80 (3H, 4.30 (2H, 6.63 7.47 (6H, m) NMR(CDCZ 1.23 (3H, t, J 8 Hz), 1.40 2.23 (2H, 2.67 3.33 (3H, 2.82 (3H, 4.33 (2H, 6,90 7.57 H(7H, m) g 21) NMR(CDC 3 C 1.27 (3H, d, J 8 Hz), 1.47 2.33 (2H, 2.7Q o 3.37 (3H, 2.88 (3H, 3.87 (3H, 4.33 (2H, 6.87 7.37 (5H, m) S22) NMR(CDCk 3 a a 1.33 (3H, t, J 8 1.67 2.07 (2H, 2.77 (2H, J 7 Hz), 3.00 (2H, q, J 8 Hz), 3.13 3.37 (2H, in), 4.22 (2H, 6.93 7.60 (6H, m) ot23) NMR(CDC 3 6 o 04 u o25 1.66 2.17 (2H, 2.40 (3H, 2.50 (3H, 2.30 169 (2H, t, J 7 Hz), 2.87 (3H, 3.16 3.43 (2H, m), 4.30 (2H, s) 6.66 7.37 (5H, m) 24) NMR(CDCk 3 )6: 1.70 2.30 (2H, 2.63 (3H, 2.87 (2H, t, J 7 Hz) 2.95 (3H, 3.20 3.47 (2H, 4.35 (2H, s), 6.80 7.90 (5H, 8.07 (1H, s) NMR(CDC 3 6: 1.37 (3H, t, J 8 Hz), 1.67 2,10 (2H, 2.60 3.37 (6H, 3.87 (3H, 4.23 (2H, 6.90 7.47 (4H, m) 26) NMR(CDC Z3) 6: 1.33 (3H, t, J 8 Hz) 1.67 2.07 (2H, m) 2.75 (2H, t, J 8 Hz), 2.97 (2H, q, J 8 Hz), 3.10 3.37 (2H, m) 3.67 (3H, 3.83 (3H, 4.23 (2H, 6.45 (IH, d, J 3 Hz), 6.78 (1H, d, J 3 Hz), 6.87 7.40 (2H, m) 27) NMR(CDC 6 3 )6: 1.70 2.20 (2H, 2.60 3.00 (2H, 2.93 (3H, s) 3.20 3.40 (2H, nm), 3.92 (3H, 4.32 (2H, s) 20 6.80 8.30 (6H, 12.30 (1H, brs) |28) NMR(CDCZ 3 )6: 1.42 (3H, t, J 7 Hz), 1.80 2.20 (2H, m) 2.82 (2H, t, J 7 Hz), 2.88 (3H, 3.17 3.40 (2H, 4.07 (2H, q, J 7 Hz), 4.32 (2H, 6.90 7.40 (5H, n) 29) NMR(CDCA 3 )6: 170 S 1.33 (3H, t, J 7 Hz), 1.66 2.10 (2H, 2.30 (3H, d, J 2 Hz), 2.77 (2H, t, J 7 Hz), 2.98 (2H, q, J 7 Hz), 3.10 3.40 (2H, 4.27 (2H, 6.73 7.50 12.97 (IH, br.) 30) NMR(CDCt 3 )6: 1.70 2.00 (2H, 2.66 (2H, t, J 7.5 Hz), 3.07 3.20 (2H, 3.45 (2H, d, J 7 Hz), 3.69 (3H, s), 4.08 (2H, 5.10 5.30 (2H, 5.80 6.00 (1H, in), 6.70 7.15 (5H, m) 31) NMR (CDC t 3 6: 1.70 2.10 (2H, mn), 2.57 (3H, 2.70 3.00 (2H, m) 3.20 3.45 (2H, m) 3.61 (2H, d, J 7 Hz) 4.34 (2H, 5.20 5.50 (2H11, 5.95 6.25 (1H, m), 4 6.90 7.40 (6H1, m) 12.61 (1H, br.) 0 '15 32) NMRP (CDC 3 6: 1.90 2.15 (2H, 2.49 (3H, s) 2.61 (3H11, s) 2,80 3.00 (2H, 3.30 3.50 (2H, 3.72 (2H, d, j 7 Hz), 4.35 (2H11, 5.40 5.60 (2H, 6.10 6.30 (1H, in), 6.85 7.45 (5H, 12.27 (1H, br.) 33) NMR(CDCk 3 6 *Of" 1.43 (3H, 1.70 2.10 (2H, 2.80 (211H, 3.10 3.30 (2H, 3.59 (2H, 4.06 (2H, 4.34 (2H, 5.10 5.50 (2H, 5.90 6.20 (1H, 6.70- 7.40 (5H, in) 5 34) NMR(CDCk3) 171 1.60 2.10 (2H, 2.73 (2H, 3.05 3.35 (2H, 3.53 (2H, d) 4.30 (2H, 5.10 5.60 (2H, m), 5.80 6.30 (1H, 6.70 7.50 (6H, m) NMR(CDCk 3 6 1.90 2.10 (2H, m) 2.64 (3H, 2.85 (2H, t) 3.30 3.40 (2H, 3.66 (2H, 4.32 (2H, 5.30 5.50 (2H, mn), 6.00 6.zO (1H, 6.90 7.50 (4H, m) 7.81 (1H, dd) 8.06 (1H, s) 36) NMR(CDC.
3 6: 1.92 2.13 (2H, 2.39 (1H, t, J 2 Hz), 2.85 (2H, t, J 7 Hz), 3.42 3.56 (2H, m) 3,48 (2H, d, J 2 Hz), 3.82 and 3.85 (3H, 4.34 (2H, 6.70 7.56 (6H, m) 37) NMR (CDC 3 6: I "^Si.93 2.12 (2H, 2.39 (1H, t, J 2 Hz), 2.85 (2H, o r.t, J 7 Hz), 3.40 3.57 (2H, ma), 3.79 (2H, d, J 2 Hz), 3.88 and 3.91 (3H, 4.34 and 4.35 (2H, s), 6.86 7.42 (5H, m) 38) NMR(CDC 3 )6: o 1.27 (3H, 1.40 2.30 (2H1, m) 2.95 (1H, q) 3.20 3.40 (2H, 3.62 (2H, 4.30 2H, 5.20 S -H(,,05.60 (2H, 5.80 6.40 (IH, 6,70 7.70 (7H, m) 359) NMR(CDC9 3 )6: 0.27 0.38 (2H, P,63 0.75 (2H, mn), 1.08 1.33 .25 (IH, 1.92 2.10 (2H, 2.85 (2H, J 7 Hz), 4 172 2.95 (2H, d, J 7 Hz), 3.52 3.64 (2H, 4.32 (2H, 6.90 7.67 (7H, m) NMR(CDC9 3
S:
0.29 0.45 (2H, m) 0.64 0.80 (2H, 1.13 1.35 '11H, m) 1.90 2.13 (2H, m) 2.75 3.04 (4H, m), 3.44 3.63 (2H, 3.89 and 3.92 (3H, 4.29 and 4.30 (211, 6.85 7.40 (5H, m) 41) NMR(CDCk 3 6: 1.27 (3H, 1.37 (3H, 1.50 2.20 (2H, 2.80 3.40 (5H, 3.87 (3H, 4.27 (2H, 6.60 7.40 (5H, m) 42) NMR(CDC 3 6: 1.23 (3H, 1.37 (3H, 1.50 2.50 (2H, 2.60 (3H, 2.70 3.50 (5H, 4.30 (2H, 6.80 .1 5 7.60 (4H, 7.79 (1H, dd), 8.07 (1H, brs) 43) NMR(CDCA 3 6: o 1.09 (3H, d) 2.20 2.50 (21H, 2.50 2.70 (1H, 0. m) 2. 70 3. 40 (2H, m) 3. 60 Z .7 0 (2H, m) 4.0 0 4.60 (2H, m) 5.20 5.60 (2H, 5.90 6.20 (1H, 20 6.70 7.40 (5H, m) %A 44) NMR(DCA 3 )6: 1.29 (3H, d, J 7 Hz), 1.64 1.85 (1H, 2.05 2.24 (1H, 2.39 t, J 2 Hz), 2.?4 3.09 (1H, 3.37 3.67 (2H, 3.81 (2H, d, J 2 Hz), 4.36 (2H, 7.04 7.68 m) 173
NMR(CDCZ
3 )6: 1.07 (3H, d) 1.36 (3H, t) 2.00 3.50 (7H, 3.86 (3H, 4.38 (2H, dd) 6.60 7.30 (5H, m) 46) NMR(CDC 3 6: 2.07 (3H, 2.40 (3H, 2.72 (3H, 3.70 3.90 (2H, m) 4.30 (2H, s) 5.60 5.80 (1H, m) 6.80 7.50 (6H, m) 47) NMR(CDC 3 6 2.05 (3H r 2.67 (3H, 3.60 3.90 (2H, 3.77 (3H, s) 4.30 (2H, 5.60 5.80 (1H, m) 6.70 7.50 (6H, m) 48) NMR(CDCPl 3 6: 2.06 (3H, 2.69 (3H, 3.50 3.80 (2H, 3.83 (3H, s) 4.33 2 H, s) 5.50 5.70 (1H, 6.70 7.50 (5H, 12.60 13.00 (1H, brs) ;49) NMR(CDC 3) 6: 1.30 (3H, 2.09 (3H, 3.00 (2H, 3.81 (2H, t 4.30 (2H, 5.70 (1H, 6.90 7.50 (7H, m), 13.04 (IH, brs) ,.20 50) NMR(CDCY 3 6: 1 1.22 (3H, 2.06 (3H, 2.95 (2H, 3.60 3.80 A ;V (2H, 3.83 (3H, s) 4.32 (21H, 5.50 5.80 (1H, 6.90 7.50 (5H, m) 51) NMR(CDCZ 3 )6: c .,25 1.88 1.98 (3H, 2.60 (3H, 3.53 (2H, t 4.29 (2H, 52) NMR (CDCk 3 )6: 0.88 (3H, t, J 3.28 3.7 (1H, d, J 15 53) NMR(CDCZ 3 )6: 1.29 (3H, t, J (3H, 2.90 1 (3H, 4.24 m) 174 s) 6.90 7.70 (7H, m) 7 Hz), 1.78 2.14 (2H, m) 2.96 (3H, 2 (2H, 4.10 (111, d, J 15 Hz), 4.56 Hz) 7.10 7.57 (7H, m) S= 6.8 Hz) 1.90 2.20 (2H, m) 2.43 3.20 (2H, m) 3.25 (2H, brs) 3.41 (1H, brs) 4.47 (2H, s) 6.9 7.6 (6H, 0 00 900 0 0
I
4 000 i' S0 0 O 01 t t 1 54) NMR(CDCZ 3 )6: 1.25 (3H, t, J 7 Hz), 1.95 (2H, brs), 2.80 3.20 (2H, 3.16 (2H, brs) 3.35 and 3.37 (3H) 3.74 and 3.77 (3H) 4.17 (1H, brs), 4.45 (2H, s) 6.7 (6H, 12.23 (1H, brs) NMR(CDCk 3 1.41 (3H, t, J 7 Hz) 2.05 2.20 (2H, m) 2.98 3.27 (2H, 3.33 3.48 (2H, 3.44 (3H, 3.89 (3H, brs), 4.23 4.34 (3H, m) 6.79 7.33 (4H, m), 7.42 (1H, dd, J 2.8 Hz) 56) NMR(CDCk 3 )6: 1.29 (3H, t, J 7.0 Hz), 1.44 (3H, t, J 6.9 Hz), 2.2 (2H, m) 2.9 3.2 (2H, m) 3.2 3.3 (2H, ml 3.42 (3H, 4 .09 (2H, q, J 6.9 Hz), 4.1 4.3 (IH, m) 4.46 (2H, s) 6.8 7.4 (5H, m) 04 0 25 175 57) NMR(CDCY 3 )6: 1.33 (3H, t, J 7.0 Hz), 2.0 2.1 (2H, 2.60 (3H, s) 2.9 3.2 (2H, 3.3 3.4 (2H, 3.39 (3H, 4.23 (1H, t, J 4.2 Hz), 4.39 (2H, d, J 5,3 Hz) 6.9 7.7 (6H, m) 58) NMR(CDC 3 )6: 1.41 (3H, t, J 7 Hz) 1.65 1.93 (IH, 2.06 2.38 (IH, m) 2.26 (6H, s) 2.88 3.12 (IH, m) 3.12 3.37 (2H, 3.40 3.61 (1H, m) 3.80 (1H, t, J 7 Hz) 3.89 (3H, brs), 4.09 (1H, d, J 15 Hz), 4.39 (1H, d, J 15 Hz), 6.80 7.23 (3H, 7.36 (1H, d, J 7 Hz), 7.52 (1H, d, J 8 Hz) 59) NMR (CDCk 3 6: 1.38 (3H, t, J 7.5 Hz), 2.04 2.12 (2H, 3.04 (2H, q, J 7.5 Hz), 3.40 3.45 (2H, 4.00 4.20 0. (2H, 4.29 (21H, 4.43 (1H, t, J 0.6 Hz), 5.15 5.35 (2H, 5.85 6.00 (1H, 7.00 7.60 (7H, m) 12.54 (IH, brs) NMR (CDCk 3 ",o30 1.40 3 H, t, J 7 Hz), 1.63 1.88 (5H, 2.10 2.22 (1H, 2.35 2.53 (2H, 2.53 2.72 (2H, in" 2.98 3.33 (2H, 3.40 3.56 (21, 3.61 (IH, t, J 5 Hz) 4.10 (IH, d, J 15 Hz) 4.44 (1H, d, J 15 Hz), 7.00 (1IH, t, J 7 Hz), 7.05 7.21 (2H, 7.21 7.45 (3H, 7.53 7.65 (IH, M) 176 61) NMR(CDCk 3 )6: 1.40 (3H, t, J 7 Hz) 2.95 06 (2H, 3.80 (3H, 3.70 3.82 (5H, 4.18 d, J 14 Hz) 4.51 (1H, d, J 14 Hz), 6.62 6.78 (2H, 7.00 (2H, d, J 4 Hz), 7.14 7.47 (3H, m) 62) NMR (CDCk 3 6: 1.41 (3H, t, J 8 Hz) 2.05 2.30 (2H, m) 2.44 and 2.42 (3H) 3.10 (2H, q, J 8 Hz) 3.44 (2H, d, J Hz), 4.00 4.60 (2H, 4.27 (3H, 5.10 5.40 (2H, m) 5.60 6.10 (1H, 7.00 7.50 (6H, 12.12 (1H, brd) 63) NMR(CDCk 3 6: 1.45 (3H, t, J 7.5 Hz), 2.05 2.20 (2H, 2.65 (3H, s) 3.13 (2H, q, J 7.5 Hz) 3.49 (2H, bs) 4.00 5 4.30 (2H, m) 4.30 (2H, s) 4.46 (1H, t, J Hz) 5.10 5.35 (2H, 5.85 6.05 (1H, 7.13 (1H, t, J 8 Hz), 7.35 (2H, dd, J 8 Hz, J 0.25 Hz), 7.50 8.20 (3H, 13.00 (1H, brd) 64) NMR(CDCX 3 )6: 1.40 (3H, t, J 7.2 Hz), 1.9 2.3 (2H, 2.9 3.2 (2H, 3.3 3.5 (2H, 4.12 and 4.33 (2H, dd, J 14.9 Hz), 7.0 7.5 (7H, 12.1 12.8 (IH, brs) NMR(CDCk.
3 hS: 1.39 (3H, t, J 7 Hz), 2.39 (3H, 2.00 3.90 (9H, 3.98 (1H, d, J 15 Hz), 4.45 (1H, d, J 15 Hz), 177 6.55 7.27 (6H, m) 66) NMR (CDC k 3 6: 1. 41 O3H, tf J 7 Hz) 1. 70 4. 00 (9H, m) 78 (3H, s) 4. 04 (1H, d, J =15 Hz) 4. 46 (1H, d, J =15 Hz), 6.80 7.40 (5H, m) 67) NMR(CDC2.
3 )6: 1. 9 2. 1 (2H, m) 2. 59 (3H, s) 3. 2 3 .3 (2H, m) 3 40 O3H s1, r3 .5 9 (2H, d, J 5. 5 Hz) 4. 23 (1H, t, J =4.3 Hz) 4.40 and 4.49 (2H, dd, J =14 Hz), 5.22 (1H, d, J =10. 3 Hz) 5. 36 (1H, d, J =16 .9 HZ) 5'.6- 6. 1 (1H m) 6. 98 (1H, t, J 7. 6 Hz), 7.21 (1H, d, J Hz) 7.36 (1H, d, 1 6.7 Hz') 7.3 7.5 (1H, brs) 7. 81 (1H, d, J 8. .5 Hz) 8. 0 2 (1H, brs) 68) NMR Ck 3 05 1. 21 (6H, s) 1. 35 (3H, t, J 7. 5 Hz) 2. 66 (3H, s), 3 3.2 7 (2H1, s) 3 53 (2H, qr J 5 Hz) 4 .6 0 (2H1, s) 6. 88 (1H, t, J 7. 0 Hz) 7. 2 8. 4 (5H, mn) 0 60469) NMR(CDCt.
3 )6: 1.40 (3H, t, J 7 Hz),t 2.75 (2H1, t, J 6 Hz) 3.09 ?o2 (2H, q, J 7 Hz) ,3.32 (3H, s) 3.55 (2H, t, J =6 Hz) 4. 34 (2H, s) 05 7. 23 (3H, m) 7. 32 (1H1, brs) 7. 51 (111, dd, J 8 Hz) 7. 60 brs) 8. 03 (1H1, dd, J 1.8 Hz)
NMR(CDCZ
3 )6: ,4f25 1.42 (3H, t, J 7. 2 11z, 1. 73 1. 96 (1H, 2. 10 -178 2. 33 (1H, mn), 2. 23 (3H, 2. 67 t, J 5. 3 Hz), 2. 88 3.10 (1H, in), 3 .10 3 3.38 (2H, 3 .48 2.70 (3H, mn), 3. 94 t, J 8 80 Hz) 4 .10 d, J= 14. 8 Hz), 4. 43 (1H, d, J 14 .8 Hz) 7. 00 7. 69 (7H, in) 71) NMR(CDCP.
3 )6: 1. 29 1. 50 (3H, in), 1. 81 2. 43 (2H, im) 2. 23 and 2.27 (3H, s) 2.65 and 2.69 (3H, s) 2.85 3.65 (4H, mn), 4.18 and 4.20 (1H, d, J 14.5 Hz), 4.44 and 4.50 (1H, d, J =14. 5 Hz) 5. 00 and 5. 91 (1H, t, J 7. 6 Hz and J 8, 3 Hz) 6. 87 7. 22 (4H, in), 7. 30 7.56 (3H, Mn) 72) NMR(CDC9 3 )6: 0.30 0.60 (4H, in), 1.38 (3H, t, J =7 Hz) 1.80 01.15 2. 00 (1H, in) 2. 00 2 2.40 (2H, mn), 2 .14 (3H1, s) 2. 15 (111, in) 3 .15 3 .35 (2H, in) 3 .35 3 3.60 (11j, in), 3 .87 (311, 3 .97 (1Hf t, J =6 .6 Hz), 4 .15 (1H, J =14 .5 Hiz) 4 .40 (111, d, J 14. 5 Hz), 6 .0 e- 7. 60 (5H, im), 12. 90 (1H1, br.) 20 73) NMR(CDCk3)6: 1.7 -1.95 (211, mn), 2.20 O3H, s) 3.50 (4H, rn) 3 .77 (111, t, J 6. 7 Hz) 3. 80 (3H, 30 (1H, d, J 13. 4 4. 41 (111, d f J 13. 4 Hz) 5. 0 1 5.30 P2H, in), 5.71 '.99 (1H, mn), 6.55 (1H1, t, J 7. 5 Hz), 6. 65 7. 44 (2Hl, in), 6. 92 (1H1, J 4 179 Hz), 7.33 (1H, d, J 7.3 Hz) 74) NMR(CDCZ 3 )6: 0.00 0.20 (2H, 0.35 0.62 (2H, 0.76 0.99 (IH, 1.41 (3H, t, J 7.1 Hz), 1.66 1.90 (IH, 2.02 2.47 (3H, 2.29 (3H, 2.83 3.09 (IH, 3.09 3.34 (2H, 3.34 3.62 (IH, m), 3.88 (3H, 4.02 (IH, t, J 6.6 Hz), 4.08 (IH, d, J 15.0 Hz), 4.38 (1H, d, J 15 Hz), 6.78 7.22 (3H, 7.34 (IH, d, J 7.3 Hz), 7.64 (1H, d, J 7.9 Hz) 75) NMR (CDCP 3 6: 1.28 and 1.29 (2H, t, J 7.0 Hz), 1.40 (2H, t, J 7.1 Hz), 1.73 2.09 and 2.22 2.48 (2H, 2.28 and 2.40 (3H, 2.87 3.11 (IH, m) 3.11 3.37 (2H, 3.39 3.60 (1H, 3.60 3.85 (2H, 3.88 015 (3H, 4.03 4.29 (2H, 4.29 4.50 (2H, i) 6.77 7.53 (5H, m) 76) NMR (CDCZ 3 6: 1.41 (3H, t, J 6.9 Hz), 1.64 (4H, brs), 2.20 2.43 (IH, 2.46 2.73 (3H, 2.73 3.13 (4H, m), 3.18 3.40 (2H, 3.89 (3H, 4.11 (IH, d, J 14.6 Hz), 4.43 (IH, d, J 14.6 Hz), 4.61 (1H, d, J 9.4 Hz), 6.72 7.54 (5N, m) 77) NMR(CDCZ 3 6: 0.72 0.91 (2H, 0.95 1.18 (2H, ih), 1.18 1.33 2 5 (IH, 1.41 (3H, t, J 7.0 Hz), 1.66- 2.28 (2H, 1, 180 mn), 2.88 (3H, 2.92 -3.62 (4H, in), 3.90 (3H, s), 4.16 (1H, d, J 14.6 Hz), 4.41 (1H, d, J 14.6 Hz), 5.30 (2H, 5.91 (1H, t, J =8.0 Hz), 6.73 7.50 mn) 78) NMR(CDC9 3 )6; 1. 30 (3H, t, J 6. 9 Hz) 1. 80 2. 10 (1H, mn) 2. 10 2.30 (1H, rm), 2.19 (3H, 2.80 3.60 (6H, in), 3.85 O3H, s) 4.15 4.55 (2H, mn), 4.95 5.30 (2H, mn), 5.70 6.10 (2H, in), 6.80 7.50 (5H, mn), 12.56 (1H, br.) 79) NMR(CDCt 3 )6: 1.34 (3H, t, J 7 Hz) 1.85 2.00 (1H, mn), 2.00 2.30 (1H, n) 2.80 3.30 (5H, mn), 3.40 3.65 (2H, mn), 3.77 (3H, 3.83 (3H, 3.70 3.83 (1H, m), 3.85 4.20 (2H, in,4.39 (1H, d, J =8.3 Hz), 5.00 5.30 (2H, in), 5.75 .0(1H, mn), 6.70 PH.5 7-, in), 7.52 (1H, d, J 7.6 Hz), 7.75 (1H, d, J =7,6 Hz), 12.90 (iN, br.) NMR (CDC k 3 6 1.41 (3H, te J =7 Hz), 2.60 -3.20 (5H, mn), 3.60- 4.00 M2, in), 3.80 (3H, 3.89 (3H, 4.15 (11H, d, J 14.5 Hz), 4.49 (iH, d, J 14.5 Hz),.6.70 7.40 in) 11.60 12.10 (iN, brs) 81) NM (CDC t 3 6: 1.34 (3H, t, J 7 Hz), 2.70 3.20 (SN, mn), 3.70- 181 4.20 (2H, 3.89 (3H, 4.36 (1H, d, J 14 Hz), 4.55 (1H, d, J 14 Hz), 6.70 7.30 (5H, m) 82) NMR(CDCZ 3 6: 1.33 (3H, J 7 Hz), 1.80 2.10 (4H, 2.80 3.20 (5H, 3.30 3.70 (6H, 3.85 (3H, 4.27 (1H, d, J 14 Hz) 4.50 (1H, d, J 14 Hz), 6.80 7.40 (5H, 12.00 12.50 (1H, brs) 83) NMR(CDC 3 1.30 (3H, t, J 7 Hz), 2.60 3.20 (9H, 3.40 3.70 (2H, 3.85 (3H, s) 3.86 (3H, s) 3.87 (3H, 4.14 (1H, d, J 14 Hz), 4.44 (1H, d, J 14 Hz), 6.70 7.40 (8H, m) 11.70 12.20 (1H, brs) 84) NMR(CDCA 3 )6: 1.41 (3H, t, J 7 Hz), 1.40 1.80 (6H, 2.80 3.30 (6H, 3.50 3.80 (5H, 4.14 (1H, d, J 14 S Hz), 4.50 (1H, d, J 14 Hz), 6.90 7.20 (7H, m), S, 11.80 12.20 (1H, brs) S" 85) NMR(CDCA 3 6: 1.40 (3H, t, J 7.0 Hi), 1.70 1.95 (1H, 2.05 2.30 (1H, 2.20 (3H, s) 2.67 (3H, s) 2.80 3.35 3.45 3.70 (1H, m) 3.97 (1H, J Hz), 4.27 (1H, d, J 14.4 Hz), 4.50 (1H, d, J 14.4 Hz), 5.05 5.35 (2H, 5.70 6.00 (1H, in), 7.00 8.30 (6H, m) 2.5 86) NMR(CDCX 3 6:
I
_t 182 1.37 (3H, t, J 7.2 Hz), 1.70 1.90 (1H, 2.00 2.25 (1H, m) 2.18 (3H, s) 2.80 3.40 (5H, m) 3.40 3.65 (IH, 3.80 4.10 (1H, 3.87 (3H, s), 4.13 (1H, d, J 14.5 Hz) 4.41 (1H, d, J 14.5 Hz), 5.00 5.40 (2H, 5.70 6.00 (1H, 6.70 7.80 m) 12.50 13.00 (1H, br.) 87) NMR(CDCk 3 6: 0.95 2.20 (10H, m) 1.28 (3H, t, J 7.0 Hz) 2.39 (3H, s) 2.55 2.80 (1H, m) 2.80 3.20 (2H, m), 3.,20 3.50 (2H, m) 3.82 (1H, t, J 4.3 Hz) 4.20 (1H, d, J 14.4 Hz) 4.31 (1H d, J 14.4 Hz) 6.80 7.50 (6H, m) 88) NMR(CDCZ3)6: 1.9 2.1 (2H, 3.1 3.3 (2H, 3.40 (3H, s), 3.5 3.6 (2H, 3.82 (3H, 4.23 (1H, t, J 4.4 Hz), 4.3 4.5 (2H, 5.1 5.5 (2H, n) 5.8 (1H, m) 6.7 7.5 (5H, m) 89) NMR(CDCk 3 )6 1.9 2.1 (2H, 2.43 (3H, 3.2 3.3 (2H, m), 3.42 (3H, 3.6 3.7 (2H, mn) 4.26 (1H, t, J 4.4 Hz) 4.46 (2H, 5.2 5.5 (2H, 5.9 6.2 (IH, 6.9 7.4 (6H, m)
NMR(CDCZ
3 6: 1.S9 (3H, t, J 7 Hz) 1.9 2.3 (2H, in) 2.62 (3H, 2.9 3.2 (2H, 3.2 3.5 (2H in) 3.42 (3H,
I
183 4.30 (1H, d, J 15 Hz), 4.44 (1H, d, J 15 Hz), 4.6 5.0 (3H, 7.0 8.1 (6H, m) 91) NMR(CDC 3 6: 1.34 (3H, t, J 7 Hz), 1.9 2.2 (2H, 2.9 3.1 (2H, m) 3.1 3.4 (2H, m) 3.5 3.7 (1H, 3.7 3.9 (2H, m) 3.82 (3H, s) 4.23 (2H, s) 6.8 7.3 1 (5H, m) 92) NMR(CDCA 3 6: 0.35 0.80 (4H, 1.36 (3H, t, J 7 Hz), 1.80 2.10 (1H, m) 2.35 2.70 (1H, 2.80 3.65 (4H, |I m) 3.87 (3H, s) 4.26 (IH, d, J 14.4 Hz) 4.34 (1H, d, J 14.4 Hz), 5.54 (1H, t, J 8.3 Hz), 6.80 7.40 m) 8.45 (11, s) 12,40 (IH, br.) S93) NMR(CDCk3)6: 1.43 (3H, t, J 7.1 Hz) 1.92 2.50 (2H, nm), 2.75, 2.87 and 2.88 (3H, s) 2.96 3.14 (IH, 3.14 3.40 (2H, m) 3.40 3.63 (1H, in) 3.91 (31, s) 4.18 (1H, d, J 14.5 Hz), 4.37 4.55 (1H, 5. 25 and l 5.79 (1H, t, J 9.0 Hz and J 8.2 Hz), 6.75 7.52 (5H, m) 94) NMR(CDC 3
CD
3 0D) 1.00 1.50 (5H, 1.36 (3H, t, J 7.0 Hz), 1.50 2.00 (6H, m) 2.11 (3H, s) 2.10 235 (111, 2.40 2.60 (1H, i) 2.85 3.10 (111, m) 3.10 3.35 (2H, 25 3.35 3.60 (1H, m) 3.88 (31, 4.05 (IH, t, J t 1- 184 15 if 209 n O, a 7 Hz), 4.19 (11, d, J 14.4 Hz), 4.44 (1H, d, J 14.4 Hz), 6.90 7.60 (5H, m) NMR(CDC 3 1.26 (3H, t, J 7 Hz) 2.99 (2H, q, JT 7 Hz) 3.80 4.00 (2H, 4.41 (2H, 6.40 6.60 (1H, 7.00 7.70 (7H, 11.65 (1H, brs) 96) NMR (CDC 3) 6: 1.32 (3H, t, J- 7 Hz) 1.6 2.0 (2H, 2. 02 (3H, 2.9 3.1 3.0 3.2 (3H, 3.86 (3H, s) 4.0 4.4 (211, 4.45 (2H, s) 6.7 7.4 m) 97) NKR (CDC 3 6: 0.60 (3H, 145 (31, 11, 1.27 (31, 1.20 1.50 (311, mi, 2,44 S) 3.10 3.35 (41, m) 3.30 (3H, 3,58 (1H, s) 4,20 (11, d, J 14.4 Hz), 4,50 (111, d, J 14,.4 Hz), 6.90 7.60 (6H, m) 98) NMRICDCL3)6: 0.90 1,10 (21, 1.10 1.,30 1.70 1.90 (11, 2.10 2.30 (18, m) 2.27 (611, 2,60 2.80 (lHr, mi), 3.20 3.40 (11, in), 35. A 3.90 (4H, in), 4.10 -4.60 (21, i r20 .60 (211, m) 6.00 6.20 (IHi 7410 0 0 (61 12,89 (11i, brs) 99) NMR(CDCA: 6 1.72 1.9" (11, 2.09 2.40 (111, in), 2.28 (6"f 2.64 (3H, 3.20 3.41 (11, 3,44 -3.77 (311, 3.82 (l1 t, t4 7.8 HZ), 4.15 and 4.19 (11, 7~~i -185 d, J 14.9 Hz), 4.50 (1H, d, J =14,9, Hz), 5.30- 5.55 (2H, in), 5.98 6.24 (1H, mn), 7.1. (H t J 7.7 Hz), 7.29 (0.5H, dp J 9.4 Hz), 7.38 (1H, d, J 7.3 Hz), 7.50 7.66 (1.5H, in), 7.73 7.90 (1H, in), 7.94 and 8.21 (1H, brs) 186 Example 157 2-Mercaptobenzimidazole (0.7 was dissolved in dimethylformamide (30 mi). Sodium hydride (60% in oil, 0.19 g) was added thereto under ice-cooling and the mixture was stirred for 30 minutes. Sequentially, a solution of 1,4-dimethyl-8-chloromethyl-1,2dihydroquinoline (0.8 g) in dimethyl formamide(5 mi) was added dropwise to the reaction mixture and the mixture was stirred for I hour under ice-cooling.
After distilling off dimethyl formamiderthe resulting residue was poured into an ice-cold water and the mixture was extracted with chloroform. The extract was dried over anhydrous magnesium sulfate, then chloroform was distilled off. The resulting residue was purified by silica gel column chromatography Leluent a Bdichloromethane-methanol (200:1)1 to give 1,4-dimethyla a 8- (2-benzimidazolyl) thiomethyl-l, 2-dihydroquinoline (0.4 g).
NMR (CDCZ 3 )6 0 2.0. (3H, d, J=I.5 Hz), 2.63 (3m '3.50-3.80 (2U, m)f /1.30 (2H, 5.50-5.70 (1H, m), 6.90-7.70 (7H, 12.87 (lI, brs) Example 158 5-tethoxy-2-chlorobenziminmdazole (0.55 thiourea (0.2 g) and ethanol (10 ml) were refluxed for 2 hours.
C
-I
187 To the reaction mixture was added a solution of l-methyl-8-chloromethyl-1,2,3,4-tetrahydroquinoline hydrochloride (0.51 g) and sodium hydroxide (0.3 g) in water (5 ml) and the mixture was refluxed for 5 hours.
After completion of the reaction, ethanol was distilled off and water was added to the resulting residue, and the mixture was extracted with chloroform. After drying over anhydrous magnesium sulfate, chloroform was distilled off. The resulting residue was purified by silica gel column chromatography [eluent n-hexaneethyl acetate to give 8-(5-methoxy-2benzimidazolyl)thiomethyl-l-methyl-1,2,3,4-tetrahydroquinoline (0.62 g).
NMR (CDCA 3 )6 15 1.60-2.00 (2H, 2.70 (2H, t, J=7Hz), 2.73 n. (3H, 2.83-3.23 (2H, 3.73 (3H, 4.30 (2H, 6.67-7.40 (6H, 12.50 (1H, br.) 'J In a manner analogous to Example 158, the same S' compounds as those obtained in Examples 2 to 157 wore produced using appropriate starting materials.
S, Example 159 8-Carboxythi,omethyl-l-methyl-1,2,3,4-tetrahydroquinoline hydrochloride (27.9 and enediamine (13.8 g) In 4N hydrochloric acid (100 ml) were refluxed for 40 minutes. The reaction mixture 41 4 4o rr 188 was cooled, neutralized with aqueous ammonia and extracted with chloroform. After drying the extract, the solvent was distilled off under reduced pressure and the resulting residue was purified by silica gel column chromatography [eluent n-hexane-ethyl acetate to give 8-(5-methoxy-2-benzimidazolyl)thiomethyll-methyl-1,2,3,4-tetrahydroquinoline (5.0 g) NMR ;CDCA3)6 1.60-2.00 (2H, 2.70 (2H, t, JA7,Hz), 2.73 (3H. 2.83-3.23 (2H, m) 3.73 (3H, s) 4.30 (2H, 6.67-7.40 (6H, 12.50 (1H, br.) In a manner analogous to Example 159, by using appropriate starting materials, the compounds prepared in Lxamples 2 to 157 were produced.
0b 15 Example 160 To a solution of 8-(5-methoxy-2-benzimidazolyl)thiomethyl-l-methyl-l,2,3,4-tetrahydroquinoline (0.80 g) in dichloromethane (30 ml) was added a solution of m.-chloroperbenzoic acid 0.51 g) in dichloromethane (10 ml) by use of a pipet at -60°C. The mixture was stirred for 30 minutes at the same temperature. Aqueous sodium carbonate was added to the reaction mixture and the mixture was extracted with dichloromethane. The extract was dried over anhydrous magnesium sulfate and 2 P5 the solvent was distilled off. The resulting residue 44
.I
-189 was purified by silica gel column chromatography [eluent ethyl acetate-n-hexane and recrystallized from ethyl acetate to give 8-(5-methoxy-2benzimidazolyl)sulfinylmethyl-l-methyl-1,2,3,4-tetrahydroquinoline (0.38 g).
Colorless needle crystal mp 137 137.5°C i In a manner analogous to Example 160, the compounds shown in the table below were produced using appropriate starting materials. In the column of "bond between the 3- and 4-positions of the quinoline skeleton" in the table, j the symbol means a single bond and means a double bond.
i
(R
1 )m N 1 t A R 2 H O i aac **r a a r* r a ,Uln r LD, Ir C1 a r: I reC 4O 14 *c C B 0.
4 ca o ar t O C C Q aCI(F C Ct C C 0 DO bond between Example 1 I2 3 the 3- and 4- Crystal form Melting point Nop R m A R R n positions of (recrystallization (oC) No. the quinoline solvent) skeleton White powder 125-125.5 161 H 1 CH 2 C2H 5 H 1 s 125-125.5 2 (diethyl ether-n-hexane) Colorless needle crystals 162 5-CH 3 1 CH 2
C
2
H
5 H 1 s (dichloromethane 141 diethyl ether) W1 CH H 1 hite powder 115-117 163 5-OCH 3 1 CH C2H 5 H 1 s (diethyl ether-n-hexane) 115-117 White powder 139-139.5 164 5-F 1 CH 2
C
2
H
5 H 1 s i e 1 3 9 1 3 9 (diethyl etheri 5-F :White powder 165 -F 2 CH 2
C
2
H
5 H 1 shitepowde 145-146 6-F (diethyl ether) 5-F White powder 166 2 CH2 2HES H 1 s 129-130.5 6 6-OCH 3 (diethyl ether) 5-OCH5 White powder 167 5-C 2
H
5 2 CH C2 H powder 117-118.5 6-F (diethyl ether-n-hexane) White powder 168 5-Ca 1 CH 2
C
2
H
5 H 1 s hitepowder 117-119 (diethyl ether) Brown colored powder 169 5-COCH3 1 CH 2
C
2
H
5 H 1 sBrowncolored powder 119-122 (diethyl ether) White powder 170 5-CF 3 1 CH 2
C
2
H
5 H 1 s Whitepowder 120-121.5 ((iethyl ether) IColorless needle crystals 171 4-CH 3 1 CH 2
C
2
H
5 H 1 s (di r l e s s n e e d l e c r y s t a l 130.5-131 (diethyl ether-n-hexane) 4-CH 3 hite powder 172 4-C H3 2 CH 2
C
2
H
5 H 1 s hite powder 139.5-140.5 6-CH 3 (ethyl acetate-n-hexane) Pale yellow powder 173 CH 3 2 CH 2
C
2
H
5 H 1 s (dichloromethane 137-138.5 6-C 3 diethyl ether) White powder 174 H 1 CH2 CH3 H 1 s h i t e p o w d 112-113 S(diethyl ether-n-hexane) 175 5-F 1 C 2
C
3 H s Colorless needle crystals 1325-133.5 __(ethyl acetate-n-hexane) 176 5-CH 3 1 CH2 3 H Colorless needle crystals 1 _(ethyl acetate-n-hexane) ii I IL r r rrcn n a C C 0o a a~ etQ. D C8 C C O C 0 i a C0b 00 0 0 o *30a bond between Example the 3- and 4- Cryrstal form Melting point E p m A R R 3 n positions oE (recrystallization 11o. the quinoline lven)C) skeleton Colorless needle crystals 177 5-C. 1 CH 2 CH3 H 1 s (chicroform-ethyl acetate 135-136.5 n-hexane) 178 4-CH 3 1 CR 2
CR
3 H 1 Colorless needle crystals 131.5-133 (ethyl acetate-n-hexane) 179 5-F White powder 159.5-160 6-OCH 3 (ethyl acetate) Whice needle crystals 180 H I CR 2
CH
2
CHT=CH
2 H 1 s (dichloromethane 127.5-128.0 -diethyl ether) White needle crystals 181 5-OCH 3 1 CR 2
CH
2
CH=CH
2 H 1 s (dichioromethane 122.5-123.5 -diethyl ether) White needle crystals 182 5-F 1 CR 2
CH
2
CH=CH
2 H 1 s (dichloromethane 135.5-136.0 -diethyl ether) White needle crystals 183 H 1 CR 2 n-CqKg H ij s (dichloromethane 118.0-119.0 -diethyl ehter) White needle crystals 184 5-CR 3 I CH 2 n-C 4 Hq H 1 s (dichloromethane 121.5-122.0 1 -diethyl ehter) White needle crystals 185 5-OCH 3 1 CH 2 n-C 4 Hq H 1 s (dichioromethane 113.0-114.0 -diethyl ehter) White powder 186 H 1 CR 2
CH
2 -CCH H 1 s (dichloromethane 145.0-146.5 -diethyl ehter) White powder 187 5-CR 3 1 CH 2
CH
2 -CECH H 1 s (dichioromethane 140.0-141.0 1 -diethyl ehter) I' 'TI C~ jg~A I 4,,z r 4L CC C0 C *p C e C 4 0 C C C 4 j C C C C C 4C CCD C C rr C Crystal form cry. Melting point (yC) solvent.) White needle crystals (dichloromethane 125.5-126.5 -diethyl ether) White powder (dichloromethane 145.0-146.5 -diethyl ether) White powder (dichloromethane 102.5-103 -petroleum ether) White powder (dichloromethane 119.5-120.5 -petroleum ether) White powder 140-140.5 (dichloromethane) White powder 128.5-129 (ethyl acetate) White powder (dichloromethane 129.5-130.0 -diethyl ether) Yellow powder (dichloromethane 123-124 -diethyl ether) White powder (dichloromethane 128-129 -diethyl ether) White powder (dichloromethane 135-136 -diethyl ether) White powder (dichloromethane 144.0-145.0 -diethyl ether)
-J
4 ii i ~sF~j i- 1 ':Z r a a 00 a rn r a bond between Crystal form elting point Example ~~the and: 4- rerystall aton mltngpon Example m A R2 R3n positions of (recrystallization o No. the quinoline solvent) skeleton 117-119 A SC 3 :C %BPale brown powder 199 5-CO 2
CH
3 1 CH2 CH Hihy Ioer (decomposi- (diethyl ether) tion) tion) 200 5-OC 2
H
5 C C H White powder 136 200 2 CH2 CH3 H 1 s (tyacae)136 6-F (ethyl acetate) White powder -F 201 5-C 2 C 2 Cg H 1 s (dichloromethane 154-155 6-CH3 -diethyl ether) 202 5-F 2 C C White powder 151-153 20-2 2 CH9 C25 H 1 s1513 6-CH 3 (ethyl acetate) Q White powder 203 5- 2
C
2
H
5 6-OCH 3 1 s (dichloromethane 144.0-145.0 2 0 3 5 I 6- d i e t h y l e t h e r 5-F Pale yellow needle 132-135 2042 K C-C Cg 1s1315 204 6-OC 2 CH2 CCH-CH 2 1 s crystals (ethyl acetate) 123 I Colorless needle crystals 205 4-CH 3 1 CH2 CH (ethyl acetate)H s 140-141 iethyl acetate) 4-CC Colorless needle crystals 206 2 CH CH(CHyCH2 t 1 s y_ __143-143.5 6-CH Iethyl acetate-n-hexane) L I 1- t *nt a So a 4! ra a ta 1 O C Br,
BCBB
LrFC 10 E- O c ne bond between Eample 1 the 3- and 4- Cyt fo melting point Rxampe RR n positions of (recrystallizat (C) No.the quinoline solvent) skeleton Colorless needle crystals 207 5-CU 3 I CH2 CR 2
CH=CH
2 (h actae 136.5-138.5 5-F 2 CH 2 CH 1White powder 144-145 208 2 1 CH2 CE2CH= 144-145 6-0H (ethyl acetate) Colorless needle crystals 209 5-CL 1 CR 2
CH
2
CH=CH
2 IH 1 Ce 135-136 (ethyl acetate) Colorless needle crystals 218 5- 3 Fi 3CRE~ ~H 2 I H 11 s128-130 210 ,(diethyl ether) White powder 211 H I CH 2 H 1 F' Hs (dichloromethane 146-147 -diethyl ether) White powder 212 5-CH3 I CR 2
CR
2 H 1 s (dichloromethane 168-169 -diethyl ethez} White powder 213 2 C 2
CR
2 0 F 1 s (dichloromethane 151-152 6-OCH 3 -diethyl ether) -White powder 214 5-OCH I CH 2 CH2CECH H 1 s (dichloromethane 131-132 -diethyl ether) White powder 215 2 CH 2
CH
2 C=C H 1 s (dichloromethane 138-139 _--diethyl ether) 21 1CCC1Colorless needle crystals 121.5 216 1 4-CH3 (diethyl ether) Ij C ks~ i i I- i Ir rC a, a S01 U 0 a q 3 'aB 30 bond between Example I the 3- and 4- Crystal form Melting point x i R 3 n positions of (recrystallization (C) No- the quinoline solvent) skeleton, 5-F Colorless needle crystals 133-135 217 6 U 2 CH 2 CHC=CZ 4-C 3 1 (diethyl ether) (decomposi- IC I tion) White powder 123-124 218 f ,1 CE 2 H-H 1 s (dichioromethane (decomposi- -diethyl ether) tion) 1 C White powder 132-133.5 219 62 CE 2 H 1 s (dichloromethane (decomposi- -diethyl ether) tion) White powder 220 H I CE 2
C
2
CF
3 H 1 s (dichloromethane 150-151 -diethyl ether) White powder 221 5-CI 3 1 CE1 2
CE
2
CF
3 1 s (dichioromethane 168.5-169.5 -diethyl ether) White powder 222 1 j CE 2 CF Ii 1 s (dichloromethane 172.5-173.5 6-OCH 3 -diethyl ether) Colorless needle crystals 223 it I CH2 4I 1 s 125-126 I I_ (ethyl acetate) 224 5-F Colorless needle crystals 135-137 6-OCE 3 (ethyl acetate) Colorless needle crystals 225___ 1_ CH_ _I(ethyl acetate) 140_141.5 226 H 1 C2 2
CE
2
CHCH
2 3-CE 3 1 Colorless needle crystals 124.5-125.5 1_ 1_ (diethyl ether) I _I i
S
i d.
enO 4 *44 a C C 48*~ C C I*b an J 4s4+ 04* C C 0* C CD E a 9, 40 A bond between E the 3- and 4- Crystal form Meltin point E m A R R n- positions of (recrystallization No. the quinoline solvent) O skleton keetn White powder 227 1 CfTa2 -IiXCR=CH 3-CH 3 1 S (diethyl ether) 137.5-138.5 White powder 228 5-OCH 3 1 CH 2 i UH 2 2TCH 2 3-CH3 1 s (ethyl acetate 124.5-125.5 -diethyl ether) 13 White powder 141-143 229 15-F I CH2 CH2CH=CHZ(diethyl ether-n-hexane) 230 5-F 2 C CH 2
CH=CH
2 3-CR 3 s Colorless needle crystals 145.5-146 6-OCH1 (diethyl ether) White powder 231 H1 1 CH 2 CHZC=-CH 4-C1 3 l S (dichloromethane- 117-119 -diethyl ether) CH3 Wiite powder 141.5-142.5 232 H 1 C: 2
CII
2
CH
2 N H 1 s (Cichioromethane- (decomposi-
ICH
3 -diethyl ether) J tion) 33 H1C2CColorless needle cry-sals 1,6-137 (ethanol-ethyl acetate) 234 5-F 2 CH2White powder 160.5-161.5 6-OCH 2 (diethyl ether) 235 5-CH 3 1 CH,' CH 3 4-CJ- 3 1 Pale yellow needle crystals (ethyl acetate 4 Yellow granules 236 5-OCH 3 1. CH 2
H
3 4-CH 3 d Ydel graul 132-133 ethei') L4_ i ~C~ 1 i i 0 0
S*I
*I 0* 10 *0 0 0 *0 0 0 09 4i 090 9*
S
9 09 bond between the 3- and 4- Crystal form Melting point E m A R 2 R n positions of (recrystallization No. the quinoline (OC) skeleton solvent) Pale yellow powder 157-159 237 3 2 CR 2
C
3 4-CR 3 1d (diethyl ether-dichioro- 4 (deconposi- 6-OCR 3 methane-n-hexane) tion) White powder 127-130 238 H 1 CH 2
C
2 5 4-CR 3 1 d (1/2 hydrate) (decomposi- (diethyl ether) tion) Pale yellow powder 140-142 239 5-F 2 CR 2
C
2
H
5 4-CR 3 1 d (1/2 hydrate) (decomposi- (diethyl ether) tion) 148-149.5 240 3-CH 3 White powder 4-CH 3 (diethyl ether) tio) tion) Yellow powder 153-154 241 H 1 CR 2 C~g 4-=0 '1 s (dichloromethane (deconposi- -diethyl ether) tion) White powder 111-112 242 H 1 CR 2
CH
3 4-OH 1 s (dichloromethane (decomposi- I -diethyl ether) tion) White powder 136-137 243 H 1 CR 3 4-OR 243 4-CRCH 3 CH3 2 s (dichloromethane (decomposi- -diethyl ether) tion) R4 2White powder 123-124 244 H -1 ORCH CH 2 s (dichloromethane (decomposi- -petroleum ether) tion) 000 245 HR 1! CR 2
ICR
3 -<jJ 1I s IND'R 1 Pale yellow powder 118-118.5 246 H 1 cHCR -,C2H 5 4I-OCH3 1 s. (dichiorcinethane (decomposi- I_ I I -diethyl ether tion) 4 ii 4_ r i i ~1 1 1I -r -r Example No.
bond between the 3- and 4positions of the quinoline skeleton Crystal form (recrystallization solvent) Melting point SColorless needle crystals 8- 247 H 1 CH 2
C
2 H5 4( 1 s 87-89 S1 s (petroleum ether) \Colorless needle crystals 248 5-CH 3 1 CH 2
C
2
H
5 4 1 s (perole neede r t 137-139 (petroleum ether) 5-F White powder 249 F 2 CH 2
C
2
H
5 4 1 s Whitepowder 153-154 6-OCH 3 (diethyl ether) Yellow powder 118-118.5 250 H 1 CH 2
C
2
H
5 4-OCH 3 1 s (dichloromethane (decomposi- -diethyl ether) tion) White powder 251 5-CH 3 1 CH 2
C
2
H
5 4-OCH 3 1 s (dichloromethane 148.5-149.5 -diethyl ether) White powder 252 5-OCH 3 1 CH 2
C
2
H
5 4-OCH 3 1 s (dichloromethane 149-150 -diethyl ether) Yellow powder 5-F 253 6-OCH3 2 CH 2
C
2
H
5 4-OCH3 1 s (dichloromethane 131-132 -diethyl ether) White powder 254 6-F 2 CH 2
C
2
H
5 4-OCH 3 1 s (dichloromethane 135-136 6-F i -diethyl ether) ~C i i i L i s -~LLII 1 4 -i was 9* *O *a C a a~ a o a 9 9 a a a 9 4 9 9 #4 a a 9 o 09 0 ft* a 9 9 99g bond between Example the 3- and 4- Crystal form Example 2 3 Melting point No. ,R 1 m A H 2 R n positions of (recrystallizaticn (OC) the quinoline solvent) skeleton White powder 255 5-COCa 3 1 CH C2H 5 4-OCH3 1 s (dichioromethane 149-150.5 -diethyl ether) Yellow needle crystals 256 H 11 Ca 2
C
2
H
5 4-N(CH 3 2 I s (dichloromethane 141-142 -petroleum ether) White powder 257 5-F 2 CH 2
C
2
H
5 4-N (CH 3 2 1 s (dichloromethane 162-163 6-OCH3 -diethyl ether) White powder 258 a 1 C 2
C
2
H
5 4-NHCH 3 1 s (dichloromethane 102-104 -petroleum ether) White powder 259 H 1 CH 2
C
2 1 5 4=NOH 1 s (dichloromethane 168-169 I_ -diethyl ether) Colorless needle crystals 12@.5-129 (ethyl acetate-n-hexane) White powder 261 H 1 CRH2 C 2 5 4=CH 2 1 s (dichloronethane 159.5-160.5 -diethyl ether) White powder 262 H 1I CH 2
C
2
H
5 -K1 s (dichloromethane 141-142 1 0_ -diethyl ether) 4c i 1 Sk*
I
trr i r,+ i II rn r
P
4, 4 *4b 4 4. 44O 4- *4~ bond between Example 3 the 3- and 4- Crystal form Meltin point Exal R m A R R n positions of (recrystallization g poin No. the quinoline olvent) (C) skeleton White powder 263 H 1 CH 2
C
2
H
5 3-COOCH 3 1 s (dichloromethane 173-174 -diethyl ether) White powder 137-138 264 H 1 CH 2 CzH 5 3-CH20H 1 s (chloroform-ethanol- (decomposidiethyl ether) tion) CH3 White powder 265 H 1 CH 2
C
2
H
5 3-CON 1 (1/3 hydrate) 133-135 I 'CH 3 (dichloromethane S_-diethyl ether) 162-165 266 H 1 CH 2
C
2 RH 3-C0 2 f 1 Colorless needle crystals (decomposi- (1/2 hydrate) (methanol) t tion) White powder 147-148 267 5-OCH 3 I CH 2
C
2
H
5 3-CHO2H 1 s (chloroform-ethanol- (decomposi- -diethyl ether) tion) 268 H 1 CH 2
C
2
H
5 4-N3 1 s NMR 1 0 1 White powder 269 5-CH 3 1 CH 2 C2HS 4-OCH 2
CH=CH
2 1 s (dichloromethane 156-156.5 -diethyl ether) Colorless needle crystals 270 5-COCH 3 1 CH 2
C
2
H
5 4-OCH 2
CH=CH
2 1 s (dichloromethane 131-133 -diethyl ether) Yellow powder 271 H 1 CH 2
C
2
H
5 4=0 1 s (chloroform 168-169 -diethyl ether) J L _r g y- i 00 $0 0 0* bond between Example A I R the 3- and 4- Crystal form melting point R AR213n positions of (recrystallization (c skeleton slet White powder 272 H 1 GCH 2
JC
2
H
5 4-OH 11 s (dichioromethane 117-118 -die thyl ether) 5-F White powder 149-150 273 6-Cg 2 CH 2
C
2
H
5 3-CH 2 0H 1 s (chloroform-ethanol- (decomposi- -diethyl ether) tioi) White powder 1435-144.3 274 5-CR 3 1 CH 2
C
2
H
5 3-CH 2 0H 1 s (dichioromethane (decomposiether) jtion) Colorless needle crystals 275 S-COCH 3 1 CR 2
CH
2
CH=CH
2 4-OCR 3 1 s (dichloromethane 129-130 ether) 27 5COHI 1 CR 2 2
R
5 4= Yellow powder 127-129 27 3,31 1C2 25-d3 1 (diethyl ether-n-hexane) 5F11CH 3 Pale yellow powder 277 5?CH 2 CR 2
CH
2
CR=CH
2 4-N( I'l s (dichloromethane 124-125 6-OR 3
CH
3 -petroleum ether)
CH
3 Pale yellow powder 278 H 1 CR 2
CH
2 CH=-CHZ 4-N N 1 s (dichloromethane 152-153 1_ NCH 3 -petroleum ether) *A.r ar a A. P r A. Ar O A d*e~ I :4 n bond between Example I m I A RZ R3 the 3- and 4- Crystal form Melting point R n positions of (recrystallization) OC) No. the quinoline solvent) skeleton
CR
3 White powder 279 H 1 CH 2
C
2 n 5 4-N I s (dichioromethane 138-139
CH
2
CH
2 OH -diethyl ether) ,/Cf White powder 280 H, 1 CH 2
C
2
H
5 4-N I s (dichioromethane 116-118
COCH
3 -Diethyl ether) 281 2CH 2
CR
5 s 1 /CH3 White powder 141-143 6-OCR 3 (diethyl ether-n-hexane) 5-F H3 Yellow powder 282 2. CH 2 H 4-N 1 s (dichloromethane 92-93 6-OCR 3
CH
2
CH=CH
2 -petroleum ether) Yellow powder 283 -F 2 CH 2
C
2 5 1 s (dichloromethane 116-118 6-OCH 3 4 NC -petroleum ether) CH3 White powder 284 5-F 2 CR 2
C
2
H
5 4 -N"i OC2H5 I s Cdichloromethane 142-143 6-OCH3 -CH- 6CF 3 -petroleum ether) Yellow powder 3 2 CR 2
C
2
H
5 1I s (dichioromethane 146-148 6-OCR 3 4-petroleum ether) -F ,CH3 White powder 286 5-F 2 CH 2
C
2 HS 4-N 1 s (dichloromethane 149-150 6-OCR 3 fCH 2 2 0R -petroleum ether) 287 2 CR 2
C
2 5 4-N 1 White powder 121-124 6-OCR 3 (diethyl ether-n-hexane) 2 CR 2 CR 4 CH2CH2CH White powder 6-OCR 3 25 0 1 (petroleum ether) ~L L I, 1~ bond between the 3- and 4- Crystal form Melting point Examnple .m A R 2
R
3 n positions of (recrystallization Oc) the quinoline sovet skeleton CH2C=CH2 289 5-F 2 CR 2
C
2
R
5 4 1 Colorless prisms 110-114 6-OCH3 5 (dethyl ether-n-hexane) CCEI 98-101 I'll CH3 White powder 290 H I OR2 C 5 3CH 2N "II II s (ityehr)(decomposi- 290 CH 5 CR3(diethyl ether) tion) CH- 1ponp White powder (1/2 hydrate) 160-162 -l H .1 CH 2
C
2 f 5 3-CON 0 1 s (dichloromethane (decomposi- -diethyl ether) tion) 5-F White powder(1/2 hydrate) 180.5-181.5 292 62 CH 2
CH
5 3-CON 0 1 s (dichloromethane (deconposi- -diethyl ether) tion) White granules 139-140 C 293 H 1 CR 2
C
2
H
5 13-CON I s (dichloromethane (decomposiI -diethyl ether) tion) 5- OC 3 White powder (hydrate) 294 6-OCH3 2 CR 2
C
2 H 3-CNH(CH 2 )2 (\9-OCH3 1 s (dichloromethane- 140-142 diethyl ether)
CR
3 293 5-CR 3 1 CR 2
C
2 HS 1-N/ sH3 -S White powder 109-111 4-N'2 (petroleum ether)
~CR
2
CR=CR
2 CH3 Pale yellow powder 296 5-COCH3 1 CR 2
C
2
R
5 4-N 1 P 115-118 _CH7CH=CH 2 (petroleum ether) 5-F 2CH 3 White powder 297 6OR 2 CRI 2
C
2
H
5 4-N 1 S(ptoem thr 111-115 6-OCH3 \CH;,C=CH2 (petroleum ether) White powder 298 5-CRH 3 1 CR 2 CZII 4-NHCH 2
CH=CR
2 1 s (dichloromethane 162-164 1 _-diethyl ether) L, 1-
I,
1 L7 n rC/ngra p. ago 0 0 C 0 p p 0~ CO e 0 0 0oar bond between the 3- and 4 Crystal formpoint Example m A R 2
R
3 n positions of (recrystallization the quinoline solvent) (OC) skeleton 299 5-CR 3 1 1H-N-H 5 White powder 135-138 5-CH CH2C2H5(petroleum e-ther) White powder 300 2 CH 2
CH
2
CH=CH
2 4-OCH 3 1s (diicloromethane 143-144 6-OCH3 -diethyl ether) Colorless needle crystals 301 5-CE 3 1 CR 2
CHZCH=CH
2 4-OCR 3 1 s (dichloromethane 129.3-130.5 -diethyl ether) White powder 302 5-COCH 3 I CR 2 1C 2 5 4-OCH 2
OCH
3 1 s (dichioromethane 132.5-133.5 -diethyl ether) white powder 303 6-O 2 CH 2
C
2 HS 4-CH 2 0H 1 s (dichloromethane 139-140 _-diethyl ether) CHE3 White powder 304 5-COC 3 1 CH 2 2
H
5 4-N 1 Witreu er 125-128 (petroleum ether)
CHO
2 C White powder1 6-C 2 CR 2 CL5 1 (diethyl ether-n-hexane) 5-F /,CH3 White powder 306 2 CR 2
C
2 HS 4-R 1 s (dichloronethane 159-160
COCE
3 -petroleum ether) CH3 Colorless needle crystal 164-168 307 2 CR 2
C
2
H
5 4-N,0 1 s (1/4 hydrate) (decomposi- (ethyl acetate-n-hexane) tion) White granules 308 H I 12- C 2
H
5 4-CF 3 1 d (diethyl ether-n-hexane) 142-144 Alp L cee 9 9 Doc 000 00 46!0 000 9 00 jbond between Cytlfr Example In R3R the 3-1 and 4- Crsaommelting point RNol. I RR 3 n positions Of (recrystallization 0
C
No the guinoline solvent) C skeleton 309 S-'H3 -1 01 2
C
2
H
5 4-OCH3 White powder 110-112 3 (petroleum ether-n-hexane) 7
CH
3 white powder15-5 310 1 CR 2
CH
2
CH=CH
2 4-N\ 1/ I S (diethyl ether-n-hexane)1515 311 RZC--CZ 4N I/CH3I S NM102) 31 5-COCR 3 1 CH 2
C
2
RC
2 4- R M CHg_ -206- 100) NMR (CDC 4 3 6: 2. 15 2 .27 (2H, mn), 2. 99 (3H, 3. 48 3. 59 (2H, in) 4.07 4.27 (4H, mn), 4.38 (2H, s) 6.88 8.00 in) 01 NMR(CDCZ, 3 )6: 1.21 and 1.27 (3H, t, J 7 Hz) 1.32 -1.49 (1H, m), 1.58 1.80 (4H, in) 1,~80 2.10 (1H, mn) 2.28 2.49 (2H, in) 2. 49 2. 70 (2H, in) 2.-7 0 2. 87 (1H, in) 2.87 -314 (3H, in), 3.35 and 3.50 (1H, t, J =5 Hz), 4.35 and 4.47 (1H, d, J 13 Hz) 4.61 and 4.78 (1H, d, J 13 Hz), 6 .78 and 6. 84 (1H, t, J 8 Hz) 7.T -7.38 (4H, in), 7.53 7.70 (2H, in) 102) NMR (CDC k 3 1 .35 2. 02 (2H, in) 2. 19 (3H, s) ,2.21 (3H, s) 2 .48 6015 2. 77 (1lH, in) 2 .68 (3H, s) 2 2.77 3 .02 (1H, in) 3.37 3.83 (3H, in) 4.35 -4.85 (2H, mn) 5.10 5.50 (2H, in) 5 .83 6 .17 (1Hi, mn) 6 .80 6 6.96 (1H, in) 7 .07 7 7.22 (1H, in), 7. 44 7. 69 (2H, in), 7. 98 (1H, dd, J 1 Hz 6 .9 Hz) 8. 27 (1H, s) 1 C
;I
207 Example 312 1,4-Dimethyl-8-(2-benzimidazolyl)thiomethyl-1,2dihydroquinoline (0.4 g) was dissolved in dichloromethane ml). To this solution was added dropwise a solution of m-chloroperbenzoic acid (0.27 g) in dichloromethane ml) at -40°C with stirring. After the mixture was stirred for 20 minutes at the same temperature, the reaction mixture was washed with an aqueous solution of sodium carbonate and extracted with dichloromethane.
The extract was dried over anhydrous magnesium sulfate and the solvent was distilled off. Diethyl ether was added to the resulting residue to precipitate crystals.
o0a The resulting crystals were recrystallized from o dichloromethane-diethyl ether to give 1,4-dimethyl-8-(2benzimidazolyl) sulfinylmethyl-l,2-dihydroquinoline (0.2 g) 4 m Pale brown powder mp 159.5 160.5 0 C (decomposition) Example 313 (l-Methyl-1,2,3,4-tetrahydroquinolin-8-yl)methyl ltthium (18.3 g) was dissolved in benzene (150 ml).
After adding (5-methoxy-2-benzimidazolyl)sulfinyl chloride (20.1 g) thereto, the' mixture was refluxed for 2 hours. The resulting lithium chloride was filtered off, and the filtrate was concentrated under C -i- 208
I
Ir 4 O a t* 1 20 reduced pressure. The resulting residue was recrystallized from ethyl acetate to give 8-(5-methoxy-2benzimidazolyl) sulfinylmethyl-l-methyl-1, 2,3,4-tetrahydroquinoline (1.1 g).
Colorless needle crystal mp 137-137.5 0
C
In a manner analogous to Example 313, the same compounds as those prepared in Examples 161 to 312 were produced using appropriate starting materials.
Example 314 8-(2-Benzimidazolyl)sulfinylmethyl-1,2,3,4-tetrahydroquinoline (14,9 g) was dissolved in dimethyl formamide (150 ml). Sodium hydride (60% in oil, 2.2 g) was added thereto with stirring undler ice-cooling, and the mixture was stirred for 30 minutes. Sequentially, methyl iodide (8.5 g) was added dropwise to the reaction mixture and the mixture was stirred for 5 hours at 70 to 80 0
C.
After distilling off the solvent, the residue was poured into water and the m.ixture was extracted with chloroform.
The residue obtained by distilling off the chloroform was purified by silica gel column chromatography and recrystallized from diethyl ether-n-hexane to give 1-methyl-8-(2-benzimidazolyl)sulfinylmethyl-1, 2,3,4tetrahydroquinolino (2.1 g).
I
209 White powder mp 112 113 0
C
In a manner analogous to Example 314, the same compounds as those prepared in Examples 1 to 173 and 175 to 313 were obtained using appropriate starting materials.
Example 315 To a solution of 8-(2-benzimidazolyl)thiomethyl-l- (3-trimethylsilyl-2-propiyl) -1,2,3,4-tetrahydroquinoline (400 mg) in tetrahydrofuran (20 ml) was added IM solution of tetra-n-butylammonium fluoride with stirring under ice-cooling, and the mixture was stirred for 30 minutes 0oo at the same temperature. After distilling off the
B
solvent, the resulting residue was extracted with dichloromethane. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off. The resulting residue was purified by silica gel column chromatography [eluent n-hexaneethyl acetate and recrystallized from dichloromethane-diethyl ether to give 8-(2-benzimidazolyl)thiomethyl-l-propargyl-1, 2,3,4-tetrahydroquinotine (0.35 mp 122 122.5 0
C
In a manner analogous to Examp>l ing r II -r 210 appropriate starting materials, the same compounds as those prepared in Examples 28, 56, 57, 73, 186, 187, 214, 215, and 231 ,ere obtained.
Example 316 To a solution of 8-(2-benzimidazolyl)thicmethyl-1methyl-4-oxo-l,2,3,4-tetrahydroquinoline (300 mg) in methanol (10 ml) was added gradually sodium borohydride mg) at 0 C. The reaction mixture was stirred for minutes, at room temperature. After distilling off the solvent, the resulting residue was extracted with dichloromethane, washed with water, and dried. Then the solvent was distilled off and the resulting residue was recrystallized from ethyl acetate-n-hexane to give 8-(2-benzimidazolyl)thiomethyl-l-methyl-4-hydroxy-l,2,3, 4-tetrahydroquinoline (238 mg).
White powder mp 144.5 145°C In a manner analogous to Example 316, the same compound as those prepared in Example 113, 242, and 272 were obtained using appropriate starting materials.
Example 317 To a solution of 8-(2-benzimidazolyl) thiomethyl-lmethyl-4-oxo-l,2,3,4-tetrahydroquinoline (300 mg) in tetrahydrofuran (10 ml) was added dropwise methyl lithium (1.5M solution in tetrahydrofuran) (1.33 ml) with ,I i i i 211 stirring at -10 0 C. Then the mixture was stirred for minutes at the same temperature. After distilling off the solvent, the residue was extracted with dichloromethane, washed with water, and dried, then the V solvent was distilled off. The resulting residue was purified by silica gel column chromatography [eluent n-hexane-ethyl acetate-dichloromethane and recrystallized from dichloromethane-diethyl ether to give 8- (2-benzimidazolyl) thiomethyl-4-hydroxy-l,4dimethyl-l,2,3,4-tetrahydroquinoline (96 mg).
Yellow powder mp 156 157 0
C
O s e In a manner analogous to Example 317, by using appropriate starting materials, the same compounds as those prepared in Examples 86, 243, and 244 were .0o obtained.
Example 318 8- (2-Benzimidazolyl) thiomethyl-l-ethyl-4-oxo- 1,2,3,4-tetrahydroquinoline (1.5 g) hydroxylamine 20 hydrochloride (458 mg) and sodium acetate (1.7 g) were ti 4 dissolved in a mixed solvent (23 ml) of ethanol-water :(20 and the solution was refluxed for 3 hours.
After completion of the reaction, the solvent was Sdistilled off and the resulting residue was poured into water. The precipitated crystals were collected by
A
~r;itlar-.
1 L~ _iil~iiCI~I i
~I
212 S0 h e filtration and recrystallized from methanol to give 8-(2-benzimidazolyl)thiomethyl-l-ethyl-4-hydroxyimino- 1,2,3,4-tetrahydroquinoline(0.94 g).
Colorless columnar crystal mp 201 202 0
C
In a manner analogous to Example 318, the same compound as that.prepared in Example 259 was obtained using appropriate starting materials.
Example 319 8-(2-Benzimidazolyl)thiomethyl--ethyl-4-oxo-l,2,3,4tetrahydroquinoline (1 g) and methylamine (40% methanol solution, 7.4 ml) were dissolved in methanol (15 ml) and the solution was refluxed for 14 hours. After allowing to cool, sodium borohydride (630 mg) was added by portions with stirring at room temperature, and the mixture was stirred for 1 hour at the same temperature. The solvent was distilled off and the resulting residue was extracted with dichloromethne. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off. The resulting residue was recrystallized from ethyl acetate to give 8-(2benzimidazolyl)thiomethy-l--ethyl-4-methylamino-1,2,3,4tetrahydroquinoline (970 mg).
Yellow powder mp 144 145 C i 01 0r 01 213 In a manner analogous to Example 319, by using appropriate starting materials, the same -Jmpounds as those prepared in Examples 97, 98, 107, 118, 119, 121, 123 to 127, 130, 131, 140 to 143, 148, 151, 155, 156, 256 to 258, 268, 277 to 279, 281 to 285, 288, 289, 295 to 299, 304, 307, 310, 311, 328 to 336 and 339 to 345 were obtained.
Example 320 To a solution of l-ethyl-4-methylamino-8-(2benzimidazolyl) thiomethyl-1,2,3,4-tetrahydroquinoline (900 mg) in methanol (20 ml) was added glyoxal (10 ml) and the mixture was stirred for 3 hours at room temperature. The solvent was distilled off and the resulting residue was dissolved in methanol, and to this mixture was added gradually sodium borohydride (1 g).
0 After stirring the mixture for 1 hour at room temperature, the reaction mixture was concentrated. The resulting residue was extracted with dichloromethane and dried over anhydrous maguesium sulfate. The residue obtained p 20 by distilling off the solvent was purified by silica gel Scolumn chromatography [eluent dichloromethane-methanol to give l-ethyl-4- [N-methyl-N-(2-hydroxyethyl)amino]-8-(2-benzimidazolyl)'thiomethyl-,2,3,4tetrahydroquinoline (510 mg).
214 NDIR (CDC 3 1.42 (3H, t, J=7.2 Hz), 1.73 1.96 (1H, m), 2.10 2.33 (1H, 2.23 (3H, 2.67 (2H, t, J=5.3 Hz), 2.88 3.10 (1H, 3.10 3.38 (2H, 3.48 3.70 (3H, 3.94 (1H, t, J=8.0 Hz), 4.10 (1H, d, J=14.8 Hz), 4.43 (1H, d, J=14.8 Hz), 7.00 7.69 (7H, m) In a manner analogous to Example 320, the same compounds as those prepared in Examples 279, 286, 334, 335 and 339 were obtained using appropriate starting materials.
Example 321 To a solution of l-ethyl-4-methylamino-8-(2oo benzimidazolyl) thiomethyl-1,2 ,3,4-tetrahydroquinoline (690 mg) in dichloromethane (20 ml) was added a solution 0" s5 of acetic anhydride (15.6 mg) in dichloromethane (2 ml) with stirring. After stirring the mixture for minutes at room temperature, the reaction mixture was washed with a saturated aqueous sodium hydrogen '6 0 carbonate and dried over anhydrous magnesium sulfate.
The solvent was distilled off and the resulting residue 6 was purified by silica gel column chromatography [eluent dichloromethane-methanol to give l-ethyl-4-(N-methyl-N-acetylamino)-8-(2-benzimidazolyl)- Sthiomethyl-1,2,3,4-tetrahydroquinoline (500 mg).
tr 215 o0 a ot0 S4 4 0060 94~ #4 0i NMR (CDCA 3 1.29 1.50 (3H, 1.81 2.43 (2H, 2.23 and 2.27 (3H, 2.65 and 2.69 (3H, 2.85 3.65 (4H, 4.18 and 4.20 (1H, d, J=14.5 Hz), 4.44 and 4.50 (1H, d, J=14.5 Hz), 5.00 and 5.91 (1H, t, J=7.6 Hz and J=8.3 Hz), 6.87 7.22 (4H, m), 7.30 7.56 (3H, m) In a manner analogous to Example 321, by using appropriate starting materials, the same compounds as those prepared in Examples 128, 129, 149, 150, 280, 287, 305, 306, 337, 338, 346 and 347 were obtained.
Example 322 To a solution of 8-(2-benzimidazolyl)thiomethyl-lethyl-i,2,3,4-tetrahydroquinoline-3-carboxylic acid (1.3 g) in tetrahydrofuran (50 ml) were added dropwise triethylamine (0.4 g) and ethyl chloroformate (0.4 g) with stirring under ice-cooling and the mixture was stirred for 30 minutes. Moreover morpholine (0.4 g) was added dropwise thereto and the mixture was stirred for 3 hours at room temperature. The solvent was distilled off and the resulting residue was dissolved in chloroform. The solution was washed with a saturated aqueous solution of sodium hydrogencarbonate and dried over anhydrous magnesium sulfate, and the solvent was distilled off. The resulting residue was purified 4 216 04 4 5 444 .4e o 44 by silica gel column chromatography [eluent dichloromethane-methanol and reuorystallized from ethyl acetate-ethanol to give 8-(2-benzimidazolyl)thiomethyl-3-morpholinocarbonyl-l-ethyl-l,2,3,4-tetrahydroquinoline (0.7 g).
White powder mp 193.5 194.5°C In a manner analogous to Example 322, by using appropriate starting materials, the same compounds as those prepared in Examples 106, 137 to 139, 265, and 291 to 294 were produced.
Example 323 A solution of 8-(2-benzimidazolyl)thiomethyl-3dimethylamido-l-ethyl-1,2,3,4-tetrahydroquinoline (2.0 g) in tetrahydrofuran (10 ml) was added dropwise to a suspension of lithium aluminum hydride (0.58 g) in tetrahydrofuran (50 ml) with stirring under ice-cooling.
Then, the mixture was refluxed for 5 hours. To the reaction mixture were added water (0.3 ml) and a solution of sodium hydroxide (0.3 g) in water (1.5 ml).
After filtering off the precipitate, the filtrate was dried over anhydrous magnesium sulfate. After distilling off tetrahydrofuran, the resulting residue was recrystallized from ethyl acetate-n-hexane to give 8-(2benzimidazolyl) thiomethyl-3-dimethylaminomethyl-l-ethyl- 44 4 D~44 r 9P
S*
'4 4 7 g, 15 Q s 15so I 4 aa *6 u fa r I,;t
IOC
*M
217 1,2,3,4-tetrahydroquinoline (1.3 g).
White powder mp 152 154 0
C
In a manner analogous to Example 323, the same compound as that prepared in Example 290 was obtained using appropriate staring materials.
Example 324 To a suspension of methyl triphenylphosphonium bromide (2.65 g)in tetrahydrofuran (50 ml) was added dropwise n-butyllithium (2.2 ml) in a nitrogen flow with stirring at -40°C. After raising the temperature to -20 0 C, a solution of 8-(2-benzimidazolyl)thiomethyl-l-ethyl-4oxo-l,.2,3,4-tetrahydroquinoline (500 mg) in tetrahydrofuran (5 ml) was added dropwise. The temper'ature was raised gradually to room temperature, and the mir.xture was stirred for 3 hours. Water was added to the reaction mixture, and the mixture was extracted with dichloromethane and dried over anhydrous magnesium sulfate.
The residue obtained by distilling off the solvent was purified by silica gel column chromatography [eluent n-hexane-ethyl acetate and recrystallized from diethyl ether-dichloromethane to give 8-(2benzimidazolyl) thiomethy.1-1-ethyl-4-methylene-1 ,2,3,4tetrahydroquinoline (390 mg).
White powder ~L j re 218 mp 148 149°C In a manner analogous to Example 324, the same compound as that prepared in Example 261 was obtained using appropriate starting materials.
Example 325 To a suspension of lithium aluminium hydride (0.3 g) in tetrahydrofuran (50 ml) was added dropwise a solution of 8-(2-benzimidazolyl)thiomcthyl-l-ethyl-3ethoxycarbonyl-1,2,3,4-tetrahydroquinoline (1,0 g) in tetrahydrofuran (10 ml) with stirring under ice-cooling.
The mixture was stirred for 3 hours at the same temperature. To the reaction mixture were added water (0.3 ml) and a solution of sodium hydroxide (0.3 g) in J water (1.5 ml). After filtering off the precipitate, the filtrate was dried over anhydrous magnesium sulfate.
After distilling off tetrahydrofuran, the resulting residue was recrystallized from ethanol to give 8-(2benzimidaolyl) thiomethyl -l-ethyl-3-hydroxymethyl 1,2,3,4-tetrahydroq'tinoline (0.7 g).
20 White powder mp 175 177°C In a manner analogous to Example 325, by using appropriate starting materials, the same compounds as those prepared in Examples 109, 114, 115, 147, 264, 267, 273, 274 and 303 were obtained.
I 219 Example 326 To a solution of 8-(5-fluro-6-methoxy-2benzimidazolyl)thiomethyl-l-ethyl-4-acetyloxymethyl- 1,2,3,4-tetrahydroquinoline (2.55 g) in methanol 1ml) was added a saturated aqueous solution of potassium carbonate (10 ml) and the mixture was stirred for 1 hour at room temperature. The reaction mixture was extracted with dichloromethane and dried. The solvent was distilled off to give 8-(5-fluoro-6-methoxy-2benzimidazolyl)thiomethyl-l-ethyl-4-hydroxymethyl- 1,2,3,4-tetrahydroquinoline (1.74 g).
NMR (CDCZ 3 1.34 (3H, t, J=7 Hz), 1.9 2.2 (2H, 2.9 3.1 (2H, 3.1 3.4 (2H, m)i 3.5 3.7 (1H, m), 3.7 3.9 (2H, 3.82 (3H, 4.23 (2H, s), 6.8 7.3 (5H, m) In a manner analogous to Example 326, by using appro.iiate starting materials, the same compounds as 4 ithose prepared in Examples 105, 109, 114, 115, 264, 267, I 20 273, 174 and 303 were obtained.
Example 327 Td a solutioi of 8-(2-benzimidazolyllsultinylmethyll-ethyl-3 -ethoxycarbonyl -1 2 4 -tetrahydroquinoline (0 .4 g) in metb nol (80 ml) was added sodium hydroxide (0.2 g) and the mixture was stirred for 2 hours at room temperature r 220 and furthermore refluxed for 3 hours. The solvent was distilled off under reduced pressure. The resulting residue was dissolved in water, and the solution was adjusted to acidic with acetic acid. The precipitate was collected by filtration and recrystallized from methanol to give 8-(2-benzimidazolyl)sulfinylmethyl-1ethyl-1,2,3,4-tetrahydroquinoline-3-carboxylic acid-1/2 hydrate (0.2 g).
Colorless needle crystal mp 162 165°C (decomposition) SIn a manner analogous to Example 327, the same S- compounds as those prepared in Examples 133 and 136 were 0'D° obtained using appropriate starting materials.
0, 15 In a manner analogous to Example 1, 158, 159 and 4 314, the compounds shown in the table below were obtained using appropriate stazting materials.
4 In the column of "bond between the 3- and 4-positions of the quinoline skeleton" in the table, the symbol means a single bond and means a double bond.
(R
3
(R
1
N
K N-S A R 2
H
L~
bond between the 3- and 4- Crystal formMetnpot Example I m A R 2
R
3 n 'positions of (recrystallization MetigC)i No. R the quinoline solvent) (C skeleton 328 5-Cr 2 CR 2
CH
2
CR=CH
2 4-NiH 2 1 s N4MR13
CH
3 White powder 329 H I CR 2
-C
2
H
5 4-N 1 s (ehlac-enhxn)145-146.5
CH
2
CH=CH
2 __(tyac.s--ene 330 5-F 2 CR 2
CH
2
CH=CH
2 4-Nw 1-1C- s NMR04 6-OH3
CH
2
CH=CH
2 331 H 1CR 2
CR
2 .=CCH3w White powder 145-147.5 331 CH CHCH C2 4N S(diethyl ether-n-hexane) 5-F 2 H C2HC2 4- 1,CH 3 s white powder1314 332 6-OCR 3 2 R RC=H -K 1 (diethyl ether) 113 ,,-H3White powder15-8 333 S-COCR 3 1 CR 2
CH
2 CH=CHz 2 H;(thlaeae
(CH
2 2 0R05 63 -OCR 3 2 CRT 2
C
2 R 4-N~ s NMRl 6-OC 2 CR 2
C
2 11 5 4-N S 1, MR16 336 1 CR 2 C2H5 4-N 1 1H s NMR07 >113 337 5F 2 CR_ 2
C
2
R
5 4-N 1 s NMR1) 6-OCR1 3
OH
338 5-COCH 3 1 CR 2
C
2
HS
5 4-N 1-OH sM19 mC"-"LI ~-~LYUL-lr~_.l_ i -222 o 0% 15 00 04 00 4.
§0 0 99 ft I-rr I s Io 0 s 103) NMR(CDCk 3 )6: 1.60 (2H, brs 1.70 1.90 (1Hi, 2.09 2.32 (1H, 3.23 3.51 (2H, 3.66(2H, d, J= 6.1 Hz), 3.89 (3H, 4.05 t, J= 5.5 Hz), 4.26 (1H, d, J= 14.5 Hz), 4.36 (1H, d, J= 14 Hz), 5.30 5.52 (2H, 5.97 6.23 (1H, m) 6.77 7.43 (5H, in) 104) NMRP,(CDCL 3 )6: 1.60 2.00 (1H, 2.10 2.30 (1H, 2.20 (3E, s), 2.90 4.,20 3.88 (3H, 5.00 5.50 (4H, m), 5.65 6.25 (2H, 6.75 7.40 (4H, m)r 7.62 (1H, d, J= 7.6 Hz), 12.00 12.50 (IHi, br.) 105) NMR(CDC 3) 6 1.42 (31, t, J= 7.1 Hz), 1.83 2.32 (1H, 2.47 -2.87 (58, 2.87 3.11 (ll, Mi), 3.11 3.35 (211, mi), 3.49 3.80 3.89 and 3.91 (3H, 4.05 (1H, brs i 4.06 (1H, d, J= 15 tlz), 4.39 (1H, d, J= Hz), 6,78 7.,68 (5H, m 106) NMR(CDC 3 6: 1.42 t, J= 7.2 Hi), 1.51 1 98 (21,i 2,24 (3, 2.02 2 74 2.87 3.35 (4i, 3.35 3.73 (2f, i3.73 4.18 (21, 3.88 and 3,91 (318, s)o 4.38 d, J= 14.9 Hz), 6,74 7.61 (51,i mi 107) NMR(CDC 6 1.01-(2t1, l$,23 (2t-i 1,39 t, 7 a 7.1 Hz) 1,65 1.90 (11, mi, 2.00Q 2.40 2.24 I- 223 (6H, 2.65 2.80 (1H, 2.90 3.40 (4H, m), 3.50 (1H 3.78 (1H, t, J= 7.0 Hz), 4.45 (1H, d, J L.7 Hz), 7.00 7.20 (1H, 7.30 7.70 (3H, m), 7.85 8.40 (2H, 13.30 (1H, br.) 108) NMR(CDC2 3 6: 1.35 (3H, t, J= 7.0 Hz), 1.80 2.40 (2H, 2.20 (3H, 2.71 (3H, 2.85 3.60 (4H, 3.87 (3H, 4.23 (1H, d, J=14.3 Hz), 4.44 (1H, d, J 14.3 Hz), 5.93 (1H, t, J 7.0 Hz), 6.85 7.50 (5H, m) 109) NMR(CDCk 3 6: 1.47 (3H, t, J 7.0 Hz), 1.80 2.50 (2H, 2.19 (3H, 2.65 (3H, 2.70 3.80 4.10 4.60 (2H, 5.90 (lH, t, J 7.0 Hz), 6.90 7.20 (2H, m), 7.35 7.60 (2H, 7..80 8.10 (2H, m) 0 In a manner analogous to Example 160, 313 and 314, the compounds shown in the table below were obtained using appropriate starting materials.
t In the column of "bond between the 3- and 4-positions of 0 20 the quinoline skeleton" in the table, the symbol "s"i means a single bond and means a double bond.
Nm N 2 HO0 Id A tafl r rr* *r roa oao i a 9 p 00 F b, i 999 9 8 r) 9 9 3 9 a 611 )9 a II i ab bond between Example _3 the 3- and 4- Crystal form Melting point R m A R 2 n ipositions of (T4ryrystallization No the quinoline solvent)C) skeleton 5-F (C7.2)20H Yellow powder 3369 2CCH 2
C
2 HS 4-N 1 s (dichloro-methane- 103-105 N.(CH)0H petroleum ether) 5 Yellow powder 340 62 CH 2
CR
2
CH=CH
2 4-NH 2 1 s (dichoromethane- 101-103 _II diethyl ether) 3 Colorless needle crystals 341 H 1 CR 2
C
2
R
5 H=CH2_ 4 1(diethyl ether-n-hexane) 119-123
HCH=CH
2 5-F Colorlezs needle crystals 342 2 H 2
CH
2
CHCH
2 4-N 1 (dehlehr 135-137
CH
2 CH=CH? (dithyl ether)
C
3 White poder11-5 343 H :I C:IH2 CH2CH=CH2 ~I 4-N CH s Wht odr110-115 343 1C 2 C1 (diethyl ether-n-hexane) A .,-CH3 White powder 344 2 CH 2
CH
2
CH=CH
2 4-N 1 S (diethyl ether-n-hexane) 345 1 HCCH 4N 3 sWhite powder 105-110 1C CH4N (diethyl ether-n-hexane) 346 5-F 2- CH2 i C2H 4-NCH White powder 115-119 46 6-OC 3 2 RN (diethyl ether-n-hexane) 5-COH3 1CH2 CH54 Pale brown powder 138-142 3 1 CR 2 C J (diethyl ether-n-hexane) 225 Preparation Example 1 8- (2-Benz imidazolyl) sulfinylmethyl- #4 p*44 4 0*4 4,4, .4 4, #44
I
I
4
II
l-ethyl-l,2 ,3,4-tetrahydroquinoline 150 g Abicel (trademark of Asahi Chemical Industry) 40 g Corn starch 30 g Magnesium stearate 2 q Hydroxypropylmethvlcellulose 10 g Polyethylene glycol-6000 3 g Caster oil 40 g Ethiiol 40 g The compound of this invention, Abicelf corn starch and magnesium stearate are milled together and tableted by means of a R 10mm punch (for sugar-coated tablets).
The resulting tablets were coated with a film coating 15 composition consisting of hydroxypropylmethylcellulose, Polyethylene glycol-6000, castor oil and ethanol.
Preparation Example 2 8- (5-Fluoro-6-methoxy-2--benizimidazoly1) sulfinylmethyl-l-methyl-le2 ,3 ,4-tetrahydroquinoline 150 g Citric acid 1.0 g Lactose 33.5 g Dicalcium phosphate 70.0 g Pruronic F-68 30.0 g Sodium laurylsulfate 15.0 g Polyvinylpyrrolidone 15.0 g Polyethyleneglycol (Carbowax 1500) 4.*5 g
A
226 Polyethyleneglycol (Carbowax 6000) 45.0 g Corn starch 30.0 g Dried sodium laurylsulfate 3.0 g Dried magnesium stearate 3.0 g Ethanol Adequate amount The compound of this invention, citric acid, lactose, dicalcium phosphate, Pruronic F-68 and sodium lauryl sulfate were mixed. The above mixture was sieved with a Screen No. 60 and turned them into wet granules using an alcoholic solution containing polyvinylpyrrolidone, Carbowax 1500 and Carbowax 6000. Alcohol, if necessary, was added to thereto to turn the powder form into a pasty mass, followed by addition of corn starch, and continued mixing untill uniform particles were formed. The result- 15 ing particles were passed through a Screen No. 10, placed them in a tray and dried for 12 to 14 hours in a 100°C oven. The dried particles were sieved with a Screen No.
a 16, dried sodium laurylsulfate and dried magnesium stearate were added thereto and mixed. The mixture was 20 pressed into desired forms with a tableting machine.
I
The resulting core was treated with a varnish and S sprayed talc thereto to prevent moisture absorption.
The around of the core was coated with an undercoat layer and varnish coating of sufficient frequency for internal
S
l 25 administration. Further, the undercoat layer-coating and a smooth-coating were applied to the coated tablets 227 to obtain perfectly round and smooth tablets, and a color coating was applied thereto untill desired color tone was obtained. After drying, the resulting coated tablets were polished to obtain the tablets with a uniform luster.
Preparation Example 3 8-(2-Benzimidazolyl)sulfinylmethyll-ethyl-1,2,3,4-tetrahydroquinoline 5 g Polyethyleneglycol (Molecular weight:4000) 0.3 g Sodium chloride 0.9 g i polyoxyethylene sorbitanmonooleate 0.4 g Sodium metabisulfite 0.1 g Methyl-paraben 0.18 g Propyl-paraben 0.02 g I t.15 Distilled water for injection 10.0 ml The above parabens, sodium metabisulfite and sodium chloride were dissolved in about a half of distilled water at 80°C with stirring. The resulting solution was cooled to 40°C, and in the solution were dissolved the compound of the invention, polyethyleneglycol and polyoxyethylene sorbitanmonooleate. Then, distilled water for injection was added to the solution to adjust the volume to the final one, and the mixture was filtered using a suitable filter paper and sterilized to prepare the injections.
-228- Pharmacological Tests The results of pharmacological tests on the compounds of this invention are shown below.
Test compounds No. 1: 1-ethyl-8-(2-benzimidazolyl) sulfinylmethyl- 1 ,2 ,3 ,4-tetrahydroquinoline No. 2: 2-ethyl-8-(5-methyl-2-benzimidazolvl)sulfinylmethyl-i 4-tetrahydroquinoline No. 3: i-ethyl-8-(5-methoxy-2.-benzimidazolyrl)sulfinylmethyl-i, 2, 3 ,4-tetrahydroquinoline No. 4: 1-ethyi-8-(5-fluoro-2-benzimidazolyl)sulfinylmethyl-i, 2,3, 4-tetrahydroquinoline No. 5: 1-ethyi-8-(5,6-difluioro-2-benzimidazolyl) sulfinylmethyl-i ,2,3 ,4-tetrahydroquinoline No. 6: l-ethyl-8-(5-fluoro-6-methoxy-2-benzimidazolyl)sulfinylmethyl-1, 2, 3,4-tetrahydroquinoline No. 7: l-ethyl-8-(5-ethoxy-6-fluoro-2-benzimidazolyl)j' sulfinylmethyl-1 4-tetrahydroquinoline No. 8: l-ethyl-8-(5-chloro-2-benzimidazolyl)sulfinylmethyl-i, 2,3, 4-tetrahydroquinoline NO. 9: l-ethyl-8- (5-acetyl-2-benzimidazolyl) sulfinylmethyl-i 2,3 ,4-tetrahydroquinoline No. 10: 1-ethy2.-8-(5-trifluoromethyl-2-benzimidazolyl)sulfinyl-i, 2 ,3 ,4-tetrahydroquinoline -229- No. 11: 1-ethyl-8- (4-methyl-2-benzimidazolyl) sulfinyl- 1 ,2,3 4-tetrahydroquinoline No. 12: 1-ethyl-8-(4,6-dimethyi-2-benzimidazolyl) sulfinyl-1 ,2,3 ,4-tetrahydroquinoline No. 13: 1-ethyl-8-(5,6-dimethyl-2-benzimidazolyl) sulfinyl-1 4-tetrahydroquinoline 2No. 14: 1-methyl-8-(2-benzimidazolyl) sulfinylmethyl- 1,2,3, 4-tetrahydroquinoline No. 15: 1-methyl-8-(5-fluoro-2-benzimidazolyl) sulfinylmethyl-i 4-tetrahydroquinoline No. 16: 1-methyl-8- (5-methoxy-2-benzimidazolyl) sulfinylmethyl-i ,2 4-tetrahydroquino~lin~e No. 17: 1-methyl-8-(5-methyl -2-benzimidazolyl) sulfinylmethyl-i 4-tetrahydroquinoline No. 18: i-methyl-8-(5-choro-2-benzim~.dazolyl) sulfinylmethyl-i 4-tetrahydroquinoline No. 19: i-methyl-8-(4-methyl-2-benzimidazo'Lyl) sulfinyl- 0 riethyl-i 4-tetrahydroquinoline No. 20: i-methyl-8-(5-fluoro-6-methoxy-2-benzimidazolyl)sulfinylmethyl-1 ,2,3 ,4-tetrahydroquinoline No. 21: i-allyl-8-(2-benzimidazolyl)sulfinylmethyl- 1, 2,3, 4-tetrahydroquinoline No. 22: 1-allyl-8- (5-methoxy-2-ben-2imidazolyl) sulfinylmethyl-i, 2, 3,4-tetrahydroquinoline No. 23: i-allyl-8-(5-fluoro-2-benzimidazolyl) sulfinylf -230methyl-i 3 ,4-tetrahydroquinoline No. 2 4: -n-butyl-8-(2-benzimidazolyl) sulfinylmethyl- 1, 2,3 ,4-tetrahydroquinoline 2, 3 ,4-tetrahydroquinoline No. 2 6: 1-propargyl-8- (2-benzirnidazolyl) sulfinylmethyli, 2,3f4-tetrahydroquinoline No. 2 7: i-benzyl-8- (2-benzimidazolyl) sulfinyirnethyl- 1,2, 3 ,4-tetrahydroquinoline No. 28:, l-benzyl-8- (5-methyl-2-benzimidazolyl) sulf inylmethyl-i, 2, 3 ,4-tetrahydroquinoline No. 2 9: 1.4-dimethyl-8- (2-benzinidazolyl) sulf inyirnethyl- 4 0 1,2,3, 4-tetrahydroquinoline No. 3 0: 1, 4 -dimethyl-8- (5-f luoro-6-methoxy-2-benzimidazolyl) sulf inylmethyl-i, 2,3 4-tetrahydroquinoline No. 31: 1-ethyl-6-bromo-8- (2-benzimidazolyl) sulf iny.methyl- 2, 3 ,4-tetrahydroquinoline N 3 2: i-ethyl-6-methoxy-8-(2-benzimidazolyl) sulfinylt 4 methyl-1,2, 3, 4-tetrahydroquinoline No. 3 3: l-allyl-8-(5-methyi-2-benzimidazolyl) sulfinylmethyl-i, 2, 3 ,4-tetrahydroquinoline No. 34: 1- 4 -f luorobenzyl) (5-nethyl-2-benzimidazoly4, sulfinylmethyl-1,2,3, 4-tetrahydroquinoline No. 35: i-cyclopropylmethyl-8- (2-benzinxidazolyl) sulfinylmethyl-i ,4-tetrahydroquinoline -231 No. 36: 1-ethyl-8- (2-benzimidazolyl) sulfinylmethyl-4mnethyl-i ,2,3 ,4-tetrahydroquinoline No. 37: 1-ethyl-8-(5-fluoro-6-methoxy-2-benzimidazolyl) sulfinylmethyl-4-methyl-1 4-tetrahydroquinoline No. 38: 1-allyl-8-(2-benzimidazolyl) sulfinylmethyl-3methyl-i ,2 ,3 ,4-tetrahydroquinoline No. 39: 1,4-dimethyl-8-(5-methyl-2-benzimidazolyl) sulfinylmethyl-1 ,2-dihydroquinoline No. 40: 1,4- dimethyl-8-(5-niethoxy-2-benzimidazolyl) sulfinylmethyl- 2-dihydroquinoline No. 41: l-ethyl-8-12-benzimidazolyl) sulfinylmethyl-4methyl-i,,2-dihydroquirioline 1/2-hydrate No. 42: 1,3,4-trimethyl-8-(2-benzimidazolyl) sulfinylmethyl-i, 2-dihydroquinoline No. 43: 1-methyl-8-(2-benzimidazolyl)sulfinylmethyl-4" oxo-1, 2, 3 ,4-tetrahydroguinoline No. 44: 1-methyl-8- (2-benzimidazolyl) sulfinylmethyl-4- 04. hydroxy-1 3,4-tetrahydroquinol~ne No. 45: 1, 4-dimethyl 8- (2-benzimidazolyl) sulfinylmethyl- 4-hydroxy-1 4-tetrahydroquinoline No. 46: 1-methyl-8-(2-benzimidazolyl)sulfinylmethyl-4ethyl-4-hydroxy-1,2,3 ,4-tetrahydroguinoline No. 47: 1-ethyl-8-(5-methyl-2-benzimnidazolyl)sulfinyl- 4 ~methy.-.-pheiyi-1 4-tetrahydroquinoline No. 46: I-ethyl-8- (2-benzimidazolyl) sulfinylniethyl-4- -23 2 4444 4 0 040
OV
*4 '00 4 0449 0 00 ~0 04 0 4* methoxy-1 ,2,3 ,4-tetrahydroquinoline No. 49: 1-ethyl-8-(5-fluoro-6-methoxy-2-benzimidazolyl) sulfinylmethyl-4-dimethylamino-1,2,3, 4-tetrahydrogtuinoline 50: 1-ethyl-8-(2-benzimnidazolyl) su],finylmethyl-4hydroxyimino-1 ,2 ,3 ,4-tetrahydroquinoline No. 51: I-ethyl-8-(2-benzimidazolyl) sulfinylmethyl-4allyloxy-1 ,2,3 ,4-tetrahydroquinoline No. 52: 1-ethy2,-8-(2-benziinidazolyl) sulfinylrnethyl-4methylene-1, 2, 3,4-tetrahydroguinoline No. 53: 1-ethyl-8- (2-benzirnidazolyl) sulfinylmethyl-3methoxycarbonyl-1 3,4-tetrahydroquinoline No. 54: I-ethyl-8-(2-benzimidazlolyl) sulfinylmethyl-3hydroxyrnethyl-1 4-tetrahydroquinoline 15 No. 55: 1-ethyl-8-(2-.benzimidazolyl) sulfinylniethyl-3dirnethylcarbamoyl-1, 2.3, 4-tetrahydroquinoline 213hydrate No. 56: 1-ethyl-8-(2-benzimidazolyl) sulfinylmethyl-3carboxy-1 ,2,3 ,4-tetrahydroquinoJline 1/2hydrate 20 No. 57: 1-ethy2l-8- (2-benzimidazolyl) si.lf inylmethyl- 4- [N-methyl-N- (2-hydroxyethyl) amino] 4-tetrahydroquinoline No. 58: 1-ethyl-8- (2-benzirnidazolyl) sulfinylniethyl-3- (1-piperizinyl) carbonyl-1 f2 f3, 4-tetrahydroquinoline No. 59: 1-ethyl-8-(2-benzimidazolyl) sulfinylrnethyl-4- '4 09 9 #0 a 0* 0 0 40 It I Ii 4 4' 4 -233 (N-methyl-N-acetyl) amino-i, 2,3 ,4-tetrahydroquinoline No. 60: 1-ethyl-B- (5-methyl-2-benzimidazolyl) sulfinylmethyl-4-allylamino-1 ,2 ,3 ,4-tetrahydroquinoline, No. 61: 1-ethyl-8-(5-methyl-2-benzimidazolyl) sulfinylmethyl-4-cyclohexylamino-1 ,2,3 ,4-tetrahydroquinoline No. 62: 1-allyJl-8- (5-methyl-2-benziritidazolyl) sulfinylmethyl-4-me thoxy-1 ,2,3 ,4 -tetrahydroquino,ine No. 63: 1-ethyl-8- (5-fluoro-6-methoxy-2-benzimidazolyl) sulfinyJlntethyl-4-hydroxymethyl-1, 2,3,4-tetrahydroquinoline No. 64: 1-ethyl-8-(5-fluoro-6-methoxy-2-benzimidazolyl) suilfinylniethyl-4- (N-methyl-N-cyclopropyl) amino- 1,2,3, 4-tetrahydroquinoline 15sulfinylmethyl-4- (N-f orniyl-N-cyclopropyl) aminoa 1 ,2,3,4-tetrahydroquinoline No. 66: 1-ethyl-8-(5-methyl-2-benzimidaolyl) silfinylmethyl-4-rnethoxy-3 ,3-dimethyl-1 ,2,3 ,4-tetrahydroguinoline No. 67: I-ethyl-8-(5-fluoro-6-methoxy-2-benzinidazolyl) sulfinylmethyl-4- (N-methyl-N-allyl) amino-i,2,,3,4tetrahydroquinoline vNo. 68: 1-ethyl-B- (5-flutoro-6-methoxy-2-benzimidazolyl) stlfinylmethyl-4- (N-methyl-N-cyc1lopropylmethyl) amino- 1, 3 ,4-tetrahydroquinoline -234- No. 69: 1-e ,hyl-8-(5-fluoro-6-methoxy-2-benzimidazolyl) sulfinylmethyl-4- [N-methyl-N- 2-trifluoro-1ethoxyethyl) ]amino-i, 2,3, 4-tetrahydroguinoline No. 70: 1-ethyl-8- (5-f luoro-6-methoxy-2-benzimidazolyl) sulf inylmethyl-4- [N-allyl-N- (4-methoxybenzyl) I amino- 1,2,3, 4-tetrahydroguinoline No. 71: 8- (5-f luoro-6-methoxy-2-benzimidazolyl) sulf inylmethyl-4- (N-allyl-N-methyl) amino-i, 2, 3, 4-tetrahydroquinoline No. 72: I-etaiyl-8- (2-benzimidazolyl) sulf inylmethyl-4trif luortimethyl-i 2-dihydroquinoline Pharmacological test 1 H K +ATPase (adenosine triphosphatase) (amount of 15 protein: 10 pg) prepared from porcine stomach was added to a Pipes-TRIS 2-amino-2- (hydroxymethyl) -1,3-propanediol] buffer solution (pH 6.1) containing 2mM of piperazine N,N'-bis(2-ethanesulfonic acid), and the mixture was let stand at room temnperature. A test compound was dissolved in dimethyl formamide, and the mixture was added to said H K +ATPase buffer solution so that the final concentration should be 1% and let stand for reaction -tor 30 minutes at room temperature. Then a 75 m.M Pi~pes- TRIS buf fer (1 ml, pH 7. 4) (containing 4 m04 MgC1 2 4 mN' Na 2 ATP, and 20 mM KCl) and a 75 mM Pipes-TRIS buffer (I ml, 4~ 4 4- 4 44 4 44 4 4 4~ 4 4, 4'
I
44 ~I L I*Y UM 235 pH 7.4) (containing 4 mM MgCl 2 and 4 mM Na 2 ATP) were added to the solution individually to make two kinds of samples and these samples were presented for reaction for minutes at 37°C. 40% Trichloroacetic acid (0.3 ml) was added to each sample to stop the reaction. The solution were subjected to centrifugal separation (3000 rpm) for minutes, and the supernatant was taken off, then the formed inorganic phosphoric acid was measured by Fiske and Subbarow's method Biol. Chem. vol. 66, 375 (1925)]. The value of deducting the amount of inorganic phosphoric acid taken from the Pipes-Tris buffer not containing 20 mM KC1 from that taken from the Pipes-Tris buffer containing 20 mM KC1 was calculated in terms of unit protein and unit hour to be defined as an activity index of enzyme. Inhibition 15 level in doses of administration was estimated by control values and activity indices of enzyme, and from the obtained inhibition level IC 50 (dose of administration of compounds to inhibit in 50%) was obtained.
The results are shown in the table below.
D a 0 1 0** 0f 0 Oi
I
Pr- 236 0000 o o 4 2> 0 o: 04 4 040 0044 0 4 ~044 04 0 440 00 04 0 444 0 40 0 04 04 0 46 04 04 0 0 4 0444 0 0444 04 04 6 0 Test compound IC 50 ITest compound 1C050 (M) No. No.
1 1.9 x 1 716 6.9 x 10-7 2 1.8 x 10 17 5.3 x 07 3 4.5 x 10-7 18 2.0 x 1- 4 1.0 x 10-6 19 4.1 x 1- 4.4 x 10-7 20 3.3 x 1- 6 6.2 x 10-7 21 3.3 x 1- 7 1.6 x 1-622 9.6 x 10-7 8 2.2 x 10- 7 23 4.9 x,07 9 2.2 x 10-6 2 4 1.8 X,1- 3.7 x 107 25 3.3 x 10-7 1.5.0 x 107 26 1.6 x 1- 12 4.2 x 10-7 27 3.9 x 10-7 13 1.7 x 10-7 28 6.5 x 0- 14 1.7 x 10- 29 2.5 x 1- 5.3 x 610-7 6. 1 x 10-7 237 Test compound IC 50 Test compound IC 50
(M)
No. No.
31 6. 4 x 110 6 46 1.8 x IQ- 6 32 9.2 x 10- 47 1.5 x Q6 33 5.8 x IQ 48 1.1 x IQ-6 34 2.1 x IQ-6 50 4. x Q6 2.5 x 10- 51 2.9 x IQ- 6 36 4,5 x 10- 52 3.9 x Q6 37 8.9 x 10-7 53 4.9 x io-6 38 8.3 x 10-7 54 1.2 x Q 39 1.3 x 10-7 55 5.1 x Q6 5.2 x 10 56 1.9 x Q 41 2.3 x IQ 58 x J0- 42 5.5 x 10-7 59 5.7 xIQ 43 6.i7 xc IQ- 6 60 3. 3 x ll 44 9.5 x 10-7 61. 1. 4 x 2.2 x 0- 62 4.0 10J-Q6 tt 4, 4 t~ 41 1 4 4
S)
A
238 Test compound IC 50(M) Test compound IC 50
(M)
No. No.
63 4.5 x 10 6 69 4.9 x106 64 4.0 x 10 6 70 3.8 x 10O6 2.8 x 10 71 5.7 x 10O 6 66 3.3 x 10 72 3.3 x106 4 #~I *4*4 4) 0~ 44 4 4 4 f- 239 ii Pharmacological test 2 Male Wistar rats (200 to 250 g of body weight) were fasted for 24 hours. A test compound was suspended in carboxymethyl cellulose solution and administered to each rat. 30 minutes after administration, 0.6 N hydrochloric acid was orally administered by 1 ml per rat. 1 hour later, the rats were sacrificed and their stomachs were extracted. After fixing the extracted stomach lightly by administering 1% formalin solution (10 ml) the area of lesion generated in stomach was measured to define an ulcer factor.
Inhibition ratio in doses of test compounds was calculated from the control value obtained from a sample administered only a 0.5% solution of carboxymethyl cellulose. The value of EDg 0 was figured out from the obtained inhibition ratio by means of probit method.
Test results are shown in the table below.
I 4 *4~ *4 44 44 4, 4L Test Compound
ED
50 Test Compound No. (mg/Kg) No. (mg/Kg) 2 2.5 14 4.6 3 5.0 16 3.4 6 7.5 19 6.8 9 1.6 20 8.8 11 3.3 21 6.4
I
240 Pharmacological test 3 Male Wistar rats weighing 160 to 180 g were presented to the experiment after being fasted for 24 hours. Aspirin was suspended in 0.5% carboxymethyl cellulose and orally administered to the rats at a dose of 200 mg/kg. 5 hours after the administration of aspirin, rats were sacrificed to extract their stomachs. Inner and outer layers of the stomach were fixed by administering 1 formalin solution ml) in the stomach and dipping into a 1% formalin solution for 30 minutes. By resectioning the stomach along the greater curvature, the length of ulcer was measured by stereoscopic microscope (10x) and tll" sum of the length is defined as ulcer factor. Test compounds were orally administered 30 minmtes before the administration of aspirin at doses of 1, 3, 10, and 30 mg/kg. Then from the inhibition ratio of the group of test compound against the control group, the ED 5 0 was calculated ly means of probit method.
Test compound No. ED 5 0 (mg/kg) 49 57 6.3 67 68 5.9

Claims (36)

1. A hydroquinoline compound of the formula (R)m N A R 2 4 (I) H (0)1 wherein A is a lower c:kylene group; R 1 is a hydrogen atom, a lower alkyl group which may have 1 to 3 halogen atoms, a lower alkoxy group which may have 1 to 3 halogen atoms, a halogen atoms, a lower alkanoyl group,.a lower S alkoxycarbonyl group or a cycloalkylcarbonyl group; R 2 is a lower alkyl group which have 1 to 3 halogen atoms, an amino- S lower alkyl group which may have a lower alkyl group on the amino group, a lower alkynyl group which have a tri-lower alkylsilyl group, a phenyl-lower alkyl group which have 1 Sto 3 amino groups which may have a lower alkyl group as a S°substituent on the phenyl ring thereof, or a cycloalkyl- S• lower alkyl group; m is an integer of 1 to 2; i is an integer of 0 or 1; and the bond between the 3- and 4- positions of the quinoline skelton is a single bond or a double bond, or its pharmaceutically acceptable salt. F A-241-
2. A hydroquinoline compound of the formula( I): (R 3 )n (R 1 m H wherein A is a lower alkylene group; R' is a hydrogen atom, a lower alkyl group which may have 1 to 3 halogen atoms. a I lower alkoxy group which may have 1 to 3 halogen atoms, a halogen atoms, a lower alkanoyl group; R 2 is a lower i alkenyl group, R 3 is a lower alkyl group, a lower alkoxy 1 i t4 group, an cxo group, a hydroxy group, a lower alkenyloxy i ,group, a lower alkylenedioxy group, a phenyl group, a i hydroxyimino group, a lower alkylimino group, a lower alkylidene group, a hydroxy-substituted lower alkyl group, a carboxy group, a lower alkoxycarbonyl group, a lower alkanoyloxy-lower alkyl group, a lower alkoxy-lower alkoxy S, group or a group of the formula: N (wherein B is a lower alkylene group or a carbonyl group; p -242- r I i i i c- ~ri is an integer of 0 or 1; R 4 and R 5 are, the same or different, a hydrogen atom, a lower alkyl group which may have 1 to 3 groups selected from the group consisting of a halogen atom and a lower alkoxy group, a hydroxy- substituted lower alkyl group, a cycloalkyl group, a cycloalky-lower alkyl group, a cycloalkylcarbonyl group, a lower alkenyl group, a lower alkanoyl group which may have 1 to 3 halogen atoms or a phenyl lower alkyl group which may have a lower alkoxy group as a substituent on the phenyl ring thereof; and R 4 and R 5 together with the bonding nitrogen atom may form a saturated 5- or 6-menbered heterocyclic group which may contain hetero atom(s) consisting of an oxygen atom, a sulfur atom or a nitrogen e 4atom); m is an integer of 1 to 2; n is an integer of 1 to 3; R is an integer of 0 oe 1; and the bond between the 3- and 4-positions of the quinoline skelton is a single bond or a double bond; provided that the oxo group for R 3 is not substituted at the 2-position of the quinoline skeleton, or "its pharmaceutically acceptable salt. i 4' 3. A hydroquinoline compound of the formula( m): (R 3)n i N N4 2 H (0) r t S r wherein A is a lower alkylene group; RI is a hydrogen atom, a lower alkyl group which may have 1 to 3 halogen atoms, a lower alkoxy group which may have 1 to 3 halogen atoms, a halogen atoms, a lower alkanoyl group, or a cycloalkylcarbonyl group; R 2 is a lower alkyl group; R 3 is a lower alkyl group, an oxo group, a hydroxy group, a lower alkenyloxy group, a lower alkylenedioxy group, a phenyl group, a hydroxyimino group, a lower alkylimino group, a lower alkylidene group, a hydroxy-substituted lower alkyl group, a lower alkanoyloxy-lower alkyl group, a lower alkoxy-lower alkoxy group, a group of the formula: IR 4 N-B--N I6 5 1 *R wherein B is a lower alkylene group; R' and R 5 are the same or different, a hydrogen atom or a lower alkyl group, or a group of the formula: 0 (CO N P* 1; S, wherein p is an integer of 0 or 1; R 4 and R5 are, the same or different, a hydrogen atom, a lower alkyl group which may have 1 to 3 groups selected from the group consisting of a halogen atom and a lower alkoxy group, a hydroxy- substituted lower alkyl group, a cycloalkyl group, a S TI -244- cycloalkyl-lower alkyl group, a cycloalkylcarbonyl group, a lowr alkenyl group, a lower alkanoyl group which may have 1 to 3 halogen atoms or a phenyl lower alkyl group which may have a lower alkoxy group as a substituent on the phenyl ring thereof; and R 4 and R 5 together with the bonding nitrogen atom may form a saturated 5- or 6-menbered heterocyclic group which may contain hetero atom(s) consisting of an oxygen atom, a sulfur atom or a nitrogen atom; m is an integer of 1 to 2; n is an integer of 1 to 3; 9 is an integer of 0 or 1; and the bond between the 3- and
4-positions of the quinoline skelton is a single bond or a double bond; provided that the oxo group for R 3 is not S substituted at the 2-position of the quinoline skeleton, when R 4 and R 5 are the same or different, a hydrogen atom, fist a lower alkyl group or a phenyl lower alkyl group, or when ttJ R 4 and R 5 are, different from each other, a hydrogen atom or a lower alkanoyl group, then at least one of R' should be a cycloalkylcarbonyl group, and when R' is a group other than a cycloalkylcarbonyl group and at least one of R 3 is a lower alkyl grou, then n is an integer of 2 or 3 and at least one of the remaining Ra should be a hydroxy group or an oxo group, or its pharmaceutically acceptable salt. m' r 4. A hydroquinoline compound or its pharmaceutically acceptable salt as claimed in claim 2, wherein A is a methylene group; R' is a hydrogen atom, a C,- t. l r -245- -r -1 ;?rrrr~rr~-~ I~CiC i-i; IIC~ Lli~ C 6 alkyl group, a CI-C, alkoxy group, a halogen atoms or a CI-Cs alkanoyl group; R 3 is a CI-C 6 alkyl group, a CI-C, alkoxy group, or a group of the formula: -N Rs wherein R4' and R" are, the same or different, a hydrogen atom or a C 1 -Cs alkyl group; n and e are integers of 1; and the bond between the 3- and 4-positions of the quinoline skeleton is a single bond. A hydroquinoline compound or its pharmaceutically acceptable salt as claimed in claim 3, 444 wherein A is a methylene group; R' is a hydrogen atom, a C 1 6446 4 C 6 alkyl group, a Cl-C6 alkoxy group, a halogen atom or a C 1 alkanoyl group; R is a C 1 alkyl group, a hydroxy group, a C 2 -C 6 alkenyloxy group, a C 1 -C 4 alkylenedioxy group, a C 1 -Cs alkylidene group, a hydroxy-substituted IT-Cs alkyl group, or a group of the formula: 4664 N p wherein p is an integer of 0 or 1; R4 and RS are, the same :6 or different, a hydrogen atom, a Ci-C 6 alkyl group, a hydroxy-substituted Ci-CS alkyl group, a C 3 -Ca cycloalky! group, a C3-Co cycloalkyl-Cl-Cd alkyl group, a C2-C. A A r~c ~E 8-246-- .4 TS r i alkenyl group, a CI-C 6 alkanoyl group; and R 4 and R together with the bonding nitrogen atom may form a piperidino group or a pyrrolidinyl group; E is a integer of 1; and the bond of the 3- and 4- positions of the quinoline skeleton is a single bond.
6. A hydroquinoline compound or its pharmaceutically acceptable salt as claimed in claim 3, wherein is an integer of 0, and R 2 is a C 1 -C 6 alkyl group.
7. A hydroquinoline compound or its pharmaceutically acceptable salt as claimed in claim 1, wherein a is an integer of 0, and Ri is an amino-C-C 6 o alkyl group which may have a CI-C 6 alkyl group on an amino o *group, a C 2 -C 6 alkynyl group which have a tri-Ci-C 6 alkylsilyl group, a phenyl-CI-C alkyl group which may have 4o1, 1 to 3 amino groups which may have a Ci-C, alkyl group as a substituent on the phenyl group thereof, or a C3-C 8 cycloalkyl-C-C 6 alkyl group.
8. A hydroquinoline compound or its o pharmaceutically acceptable salt as claimed in claim 3, wherein R is an integer of 1, and RI is a Ci-Ce alkyl group.
9. A hydroquinoline compound or its o* 'pharmaceutically acceptable salt as claimed in claim 1, wherein, is an integer of 1, and R 2 is an amino-Ci-C-C -247- 04. r i. T-7 r 2 4CS,44 4 44O O~4 j 4 4 4 4 44 44 4 4, 4 41 4 44 alkyl group which may have a CI-C 6 alkyl group on an amino group, a C 2 alkynyl group which have a tri-Ci-Cs alkylsilyl group, a phenyl-C,-C 6 alkyl group which may have 1 to 3 amino groups which may have a CI-C, alkyl group as a substituent on the phenyl group thereof, or a C 3 -Ca cycloalkyl-Ci-C 6 alkyl group. A hydroquinoline compound or its pharmaceutically acceptable salt as claimed in claim 3, wherein RI is a C3-C 8 cycloalkylcarbonyl group.
11. A hydroquinoline compound or its pharmaceutically acceptable salt as claimed in claim 3, wherein R! is a hydrogen atom, a Ci-C6 alkyl group which may have 1 to 3 halogen atoms, a CI-C 6 alkoxy group which may have 1 to 3 halogen atoms, a halogen atom, a CI-C, alkanoyl group.
12. A hydroquinoline compound or its pharmaceutically acceptable salt as claimed in claim 9, wherein RI is a hydrogen atom, a CI-C 6 alkoxy group which may have 1 to 3 halogen atoms, a Ci-Cq alkanoyl group, or a halogen atom.
13. A hydroquinoline compound or its pharmaceutically acceptable salt as claimed in claim 9, wherein R I is a Ci-C 6 alkyl group which may have 1 to 3 halogen atoms, or a C|-C6 alkoxycarbonyl group.
14. A hydroquinoline compound or its *4 4 4 4 4* -248- A i pharmaceutically acceptable salt Js claim' i laim 11, wherein R' is a hydrogen atom, a CI"Cs alkoxy group which may have 1 to 3 halogen atoms, a G0-C 6 alkanoyl group, or a halogen atom. A hydroquinoline compound or its pharmaceutically acceptable salt as claimed in claim 14, wherein R3 is a C-C 6 alkyl group, an oxo group, a hydroxy group, a C 2 alkenyloxy group, a CI-C 4 alkylenedioxy group, a phenyl group, a hydroxyimino group, a CI-C 6 alkylimino group, a CI-C 6 alkylidene group, a hydroxy- substituted CI-C 6 alkyl group, a C1-C, alkanoyloxy-Cl-C, alkyl group, or a CI-C 6 alkoxy-C,-C6 alkoxy group. 0q4
16. A hydroquinoline compound or its pharmaceutically acceptable salt as claimed in claim 14, os wherein RI is a group of the formula: Rn 4 o 0 CQ0 N *Cr *wherein R I, R and P have the same meanings as defined above. 0 J. 4 0" 4 17. A hydroquinol.ine compound or its "a D pharmaceutically acceptable salt as claimed in claim 1 4, b 9o wherein RI is a group of the formula: R~ 4t 'll a-249- tor wherein R" R 5 and B have the same meanings as defined above.
18. A hydrcxquinoline compound or its pharmaceutically acceptable salt as claimed in claim -wherein RI is an oxo group, a hydroxy group, a 2C alkenyloxy group, a Ci-Ch. alkylenedioxy group, a phenyl group, a hydroxyimino group, a C 1 -CG alkylimino group, a C 1 -C 6 alkylidene gr~oup, a hydroxy-substituted CI-C 6 alkyl group, a CI-C 6 alkanoyloxy-C,-C6 alkyl group, or a C,-C 6 alkoxy-Ci--CQ alkoxy group.
19. A hydroquinoiline ccyipound or its pharmaceutically acc~ptable salt as claimed in claim 4, Swherein RI is a C 1 -CQ alkyl group, or a CI-Ce alIkoxy group. A hydroquinoJline compound~ or it's V4pharmaceutically acceptable salt as claimed in claim 2, wherein R 3 i~s a group of the formula: 4 p w~herein V~ 0 and P hnve the same meanings as defined abova..
21. A hydroquinoline compound or its -250- ~r- I 7 il 3 .liy ~q~~PTdO*BI~CQ I~ 3ti 4 a eo a 4 0 4ee *0 £t 4* 4 «I i 0 t tP 4 Ot t rt pharmaceutically acceptable salt as claimed in claim 16, wherein P is an integer of 0.
22. A hydroquinoline compound or its pharmaceutically acceptable salt as claimed in claim 16, wherein P is an integer of 1.
23. A hydroquinoline compound or its pharmaceutically acceptable salt as claimed in claim wherein P is an integer of 0.
24. A hydroquinoline compound or its pharmaceutically acceptable salt as claimed in claim wherein P is an integer of 1. A hydroquinoline compound or its pharmaceutically acceptable salt as claimed in claim 21, wherein R 4 and R 5 are, the same or different, a hydrogen atom, a Ci-C 6 alkyl gro" which may have 1 to 3 groups selected from the group consisting of a halogen atom and a CI-C6 alkoxy group, a Ci-C 6 alkanoyl group which may have 1 to 3 halogen atoms, a hydroxy-substituted CI-C 6 alkyl group, a C3-C cycloalkyl group, a Cs-C 8 cycloalkylCi-C6 alkyl group, a C 3 cycloalkylcarbonyl group, a Cz-C 6 alkenyl group, or a phenyl-C-C6 alkyl group which may have a CI-C, alkoxy group as a substituent on the phenyl ring thereof.
26. A hyroquinoline compound or its pharmaceutically acceptable sal' as claimed in claim 21, wherein R* and RI together with the bonding nitrogen atom -251- form a saturated heterocyclic group consisting of a pyrrolidinyl group, a piperazinyl group, a piperidino group, a morpholino group, and a thiomorpholino group.
27. A hydroquino' ,ne compound or its pharmaceutically acceptable salt as claimed in claim 23, wherein R' and R 5 are, the same or different, a CI-C, alkyl group which may have 1 to 3 groups selected from the group consisting of a halogen atom and a alkoxy group, a CI-C, alkanoyl group which may have 1 to 3 halogen atoms, a hydroxy-substituted CI-C, alkyl group, a C 3 -Cs cycloaikyl group, or a Cz-CG alkenyl group.
28. A hydroquinoline compound or its I pharmaceutically acceptable salt as claimed in claim wherein R4 and R 5 are a Ct-C, alkyl group which may have 1 to 3 groups selected from the group consisting of a halogen oatom and a CI-C 6 alkoxy group.
29. A hydroquinoline compound or its pharmaceutically acceptable salt as claimed in claim wherein R 4 is a CI-CQ alkyl group which may have 1 to 3 0° 1 groups selected from the grlup consisting of a halogen atom o f and a CQ-C 6 alkoxy group, and R 5 is a CI-C 6 alkanoyl group which may have 1 to 3 halogen atoms, a hydroxy-substituted n Ci-C 6 alkyl group, a C3-Ca cycloalkyl group, or a C 2 -C 6 alkenyl group. A hydroquinoline compound or its pharmaceutically acceptable salt as claimed in wherein the bond between the 3- and 4-positions of the quinoline skeleton is a single bond, and R 3 is attached to the quinoline skeleton at the 4-position thereof.
31. A hydroquinoline compound or its pharmaceutically acceptable salt as claimed in claim 28, wherein the bond between the 3- and 4-positions of the quinoline skeleton is a single bond, and R 3 is attached to the quinoline skeleton at the 4-position thereof.
32. A hydroquinoline compound or its pharmaeutically acceptable salt as claimed in claim 29, wherein the bond between the 3- and 4-positions of the quinoline skeleton is a single bond, and RI is attached to a0,0 *00 athe quinoline skeleton at the 4-position thereof.
33. A hydroquinoline compound or its o pharmaceutically acceptable salt as claimed in claim 27, wherein the bond between the 3- and 4-positions of the quinoline skeleton is a single bond, and R 3 is attached to *'oo the quinoline skeleton at the 4-position thereof. 040*
34. A hydroquinoline compound or its t pharmaceutically acceptable salt as claimed in claim wherein the bond between the 3- and 4-positions of the ,quinoline skeleton is a double bond. S 35. A hydroquinoline compound or its pharmaceutically acceptable salt as claimed in claim 28, S-253- .A 0hit wherein the bond between the 3- and 4-positions of the quinoline skeleton is a double bond.
36. A hydroquinoline compound or its pharmaceutically acceptable salt as claimed in claim 29, wherein the bond between the 3- and 4 -positions of the quinoline skeleton is a double bond.
37. A hydroquinoline compound or its pharmaceutically acceptable salt as claimed in claim 27, wherein the bond between the 3- and 4-positions of the quinoline skeleton is a double bond.
38. A hydroquinoline compound or its pharmaceutically acceptable salt as claimed in claim wherein R 2 is a CI-C 2 alkyl group, and RI is a methyl group 0 0 or a methoxy group by which the hydroquinoline skeleton is oee substituted at the 4-position thereof. S39. A hydroquinoline compound or its pharmaceutically acceptable salt as claimed in claim I wherein R 2 is a CI-C 2 alkyl group, and R 3 is a hydrogen a 0 a atom. a 40. A hydroquinoline compound or its pharmaceutically acceptable salt as claimed in claim 28, wherein R 3 is a dimethylamino group by which the I- a. hydroquinoline skeleton is substituted at the 4-position B thereof, and R y is a Ci-Cc alkyl group.
41. 8- (5-fluoro-6-methoxy-2-benzimidazolyl) -254- sulfinylmethyl-1-ethyl-4-(N-methyl-N-allyl)amino-1,2,3,4- tetrahydroquinoline or 8-(5-fluoro-6-methoxy-2- benzimidazolyl)sulfinylmethyl-1-ethyl-4-(N-methyl-N- Scyclopropyl)amino-1 ,2,3,-tetrahydroquinoline according to claim 32.
42. 8 -(5-Acetyl-2-benzimidazolyl)sulfinylmethyl-1- allyl-4-dimethylamino-1,2,3,4-tetrahydroquinoline, 8-(5-fluoro-6-methoxy-2-benzimidazolyl)sulfinylmethyl-1- allyl-4-dimethylamino-1,2,3,4-tetrahydroquinoline, or 8 2 -benzimidazolyl)sulfinylmethyl-1-allyl-4-dimethylamino-1, 2,3,4-tetrahydroquinoline according to claim 33. U 43. A pharmaceutical composition comprising a therapeutically effective amount of a compound of the formula or its pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier.
44. A pharmaceutical composition comprising a therapeutically effective amount of a compound of the formula I or its pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier. A pharmaceutical composition comprising a therapeutically effective amount of a compound of the formula Ill) or its pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier. -255- 4r -zs
46. A process for preparing a hydroquinoline compound of the formula I or its pharmaceutically acceptable salt, as claimed in claim 1, which comprises (I b): (R 1 )m N R0 (I b) HO cmu o or its pharmaceutically acceptable salt, win the above formulas, R'o R 2 A m and the bond between the 3- and 41-positions of the quinoline skeleton have the same ^N A R 2 da H 0 ithe abovedformulasn Rto Ride an thempound bete theua meanings as defined in claim 1, I t _56- b" F')4 'rnU if 0 b) reacting a compound of the formula( (R )m |H I -2) H with a compound of the formula I -3) Q Q( I -3) X 2 -A R 2 to provide said compound of the formula Ia) or its pharmaceutically acceptable salt, in the above formulars, R 2 A, m and the bond between o. ;the 3- and 4-positions of the quinoline skeleton have the same meanings as defined in claim 1, and X' and X 2 are S..i respectively a mercapto group, a halogen atom, a lower alkanesulfonyloxy group, an arylsulfonyloxy group or an aralkylsulfonyloxy group, provided that when X' is a t t i t mercapto group, X 2 is a halogen atom, a lower 'alkanesulfonyloxy group, an arylsulfonyloxy group or an aralkylsulfonyloxy group, and when X 2 is a mercapto group, I t -257- r ~.k XI is a halogen atom, a lower alkanesulfonyloxy group, an arylsulfonyloxy group or an aralkylsulfonyloxy group, c) reacting a compound of the formula(I -2a): (R 1 )m N X 3 a I-2a) with thiourea, and then subjecting the resultant product to a reaction with a compound of the formula( I -3a): 3b X -A R 2 I- cs) 044@ 04 4 4 0*4 O* 4 44 .4* 4 t 44 ,i 4 .4( to provide said compound of the formula I a) or its pharmaceutically acceptable salt, in the above formulas, R2, A, m and the bond between the 3- and 4-positions of the quinoline skelet n have the same meanings as defined in claim 1, arnd X and X"b represent, the same or different, a halogen atom respectively, uJ 4* 44 *r 4 a 4 64 ,r t71!&. -258- q E, d) reacting a compound of the formula NH2 (Ri)m2 (I with a compound of the formula HOOC-S-A R 2 (1-6) to provide a compound of the formula I c): (R 1 )m N N _5 -A 2 (1) .N' or its pharmaceutically acceptable salt, L Od in the above fo'mulas, R I, R, A, m and the bond between the 3- and 4-positions of the quinoline skeleton have the same meanings as defined in claim 1, or 4 t IkIA s i L -259- 4 0 r e) reacting a compound of formula( 1-7): (R 1 )m &N S-R6 1 -7) H 0 with a compound of the formul I CN( -8) R 7 (A)q R 2 to provide a compound of the formula (Id) N asN, d) CHz-( )9 )q R2 9 H 0 6*00 or its pharmaceutically acceptable salt, in the above formulas, R 2 m and the bond between the 3- and 4-positions of the quinoline skeleton have the samnie 0 meanings as defined in claim 1, A' is a lower alkylene group and q is an integer of 0 or 1 R and R7 represent a halogen atom or a group: -CH 2 -M (wherein N is an alkali E, 9 4U C. 6 e~5- ii: 260- A, metal), provided that when R' is a group: -CH 2 -M R 7 is a halogen atom, and when H 6 is a halogen atom, R 7 is a group: -CH 2 -M and the group -CH 2 does not exceed 6 in carbon number.
47. A process for preparing a hydroquinoline compound of the formula or its pharmaceutically acceptable salt, as claimed in claim 2, which comprises a) reacting a compound of the formula( -'R 3 n R SN A R 2 a) H with an oxidizing agent to provide a compound of the formula b) (Rlm )m J A IR 2 N i SH 0 or its pharmaceutically acceptable salt, Sin the above formulas, R 2 R 3 A, m, n and the bond between the 3- and 4-positions of the quinoline skeleton t' have the saMe. dmeanings as. defined in claim 2, L A' *-26 1 CR)' R (jj b 43 b) reacting a compound of the formula( ]I im (R1N N X (N -2) H with a compound of the formula I I I -3) XL-A R 2 to provide said compound of the formula Ia) or its pharmaceutically acceptable salt, T in the above formulars, R R 2 R A, n and the bond between the 3- and 4-positions of the quinoline skeleton I Il have the same meanings as defined in claim 2, and XI and X are respectively a mercapto group, a halogen atom, a lower alkanesulfonyloxy group, an arylsulfonyloxy group or an aivalkylsulforyloxy group, provided that when XI is a mercapto group, X is a halogen atom, a lower alkanesulfonyloxy group, an arylsulfonyloxy group or an aralkylsulfonyloxy group, and when XI is a mercapto group, X L4 -262- t I I I is a halogen atom, a lower alkanesulfonyloxy group, an arylsulfonyloxy group or an aralkyls .,fonyloxy group, c) reacting a compound of the formula( 1-2a): (R1)m N (a (H -2a) with thiourea, and then subjecting the resultant product to a reaction with a compound of the formula(J-3a): A b 0 'I4 444 44* I 0 v3b_ R -3a) or 0 41 E' 0 4* 4 a I to provide said compound of the formula Ha) or its pharmaceutically acceptable salt, in the above formulas, R 2 RI, A, m, n and the bond between the 3- and 4-positions of the quinoline skeleton have the same meanings as defined in claim 2, and X 3 and X 3b represent, the same or different, a halogen atom respectively, t$ c 0 -263- 2 d) reacting a compound of the formula( I (R1mA- NH2 N H2 H with a compound of the formula n 1 -6) HOOC-S- A to provide a compound of the formula (B c): 11 *4* 9* *X 9 0 °o *9*9 09 0* 1'4 9 (R)m H' A H II c) or its ph armaceutically acceptable salt, in the above formulas, R 2 R 3 A, m, n and the bond between the 3- and 4-positions of the quinoline skeleton have the same meanings as defined in claim 2, or I -264- k e) reacting a compound 0u' formula( I-7): n NH .H 0 1-7) with a compound of the formula H-8): n-8) R 7 (4)q R 2 veep oil o 0o 00 0000 0b 00 0 0 0 000 00 00 oo 0 Bo to provide a compound of the formula (Id): (R 1 )m R CH2-(A R2 H O E d) 0000 0 '0 0000 00db 0 0 0~ 0 00 0 00 0 0 00 00 0 0 '4 O 0 04 0 0 40 0 00 or its pharmaceutically acceptable salt, in the above formulas, R 2 R 3 m, n and the bond between thd 3- and 4-positions of the quinoline skeleton have the same meanings as defined in claim 2, A' is a lower alkylene group and q is an integer of 0 or 1, R' and R 7 represent a halogen atom or a group: -CH 2 -M (wherein M is an alkali fr -26$- 'f metal), provided that when R 6 is a group: -CH 2 -M R' is a halogen atom, and when R' is a halogen atom, R' 7 is a group: -CH 2 -M and the group -CH 2 does not exceed 6 in carbon number.
48. A process for preparing a hydroquinoline compound of the formula (Il) or its pharmaceutically acceptable salt, as claimed in claim 3, which comprises a) reacting a compound of the formula(lna): (R 3 )n (R'e) 2 a ^AN/ S-A R H with an oxidizing agent to provide a compound of the formula (ilb) 0 i 1 b) R(R 3 )n V. (R)m A R2 K',N S (AR]b) H O 1 14 1 or its pharmaceutically acceptable salt, in the above formulas, R 2 R 3 A, m, n and the bond 1 between the 3- and 4-positions of the quinoline skeleton have the same meanings as defined in claim 3, b) reacting a compound of the forinula( 11-2): H (1-2) 4 with a compound of the formula (1I1-3): (R 3 )ci X-A R 2 to provide said compound of the formula, ]HIIa) or its pharmaceutically acceptable salt, 000in teaoeformulars, RI, A, mn, n and the bond 008#0.between the 3- and 4-positions of the quinoline skeleton o o* have the same meanings as defined in claim and XI and XI are respectively a mercapto group, a halogen atom, a lower alkanesulfonyloxy group, an arylsuJlfonyloxy group or an *tat Asttaralkylsulf'onyloxy group, provided that when XI is a mercapto group, XI is a halogen atom, a lower alkanesulfonyloxy group, an arylsu2lfonyloxy group or an aralkyisulfonyloxy group, and when XI is a inercapto group, X is a halogen atom, a lower alkanesulfonyloxy group, an arylsulfonyloxy group or an aralkylsulfonyloxy group, c) reacting a compound of the formula(l-2a): -X 3 a (IM -2a) H with thiourea, and then subjecting the resultant product to a reaction with a compound of the formula( 1I-3a): (R 3 m N l -3a) X- A R 2 0 to provide said compound of the formula Ia) or its pharmaceutically acceptable salt, in the above formulas, R 2 R 3 A, m, n and the bond between the 3- and 4-positions of the quinoline skeleton have the same meanings as defined in claim 3, and X 3 and X A^ a represent, the same and different, a halogen atom respectively, 6A* 4I *J r V. d) reacting a compound of the formula( &NH2 E with a compound of the formula (IiM HOOC-S- A 'R 2 (Il-6) f I to provide a compound of the formula ]ff c): SR 3 )n 040 A a 0 *0 0 0 0 00 0004 00 6*60 WO -9 IIIC) S- A R 2 or its pharmaceutically acceptable salt, in the above formulas, RI R 2 R 3 A, m, n and the bond between the 3- and U-positions of the quinoline skeleton halve the same meanings as defined in claim 3, or 0* 00 00 0 0 0I 4 4 00 0 -269- e) reacting a compound of formula( J1 (RN S R 6 (11-7) N 3 H O with a compound of the formula (MI-8): -a (R 3 )m N n(-8) i R7-( 2 R 7 (A)q 2 to provide a compound of the formula (Ind) 0000 (R J 440 (R16 CNIN~ N 2 H d) 0 0 S CH2- (AN) R (d HO or its pharmaceutically acceptable salt, in the above formulas, Ri, R 2 R m, n and the bond between q the 3- and 4-positons of the quinoline skeleton have the 4 same meanings as defined in claim 3, A' is a lower alkylene I' group and q is an integer of 0 or 1, R6 and R7 represent a halogen atom or a group: -CH2-M (wherein M is an alkali I r AN -270- "I rt~ A metal), provided that when R I is a group: -CH 2 -M R 7 is a halogen atom, and when R' is a halogen atom, RI is a group: -CH2H ,and the group -CH 2 q-does not exceed 6 in c~rbon number. 4. A hydroquinoline compound of formula (I) substantially as disclosed herein in conjunction with any one of the Examples not being a Reference Example.
50. A process for preparing a hydroquinoline compound ofl formula substantially as disclosed herein. 4 a- I 4 :1 DATED this 20th day of February 1990 YOSHINARI HIGUCHI By his Patent Attorney ~iF F iTH HACE co. -271-
AU70749/87A 1987-03-30 1987-03-30 Hydroquinoline compounds, compositions containing same and process for preparing same Ceased AU597628B2 (en)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU6174586A (en) * 1985-08-24 1987-02-26 Hoechst Aktiengesellschaft Substituted toluidines, a process for their preparation pharmaceutical formulations containing them, and their use as inhibitors of gastric acid secretion
AU580607B2 (en) * 1984-07-06 1989-01-19 Fisons Plc Benzoxazole, benzthiazole and benzimidazole derivatives

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU580607B2 (en) * 1984-07-06 1989-01-19 Fisons Plc Benzoxazole, benzthiazole and benzimidazole derivatives
AU6174586A (en) * 1985-08-24 1987-02-26 Hoechst Aktiengesellschaft Substituted toluidines, a process for their preparation pharmaceutical formulations containing them, and their use as inhibitors of gastric acid secretion

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