PH27123A - Saturated heterocyclic carboxamide derivative - Google Patents

Description

i ~~ Yr \-

SATURATED HETEROCYCLIC CARBOXAMIDE DERIVATIVES

This Application 1s a Continuation-In¥pPart of Serial No. 36496 filed on February 12, 1988.

FIELD OF THE INVENTION

: This invention relates to novel saturated heterocyclic carboxgmide derivatives and salts thereof which have platelet activating factor (PAF) antagonizing (anti-PAF) activity.

BACKGROUND OF THE INVENTION

A PAF is a chemical substance released from human end other animal cells and is an acetyl- glyceryl ether of phosphorylcholine as represent- ed by the following formula

GH, O(CH, ) CHy : CH5CO0-GH 0

CH, 0-B=0(CH, )p=N"(CHy) 5 0 . " wherein is the integer 15 or 17.

PAF is physiologically active and causes contraction of the alrway smooth muscle, increased . vascular permeation, platelet aggregation and blood pressure fall, among others. It is though ) to be a factor inducing asthma, inflammation, thrombosis, shock and ether symptoms. Therefore, studies of substances capable of antagonizing the physiological activities of PAP are under way and several anti-PAF agents have been reported (e.g.

ay a. 13

European Patent Application No. 178,261 (a), U.S. patents 4,539,3%2, 4,656,190, and 4,621,038,

Furopean Patent No. 115,979 (B), and British

Patent Application Ko. 2,162,062 (A) ).

The present inventors found that novel satu- rated heterocyclic carboxamide derivatives difer- ring in chemical structure from the known anti-PAF agents having platelet activating factor antagoni- zing »uti.¢ty and, based on this finding, they have now completed the present invention. to SUMMARY OF THis INVENTION

The invention thus provide saturated hetero- cyclic carboxamide derivatives of the following } genaral formula (I) and salts thereof. : 15 , - Ww Se rg LT \ In the above formula (I), R! represents a - 20 substituted or unsubstituted 5- or 6-membered he- terocyclic group, which may be condensed with a benzene ring; Rr? represents a hydrogen atom, a = lower alkyl group, or an R] group detined above o x! represents an oxygen atom, a sulfur atom, or a methylene group, which may be substituted by a low=- er alkyl group; y! reprecents an oxygen atom, a sulfur atom, or a group of the formula N-g4 wherein gt is a hydrogen atom, a lower alkyl, a

Ee 29 carboxyl group, an acyl group or a lower alkoxy- carbonyl group; A! represents a methylene group or an ethylene group, each of which may be substitu- ted by a lower alkyl group; Rw represents a - 5 AZ . group of the formulae Re , 4 AS - ) ' Ad a3 iS 10 5 -RHNZp9 , and Nop?! wherein one of R” and 8 is a hydrogen atom, or a substituted or un- | substituted hyarocarbon group, and the other 1s

K : a substituted or unsubstituted 5- or 6-membered : heterocyclic group, which may be condensed with a benzene ring, AZ and A, which may he the same or dl ferent, each represents a substituted or un- gubetituted lower alkylene group, 4 is a methine group (> CH=) uv a nitrogen atom, Rr! is a hydrogen atom,a substituted or unsubstituted hydrocarbon group or a carboxyl, acyl, lower alkoxycarbonyl, carbamoyl, or monoc- or di-lower alkylaminocarbonyl o 20 greup, and x8, K, #10 and rl, which may be the same or (different, each represente a hydrogen atom, a lower alkyl group, an aralkyl group or an aryl groupe

In the above formula (I), it ic preferred that R! is a pyridyl group, a nquinolyl group, a pyrrolyl group, a piperidyl group, a pyrazinyl group or a furyl group, each of which may be sub- stituted by one of two substituents eacn selected from the group eonsisting ot a Lower alkyl group, a lowe. alkoxy group, a lower alkoxycarbonyl group and a dimethylamino group, said pyridyl group may ox

- Ed be in the pyridone form; R® is a hydrogen: xtoi, a lower alkyl group, or & pyridyl group; x! is a gulfur atom, an oxygen atom or a methylene groups y! is an oxygen atom or N-r? wherein wt is a hydrogen atom, a lower alkyl group, an acyl group or a lover alkoxycarbonyl group; al! is a methylene or ethylene group, which may be substituted by one : or two lower alkyl groups RS ie Eg , ~E he 8 of a-r', -N 50, o0r nun Ry, in which one “AY — a? R of n> and. 18 is a hydrogen atom or a lower alkyl group and the other is a substituted or unsubsti- tuted hydrocarbon group or a substituted or unsub- stituted 5- or 6-membered heterocyclic group; A? : 15 Ah 37, which = v be the same or different, each is a substituted or unsubstituted alkylene groups 7 is a methine group or a nitrogen atom, Rl is a hydrogen atom, a substituted or unsubstituted se “hydrocarbon group, or an acyl group, a lower al- loxycarbonyl group, & carbamoyl group, Or & mono-= or di-alkylaminocarhonyl group; and r8 and J, which may be the same or different, each is a hy- drogen atom, a lower alkyl gioup or an aryl groupe. oo Further, it is more preierred that rR is a pyridyl group, which may be substituted by one or two substitudnte euch selected from the group con- gistyng of a lower alkyl group, a lower alkoxycar- bonyl group, Or a dimethylamino group; 2 is a 4 BAD ORAL Si hydrogen atom; x! is a sulfur atom; y! is N-gr* ’ in which rt ia a hydrogen atom, a lower ~lkyl, an acyl group or a lower alxo¥ycarbonyl groups Al is a methylene group, which may be substituted by one ; 5

LL 5 or two dower alxyl group; 2 1s -n Re ,

A? 12 | ) f

NE v8 -N 4-R'y -K 0 , or ~NHNJ g » in which

AN \ R oo

Neds ~p3 ; Con { JR? 5 one of as defined above, preferably -NJ 6 o

AS ; ’ / N\ 7 ! { “ ' , -N Z-R'. Co EE :

Among these. substituents in the above. formula . / - NY . Ve " (1), 1t is partignlerly preforred that Rr! is a. hi \ Cah : . 15 pyridyl group; R® 1s a hydrogen atom; x! is i sul" fur atom; Y' is NH; Al te a mathylene group and Co

Va Vy

R® 1s -N_ FT, in which R! 18 an aryl-lowed Bl- _ \ - kyl group. : LN a From the chemical structure viewpoint, the compounds of the invention are characterized in : that they are saturated heterocyclic carboxamide : derivatives whose specific saturated heterocykle ie always substituted by a spzacific heterocycle and a specific earboxamide ab respective specific positions.More specifically, the chemical structure of the compounds according to the invention, which are represented by formula (I) (1 "n Ja :

A ] h Non, 1

B ; s- Zoom ) o oe a 11) i8 characterized in that the saturated heterocycle 1

Xo

J

ARI which is a 5- or 6-membered saturated heterocycle, is always substituted, at a specific position thereof, by a specific heterocycle, namely the group

R! whic Is a 5- or 6-membered heterdcycle, which may be condensed with a benzene ring, and, at ano- ther specific poeition, by the group ~COR’ which is a specific substituted carboxamide group.

Various saturated heterocyclic carboxamide derivatives similar to the compouduc (1) according ) to the invention have been known Bo far. For instance

German Patent No. 2,729,414 discloses that compounds of the formula on Ain ‘ Moot 4 \ // AEN 2 - wherein R, is an alkanoyl group of 2 to 17 carbon ~ atoms and R, is a carboxyl group or an ester or amide thereof, have litholytic activity and U.8.

Patent 3,592,905 discloses that compounds of the formula ‘ a

Jem, rm opm

HN = -6 - BAD UriGiivaL cl

Ca Ce Yi

. AX)? wherein R is a hydroxy, alkoxy or amino group, have antiinflammatory activity. However, those compounds that have the chemical structure charac- teristics mentioned hereinbefore in accordance } 5 with the invention have not been known in any spe-~ cific manner.

DETAILED DESCRIPTION OF THE INVENTION

The compounds of the invention are described in more detail hereinbelow.

In the definitions of the substituents used ! herein in the general formulas, the term "lower" means, unless otherwise specified, that the rele-~ vant group includes a straight or branched carbon chain containing 1 to 6 carbon atoms.

Accordingly, the "lower alkyl group" includes, among others, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl (amyl), #sopentyl, neopentyl, ‘tert-pentyl, {-methyl= "butyl, 2-methylbutyl, 1,2ydimethylpropyl, hexyl, isohexyl, 1-methylpentyl, 2-methyloentyl, 3-methyl- pentyl, 1,1-dimethglbutyl, 1,2~-dimethylbutyl, 2,2- " dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1- ethyl-1-methylpropyl and 1-ethyl-2-methylpropyl.

The "mono- or di-lower alkylaminocarbonyl group" means a carbamoyl group whose amino group is a mono- or di-substituted by the above-mentioned "lower alkyl group or groups" and, more specifically, includes methylaminocarbonyl, ethylaminocarbonyl, propylaminocarbonyl, isopropylaminocarbonyl, bu=- tylaminocarbonyl, isobutylaminocarbonyl, pentyl- - J =

2H aminocarbonyl, isopentylaminocarbonyl, hexylamino- carbonyl, isohexylaminocarbonyl, dimethylamino- carbonyl, diethylaminocarbonyl, dipropylamino=- carbonyl,diisopropylaminocarbonyl, dibutylamino- oo 5 carbonyl, dipentylaminocar onyl, dihexylaminocar- _bonyl, ethylmethylaminocarbonyl, methylpropylamino- carbonyl, ethylpropylaminocarbonyl, ethylisopro- pylaminocarbonyl, butylmethylaminocurbonyl and butylpropylaminocarbonyl, among others.

The term "hydrocarbon group" as used herein - means a monovalent group derived from a hydrocar- bon, which is a generic name of a compound consis- ting of carbon and hydrogen atoms, by removal of one hydrogen atom therefrom. Preferred examples of the hydrocarbons group are acyclic hydrocarbon groups such as an alkyl group, which is a satu- rated monovalent hydrocarbon group, and cyclic hyirocarbon groups such as a-cycloalkyl group, which is a monocyclic saturated monovalent hydro- carbon group, an aryl group, which is an aromatic monocyclic or polycyclic monovalent hydrocarbon group, a nonaromatic condensed polycylic hydro- carbon group, and an aralkyl or aralkenyl group, which is a monovalent group derived from an aroma- tic monocyclic or polycyclic hydrocarbon having a side chain by removal of one hydrogen atom from said side chain.

The "alkyl group" mentioned above is prefer-

ably a straight or branched alkyl group containing 1 to 20 carbon atome and includes, in addition to the above-mentioned examples of the "lower alkyl group" , heptyl, b-methylhexyl, octyl, o-methyl- heptyl, nonyl, T-methyloctyl, decyl, 8-methyl- nonyl, undecyl, 9-methyldecyl, dodecyl,, 10-methyl- undecyl, tridecyl, 11-methyldodecyl, tetradecyl, 12-methyltridecyl, pentadecyl, 13-methyltetrade~ cyl, hexadecyl, 14~-methylpentadecyl, heptadecyl, 15-methylhexadecyl, octadecyl, 16-methylheptadecyl, nonadecyl, 17-methyloctadecyl, eicosyl, 18-methyl- nonadecyl and so forth,

The "cycloalkyl group" preferably contains 3 to 7 carbon atoms and includes cyclopropyl, . 15 eycloputyl, cyclopentyl, cyclohexel, cycloheptyl, etc.

Preferred examples of the "aryl group" are phenyl and naphthyl. .

The "aralkyl group" is preferably a group ) 20 derived from the above-mentioned "lower alkyl group" by substitution of any hydrogen atom by the above- mentioned "aryl group" and includes,among others, Bh benzyl, phenetyl, 1-phenylethyl, 3-phenylpropyl, 2-phenylpropyl, 1-phenylpropyl, {-methyl-2-=phenyl- ethyl, 4-phenylbutyl, 3-phenylbutyl, 2-phenylbutyl, 1{-phenylbutyl, 2-methyl-3-phenylpropyl, 2-methyl=- 2=-phenylpropyl, 2~-methyl-1-phenylpropyl, 1-methyl=~ 3-phenylpropyl, {-methyl-2-phenglpropyl, 1-methyl-

oo NER 1-phenylpropyl, 1-ethyl-2-phenylethyl, 1,1-dimethyl~ 2-phenylethyl, 5-phenylpentyl, 4-phenylpentyl, 3- phenylpentyl, 2-phenylpentyl, 1-phenylpentyl, 3 methyl-4-phenylbutyl, 3-methyl-3-phenylbutyl, 3- methyl-2-phenylbutyl, 3-methyl-1-phenylbutyl, 6- phenylhexyl, 5-phenyl-hexyl, 4-phenylhexyl, 3=- phenylhexyl, 2-phenylhexyl, 1-phenylhexyl, 4-methyl-~ 5-phenylpentyl, 4-methyl-4-phenylpentyl, 4-methyl- 3-phenylpentyl, 4-methyl-2-phenylpentyl, 4-methyl- t{-phenylpentyl, 1-naphthylmethyl, 2-naphthylmethyl, 2-(1%naphthyl)ethyl, 2-(2-naphthyl)ethyl, 1-(1- : paphthyl)ethyl, 1-(2-naphthyl)ethyl, 3-(1-naph- . thyl)propyl, 3-(2-naphthyl)propyl, 2-(1-naphthyl)- propyl, 2-(2-naphthyl)propyl, 1-methyl-2-(1-naph-

: 15 thyl)ethyl, 1-methyl-2-(2-naphthyl)ethyl, 4-(1- naphthyl)butyl, 4-(2-naphthyl)butyl, 3-(1-naphthyl)- butyl, 3-(2-naphthyl)butyl, 2-(1-naphthyl)butyl, 2~(2-naphthyl)butyl, 1-(1-naphthyl)butyl, 1-(2-

naphthyl)butyl, 2-methyl-3-(1-naphthyl)propyl, 2-

- 20 methyl-3-(2-naphthyl)propyl, 2-methyl=-2:-(1-naph- thyl)propyl, 2-methyl=2=-(2-naphthyl)propyl, 2- . methyl-1-(1-naphthyl)propyl, 2-methyl~1-(2-naph- thyl)propyl, 5-(1-naphthyl)pentyl, 5-(2-naphthyl)- pentyl, 4-(1-naphthyl)pemtyl, 4-(2-naphthyl)pentyl, 3-methyl-4-(1-naphthyl)butyl, 3-methyl-4-(2-naph- thyl)butyl, 6~-(1~-naphthyl)hexyl, 6-(2-naphthyl)- hexyl, 5-(1-naphthyl)hexyl, 5-(2-naphthyl)hexyl, 4-methyl-5-(1-naphthyl)pentyl, 4-methyl-5-(2-naph=~

. 2x thyl)pentyl, diphianylmethyl (benzhydyyl) and tri- tyl (triphenylmethyl).

The "aralkenyl group” is a group resulting from binding of the above-mentioned "aryl group" } 5 to a lower alkenyl group and includes, among others 2~phenylethyl, 3-phenyl-1-propenyl, 3-phenyl-2- propenyl, 1-methyl-2-phenylbutenyl, 4-phenyl-1- butenyl, 4-phenyl-2-butenyl, 4-phenyl-3-butenyl, : 5-pheyl-1-pentenyl, 5-phenyl-2-pentenyl, S-phenyl= 3-pentenyl, 5-phenyl-4=pentenyl, 6-phenyl-1-hexenyl, ; 6-phenyl-2-hexenyl, 6-phenyl-3-hexenyl, 6-phenyl- 4-hexenyl, 6-phenyl-5-hexenyl, 2-(1-naphthyl)- ethenyl, 2-(2-naphthyl)ethenyl, 3~(1-naphthyl)=-2- propenyl, 3=(2-naphthyl)-2-propenyl, 4-(1-naphthyl)- 3-butenyl, 4-(2-naphthyl)-3-butenyl, 5-(1-naph- thyl)-2-pentenyl, 5-(2-naphthyl)-<-pentenyl, 5- : (1-naphthyl)-4-pentenyl, 5-(2-naphthyl)-4-pentenyl, 6~(1-naphthyy¥)-2-hexenyl, 6-(2=naphthyl)-2-hexenyl, 6-(1-naphthyl)-5-hexenyl and 6-(2-naphthyl)-5- - 20 hexenyl.

Examples of the "non-aromatic condensed poly- cyclic hydrocarbon group" are indenyl, which may be represented by the formula

Ns which io avallable for bonding at any optional position on the benzene ring or saturated ring

CC YI

(the same shall apply when the same manner of for-

ZN TN mula representation is used), indenyl (eee =H)»

SS TT tetrahydronaphthyl (| ETT) dihydronaphthyl (e.g. of (—— 1,2-benzo=-1-cycloheptenyl (fo )

Poo ERE w= nyL - ef ’ ~ .. ~~.

Zl TTR fluorenyl (erg fy 2,3-dihydro-1H-benz-

NN emma Pe

ZF FT

(£f)indenyl (| ZN), 1H-benz(f)indenyl “. oN ——

ERNST

(1 A=) and the like condensed polgcyclic hydrocarbon groups other than aromatic hydrocarbon groups.

In the compounds of the invention, the "5- or 6-membered heterocyclic group, which may be cone densed with a benzene ring" represented by rt, R®,

Rr’ or r® is preferably an oxygen-, sulfur- and/or nitrosen-containing, saturated or unsaturated he- terocyclic group and, more specifically, includes pyrrolyl, pyrrolinyl, pyrrolidinyl, imidaxolyl, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazo- 1linyl, pyrasolidinyl, triazolyl, tetrazolyl, indO- 1yl, ben:imidazolyl, indazolyl, pyridyl, dihydro- pyridyl, tetrahydropyridyl, piperidinyl, pyrimidi- nyl, pyridazinyl, pyrazinyl, piperavinyl, quinolyl, quinazolinyl, quinoxalinyl, phghalazinyl, cinnolyl and other monocyclic or bicyclic, saturated or un- saturated heterocyclic groups containing one or more nitrogen atoms alone as hetero atoms; thiazo- linyl, thiazolidinyl, isothiazolyl, thiadiazolyl,

~ | JF benzothiazolyl, benzoisothiazolyl and other nitro~- : gen and sulfur atoms-containing, mono- or bicy- clic, saturated or unsaturated heterocyclic groups} oxazolyl, oxazolinyl, oxazolidinyl, iso- xazolyl, oxadiazolyl, benzoxazolyl, benzisoxazo- . 1yl and other nitrogen and oxygen atoms-contai- ning, mono- or bicyclic, saturated or unsaturated heterocyclic groupsj and, furthermore, heterocy- clic groups containigg one or more sulfur or oxy- gen atoms, such as thienyl, tetrahydrothienyl, fu-

A ryl, tetrahydrofuryl, pyranyl, tetrahydropyranyl, ' dioxolyl, benzofuryl, benzopyranyl and benzodio- xolyl.

These heterocyclic groups are avallable for bonding at any optional position, either on the he- terocycle or on the benzene ring, through a ring- forming carbon atom or a ring-forming nitrogen atom. :

The "lower alkylene group" represented by - 20 each of AZ and A> is preferably a straight alky- lene group containing 1 to 3 carbon atoms and, more specifi-~lly, Includes methylene, ethylene and trimethylene. : As the tacyl group", there may be made par- ticular mention of lower alkanoyl groups such es formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl and hexane i, aral- kanoyl groups such as benzylcarbonyl, 3~-phenyl-

: ; 3 2 27 propanoyl, 2-phenylpropanoyl, 1-phenylpropanoyl, 4-phenylbutanoyl, 3-phenylbutanoyl, 2-phenylbuta- noyl, 1-phenylbutanoyl, 2-methyl-3-phenylpropa- . noyl, 5-phenylpentanoyl, 4-phenylpentanoyl, 3-phe- ~ 5 nylpentanoyl, 2-phenylpentanoyl, 1-phenylpentanoyl, : 3-methyl-4-phenylbutanoyl, 3-methyl-2-phenylbuta- noyl, 6-phenylhexanoyl, 5-phenylhexanoyl, 4-phe- nylhexanoyl, 3-phenylhexanoyl, 2-phenylhexanoyl, 1-phenylhexanoyl, A4-methyl-5~phenylpentanoyl, 4 ~ metayl-3-phenylhexanoyl and 4-methyl-2-phenylhe-

Ww. xanoyl, and substituted or unsubstituted arylcar- . bonyl groups such as benzoyl, 1-naphthoyl, 2-niaph=- thoyl, (0-, m- or p-)toluayl, (o-, m- or p-)fluo- robenzoyl, (o-, m- or p~)chlorobenzoyl, (o-, m- or p-)broaobenzoyl and varlous fluoronaphthoyl, chlo- ronaphthoyl,and bromonaphthoyl groups. The "lower alkoxycarbonyl group" includes, among others, me- thoxyearbonyl, ethoxycarbonyl, propoxycartonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycar- - 20 bonyl, geo-butuxycarbgnyl, tertbutoxycarbonyl, pen- tyloxycarbonyl, 3-methylbutoxycarbonyl, hexyloxy- carbonyl and 4-methylpentyloxycarbonyl.

As prefcrred examples of the "aralkyl group" or "aryl group" represented by any of RS, RI, R10 and r11, there may be mentioned those aralkyl groups or aryl groups specifically mentioned in relation to the term "hydrocarbon group".

The above-mentioned "hydrocarbon group" and/

: RENE or "5~ or 6-membered heterocyclic group, which may be condensed with a benzene ring" may further have, on any of 2, ®°, iW, 7! and R2, one or more sub- : stituents each selected from among halogen atom, ] 5 lower alkyl group, hydroxy and related groups (hy- droxy, mercapto, alkoxy, lower alkylthio, cycloal- kyl-lower alkoxy, cycloalkyl-lower alkylthio, aralkyloxy, aralkylthio, aryloxy, arylthio, ory- loxy~lower alkoxy, aryloxy-lower alkylthio, aryl- thio-lower alkoxy, aryltiiio-lower ulkylthio), oxo and related groups (oxo, thioxo), carboxyl and re-

Tated groups (carboxyl, lower alkoxycarbonyl, a acyl), cyano, carbanoyl and related groups (car-~ bamoyl, mono- or di-lower alkglaninocarbonyl), nitro, amino and related groups (amino, monc- or di-lower alkylamino, mono- or diaralkylamino, N= © aralkyl-N-lower alkylamino) and, for i or RO, nitrogen-c ntaining heterocyclic graups.

Preferred as the "hairogen atom" is a fluorine, chlorine cr bromine atom. The "jower alkyl group" includes thone mentioned hereinbefore.

The »aiaxy_ group” is suitably a straight or branched one containing 1 to 10 carbon atoms and includes methoxy, etnoxy, propoxy, 130propoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pen- tyloxy (amyloxy), 1sopentyloxy, tert~pentyloxy, neopentyloxy, 2-methylbutoxy, 1,2-dimethylpropoxy, 1-ethyl propoxy, nexyloxy, heptyloxy, 5-methyl-

23 1 hexyloxy, octyloxy, 6-methylheptyloxy, nonyloxy, 7- methyloctyloxy, decyloxy, 8-methylnonyloxy, and so on. fhe "lower alkoxy group" includes those alko- xy groups mentioned hereinbefore in relation to the "alkoxy group" which contain 1 to 6 carbon atoms.

The "lower alkylthio group" corresponds to the above-mentioned lower alkoxy group iu the sensethat the former contains a sulfur atom in -

CL .place of the oxygen atom in the latter. Examples are methylthio, ethylthio, propylthio, isopropyl- ; thio, butylthio, sec-butylthio, tert-butylthio, pentylthio, neopentélthio, 2-methylbutylthio, 1, “15 2~dimethylpropylthio, 1-ethylpropylthio and hexyl- ' thio,

The "ocycloalkyl-lower alkoxy group" or "cy- cloelkyl-lower alkyltnio group” means a group re- sulting {rom substitution of one optional hydrogen . 20 atom of the above-mentioned "lower alkoxy group" or "lower alkylthio group", respectively, by the ~ above-mentioned "cycloalkyl group" and specifical- ly incindes, among others, cyclopropylmethoxy (or methylthio) for denoting cyclopropylmethoxy or cyclopropylmethylthio; hereinafter the same shall apply , 2-cyclopropyl-ethoxy (or ethylthio), 1- cyclopropyl-ethoxy (or ethylthio), 3-cyclopropyl- propoxy (or propylthio), 1-cyclopropyl-propoxy

(or propylthio), 1-cyclopropyl-propoxy (or propyl- thio), 2-cyclopropyl-1-methyl-ethoxy (or ethylthio), 4-cyclopropyl-butoxy (or butylthio), S-cyclopropyl- : pentyl-oxy (or thio), 6-cyclopropylhexyl-oxy (or thio), cyclobutyl-methoxy (or methylthio), 2-cy~ clobutyl-ethoxy for ethylthio), 1-cyclobutyl- ethoxy (or ethylthio), 3-cyclobutyl-proooxy (or propylthio), 2-cyclobutyl-propoxy (or propylthio), 1-cvelobutyl-propoxy (or propylthio), 2-cyclo- butyl-1-nethyl-ethoxy (or ethylthio), 4-cyclo-

Co butyl-butoxy (or butylthio), 5-cyclobutylpentyl=- ory (or thio), 6-cyclobutylhexyl-oxy (or thio), cy- clopentyl-methoxy (or methylthio), 2-cyclopentyl- ethoxy (or ethylthio), 1- cyclopentyl-ethoxy (or ethylthio), 3-cyclopentyl-propoxy (or propylthio), 2~cyclopentyl-propoxy (or propylthio), 1-cyclopen- tyl=-proprxy (or propylthio), 2-cyclopentyl-1- methyl- ethoxy (or ethyléhio), 4- cyclopentyl-buto- .. xy (or butylthio), 5-cyclopentyl-pentyl-oxy (or thio), 6-cvclepentylhexyl-oxy (or thio), cyclo- hexyl-methoxy (or methylthio), 2-cyclohexyl-ethoxy . (or ethylthio), t1-cyclohexyl-ethoxy (or cthylthio),

Z-cyclohexyl-propoxy (or propylthio}, 2-cyclo=- hexyl~propoxy (or propylthio), 1-cyclohexyl-pro- poxy (or proprlthio), 2-cycloheryl-1-methyl-ethoxy (or othylthio), 4-cycloheptyl-hutoxy (or butyl- thio), 5-cycloheptylpentyl-oxy (or thio) and 6- cycloheptylhexyl-oxy (or thio).

2% 1%

The "aralkyloxy group" or "aralkylthio group" means a group resulting from substitution of one optional hydrogen atom of the above-mentioned "lo- wer alkoxy group" or "lower alkylthio group" by the above-mentioned "aryl group" and, more specifically, : includes the following examples in which the "aryl group" is typified by a phenyl group alone: ben- zyloxy (or thio), phenethyl-oxy (or thio), 1-phe- nyl-ethoxy (or ethylthio), 3-phenyl-propoxy (or propylthio), 2-phenyl-propoxy (or propylthio), 1- i phenyL-propoxy (or propylthio), 2-phenyl-1-methyl- ethoxy (or ethylthio), 4-phenyl-butoxy (or butyl- thio), 5-phenylpentyl-oxy (or thio) and 6-phenyl=- hexyl=-oxy (or thio).

Examples of the "aryloxy group" or "arylthio

Co group" are phenoxy (or phenylthic), naphthyl-oxy (or thio) and other ether or thioether residues derived fron aromatic mono- or polycyclic hydco- carbon hydroxy or mercapto compounds. - 20 The "aryloxy-lower alkoxy group", "aryloxy- lower alkylthio group", "arylthio-lower alkoxy group" or "arylthio-lower alkythio group" means a group resulting {rom substitution of one optional hydrogen atow of the above-mentioned "lower alkoxy group" or " lower alkylthio group" by the above- mentioned "aryioxy group" or tgryltilo group" and, more specifically, includes the tollowing exanples wherein the "aryloxy group" or "arylthio group"

2H) f is typified by a phenoxy (or phenylthio) group alone: phenoxy (or phenyltnhio)-metnoxy (or me- thylthio), 2-phenoxy (or phenylthio)-ethomry (or- ethylthio), 1-phenoxy (or phenylthio)-ethoxy (or ethylthio), 3-phenoxy (or phenylthio)-propoxy (or propylthio), 2-phenoxy (or phenylthio)-propoxy (or propylthio), 1- phenoxy (or pheunyltiio)-propoxy (or propylthio), 2-phenoxy (or phenylthio)=1- methyl-ethoxy (or ethylthio), 4-phenoxy (or phe-~ nylthio)-butoxy (or butylthio), S5-phenoxy (or phe- nylthio)pentyl-oxy (or thio) and 6-nhenoxy (or phe- nylthio)hexyl-oxy (or thio).

As examples of the "acyl group" or "mono~- or di-lowar alkylaminocarbonyl group", there may be

Co 15 mentioned those specific groups that have already been given hereinabove.

The "mono- or di-lower alkylamino group" means a group resulting from substitution of one or two hydrogen atomg of an amino group by "lower alkyl ) 20 groups" mentioned hereinbefore and, more specifi- cally, includes monoalkylaminoggraups in which the substituent alkyl group is a straight or branched alkyl group containing 1 to 6 carbon atoms, such as methylamino, ethylamino, propylamino, lsopro- pylamino, butylamino, isobutylemino, pentylamino, isopentylamino, hexyamino, and idohexyamino, sym- metrical dialxylamino groups in which the two sub- stituent alkyl groups are the same and each is a oo 27 [27 gtraight or branched alkyl group containipe 1 to 6 carbon atoms, such as dimethylamino, diethylaaino, dipropylamino, diisopropylamino, dibutylamino, di- : pentylamino and dihexylamino, and asymmetrical dial- kylamino groups in which the two substituent alkyl . groups are different from each other and each is a straight or branched alkyl group containing 1 to 6 carbon atoms, such as athylmethylaminn, methylpro- pylamino, ethylpropylamito, tutylmethylamino, butyl- ethylamino and butylpropylamino. ol As the Mmono- or diaralkylamino group", there may be mentioned monoiralizylamivo groups such as benzylsaumino, phenethylanino, %-pheunylpropylamino, 4-phenylbutylanino, 5-phenylpentylamino, 6-phe-~ nylhexylanino, {-naphthylmethylanino, 2-naphthyl- methylamnino, 1-naphthylethylumino, 2-naphthyl- ethylarico, 1-nophthylpropylauine, 2-naphthyl- projylamino, 1- naphthylbutylamino, 2-naphthylbuty- ~ Jamino, diphenylmethylomino, ?2,2-diphenylethylamino, - 20 3,3-diphenylpropylamino, 4 ,4-diphenydbutylamnino and trivhenylmethylamino, symmetrical diaralkyamino groupe such as dibenzylunino, diphenethylamino, bie (S-phenylpropyl)anino, bie (4-phenylbutyl )ani- no, bis (5-phenylpentyl)emino and bis(6-phenyl- hexyl )amino, and asymnec trical diaralkylamino greupn such os N-benzylphenethylamino, N-benzyl-

F-phenylpropylamino, M-benzyl-4-phenylbutylamino,

N-benzyl-5-phenylpentylamino, N-henzyl-6-phenyl- . - 20 - : »

BAD ORIGINAL J oo 2H? 27123 hexylauino, N-(3-phenylpropyl)-4-phenylbutylanino,

N~(3-phenylpropyl)=-5phenylpentylamino, N-(3-phe- nylpropyl)-6-phenylhexylamino, N-(4-phenylbutyl)- 5-phenylpentylamino, N-(4-phenylbutyl)-6~phenyl- jtexylanino and N-(5-phenylpentyl) o-phenylhexyl=- amino.

The "H-aralkyl<N-lower allyl group" MEANT a group resulting from substitution of the above- mentioned "lower alkyl group" on the amino group of the ubove-mentioned " wonosralkylamino group" for renderiig the amino group tertinyy and typi- cally includes N-methylbenzylamino, N-athylben- wylamino, N-propylbenzylamino, N-butylbenzyl- amino, H-pentylbenzylanino, l-hexylbenzylamino, ti-methylphenethylauino, N-ethylphenethylamino,

N~propylphenethylumnino, N-butylphenethylamino, N= pengylphenethylawiso, I-hexylphenethylamino, N- methyl-3-phenylpropylaniino, N-ethyl-3-phenylpro- pylamino, N-propyl-3=-phenylpropyluaino, N-butyl- 3~phenylpropylunino, N-pentyl-3-phenyljropylinui- uo, N-hexyl-3-phenylpropylamino, N-methyl-4-phe- nylbutylamino, N--ethyl-4-phenylbutylamino, N-pro- pyl=-4=phenyl Sylamino, N-butyl-4-pheyulbutylani- 10, He-pentyl-4-phenylbutylaniino and N-hexyl-4- phenylbutylamino. he "nitrogen-céntuining heterocyclic group" ai a dubstlitaent on W2 and/or i® means a saturated or unsaturated, 5- or 6-membured heterocyclic

Pe aia group which contains at least one nitrogen atom as a hetero aton and optionally a sulfur atom and/or en oxygen atom, and may Le condensed with a ben- zene ring. Ae examples of said grcap, there msy be : 5 mentioned those hetrocyclic groups containing at least one ailtrogen aton as selected from among the examples glven hereinbefore io exanples of the "5- or G-membercd hetrocyclic group, which may be con- densed with a benzene fing." :

In this case, too, such heterceyclic groups

E may be available for bonding at any position on the heterocycle or benzene ring either via a ring-for- ning carbor atom or via a ring-Tforming nitrogen atom, as mentioned hereinabove, _Preierrcd as the substituent which 2 and/or : Ie pay have are lower alkyl, aralkyl and &ayl groups and, in perticulzr, those groups specifi- celly mentioned ir relation to the above-mentioned "lower alkyl group'and, in the case of aralkyl and aryl groups, in relation to the "hydrocerbon group".

The compounds (I) according to the invention C can form salts. The:scope of the invention includes salts of the compounds (I). Such salts include acid addition salts with inorganic acide such as hydro- chloric scid, sulfukic acid, nitric acid, phopphéwmic acid, hydrobromic acid and hydroiodic acid and with ore nic acids such as acetic acid, oxalic acid, succinic acid, citfic acid, malelc acid,

Ca BAD ORIGIN AD malic acid, fumaric acid, tertaric acid, picrié aicd, methanesulfonic acid and ethanesulfonic a¢ld, calte with acidic amino alcde such as rlu- tamic acid and aspartic acid, quaternary ammonium salts resulting from quaternization with alkyl halides such an methyl chloride, methyl bromide and methyl iodide, and so forth.

The compaunde (T) provid«d ty the present invention hove at least two asymmetric carbon atoms } nnd there cnn exist isomers due to the presence of ' auch e¢arban atoms, Tu cert in instances, ketneenal , tautomerisn may be encountered between a compound

LL having a hydroxy or mercapto group on a heterocy- gle and a eam-omd having on oxo »r thioxe group on a heterocycle. uch losners all fall within the pecope of the present invention either iu each indi- vidua? isolated form or in « mixture form.

Specific eramples of particularly preferred compound (If and salts thereof iy the invention in- clude 1-(3-phenylpropyl)-4- 2-(Z-pyridyl)thiazolidin- 4-ylecarbon-yl piperazine, 1-decyl-4- 2-(3-pyridyl) thiazolidin-4-ylcerbonyl piperasuine, 1-(4-oxo-4- phenylbutyl)-4- 2-(*-pyridyl)thiazolidin-4~ylcarbo- nyl piperazine or =n acid addition salt thereof, etc., but the present invention Bhould not be construéd as : being limited thereto.

The compounds (I) cccording to the invention can be produced by applying varicus synthetic methods 83 BAD ORIGINAL 9

Ve talking advantage of tne chnrocteristics of the sole- letul structure and vardous substituents. Vypical examples of apjlicuble production processes are civen betow.

Process 1 (amidation A)

R

~ 1 . a or its tractive + HR]

J jerive ]

Ru v ~ceon derivative (111) (11) 4

RX

XI es Yo co-R

Deprotection as necessary (1)

Process 2 (Amidation 1) 12 1

R13 eo - Hox? 0 (1v) : 1 “NY ee ee tt om rms } ? R —_ co-p3

Détirotection as H

NeCessury (Ia) r we - - -— AY 24 BAD ORIGINAL A

Process 3 (Amidation C)

A . " * a Nai Lhe \/ : or its reactive | no

I 1 NM

Ne A derivative + h

I (VI) i ‘ / Sa ete et tt retorts roar) RS : vu ;

Deprotection as oe Son necessary or (Ib)

Process 4 (N-Acylation A)

WY X Salt

X . EN + R'8-coon or its reactive

WANT MH derivative

NN

(VIII) (vii) 1 uv! . 7 a, ,

A | ~5N . rere rete tertiary} we VN -N N=-CC=-R

Deprotection as No AS necessary (Ic) - 25 =

BAD ORIGINAL Ei

Process 5 (N-Acylation B) : 1 al sx ~ 1

AVA. 18

X | + R'®-COOH or its forititvé a ALERT derivative (x) : (1X) .

TN 2X ~ }

A of \ AN

Deprotection as Hl Jen necessary I I.

Process 6 (N-Acylation C)

He) rh ) x ) -x/ 18

Yoo + R “=COOH or its reactive / NE 4 i MIRAE derivative . (X11) (x1) 2 a Ca !

Woof =N A . x 5 ( ~ NC ~n' “ — y cA

Deprotection as we necessary (Ie)

A

NL) 7H “ Process 7 (Etherification or thioetherification A) 0 x 1

A id i | 17

Sh 1 + p2-g2> a TT Ne

R SUN. oo (XV) (XIV) ) 1 \ LR ~ : / fy

Nf ]

Soo ow

Deprotection as oo ce NT necessary AT - (1f)

Process 8 (Etherification or thioetherification B)

La 1

K J X aA \ | “\ p2-g23

LA i N . - 8 AR Le Ny gy 7-0-1 + R

AN rd (XVII) (XVI) 1 IK ® X al 3 | Al ee ra) I / N\ 4 A 7 0N Aa - vo Td -N ZA hm

Deprotection as 2S necessary A (1g) - 27 = , i

BAD ORIGINAL 9 boa

Process 9 (Etherification or thioetherification C)

In A v R 4 = ad + Dp2-R%? we! vo Yoon (XIX) (XVIII) : : A rot , X “~t re reread J \ A : .

Deprotection as 0 *Y Tee necessary (1h)

Process 10 (Cyclization) axl

Co-y (xx) (XXI) \ ! J _ Ad

Deprotection as ae LR necessary (11) -

BAD ORIGINAL &)

Amin rm

AFL?

Process 11 (N-alkylation A)

Ve Loe g 4 . : ty JR aN EA . x " a ' a p3-g2? bv A NC Tred : XXIII he (XX11) Deprotection as (13) necessary

Process 12 (N-Alkylation B) : (1) pS_g26 {(XXV)

IN - py as desired (-N ~ att (3) Deprotection as necessary (XXIV) 31 !

R 2!

N/ . 5

LIN 1 a A at’

REY Nn ae . ~R (1k)

BAD ORIGINAL Jd - 29 =~ \ HE

Process 13 (N-Alkylation C) he AN 2

VY pl + DI-R%? of To TON ho en Ne (XXVIII) + Ly \. as a ne (XXVII)

WI x \ J ~N 3 ree) Y | re of Nt ZN :2

Deprotection as H NT SN 0-N N-RE y / ' 10 necessary Nav (11)

Process 14 (N-Alkylation D)

SL Koy . p3.g25

LN 14 5 ~Y Lt -R

I

(XX1x) (XxX)

TN

25.7 g ]

IN BX

R WARY

—_———— ~~ 2 \ Y PEN . 3

Deprotection as necessary R LO-R (Im)

Process 15 (N-Alkylation E) (XXX1)

NL ‘

Lo AEA (1) D05-r%® (xax1r) CL (2) D-R21 (XXXII) vo as desired (3) Deprotection as (In) necessary

Process 16

Sood of - Chloe

Co Poor . : } ESE rd = a + + r'_cHoO (XXXIV) (XXXV) n ) \ BN TT meee ee > e CLC

Deprotection as o necessary po! (Io) - 31 ~ dP

BAD ORIGINAL Py

2% 127

Process 17 (Reduction) ! Eo A Q' A 1 : H, 3 A " NE RONG : (XXXVI) (Ip)

In the above reaction fromulas, rt, 2, Rr, r4, R?, al, 1! and 2 each are as defined in above formula (I) and the other substituents are defined ag follows: : RZ; the same group as RY, which however may have a protective groups; r'3, the same group as Pt, which however may have a protective groups v2 t the same group as 1, which however may have a protective group;

R14, the same group as Rr, which however may have a protective groups ’

R19, the same group as Rr, which however may have a protective groups at : a divalent hydrocarbon group; pl and R17, a hydrogen atom or a lower alkyl group; R16 and R17, which may be the same or dif- ferent, a hydrogen atom or a lower alkyl groups

R18; the residue of an acyl group after remo- val of the carbonyl group therefrom;

N By a nitrogen-céntaining 5- or 6~member- ed heterocyclic group in which the nitrogen atom

TT opp ORIG 9 as ce

LHL

. is not a tertiary one and which may te condensed with a benzene ring; 719, a hydrogen atom, a lower alkyl group or a group of the formula H-N Berar 3 720; the same group as R1, which however may have a protective group; 821; the same group as RZ, which however may have a protective group; 12 s+ the same group as vt, which however may have a protective group;

R%2, the same group as 2, which however may have a protective group;

A: the same group as A or a divalent group of the formula Atox2oab

X° 1 an oxygen atom or a sulfur atom} ab { a lower alkylene groupj nt and n2: one is a hydroxy group, 2a mercapto group, or an alkali metal-substituted hydroxy or mercapto group and the other is a halogen atom or an organo sulfonyloxy group) rR? an alkyl of 1 to 10 carbon atoms, a cy- cloalkyl-lower alkyl group, an aralkyl group, an aryl group, an aryloxy-lower alkyl group or aryl- thio-lower alkyl group; x3 : an oxygen atom or 8 sulfur atom}

AT : a divalent 5- or 6-membered heterocyclic group, which may ve condensed with a benzene ring, or a group of the formula ~26_%2-28-;

AB 1 a divalent 5- or 6-membered heterocyclic group, which may be condensed with a benzene ring;

R24, the same group as rR’, which however may have a propective group; xt t an oxygen atom or a sulfut atoms vt : an oxygen atom, a sulfur atom or an imino group (-NH-); p> : a halogen atom or an organo sulfonyloxy group;

R22: a lower alkyl group, a lower alkoxycarbo- nyl group or an acyl group; ot and he one is an amino group, which may have a protective group, and the other 1s a halo- gen atom or an organo sul fonyloxy group; . 15 720, a hydrogen atom, : lower alkyl group or an aralkyl group when D° is an amino group which may have a protective group; a lower alkyl group or an aralkyl group when D° is a halogen atom or an or- gano sulfonyloxy acid group; po-g26 may bé potasws’ sium phthalamide, provided that pt is a halogen atom or an organo sulfonyloxy group}

R27, a lower alkyl group or an aralkyl group, which may be the same as or difterent from 2°, r28, a hydrogen atom or she same group as p26 or re7;

R29; a hydrogen atom, a lower alkyl group or a group of the formula pt_a8-;

RO; a hydrogen atom, a lower alkyl group or

ALE an aralkyl or an aryl group; p31, a hydrogen atom, a lower alkyl group, an aralkyl group or an aryl group

X° : an oxygen or a sulfur atom, a methylene group which may have a lower alkyl group as a sub- ‘stituent or a methine group which may have a lower alkyl group as a substituent (i.e. H- or lower al- kyl-C= or H~- or lower alkyl-C-); -~-: one bond is a double bond.

Referring to the above definitions, the protec- 3 tive group includes amino-protecting groups, carboxy- protecting groups, mercapto-protecting groups and _hydroxy-protecting groups. As the amino- protecting groups, there may te mentioned urethane-forming . 15 protective groups such as benzyloxycarbonyl, p-me- thoxybenzyloxycarbonyl, p-methylbenzyloxycarbonyl, p- chlorobenzyloxycarbonyl, p-nitrobnezyloxycarbo- nyl, p-phenylazobenzyloxycarbonyl, p-methoxyphenyl- azobenzyloxycarbony¥l, 3,5-dimethoxybenzyloxycarbon- yl, 3,4 ,5-trime thoxybenzyloxycarbonyl, tert-buto- xycarbonyl, tert-amyloxycarbonyl, p-biphenyliso- propyloxycarbonyl and dilsopropylmethyloxycarbonyl, acyl-type protective groups such as formyl, acyl, trifluoroacetyl, phthalyl, tosyl, o-nitrophenyl- sulfenyl, p-methoxy-o-nitrophenylsulfenyl, benzoyl and chloroacetyl, alkyl-type protective groups such as trityl, benzyl, 2-benzoyl-1-methylrinyl and tri- methylsilyl, and allylidene-type protective groups

FRY. such as beuzylidene and 2-hydroxy-allylidene.

As the carboxy-protecting groups, there may be mentioned ester residues such as benzyl, p-nit- robenzyl, p-methoxybenzyl, 2,4,6-trimethylbenzyl, . > pentamethylbenzyl, methyl, ethyl, tert-butyl, benzhydryl, trityl, phthalimidomethyl, cyclopen- tyl, 2-methylthioethyl, phenacyl and 4-picolyl.

As the mercapto-protecting groups, there may be mentioned benzyl, p-methoxyberizyl, p-nitroben- 1° zyl, benzhydryl, trityl, benzyloxycarbonyl, ben- . zoyl, ethylcarbamoyl, acetamidomethyl, aethylthio, benzylthiomethyl, and so forth. As the hydroxy- protecting groups, there may be mentioned benzyl, = tert-butyl, acetyl, trifluoroacetyl, benzyloxy- : "? carbonyl, and su on. .

The "divalent hydrocarbon group" corresponds to the subctituted hydrocarbon group in Rr’, RO or

Rr! and preferably is an alkylene group, a cyclo-~ 2 00 alkanediyl group, an arylene group, 8 divalent nonaromatic condensed polycyclic hydrocarbon group, an aralkylene group or an aralkbny}dne- group.

The "alkylene group" preferably contains 1 to 20 carbon stoms, which may be straight or branched and, more specifically, includes, among dhers, me- thylmethylene, ekhylene, trimethylene, propylene, tetramethylene, 1-mthyltrimethylene, 2-methyltri-

. 29H? 27123 methylene, 3-methyltrimethylgne, pentamethylene, 1- methyltetramethylene, 4-methyltetramethylene, hexa- methylene, 5-methylpentamethylene, heptamethylene, octamethylene, nonamethylene, decamethylene, unde- . 5 camethylene, dodecamethylene, tridecamethylene, te- tradecamethylene, pentadecamethylene, hexadecame- thylene, heptadecamethylene, octadecamethylene, no- nadecamethylene, and eicosamethylene.

The "cycloalkanediyl group" includes various cyclopropanediyl groups, various cyclobutanediyl groups, various cyclopentanediyl groups, various cyclohexanediyl groups and vafious cycloheptane- diyl groups.

As the "divalent nonaromatic condensed poly- cyclic hydrocarbon group", there may be menthoned various indanediyl groups, various indenediyl groups, various tetrahydronaphthalenediyl groups, varbous dihydronaphthalenedlyl groups, various 1, 2-benzo-1-cycloheptenediyl groups, various fluo- redediyl groups, various 2, 3-dihydro-IH-benz f indenediyl group: and various 1H-benz f indene- Co diyl groupe, among others.

As the "arylene group", there may be mentioned phenylene groups (o-, m- and p=), various naphtha- jenediyl groups, and so forth. The "aralkylene group" means a divalent group of an arylalkene as resulting from bonding of the above-mentioned "ary- lene group" to a lower alkylene group containing

1 to 6 carbon atoms and 1s, for example,

SCI id | i when the arylene group is phenylene and the lower alkylene group is methylene.

As the alkali metal atom for forming an alco- holate (phenolate) or thiolate (thiophenolate), there may bé mentioned potussium and sodium, among others.

As said "residue of an acyl group after remo- val of the carbonyl group therefrom", lower alkyl groups, aralkyl groups, halo-substitutéd er unsub- gtizyted. aryl groups and lower alkoxy groups are particularly preferred. As gpecific examples of such groups, there may be mentioned those mentioned hereinbefore.

The "itrogen-containing 5- or 6-membered hete- rocyclic group in which the nitrogen atom is not a tertiary one and which may be condensed with a ben- gene ring" means a group which belongs to the class of the "5- or 6-membered heterocyclic group, which may be condensed with a benzene ring" as represented by Rr’ and Jor R? and contains at least one nitrogen atom and in which at least one nitrogen atom 1s not yet a tertiary one. Examples of such group are thus as follows: 1H-pyrrolyl, 2. or 5 _pyrmolinyl, pyrrolidinyl, imidazolyl, imidazolinyl, imidazoli- dinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, 1H-

JF

1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-tria- golyl, 4H-1,2,4-triazolyl, 1H-1,2,3,4-tetrazolyl, indoyl, benz-imidazolyl, 1i~-indazolyl, 2H-indazolyl, 1,4-dihydropyridyl, tetrahydropyridyl, piperidiwmyl, plperazinyl, 4 _.thiazolidinyl, thiz-olidinyl, 4. oxazolinyl, oxazolidinyl, 4 _isoxazolinyl and isoxa- zokidinyl.

The "halogen atom" represented by ol, p?, Dp’, pt or IE is, for example, an iodine, broaine or ciorine atom, whereas the "organo sulfonyloxy group" is, for example, =an aldylsulfonyloxy group cuch as methanesul fonyloxy or ethnesulfonyloxy, 2a benzenesul- fonyloxy, or an arylsulfonyloxy group such as toluene- (in particular p-toluene~) sul fonyloxy group.

The "cycloalkyl-lower alkyl group " represented : by R23 indicated a group resulting from substitution of one optional hydrogen atom of the above-mentioned "lower alkyl group" by the above-mentioned “cycloal- kyl group". Thus, for instance, when the lower alkyl group is methyl aad the cycloalkyl group is cyclohe- xyl, said group 1s cyclohexylmethyl.

Similarly, the "aryloxy-lower alkyl group " or "arylthin-lower alkyl group" means & group resulting from substitution of one optional hydrogen atom ofthe above-mentioned "lower alkyl group" by the abovedmen- tioned"aryloxy eroup" or "arylthio group” ,respective- ly. Thus, for instance, when the lower alkyl group is propyl and the aryloxy or arylthio group is phenoxy

2A (or phenyltiio), the group in question is phenoxy- (or phebylthio-)propyl.

The "divalent 5- or 6-membered heterocyclic group which may be condensed with a bensene ring"as repre- sented by AT and/or AB corresponds to the "S5- or 6- membered heterocyclic group, which may be condensed with a benzene ring" as represented by R and/or RZ,

Thus , more specifically, for the pyridine ring, there may be mentioned various pyridinediyl zroups, namely pyridine-2, 3-diyl, pyridine-2, 4-divl, pyridine-z, 5-diyl, pyridine-2,6-diyl, pyridine-3,4-diyl and py- ridine-3, 5-diyl, repectively represented by? 2 A —— Zs A ar

GLb hy al ome iy

The other groups are as glready mentioned in the above formula (I). :

The production processes .are now described in m more detail. process 1

Phe compourds (I) of the invention can be pro- duced by reacting = heterocyclio carboxylic acid of gener: 1 formula (11), which may have a protective group, or a reactive derivative thereof with an &mine of general formula (111), whic h may have a protecti- ve group, if necessary followed by deprotecting (re- moving the protective group or groups). \ As the recative derivative of compound (II), there

JANY may be mentioned ncid halides such as acid chloride and acid bromide; acid azide; active esters with N- hydroxy-ovensotrlazole, N-hydroxysuccinimide, etc.; symmetric acid anhydride; and acid anhydrides with alkylcarbonlc acids, p-toluenesulfonic acid, etc. when the compound (II) is used in the free car- boxyllic acid foom, it is advantageous to carry out the reaction in the presence of a condesing agent such a8 dicyclohexylecarbodifmide or 1,1'-carbonyldiimida- sole.

The re-ction conditions may vary to some extent depending on a starting compound, particularly on the kind of resctive derivative of compound (II).

Generally, aowever, 1t is adventageous to carry out : 15 the reaction in an or_unic solvent inert to the reac- tion, such as pyridine, tetrahydrofuran, dioxane, ethey,

N,N-dimethylformamide, benzene, toluene, xylene, me- thylene chloride, dichloroethane, chlorofewm, ethyl . apcetate or acetonitrile, using the starting compounds (II) and (III) in equimolar amounts or using one of them in excess.

According to the kind of reactive derivative ,or when the starting(IIl) is used in a salt form, it is in some imstances advantageous to carry out the reac- tion in the presence of a bate, for eiample an orga- nie base such us trimethylamine, triethylemine, py- ridine, picoline, lutidine, dimethylaniline or N- mehylmorpholine, or an inorganic base such as pota- saium carbonate, sodiom hydrogen carbonate, sodium

2FI2Y hydroxide or potassium hydeoxide. It is also possible to promote the reaction by using the starting compound (TTT) in excess. Pyridine can serve also as a solvent.

The reaction temperature may very, hence chould . 5 suitably be selected, depending on the kindof said re- active derivative.

It ig favorable to the re:ction that a mercapto group, a reactive amino group, a carboxyl group and a hydroxy (roup be absentl It is possible, howecer, to obtain desired compounds having such groups by means of protective group introduction prior to reac- tion and deprotection after reaction.

The method of deprotection may vary depending qn : the protective group .

For instance, when subtituted or unsubstituted benzyloxycarbonyl is used as an amino-protecting group the deprotection is preferably carried out in the man- nerof c-talytic reduction «nd: in certain instances 4n the manner of acid tre:tment with hydeobromic acid/ acetic acid, hydfobromic acid/trifluoroacetic acid, hydrofluoric acld, etc. Other urethane-forming protec= . tive groups, €.f. tert-butoxycerbonyl, can advanta- geously be removed by acid tre-tment using hydrobre- mic acid/acetic acid, trifluoroacetic acid, hydrochlo- ric acid, hydrochloric acid/acetic acid, hydrochloric pcid/dioxane, etc.

When methyl or ethyl group 1s used as a carbdxy- protecting group, deprotection can easily be effected

AFL” by saponification. Benzyl and various subetituseéd benzyl groups as carboxy-protecting groups can be eliminated with ease by catalytic reduction or saponif ication. Carboxy-protecting tert-butyl } 5 group can easily be removed by the same acld treat- “ment as mentioned above, and trimethylsilyl group by contact with water.

Mercapto- or hydroxy-protecting groups cen be removed in most cases by treatment with godium 1i- quid:ammonia or with hydrofluoric acid. In some ] cases (e.g. o-benszyl, o-benzyloxycarbonyl, s-p- nitrobenzyl), they can be removed also by applying : catalytic reduction. when they are acyl groups, they can be eliminated by treatment with an acid or alkali. :

The deprotection treatments mentioned above can be performed in the conventional manner.

Those compounds of general formula (Ia) in ” 20 which vy! is an imino group can be produced also by reacting an ox1zolidinedione ring-condensed heterocyclic compound of general formula (IV) with a compound (III).

The compound (IV) is a compound in which ’ the C-terminus of compound (II) is in an activated form and at the same time the anino group of com- pound (II) is in a protected form. Hence, the reacé tion also fall under the category of amidation.

In respect to reaction conditions, protective groups and methods of deprotection, this process is substantially the same as in Process 1.

Frocess 3 } 5 The compounds of the invention include those . amide compounds in which IE is an amino group sub- stituted by a hydrocarbon group having a carbamoyl, mono- or di-lower alkylaminocarbonyl group. Such compounds, which are represented by general formula (1b), can be produced by reacting a side chain car- boxylic acld of general formula (V) or a reactive derivative thereof with an amine of general formula (v1), if necessary followed by deprotecting. : In respect of reaction conditions and so forth, this process is substantially the same as in Process

Te

Process 4

The compound of the invention which have the oo general formula (Ic) can be produced by reacting a corresponding cyclic secondary amine (VII) with a carboxylic acid of general formula (VIII) or a re- active derivative thereof, if necessary followed by deprotecting.

This N-acylation reaction can be carried..out in the same manner as in Process 1.

Process 5

Those compounds of the invention which are represented by the general formula (Id) can be

99H) produced by reacting a corresponding heterocyclic pecondary amine (IX) with a carboxylic acid of ge- "- neral formula (X) or a reactive derivative thercof, if necessary followed by deprotecting. y 5 The reaction conditions and the like are substantially the same as in Process 1.

Processub

The compound: of the invention include those compounds (le) in which gr! (or i! and K each) 1s a heterocyclic group comtainigg a cyclic secondary _. amine-forming nitrogen atom with an acyl group bon- ded to the nitrogen atom. They can be produced by reacting a compound (XI) with a compound (XII) or a . resctive derivative thereof in the same manner as in : 15 Process 1.

Process 7 ‘the compounds of .the invention include ether or thioether compounds. Such- compounds can be pro- duced by applying a conventional method of etheri- fication or thioetherification.

Among the conventional methode, the moet ge- neral method which comprises reacting an alcohod or mercaptun or an alkali metal derivative thereof with a halide or sulfonate can se uded — advaen- tageously. thus, the ether or thioether compounds of ge- neral formula (If) can be produced by reacting a hydroxy or mercapto compound of general formula

(XIV) or an alkali metal derivative thereof with a halide or sultonate compound of general formula (XV) or reacting a halide or sulfonate compound of general formula (XIV) with a hydroxy or mercapto compound of general formula (XV) or an alkall me- tal derivative thereof.

The reaction ig carried out in an organic sol- vent such as N,N-dimethylformamide, dimethyl sul- foxide, acetone, methyl eluyl ketone (2-butanone), me thanol, ethanol, ethylene .chloride, chloroform, : ether, tetra-hydrofuran or dioxane, or water, or in a mixed solvent composed of water and such an orga- : nic solvent, ueing the compounds (X1V) and (XV) in substantially equimolar amounts or using either of them iu slight excess. ¥hen the starting hydroxy or mercapto compound (XIV) ox (AV) is nét in the alkall me tal-substituted form, the reaction is carried out in the presence ‘of a base, preferred exaaples of which are sodium hydroxide, potassium hydroxide, sodium hydride, podium carbonate, potassium carbonate and Triton B.

Although the reaction temperature is not criti- cal, the reaction ips usually carried out at room temperature or with heating.

When the starting compound (AIV) contains an additional free or alkali me tal-substituted mercap- togroup, thioetherification generally takes place simultaneously on the group.

AFH

According to the kind of substituent, it is preferable to carry out the reaction after intro- duction of a protective group so that the expected side reaction can be inhibited. In that case, post- reaction deprotection can bc elfected by treating in the same manner as described In relation to

Process 1.

Irocess 8

The ether or tniocether compounds of general formula (Ig) can be produced by rescting a compound (XV1) with a compound (XVII). Phe reaction condi- tions and the like are the same as in Process Te

Process 9

The ether or thioether compounds ol general formula (Ih), too, can be produced by reacting and treating in the same manner as in Process 7 with a compound (AV11I) and a compound (XIX) as the stur- ting compounds. .

Process 10

Among the compounds of the invention, those ’ compounds (Ii) in which x! is an oxygen or sulfur atom can be prodiced by applying a cyclization or ring closure reaction using a kotone (or aldehyde) of general formula (XX) and a diol, dithiol, hylro- xy-mercaptan, amino~-alcohol or amino-mercaptan con- pound of general formula (¥x1) as the starting com- pounds.

The reactio: is carriea out in a so¥vent such

1? 122 as an alcohol (e.g. methanol, ethanol, isopropanol) or an aqueous alcohol and generally at room tempe- rature using the compounds (XX) and (XXI) in almost enruimolar amounts or using either of them in slight

B 5 excess, It is also possible to conduct the reaction . while reuoving by-product water as an azeotrope with such a solvent as benzene or toluene using «a

Dean-:itark trap or the like, It is fovorable to this reaction that additional reactive groups such ar mercapto, amino and carboxyl are absent. Protection of such groups, however, renders the reaction prac- ticable. In that case, deprotection can be effected in the same manner as in Process 1.

Procecs 11

The N-substituted compounds of general formula (Ij) can be produced by reacting a corresponding cyclic secondary amine of general formula (XXII) with a halide or sulfonstc of general formule (XXIII), if neccessary followed by deprotecting. - 20 Yhen the starting compound (XXIII) is a ha- lide, the reaction is advantageously carried out in a solvent such as mentioned above for Procens 7, at room temperature or with heating or reflu- xing, using the compounds (XXII) and (XXIII) in approximately equimolar amounts or using either of them in slipht ercess.

In some instancas, the addition of a secon- dary or tertiary base such as pyridine, plcoline, “AB ~

27 12

N,N-dithethylaniline, N-methylmorpholine, trimethy- lamine, triethylamine or dimethylamine or of an in- organic base such ue potassium carbonate, sodium carbonate, sodium hydrogen carbonate, sodium hy- , 5 droxide or potassium hydroxide can advantageously cause the reaction to proceed smoothly. 4hen the starting compound (XXIII) is a com- pound substituted Ly an organo sulfonyloxy group, the reaction is advantageously carried out, 11 a solvent such os mentlonsd nbove in relation, to

Process 7, with cooling or at room temperature, ’ \ neing the compounds (XXII) and (XXIII) in a ppp wimately equimolar amounts or ueing elther of then - in slight excess. the resction period should be 15. selected in due consideration of various reach . tion conditions. ‘he absence of such groups ag nercapto, ke- active carboxyl and reactive hydroxy group 4 fa- vorable to this reaction, too. However, protdotive group intrcduction prior to the reaction makes Mt i possitle to obtained desired compounds. Wher thaye is additéonally a reuctive amino group, the aus ind group may also be subject to simultaneous fi-aliy lation. In that case, it is possible to obtain det 2> sired compounds when an easily eliainable prosec- i - tive group is introduced prior to lhe reaction end is removed after reaction. / EB heprotection can be effected as described

Co ] AN ~ 49 = 2

BAD ORIGINAL PN above relative to Irocess 1.

Process 12

Those compounds of the Invention in which n? i~ » diamine type cubstituent conbe produced by } 3 applying the metiind couprising reacting anes amine of renval formula (XXIV) with a halide or sulfonate of eneral formuls (AsV) or reacting a halide or gulfonute of general fommula (XX1V) with an amino (XxV). shen symnetrically disubstituted wwino compounds oo are produced, one of the compounds (XXIV) and (XxV) is used in an amount of #bout 2 oles per mole of the other,as the case may be. Prelersbly, the com- pound (XXIV) is nn wine znd the compound (XxV) {ig a halide or sulfonate, ond the halide or sulfo- ; nate compound (2XV) is ued in sn amount of about 2 moles ver mole ot the amine compound {(xXIV). #%hen the derived aeomponunds are monosubstitnted amines or " when disubstituted amines arc to be produced #sing monosubstituted amines us st.rting materials, both the reactants are used in approximately equimolar . amounts. Other resction conditions, such as shbvent, temper;tare, additisn o1 base and deprotection con- ditions, are subrtantially the name ae in Process 11.

In producing monosubstituted aumives an the doe- sired compounds, it is desir: ble to inhiblé tertiary amine formation so that the desired products con he produced in gond ylelds. For that purvose, the

BAL Liisa = Z - 50 - i v7 22 amino group of pd or pn? should preferably be cone verted in advance to a secondary amine form by in- troducing a protective group £or preventing ter- tiary amine formation, such as toluenesulfonyloxy, . 5 sulfonyloxy, acetyl, phenacylsulfonyl,= trifluoro- . methane sulfonyl or bisbenzenesulfonyl.

When primary amines are to be produced by using a halide or sulfonate compound (XXIV) in which pt is a halogen atom or an organo sulfonyloxy group as

Co 10 one starting material, the compound (XXV) may be “er an ammonia. It is advuaantageous, however, tb apply , the method comprising carrying out the reaction using the potassium salt of phthalimide and there- after rvmoving the protective group.

Process 13

Those compounds of the invention which have the genral formuls (I}) can be produced by reacting a corresponding cyclic secondary amine (XXVII) with a compound (XXVIII). The reactlon conditions and so forth are approximately the same as in Process 11.

Process 14

The compounds (im) can be derived from the starting compounds (XXIX) and (XXX) by treating in the same manner as in Process 11.

Process_15

Those compounds of the invention which have the formula (In) and have an amino group, or a mono- disubstituted amono group on i! and for R% can be produced by treating the reactants in the same man-

LAI ner as in Process 12.

Process 16

For producing those compounds (Io) of the invam$- ion in which

AZ

3 7 NRT ‘R” is the group -N N-R' forming a S-membered

Naz ring, namely imidazolidine compounds, various methods of synthesizing 1,3-diazoles are applicable, Among them, an advantageous method of producing the com- pounds (Io) comprises subjecting to ring closure or cyclization a corresponding ethylenediamine com- pound (starting compound) of general formula (XXXIV) } in which one of the dtwo ethylenediamine nitrogen atoms is in an amide form, While various carbonyl ; 15 compounds cin be used as ring closure reagents, an aldehyde of gemeral formula (XXXV) is preferred when the intpoduction of a hydrocarbon-derived shb-~

J sti tuent is taken into con:ideration. - The reaction can be effected by heating the compounds (XXXIV) and (XXXV) in ean inert organic solvent (e.g. toluene) with a molecular sieve added.

While the abscence of additi nal reactive groups such as mercapto, amino, carboxyl in the starting compounds is favor.ble to the reaction, a starting compound having such a protective group can be submitted to the reaction without difficulty when sald group is protected beforehand, as the case may be. In th:t case, deprotection can be carried

27 127 out in the same manner as in Process 1.

PricEus 17

Among the compounds of the invention, there are various compounds whtéh can be obtained by applying a reductive means (e.g. reduction of C=C to ¢-C, C=C to C=C or C-C, NO, to NH,, S-8 to SH).

In the process given above by way of example, the basic saturated heterocycle skeletons of the compounds according to the invention are dormed by reduction of the corresponding unsaturated or in- completely hydrogenated heterocycles.

The reduction is advantageously carried out catalytically in the presence of a reduction cata- lyst such as platinum black, platinum oxide, pal- ladium-on-carbon or Raney nickel.

Other production Processes

In the fore;oing, detailed mention hae been made of amidation, ekkerifidation or thioetherifi- . ‘ cation, cyclimtion and N-alkylation reactions, a- mong others. H_ wever, the compounds of the inven- tion contain various functional groups and therefdre . can be produced by applying various methods selected according to the characteristics of such groups.

For instance, the compounds (I) of the inven- tion which has a free carboxyl group as & pubeti-~ tuent can be produced from a corresponding ester by eliminating the ester residue by a conventional method. Conversely, those compounds which have a lower alkoxycarbonyl group, an esterified carboxyl

LF) group, as a substithent cah be produced by reacting a corresponding carboxylic acid or a reactive de- rivative thereof with a lower alcohol or a reactive derivative thereof such as a lower alkyl halide in : the conventional manner for ester formation. '5 : The thus-produced compounds (1) of the inven-~ : tion are isolated in the free form or in the form of salts thereof and purified. The salts can be pro- duced by subjecting $he free-form compounds to a - conventional salt formation reaction. . 10 Isolation and purification can be performed by applying ordinary procedures in chemistry, such as extraction, concentration, crystallization, fil- tration, recrystallizationand various forms of chromatography.

A8 already mentioned hereinbeiore, the compounds : of the invention may occur as optical isomers xuch as r-cemic modifications, optically active subtances and diastereomers, geometric isomers, namely cis and trins forms, and tautomeric isomers, namely keto and enol forms, either singly or in the form of a mixtute. ilacemic compounds cun be led to stereo- chemically pure isomers by using appropriate. start- ing compounds or by using a general method of opté- cal resolution (e.g. the method which comprises con- version to diastereomers salts with an optically active acid in general use (e.g. tartaric acid)).

Separation of diastereomer mixtures cun be realized in the conventional manner, for example by fraction-

oo 251 al crystallization or chromatogr.phy. Geometric isomers can be separated from each other by uth- lizing a difference in physicochemical property therebetween.

The compounds (I) and salts thereof accord- ing $o the invention have PAF-antagonizing acti- vity and are useful in th. treatment and prevent- ion of various diseases bgused by PAF. In parti- cular, they can be used as antiastnmatics, anti- inflammatory agents, antiulcer agents, shock symptom alleviating agents, therapeutic agents for {echemlic henrt and brain diseases, liver diseases " thrombosis anu pephritis, rejection inhibitors for use in organ transplantation, etc. “ some of the compounds of the invention ahave vapodilating activity and such compounds are useful v as vasodilators us wells.

The compounds ot this invention shown by the . general formula (I) or the salts thereof can be orally or parenterally administered as they are or as medical compositions composed ofl thes compounds and pharmaceutically nermissible ca riers or ex- cipients (e.g., tablets, injections, inhalants, suppositories, etc.). The dose depnde upon the patients, administration routes, symptoms, etc., but is usually 0.1 to 500 mg, preterably 1 to 200 mg per adult per Jay and is orally or paren- terally administered 2 or 3 times per day.

The following examples are further illuastra- tive of the present invention.

The above-mentioned starting compounds con- tain novel compounds and their production are des- ‘ 5 ceribed in the reference examples.

In the following, N¥R indicates a nuclear mag- . netic resonance spectrum with TMS as an integn:.i standird, HS mass spectrum, LAH lithium aluminum hydride, HOBT 1-hyiroxybenzotriazole, DCC dicyclo- hexylearbodiiuide, THF tetrahydrofuran, and DMF N,N- dimethyl formamide.

REFERLNCE EXAMPLE { <0 Na

SL + (CHz)3C CO 0 C) C(Ciig), . So —_— - I N . “COOH

TN voce (CH 3 } ; Di-ter-butyl diearbonate (2.4 g) and 10 ml of 1 N aqueous sodium hydroxide were added to a mix- ture of 2.1 g of 2-(3-pyridyl)thiazolidine-4~-car- - boxylic acid (preprred from L-cysteine and pyri- dine=-3~carboldehyde), 20 ml of water and 40 ml of dioxane at a temperature not higher than 4 C, and the mixture was stirred at room temperature for 30 minutes. Thereaction mixture was concentrated under reduced pressure, 30 ml of water was added, the pH was adjusted to 2 to 3 by addition of 0.5 M aqueous

: tL? 27123 éitric acid, and the mixdmere was extracted with ethyl acetate. The extract was washed with water, dried over anhydrous podium sulfate and concentrated under reduced preasare, and the residue was re- crystaliized from ethyl acetate to (ive 1 g of

N-tert-butoxycarbonyl-2-(3-pyridyl)-thiazolidine- 4-carboxylic acid. Melting point 167 - 169°C.

REFERENCE EXAMPLE 2

CH, OH oe Ha N~ Ln - eH )

LC | CN La - CLOTH

EY NS

Pyridine-4-carbaldehyde (1.07 g) and 1.21 g of L-cysteine were in 60% ethanol at a refluxing temperature for 4 hours. activated charcoal (100 mg) was added to the reaction mixture while it was warm. The mixture was filtered. After cooling, the resultant crystalline precipitate was collec- ted by filtration and washed with ethanol to give 1.2 g of 2-(4-pyridyl)-thiazolidine-4-carboxylic . acid. Melting point 171-173°C.

NMR (DMSO-dg) : 3.0-3.5 (2H), 3.9~4.2 (1H), 5.56 and 5.7¢ (8s, respectively 1H), 7.4— 17.6 (2H), 8.5= 8.6 (2H)

REFERENCE EXAMPLE 3

CH, =H and oy — = ~ gy”

Quinoline-3-carbaldehyde (1.57 g& ) and 1.21 ¢g of L-cysteine were dissolved in 50 ml of 50% ethanol, and the solution was stirred at room temperature for 1 hour. The resultant crystalline preclcipitate was . 5 collected by suction.filtration, washed with 50% . ethanol and dired to give 1.95 g of 2-(3-quinolyl) thiazolidine-4-carboxylic acid. Melting point 173- 175°C (decomposition).

REFERENCE EXAMPLE 4 0m - Fa

J md oH + w] © ¢ — “3 tn hn solution of 1.20 g of p-chloromethyl-(4-phe- nylbutoxy)benzene and 1.15 g of potassium phthali- mide in 20 ml of N, N-dimethylformamide was stirred at 100°C for 3 hours. The reaction mixture was di- _ luted with ehtyl acetate, and the dilution was washed with three portions of water and then with saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate. The solvent was dis- tilled off under reduced pressure, and the residual golid was recrystallized from ethyl acetate to give 1.85 g of N- p-(4-phenylbutoxy)-benzyl phthalimide.

Melting point 106-107.5°C. (2) oy Menge Ny

_— So ————— ee eee . — #17

A solution of 920 mg of N- p-4-phenylbutoxy)- benzyl phthalimide obtained in (1) and 200 mg of hydrazine hydrate in 10 ml of ethanol was refluxed for 3 hours. After cooling, the solid precipitate was filtered off, and the filtrate was concentra- ted. Chloroform was added to the residue, and the insoluble matter was filtered off, The filtrate was concentrated to give 190 mg of p-(4- prenylbuto- xy )ben..zylamine.

NMR (CDC13) © 63 1.6-1.9 (4H), 2.5~2.8 (2H), 3.75 (2H, br), 3.84.0 (2H), 6.7-6.9 (24), 7.1-T.3 (7H) ’

REFERENCE EXAMPLE 5 we 5) LAH

Cl), AN Cg,

A solution of 1.25 g of sodium szide in 2.5 ml of water was added to a solution of 900 mg of p-chle- romethyl-(heptyloxy)benzene in 25 ml of NyN-dimethyl- - formamide, and the mixture wes stirred at 100°C far 6 hours. After cooling, the reaction mixture was diluted with water, and the product was extracted with ether. The ether layer was washed in sequence with water and saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. A solu- tion of the thus-obtained residual oil in 10 ml of tetrahydrofuran was added dropwise at 0°C over 5 minutes to a suspension of 200 mg of lithium alu- } 5 minum hydridein 15 ml of tetrahydrofuran. The re- sultant mixture was stirred at the sameltempera- ture for 1 hour and then at room temperatume for 1 hour. Then, sodium sulfate decahydrate ded to decompose the excess lithium aluminum hydride.

Phe insolubde matter was filtered off, and the filtrate was concentrated under reduced pressure to give 860 mg of p-heptyloxybenzylamine.

MS: m/z 221 (M')

NMR (CLC15) ¢ 15 §: 0.8-1.0 (3H), 1.2-1.5 (10H), 1.6-1.9 (21), 3.80 (2H, 8), 3.94 (2H, t), 6.87 (2H, 4), 7.22 (2H, 4d)

REFERENCE EXAMPLE 6 (1) ha Cre

A A

Cee Cd 1 ~~ 0-H a Nee

A solution of 380 mg of m~hydroxybenezaldehyde, 600 mg of 1-bormo-4-phenylbutane and 580 mg of po- tasgiun carbonate in 3 ml of N,N-dimethylformamide was stirred overnight at room temperature. After dilution with ekhyl acetate, the reaction mixture was washed with water, 1 N sodium hydroxide I ~ oo 17122 water and saturated aqueous solution of sodium chloride, in that order, and then dried over an- hydrous magnesium sulfate, ‘the ethyl acetate was concentrated under reduced pressure to give 660 mg of m~(4-phenylbutoxy)benszaldehyde.

MS: m/z 254 (M*)

NMR (CDC14) §: 1.6-1.9 (4H), 2.6-2.8 (21), 4.06 (2H, t), 7.2 7.4 (9H), 9.96 (1H, 8) (2) (HH

J _ — 5 Cl,

Sodium borohydride (200 mg) was added to a so- lution of 660 mg of m-(4-phenylbutoxy) benzaldehyde in 10 ml of methanol, and the mixture was stirred at room temperature for 2 hours. The reaction mix- ture was concentrated under reduced pressure, 5% hydrochloric acid was added to the residue, and the product was extracted with ethyl acetate. The ethyl layer was washed with water, dried over an- hydrous magnesium sullate and concentrated under reduced pressure to give 510 mg of m-(4~phenyl- butoxy )benzyl alcohol.

NMR (CDC14) §: 1.6-1.9 (4H), 2.6-2.8 (2H), 3.9-4.1 (2H), 4.60 (2H, 8), 7.2-7.5 (9H)

HL

(3) nor ~

To Rg

CAH m-(4-Phenylbutoxy)benzyl alcohol (510 mg) was dissolved in 5 ml of benzene, 1.4 g of thionyl chloride was added, and the mixture wae stirred at room temperature for 4 hours. The reaction mix was concentrated under reduced pressure to give 520 mg of m-chloromethyl-(4-phenylbutoxy)bmenzene.

This compound was then treated by the procedure of

Reference Example 4 to gise 470 mg of m-(4-phenylbu- toxy) benzylamine. © MS: m/z 255 (M*) 15 . NMR (CCl) 4: 1.6-1.9 (4H), 2.6~2.8 (2H), 5.6-3.9 (2H), 3.9-4.1 (2H), 6.7-6.9 (3H), 7.2-7.4 (6H)

REFERENCE EXAMPLE 7 ’ J “0 ac 2 EE i ” nn ey HyN “5 8~ (CHy),™

A solution of 320 mg of Z-amino-5-mercapto-1,3, 4-thiadiazole, 430 mg of 1-bromo-4-phenylbutane and 350 mg of potarsium carbonate in 5 md of N,N-Himethy- lformamide was stirred overnight at room temperature.

After dilution with ethyl acetate, the reaction mix-

A717 ture was washed in sequence with water, 1 N sodium hydroxide, warer and saturated aqueous solution of sodium chloride, then dried over anhydrous sodum sul- fate and concentrated under reduced pressure. The residue obtained was recrystallized from ethyl ace- tate to give 300 mg of 2-amino-5-( (4-phenylbutyl)- thio)-1,3,4~thiadlazole. Melting point 111°C.

Elemental analysis (for Cy H,5N35,):

Cc (#) BH (%) N (#5) s(%)

Calculated: 54.31 5.70 15.83 24.16 . Found: 54.29 5.69 15.88 23.00 } REFERENCE EXAMPLE 8

COCH, CH COCH

HO" _BrCHeCHiCH Bry HOY | i

CH3 (CH 2) Oft3 (CHg Jy, ty Cy Gra

A mixture of 5.0 g of 2,4-dihydroxy-3~propyl- acetophenone, 11.1 g of 1,3~dibromobutane, 6.0 g of potassium carbonate and 50 mg of tetra-n-butylammonium bromide in 130 ml of acetone was refluxed overnight. “

After cooling, the insoluble matter was filtered off, and the filtrute was concentrated. The residue was purified by silica gel column chromatogruphy (eluents hexene-ethyl acetote=8:1) to give 2.47 g of 1-(4-(3- bromobutoxy)-2-hydroxy-3-propylphenyl)ethanone. Mel- ting point 53-55°C.

Elemental analysis (for CygHy 4 05Br):

c (%) H (4) Br (%)

Calculated: 54.72 6.43 24.27

Found: 54.98 6.40 23.91 . > rq

J (cn) Br + AN N COOCH CH, £.00, NaOH, a = NN FR { \er), f hm ‘ - A solution of 2.47 g of 1-bromo-4-phenylbutane in 5mo of 2-butanone was added to a mixture of 1.93 g of {-ethoxycarbonylpiper..zine, 1.76 g of potassium carbonate and 15 ml of 2-butanone at room temperature.

After stirring at 80%¢ for 12 hours, the mixture was . cooled and, after addition of water, extracted with ? ethyl acetate. The extract was washed with water and : saturated aqueous solution of sodium chlaride in that order and dried over anhydrous sodium sulfate . The residue obtained after concentration under redueed pressure was purified by silica gel column chromato- graphy (eluent: hexane-ethyl acetate=4:1) to give 1~ethoxyearbonyl-4-(4-phenylbutyl)-piperazine. The op compound obtained was dissolved in 20 ml of ethanol and 20 ml of 10 % aqueous solution of sodium hydro- xide, and the solution was stirred at 100% for 12 hours. After cooling, the reaction mixture was ext- raoted with ethyl acetate, and the extract wus washed withsaturated aqueous solutiog of sodium chloride and

Pe ( dried over anhydrous sodium sulfate. After concentra- tion under reduced pressure, the residue was purified ‘ by silica gel column chromatography (eluent: chlo- roform-methanol-25% aqueous ammonia=100:10:1) to give 1.5 g of 1-(4~phenylbutyl) piperazine as an oil. : NMR (¢DC14) §: 1.34-1.86 (4H,m), 2.20-3.14 (12H,m), 7.04 7.40 (5H, m)

Ms: m/z 217 (mY)

LEFERENCE EAAMPLE 10 3 A {Non NN 1-Ethoxycarbonylpiperazine and 1-bromo-3-phenyl- propane were used as the starting materials and trea- ted in the same manner as in Reference Example 9 to give 1-(3-phenylpropyl)piperazine.

NMR (CCL) : &§: 1.63~1.97 (2H, m), 2.44-3.,00 (12H, m), 7.0 (5H, m)

MS: m/z 203 (M1)

REFERENCE BXAMFLE 11

Na. OH ni Nn + (CH ;),CC00C0C(CH 3); -——————> 7 N(en ,), Br CR ;COOH (CH 3 ;CUCONH { Non my i K, COy and 0 (cH),

A solution of 6.43 g of di-tert-butyl dicarbo- nate in 5 ml of TH was ad ed to a mixture of 3,06 g of p-aminophenol and 30 ml of 10" aqueous solution of sodium hydroxide at room temperature. The mixture wae stirred at 50°C for 12 hours, then cobled and extracted with ethyl ecetate. The extract wi deied . 10 over anhydrous sodium sulfate and concentrated under reduced pressure, The residue obtained was purified by silica gel column chromatography (eluent:hexane- ethyl acetnte=4:1) to give 4.35 g of p-(tert~butoxy=- carbonylamino)phenol. A mixture of 300 mg of the thus- 15 obtained compound, 210 mg of potassium carbon=tedand ml of 2-butancne wze etirred at room temperature for 30 minates, then a solution of 310 mg of 1-bro- mo-4 -phebylbutine in 5 ml of 2+butanone was added, and the mixture wos ctirred at 80°C for 12 hours.

After cooling, w. ter was added to the reaction mix- ture , and the or anic matter was extracted with ethyl acatate. The extract was washedin sequence with wa-~ ter and satursted aqueous solution of sodium chlordde, dried over anhydrous sodium sulfate and concontrated under reduced pressure. The residue was purified by gilica gel column chromatography (eluent: hexane-ethyl aceta e=10:1) to give 1-( ter t -butoxyc- arbonylamino ) - 4 - ( 4-phegylbutoxy)

1 13) berzene (0.2 g). Tritluorocacetic acid (5 ml) was added to the compound obtained with ice coo- ling, and the mixture was stirred with ice for 30 minutes. The reaction mixture wes concentra- } 5 ted under reduced pressure, washed with saturated gqueons solution ol sodium hydrogen carbonate and then witn saturated aqueous solution of sodium chlorile, dried over anhydrous sodlus sulfate, and concentrated under reduced pressure to (ive 0.13 g of p- (4-phenylbutoxy)aniline.

NAR (C15) §: 1.66-1.90 (4H, m), 2.67 (2H, t), 3.90 (zH, t), 6.50=6.82 (4H, m), T.13~-7.33 (50, m)

MS: m/z 241 (NM)

REFERENCE EXAMFILE 12 { N- (cHz)g= OH eos { (cHa)g — Br

A mixture of 20 g of 5-phenylpentan-1=-o01 and ’ 30 ml of 47% hydrobromic acid was refluxed for 6 hours. The reaction mixture was cooled and extrac- ted with n-hexane. The extract was washed with water, dtied over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel coluwm chromatography (eluent: n-hexane-ethyl acetate=100:1) to give

16.87 g¢ of 1-bromo-5-phenylpentane.

MR (CDC 4) §1 1.2872.03 (6H, m), 2.63 (2H, t); 3.42 (24, t), 7.0877.40 (5H, m)

MS: m/z 228 (M'e1)

REFERENCE EXAMPLE 13 (1) [cmon ——————y (>-emosozen

Methanesulfonyl chloride (1.52 g) was added dropwise to a solution of 1.11 g of cyclopentane- methanol and 1.50 g of triehtylamine in 30 ml of dichloromethane with eooling on an ice bath over 5 minutes. "he reaction mixture was stttred at room temperature for 30 minutes and then washed in sequence with three portions of watdr and one portion of saturated aqueous solution of sodium chloride. The organic layer was dried over an- hydrous magnesium sulfate and concentrated under reduced pressure to give 2.06 g of cyclopentane- methyl me thanesulfonate.

NMR (CDCI) §: 1.11.9 (8d), 2.172.5 (1H, m), 2.02 (3H, 8), 4.15 (24, 4, J=THz),

MS: m/z 176 (MY) (2) | § > ved Noon

IPH

A mixture of 0.80 g of cyclopentansmetiiv] ivie- thonesnl fonate obtainod in (1), 0.60 g of p~hyiro- xybenuildehyde and 0,93 g of anhydrous potassium carbonate in 6 hl of N,N-dimethylfornamide was oo : 5 atirred overnight at 70°C. The reactinn mixture was diluted with ethyl ncetate and washed with ‘ water. The organic layer was washed with 1 N godiun hydroxide, water and saturated aquenus _~ solution of sodium chloride in that order, then dried over anhydrous m:gnesjun sulfate, and con- centrated uncer reduced pressure to give 460 mg of p-cyclepentanemethoxybensaldehyde.

NR (2nC15) §: 1.2-2.0 (8H), 2.40 (1H, quintet, J=THz), 3.92 (24, 4, J=THz), 6.99 (2H, 4, J=10

Az), 7.86 (2H, 4, J=10Hz), 9.88 (1H, 8)

MS m/z 204 (M7)

REFERENCE EXAMPLE 14 - 20 one Non ——s ocd N-o-ch oor <gy?

A mixture of 1.00 g of p-hydroxybenzelde- hyde, 1.46 g of isoumyl and 1.80 g of potassium carbonate in 15 ml of NW,N-dimethylformamide was stirred at room tenpevature for 2 days. Water was added to the reaction mixture, and the pro- duct was extracted with ethyl acetate.

—_— a _— —_ _—_—_————— 13127

The ethyl acetate l.yer was washedin sequence with 1 N sodium hydroxide, water and saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated undrr reduced nL 5 pressure to give 1.34 g of p-(3-methylbutoxy)benza- ldehyde.

NMR (ChCls) §1 0.97 (6H, 4d, J=7Hz), 1.6-1.9 (31), 4.08 (28, t, J=THz), 6.99 (°H, d, J=8lx), 7.87 («H, 4, J=8Hz), 9.90 (1H, a)

MG: m/z 192 (MY)

BE RENGE_BIANPILS 15 20 17

Phe following compounis were obteainedin the same } manner as in Reference Lxumple 14.

Ref. Fx. 15 Physicochemical properties

NMR (opel) st 2.18 (2H, m), 2. 83 . (211, vr t), 4.03 (211, ono{ Yo ony) 4, J=THg), 6.87 (2H, p=(3-Chehylpropoxy )benz= da, J=9Hz), 7.22 (5H, aldehyde br), 7.82 (24, a4,

J=9Hz), 9.88 (1H, s)

Ms: m/z 240 (M7)

Ref. Bx. 16 Phynicochemical properties

NMR (CD01) 8: 2.30 (21, quintet, onc! “o- (ciy)04 J=6Hz), 4.19 (2H, t,

J=6Hz), 4.39 (2H, t,

2H 127 p-(3-Phenoxyprovoxy )benz- J=6Hz), 6.7-7.3 (7H), aldehyde 7.87 (2H, d, J=9Hz), 9.93 (1H, 8)

MS: m/z 256 (M') - 5

Ref. Ex. 17 Physicochemical properties

NMR (CuCl) 3 8 1.6-2.0 (4H) 2.6-2.8 oncd_\-o- (city), 7

OCH - (28), 3.90 (3H, 8), 3 4.10 (2H, br, t), 6.93 3-Methoxy-4-(phenyl- (2H, 4, J=9Hz2), T.1-7.5 butoxy)benzaldehyde v) 4 (78), 9.85 (1H, s)

M3: m/z 284 (MT)

REFERENCE EXAMPLE 18 — CH. NH, ocoCH, one! No-one 0 AS

Ne CH, Na BH,OR 3 aN ] CH

H,oN-CHa¢ - 0- Ci + CH

C3 ;

Sodium cyanoborohydride (330 mg) was added to a solution of 770mg of p-isopropoxybenzaldehyde and 4.0 g@ of ammonium acetated in 20 wl of methanol, am the mixture was stirred at room temperature for 40 hofirs. The reaction mixture was adjusted to pH 2 or less by addition of ancentrated hydrochloric acid, and then concentrated. The residue wae dissolved in water and the solution was washedwith ethyl acetate. -T1-

heey

The aqueous layer was adjusted to pH 11 or more by ad. i1tion of solid peotoegeium hydrovide, and the vro- duct wie extracted with ethyl acetated The ethyl ace- tated leyer wos worhed with water and saturated aque- ous solution of sodium chloride in thot order, dried over anhydrous sodium culfate and concentrated under reduced pressure to give 110 mc of p-isopropoxyben-

Zz yleamine.

NMR (Chel 4) $s 1.28 (61, 4d, J=tHz), 1.50 ( 2H, ex~hnnge with oo 0,0), 3.71 (2H, s), 4.46 (1H,hep.,J=hlz),6.75 (20,4, J=tNz), 7.14 (2H,d, J=0Hz)

MS: m/z 165 (M7) 3 REFS FOE BXAVULES 19 10 21

The following compounds were obtainedin the same manner as in Reference Lrample 18.

Ref Bx, 19 Fhysicochemical properties

MK (¢vel,) 0 mn-on]_Jo-cien< §: 1.02 (6H, 4, J=Tliz), 3 1.5 (2H, exchenge with

D,0),2.06, (1H), 3.70 p-(2-¥ethylpropoxy)- (¢H, 4, Jd=6lz), 3.77 benzylamine (2H, 8), 6.84 (2H, a,

J=9Hz), T.£0 (2H, 4,

J=9Hz) vse m/z 179 (M7)

Ref. ix. £0 Physicochemical properties

Nik (ubely) -72- r LA “3

BAD ORIGINAL oy

Routt

VF [2

Vv : 0.97 (6H, a, J=6Hz),

Reon) o-cryonon en 73 1.5 (2H,excliange with vd | CH 0,0), 1.3.2.1 (5H),3.78

Wh p=(#~Ho bhyLpén ty Loxy )= (en, =), 3.95 (2H, *, 51 benzyl unine Juin), 6.86 (2M, 4 } > lz), 6.86 (24, 4,

J=9Hz), 7.23 (2H, d,

J=allz)

MSs m/z cul (1h)

Ref. ix. 21 Thg¢s2cochenical properties

Hie (GHC) = _ §: 1.2-1.9 (10H), 1.38 fy Hy o-ciy | (11, m), 5.80 (2H, =a), %.83 (2H, d, J=THz), p-Cyclopentylme thoxy- 6.37 (2u, 4, J=0uUz), benzylamine 7.2% (21, d, J=OHz) . | MG: m/% 205 (M)

REFEREHGHE BXANPLE 22 i Cm 1)N1L, O11 00 one’ S-o-(utty)4 ET tpN-ciy{ 0=(0H,) 5d \

A solutiodn of 750 mg of p-(3-phenylpropoxy)- banzaldehyde and 2.3 g of hydroxylanine hydrochloride in 20 ml of methaiol was adjusted to pH 8 by addi=- tion of 10% sodium hydroxide under coolinge The mix- ture was stirred for 1 hour and , then, the methinol

VFI

«a8 evaporated. Water was added to the residue, and the product was extracted with ethyl acetate. The ethyl acetate layer wus washed with water and satu- rated queous solution of sodium choride, deied over - 5 snhydroua sodium sulfrte and concentrated to give 750 me of p-(3-phenylpropoxy)benzaldehyde oxime. A solution of this compound in 10 ml of tetrahydrofu- pan veg od ted dropwise to a surpeneion of Jud my of 1ituium aluminum hydride in 6 ml of tetrahydrofuran

C10 at -30°0. After 20 minutes of stirring at -30°C, the temcer. ture wos raised to room femperature znd stirring » = continued for 2 hours. The excess 1it-

Yium ~luminum hydride was decomposed with sodium gulf te decahydr te, and the reaction mixture was filtered. The filtrate was diluted with ethyl acet- ate ond wasnedwith 10% hydrochunoric acid. The hy- drochnoric acid layer was msde alkaline with solid potassium hydroxide, and the product was extracted with ethyl scetate. The ethyl acetate layer was £0 washed in semence with water nnd saturated aqueous solution of sodium chbride, dried over anhydrous sodiun sulfate and cancentrated under reduced pres- sure to gve 260 mg of p-(3-phenylpropoxy)benzylamine. war (£9C1,) §: 1.6 (2H, exchange with D0), 2.00-2.35 (2H,m), 2,70-3.00 (2H, m), 3.81 (2H, 8), 3.97 (2H, t,

J=6Hz), 6.87 (28, 4, J=9Hz), 7.24 (2H, 4,

J=9Hz), 7.25 (5H, 8)

oo 27

MS: m.z 241 (MY) nErEhaiCE EXAMPLES 23 TO 27

The following compounds were obtained in the sane manner as in Reference Example 22.

Ref. Bx. 23 Physicochemical Properties

J. _ Nii (CDC 5)

NU eas $1.7, (2H, exchan,e with 0,0), 2.23% (2H, quintet, 2-(3-rhenoxypropoxy)- J=6lz), 3.76 (2H, s), 4. benzylamine 14 (48, t, J=6liz), 6.8 7.4 (9)

MSs m/z 257 (if)

Ref. x. 24 thysicochenical Iroperties

NHR (Cae) a-cigd Neg, : 0.91 (3H, t, J=71z), 1.2 1.7 (4H), 1.6 (21, exchange with 1,0), p=-Butvlbensylanine . 2.60 (21, t, J=THz), 5.82 (2H, 8), 7.1 7.3 (an)

MS: m/z 163 (UM) ef. Bx. 25 Physicochemical Properties

NMR (Cooly) : 1.24 (6H, 4d, J=THz),

CHa

Hpl-0M,=¢ ~CH <i; 1.60 (2H, exchange with 0,0), 2.90 (11, p-Isopropylbenzylanine heptet, J=THz), 3.83 (24, 8), 7.23 (4H, br 5) ~T5=

' : 1F 147

MS: m/z 149 (MI)

Auf. Dx. 26 Physicochemical Properties

NMR $CnCls) sr 2.02.3 (2H), 242 (1H,

H 7 3% a ot \ -{( { \ wen yr . - 5 Re CH, { (a5 exchange with 0,0), 2.4% (54, 8), 2.72.9

N-Me thyl=He=(p=~(3=phenyl- (211), 5.09 d2R, 8), projosy)benzyl)amine 7,96 (20t, t, J=THz), 6.8% (21, d, J=9Hs), 7.0% (2H, d, J=9Hz), 7.24 (51)

Mo: m/w 295 (MY)

Ref. wx. 21 Ihynicochanicnl iroperties

HER (ene) 7 \ 8: 1.5-1.9 (6H), 2.7 (2H, ai 4 No_(o { . aN 0cl 4 3.87 (31, 8), 4.0 (2H, (3-tathexy=-4-(4=-phenyl- om), 6.8-7.0 (3H), butoxy) )benrylanine 707.3 (5H) } 20 wie m/z 289 (M*)

BUF RENCE BXoMPLY E8_ 'H LAH cns-{ No-cit,H, CH <0 LIS = - CH

CH S0C1.

HO-CH, = No-cit, gil, uf $2 eee Bee - ; Z c 1 -— CH 0 NaN -s CH, a c1-ot,=( So-en,em,en < 5 3 — ch, 2

— ; ncn, ~0-CH,, CH, CH <* mm oo 3 1 N-Cil, {o-cu on, < 0 3 - 5 © Tithium alwiinun hydyide (350 mg) wan added pradually to a solution of 1.35 g of p-( 3-methylbutoxy)- benzaldchyd.: in 50 ml of teprahydrofurin at -10°C.

Af- toy sticcing at room temper: ture for 1 honar, the excess iithium aluminan hydride was decomposea with sodium sulfate accahydrate.

The insoluble matlielr Wal filtered off from the mixture, and the filtrate was concentrated to give 1.32 yg of p-(3-nethylbutoxy benzyl alcohol.

Thi- onylchloride (» ¢) was added to a solution oi the com- pound obtained in 2% ml oi benzene, and the mixture was sirred at room temperature tor 2 hours.

The reaction mixture was ecnmecentrated under Leduced pressure to give 1.45 g of p-(3-mna th 1butoxy )bensyl chlorides To a solu- tion of this compound in 50 ml of i ,N~ddmethyltormamide, there was ad.ed a solution of 3.3% g of sodium azide in 14 ml of watorwl th ice cooling.

After overnight stirre ing at room tempers ture, the reaction mixture was dilu- ted with wi ter, snd the prouuct was extructed with et- ; hyl acetute.

The ethyl ccetute Layer wus washed with water and coturated aqueous solution of sodium chlo- ride, dried over snhycrous megnesium sulfate and con- centr ted under reduced pressure to give 1.48 7 of p= ’ (3=metnyltutoxy)benzyl azide.

To a solution of this compoundin 3C ml cf tetrahydrofuran was added 500 mg

I 13127 of lithium @luwinum hydride with ice cooling. The temperature of the reaclion mixture wus allowed to gradually rise to roou temperature, and the miztuve was stirred for 2 hours. The excecs Tithium aluwnian, hiy=- - 5 dride vas decoaposed sith sodium sulfute decuhjyarate. “Phe Insoluble msitter wee filtered oft, and the filtra- te wag concentroeted under reduced preccure oo pive 1.13 ¢ of p=(3-nethylbnboyy )benrylinines

Hil (cued ,) $1 0.95 (OH, d, o=(l'n), 1.5 (I, exchange with 0,0), .6-0,9 (0), Z.u0 (2H, £), %.92 (2H, t,

J=7Hz), 6.67 (=H, d, J=9Hz), 7T.24 (2H, d,J=9Hz)

MS: m/z 19% (MW)

Lil URERCE BALMILE £9 4 1)clC OOCH, CH CY oH

C A T8A/ THF

N ee mmr me) i

GOOCH, CL, 2)RaBli, /H,0 COOCH, CH,

A eolution of 0.67 g of ethyl chloroformate in 2 ml of tetrahydrofuran was added to a =olution of 1.01 rr of ethyl A-corboxypiperidine-l-carboxylate and 0.72 ¢# of triethylamine in 20 ml of tetrahydrofuran at -10 to -5%a, and the mixture was stirrd for 30 minutes.

The r sultant crystalline nreeicpitate was filtered off, the filtrate was adied to nn solution of 0.57 g of sndiunm horohydride in 10 ml of water with ice cool+ ing over 30 minutes, and the mixture was stirred at room 34 “Te aD ORIGINAL ——

27 P? temperature for 30 minutes. ‘he reaction mixture was made acidic with 1 N hydrochio ric acid with ice cooling and then extra ted with ether. The ether layer was washed in sequence with water, saturated - 5 aqueous solution of sodium hydrogen carbonate and subwostel oqueons aolutbion of sodiwg eiloride, then dried over aialosdeons mognesi oan guliate, ana concen- trate) under reduced prergsore. The residue was subjected to silica gel column chromatography. lo= tian with o hewane=ethyl acetate (1:1) v/v) mixture pave 0.609 « of ethyl 4-hydremetlylpiperidine-i-cor- boxylate. nu (Che 5) g: 0.£8-1.42 (1H, br), 1.30 (34, t , J=R.0Hz), 1.42 2.00 (51, m), 2.77 (214, dt, J=12.0, 3.uHz), 2.52 (21, d, J=6.CHz), 4.15 (211, q,

J=T7.0Hz), 4.004.356 (24, m) wis m/z 107 (1h) : / (2)

CE

Heated N

COA Lf \

SURRY (LOCH Hy

A soc'ution ot 1.97 zz of 1inekhyl sultfoxiae in 5 aT of dichioroseth. ns was added to a sotution oln 1.59 1 of oxalyl chloride in 30 m1 of dichlerometuane at a beaperature within the rangge of -50 to =50° C. - 79 - oil

AD ORIGINAL J me

JF

Five minutes layer, a solution of 2.11 g of ethyl 4- hydromethylpip:ridine-1-carboxylate in 10 ml of di- chlowome bthune was added dropwise, and the resultant mixture was stirreu for 15 minutes. Triethylamine - 5 (5.73 g) was added to the reaction mixture, the whole was stirred for 5 minutes and then at room temperature for 15 minutes, Water was added to the reaction mix- ture, ud the resultant alxture was extracted with dichloromethane. The orgunic and the organic layer was washed with ssturated agueous sotution of sodium chilnvide, uricd cover anhydrous macnesium gukfate and concen trated under reduced pressure, The residue w.: subjected to purification by silica gel column chroma bos raphy (35 5). Blution with a hexane-ethyl acetute (3:1) mixture pave 1.13 g of ethyl 4+styrvl- piperidine-t1-carhoxyl-ite.

A (Cio, &: 1.29 (31, t, J=7.0Hz); 1.10-1.95 (4H, m), 2 0=2.55 (1H, m), 2.58=3.05 (2H, m), 4.16 (Z1iy iq, J=(.0hz), 5.88-4.40 (2H, m), 5.46 (1/11, dd, J=12.0, 10.0iz), 6.13 (6/7H, dd,

J=16.0, w.0Hz), 6.42 (1/7i, 4d, J=12.0liz),

Gods (6/7, dy J=10,0Mz), 7.08=7.45 (5li, nm)

M3: w/z 253 (4) (4) a acid ems oq a ~t-7

COOH LH,

BAD ORIGINAL g5i

Niemi

A mixture of U.80 g of ethyl 4-styrylpiperidine- {-cotrboxylste and £C mg of 107% palladium-en-carbon in ethyl acetate (40 ml) was subjected to catalytic reducthén at room temperature until stopoimg of hy- - 5 drogen absorption. The catalyst was filterel off, and the filtrate was concentrated under reduced pres- cure to give 0.80 g ol etayl 4-(2-phenylethyl)piperi- dine~1-crriokylate.

NNR (Chet 4) 8: 1.78 (34, t, J=6.0Hz), 0.72-2.01 (7H, m), 2.507.986 (4H, m), 3.89-4.42 (2H, m), 4.14 (2H, q, J=B.0Hz), 7.02-7.54 (5H, m) we: m/z 261 (0%) (5) _. i cwgerg Y 47 7 Wor AT es

H

A mixture of 0,70 ¢ of ethyl 4-(2-phenylethyl)- piperidine-1-carto¥ukate in 6 ml of AT} hydrobromic : acid was hested under refius at 10° ¢ tor 6 hours.

A amall cwonnt of wot rowan aaded for dissolution of the reeultont crvetols, the solution was gdshad with ether, and the agueous lover was mede alkaline with 20% sodium hydroxide. fter salting out with sodium chloride, the aqueous layer vis extracted with ether,

The oreanic layer was wasned with saturatod solution - Bl = A

BAD ORIGINAL 30 (—

WV of sodium chloride, dried over anhydrous podium gultn'e snd concentrated under ve d ue ed pres- gure to rive 0.40 of 4-(2-phenyletiiyl)piperidine.

NMR (cnet) 8: 0.78-2.06 (8H, m), 2.30-2.80 (4H, m), 2.86 : 3.32 (2H, m), 6.95-7.50 (5H, m)

MSs m/y 199 (MY)

REFENELLE BXAUPLES 30 10 32

The ethyl 1-(4=-forinyl)piperidinecarboxylnte of neference ©xample 29 (2) and pn(Ci,) PB Ph, Br (u=2 to 4) were used and treated in the same manner as in Reference ixample 29 (3) to (5) to give tne fol- lowing compounds:

Ref, 2x. 29 Physicochemical Properties

HMR DCT 5) = 7 8: G.792.05 (10, m),

HN mr); ’ 7 2 o0m2.76 (4b, wm), : coBs=5.24 (21, m), 7.04=7.49 (511, m) 4-(3-Thenylpropyl)- MS: m/z 203 (nh) piperidine

Ref, bx. J1 Ihysicochemical Properties

NME (CDC15) 8: 0.76-1.82 (11H, m), 05 We (Oh JN 1.12 (1, 8),

Lahm 20 1s (AH, m), 2. 04=3.21 (2H, m),

A~(A-Phenylbutyl )- T7.04=T.4% (Bit, 0) piperidine woe m/z 217 (nh)

ethyl 1-homopiperazinecarboxylate.

NAR (CDUTS) 8: 1.28 (3H, t, J=THz), 1.607.399 (3H, mn), 2.75 3,04 (4H, un), 3.30 3.65% (4H, m), 4.15 (21, q,

J="THz)

Csr m/z rie (ut) (2) { N-cwe

Ns thio Oct N- id nT > CH CH, OCON N CH, _

THF : totassium carbonate {0.80 g) was added to 2 so- lution of L.tb g otf ethyl 1-homoplperazinecarboxylate and 0.90 g of btenzylbromlde in 5 ml of tetrahydrofu- ran, and the mixture wos refluxed for 4 hours. There- after, wat r wos asded, and the amizture was extracted with ethyl acatate, and the orgonic layer was washed with satureted aguecus solution of sodium chloride, dried over annydrous sodium suliate and concentrated ander reduced pressure. The residue was subjected to siliea ge) colunm chromatography. Elution with a he- » xane-ethyl acelale (2:1) mixture gave 1.06 g of etnyl 4-benzylhomoplperazine-1-curboxylate.

RMR (UU) : 8: 1.75 3H, t, J=THz), 1.02 2.05 (2H, m), 2.50

Fo (AH, ), %.35275.75 (4, m), 3.61 (2d, 8), dod (24, q, J=THz), 7.29 (5H, 8) -

ME: m/z 60 (ih) - B4 -

YT14Y (3) a

HEE wi p- end) ol 5 fn omisture of 0.80 g ol etayl d-penzylhonopiperu- mine=1-catrboyylate 2nd & nl of 17% hydrobronte acid wns heated ot 100° for 10 hours. After addition of wosmall cunnact of waiter, tas rauc tion mixture wos washed with ethyl acetate. The aqueous layer was nade lu: Line with 304 sodium hydroxide und, after . salting ont with sodivm chierlde, extracted with ethyl acetate. The or:onic Lleyer was woshed with saturated : aqueous so ution of sodiun chloride, dried over unhy- - drous sndiun suliate and concentrated under reduced : 15 pressure to give U.dd> 2 of 1=bengylhomopiperaszine.

NMWK (cnet) 8: 1.60-1,96 (2H, wm), 1.91 (1H, 8), 2.5272.80 (411, "), 2.0073.07 (4H, m), 3.68 (2H, s), 7.12=7.45 (5H, m)

Ms: m/z 190

REFERENCE pXaMPLES 3410 31 .

The following compounds were obtained in the game aanner so jn lelerence mxample 35 (2) and (J) ef, ix. 34 Physicochemical broperiles — NHR (C315) i (ihe) g: 1.00-1.92 (2H, n), 2.05 (1H, 8), 2.53 3.09 (121, nm), - 05 a BAD ORIGINAL =

Lo no AI? 7.05-7.43 (54, m) 1-(2-Thenylethyl) #S: m/z 204 (M') homopiperazine nef, hx. 39 Physicochemical Properticse

NMR (Coes) eel : tom (411, m),

PN — 2.08 (141, 8), 2.12018 (8H, m), 2.78-3.02 (4H, m), 1=(3=-theryLlpropyl) 6.9% 7.45 (5H, m) i horo piperazine “Grown 218 (Mh)

Ref, ux. 5% Physicochemical Jropcrties

NMR (CDC 4)

HN NH en POE Le, Teen), oy FR: 0.96-2.91 (7TH, i), 2.11 (1H, 8), 2.357 2.57 (2H, m), 1~(4-Methylpentyl) 2.57 2.79 (4H, m), homopiperazine 2.80-3.04 (41, m) | MS: m/z 184 (mt)

Ref, Ex, 37 fhysicochemical Properties ..

NMR (ene)

The) : 0.73-1.01 (3H, m),

Nd To 1.06-1.61 (11H, m), 1.63-1.93 (2H, m), 2.3%32-2,80 (6H, m), 1-Hentylhamopinerazine 2.82- 5.08 (44, m)

REFERENCE EXAMPLE 38 }

2H

I edn yy I EE

I crn ~y Mel) ro ee er ee rm me rere 3 ai Me dh 1s

NE

A mixture of 2.02 g of et yl 1-piperazinecnrboxyl- ate, 1.92 g of anhydrous potassium carvonate, 3.08 pu of decyl bronive and 20 mil ol Z-butunone was stirred over- night +b «0 4, After addition of vater, the rewciion mixtire was extracted with ethyl acetate. The ebayl acetile layer was extracted: with 3 N hydrochloric acid.

The extract was maie alikaline witn potassium carbonate and Lhen 2xtracted with ethyl acetute. The extract wan vauphed with sater, dried over auhydrous sodin sul-

Co fate and concenbrated ander reduced pressure. Sthanol (20 a1) and 20 ml 10% aqueous sodium hydroxide were . added bo the residue, amd tie aixture was stlrred over- night at 100 ‘$, The reaction misture was covled and extracted with ethyl aceta.e. The extract wes washed : with apter, dried over smnydrous scdium sulfate ond con= canbi hea aia. roaduced pressure to give G.38 g od 1- deecylpiper aiie ao on odo.

JMR (cnet) 8: 0.731.774 (19H, m), 2.1672.52 (6H, mn), 1.04 2.08 (471, m)

HG as 226 (UT)

The Tollowing cowpounds were obtained in tne same manne, ef in geference bxample 3b. - 87 - N

BAD ORIGINAL

L

: L1H

Ref. Ix. 43 Physicochemical Properties

NMR (cnc) a §t 0.90 (6H, 4),

PN te Tei bod 1.12-1.40 (124, m), 2.16-2.56 (6H, m), 2.60-3.00 (4H, m) 1=-0ctylpiperusnine WSs m/z 170 (4%) hela bx. 44 Iaysicochemical [froperties

ME (Sod, = - FE (Snes)

AN TARR a: 1.0d-2.52 (151, mn), 2.805.060 (41t, wm) 1-Cyclopentylmetiyl- pipor=sine

Rofo xe 45 shysleovhen dual Lrovertion 15 . Tit (01) "

ADA JN &1 1.7273.20 (14H, m), -! b —- . . ~ r 7.677.040 (3H, m),

Sf.uuTe.10 (2H, m) 1-(4=-Oxo0-phienylbutyl)- plpe-coinc Wrom/e 201 (ut) ief. Ix. 40 fhysdcociemicel Iroperties . i I { ut : . i. Lie | uly)

Wee Le $1 1.00200 (41 a), _- so a . cect doo (61, m), co 12 ZU (45h, m), : {= 4e(p~Prosnphenyl)-4- Tete T1eTE (2 a), oxobutylpiperczire fou 2.00 (2H, m) - £9 - pd

NY

BAD ORIGINAL ) 4

Lo.

XY 12>

Ref. Ex. 47 Physicochemical Properties

HMR (1001) an Wd I] “0 76 (411, " , oS ao 2.7675.012 (4H, 1), 5 3.00 (21, 8), 7.227 7.04 (311, in), 1=(?=Cxo-2=pheaylet v1) 7.287 2,14 (21), a) pivernine Sema 204 (ah) def, wx. AY thypsieochentval froperties _ wig fuer)

Hi N(CH), 4 $: ST (12H, m), 7.1077.56 (5H, wm) {=(2=Pharslethy))= ee m/e rey (4) piprenui-ce def, ox, 49 Physicochemical Properties eng (nL)

TRA Ca

HNN (Ca)s $1 1.141.204 (6H, n),

CPT 02 (8H wm), 2.875.002 (4H, 11), 1-(5-hewylpentyl)- 7.04=7.40 (5H, m) piperaziie ase m/z 231 (at) . ref, Fx. 50 thysieoshendcal Properties — va WALK (Cet 5)

HNN (CHa) : 8: 1.072.3 (20, m), ah 2.473.,2 (10H, m), 1-(3-Fhengxynropyl)= 4.00 (21, t), piperazine 6.77.5 (5H, m) - a0 - BAD ORIGINAL fo:

Nm bitiad

REFERENCE BXAMULE 51

JT / \

Sado, ear WH HN ey “ Vd Te

PTT / fa i Lt of Le in ) Sodium borohydride (500 mg) was added to a mixture nf 1.6 g of 2thyl 1-pipsrazinecarboxylate, 1.3 of p- totuzlidchyde and 30 ml of ethanol, and the mixture was 15 stirred overnight at room temperature. The reaction gisture wos concentraved ung or» reoewe pressure, HU ml : of water was added, and the resultant mixture wes ex- tracted with ethyl actuate. The etuyl acetate extract was then extracted with diluted nyorochloric acid. Fhe ; 20 diluted hyarochloric acid extract was washed with «thyl acetate, nade ¢lkaline with sodium hydrogen carbonate » and extrucicu with etuyl acctite. The extract was washed with water, dricd over anhydrous potassiwn car borate and concenlrated unacs pressure to give vet gr of ethyl 4-p~tolylactiyl-1-piperazinecartoxylate as on oil.

Mile was aéprived of the carboethaxy group by the method described in heterence sraingle 38 to give 0.36 g of 1-p- tolylmetinylpipseezine as an oil. <

BAD ORIGINAL oA

S

NMR (Coots) &: 2.42 (3H, 8, Cli), 2.57.6 (4H, m), 2.7 3.1 (411, m), 3.43 (2H, s, ci, ), 7.14 (4H, =)

REFERENCE EXAMILE 52 . 5 A {HR "N — pe

HN N-CH--CH . ) a

Shy) P=niperasineciarboexy bate aud einmamaldehyde wore usoa og bhe boarding soborio le aan Lre..ted 10 the } Gone aaa: an an Reference Saoole 51 to give 1-cinna- aylpiporocine anon oli.

Sei (eo 5

Qs: c.o 2.6 (AH, m), £.875.6 (di, m), 3.16 (21, 4d,

Cll, )y eit (1, db), B.0o (1H, 4), 7.077.5 (il, a)

Sut nhagh BAANELE 52

CH, SH .

Hy ’ - HC 5 p> NCH Coon J — ~~ CHO 3 : :

Cl (L] -Y NN C00H eee >

Al N- CHa

A mixtape of 1.0 p of I-li-netaylcysteine, 1.07 good nlcobine biehyue nd 2 ml oof watber was stirred a) nw, coon Loner bare for ZF aears. Fvridine (0.8 ml) nd 1 al of! £thenel weile added to the reaction mix- ture, anc the resultent cryetollice precipitate was collected Lo i1t = Hioe, washaos with ethanol ans dried - 92 -

BAD ORIGINAL J :

BE pa to give 0.74 g of 3-methyl-2-(3-pyridyl)thiaszolidine~4- carbokyiic acid.

NMR (DESO0-d, ) 81 2.24, 2.32 (31/2%2, =, H-Cliy), 3.003.64 : 5 (5/21, m), 4.1674.32 (1/2, Wn), 4.92, 5.36 : (M/2x2, s), 7.10°7.32 (1H, m), 7.£078.00 (11, =m), 2.44-8.72 (2H, wu) ve (eal) :on/u 22u (Mei)? firey Benin og iH BS]

Za doe : Hy

Ly! [L] 20 ;

Cm me ee am een | “WoUTS TH

Rl H ) 15 Aomlvture of Fu6s g of Descet lporidine, 000 ¢ of

L-cysteine, <Y wl of witer sud 295 al ol ethonos wo re- : flusred tor -4 hours. The reaction ixtare wag coocen= tye d unde eo opesmced proscar, bsopropanol was adued tn thr residoe, and the recaltant cowuaer was collected

Ly tiltrotion. wthanol wags ad led to the poraer, the {naotuble matter was filtered oll, and the [illrase “ van concentrated to dryness. The rosidae was dissolved 1 water and adjuster to pH 6 by addition of dilated hydrasialoric aid weer 102 cooling ond sbireing, and 2h tae resalbant sowier was collected Ly tiltrotion, waisned witn ethanol and dried to Jive 2.04 ¢ of 2- mati l= G=nvriiel)hinsolidine~4-corbory ic acid.

Nid (omd0=d -) - 93 -

BAD ORIGINAL A

SS: 1.70 and 1.88 (8, respectively 31), 2.923.506 (2H, m), 3.5674.38 (1H, m), 7.20-7.44 (10, m), 7.80-9.08 (1, m), 9.52-9.52 (1H, m), °.6B70.86 (1H, m)

JS (bab): m/z 225 (wen) : ALBPERLUCE mXu wild 2

CH, SH

TT ~ GOH y HH, N-CH- COU { \ HN H yo

N-- iu) a . N : = mmm NS 1m N-- Ye ~~ ~ ar MN N COOK _ / A\ H

Nerenee

Woda Sue of Sent poof di=leriridyl kotone, 2h i 0 of s-oysloine, sh onl of weter ona #% ml ot ethenol 19 wag coflused for 3.9% hours. niter allowing the wix-~ ture to cool, the insoluble wetter wae filtered off, and the 1iltr te was concentrated to aryness aunor yedueed pressure, The residue wis wuehed in seanuence with ethyl ncebate ond ether to vive 0.63 p of 2,7-di ¢0 (2-pyridyl)thiszolidine-A-curboxylic aeid.

MIR (prse-4;) $1 2.0% 1.1% (35, a), 1.20 8.00 (£H, n)

BSEERERCE USAR) LE 56 “0 CO UH OH no CH OH (7

N. . + “ N Le

H

COLL (CH3)3 1 7 ~ op - BAD ORIGINA 27 bao oe

Co 2 :

Di-tert-butyl dicarbonate (7.85 g) and 35 ml of 1 N sodium hydroxide were added to a solution of 4.00 g of 3-piperidinemethanol in 50 ml of dioxane plus 30 ml of water at 0O'C. The reaction mixture was allowed to rise to room temperature and then stirred for 1.5 “hours. The product was extracted with ethyl acetate.

The ethyl acetate layer was washed in sequence with water .and saturated aqueous solution of sodium chlo- ride, dried over anhydrous magnesium sulfate and con- centrated under reduced pressure to give 7.20 g of 1- i tert-butoxycarbonylpiperidine-3-methanol. Melting point 77-79°C.

NMR (CDC 4) 8: 1.48 (9H, 8), 1.4.1.9 (8H), 2.6.3.2 (4H), : C15 3.6.3.9 (4H) © Ms: m/z (MY)

REFERENCE EXAMPLE 57 nr CH OH CHO —>

SNC ~N

Loo (ily) COCC (C3);

Dimethyl sulfoxide (0.85 ml) was added to a so- lution of 0.50 ml of oxalyl chloride in 10 ml of di- chloromethane at -60°C and, 3 minutes later, a solution of 1.08 g of 1-tert-butoxycarbonylpiperidine~3-methanol in 10 ml of dichloromethane was added dropwise over 5 minutes. After stirring for 15 minutes, 3,0 ml of tri-

av ethylamine was added to the reaction mixture. After further 5 minutes of stirring, water (20 ml) was added to the reaction mixture and, after shaking, the dichlo- romethane layer was separated. The dichloromethane layer was washed with 1 N hydrochloric acid, water, sa- turated aqueous solution of sodium hydrogen carbonate, water and saturated aqueous solution of sodium chloride in that order, then diled over anhydrous magnesium sul- fate, and concentrated under reduced pressure to give 0.98 g of 1-tert-butoxycarbonylpiperidine-3~carbaldehyde. } NMR (Cnety) g: 1.46 (9H, 8), 1.42.0 (4H), 2.40 (1H, m, w/z=21Hz), 3.10 (1H, dd, J=8.5 and 14Hgz), 3.65 (1H, ddd, 5 and 12.5Hz), 3.94 (1H, ad, i 15 J=4 and 14Hz), 9.68 (1H, 8)

MS: m/z 213 (M')

REFERENCE EXAMPLE 58 TO 67

The following compounds were..obtaindéd in the same manner as in Reference Example 2.

Desired Product

Chemical Structure and Chemical Name o

Ref. Ex. 58 Physicochemical Properties

Hy ou NMR (DMSO-d)

NE

: 25 \ J §: 2.85 (6H, 8), 2.98

Ce 3.56 (2H, m), 3.72

AE 4.44 (1H, M), 5.68, 5.92 (1H, 8B), 6.80

SE 1H) pyridyl) thiazolidide- (1H, m), 8.60-8.75 (1H, m) 4-carboxylic acid MS (FAB): m/z 254 (M+H)?

Bef. Ex. 59 Physicochemical Properties . 5 Melting point: 154-155°C ce A (decomposition) x In coou MS (FAB): m/z 271 (m+n)?

CH O/H H 2- 3-(5,6-Dimethoxy- pyridyl) thiazolidine- 4-carboxylic acid

Ref. Ex. 60 Physicochemical Properties

NMR (DMSO-d) [4 ~ J : 2.60 H, 8 2.80 4.60 c i 1 ) J (34, 8), 4 lg NC (3H, m), 5.70-6.00 ) (1H, 8), 7.00-8.50 (3H, 2- 3-(2-Methylpyridyl) - m) thiazolidine-4-carboxylic

Ref. Ex. 61 Physicochemical Properties

Melting point: 169-171°C

S. (decomposition)

A

(, Nu Neen NMR (CUC15+DMSO-dg)

H

\

CenC{ins)s $1 1.48 (9H, 8), 1.42.1 (5H), 2.6 -3.0 (1H), 2-(1-tert-Butoxycarbonyl- 2.95 (1H, dd, J=T7 and 4-piperidinyl)thiazo- 104iz), 3.22 (1H, dd, l1idine-4-carboxylic acid

J=7 and 10Hz), 3.6 4.0 (14), 3.96 (1H, t, J=THz), 4.49 (1H, d, J=8Hz), 6.3 (2H, br, exchange with D,0)

Ref. Ex. 62 Physicochemical Properties

Melting point: 144-146 C

MN = (decomposition) _ * ~ Elemental analysis (for CgHgN;0,5): 2~(2=-Pyrazyl)thiaso- C(%) H(%) N(%) S(%) lidine-4~-carboxylic Calcd: 45.49 4.29 19.89 15.18 acid Found: 45.20 4.18 19.76 15.43

Ref. Ex. 63 Physicochemical Properties

Melting point: 204-207 C “ MS: m/z 225 (M'+1)

Sr

TN

2-(3-Pyridyl)-3,4,5,6- tetrahydro-2H-thiazine- 4 -carboxylic acid

Ref. Ex. 64 Physicochemical Properties . : Melting point: 165-167 C -

AR Elemental analysis

CN “a “oy (for CgHgNO,S, ) 7 C(%) H(%) N(%) 5(%) } 2-(3-Thienyl)thiazoli Calcd: 44.63 4.21 6.51 29.79 dine-4-carboxylic Found: 44.57 4.23 6.49 29.99 acid i ] Co ' pK 137 ~ : Ref. Ex. 65 Physicochemical Properties

Meltiyg point: 169-170 © / £ (decomposition) i» fo wo al Elemental analysis (for CalgN035): 2~(3-Fyryl)thiazo~- C(%) H(%) m(%) s(*) - lidine-4-carboxylic Calcd: 48.23 4.55 7.03 16.09 n acid Found: 48.03 4.51 7.00 16.28 . Ref. Ex. 66 Physicochemical Properties

Melting point: 148-147 C oo (decomposition)

JN , soH Te MS (FAB): m/z 213 (M'+1) : ! " { 2- 3-(1-Mehhylpyrro- : { 1yl) ~thiazolidine-4- - ‘ carboxylic acid )

Ref. Ex. 67 Physicochemical Properties oC Melting point: 143-144" C - ly MS (FAB): m/z 1239 (M'+1) : ~ 20 EI

I | MoS Po oo TN 3 CY

IE 5,5-Dime thyl-2=(3= . pyridyl)-thiazolidine- 4~carboxylic acid . 2 5 : .

REFERENCE EXAMPLE 68 > fa | - } or ) ZF A { No = ee em ear eo > ~~ . I. N ! \ He { oe | oot

Ll Cn Lo “

PNT cn), SN Tr . - [& . _ 99 - :

Co I Ta . PE SE 1 . Sh C- Ch a t : REE EET A 2 ah . EA rn ' :

oe | 2312 27123

Oxalyl chloride (1.31 ml) and 50 mg of N,N- dimethyl formamide were added to a solution of 3.10 g of 3-tert-butylearbomyl-2-(3-pyridyl)thinzolidine-4- carboxylic acid in 30 ml of dichloromethane at -78 T. oo 5 The reaction mixture was slowly warmed to room tem perature and then stirred for 12 hours. The resul- tang precipitate was collected by filtration and dried to give 1.90 g of 1,3-dioxo=-5=-(3-pyridyl)thiazolidino (3,4-c)oxazolidine nydrochloride. Melting point 170°C (decomposition).

Elemental analysis (for C,ollgC1N3058) ¢c(#) H (3) N (3) Ss (%) c1(%)

Calculated: 44.04 3.33 10.27 11.76 13.00

Found: 43.94 3.37 10.24 11.76 13.30

REFERENCE EXAMPLE 69 , H, Va . CA ! Vm (HTH HE med (MH {Tn od 10% Palladium-on-carbon (200 mg) was added to a solution of 5.34 g of 4-methoxycinnamic acid in metha- nol, and the mixture was stirred under hydrogen until hydrogen gas absorption ceased. The catalyst was fll- tered off, and the filtrate was concentrated under re- duced pressure to give 5.43 g of 3-(4-methoxyphenyl) propionic acid.

NMR (c0C13)

Co pi $1 2.34 3.1% (4H), 3.76 (3H, s), 6.64 7.30 (an), 11.00 (11, 8)

REFLRENGE SXAMPLE 70 - . 5

Cr 7 no Lo vi ML RT VAR yn \.__/ =

A solution of the 3-(4-methoxyphenyl)propionic acid in 100 ml of anhydmous ether was added dropwise to a suspension of 1.10 g of lithium aluminum hydride in 50 ml of anhydrous ether with stirring at room tem- perature over 20 minutes. after stirring at room tem- perature for 30 minutes, the mixture was refluxed for ) 15 1 hour. After cooling, water was added with ice coo- . ling, and the mixture was made acidic by furkher addi- tion of 10% hydrochlorie acid and then extracted with . ether. The arganic layer was washed with saturated aqueous solution of sodium chloride, driven over anhy- drous magnesium sulfate and concentrated under reduced ) pressure to give 5.06 g of 3-(4-methoxyphenyl)propanol.

NMR (Cpcty) 8g: 1.60-2.16 (2H), 2.38-2.95 (3H), 3.69 (2H, t,

Je6Hz), 3.80 (3H, 8), 6.717.530 (4H)

REFERENCE EXAMPLES 71 TO 74

The following compounds were obtained in the: nwuae manner as in Reference DLxamples 69 and 70. In Reference

Examples 73 and 74, platinum oxide was used as a catalyst - 101 - | oo 1

BAD ORIGINAL )

for the catalysics reduction.

Desired Compound

Chemical Structure

Ref, Lx. 71 Physicochemical Properties

NMR (Coet) wt t 3 ee §: 1.58.10 (2H), 2.26 (3H, 8), 2.49-2.83 3-(4-"etliylphenyl) (311), 3.60 (21, t, propanol J=6112), 7.00 (41, 8) ef. Ex. 2 Physicochemical lroperties

RL Nua (CDC)

J a), 8: 1.60-2.14 (21), 2.49 cn 2.90 (3H), 3.65 (21, "15 3-(3,4~himethoxyphenyl)- t), 3.82 (6H, 8), 6.73 propanol (34, =)

Ref. Ex. 13 Physicochemical Properties

NMR (CDC14) oo a wn 51 1.60-2.14 (2H), 1.77 (1H, 8), 2.54-2.90 3-(4-Chlorophenyl) (2H), 3.65 (21, t), propanol 6.95-7.40 (4H)

Ref. Ix. 74 Bhysicochemical Properties

Nila (C014) = Ni) 81 1.55-2.16 (2H), 2.01 - (14, 8), 2.48-2.86 3-(4=Iluorophenyl) (211), 3.65 (2H, t), propanol 6.65-7.31 (4H) - 102 =- r Be:

BAD ORIGINAL Bs

REFERENCE EXAMPLE To yo cst TT

FNS a eee A SoHE . 5

A mixture of 5.20 g of p-nitrocinnamic acid, 10.4 g of methyl iodide, 10.4 g of anhydrous potassium carbonate and 20C¢ ml of acetone was stiried at room temperature for 2 days. The resullan.t precipijate was filtered off, the filtrate was concentrated under reduced pressure and, after addition ot water, the residue was extracted with ethyl acetate. The orza- nic layer was washed wlth saturated solution of so- dium hydrogen carbonate and saturated aqueous solu- tion of sodium chloride, dried over anhydrous mag- nesium sulfate and concentrated under reduced pree- sure to give 3.30 g of methyl 4-nitrocinnamate.

NMR (CpCly) &: 3.83% (3H, 8), 6.52 (1H, 4, J=16Hz), 7.50 7.95 (31), 8.21 (21, 4, J=911z).

REFERENCE EXAMPLE 76 a {A Veoh i . 4 = 5 ‘ Zs r EE ~ Lo “~ ~1 pL Tel LN Leo fH

A solution of 1.20 g of o-tolualdehyde in 20 ml - 103 -

Fr RY

AD ORG AL Py b of anhydrous tetruhyaroifuran was added to a suspen- sion of .67 g of methyl (triphenylphosphoranylidene) acetate in 20 ml of anhydrous tetrahydrofuran at room temperagure, and the mixture was refluxed for 15 - 5 ‘oyrs. ~The solvent wae then distilled oft under re- duced pressure, and the residue was subjected to si- lica gel column chromatography (40 g). Elution with hexane-etnyl acetate (2:1) gave 1.65 g of methyl 2- methvlcinnamate.,

NMR (CiClz) s: trans-form, 2.45 (3H, s), 3.80 (3H, 8), 6.34 (11, 4, J=16Hz), 6.99_7.66 (4H), 7.97 (1H, da, J=16Hz) cis-form, 2.29 (8), 3.63 (8), 6.03 (4d,

J=12Hz)

HEFERENCE EXAMPLES 77 aND 78

The following compounds were synthesized in the same manner as in Reference DIxamples 69 and 70.

Desired Gompound

Chemical Structure and Chemical Name

Ref. Ex. 71 Physicochemical Properties ow NMR (CC14)

Co §1 1.57-2.11 (20), 1.86 (1H, 8), 2.51-2.90 3.(2-Methylphenol) (2H), 3.69 (2H, t, propanol J=6Hz), 7.10 (4H, 8)

Lef., Ex. 18 Physicochemical Properties

NUR (CDC15)

NL ey - &t 1.54-2.10 (2H), 2.40 3-(4-Aminopherol) 3.10 (51), 3.62 (2H, - 5 propanol t, J=6Hz), 6.46 7.10 (a1).

REFEWANCE EXAMPLE 19 so poh J br so Sa Cy ees & ed) OH

Tilt oo

A solution of 1 # superhydride/tebrahydrofuran (3.3 ml) in annydrous tetrahydrofuran (5 ml) was cooled to =50 to 60 C under an argon gas stream. fhereto wus added dropwise a solution of 210 mg of metinyl 3-(4-cyanophenyl)-proplonate synthesized from 4~cyanobenzaldehyde and methyl (triphenylphosphofa- ) nylidene acetate by the procedure of Reference Lxam- ples 69 and 76) in 2 ml of tetrahydrofuran. The re- aultant mixture wae stirred at that temperature for 10 minutes, then made acidic by addition of water and 1 N hydrochloric acid in that order at the same temperature, and extracted with ethyl acetate. The organic layer was washed with saturated aqueous so- lution of sodium chloride, dried over anhydrous mag- neslum sulfate and concentrated under reduced pres- sure to give 120 mg of 3-(4-cyanophenyl)propanol. - 105 =~ BAD Gre a

17 V7

NMR (ene) 8: 1.61.2.20 (3H), 2.60-3.06 (2H), 3.63 (2H, t, J=6Hz), 7.103.75 (4H)

REEERENCE EXAMPLE €0 al a, 4 he and yor “ EE Ne TM 3-(4-Methylphenyl)propanol (2.13 g) was heubeu in 7 ml of 47% aqueous hydrobromic acid under reflux for 5 hours. The solvent was then distilled off un- der redueced pressure and, after addition of water, the residue was extrscted with ether. The orgunic layer was washed with saturated nqueous solution of sodium chloride, dried over anhydrous magnesium sul- fate and concentrated under reduced pressure. The residue was distilled under reduced pressure to give 1.75 g of 3-(4-methylphenyl)propyl bromide. Boiling point: 65 C/0.7 mmHg.

NMR (Coel5)

S: 1.85 2.43 (2H), 2.32 (3H, 8), 2.55 2.95 (2H), 3.39 (2d, t, J=6Hz), 7.04 (44H, 8)

REFERENCE EXAMPLE 81 con RTE ptt Len Ln CH)

Methanesulfonyl chloride (3.8 g) was gradually

BAD ORIGINAL 9 added dropwise to a solirtion of 5 g of 3-(4-methoxy- phenyl )propancl in 50 ml of anhydrous pyridine with jee cooling, and the resultant mixture was stirreo at the same temperature for 3 hours. Phe solvent was . 5 distilled off under reduced pressure and, after addi- tion ofwater, the residue was mode aclidde with 105 hydrochloric acid and then extracted with ethyl ace- tate. The organic layer was washed with hydrochloric acld, saturated aqueous solution of sodium hydrogen cnrbonate and saturated aqueous solution of sodium chloride in that order, dried over anhydrous sulfate and concentrated under reduced pressure to give 0.23 g of 3.(4-methoxyphenyl)-propyluethanesulfonate.

NMR (CIEY €1 1.75-¢.56 (21), 2.552.935 (2H), 3.00 (3H, g), 3,80 (31, s), 4.24 (2H, t, J=6Hz), 6.70-7.30 (41).

REFERCE BXAMPLE 82 (gd A Nora) aH or ae? Nn). -1 _— : - TNL ‘

A solution of 6.30 g of 3~(4-methoxyphenyl) propylmethanesulfonnte and 11.1 ¢ of sodium lodtide in 100 ml of acetone was gefluxed for 15 hours. The reaction mixture was concentrated under reduced pres- sure and, after addition of water, the residue was

J

% extracted with ehther. rhe organic layer was washed with saturated aqueous solution ofreddainm chloride, dried over anhydrous magnesium sulfite ant concels proted ands T reuuce:l pregenye to give 6.67 + OF Be (4 -me bnosy phenyl) propyl iodide.

NMR (net)

St 1.081 2.35 (211), 0,48 (2H, br t, J=Tiz) 2,16 (2it, t, J=612), 3,80 (3H; sg), 6.11 7.30 (A).

REFERBNCE EXAMPLE 83

The following compound Wits obtained in the same : manner a8 in Reference nxample 82.

Desired Compound

Chemical GEructure and Chemical Name

Ref, Ex. 83 physicochemical Properties t a. Ai Tn

Ea MR (cDC13)

CHO Ts ~(CHy) St 1.80 2.54 (2H), 2.60 5-(3,4-Dimethoxy phenyl) 5,12 (2H, t, J=6Hz), propyl jodi de 3,81 (6H, 5), 6.99 (3H, 8).

HE x BENGE LXANPLE 84 [y te ord N(en )5-T cl \ (CH, )5-OH — a 2°35

PPH4

DMF

-~- 108 - od oo

SE 1y1#

To a solutiono of 1.55 g of 3-(4-chlorophenyl)- propanol and 2.51 g of triphenylphosphine in 10 ml of

NyN-dimethylformamide, there was gradually adued drop- wise at room temperature a solution of 2.42 g of iodine in 8 ml of N,N-dimethylformamide while confirming the consumption of iodine. When the color of the resction mixture ceased to disappear any more, woter was added to the reaction mixture, the excess iodine was reduced bs ad ition of 5% asueous sodium thiosulfute, and the mixture woe exhracted with ethyl acevate, The organic layer was washed wtih paturatedaqueous solution ot so- dium chloride, dried over anWkdrous magnesium sulfate . and concentrated under reduced pressure. The residue » was subjected to siiica gel columnchromatography (20g).

Elution with hexane gave 1.82 g of 3-(4-chlorophenyl) propyl iodide.

MMR(0DC1 40 st 1.92 2.40 (2H, 2.71 (2H, br t, J=THz), 3.13(2H t, J=6Hz), 6.91-7.40 (4H).

The following compounds were obtainedin the same menner as in Reference Example 84.

Desired Compound

Chemical Structure : 25 and Chemical Name

MMR (CDCl) ne-{ \-(Cip) 5-1 §: 1.79-2.35 (2H), 2.70 (28, t, J=THz), 3.80

Xl 3-(4=-Fluorophenyl)propyl (2H, t, J=6Hz) iodide 6.55 7.45 (4H).

Ref, Ex. 86 Physicochemical Properties

MMR (CDCl) . 5 C1 §:1.90°2.47 (2H, 2,32 ~ (CH -

A ( 2)3 I (54, 8), 2.55°2.90 3-(2-Methylphenyl)propyl (2H), 3.22 (2H, t, iodide

J=6Hz), 7311 (4H, 8).

Ref. Ux. 37 Physicochemical Properties

MMR (¢nely)

NC {ON -ny) yer §1 1.86 2.42 (2H), 2.14 3.00 (2H), 3.16 (2H, 3-(4-Cyanophenyl) propyl t, J=6Hz), 7.13 7.71 iodide (411). \ 15

RES LRENCE BXAMILE 89

C.HNO : 3 0, i ¢.H,80 { V- YH.) 274 - - (CH, ) Br > ON (CH, ) 4 Br : 20 — : Phenylpropyl bromide (5.01 g ) was added dropwise to a mixture of 10 ml of concentrated nitric acid (65%) and 10 ml of concentrated sulfuric acid with ice cooling over 5 minutes. The mixture was stirred at the same tempersture for 1 hour and then allowed to stant at room temperature for 1 week. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chroma- topraphy (150 g). Blntion with hexane-ethyl ace- tate (10:1) gave 5.50 g of 2,3-dinitrophenylpropyl bromide.

Ref. Lx. B87 Ihysicochemical Properties

MMR (Livi)

NC 4) (cho); -L §: 1.50-2.42 (21,), 2.14

Bh 3.00 (2H), 3.16 (2H, 3-(4-Cyanophenyl)propyl t, J=6Hz), T.13-7.71 iodide (41) -

REVEBNCE BAAMPLE ©)

C.HNO3 NO, { N-cas-er _ CH ond (CH7)3 Br

Phenylpropyl bromide (5.01 gz) was added dropwise to a mixtura of 10 ml of concentrated nitric acid (654) and 10 ml of concentrated sulfuric acid with ice cooling over 5 minutes. The mixture was stirred at the same temperature for 1 hour and then allowed to atand at room temperature for 1 week. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated aqueous solution of sodium chloride, dried over anhy-

+7 drous magnesium sulfate and concentrated under re- duced pressure. The residue was subjected to sili- ca gel colnun chromatography (150 rr). Elution with hexane-ethyl acetate (10:1) gave 5.50 g of 2,3-d1i- _ 5 nitroohenylpropyl bromide.

NMR (cnet) ¢ 2.08-2.51 (2H) 3.20 (2H, dd, J=THz} J=0lz) 3.50 (24, t, J=6Hz) 7.68 (1H, d, J=91z) a. (11, Ad, J=3H=, J=2z) 8.79 (11, 4,

J=3Mz)

REFERENCE EXAMPLE 90

Nd Neen), - 08 mech), HB

A solution of 0.51 g of 3-(4-aminophegyl)propanol in 5 nl of 47% agqueous hydrobromic ccid was refluxed for 6 hours. The solvent wae then distilled off un- der reduced pressure. Methanol and toluene were ad- ded, and then polvents were distilled off under re- duced pressure, and this procedure was repeated, whereupon 1.04 g of 3-(4-amlnoohenyl)propyl bromide hydrobromide was obtained.

HMR (DWS0-d +CDC1, (3:1)) §:1.91-2.47 (21) 2.64-3,03 (21) 3.43 (24, t,

J=6Hz) 4.85 (3H, br s) 7.40 (4H, 8)

REFERENCE EXAMPLES 91 TO 101

The following compounds were obtained in the

Ce 1h = 27 127

Ooranrde $3 game manner as in Referenc wxamnple (2) and (3).

Desired Product

Chemical Structure and chemical Name iE 5 Ref, Fx. 21 Physicochemical Propertics 1) NMR (DMSO-d) : I

HN N-)4 Mon 8: 1.9271.84 (21, n) wt — 2.0472.93 (12H, m) 4.5075.20 (2H, br) 1~ 3=-(4-Hydroxyphenyl)- 6.65 (1H, 4, J-2Hz) propyl piverasine 6.96 (1H, 4, J=9Hz) 2) MS: m/z 216 (M)

Ref, fix. 92 Physicochenical Properties 10 NMR (Chet)

Cor

HN N-(n)d Ne §: 1.5072,05 (2H, m) 1.64 (1H, =) 2,063,071 (8H, m) - — -{} I " —-— 1- 3-(4-Chlorophenyl) : 2.90 (4H, t, J=SHz) propyl piperazine 6.80-7.51 (4H, m) 2) MS: m/z 238, 240 (M%)

Ref, Ex. 93 Physicochemical Properties 1) NMR (cnc)

STN — . —/ 1.80 1H, 8) 2.1972.78 (8H, m) 1- 3-(4-Flaofophenyl)- 2.95 (4H, t, J=5hz) propyl piperazine 6,807.36 (4H, m) 2) Wi: m/z 223 (M41)

Ref, fx. 94 Physicochemical Properties 1) NMR (coe) — &: 1.64 2.13 (2H, m) (eds Noes 2.04 (1H, 8)

NO, 2.22 2.53 (6H, m) 2.88 (4H, t, J=5lz) 3.05 (2H, t, J=THn) 7.61 (1H, 4, J=9Hz) 8,38 (1H, da, J=3Hz, 97) 8.64 (11, dd, J=3Hz)

Ref. Ex. 95 Fhysicochemical Properties 1) NMR (cne14) uy N= (od Nam, &: 1.56.93 (2H, m) 2.18-2.64 (11H, m) 2.89 (4H, t, J=5Hz) 1- 3-(4-Aminophenyl)- 6.60 (2H, da, J=9Uz) : propyl piperazine . 6.95 (2H, 4, J=9liz) 2) MS: m/z 219 (M')

Ref, Ex, 96 Physicochemigal Properties 1) NMR (cnet) »

Pn A St 1.53.1.92 (2H, m) of rsd 2.28 (3H, 8)

Chg 2.20-2.70 (8H, m) 2.88 (4H, t, J=5Hz) 1- %-(2-Methylphepyl)- 7.09 (4H, s) propyl plperazine 2) MS: m/z 218 (M)

gpm = 2H)

Ref. ix. 97 Fhysicociemical Properties

NHR (CDC) — S$: 0.90 (38, t)

HA N(CH) (Wy wt So 1.12-1.72 (86i, m) = 5 2.2072.52 (6H, m) 2.82-3,00 (4H, m) 1-Hexylpieerazine MS: m/z 170 (ht)

Ref. Lx. 98 Physicochemical Properties

NMR (CDhC1 7 ( 3)

Vo &: 2.20 2.48 (41, uw)

HN HCH i \__/ N

NOY 2.76 3.04 (4H, m) 4.23 (1H, 8) 1-Niphenylmethyl pipera-~ 7.04 7.52 (101, m) zine MS: m/z 252 (MY) hef, bx. 99 Physicochemical Properties

NMR (Cue) ro vA N\, &1 1.62 1.98 (2H, m)»

HNN (Ch) << ’ : 1.76 (1H, 8), 2.20 2.48 (6H, m), 1- 3-(4-Methylphenyl)- 2.35 (3H, 8), propyl piperazine 2.57 (2H, t, J=8Hz), 2.88 (4H, t, J=5Mz), 7.08 (4H, s).

MS: m/z 218 (M')

Ref. Ex. 100 Physicochemical Yroperties

NMR (CDC1_) — 3

HN 3-57 Yoon $§: 1.60 2.01 (2H, nw), et == , 1.92 (1H, 8),

Co. "1 2H 2.18-2.65 (81, m), 2.87 (4H, t, J=5Hz), 1-(3-(4-Methylphenyl)- 3.71 (3H, =), propyl) piperazine 6.80 (1H, 4, J=9lz), 7.04 (11, 4d, J=9H=n).

Ms: m/z 254 (MD)

Ref. Bx. 101 Physicochemical Properties

NMR (Coury)

OCH, ~ &: 1.58 2,00 (2H, u) 0 an 1 -(ory)3 { Y och Co h 1.80 (1d, s), 2.23 2.01 (8iiy mn), 2.91 (4H, t, J=5ilu), - -— ( - ne - he 1-(3- (3,4-Dimethoxy 5.04 (6H, 8), phenyl )opropyl)piperazine 6.50 6490 (31, m)

MS: on/z 264 (MY)

RIFERENCE_EXAMPLE 102 (Yo

C.H50CONHCH, CH NH —mrm—eromeoe—meoeoroeoonoo—>

By Ky C03 oH © CoH COONRCH, CH 0700 ((Hy)s LY

AM CoH3 OCONHCH) Cl NH ~ (02) 4)

A solution of 0.88 g of carhoethoxyethylenedia- mine, 1.35 ¢ of Z-phenylpropyl bromide and 1,0 g of anhydrous vpotanssinm carbonate in 10 ml of telreshy- drofuran was heated overnight nnder reflux. The in-

soluble matter was filtered off, the filtrate wus concentrated under reduced pressure, and the residue wir enb jected to alumina corumn chromate rephy (25 1). lution with heaane-ethyl ceebote (S21 v/v) gave C.54 ¢ 01 i=cerboethoxy-i', L'-bis(3-phenylpropyl Jethyl- ercdivmine (1) and 0.60 g ol h=curboetboxy-It'-(5- phernylpropyl)ethylenediamine (2). ial (one, (Grind 8S: 1.25 (3H, t, J=THz), 1.56 =.02 (4H, nj, 2.202.070 (10H, mi), 5.00 0.4% (2i, m), hole (2liy ty, J=Thz), 5.13 (14, brj, 7.21 (10h, 8)

AR (C0,

Mai ( Ul) 8: 1.21 (ti, su), 1.2% (3H, t, J=THz), 1.61 14 2.10 (21, 1), Z.4>2.23 (5H, m),y 3.29 (2H, q, J=6Hz), 4.15 (&i, t, J=THz), 5.15 (14, br), 7.21 (5%, &)

Kel'tRENCE EXAMILE 103

FN eC Ry ai (apa si wen, Cy (OR) 7 \ -2 HC)

A solution of 540 my of d=crrboethoxy=N'=(3- phenylpropyl)etayleaediamine in 10 aml of concentra- ted hydrochloric acid was heated in a sealed tube at 120% awepnicht, The alzture wos concentrated unites reduced pressure. Toluene was added and the - 117 - f «

BAD ORIGINAL 2) be &

mixture was ag:ein concentrated. Two repetitions of this procedure gave 030 mg of N-(3-phenylpropyl) ethylenediamine dihydrochloride. This product was submitted to the next step without paritication.

Na (DA30-d) 8: 1.76-2.20 (24, m), 2.48.3.10 (2H, a), 3,22 (41, 8), 7.28 (5H, 2), €.0-10.0 (5H, br)

Ms: m/z 179 (M41)

NEEERENCS EXAMPLE 104 he following compound wag obtuined in the cue manner as in kelerence Examples 102 and 103.

Desired Product

Chemical Structure and Chemical Name Physicochemical Properties 1) NMR (DMSO-d) esl $0 1.76-2.24 (411, 0)»

NCR CHIN a : 2.45-2.81 (41, n),

OO 2.92-3,60 (4H, m), 73,38 (8H, s), 7.26 (10H, 8) . 2) MS: m/z 297 (M41)

REFUHENCE EXAMPLE 105 “2 NC 4 Vena — id Rens dN CN

A solution of 250 mg of %-(4-cyanophenyl) propyl fodide, 0.4% g of anhydrous piperazine and 0.5 p of potasaium carbonate in 10 ml of tetrahydrofuran wos refluged for 2 hours. The reaction mitture wns con= . 5 centrated under reduced pressure and, after addition of saturated aguecus solution of sodium chloride, the residue wins extracted with ethyl acetate. The orgu- nic layer was washed with saturated aqueous solution of scdium chloride, dried over anhydrous sodium sul- 10 fate and concentrated under reduced pressure to vive 140 ne of 1-(3-(4-cyanophenyl)-propyl)piperazine.

HNMR (nets)

Ss: 1.602.10 (28, m), 2.04 (1H, 8), 2.19 2.54 (61, m), 2.69 (2H, t, J=8Hz), 2.89 (4H, t, 15 J=5hz), 7.27 (21, 4, J=9Hz), 7.56 (21, 4,

J=00z)

MS: m/z 229 (M7)

REFERENCE EXAMPLE 106 0 {Vou cn, (enydy NCO == et

I cfy neom (ev lzcry

TTT ns 25 A solution of 1.0 g of n-butyl isocyanate in ml of tetrahydrofuran was added to a solution of 1.76 7 of {-henzylpiperazine in 20 ml of tetrahy- drofuran with ice cooling. Phe mixture was stirred - 119 =~ BAD ORIGINAL don

Nios gy at room temperature for 2 hours and, then, concen- trated unler reduced pressure to give 2.8 5g of crude 1-benzyl-4-hutylaminocarbonyl piperazine. The inter-~ dediate was submitted to the next step without phri- - 5 fication.

Nik (CbC14) 8: 0.90 (3H, t), 111.7 (44, m), 2,272.0 (4H, ®), 3.075.6 (OH, m), 3.30 (2H, 8), 4.5 (1H, brs), T.077.% (54, m)

REFBLENCE EXAMPLE 107 7 DCC {Nand NH r{ Honcho — = Ns = {Neuf - cor)

Nieyclohesylearbodijuaide (1.5 g) was added to a mixture of 3.52 ¢ of 1-benzylplperasine, 3.5 p of >= phenylpropinonic acid and 20 ml of tetrahydrofuran, and the mixture weno stirred overnight at room teum- perature. The resultant dicyclohexylurea was fil- tered off, and the mother liquor was concentratzd uncer reduced pressure. Bthyl scetate (100 ml) and 50 ml of water were added to the residue, and the nixture was made alkaline with potassiun carbonate and then allowed to undergo phase separation. The ethyl acetate layer was washed in sequence with wa- ter and saturateu aqueous soiution of sodium chlo- riae, dried over anhydrous sodium sulfate and con-

AT centr: ted andar rodnesd prossure to give 6 x of 1=- benzyl-4-(3-phenylpropionyl)piperazine. a (Ube.

NR ( 15)

Sg: 2.17205 (Ail, m), Z.175.2 (41, nv), 3.33, i 5 (An, mJ, 3.45 (zn, $2), Te177.4 (10it, m)

HBEDENGE DLAUTLE 108 a NCONH (CH;)3 (Hy —_——— /

HN NCONH (CH) )3 (Hy nn 10% Palladium-on=-carbon (250 ns) was wdded Lo aosolutlon nf 2.8 of T=bonpyl-4-aontylaminon Veli] piperazine in 15 um! of ebhinpl, =r. catalytic reduc- bion was carried out until cessation of hydrogen ahsorption. The catalyst was then filtered off, and the filtrate was concentrated under reduced pres sure to give 2.2 p of T-butylaminocartonylpiperazine.

This product wes subnitted to the next step without purification,

NMR (DCT, | Ja (20C1) §:0.92 (3H, IP), 1.1-1.7 (4H, m), 2.773.0 (4ir, n), 2.075.5 (60, m)

REFRIEESS_ SAMPLE 109 \ ST

J N\-cu,nN NOCH and — => HN HCOOH (H 4 )

Nee" 27 2 ’ Nee \N_./ 2 —

BAD ORIGINAL 9 = let - kam mee

1-(3-Phenylpropionyl)piperazine was obtained in : the same manner as in Helerence twxample 106 using 1- bensyl-4-(3-phenylpropionyl )pkperarine aus the stir- ting material.

NS: m/z 216 (W')

Lb LRG BARN LE 116

CH, O04 { cious COh-com _ \ N-empons-ci -CON N-(C md) — \ -

Dicyclohexylcarbodiimive (1.58 g) was added to an ice cooled solution of 2.0 g od ri-carbobenzyloxy- serine, 1.57 g of 1=~(%=-phernylpropyl piperazine and 104 pg of 1-hydroxybenzotiazoie in 30 ml of N,N-dime=~ thyliormamide, lhe mixture was stirred at room tem- perature for <4 hours, then dilutes with ethyl ace- tate, washed in sequence with the portions of 4% aqueous sodium hylrogen carbonate, end portion of wi- ter and one portion of suturatcd aqueous solution of oo sodium chloride, dried over anhydrous sodium sulflate and concentrated under reduced pressure, The regiduc was purified by siiica gel co uan chromatography to give 2.39 g of 1-(2-(benzyloxycarbonylamino)=3-hydro- xypropionyl)-4-(3-phenylpropyl)plperazine. Melting print 95-97 8. “lemental analyeis (for Cogllg N30.)

0177 7 (4%) 1n(%) n(%)

Calculated: H7.74 7.34 9.87

Found; 67.74 7.26 9.88

REFERENCE EXAMILE 111

CH, 0M { \\- CH; OCONH CH = CON N= (cH) { \ ey,

HO

“ch, \

CH, 7 \

PN CoN N-(CH5) {

H, 2/3 _; 10% palladiun-on-cafbon (100 mg) was added to a solution of 1.12 go of 1-(2-(benzyloxycarbonylamino) -3-hydroxyproplonyl)=-4-(3-phenylpropyl) piperazine iu 30 ml of ethanoi, and the aitture was stirred under a hydrogen gas stream until cessation of hydrogen absorption. The catalyst was then filtered off, and the filtrate was concentrated under reduced pressure to give S00 mg of 1-(2-amino-3-hydroxypropionyl)-4- } (3-phenylpropyl)piperazine.

NMR (CDC.

IMR (CDC)

St 1.72.0 (2H), 1.872.606 (3¢¥, exchange with n,0), 2.32.8 (BH), 3.4-5.8 (TH), 7.177.535 (51) t ”~ +

MG: om/n 291 (M7)

171+

REFERENCE EXAMPLE 112

HO. i" \

CH + pend No-one chs —_— : . wo COOH = b

HOS cn, \ 0 comen{)-o-(cadcy

Dieyelohexylearbodiimide (160 mr) was added to a solution of 200 mg of p-heptyloxylamine, 150 mg of glyceric acid (65% aqueous solution) and 110 mg of 1- hydroxybenzotriazsole in 2 ml of N,N-dimethylformamide.

Phe reaction mixture was gtirred at room temperature 1H for 16 hours, then diluted with ethyl acetate, washed in sequence with gaturated aqueous solution of sodium hydrooen carbonate, water and saturated aqueous solu- tion of sodium chloride, dried over anhydrous mag- nesium sulfate, and concentrated under preduced pres ) 20 gure. ‘The residue was purified by preparative silica gel thin layer chromatography to give 80 mg of N=(p- heptyloxybenzyl)-glyceramide.

HAIR (Coe) &: 0.90 (31, br t), 1.2 1.5 (8H), 1.71.9 (211), 3.0 (1H, exchange with 0,0), 3,8 4.0 (211), 3.9 (1, exchonge with 0,0)

A.1 4.5 (1), 4.38 (20, d, J=6dz), 6.08 (2H, a, J=8liz), 7.18 (2H, 4, J=8liz}),

pr 7.0 7.5 (11, exchange with h,0)

MS: m/z 309 (ud)

AEFERENCE BXadrbi 113 5H on lem _

SN HOBT

HBr Dec

OME

EP -(CHy) (M3

WH \__/

N

A mixture of 1.15 gof 2-(2-pyridyl)-1=-pyrrolime- 4-carboxylic acia monohylolromide, 770 mg of 1-heptyl ~piperazine, £60 my ol dicyeclohexylecarbodiimide and 560 mg ol 1-hydroxyhenzotriszole in 1% ml of N,N-di- me thylformamive was stirred at room temperature for 3 days. Alber dilution of the reaction mixture with ethyl acetate, the insoluble matter vas fiitered off, the {iltrate was concentrated under reduced pressure and, after addition of 0.5 N aqueous sodium hydro- <0 xide, the reisude wus extracted with ethyl acetate.

Phe organic layer was extracted with 1 N hydrochlo~- ric acid. The ggueous layer was adjusted to pH 10 by addition of potassium carbonate and extracted again with ethyl acetate. [he organic layer was wabhed with saturated aqueous solution ot sodium chloride, dried over znhydrous sodium sulfate and concentrated miler reduced pressure. The residue was subjected to silica gel column chromatography

(15 g). Flution with ethyl acetate gave 1.01 ff of 1=henbtvl-4=(2-(3-1y rilvl)=2=pyrrolin=S-ylearbonil) . niperazine.

NVR (Cnet 5) - 5 8g: 0.01 (7H, +t, J=61in), 1.12-1.72 (100, mw), 1.92-7.9% (9H, m), 2.95-5.26 (2, m), 3,37-4.30 (3H, m), 5.04-5.30 (1H, m), 7.26-7.46 (1H, ddd, J=11u) J=5lg, J=£iz)> 2.18 (1H,

SLT ra, J=20g, J=nlz), 2.69 (1H, dd, d=C0ln ty

J=GH%), 9.05 (1H, dd, J=1ln, J=2H2)

MS: m/z 356 (M7)

REPSRENGE ZXAYVFLE 114

The following compounds was obbained in the soae manner an in Refernn:e bx mle 115. | pesired Product

Ohemical Structure ani! Chemical Name Piygicochenicel Properties 1) HR (unc)

WR | RE

CP v= ) &: 1.6772.08 (2H, m)»

H nf — 50 N 2,0872.9% (9H, m), 2.9%~3,28 (2:, wm), 1-(3-Fhenylpronyl)-4=(2~ 3.3074.32 (3H, n), (3-pyridyl)-2-pyrrolin- 5.0075.33 (1, n), 5-7lcarbonyl) piperazine 7.0571.52 (6H, m), #.19 (11, dt, J=2lz,

JT=8Hz) , 2.69 (1, dd, J=2Hz,

J=5Hz), 9,05 (1H, dad, J=2Hz,

J=2i7) 2) we o/s 3Tu (0)

Hessel sXacliiih 11D at \ 3 9 He th

C 4 —isromo=j3—-piaeny Loutane was obtained Li wie meuwse manger a3 lo nelerance Sxanple ou.

BN AAR (Cues) §: 1.27 (3, d, J=Tiz), 2.11 (2H, 4, J=Tiin ) 2.04 3.50 (5d, mm), 1.24 (oil, fg) ed ugh Basil 110 he following compournsi wigs obhained in Lhe frome manner as in cel vence wxamnln 10/7,

CHy bo

CoMe0C-N N=CHyCHy CH - )

NS

Dthyld h=(s=phenylbutyl)-piporanine-1-carborylate

NHR (Chor, ( 3)

St: 1.1171.50 (6H, my), 1.50735.05 (7H, my, 3.50 (411, t, J=olz), 4.19 (el, u, J="fHz), 7.24 (5il, s)

REFERENCE sSXadMPLi 117 the following compound was obtained in the s:iune manner as in leteeence dxample 103.

ORIGINA a9

D Lnivet nL - 127 = BA be. me pond ds I § 8a bd oT fy co el CT i) oe

J. SL iby PRCA. <r) i. GeEmel FY n ro glad tn = $n gg is 8 E AE er EES si RE tl ER] AWE I gi = gro hh 4+ Sogn oe yin cdot i ' ih ER > kd % NEE Gy if he a i

Far memory he + Yagek LRT wo TART :

LoL ET — hy pa # Sh A ; HN N- CH, Hy CH { oa os He « wf - Ae a oe fo oo

SL ny

Lk ; os 1-(3-Phenylbutyl )piperaszine

A na, . . to Co > NUR (CDOT)

Fo v ; : 1.24 (3H, 4, J=7Hz), 1.76 (2H, gq, J=THz),

So = 1.93 (1H, 8), 2,102.46 (6H, m); 2.512.917 [CR . ‘

Lx pS Sn ¢ tL \ - Ct + od : Ms: (m/z): 218 (M7)

BOE pga REFPEZRENCE EXAMPLE 118 ' :

Toa og hed od Cl Coy 4b Tory cH Ln Mes

EH He it od = WEE 1 wr Lo — . ! vl CR LH : = !

Eon wl Fu Eo cH So Cpl ST Co os boon 15 3 LL pele

Foie ml oF 2 - PRETRIN

Fog 2 on Lo Thar oo de FE 3.Methyl-3-phenylbutanoic acld (0:90 g) was - Vth. yup

Ea Ey dropwise added to a suspension of lithium aluminum’ % SE £0 Re EE aad ial :

Pon car ! } , PoE a Cw ew SD } ol wor 0 "| hydride (0.2 g) in 15 ml of tetrahydrofuran. at roém%. i: » wo TAL Lp . v eo ea Sit PRS Lo 13d i ER 5 ne enn rap RE ge i Ee 20 temperature and the mixture was stitred for 30 mine

Sn SER : CL ERA TUE oh noon Ee a : . CL Ea ul REESE aoa & ww "utes, To the reaction mixture was added a saturated Lg’ oo Ae + : : aA Like dB dE Broad ~~. ‘aqueous solution of sodium bicarbonnate under ioe SS 3: on ; . . Lo. , SL Ly Sf To cot .

ES Cod CC foo Ce iH 5 al cooling, and the reaction sbiution was “extracted with : op Bye so bon TT tape de or Goon Ea ethyl acefate. The organic layer wab washed with g x Sv

Sob wd Lo RR SE

Toe dhe 25 saturated aqueous solution of sodtum chloride, dried : .,. wo EE ) : } FOTN sat ge ooh Ee Lh +1 Ala TL conn Eo over anhydrous magnesium sulfate and concentrated; oF

Co So rp : ‘ %. i Eom : wa Ro

So Re under reduced pressure. The resultant rapidun was’

Fo a CREE AY ewe. LT 5 } fa AT Co § CA . i i 3 a mo :

Eo ay subjected to silica gel column chromatégraphy (20:8)e + © 0 § Fd EA : J ar so Bo ©.

A Sd A! © ! : ’ - i ' ag

Ao Tod ct A + 3 o& a Eu | 128 « oy Th

Foor = . “i Dn

FT Cy

Elution with a hexane-ethyl acetate (5:1) mixture gave 0,75 g of 3-methyl-3-phenylbutanol.

NMR (CDC15) &1 1.10 (1H, 8), 1.34 (6H, 8) 1.92 (2H, t, J=THz), 4.48 ~ 5 (2H, t, J=THz) 7.03-7.52 (5H, m)

REBRENCE EXAMPLE 119 “Hy { M-¢ = CH, (Hy Br =, 3-Methyl-3-phenylbutanol (0.82 g) was refluxed in 47% hydrobromic acid (5ml) under heating for 7 hours. To the reaction solution was added water and the solution was extracted with ether, After washing with a saturated aqueous solution of sodium

B chloride, the ether layer was dried over anhydrous magnesium sulfate, and the residue was then subjec- ted to silica gel column chromatography. Elution with a hexane-ethyl acetate (10:1) mixture gave 1.02 g of 1-bromo-3-methyl-3-phenylbutane.

NMR (CDC15) & 1 1.33 (6H, 8), 2.04-2.33 (2H, m) 2.95-3.21 (2H, m), 7.02-7.43 (5H, m)

REFERENCE EXAMPLE 120

: CE Ga

EE Seon

Ha Se fo el

Cadena hE

Camp Chia

Chi Tn

RT 7 / Se

EL CH, CH, 0000 N= CH CH; € 4 Ra nT rvs TA = CR

Cd A solution of 1-bromo-3-methyl-3-pheiylbutane 30.13 g), ethyl piperazinecarboxylate (0.54:g) and

SE SE

““mnhydrous potssium carbonate (0.50 g) in $&trahy- ““grofuran (5 ml) was refluxed under heating “for 36 “hours. To the reaction solution was added water

SS Fane wand. the solution was extracted with ethyl ‘acetate. dE EA

After washing with a saturated aqueous solution of ged ium chloride, the ethyl acetate layer was dried idver anhydrous sodium sulfate and concentiated un-

Fider reduced pressure. The resultant residue. was “Shubjected to silica gel column chromatography {15 g) and elution with a hexane-ethyl acetdte “ik241) mixture gave 0.80 g of ethyl 4-(3-methyl=3- lh TEL iphenylbutyl)piperazine-i-carboxylate. Lh x

SESLONMR (ODC15) df 1.42 (BH; %, J=THz) , 1:32 )

EN Li

Sg (6H, so) Th » cE 1.60-2.16 (2H, m), 2515-2.46

EL Te

SEE (64, m) ti g ee 3.43 (4H, t, J=6Hz) 7 i 4.13 (2H, q, J=THz), Fx03=7.50

Eh ped

HE (58, m) BE

EE ih

Se wh

EE REFERENCE EXAMPLE 121 Cg

JRE ise

El 2

EYRE - 130 - ie : i

SE Rh Lo 5 Hi

SR Ch

CE RE

SE CE

: Ln Set

RUE CE

: M23

A solution of methyl phenylacetate (7.80 g) and 60% sodium hydride (2.1 g) in N,N-dimehtyl- formamide (70 ml) was stirred for one hour at room temperature. To the resultant mixture was dropwise added methyl iodide (10 g) under ice cooling and stirred for 3 hours at 50°C. After cooling, the resultant crystals were filtered off.

To the filtrate was added 60% sodium hydride (2.1 g) and then the resultant mixture was treated as mentioned above. Again, to the resultant filtrate was added 60% sodium hydride (0.4 g) and the mix- ture was heated for one hour at 50°C. To the mix~ ture was heated methyl iodide (2.0 g) under ice cooling and stirred for 15 hours. After adding dropwise water to the reaction solution under ice cooling, the solution was concentrated under re- duced pressure. To the residue was added water and the mixture was extracted with ether. After washing twice with water, the ether Wayer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resi=- due thus obtained was pubjected to silica gel co~-

Jumn chromatography (200 g). Flution with a hexane- ethyl acetate (1031) mixture gave 8.04 g of methyl 2-methyl-2-phenylpropionate.

NMR (CDC14) &1 1.60 (6H, 8), 3.68 (3H, 8) 7.35 (5H, br 8)

. . 272g

REFERENCE EXAMPLE 123

H, cH ry ~ noc am {Mc cn, on . =, THe = Lu,

To a suspension of lithium aluminum hydride (1.71 g) in tetrahydrofuran (50 ml) was dropwise added a soluiton of methyl 2-methyl-2-phenylpropio- nate (7.97 g) in tetrahydrofuran (20 ml) under ice cooling and the mixture was stirred at room tempe=~ rattre for 30 minutes. To the reaction solution was dropwise added water and then a saturated aqueous solution of sodium bicarbonate, and the solution was extracted with ether, The ether layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The re- sultant residue was subjected to silica gel (100 g) column chromatography. Elution with a mixture so- lution of hexane-ethyl (2:1) gave 6.32 g of 2-me- thyl-2-phenylpropanol.

NMR (CnC) &: 1.32 (6H, s), 1.72 (1H, 8) 3,61 (2H, 8), 7.10-7.61 (5H, m)

REFERENCE EXAMPLE 124 oo | DIRS

Cr Cry { Nc Soon 5 NC aw

Tony = cy ) 5 To a solution of oxalylchloride (4.1 ml) in dichloromethane (100 ml) was added dropwise a so- lution of dimethylsulfoxide (7.14 g) in dichloro- methane (10 ml) at -60° C, and the mixture was stirred for 10 minutes. Yo the resultant mixture was added a solution of 2-methyl-2-phenylpropanol (6.16 g) in dichloromethane (15 ml) at &he same temperature, After stirring for one hour, to the mixture was added triethylamine (20.7 g). The mix- ture was further stirred for 30 minutes and allowed to room temperature, After adding water, the mix- ture was extracted with dichloromethane. The extract was washed with a sattmated aqueous solution of so- dium chloride, dried over anhydrous magnesium sul- - fate and concentrated under reduced pressure. The resultant residue was subjected to silica gel (40 g) column chromatography and elution with 2% ethyl ace- tate~hexane solution gave 4.93 g of 2-methyl-2~phe- nylpropanol.

HMR (Cet) & : 1.46 (6H, 8), 7.38 (SH, 8) 9.51 (1H, s)

ITR3

REFERENCE EXAMPLE 125

CHy CH 1 Ph, PCHCOOCH 3 { Y-¢ owe Amd { M¢ CCi=CH-C00CH, wr | ral \

CH, (Hy

A solution of 2-methyl-2-phenylpropanol (0.30 g) and methyl triphenylphosphylideneacetate (0.74 g) in tetrahydrofuran (7ml) was refluxed under heating for 6 hours and the reaction solution was concen- trated under reduced pressure. The resultant re- sidue was subjected to silica gel (25 g) column chromatography and elution with hexane-ethyl ace- tate (2:1) mixture gave 0.37 g of methyl 4-methyl-4- phenyl-2-pentenoate. 0

NMR (cDC15) #1 1.46 (6H, 8), 3.75 (3H, 8) 5.82 (1H, 4, J=17Hz) 7.19 (1H, 4d, J=17Hz) 7.30 (5H, 8)

RIEFRRENCE EXAMPLE 126

CH, Hy { N- (= (H=CH=CO0CH; — (ent coocts png t om cH CH 3 }

To a solution of methyl 4-methyl-4-phenyl-2-

pentenocate (0.3 g) in absolute methanol (10 ml) was added metallic magmesium ribbons (0.36 g) and the mizture was stirred at room temperature for 2 hours. To the reaction mixture was added 10% hy- - 5 drochloric acid and then the mixture was extracted with ethyl acetate. The extracttwas washed with a gaturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concen- trated under reduced pressure to yield 0.30 g of methyl 4-methyl-4-pheuylpentanocate.

NMR (CDC15) 4&1 1.35 (64, 8), 2.05 (4H, 8) 3.63 (3H, 8), 7.01=7.52 (5H, m)

REF RENCE BXAMPLE 127

The following compound was obtained in the game manner as in Reference Lxample 118. oo Cs {YC - cng Cu 00 4-Methyl-4-phenyl-pentanol

NMR (cnc 4) 81 1.32 (6H, s), 1.10-1.92 (4H, m) 1.56 (1H, 8), 3.51 (2H, +t, J=THz) 7.05-7.50 (5H, m)

S123

REFERENCE RXAMPLE 128

The following compound was obtained in the same manner as in Reference Example 119.

Co a = Cy Cy BE

Ve ily t1-Bromo-4-methyl-4-phenyl- pentane

NMR (cnet) &: 1.32 (6H, 8), 1.40-1.91 (4H, m) 3.29 (2H, t, J=6Hz), T¢e11=T7.48 (5H, m)

REFERENCE EXAMPLE 129

The following compound was obtained in the same manner as in Reference Example 120. i. 1 - pr 3 / ™ - 7

CH, CH DEON N= CHC C8) ¢ 4 (Hy

Ethyl 1-(4-methyl-4-phenyl- pentyl )-piperazine-4-carbo- xylate

NMR (CDC) &: 1.25 (3H, t, J=THz), 1.32 (6H, 8) 1.08-1.93(4H, m), 2.08-2.53(6H, m)

- Mls 2/123 3.48 (4H, t, J=6Hz), 4.29(2H, q,

J=THz) 7.09-7.52(5H, m) - 5 REFERENCE EXAMPLE 130

The following compound was obtained in the game manner as in Reference fixample 121. (My

IN !

HA N= City CH, CH, = C <4 \./ ’ : ' mms hg 1-(4=Methyl-4-phenylpentyl) piperazine

NHR (CnC14) gt: 1.07-1.45(2H, m), 1.32(6H, 8) 1.45-1.77(2H, m), 1.70(1H, 8) 2.08-2.45(HH, m), 2.87(4H, t,

J=6Hg ) 7.01-7.43(51, m)

MS{m/z) : 246 (mh)

Lt Pot J [#8

EXAMPLE 1 (MN (1, CH; 5CH3

A mei

Sy ; : ’ cOoC(CHy hy

To a solution of 600 mg of N-tert-butoxycarbo- nyl-2-(3-pyridyl)thiazolidine-4-carboxylic acid in ml of tetrahydrofuran, there were added, at 4°c or below, 390 mg of L-methionine methyl ester hy- 10 drnchloride, 390 mg of 1-hydwoxybenzotriazole, 190 mg of N-methylmorpholine and 440 mg of dicyclohexy- lcarbodiimide, ig that order, The mixture was stirred at 4°C or below for 1 hour and then at room temperature for 1 hour. The resultant precipitate was filtered ofi, the filtrate was concentrated un- der reduced pressure, 50 ml of ethyl acetate was added, the insoluble matter was filtered off, and the filtrate was washed in sequence with 0.5 M aqueous citric acid, water, 5% aqueous sodium hy- drogen carbonate and water, dried over enhydrous ) sodium sulfate and concentrated under reduced pres= sure to give 440 mg of (H-tept-butoxycarbonyl-2-(3- pyridyl)thiazolidine-4-carbonyl)-L-methionine me- thyl ester as an abl.

NMR (CnC) ©y 1.36 (9H, 8), 1.8-2.2 (3H, m), 2.2-2,.6 (20, m), 3.26 (1H, 4d), 3,6 (1H, dd), 3.78 (3H, s), 4.6-4,8(1H, m), 4.86 (1H, dd), 6.02 (1H, 8), 7.3 (1H, dd), 7.8-80

- ope (1H, m), 8.52 (1H, dd), 8.65 (1H, dd)

EXAMPLE 2 /° 1 lp CH) gril ; CY CONRCHLOOCH,

CHO

To a solution of 1.3 g of N-formyl-2-(3-pyridyl) -thiazolidine~4-carboxylic acid in 50 ml of tetrahy- drofuran plus 10 ml of N,N-dimethylformamide, there were added, at 4°C or below 1.16 g of L-methionine methyl ester hydrochloride, 1.17 g of 1-hydroxyben- zotriazole, 560 mg of N-methylmorpholine and 1.32 g of dicyclohexylcarbodiimide, in that order. The mixture was dtirred at 4° ¢ or below for 1 hour and then at room temperature for 1 hour. The reaction mixture was then treated in the same manner as in

Example 1. Purification by silica gel column chro- matography (eluent: chloroform-methanol (9:1)) gave . 820 g of (N-formyl-2-(3-pyridyl)thiazolidine-4-car- bonyl)-L-methionine methyl ester as an oil,

Elemental analysis (for C, Hp N5987)

N (%)

Calculated: 10.96

Found: 10.62

NMR (€nci,) §: 2.08 (3H, 8), 1.8-2.6 (4H, m), 3.2-3.5 (1H, m), 3.8 (3H, 8), 3.5-3.8 (1H, m), 4.5-4.8 (1H, nm), 4.8-5.1 (1H, m), 6.1 4nd 6.41

(s, respectively 1H), T7.2-7.5 (1H, m), T7.8=- 8.0 (1H, m), 8.34 (1H, 8), 8.4-8.9 (2H, m)

EXAMPLE 3 - 5 77 Cl Ch ety ah N A CONHCHCO0CH

THY L200) prifluoroacetic acid (5 ml) was added to 430 mg of (N-tert-butoxycarbonyl-2-(3-pyridyl)thiazolidine- 4-carbonyl )-L-uethionine methyl ester with ice coo- ling, and the mixture was stirred at room tempera- ture for 2 hours. The reaction mixture was concen- trated under reduced pressure. Ethyl acetate was added to the residue, and the mixture was again con- centrated under peduced pressure. The residue was dissolved in 5 ml of ethyl acetate, and 1 ml or 4 N hydrochloric acid in dioxane was added with ice coo- ling. The resultant crystalline precipitate was collected by filtration, washed with ethyl acetate and dried to give 300 mg of (2-(3-pyridyl)thiazoli- dine-4-carbony¥)-L-methionine methyl ester dihydro- chloride.

Melting point 110 ¢.

Rlemental analysis (for C,5tpgN5048,01) c (%) H (%) N (%)

Calculated: 40.36 5.64 9.41

Found: 40.00 5.35 9.24

JR?

EXAMPLE 4 ) CH nz on 1) not

Af ~ COOH + Hy NCH —_— \

NY i | 7) (F3CO0H

COL (CY); COOCH, - HC 3) Hel tel () cnc on, aid nN CONHCHCOOCH

SN S20

To a solution of 600 mg of N-tert-butoxycarbo- nyl-2-(3-pyridyl)thiazolidine-4-carboxylic acid in 5 ml of tetrahydrofuran, there were added, at 2°c or below, 350 mg of L-leucine methyl ester hydro- chloride, 390 mg of 1-hydroxybenzotraizole, 190 mg of N-methylmorpholine and 440 mg of dicyclohexyl ~ carbodiimide, in thet order, and the mixture was stirred overnight in an icehouse. The resultant precipitate was filtered off, the filtrate was concentrated under reduced pressure, 50 ml of ethyl acetate was added, the insoluble matter was fil- tered off, and the filtrate was washed in sequence with 0.5 M aqueous citric acid, water, saturated aqueous solution of sodium hydrogen carbonate and water, dried over anhydrous sodium sulfate and con- centrated under reduced pressure to give 830 mg of oily (N-tert-butogycarbonyl-2-(3-pyridyl)-thiazo- 1idine-4-carbonyl)~L-leucine methyl ester. Tri- fluoroacetic acid (3 ml) was added to 800 mg of the thus-obtained compound with ice cooling, and the mixture was stirred at room temperature for 3 hours.

The reaction mixture was concentrated under reduced pressure, 10 ml of ethyl acetate was added and the solution was again concentrated under reduced pres- sure. The residue was dissolved in 10 ml of ethyl acetate, 3 ml of 2.2 N hydrogen chloride solution in dioxane was added with ice cooling, and the mix- ture was allowed to stand overnight in an icehouse.

The resultant crystals were collected by filtra- tion, washed with ethyl acetate and dried to give 510 mg of (2-(3-pyridyl)thiazolidine-4-carbonyl)-L- leucine methyl ester dihydrochloride. Melting point 97-100"C.

Elemental analysis (for C,H, 3N5035.2HC .4/5H,0)

Cc (%) H(%) nN (%) s (%)

Calculated: 45.24 6.31 9.89 7.55

Found: 45.21 5.98 9.85 T+55

EXAMPLE 5 al CHa CH

CY CONMCHCOD CH * 24CH - nd M

N-tert-Butoxycarbonyl-2-(3-pyridyl)thiazolidine -A-carboxylic acid and D,I-c-aminobutgric acid me- thyl ester hydrochleride were used as the starting materials and treated in the same manner as in Exam- ple 4 to give 2-(2-(3-pyridyl)thiazolidin-4-yl)car-

Hie3 bonylaminobutyric acid methyl ester dihydrochloride.

Melting point 98-100" C.

Elemental analysis (for Cy4H{gN3058.2HC1.H,0)

Cc (%)

Calculated: 42,00

Found: 42.08

EXAMPLE 6

S CH, (Hy SCH;

A J ! - JHC

CY NS CONHCRLOOC Hg

JH

N-tert-Butoxycarbonyl-2-(3-pyridyl)thiazolidine -4~carboxylic acid and D-methionine ethyl ester hy- drochloride were used as the starting materials and treated in the same manner as in Example 4 to glve (2-(3-pyridyl)thiazolidine-4-carbonyl)-D-methionine ethyl ester dihydrochloride. Melting point 94-96°C. - * 1 H a * 1

Elemental analysis (for C,etasNg035, 2HC1.4/5H,0) ¢ (4) H(%) N(%) C (#) C1 (%)

Calculated: 42.07 5.87 9,20 14.04 15.52

Found: 42.17 5.89 8.89 13.77 15.68

EXAMPLE 7

S City CHy SCH

A ) MEE ua

Cl N~ CONNCICONR

Wo) H

N-tert-Butoxycarbonyl-2-(3-pyridyl)thiazolidine -4-carboxylic acid and L-methioninamide hydrochloride were used as the starting meterials and treated in the same manner as in Example 4 to give (2-(3~ pyridyl)thiazolidine-4-carbonyl)-L-methioninamide dihydrochloride. Melting point 131°C.

C 5 MS: m.z 340 (MY-2HC1) : EXAMPLE 8

OY.

CY CONHCH,CO0C Hy - 24H nto"

N-tert-Butoxycarbonyl-2-(3-pyridyl)thiazolidine ~-4-carboxylic acid and glycine ester hyrochloride were used as the starting materials and treated in the same manner as in Example 4 to glve (2=-(3-pyri- dyl)-thiazolidine-4-carbonyl)glycine methyl ester dihydrochloride. Melting point 116-118 C.

Elemental analysis (for Cy Hy 5N5038.2HC1.H,0) c (#) - HH (F) N (%)

Calculated: 38.72 5.14 11.29

Found: 38.99 4.62 10.99 ‘ 1) Ni, Cg (Hy CH) SCH3

Z A coon | Dehe ’s CJ Cooley) HNHA a

A whoa

XN- 2 HA

$}RS ! To a solution cf 600 mg of N-tert-butoxycarbonyl —2-(3-pyridyl)thiazolidine-4-carboxylic acid in 10 ml of tetrahydrofuran, there were added, at 4" C or ; below, 200 mg of %-methylthiopropylamine, 390 mg of nN 5 1-hydroxybenzotriazole and 440 mg of dicyclohexyl- carbodilmide, ig that order, and the mixture was stirret at room temperattre {for 3 hours. The resul- tant precipitate was filtered off, the filtrate was concentrated under reduced pressure, and the resi- due was dissolved in 50 ml or ethyl acetate. The ethyl acetate so.ution was washed in sequence with 0.5 M aqueous citric acid, water, saturated aqueous solution of sodium carbonate and water, dried over anhydrous sodiui sulfate and concenirated under re- duced pressure %o0 give 250 mg of M=-(3-methylthio- . propyl )-3-tei t-butoxyearbonyl-2-(3-pyridyl)thiazo= 1idine-4-carboxamide. prifluoroacetic acid (2 ml) added to 250 mg of the thus-obtained compound with jce cooling, and the mixture was treated in the same manner as in Example 4 to give 130 mg of N-(3- methylthiopropyl)-2-(3-pyridyl)thiazotidine-4-carbo= xamide dihyirochloride as an oll. .

Hi (DI50-d¢) gs: 1.6-1.9 (2H), 2.08 (31), 2.4-2.6 (2H), 3.0-3,7 (41), 4.50 (11), 5.9-6.1 (1H), 7.4-9.2 (4H)

27 123

EXAMPLE 10 @®

OY conn) cy wa

SN

} 5 N-tert-Butoxycarbonyl-2-(3-pyridyl)thiazoli- dine-4-carboxylic acid and n-heptylamine were used as the starting materials and treated in the same manner as in Example 9 to give N-n-heptyl-2-(3-py- ridyl)thiazolidine-4-carboxamide dihydrochloride.

NER (0180-1, ) €1 0.6-1.1 (3H), 1.1-1.8 (10H), 2.9-3.9 (4H), 4.4-4.7 (1H), 6.20 (1H), 8.0-8.3 (1H), 8.6-9.3 (3H)

EXAMELE 11

BN Q

~ Jhon) - ING

CY

SN .

N-tert-Butoxycarbonyl-2-(3-pyridyl)thiazoli- dine~4-carboxylic acid and 2-aminopyridine were . used and treated in the same manner as in Example 9 to give N-(2~-pyridyl)-2-(3-pyridyl)thiazolidine -4-carboxamide trihydrochloride. Melting point 145°C.

Elemental analysis (for Cially78,08C15)

Cc (%) H (%) 5 (%)

Calculated: 42.49 4.33 8.10

Found: 42.83 4.58 8.03

EXAMPLE 12 a end) C2H0 nN OCH, 5 . N-tert-Butoxycarbonyl-2-(3-pyiidyl)thiazoli- dine-4-carboxylic acid and o-anisidine were used and treated in the same manner as in Example 9 to give N-(2-methoxyphenyl )-2-(3pyridine)thiasolidine -4-carbovamide dihydrochloride. Yield, 68%. Mel- ting point 129°,

Flemental analysis (for Cig gli50,5C15) ¢c (%) H (#%) no)

Calculated: 49.49 4.93 10.82

Found: 49.29 5.18 10.38

SEAMFLE 13 — = fmpne) OCH; + 2HC

A mixture of 630 mg of 2-(3-pyridyl)thiazoli- Ce dine-4-carboxylic acid, 350 mg of m-anisidine, 650 mg of dicyclohexylcarbodiimide and 430 mg of 1-hy- droxybenzotriazole in & ml of dimethyl formamide was stirred overnight at room temperature. The reaction mimture was diluted with 50 ml of ethyl acetate, and the insoluble matter was filtered off.

The filtrate was washed with two portions of water, and then with aqueous solution of sodium hydrogen carbonate, water and saturated aqueous solution of sodium chloride in that order, dried over anhydrous sodium sulfate and concentrated under reduced pres- sure. The residue thus obtained was purified by preparative thin layer chromatography to give 230 mg of N-(3-nethoxyphenyl)=-2-(3-pyridyvl)thiazolidine -4A-carboxamide. This compound was dissolved in eth- yl acetate, and 1 ml ot 2 N hydrogen chloride solu- tion in dioxane was added. The resultant solid was collected by filtration, washed with ethyl acet:te and dried to give 250 mg of N-(3-methoxyphenyl )-2- (3-pyridyl)thiazolidine-4-carboxamide dihydrochlo- ride. Melting onint 129°C.

Elemental analysis (for CigHighs0,8¢1,)¢ c (4) H (%) N (%) s (#%)

Calculated: 49.49 4.973 10.82 8.26

Found: 49.49 5.08 10.56 8.24

EXAMPLE 14

Fo 0 yi om . 2HC1 -

N

The procedlure of Example 13 was followed using 2-(3-pyridyl)thiazolidine-4-carboxylic acid and 2- phenyl-ethylamine to give N-(2-phenylethyl)-2-(3- pyridyl)thiazolidine-4-carboxamide dihydrochloride.

Yield, 81%. Melting point 115 C.

Rlemental analysis (for Cyl, N508C1,)1

D7 123

C(#) H(%) N(#) S(%)

Calculated: 52.85 5.48 10.88 8.30

Found: 52.25 5.74 10.77 8.16 : 5 EXAMPLE 15 57

J con (city ) sci; 2HoL

Lg

N-(3-Methylthiopropyl)=-2-(4-pyridyl)thiazoli- dine-4-carbéxanide dihydrochloride was obtained from the compound obtained in Reference Example 2 and

F-methylthiopropylanine by following the proeédure of Example 13. Melting point 70°C. :

Elemental analysie (for Cy3Hy N508,C15)

C(%) H(%) N(%)

Calculated: 42,16 5.72 11.35

Found: 41.65 5.83 10.87

EXAMPLE 16 3 7] © A CONH(CH, ) 55CH5 101

Su H

N

A solutionof 1.50 g of pyridine-2-carboxalde=- hyde and 1.70 g of L-cystelinr in 50% ethanol was stirred at room temperature for 4 hours. The inso- lubde matter was filtered off, and the filtrate reaction mixture was concentrated under reduced pres- gure. The thus-obtained syrupy substance was dissolved in 35 ml of tetrahydrofuran. To the molution were added 2.89 g of dicyclohexylcerbodiimide, 1.89 g of 1-hydréxybenzotriazole and 1.62 g of 3-methyl- thiopropylawine, and the mixture was stirred over- night at room temperature, The reaction mixture was diluted with ethyl acetate, and the insoluble matter was filtered off. The filtrate was washed with water (twice), ngueons sodium hydrogen carbonate, water (twice) and saturated aqueous solution of sodium chloride in that order, dfled over anhydrous sodium - sulfate and concentrated under reduced pressure. The residue obtained was purified by column chromato=- graphy (eluent: tolueneethyl acetate=1:1) to give 1.50 4 of H-(3-methylthiopropyl)-2-(2-pyridyl)thia- solidine-4-garboxamide. A 800-mg portion of this com- pound was disso¥ved in ethyl ‘acetate, and 2N hydrogen chloride solution in dioxane wos added. The solvent was distilled off, and the residue was dried to give 830 my of l-(3-methylthiopropyl)-2-(2-pyridyl)- . thiazolidine-t-carboxamide hydrochloride. Melting point 65°C.

Elemental analysis (fou Cy5H,,N50,8,01) c(%) H(%) N(%) S(%)

Calculated: 44.31 6.30 11.94 18.22

Found: 44.59 6.09 11.79 18.38

EZAMPLE 17 i" — n JUL - 5 ~r- COOH H, OCH, BN ~ EE 4 : DCC, HOBT 2) HCl 908s be Cy

CJ I oo, - 2HOL

HB

A mixture of® 630 mg of 2=(3-pyridyl)thiazoli- dine-t-carboxylic acid, 520 mg of 3,4,5-trimethoxy- aniline, 650 mg of dicyclohexylcurbodiimide and 430 mg of 1-hydroxybenzotriazole in 8 ml of N,N-dimethyl- formamide was stirred overnight at room temperature.

The reaction mixture was diluted with ethyl acetate and the insoluble matter was filtered off. The fil- trute was washed in sequence with aqueous sodium hydrogen carbonate, water and saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Purification of the residue by silica gel column chromatosraphy (eluent: ethyl acetate ) gave 370 mg of N-(3,4,5-trimekhoxyphenyl)=2-(3= pyridyl)thiazolidine-4-carboxamide. This compound was dissolved in 10 ml of ethyl acetate, and 2 ml of 2 N hydrogen chloride solution in dioxane was addedl The resultant eolid was collected by filtra- tion, washed with ethyk acetate and dried to give 200 mg of N-(3,4,5-trimethoxyphenyl)-2-(3-pyridyl)- thiazolidine-4-carboxamide dihydrochloride. ‘Melting point 130-132°C.

Elemental analysis (for C,ygtiozN30,5 Cl,): c(%) H(#) N(%) S(%)

Calculated: 48,22 5.17 9.37 T.15 : 10 Found: 48,23 5.35 9.02 T.12

EXAMPLE 18 eo net b 15 . YY CONH + 2HCL

WJ oH

N-Phenyl-2-(3-pyridyl)thiaz olidine-4~-carboxa- mide dihydrochloride was obtained from 2-(3~-pyridyl)- thiazolidine-4-carhoxylic acid and aniline by follow=- ing the procedure of Example 17. Melting point 145-148°C.

NMR (DMs 0-4.)

Ht 3.4-4.2 (2H), 4.96 (1H, t), 6.31 and 6.35 (respectively 1H), 7.0-7.4 (3H), 7.6-7.8 (2H), 8.10 (11,44), 8.9-9.0 (2H), 8.3 (1H)

9Fi2%

EXAMPLE 19

J

20H, — 1) H,N CH, IY « H , 3 : N 2) HCl - conti-ci,—(_)

H = ~~ °2HC1 :

N-Benzyl-2-(3-pyridyl)thiazolidine-4-carboxa- mide dihydrochloride was obtained from 2-(3-pyridyl)- thiazolidiine-4-carboxylic acid and benzylamine by following the procedure of Example 17.

Melting point 126-130°C.

NMR (DMSO-d) 5: 3.2-3.7 (2H), 4.3-4.6 (3H), 6.08 and 6.14 (respectively 1H), 7.3 (5H), 8.06 \ (1H, dd), 8.7-9.0 (2H), 9.1-9.2 (1HO ”

EXAMPLE 20 §—

CJ A= conit=0ti,—{ y— CH .2HC1 x I

N-(p-Methylbenzyl)-2-(3-pyridyl)thiazolidine- 4-carboxamide dihydrochloride was obtained from

EXAMPLE 19

J Y

1) H, NCH, — lL | H —_— “N 2) HCl

I ) ~ N CONH=CHy —{ 3

X | H —

N° *2HC1

N-Benzyl-2-(3-pyridyl)thiazolidine-4-carboxa- mide dihydrochloride was obtained from 2-(3-pyridyl)=- thiazolidine-4-carboxylic acid and benzylamine by following the procedure of Example 17.

Melting point 126-130°C.

NMR (DMSO-d)

Fy 3,2-3,7 (2H), 4.3-4.6 (3H), 6.08 and 6.14 (respectively 1H), 7.3 (5H), 8.06 (1H, dd), 8.7-9.0 (2H), 9.1-9.2 (1HO

EXAMPLE 20 ;

I N CONH~CH, —( )—- CH .2HC1 «N. H Nome / :

N-(p-Methylbenzyl)-2-(3-pyridyl)thiazolidine- 4-carboxamide dihydrochloride was obtained from

Ales 2-(3-pyridyl)thiazolidine-A-carboxylic acid and p-methylbenzylamine by following the procedure of

Exampla 17. Yield, 58%. Melting point 130-136°C.

Elemen&al analysis (for CyqHy 4 N505C1,) 8 » 5 Cc (%) H (#) N (%) S (%)

Calculated: 52.85 5.48 10.88 8.30 © XAMPLE 21

Sa 3 -(c A 20 4 CONH-(CH,) , 7) 2CH1

N

N-(4-Phenylbutyl)-2-(3-pyridyl)thiazolidine-4- carboxamide dihydrochloride was obtained from 2-(3=- pyridyl)thiazolidine-4-carboxylic acid and 4-phenyl- butylamine by following the procedure of Example 17.

Yield, 63%. Melting point 100-104°C,

Elemental analysis (for C,gHy5N305C1,0.2H,0)1

C(%) H(%) N(%) 8 (%£) C1 9%)

Calculated: 54.36 6.15 10.01 7.64 16.84

Found 54.44 6.16 10.08 7.68 16.59

EXAMPLE 22 8

CH

ST es = N~"CON TN

C cend Ny W2HCH 0 H A

: ~~. o’7 123 :

N-Benzyl-N-methyl-2-(3-pyridyl)thiazolidine-4- carboxamide dihydrochloride was cbtained from 2-(3- pyridyl)thiazolidine-4-carboxylic acid and N-methyl- benzylamine by following the procedure of Example 17.

Melting point 105-110°C.

Elemental analysis (for Cy7Hy4N508C1,H,0):

Cc (%) H(%) N (%) 8 (%) C1 (#)

Calculated: 50.50 5.73 10.39 7.93 17.54

Found: 50.63 5.60 10.43 7.98 17.26

EXAMPLE 23 : I | 1) H n-oiiz{_-o-(c 7

C N COOH 2 2 274 \_ ;

N / 2) HCH 5

Jo ~~ -— / ~~ J 4 N- CONH cng Yo (CH, ), { )

N~ + 2HC

N-(p-(4-Phenylbutoxy)benzyl)-2-(3-pyridyl)thia- z0lidine-4-carboxamide dihydrochloride was obtained from 2~-(3-pyridyl)thiagolidine-4-carboxylic acid and p-(#-phenylbutoxy)benzylamine by following the proce- dure of Example 17. Yield, 72%. Melting point 133=~ 135°C.

Elemental analysis (for CogHzqN30,501,°0.2H,0)1

Cc (%) H(#%) N(%) s (%) C1 (#)

Calculated: 59,58 6.04 8.02 6.12 13.53

Found: 59.58 6.02 7.96 6.23 13.58

BXAMPLE 24

S—

OY r-oomon-o-con ), 2HC1 «FH Nore 26

N-(p-Heptyloxybenzyl)-2-(#-pyridyl)thiazolidine-4- carboxamide dihydrochloride was obtained from 2-(3-py- ridyl)thiazolidine-4-carboxylic acid and p-heptyloxy- benzylamine by following the procedure of Example 17.

Melting point 155-160°C.

Elemental analysis (for C,5H35N50,C1,0.3H,0):

Cc (%) MH (%) N(%) 8 (%) C1 (%)

Calculated: 56.16 6.88 8,54 6.52 14.41

Found! 56.11 6.84 8.47 6.53 14.50

EXAMPLE 25

S- oy aeons + 2HC1 <x) o-(eny nf)

N-(m-(4-phenylbutaxy)benzyl)-2-(3-pyridyl)thia- zoljdine-carboxamide dihydrochloride was obtained from 2-{3-pyridyl)thiazolidine-4-carboxylic acid and m-(4-phenyl-butoxy)benzylamine by following the procedure of Example 17. Yield, 41%.

Melting point 88-93°0C.

Elemental A nalysie (for C, Hz N30,8C1 *0.5H,0) t

T7423 uy

C(%) H(%) N(%) 8(%) 0CL(%)

Calculated: 58.97 6.09 7.94 6.06 13.39

Found: 58.96 6.07 7.96 6.11 13.36

E 5 EXAMPLE 26 1 or “conna—ch,—( \ * 2HC1

H = 0-(CH, ) (CH

N-(m-Heptyloxybenzyl)-2-(3-pyrtdyl)thiazolidine- 4-carboxamide dihydrochloride was obtained from 2-(3-pyridyl)thiazolidine-4-carboxylic acid and m-heptyloxybenzylamine by following the procedure ! 15 of Example 17. Melting point 135-140°C.

Elemengal analysis (for C,5li55N50,8C1,):

C(%) H(%) N(%) S(%)

Calculated: 56.76 6.84 8.64 6.59

Found 56.68 6.85 8.69 6.62

EXAMPLE 27 ry conn I § . 1 LL xN 3-(CH,), a, 2HC1

N-(5-((4-phenylbutyl)thio)-1,3,4-thiadiazol~ 2-yl)-2-(3-pyridyl)thiazolidine-4-carboxamide dihy-

drochloride was obtained from 2-(3-pyridyl)thia- zolidine-4-carboxylic acid and 2-amino-5-((4- phenylbutyl)thio)-1,3,4~thiadiazole by following the procedure of Example 17. Melting point 99-105°¢C.

Elemental analysis (for Cy Hy5053C1,)¢

C(#) H(%) N(%) S(%)

Calculated: 47.54 4.75 13.20 18.13

Found: 47.58 4.84 13.09 18.28

EXAMPLE 28 x oP H CONH- (CH, )5=5-CH, *2HC1

N-(3-Methylthiopropyl)=-2-(3-quinolyl)thiazo~ lidine-4-carboxamide dihydrochloride was obtained from 2-(3-quinolyl)thiazo}idine-4=-carboxylic acid ) and 3-methylthiopropylamine. Melting point 122- 126°C.

Elemental analysis: (for 07M, 5NgS,01,° 0. 5H 0):

C(%) H(%) N(#) 8(%) CL(%)

Calculated: 47.55 5.63 9.78 14.93 16.51

Found: 47.57 5.72 9.75 15.02 16.47

S123

EXAMPLE 29 5] /

SN coNER (CHL) ) 2HO

Q H 2° __,

SNE

: N-(4-Phenylbutyl)-2-(3-quinolyl)thiazolidine- 4-carboxamide dihydrochloride was obtained from 2-(3-quinolyl)thiazolidine-4-carboxylic acid and 4-phenylbutylamine by following the procedure of

Example 17. Yield, 53%. Melting point 116-122°¢C.

Elemental analysis (for CygHyqN505C1 4):

Cc (%) H (%) N (%) 8 (#)

Calculated: 59.48 5.86 9.05 6.90

Found 59.13 5.84 8.99 7.14

EXAMPLE 30 5

DCC

- 20 oo id ] SN HOBT HCY ] N-GcooH + HN J — | —— ~g- EH “. (7

Oy ihe 0) .2HC1

NN I \ . 25 2-(3-Pyridyl)thiazolidine-4-carboxylic acid and pyrrolidine were used as the starting mate- rials and treated in the same manner as in Exam-

- dfies ple 17 to give 1-(2-(3-pyridyl)thiazolidine-4- ylcarbonyl)pyrrolidine dihydrochloride. Mel- ting point 136°C.

NMR (DMSO-6.) &: 1.60-2.13 (4H, m), 3.0-3.90 (6H, m), 4.55 -4.71 (1H, m), 6.09 and 6.26 (s, respec- tively 1H), 8.08 (1H, dd), 8.72-9.20 (3H, m)

EXAMPLE 31 ¢) —_ DCC HCY oy N ~cooit + 0 HOB 3 1 Cy de £0 Lene “ H / 2-(3-Pyridyl)thiazolidine-4-carboxylic acid and morpholine were used as the starting materials and treated in the same manner as in kxample 17 to give 4-(2-(3-pyridyl)thiazolidin-4-ylcarbonyl)mor- ) pholine dihydrochloride. Melting point 143°C.

NMR (DMSO-d) st 2.97-3.78 (10H, m), 4.62-4.78 (1H, m), 6.00 and 6.23 (s, respectively 1H), 8.05 (14, dd), 8.71-9.10 (3H, m)

EXAMPLE 32 ped : ] anya HOB

C] N- COOH + HN Y-/ \ ee eer mre)

N- H Net

S.

AAA EO

N “5 — *3HC1

J po C0 ON ’ 2-(3-Pyridyl)thiazolidine-4-carboxylic acid and 1-phenylpiperazine were used as the starting mater- {als and treated in the same manner as in Example 17 to give 1-phenyl-4-(2-(3-pyridyl)thiazolin-4-ylcarbo- ) nyl)piperazine trihydrochloride. Yoeld, 79%. Mel- ting point 169°C.

NMR (DMSO-d) 81 3.04-4.20 (10H, m), 4.64-4.84 (1H, m), 6.00 and 6.23 (8s, respectively 1H), 7.04-7.64 (5H, m), 7.99-8.14 (1H, m), 8.70-9.16 (3H, m)

EXAMPLE 33

S o ~ A /\ hope HC!

Cl N~ “COOH + HN D __HoBT 5 ~ H NL "N

Lo) ~~ JR .2HC

CY N~ Co \_/

H

© odes

I

27123 2-(3-Pyridyl)thiazolidine-4~-carboxylic acid and piperidine were used as the starting materials and treated in the same manner as in Example 17 to give 1-(2-(3-pyridyl)thiazolin-4-ylcarbonyl)pipe- - 5 ridine dihydrochloride. Yield, 48%. Melting point 172°C. flemenkal analysis (for Cy 4H N508C1, +0. 30,0)

Cc (#) H ($6) N(#) s (%) C1 (%)

Calculated: 47.27 6.12 11.81 9.01 19.93

Found: 47.36 6.03 11.75 9.01 19.71

KXAMPLE 34

Bl = i DCC “w Hw HOBT HC1

Ny,» H COOH + HN my ) 15 2 — £) g _.

C) SN conn! 1) PIC

N B . a 2-(3-pPyridyl)thiazolidine-4-carboxylic acid and cyclohexylamine were used as the starting ma- terials and treated in the same manner as in Kxam- ple 17 to give N-cyclohexyl-2-(3-pyridyl)thiazoli- dine-4-carboxamide dihydrochloride. Melting point 139°C.

NMR (DMs0-4,) §: 0.90-1.95 (11H, m), 3,06-%.69 (3H, m),

4.39 (1H, dad), 6.07 and 6.14 (8s, respec- tively 1H), 8.03 (1H, dd), 8.46-9,13 (3H, m)

EXAMPLE 35 5 /® DCC () _ CH HOBT HCH

C) y COOH + HyN-CilyOH CH Foy ———

SN 3 §~ ( ] CH = J CONH~CH, CH,CH- _ 3*2HC1

N- 2 2 CH 2-(%-Pyridyl)thiazolidine-4-Carboxylic acid and isoamylamine were used as the starting mater- jals and treated in the same manner as in tixample 17 to give N-(3-methylbutyl)-2-(3-pyridyl)thiazo- 1idine-4~-carboxamide dihydrochloride. Yield, 47%.

Melting point 115°C. :

Flemental analysis (for C4 4HypN505C1,°0.3H,0)1 1 g

Cc (#) H(%) nr (5) 8 (%)

Calculated: 47.14 6.39 11.78 8.99

Found: 47.24 6.59 11.56 9.10

KXAMPLE 36

A) DGC g TN [ ) HOBT HCA a N- Coon + HN at, —_—

No i AN - 5

Cd () N° con eH,

H mT Tr “N «2HC1

2-(3-pPyridyl)thiazolidine-4-carboxylic acid and 4-benzylpiperidine were used as the starting materials and treated in the same manner as in

Example 17 to give 4-benzyl-1-(2-(3-pyridyl)thia- . 5 zolidin-4-ylcarbonyl)piperidine dihydrocaloride.

Yield, 60%. “Melting point 135°C.

NMR (DitS0-dg) s1 0.76-2.06 (51, m), 2.35-4.54 (8H, m), 4.60-5.08 (14, m), 6.08 and 6.28 (8, resnectively 1H), 7.06-7.23 (5H, m), 8.07 (11, ad), 8.71-9.30 (3H, m)

EXAMPLE 37 $s ol 7 . Fy hee WOT {_ JH(CHy ~~ I HOBT en

NH- — 3 HCH 2-(3-pyridyl)thlazolidine-4-cagboxylic acid and 1-(35-phenylpropyl)plperasine were used as the starting materials and treated in the same manner as in Examnple 17 to give 1-(3-phenylpropyl)-4-(2- (3-pyridyl)thiazolidin-4-ylcarbonyl)piperazine trihydrochloride. Yield, 60%, Melting point 144 °c.

NMR (DMSO-d) §1 1.85-4.86 (1711, m), 5.97 and 6.18 (s, respectively 1H), T.10-7.48 (5H, m), 8,06 (1H, dd), 8.65-9.12 (3H, m) : 5 EXAMPLE 38

Cf J N J \ bec - lier wy HCOOH +HRL 0H); 7 jonr ’ /5 N oN } J 7 N\

CONN 4 No. \ ( | cow {Do on

N — —_— .2HC1 2-(3-Pyridyl)thiazolidine-4-carboxylic acid and p-(4-phenylbutoxy)uniline were used as the starting materials and treated 1n the same manner as in Example 17 to give N-(p-(4-phenylbutoxy)phe- nyl)-2-(3-pyridyl)thiazolidine-4-carboxamide dihy- drochloride. Yield, Ad%, Melting point 117°C.

Elemental analysis (for C,5HygN50,8C1,)

C (A) H (FH) M(H) 5 (A)

Calculated: 59.28 5.77 8.30 6.33

Found: 59.65 5.76 8.40 6.29

EXAMPLE 39

S

Ar DCC "coon + 1, N-(CH, J), CH a

N 5 ~ A

CY n CONH-(CHy) 1 gCH3 iN CN

SS.

A solution of 500 mg of dicyclohexylcarbodii- mide in 3 ml of tetrahydrofuran was added dropwise to a mixture of 510 mg of 2-(3-pyridyl)thiazolidine -4~-carboxylic acid, 490 mg of 1-hydroxybenzotria- zole, 680 mg of nonadecylamine and 12 ml of tetra- hydrofuran with ice cooling, and the resulting mix- ture was stirred with ice cooling for 1 hour and then at room temperature for 12 hours. The reac- tion mixture was diluted with 30 ml of ethyl ace- tate, and the insoluble matter wan: filtered off.

The filtrate wes washed in sequence with saturated aqueous solution of sodimm hydrogen carbonate, wa- ter and saturated aqueous solution of sodiwn chloride, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate) and recrystallized from ethyl acetase to give 250 mg of N-nonadecyl-2-(3-pyridyl)shiazolidine -4-carboxamide. Melting point 108-110°C.

Elemental analysés (for CoH, gh508°1/51,0)

G(F) H(A) N(#) 5 (8) -

Calculated: 70.30 10.20 8.78 6.70

Found: 70.37 10.34 8.83 6.80

= TT - -— SS

J(23

EXAMPLE 40 5S / ] Dee ‘8 AC00H + IH N-(CH,) CH, ——HOBL 2 279773

H

SNH

/ )

C I “CONH= (CH, ) (CH. i H 27973 “N . 2-(3-Pyridyl)thiazolidine-4-carboxylic acid and decylamine were used as the sturting materials and treated in the same manner as in fAxample 39 to give N-decyl-2-(3-pyridyl)thiazolidine-4-carboxa- mide. Yield, 80%. Melting point 88°C.

Elemental analysis (for Cy glizolz08):

Cc (Ys H(A) N (3%) S (%)

Calculated: 65.48 8.68 12.06 9.20

Found: 65.16 8.80 11.91 9.04

EXAMPLE 41 5.

B A N\ y 7 AJ soon + H,N-(CH { Jog — RE

I 2 2/2 __ HORT .

SN 000 (0H, ) oF 4 JS 3 3 / 5

A 1 J

N-“conl- (CH Wf Nox ~ 2 FN /

SN i =

COOC(CHy) 5

N-tert-Butoxycarbonyl-2-(3-pyridyl)thiazoli- dine~4-carboxylic acid and_tyramine were used as the starting materials and treated in the same manner as in Example 39 to give N-(2-(p-hydroxy- phenyl )ethyl)-3-tert-butoxycarbonyl-2-(3-pyridyl) thiazolidine-4-carhoxamide. Yield, 100%, Mel- ting point 76°C.

NMR (CDU1.,) 5 &: 1.354 (oi, m), 2.72 (2H, tt), 3.22 (1H, a4), 3.43-3.70 (3H, m), 4.80 (1H, 4d), 5.99 (1H, 8), 6.70-7.03 (4H, m), T7.19-7.32 (14, mj, T.75- 7.84 (1H, m), 8.51 (1H, dd), 8.63 (1H, 4) | EXAMPLE 42 (5) _— DCC 1 N COOH + hpN-0a0h - VHC HOBT

H v— _— ™~ ~

N § 1B -chy,

BS N_/

A ] H THF [ | n con ( x . “yo H 0-CH,—/ \

N=

HCA mm) 2HCA

A solution of 490 mg of dicyclohexylcarbodii- mide in 5 ml of tetrahydrofuran was added dropwise to a mixture of 500 mg of 2-(3-pyridyl)thiazoli-~ dine-4-carboxylic acid, 380 mg of O-benzylhydroxy-

lamine, 480 mg of 1-hydroxybenzotriazole, 240 mg of N-methylmorpholine and 15 ml of tetrahydrofu- ran with ice cooling, and the resultant mixture wae stirred with ice cooling for 1 hour and then at room teperature for 12 hours. The reaction mixture was diluted with 30 ml of ethyl acetate, and the insoluble matter was filtered off. The filtrate was washed in sequence with saturated aqueous solution of sodium hydrogen carbonate and saturated aqueous solution of sodium chlo- ride, dried over anhydrous sodium sulfate and con- centrated under reduced pressure. Purification of the residue by silica gel column chromatogra- phy (eluent: ethyl acetate) gave 260 mg of N-ben- zyloxy-2-(3-pyridyl)thiazolidine-4-carboxamide.

Thié compound was dissolved in ethyl acetate, and 1.5 ml of « N hydrogen chloride solution in dio- xane was added. The resultant solid was collec- ted by filtration, washed with ethyl acetate and dried to give 240 ag of N-benzyloxy-2-(pyridin-3- y1)thiazolidine~-4~carboxamide dihydrochloride,

Melting point 115°C.

NMR (DMSO-d) §1 3.02-352 (2H, m), 4.07-4.20 (1H, m), 4.90 (2H, ss), 6.00 and 6.08 (8, res- pectively 1H), 7.28-7.53 (5H, m), 8.07 (1H, dd), 8.64-9.26 (34, m)

H7l1e3

SA hops urge ” y N “00H HEY Clg tose J CFCOOH HCY, - 5 ne C003 (Clg) r 1 ‘Wohcoll Cll ~N H - .2HC

A solution of H4U mg of Aicyclonexylcarbodii- mide in 5 m) of tetrahydrofuran was added dropwise to = mixture of 810 mg of fM-tert-butoxycarbonyl-2- (3-pyridyl)thiazolidine~-4-carboxylic ated, 260 mg of 4-methylpiperidine, 530 mg of 1-hydroxybenzotria- zole and 10 ml of tetrahydrofuran with ice cocling, and the mixture was stirred with ice cooling for 1 hour and then at room temperattre for 12 hours. The reaction mixture was diluted with 30 ml of ethyl - 20 acetate, and the insoluble matter was filtered off.

The filtrate was washed in sequence with saturated aqueous solution of sodium hydrogen carbonate and saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate and concegkin=- ted unier reduced prepsure to gived-methyl~a-(3- tert-butoxycorbonyl-2-(3-pyridyl)shiazolidin-4- ylcarbonyl)piperidine. Trifinoroacetic acid (5 ml) was added to the thus-obtained compound, and the

AY (23 mixture was stirred atroom temperature for 1 hour.

The reaction mixtute was concentrated under re- duced pressure, tne residue was dissolved in ethyl acetate, and the solution was washed in sequence with saturated aqueous sodution of sodium hydrogen carbonate and saturated aqueous solution of sodium chloride, dried over anhdyrous godium sulfate and concentrated under reduced pressure. The residue thus obtained was purified by silica gel column chromatography (eluent: ethyl acetate) to give 4- methyl-1-(2-/3-pyridyl)thiazolidin-1-carbonyl)pi~ peridine. [hig compound was dissolved in ethyl acetate, and 3 ml of 2 N hydrogen chloride solu- tion in dioxane mas added. The reaul tant solid 1% was collected by filtration, washed with ethyl ace- tate and dried to give 530 mg of A-methyl-1-(2-(3=- pyridyl)thiazolidin-3-ylearboryl)olperidine dihy- drochloride. ilelting point 130°¢,

Rlemental analysis (for Cg, 5N508C1,) ¢ (nuh) w(B 8 (A)

Oalculated: 49.45 6.39 11.55 8.80 ee

Found: 49.59 6.60 11.47 3.63

LXAMPLE 44 °) OH, CF COOH of cools non cn 10 0 REC 2 Met 5

NT CH HOBT

500C (Cll) 5

A) Ll

C { N CONH-CH, CH, N{

N- H CH 3HCA

N-tert-Butoxycarbony!-2-63-pyridyl)thiazoli- dine-4-carboxylic acid and M,N-dimethylethylene- dlamine were used oo the starting materiale and treated in Lhe same manner as in Bxample 43 to give N-(2-N¢, N'-dimethylamino)ethyl)-2-(3-pyri- ‘dyl)thinzolidine-4-carboxamide trihydrochloride.

Melting point 150°¢.

NMR (Lis0-d)

E31 2.65-%.80 (12H, m), 4.26-4.50 (1H, m), 6.01 and 6.06 (s, respectively 1H), 5.06 (11, 4d), 8.70-2.18 (3H, m)

A ) Chg Hope CF C001 He

LG) coon + I Cede me

Co0C(Sly) 5 —

G~ _ A J OH [ | N CONN ¥ oueq He l-tert-Butoxycarbonyl-2-(3-pyridyl)thiazoli- dine-4-carboxylic acid and N-methyl-N-phenylhydra- zine were used as the starting materials and froo- ted in the same manner as in Example 43 to give N! —methyl=N'-phenyl—2-(3-pyridyl)thizzolidine-4-car- bohydiazine dihydrochloride. Yield, %8%. Melting point 145°C.

oles

NMR (DMSO-d. ) 8: 3.04-3%.72 (SH, m), 4.28-4.50 (1, m), 6.03 and 6.12 (s, respectively 11), 6.70-7.32 (5H, m), 8.07 (14, dd), B.69- . - 5 9.17 (3H, mn)

EXAMPLE 46

A © poe

ON Lm HOBT CF,CO0H HCA

T N"COOH + HN NAN —s CEA es “N | Ls ———t 10 cout (ci) ~

SY

7 non Al 3

TNC H tr 2HCH

N-tert-Butoxycarboiyl-2~(3-pyridyl)thiazoli- dine-4-carboxylic acid and 4-phenylpiperidine were used as the starting materials znd treated in the came manner as in Lxample 43 to give 4-phenyl-1-(2 -(3-pyridyl)thiazolidin-4-ylearbonyl)plperidine dihydrochloride. Yield, 48%. Melting point 115%.

NMR (DASO-d) §: 1.32-2.08 (45, 1), 2.58-3.82 (6H, m), 5.96 -5.00 (21, m), 6.04 and 6.28 (8, resoecs. tively 1H), 7.08-7.44 (5H, m), 8.06 (1H, ad), 8.68-9,16 (3H, m)

les

EXAMPLE 47 2S ™ hee

AN So HOBT C¥.,CO0H HC1 a NCOOH 4 HN NA \ ——y Ay

NT Nd Nome 100 Le i com (Cll) . a aa . NN 7 N coll YN 2HC1

N-tert-Butoxycarbonyl-2-(3-pyridyl)thiazoli- dine-4-carboxylic ecid and 4-pheryvlpiperidine were used as the starting materiale and treated in the game manner as in Example 43% to give A-phenyl-1-(2 ~(3-p.ridyl)thiaznolidin-4-ylcarbonyl)piperidine dihydrochloride. Yield, Ard, Melting point 115°C.

HER (DH30-d,) §: 1.32-2.08 (44, m), 2.58-5.82 (6H, m), 3.96 -5.00 (2H, m), 6.04 »nd 6.28 (8, respec- ad), £.68=0.,16 (54, m) : LXAMPLE 47 / 5 ] bce ” \ HOBT C¥,COOH C1 al N. "COOH + HN li-CH 4 2 —

CO0C (CH) 5

Se

A /7TN ’

AF TN

[8 eon neva

SNS AN J

3H

Hz

N-tert-Butoxycarbonyl-2-(3-pyridyl)thiazoli- dine-4-carboxylic acid and 1-methylpiperazine were used as the gtarting materials snd treated in Lhe same manner as in Example 43 to give 1-methyl-4- (2-(3-pyridyl)taiazolidin-4-ylearbonyl)piperzzine trihydrochloride. Melting point 182°C.

NMR (Dus0-dg) 8: 2.62-5.00 (14H, m), 6.05 and 6.22 (s, ree- pectively 14), 8.09 (1H, dd), 8.70-2.20 (38, m)

BXAGLLE 48 2) nee I .

Cn ‘Cool 4 i tong Ns 5500, =

To soon(ong), oh 1 2

SENNON A \ /

LL) y con ong \

Fhe

N-tert-Butoxycarbonyl-2—-(3-pyridyl)thiazoli- dine-4-carboxylic acld and 1-benzylplperazine were 5 used as the starting materials and treated in the gane manner as in Example 47 to give 1-benzyvi-4-(2 ~(3-pyridyl)thiazolidin-4-ylearbonyl)piperazine 29 trihyirochlaride. Yield, 63%. Melting point 165°C.

NMR (DMSO-d) &: 2.76-4.80 (13H, wm), 5.95 and 6.15 (8, res- pectively 1H), 7.36~7.80 (5H, m), 8.03 (1H, dd), 8.62-9.10 (3H, m)

I7(23

SXAMILE 49

PCI oo A | 7 / bee CF;CO0H HCH

C7) N Ccoofl «+ Hil i-ony)f y > Ey . N \ - <= HOB 7 CO0C (C15) : Ju ’ ' Erp, oN i 4 \ TN “0 "N CCON N-(CH.,,)¢# NN *3HCH , ym IH Ses : “MN -

N=tert-Rutoxycarbonyl-2-(3-pyridyl)thiazoli- dine-4~carhoxylic acid and 1-(4-phenylbutyl)plpe- razine were used as the starting materials and ~~ ... - treated in the same manner as in Example 43 to give 1-(A-phenylbutyl)-4=-(2-(5-pyridyl)thiazolidin-4- ylcarbonyl)vinerazine trihydrochloride. Yield, 08%, Melting point 157°.

NMR (Lis0-a ) 0 &: 1.33-1.85 (4H, m), 2.50-2.76 (8H, m), 2.86 -3.78 (6H, m), 3.99=4.30 (1H, m), 5.906 and 6.17 (uv, respectively 11), T.12-T7.44 (61, m), 8.12 (1H, ad), 8.72-9.17 (2H, m)

EXAMPLE 50 3 / 2 A] sen WoC CF COOH cl “coon + H,N-NH{ yy —— ————

Se - — HOBT

G00C (CH, ) /°

CY Nom 0 , il \__/

A solution of 450 mg of dicyclohexylcarbodi- imide in 5 ml of tetrahydrofuran was added drop- wine to a mixture of 680 mg of N-tert-butoxycar- bonvl-2~(3-pyridyl)thiazolidine-4-carboxylic acid,

240 mg of phenylhydrazine, 450 mg of 1-nydroxyben- zotviazole and 20 ml of tetrahydrofuran with ice cooling, andithe resultant mixture was stirred with ire cooling for 1 nour 2nd then zt room tem- perature for 12 hours.

The reaction mixture wan diluted with 30 ml ofcthyl acetate, rnd the inec- luble matter vas filtered off. he filtrate wae washed in sequence with saturated anueous solntion of andinm hydrogen carbonete and saturated aqueous solution of sndium chloride, and dried over anhy-

drous sodinm sulfate.

Concentration under reduced pressure cave £44 mg of N'-pheryl-3-tert-butoxy- carbonyl-2-(3-pyridyl)thiasolidine-4~-carbohydra- zide.

Trifluorcacetic acid (5 wml) was added to the thus~-obtained conpound, and the mixture was stirred at roon temperature for 1 hour.

The reaction mix- ture was concentrated under renuced pressure, the residuie was dissolved in ethyl acetate, and the co- lution was washed in requence with saturated aqueous golution of sodium hydrogen carbonate and saturated aquecud solution of godium chloride, and dried over anhydrous sodium sulfate.

Concentration under re- duced pressure gave crystals, which were recrystal- lized fron ethyl wccetate.

Thus was obtzined 180 mg

, of N'-phenyl-2-(3-pyridyl)thiazolidine-4-carbohy- drazide. delting point 155°C:

Nii (CDC + D480-d) & : 3,22=3.496 (2H, m), 4.22-4.,36 (11, m), 5.60 and 5.72 (8, regpeckively 1H), 6.72-7.41 (6H, m), 7.81-7.95 (1H, m), 8.56 (1H, 24), 2,79 (1H, a)

VARRELE 51 8 __

Cr — — kK. CO i | ~N coni- (cif _Y OH + Br-(cayd E> eT : of - ~f 3 ¢ i" ¢00c( Ha) _ CF, COOH JHC 3 ain / ’ l. Th ie x . sq CONH-(CH, Jy { Yoon, if) 2 HCl

A solution of 280 mg of 1-bromo-4-phenylbutane in 5ml of N,N-dimethylformamide was added to a mix- ture of 540 mg of N-(2-(p-hydroxyphenyl)ethyl)-3- tert-butoxycarbonyl=2-(3-pyridyl)thiazolidine-4- carboxamide

29(23 ~ 180 mg of potassium carbonate and 10 ml of N,N-dime- thylformamide at room temperature. The mixture was stirred at 80°C for 2 days. After cooling, 20 ml of water was added to the reaction mixture, and the organic matter was extracted with ethyl acetate.

The organic layer was washed in sequence with water and saturated ggueous solution of sodium bhhabwidée and dried over anhydrous sodium culfate and concen- trated under reduced pressire. Purification of the residue by silica gel column chromatography (eluent: hexane-ethyl acetate=1:3) pave 360 mg of N-(2-(p-(4~- phenylbutoxy)phehyl)ethyl)=3-tert-butoxycarbonyl-2- (3-pyridyl)thinzolidine=-4-curboxamnide. Prifluoro- soetic acid (5% ml) was added to tae compound obtained, and the mixture wan sbtirrad at room temperature for 1.5 hours. The reaction nixture was concentrated un- der reduced pressure, the residue was dissolved in ethyl acetate, aul the goinbion wag wnghed in ae- quence wlth gaturated aqueous solution of sodium hy- drogen carbonate and saturated agneous solution of sodium chloride, and dried over anhydrous sodium sul- ne fate and concentrated under reduced pressure. The re- sidue was purified by silica gel column chromato- graphy (eluent: ethyl acetate) to give 230 mg of

N-(2-(p-(A-ph=nylbutoxy)phenyl)ethyl)=2-(3-pyridyl)- thiazolidine-4-carboxamide. This compound was dissolved in ethvl acetate, and 1 ml of 2 N hydrogen chloride golution in dioxane was added. ‘the resultant solid was collected by tiltratinon, washed with ethyl acetate and dried bo give 120 wg of N-(2-(p-(4- plieaylbutogy )-phenyljetiyl)=2=(3=-pyridyl) thisn- zolidine-d-carboxamide dihydrochloride. Melting point 102°C.

Llemental adelysis (for Cig 5ilz0,50, 01

C (5) Hn ($F) N(F) 8 (F)

Calcul bed: 60.67 6.22 7.86 6.00

Found: 60.01 6.10 1.94 5.27

SALLE 52

J

AN Va sn EL, U0.

Co coi= any) ons weit) N22,

C00C(CHs) 3

DTN

Lo /

CF,COOH HU Loh — 23 HY Nome end Nooo — > C0 gomn-(cn, yg 0- (eit) 21C1

H-(2-{ p-Hydroxyphenyl)ehtyl)=3-tert-bytoxycars- bouyl-2=-(35-pyridyl)thidszolidive~4-carboxaniae and 1-bromo-3-phenylpropiae wereinsed as the starting materials and treated in the same manner us in Exam- ple 51 to give N=(2-( p-(3-phenylpropoxy)phenyl)ethyl) —2~(3=-pyridyl)thinzolidine-4~carboxaiide dihydrochlo- ride. Melting point 98°C. nlemental analysis (for C,H 50,801,°043H,0))

Co(#) H(p) NW (B) Ss (A) C1 (#)

Calculated: 59.38 6,06 7.99 6.10 13.48

Found: 59.37 6.05 8.01 6.09 13431 - 182 - i

BXAHPLE 53

Zn sonn-gur, ),7 OH + aro, oig FBO

SNS : SE Le 5 COO (Uli)

Se croeool met 2 s’ J SN 7 \ 3 ls |] n cout-(uity 5 to-cityonsd 2HCH

N=-(2-(p-liydroxyphenyljcthyl)=3-tert-butoxycar- bonyl-2-(3-ryridyl)thiuzsolidine-4-carboxamide and 1-broao=-2-phenyvliethane were usel ag the starting materials and treated in the same manner as in Exam- ple 51 to give K-(2-(p-(2-phenylethoxy )phenyl)ethyl) -2-(%-pyridyl)thiazolidine-4-carboxamiae dihydro- chloride.

NMR (DMSO-d) . §: 2.58=3.64 (8H, m), 4.11-4.40 (31, m), 6.03 (1H, 8), 6.83=7.35 (5H, m), B.02 (1H, dd), 8.66=-3.085 (1d, m), 8.88-9.01 (11, m), 9.07 } (11, dd)

M3: m/z 433 (Mh ~2xHCT) / 00)

AN A ARS oo (Chis i. AL 3 (1) 1) DCC, HOBI ll N Ls 's rN jn CONH-CH2\__ CH2CH2CH OH 2) HCH .2HC1 ’

A mixture of 1.13 g ot p=(3-methylvutoxy)ben- sylamine, 1.29 g of z-(J-pyridyl)thianolidine-4- carboxylic acid, 1.29% g of dicyclohexylcaorbodii- mide and 0.82 g of 1-hyaroxybenzotriazole in 20 ml of N, N-dimetvhylformamioe woe stirred overnight »t room temperature. [he reacticr mixture wae diluted with 100 ml of ethyl zcebtzte, and the insoluble matter wzs (ilteved off. The filtrate was washed in sequence with saturated agueous solution of so- dium hydrogen carbonate, water and saturated ani- eous solntio. ol sodium chlorine, aried over anhy- drons mrgnezium sulfate, and corcentrated under reduced pressure. Purification of the thus-obtained residue by silica gel column chromatography (eluant: ethyl acetate) gave 2.20 g of H-{p=~(3-methylbutoxy) venrvl)-2~(3-pyridyl)shiazvclidine-4-carboxanide.

To 1 solution oi this compound in 60 ml of ethyl acetate was added 4 ml of 4 N hydrogen chloride so- lution in dioxane. The precipitate solld was col- lected by filtration, washed with etnyl scetave and dried under reduced pressure to give 2.30 g of N-(p . -(3-methylbutoxy)benzyl )-2-{3~-pyridyl)thiazolidine~ 4-carboxanide dihydrochloride. Me) ting point 120- 128°C.

Elemenkal analysis (for Cy yHygN50,8C1, 0.4K, 0) 1

C (4) H(A) N (A) 5 (#4) C1 (GF)

Calculated: 54.17 6.45 9.02 6.89 15.23

Found: 54.23 6.51 8,960 7.00 15.16

Il23 9 YAR ES / i ! a A '

ROFERENC.S SAAMLLES 55 TO 80 the followinpy compounds vere obtained in the game manner ag in lmnmoiple D4.

Degired Product

Chemical Strenctnre and Chemical Hame

Exe 55 { ) OH

AE a 2 SH, den? o-sion

N Ii J pI

N Ui, 2181 je(p-2-Metiylpropoxy )bensyl )=d~3- pyriayl)thiasnolidine-s-carvna- mide dihyirocniocride

Physlicochenical lroperfleg 1) Melting point: 105-133°C 2) Elemental analysis (for Cling i50,8C,)

C H Id S

Ueleculated: 54 409 Holz YedYH Te22 (3)

Found: 5% 69 6.12 9.32 6.97 (5)

Ex. 56

JB CH

AA 7 Sits

NOUCORH=CH Vv G=( CH, ) CHA

Cl NTOORH=CH = (CH, ) CHG yy tor H 3

Ti 2181

- A. { $125

N-(p-(4-Methylpeulyloxy )henzyl)=-2- (3-pyridyl)thinzolidine~4-carboxa- mide dihydrochloride DPhysicochenical Properties © 1) Melting point: 124-128°C 2) #lementul analysis (for CopllzN20,501,): ¢ H N » C1

Calculated: 54,60 0,70 RUT 6.66 14.73 (*)

Found: 54.79 6.69 &,70 6.48 14.80 (45) dix. 91

M- LohH-CHs 7 NL 0=CHsL ] HO “HOW “ee cn

H-(u-Cyclopentyluethoxybenzyl )-2- (3-pyridyl)thinzolidiné-1-carboxa- mide dihyirocnloride

Physicochemical Propestice 1) Melting point 55-6020 2) Flemental analysis (tor CyoHyNg0,8U1,) 8 i i i RN] dalculated: 56.17 621 £.93 6.82 (%) )

Found 55.85 6.11 8.05 6.84 (7%)

3 129

Ex. 58 on coueongl onto a

NS H — 2 —

N + 2HC1 5

N-(p~-(3-Phenylpropoxy benzyl )=2- (3-pyridyl)thiazolidine-4-carboxa~- mide dihydrochloride

Physicochemical Properties 1) Melting point: 110-116°C 2) Elemental analysis (for Co5HyoN30,5C1,)¢

Cc H N S C1

Calewiated: 59.28 5.77 8.30 6.33 14.00

Found: 58,95 5.74 8.21 6.36 13.93 (%)

Ex. 59 9!

N cont-caiz{_Y-o-(ou ), = \ 2 \— 274 \

No H \

OCH .2HC1

N-(3-Methoxy-4-(4-phenylbutoxy)-ben- zyl)-2-(3-pyridyl)thiazolidine-4- carboxamide dihydrochloride

Physicochemical Properties 1) Melting point: 88-95°C 2) Elemental analysis (for C,7H33N5055C1,)1

C H N S C1

Calon ated: 58,30 6.04 7.63 5.82 12.88

Found! 58.52 6.02 T.59 5.82 12.48

' v 97123

Ex. 60

AL oommon ~0-(CH,) 2-0-0 \ ~ | H 2 3

SN oo Ed .2HC1

CL 5 }

N-(p-(3-Phenoxypropoxy)benzyl)-2-(3- pyridyl )thiazolidine-4~carboxamide dihydrochloride

Physicochemical Properties 1) Melting point: 101-110°C 2) Elemental analysis (for Cp5hygN3038C1,)1

Cc H N S C1

Calculated: 57.47 5.59 8.04 6.14 13.57

Found: 57.42 5.77 7.90 5.98 13.35

EX. 61 "J :

Nsonond No ar CONH-CH{_V—(CH,)5CHy

N

.2HC1 .

N-(p~Butylbenzyl)-2-(3-pyridyl)- thiazolidine-4-carboxamide dihydrochloride

Physicochemical Pro erties 1) Melting point: 110-115°C

2) Elemental analysis (for CpolyqN30SC, *0.4H,0):

Cc H N S C1

Galen ged! 55.14 6.43 9,65 7.36 16.28

Found: 55.27 6.50 9.63 T.23 16.06 (%) - 5

Exe, 62

S

£{ ) Ne OH

N-~comn-oliy{ CHS lH _ CH } “N° «2HC1

N-(p-(1-Methylethyl)bengyl)-2- (3-pyridyl)thiazolidine-4-carbo- xamide dihydrochloride

Physicochemical Properties 1) Melting point: 133-142°C 2) Elemental analysis (for C,qgHy5N505C1,.0,6H,0)1

Cc H N S C1

Oaley sted 53.67 6.21 9.88 7.54 16,68

Found! 53.75 6.17 9.83 7.52 16.37 . (%)

Ex. 63 ) 73 °N cof N-cud N-c o) H \ = « 3HCA 1-(p-Methylbenzyl)-4-(2-(3-pyridyl)-

JI23 thiazolidin:-4~-ylcarbonyl)piperazine trihydrochloride

Physicochemical Properties - 5 1) Melting point: 168°C 2) NMR (DMSO-dg) &t: 2.38 (3H, 8), 2.5-3.5 (8H, m), 4.0-4.6 (4H, m), 4.4-4.9 (1H, m) 5,96 and 6.18 (8s, respectively 111), 7.26 and 7.56 (4H, dd, ABq), 6.9-7.2 (1H, m), 7.6-8.2 (3H, m)

Ex. 64 3

Fama”

J H CON NCH, Cl » HCA 1-(3-Phenyl-2-propenyl)-4-(2-(3- pyridyl)thiazolidin-4-ylcarbonyl)- piperazine trihydrochloride

Physicochemical Properties 1) Melting point 1 180°C 2) NMR (DMSO-d.) gi: 2.38-3.8 (BH, m), 3.8-4.1 (2H, m), 4.0-4.8 (34, m), 5.98 and 6.18 (s, respectively 1H), 6.3-6.7 (1H, m), 6.8 and 6.86 (s,

respectively 1H), 7.2-7.6 (5H, m), 8.0-8.2 (1H, m), 8.6-9.2 (3H, m),

Ex, 65 5 \ JN “\ « “NN - - \ [ + CON N (CH, ) 4 od

N

« 3HC1 1-(3-Phenoxypropyl)-4-(2-(3- pyridyl)thiazolidin-4-ylcarbonyl)- piperazine trihydrochloride

Physicochemical Properties 1) MS: m/z 412 (M'-3HC1) 2) NMR (DMSO-d) § 8 2.,0-2.6 (2H, m), 2.6-3.9 (10H, m), 4,09 (2H, t), 4,0-4.9 (3H, m), 6.0 and 6.2 (8, respectively 1H), 6.8-T.1 (3H, m), 6,2 6.42 (2H, m), 8.0-8.2 (1H, m), 8,6-9.,2 (3H, m)

Ex. 66

A) a N ~~CON N-CH,-CO 4 sN H n_/ 2 == oo . 3HC1

1-((2-0Oxo-2-phenyl)ethyl)-4-(2-(3~ pyridyl)thiazolidin-4-ylcarbonyl)- piperazine trihydrochloride

Physicochemical Properties : 1) Melting point: 147°C 2) NMR (DMSO-d) §: 2.94-4,32 (12H, Mm), 4,52-4.80 (1H, m), 5.96 and 6.16 (s, respectively 1H), 7.44-7.84 (3H, m), 7.94-8.20 (3H, m), 8.60-9,20 (3H, m)

Ex. 67

Va hadron C0 ‘ 15 N-~-~CON N-(CH -C —B (7) goon f-(ohp)ymo0 mh

SHA

« HCH 1-(4~-(p-Bromophenyl)-4-oxobutyl)- 4-(2-(3-pyridyl)thiazolidin-4- ylearbonyl)piperazine trihydro- chloride physicochemical Froperties 2 > " 1) Melting point: 139° 2) Elemental analysis (for C,3Hz,N, 0,8BrCl 3)4

C H N S Br+C1

Calculated: 45.08 4.93 9.14 5.23 30.39

ITs

Found: 44.90 5.17 9.24 5.41 30.29 (%)

Ex, 68

HC S

©, N CON N-(CHy)jz / \

N H N Nee + 3HC1 1-(2-Methyl-2-(3~pyridyl)thia- zolidin-4-ylcarbonyl)-4~-(3-phenyl- propyl)piperazine trihydrochloride ‘ ) Physicochemical Properties 1) Melting point: 129°C 2) NMR (D¥S0-dg) &§: 1.88 and 1.96 (s, respectively 31), 1.68-2.28 (2H, m), 2.44-2.80 ¢ (21, m), 2.88-4.64 (13H, m), 7.12-7.48 (6H, m), 7.96-8.18 (1H,

Exe 69

N= } em

N CON N= (ofp) 5 { J 3HC1

N H ’ = . 1-(2,2-Di(2-pyridyl)thiazolidin- 4-ylearbonyl)-4-(3-phenylpropyl)- plperazine trihydrochloride

Physicochemical Properties 1 ) Melting point: 111°C 2 ) HMR (DMSO-d) § i: 1.90-2.28 (2H, m), 2.46-2.80 (2H, - 5 m), 2.86-3.74 (12H, m), 4.12-4.68 (14, m), 7.16-7.40 (5H, m), 7.44-8.88 (8H, m)

Ex. 70

S

Yn odin 50)

N _/ 7

CH

« 3HC1 1-(3-Methyl-2=-(3-pyridyl)thiazol- idin-4-ylcarbonyl)-4-(3-phenyl- propyl )piperazine trihydrochloride

Physicochemical Properties 1) Melting point: 130°C 2) NMR (DMSO-d) & 1 1.88-2.24 (2H, m), 2.36 and 2.52 (s, respectively 3H), 2.56-2.78 (2H, m), 2.78-4.60 (134, m), 5.58 and 5.82 (s, respectively 14), 7.08-7.44 (6H, m), 7.86-8.20 (1H, m), 8.58.-9.02 (21, m)

H]23

Ex. 1 /5° - Lr ~ Ayo N- (CH, ) qCHz + BUC 1. \ J 2 8 3 «gt H Co - 5 : 1-Heptyl-4-(2-(3-pyridyl)thiazol- {din-4~-ylcarbonyl)piperazine trihydrochloride thysictechemical Properties 1) Melting point: 139°C 2) Elemental analysis (for CooHzgNy0SC1 5. 1.5H,0)

C H N S C1

Caley sted: 46.8% T.47 10.92 6.25 20.73 ¥ound: 47.09 7.29 11.89 6.36 20.47 (%) kx. 12 , 5 ! ) rams “A 2 \nocoN (eH) N Lane . Cl H CTA 4-(2-Phenylethyl)=1-(2-(3-pyridyl)- thiazolidin-4-ylcarbonyl)piperidine dihydrochloride

Physicochemical Properties 1) Melting point: 110-117°¢ 2) Elemental analysis (for CypllygN508C15.0.8H,0)

: H7123 ¢ H N S C1

Caloylateds 56,36 6.58 8,96 6.84 15.12

Found: 56.27 6.55% 8.92 6.94 15,02 (%) . 5 Ex. 13 8 .

JR CT \ TTY

To N CON - (UHp)g © 2861

N

4-(4~-Phenylbutyl)=-1-(2-(3-pyridyl)- thiazolidin-4=ylearbonyl)piperidine dihydrochloride

Physicochemical Properties 1) Melting point: 10&-112°0 2) Elemental analysis (for Cy 5H5 N508C1,.0.4H,0)1 u H N S Cl

Calculated:58.07 6.74 8.85 6.74 14.91 (#)

Found: 58.03 6.64 8.80 6.81 14.96 (%) -

A EX. 14

S

A ; ” Tr wk CON (CH, )y, -- 2HC1 xp) 274

N- H 4-(4-Phenylbutyl)=1=(2=(3-pyridyl)- this.oliidin-4-ylearbonyl)piperidéne dihydrochloride

B &ie 2

Physicochemical Properties 1) Melting point: 108-116°C 2) Elemental analysis (for Cpylix3N305C154048H,0)1 ¢ H N 5 C1 . Found: 57.80 6.77 B.43 6.59 14.42 (%)

Bx. 15

S- 10 . N com (cH, )e L210 i H ~ tJ

N

4-(5-Phenylpentyl)-1-(2-(3-pyridyl)- thinzolidin-4-ylcarbonyl )piperidine “ 15 dihydrochloride

Physicochemical Properties 1) Melting point: 110-118°C 2) Elemental analysis (for C,cH;;N;08C1,.0.5H,0)1 u H N s C1

Calon ated: 59.40 7.18 8.31 6.36 14,03

Found: 59.56 7.21 8.36 6.47 13.89 (%)

Ix. 76 : 8 : “7 "'N CON N-CH7' .3HC1

I. H vi en

R .

4-Bengzyl®1-(2-(3-pyridyl)thiazolidin- 4-ylcarbonyl )homopiperazine trihydrochloride

Physicochemical Properties 1) Melting point: 168-175°C 2) NMR (DMS0-g;) &: 1.80-2.50 (2H, m), 2.82-3.86 (8H, m), 3.86-4.73 (3H, m), 4.36 (2H, bre), 5.50-6.49 (3H, br), 5.94 and 6.16 (s, respectively 1H), 7.35-7.57 (31, m), 7.57-7.81 (2H, m), 7.92-8.17 (1H, m), 8.57-9.14 (3H, m), 11,08-11.60 (1H, br) 3) MS: m/z 382 (M'-3HC1) Co

Ex. 71 3 + | con H-(cH,); . 3HC1

N

4-(2-Phenylethyl)-1-(2-(3-pyridyl)- thinzolidin-4-ylcarbonyl )homo- piperazine trihydrochloride

Physicochemical properties 1) M~ ting point: 161-169°C 2) NMR (DMSO-d)

FIs t 1.91-2.45 (2H, m), 2.95-4.34 (14H, m), 4.45-4.92 (1H, br), 6.02 and 6.21 (8, respectively 11), 6.40-7.09 (3H, br), 7.31 (5H, 8), 7.95-8.20 (1H, m), 8.67- 9.22 (3H, m), 11.36-11.87 (1H, br)

US: m/z 396 (M'-3HC1)

A rm

Cl noo =o 5) «SHC

N- 4-\3-Phenylpropyl)-1-(2-(3-pyridyl)- thiazolidin-4-ylcarbonyl)homo- piperazine trihydrochloride

Physicochemical Properties 1) Melting point: 162-170%C . 2) NMR (DMSO-d) §: 1.79-".30 (4H, m), 2.64 (2H, t, J=THz), 0.85-4.31 (12H, m), 4.36-4.75 (1H, br), 5.,25=6.10 (38, br), 5.94 and 6.16 (8, respectively 14), 7.29 (5H, 8), T.92- 8.16 (1H, m), 8.59-9.15 (3H, m), 11.15- 11.60 (1H, br) 3) MS: m/z 410 (M'-3uC1)

JF28

Ex. 19 /S ™

A CTI TEL

Lg | H TV 237 CH, : 5 : 4-(4-Vethylpentyl)-1-(2=(3=-pyridyl)- thiazolidin~-4-ylcarbonyl)homo- piperazine trihydrochloride

Physicochemical Properties 1) NMR (DMSO-d) 8s: 0.87 (64, 4, J=THz), 1.02-1.30 (2H, m), 1.39-2.42 (3H, m), 2.82-4.28 (14H, m), 4.50-4.93 (11, br), 6.03 and 6.21 (8, respectively 1H}, 6.11-6.90 (3H, br), 7.96-8.22 (1H, m), B.66-9.20 (Bik, m), 10.95-11.40 (H, br) 2) MS: m/z 376 (M*-3HC1) :

Ex. 80 os

OY eh ony )gony . 3HCA

No 4-Heptyl-1-(2~(3-pyridyl)thiazolidin-

A-ylcarbonyl)homopiperazine trihydrochloride re - ]

Hes BY vq €) ¢ ; of 129 yhysicochemical froperties 1) Kun (Dmi0-dg) g 1 u.B (31, by J=6Hz), 1.08-1.46 (EH, br 8), 1.54=1.89 (2H, m), 2.04-2.61 (2H, : 5 m), 2.83=4.36 (14h, m), 4.52-4.96 (1H, m), 6.05 and 6.24 (8s, vaspectively 11),

T.07-68.23% (1H, mn), B.67-9.60 (6H, m), 11.20=11.05 (1d, br) 2) 45: m/z 590 (4 -34HC1)

EXANILE FL

3 a TX souH + an = (3H, ) CH, a } Ty i Co - } JH . H Sot H=(CHy gM « 3HCY 29

Dicyelohexylcarbodilnlde (0.34 g) was added to a mixture of 0. %4 5 of z~(3-pyriayl)thlazolidine-4~ cerbox .ic neid, 2.37 g of 1=iacyLlpiperazine, 0.33 g of V-nyircxybenzotriazole and 10 nk of N,N-dine- thylformauide with ice cooling, and the resultant micture wan stirred overnight at room temperature.

The re.-tion nlxbare way diiabed with ethyl ace- tate, and tha insoluble matter wue [ilteved off.

7 } oo or (253.

J -

The I'iltrate war veshed with saturated aqueous so- lution of codiun Fyirepen cartonste ind then with entrrated squeouns anlution of sodlur chloride, dried over aphydrous sodium suilate znd concentrated under reduced pressure. bthyl scetate (5 ml) wae addea ’ to the residue, and the insoluble matter was filtered nff, 2 F Vydeogen chloride solution in dioxane was added to the {ilirate. The resultant crystals acre collected by filtrution, washed with 2thyl acetate and dried tn jive 0.63 5 of 1~decyl-4-(2-(3=-pyridyl, thinzo'idin-4-ylecarbon.1)plserasine trihydrochlo- rile, Neliing point 170%, 0 antal analvei: r LL, 000, 05C1 , H,0):

Tlamental analysis (for 25st q7, } 1 H,0)

O(N md) KN (ft) 3 (%) C1 (%)

Calculated: 50.59 7.94 10.26 5.97 19,48

Found: 30.50 7.51 10.2¢ 6.07 19.47

The following coxpounes rece ontulned in the same manner ae in fxamnple £1,

Desired Froduct

Cherical Structure and Chemicol lame z5 ox. 82 . . 8. : i age CH. ’ | co m=O), CH sr

N vo a J 4 3 « JHCH yr - 202 - pr M

BAD ORIGINAL 0

1-(B-¥ethylbutyl)-4-(2=-(3~pyridyl)- thiazollidin-4-ylcarbonyl)piperazine trihydrochloride

Physicochemical Properties 1) Melting point: 153°C 2) Elemental analysis (for Cygl3qty 0SC1501.TH,0) 1

C H H 8 C1

Calepiated: 44.26 7.10 11.47 6.56 21.1717 rou 44.28 6.97 11.47 6.74 21.57

Ex. 83

Co / 5 i . | fi pH N-(CH,)4-CO- « SRO 1-(4-0x0-4-phepylbutyl)-4-(2-(3~ pyridyl )thiazolidin-4-ylecarbonyl)~- piperazine trihydrochloride

Physicochemical Properties 1) Melting point: 145°C 2) Llemental analysis (for CyatzoNs 0,5C15.3/20,0)1

C Hu N 5 C1

Galen grot: 49.25% 6.11 $.499 572 18.96 (7

Found 49.40 5.97 9.79 5.92 18.81

Ex. 04

CN Ui i={Uil,),

H 22 4 5 .2 hii 1-(2-rhenylsthyl)=-4-(2-(3-pyridyl)- thiszolidin-4-ylcartonyl piperazine srihyirocnicriie

Lhyeicocheanical Sroperiies 1) Melting point: 155°¢ 2) dieaenlal wmeliysts (for Tag gla Ot. 2/500)

C ;. nN 3

Calculated: 50.64 5.83 11.25 6.44 (%)

Found: 50.74 HL. 11.21 v.44 (%) . Ex. 85 -

Co a JON d=(Cily)g BN

N

. 0 He 1-(5=-the iy) pentyl) -4-(2-(3-pyridyl)- thirzolidiu~4=-ylecartonyl)iperaz digg ~ » trihydrochiori te EAD ORIGINA.

: JFl23

Physicochemicel Ironerties 1) Melting point: 136°C “1 J i. - J 5 > * [3 : 2) Klemental analysis (for Cp fig Hy 0501 5 1.0)

C J N 8 C1

Caleulated: 52.272 6.76 10.15 5.81 19.27 sof (2)

Found 51.98 6.71 10.12 5.93 19.456 {")

FRAMELT 80 2

UN CON Ne(CH,) yl meme)

Cd “2

N

5

Ci . :

CON K-(Cii,) vo 273

Uno 70 a solution of 40 mg of 1-(3-phenylpropyl)-4- (7-(3-nyridyl)thiazolidin-4-ylcarbonyl)plperazine in 5 a" of dichloromethane, thore wos added 0.5 ml of a formic acid-scetic snhyiride (5:17, v/v) mixture, and tha resultant mixture was nitirred overnight at room temperature. Rthyl acetate (20 ml) was added to the conction mixtura, the 4ilution was wanhed with S54 aguenua sodium hydrogen carbonute and with water, dried over anhydrous magnesium sulfate and concen- tratad under reduced oreseure to give 30 mg of 1-(3- formyl-2-(3-pyridy] Jthiazolidin-4-ylcarbonyl)-4-(3- r Co ly

BAD ORIGINAL &i oo OR :

1 » 0123 phenylpropyl )ninerazine as an oll.

AONE (OCT.

SEER OUST

§ 1 1.65=2,0 (2, a), 2.2-2.2 (81, mn), 3.0-5.4 (21, m), 3.63.9 (li, a), 5.0-5.7 (11, nu), 6.14 ord Gob (s, rococcosiveY 1H), To0-T.5 (51, m), 7.6-7.9 (1h, =m), &.24 (1H, s), 8.4-0.08 [H, x) us: m/z 424 (nh)

SFANITE £7 / Re

No oood a TT E-(O)0 0 meme) to HODY z ; : TOU (DH,) g

WH CON N-(CH, ) :

N

COOC (LH, } HOO ( Hids

F-tert-Putoryecarbonyl-2-(3-pyridyl)shiszolidine «d=carbeory le actd (650 ag) and 1-{3=-phanylpropyl) plrerr-aine (400 me) were used ng the ntarting mate rials and treated ia the sere manner «0 in Example 54, Without conversion to ihe hydrochloride, the product was purifizd ty e1lica rel column chromato- graphy (eluent: etayl aestate), Thus was obtdined 1-(3-(tert-tutoxycarbony'!)-2-(3-pyridyl)thiazolidin- - 206 - ! .

Ea

BAD ORIGINAL £3)

Co = 3 ~-4-ylcarbonyl)-4-(3-phenylpropyl)piperazine (560 mg) as an oil.

NMR (CDC14) 4t 1.40 (9H, 8), 1.6-2.1 (2H, m), 2.2-2.8 (BH, m), 3.0-3.4 (2H, m), 3.4-4.0 (6H, m), 5.08 (1H, br t), 6.16 (1H, br 8), 7.0-7.% (54, m), B.4-8.8 (4H, m), ws: m/z 496 (uM)

DXAMPLES 68 AND 89

The following compounds were obtained in the same manner as in JSxample B87,

Desired Froduct

Chemical Structure and Chemical lame _

Ex. 88 5H . / CH © BR CORH-CH,\ 0-CH._° y 0H to CH,

N-(p-(2-Methylethoxy)benzyl)-2-(3~ pyridyl )thiazoildine-4-carbvoxamide

Physicochemical Properties 1) #S: m/z 357 (M*) 2) NMR (CDC1y) &: 1.34 (6H, d, J=THz), 2,5 (11, br, exchange - 207 =~ Lo r

BAD ORIGINAL dP oo 1 : \ . JH 23 with D,0)s 3.38 (1H, dd, J=13, 8Hz), 5,73 (14, dd, J=13, 5Hz), 3.98 and 4.40 (m, respectively 1H), 4.3-4.6 (3H), 5.40 and 5.60 (8, respectively - 5 1H), 6.6-6.9 (2H), 7.1-T.4 (3H), T.4 (1H, br, exchange with 0,0), 7.80 (1H, m), 8.54 (11, m), 8.68 (1H, m) 5. cL ARs

CR en co o-(oiy)s 7

N 2 : -

N-Methyl sN«(p-(3-phenylpropoxy)- benzyl )-2-(3-pyridyl)thiazolidine- 4-carboxamide

Physicochemical Properties 1) MS: m/z 447 (WM) 2) NMR (CDC15) &y 2,0-2.3 (2H), 2.6-3,5 (5H), 3.01 and 3.03 (8, rospectively 3H), 3.96 (2H, t, J=TMz), 3.9-4.1 (1H), 4.6 (2H, br 8), 5.58 and 5.98 (8, respectively 1M), 6.6=7.4 (10R), 7.7-8.0 (1H), 8.4-8.7 (1H), 8.75 (1H, br 8)

oH 23

EXAMPLE 90

Sg 7 = 1) DCC, HOB # lI N COOH + HN K-(CH, )qCHy eee) : H 2) ROOC-CH

CHCOOH

3 CHCOOH \ \ i Co ’ . R CON N=-(CH,),CH,.HOOUCH . 5 2/73

Dicyclohexylcarbodiimide (0.82 g) was added to a mixture of 0.84 gcaf 2-(3-pyridyl)thiazolidine-4-car- boxylic acid, 0.79 g of 1-octylpiperazine, 0.54 g of 1-hydroxybenzotriazole and 20 ml of N,N-dimethylfor-~ . 15 mamide with ice cooling, and the resultant mixture was stirred overnight at room temperatare. The reaction mixture was diluted with ethyl acetate, and the inso- juble matter was filtered off. The filtratc was washel in sequence with saturated aqueous solution of sodium hydrogen cartonate, water and saturated aquevus solution of sodium chloride, and dried over anhydrous magnesium sulfate. The molvent was then distilled off under reduced pressure. Fthyl acetate was added to the residue, the insoc.uble matter was filtered off, and the filtrate was concentrated un- der reduced pressure. The resddde was purified by ) silica gel column chromatography (eluent: 10% metha- nol-ethyl acetate), the oil obtained was dissolved

Cf ies in 25 ml of ethanol, and 0.32 g of fumaric acid wap added. After allowing the mixture to stand for 2 days, the resultant crystals were collected by filtratdon, washed with cold ethanol end dried. } 5 Thus was obtained 0.72 g of 1-octyl-4-(2-(3-pyridyl) ~ thiazolidin-4-ylcarbonyl)plperauine fumarate. MNel- ting point 135°C.

Tlemental analysis (for C)gHagh, 055)

Cc (%) H (%) N (#) 8 (#)

Calculated: 59.27 7.56 11.06 6.33

Found : 59.01 7.66 10.95 6.27

EXAMPLES 91 TO 94

The following compounds were obtained in the : 15 game manner as in ¥xample 90.

Desired Product

Chemical Structure . and Chemical Name

Exe 91 3

Co x ‘CON - (chy) 5”

N

HOOCCH i

CHCOOH

1-(3-Phenylpropyl)-4-(2-(3-pyridyl)- thiazolldin-4-ylcarbonyl)piperazine fumarate oo S723

Physicochemical rropertivs 1) Melting points 175°¢ 2) Flemental analysis (fcr Coglizaty 058):

C H N 3 - 5 Caloulated: 60.92 6.29 10.93 6.26 {4

Found 60.62 6.25 10.79 6.17 (%)

LXe 92 3

Ro cox H- (CH, ) CH,

H

} HOOCCH il

CHCOOH

1-Hexyl-4-(2-(3-pyridyl)thiazolidin~- 4-ylearbonyl jpiperazine fumarate

Physicochemical Properties 1) Melting point: 128°C 2) tlemental analysis (for Colla lig 058)

C H H S

Galen ged: 57.12 7.16 11.7 6.70 )

Found: 57.60 7.22 11.61 6.60 (#)

Ex. 93 9 - CH ; ‘a ' 1 1 / 3

X coi N- (CH, ) 5CH oy

R 3

HOCOCH

CHCOOH

+ . JT { 29 1-(4-Methylpentyl)-4-(2-(3-pyridyl)- thiszolidin~-4-ylcarbonyl)plperazine fumarate

Physicochemical Properties 1) ¥eltinz point: 146°C

E ane 7 r CL. . 2) Elemental analysis (for C,3HyNy0:8)1 8

Calculated (%): 6.70

Found (%): 6.78

Ex. 94 8

Ax J an a 4 TON H-(CH,) CH = N- A < 3 ‘ 15 OOCUH

I

CHC QOH

1-Heptyls4-(2-(3-pyridyl)shiazol- idin-4-vlcarbonyl)piperazine funarate

Physicochemical Properties 1) Melting point: 153°C 2) &lemental analysis (for CpyH3gN 055)

C 1 H 8

Caloulated: 58,51 7.37 11.37 6.51 fd

Found: 54,45 7.37% 11.28 6.63

Co 97123

EXAMPLES 95_10 131

The following compounds of dxamplee 95 to 105 compounds of Examples 106 to 116 and compounds of

Examples 117 to 131 wers obtained in the same man- ner &a in oxamplen 54, 87 and 20, respectively.

Desired Product

Chemical Structure and Chemical Name 3x. 95 } [8D . .3 HCH 1-(5,5-Dimethyl-2-(3-pyridyl)- thiszolidin-4-ylcarbonyl)-4-(3- phenylpropyl)piperazine trihydro- chloride . - 20 Physicochemical Properties 1) Nun (Dus 0-d,) §1 1.22-1.80 (£11, nm), 1.92-2.28 (1H, nm), 2.442.800 (2i1, m), 2.84-4.88 (11H, m), 6.00-6.18 (1H), 7.12-7.48 (51, m}, 7.92-2,12 (1H, mw), B.52-8,72 (1H, m), ; ©, Th-9.04 (2H, m)

: 723

Ex. 96 cd, CH “NTE ” | y Con N-(CH, 03

N

.3 1H ~ 2 1-(2-(4-Dimethylamino-3-pyridyl)- thiazolidin-4-ylcarbonyl)-4-(3- prhenyluropyl)piperazine trihydro- chloride

Cy Physicochemical Propertics 4 — 1) 'eltlng point: 14 5-145°C 2) Flemental analysis (for Cy 4H 5, B50801 5. 20,0) ¢ il MN 8 C1

Caleyliteds 49.27 6.89 11.97 5.48 18.18 6)

Found} 49.735 6.50 11.55 5.65 17.91 (3

Ex. 91 ' ; a - A I /TN “X ” i \§ ook Non) 5d ’ “NON H No

CR; .3 HCH {-Benzhydryl-4-(2-(3-pyridyl)thia- zolldin~4-ylcarbonyl)piperazine trihylrochloride

2 FH23

Physicochemical Properties 1) Melting polintt 138-140°C 2) Elemental analysis (for Cp3Hz3N, 08015)

Cc H N 3 . 5 Calculated: 49.63 6.71 10.08 5.77 (®)

Found? 49.78 6.51 9.97 5.74 +

Ex. 58 5. J \ , J ~ N - COK H-lH . x — 3HCL {-Benzhydryl-4-{2-(3-pyridyl)thia- zolidin-4=-ylearbonyl)plperazine trihydrochloride

Physicochemical rroperties i 1) Melting point: 173-174°C 2) Elementzl analysis (for CpgH 54, 08015" 1.B1,0): 0 H R g

Calculated! 53.25 5.95 9,55 5.47 (%)

Found? 53.41 5.83 2.48 5.27

Tr ' ik 5 .

Ex. 101

S.. _ 7 i CN ~ I N CUE NOOUC,Hg + 2HCL

N

1=REthoxycuibonyl=4=(2-(3-pyridyl)- thiszolidin-4-ylcarbonyl)pl;eriuine dihydrochloride

Physicochemical Properties 1) Melting woint: 168°¢C 2) TW%lenental analysis (for Cys H, 05501, ) 1

C H K

Calculated: 45.39 5.71 13.23 (%) . 15 Found: 45.12 5.52 15.02 (%)

Ex. 102 : ) = 20 } gS. . on y ld a! oe ) ~ pd [ ] i Com- (CH, J, N 'N 3HCL

N-(2-(2-Pyridyl)ethyl)-2-(3-pyridyl)- thizazolidine~4~curbozamide tri- “> hydrochloride - 216 - i es 3

BAD ORIGINAL 9 ba

0925

Physicochemical lroperties 1) Melting point: 65-7020 2) Elemental analy:iis (for Cyl Ng 08C1 4° 136H,0) . 5 Cc H N 3 CL caleulatedt 12.46 5.39 12,37 7.08 23.50 (0)

Found: 42.41 5.353 12.13 6.91 23.46 (#)

Ex. 103 3 — J 2) | pre e

SV joocomiony 8 * 2HCY1

N-(2-Thienylnethyl)=-c=(3-pyridyl)- thianolidine-4-carboxamiie dinydro- chloride

Physicochemical Propertics 1) Melting point: 109-111°C 2) Flemental znulysis (for Cy,Hy¥508,C150.9M,0): c H N 5

Calculated: 42.62 4.80 10.65 16.25 (%)

Found 42.82 ATT 10.74 16.00 : (5%)

Bx. 104 8 i FT 7 2" No Cubkl= 8

SN RL

N

+ 2H01

N-(2~1ndanyl)-2=-(3-pyridyl)thiazcl- {dn e~4-carboxamide dih drochloride

Physicochemical Properties 1) Melting jolrt: 124-127°C o 2) TFlament.~l onzlycls (for Cog Haltily)e

C H H S

Caleculnt-d: 54.27 5.21 10.5: 8.0% (%)

Found: 54.11 5.30 10.31 7.25 () 5 Ex, 105 5s “NC cof hoooh,oHy =

N i « 2HUL 1=(3-Phenyl :rcylonyl)-4-{(2=-(3~ pyridyl)thiazolidin-4-ylcarbonyl)- piperazine dihydrochloride { 2 - 28 - BAD ORIGINAL 9

Love ee

Thynicochemical Pro ertics 1) Melting roint: 130°C 2) MMR (pMS50-dg) &* 2.6-2.8 (44m), 3.3~-3.8 (8H,m), 4,5-4.9 (1H, m), 5.98 and 6.20 {s, respectively 1H), 7.26 (SR, 8), 7.9-8.2 (1H, m), 8.6-9.2 (3H, m)

Ex. 106 . Ss

CH,0 oo OS 0 n cor N—(on). LJ 1 273 cio 3 1-(2-(5,6-Dimethoxy-3-pyridyl)- thiazolidined=-ylcartonyl )=4~(3- phenylpropsl)plpera:.ine

Physicochemical Properties 1) NNR (Dus0-d.) “3 1.52-1.96 (zh, m), 2.18-2.72 (8K, mn), 2.90-4.40 (131, m), 5.40-5.84 (14, mn), T.12-7,40 (5H, m), 7.40-7.50 (11, =), 7.70-7.84 (1H, m) 2) 5: m/z 456 (i+)

¢ 7/23

Ex, 107

BE 8. as /7 J pone ponte’ N=CH,- C2 . il H s 2 of

N

N-(1-Benzyl-4-piperidinyl)-2-(3- pyridy1)thiazolidine-4-c rboxamide lhysicochenical Properties 1C — 1) ielting soirt: 121-134°C — 2) ¥lemental analysis (tor Cy qHogl 05)

C H Ni 8

Calenlated: 65.94 6.85 14.65 8.38 (#) 19

Found: 65.69 6.83 14.46 8.43 (%)

Ex. 103 ; 20 ~8

Fy NT con niehy)y 4) 5 it p SE 1-(3-Phenylpropyl)-4-(2-(3~pyridyl)- thiazolidin-4-ylc rbonyl)piperazine

Physicochemical Properties 1) NHR (cnely)

oo 273 b 1) ¥¥R (CNCl4) 4 1.6-2.0 (2A, m), 2.2-3.8 (14H,m), 3.8.4.2 (1H, m), 5.62 and 5.98 (4, resoectively 1H), 7.0-7.5 6H, m), 71.7-8.0 (1H, m), 8.4-8.7 1H, m), &.7-8,9 (1H, m)

Ex. 199

A oA - , rT NT comi-(eny), To

H

N=(2-(3-Indolyl)ethyl)~2-(3~ pyridyl)thiazolldiine-4- carbocamide

Physlcozhduical Eropsarties 1) Melting point: 163-170°¢C 2) Rlemental analyeis (for CqqHygtiy 08)

Cc H N 8 geleulated: 64.75 5.72 15.90 9.10 (#4)

Found : 64.52 5.67 15.70 9.07 (%)

Ex, 110

S ... ‘

UR cowl

Lg H “

He (g=Fluorenyl)=2=(3=pyridyl)- thiszoliiine~4-carbovamide

Co d7123 ’

Physicochemical Properties 1) Melting point: 194-196°C 2) Elemental analysis (for Coot gN508)1 ¢ H N 8

Calculated: - 70.75 5.13 11.25 8.59

Co (#)

Found: 70.51 5.16 10.99 8,51 (%)

Ex. 111

L 5. 0 / IN

CY sof N-CNR(CH,), CH,

Co Neer 22 1-Butylaminocartonyl-4-(2-(3- , pyridyl) thianelidin-d~yleortonyl) piperazine

Physicochemical Properties . we (0nc2., 1) mr (00014) §: 0.94 (3H, t), 1.1-1.7 (4H, m), 3.0-3.8 (12H, m), JeB-4.3 (1H, nm), 5.58 and 5.94 (8, respectively 14), T.2-7.4 (14, m), 7.7-8.0 (1H, m), .4-8.6 (11, m), B8.6-8.8 (1H, m)

Bx. 112 5

CA v f N" conn-cH { O

H

: J7l23 =

N-{2~Benzimidazolyl)wethyl-2- (3-pyridyl)thlazolidine-4- carboxamide

Physicochemical Properties 1) delving point: 96-99°¢ © 2) NMR (Cuely) i: 3.2-3.7 (2H), 4.3 (1H, m), 4.6-4.8 (21), 5ed=5.6 (11), T.2-T.4 (7H), 1.5-7.6 (3H), 7.7-7.9 (1H), B8.4-8.6 (24), 8.66 (11, d, J=3Hz) 5) Ws: m/e 339 (al)

Ex. 113 8

A ik anon) {) wo 8B \ + 8000 (CH3) 3

Co 20 1-(2-(1-tert-Butoxycartonyl=3- vipericdinyl)thiazolidin-4yl- carbonyl)-1~(3-phenylpropyl)- piperazine physicochemical Fropertles 1) Elemental analysis (for CyqHyoN048)1

G H K 8

Calculated: 64.51 8.42 11.14 6.38 (#)

Found 64.21 8.45 10.83 6.38 oo ips vr’ 2) xs: m/z 502 {(i')

Ex. 114 » > oo

NN. J

C | DR CO Nun, ) 4 2) : SNH “72 = 1=(%~2henyloropyl)-4~(c-(2~ pyranyl Jthinsolidine-4-y1- caroonyl)atlperaLine : Physicochend sal lropevties : 1) NR (Ciils) ¢t 1.6-2.0 (2, m), 2.2-2.8 (a, m), ' 15 2,0=-3.4 (2H, mn), 5.5-4.0 (44, m), : 1.0-4.2 (tit, m), 5.67 and 5.80 (s, reaspasctively 14), 7T.1-7.5 (54, m), 8,0-3.3 (3H, m) . \ . 20 2) us: w/z 397 (M7)

Ex. 115 Bh

Ow hooon, su wi (ony), -{)

NT H © =

K-{3-Phenyloropylamincethysl)- 2-(%-pyridyl)thiazolldine-4- curboxamide

Physicochemical iroperties 1) WIR (cael) e 1.45-2.16 (4H, nn), 2.45-3.05 (61, m)y 5.10-%.75 (4H, nm), 4.08-4.40 (1H, Lr), 5.3(=-5.70 (18, br d,

J=10n), 6.92~7.41 (6H, n), 7.53 (15, br =n), 7.66-7.96 (1H, m), 2. 40-2:,82 (el, a) 2) Mir n/z 371 (2*+1)

Ere 115 8 (CHy) 4 “TN CORHCH, CH, ‘5 vB (iy) 5 }

Sel Zenner yi propy i aninoc thyl-2=(5- prridyl)thiasotlidine-d-carboxamide prhyelescaenlonl Fropusbivh 1) 8.1 (101) . §: 1.30=2,10 (5H, wm), 2.3:-2.75 (10H, a), Lr STOTT WE, my de 1i=4,40 (ti, my), 5.43 (0.74, 4, J=12Hz), 5.53 (G.5H, 4, J=12i%), T.00-7.41 (114, m), T.41-7.93 (¢H#, =m), B.46~ ) n,T4 (25, m) 2) us: w/z 489 (M141) . LL ia - 25 - aD ORIGINS J

Ex, 117 / “

Ww. PT dN yak N= (Cli, ) sil ? CHCOONL : deooon f-liexyl-4-(é-{5-pyridyl)thiazol- fdin-4-ylecarbonyl)piperazine furarate

Physicochemical rroperties 1) Melting nroint: 128°C 2) Flemental mnalycie (for Cyl Fy O58)

C Ii 5

Galopsgtoa: 57.7 7.16 11.71 6.70

Found: 27.60 7.22 11.51 ¢.61 (%)

Ex. 118 - Z0 g— : : VARY CH

Aiko N= (ud, ) 5Cil 3

LJ = Net “Cli

Ng

SHOOUH

: fl

HOOCCH

1-(4=-Nethylp2ntyl)-4-(2-(3~pyri1dyl) thiazolidin-d~ylcarbonyl)piperazine funarate

Co , FJj#3

Ihysicochemnical Froperties 1) Veltine noint: 145-142% 2) X¥A (D50-d ) &: 2.83% (5H, 4, J=56iHz), C.9T7-1.16 (SH, mn), 2,04-2,76 (6H, m), 2.94-3.90 (6d, m), 4.29 (14, a, J=THEz), 3.38 (0.5H, 8B), ’ 5.86 (0.0H, 8), 6.61 (211, 8), 7.25=-T.57 (1H, =), T.15=-8.08 (1ii, a), B.39-8,80 (2H, m) 3) Ws: m/z ie (N-C,i,0,)

Ex. 119 a

A] —~

TN IN

Cy UCN ne (CH, D5? us, «NS Nw 273 Nee 5

CHCOOH

I

HOOCCH

1~(2-(3=-ryridyl ;thinzolidin~-4~ ylearbonyl)~-4-(35-(p-tolyl)- propyl )plperazine fumarate

Physicochemical Fropertie: 1) Melting point: 178-161°%¢C 2) Elemental analysis (for Cypligyify 055): 2 if 0" 3 (»

Found: Hladl 6.47 10.52 6.26

Ce 97/23 r . .

EX. 120

A °

ZY Cal LN N\

JON N-(CH, )= 3»

Ly no CON K ( re oct ’ CHUOOH : HOOCCH 1=(3-(p-ethoxyphenyl)propyl)=-4- (2=(3~pyridyl)thiezoliiin-4=-yl- caroonyl )piperazine fumarate

Physicochemical Provertier 1) Weltinz point: 141-143% 2) ®lemantal analysls (for Taga N, 068)

Cc A 5 3

Calculated: 59,76 6.32 10,32 5.41

Found: 57.50 6.31 10.28 5.98

Ex. 121 5 ad . : — . ~ wo A i / \.

Lo 5 SOM n-(CK, of Neon noo —! —

CHCOOH

C0O0CCH 1-(3-(v-Hyaroxyphenyl )rropyl)-4-(2~ (3-pyridyl)thiazolidin-4-ylcarbonyl)- piperszine fumarate oes 2

Physicochemical Froperties 1) telting joint: 132-1550 2) slemental =znalysis (for CoglizoNg 065) ° i N S

Serene: 55.01 0.10 10.30 0.07 tound: 58.50 6.03 10.41 6.01 (+) uXe 1 ec 0 o 1 1 ’ 0 Clg

Poo eon Tie (UML), LOR

N i . c’% 3

CHC OOH

HooueH 1% 1={3=(54i~Dinethoxypbenyl propyl )-4=~ (z=(H=pyriuyl)iniage idin-4-ylcarbon- 71) piperazine fumarate thysicochenicel Yroperiies £0 1) Kid (Lr50-dg) § 1 1.35-1.95 (2H, m), 2.20-2.68 (8H, m), 2.R5-3,20 (61, m), J.72 (3H, 8), 3.74 (7, ©), 4.¢8 (11, q, J=Thz), 5.55 (0.51, 2), 5.£8 (0.35, s), 6.65 (2H, 8s), 6.68-6.95 (3H, m), 7.25-7.51 (1H, nw), T.74=-5.C5 (11, m), 8.39-8.74 (24, ’ mn) 2) 5: m/z 4% atet-C,d, 0 2) 5: m/z 45T (id 41 Cail Oy)

1 - F722

Ex. 123 /

ZN NAT r ] 3 ofl =i) / N_pq

NE \/ Nee

HCOOH

I

} HONGCCH 1-(3-(p-Chlorophenyl)propyl)-

A-(2=(3=-pyridyl)thiasolidin-4- yleartonyl)pliperazine fumarate

Fhysicochemical froperties 1) ielting polne: 187-129°C 2) Elemental analysis (for pty i, 05501) 19 2 i! i 1 3

Calculated! £7.00 3.71 10.54 H.47 5.86

Found 57.27 5.71 10.17 5.26 5.82 (#)

Ex, 124 { S

ZN ] TN N\

C0) eon Noon) 4 — ¥

Np ! nf €'5 vy i1oooH

Hooch 1-(3-(p-Fluorophenyl}ornpyl)-4- (2={3-nvxtly1)tatazol tdin-4-y1- ) carbon.) piperazine funarate - 230 =~

Pais

L é

BAD ORIGINA J

. Hips

Physicochemical Properties 1) melting point: 171-172°C 2) Flemental nnalynis (for GC gHs Ng OgF) ¢ H N F s

Calculated: 58.2% 5.89 12,56 3,58 65.Mn1 : (8)

Found 58.82 5.93 10,50 3.3% 6.21 (3)

Exe 125 3 NO : 5 I wf \ i y . i Aon £1 {erly ds NO,

CHCOOA

HOOCEH ; 1-(%-(¢,4-Linitrophenyl) propyl) -4- (¢=(3-pyridyl)tidevrolicinad-yl- carbonyl )piperzeine funarate yayelcocherical Properties 1) wake (ms0-d.) 8: 1.60-2.05 (2H, m), 2.19-2.65 (6H, m), 5.80-5.7% (8H, m), 4.10-4.42 (1H, a), 5.58 (0.37, #)y 3.3 (2.54, 8), 6463 (?H, 8), 7.26=T7.517 (1, m), 7.72-6,08 (211, m), B.3v-2.84 (4H, 1") 2) na: m/z 487 (4'er-c 1,0.)

BAD ORIGINAL oF

Nitin oni i}

Co. 231 -

¥ .

If l22

Ex, 126 “UN

A ) yo ~

C | a udk B-tuity) gd - Ril

Sy OR 270 eee 2 5 . creo

I

NOOLCCH

1-(3-( p-Aiminophenyl jpropyl)-4- (2-(3-vyridyl)thiazolidin-4~-yli- coxrbonyl)piperazine furarate . Physicochemical Yroperties 1) Mud (D:S0-dg) 61 1.48=1.89 (2H, m), 2.18-2,68 (8H, m), 218-3076 (DF, mm), 1.16=-4.45 (1H, m), 5.58 (USL, 8), Seb (Leo, 8), 6.40 (1H, 4, J=9Hz), 6.63 (28, 8), 6.53 (1H, a, J=9Hz), T.23=T.52 (1d, m), 7. =2013 Dhan), @.41-8.81 (2H, m) } £Q Z NG iz 41 og z 2) ¥51 1, P1Y (Kk CaligCy)

Ex. 127 2: CH \

ZZ | I \ 7

CY ib CON B-{CH,) ad y : — 23 —

KN H

CBCOOR

I

HCOCUCH

J

- 2 - BAD ORIGINAL J

Loo

7l23 : 1-(3-(0o-Methylphenyl)propyl)-4- (2-(3-pyridyl)thiazolidin-4-yl- carboryl)piperazine fumarate

Physicochemical Properties 1) Melting point: 151-1535"¢ 2) Blemental unulysis {for Cy qligy By 0yn)s

C i tN S

Calon ated! 61.57 6.51 10.64 6.CY

Found 651.3% 6.41 10.58 6.1C (%)

Ex. 128 : A

AN ] IT :

L | nTood i-cen)5d)- CN i i] nf : -

CHCOUH

1

HOOUCH

1-(3-(p-Cyanophenyl propyl )-4=~ (2-(3-pyridyl)thiesolidin-4-~yl- carbonyl )viperazire fumarate -

Physicochemical Properties 1) NMR (DIE0-,) 8 1 1.656-1.02 (2i, m), £.16-2.080 (RH, m), 2.80-3,60 (Gl, m), 4.12-4.42 (1H, m), 5.55 $0. 3R, 8), 5.87 (0.74, 3), 6.05 (2H, 8), 7.25-7.53 (3H, m), 7.65-8,03 ( 9

Co .

J7(23 (3H, m), 8.36-8.73 (2H, m) . + _o 2) Ms: m/z 421 (M CoHa04)

Le 5 i

CR x HB CON R-(CHy)y.

CHCOOH i

HOOCCH

1-(3~-Phenylpropyl )-4-(2-(3- pyridyl)=-3,4,5,6-tetrahydro-2H~ thiazin-4-yl-carbonyl)piperazine fumarate

Physicochemical Properties 1) NMR (DMSO-d, )

St 1.59-1.9 (44, m), 2.2=2. (8H, m), 2.8=-3.6 (6H, m), 3.9-4.2 (1H, m)? oo 20 5.6 (1H, 8), 6.66 (2H, B), T.1~-T«6 (6H, m), 7.6-8.0 (1H, m), B8.4-8.8 (28, m) © + 2) MS: m/z 410 (M ~Cy Hi, 0,)

Ex. 130

S

J J FN

/ N° CON N-(CH,)y._./ { H 2/3 8 CHCOOH )

HOOCCR

- 234 - Ca

BAD ORIGINAL [5

0 2723 1-(3-Fhenyipropyl)-4-(2-(3- thienyl)thiazolidin-4-yl- carbonyl )plperazine fumarate : 5

Physicochemical Properties 1) Melting point: 152-155°C (decomposition) ] 2) Elemental analysis (for CystyyN055,)1 c H N 8

Calculated: 58.01 6.04 8.12 12.39 ! Found) 58,04 6.04 8.11 12.62 (%)

Ex. 131

S

: : oo / AR : | pl CON N-(CHy)g ° 0 CHCOOH . ROOT 1-(3-Phenylpropyl)-4-(2-(3=-furyl)- thiazolidin-4~-ylcarbonyl)piperazine fumarate

Physicochemical Properties 1) Nelting point: 173-175°0 2) Elemental analysis (for Cpls N30g8)

Cc H N 8

Calculated: 59,86 6.23 B.,38 6.39

Found)’ 59.76 6.14 8.37 6.47

; ) S23

EXAMPLE 132 7 Wo con H-(CH) CH DHE,

N 2) H,0-EtoH i | ANHC1/dioxane, ethyl 2 acetate 2 b q adh N-(eny)g

ET Re {-Heptyl-4~-(2-(3-pyridyl)-2-pyrrolin-5-ylcarbon= yl )piperazine (570 mg) was catalytically reduced in 20 ml of water plus 20 ml of ethanol in the presence of platimum oxide as the catalyst until cessation of the absorption of hydrogen. The catalyst wan f{il- tered off, the filtrate was concentrated under re- duced pressure, and the residue was subjected to sili- - ca gel column chromatography (5 g). Elution with eathnuol-ethyl acetate (1:10, v/v) gave 250 mg of 1- heptyl-d-(5-(3-pyridyl)pyrrolidin-2-ylearbonyl)pipe= ragine. This product was converted to ites trihydro- chloride (180 mg) in the same manner as in Example 54.

Melting point 138-143°C.

Elemental analysis (for C, Hyg, 0C15.1.8H;0)3 c (%) 8 (%) N (%) ct (%)

Calculated: 50.41 8.18 11.20 21.26

Found: 50.49 7.83 11.09 21.10

. ——— + - Hes

EXAMILS 133

The followins compound was obtained in the same manner as in Example 132 excdpt that the treatment with 2 hydrogen chloride was not carried out.

Desired Product

Chemical Structure and Chemical Name Physicochemical Properties 1) NMR (coe 4) 1 TN J . ' 2) con i-cony) 50 3.43-3.90 (4H, m)s sys MH = = 3.99-4.34 (2H, m), - + 3HCH 7.04-7.44 (61, m), 7.91 (1H, dt, J=2Hz, 1-(3-Phenylpropyl )-4-(5~ J=8Hz), B.53 (1H, dd, (3-pyridyl)pyrrolidin-2- J=2Hz, J=5Hz), 8.65 ylezrbonyl)piperuzine (1H, 4, J=2Hz) 2) us: m/z 3718 (M%)

EXANPLE 134

JO 3 4 \.. 51 h, CH, Ol i= ( Cy) 5) s 2101 oT 20 NANCO,H a H 2 HOBT wh DCC —

MeN O

Nn

DMF

/ 0 CH,~CH 2 | 2 cr N-~CONH NB-(CHy)5{ - H = .2HCY

SLE -

To a oolution of 200 me of J-phenylpropylethy- lenedianine and 81 mg of H-methylmorpholine in 5 ml of dimethylformamnide, there were addea in sequence 120 ag of 1-hydroxybenzotriazole, 180 mg of dicyclo- hexylearbondiimiie and 170 mg of 2-(3-pyridyl)thia- zolidine-4-carboxylic acid. The mixture was stirred overnight at room temperature. fhe reaction mixture was diluted with ethyl acetate, the insoluble mat- ter was filtered off, and the filtrate was concen trete! under reduced pressure. After addition of 0.5 N ajuecus sodium hydroxide, the residue was ex- trected with ethyl acetate. The organic layer was extracted with 1 N hydrochloric acid, snd the aqueous layer was adjusted to pH 10 with potassium carbonate and extracted again with ethyl acetate.

The organic layer was washed with saturated aqueous golution 6f sodium chloride, dried over anhydrous sodium sulfate and concentrated under reluced pres- gure. The residue was subjectad to alunina column chromatography (20 g). Zlution with me thanol-ethyl acetate (1:10) gave 150 mg of N-(3-phenylpropylamino~ i} ethyl)-2-(3-pyridyl)thiazolidine-4-carboxamide. The

NMR and 4S data for this compound were in agreement with thoass given in Examples 115.

EXAMPLE 13553 sS S 7 J / 2 os a veto! 0 “y Ne 3 «HC

BAD ORIGINAL d oo, . A= ~

A solution of 40 mg of 1-(3-phenylpropyl)- piperazine in 0.5 ml of dimethyl sulfoxide was added to a solution of SO mg of 1,3-dioxo-5-(3- pyridyl)thiazolidino-{3,4-c)oxeazolidine hydro- chloride in 1 ml of dimethyl sulfoxide at room tem- perasive. The reaction mixture was stirred for 2 hours at room temperature, then diluted with ethyl acetate, washed in sequence with saturated aqueous solytion of sodium hydrogen carbonate, water and saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate and concentrated unrer . reduced pressure to give T0 mg of 1-(3-phenylpropyl)- 4-(2-(3-pyridyl)thiazolidin-4-ylcarbonyl)piperazine,

The physicochemical properties of this product were in agreement with those of the compound of Example 108.

EXAMPLE 136

The following compound was obtained in the same manner as in Example 135.

Desired Product

Chemical Structure and Chemical Name 8

A econs-(ot,) 5 3 .3HC1 yl BH \—

i v :

JI23

N-(3~-morpholinopropyl)-2- (3-pyridyl)thiazolidi e-4- carboxamide trihydrochloride } 5 Ihysicochemical Froperties 1) Melting point: 92-96°C , oY ~ 1 qf : ’ 2) Elemental analysis (for CqgHngtia0ptClgeted B,y0)3

C | HN 3 CH

Calon gre: 40.64 6.39 11.85 6.78 22.49 (?

Found 40.72 6.12 11.50 6.90 22,62 (%)

IXANFPLE 137 8 1) trifluoroacetic oN vo acid , 15 1 N CON H-(CHy) 5 ee rem eremtmtesersl

SH H to oC 2) HCH

COOC(CHy)4 rR

JR con R=(CH, ) 57 \

H oe Re

BN n .31C1 1-(2-(1-%ert-Butoxycarbonyl-3-piperidinyl)thinzol- fdin-4-ylearbonyl)-4~(3-phenylpropyl)piperazine (430 mg) won dissolved in 3 ml of dichloromethane, followed £5 by addition of 2 ml of trifluoroacetic acid. The mix- ture was stirred at room temperature for 6 hours. The reaction mixture was poured into 60 ml of saturated aqueonn soluticn of sodium hydrogen carbonate, and the product was extracted with ethyl acetate. The ethyl

BE H1(73 acetate layer was washed with saturated aqueous so- lution of sodium chloride, dried over anhydrous sodium sulfate and concentrated under reduced pres- sure to give 28G mg of t-(3-phenylpropyl)-4-(2-(3~ piperidinyl)thiarolidin-4-ylcarbonyl)piperazine.

This compound was dissolved in 8 ml of ethyl acetate, and 1 ml of 4 ¥ hydrogen chloride solution in dioxane was added. After 30 minutes of stirring, the resul- tant solid was collected by filtration and dried to give 200 mg of 1-(3-phenylpropyl)-4-(2-(3-piperidinyl) thiazolidin-4-ylcarbonyl)piperazine trihydrochloride.

Melting point 174-118%C.

Llemental analysis (for C, HynN, 08C15.1.5H,0)¢

Cc (%) H (%) N (%) 5s (%)

Calculated: 49.02 7.48 10.39 5.95

Found: 49,02 7.40 10.29 6.00

EXAMPLE 138

CHO HO

- OA nt + PH

CH-_ / \_ (

Ho” CONHOHZ _ ) 0 (CH, ) CHa

Aol 0 Loomuongd 0- (CH CH “) 5{__)0- (Oiy)gClis p-Toluenesulfonjc acid (5 mg) was added to a solution of 70 mg of N-(p-heptyloxybenzyl)glycera-

i « 92.3 mide and 50 ng of pyridiac-L-carboxazldehyde in 70 nl of benzene plus 2.9% mi of pyridine, and the mixture was refluxed for 12 hours for azeotreopic dehydration, After cooling, the reaction nixture - 5 was washed with two portions of saturated aqueous aolution of sodium hydrogen carbonate, three por- tions of water and one pertion of snturated urgucons solution of sodium chloride, then dried over anhy- drous sodium sulfate, and conuentrated under re- duced pressure. The residue obiained was purified by preparative silica g2l thin layer chromatography tn give 60 mg of N-(p-heptyloxybenzyl)-2-(3-pyridyl) -1,3-dioxolane-4~-cacrboxamide.

NMR (0DC1,) &: 0,90 (3H, Lr &), 1.2-1.5 (8H), 1.6-2.0 (21), 3,95 (2H, t, J=7Hz), 4.1-4.8 (58), 5.89 and 5.99 (respectively 1H), 6.6-7.2 (1H, exchange with D,0), 6.6-7.4 (54) 7.6-7,8 (1H), 8.6- oo 8.7 (24)

MS: m/z 398 (M%)

EXAMPLE 139 or ON on,

R- * . edi cony) 5d) —_— 2 —/ == 0 _ A hed Mon 5)

Cl HoT Re AN

N

- 242 - { ;

BAD ORIGINAL N eT

Co 7123 1-(3~Phenylpropyl )~-4-(2~(3-pyridyl)oxasoli~ din~4~ylcarbonyl)pliperasine was obtained from 1- (2-antno-3-hyroxypropionyl)-4-(3-phenylpropyl)pi- perazine and pyridine-j-carboxaldehyde by follo=- wing tune procedurc of Example 138. Yield, 50%.

Slemernital analysis (for CopHogliy0y): ¢ (5) H (5) No(8)

Culculated: 69.45 7.42 14.72

Found: 99.16 7.38 1.1.58 #5: m/n 380 (1)

Ladi 140 : GHO © © 5 | Gity=Cilp , en,

CLE oo He(Oy) ems

N H toluene molecular aleve : 5: ; x COR H=(ety) 5 © .

N

: 20 A Clig

A mixture of 50 mg of N-(3-phenylpropylamino~- LL ethyl )=2-(pyridyl)thi:zolidine-4-carboxamide, 17 mg of p~tolualiehyde, 100 ig of molecular sieve (44) and 2 ml of toluene wan heated in a sealed tube at 120°C for 8 hours. The reaction mixture was filtered the filtrave was concentrate! under reduced pressure, and the resldue was subjected to preparative thin leyer chromatography (develiorment with 2% methan 1-

Co SF195 ethyl acetate being mde twice; Ra vrluen0,15) to give 3.3. mm of 1=(3-phenyl ropy)-3-(2-(pyridyl) thiazolidin-4-ylc: ~bonyl )-2-(4-tolyl)imidarokiiine,

NR (ene)

Cp 1.55-1.95 (3H, m), 2.39 (3, =), 2.42- 2.87 (8H, m), 3.C9 (11, dd, J=8Hz), 3.41 (1H, da, J=4Hz, J=120z), 4.C7-4.2C (11, =), 5.16 (1H, 8), 5.%2 (1H, 5), T.03=7.427 (10H, m), 7.60-T.21 (1H, m), 6.44 (1H,

IC ad, Je2ily, detl ), B.€3 (1H, 4, J=0H)

Ms: m/z A12 (81) Bl

BAMNCLE 181 o . 50 we —\ enon HOON R-(CHy)y 7 °° — To

Cy0 coi 3-(ony), £3

Lo oO N H = == i 1-(2-(5,6-Dimenthoxy-3-pyridyl)thiagolidin-4- ylearbtonyl)-4-(3-phienylyropyl)piperazine (730 mg) was dissolved in 25 ml of ethyl acetate. To the so- lution was added with stirring at room temperature 2 N hydrogen chloride soiution in dioxane. The re- sultant ,owder was collected by filtration and dis~ solved in saturated sodium carbonate solution. - 244 - a

BAD ORIG. + 20 onc

Mt ' 97123 : Thy) anetetin wae added, the ozponie lever wns see aarnted and weshed ofth watsr, nel the solvent wes dirtitied off under reduced resesure. The residue was -marified by cilica gel column chrometogrephy (2i1ica gel 29% mi; 10% nethanol-ethyl acetate ) to sive 210 mg of of 1-(2=~(5~methary-b=cx0=5,0-dihydro-3-pyridyl) thinrolidin~-4-ylcoriony 1 j-4-(3~-pher yl xopy Jpipera= zine, nan (1nee-d,) 5! 1.56-1.24 (20, =), 2.20-2.80 (€H, a), 2.9C -4.40 (104, mn), 5.28-5.66 (1H, m), 6.80 -7.44 (TH, m)

MS: m/z 442 (M*)

EXAM:LE_142

The following compound was obtained in the vame manner as in Fxample 90. - 20 . CH ~ A oad ! Ta CHCOCH

Cl NS 3ON N-CH, CH, CH G

NL : N=" HOOCCH 1-(3-Phenylbutyl })-4~(2-(3--pyridyl)thiazol- {din-4~ylecarhonyl piperazine fuaarats

Melting point 166-168°C . oe y ey N S :

Elenental analysie (for Cpqlay 8, Cg ) r - 245 =~ BAD ORIGINAL 9

Soe. 212%

Cc (#) H (%) N (%) 8 (s%)

Colaulated: 1.58 Deh 10.64 6.09 rounds H1.d1 Laity 10.580 GAC uy oar 41) (1 = Hy 0) : 5 LiahlLs 143 . fables conpuaitiom (per tablet)

The product obtuinuu 20 mg wxample 31

Lactose 57 my

Corn starch 33 ng ! Hydroxypropslcellulouve 4 mg

Jagneolum stearate t ng

Total 120 mg

A homogeneous mixture is prepared from 20 g of the product obtaincd In Ixample 91, 57 g of lactoce and 38 g of corn starch. Then, 40 g of 10% hydro- xypropylecellulocoe solution is added, and %he nix- ture in subjected to wet granulation. The granules are forced through a nleve and then dried. One - 20 gram of magnesium stearate Is added to the thus-ob- toinuvd granulation product. hfter thorough mixing, the mixture is formed into tablets using a table- ting machine (Jdie-punch sizes T mm, 5.6 R).

EXAMPLE 144

Capsule composition (per capsule)

The product ovtained in 15 mg

Trample 91

Jrystallline celluluse 40 mg - 246 = } . »

BAD ORIGINAL 0.

. . v - ‘ 712%

Crystalline lactase 144 me

Magneainn sbearats 1 mg fot 200 np

A homogeneous miwture is prepared from 15 g of h the wroduet obtained in “xample 91, 40 pf of oryr- talline cellulose, 14d go ~f erratalline leretose ond 1 i of asmnesiun stearate snd filled into Fo. 3 capsules unine a cansule~{111ing nachine,

Tyopailized prevaration comporition (ner vinl)

The fumarate ontained in 1 me - wxample 91

D=dannitol 5.0 me

In 800 ml ofl water ar» dissolved 1 g of the product obtained in kxample 91 and 50 g of D-man- nitol in that order. Water is ad:!led to make the whole volume 1 liter. This solution is aseptically filtered, then filles in 1-ml- portions into vials, and lyozhilized. h 20 The anti-i AF rctivity of the compounds accor- ding to the invention has been confirmed by the . following test: Rifdct on platelet activating fac- tor (FPAF)-1nduced platelet aggregation in plasma vethod: Nine volumes of blood were drawn from the central ear artery of male rabbit (Japan white, 3 kg) directly into plastic syrivge containing 1 vo- jume of %.8% sodium citrate, The blood was centri- fured at 270 x g for 10 minutes at room temperature - 247 - BAD ORIGINAL 9 [

i J - 9F(23 and the platelet rich vlasma (PRP) was remcved.

The neolles was further centrifugea ut 1,100 x g for 15 ninwtes. The supernatant was uoned as platelet poor olagma (112). The pletelet concentration was . 5 odjusted to 5x10” celle/ul with PPP. Platelet ag- gregatlon was me.sured by the method of G.V.il. Porn ant #.J. Uroes (Journal of Fhysiology, 16&, 179-195 (1963)) using a tila HAJ R (I'ikou Bio Sclence,

Japan). Verying concentration of comvound:s were edded to the PE 2 minutes prior to af (1070 3),

The extent cr platelet aggregation was determined - by the meximun change of light transmisoion, avslig n- ing the transmiseion of unetimulatcd IR) to be 0g and that of YPP to be as 100%. Fercent inhibition with compound was calculated by dividing the per- cent aggregation in the presence of compound Ly that in the contrcl, and then the Cg values were calculated. .

Results: As shown in Table 1, a lot of compounds of the present invention inhibited the PAF-induced rab=- bit platelet aggregation in plasma (IC, value of _ at least 10-2 #). rsspecially, the compounds of

Examples 371, 49, 67, 11, 81, 83, 85, 90, 91, 119 and 142 were potent inhibitors having ICs0 values of 2.8x10~" to 8.5x107" », while these compounds did not inhibit tne platelet aggregation induced by

Ab? (3x10-6 u), arachidonlc acid (1x10™% 4) or col- lugen (10 mg/ml) (data not shown). (These results

No Bab OniGiNAL J)

A ,

07123 gur-~c* thst the coneoundz of thizc invention are specific antazoniste of TAL.

CHALTTE 146 © . tt (1) eee ci,

J

A osointion of Z-(3-pyridyl)thiazolidin-4- carboxylic acld (0.81 g), 1={3=-methyl=-3-phenylbu- tvl)piperarine (0.72 g), 1-hycoroxybengotrieszole (C.80 3) and diceycinhexylecerbodiimide (0.76 ¢£) in

U,N~dinethyl formamide (7 ml) war ptlirred under room 14% temperature for 12 hours. To the renctien solution was noded ebtnyl acetnis (10 =1) and the fncoluble metter was flltere! off, To the flltrate wrs addeu 0.5 i sodium hydroxide and the cojution was extrac- ted with cthyl accelate, The ethyl acetate larer - cu was extracted with 1 ¥ hydrochloric acid. The ayuesus layer wae mode vasic with potassium cuarbo- nate and extrocted with otlyl weetate, The veosul- tant othyl acetate layer was washed with a aantura- ted asueoun sojusion of seitrum chloacida, dried over

A) anhydrous codiur sulfite and concentrazed under re- ducel nrecsure., “he reoidue wus subjected to sili- ca se! onlumn cavers tosraphy and elation with wn ethyl scetate = aetiinol (1731) alxsare gave: 1000 gf 0

BAD ORIGINAL gl - 249 = bse -

EE

“(28 of 1-(3-methyl-3-phenylbutyl)-4-(2-(3-pyridyl)thlia- zo) td in-4-vicurbon:l )oierazine.

MA (ns) 8: t.on (OH, 6), 1.65-1.97 (28, m) 1.97-2.46 (TH, m}, 2.78=-3.73 (6, 1) 3070-4030 (1H, m) 3.57 (0.84, br.d, J=12Kz) "935 (0.511, br.d, J=Hlz)

FoUS=Ter 3 (Gi, 1), [.71=7.9¢ (if, 0)

N.13-2,63 (1d, in), 8.5 ns (m/z) + (WY) 5 S11. . 3 creo (11) In on CON N=CRoCH,0 ’ \ Hoc

Ch Lo

Ty a solution of 1-(3-methyl-3-phenilbutyl)-4- (2-(3-pyridyl)thiazoiidin-4=-ylearbonyl)piparozine (1.22 £) in ethanol (6 m)) wae ndicd fuparie neid ! 20 (0.32 #) and the mixture wun dissolved, The aolu- tion was stirre ot room temperature for z hours. and allowed to cdind nat room temperature for 2 doy. . } Tha roaultant cryodala were collected by filtrntiecn, wanhed with ethrnol and then dried to give 1.08 ¢ of

Y={3~nethyl-3-phaenylbutyl)-4-(2-{3-pyridyl)thianoli~

Afn-4-vlearbonyl )pivernzince funarate.

Mal ting point 172-173°C. )ementel analysis (for 0, qMs6N 053) r ] oo - 250 - GAD ORIGINA= ee sh . 2123

Cc (%) H (%) N (#) s (7%)

Cale. 62.20 6.71 10.306 5.93

Found 61.92 6.07 10.17 6.09

ZAAMPLE 147

The following compound was obtalaned in the game manner 18 in Example 146. 5 CH co p33

TN ' YN 10 Mn 0 2 \, Yoryeys 5 [ n GOR H Cil,CH, CH, y CL GAC00H ha 4 oil HOOG 2H 1-(4-"ethyl-4--phenylpsutyl) ~4~(2-(3-pyridyl)thiazali- din-4-ylcarbonyl )piperazine fumarate

NAR (CD14) 8: 1.05-1.47 (24, m), 1.35 (6H, 8) 1.47-1.86 (2H, m), 2.09-2.063 \6H, =m) 2.73-3.76 (6H, m), 4.27 (11, q,

J=6Hz) 5.58 (0.51, 8), 5.89 (0.5, £8) 6.685 (2H, 8), 7.05=7.53 (6H, nm) 7.75-8.05 (14, m), 8.38-8,7175 (2H, m) us (m/z) + (M*- C,Hy04) = 251 = BAD ORIGINAL 9

St Vd 20 ATL the followin aoa pY kind were obtained in the fame manner A Lin “Xample 24. agsired Product

Jhamical Struc bar

Xa 148 . S TY

Lhe ‘ ; - vity hy | NO ONM N-UNL od “ H n & - an + + 3 , CQUH ’ LISI 1 £hyss sicocaenical Fropertlize 1) Hair (Ssu=ig)

Qi 1.0 16H, ad), 2.2=2.6 (ii, Ys 2.5=-3.9 (3, n)y Sed=3.8 vod in) d1-1.4 Hi, Mn) Hedy 5.849 0 (a, roso2cbively 1), 6.94 (2d, 3), 7.12 iH, a), 1.2-7.0 (15, mm) 7.7=-3.1 (1:4, a), 3,-8.4 {24, x) 2) "5 z 9 (T-3,:4,C 2) US: m/z 4190 {: 44 4) “Xe 143 5

GH

) : 3 fe Hf wpe! : --Jt, CH wy” 3

H Jin A=, 2 TED 27"

N oH 3

CQOH

HooC r N - 252 - ND

BAD ORIGINAL [i

AH 12%

Physicochemical Properties 1) Hy (D¥30-dg) & 0.94 (6H, d), 1.4-1.9 (4H, m), 2.2-2.,5 (AH, m), 2.6-3.2 (24, Mm), 2.2-3%.8 (71, m), 3.96 (2H, t), 4.1-4.4 (1H, m), 5.56, 5.88 (a, respectively 1H), 6.65 (24, 8), 6.88, 7.25 (4H, ABq, J=3.7Hz), 7.3-7.5 (1H, m),

T.7-8.0 (1H, m), 8,4-R.7 (24, m) 2) 29: m/z 454 (M*-C, B04) : {

Ex. 20 3

Bi A ] BN Ch id IVE NGok weomomd oN . CON N=-CH,CH,C 4

Ny | “. oN \ ee

COCH. Chis 3

Physicochemical Properties . 1) RMR (cnet) oT 20 §t 1.36 (64, 8), 2.07 (3H, 8), 1.8-2.2 (2H, m), 2.3-2.6 (44, m), 3.16 (2H, 4d), 2.4-4.,0 (44, m), 5.12 (18, t), 6.10 (14, a), 7.2-7.5 (6H, m), 8.4-8.8 (31, m) 2) ¥S: m/z 466 (o')

Bx. 151 oA ol Hoey an SHC

SN H wv NC «JI

Physicochanmical Proverties - 1) Melting noints 165°C 2) Nit (DA50=-d,)

St 2.,9=35.3 (4H, m), 3.2-3.8 (24, m), 3.6~4.7 (4H, m), 4.4-4.8 (24, nm), $.92, 6.08 (a, : respectively tH), 7.9=8.2 (1H, m)

BR,6=-9.2 (31, m)

Ex, 152 { 5 - Ea oo So ro = MO. / © CON N-(CH,) 4-7 pg ' H NL ( 2)3 Yom 0 COOH ‘

HNDOC oC (d-isomer)

Physicochemical Properties 1) Melting point: 189-191°C 2) Rlemental asnalyeis (for Gogh N, 058)

C H N 3S

Calculated: 60,92 6.29 10.93 6.26 : (s

Found 60.68 6.15 10.86 6,13 (7)

EX. 123 ro a / / {Nee

LT IN N el roe . /

Lo i CON R-C { “N No v Ne

J

SN

A123

EBhg3icochamical Propertiss 1) 14 (2430-4)

St 1.3=2.4 (44, 1), 2.6-3.4 (24, nm), 2.9=-2.%9 (41, mn), 2.3-3.2 (24, mn), 3.51, 3 5.082 (4, respectively 10), T.1-T7.6 (16H, m), T.6-5.0 (11, m), 8.38-2.7 (21, m) 2) Ws m/z 520 (i)

Exe 101 10 — The N , . 0 y COX | N-CH,CH,0 }

UOnNd

HOU ’ v ihysicocnemicul iropertics 1) WR (0.:80-dg) . 8 ced =Z.0 (41, m), 2.76 (2d, t), 2e4=3.5 or 20 (2H, m), 3.4~3.8 (41, m), 4.12 (21, t), 4.1-4.% (th, m), 5.58, 5.99 (sg, respec- sively 1h), 6.64 (<H, 8), 6.8-T1 (2H, un),

Te1=7.6 (4H, m), 1.7=8.1 (1H, m), B.4~ 8.6 (2k, m) 2) NS: a/7 398 (W' =) H,0,) nXe 152 = \ i - oo

IN N ns / wm comm COCHy - 255 = a

BAD oH] 123 5

Physicochemical Propertics 1) deiting noint: 1354-15776 2) Elemental analysis (for Cy 41154 N, 0,3) q H N 8

Calculated: 63.61 6.10 14.13 3.09 (4

Found: H3.4YH 6.12 13.93 8.26 (7) ix. 156 19 , 1m vis a Tivesd Noid 1 1 ; ' x i ey N=CH, 0H, 0 —( \ - "UH, ; oT 3 Cit 5 eo

HOC

15 .

Physicochemical Properties 1) Melting point: 15°0C 2) Nam (R450~d,.) : §: 0.51-0.90, 1.08-1,35 (m, respectively iY, 70 1.30 (a, 6H), 1.50-4.53 (m, 131), 5.55, 5.089 (=a, respectively 1H), 6.64 (6, 21), T.00=T.18 (=m, 6H), T.69-8.00 (m, 11), B.40-8,6% (m, 2H)

Bx. 157 *

Pa . ST ,

I. | “no cop w-(cH,) on? wo 2’3 7 t=

Dus oo BOOH 1000 - 25% - BAD ORIGINAL J be w ! - ;

Shoudene only To Ske 1) Anlting polns: 120-1322 - Mme =: aval rsd a SHR. > ny 2) Oleaent dd aaalrsis (for Ctl Ma Of )

UJ { i 5

Jala tiated 60,41 hohe 1.06 5.16 (4) , founds set) Baa Goh) (7)

Axe A072 ii / 8 : co 4 Son d(31,)g Oui - 1 ¥ joan

Hoou raysleochenscal frope: lies 1) Wdelbing points 14y-140"C 2% Bioner bal eralysts (For Ug plig, lig Oct 2) Bion tai vralysis (for pally lig fe ) ed Ss’ CK h 9 valculnted: 53.85 Hea tel 6.44 (#) oo found LWhLTD Hah 1a beh Y (1)

Lx 109 £5 :

Ll p \ t Nog a Le oo

N H ful n-din UH DH - ,

COOH

1

HouC = 257 = BAD ORIGINAL Dd (PO. - . i

Lets

I) ’

Pasi icocaenical Sroavslbier 1) Meld sing nolo: 16u-172"¢ 2) Mlement 1 snalysls (Tor Uant,, MgO)

Je afd ") 0 it i 3

Y Caled hed: Bh. 79 L. 1b Yond HedH 9

Joan G3.00 5.10 9.44 5.79 (4)

IX 1D) / B : ’ - hy VAR i a 30% =n) ~{ - 7 i” Nf 3 Ne

C1 oe oo] 15 cayalcochenical Properties 1) Heltine polat: 143-156°8 2) Alemental -nalycis (Tor Cpgilgqng Ign) 0 1 il i) 31

Gulculated; 97.00 5.71 10.24 5.80 6.48 (%) . ] Cae

Fount 57.04 3.65 10.19 3.74 6.67 (#)

Exe 101 — 9

A 1 ~ ’ 5 I Col N=(CH_}, — ) ed A) N NE; ( 2's \ _/

Cy ha

HOOC— . BAD UriGlHivAL wil > 7! Oe re ’ bi

29(23 fnysavochemical lroparties 1) #9 (D¥S0-d ) je] 8: 1.22~1.9c (2d, m), 2,122.74 (11H, m) 2.83-3.71 (94, nm), 4.20 (1H, q, J=Hz), 5.52 (0.54, 8), 3.80 (0.%H, 8), 6.53 (2H, 8), {eU0=1440 (ond, m), 7.60-7,89 (1H, m), B.41-2,60 (111, n) . cris + 2) 5: m/z 410 (4 CH, 04)

Ex, 162

A

— 27s , — -

CN co A-(emy), 4

Lt nooCoN -(CH))s—{ ) \

BUH, Dlg 00H ’ 1

HOUE ~~

Physicochemical Properties - 1) Nii (uLey) 7 20 81 1.38 (3H, t, J=THz), 1.62-2,04 (2H, m), 2,22-2,82 (BH, m), 2.84-5.86 (9H, m) 3.99-4.39 (1H, m), 5.84 (14, br 4, J=14Hzn), 6.00 (1H, br s), 6.90~7.46 (6H, m),

T.63-7.98 (1H, m), 8.41-2,60 (1H, m) 2 MS toe 5 2) MSt m/z 410 (W C,1,0,)

Ex, 163 8 a I

N-~CON N-(CH,) +

L I H “/ ( 2)3 /

N C1 jj coo

HooC ~~ ot 2)

BAD ORG

’ » > v ; J 7123

Phveicochenical lropeivies 1) Hil (Bo 80=-dy) 81 1.32=1,92 (2, mn), 2.16-2.84 (tl, a),

PARSE ILE (LH, mj, 4,124,460 \1H, my,

S074 (G.4H, wv), 5.02 (0.80, 8), 6.62 (ZL, ¢), T.ul=T.54 (Hl, m), T.0e=-0.42 (2H, mn) . a. ; wt A 2) Ar omSzn Aon, al. (x —a ty Cy)

Lx. 16% 19 Fo i" ; a CH i

N A |S N\

A ol GOR B= (CH, ) 5 : Sy I ET ! Cliy

Ti 1 Rous

Ihysicoenzaicil FPropecties 1) Naltinz ~oint: 75°C . 2) BuR (CRC, M30 ) = 81 D.95=1.724 Lm, 5), 1.55=1.43 (n, 21), 2. 50-444 Sm, 131), 5.52 (8), Y.935 (4) (respectively 1h), 5.70 (8s, 24), 7.07~ 7.42 (ra, 04), TTT=1.97 (a, 1), 8.40 2,50 (m, 14), HeHU=R TT (om, 11) eh xe 155 3 CH. a 3 }

A lL Te hn end D [I Na 27 2 Nm

N° [oe \ > . nooc—" Wp i»

Bro oh, 07143 : =

Lhysieeenemical rope rtity 1) teiting point: A 2) MAH (VibU=d go)

St 0.9%5-1.24 (m, 3H), 1.35=1.94 {n, 2H),

Ceeh=da fs (my BH), 2.805068 (a, 1), : 4.154.571 (m, 1H), 5.57, 2.8% (8, reape-ssively 1H), 6.0% {a, 24), T+13~ 7.48 La, wi), 7.74-8.01 (m, 1H), 8,40=- 8.69 (m, 24) \

Ex. 155

Bh a uu

Arh nb

CT 0 Sued HGH, LL fhysicochemical rroperties 1) Wu (Coi1g)

S81 1.6=2.¢ (2il, Mm), 2.¢=27T (BUH, m), 2.8=3.2 (281, m), 3.00 (34, 8), 5.6-3.8 (41, m), 4.,0-4.4 (2H, m), 5.6, 6.0 (m, resacctively 14), T.2=T.6 (oH, m), T.i=6,0 (14, m),

Ro4=2,0 (1, m), B.7=53.9 (1H, n) 2) us: m/z 426 (MY)

Ex. 161 8

EL cry N-oity6 A yy 0 ™

Lea Li ws - 61 - JR a

Physicochemical Properties : 1) NMR (CnC1.,): 8: £.56-2.83 (4H, m), 2.85=-4.3% (10H, m), 3.52 (0.58, brs), 5.69 (0.51, a), 7.190-2,16 (108, m), 2.45-8.60 (2d, m), ro11-8.85 (1H, mm) 2) ds: m/z 472 (nh) nx. 163 i { y a ™ (Hy —- Zz on 7

C1] Ce - gC W-CK, CHU ~ \

N- | _/ z “| ee a CH

COCLOC, Hg 3 ro

H00C

Thyricochenica} Iroperties ) 20 1) Melting voint: 290°C 2) ®Bleaen* 1 analysis (for 0, pa3N,0,3.H,0) 3 H N 3

Jalenlated: 58. 54 H.45 2,50 4.87 (:%)

Tround: va, 24 5,22 8.372 ATE (>) £x..159 oO

ES a -\ 0 ’ TN il

C.) NN oon H-(oB,). 5.7 N sn Ls Be [Coon 3

HOOC— <0) [ REL ch - BAO

Cw , 2323

Physicochemical Properties 1) NMR (DMSO-dg ) 51 1.42-1.94 (2H, m), 2.11-2.61 (6H, m), 2.64-3.19 (2H, m), 3.19-3.72 (6H, m), 4.15-4.43 (1H, m., 5.61 (0.5H, 8), 5.92 (0.5H, 8), 6.67 (2H, 8), 7.30-8.09 (7H, m), 8.45-8.78 (2H, m) + 1 2) NS: m/z 445 (M+ 1-C,H,0,)

Ex. 170 ] A 0

AY \ NN CON N-(CH,) 54)

L H —/ 23 b —

N

Ta

HOOC—

Physicochemical Properties 1) NMR (DMSO-d) $3 1.48-1.91 (2H, m), 2.,12-2.60 (6H, m), 2.79-3.74 (8H, m), 4.,08-4.317 (1H, m), 5.56 (1H, 8), 5.87 (1H, 8), 6.63 (2H, 8), 7.24=-7.51 (1H, m), T7.51-8.02 (6H, m), 8.39-8,73 (2H, m) 2) MS: m/z 460 (M'-0,H,0,)

Table 1

Example No. Iq, (un) 32 0.490 34 0.950 36 > 0.860 37 0.054 46 0.650 48 0.450 49 0.085 : 50 0.800 ~ 54 0.240 55 0.160 56 0.120 57 0.200 58 0.390 59 0.210 60 0.760 61 0.770 . 63 0.500 64 0.390 65 0.120 66 0.430 67 0.071 : 71 | 0.064 12 0.900 76 04900 77 0.430

Table 1 (cont'd)

Example No, 1Csq (uM) 78 0.280 80 0.340

B81 0.028 82 0.160 83 0.034 84 0.220 85 0.072 ] 89 0.400 90 0.067 91 0.071 92 0.260 93 | 0.630 97 0.120 105 0.940 17 . 0.260 118 0.630 119 0.079 120 0.170 121 0.19 123 0.18 124 0.18 125 0.45 126 0.18 127 0.46 128 0.97

Pw be

A123 ——

While the inveniion has been described in de- tail and with reference to specific embodiments thereof, it will be apparent to one skilled in the art that various changes and modifications can be made therein without departing from the Bpirit ang gcope thereof,

Claims (6)

Crow, Of 2 ’ 71° : 3 : Claims

1. A sa*urated heterocyclic carboxamide deri- vative of the general formula (I) or a salt thereof: 1 Ao (1) : Ap wherein rn! represents a heterocyclic group reelected from the grouv consisting of a pyridyl group, a ni- peridyl group, a pyrazinyl group, a pyrrolyl group, a thienyl group and a furyl group, which may be - subatituted with 1 to 3 subastituent(s) selected fron the group consisting of halo, Cie alkyl, hydroxy, Cio6 alkoxy, Cy 6 alkylthio, oxo, carboxyl, Cy 6 alkoxycarbonyl, and mono or ¢i-C, 6 alkylamino, Rr? represents a hydrogen aton, x! represents a sulfur atom, 1! represents a group of the formula SsN-R4 wherein rt ls a hydrogen atom, a Ci6 alkyl group, - a carboxyl group, a Cie alkanecyl group, a Cis6 alkoxyoxalyl group, or a C._6 alkoxycarbonyl group, A! represents a methylene group, R’ represents a group of the formulae 2 2 A A : ve N . 7 ~ } ® Pi . O~ : 25 Ne 37 Ne 3S R R in which A% and A2, which may be the same or diffe- rent, each represents a Cio3 alkylene group which may be substituted with 1 to 3 substituent(s) each

3 oun i selected from the group consisting of a Ci 6 alkyl group, a phenyl group, and a phenyl group substi- tuted with 1 to 3 C, ¢ alkyl group (s), Z represents a methine group (>OH-) or a nitro- gen atom, rR! represents a hydrogen atom; a hydrocarbon group each is selected from the group consisting of a Cy_q2 alkyl group, a phenyl group, a Cit alkyl group substituted with 1 to 3 phenyl group (s), and a phenyl -Coe alkenyl group, any of which may be Co substituted with 1 to 3 substituent (s) selected - from the group consisting of halo, Cit alkyl, hy- droxy, Ci.8 alkoxy, phenoxy, phenylsulfinyl, phenyl- sulfonyl, oxo, Cig alkanoyl, benzoyl, phenyl-benzoyl, halo-benzoyl, phenyl-C, ¢ alkanoyl, cyano, nitro, and amino; a carboxyl group; a C,y_6 alkanoyl group; a bengoyl group; a Cy_6 alkanoyl group substituted with 1 to 3 phenyl group (8) a Ci6 alkoxycarbonyl group; or a mono- Or di-C, _¢ Bh 20 alkylaminocarbonyl group, r'C represents a hydrogen atom, and rR represents a phenyl-C, ¢ alkyl group.

2. A saturated heterocyclio carboxamide deri- vative or a salt thereof as claimed in Claim 1, wherein R! is a pyridyl group, R? is a hydrogen atom, x! is a sulfur atom, 1! is a group of the formula >NH, a! is a methylene group, R> is a group of the formula SEN -N z-R', Ns i o 7/23 ; in which RY is a hydrogen atom; a hydrocarbon group each 18 selected from the group consiating of a C412 alkyl group, a phenyl group, a Cie alkyl group substituted with 1 to 3 phenyl group (e), and a phenyl-C, _¢ alkenyl group, any of which may be sub- stituted with 1 to 3 pubstituent:(s) selected from the group consisting of halo, Cy6 alkyl, hydroxy, Co Cin alkoxy, phenoxy, phenylsulfinyl, phenylsulfo- : nyl, oxo, Ci-6 alkanoyl, benzoyl, phenyl-benzoyl, halo-bengoyl, phenyl-C, ¢ alkanoyl group} a benzoyl : et groupg a Ci-6 alkanoyl group substituted with 1 to 7 3 phenyl group (8); a C,_, alkoxycarbonyl group} or a mono- Or di-C, ¢ alkylaminocarbonyl group.

J . 15

3, A saturated heterocyclic carboxamide deri- ) vative and a salt thereof as claimed in Claim 2, . wherein i! is a pyridyl group, RZ is a hydrogen atom, x! is a sulfur atom, 1! is a group of the / * | formula NH, Al is a methylene group, and rR is Co 20 x EL a group of the formula in which RT is a Cy.6 alkyl group substituted with 1 to 3 phe- nyl group (8). i 25

4. A saturated heterocyclic carboxamide deri- : vative and a salt thereof as claimed in Claim 1, which is 1-(3-phenylpropyl)-4-(2-(3-pyridyl)thia- : zolidin-4-ylcarbonyl)piperazine or an acid addition salt thereof. 7 - 269 - bo rE gare ~ / “N — i — o#[23 dr

5. A saturated heterocyclic carboxamide deri- vative and a salt thereof as claimed in Claim 1, which is 1-deeyl-4-(2-(3-pyridyl)thiazolidin-4-y1- carbonyl )piperazine or an acid addition salt there- of,

6. A saturated haterocyeclice carboxamide deri- vative and a salt thereof as claimed in Claim 1, which is 1-(4-0x0~4~pherylbutyl)-4-(2-(3-pyridyl )- o 10 thiagolidin-4-ylcarbonyl)piperazine or an acid addi- Soe tion calt thereof.