AU743723B2 - Aroyl-piperazine derivatives, their preparation and their use as tachykinin antagonists - Google Patents

Description

P:'OPER\MKR\SPEC1\76750-98-316 do-13/ 1/01 -1- PIPERAZINE DERIVATIVES TECHNICAL FIELD The present invention relates to new piperazine derivatives and a salt thereof.

More particularly, it relates to new piperazine derivatives and a salt thereof which have pharmacological activities such as Tachykinin antagonism, especially Substance P antagonism, Neurokinin A antagonism, Neurokinin S 10 B antagonism, and the like, to a process for preparation thereof, to a pharmaceutical composition comprising the same, and to a use of the same as a medicament.

BACKGROUND ART 15 Some piperazine derivatives having pharmaceutical activities such as Tachykinin antagonism have been known as described in EP 0655442 Al and WO 97/22597 Al.

DISCLOSURE OF INVENTION S 20 The present invention advantageously provides piperazine derivatives and a salt thereof which have pharmacological activities such as Tachykinin antagonism, especially Substance P antagonism, Neurokinin A antagonism, Neurokinin B antagonism, and the like.

P:\OPER\MKR\SPECI\76750-98-316 doc-13/1/01 -2- Another aspect of this invention provides processes for the preparation of said piperazine derivatives and a salt thereof.

A further aspect of this invention provides a pharmaceutical composition comprising, as an active ingredient, said piperazine derivatives and a pharmaceutically acceptable salt thereof.

A still further aspect of this invention provides use of the said piperazine derivatives or a pharmaceutically 10 acceptable salt thereof as Tachykinin antagonist, especially Substance P antagonist, Neurokinin A antagonist or Neurokinin B antagonist, and for the manufacture of a medicament useful for treating or preventing Tachykininmediated diseases, for example, respiratory diseases such as 15 asthma, bronchitis, rhinitis, cough, expectoration, and the like; ophthalmic diseases such as conjunctivitis, vernal conjunctivitis, and the like; cutaneous diseases such as contact dermatitis, atopic dermatitis, urticaria, and other eczematoid dermatitis, and the like; inflammatory diseases 20 such as rheumatoid arthritis, osteoarthritis, and the like; pains or aches migraine, headache, toothache, cancerous pain, back pain, etc.); and the like in human being or animals.

P:'OPER\MKR\SPECI\76750-98-316doc-13/1 1/01 -3- According to one aspect of this invention there is provided a compound of formula 0

Y-R

2 R--C-N N-R 4

(I)

R

3 wherein Y is lower alkylene, R is phenyl which has 1 or 2 substituent(s) selected from the group consisting of trihalo(lower)alkyl, halogen, lower alkylamino, di(lower)alkylamino and nitro,

R

2 is phenyl or indolyl, each of which is substituted by hydroxy and a substituent selected from the group consisting of lower alkyl, trihalo(lower)alkyl, lower alkylenedioxy, hydroxy, hydroxy(lower) alkyl, lower 15 alkoxy, lower alkylamino and di(lower)alkylamino,

R

3 is hydrogen, and

R

4 is morpholinyl(lower)alkyl which has 1 or 2 substituent(s) selected from the group consisting of ethyl, hydroxy(lower)alkyl, halo(lower)alkyl and lower alkoxy(lower)alkyl; morpholinyl(lower)alkynyl which may have 1 or 2 substituent(s) selected from the group consisting of ethyl, propyl, isopropyl, isobutyl, spirocyclo(lower)alkyl, lower alkoxy(lower alkyl, hydroxy(lower)alkyl, carboxy(lower)alkyl, di(lower alkyl)carbamoyl, lower alkoxycarbonyl and halo(lower)alkyl, or a salt thereof.

P:IOPER\MKR\SPECI\76750-98-316 doc-13/l1101 -4- It is to be noted that the compounds of formula may include one or more stereoisomers due to asymmetric carbon atom(s) and double bond, and all of such isomers and a mixture thereof are included within the scope of the present invention.

It is further to be noted that isomerization or rearrangement of the compounds of formula may occur due to the effect of the light, acid, base or the like, and the compound obtained as the result of said isomerization or S: 10 rearrangement is also included within the scope of the present invention.

It is also to be noted that the solvating form of the compounds of formula hydrate, etc.) and any form of the crystal of the compounds of formula are included 15 within the scope of the present invention.

According to the present invention, the compounds of formula or a salt thereof can be prepared by processes which are illustrated in the following schemes.

P.\OPERMKR\SPEC7675-98-3 16 do-13/1I JO0I Process 1 o Y-R 2 R -C-N N-H

(IV)

or a salt thereof o Y-R 2 or a salt thereof (I I) a. a a a or its reactive derivative at the imino group or a salt thereof a a a a a a. .a a a a a f~*z.

y WO 98/57954 Process 2 PCT/JP98/02613

Y-R

2 0 Rl- -N N- Z,-R 5 or a salt thereof reduction Y-R R! -N N-X 1

-R

(lb) or a salt thereof Process 3

Y-R

2

Y-R

2 0 0 0 0- 2 CO (V R-dN

-X---NR

\3 or a salt thereof

(III)

or its reactive derivative at the carboxy group or a salt thereof (I C) or- a salt thereof Process 4 Y-R2 Y-R 2 0

NX-

2 H-R 7 (VI) 4I) 3 or a salt thereof

(VI)

or a salt thereof (Id) or a salt thereof WO 98/57954 PCT/JP98/02613 7 Process

Y-R

2

Y-R

2 0 H-R8

O

Rl-N N-Z 2

-W

3 R 1 -N-Z 2

-R

8 (IX) 3 or a salt thereof (VIII) (Ie) or a salt thereof or a salt thereof Process 6 Y-R2

Y-R

2 015 R-

H-R

9 R -N N-Z 3

-W

4 R1--N

-Z

3

-R

9 (XI) \le 3 or a salt 3 thereof (If) or a salt thereof or a salt thereof wherein Y, R 1

R

2

R

3 and R 4 are each as defined above,

X

1

X

2 and X 3 are each lower alkylene,

Z

1 and Z 3 are each lower alkynylene, Z2 is lower alkenylene, R is 2-pyridyl which may have 1 to 3 substituent(s) selected from the group consisting of lower alkyl, lower alkoxy, lower alkoxycarbonyl, mono(or di or tri)halo(lower)alkyl and halogen; or 3-pyridyl which may have lower alkoxy or amino, 6 R is saturated heterocyclic which may have substituent(s),

R

7 is pyridyl(lower)alkylamino; N-(lower alkyl)-N-[pyridyl(lower)alkyl]amino; 1-imidazolyl which may have 1 or 2 substituent(s) selected from the group consisting of lower alkyl, lower WO 98/57954 PCT/JP98/02613 8 alkynyl, ar(lower)alkyl, pyridyl(lower)alkyl, mono(or di or tri)halo(lower)alkyl and halogen; 1-pyrazolyl which may have hydroxy(lower)alkyl, carboxy(lower)alkyl, lower alkoxycarbonyl(lower)alkyl, morpholinyl(lower)alkyl or morpholinylcarbonyl(lower)alkyl; piperidino which may have hydroxy(lower)alkyl or lower alkoxy; morpholino which has 1 or 2 substituent(s) selected from the group consisting of ethyl, hydroxy(lower)alkyl, halo(lower)alkyl and lower alkoxy(lower)alkyl; morpholino which has lower alkyl and lower alkoxy(lower)alkyl; morpholinylamino which may have lower alkanoyl; homomorpholinylamino; or thiomorpholinylamino, R is morpholino which may have lower alkyl or lower alkoxy(lower)alkyl,

R

9 is pyrrolidino which may have lower alkoxy(lower)alkyl; morpholino which may have 1 or 2 substituent(s) selected from the group consisting of ethyl, propyl, isopropyl, isobutyl, spirocyclo(lower)alkyl, lower alkoxy(lower)alkyl, hydroxy(lower)alkyl, carboxy(lower)alkyl, di(lower alkyl)carbamoyl, lower alkoxycarbonyl and halo.(lower)alkyl; morpholino which has methyl and lower alkoxy; dimethylmorpholino; or homomorpholino which has halogen, W11 W 2

W

3 and W 4 are each a leaving group.

As to the starting compounds (III), (VII), (VIII), (IX) and some of them are novel and can be prepared by the procedures described in the Preparations and Examples mentioned later or similar manners WO 98/57954 PCT/JP98/02613 9 thereto.

Suitable salts of the starting and object compounds are conventional non-toxic and pharmaceutically acceptable salt and include an acid addition salt such as an organic acid salt acetate, trifluoroacetate, fumarate, maleate, tartrate, methanesulfonate, benzenesulfonate, formate, toluenesulfonate, etc.), an inorganic acid salt (e.g.

hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate, etc.), or a salt with an amino acid (e.g.

arginine, aspartic acid, glutamic acid, etc.), or a metal salt such as an alkali metal salt sodium salt, potassium salt, etc.) and an alkaline earth metal salt (e.g.

calcium salt, magnesium salt, etc.), an ammonium salt, an organic base salt trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt, etc.), or the like.

In the above and subsequent descriptions of the present specification, suitable examples and illustrations of the various definitions which the present invention intends to include within the scope thereof are explained in detail as follows.

The term "lower" is intended to mean 1 to 6, preferably 1 to 4, carbon atom(s), unless otherwise indicated.

Suitable "lower alkylene" may include straight or branched one having 1 to 6 carbon atom(s), such as methylene, ethylene, trimethylene, propylene, .tetramethylene, methylmethylene, methyltrimethylene, hexamethylene, and the like, in which the preferred one is methylene, ethylene, trimethylene or methylmethylene.

Suitable "lower alkenylene" may include straight or branched one having 2 to 6 carbon atom(s) such as vinylene, propenylene, l-(or 2-)butenylene, l-(or 2- or 3-)pentenylene, 1-(or 2- or 3-)hexenylene, methylvinylene, ethylvinylene, WO 98/57954 PCT/JP98/02613 1-(or 2- or 3-)methylpropenylene, 1-(or 2- or ethylpropenylene, 1-(or 2- or 3- or 4-)methyl-l-(or butenylene, and the like.

Suitable "lower alkynylene" may include one having 2 to 6 carbon atoms, such as ethynylene, propynylene, butynylene, and the like, in which the preferred one is propynylene or butynylene.

Suitable "halogen" and "halogen" moiety in the terms "mono(or di or tri)halo(lower)alkyl", "mono(or di or tri)halo(CI-C4)alkyl", etc. may include fluorine, chlorine, bromine and iodine.

Suitable "lower alkyl" and "lower alkyl" moiety in the terms "pyridyl(lower)alkylamino(lower)alkynyl", "N-(lower alkyl)-N-[pyridyl(lower)alkyl]amino(lower)alkyl", etc. may include straight or branched one having 1 to 6 carbon atom(s), such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl and the like, preferably one having 1 to 5 carbon atom(s).

Suitable "lower alkenyl" moiety in the terms "3-pyridyl(lower)alkenyl", "saturated heterocyclic(lower)alkenyl", etc. may include vinyl, 1-(or 2-)propenyl, l-(or 2- or 3-)butenyl, l-(or 2- or 3- or 4-)pentenyl, l-(or 2- or 3- or 4- or 5-)hexenyl, methylvinyl, ethylvinyl, 1-(or 2- or 3-)methyl-l-(or 2-)propenyl, l-(or 2or 3-)ethyl-1-(or 2-)propenyl, l-(or 2- or 3- or 4-)methyl-l- (or 2- or 3-)butenyl, and the like, in which more preferable example may be C 2

-C

4 alkenyl.

Suitable "lower alkynyl" moiety in the terms "pyridyl(lower)alkylamino(lower)alkynyl", "(2-pyridyl)- (lower)alkynyl", etc. may include ethynyl, 1-propynyl, propargyl, l-methylpropargyl, l-(or 2- or 3-)butynyl, l-(or 3-)methyl-2-butynyl, 1-(or 3-)ethyl-2-butynyl, l-(or 3-)propyl-2-butynyl, l-(or 3-)isopropyl-2-butynyl, l-(or 2- or 3- or 4-)pentynyl, l-(or 2- or 3- or 4- or hexynyl and the like, in which more preferable example may be WO 98/57954 PCT/JP98/02613 11

C

2

-C

5 alkynyl.

Suitable "aryl" may include phenyl, naphthyl, and the like, in which the preferred one is C 6 -C1 0 aryl and the most preferred one is phenyl or naphthyl.

Suitable "lower alkanoyl" and "lower alkanoyl" moiety in the term "lower alkanoyl(lower)alkoxy(lower)alkyl" may include formyl, acetyi, propanoyl, butanoyl, 2-methylpropanoyl, pentanoyl, 2,2-dimethylpropanoyl, hexanoyl and the like.

Suitable "lower alkoxy" and "lower alkoxy" moiety in the terms "hydroxy(lower)alkoxy(lower)alkyl", "lower alkanoyl(lower)alkoxy(lower)alkyl", etc.

may include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, t-butoxy, pentyloxy, t-pentyloxy, hexyloxy and the like.

Suitable "saturated heterocyclic" and "saturated heterocyclic" moiety in the terms "saturated heterocyclicimino(lower)alkyl", "saturated heterocyclicaminocarbonyl(lower)alkyl", etc. may include saturated 3 to 8-membered (more preferably 5 to 7membered) heteromonocyclic group containing 1 to 4 nitrogen atom(s), for example, pyrrolidinyl, imidazolidinyl, piperidyl, piperazinyl, hexamethyleneimino, etc.; saturated 3 to 8-membered (more preferably 5 or 6membered) heteromonocyclic group containing 1 or 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), for example, morpholinyl, homomorpholinyl, sydnonyl, etc.; saturated 3 to 8-membered (more preferably 5 or 6membered) heteromonocyclic group containing 1 or 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), for example, thiazolidinyl, thiomorpholinyl, etc.; saturated heterobicyclic group of the formula WO 98/57954 PCT/P98/02613 12

(CH

2 )u (wherein u, m and n are each CH2) integer of 1 to 6); C)2in saturated heterobicyclic group of the formula y(CH 2 )q -N (C 2)s (CH 2 )t (wherein q, r, s and t are each C2) L )integer of 1 to and the like.

Suitable "substituent" in the terms "aryl which may have substituent(s)", "aryl or indolyl, each of which may have substituent(s)", "pyridyl, thiazolyl, imidazolyl or pyrazolyl, each of which may have substituent(s)" and "saturated heterocyclicimino(lower)alkyl, saturated heterocyclicaminocarbonyl(lower)alkyl or saturated heterocyclic(lower)alkoxy(lower)alkyl, each of which may have substituent(s)" may include lower alkyl methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, neopentyl, tert-pentyl, hexyl, etc.), cyclo(lower)alkyl cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.), lower alkylenedioxy methylenedioxy, ethylenedioxy, propylenedioxy, etc.), lower alkoxy methoxy, ethoxy, propoxy, isopropoxy, isobutoxy, tert-butoxy, pentyloxy, neopentyloxy, tertpentyloxy, hexyloxy, etc.), lower alkoxy(lower)alkyl methoxymethyl, ethoxynethyl, l-methoxyethyl, 2 -methoxyethyl, l-ethoxyethyl, 2-ethoxyethyl, etc.), lower alkanoyl formyl, acetyl, propionyl, butyryl, isobutyryl, etc.), lower alkoxycarbonyl methoxycarbonyl, ethoxycarbonyl, propylcarbonyl, WO 9&5"54 PCTAPP98/02613 13 isopropylcarbonyl, etc.), lower alkenyl vinyl, 1-propenyl, allyl, 1-methylallyl, 1 or 2 or 3-butenyl, 1 or 2 or 3 or 4-pentenyl, 1 or 2 or 3 or 4 or 5-hexenyl, etc.), lower alkynyi ethyrivi, 1-propynyl, propargyl, l-methyipropargyl, 1 or 2 or 3-butynyl, 1 or 2 or 3 or 4-pentynyl, 1 or 2 or 3 or 4 or 5-hexynyl, etc.), mono(or di or tri)haio(lower)alkvl fluoromethyl, difluoromethyl, trifluoronethyl, chloromethvl, dichioromethyl, trichloromethyl, bromomethyl, dibromomethvl, tribromomethyl, 1 or 2-fluoroethyl, 1 or 2-bromoethyl, 1 or 2-chioroethyl, ,1-difluoroethyl, 2,2-difluoroethyl, etc.), halogen chlorine, bromine, fluorine and iodine), carboxy, protected carboxy, hydroxy, protected hvdroxv, aryl phenyl, naphthyl, etc.), ar(lower)alkyl such as phenyl(lower)alkyl benzyl, phenethyl, phenylpropy., etc.), carboxy(lower)alkyl wherein lower alkyl moiety can be referred to the ones as exemplified above, protected carboxy(lower)alkyl wherein lower alky! moiety can be referred to the ones as exemplified above, nitro, amino, protected amino, lower alkylamino methvlamino, ethylamino, isopropyiamino, etc.), di (lower)alkylamino dimethylamino, diethylamino, diisopropylamino,.

ethylmethylamino, isopropylmethylanino, ethylisopropylamino, etc.), hydroxy, hydroxy(lower) alkyl hydroxymethyl, hydroxyethyl, etc.), protected hydroxy(lower)alkyl, acyl, cyano, oxo, mercapto, lower alkylthio methylthio, ethylthio, propylthio, isopropylthic, butylthio, etc.), lower alkvlsulfinyl methylsujfinyl, ethylsulfinvl, propylsulfinyl, isopropylsulfinyl, butylsulfinyl, etc.), imino, morpholinyl 2-morpholinyl, 3-morpholinyl, morpholino), bivalent group of the formula WO 98/57954 PCT/JP98/02613 14A carboxy(lower)alkyl carboxyethy, carboxyethyl, carboxypropyl, etc.), lower alkcxvcarbonyl methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, neopentyloxycarbonyl, tert-entvloxvcarbonyl, hexyloxycarbonyl, etc.), spirocyclo(lower)alkyl spirocyclopropyl, spirocyclobutyl, soirocyclopentyl, et ar (lower)alkoxycarbonyi(lower)alkyl benzyloxycarbonylmethyl, benzyloxycarbonylethyl, benzyloxycarbonylpropyl, etc.), pyridyl(lower)alkyl pyridylmethvl, pridylethyl, etc.), carbamoyl, lower alkylcarbamoyl methylcarbamoyl, ethylcarbamoyl, etc.), di(lower alkvl)carbamoyl direthylcarbamoyl, diethylcarbamoyl, etc.), and the like.

Suitable "leaving group" may include lower alkoxy (e.g.

methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, t-butoxy, pentoxy, etc.), aryloxy phenoxy, naphthoxy, etc.), an acid residue or the like.

Suitable "acid residue" may be halogen chlorine, bromine, iodine, etc.), sulfonylcxy methanesulfonyloxy, phenylsulfonyloxy, mesitylenesulfonyloxy, toluenesulfonyloxy, etc.) or the like.

Preferred embodiments of the object compound are as follows Y is lower alkylene (more preferably C 1 -C4 alkylene, most preferably methylene); 1 R is aryl (more preferably C 6 -0 10 aryl, most preferably phenyl) which may have 1 to 3 (more preferably 1 or 2, most preferably 2) substituent(s) [more preferably substituent selected from the group consisting of mono~or di or tri)halo(lower)alkyl (more preferably WO 98/57954 WO 9857954PCT/JP98/02613 trihalo (lower) alkyl, most pref erabl y tri fluoromethyl) halogen (more preferably chlorine), lower alkylamino (more preferably Cl-C 4 alkylamino, most preferably methylamino), di (lower) alkylamino (more preferably di(0 1

-C

4 )alkylamino, most preferably dimethylamino) and nitro]; Ris aryl (more preferably C 6 -Cj 0 aryl, most preferably phenyl or naphthyl) or indolyl, each of which may have 1 to 3 (more preferably 1 or 2) substituent(s) [more preferably substituent selected from the group consisting of lower alkyl (more preferably C,-C4 alkyl, most preferably methyl), mono(or di or tri)halo(lower)alkyl (more preferably mono(or di or tri~halo(0 1 -%alkyl, most preferably trifluoromethyl), lower alkylenedioxy (more preferably

C

1 -C4 alkylenedioxy, most preferably methylenedioxy or ethvlenedioxy), hydroxy, hydroxy (lower) alkyl (more preferably hydroxy(Cl-C 4 )alkyl, most preferably hydroxvmethyl), lower alkoxy (more preferably

C

1

-C

4 alkoxy, most preferably methoxy), lower alkylamino (more preferably C 1 -C4 alkylamino, most preferably methylamino) and di(lower)alkylamino (more preferably di (Cl-C 4 )alkylamino, most preferably dimethylamino)];

R

3 is hydrogen; and

R

4 is pyridvl(lower)alkylamino(lower)alkynyl (more preferably pyridyl(C 1

-C

4 )alkylamino(C 2

-C

4 )alkynyl, most preferably 4- [(3-pyridylmethyl) amino]-2-butynyl); N- (lower alkyl)-N-[pyridyl (lower) alkyliamino (lower) alkyl [more preferably N- (C 1

-C

4 alkyl) [pyridyl (Cj-CA)alkyllamino(Cl-C4)alkyl, most preferably 2-[N-methyl-N- (3-pyridylmethyl) amino] ethyl] hydroxy(lower)alkoxy(lower)alkyl (more preferably hydroxy(C,-C4)alkoxy(C 1

-C

4 )alkyl, most preferably (hydroxyethoxy) ethyl); lower alkanoyl (lower) alkoxy(lower) alkyl (more preferably WO 98/57954 PCT/JP98/02613 16

C

1

-C

4 alkanoyl(C 1

-C

4 )alkoxy(C 1

-C

4 )alkyl, most preferably formylmethoxyethyl); phenyl(lower)alkyl (more preferably phenyl(C 1

-C

4 )alkyl, most preferably benzyl) which has hydroxy(lower)alkyl (more preferably hydorxy(C 1

-C

4 )alkyl, most preferably hydroxymethyl) or morpholinyl(lower)alkyl (more preferably morpholinyl(C 1

-C

4 )alkyl, most preferably morpholinomethyl) [more preferably a-(hydroxymethyl)benzyl or a-(morpholinomethyl)benzyl]; ar(lower)alkoxycarbonyl (more preferably

(C

6

-C

10 aryl)(C 1

-C

4 )alkoxycarbonyl, most preferably phenylmethoxycarbonyl); (2-pyridyl) (lower)alkyl (more preferably (2-pyridyl)-

(C

1

-C

4 )alkyl, more preferably (2-pyridyl)propyl or (2-pyridyl)butyl) which may have 1 to 3 (more preferably 1 or 2) substituent(s) selected from the group consisting of lower alkyl (more preferably C 1

-C

4 alkyl, most preferably methyl), lower alkoxy (more preferably

C

1

-C

4 alkoxy, most preferably methoxy), lower alkoxycarbonyl (more preferably C 1

-C

4 alkoxycarbonyl, most preferably methoxycarbonyl), mono(or di or tri)halo(lower)alkyl (more preferably trihalo(C 1

-C

4 alkyl, most preferably trifluoromethyl) and halogen (more preferably fluorine)); 3 -pyridyl)propyl (more preferably 3-(3-pyridyl)propyl) which may have lower alkoxy (more preferably

C

1

-C

4 alkoxy, most preferably methoxy); (3-pyridyl)butyl (more prefer@bly 4-(3-pyridyl)butyl); pyridyl(lower)alkenyl (more preferably pyridyl(C 2

-C

4 alkenyl, most preferably 3 -(3-pyridyl)-2-propenyl); (2-pyridyl)(lower)alkynyl (more preferably (2-pyridyl)-

(C

2

-C

4 )alkynyl, most preferably 3 -(2-pyridyl)-2-propynyl or 4 2 -pyridyl)-3-butynyl) which may have 1 to 3 (more preferably 1 or 2) substituent(s) selected from the group consisting of lower alkyl (more preferably WO 98/57954 PCT/JP98/02613 17

C

1

-C

4 alkyl, most preferably methyl), lower alkoxy (more preferably C 1

-C

4 alkoxy, most preferably methoxy), lower alkoxycarbonyl (more preferably C 1

-C

4 alkoxycarbonyl, most preferably methoxycarbonyl), mono (or di or tri)halo(lower)alkyl (more preferably trihalo(C 1

-C

4 )alkyl, most preferably trifluoromethyl) and halogen (more preferably fluorine); (3-pyridyl) (lower)alkynyl (more preferably (3-pyridyl)-

(C

2

-C

4 )alkynyl, most preferably 3-(3-pyridyl)-2-propynyl or 4 -(3-pyridyl)-3-butynyl) which may have lower alkoxy (more preferably C 1

-C

4 alkoxy, most preferably methoxy) or amino; pyridyl, thiazolyl, imidazolyl or pyrazolyl, each of which may have 1 to 3 (more preferably 1 or 2) substituent(s) [more preferably substituent selected from the group consisting of lower alkyl (more preferably C 1

-C

4 alkyl, most preferably methyl or isopropyl), ar(lower)alkyl (more preferably phenyl-

(C

1

-C

4 )alkyl, most preferably benzyl) and pyridyl- (lower)alkyl (more preferably pyridyl(C 1

-C

4 )alkyl, most preferably pyridylmethyl)]; imidazolyl(lower)alkyl (more preferably imidazolyl-

(C

1

-C

4 )alkyl, most preferably 3-(1H-imidazol-4-yl)propyl) which may have 1 or 2 substituent(s) selected from the group consisting of lower alkyl (more preferably C 1

-C

4 alkyl, most preferably methyl or isopropyl), lower alkynyl (more preferably

C

2

-C

alkynyl, most preferably propargyl), ar(lower)alkyl (more preferably phenyl(C 1

-C

4 )alkyl, most preferably benzyl), pyridyl(lower)alkyl (more preferably pyridyl(C 1

-C

4 )alkyl most preferably pyridylmethyl), mono(or di or tri)halo(lower)alkyl (more preferably trihalo(C 1

-C

4 )alkyl, most preferably trifluoromethyl) and halogen (more preferably fluorine); pyrazolyl(lower)alkyl (more preferably pyrazolyl(C 1

-C

4 WO 98/57954 PCT/JP98/02613 18 alkyl, most preferably (1H-pyrazol-4-yl)methyl or 3-(1Hpyrazol-1-yl)propyl) which may have hydroxy(lower)alkyl (more preferably hydroxy(C 1

-C

4 )alkyl, most preferably 2-hydroxyethyl), carboxy(lower)alkyl (more preferably carboxy(C 1

-C

4 )alkyl, most preferably carboxymethyl), lower alkoxycarbonyl(lower)alkyl (more preferably C 1

-C

4 alkoxycarbonyl(C 1

-C

4 )alkyl, most preferably tertbutoxycarbonylmethyl), morpholinyl(lower)alkyl (more preferably morpholinyl(C 1

-C

4 )alkyl, most preferably 2-morpholinoethyl) or morpholinylcarbonyl(lower)alkyl (more preferably morpholinylcarbonyl(C1-C4)alkyl, most preferably morpholinocarbonylmethyl); thiazolyl(lower)alkyl (more preferably thiazoly(C 1

-C

4 alkyl, most preferably 4-thiazolymethyl) which may have lower alkyl (more preferably C1-C4 alkyl, most preferably methyl); piperidyl(lower)alkyl (more preferably piperidyl(C 1

-C

4 alkyl, most preferably piperidylethyl) which may have hydroxy(lower)alkyl (more preferably hydroxy(C1-C4)alkyl, most preferably hydroxymethyl) or lower alkoxy (more preferably C1-C4 alkoxy, most preferably ethoxy); morpholinyl(lower)alkyl (more preferably morpholinyl-

(C

1

-C

4 )alkyl, most preferably morpholinylethyl or morpholinylpropyl) which has 1 or 2 substituent(s) selected from the group consisting of ethyl, hydroxy- (lower)al-kyl (more preferably hydroxy(C 1

-C

4 )alkyl, most preferably hydroxymethyl), halo(lower)alkyl (more preferably halo(C1-C 4 )alkyl, most preferably fluoromethyl) and lower alkoxy(lower)alkyl (more preferably C1-C4 alkoxy(C1-C 4 )alkyl, most preferably methoxymethyl); morpholinyl(lower)alkyl (more preferably morpholinyl-

(C

1

-C

4 )alkyl, most preferably morpholinoethyl or morpholinopropyl) which has lower alkyl (more preferably C1-C4 alkyl, most preferably methyl) and lower WO 98/57954 PCT/JP98/02613 19 alkoxy (lower) alkyl (more preferably C 1-C4 alkoxy-

(C

1

-C

4 )alkyl, most preferably methoxymethyl); S-dimethylmorpholino) (lower)alkyl (more preferably 3 5 -climethylmorpholino)

(C

1

-C

4 )alkyl, most preferably 3 ,5-dimethylmorpholino) ethyl); morpholino (lower) alkenyl (more preferably morpholino-

(C

2 -0 4 )alkenyl, most preferably 4 -morpholino-2-butenyl) which may have lower alkyl (more preferably Cl-C4 alkyl, most preferably isopropyl) or lower alkoxy (lower) alkyl (more preferably 01-04 alkoxy(0 1

-C

4 )alkyl, most preferably methoxymethyl); or 3-morpholinyl) (lower) alkenyl (more preferably (2or 3 -morpholinyl)

(C

2 -0 4 )alkenyl, most preferably 3-12or 3 -morpholinyl)-2-propenyl) which may have lower alkoxycarbonyl (more preferably 01-04 alkoxycarbonyl, most preferably tert-butoxycarbonyl) pyrrolidinyl (lower) alkynyl (more preferably pyrrolidinyl

(C

2 -0 4 alkynyl, most preferably 4 -pyrrolidino-2-butynyl) which may have lower alkoxy (lower) alkyl (more preferably Cl-C 4 alkoxy(Cl-C 4 )alkyl, most preferably methoxymethyl); morpholinyl (lower).alkynyl (more preferably morpholinyl- (02-04) alkynyl, most preferably 4-morpholino-2-butynyl or 3 3 -morpholinyl)-2-propynyl) which may have 1 or 2 substituent(s) selected from the group consisting of ethyl, propyl, isopropyl, isobutyl, spirocyclo (lower) alkyl (more preferably spirocyclo-

(C

3 -0 6 )alkyl, most preferably, spirocyclopropyl), lower alkoxy (lower) alkyl (more preferably 01-04 alkoxy(0 1

-C

4 alkyl, most preferably methoxymethyl. or ethoxymethyl), hydroxyclower)alkyl (more preferably hydroxy(C 1 -c 4 alkyl, most preferably hydroxymethyl), carboxy(lower)alkyl (more preferably carboxy(0 1

-C

4 )alkyl, most preferably carboxymethyl) di (lower) alkylcarbamoyl (more preferably di (Cl-- 4 )alkylcarbamoyl, most preferably WO 98/57954 PCT/JP98/02613 dimethylcarbamoyl), lower alkoxycarbonyl (more preferably Cl-C4 alkoxycarbonyl, most preferably ethoxycarbonyl) and halo(lower)alkyi. (more preferably halo(Cl-C 4 )alkyl, most preferably fluoromethyl); morpholinyl(lower)alkynyl (more preferably morpholinyl-

(C

2

-C

4 )alkynyl, most preferably 4 -morpholino-2-butynyl) which has methyl and lower alkoxy(lower)alkyl (more preferably Cl-C 4 alkoxy(Cl-C 4 )alkyl, most preferably methoxymethyl); (dimethylmorpholino) (lower)alkynyl (more preferably (dimethylmorpholino)

(C

2 -0 4 )alkynyl, most preferably 4- 3-dimethylmorpholino) -2-butynyl, 4- G-dirnethylmorpholino) -2-butynyl or 4- 5-dimethylmorpholino) -2-butynyl); homomorpholinyl(lower)alkynyl (more preferably homornorpholinyl

(C

2

-C

4 alkynyl, most preferably 4 -homomorpholino-2-butynyl) which may have halogen (more preferably fluorine) morpholinylaminopropyl (more preferably 3- (morpholinoamino)propyl) which may have lower alkanoyl (more preferably

C

1

-C

4 alkanoyl, most preferably formyl); thiomorpholinyl (lower) alkynyl (more preferably thiomorpholinyl

(C

2

-C

4 alkynyl, most preferably 4 -thiomorpholino-2-butynyl); homomorpholinylarnino (lower) alkyl (more preferably homomorpholinylamino (01-04) alkyl, more preferably homomorpholinoaminopropyl); thiomorpholinylamino (lower) al,kyl (more preferably thiomorpholinylamino(Cl-C 4 )alkyl, more preferably thiomorpholinoaminopropyl); or saturated heterocyclicimino(lower)alkyl (more preferably saturated heterocyclicimino(C 1 -c 4 )alkyl, most preferably saturated heterocycliciminoethyl), saturated heterocyclicaminocarbonyl (lower) alky. (more preferably saturated heterocyclicaminocarbonyl (01-04) WO 98/57954 PCT/JP98/02613 21 alkyl, most preferably saturated heterocyclicaminocarbonylmethyl) or saturated heterocyclic(lower)alkoxy(lower)alkyl (more preferably saturated heterocyclic(C 1

-C

4 )alkoxy(C 1

-C

4 )alkyl, most preferably saturated heterocyclicethoxyethyl) [wherein "saturated heterocyclic" moiety is saturated 3 to 8membered (more preferably 5 to 7-membered) heteromonocyclic group containing 1 to 4 (more preferably 1 or 2) nitrogen atom(s) (more preferably pyrrolidinyl, piperidyl or piperazinyl); saturated 3 to 8-membered (more preferably 5 to 7membered) heteromonocyclic group containing 1 or 2 (more preferably 1) oxygen atom(s) and 1 to 3 (more preferably 1) nitrogen atom(s) (more preferably morpholinyl or homomorpholinyl); saturated 3 to 8-membered (more preferably 5 or 6membered) heteromonocyclic group containing 1 or 2 (more preferably 1) sulfur atom(s) and 1 to 3 (more preferably 1) nitrogen atom(s) (more preferably thiomorpholinyl); or saturated heterocyclic group of the formula (CH2 N

(CH

2 )s (CH 2 )t (wherein q, r, s and t are each Sas defined above)

(CH

2 )r (more preferably 3-azabicyclo[3.2.2]non-3-yl)], each of which may have 1 to 3 (more preferably 1 or 2) suitable substituent(s) [more preferably substituent selected from the group consisting of cyclo(lower)alkyl (more preferably cyclohexyl), lower alkanoyl (more preferably

C

1

-C

4 alkanoyl, most preferably formyl), lower alkyl (more preferably C 1

-C

4 alkyl, most preferably methyl, ethyl, isopropyl or isobutyl), mono(or di or tri)halo(lower)alkyl (more preferably monohalo(C 1

-C

4 WO 98/57954 PCT/JP98/02613 22 alkyl or trihalo(C 1

-C

4 )alkyl, most preferably fluoromethyl or trifluoromethyl), lower alkoxy (more preferably C 1

-C

4 alkoxy, most preferably methoxy), lower alkoxy(lower)alkyl (more preferably

C

1

-C

4 alkoxy(C 1

-C

4 alkyl, most preferably methoxymethyl), halogen (more preferably chlorine or fluorine), aryl (more preferably phenyl), cyano, oxo, bivalent group of the formula C carboxy(lower)alkyl '(more preferably carboxy(C 1

-C

4 alkyl, most preferably carboxypropyl), lower alkoxycarbonyl (more preferably C 1

-C

4 alkoxycarbonyl, most preferably tert-butoxycarbonyl), spirocyclo(lower)alkyl (more preferably spirocyclo-

(.C

1

-C

4 )alkyl, most preferably spirocyclopropyl), ar(lower)alkoxycarbonyl(lower)alkyl (more preferably benzyloxycarbonyl(C 1

-C

4 )alkyl, most preferably benzyloxycarbonylpropyl), hydroxy(lower)alkyl (more preferably hydroxy(C 1

-C

4 )alkyl, most preferably hydroxymethyl), carbamoyl, lower alkylcarbamoyl (more preferably C 1

-C

4 alkylcarbamoyl, most preferably methylcarbamoyl) and di(lower alkyl)carbamoyl (more preferably di(C 1

-C

4 alkyl)carbamoyl, most preferably dimethylcarbamoyl)].

More preferred embodiments of the object compound (I) are as follows Y is lower alkylene (more preferably C 1

-C

4 alkylene, most preferably methylene); R is phenyl which may have 1 or 2 substituent(s) selected from the group consisting of mono(or di or tri)halo- (lower)alkyl, halogen (more preferably chlorine), lower alkylamino, di(lower)alkylamino and nitro [more preferably bis(trihalo(lower)alkyl)phenyl or WO 98/57954 PCT/JP98/02613 23 dichlorophenyl, most preferably bis(trifluoromethyl)phenyl];

R

2 is phenyl which may have 1 or 2 substituent(s) selected from the group consisting of lower alkyl, mono(or di or tri)halo(lower)alkyl, lower alkylenedioxy, hydroxy, hydroxy(lower)alkyl, lower alkoxy, lower alkylamino and di(lower)alkylamino [more preferably di(lower alkyl)phenyl or [trihalo(lower)alkyl]phenyl, most preferably dimethylphenyl or (trifluoromethyl)phenyl], naphthyl or indolyl; R3 is hydrogen; and R is pyridyl(lower)alkylamino(lower)alkynyl (more preferably pyridyl(C 1

-C

4 )alkylamino(C 2

-C

4 )alkynyl, most preferably 3 -pyridylmethyl)amino]-2-butynyl) or (2-pyridyl) (lower)alkyl (more preferably (2-pyridyl)-

(C

1

-C

4 )alkyl, more preferably (2-pyridyl)propyl or (2-pyridyl)butyl, most preferably 3-(2-pyridyl)propyl.

Another more preferred embodiments of the object compound are as follows Y is lower alkylene, R is C6-C10 aryl which may have 1 or 2 mono(or di or tri)halo(lower)alkyl,

R

2 is C 6

-C

10 aryl or indolyl, each of which may have 1 to 3 substituent(s) selected from the group consisting of lower alkyl, mono(or di or tri)halo- (lower)alkyl, lower alkylenedioxy, hydroxy, hydroxy(lower)alkyl, lower alkoxy, lower alkylamino and di(lower)alkylamino,

R

3 is hydrogen, and

R

4 is pyridyl(lower)alkylamino(lower)alkynyl; 2 -pyridyl)propyl which may have 1 to 3 substituent(s) selected from the group consisting of lower alkyl, lower alkoxy, mono(or di or tri)halo(lower)alkyl and halogen; WO 98/57954 PCT/JP98/02613 24 pyridyl, thiazolyl, imidazolyl or pyrazolyl, each of which may have 1 or 2 substituent(s) selected from the group consisting of lower alkyl, ar(lower)alkyl and pyridyl(lower)alkyl; imidazolyl(lower)alkyl which has 1 or 2 substituent(s) selected from the group consisting of lower alkynyl, ar(lower)alkyl, pyridyl(lower)alkyl, mono(or di or tri)halo(lower)alkyl and halogen; (2-methyl-lH-imidazol-4-yl) (lower)alkyl which has 1 or 2 substituent(s) selected from the group consisting of isopropyl, lower alkynyl, ar(lower)alkyl, pyridyl(lower)alkyl, mono(or di or tri)halo(lower)alkyl and halogen; (5-methyl-lH-imidazol-4-yl) (lower)alkyl which has 1 or 2 substituent(s) selected from the group consisting of isopropyl, lower alkynyl, ar(lower)alkyl, pyridyl(lower)alkyl, mono(or di or tri)halo(lower)alkyl and halogen; piperidyl(lower)alkyl which may have hydroxy(lower)alkyl or lower alkoxy; morpholinyl(lower)alkyl which has 1 or 2 substituent(s) selected from the group consisting of ethyl, hydroxy(lower)alkyl, halo(lower)alkyl and lower alkoxy- (lower)alkyl; morpholinyl(lower)alkyl which has lower alkyl and lower alkoxy(lower)alkyl; (lower)alkyl; morpholino(lower)alkenyl which may have lower alkyl or lower alkoxy(lower)alkyl; or 3-morpholinyl)(lower)alkenyl which may have lower alkoxycarbonyl; pyrrolidinyl(lower)alkynyl which may have lower alkoxy(lower)alkyl; morpholinyl(lower)alkynyl which may have 1 or 2 substituent(s) selected from the group consisting of WO 98/57954 PCT/JP98/02613 ethyl, propyl, isopropyl, isobutyl, spirocyclo(lower)alkyl, lower alkoxy(lower)alkyl, hydroxy(lower)alkyl, carboxy(lower)alkyl, di(lower alkyl)carbamoyl, lower alkoxycarbonyl and halo(lower)alkyl; morpholinyl(lower)alkynyl which has methyl and lower alkoxy(lower)alkyl; (dimethylmorpholino)(lower)alkynyl; or homomorpholinyl(lower)alkynyl which may have halogen.

The Processes 1 to 6 for preparing the object compound of the present invention are explained in detail in the following.

Process 1 The object compound or a salt thereof can be prepared by reacting the compound (II) or its reactive derivative at the imino group or a salt thereof with the compound (IV) or a salt thereof.

Suitable reactive derivative at the imino group of the compound (II) may include Schiff's base type imino or its tautomeric enamine type isomer formed by the reaction of the compound (II) with a carbonyl compound such as aldehyde, ketone or the like; a silyl derivative formed by the reaction of the compound (II) with a silyl compound such as bis(trimethylsilyl)acetamide, mono(trimethylsilyl)acetamide, bis(trimethylsilyl)urea or the like; a derivative formed by reaction of the compound (II) with phosphorus trichloride or phosgene and the like.

The reaction is usually carried out in a conventional solvent such as water, alcohol methanol, ethanol, etc.], acetone, dioxene, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, pyridine or any other organic solvent which does not adversely influence the reaction. These conventional solvents may also be used in a mixture with WO 98/57954 PCT/JP98/02613 26 water.

The reaction may also be carried out in the presence of an inorganic or organic base such as alkali metal carbonate, alkali metal bicarbonate, tri(lower)alkylamine, pyridine, N-(lower)alkylmorpholine, N,N-di(lower)alkylbenzylamine, or the like.

The reaction temperature is not critical, and the reaction is usually carried out under cooling to heating.

Process 2 The object compound (Ib) or a salt thereof-can be prepared by subjecting the compound (Ia) or a salt thereof to a reduction reaction.

The reaction can be carried out in the manner disclosed in Example 3 mentioned later or similar manners thereto.

Process 3 The object compound (Ic) or a salt thereof can be prepared by reacting the compound (III) or its reactive derivative at the carboxy group or a salt thereof with the compound or its reactive derivative at the amino group or a salt thereof.

Suitable reactive derivative at the carboxy group of the compound (III) may include an acid halide, an acid anhydride, an activated amide, an activated ester, and the like. The suitable example of the reactive derivative may be an acid chloride; an acid azide; a mixed acid anhydride with an acid such as substituted phosphoric acid dialkylphosphoric acid, phenylphosphoric acid, diphenylphosphoric acid, dibenzylphosphoric acid, halogenated phosphoric acid, etc.], dialkylphosphorous acid, lower alkanesulfonic acid [e.g.

methanesulfonic acid, ethanesulfonic acid, etc.], sulfurous acid, thiosulfuric acid, sulfuric acid, aliphatic carboxylic acid acetic acid, propionic acid, butyric acid, isobutyric acid, pivalic acid, valeric acid, isovaleric acid, WO 98/57954 PCT/JP98/02613 27 2-ethylbutyric acid, trichloroacetic acid, etc.] or aromaticcarboxylic acid benzoic acid, etc.]; a symmetrical and anhydride; an activated amide with imidazole, 4-substituted imidazole, dimethylpyrazole, triazole or tetrazole; or an activated ester [e.g.

cyanomethyl ester, methoxymethyl ester, dimethyliminomethyl

[(CH

3 2 ester, vinyl ester, propargyl ester, p-nitrophenyl ester, 2,4-dinitrophenyl ester, trichlorophenyl ester, pentachlorophenyl ester, mesylphenyl ester, phenylazophenyl ester, phenyl thioester, p-nitrophenyl thioester, p-cresyl thioester, carboxymethyl thioester, pyranyl ester, pyridyl ester, piperidyl ester, 8-quinolyl thioester, etc.], or an ester with a N-hydroxy compound [e.g.

N,N-dimethylhydroxylamine, l-hydroxy-2-(1H)-pyridone, N-hydroxysuccinimide, N-hydroxyphthalimide, 1-hydroxy-1Hbenzotriazole, etc.], and the like. These reactive derivatives can optionally be selected from them according to the kind of the compound (III) to be used.

The reaction is usually carried out in a conventional solvent such as water, alcohol methanol, ethanol, etc.], acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, pyridine or any other organic solvent which does not adversely influence the reaction. These conventional solvents may also be used in a mixture with water.

In this reaction, when the compound (III) is used in a free acid form or a salt thereof,.the reaction is preferably carried out in the presence of a conventional condensing agent such as N,N'-dichlorohexylcarbodiimide; N-cyclohexyl-N'-morpholinoethylcarbodiimide; N-cyclohexyl-N'-( 4 -diethylaminocyclohexyl)carbodiimide; N,N'-diethylcarbodiimide; N,N'-diisopropylcarbodiimide; N-ethyl-N'-( 3 -dimethylaminopropyl)carbodiimide; pentamethyleneketene-N-cyclohexylimine; WO 98/57954 PCT/JP98/02613 28 diphenylketene-N-cyclohexylimine; ethoxyacetylene; l-alkoxy-l-chloroethylene; trialkyl phosphite; ethyl polyphosphate; isopropyl polyphosphate; phosphorus oxychloride (phosphoryl chloride); phosphorus trichloride; diphenyl phosphorylazide; thienyl chloride; oxalyl chloride; lower alkyl haloformate ethyl chloroformate, isopropyl chloroformate, etc.]; triphenylphosphine; 2-ethyl-7hydroxybenzisoxazolium salt; isoxazolium hydroxide intramolecular salt; 1-(p-chlorobenzenesulfonyloxy)-6-chloro-1H-benzotriazole; 2 -chloro-l-methylpyridinium iodide; 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride; so-called vilsmeier reagent prepared by the reaction of N,Ndimethylformamide with thionyl chloride, phosgene, trichloromethyl chloroformate, phosphorus oxychloride, etc.; or the like.

The reaction may also be carried out in the presence of an inorganic or organic base such as alkali metal carbonate, alkali metal bicarbonate, tri(lower)alkylamine, pyridine, N-(lower)alkylmorpholine, N,N-di(lower)alkylbenzylamine, or the like.

The reaction temperature is not critical, and the reaction is usually carried out under cooling to warming.

Process 4 The object compound (Id) or a salt thereof can be prepared by reacting the compound (VI) or a salt thereof with the compound (VII) or a salt thereof.

The reaction can be carried out in the manner disclosed in Example 30 mentioned later or similar manners thereto.

Process The object compound (Ie) or a salt thereof can be prepared by reacting the compound (VIII) or a salt thereof with the compound (IX) or a salt thereof.

WO 98/57954 PCT/JP98/02613 29 The reaction can be carried out in the manner disclosed in Example 35 mentioned later or similar manners thereto.

Process 6 The object compound (If) or a salt thereof can be prepared by reacting the compound or a salt thereof with the compound (XI) or a salt thereof.

The reaction can be carried out in the manner disclosed in Example 8 mentioned later or similar manners thereto.

The object compound and a pharmaceutically acceptable salt thereof have pharmacological activities such as Tachykinin antagonism, especially Substance P antagonism, Neurokinin A antagonism or Neurokinin B antagonism, and therefore are useful for treating or preventing Tachykininmediated diseases, particularly Substance P-mediated diseases, for example, respiratory diseases such as asthma, bronchitis chronic bronchitis, acute bronchitis and diffuse panbronchiolitis, etc.), rhinitis, couph, expectoration, and the like; ophthalmic diseases such as conjunctivitis, vernal conjunctivitis, and the like; cutaneous diseases such as contact dermatitis, atopic dermatitis, urticaria, and other eczematoid dermatitis, and the like; inflammatory diseases such as rheumatoid arthritis, osteoarthritis, and the like; pains or aches migraine, headache, cluster headache, toothache, cancerous pain, back pain, neuralgia, etc.); and the like.

Further, it is expected that the object compound and a pharmaceutically acceptable salt thereof of the present invention are useful for treating or preventing ophthalmic diseases such as glaucoma, uveitis, and the like; gastrointestinal diseases such as ulcer, ulcerative colitis, irritable bowel syndrome, food allergy, and the like; WO 98/57954 PCT/JP98/02613 inflammatory diseases such as nephritis, and the like; circulatory diseases such as hypertension, angina pectoris, cardiac failure, thrombosis, Raynaud's disease, and the like; epilepsy; spastic paralysis; pollakiuria; cystitis; bladder detrusor hyperreflexia; urinary incontinence; Parkinson diseases; dementia; AIDS related dementia; Alzheimer's diseases; Down's syndrome; Huntington's chorea; carcinoid syndrome; disorders related to immune enhancement or suppression; disorders caused by Helicobacter pylori or another spiral urease-positive gram-negative bacterium; sunburn; angiogenesis or diseases caused by angiogenesis; and the like.

It is furthermore expected that the object compound (I) and a pharmaceutically acceptable salt thereof of the present invention are useful for treating or preventing chronic obstructive pulmonary diseases, particularly chronic pulmonary emphysema; iritis; proliferative vitreoretinopathy; psoriasis; inflammatory intestinal diseases, particularly Crohn's diseases; hepatitis; superficial pain on congelation, burn, herpes zoster or diabetic neuropathy; tenalgia attended to hyperlipidemia; postoperative neuroma, particularly of mastectomy; vulvar vestibulitis; hemodialysis-associated itching; lichen planus; laryngopharyngitis; bronchiectasis; coniosis; whooping cough; pulmonary tuberculosis; cystic fibrosis; emesis nausea, retching, vomiting, acute emesis, delayed emesis, anticipatory emesis, post operative nausea and vomiting (PONV), acute and/or delayed emesis induced by drugs such as cancer chemotherapeutic agents, etc.); mental diseases, particularly anxiety, depression, dysthymic disorders and schizophrenia; demyelinating diseases such as multiple sclerosis and amyotrophic lateral sclerosis; attenuation of morphine withdrawal; oedema, such as oedema caused by thermal injury; small cell carcinomas, particularly small cell lung cancer (SCLC); hypersensitivity disorders such as poison ivy; fibrosing and collagen diseases such as WO 98/57954 PCT/JP98/02613 31 scleroderma and eosinophilic fascioliasis; reflex sympathetic dystrophy such as shoulder/hand syndrome; addiction disorders such as alcoholism; stress related somatic disorders; rheumatic diseases such as fibrositis; and the like.

Furthermore, the object compound and a pharmaceutically acceptable salt thereof of the present invention are Central Nervous System (CNS) penetrant.

For therapeutic purpose, the compound and a pharmaceutically acceptable salt thereof of the present invention can be used in a form of pharmaceutical preparation containing one of said compound, as an active ingredient, in admixture with a pharmaceutically acceptable carrier such as an organic or inorganic solid or liquid excipient suitable for oral, parenteral, external including topical, enternal, intravenous, intramuscular, inhalant, nasal, intraarticular, intraspinal, transtracheal or transocular administration.

The pharmaceutical preparations may be solid, semi-solid or solutions such as capsules, tablets, pellets, dragees, powders, granules, suppositories, ointments, creams, lotions, inhalants, injections, cataplasms, gels, tapes, eye drops, solution, syrups, aerosols, suspension, emulsion, or the like. If desired, there may be included in these preparations, auxiliary substances, stabilizing agents, wetting or emulsifying agents, buffers and other commonly used additives.

While the dosage of the compound will vary depending upon the age and condition of a patient, an average single dose of about 0.1 mg, 1 mg, 10 mg, 50 mg, 100 mg, 250 mg, 500 mg and 1000 mg of the compound may be effective for treating Tachykinin-mediated diseases such as asthma and the like. In general, amounts between 0.1 mg/body and about 1,000 mg/body may be administered per day.

In order to show the utility of the object compound (I) WO 98/57954 PCT/J'P98/02613 32 and a pharmaceutically acceptable salt thereof, the pharmacological test data of some representative compounds of the present invention is shown in the following.

A. Evaluation of NKI antagonist transport efficiency to the cental nervous system using a h-NK 1 receptor binding assay Test Method Administration of test compound and extraction of the compound from brain Male SD rats were given an i.v. injection of a solution containing a test compound (1 mg/kg). 5 Min later the animals were anesthetized by ether, bled and perfused through the aorta ascendens with 20 ml of saline. The brain was rapidly removed, weighed and homogenized in 4 vol. ice-cold distilled water by using Polytoron (KINEMATICA). To extract the test compound, 500 p.1 of the homogenate, 100 [pl of methanol, 500 p1l of 0.1 N NaOH and 4 ml of ethyl acetate were mixed by shaking for 10 min at room temperature. The organic phase (2.5 ml) was recovered by centrifugation at 3,000 rpm for 10 min, dried and dissolved in dimethyl sulfoxide.

h-NK 1 receptor binding assay Crude CHO cell membrane preparation CHO cells permanently expressing h-NK 1 receptors were harvested and homogenized with a Dounce homogenizer at 4 0 C in a buffer (0.25 M sucrose, 25 mM Tris-HCl (pH 10 mM MgCl 2 1 mM EDTA, 5 pg/ml p-APMSF). The homogenate was centrifuged (500 x g, 10 min), and the pellet was resuspended in the same buffer, homogenized, and centrifuged. The two supernatants were combined and centrifuged (100,000 x g, 1 WO 98/57954 PCT/JP98/02613 33 hour). The crude cell membranes thus isolated were resuspended in a buffer (25 mM Tris-HC1 (pH 10 mM MgCl 2 1 mM EDTA, 5 pig/ml p-APMSF) and stored at -80°C until use.

1 2 5 I-BH-Substance P binding to the prepared membrane Cell membranes (6 [g/ml) were incubated with 125

I-BH-

Substance P (0.1 nM) with or without the extracted compounds in 0.25 ml of a medium (50 mM Tris-HCl (pH 5 mM MnC1 2 [g/ml chymostatin,. 40 ~g/ml bacitracin, 4 pg/ml leupeptin, pg/ml p-APMSF, 200 g/ml BSA) at 22°C for 90 min. At the end of the incubation period, the contents were quickly filtered through a Blue Mat 11740 filter (pretreated with 0.1% polyethylenimine for 3 hours prior to use) by using SKATRON Cell Harvester. The filter was then washed with a washing buffer (50 mM Tris-HCl (pH 5 mM MnCl 2 The radioactivity was counted by using an auto gamma counter (Packard RIASTAR 5420A). All data presented are specific binding defined as that displaceable by 3 RM unlabeled Substance P.

[II] Test Result All of the following Test Compounds showed more than inhibition rate of 1 2 5 I-BH-Substance P binding to h-NK 1 receptors at the dose of 1 mg/kg.

Test Compounds The object compounds of the Examples 15, 17, 18, 22, 29, 30, 38, 40, 45, 56-(2), 68, 71-(3), 76-(1), 77, 79-(1), 80-(4), WO 98/57954 PCT/JP98/02613 34 81-(3), 81-(10), 82, 84, 89-(2), 90-(5) and 90-(6) B. Emesis in the ferret Test Method Individually housed adult male ferrets (Marshall Farms, 1.4 to 2.2 kg) were given an i.v. injection of a solution contatining a test compound. 30 Min later the emetic responses (retching and vomiting) were induced by administration of intra-gastric copper sulfate (40 mg/kg/ml) and observed for the next 30 min. The timing and number of .retches and vomits observed were recorded for each animal.

An individual animal was tested with at least 10 days between experiments.

[II] Test Result All of the following Test Compounds showed 100% inhibition rate of emesis in the ferret at the dose of mg/kg.

Test compounds The object compounds of the Examples 26, 29, 40 and 41 (to be continued on the next page) WO 98/57954 PCT/JP98/02613 The following Preparations and Examples are given for the purpose of illustrating this invention.

Preparation 1 A mixture of 3-bromopyridine (6.25 ml), propargyl al.cohol (4.9 ml), bis(triphenylphosphine)palladium(II) chloride (0.45 g) and copper iodide (125 mg) in triethylamine (100 ml) was stirred under reflux for 1.5 hours. After being cooled at room temperature, the reaction mixture was filtered and the insoluble material on the filter was washed with ethyl acetate (about 200 ml). The filtrate and the washing were combined and evaporated under reduced pressure. The resulting residue was purified by column chromatography on silica gel using a mixed solvent of hexane and ethyl acetate as eluent. The fractions containing the objective compound were collected and evaporated under reduced pressure to give 3-(3-pyridyl)-2-propyn-l-ol (7.9 g) as brownish crystals.

-i IR (Nujol) 3160, 1480, 1460, 1400 cm- 1 NMIR (CDC1 3 6) 3.87 (1H, t, j=5.9Hz), 4.51 (2H, d, J=5.9Hz), 7.24-7.30 (1H, nm), 7.73 (1H, dd, J=1.9 and 7.4Hz), 8.52 (1H, d, J=5.1Hz), 8.78 (1H, d, J=1.9Hz) MASS 134 Preparation 2 The following compounds were obtained according to a similar manner to that of Preparation 1.

4-(3-Pyridyl)-3-butyn-l-cl NMR (CDC1 3 2.61 (1H, 2.71 (2H, t, J=6.3Hz), 3.85 (2H, t, J=6.3Hz), 7.19-7.25 (1H, 7.70 (1H, dd, J=2.0, 8.0Hz), 8.48 (1H, dd, J=1.4, 8.63 (1H, d, J=1.4Hz) MASS 279, 148 WO 98/57954 PCT/JP98/02613 36 3-(6-Methoxypyridin-3-yl)-2-propyn-1-ol IR (Nujol) 3300, 1610, 1560, 1490, 1460, 1370, 1350, 1310, 1300 cm 1 NMR (CDC1 3 5) 3.94 (3H, 4.52 (2H, 6.70 (1H, dd, J=0.7, 8.6Hz), 7.60 (1H, dd, J=2.2, 8.6Hz), 8.30 (1H, d, J=2.2Hz) MASS 164 134 3-(4-Methoxypyridin-3-yl)-2-propyn-l-ol -1 IR (KBr) 3172, 2854, 1585, 1498 cm- NMR (CDC13, 5) 3.90 (3H, 4.33 (2H, d, 5.38 (1H, t, J=4.0Hz), 7.12 (1H, d, J=5.8Hz), 8.24 (2H, br s) MASS 164 134 3-[6-(tert-Butoxycarbonylamino)pyridin-3-yl]-2propyn-1-ol IR (Nujol) 3500, 3210, 1725, 1625, 1600, 1580, 1430, 1380 cm 1 NMR (CDC1 3 5) 1.54 (9H, 4.99 (2H, 7.70 (1H, dd, J=2.2, 8.7Hz), 7.97 (1H, d, J=8.7Hz), 8.40 (1H, d, J=2.2Hz), 8.51 (1H, br s) MASS 217 175 Preparation 3 Thionyl chloride (11.9 g) was added dropwise to a solution of 3-(3-pyridyl)-2-propyn-l-ol (13.3 g) in dichloromethane (266 ml) at room temperature. After completion of the addition, the mixture was stirred for 2 hours at room temperature. The resulting precipitates were collected by filtration and washed with diethyl ether to give 1-chloro-3-(3-pyridyl)-2-propyne hydrochloride (14.5 g) as brownish crystals.

Preparation 4 WO 98/57954 PCT/JP98/02613 37 The following compounds were obtained according to a similar manner to that of Preparation 3.

l-Chloro-3-(6-methoxypyridin-3-yl)-2-propyne hydrochloride 1-Chloro-3-(4-methoxypyridin-3-yl)-2-propyne hydrochloride Preparation Isobutyl chloroformate (4.4 ml) was added dropwise to a suspension of (E)-3-(3-pyridyl)acrylic acid (5.0 g) and N-methylmorpholine (4.05 ml) in 1,2-dimethoxyethane (50 ml) under -18°C. After being stirred at the same temperature for 0.5 hour, a solution of sodium borohydride (1.86 g) in water mi) was added to the mixture all at once. The resulting mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine and dried over magnesium sulfate, and evaporated under reduced pressure.

The residue was purified by column chromatography on silica gel using a mixed solvent of hexane and ethyl acetate as eluent. The fractions containing the objective compound were collected and evaporated under reduced pressure to give (E)-3-(3-pyridyl)-2-propen-l-ol (1.0 g) as an oil.

NMR (CDCI 3 5) 4.40 (2H, d, J=4.0Hz), 6.52 (1H, dt, 16.1Hz, trans), 6.65 (1H, d, J=16.1Hz, trans), 7.45 (1H, dd, J=5.6, 8.0Hz), 7.89 (1H, d, 8.44 (1H, d, J=5.6Hz), 8.58 (1H, s) MASS 136 (M+H) Preparation 6 Methane sulfonyl chloride (0.22 ml) was added to a mixture of (E)-3-(3-pyridyl)-2-propen-l-ol (0.36 g) and triethylamine (0.74 mi) in dichloromethane (5 ml) under -10 0 C. After being stirred at the same temperature for WO 98/57954 PCT/P98/02613 38 hour, the reaction mixture was washed with saturated sodium bicarbonate, dried over magnesium sulfate and evaporated under reduced pressure to give (E)-3-(3-pyridyl)-2-propen-lyl methanesulfonate.

The crude mesylate was used at next step without further purification.

Preparation 7 4-(3-Pyridyl)-3-butyn-l-yl methanesulfonate was obtained according to a similar manner to that of Preparation 6.

Preparation 8 The solution of 3-(3-pyridyl)-2-propyl-l-ol (300 mg) in methanol was hydrogenated using Lindlar catalyst for 4 hours at atmospheric pressure. After removal of catalyst by filtration, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using ethyl acetate as eluent. The fractions containing the objective compound were collected and evaporated under reduced pressure to give (Z)-3-(3-pyridyl)- 2-propen-l-ol (50 mg) as an oil.

IR (Nujol) 3600-2700, 1590, 1575, 1480 cm 1 NMR (CDC1 3 5) 4.42 (2H, dd, J=1.6, 6.4Hz), 6.04 (1H, dd, J=6.4, 12.0Hz, cis), 6.52 (1H, d, J=12.0Hz, cis), 7.25-7.31 (1H, 7.55 (1H, d, 8.30-8.70 (2H, br s) MASS 136 (M+H) Preparation 9 A mixture of 4-formyl-l-methylimidazole (3.0 g) and triethylphosphonoacetate (6.3 g) in N,N-dimethylformamide ml) was stirred under ice-cooling. After several minutes, sodium hydride (1.63 g, 60% in mineral oil) was added to the mixture, which was stirred for 30 minutes at the same temperature. The resulting mixture was poured into ice- WO 98/57954 PCT/JP98/02613 39 water, neutralized with aqueous ammonium acetate solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and concentrated under reduced pressure to give ethyl (E)-3-(l-methyl-1Himidazol-4-yl)acrylate (4.63 g).

IR (Nujol) 2900, 1700, 1625 cm-1 NMR (CDC1 3 6) 1.31 (3H, t, J=7.1Hz), 3.70 (3H, s), 4.23 (2H, q, J=7.1Hz), 6.53 (1H, d, J=15.6Hz), 7.07 (1H, 7.45 (1H, 7.54 (1H, d, J=15.6Hz) MASS 181 (M+H) Preparation A solution of ethyl (E)-3-(1-methyl-lH-imidazol-4yl)acrylate (2.5 g) in tetrahydrofuran (100 ml) was hydrogenated over 10% palladium activated carbon (0.2 g) at room temperature under 2 atmospheric pressure. After removal of catalyst by filtration through Celite pad, the filtrate was concentrated under reduced pressure to give ethyl 3-(1methyl-1H-imidazol-4-yl)propionate (2.63 g).

IR (Neat) 2900, 1720 cm 1 NMR (CDC1 3 5) 1.24 (3H, t, J=7.1Hz), 2.62 (2H, t, J=7.4Hz), 2.89 (2H, t, j=7.4Hz), 3.62 (3H, 4.16 (2H, q, j=7.1Hz), 6.64 (1H, 7.33 (1H, s) MASS 183 (M+H) Preparation 11 To an ice-cooled solution of ethyl 3-(l-methyl-1Himidazol-4-yl)propionate (2.63 g) in tetrahydrofuran (26 ml) was added lithium aluminum hydride (0.55 g) by small portions under nitrogen atmosphere. After the mixture was stirred for hour, water and 15% aqueous sodium hydroxide solution were added successively to the mixture. The resulting precipitates were filtrated off through Celite pad and the filtrate was extracted with ethyl acetate. The organic layer was washed with water and brine successively, dried over WO 98/57954 PCT/JP98/02613 magnesium sulfate and concentrated under reduced pressure.

The resulting residue was purified by column chromatography on silica gel using dichloromethane-methanol (100:1) as eluent to give 3-(1-methyl-1H-imidazol-4-yl)-l-propanol (940 mg).

IR (Neat) 3250, 2900 cm n NMR (CDC1 3 5) 1.86 (2H, 2.69 (2H, t, J=6.7Hz), 3.63 (3H, 3.73 (2H, t, J=6.0Hz) 6.62 (1H, s), 7.34 (1H, s) MASS 141 (M+H) Preparation 12 To a solution of oxalyl chloride (0.361 ml) in dichloromethane (10 ml) cooled below -65°C with a dry iceacetone bath, a solution of dimethyl sulfoxide (0.381 ml) in dichloromethane (1 ml) was added with efficient stirring over minutes. After 20 minutes below -65C, a solution of 3-(l-methyl-1H-imidazol-4-yl)-1-propanol in dichloromethane (2 ml) was added to the mixture over 10 minutes below and the mixture was stirred at the same temperature for minutes and then at -45"C -40°C for 30 minutes. After addition of triethylamine (1.0 ml) dropwise to the mixture over 1 minute followed by stirring for 30 minutes, the reaction mixture was concentrated in vacuo. The resulting residue was purified by column chromatography on silica gel using dichloromethane-methanol (20:1) as eluent to give 3-(1methyl-1H-imidazol-4-yl)propanol (103 mg).

IR (Neat) 1715 cm 1 NMR (CDCl 3 6) 2.85 (4H, 3.63 (3H, 6.63 (1H, 7.34 (1H, 9.83 (1H, s) MASS 139 (M+H) Preparation 13 The following compound was obtained according to a similar manner to that of Preparation 12.

WO 98/57954 PCT/JP98/02613 41 4-Formyl-l-(triphenylmethyl)pyrazole NMR (DMSO-d 6 5) 7.05-7.10 (6H, 7.36-7.41 (9H, 8.15 (2H, 9.81 (1H, s) Preparation 14 To a solution of (3R)-4-benzyl-3-(hydroxymethyl)morpholine (13.67 g) in methanol (140 ml) and water (10 ml) was added ammonium formate (10.4 g) and palladium on activated carbon 1.4 g) The resulting mixture was stirred at 60°C for 3 hours. After removal of insoluble material by filtration, the filtrate was concentrated under reduced pressure to give crude amine (16.43 To a solution of the obtained amine in tetrahydrofuran (160 ml) were added triethylamine (32.2 mi) and di-tert-butyl dicarbonate (50.4 g) at 0°C. After stirring at room temperature for 12 hours, the mixture was quenched with water and extracted with ethyl acetate three times. The organic layer was washed with brine, dried over magnesium sulfate, and evaporated under reduced pressure to give crude oil which was purified by column chromatography on a silica gel using a mixture of ethyl acetate and hexane as eluent to give (3R)-4-(tert-butoxycarbonyl)-3-(hydroxymethyl)morpholine (8.64 g) as a colorless solid.

NMR (CDC1 3 6) 1.47 (9H, 3.16-3.24 (1H, m), 3.40-3.61 (2H, 3.71-4.00 (6H, m) Preparation The following compound was obtained according to a similar manner to that of Preparation 14.

(2R,2S)-4-(tert-Butoxycarbonyl)-2-(hydroxvmethvi)morpholine IR (Neat) 1695 cm 1 NMR (CDC1 3 5) 1.47 (9H, 2.03 (1H, t, j=6.7Hz), 2.70-3.00 (2H, 3.45-3.74 (4H, 3.84-3.95 WO 98/57954 PCT/JP98/02613 42 (3H, mn) Prepoaration 16 The following compounds were obtained according to a similar manner to that of Prepoaration 12.

(tert-Butoxycarbonyl) -3-forinylmorpholine IR (KBr) :1734, 1695 cmn1 NINR (CDCl 3 5) :1.47 (9H, 3.00-3.30 (1H, in), 3.48 (1H, dt, J=2.8, 11.7Hz), 3.67 dt, J=4.2, 12.1Hz), 3.60-3.90 (2H, mn), 4.25-4.50 (2H, mn), 9.66 (1H, s) (2R,2S) (tert-Butoxycarbonyl)-2-formylnorpholile IRP (Neat) :1737, 1681 cm- 1 NMR (OD1 3 5 1.47 (9H, mm), 2.80-5.00 (7H, mn), 9.65 (1h, mn) Pre-paration 17 The following compounds were obtained according to a similar manner to that of Preparation 9.

Ethyl (2E) (tert-butoxycarbonyl)morpholin- 3 yl] acrylate IR (Neat) 2978, 1716, 1697 cm 1 i NNT-R (CDCl. 5) 1. 26 (3H, tL, J=7. 4Hz) 1. 46 (9H, s) -3.16 (l1H, dt, J=3.7, 13.2Hz), 3.49 (1H, dt, J=2.9, 11.9Hz), 3.69 (1H, dd, J=13.6, 11.7Hz), 3.80-3.99 (3H, mn), 4.21 (2H, a, J=7.lHz), 4.50-4.60 (1H, in), 5.93 (1H, dd, J=1.8, 15.9Hz), 6.99 (1H, dd, J=5.3, 9Hz) Ethyl (2E)-3-[(2R,2S)-(4-tert-butoxvcarbonyl) morpholin- 2-yl] acrylate IR (Neat) :1737, 1681 cm 1 i WO 98/57954 PCT/JP98/02613 43 NMR (CDC1 3 6) :1.2-7 (3H, t, J'=3.3Hz), 1.47 (9H, S), 2.30-3.10 (31, mn), 3.57 (1H, dt, J=2.7, 11.3Hz), 3.80-4.20 (3H, in), 4.21 (2H, a, 6.12 (l1H, dd, J=1.7, 1-5.8Hz), 6.83 (1H, dd, J=4.2, 15.8Hz) Pre-oaration 18 To a solution of ethyl (2E)-3-[(3R)-4-(tertbutoxycarbonyl)morpholi-'n-3-yliacrylate (1.0 g) in toluene ml) was added diisobutylaluminun hydride (1.02 M in toluene, 7.6 ml) at -78 0 C 400C. After stirring for 2 hours at 000, the mixture was quenched with methanol (1.2 ml), and stirred for 1 hour at room temperature. After the resulting precipitate was filtered off, the filtrate was evaporated and purified by column chromatography on a silica gel using a mixture ethyl acetate and hexane (3:7 as eluent to give (tert-butoxycarbonyl) (E)-3-hydroxy-1propenyliinorpholine (0.71 g) as a colorless oil.

IR (Neat) 1691 cin 1 NIVIR (CDC1 3 6) :1.47 (9H, 3.17 (1H, dt, J=3.7, 12.2Hz), 3.48 (1H, dt, j=2.7, 11'-.3Hz), 3.65 (1H, dd, j=3.4, 11.6Hz), 3.70-3.91 (3H, in), 4.17-4.19 (2H, in), 4.40-4.50 (lE, .5.82-5.93 (2H, in) Pre-paration 19 The following compound was obtained according to a simnilar manner to that ofE Preparation 18.

(2R, 2S) (tert-Butoxycarbonyfl)-2-[(E) -3-hvdroxy-1propenvl I roorpholine -NMR (CDC1 3 6) :1.47 (9H, 2.62-3.00 (2H, in), 3.56 (IH, dt, J=2.7, 11.4Hz), 3.81-3.94 (4H, in), 4.18 (2H, d, J=5.OHz), 5.64-6.04 m) Preparation The following compounds were obtained according to a WO 98/57954 PCT/JP98/02613 1 44 similar manner to that of Preiparation 6.

(3Rv)-4- (tertu-Butoxycarboflyl)- 3 -3-methanesulfonyloxy-1-propenyl ]morpoholine NMR (CDCl 3 6) 1.47 (9H, 3.02 (3H, 3.10-3.25 (1iH, in), 3.48 (1H, dt, J=2.8, 11.5Hz), 3.63-3.93 in), 4.45-4.55 mn), 4.74 (2H, d, J=6.2Hz), 5.75-5.86 (1H, mn), 6.05 (1H, dd, J=5.5, 15.6Hz) (2R,2S)-4-(tert-BUtoxycarbonyl)-2-[(E)-3-methanesulfonyl-oxv-1-prcpenyl ]morp~holine N1-4R 1.47 (9H, mn), 2.60-2.72 (lH, in), 2.89-3.02 (1H, mn), 3.02 (3H, 3.55 (1H, dt, j=2.7, 1-1 3.82-4.00 (4H, mn), 4.73 (2H, d, J=S. lHz) S. 79-6. 01 (2H, in) Preparation 21 To a mixture of 1-arnino-1-cyclopropanenethaflol hydrochloride (1.1 benzaldehyde (945 ig) and triethylamine (1.24 ml) in 1,2-dichioroethane (10 ml), sodiumtri-'acetoxyborohydride (5.66 a) was added with ice-cooling over 5 minutes. Affter being stirred at room temperature for 13 hours, the mixture was uoured into aqueous sodium bicarbonate solution and stirred for several hours. The organic layer was separated, dried over magnesium sulfate and evaroratei under reduced pressure to give !-(N-benzylamino)- 1-cyclopropanemethanol (641 mng).

IR (Nujol) 3300-2700 crin'- INR (CDC1 3 5 0.50- 0.7- 7 (4H, in), 3.5S1 (2H, s), 3.84 (2H, s) 7.19-7.36 MIAS S 178 Preloaration-22 The following compound was obtained according to a similar manner to that o-f Preparation 19.

WO 98/57954 PCT/JP98/02613 (2S)-2-(N-Benzylamino)-4-methyl-l-pentanol NMR (CDC1 3 5) 0.84-0.94 (6H, 1.17-1.70 (3H, m), 2.72-2.81 (1H, 3.28 (1H, dd, J=6.0, 10.6Hz), 3.66 (1H, dd, J=3.9, 10.6Hz), 3.78 (2H, 7.20- 7.38 (5H, m) MASS :208 (M+H) Preparation 23 Chloroacetyl chloride (421 mg) was added dropwise to a mixture of l-(N-benzylamino)-1-cyclopropanemethanol (600 mg) and powdered potassium carbonate (702 mg) in dichloromethane (6 ml) with ice-cooling and then the mixture was stirred at room temperature for 2 hours. The resulting mixture was washed with diluted hydrochloric acid and brine successively, and concentrated under reduced pressure. A mixture of the oil obtained by the above procedure and potassium tertbutoxide (380 mg) in tert-butanol (6 ml) was stirred for 2 hours under reflux. After being cooled to room temperature, the mixture was diluted with ethyl acetate (10 ml). The resulting mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was dissolved with ethyl acetate and the ethyl acetate solution was washed with diluted hydrochloric acid and brine successively, dried over magnesium sulfate and concentrated under reduced pressure to give a solid of 4-benzyl-5-oxo-7oxa-4-azaspiro[2.5]octane (695.3 mg).

IR (KBr) 3100-2800, 1643 cm 1 NMR (DMSO-d 6 5) :0.64-1.02 (4H, 3.69 (2H, s), 4.43 (2H, 4.45 (2H, 7.17-7.37 (2H, m) MASS 218 (M+H) Preparation 24 The following compound was obtained according to a similar manner to that of Preparation 21.

WO 98/57954 PCT/JP98/02613 46 (5S)-4-Benzyl-5-(2-methylpropyl)-3-morpholinone IR (Neat) 1655 cm-1 NMR (CDC13, 6) 0.83 (3H, d, J=6.3Hz), 0.95 (3H, d, J=6.4Hz), 1.33-1.60 (2H, 1.79-1.92 (1H, m), 3.08-3.17 (1H, 3.56-3.79 (1H, 3.82 (2H, d, J=15.0Hz), 4.23 and 4.27 (2H, ABq, J=16.7Hz), 5.47 (1H, d, J=14.9Hz), 7.24-7.39 (5H, m) MASS 248 (M+H) Preparation A solution of 4 -benzyl-5-oxo-7-oxa-4-azaspiro[2.5]octane (695.3 mg) in tetrahydrofuran (8 ml) was added dropwise to an ice-cooled suspension of lithium aluminum hydride (112 mg) in tetrahydrofuran (5 ml) over 20 minutes and then the mixture was stirred at 50°C for 2 hours under nitrogen atmosphere.

After being cooled to room temperature, sodium fluoride (495 mg) was added to the mixture. The mixture was stirred vigorously and cooled with ice-bath. Water (0.16 ml) was added thereto and the mixture was filtered. The filtrate was concentrated under reduced pressure to give an oil. The oil was purified by column chromatography on silica gel using a mixture of hexane and ethyl acetate as eluent to give 4 -benzyl-7-oxa-4-azaspiro[2.5]octane (334.8 mg).

4 -Benzyl-7-oxa-4-azaspiro[2.5]octane in ethanol (8 ml) was hydrogenated over palladium hydroxide on carbon for 2 hours at atmospheric pressure. After removal of the catalyst by filtration, the filtrate was treated with 4N hydrogen chloride in ethyl acetate (2 ml) and concentrated under reduced pressure to give 7 -oxa-4-azaspiro[2.5]octane hydrochloride (81 mg).

IR (KBr) 3350, 3000-2400 cm- 1 NMR (CDC1 3 6) 0.84-1.10 (4H, 3.75 (2H, s), 3.90-4.10 (4H, 10.11 (1H, br s) MASS 114 (free) WO 98/57954 WITUPWO2613 47 Preparation 26 The following compound was obtained according to a similar manner to that of Preparation 23.

(3S) -4-Benzyl-3- (2-iethylpropyl)morpholine MR (CDCla, 6) 0.89 (3H, d, J=6.2Hz), 0.93 (3H, d, J=6.3Hz), 1.20-1.40 in, 1.46-1.61 Qn, 2.17-2.27 (1H, mn), 2.40-2.50 (1K, Qn, 2.59-2.68 (1K, mn), 3.16 (1H, d, J=13.3Hz), 3.40 (1H, dd, j=11.2, 7.8Hz), 3.59-3.83 Qn, 4.04 (1H, d, J=13.3Hz), 7.21-7.36 (5H, m) MASS :234 Prenaration 27 The following compound was obtained according to a similar manner to that of Preparation 23.

(3S) (2-Methyipropyl)morpholine hydrochloride NNR (DMSO-d 6 6) :0.87 (3H, 0.90 (3H, s), 1.26-1.52 (2H, mn), 1.65-1.78 (1K, mn), 3.12-3.48 W4, Wn, 3.69 (1H, dt, j=3.4, 12.3Hz), 3.87-3.95 (2H, in) MASS 144 (free) Preparation 28 A solution of 2-amino-5-broinopyridine (5.0 g) and ditert-butyl dicarbonate (6.39 g) in tert-butanol (100 ml) was stirred at room temperature for 15,hours. The resulting suspension was concentrated under reduced pressure and the residue was crhromatographed on a silica gel using dichloroinethane eluent. The fractions containing the objective compound were collected and concentrated under reduced pressure to give broinopyridine (3.25 g).

IR (Nujol) :3210, 1720, 1580, 1525, 1460, 1370 cm'1 WO 98/57954 PCT/JP98/02613 48 NMR (C D-l 1 1 .56 (9TK, 7 7.6 (1KH, dd, J= 2. 8. 9Hz) 7. 95 (1K, d, J=S.9Hz) 8. 38 (1H, d, 8.93 (1H, br s) Prenaration 29 To a solution of (2R)-4-benzvJ.-1- 2- 4-di':methylbenzyl)pi-perazine (5.03 g) in dichiorompethane ml) was added 1-chioroethyl chioroformate (1.51 m!) slowlIy at O'C, and then the mixture was heated at reflux under stirring. After 5.5 hours, the solvent was removed in vacuo and then the resulting residue was dissolved in methanol (20 ml) and refluxiEd for 0.51 hour. After removal of the solvent, the resulting -residue was triturated with isopropyl ether to afford (2R) -1-(3,r-dichlorobenzoyl) -2- 15(3,4-dimethyibenzvl)pioerazine hydrochloride (4.84 g).

I-R (Nujol) :3350, 1625 crm 1 NMR (DY.SO-d 6 5) :2.10-4.60 (15H, in), 6.50-9.70 (6KH, mn) MASS :377 (free) Prenaration The following compounds were obtained according to a similar manner to that of Preparation 29.

(2R.)-l-(35-Dichiorobenzov-5-[HlK-i-ndol-3-vl)methyl]piperazine hydrochloride IR (KBr-) :1637 cm1 NR(DMSO-d 6 6) :2.80-4.80 (9K, mn), 6.80-10.20 (8H, mn) MASS :388 (M-t-KJ (free) 5-Dichlorobenzovl)-2-(2-na-ohthyilmethyl),oi-oerazine hydrochloride MR (DMSO-d 6 6)2.80-4.70 (9H, in), 6.50-8.00 (10H, m) MASS :399 (free) (2R)-1-(3,5-Dichlorobenzovl)-2-[4-(trifiuoromethy-)- WO 98/57954 PCT/JP98/02613 benzyl]piperazine dihydrochloride I-R 3430, 2930, 2790, 1648, 1164 c- NMR (DMSO-d 6 2.70-5.30 (9H, mn), 6.50-7.90 (7H, mn), 9.62 (1K, br s) MASS :417 (M+HK-(free) (2R) 1[3, 5-Bis (trifluoroinethyl)benzovil]-2- (2-naphthvlmnethyl) pipoerazine hydrochloride IR 3700-3200, 1639, 1281, 1136 cr 1 NI'MR (DMSO-d 6 5) 2.90-3.80 (7H, 4.40-5.30 (2H, mn), 6.90-8.30 (10H, mn) M-AS S 317 (free) Preparation 31 1s (2R)-1-[3,5-Bis(trif"Luoroinethyl)benzoyl),-2-(2naphthylrnethyl)piperazine fumarate (2 g) was treated with aqueous sodium hydroxide solution (14 ml) and dichioroinethane (14 m1) The organic layer was separated, washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. A mixture of free piperazine derivative obtained by the above procedure, potassium carbonate (0.76 g) and 1.4-dichloro-2-butvne (0.43 ml) in N,N-dimethyIforinamide ml) was stirred for 4.5 hours at room, temperature. The reaction mixture was poured into water (75 ml1) and extracted 2S with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate and eva-oorated under reduced pressure.

The residue was purified by column chromatography on silica gel using a mixed solvent of toluene and ethyl acetate (10:1) as eluent to give (2R)-1L-[3,5-biLs(tLrifluoromethyl)benzoyl]- 4- (4-chloro-2-butynyl)-2- (2-naphthylinethyl)piperazine (1.18 g).

!R (Neat) 3600-3100, 1638, 1275, 1127, 900 crn 1 NMIR (CDC.

3 5 2.31-5.30 (13H, mn), 6.90-7.95 (10H, mn) MAS 553

T

WO 98/57954 PCT/JP98/02613 Example 1 A mixture of (2R)-1-[3,5-bis(trifluoromethvl)benzoyl]-2- [(1H-indol-3-yl)methvl piperazine (0.67 i-chloro-3-(3pyridyl)-2-oropyne hydrochloride (0.3 g) and potassium carbonate (0.52 g) in N,N-dimethylforramide (5 ml) was stirred for 5 hours at 50 0 C. The mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was nurified by column chromatography on silica gel using ethyl acetate as eluent to give (2R)-1-[3,5-bis(trifluoroiethyl)benzoyl]-2- [(1H-indol-3-yl)methyl]-4-[3-(3-pvridl)-2-propynyl]piperazine (0.25 g) as a syrup.

The following compound was prepared by treatment of 5-bis(trfluoromethyl)benzolj-2-[(1H-indol-3-yl)methyl]-4-[3-(3-pvridvl)-2-ropynvl]Diperazine with aN hydrochloric acid in ethyl acetate- 5 -Bis(trifluoromethyl)benzoyll-2- (1H-indol-3yl)methyl)-4-[3- (3-pyridyl)-2-propynvl]Diperazine dihydrochloride mr) 180-1900C [a4.6 -10.50* MeOH) IR (Nujol) 3600-3200, 2700-2500, 1643, 1530, 1428, 1361, 1280 cm NMR (DMSO-d 6 6) 3.20-5.20 (11H, 6.40-8.30 (1OH, 8.74-8.80 (1H, 8-85-8.90 (2H, 10.90- 11.10 mn) MA SS 571 (free) Elemental Analysis Calcd. for C 30

H

2 4

F

6

N

4 j02HCl-1.8H 2

O

C 53.31, H 4.41, N 8.29 Found C 53.28, H 4.53, N 7.87 Exarnle 2 WO 98/57954 PCT/JP98/02613 The following compounds were obtained according to a similar manner to that of Examrle (2R)-1-[3,5-Bis(tri fluoromethvl)benzoyll-2-(3,4dimethylbenzyl)-4-[3- (6-.mezhoxypyridin-3-yl) -2propynyl piperazine dihydrochloride 160-1700C L T-1 -i4.720 (C=0.55, MeOH) IR (KBr) 3600-3300, 2700-2500, 1648, 1617, 1494, 1430, 1280 cm NNR (DMSO-d 6 5) 2.05-2.20 (6H, 2.80-5.20 (11H, 3.90 (3H, 6.50-8.40 (9H, m) MASS 590 (free) Elemental Analysis Calcd. fr C 31

H

29

FN

3 0 2 2C1 0 .5 2 C 55.45, H 4.80, N 6.26 Found C 55.28, H 4.86, N 6.12 5-Bis (trifluoromethyl)benzovl-2- (1H-indol-3yl)methyl]-4-[3-(6-methoxpyridin-3-yl) -2-propynyl]- Dlperazine dihydrochioride mp 183-1890C 23.9 21.0' (C=0.55, MeOH) IR (KEr) 3600-3300, 270,-2500, 1644, 1602, 1494, 1428, 1280 cm- -MR (DMSO-d 6 5) 3.20-5.20 (11H, 3.90 (3H, s), 6.60-8.40 (11H, in), 10.95 (1H, br 12.00-12.40 (2H, i) MAkSS 600 (free) Elemental Analysis Calcd. for C 31

H

26

F

6

N

4 0 2 2K bK 2 0 C 53.85, H 4.37, N 8.10 Found C 53.90, H 4.36, N 8.02 (2R) 1- 3, 5-Bi s (tr i f luo romethyl) ben zoyl] 2 (1H- i ndo 1- 3 yl) methvl-4-[3- (2-pridyl)-2-propynyl]piperazine WO 98/57954 PCT/JP98/02613 52 Exam-ole 3 (2R) 3, 5--Bis (trifluoromethvl)benzoyl] dimethvlbenzyl) (2-pyridyl) -2-porop~ynyi]piperazine dihydrochioride (0.2 g) was made free with saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate.

The extract was dried over magnesiumt sulfate and evaporated under reduced pressure. The resulting residue dissolved in methanol (10 ml) and the solution was hydrogenated over 10%0 palladium on activated carbon (50 mg) at room temperature under 2-3 atoms. After removal orf catalyst by filtration, the filtrate was concentrated under reduced pressure. The residue was treated with 4N hydrogen chloride in ethyl acetate solution to give 5-bis (trifluoromethyl) benzoyll-2- 4-dimethylbenzyl) [3-(2-pyridvl)propoyl 1piperazine dihydrochioride.

mp 120-130'C [a1D -12.81' (C=0.32, MeOH) IR (Nujol) 3600-3300, 2700-2500, 1635, 1450, 1380, 1280 cm NNR (DMSO-d 6 5) :2.00-5.20 (21H-, in), 6.60-7.80 in), '7.80 (1H, d, J=8.OHz), 7.88 (1H, t, J=7.OHz), 8.18 (1H, 8.49 (1Hi, t, J=7.lHz), 8.81 (1H, d, J=5.2Hz), 11.20-12.20 (211, mn) MASS 564 (free) Elemental Analysis Calcd. for C 3 0

H

3 lF 6

N

3 02HC>-2.7H 2 0 C 52.59, H 5.63, N 6.13 Found C 52.66, H 51-.78, N 5.77 Example 4 (2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-[(1H-indol-3 yl)methyll-4-[3- (3-pyridyl)propyllpipoerazine dihvdrochloride mp :150-160*C r22.9- -9.86- (C=0.42, MeOH)I' IR (KBr) 3600-3000, 2700-2010, 1641, 1534, 1461, WO 98/57954 PCT/P98/02613 53 1428, 1280 cm- NTMR (DMSO-d 6 5) 2.10-5.20 (iSH, 6.60-8.30 (9H, 8.45-8.55 (1H, 8.80-9.00 (2H, 10.95- 11.05 (1H, 11.90-12.00 (2H, br s) M4ASS 575 (free) Elemental Analysis Calcd. for C 30

OH

9 8 F6Nd2HC1.2H 2

O

C 50.71, H 5.25, N 7.89 Found C 50.65, H 5.35, N 7.20 (2R)-1-[3,5-Bis(tri fluoromethyl)benzoyl]-2-[ (1H-indol-3vl)methyl]-4-[3-(2-pyridvl)propyljpierazine dihvdrochloride ID 80-100*C 2-3. 1 -5.290 (C=0.86, MeOH) (KBr) 3600-3300, 2700-2500, 1637, 1617, 1460, 1282 cm 1 i NMR (DMSO-d 6 5) 2.20-2.40 (2H, 3.10-5.20 (13H, 6.60-8.30 (10H, 8.49 (1H, d, J=7.8Hz), 8.80 (1K, d, J=5.OHz), 10.90-11.05 (1H, br s) MIASS 575 (M+H)I (free) Elemental Analysis Calcd. for C 30

H

2 8 FNAO2HCld.2H 2

O

C 53.85, H N 8.37 Found C 53.92, H 5.30, N 7.66 (2R)-1-[3,5-Bis(trifluoroethvl)benzoyl]-2-[ (1H-indol-3yl)methyl]-4- [4-(3-pyridyl)butvl Diperazlne dihvdrochloride Mnc 140-145SC 'a]22.3 -8.33* (C=0.30, MeO) (Nujol) .3600-3000, 2700-2300, 1641, 1465, 1430, 1280 cmf' NMR (DMSO-d 6 5) 1.60-5.20 (17H, 6.60-9.00 (12H, 11.00 (1H, br 11.59 (2H, br s) MASS 589 (M+KJ (free) Elemental Analysis Calcd. for C 3 1

H

3 0 FOL 0-2HC1PH20 WO 98/57954 PCT/JP98/02613 C 53.38, H 5.20, N 8.03 Found C 53.47, H 5.28, N 7.51 Example Methanesulfonyl chloride (0.094 ml) was added to a mixture of (Z)-3-(3-pyridyl)-2-propen-l-ol (0.15 g) and triethylamine (0.2 ml) in dichloromethane (2 ml) under After being stirred at the same temperature for 0.5 hour, the reaction mixture was washed with saturated sodium bicarbonate, dried over magnesium sulfate and evaporated under reduced pressure. The obtained mesylate was added to a mixture of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-[(1Hindol-3-yl)methyl]piperazine (0.5 powdered potassium carbonate (0.61 g) and catalytic amount of potassium iodide in a mixed solvent of acetonitrile (10 ml) and N,Ndimethylformamide (2 ml). The resulting mixture was stirred at 50°C for 1.5 hours and then filtered. The filtrate was evaporated under reduced pressure and the resulting residue was purified by column chromatography on silica gel using a mixed solvent of dichloromethane and methanoi as eluent. The fractions containing the objective compound were collected and evaporated under reduced pressure to give bis(trifluoromethyl)benzoyl]-2-[(lH-indol-3-yl)methyl]-4- [(Z)-3-(3-pyridyl)-2-propenyl]piperazine (0.49 g) as a syrup.

NMR (CDC13, 5) 1.80-5.20 (11H, 5.97 (1H, dt, J=6.6, 11.7Hz, cis), 6.60 (1H, d, J=11.7Hz, cis), 6.80-8.00 (10H, 8.23 (1H, 8.45-8.60 (2H, m) MASS 562 (M+H) The following compound was prepared by treatment of (2R)-1-[3,5-bis(trifiuoromethyl)benzoyl]-2-[ (H-indol-3-yl)methyl]-4-[(Z)-3-(3-pyridyl)-3-propenyl]piperazine with 4N hydrogen chloride in ethyl acetate.

(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-[ (H-indol-3- WO 98/57954 PCT/JP98/02613 yl)methyl-4- (3-Dyridvl)-2--propenyl]Diperazine dihvdrochloride M00 165-1770C [a]22-9 +14.90 (C=0.50, MeC!) S I (KBr) 3600-3300, 2700-2500, 1641, 1457, 1427, 1359, 1280, 1184 cm 1 NMR (DMSO-d 6 5) 3.00-5.20 (11H, in), 6.40-8.40 (12H, in), 8.70-8.85 (2H, 11.05 (1K, br 12.00 (2H,

M)

0 -MASS 573 (free) Elemental Analysis Calcd. for C 3 oH 26

F

6 N-AO-2HC1-2.5H20 C 52.18, H 4.82, N 8.11 Found C 52.34, H 4.73, N 8.01 Examinle 6 The following compounds were obtained according to a similar manner to that of Examile (2R)-l-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4dimethylbenzyl)-4-[(E)-3-(3-pyridvl) -2-prooenyl]piperazine dihydrochioride ID 170-174 0

C

24.1 -8.500 (C=0.20, MeQE) IR 3600-3300, 2700-2500, 1643, 1554, 1432, 1367, 1280 crn 1 NTR (DMSO-d 6 5) 2.00-2.30 2.80-5.20 (6H, 6.60-9.05 (12H, m) MASS 562 (free) Elemental Analysis Calcd. for C 3 0

H

2 9

F

6

N

3 O2HC12.H 2 0 C 53.74, H 5.26, N 6.27 Found C 53.71, H 5.33, N 5.83 (2R,)-1-[3,5-Bis(trifluororethvl)benzovl]-2-[ (1H-ind 1-3yl)methvl]-4-[4-(3-yridvl)-3-buvny1]piperazine NMR (CDCl- 5) 2.20-5.20 (13H, in), 6.80-8.00 WO 98/57954 PCT/JP98/02613 8.15 (1H, 8.49 (1H, d, J=3.8Hz), 8.64 (1H, br s) MASS 585 i-[3,5-Bi s(trifluoromethyl)benzoyl]-2-(3,4dimethylbenzyl)-4-[3-(lH-cyrazol-l-vl)prooyllpiperazine hydrochloride mp 73-75*C 24.7.

[a]D -7.300 (C=0.50 MeOH) IR (KBr) 1640 cmn 1 INI (DMSO-d 6 5) 1.85-5.20 (21H, 6.20-8.30 (9H, n) MASS 553 (M+H) T (free) Elemental Analysis Calcd. for Cq 8

H

31 C1CF 6 NA0-2HO C 53.80, H 5.64, N 8.96 Found C 53.67, H 5.56, N 7.83 Examiple 7 The following compounds were obtained according to a similar manner to that cf Example (2R)-1-[3,5-Bis(trifluoromnethyl)benzoyl]-2-[(IH-indol-3yl)methyl] -4-13- yridyl) -2-propynyl piperazine dihydrochioride MIO :160-166 0

C

4.7 -16.800 (C=0.50, MeOH) IR (KBr) 3600-3200, 2700-2500, 1643, 1540, 1380, 1280 cmn NM? (DMSO-d 6 5) 3.20-5.20 (1lH, 6.60-8.30 (11H, 8.65 (1H, d, J=2.7Hz, 10.90-11.05 (1H, in) 1-AS 571 (M+H)V (free), 60*7 Elemental Analysis Calcd. for C 30

H

2

F

6 NO 2H l1.5H 9

O

C 53.74, H 4.36, N 8.36 Found C 53.73, H 4.66, N 7.71 (2R)-1-[3,5-Bis(trifluoromethyl)benzoyl-2-[ (lH- indol-3yl)rethyll-4-[4-(3-pyridyl)-3-butynyl]piperazine WO 98/57954 PCT/JP98/02613 97 dihydrochloride mp 175-185°C 21.7 [a]D 7 -10.30° (C=0.50, MeOH) IR (KBr) 3600-3300, 2700-2500, 1641, 1459, 1428, 1368, 1282 cm NMR (DMSO-d 6 5) 3.20-5.20 (13H, 6.60-8.30 (9H, 8.65-8.85 (2H, 10.99 (1H, 11.90-12.10 (2H, m) MASS 585 (M+H) (free) Elemental Analysis Calcd. for C 31

H

26

F

6

N

4 0O2HC-1.2H20 C 54.83, H 4.51, N 8.25 Found C 54.79, H 4.87, N 7.67 Example 8 A mixture of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2- [(1H-indol-3-yl)methyl]-4--(4-chloro-2-butynyl)piperazine (0.25 (R)-2-(methoxymethyl)pyrrolidine (0.10 g), potassium carbonate (0.25 g) and potassium iodide (10 mg) in dry N,N-dimethylformamide (5 ml) was stirred for 5 hours at room temperature. The mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using ethyl acetate as eluent and treated with 4N hydrogen chloride in ethyl acetate solution to give (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2- [(lH-indol-3-yl)methyl]-4-[4-[(2R)-2-(methoxymethyl)pyrrolidinoj-2-butynyl]piperazine ihydrochloride (0.19 g).

mn 190-195 0

C

24.8 [a]D +9.3 (C=0.50, MeOH) IR (Nujol) 3600-3300, 2700-2500, 1641, 1552, 1428, 1280 cmI NMR (DMSO-d 6 5) 1.6-2.40 (4H, 3.10-5.20 (18H, 6.60-8.30 (8H, 11.50-11.70 (3H, m) MASS 621 (M+H) (free) WO 98/57954 PCT/JP98/02613 s Elemental Analysis Calcd. for C 32

H

34 FN0HC150 C 53.34, Hi 5.46, N 7.78 Found C 53.35, H 5.54, N 7.60 s Exam-ole 9 To a mixture of 3,5-dichlorobenzoic acid (2.6 (3R)- I benzyl-3- 4-dirnethylbenzvl)piperazine dihydrochioride g) and triethvlamine (8.54 ml) in dichioromethane ml) was added 2-chloro-l-methylipvridinium iodide (3.83 g) under ice-cooling, and then the mixture was stirred at room tempoerature for 1 hour. The mixture was evaporated under reduced pressure, and the resulting residue was dissolved into ethyl acetate. The ethyl acetate solution was filtrated and evapoorated under reduced poressure. The resulting residue was pourified by column chromatography on silica gel using hexane-ethvl acetate (10:1) as eluent to give (2R)-4-benzvl- 1- S-dichlorobenzoyl) 4-dimethylbenzyl)piperazine (5.58 g).

!R (Nujol) 2500, 1635 cm'1 MR (DMSO-d 6 6) :1.90-2.30 (8H, in), 2.55-4-80 (9H, in), 6.50-7.15 mn), 7.20-7.40 (SH, mn), 7.59 (1H, br) MAS S: 467 (M+HJ Examiple The following compound was obtained according to a similar manner to that of Example 9.

(2R) -4-Benzyl-l- 5-dichlorobenzovl) [4- (trifluoromethvl) benzyl Ipi-peraz ine 1R (Neat) 2942, 2809, 1641, 1070 cir7- MAR (DMSO-d 6 2.00-4.90 111H, in), 6.59 (lH, s), 7.10-7.70 (l11H, in) IM-ASS 5 07" WO 98/57954 WO 9857954PCT/JP98/0261 3 Examrple 11 Io a solution of (3R)-l-benzyl--3-(2naphthylmethyl)piperazine (3.23 g) and triethylamine (4.3 ml) in dichlorornethane (60 nil) was added a solution of dichlorobenzov! chloride (6.0 g) in dichloromethane (10 ml) at 000. After stirring at room temperature for 3 hours, the mixture was auenched with water and extracted three times with ethyl acetate. The combined extracts were dried over magnesium sulfate, and evap.orated under reduced pressure.

The obtained residue was tritur-ated with a mixture of dichioromethane and hexane to give (2R) -4-benzyl-1- 5-dichlorobenzoyi) (2-naphthvlmethyl) oinerazine.

NMR (DMSO-d 6 5) :3.00-4.70 (9H, in), 6.66-7.86 (17H, mn) 689 (free) Exainle 12 The following compound was obtained according to a similar manner to that of Example 11.

(2R) -4-Benzvl-1- 5-dichlorobenzoyl) (1H-indol-3yl maethyl I piperaz ine NMR (DMSO-d 6 ,5 2.10-4.60 (9H, rrn), 5.76 (2H, s), 6.70-7.68 (13H, mi) MASS 388 (free) Examiple 13 The following cormound was obtained according to a similar manner to that of Example (2R) 5--Bis (trifiuoromethvl)benzoyl]-2- (2naphthylmethyl) (3-pyridyl)-2 -propynyl] piperazine dihvdrochloride mp 140-150C 3525.9 (C=0.50, MeOH) WO 98/57954 PCT/JP98/02613 IR (KBr) 3700-3200, 3000-2300, 1644, 1550, 1428, 1367, 1280cm NMIR (DMSO-d 6 2.20-5.20 (11H, mn), 7-00-8.65 (14H, m) HAS S :582 (free) Elemental Analysis Calcd. for C 3 lH? 5

F

6 NO02HC1-2.57H 2 0 C .54.85, H- 4.62, N 6.00 Found: C 54.85, H .4.56, N 5.86 Example 14 Lindlar catalyst (Pd-CaCO 1 PbO) (86 mng) was added to a solution of (2R) 5-bi-s (trifLluoromethyl) benzoyl] (2naphthylmethyl) (3-ryridvl) -2-oropynvilpiperazin-e in methanol (20 ml) The mixture was stirred for 2 hours under hydrogen at 25'C and filtered. The filtr-=-L was concentr-ated 's under reduced poressure and the resulting residue was chromatocgraphed on silica gel using a mixed eluent of hexane and ethyl acetate. The faster eluti-ng fractions were collectCed, concentrated under reduced pressure and treated with 4N hydrogen chloride in ethyl acetate to give (2R)-l- 5-bis (trifluoromethyl)benzoyli -2-(2-naphthylmetLhyl) -4- (2Z) (3--pyridvl) -2-propenvl] piperazi-ne dihvdrochloride.

M0:13 0-1510 C r27.5 25.200 (C=0.25, MeOF) (KBr) :3700-2200, 1-046, 1280 craf' NM~R (DMSO-d 6 2.00-5.20 (11H, mn), 6.30-8.90 (16H, m) MASS :584 (free) Elemental Analysis Calcd. for- C 3 1 2

H

2 7

F

6

N

3 O-2HCl-3.7H 2

O

C 53.19, H 5.07, N 5.82 Found C 53.19, H 5.21, N 5.61 (21) The slower eluting fractions were collected, concentrated under reduced p~ressure and treated with 4N hydrogen chloride in ethyl acetate tLo give bis (trifluoromethyl) benzoyl] (2-n-aphthylmethyl) [3- (3-pyridyl) propyl] piperaz ine dihydrochloride.

WO 98/57954 PCT/JP98/02613 MD 138-14 00C 26. 28.60' (0=0.251, MeOH) IR :3700-2200, 1,646, 1280, 1135 cm- 1 NT'R (DMSO-d.

6 2.00-5.20 (15H, mn), 6.30-8.90 (14H1, m) MVAS S 586 (free) Elemental Analysis Oalcd. for C 32

H

29

F

6

N

3 02HC1P2.9H 2 0 C 54.10, H 5.22, N 5.92 Found :C 5,4 11, 11 5. 37, N 5 .7 0 Examiple Ak mixture of (2R)-1-(3,5-dich-lorobenzoyl)-2-(3,4dimethylbenzyl)piperazine hydrochloride (400 mg) and 4-(4chloro-2-butynvl)morpholine hydrochloride (223 rig) in dried acetonitrile (4.0 was stirred at 5000 in the presence of powdered potassium carbonate (534 mg) and potassium iodide (32 mg) After 3 hours, the reaction mixture was filtered and the insoluble material on the filter was washed with acetonitrile. The filtrate and the washing were combDined. and then concentrated in vacuo. The resulting residue was purified by column chromatography on silica gel using a mixture of ethyl acetate and methanol as eluent. The product obtained was dissolved in ethyl acetate and treated with 4N hydrogen chloride in ethyl acetate to give (2R)-l- 5-dichlorobenzoy-) 4-dimethylbenzvl) (4-morpoholino- 2-butvnyl)piperazine dihydrochioride (221'mg).

rLp' 17500 (dec.) 27. 6.800 (C=0.50, MeOH) TR (Nujol) :2400, 1640, cm-i NMP (DMSO-d 6 5) :2.10-4.40 (21H, in), 6.69 (3H, br), 7.06 (2H, br), 7.61 (1H, br) LAS S :514 (free) Elemental Analysis Calcd. fo 0 28

H

33 Cl 2

N

3

O

2 -2HC1l2H 2

O

C 53.94, H 6.30, N 6.74 Found :C 53.86, H 6.15, N 6.41 WO 98/57954 PCT/JP98/02613 62 Examnle 16 The following compounds were obtained according to a similar manner to that of Example 2R)-l-(3,5-Dichlorobenzovl)-2-(3,4-dimethylbenzyl)-4- (4-thiomorpholino-2-butynvl)piperazine dihydrochioride m'D 12800 (dec.) 28.0 +6.400 (C=0.50, MeOH)

~-D

!R (Nujol) 2400, 1635 cm i NMR (DMSO-d 6 6) 2.05-4.70 (21H, 6.71 (3H, br), 7.04 (2H, br), 7.61 (1H, br) MASS 530 (free) Elemental Analysis Calcd. for C 2 8

H

3 3 C1 2

N

3 ,OS-2HCI-2H 2 C 52.59, H 6.15, N 6.57 Found C 52.72, H 6.19, N 6.35 (2R)-l-(3,5-Dichlorobenzoyl)-2-(3,4-dimethylbenzyl)-4- [(E)-4-moroholino-2-butenyllpiperazine dihvdrochloride mp >2300C [c~25.3 +5.800 (C=0.50, MeOH) IR (KBr) 3426, 2927, 1120, 970 cmJ 1 NMR (DMSO-d 6 6) 2.10-4.70 (23H, m) 6.17 (2H, br), 6.69 (3H, br), 7.07 (2H, br), 7.63 (1H, br) MAS S 516 (free) Elemental Analysis Calcd. for C 28

H

37 C1 4 3 0 2

O.SH?

2 0 C 56.20, H 6.40, N 7.02 Found C 56.20, H4 6.29, N 6.89 (2R)-1-(3,5-Di chlorobenzovl)-2-[(lH-indol-3- yl) methyl]V 4-(47thiomorpholino-2-buynyl)piperazine dihydrochioride mo 17500 (dec.) 26.0 +26.0' (C=0.50, MeOH)

[I(XD

IR 3407, 2543, 1639 cm- NMIR (DMSO-d 6 5) 2.60-5.10 (21H, 6.70-7.80 (8H, 11.02 (1H, br s) WO 98/57954 WO 9857954PCT/JP98/02613 MAPS S :541 (free) Elemental Analysis Calcd. for C 2 8

H

3 2 C1 4

N

4 0OS*1.5H?0 C 52.43, H 5.50, N 8.73 Found C 52.34, H 5.60, N 8.42 (2R)-1-(3,5-Dichl-orobenzoyl)-2-[ (lH-indol-3-yl)methyl]- 4- (4-morpholino-2-butynyi)pioerazine dihvdrochloride MD 16 500C (de c.) 26.0 +j.27.500-O (C=0.50, Me0jH) T73. 'KBr) 3407, 1639, 1126 cri- NIMR (DYMSO-d 6 2.80-5.20 (21H, in), 6.70-7.8S (8H, mn), 11.00 (1H, br s) MAS S 525 (free) Elemental Analysis Calcd. for Cq 8

H

3 2 C1 4

N'

4 0 2 '3H 9 0 C 51.55, H 5.87, N 8.59 Found C 51.59, H 5.52, N 8.33 (3,5-Dichloro~benzovl) -2-(2-nap~hthylmethyl)-4- (4thi-'oiorpholino-2-butynyl) pi-erazine dihydrochloride M.D 15400 (dec.) 23.8 -14.1-C* (C=0.50, MeOH) 13. 3417, 2933, 2537, 1641 c- NNKPI (DYISO-d 6 2.70-5.20 (21H, 6.56 (1H, br), 7.08 (lH, br), 7.53 (4H, br), 7.89 (4H, br) MASS 552 (free) Elemental Analysis Calcd. for C 30

H

3 3 C16N 3 C 55.22, H 5.56, N 6.44 Found C 55.09, H 5.64, N 6.31 (2R)-1-(3,S-Dichlorobenzoyl)-2-(2-naphthvlinethyl)-4-(4inoroholino -2-butynyl) pi-oerazine dihvdrochloride mo 1710C (deC.) 23.3 -15.10' (C=0.50, MeOH) IR 3407, 2931, 2561, 1641, 971 cminL NR(DMSO-d 6 5) 3.00-5.20 (21H, in), 6.56 (1H, br), WO 98/57954 PCT/JP98/02613 64 7.08 (1H, br), 7.53 (4H, br) 7.89 (4H, br) MASS 536 (free) Elemental Analysis Calcd. for C 3 0

H

3 3Cl6N 3 0 2 0*Hq C 57.43, H 5.62, N 6.70 Found C 57.67, H 5.68, N 6.31 (2R)-1-(3,5-Dichlorobenzoyl)-2-[4-(trifluoromethyl)benzyl]-4-(4-thiomoroholino-2-butynvl)iperazine dihydrochioride MD 1720C (dec.) 25.4 15.80' (C=0.50, MeOH) [aD IR (KBr) 3430, 2917, 2524, 1641, 1068 cm 1 i .MAR (DMSO-d 6 5) 2.70-5.20 (21H, in), 6.69 (1H, s), 7.10-7.30 (2H, mr), 7.63 (4H, br) MASS 570 (free) Elemental Analysis Calcd. for C 2 7

H

3 ClaF 3

N

3 0S-0.5H 2

O

C 49.71, H 4.79, N 6.44 Found C 49.37, H 5.09, N 6.30 ,5-Dichlo robenzov)-2-[4-(trifluoromethyl)benzyl]-4-(4-morpholino-2-butynyl)piperazine dihydrochloride mo 1860C (dec.) 25.4 +17.500 (C0.50, MeOH) IR (KBr) 3421, 2935, 2553, 1644, 1068 crm 1 NMR (DMSO-d 6 5) 2.80-5.20 (21H, rn), 6.72 (1H, s), 7.10-7.40 (2H, 7.64 (4H, br) MASS 554 (N+HJ- (free) Elemental Analysis Calcd. for C 2 7

H

3 0 C1 4

F

3

N

3 0 2 0.5H 2 0 C 50.96, H 4.91, N 6.60 Found C 50.57, H 5.05, N 6.52 Examole 17 A mixture of (2R)-1-(3,5-dichlorobenzovi)-2-(3, 4dimethylbenzyl)piperazine hydrochloride (300 mg), 3-bromo-1- WO 98/57954 PCT/P98/02613 propanoi (121 mg), potassium carbonate (251 mg) and potassium iodide (24 mg) in dried acetonitrile (3 ml) was stirred at for 10 hours. After being cooled to room temperature, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using ethyl acetate as eluent to give (2R)-1-(3,5-dichlorobenzoyl)-2-(3, 4-dimethylbenzyl)-4-(3-hydroxypropyl)piperazine as a syrup.

Methanesulfonyl chloride (58 mg) was added to an ice-cooled solution of the alcohol obtained at above procedure (210 mg) and triethylamine (97.6 mg) in dichloromethane (4 ml) over hours. After being stirred for 1 hour, the reaction mixture was washed with saturated sodium bicarbonate solution, dried over magnesium sulfate and evaporated under reduced pressure to give the corresponding mesylate. A mixture of the mesylate obtained by the above procedure, 4-aminomorpholine (59.1 mg) and triethylamine (73.2 mg) in methanol (4 ml) was stirred under reflux for 4 hours. The reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel using ethyl acetate as eluent and treated with 4N hydrogen chloride in ethyl acetate solution to give (2R)-1- (3,5-dichlorobenzoyl)-2-(3,4-dimethylbenzyl)-4-(N-morpholino- 3-aminopropyl)piperazine dihydrochloride.

mp 71 0 C (dec.) +1.00° (C=0.50, MeOH) IR (Nujol) 3400, 2950, 1640, 1100 cm 1 NMR (DMSO-d 6 5) 2.10-4.70, (23H, 6.68 (3H, br), 7.06 (2H, br), 7.63 (1H, br) MASS 519 (M+H) (free) Elemental Analysis Calcd. for C 2 7

H

3 8 gC1N 4 022.5H20 C 50.87, H 6.80, N 8.79 Found C 51.03, H 7.15, N 8.84 Example 18 WO 98/57954 PCT/JP98/02613 66 Under nitrogen atmosphere, to a mixture of (2R)-l-(315bis (trifluoromethyl)benzoyl]-2- 4-dimethylbenzyl)piperazine (315 mg) and 3-(l-methyl-1H-iimidazol-4-vI )propanal (98 mg) in dichioromethane (6 m1) was added sodium triacetoxyborohydride (225 mg) and stirred at room temperature. After 4 hours, aqueous sodium bicarbonate solution was added to the -mixture and the mixture wa s stirred for several minutes. The organic layer was separated, dried over sodium sulfate and evaporated under reduced pressure. The resulting residue was purified -0 by column chromatography on silica gel using dichloromethanemethanol (10:1) as eluent and treated with 4N hydrogen chloride in ethyl acetate solution to give bis(trifl'Iuorcmethy-L)benzovi*L -2-13,4--dimethvlbenz v1)-4- !i3- (1-me-Lhy1-lH-imidazol-4-vl)oroDvljoi-oeraz-Ln-e dihydrochloride (187.1 mg).

Ip 91 0 C (dec.) 24.2 ~1l.20' (C=0.50, NeOH) [a]D IR (Nuj'ol) :1640 cn'7 1 l NNR (DMSO-d 6 6):2.00-5.20 (21H, in), 6.67 (1H, br s), 6.90-7.20 mn), 7.44 (1H, br 7.56 (iH, br 7.67 (l17H, 1)r 8.18 (1H, br 9.03 (1Hi, br s) MASS :567 (free) Elemental Analysis Calcd. 'for C 29

H

34 Cl9F 6

N

4 O-3.5H 2

O

C 49.58, H 5.88, N 7.97 Found :C 49.71, H 5.90, N 7.79 Examnle 19 A -mixture of (2R)-1-[3,5-bistI-rifluoromethvl,)benzovl]-2- (3,4-diiethylbenizvl)piperazine %1500 mg), 2-(2-chloroethoxy) ethanol (168 mg), potassium carbonate (233 mng) and potassium iodide (56 mng) in N,N-dimethylformamide (2 ml) was heated with stirring at 5000 for 17 hours, 60'C for 13 hours and for I hour. The reaction mixture was roartitioned between ethyl acetate and water. The oraanic layer was WO 98/57954 PCT/JP98/02613 washed with brine and dried over magnesium sulfate. After evanoration of the solvent, the resulting residue was purified by column chromatography on silica gel using dichloromethane-methanol (10:1) as eluent to give (2R)-1- [3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-- [2-(2-hydroxyethoxy)ethyl]piperazine (359 mg).

IR (Neat) 3450, 1640, 1440, 1280, 1130 cm NMR (DMSO-d 6 5) 2.03-4.93 (23H, 6.60-8.20 (6H, m) MASS 533 Example To a stirred solution of oxalyl chloride (151 mg) in dichloromethane (3 ml) was added dropwise a solution of dimethylsulfoxide (123 mg) in dichloromethane (0.25 ml) at -78°C under nitrogen atmosphere. After 15 minutes, (2R)-1- [3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4- [2-(2-hydroxyethoxy)ethyl]piperazine (317 mg) was added at the same temperature. After 15 minutes, the resulting mixture was stirred at -45 0 C for 1 hour. Triethylamine (446 mg) was added at -45cC, and the whole was stirred at 0°C for minutes and then treated with aqueous solution of ammonium chloride (2 ml). The organic layer was separated and dried over magnesium sulfate. After evaporation of the solvent, the resulting residue was purified by column chromatography on silica gel using ethyl acetate as eluent to afford (2R)-1- [3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4- [2-(formylmethoxy)ethyl]piperazine (171 mg).

IR (Neat) 3450, 1740, 1640, 1440, 1280, 1130 cm 1 NMR (DMSO-d 6 5) 1.91-4.91 (22H, 6.53-8.20 (6H, m) MASS 351 (M+H) Example 21 To a stirred mixture of 3,3-dimethylmorpholine hydrochloride (63 mg) and triethylamine (42 mg) in dichloromethane (5 ml) were added WO 98/57954 PCT/JP98/02613 68 bis fluoromethyl)benzoyll-2- 4-dimethylbenzvl) (formylmethoxy)ethyl]Dioierazine (200 mg) and sodium triJacetoxyborohydride (120 mg) at roomr temperature. The resulting mixture was stirred f-or '1 hour and then -treated with aaueous sodium bicarbonate solution. The organic layer was separated and dried over magnesium sulfate. After evaporation of the solvent, the residue was purified by column chromatography on silica gel using dichloromethanemethanol (10:1) as eluent and treated with 4N hydrogen chloride in ethyl acetate to give bis (trifluoromethyl)benzovl] 4-dirPethvlbenzyl) -4- K 3-dimethvlmorrholino) ethoxy] ethyl p ioera z ne dihydrochloride (193 mg) as a powder.

23 -18.200 (C=0.50, MeOH) (Neat) 3450, 2600, 1640, 1430, 1280, 1140 cm- 1 NM?. (DMSO-d 6 6) 1.33 (6H, 2.04-5.23 (29H, in.), 6.60-8.26 (6H, mn) MASS 630 (free) Elemental Ana'lysis Calcd. for C 32 H,4 1

F

6

N

3

O

3 -2HCl-3.32H 2

O

C 50.41, H -6.56, N 5.51 Found C 50.41, H 6.29, N 3.31 Examnple 22 The following compound was obtained according to a similar manner to that of Example 21.

5-Bis -(trifluoromethvl)benzoyll-2- (3,4dimethylbenzyl)-4-[2- (2-m-orrho-,-Lnoethoxy) ethyl'-piperazine dihydrochloride 23 -21.40 (C=0.50, MeOH) [a]D (Neat): 3450, 2600, 1640, 1430, 1280, 1180, '1135 cm'i NM?. (DMSO-d 6 :2.08-5.20 (31H, mn), 6.60-8.24 (6H, mn) LAS S :602 T (free) Elemental Analysis Calcd. fo C 3

H-F

6 3 3 2HCl-2.66H9O C 49.87, H. 6.18, N 5.82 Found C 49.87, H 6.25, N 5.65 WO 98/57954 PCT/JP98/02613 69 Example 23 A mixture of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2- [(1H-indol-3-yl)methyl]-4-(3-methylsulfonyloxypropyl)piperazine (250 mg), 4-aminothiomorpholine (90 mg) and sodium carbonate (180 mg) in methanol (5 ml) was stirred at reflux temperature for 3 hours. The reaction mixture was filtered and the filtrate was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using ethyl acetate-methanol (10:1) as eluent and treated with 4N hydrogen chloride in ethyl acetate (3 ml) to give (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-[(lH-indol-3-yl)methyl]-4-[3-(thiomorpholinoamino)propyl]piperazine dihydrochloride (62 mg) as a powder.

97 [at 7 -5.80 (C=0.50, MeOH) IR (Neat) 3300, 2500, 1630, 1420, 1275, 1130 cm 1 NMR (DMSO-d 6 5) 2.03-5.20 ;23H, 6.60-8.24 (8H, 10.95 (1H, s) MASS 614 (M+H) (free) Elemental Analysis Calcd. for C 2 9

H

3 5 C1 2

F

6

N

5 0S-3H20 C 47.10, H 5.37, N 8.88 Found C 47.03, H 5.58, N 9.46 Example 24 A mixture of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2- (3,4-dimethylbenzyl)-4-(2-methylsulfonyloxyethyl)piperazine (200 mg), 3-hydroxymethylpiperidine (44 mg) and triethylamine (73 mg) in methanol (5 ml) was stirred at reflux temperature for 2.5 hours. The reaction mixture was evaporated under reduced pressure and the residue was nartitioned between ethyl acetate (30 ml) and water (10 ml). The organic layer was dried over magnesium sulfate and then evaporated under reduced pressure. The obtained residue was purified by column chromatography on silica gel using dichloromethanemethanol (10:1) as eluent and treated with 4N hydrogen chloride in ethyl acetate (0.2 ml) to give (2R)-1-[3,5-bis- WO 98/57954 PCT/JP98/02613 (trifluoromethyl) benzoylj 4-dimethvlbenzvl) (3hydroxymethvlpiperidino) ethyl] piperazine dihydrochioride mg).

-5.30' (0=0.50, MeOH) IR (Neat) :3350, 2500, 1640, 1420, 1280, 1180, 1130 cm'1 NM4R (DMSO-d 6 5) :1.0-5.20 (30H, ra), 6.66-8.31 (6H, mn) IMASS :586 (free) Elemental Analysis Calcd,. for C 30 H 9 iF 6

NO

2 -3H-)O C 50.58, H 6.36, N 5.90 Found C 50.58, H 6.24, N 5.87 Examnle A mixture of (2R)-1-f3,5-bis(tri-flIuoromethyl)benzoyl]-4- (4-chloro-2-butvnyl) (2-naphtLhyimethyl)piierazine (600 mg), 3,3-dimethvlmorpho'line hydrochloride (197 rig) and potassium carbonate (420 mg) iJn N,N-dimethvlformanide (10 ml) was stirred at room temperature in the presence of potassium iodide (10 mg) for 2 days. The reaction mixture was partitioned between ethyl acetate (50 ml) and water (100 ml) and the organic layer was separated, washed with brine and dried over magnesium sulfate. After evaporation of the solvent, the residue was purified by column chromatography on silica gel using a mixture of ethyl acetate-hexane (10:1).

The obtained product was dissolved in ethyl acetate and treated with 4N hydrogen chloride in ethyl acetate to give (2K) 5'-bis (trifLluoromethyl) benzovl] (3,3dimethylmorphol1ino) 2-butyvnyl-2 -naphthvlmethy 1) pipera zine dihydrochloride (360 na).

IR :3401, 2929, 2578, 2512, 1644, 1284, 1135 c-rrA- NMR (DMSO-d6, 5) 1.32 3'H, s) 1.319 3.0-3.4 (19H, mn), 7.0-8.2 (10H, mn) MASS :632 (free) Elemental Analvsis Calcd. for C 34

H

37 C1 2

F

6

N

3 0 2 -2.5H 2 0 S 54.48, H 5.65, N 5.61 WO 98/57954 PCT/JP98/02613 71 Found C 54.25, H 5.53, N 5.39 Example 26 Acetic anhydride (209 mg) was added to formic acid (94 mg). The resulting mixture was allowed to warm at 50°C for minutes and then added to (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-[3-(morpholinoamino)propyi]piperazine (200 mg) at room temperature. The whole was stirred overnight and then evaporated under reduced pressure. The obtained residue was dissolved in ethyl acetate and treated with 4N hydrogen chloride in ethyl acetate (0.2 ml) to give (2R)-1-[3,5-bis(trifluoromethyl)benzoyl] -2-(3,4-dimethylbenzyl)-4- (N-formylmorpholinoamino)propyl]piperazine hydrochloride (112 mg).

[a]3 -16.3° (C=0.50, MeOH) IR (Neat) 3450, 2800, 2620, 1660, 1430, 1280, 1185, -1 1140 cm- NMR (DMSO-d 6 5) 1.94-5.16 (29H, im), 6.62-8.35 (7H, m) MASS 615 (free) Elemental Analysis Calcd. for C 30

H

37 ClF 6

N

4 0 3 *1.36H 2 0 C 53.34, H 5.93, N 8.29 Found C 53.33, H 5.79, N 8.06 Example 27 To a mixture of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)piperazine (3.71 g) and 4-formyl-l-(triphenylmethyl)pyrazole (3.66 g) in 1,2dichloroethane (80 ml) was added sodium triacetoxyborohydride (2.86 After stirring at room temperature for 3 hours, aaueous sodium bicarbonate solution was added to the mixture and the mixture was extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The resulting residue was dissolved in dichloromethane (40 ml) and added to a mixture of trifluoroacetic acid (30 ml) and anisole (15 ml).

WO 98/57954 PCT/JP98/02613 72 After stirring for 7.5 hours at room temperature, the mixture was auenched with sodium hydroxide (150 ml) and aqueous sodium bicarbonate and extracted with dichloromethane. The extract was washed with aquecus sodium-. bicarbonate solution and brine successively, dried over magnesium. sulfate, and evaporated under reduced pcressure. The residue was purified by column chromatography on silica gel using a mixture of ethyl acetate and hexane to give (2R)-l-113,5bis (trifluoromethyl) benzoyl 1-2- 4-diinethylbenzyl) (4pyrazolvlmethyl)piperazine (2.84 g).

NMR (DMSO-d 6 6) :2.04-2.14 in), 2.60-4.76 (11H, mn), G'.49-6.54 (li-i, in), 6.86-6.96 7.45 (2H, br 7.64-7.68 mn), 8.14 (1H, mn) MASS :525 (M+HJ- Example 28 Potassium carbonate (158 mg) and 2-bromoethanol (0.045 ml) were added to a solution of bi-s(trifLluoromethyl)benzovli-2- 4-dimethvlbenzyl)-4- (4pyrazolylmethyl)piperazine (300 mng) in N,N-dimethvlfornaiide (3 -al) at room temperature with s'tirr--in-, After stirring at- 100 0 C for 5 hours: the reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, and evaporated under reduced pressure. The obtained residue was rourif.ied' by column chromatography (30 mlP.) on silica gel using a -mixture of" ethyl acetate and hexane to give 5-bis (tri:fluoromnethyl) benzoyl 4-dimethylbenzyl) -4- (2-hvdroxyethyl) -lH-pyrazol-4-yljinetlhyllpiperazine (255.2 mg).

IR :1640 cm- 1 NNR (DMSOD-d 6 2.04-2.15, (6H, im), 2.60-4.80 (11H, mn), 3.67-3-75 (2H, in), 4.10 t, J=5.7Hz), 4.86 (1H, t, J=5r.3Hz), 6.50-6.56 (1H, mn), 6.90-6.98 (2H-, yrn), 7-36 br 71.43 br 7.61 (iH, br WO 98/57954 PCT/JP98/02613 73 7.67 (1H, br 8.13 (1H, br s) MASS 569 Example 29 To a solution of (2R)-l-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-[[1-(2-hydroxyethyl)-1Hpyrazol-4-yl]methyl]piperazine (152 mg) in ethyl acetate (2 ml) was added triethylamine (0.048 ml) and methanesulfonyl chloride (0.027 ml) at room temperature. After stirring for 10 minutes, the mixture was quenched with water and extracted with ethyl acetate. The combined extracts were washed with water and brine successively, dried over magnesium sulfate, and evaporated under reduced pressure. The obtained residue was dissolved with N,N-dimethylformamide (2 ml) and added morpholine (0.028 ml), potassium carbonate (74 mg) and potassium iodide (13 mg). After stirring at 70°C for 6 hours, the mixture was quenched with water and extracted with ethyl acetate. The combined extracts were washed with water and brine successively, dried over magnesium sulfate, and evanorated under reduced pressure. The obtained residue was dissolved in ethyl acetate and treated with 4N hydrogen chloride in ethyl acetate (0.2 ml) at room temperature. The mixture was added hexane, filtered, and dried over reduced pressure to give (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4- [[1-(2-morpholinoethyl)-1Hpyrazol-4-yl]methyl]piperazine dihydrochloride (188.7 mg) as a solid.

mD 115-116°C [1C 5 -9.70° (C=0.50, MeOH) IR (KBr) 1640 cm" NMR (DMSO-d 6 5) 2.06-2.16 (6H, 2.85-5.00 (23H, 6.60-6.64 (1H, 6.91-7.08 (2H, 7.57 (1H, 7.74 (1H, br 7.78 (1H, br 8.10 (1H, br 8.18 (1H, br s) MASS 638 (M+H) (free) WO 98/57954 PCT/JP98/02613 74 ExamPle A solution of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]- 4-(4-chloro-2-butynyl)-2-(2-naphthylmethyl)piperazine (200 mg) 3-(aminomethyl)pyridine (47 mg), and triethylamine (0.08 ml) in acetonitrile (2 ml) was stirred under reflux for 3 hours and evaporated under reduced pressure. The obtained residue was purified by column chromatography on silica gel ml) using dichloromethane-methanol (30:1) as eluent. The obtained oil was dissolved in ethyl acetate and treated with a solution of 4N hydrogen chloride in ethyl acetate. The mixture was evaporated under reduced pressure to give (2R)-1- [3,5-bis(trifluoromethyl)benzoyl]-4-[4-(3-pyridylmethylamino)-2-butynyl]-2-(2-naphthyimethyl)piperazine trihydrochloride (60 mg) as a powder.

[a]D -20.80° (C=0.25, MeOH) IR (Neat) 3650-3100, 2750-1950, 1630, 1273, 1122 cm-1 NMR (DMSO-d 6 2.60-5.30 (16H, 7.00-9.10 (14H, m) MASS 625 (free) Elemental Analysis Calcd. for C 34

H

33 Cl 3

F

6

N

4 03.3H 2 0 C 51.43, H 5.03, N 7.06 Found C 51.42, H 4.91, N 6.78 Example 31 A mixture of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]- 4 (4-chloro-2-butynyl)-2-(2-naphthyimethyl)piperazine (300 mg), cis-2,6-dimethylmorpholine (94 mg) and powdered potassium carbonate (210 mg) in dry N,N-dimethylformamide (5 ml) was stirred at room temperature overnight. The reaction mixture was poured into water (50 ml) and extracted with ethyl acetate. The extract was washed with brine and dried over magnesium sulfate. After evaporation of the solvent, the obtained residue was purified by column chromatography on silica gel using a mixture of ethyl acetate and hexane (4:1) as eluent. The obtained product was dissolved in ethyl acetate and treated with 4N hydrogen chloride in ethyl acetate to give (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-4- WO 98/57954 PCT/JP98/02613 (cis-2, 6-dimethylmorpholino) -2-but-ynyl]-2- naphthylmethyl)piperazine dihydrochioriLde (170 mng).

IR :3428, 2931, 2559, 1644, 1432, 1282, 1184 cnf 1 l NTIR (DMSO-dc-, 5) 1.13 1.16 (3H, s), 2.60-5.40 (21H, mn), 7.00-8.15 (10H, mn) MASS :632 (fLree) Elemental Analysis Caicd. for C 34

H

37 C1 9 FON3O 2 -2H 9 o C 55.14, H 5.58, N 5.67 Found C 54.89, H -5.59, N 5.31 Examnoie 32 The following compound was obtained according to a similar manner to that of Example 311-.

is l, 3 -[Bis(tri-fluoroi.nethvl)benzovl]-4-[4-(2-methylthiazoi- 4-yl)inethyl]-2-[ (1H-indol-3-vl)inethyllpiperazine h ydr o c NMR (DMSO-d 6 5) 2.65 (3K, 3.00-5.20 (11H, mn), 6.80-8.24 (9H, mn), 10.93 (1H, br d) MASS 567 (free) Examnple 33 To a stirred mixture of (2R)-[3-,5-bis(tri-fluoroinethyl)benzovl]-2- 4-dimethylbenzyl)pioerazine (943 mng) and potassium carbonate (880 mng) in dimethyfornaiide (10 ml) was added propargyl broinide (0.2 ml.) at room teinoerature. After 1 hour, the reaction mixture was noured into water (100 ml) and extracted with ethyl acetate. ,The extract was washed wiJth brine and concentrated under reduced pressure. The obtained residue was purified by column chromatography on slica gelI using a mixture of hexane and ethyl acetate (5:1) as eluent to gve 2 R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2- 3 4 -diiethylbenzyl)-4-oropargylpiperazine (1.09 g) as an oil.

NI'MR (DY!SO-d 6 :2.00-2.20 (6H, in), 2.20-5.00 (12H, WO 98/57954 PCT/JP98/02613 76 mn), 6 .60-8. 20 (6H, in MALS S 483 (M+HJ- Examnle-34 mPixture o-f 2 R)-'L3,5-bis(tr-ifluoromethvl)benzoyI]-2- 4--imethylbenzyl-) -4-propoargryl-oiperazine (286 mg), (3S)-3isopropylmorpholine hydrochlor-ide (118 rag) and N,-Ndiisopropvlamine (92 mg) in dioxane (3 ml) was stirred at roomp temnerature. Paraformaldehvde (22 mg) and copper(l) chloride (10 mg) were added and the whole was stirred for mninutes' and then heated at 800C for 4 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced poressure. The obtained residue was purified by column chrornatoaranhv cn siliCa gel using a mixture of hexane 1s and ethyl acetate as eluent. The obtained product was dissolved in ethyl acetate and treated with 4N hydrogen chloride in ethyl acetate to give (2R)-1-[3,5-biJs(trifluoromethyl)benzoyl]-4-[4-( (3S)-3-isoporopylmorpholino) -2-butynyl] 2- 4-dimethylbenzvl)piperazine dihydrochioride (190 mg).

IR (KBr) 3438, 2971, 2551, 1-044, 1438, 1282, 1216, 1135 c NMIR (DIMSQ0-d 6 5) 1.01 (6H, d, j=6.8Hz), 2.09-2.17 (6H, m) 2.36 2.60-5.30 (22H, in), 6.60- 8.30 (6H, m) TMAS S 624 (free) Example Amixture of- (2R)-1-[3,5-bi-s(t-ri'fluoromethyl)benzovl]-4- (4-chloro-2-butenyl) 4-dimtethvibenzv1)piperazine (150 mg) (3S) -3--isotrooylmorp~hollie hydrochloride (47 mg) and powdered potassium carbonate (117 mg) in dry N,Ndimethylformamide (1 m~l) was stirred at 50 0 C for 1.5 hours.

The reaction mixture was poured into water (10 ml) and extracted with ethyl acetLate. The extract was washed with brine and dried over magnesium sulfate. After evaporation of WO 98/57954 PCT/JP98/02613 the solvent, the obtained residue was purified by column chromatography on silica gel using ethyli acetate as eluent.

The obtained product was dissolved in ethyl acetate and treated with 4N hydrogen chloride in etLhyl acetate to give (2R)-1-[3,5-bis(trifluoromet-hyl)benzoyvl]-4-[4-((3S)-3isopropylmorpholino) -2-butenylli-2- 4-direthylbenzyl) Dlperazine dihvdrochloride (110 mng).

TR (KBr) 3430, 2971, 2661, 1644, 1434, 1280, 1135, 985, 680 cm~ M-MR (DMSO-d 6 5) 01 (6H, mn), 2. 00-2.20 (6H, m) 2.40 (lH, in), 2.60-5.20 (24.1, mn), 6.60-8.20 mn) MA SS 626 (free) Elemental -Aralysi-Ls Calcd. for C 33

H

43 C19F N-.O 9 -3H 9

O

C 502.66, H 6.56, N 5.5S8 Found :C 52.45, H 6.355, IN 5.49 E xamip e 360 To a stirred solution of (2R)-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-[2-( (3R,',3S)-3-hydroxvmethylpi-oeridino)ethyllpiperazine (133 mng) in N,N-dimethylformamide (1 ml) was added 60"t sodium hyidride (109 mng) at ice-salt bath temperature. A solution of ethyl iodide (53 mng) in N,N-dimethvlformamide (0.5 ml) was added and the whole was stirred for 15 minutes and then at room temp~erature for 1 hour. The reaction mixture was noured into water (20 ml) and extracted with ethyl acetate. The extract was washed with brine and concentrated under reduced pressure. The obtained residue was purified by column chromatography on silica gel using a mixture of dichloromethane and methanol (10:1) as eluent. The obtained product was dissolved in ethyl acetate an-d treated with 4N hydrogen chloride in ethyl acetate to give (2R)-.3,5-bisktrifluoromethvl)benzoyl]-2-(3,4diinethylbenzyl)-4- 3S)-3-ethoxyrnethylpiperidino)ethyllpiperazine dihydrochoride (101 mg).

a)23 8.0' (C=0.50, MeOH) WO 98/57954 PCT/JP98/02613 78 IR (KBr) 3400, 2630, 2540, 1645, 1435, 1280, 1180, 1135 cm NMR (DMSO-d 6 6) 0.72-5.24 (32H, 1.12 (3H, t), 6.62-8.26 (6H, m) MASS 614 (free) Example 37 The reauisite mesvlate was orepared by the treatment of (2R)-1-[3,5-bis (trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-(2-hydroxyethyl)piperazine with methanesulfonyl chloride. A mixture of the mesylate (200 mg) and 4-hydroxymethylpiperidine hydrochloride (66 mg) in methanol (1 ml) was heated at reflux in the presence of potassium carbonate (150 mg). After 3 hours, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography on silica gel using a mixture of dichloromethane and methanol as eluent. The obtained product was dissolved in ethyl acetate and treated with 4N hydrogen chloride in ethyl acetate to give (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-4- (4-hydroxymethylpiperidino) ethyl]-2- (3,4-dimethylbenzyl) piperazine dihydrochloride (32 mg).

26 [a]6 -5.8 (C=0.50, MeOH) IR (KBr) 3370, 2600, 1645, 1430, 1280, 1180, 1140 cm 1 NMR (DMSO-d 6 5) 1.40-5.24 (30H, 6.60-8.24 (6H, 8.45 (1H, s) MASS 586 (M+H) (free) Elemental Analysis Calcd. for,C 30

H

37

F

6

N

3 02-2HC1 4.85H20 C 48.36, H 6.57, N 5.64 Found C 48.31, H 5.95, N 4.96 Example 38 A mixture of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-4- (4-chloro-2-butynyl)-2-(3,4-dimethylbenzyl)piperazine (150 mg), (3S)-3-ethylmorpholine hydrochloride (47 mg) and WO 98/57954 PCT/JP98/02613 79 powdered potassium carbonate (117 mg) in dry N,Ndimethylformamide (1 ml) was stirred at 50°C for 1.5 hours.

The reaction mixture was poured into water (10 ml) and extracted with ethyl acetate. The extract was washed with brine and dried over magnesium sulfate. After evaporation of the solvent, the obtained residue was purified by column chromatography on silica gel using ethyl acetate as eluent.

The obtained oroduct was dissolved in ethyl acetate and treated with 4N hydrogen chloride in ethyl acetate to give (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-4- ethylmorpholino)-2-butynyl]-2-(3,4-dimethylbenzyl)piperazine dihydrochloride (177 mg).

26 [a] 6 4.8 (C=0.50, MeOH) IR (KEr) 3430, 2580, 1645, 1435, 1280, 1180, 1135 cm 1 NMR (DMSO-d 6 5) 1.27 (3H, 1.45-5.20 (28H, m), 6.64-8.28 (6H, m) MASS 610 (free) Elemental Analysis Calcd. for C 32

H

37

F

6

N

3 0 2 -2HC13.5H20 C 51.55, H 6.22, N 5.64 Found C 51.61, H 6.02, N 5.60 Example 39 The requisite mesylate was prepared by the treatment of (2R)-1-[3,5-bis(triflucromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-(2-hydroxyethyl)piperazine (150 mg) with methanesulfonyl chloride (37 mg). A mixture of the mesylate and (3S)-3-ethylmorpholine hydrochloride (51 mg) in N,Ndimethylformamide (1 ml) was heated at 50°C in.the presence of potassium carbonate (85 mg). After 2 hours, the reaction mixture was poured into water (10 ml) and extracted with ethyl acetate. The extract was washed with brine and dried over magnesium sulfate. After evaporation of the solvent, the obtained residue was purified by column chromatography on silica gel using ethyl acetate as eluent. The obtained product was dissolved in ethyl acetate and treated with 4N WO 98/57954 PCT/JP98/02613 hydrogen chloride in ethyl acetate to give (2R) 5-bis (tr ifluoromethyl)benzoyl]j-4- -3-ethvlrnorpholino)ethyl]-2- 4-dimrethylbenzvl) piperazine dihydrochioride (45 mg) f(Y] n 1.60' (C=0.50, MeOH) I-R (KBr-) :3430, 2610, 1645, 14135, '280, 1180, 113 5. cM NIAR (DMISO-d 6 6) 0.95 (3H, 1.16-5.20 (28H, mn), 6.64-8.24 (6H, mn) MASS 586 (free) Elemental Analysis Calod. for C 30

H

37

F

6

N

3

O

2 -2HC1-l.8H 2

O

C 52.15, H 6.21, N 6.08 Found C 52.15, -H 60.42, N 6.00 Examiple A mixture of (2R)-l-[3,5-bis(tri-luoromethyl)benzoyl]-4- (2-methvlsulfonvloxyethyl) (2-naphthylmethyl)piperazine (200 mg), 3- (N-methvlaminomethy'l)pyridine dihydrochloride (73 mng) and triethylamine (120 mg) in dry methanol (5 ml) was refluxed for 4 hours. The reaction mixture was concentrated under reduced pressure and the resulting residue was partitioned between ethyl acetate and aaueous sodium bicarbonate solutIEion. The organic Layer was washed with brine and dried over magnesium sulfate. After evaporation of the solvent, the residue was ourifi ed by column chromatography on silica gel using a mixture of ethyl acetate and methanol (10:1) as eluent to afford an oily product, which was treated with 4N hvdr-oaen chloride in ethyl acetate ml) to gi-*ve (2R)-l-[3,5-bisltrifluorom-iethyl)benzoyl1-4f(N-methyl-N- (3-rovridylmnethvl) amino]I ethyl]1 (2naphthylmethyl)piJperazine dihydrochloride (78 mng).

2 5 :-12.90 (t=0.50, MeOH) IR (KBr) 3410, 2600, 1640, 1430, 1280, 1180, 1135 cm 1 NMR (DMSO-d 6 6) :2.40-5.28 (15H, mn), 2.74 (3H, s), -7.00-9.10 (14H, mn) MASS 615- (N+H)

T

(free) WO 98/57954 PCT/JP98/02613 Elemental Analysis Calcd. for C 3 3

H

3 2

F

6

N

4 0-2HCl*4.6H 2 0 C 51.45, H 5.65, N 7.27 Found C 51.40, H 5.37, N 7.07 Exam-ole 41 The following compoound was obtained according to a similar manner t o that of Examp~le (2R) 5-Bis (trif luoromethvl,)benzoyl] (IH-indol-3vl )metLhyl] EN-methyl--N- (3-o~vricivlmethyl) amrinolethylloi~erazine dihvdrochloride MD, 4 ~0 8 C= 0. 5 0, MeOH) IR (KBr) :3400, 2600, 1640, 1280, 1-180, 1135 crrJ INMR (DMSO-d 6 6) 1.12-5.20 (15H, m)4, 2.84 (3H, s), 6.63-9.00 (12H, rL), 10,95 (1H, s) MASS 604 Elemental Analysis Calcd. for C 3 lH 3 1

F

6

N

5 02HC1l-4.5H 2 0 C 49.15, H 5.59, N 9.24 Found C 49.19, 5.41, N 9.08 Exarmie 42 To a stirred mixture of (2R)-l-(3,5-rbis(trifluoromethyl)benzoyll-2-[ (lH-indol -3-yl)methvl]-4-[N-(lpiperazinvl) carbamoylmethyl]piperazine dihyldrochloride (500 mng) and triethylamine (302 mag) in tetr-ahydrofuran (10 ml) was added a solution o-F benzv! 4-brornobutanoat-e (192 mg) in tetrahydro-furan (2 mIl) atroom temperature for 24 hours. As a part of starting material remained, the reaction -mixture.

was filtered and the filtrate was concentrated under reduced pressure. To the resulting residue were added benzyl 4-brornobutanoate (192 mng), potassiumn carbonate (310 mg) and N,N-dimqethvlformamide (2 ml) The whole was stirred at room temoerature for 7 hours and then diluted with ethyl acetate and flee.The filtrate was washed wiLth brine and dried over magnesium sulfate. After eva-coration of solvent, the WO 98/57954 PCT/JP98/02613 82 residue was purified by column chromatography on a silica gel using a mixture of ethyl acetate and methanol as eluent to afford 2 R)-l-[3,5-bis(trifluorornethyl)benzoyl]-4-[N-[4- 3 -benzyloxycarbonylrorl)iperazin-l-vL]carbamoylmethyl]-2- [(lH-indol-3-yl)methvl]piperazine (296 mg).

R Neat) 3250, 1720, 1670, 1630, 1630, 1350, 1270, 1120 cm (ODC1 3 1.60-3.66 (25H, 5.10 (2H, s), 6.80-7.86 (8H, mi), 7.32 (SH, 8.21 (iH, s) MIASS 773 Examole 43 A mixture of 2 R)-1-[3,5-bis (triflurcmethyl)benzovl- 4- N-[4-(3-benzyloxycarbonvloropyl)pioerazin-i-vacarbamoylrethyl]-2-[(1H-indol-3-yl)methyllciperazine (1.3 g), ammonium formate (265 mg) and 10% palladium on activated carbon (130 mg) in water (2.5 ml) and ethanol (25 ml) was heated at 70'C with stirring under a nitrcgen atmosphere.

After 1 hour, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The product was triturated with ethyl ether to give bis (trifluoromethyl)benzoyl]-4- [4-(3-carboxynropyl)piperazin- ylcarbamovylmethyv9 (1H-indol-3-yl)methylipiperazine (1.19 g) as a powder.

8 -18.60' (C=0.50, MeOH) IR (Neat) 3200, 1680, 1620, 1425, 1275, 1120 cm 1 NMR (CDC 3 5) 1.72-4.60 (25H, 6.71-7.93 (8H, i) MASS 683 (M+H) Examole 44 The following compounds were obtained according to a similar manner to that of Example 2 3 ,5-Eis(trifluoromethyl)benzo i a4r(2E)-3- (tert-butoxcarbony')in orpholin-3-yl1-2- WO 98/57954 PCT/JP98/02613 83 propenyl 4-dimethylbenzvl)pioie razi ne IR (Neat) 2973, 1697, 1645 cm NMR (CDCi 3 5) 1.39 (9H, 2.00-2.16 (6H, m), 2.48-5.00 (18H, 5.40-5.80 (2H, 6.60-6.80 (1H, 6.90-7.20 (2H, 7.30-7.70 (3H, 8.13 (1H, br s) MA4SS 670 (2R)-1-f3,5-;-is(trifloromethv1)benzovl]-4-f'(2E)-3f(2R,2S)-4-(tert-butoxycarbonvl)moroholin-2-yl]-2propenvl]-2-(3,4-diiethylbenzyl)piperazirie NMR (DMSO-d 6 5) 1.41 (9H, 2.08-2.16 (6H, m), 2.50-4.80 (18H, 5.55-5.85 (2H, 6.60-6.80 (1H, 6.90-7.20 (2H, 7.30-7.70 (2H, 8.13 (1H, br s) MASS 670 Example A solution of (2R)-1-[3,5-bis(trifluoromethvl)benzoyl]- 4-[(2E)-3-[(3R)-4-(tert-butoxycarbonyl)morpholin-3-vl]-2propenyl]-2-(3,4-dimethylbenzyl)piperazine (1.36 g) in ethyl acetate (13 ml) was treated 4N hydrogen chloride in ethyl acetate (3.12 ml) at room temperature for 18 hours and then at 40'C for 5 hours. The solution was diluted with hexane and stirred for 1 hour. The resulting precipitate was collected by filtration and dried under reduced pressure to give (2R)-l-[L3,5-bi s(trifluoromethvl)benzoyll-2-(3,4diiethylbenzyl)-4-[(2E)-3-[(3R)-3-nlorpholinyl]-2-propenyl]piperazine dihydrochloride (1.11 gi as a white powder.

in 225S232oC Sa] -12.000 (C00.50, MeOH) IR (KIB r) 1645 cin MR (DMSO-d 6 2.10-2.18 (6H, 2.70-5.10 (18H, 5.80-6.25 (2H, 6.60-6.70 (1H, 6.90-7.20 (2H, 7.39-7.69 (2H, 8.15-8.20 (1H, n), WO 98/57954 PCT/JP98/02613 9.60-10.0 (2H, i) MrA-S S 570 (free) Elemental Analysis Calcd. for C 2 qH 33

F

6

N

3

O

2 -2HCl-1.0H 2

O

C 5273, H 5.65, N 6.36 Found C 52.65, H 5.76, N 6.26 Examrple 46 To a solution of (2R)-l--3,5-b-'is(trifluoromethyl)benzoyl] 4-dimetLhylbenzvl) (4-pyDrazolylmethyl) piperazine (500 mng) and tert-butLvl brornoacetate (225 mng) in N,N-dimethylformamide (7.5 ml) was added potassium, carbonate (390 mng) and the mixture stirred at 600 3 C for 7 hours.

Water was added to the mixture and the resulting mixture was extracted with ethyli acetate. The organic layer was washed with brine, dried over magnesium sulfate, evaporated under reduced pressure, and purified by column chromatography on a silica gel using a mixture of ethyl acetate and hexane (1:1) as eluent to give (2R)-l-[3,5-bis(trifLluorornethyl)benzoyl]-4- (tert-butoxycarbonylmetLhvl)-lH-pyrazol-4-yl~methyl] -2- (3,4-dimethylbenzyl)piperazine as an oil.

NINR (DNSO-d 6 5) :1.01 (9H, 2.05-2.15 (6H, s), 2 .52 -4t. 90 (11 H, in) 4 90 (2 H, s 6.5 3- 6.580 1H, mn), 6. 90 7.-00 (2 H, in), 7. 41 (2 H, 7. 63 (2KH, s), 8.13 br s) MASS :639 Example 47 A solution of (k2R) 3, 5-b-s (tLri'lLuoromethvl) benzoyl- 4- [[1-(tert-butoxvcarbonylmethy'L)-lH-pyvrazol-4-v--lmtyl2 4-dimethvlbenzyL) pipera zine (425 mac) iLn dichloromethane ml) was treated with trifluoroacetic acid (2.5 ml) at room- teinoera=ture for 1 hour. The mixture was adjusted to pH 7.4 with aqueous sodium bicarbonate solution and evaporated under reduced poressure. The residue was washed with a mixture of dichloromethane and methanol and the WO 98/57954 PCT/JP98/02613 solution was evaporated under reduced pressure and purified by column chromatography on a silica gel using a mixture of methanol and chloroform as eluent and subseauent crystallization from ethyl acetate, isopropyl ether, and hexane to give 2 4-[[1-(carboxymethyl)-1H-pyrazol-4-yl]methyl]-2-(3,4-dimethyl benzyl)piperazine (395 mg) as a white powder.

mp 223-230°C [a]c 5 -15.10° (C=0.50, MeOH) IR (KBr) 1683, 1604 cm NMR (DMSO-d6, 5) 2.06-2.15 (6H, 2.52-4.90 (11H, 4.54 (2H, 6.50-6.60 (1H, 6.90-7.00 (2H, 7.31 (1H, 7.40 (1H, 7.57-7.64 (2H, m), 8.14 (1H, s) Example 48 To a solution of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-4-[[1-(carboxymethyl) -IH-pyrazol-4-ylmethyl]-2- (3,4-dimethylbenzyl)piperazine (120 rng) in tetrahydrofuran (1 ml) were added 1-hydroxybenzotriazole hydrate (176 mg), 1ethyl-3-(3-dimethylamniopropyl)carbodiimide hydrochloride (240 mg) and morpholine (0.11 ml) at room temperature, and the mixture was stirred at room temperature overnight. The mixture was quenched with water, and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, and evaporated under reduced pressure.

The residue was purified by column chromatography on a silica gel using a mixture of methanol and ethyl acetate as eluent to give a crude oil (76.7 mg). The oil was dissolved in ethyl acetate (0.7 ml) and added 4N hydrogen chloride in ethyl acetate (0.15 ml) at room temperature. After the addition of isopropyi ether, the resulting precipitate was filtered off and dried under reduced pressure to give (2R)-1- [3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4- [[1-(morpholinocarboxymethyl)-1H-pyrazol-4- WO 98/57954 PCT/JP98/02613 ilmethyl]piDerazine hydrochloride (40 mg) as a poowder.

imp, 120-1300C 19.400 (C=0.25, PIeOH) K~r) 16.49 cmTr NNR (DMSO-d 6 5) 2.06-2.16 (6H, 2.52-5.00 (19H, mn), 5.19 (2111, 6.5F.-6.62 (1H, in), 6.92-7.03 (2H, mn), 7.44 (11H, 7.66-7.68 (2H, in), 7.92 (1H, br 8.19 (1H, br s) MAS S :652 (M+11) (f-ree) Elemental Analysis Calci. for C- 2 2 H zF N 5 O- .HCl-2.6HO C 52.30, H 5.65, N 9.53 Found C 52.38, H: 5.63, N 9.22 Examnle 49 The following compound was obtained according to a similar maniner to that of Example3.

(2R) 5-Bis (tr-ifluoroinethyl)benzovli] (3,4diinethylbenzvl) (3S) (2-mPetuhyl-oropy'L)m-or-ho'ino] -2butyny1]pi-perazine dihvdrochloride MI 2 5-13 801- 2S~ :.13.90' (C=0.50, MeOH) TR (KBr) 1645 cm- 1 NMR (DMSO-d 6 5) 0.80-1.80 (9H, mn), 2.09-2.18 (6H-, mn), 2.83-5.13 (208H, 6.6 0 181, mn), 6. 96 714 28 mn), 7. 46 1 i, br s) 7.67 (1H, br s), 8.16 (1H, br s) MA.S S 638 (M (free) Elemental Analysis Calcd. for C 34

H

4 3 C1 2

F

6

N

3 Oy- 1H 9 C 55.91, H 6.24, N 5.75 Found C 56.24, H 6.75, N 5.74 Example The following comnound was obtained according to a similar manner to that of Example 31.

WO 98/57954 PCT/JP98/02613 87 (2R) 5-Bis (trifluoromethyl) ben zoyl]1 4dimethylbenzyl) (7-oxa-4-azaspiro octan-4-yl] -2butynylilpiperazine dihydrochioride 27. -9.70- (C=0.50, MeOH) IR (KBr) 3700-3000, 2700-2200, 1645, 1534, 1463, 1280, 1184 cmn1 NI4R (DMSO-d 6 6) 0.90-1.00 (4H, mn), 3.00-4.70 (19H, in), 6.60-8.20 (6H, mn) MASS 608 (free) Elemental Analysis Calcd. for G 32

H

35

F

6

N

3

O

2 -2HC1P2H 2

O

C 53.64, H 5.77, N 5.86 Found C 53.92, H 6.05, N 5.61 Example 51 The following compounds were obtained according to a similar manner to that of Example (2R) 5-Bis (trifluoronethyl) benzoyl] (H-iridol-3yl)methyl] (4-methoxypyridin-3-yl) -2-propynyllpiperazine NMR (CDCl 3 1 5) 2.00-5.20 (11H, mn), 3.92 (3H, s), 6.80-8.00 (11H, mn), 8.30 (1Hi, br s) MASS 601 (free) (2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4dimethylbenzyl) (4-methoxypyridin-3-yl) -2propynyl] piperazine NNR (CDCl 3 6) 2.00-5.20 (17H-, in), 3.93 (3H, s), 6.60-8.80 (9H, in), 8.02 (iH, 8.30-8.50 (1H, in) MASS. 590 Example 52 The following compounds were obtained according to a similar manner to that of Example WO 98/57954 WO 9857954PCT/JP98/02613 (21R) (3,S-Bis (trifluoromethy1) benzoy1--2-1 (1H-indol-3yi',,methy j r 3- (4-methoxvpvridin-3-yl) -2--Dropynylpiperazine dihydrochioride mp :162-167 0

C

[X]26.6 +~4.900 (C=0.50, MeOH) T R (KBr) 3700-3300, 2700-2300, 1641, 1502, 1430, 1363, 1280 c77" NMR (DMSO-d 6 -3-00-5.20 (14KH, mn), 6.60-8.3C (9H, mn), 8.80-9.90 (2H, mn), 10.96 br s) MASS :601 (M+H) T (free) Elemental Analysis Calcd. for C 3 jH2 6

F

6

N

4

O

2 -2HC1-2.2H 2 0 C 52.16, H 4.91, N 8.32 Found C 52.21, H 4.58, N 7.86 (2R)-i-[3,5-Bis.'trifluoromethyl)benzoyl]-2-(,3,4diinethylbenzyl) (4-iethoxypyridin-3-y1) -2propyny1]piperazine dihvdrochJloride mp :150-153 0

C

[ID

4 -7.45- (C=0.55, MeOH) IR 3600-3300, 2700-2200, 1639, 1500, 1430, 1317, 1280 cm -1 INYR (DMSO-d, 6 6) :2.00-2.20 (6H, mn), 2.80-5.20 (ilH, 6.60-7.80 (6H, mn), 8.20 br 8.81-8.97 (2H, m) MASS 5 90 (free) Elemental Analysis Calcd. for C 1 2 FN 0-2HCl-2.2H0 C 52.9-7, H 5.27, N 5.93 Found IC 53.03, K 5.08, N 5.98 Examole _53 The following compounds were obtained according to a similar manner to trhat off Exampole 3.

(2-R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-[ (lH-indol-3vl)inethyl], L3- (4-iTnethoxypoyridin-3-vl) propyl- 1]piperazine WO 98/57954 PCT/JP98/02613 89 dihydrochloride M'D 165-170"C a24,9 D, -1.910 (C=0.55, MeOH) IR (KBr) 3700-2300, 1643, 1502, 1432, 1363, 1280, 1222 cm NM?.-R (DMSO-d 6 5) 2.00-2.30 (2H, 2.60-5.20 (16H, m) 6.60-8.30 (9H, 8.70-8.90 (2H, 10.95 (1H, br 11.60-11.80 (2H, i) LASS 605 (free) Elemental Analysis Calcd. for C 3 1

H

30 FNjO 2 -2HCi-2.8HqO C 51.15, H 5.21, N 7.70 Found C 51.11, H -5.40, N 7.61 (21R) S-Bis (tri-fluoromet~h-yl)benzoyl] 4diiethylbenzvl))-4-[3-(4-methcxypyridin-3-yl)propyl]piperazine dihydrochloride pin 159-168 O 26.9 'ccI D -10.91" MeOH) -R (KBr) 3600-3300, 2700-2300, 1643, 1502, 1430, 1361, 1280 cm 1 INMR (DMSO-d 6 5) 2.00-5.20 (21H, 4.13 (3H, s), 6.60-7.80 (6H, 8.20-8.30 (lH, 8.70-8.90 (2H, 11.60-11.90 (2H, m) MASS 594 (free) Elemental Analysis Calcd. for C 3 1

H

3 3

F

6

N-

3

O

2 -2HC1-2.4H 2 C 52.50, H 5.97, N 5.60 Found C 52.46, H 5.65, IN 5.92 Exainle 54 .A solution of 2- (1H-indol-3-y imethyll-4- (tert-butoxycarbonylamino) pyridin-3-yl]-2-propynyl]pfperazine (127 mg) prepared by a similar manner to that of Example and trifluoroacetic acid (5 ml) in dichioroiethane (5 ml) was stirred at room temperature for 2 hours. The reaction mixture was WO 98/57954 PCT/JP98/02613 concentrated under reduced pressure and the residue was partitioned between saturated. aqueous sodiJum bicarbonate solution. The organic 'Layer w,,as separated, dried over magnesium sulfate anid concentrated under reduced pressure.

The syrup obtained was dissolved into ethyl acetate and treated with 4N hydrogen chloride in ethyl acetate to give me thyl] [3-C 6-arinopyvridin-3-yl) -2-propynyi]pipoerazine dihydrochioride (80 mg) MID 90-195 0

C

ct24.0 -13.47* MeOH) IR (KBr) 3600-3000, 2700-2500, 1668, 1619, 1428, 1L359, 1280 cm 1 i NMR (D.MSO-d 6 5) :3.00-5.20 (11H, in), 6.60-7.50 (6H, mn), 7.70-8.30 (5H, im), 8.20-8.50 (2H, 11.95- 11.10 (1H, br s) MLksS~ 586 (-free) Elemental Analysis Calca. :or C 30

H

25

F

6 N50-2HCP-2.5H 5

-O

C 51.22, H 4.58,, N 9.95 Found C 51.17, H 4.40, N 9.27 ExamplIe The following comp~ound was obtained according to a similar manner to that of ExaiDle 54.

(2R) 5-Bis (trifluoroinethvl) benzoylj (3,4dimethylbenzyl) (6-aiinopyridin-3-yl) -2-propynyl] piperazine dihydrochioride MI l 83-1890C IR (KBr) :3600-2500, 1644, 1596, 1525, 1375, 1280 cm- 1 NMR (DMSO-d 6 5) 2.00-2-25 (6H, 2.80-5.25 (13H, 6.60-8.40 (9H, in), 8.00-8.80 in) AS: 575 t (free) Elemental Analysis Calcd. -for C 30

H

28

F

6

N

4 60-2HC1*1.5H 2

O

C 53.42, H 4.93, N 8.31 WO 98/57954 PCT/JP98/02613 Found C 53.08, H 5r.01, N 8.12 Example 56 The following compounds were obtained according to0 a similar manner to that of Example (2R)-1-[3,5--Bis(triffluoromethyl)benzoyll-2-(2- .nhthI-ylmethyi) 13- (2-p~yriLdvl) -2-propynyl~piperazine TR (KBr) 3700-3200, 164-, 1278, 1113 6 cm'- NWIR (DMSO-dg, 2.20-4.00 (9H, mn), 4.30-5.20 (2H, in), 7. 00-8. 65 14 H, YLAS S 582 46-7 (2R) -I-['L3,5S-Bi s(trif-Lluoromethvl) benzoyl]jl-2-[ (1H- indol-3vl) methyl]1-4- I 2 E) 3-(3-pvr-idyl) -2-pDropenyl piperaz ine dihvdrochloride 2 o 195-203 C -11.20- (C=0.50, MeOH) IR (KBr) 3600-3300, 2700-2500, 1644, 1430, 1363, 1280, 1184 cmi NMR (DMSO-d 6 5) 3.00-5.20 (11H, in), 6.60-7.60 (6H, in), 7.70-9.00 (8H, mn), 11.00 (lH, br 12.00- 12?.40 (2H, in) MAS S 573 Elemental Analysis Calcd. for C 30 oH 2 6 6 NtO-2HCl-2.5Ho C 52.18, H 4.82, N 8.11 Found C 51.94, H 4.77, N 7.77 (2R)-1--[3,,5-Bis',trifJ-uoroinethyl)benzovl]-2-(3,4diinethylbenz'L) (-Pyridyl) -2-p~ropenyli n~inerazine dihvdrochloride 17 0-17 4OC 23.0 -7.30* (C=0.50, MeOH) IR (KBr) 3600-3300, 2700-2500, 1644, 1550, 1430, 1363, 1280 cm-i- WO 98/57954 PCT/JP98/02613 92 NMR (DMSO-d 6 5) 2.00-2.30 (6H, iv), 2.80-5.20 (1lH, 6.40-8.40 (1H, 8.70-8.85 (2H, 12.00- 12.20 (2H, m) MRASS 362 (free) Elemental Analysis Calcd. for C 30

H

2 9

F

6 N-0-2HCl-2.5H 2 0 C 53.03, H 5.34, N 6.18 Fcund C 52.99, H 5.41, N 5.91 (2R) -1-3,5-Bis('tri f luoromethvl)benzoyl]-2-[ (1H-indol-3yl)methyl]-4-F4-(2-pyridyI)-3-butynylipiperazine NIMIR (C=Cl 3 5) 1.80-5.20 (131-1, 6.80-8.00 (12H, in), 8.19 (1H, 8.55 (iH, d, JT=4 OHz) MLASS 585 Example 57 The following compounds were obtained according to a similar manner to that of Exainole (2R)-1-[3,5-Bis(trifluoronethvi)benzovl)-2- (3,4dimethylbenzyl)-4-r3-(6-metoxypvridin-3-vl)propyllpiperazine dihvdrochloride mp 127-137 0

C

15.93 (C=0.16, MeOH) IR (KBr) 3600-3300, 2700-2500, 1646, 1556, 1434, 1280, 1184 cmn 1 NNR (DMSO-d 6 5) 1.90-5.20 (21 I, 3.84 (3 H, s) 6.60-7.30 (4H, 7.40-7.80 m) 8.00-8.30 (2H, i) MASS 594 (M+H) T (free) Elemental Analysis Calcd. for C 3 1

H

33

F

6 N 3 0 2 9 -2HC-1.2H 2 0 C 54.11, H 5.48, N 6.11 Found C 54.09, H 5.75, N 5.83 5-Bi s (trifluoromethvl)benzoy i (1--indol-3vl)methyl]-4-[3-( 6 -methoxypyridin-3-vl)prooyllpiperazine WO 98/57954 PCT/JP98/02613 93 dihydrochioride rm 195-200 0

C

22.6 -2.030 (C=0.32, MeOH) 1K (KEr) 3600-3300, 2700-2300, 1644, 1556, 1494, 1432, 1363, 1280, 1180 cm 1 NMR (DMSO-d 6 5) 2.20-5.20 (15H, 3.79 (3H, s), 6.60-8.30 (11H, 10.95 (iH, br 11.60-11.80 (2H, mn) MASS 605 (free) Elemental Analysis Calcd. for C 3 lH 3 0

F

6

N

4 0 2 -2HC-11.5H 2 0 C 52.58, H 5.01, N 7.95 Found C 52.89, H 5.40, N 7.63 (2R.-1-rl)3, 5-Bis(--trifluoromethvi)benzoyli-2-(2naphthylmethyl)-4-[3- (2-ovridvl)proy ilp iperazine dihvdrochloride 26.8 [2]D -27.60* (C=0.50, MeOH) 1K 3700-3000, 2700-2200, 1647, 1279, 1136 cm- 1 NMR (DMSO-d 6 5) 2.20-4.30 (13H, 4.40-5.40 (2H, 7.00-8.90 (14H, m) MASS 586 (M+H) T (free) Elemental Analysis Calc. for C 3 2

H

2 9

F

6

N

3 02HC1-2.5H 2 0 C 54.63, H 5.16, N 5.97 Found C 54.55, H 5.37, N 5.56 (2R)-1-[3,5-Bis(tri f luoromethvl)benzoyl]-2-[ (lH-indoi-3yl)methylj-4-[4-(2-py ridyvl)but i piperazine dihydrochioride M*O 155-160 0

C

21.0 CO0 eH Nra] +9.500 (C0.10, NeO) T (KPr) 3700-3000, 2700-2200, 1641, 1459, 1428, 1280, 1137 ct, 1 NMR (DMSO-d 6 5) 1.70-2.20 (4H, 2.60-5.20 (13H, 6.60-8.80 (12H, 11.00 (1H, br 11.40- 11.80 (2H, m) WO 98/57954 PCT/JP98/02613 94 MASS :589 (M+H) (free) Elemental Analysis Calcd. for C 3 1

H

3 0

F

6

N

4 02HC1-2.0H 2 0 C 53.38, H 5.20, N 8.03 Found C 53.34, H 5.38, N 7.78 Example 58 A mixture of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2- [(1H-indol-3-yl)methyi]piperazine (0.83 methyl a-bromophenylacetate (0.42 potassium carbonate (1.0 g) in N,N-dimethylformamide (5 ml) was stirred at 50°C for 3 hours. The reaction mixture was poured into water and the resulting precipitates were collected by filtration. The precipitates were purified by column chromatography on silica gel using a mixture of dichloromethane and ethyl acetate as eluent to give a mixture of diastereoisomers, methyl (2R,2S)- 2-[(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-[ (H-indol-3yl)methyl]piperazin-4-yl]-2-phenylacetate (1.00 g).

NMR (CDC1 3 2.00-5.20 (4H, 3.69 (3H, s), 6.70-8.20 (14H, m) MASS 604 (M+H) (free) Examole 59 A solution of the mixture of diastereoisomers, methyl (2R,2S)-2-[(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-[(1Hindol-3-yl)methyl]piperazin-4-yl]-2-phenylacetate (360 mg) and IN sodium hydroxide (1.5 mi) in methanol (5 ml) was stirred at 50°C for 2 hours. The mixture was concentrated under reduced pressure until aqueous solution. The solution was diluted with water and the solution was made acidic (about pH 5) with diluted hydrochloric acid and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure to give a mixture of diastereoisomers, bis(trifluoromethyl)benzoyl]-2-[(lH-indol-3-yl)methyl]piperazin-4-yl]-2-phenylacetic acid (0.33 g).

WO 98/57954 PCT/JP98/02613 NMR (CDC1 3 2.20-5.80 (10H, 6.60-8.20 (14H, m) MASS 590 (free) Example Isobutyl chloroformate (0.116 ml) was added dropwise to a suspension of the mixture of diastereoisomers, (2R,2S)-2- [3,5-bis(trifluoromethyl)benzoyv]-2-[(H-indol-3-yl)methyl]piperazin-4-yl]-2-phenylacetic acid (0.5 g) and N-methylmorpholine (0.103 ml) in 1,2-dimethoxyethane (3 ml) under -180C. After being stirred at the same temperature for minutes, a solution of sodium borohydride (32 mg) in water ml) was added to the mixture all at once. After being stirred at room temperature for 30 minutes, IN sodium hydroxide solution was added to the mixture and the whole was stirred at room temperature for 1 hour. The mixture was neutralized with diluted hydrochloric acid, and extracted with ethyl acetate. The extract was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using a mixed eluent of dichloromethane and methanol. The fractions containing the objective compound were collected and evaporated under reduced pressure to give a mixture of diastereoiscmers, (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2- [(lH-indol-3-yl)methyl]-4-[(1R,1S)-i-phenyl-2-hydroxyethyl]piperazine (0.42 g).

NMR (CDCl 3 6) 1.90-5.20 (13H, 6.60-8.20 (14H, m) MASS 576 (M+H) Example 61 Methanesulfonyl chloride (0.058 mi) was added to a solution of the mixture of diastereoisomers, bis (trifluoromethyl)benzoyl]-2-[(lH-indol-3-yl)methyl]- 4 [(lR,1S)-l-phenyl-2-hydroxyethyl]piperazine (0.36 g) and triethylamine (0.16 ml) in dichloromethane (10 ml) under -18°C. After being stirred at the same temperature for WO 98/57954 PCT/JP98/02613 96 minutes, additional methanesulfonyl chloride (0.058 ml) and triethylamine (0.16 ml) were added to the mixture. After being stirred at the same temperature for further 30 minutes, the reaction mixture was washed with water, dried over magnesium sulfate and evaporated under reduced pressure to give the corresponding mesylate. A mixture of the mesvlate and morpholine (0.4 ml) in 1,4-dioxane was stirred at 50° for 3 hours. The reaction mixture was concentrated under reduced pressure to give a syrup, which was partitioned between water and ethyl acetate. The organic layer was separated, washed with brine, dried over magnesium sulfate.and concentrated under reduced pressure to give the crude mixture of diastereoisomers, which was purified by column chromatography on silica gel using a mixed eluent of dichloromethane and methanol. The faster eluting fractions were collected, evaporated under reduced pressure and treated with 4N hydrogen chloride in ethyl acetate to give a diastereoisomer of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-[(lH-indol-3yl)methyl]-4-[(1R or 1S)-l-phenyl-2-morpholinoethyl]piperazine dihydrochloride.

mD 203-207°C -6.0 (C=0.25, MeOH) IR (KEr) 3700-3300, 3100-2200, 1641, 1450, 1432, 1363, 1280 cm 1 NMR (DMSO-d 6 5) 2.40-5.20 (20H, 6.60-8.30 (8H, 10.95 (1H, s) MASS 644 (free) Elemental Analysis Calcd. for C- 4

H

34

F

6 N402-2HC1-2/3H20 C 55.97, H 5.16, N 7.68 Found C 55.98, H 5.48, N 7.26 The slower eluting fractions were collected, evaporated under reduced pressure and treated with 4N hydrogen chloride in ethyl acetate to give a diastereoisomer of bis(trifluoromethyl)benzoyl]-2-[(iH-indol-3-yl)methyl]-4-[(1S WO 98/57954 PCT/JP98/02613 97 or 1R)-1-phenyl-2-morpholrinoethvilpiDerazine cihvdrochloride.

m, :207-212'C !21.7 -3.330 (C=0.94, MeO) TR (KIr) 3700-3200, 3000-2300, 1643, 1450, 1432, 1280, 1182 cmK NR (DMSO-d 6 5) 2.40-5.20 (20H, 6.55-8.35 (8H, 10.95 (1H, 11.00-12.10 (2H, m) MASS 644 (free) Elemental Analysis Calcd. or C 3 4

H

3 4

F

6 NAOn2HC1-0..SH C 56.20, H 5.13, N 7.71 Found C 56.15, H 5.52, Iq 7.32 Examnle 62 The following compound was obtained according to a similar manner to that of Example 5-Biss(trifluoromethvl)benzovl]-2-(3,4dimethvlbenzvl)-4-[3-[ 12R,2S)-2-morphclinv1-2-propenv1]pioerazine dihydrochioride no 160-163 0

C

S]D 12.500 (C=0.50, MeO) !R (KBr) 1645 c 1 NNR (DMSO-d 6 5) 2.08-2.18 (6H, 2.55-5.10 (18H, 5.80-6.20 (2H, 6.60-6.70 (1H, 6.90-7.20 (21, in), 7.47-7.70 (21, in), 8.15-8.20 (1H, i) MASS 570 (M+Hyr (free) Elemental Analysis Calcd. for C 29

H

3

-F

6

N

3 O-2HCII.0H 9

OH

C 52.59, H 5.65, N 6.34 Found C 52.85, H 5.97, N 6.16 Examnle 63 A mixture of (2P,)-1-[3,5-bis itrifluoromethyl)benzoyll-2- 4-d imethvlbenzvl)piperaz ine (500 ng) and 1,8diazabicvclo[5.4.0]undec-7-ene (1.5 41) in tetrahydrofuran (2.5 ml) was cooled to -30'C with stirring under nitrogen WO 98/57954 PCT/JP98/02613 98 atmosphere. Acrolein 0.225 ml) was added to the mixture while maintaining the temperature at -20 -40°C for a period of 10 minutes and then the resulting mixture was stirred at 0°C. After 6 hours, the reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with brine and dried over magnesium sulfate. After evaporation of the solvent under reduced pressure, the resulting residue was chromatographed on a silica gel using a mixture of hexane and ethyl acetate as eluent to give (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2- (3,4-dimethylbenzyl)-4-(2-formylethyl)piperazine (332 mg) as an oil.

NMR (DMSO-d 6 5) 1.60-4.90 (19H, 6.55-6.75 (1H, 6.90-7.15 (2H, 7.30-7.75 (2H, 8.13 (1H, br 9.70 (1H, s) MASS 501 Example 64 To a stirred mixture of 4-amino-3,3-dimethylmorpholine dihydrochloride (122 mg) in dichloromethane (5 ml) was added triethylamine (61 mg) at ice bath temperature. A solution of 3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-(2-formylethyl)piperazine (150 mg) in dichloromethane (2 ml) was added and the resulting mixture was stirred at room temperature. After 30 minutes, the reaction mixture was concentrated under reduced pressure.

The resulting residue was chromatographed on a silica gel using a mixture of hexane and ethyl acetate as eluent and the desired product was treated with 4N hydrogen chloride in ethyl acetate to give (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-[3-(3,3-dimethylmorpholinoimino)propyl]piperazine dihydrochloride (122 mg).

IR (KBr) 3425, 2700, 2625, 1645, 1430, 1280, 1180, 1135 cm 1 NMR (DMSO-d 6 5) 1.06-1.40 (6H, 2.00-2.40 (6H, WO 98/57954 PCT/JP98/02613 99 2.60-5.80 (19H, 6.64-8.30 (6H, 10.00- 12.18 (2H, m) MASS 613 (M+H)'(free) Elemental Analysis Calcd. for C 31

H

38

F

6

N

4 0 2 -2HCl-2H 2 0 C 51.60, H 6.15, N 7.76 Found C 51.82, H 6.49, N 7.29 Example To a stirred mixture of 4-aminohomomorpholine dihydrochloride (100 mg) in dichloromethane (5 ml) was added triethylamine (107 mg) at ice bath temperature. A solution of (2R)-l-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4dimethylbenzyl)-4-(2-formylethyl)piperazine (200 mg) in dichloromethane (2 mi) was added and the resulting mixture was stirred at room temperature. After 30 minutes, the reaction mixture was concentrated under reduced pressure.

The resulting residue was chromatographed on a silica gel using a mixture of hexane and ethyl acetate as eluent to give (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4dimethylbenzyl)-4-[3-(homomorpholinoimino)propyl]piperazine (110 mg) and an intermediate. This compound was dissolved in methanol (5 ml) and sodium borohydride (17 mg) was added at ice bath temperature. After 2 hours, additional sodium borohydride (40 mg) was added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with water and then extracted with dichloromethane. The extract was washed with brine and dried over magnesium sulfate. After evaporation of the solvent, the resulting residue was purified by a silica gel column chromatography using a mixture of dichloromethane and methanol (50:1) as eluent to give the desired product, which was dissolved in ethyl acetate and treated with 4N hydrogen chloride in ethyl acetate to afford (2R)-1-[3,5-bis- (trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-[3- (homomorpholinoamino)propyl]piperazine dihydrochloride (66 WO 98/57954 PCT/JP98/02613 100 mg).

7 -13.7 (C=0.50, MeOH) IR (KBr) 3450, 2700, 2620, 1645, 1430, 1280, 1185, 1135 cm-1 MASS :601 (free) Elemental Analysis Calcd. for C 30

H

38

F

6

N

4 0 2 -2HCl-0.7H20 C 52.51, H 6.08, N 8.17 Found C 52.51, H 6.05, N 7.86 Preparation 32 Di-tert-butyl dicarbonate (29.4 g) was added to a mixtuure of (2R)-2-(3,4-dimethylbenzyl)-4-benzylpiperazine dihydrochloride (45.0 g) and triethylamine (59.6 ml) in tetrahydrofuran (900 ml) under ice-cooling. After 3 hours of stirring at the same temperature, stirring was continued at room temperature for 9 hours. The mixture was poured into ice-water (1 and extracted with ethyl acetate (2.5 The extract was washed successively with IN hydrochloric acid and brine, dried over sodium sulfate and evaporated under reduced pressure to give a crude oil of (2R)-4-benzyl-l-tertbutoxycarbonyl-l-(3,4-dimethylbenzyl)piperazine (49.6 g).

NMR (CDC1 3 5) 1.40 (9H, 1.90-2.06 (2H, m), 2.15-2.17 (6H, 2.60-4.4 (9H, 6.86-7.05 (3H, 7.20-7.39 (5H, m) MASS (APCI) :395 (M+H) 339, 295 Preparation 33 A solution of (2R)-4-benzyl-l-tert-butoxycarbonyl-2- 3 ,4-dimethylbenzyl)piperazine (48.5 g) in methanol (730 ml) was hydrogenated over 20% palladium hydroxide-carbon (0.3 g) at room temperture under atmospheric pressure. After removal of the catalyst by filtration, the filtrate was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using a mixed solvent of dichloromethane and methanol The fractions WO 98/57954 PCT/JP98/02613 101 containing the objective compound was collected and evaporated under reduced pressure to give an oil of (2R)-1tert-butoxycarbonyl-2-(3, 4 -dimethylbenzyl)piperazine (33.7 g).

NMR (DMSO-d 6 5) 1.26 (9H, 2.15-2.17 (6H, m), 2.30-4.05 (10H, 6.86-7.05 (3H, m) MASS (APCI) :305 249, 205 Preparation 34 A mixture of 2 R)-l-tert-butoxycarbonyl-2-(3,4dimethylbenzyl)piperazine (29.0 3,3-dimethyl-4- (4-chloro- 2-butynyl)morpholinine hydrochloride (22.7 potassium carbonate (39.5 g) and potassium iodide (1.58 g) in N,Ndimethylformamide (145 ml) was stirred at room temperature for 2 hours, followed by 53"C for 3 hours. After beina cooled to room temperature, the mixture was poured into icewater (1.2 and extracted with ethyl acetate (1.2 The extract was washed with water (1 and re-extracted with 1N hydrochlioric acid (190 ml). The acidic aqueous layer was separated and the pH of the solution was made to 10 with 1N sodium hydroxide. The alkaline solution was extracted with ethyl acetate (1.1 and the extract was washed with brine, dried over sodium sulfate, and evaporated under reduced pressure to give an oil of 2 R)-1-tert-butoxycarbonyl-2-(3,4dimethylbenzyl)-4-[4-( 3 3 -dimethylmorpholino)-2-butynyl]piperazine (43.1 g).

NMR (DMSO-d 6 5) 0.95 (6H, 1.26 (9H, s), 2.03-4.20 (25H, 6.80-7.05 (3H, m) MASS (APCI) 470 Preparation A solution of 4N hydrogen chloride in ethyl acetate was added to a solution of 2 R)-l-tert-butoxycarbonyl-2-(3,4dimethylbenzyl)-4-[4-(3, 3 -dimethylmorpholino)-2-butynyl] piperazine (40.0 g) in ethanol (120 ml) at room temperature WO 98/57954 PCT/JP98/02613 102 and the whole was stirred for 12 hours. The reaction mixture was concentrated under reduced pressure and the residue was partitioned between ethyl acetate (500 ml) and potassium carbonate solution. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (300 ml). The combined extract was dried over sodium sulfate and evaporated under reduced pressure, and the residue was purified by column chromatography on silica gel using a mixed solvent of n-hexane and ethyl acetate The fractions containing the objective compound were collected and evaporated under reduced pressure, and treated with 4N hydrogen chloride in ethyl acetate to give (3R)-3-(3,4-dimethylbenzyl)-1-[4-(3,3dimethylmorpholino)-2-butynyljpiperazine trihydrochloride (37.7 g).

mD 264-272°C [a] 7 -23.60 MeOH) IR (KBr) 3500-3400, 2900, 2570, 2480, 1637, 1626, 1508, 1455, 1180 cm" NMR (DMSO-d 6 6) 1.33 (3H, 1.39 (3H, 2.21 (6H, 2.80-4.60 (20H, 6.90-7.20 (3H, m), 9.90-10.40 (3H, m) MASS (APCI) 370 (free) Preparation 36 1-( 3 -Dimethylaminopropyl)-3-ethylcarbodiimide (0.22 ml) was added over 5 minutes to a mixture of dimethylbenzyl)-1-[4-(3,3-dimethylmorpholino)-2-butynyl]piperazine trihydrochloride (0.48 g) and acid (0.27 g), 1-hydroxybenzotriazole (0.15 g) and triethylamine (0.35 ml) in dichloromethane (10 ml). After 2 hours of stirring at room temperature, the reaction mixture was directly purified by column chromatography on silica gel using a mixed solvent of dichloromethane and methanol The fractions containing the objective compound was collected and WO 98/57954 PCT/JP98/02613 103 evaporated under reduced pressure. The residue was treated with 4N hydrogen chloride in ethyl acetate and recrystallized from a mixture of acetone and water to give colorless crystals of 2 R)-l-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4dimethylbenzyl) -4-[4-(3,3-dimethylmorpholino)-2-butynyil]piperazine dihydrochloride (525 g).

np 180-190°C 3 -7.24" (C=1.05, MeOH) IR (Nujol) 3300, 2700-2400, 1635 cm 1 NMR (DMSO-d 6 5) 1.30-1.40 (6H, 2.00-5.22 6.60-8.20 (6H, 12.05-12.20 (2H, m) MASS (APCI) 610 (M+1H) (free) Elemental Analysis Calcd. for C 3 2

H

3 7

F

6

N

3 022HCl*2.5H20 C 52.82, H 6.09, N 5.68 Found C 52.84, H 5.89, N 5.78 Preparation 37 3,3-Dimethylmorpholine hydrochloride (5.3 g) was added by small portions over 1 hour to a mixture of 1,4-dichloro-2butyne (6.9 ml) and potassium carbonate (9.8 g) in N,Ndimethylformamide (100 ml). After 20 hours of stirring, the mixture was poured into ice-water (200 ml) and extracted with isopropyl ether (100 ml) two times. The extract was washed with brine (100 ml), dried over magnesium sulfate, and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using a mixed solvent of n-hexane and ethyl acetate The fractions containing the objective compound was collected and evaporated under reduced pressure, and treated with 4N hydrogen chloride in ethyl acetate to give brownish powders of 3,3-dimethyl-4-( 4 -chloro-2-butynyl)morphlinine hydrochloride (5.32 g).

NMR (DMSO-d 6 6) 1.35-1.39 (6H, 3.20-4.40 (8H, 4.56 (2H, 11.50-11.90 (1H, m) MASS (APCI) 202 (free), 204 WO 98/57954 PCT/JP98/02613 Preoaration 38 A mixture of 2 R)-l-[3,5-bis(t'rifluoromethyl)benzoylV2- 4 -dime thylbenz yl) piperazine 0 g) propargyl bromide (0.84 g) and potassium carbonate (1.17 g) in N,Ndime thyl forinamide (300 ml) was stirred at room temperature for 1.5 hours. The mixture was poured into ice-water and extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate and evaporated under reduced Doressure to give a syrup of (2R)-1-[3,5-bis- (trifluoromethyl)benzoyl-2-(3, 4-dimethylbenzyl)-4- (2propynyl)piperazine (3.80 g).

NN.R (DMSO-d 6 6) :2.00-5.00 (18H, in), 6.66-8.20 (6H, mn) MASS (APOT) 4 83 Preiparation 39 A mixture of 2 R)-l--[3,5-bis(trifluoromethyl)benzoyll-2 4-dimethylbenzyl) (2-propynyl )pinerazine (0.49 3,3dimethylmorpholine hydrochloride (0.185 paraformaldehyde (62 mng), diisopronylethylamine (0.21 ml), and copper (1) iodide (20 mng) in 1,4-dioxane (5 ml) was stirred at 700C for hours. After removal of the solvent by evaporation, the residue was Purified by column chromatography on silica gel using a mixed solvent of dichloroinethane and methanol (40:1).

The fractions containing the objective compound was collected and evaporated under reduced pressure to give a syrup of 2 3 ,S-bis(trifluoromethyl)benzoyl]-2(3,4...

diinethylbenzyl) 3-dirnethylinorpoholino) -2-b -utvnyl] piperazine (0.45 g).

NMR (CDC1- 0.9-1 (6KH, 2.03-5.00 (25H, '.6-8.23 (6H, mn) (ARCI) :610 (M+HK_ 5113 its hydrochloride IflD 185-186 0

C

[X 1 8 8.6' (C=0.18, YNeOH) WO 98/57954 PCT/JP98/02613 1.05 IR (KBr) 2928, 2585, 2515; 1633, 1433, 1279, 1180, 1132 cm-1 NMR (DMSO-d 6 6) :1.33-1.40 (6H, 2.09-2.18 (6H, 2.50-5.20 (19H, 6.66-8.15 (6H, m) MASS (APCI) :610 (free) Preparation A mixture of 37' aqueous formaldehyde (0.21 (2R)-1- [3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)piperazine (0.75 propargyl alcohol (0.11 ml), copper(II) sulfate pentahydrate (1.3 mg) and potassium iodide (2.8 mg) in 1,4-dioxane was stirred at 100 0 C for 2 hours. After being cooled to room temperature, the mixture was made basic with aqueous saturated sodium hydrogen carbonate solution. The resulting mixture was filtered and the filtrate was extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate and evaporated under reduced pressure.

The residue was purified by column chromatography on silica gel using a mixed solvent of n-hexane and ethyl acetate The fractions containing the objective compound was collected and evaporated under reduced pressure to give (2R)- 1-[3,5-bis(trifluoromethyl)benzoyl -2-(3,4-dimethylbenzyl)-4- (4-hydroxy-2-butynyl)piperazine (0.78 g) as a syrup.

NMR (CDC1 3 6) 1.99-5.00 (19H, 5.15 (1H, t, J=5.9Hz), 6.66-8.23 (6H, m) MASS (APCI) 513 (M+H) 499, 483 Preparation 41 The following compound was.obtained according to a similar manner to that of Example 39.

(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4dimethylbenzyl)-4-[4-(3,3-dimethylmorpholino)-2-butynyl]piperazine NMR (CDCl 3 5) 0.97 (6H, 2.03-5.00 (25H, m), WO 98/57954 PCT/JP98/02613 106 6.66-8.23 (6H, m) MASS (APCI) 610 513 Preparation 42 A mixture of 3,3-dimethylmorpholine hydrochloride (30.0 propargyl bromide (16.4 ml) and potassium carbonate (63 g) in N,N-dimethylformamide (300 ml) was stirred at 45 48°C for 1.5 hours. After being cooled to room temperature, the mixture was poured into ice-water (800 ml) and extracted with ethyl acetate (500 ml) two times. The extract was washed with brine (400 mi), dried over magnesium sulfate and filtered. The filtrate was treated with 4N hydrogen chloride in ethyl acetate (98 ml) under ice-cooling. The solution was concentrated under reduced pressure to give a crude solid, which was collected by filtration and washed with isopropyl ether to give brownish crystals of 3,3-dimethyl-4-(2propynyl)morpholine hydrochloride (35 g).

IR (KBr) 3500-3400, 2900, 2570, 2480, 1637, 1626, 1508, 1455, 1180 cm NMR (DMSO-d 6 6) 1.20-1.50 (6H, 3.20-4.20 (9H, 11.91 (1H, s) MASS (APCI) 154 (free) Preparation 43 A mixture of 3,3-dimethyl-4-(2-propynyl)morpholine hydrochloride (0.24 37% aqueous formaldehyde (0.16 ml), 3,5-bis (triflucromethyl)benzoyl]-2-(3,4dimethylbenzyl)piperazine (0.57 copper(II) sulfate pentahydrate (5 mg) and potassium iodide (20 mg) in 1,4-dioxane (0.7 ml) was stirred at 900C for 1 hour. After being cooled to room temperature, the mixture was poured into ice-water and the aqueous mixture was made alkaline with saturated aqueous sodium hydrogen carbonate solution. The resulting mixture was extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate WO 98/57954 PCT/JP98/02613 and evap~orated under reduced Doressure. The residue was purified by column chromatography on silica gel using a mixed solvent of dichioroinethane and methanol The fractions containing the objective comp~oundi was collected and evapoorated under reduced pressure and treated with 4N hydrogen chloride in ethyl acetate solution. The resulting mixture was evaporated under reduced pressure and the residue was recrystallized from a mixture of acetone and water to give colorless crystals of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2- (3,4-dimethylbenizvi)--4-[4- 3-diinethylmorpoholino)-2-butynylpioerazine dihydrochioride (0.64 g).

miD 1 80-190 0

C

283. -7.4 1 MeOH) TR (Nujol) 3300, 2700-2400, 1635 crn 1 NY?. (DMSO-d 6 5) 1.30-1.40 (6H, mn), 2.00-5.22 in), 0'.60-8.20 (6H, mn), 12.05-12.20 in) MASS (APCI) :610 (M+1H) (free) Elemental Analysis Calcd. for C 32

H

37

F

6 C 52.82, H 6.09, N 5.68 Found :C 502.84, H. 5.89, N 5.78 Prenaration 44 The following comp~ounds were obtained according to a similar manner to that of PreparatiJon 1 (4-Methoxy)pyridyll-2-pcrop~yn-1-ol (KBr) :3130, 1598, 1562, 1471, 1425 cm> 1 NY. (DMSO-dr, 5) :3.84 (3H, 4.31 (21K, d, J=6.OHz), 5.41 t, J=6.OHz), C'.97 (I111, dd, J=2.6, 5.8Hz), 7.06 d, J=2.6H-z), 8.35 d, j=5.8Hz) MA.SS (APOT) :164 (M+HJ 13 (4-Methoxvcarbonvl)pyridylj-2-propyn-l-ol (KBr) 3133, 1598, 1568, 1430 cm- 1 NMI. (DMSO-dc,, 6) 3.91 (3H, 4.35 (2H, d, J=6.OHz), WO 98/57954 PCT/JP98/02613 108 5.75 (1H, d, J=6.0Hz), 7.70-7.80 (1H, 8.68 (1H, d, J=5.0Hz), 8.78 (1H, d, MASS (APCI) :192 Preparation To a stirred solution of chloropyrazine (1.14 g) and [1,2-bis(diphenylphosphino)ethane]nickel(II) chloride (106 mg) in dry tetrahydrofuran (40 ml) was added a solution of 3, 4 -methylenedioxybenzylmagnesium chloride (0.6 M in tetrahydrofuran, 29 ml) at 5°C under nitrogen atmosphere over minutes. After 1 hour of stirring at 5°C, 3N hydrochloric acid was added slowly under nitrogen atmosphere and the mixture was stirred for 1 hour. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined extract was washed with water and dried over magnesium sulfate. The usual work up followed by flash chromatography on silica gel with a mixture of n-hexane and ethyl acetate (10:1-4:1) gave 2-(3,4methylenedioxybenzyl)pyrazine (454 mg) as a colorless oil.

NMR (CDC1 3 5) 4.59 (2H, 5.93 (2H, 6.75-6.88 (3H, 8.44-8.56 (3H, m) MASS (APCI) 215 (M+H)I To a stirred solution of 2-(3,4-methylenedioxybenzyl)pyrazine (317 mg) in dry tetrahydrofuran (12 ml) was added a solution of diisobutylaluminum hydride (0.95 M in n-hexane, 15.6 ml) at 5°C under nitrogen atmosphere. After 1 hour of stirring at 5°C, the mixture was added saturated sodium sulfate solution until gas evolution ceased. The insoluble materials were removed by filtration through Celite® and the organic layer was separated, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved in ethyl acetate and treated with 4N hydrogen chloride in ethyl acetate to give 2-(3,4-methylenedioxybenzyl)piperazine dihydrochloride (125 mg) as a powder.

WO 98/57954 PCT/JP98/02613 109 NMR (DMSO-d 6 2.79-3.66 (9H, 6.02 (2H, s), 6.74-6.94 (3H, 9.79 (4H, br s) MASS (APCI) 221 (M+H) (free) Preparation 46 To a stirred solution of 4 -bromo-2-methylbenzoic acid (10.75 g) in tetrahydrofuran (50 ml) was added boranetetrahydrofuran complex (1 M in tetrahydrofuran, 150 ml) by syringe under nitrogen atmosphere at 5C and the mixture was heated under reflux for 18 hours. After cooling, water ml) and potassium carbonate (20 g) were added to the solution at 5°C. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined extract was washed with water, dried over magnesium sulfate, and concentrated under reduced pressure to give 4-bromo-2methylbenzyl alcohol (9.55 This compound was used to the next reaction without further purification.

Tert-butylchlorodiphenylsilane (13.06 g) and imidazole (9.7 g) were added to a solution of 4 -bromo-2-methylbenzyl alcohol (9.55 g) in N,N-dimethylformamide (80 ml) at 5°C and the mixture was allowed to warm to room temperature, and stirred for 18 hours. The mixture was extracted with ethyl acetate and the extract was washed with water, dried over magnesium sulfate, and concentrated under reduced pressure to give l-bromo-4-(tert-butyldiphenylsilyloxynethyl)-3methylbenzene (20.5 g) as a colorless oil.

NMR (DMSO-d 6 6) 1.03 (9H, 2.14 (3H, 4.70 (2H, 7.34-7.71 (13H, m) To a stirred solution of l-bromo-4-(tertbutyldiphenylsilyloxvmethyl)-3-methylbenzene (2.19 g) in tetrahydrofuran (30 ml) was added 1.6 M butyllithium in hexane (4.69 ml) by syringe under nitrogen atmosphere at -78°C. After 30 minutes of stirring at -78C, N,N- WO 98/57954 PCT/JP98/02613 110 dimethylformamide (1.16 ml) was added to the solution at -78°C and then the mixture was allowed to warm to 5"C over hours. Saturated ammonium chloride solution (10 ml) was added to the mixture and the organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The combined extract was washed with water, dried over magnesium sulfate, and concentrated under reduced pressure to give 4- (tert-butyldiphenylsilyloxymethyl)- 3 -methylbenzaldehyde (1.90 g) as a colorless oil.

NMR (DMSO-d6, 5) 1.06 9H, 2.20 (3H, 4.38 (2H, 7.37-7.83 (13H, 9.97 (1H, s) MASS (APCI) :389 (M+H) To a stirred mixture of 4-(tertbutyldiphenylsiiyloxymethy)-3-methylbenzaldehyde (1.94 g) and 1,4-diacetyl-2,5-piperazinedione (991 mg) in a mixture of N,N-dimethylformamide (10 ml) and tert-butanol (10 ml) was added potassium tert-butoxide (561 mg) at 5°C. The mixture was stirred for 1 hour at room temperature and then poured into water (300 ml), and stirring was continued for 18 hours at room temperature. The resulting precipitates were collected by filtration and washed with water and isopropyl ether, and dried under reduced pressure to give 1-acetyl-3- 4 -tert-butyldiphenylsilyloxymethyl-3-methylphenyl)methylene- 2 5 -piperazinedione (1.88 g) as a powder.

NMR (DMSO-d 6 5) 1.05 (9H, 1.99 (3H, 2.19 (3H, 4.37 (2H, 4.77 (2H, 6.93 (1H, s), 7.40-7.69 (13H, 10.37 (1H, s) MASS (APCI) :527 (M+H) A solution of l-acetyl-3-(4-tertbutyldiphenylsilyloxymethyl-3-methylphenyl)methylene-2,5piperazinedione (6.3 g) in methanol (300 ml) was hydrogenated over 10% palladium-carbon (50% wet) for 4 hours at atmospheric pressure. After removal of the catalyst by WO 98/57954 PCT/JP98/02613 11l filtration, to the filtrate was added hydrazine monohydrate (721 mg). The mixture was stirred for 1 hour at room temperature and concentrated under reduced pressure. The residue was triturated with a mixture of isopropyl ether (200 ml) and n-hexane (400 ml) and the precipitates were collected by filtration, and washed with isopropyl ether to give a crude product. This was purified by flash column chromatography on silica gel using ethyl acetate and a mixture of dichloromethane and methanol (15:1) as eluent to give 3-(4-tert-butyldiphenylsilyloxymethyl-3-methylbenzyl)- (4.67 g) as a powder.

NMR (DMSO-d 6 5) 1.02 (9H, 2.12 (3H, s), 2.77-3.18 (3H, 3.37 (1H, 4.04 (1H, 4.72 (2H, 6.97-7.04 (2H, 7.29-7.66 (11H, m), 7.94 (1H, 8.14 (1H, m) MASS (APCI) 487 (M+H) To a stirred solution of 3-(4-tertbutyldiphenylsilyloxymethyl-3-methylbenzyl)-2,5piperazinedione (1.46 g) in a mixture of tetrahydrofuran ml) and 1,2-dimethoxyethane (40 ml) was added lithium aluminum hydride (683 mg) under nitrogen atmosphere at 5 C and the mixture was heated under reflux for 6 hours. After cooling, the reaction mixture was quenched by sequential addition of water (1.5 ml), 15% sodium hydroxide solution ml), and water (4.5 ml). The insoluble materials were removed by filtration through Celite®. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure to leave an oil which was purified by flash column chromatography on silica gel using a mixture of dichloromethane and methanol (50:1 20:1) to give 1,4bis (benzyloxycarbonyl) (4-hydroxymethyl-3methylbenzyl)piperazine (242 mg) as a powder.

NMR (DMSO-d 6 6) 2.09 (3H, 2.58-3.22 (5H, m), 3.64-4.50 (6H, 4.82-5.21 (5H, 6.86-7.72 WO 98/57954 PCT/JP98/02613 112 (13H, m) A solution of 1,4-bis(benzyloxycarbonyl)-2-(4hydroxymethyl-3-methylbenzyl)piperazine (6.3 g) in methanol (5 ml) was hydrogenated over 10% palladium-carbon (50% wet, 22 mg) for 6 hours at atmospheric pressure. After removal of the catalyst by filtration, the filtrate was treated with 4N hydrogen chloride in ethyl acetate and concentrated under reduced pressure to give 2-(4-hydroxymethyl-3methylbenzyl)piperazine dihydrochloride (96 mg) as a powder.

MASS (APCI) :221 (free) Preparation 47 The following compound was obtained according to a similar manner to that of Preparation 46-(4).

l-Acetyl-3-[1,4-benzodioxan-6-yl)methylene]-2,5piperazinedione NMR (DMSO-d 6 2.48 (3H, 4.28 (4H, 4.35 (2H, 6.86-7.16 (4H, 10.30 (1H, s) MASS (APCI) 303 (M+H) The following compound was obtained according to a similar manner to that of Preparation 46-(5).

4 -Benzodioxan-6-yl)methyl]-2,5-piperazinedione NMR (DMSO-d 6 6) 2.75 (1H, dd, J=13.6, 4.9Hz), 2.94 (1H, 3.00 (1H, 3.43 (1H, dd, J=17.4, 2.7Hz), 3.97 (1H, 4.20 (4H, 6.57-6.77 (3H, 7.93 (1H, 8.10 (1H, m) MASS (APCI) :263 (M+H) To a stirred suspension of 3 -[(1,4-benzodioxan-6- (564 mg) in tetrahydrofuran (100 ml) was added borane-tetrahydrofuran complex (1 M in WO 98/57954 PCT/JP98/02613 113 tetrahydrofuran, 21 ml) by syringe under nitrogen atmosphere at room temperature and the mixture was heated under reflux for 18 hours. After cooling, the reaction mixture was filtered, and the filtrate was slowly added 12% hydrogen bromide in acetic acid (10 ml). To the mixture was added n-hexane (100 ml) and the whole was stirred for 1 hour at The resulting precipitates were collected by filtration and dried under reduced pressure to give 2-[(1,4-benzodioxan- 6-yl)methyl]piperazine dihydrobromide (831 mg) as a powder.

NMR (DMSO-d 6 6) 2.62-3.80 (9H, 4.23 (4H, s), 6.71-6.88 (3H, m) MASS (APCI) :235 (M+H) (free) Preparation 48 The following compound was obtained according to a similar manner to that of Preparation 46-(4).

l-Acetyl-3-[(4-methoxy-3-methylphenyl)methylene]-2,5piperazinedione NMR (DMSO-d 6 6) 2.17 (3H, 2.49 (3H, 3.83 (3H, 4.35 (2H, 6.90 (1H, 6.94 (1H, d, J=15.7Hz), 7.32 (2H, 10.28 (1H, s) MASS (APCI) :289 (M+H) The following compound was obtained according to a similar manner to that of Preparation 46-(5).

3-(4-Methoxy-3-methylbenzyl)-2,5-piperazinedione NMR (DMSO-d 6 6) 2.09 (3H, 2.73-3.04 (3H, m), 3.34 (1H, 3.75 (3H, 3.99 (1H, 6.81-6.97 (3H, 7.89 (1H, 8.11 (1H, m) MASS (APCI) :249 (M+H) The following compound was obtained according to a similar manner to that of Preparation 47-(3).

WO 98/57954 PCT/JP98/02613 2- 4 -Methoxy-3-methyilbenzvl)piperazine dihvdrobromide NMR (D-MSO-d 6 5 2.09 (3H, 2.60-3.72 (9H, in), 3.78 (3H, ),6.55 (2H, mn), 6.87-7.14 (3H, mn), 9.09 (2 H, mn MSS(APCI) 222. (M+HV) (free)I Preiparation 49 The following compDound was obtained according to a similar manner to that of Preparation 46-(4).

1-Acetyl--3- 3-dimetLhoxyphenyl)inethvlene]-2,5piperazinedione !R (KBr) 17 12, 169 7, 16 85, 1647, 16 24, 13 73, 12 71, 1225 cm'1 MRP (DMSO-d 6 5) :2.51 (3H, 3.74 (3H, 3.83 (3H, 4.35 (2H, 7.03-7.16 in), 10.07 (1H, s) MASS (APCI) 305 A solution of 1-acetyl-3- ii(2, 3-dimethoxyphenvi) (2.40 g) i-'n a mixed solvent of tetrahvdrofuran (120 ml) and methanol (80 ml) was hydrogenated using 10% palladium-carbon (509c wet, 0.55 g) at atmospheric pressure for 3 hours. The catalyst was removed by filtration and the filtrate was concentrated under reduced pressure. The resulting precipitates were collected by filtration to give gray solid of l-acetyl-3-(2,3- (2.55 g).

IR 3265, 1726, 1711, 1689, 1487, 1460, 1358, 1275, 1257 cin MR (DIMSO-d 6 5) 2.42 (3H, 2.90-3.20 (2H, mn), 3L*57-3.83 mn), 3.72 O3H-, 3.79 (3H, S), 4.14-4.23 (2H, mn), 6.74-7.04 (3H, mn), 8.341 (1H, s) IMA SS (APCI) :307 WO 98/57954 PCT/JP98/02613 115 To a suspension of l-acetyl-3-(2,3-dimethoxybenzyl)-2,5piperazinedione (2.49 g) in tetrahydrofuran (38 ml) was added hydrazine monohydrate (0.43 ml) at room temperature and the mixture was stirred at the same temperature for 30 minutes.

The resulting precipitates were collected by filtration and washed with tetrahydrofuran to give powders of 3-(2,3- (1.40 g).

IR (KBr) 3195, 3053, 1682, 1658, 1460, 1271, 1078 cm- NMR (DMSO-d 6 6) 2.87-3.09 (2H, 3.42-3.54 (2H, 3.73 (3H, 3.79 (3H, 3.88-3.96 (1H, m), 6.73-7.02 (3H, 7.94-8.00 (2H, m) MASS (APCI) :265 (M+H) A suspension of 3-(2,3-dimethoxybenzyl)-2,5piperazinedione (1.26 g) in a mixed solvent of tetrahydrofuran (50 ml) and 1,2-dimethoxyethane (50 ml) was heated at 60°C with stirring and lithium aluminum hydride (0.905 g) was added thereto portionwise carefully. After the reaction mixture was heated at 70°C with stirring for 3 hours, lithium aluminum hydride (0.20 g) and tetrahydrofuran ml) were added thereto again and the suspension was stirred at the same temperature for 12 hours. After being cooled with ice-water, the mixture was quenched by sequential addition of water (1.3 ml), 15% aqueous sodium hydroxide (1.3 ml), water (3.8 ml) and the whole was stirred at room temperature for 2 hours. The resulting insoluble materials were removed by filtration and the filtrate was dried over sodium sulfate, and evaporated under reduced pressure to give light yellowish oil of 2-(2, 3 -dimethoxybenzyl)piperazine (0.97 g).

IR (KBr) 2941, 1481, 1475, 1275, 1080 cm- 1 NMR (DMSO-d 6 5) 2.07-3.60 (9H, 3.69 (3H, s), 3.78 (3H, 6.71-7.00 (3H, m) MASS (APCI) 237 (M+H) WO 98/57954 PCT/JP98/02613 116 A solution of benzyloxycarbonyl chloride (0.59 g) in dichloromethane (3.0 ml) was added dropwise to a solution of 2-(2,3-dimethoxybenzyl)piperazine (0.91 g) and triethylamine (0.64 ml) in dichloromethane (18 ml) below 5°C over 5 minutes under ice-cooling, and the reaction mixture was stirred at the same temperature for 15 minutes. After 2 hours of stirring at room temperature, the mixture was poured into a mixed solvent of water (40 ml) and dichloromethane (25 ml) and the whole was adjusted to pH 9 with aqueous sodium hydrogen carbonate solution. The organic layer was separated, washed with brine, dried over sodium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (20 g) using a mixed solvent of dichloromethane and methanol The fractions containing the objective compound were collected and evaporated under reduced pressure to give colorless oil of 1-(benzyloxycarbonyl)-3-(2,3-dimethoxybenzyl)piperazine (0.68 g).

IR (KBr) 1714, 1699, 1685, 1273, 1244, 1225 cm-1 NMR (CDC1 3 6) 1.71 (1H, 2.23-3.00 (9H, m), 3.82 (3H, 3.86 (3H, 5.13 (2H, 6.74-7.03 (3H, 7.34 (5H, s) MASS (APCI) 371 Preparation A solution of 1-[3,5-bis(trifluoromethyl)benzoyl]-4- (benzyloxycarbonyl)-2-(2,3-dimethoxybenzyl)piperazine (0.81 g) in methanol (20 ml) was hydrogenated over 10% palladiumcarbon (50% wet, 0.30 g) at room temperature under atmospheric pressure for 90 minutes. After removal of the catalyst by filtration, the filtrate was evaporated under reduced pressure to give colorless oil of 1-[3,5bis(trifluoromethyl)benzoyl]-2-(2,3-dimethoxybenzyl)piperazine (0.64 g).

IR (KBr) 1645, 1635, 1281, 1184, 1134 cm-i WO 98/57954 PCT/JP98/02613 NMR (CDC1 3 6) 2.60-5.30 (10H, 3.81 (3H, s), 3.82 (3H, 6.40-7.10 (3H, 7.20-8.49 (3I, i MASS (APCI) 477 Prenaration 51 The following compound was obtained according to a similar manner to that of Preparation 46-(4) 1-Acetyl-3-[(1H-indol-2-yl)iethylene]-2,5piperazinedione IR 3332, 1714, 1685, 1668, 1419, 1221 cm 1 NTI (DMISO-d 6 6) 2.50 (3H, 4.38 (2H, s), 6.52-8.21 (6H, 9.84-12.00 (2H, br) MVASS (APCI) 284 (NM+H)+ The following compound was obtained according to a similar manner to that of Preparation 49-(2).

1-Acetyl-3-[(1H-indol-2-vl)iethvlj-2,5-iperazinedione IP (KBr) 3325, 1730, 1697, 1682, 1653, 1456, 1205 cmi NM. (DMSO-d 6 6) 2.43 (3H, 2.80-5.25 (5H, m), 6.18-3.73 (6H, 10.96 (1h, s) MASS (APCI) 286 The following compound was obtained according to a similar manner to that of Preoaration 49-(3) 3-f(11-indol-2-l)mlethvll-2,5-z-piperazinedione IR (KBr) 3363, 3317, 1682, 1645, 1456, 123 cm-1 NMR (DM-SO-d 6 5) 3.03-3.61 (4H, 4.09-4.15 (1H, 6.18 (1H, 6.89-7.05 (21, zn), 7.31 (1H, d, J=7.9Hz), 7.43 (1H, d, J=7.2Hz), 7.99 (1H, 8.11 (1H, 10.85 (1H, s) MAkSS (APCI) 244 WO 98/57954 PCT/JP98/02613 118 The following compound was obtained according to a similar manner to that of Preparation 49-(4).

(lH-Indol-2-yl)methyl]piperazine IR (KBr) 3305, 2941, 1653, 1456 cm NMR (DMSO-dg, 5) 1.80-3.70 6.12 (1H, s), 6.87-7.02 (2H, 7.27 (1H, d, J=7.9Hz), 7.40 (1H, d, J=6.9Hz), 10.89 (1H, s) MASS (APCI) :216 (M+H) The following compound was obtained according to a similar manner to that of Preparation 49-(5).

1-(Benzyloxycarbonyl)-3- (1H-indol-2-yl)methyl]piperazine IR (KEr) 3303, 2908, 1697, 1684, 1456, 1433, 1248 cm 1 NMR (DMSO-d 6 6) 2.34-2.90 (SH, 3.78-3.89 (2H, 5.03 (2H, 6.17 (1H, 6.90-7.04 (2H, m), 7.26-7.43 (7H, 10.93 (1H, s) MASS (APCI) 350 (M+H) Preparation 52 The following compound was obtained according to a similar manner to that of Preparation 1-[3,5-Bis(trifluoromethyl)benzoyl]-2-[(lH-indol-2-yl)methyl]piperazine IR (KBr) 1653, 1647, 1635, j281, 1184, 1136 cmn1 NMR (DMSO-d 6 5) 2.50-4.90 (10H, 5.98-6.28 (1H, 6.90-7.42 (5H, nm), 7.76-8.48 (2H, 10.59- 11.03 (1H, m) MASS (APCI) :456 (M+H) Preparation 53 The following compound was obtained according to a WO 98/57954 PCT/JP98/02613 119 similar manner to that of Preparation 46-(4) l-Acetyl-3-(3-methoxyphenyl)methylene-2,5piperazinedione 5 NMR (DMSO-d 6 5) 2.50 (3H, 3.79 (3H, 4.36 (2H, 6.9-7.0 (2H, 7.1-7.2 (2H, 7.3-7.4 (1H, 10.4 (1H, br s) MASS (APCI) 275 (M+H) The following compound was obtained according to a similar manner to that of Preparation 49-(2).

1-Acetyl-3-(3-methoxybenzyl)-2,5-piperazinedione NMR (DMSO-d 6 6) 2.42 (3H, 2.9-3.1 (2H, 3.33 (1H, d, J=17Hz), 3.71 (3H, 4.02 (1H, d, J=17Hz), 4.3-4.4 (1H, mi), 6.7-6.9 (3H, 7.1-7.3 (1H, 8.43 (iH, br s) MASS (APCI) :277 The following compound was obtained according to a similar manner to that of Preparation 49-(3).

3-(3-Methoxybenzyl) NMR. (DMSO-d 6 5) 2.8-3.5 (4H, 3.71 (3H, 4.1 (1H, 6.7-6.9 (3H, 7.1-7.3 (1H, 7.91 (1H, br 8.13 (1H, br s) MASS (APCI) :235 (M+H) The following compound was obtained according to a 30 similar manner to that of Preparation 49-(4).

2-(3-Methoxybenzyl)piperazine NMR (DMSO-d 6 5) 2.2-2.9 (9H, 3.5-3.8 (2H, m), 3.73 (3H, 6.7-6.8 (3H, 7.1-7.3 (1H, m) MASS (APCI) .207 (M+H) WO 98/57954 PCT/JP98/02613 120 A solution of di-tert-butvl dicarbonate (1.99 g) in tetrahvdrofuran (20 ml) was added drorpwise to a mixture of 2- (3-methoxybenzyl)piperazine (1.88 and triethylamine (1.90 *ml) in tetrahydrofuran 119-mi) with ice-water cooling. After 1 hour of stirring, ethyl acetate (100 Tal) and water (50 ml) were added to the mixture. The organic layer was sepoarated, washed with brine, dried over sodiJum sulfate, and evaporated in vacuo. The residue was purified by column chromatography on silica gel using a mixture of dichioromethane and methanol (40:1) to give 2- (3-methoxybenzyl) -4-(terh--tbutoxycarbonyl)piperazine (1.18 g) as an oil.

NMR (DMSO-d 6 5) :1.34 (9H, 2.1-2.9 (8H, in), 3.6-3.8 (2H, mn), 3.73 (Mi, 6.7-6.8 (3H, mn), ASS (APCI) 307 The following compound was obtained according to a similar manner to that of Example 86.

1- 5-Bis (trifluoromethyl)benzovli -4-tertbutoxycarbonyl-2- (3-methoxvbenzyl) p-i-erazine NMR (DYISO-d 6 5) :1.44 (9H, 2.5-5.0 (12H, mn), 6.5-8.3 (7H, mn) MASS (APCI) :447 The following compound was obtained according to a similar manner to that of Prepoaration 1- 5-Bis (trifluoromethvl)benzovl] -3-(3-inethoxvbenzyl)piperazine hydrochloride NNMR (D-MSO.-d 6 6):2.7 5.2 12H, 6 4-8.3 (7 H, m) 9.4-10.2 mn) MASS (APCI) :447 (free) Preoaration 54 WO 98/57954 PCT/P98/02613 121 3,4-Dimethylbenzyl chloride (10.2 g) and diethyl acetamidomalonate (14.3 g) were added successively into a solution of sodium ethoxide (4.94 g) in ethanol. The mixture was stirred under reflux for 2 hours and filtered through Celite The filtrate was concentrated under reduced pressure to give crystals which were collected by filtration and washed with isopropyl ether to give colorless crystals of diethvl 2 -acetylamino-2-( 3 4 -dimethylbenzyl)malonate (11.8 g)mp 107-109°C IR (KBr) 3335, 3275, 1750, 1645, 1520, 1460, 1380, 1280, 1185 cm- NMR (DMSO-d 6 5) 1.17 (6H, t, J=7.2Hz), 1.90-1.93 (3H, 2.02-2.20 (6H, 3.30-3.50 (3H, 4.14 (2H, q, J=7.2Hz), 6.60-7.05 (3H, 7.97, 8.07 (1H, 2s) MASS (EI) 335 276, 119 Diethyl 2-acetylamino-2-(3,4-dimethylbenzyl)malonate (13.8 g) and potassium hydroxide (2.76 g) were dissolved into a mixed solution of ethanol (138 ml) and water (138 ml) and the solution was stirred under reflux for 8.5 hours. After being cooled to room temperature, the solution was concentrated under reduced pressure and the resulting aqueous solution was adjusted to pH 10 with aqeuous saturated sodium hydrogen carbonate solution. The solution was washed with ethyl acetate and made acidic with diluted hydrochloric acid, and extracted with ethyl acetate. The extract was dried over magnesium sulfate and evaporated under reduced pressure to give crystals of N-acetyl-3,4-dimethyl-DL-phenylalanine (5.42 g).

mp: 136-139°C IR (Nujol) 3337, 2700-2400, 1710, 1610, 1540, 1450, 1380, 1355 cm'-

\N

MR

(DMSO-d 6 5) 1.67 (3H, 2.17-2.21 (6H, m), WO 98/57954 PCT/JP98/02613 122 2.60-3.15 (2H, 4.25-4.40 (1H, 6.90-7.05 (3H, 8.10-8.25 (1H, m) MASS (EI) :235 (M) 176, 119 N-Acetyl-3,4-dimethylphenyl-DL-alanine (498.0 g) was dissolved into a mixture of 1N sodium hydroxide (2.12 L) and water (2.49 Cobalt dichloride hexahydrate (2.49 g) and acylase (Acylase Amano 15000, 24.9 g) were added to the solution and the mixture was stirred at 37°C for 20 hours with controlling the pH of the reaction mixture to 7.5 with 1N sodium hydroxide. The resulting precipitates were collected by filtration and washed with water (500 ml x 2) to give crystals of L- 3 ,4-dimethylphenylalanine (120.7 The pH of the filtrate was adjusted to 1 with aqueous diluted hydrochloric acid and the solution was extracted with ethyl acetate. The extract was dried over magnesium sulfate and evaporated under reduced pressure to give a solid of N-acetyl- 3 ,4-dimethylphenyl-D-alanine (160.72 g).

mp 156-159°C IR (Nujol) 3400, 3350, 2500-2400, 1710, 1620, 1560, 1450 cm 1 NMR (DMSO-d 6 6) 1.78 (3H, 2.16 (6H, 2.68- 3.20 (2H, 4.28-4.40 (1H, 6.90-7.05 (3H, 8.18 (1H, d, J=8.0Hz), 12.61 (1H, s) MASS (EI) 235 (M) 176, 119 A solution of N-acetyl-3,4-dimethylphenyl-D-alanine g) in a mixture of concentrated hydrochloric acid (50 ml) and acetic acid (50 ml) was stirred under reflux for 20 hours.

After being cooled to room temperature, the resulting precipitates were collected by filtration and washed with ethyl acetate to give colorless crystals of 3,4dimethylphenyl-D-alanine hydrochloride (3.75 g).

mp >250°C [a]2 6 MeOH) WO 98/57954 PCT/JP98/02613 123 IR (Nujol) 2800-2400, 1730, 1600, 1500, 1480 cmn 1 NMR (DMSO-d 6 6) 2.19 (6H, 3.07 (2H, di, J=6.2Hz), 4.07 (1H, tL, J=6.2Hz), 6-90-7.10 in), 8.30-8.60 (3H, m) MA SS (APOTI) 194 (free) Thionyl chloride (5.4 ml) was added dropwise to methanol ml) below Soc with ice-salt bath cooling and stirring was continued for 10 mninutes at the same temperature. 3,4- Direthylphenyl-D-alanine hydrochloride (3.0 g) was added to the mixture by smnal-I portions over 20 minutes at 150and the whole was stirred at room temperature for 6 hours, and evaporated under reduced poressure. The resulting solid was triturated with iso-propyl ether to giJve colorless cr-ystals of is 3 4 -dimethylpchenyl-D-alanine methyl ester hydrochloride (3.10 g).

mp 190.0-190.5*c [3] 0 -10.36' (C=0.55, MeOH)

D~

!R (Nujol) 3400, 1735 cm NIMR (,DMSO-d 6 5) 2.19 (6H, 3.03 '1H, dci, j=7.3, 3.-15 (1K, dci 14.0Hz), 3.66 (3H, .4.16 (1H, dd, j=7.3, 3.7Hz), 6.93 (IH, J=7.6Hz), 6.99 (1K, 7.08 (11H, d, J=7.6Hz), 8.78 '3H, s) MASS (APOI) 208 (free) Potassium carbonate (5.45 g) vias added by small portions with ice-cooling to a mixture o*f 3 ,4-dimethylpheny1I-D-alanine methyl ester hvdrochloride (4.81 g) in a mnixed solvent of dichloromethane and water. Chloroacetyl chloride (2.20 ml) was added to the mi xture below Soc over 10 minutes and the whole was stirred for 30 minutes. The organic layer was sep~arated, washed with brine, dried over magnesium sulfate, and evaporated under reduced pressure to give an oil of methyl (2R) 2 '-chloroacetvlampi-no) 4-dimethvlphenvl) WO 98/57954 PCT/JP98/02613 -124 propionate (6.01 g).

IR (Neat) :3400, 1735, 1650, 1460 cm- 1 NINR (CDCl 3 6) :2.22 (6H, 3.08 (1H, d, J=5.7Hz), 3. 7 4 (3H, s) 4 .02 (2H, s) 4 .7 7-4. 87 (1H, in), 6.80-7.10 (4H, m) MASS (APCI) 283 (M H) ~,441 Benzvlamine (5.4 ml) and potassium carbonate (4.08 g) were added successively to a solution of-' methyl chl-oroacetylamino)-3- 4 -dimethiylphenvl)propionate (S.33 g) in N, N- dime thyl formamide (25 ml) at 20 0 C. After 3 hours of stirring at 35 0 C, the mixtLure was -ocured into a mixture of ice-water (40 ml) and dichloromethane (40 ml.) After the mixture was adjusted to o)H 0' with concentrated hydrochloric acid (ca. 1.4 ml), the organic laver was separated, washed with brine (20 ml), dried over magnesium sulfate, and evaporated under reduced pressure. The residue was triturated with n-hexane and filtered to give colorless powders of (3R)-1-benzvl-3- 4-dirnethylbenzyl)-2,5piperazinedione (1.51 g) The filtrate was evap~orated under reduced pressure to give an oi< of methyl ben zyl aminoacet y1) amino]-3 L'-dirieth vlnhenyi) prop ionat e (5.67 g).

IR (Neat) 3400, 1735, 1650, 1460 cm- 1 NMR (ODC1 3 6) :2.12-2.21 mn), 3.04-3.10 (2H, in), 3.29 d, J=2.OHz), 3.66 (2H, 3.74 (3H, s), 4.80-4.90 6.80-7.40 (9H, in), 7.90-8.05

M)

MASS (APCT) 355 A mixture of methyl 2 R)-2-I(2-benzviaminoacetyl)amino]- 3 3 4 -dime thylphenyl) propiona te (2.5 g) and acetic acid (0.2 ml) in isopropyl alcohol (8.8 ml) was stirred for 5 hours under reflux. After being cooled to room temperature, isopro-oyl ether was added to the mixture. The resulting WO 98/57954 PCT/JP98/02613 125 precipitates were collected by filtration and washed with isopropy! ether to give colorless crystals of (3R)-l-benzyl- 3-[(,4-dimethylbenzy)-2,5-piperazinedione (1.26 g).

mp 191-192*C 5 -23.3o

DMF)

IR (Nujol) 3180, 1640, 1500, 1340 cri 1 NMR (DMSO-d, 2.11 and 2.16 (3H, 2s), 2.82 (1H, dd, J=4.8, 13.5Hz), 3.13 (1H, dd, J=4.2, 13.5Hz), 2.76 (1H, d, J=17.lHz), 3.46 (IH, d, J=17.lHz), 4.22 (1H, d, J=14.5Hz), 4.55 (1H, d, J=14.5z), 4.2-4.3 (lii, 6.7-6.9 (3H, 7.0-7.1 (2H, 7.2-7.3 (3H, 8.31 (1H, s) MASS 323 (M+1) The following comrnound was obtained according to a similar manner to that of Prelaration 49-(4).

(3R)-1-Benzyl-3-(3, 4 -dimetvlbenzyl)piperazine IR (Neat) 3000-2750, 1670, 1500, 1450, 1360, 1320 cmJ 1 NNR (CDC1 3 5) 2.26 (6H, 1.8-3.0 (9H, 3.4-3.6 (2H, 6.9-7.1 (3H, 7.2-7.5 (5H, m) MASS 295 (M+1) its hydrochloride mp 186-1880C 9 2 +12.720 (0=0.55, MeOH) IR (Nujol) 3500, 2350 cm NMR (DMSO-d 6 5) 2.20 (6H, 2.73-3.90 (9H, m), 4.34 (1H, d, J=13.Hz), 4.42 (1H, d, J=13.lz), 6.97 (1H, d, U7=':7.06H), 7.02 (IH, 7.11 (1,d, j=7.6Hz), 7.36-7.65 m) MASS (AECI) 295 (free) The following compound was obtained according to a similar manner to that of Example 86.

WO 98/57954 PCT/JP98/02613 126 2 R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4dimethylbenzyl)-4-benzylpiperazine IR (Neat) 3000-2700, 1640, 1500, 1430, 1350 cm 1 NMR (CDC13, 6) 2.1-2.3 (6H, 2.1-2.2 (2H, 2.6- 3.7 (8H, 4.5-5.1 (1H, 6.5-6.7 (2H, 6.9- 7.6 (7H, 7.8-7.9 (2H, m) MASS 535 (M+1) (11) A mixture of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2- (3,4-dimethvlbenzyl)-4-benzylpiperazine (2.94 ammonium formate (1.74 g) and 10% palladium-carbon (0.58 g) in a mixed solvent of methanol (11.8 ml), water (5.9 ml) and tetrahydrofurane (10 ml) was stirred for 5.5 hours at under nitrogen atmosphere. The reaction mixture was cooled to room temperature and filtered through Celite® pad. The filtrate was concentrated under reduced pressure and the residue was dissolved in ethyl acetate. The solution was washed with water and brine, dried over magnesium sulfate, and evaporated under reduced pressure. The residue was dissolved in methanol and treated with fumaric acid (468 mg) to give colorless powder of fumaric acid salt of (2R)- 1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)piperazine (0.24 g).

mp 186-188°C [a]1 -23.99* (C=0.55, MeOH) IR (Nujol) 2320, 1720, 1705, 1630, 1270 cm.

NMR (DMSO-d 6 6) 1.57-2.34 (6H, 2.56-5.08 (9H, 6.10-8.52 (11H, m) MASS (APCI) :445 (M+H) (free) Preparation Benzaldehyde (17.4 ml) was added dropwise to a solution of 2 -amino-2-methyl-1,3-propanediol (20 g) in methanol (200 ml) at 0°C and the whole was stirred at room temperature for 2 hours. Sodium borohydride (11.5 g) was added thereto in WO 98/57954 PCT/JP98/02613 127 portions at 0°C and the mixture was stirred for 10 minutes.

IN Sodium hydroxide solution and ethyl acetate were added and the organic layer was separated, dried over magnesium sulfate, and evaporated in vacuo to give 2 -benzylamino-2methyl-1,3-propanediol (28.54 g).

TNMR (CDC1 3 5) 1.08 (3H, 3.54 (4H, 3.73 (2H, 7.20-7.45 (5H, m) MASS (APCI) 196

T

Chloroacetyl chloride (14.0 ml) was added dropwise to a mixture of 2 -benzylamino-2-methyl-1,3-propanediol (28.5 g), potassium carbonate (30.3 g) in dichloromethane (150 ml) and water (150 ml) at C0C, and the whole was stirred at room temperature for 2 hours. The mixture was extracted with dichloromethane and the extract was washed successively with water, IN hydrochloric acid and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was dissolved in tert-butanol (400 ml) and the solution was added potassium tert-butoxide (16.38 g) portionwisely and the whole was refluxed for 30 minutes. After cooling, the solvent was removed by evaporation and ethyl acetate and water were added thereto. The organic layer was separated, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by column chromatography on silica gel with a mixture of ethyl acetate and n-hexane as an eluent to give 4 -benzyl-5-hydroxymethyi-5-methyl-3-morpholinone (10.89 g).

NMR (CDC1-3, 5) 1.12 (3H, s, 2.50 (1H, br 3.44 (1H, d, J=11.7Hz), 3.56 (1K, d, J=11.9Hz), 3.67 (1H, d, J=11.7Hz), 3.98 (1H, d, J=11.9Hz), 4.29 (2H, 4.67 (2H, 7.10-7.40 (5H, m) MASS (APCI) 236 (MH) Sodium bis( 2 -methoxyethoxy)aluminum hydride (3.46 M solution in toluene; 42 ml) was added to a solution of 4- WO 98/57954 PCT/JP98/02613 128 benzyl-5-hydroxymethyl-5-methyl-3-morpholinone (10.77 g) in toluene (100 ml) at 0°C under nitrogen atmosphere and the whole was stirred at room temperature for 1 hour. Ethanol ml) was added to the mixture at 0°C and the pH of the mixture was adjusted to 12 by 1N sodium hydroxide solution.

The organic layer was separated, added 1N hydrochloric acid and the acidic aqueous layer was separated. This procedure was repeated twice and the combined aqueous layer was made alkaline with 4 M sodium hydroxide solution. It was extracted with ethyl acetate, dried over magnesium sulfate and evaporated in vacuo to give 4-benzyl-3-hydroxymethyl-3methylmorpholine (9.35 g) as an oil.

NMR (CDC13, 6) 1.12 (3H, 2.50-2.64 (2H, 3.10- 4.05 (8H, 7.20-7.50 (5H, m) MASS (APCI) 222 (M+H) A solution of 4-benzyl-3-hydroxymethyl-3methylmorpholine (1 g) in tetrahydrofuran (10 ml) was added dropwise to a suspension of sodium hydride (60% oil .suspension; 0.27 g) in tetrahydrofuran (20 ml) at room temperature under nitrogen atmosphere and the whole was stirred at 70 0 C for 1 hour. After cooling, methyl iodide (0.34 ml) was added to the mixture and the whole was stirred at 40*C for 1 hour. After cooling, ethyl acetate and water were added to the mixture and the organic layer was separated, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel with a mixture of ethyl acetate and n-hexane (1:4) as an eluent to give 4-benzyl-3-methoxymethyl-3methylmorpholine (0.77 g) as an oil.

NMR (CDC1 3 6) 1.15 (3H, 2.30-2.64 (2H, m), 3.20-3.70 (8H, 3.36 (3H, 7.14-7.40 (5H, m) MASS (APCI) :236 (M+H) A solution of 4 -benzyl-3-methoxymethyl-3- WO 98/57954 PCT/JP98/02613 129 methylmorpholine (0.77 g) in methanol (20 ml) was hydrogenated in the presence of 10% palladium-carbon (80 mg) at room temperature. After 1 hour, palladium-carbon was removed by filtration and the filtrate was evaporated in vacuo. The residue was dissolved in ethyl acetate (20 ml) and the solution was added 4N hydrogen chloride in ethyl acetate (4.08 ml). The mixture was evaporated in vacuo to give 3 -methoxymethyl-3-methylmorpholine hydrochloride (0.4 g) as a white solid.

mp 80-90°C IR (KBr) 3240-3270, 2976, 1090, 1049 cm 1 NMR (DMSO-d 6 1.29 (3H, 3.00-3.92 (8H, m), 3.36 (3H, s) MASS (APCI) 146 (free) Preparation 56 A solution of 3 R)-4-benzyl-3-hydroxymethylmorpholine (0.94 g) in tetrahydrofuran (10 ml) was added dropwise to a suspension of sodium hydride (60% oil suspension, 0.22 g) in tetrahydrofuran (20 ml) at room temperature under nitrogen atmosphere and the whole was stirred at 70C for 1 hour.

After cooling, methyl iodide (0.31 ml) was added thereto and the mixture was stirred at 40"C for 1 hour. After cooling, the mixture was poured into ice water, and extracted with ethyl acetate. The extract was dried over magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel with a mixture of ethyl acetate and n-hexane as an eluent togive (3R)-4-benzyl-3methoxymethylmorpholine (0.88 g) as an oil.

NMR (CDC1 3 5) 2.20-2.40 (1H, 2.56-2.86 (2H, m), 3.26-4.26 (8H, 3.34 (3H, 7.20-7.48 (5H, m) MASS (APCI) 222 The following compound was obtained according to a similar manner to that of Preparation 55-(5).

WO 98/57954 PCT/JP98/02613 130 (3R)-3-Methoxymethylmorpholine hydrochloride mp 150-152°C +16.310 (C=0.42, MeOH) IR (KBr) 2964, 2947, 2929, 2897, 2887, 2835, 2810, 2789, 2765, 2727, 2698, 2490, 1450, 1311, 1194, 1136, 1111, 1095 cm-i NMR (DMSO-d 6 5) 2.94-3.24 (2H, 3.31 (3H, s), 3.36-3.78 (5H, 3.80-3.98 (2H, 9.52 (2H, br s) MASS (APCI) 132 (free) Preparation 57 The following compound was obtained according to a similar manner to that of Preparation 56-(1).

(3S)- 4 -Benzyl-3-methoxvymethylmorpholine NMR (CDC1 3 6) 2.15-2.34 (1H, 2.54-2.72 (2H, m), 3.33 (3H, 3.33 (1H, d, J=13.5Hz), 3.40-3.90 (6H, 4.07 (1H, d, J=13.5Hz), 7.18-7.40 (5H, m) MASS (APCI) 222 The following compound was obtained according to a similar manner to that of Preparation 55-(5).

(3S)- 3 -Methoxymethylmorpholine hydrochloride mp 150-152°C -14.70* (C=0.50, MeOH) IR (KBr) 2964, 2947, 2929, ,2887, 2833, 2810, 2789, 2765, 2727, 2698, 2490, 1450, 1311, 1194, 1136, 1111, 1095, 1041 cm-- I\NR (DMSO-d 6 5) 2.94-3.24 (2H, 3.31 (3H, s), 3.38-3.75 (5H, 3.84-3.96 (2H, 9.45 (2H, br s) MASS (APCI) :132 (M+H) (free) WO 98/57954 PCT/JP98/02613 131 Pre-oaration 58 The following compound was obtained according to a similar manner to thatL of Prepoaration 56-(1) (3S) 4 -Benzyl-3-ethoxymethvlmorpholine !NR4. (CDCl- 6) 1.20 (3H, t, J=7.OHz), 2.15-2.40 (iH, in), 2.54-2.84 (2H, mn), 3.24-4.20 (10H, mn), 7.20- 7.45 (5H, m) MASS (APCI) 236 The following compound was obtained according to a similar manner to that of Preparation (3S) -3-Ethoxyinethvlmorpho'Line hydrochloride mup :100-115*C [27 -13.070 (C=0.5051, MeOK) faD IR (KBr) 2976, 2922, 2900, 2866, 2790, 2767, 2746, 2721, 2468, 14580, 1450, 1435, 1309, 1176, 1147, 1126, 1101, 1043, 1030 cm- NM?. (DMSO-d 6 6) 1. 15 (3KH, 2. 94-3.2 8 (2H, in), 3.28-3.80 (7Hn, 3.80-4.00 (2H, in), 9.47 (2H, br s) MASS (APOI) 146 (free) Prepoaration 59 The following compound was obtained according to a similar manner to thatL of Prenaration 55- (3S) -3-Hvdroxvmrethvlmorrpholine hydrochloride mp :123-126'C Ict] D -15.80' (C=0.44, MeOH) TR 3290-3480, 2945, 1105, 1047 cm- 1 NM?. (DYSO-d 6 5) :2.86-4.00 (9H1, in), 5.41 (1H1, br s), 9.25 (1KH. br 9.5,6 (1KI, br s) MASS (APOI) :118 (free) WO 98/57954 PCT/JP98/02613 132 Preparation Hexafluoropropene diethylamine complex (1.58 ml) was added dropwise to a solution of (3R)-4-benzyl-3hydroxymethylmorpholine (1.5 g) in dichloromethane (100 ml) at -30 0 C under nitrogen atmosphere and the whole was stirred at room temperature for 3 hours. The solution was washed with water and saturated sodium hydrogen carbonate solution, dried over magnesium sulfate and evaporated in vacuo. The residue was dissolved in methanol (100 ml) and the solution was added 30% sodium methoxide solution in methanol (2.9 ml) After 30 minutes of stirring, acetic acid (0.9 ml) was added to the mixture and the whole was evaporated in vacuo.

Dichloromethane and water were added to the residue and the organic phase was separated, dried over magnesium sulfate, and evaporated in vacuo. The reside was purified by column chromatography on silica gel to give a crude mixture (2.26 g) containing mainly (3R)- 4 -benzyl-3-fluoromethylmorpholine and 4-benzyl-6-fluoroperhydro-l,4-oxazepine. The obtained mixture was used to the next reaction without further purification.

The crude mixture (2.2 g) obtained by the previous procedure, which contained mainly (3R)-4-benzyl-3-fluoromethylmorpholine and 4-benzyl-6-fluoroperhydro-1,4-oxazepine, was dissolved in methanol (50 ml). The solution was hydrogenated in the presence of 10% palladium-carbon (200 mg) at room temperature. After 1 hour of stirring, palladiumcarbon was removed by filtration and the filtrate was evaporated under reduced pressure. The two isomers were separated by column chromatography using 2% of methanol in dichloromethane as an eluent to give (3R)-3fluoromethylmorpholine and 6-fluoroperhydro-1,4-oxazepine (the former was less polar). The products were converted to their hydrochloride as a conventional manner using 4N hydrogen chloride in ethyl acetate, respectively.

WO 98/57954 PCT/JP98/02613 133 (3R)- 3 -Fluoromethylmorpholine hydrochloride (0.21 g) NMR (DMSO-d 6 5) 3.02-3.34 (2H, 3.48-3.82 (3H, 3.82-4.10 (2H, 4.57 (1H, d, J=4.0Hz), 4.80 (1H, d, J=4.0Hz), 9.84 (2H, br s) MASS (APCI) 120 (M+H) (free) 6-Fluoroperhydro-1,4-oxazepine hydrochloride (0.26 g) NMR (DMSO-d 6 5) 3.10-3.32 (2H, 3.40-3.60 (2H, 3.68-4.16 (4H, 4.94-5.30 (1H, m) MASS (APCI) 120 (M+H) (free) Preparation 61 Triphenylphosphine (7.31 g) was added to a solution of carbon tetrabromide (4.62 g) in dichloromethane (15 ml) at 0°C and the mixture was stirred at 0°C for 15 minutes. A solution of (3S)-4-tert-butoxycarbonyl-3-formylmorpholine g) in dichloromethane (15 ml) was added dropwise to the solution over 10 minutes at 0°C and stirred for 3 hours, and the mixture was added saturated sodium hydrogen carbonate solution. The organic layer was separated and the aqueous layer was extracted with ethyl acetate three times. The combined organic layer was washed with brine, dried over magnesium sulfate, and evaporated under reduced pressure.

The residue was purified by column chromatography on silica gel using a mixture of ethyl acetate and n-hexane to give (3R)-4-tert-butoxycarbonyl-3-(2, 2-dibromoethenyl)morpholine as an oil.

This oil was dissolved in tetrahydrofuran (15 ml) and butyllithium (1.62 M in hexane, 9.45 ml) was added to the solution at -78*C. After 30 minutes of stirring at -78°C, the mixture was quenched with water and extracted with ethyl acetate twice. The combined organic layer was washed with brine, dried over magnesium sulfate, and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using a mixture of ethyl acetate WO 98/57954 PCT/JP98/02613 134 and hexane to give (3R)-4-tert-butoxycarbonyl-3ethynylmorpholine (1.385 g) as a pale yellow oil.

NMR (CDC1 3 6) 1.48 (9H, 2.31 (1H, d, J=2.3Hz), 3.19-3.96 (6H, 4.74 (1H, br s) MASS (APCI) :112 (M-Boc) Preparation 62 The following compound was obtained according to a similar manner to that of Preparation 55-(5).

(3S)-3-Ethoxycarbonylmorpholine hydrochloride NMR (CDC1 3 6) 1.33 (3H, t, J=7.1Hz), 3.20-3.75 (2H, 3.90-4.30 (5H, 4.32 (2H, q, J=7.1Hz), 10.04 (1H, br 10.74 (1H, br s) MASS (APCI) 160 (M+H) (free) A mixture of 3 S)-3-ethoxycarbonylmorpholine hydrochloride (0.3 propargyl bromide (0.34 ml) and potassium carbonate (0.91 g) in N,N-dimethylformamide (10 ml) was stirred at room temperature for 1 hour and then the solvent was removed under reduced pressure. Ethyl acetate and sodium hydrogen carbonate solution were added to the residue and the organic layer was separated, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by column chromatography on silica gel with a mixture of ethyl acetate and n-hexane as an eluent to give (3S)-3-ethoxycarbonyl-4-(2-propynyl)morpholine (0.22 g) as an oil.

NMR (CDC1 3 5) 1.29 (3H, J=7.1Hz), 2.28 (1H, t, J=2.5Hz), 2.70-2.95 (2H, 3.40-4.05 (7H, m), 4.21 (2H, q, J=7.1Hz) MASS (APCI) 198 (M+H) Preparation 63 Sodium triacetoxyborohydride (4.63 g) was added WO 98/57954 PCT/JP98/02613 135 portionwisely to a mixture of 2 -amino-l-butanol g) and benzaldehyde (1.79 g) in dichloromethane (50 ml) at 0°C and the whole was stirred at room temperature overnight.

The mixture was washed with sodium carbonate solution and brine, dried over sodium sulfate, and evaporated in vacuo to give (R)-2-benzylamino-l-butanol (2.69 g) [IR (Neat) 3292, 1460, 1350, 1136, 1061 cm 1 A solution of chloroacetyl chloride (2.1 g) in tetrahydrofuran (4 ml) was added to a mixture of the obtained oil (2.69 g) and potassium carbonate (4.6 g) in a mixture of acetone (20 ml) and water (20 ml) at 0°C. After 1 hour of stirring, the solvent was replaced with ethyl acetate. The organic layer was separated, washed with brine, dried over sodium sulfate, and evaporated in vacuo.

The residue was purified by column chromatography on silica gel to give N-benzyl-N-[(2R)-2-(1-hydroxybutyl)]-2-chloroacet amide (2.73 g) [IR (Neat) :3430, 1640, 1450, 1420, 1355, 1045 cm 1 MASS (APCI) 256 220] as an oil.

Potassium tert-butoxide (1.22 g) was added to a solution of the above obtained oil (2.7 g) in tert-butanol (20 ml) portionwisely at room temperature and the whole was stirred overnight. The mixture was evaporated in vacuo, and ethyl acetate and water were added to the residue. The organic layer was separated, washed with brine, dried over sodium sulfate, and evaporated in vacuo to give (5R)-4-benzyl-5ethyl-3-morpholinone (2.33 g) as an oil.

IR (Neat) 1655, 1640, 1450, 1430, 1360, 1340, 1260, 1155, 1128 cm 1 NMR (CDC1 3 5) 0.91 (3H, t, J=7.5Hz), 1.60-1.96 (2H, 2.94-3.14 (1H, 3.55-3.94 (2H, 3.92 (1H, d, J=15.0Hz), 4.21 (1H, d, J=1.6.7Hz), 4.31 (1H, d, J=16.7Hz), 5.43 (1H, d, J=15.0Hz), 7.20-7.44 m) MASS (APCI) :220 (M+H) WO 98/57954 PCT/JP98/02613 136 A solution of (5R)- 4 -benzyl-5-ethyl-3-morpholinone (2.3 g) in tetrahydrofuran (7 ml) was added portionwisely to a suspension of lithium aluminum hydride (0.4 g) in tetrahydrofuran (15 ml) and the whole was refluxed for 2 hours. After cooling, 50% aqueous tetrahydrofuran solution (4 ml) was added thereto and stirring was continued for minutes. The mixture was filtered through Celite® pad, and the pad was washed with tetrahydrofuran. The combined filtrate was evaporated in vacuo and the residue was purified by column chromatography on silica gel to give (3R)-4-benzyl- 3-ethylmorpholine (1.44 g) as an oil.

IR (Neat) 1495, 1450, 1355, 1130, 1060 cm 1 NMR (CDC1 3 6) 0.93 (3H, t, J=7.5Hz), 1.44-1.94 (2H, 2.08-2.45 (2H, 2.54-2.70 (1H, 3.15 (1H, d, J=13.3Hz), 3.55-3.86 (4H, 4.06 (1H, d, J=13.3Hz), 7.15-7.40 (5H, m) MASS (APCI) :205 (M+H) A solution of the obtained oil (1.44 g) in ethanol ml) was hydrogenated using 10% palladium-carbon (200 mg) at atmospheric pressure. After the reaction was completed (7 hours), the catalyst was removed by filtration. The filtrate was added 4N hydrogen chloride in ethyl acetate (2.5 ml) and the whole was evaporated in vacuo. The residue was triturated with ethyl acetate and the resulting precipitates were collected by filtration and dried to give (3R)-3-ethylmorpholine hydrochloride (1.0 mp 223-225°C [a]8 +9.5 MeOH) IR (KBr) :2729, 2696, 2472, 1458, 1427, 1360, 1313, 1109, 1061 cm- 1 NMR (DMSO-d 6 0.93 (3H, t, J=7.5Hz), 1.40-1.78 (2H, 2.88-3.55 (4H, 3.60-4.04 (3H, 9.60 WO 98/57954 PCT/JP98/02613 1 37 b- s) MALSS (APCI) 116 (-Free) Prepar-ation 64 5 The following compound was obtained according to a similar manner to that of Pre-paration 63-(1).

4 -Benzv-S-et-hvl-3-rrnoroholinone IR (,Nea=t) 16531 1462, 1348, 12603, 1155, '11122 cmn-' NMIP (CDC1 3 5 0. 91 (31H, t, J-7. S:Hz) 1.60-1. 96 (2H!, in), 2.95-3.14 mn), 3.58-3.94 (2141, 7m), 3.92 (1H, d, J=15.OHz), 4.21 d, J=16.7H-z), 4.30 (1H, d, J=16.7-z), 5.43 (1H, d, J=15.1-z), 7.15-7.44 KMASS (APCT) 220 (M+HJ The following compcound was obtained according to a similar manner to that of Preparation 63-(2).

(35) ,-3-EthylmorpholiJne hydrochloride MID 221-2240C 26X D 11.2' MeOH) IR (~r)2729, 2625, '2472. 14541, 1356, 1313, 1109, 1061 cm -m NNR (.DMSO-d 6 :0.93 t, J=7 .5Hz) 1. 40 1.7 8 (2H, m) 2.90-3.54 mn), 3.60-4.04 (3H, mn), 9.57 br s) MASS (APCI) 116 (M+Hr (free) Preparation A mixture of 7-oxa-4-azaspoiro,[2.5]-,octane hydrochloride (200 mng), 2-bromoethanLol (10.28 ml) and 'ootassium carbonate (550 mng) in N,N-dimethylformaraide (2 was stirred at 9000 for 48 hours and cooled. The mixture was Poured into brine and extracted with dichloromethane. The extract was dried WO 98/57954 PCT/JP98/02613 138 over magnesium sulfate and evaporated under reduced pressure, and ourified by column chromatography on silica gel using a mixture of methanol and chloroform (2:98) to give 4-(2hydroxyethyl)- 7 -oxa-4-azaspiro[2.5]octane as an oil. This oil was dissolved in ethyl acetate (5 ml) and the solution was added methanesulfonyl chloride (0.16 ml) and triethylamine (0.3 ml). After 30 minutes of stirring at room temperature, the mixture was filtered, evaporated, and purified by column chromatography cn silica gel usina a mixture of ethyl acetate and n-hexane (20:80 30:70) to give 4-( 2 -chloroethyl)-7-oxa-4-azaspiro[2.5]octane (140 mg) as an oil.

NMR (CDC1 3 0.61-0.67 (2H, 0.95-1.05 (2H, m), 3.10-3.15 (2H, 3.22 (2H, t, J=6.9Hz), 3.50 (2H, br 3.54-3.64 (2H, 3.80 (2H, t, J=4.7Hz) MASS (APCI) 176 Prenaration 66 A mixture of 3 R)-3-ethylmorpholine hydrochloride (0.2 1,4-dichloro-2-butyne (0,5 ml) and potassium carbonate (0.71 g) in N,N-dimethylformamide (10 ml) was stirred at room temperature for 2 hours. After removal of the solvent, ethyl acetate and sodium hydrogen carbonate solution were added thereto. The organic layer was separated and the aaueous layer was extracted with ethyl acetate twice. The combined organic layer was dried over magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel with a mixture of ethyl acetate and n-hexane as an eluent to give 3 R)-4-(4-chloro-2-butynyl)-3ethylmorpholine (0.2 g) as an oil.

NMR (CDC1 3 6) 0.89 (3H, t, J=7.5Hz), 1.20-1.74 (2H, 2.42-2.84 (3H, 3.20-3.90 (6H, 4.18 (2H, t, MASS (APCI) 202 (M+H) WO 98/57954 PCT/JP98/02613 139 Preparation 67 A mixture of 3 S)-3,5-dimethylmorpholine hydrochloride (8.3 di-tert-butyl dicarbonate (14.34 g) and sodium hydroxide (5.48 g) in water (30 ml) were stirred at room temperature overnight. Water (50 ml) and isopropyl ether were added to the mixture and the organic layer was separated, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by column chromatography on silica gel with a mixture of ethyl acetate and n-hexane (1:9) as an eluent to give (3S,5S)-4-tert-butoxycarbonyl-3,5dimethylmorpholine (3.55 g) and meso-4-tert-butoxycarbonyl- (2.84 g) (the former was less polar).

4 -tert-Butoxycarbonyl-3,5-dimethylmorpholine (3.55 g) was dissolved in a mixture of dichloromethane (20 ml) and trifluoroacetic acid (20 ml) and the mixture was stirred at room temperature for 2 hours. After removal of the solvent under reduced pressure, 1N sodium hydroxide solution (20 ml) and dichoromethane were added thereto. The organic phase was separated, dried over magnesium sulfate, and was added 4N hydrogen chloride in ethyl acetate (20 ml). The mixture was evaporated in vacuo and the residue was triturated with a mixture of dichloromethane and isopropyl ether to give (3S,5S)-3,5-dimethylmorpholine hydrochloride (1.56 g) as a white solid.

mp 172-173 C [a]D +16.370 (C=0.333, MeOH) IR (KBr) 3049, 2993, 2978, 2970, 2935, 2916, 2873, 2829, 2817, 2800, 2785, 2742, 2723, 1460, 1433, 1385, 1136, 1107, 1028 cm 1 NMR (CDC1 3 1.50 (6H, d, J=6.5Hz), 3.44-4.08 (6H, 9.97 (2H, br s) MASS (APCI) 116 (M+H) (free) hydrochloride (2.84 g) was prepared from meso-4-tert-butoxycarbonyl-3,5- WO 98/57954 PCT/JP98/02613 140 dimethylmorpholine in a similar manner to the preparation of (3S,5S)-3,5-dimethylmorpholine hydrochloride (1.84 g).

mp 85-90°C IR (KBr) 2981, 2945, 2929, 2873, 2860, 2808, 2802, 2773, 2748, 2735, 2727, 1672, 1624, 1205, 1182, 1138, 1117, 1057 cm 1 NMR (CDC1 3 1.35 (6H, d, J=6.6Hz), 3.22-4.00 (6H, 9.44 (1H, br 10.22 (1H, br s) MASS (APCI) :116 (free) The following compound was obtained according to a similar manner to that of Preparation 66.

(3S, 5) -4-.(4-Chloro-2-butynyl) NMR (CDC1 3 6) 1.06 (6H, d, J=6.5Hz), 2.95-3.14 (2H, 3.34-3.54 (4H, 3.72 (2H, dd, J=11.0, 3.1Hz), 4.16 (2H, t, J=2.1Hz) MASS (APCI) 202 (M+H) Preparation 68 The following compound was obtained according to a similar manner to that of Preparation 2-(3,3-Dimethylmorpholin-4-yl)ethanol NMR (DMSO-d 6 0.91 (6H, 2.3 (2H, t, J=6.7Hz), 2.4-2.5 (2H, 3.19 (2H, 3.3-3.4 (2H, m), 3.5-3.6 (2H, 4.27 (1H, t, J=5.4Hz) MASS (APCI) 160 (M+H) The following compound was obtained according to a similar manner to that of Preparation 2-(3, 3 -Dimethylmorpholin-4-yl)ethyl methanesulfonate The compound was used to the next step without further WO 98/57954 PCT/JP98/02613 141 purification.

Preparation 69 The following compound was obtained according to a similar manner to that of Preparation 62-(2).

4- (3-Chioropropyl) 3-dimethylmorpholine MR (DMSO-d 6 6) :0.92 (6H, 1.77 (2H, qui, J=6. 4Hz) 2. 3-2. 5 (4H, mn), 3. 19 (2H, s) 3.55S-3. (2H, in), 3.67 t, J=6.4Hz) MASS (APCI) 192 Preparation The following compound was obtained according to a similar manner to that of Preparation 53-(5) starting from (3R)-1-benzyl-3-[ (1H-indol-3-yl)methyllpiperazine.

(2R) -4-Benzyl-l-tert-butoxycarbonyl-2- (H-indol-3-yl) methyl] piperazine mp :143-145*C IR (KBr) 3305, 2976, 2922, 2810, 1664, 1454, 1425, 1367, 1-336, 1299, 1261, 1223 cm- 1 MR (DMSO-d 6 6) 1.00-1.50 (9H, mn), 1.80-2.10 (2H, mn), 2.60-4.30 (9H, mn), 6.80-7.70 (10H, in), 10.72 (1H, br s) MASS (APCI) :406 The following compound was obtained according to a similar manner to that of Preparation 33.

(2R) -l-tert-Butoxycarbonyl-2- (H-indol-3-yl)methyl] piperazine IR (KBr) 3410, 3311, 2976, 2924, 1672, 1454, 1417, 1365, 1259 cm- 1 NNR (DMSO-d 6 6) 1.22 (911, br 2.2S-4.20 (10H, mn), WO 98/57954 PCT/JP98/02613 142 6.88-7.70 (5H, m) 10.78 (1H, br s) MASS (APCI) 316 The following comocound was obtained accordina to a s simiar manner to that of Preparation 34.

2 R)-l-tert-But-oxycarbonyl-4. (3,3-dimethlmnoriDholino)-2-butynyl]-2- I(lH-indol-3-yl)methyllpiperazine IR (KBr) 3500-3300, 2972, 2935, 1687, 1456, 1417, 13 6 1 3 33, 1 2 2 7 NNIR (DMSO-d 6 6) 0.94 1 .21 s) 1 .82- 2.20 (2H, in), 2.50-4.30 (17F-, ma), 6.85-7.66 in), 10. 81 br s) MASS (APCI) 481 (M+Hyr; The following comoound was obtained according to a s im~ Iar mranner t o that of- Pre~oara tion (3)l[-33Dmtvmr~oi~)2btnl--'H indol-3-yl )metCh§'lpiperazine trihvdrochrolide MD:209-2300C IR (KBr) 3600-3300, 2900, 92700-2400, 1645, 1628, 1539, 1516, 1454, 1429, 1344cm -NN.R fDMSO-d 6 r) 1- I 20-1-.50t- in), 3.10-4.42 mn), 6.95-7.80 mn), 9-90-10.25 (2H, mr), 11.15 (1H, br 11.90 b- s) IIASS (APOT) 381 (M+HV (free) Preiparation 71 Acetic acid (5.4 ml) was added to a solution of 2-ampino- 2 -inethvl-l-pnrorpanol! (8.4 g) and benzaldehyde (10 a) in 1,2dichloroethane (140 ml) under ice-cooling. After 30 minutes of stirring at the same temperature, sodiumn WO 98/57954 PCT/JP98/02613 143 triacetoxyborohydride (26 g) was added by small portions to the solution over 10 minutes. After 2 hours of stirring at room temperature, the mixture was poured into a solution of sodium hydrogen carbonate (48 g) in water (300 ml). The aqueous layer was separated and adjusted to pH 12 with 24% sodium hydroxide aqueous solution. The alkaline solution was extracted with ethyl acetate (2 times) The extract was dried over sodium sulfate and evaporated under reduced pressure to give colorless crystals of 2-benzylamino-2methyl-i-propanol (13.2 g).

mp 46.0-47.0°C IR (Nujol) 3330, 3100, 2900, 1450, 1380, 1355 cm-1 NMR (DMSO-d 6 6) 0.99 (6H, 3.23 (2H, d, J=3.9Hz), 3.62 (2H, 4.50-4.60 (1H, 7.16-7.36 (5H, m) MASS (APCI) 180 (M+H) 2 -Benzylamino-2-methyl-1-propanol (6.0 g) and potassium carbonate (6.95 g) were dissolved in a mixture of dichloromethane (30 ml) and water (30 ml) under ice-cooling.

Chloroacetyl chloride (2.95 ml) was added to the mixture over minutes and the whole was stirred for 2 hours at room temperature. The organic layer was separated, washed with diluted hydrochloric acid and brine successively, dried over magnesium sulfate and evaporated under reduced pressure. The residue was dissolved into tert-butyl alcohol (40 ml) and potassium tert-butoxide (3.76 g) was added to the solution.

The whole was stirred for 4 hours under reflux under nitrogen atmosphere. After cooling to room temperature, the insoluble mass was filtered off and washed with ethyl acetate. The filtrate and washing were combined and the whole was washed with diluted hydrochloric acid and brine successively, dried over magnesium sulfate and evaporated under reduced pressure.

The residue was triturated with a mixture of hexane and diisopropyl ether and the resulting crystals were collected by filtration and washed with a mixed solvent of WO 98/57954 PCT/JP98/02613 144 hexane and diisopropyi ether to give colorless crystals of 4-benzylamino-5,5-dimethyl-3-morpholinone (4.53 g) mr 76-77°C IR (Nujol) 1635, 1600, 1490, 1460, 1380, 1355 cm-1 NMR (CDC1 3 5) 1.20 (6H, 3.61 (2H, 4.32 (2H, 4.64 (2H, 7.18-7.36 (5H, m) MASS (APCI) 220 (M+H) 4 -Benzyl-5,5-dimethyl-3-morpholinone (4.45 g) was added to an ice-cooled suspension of lithium aluminum hydride (0.77 g) in dried tetrahydrofuran (20 mi) under nitrogen atmosphere. After 5 hours of stirring at 50°C, the reaction mixture was cooled below 5°C, and water (0.36 ml), 12% sodium hydroxide aqueous solution (0.36 ml) and water (1 ml) were added thereto successively. After 30 minutes of stirring, the mixture was filtrated through Celite® pad, and the cad was washed with ethyl acetate. The filtrate and washing were combined and the whole was dried over magnesium sulfate, and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using a mixture of n-hexane and ethyl acetate. The fractions containing the objective compound were collected and evaporated under reduced pressure to give 4 -benzvl-3,3-dimethylmorpholine as an oil. The obtained oil and ammonium formate (5.7 g) were dissolved into a mixed solvent of ethanol (35 ml) and water ml), and the whole was stirred under reflux for 1 hour under nitrogen atmosphere. After cooling, the mixture was filtrated through Celite® pad. The filtrate was evaporated under reduced pressure. The residue was dissolved into methanol and 4N hydrogen chloride in ethyl acetate solution was added thereto. The whole mixture was evaporated and the residue was triturated with a mixture of ethanol and n-hexane The resulting crystals were collected by filtration and washed with a mixed solvent of ethanol and n-hexane to give colorless crystals of 3,3- WO 98/57954 PCT/JP98/02613 145 dimethylinorpholine hydrochloride (1.56 g).

mp :196-197 0

C

IR (Nujol) :3300, 2750, 2650, 2500, 1590, 1460 cm'1 MR (DMSO-d 6 6) :1.21 (6H, 3.05-3.11 (2H, mn), 3.51 (2H, 3.76-3.81 (2H, mn), 9.66 (2H, br s) Example 66 Paraformaldehyde (30 ing) and copper(I) iodide (9 mg) were added to a mixture of 2 benzoyl]-2--(3,4-dimethylbenzyl)piperazine (0.16 (3S)-3ethoxycarbonyl-4- 2 -propynyl)morpholine (0.08 g) and N,Ndiisopropylethylamine (0.09 ml) in 1,4-dioxane (10 ml) and the whole was stirred at room temperature for 30 minutes, and then heated at 90 0 C for 30 minutes. After cooling, ethyl acetate and sodium hydrogen carbonate solution were added to the mixture. The organic layer was separated, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by column chromatography on silica gel with a mixture of ethyl acetate and n-hexane as an eluent to give 2 R)-l-[3,5-bis(trifluoromethyl)benzoly>.2-(34.

dimethylbenzyl) -3-ethoxycarbonylmorpholino) -2butynyllpiperazine (0.21 g).

MR (ODC1 3 6) :1.20-5.30 (31K, in), 6.55-7.90 (6H, in) MASS (APCT) 654 Example 67 The following compound was obtained according to a similar manner to that of Example 66.

2 3 ,S-Bis(trifluoromethyl)benzoyl.2-(3,4..

diinethylbenzyl)-4- 4 -tert-butoxycarbonyl)morpholin- 3-yl] 2 -propynyllpiperazine NMR (DMSO-d 6 6) :1.39 (9H, 2.09-2.17 (6H, in), 2.30-5.00 (18H, mn), 6.60-8.15 (6H, mn) MASS (APCI) :668 (free) WO 98/57954 PCT/JP98/02613 146 Example 68 To a solution of (2R)-l-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-[3-[(3R)-(4-tertbutoxycarbonyl)morpholin-3-yl]-2-propynyl]piperazine (1.607 g) in ethyl acetate (16 ml) was added hydrogen chloride (4N in ethyl acetate, 3 ml). After 8 hours of stirring at room temperature, the mixture was evaporated under reduced pressure to give (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2- (3,4-dimethylbenzyl)-4-[3-[(3R)-morpholin-3-yl]-2-propynyl]piperazine dihydrochloride (1.43 g) as a solid.

mp 190-191 C [a]7 -14.00 MeOH) IR (KBr) 2927, 1643 cm-1 NMR (DMSO-d 6 6) :2.10-2.18 (6H, 2.80-5.25 (18H, 6.65-8.25 (6H, m) MASS (APCI) :568 (M+H) (free) Example 69 Paraformaldehyde (0.034 g) and copper(I) iodide (12 mg) were added to a mixture of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2- 4-dimethylbenzyl) (2-propynyl)piperazine (0.21 (3S)-3-methoxymethylmorpholine (0.09 g) and N,Ndiisopropylethylamine (0.1 ml) in 1,4-dioxane (5 ml) and the whole was stirred at room temperature for 30 minutes and then heated at 70*C for 2.5 hours. After cooling, ethyl acetate and sodium hydrogen carbonate solution were added to the mixture. The organic layer was separated, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by column chromatography on silica.gel with 3% of methanol in chloroform as an eluent to give (2R)-1-[3,5-bis- (trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-[4-((3S)- 3-methoxymethylmorpholino) -2-butynyl] piperazine. It was dissolved in ethyl acetate and the solution was added 4N hydrogen chloride in ethyl acetate. The mixture was evaporated in vacuo and the residue was triturated with a WO 98/57954 PCT/JP98/02613 147 mixture of ethyl acetate arid isopropyl ether to give (2R)-1- 5-bi's (trifluoroinethvl)benzoyl] 4-dimethylbenzvl) -4- 3 -inethoxviethvlmorpoholino) -2-butynyl Ipiperazine dihydrochloride (0-16 g)m~60-70cC (C=0.25, MeO-I.) IR 1684, 1645, 1512, 1460, 1448, 1431, 1371, 1365, 1325, 1281, 1184, 1136, 1072 cmn' NNR-,, (DMSO-d 6 3) 2.00-2.28 (6H, mn), 2-60-S.30 mn), 6.60-8.30 (6H, m) M4ASS (APCI) 626 (-free) Example The following compounds were obtained according to a similar manner to that of Example 69.

(2R)-1-[3,5-Bis(t-riLfluoroine-hvl)benzovl)-2-( 3,4diinethylbenzvl) -3-fluoroinrethvrLorpholino) -2butynvl] oiperazine dihvdrochioride 1--,8-128OC (C=0.25, MeOH) (KBr) 16'45, 1502, 1435, 1365, 1321, 1282, 1182, 1136, 1049 cm-, NTIR (DMSO-d 6 5) 2-00-2.1-0 (6Hn, 2.60-5.30 (22H, mn), 6.60-8.30 mn) MA-SS (APCI) 614 (free) (2)1 (2R) -1-[Lf3, 5-Ri s (trifuoehvI) benzoyl'i- 2 diinethylbeTnzvl) (tetLrahvciro-6'-f Luoro-1., 4-oxazeoin- 4(5H)-yl)-2-butynyl]Diperazine dihydrochloride MO:90-100C L ~+1.60 (C=0.25, MeOKH) TR 14.1504, 1433, 1373; 1365, 1323, 1282, -1219, 1182, 11.36 c r, NR(DMSO-d 6 2.00-2.30 (6H, 7n), 2.60-5.30 (22H, WO 98/57954 PCT/JP98/02613 14 R mn), 6.60-8.28 mn) M4ASS (APCI) 614 (M+HK (ffree) Examnl1e 71 S The following compounds were obtained according to a similar manner to that of Exampl1e 31.

I1 2 f 3 5Sis (triiuoromnethv)benzoyi9-..3,4diinethvibenzyl)-4- 14- (J-methoxymet-hyl-3inethvlrnorpholino) 2 -butvnyl~piLperazine dihydrochioride iflD l51600C 11.60 (C=0.25, Me0Oi) !R (KBr) 1645, 1437, 1362, 1323, 1281, 1219, 1182, 1138, 105,5 n- INMNR IDMSO-d 6 5) .20-1.50 in), 2.05-2.26 (6H, mn), 2.60-5.20 k241i, 6.60-8.30 (6H, mn) MASS (APOT) :640 (M (free) 2 3 5 -Bis(rifluoromethy)benzoy2(3,4 dirnethylbenzyl)-4-[4- -3-ethoxvmethylinorpholino)-2butvnylpiperazine dihvdrochioride Mnr 155-160 0

C

L J D 0.6c (C=O.295, MeOH) TP\ (KBr) 1645, 1439, 1371, 1281, 17217, 1182, 1136, 1072, 1032 cmn 1 NMR (D.MSO-d 6 5) 1.13 (3H, t, J=7.0Hz), 2.02-5.24 1k30H, 6.60-8.28 mn) MASS kAPOIL) 640 "-free) 2 R) -I F3, 5- Eis (t r Fluoromnethvl)benzovl-?-(34 diinethylbenzyl)-4-[4- SS)--3',5-dirnmethy"Lmorpholino)-2hut vnvl] piperazine dihydrochloride MD 16 0 -16 5 0

C

X126 14.20 (C=0.25, MeOH) 1R (KBr) 1657, 1649, 1643, 1433, 1356, 1281, 1186, WO 98/57954 PCT/JP98/02613 19 1136, 1109 cmn1 TNMR (DMSO-d 6 :1.10-1.45 (6H, Mn), 2.00-2.28 (611, mn), 2.60-5.20 (19H, mn), 6.60-8.28 (6H, mn) MASS (APOI) 610 (free) (R-i-f 3 5 -Bis(trifiuoroineth-v.)benzoyl]>2( 3 dimethylbenzyl) F 4- (3S) 3 -hydroxymethylinorphol ino) -2butynylipiperazine dihvdrochloride Mp 130-150 0

C

108 2.60 (C=0.295j MeOH) IR (KBr) 1691, 1645, 1512, 1458, 1442, 1433, 1371, 1365 1325, 1281, -1217, 1'82, 1136, 1059 crL<- NMR (DMSO-d.,, 5) 2.00-2-30 k(Gi, mn), 2.60-5.30 (22H, mn), 6.60-8.28 (6H, mn) MASS (APOI) 612 (M+HV- (free) 2 3 ,5-Bis(trifluoroiethyl)benzoylj52(3,4 diiethylbenzyl)-4- -2-methoxvmethylmorpholino) -2butynylipiperazine dihydrochn.Loriie MID 83950r.

4.71-l (C=0.255, MeOH') IR (KBr) :1641, 1631, 1442, 1281, 1134 cmf 1 NMR (DMSO-d 6 6) 2.00-2.30 (6H, mn), 2.60-5.28 mn), 6.60-8.30 (6H, mn) MASS (APOI) 626 (free 2 R)-l-[3,5-Bis(rifL 'uoromethy)berzoy1i>-(3,4 diinethvlbenzyii (2R) -2-me thoxyinethvlmorpholino) -2butvnyllpiperazine dihydrochloride mo 80-90 0

C

[aL]21 -15.00' (C=0.24, MeOH) TR (KBr) 1657, 1649, 1641, 1631, 1441, 1431, 1281, 1186, 1176, 1136, 1109 cm- 1 NMR (DMSO-d 6 6) 2. 00-2.30 (6Hn, 2. 60-5.20 mn), 6. 60-8S. 30 6H, in.) WO 98/57954 PCT/JP98/02613 150 MASS (APCI) :626 (M+H) (free) (2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3, 4dimethylbenzyl)-4-[(E)-4-((3R)-3-methoxymethylmorpholino)-2-butenyl]piperazine dihydrochloride mp 240-250°C [a]D -19.47° (C=0.19, MeOH) IR (KBr) 1647, 1635, 1618, 1456, 1435, 1379, 1281, 1186, 1132, 1108 cm-1 NMR (DMSO-d 6 5) 2.00-2.28 (6H, 2.60-5.20 5.80-8.30 (8H, m) MASS (APCI) :628 (free) Example 72 A mixture of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2- (3,4-dimethylbenzyl)-4-[4-chloro-2-butynyl]piperazine (1.2 g) and (3S)- 3 -ethoxycarbonylmorpholine hydrochloride (0.43 g), potassium carbonate (1.09 g) and a trace of potassium iodide in N,N-dimethylformamide (50 ml) was stirred at 55°C for 12 hours. After cooling, the solvent was removed by evaporation, and ethyl acetate and water were added thereto.

The organic layer was separated, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by column chromatography on silica gel with a mixture of ethyl acetate and n-hexane as an eluent to give (2R)-1- [3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4- 3

S)-

3 -ethoxycarbonylmorpholino)-2-butynyl]piperazine (0.29 g) as an oil.

NMR (CDC1 3 6) 1.20-5.30 (31H, 6.55-7.90 (6H, m) MASS (APCI) 654 (M+H) Example 73 The following compounds were obtained according to a similar manner to that of Example 72.

WO 98/57954 PCT/JP98/02613 151 2 R) 5-Bis (trifluoromethyl) benzoyl 1 4 cimethylbenzyl)-4- (3R) -3-ethylmorpholino) -2butynylipiperazine dihydrochioride [(X]27 -22.70 MeOH) IR (KBr) 3600, 1645, 1460, 1280, 1180, 1135 cm-1 NMR (DMSO-d 6 6) 0.83-5.17 (31H, i), 6.62-8.24 (6H, in) MASS (APCI) 610 (free) 2 R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-4-[4-( (3S)-3ethylmorpholino)-2-butynyl]-2-[(1H-indol-3-yl)methyljpiperazine dihydrochioride 28 +11.20 MeCH) [aD IR 3365, 2600, 1645, 1430, 1280, 1180, 1135 cm 1 NMR CDMSO-d 6 6) 0.67-5.20 (25H, 6.60-8.28 (8H, 10.96 (1H, s) MASS (APCI) 621 (free) 2 R)-1-3,5-Bis(trifluoromethyl)benzoylp-2-(3,4diiethylbenzyl)-4-[(E)-4-((3S)-3-methoxymethylmorpholino)-2-butenyl]piperazine dihydrochoride mp 130-1400C 27 27i] +2.00 (C=0.25, MeOH) IR (KBr) 1653, 1647, 1637, 1282, 1188, 1134 cm 1 NNR (DMSO-d 6 6) 2.00-2.28 (6H, 2.70-5.28 6.00-8.32 (8H, m) MASS (APCI) 628 (free) Example 74 A solution of (2R)-1-[3,5-bis(trifluoroiethyl)benzoyl]- 2- 4-diiethylbenzyl) -3-ethoxycarbonylmorpholino)-2-butynyl piperazine (0.42 g) in ethanol (30 ml) was added 1N sodium hydroxide solution (30 ml) and the whole was stirred* at room temperature for 2 hours. The solvent was removed under reduced pressure and the residual aqueous WO 98/57954 PCT/JP98/02613 solution was neutralized with conc. hydrochloric acid. The solution was extracted with dichloromethane. The extract was dried over magnesium sulfate and evaporated in vacuo to give (2 )!-35bs',-ilooety~ e zy ]2 -ieh l ben zyl) 3 S) -3--carboxvmorpholino) 2 -butynyliipiperazine (0.26 g) as an oil.

NIAR CD~l, 5) 2.00-5.28 (26H, in), 6.50-7.90 (6H, m) MASS (ACI) 626 Exarnole A tetrahydro-furan solution of dimethylamine (2 M, 0.32 ml) was added to a mixtur-e of 2 R)-1-[3,5-bis(trifluoromethyl)benzoylj-2-(3,4-dimethylbenzyl)-4-[4-(3S)-3.

carboxyinoroholino)-2-but-Lyny;l~pipLerazine (0.13 1hvdroxybenzotr iazo! e (85 mg) and l- (3-dimethylarninoprooyl) -3ethylcarbodiimide hydrochloride (0.12 g) in N,Ndimethv f ormanide (S m1) and the whole was stirred at room temperature for 5 hours. A-fter the solvent was removed by evap~oration, dichloromethane and sodium hydrogen carbonate solution were added to the residue. The organic 'Layer was separated, dried over magnesium sulfate, and evapoorated in vacuc. The residue was purified by column chromatography on silica gel with 3% of methanol in dichloromethane as an eluent to give (2R) -1-{3,5-bis (tLri-fluoroineth\vl)benzoylj-2- 4-dimethylbe-nzyl)-4-[4- ((3Sc)-3-dimethiylcarbamovliorphol-'Ino)-2-butynyljpiperazine. Tt was dissolved in ethyl acetate (10 -ml) and the solution was added 4N hydrogen chloride in ethyl acetLate (0.26 ml) The mixture was evaporated in vacuo and the residue was triturated with a mixture of ethvl acetate and isopropyl ether to give (2R) -1- 3-bis (tr-,,iffuoromethyl)benzov1 4-dJimethvlbenzyl)-4- 3 -diLmethvicarbamoylmorpholino) -2-butynilipiperazine dihydrochloride (0.1.2 g) as a solid.

mr) 150-160"C [a12 7 -33.20 (C=0.25, MeOH-I WO 98/57954 PCT/JP98/02613 3 T R (1(Br) 1653, 1-506, 1433, 1371, 1325, 12-1, 1182, 1-136, 1063, 1026 cm1 NMR (DMSO-d6, 5) 2.00-2.30 iL), 2.60-5.20 (26H, mn), 6.60-8.30 (6H, in) MASS (APC"I) 653 (free) Examnle 76 The following compounds were obtained according to a similar manne'r to that of Examp~le 2 1R) 3 5-Bis (trifluoroi~ethl)benzoyl (1H-indol-3vl)methyl] (4-methoxy) pyridyl]-2-propynyl)piperazine dihydrochioride MO 130-135 0

C

2 8 MeOH) TR (KBr) 3600, 3314, 1640, 1625, 14130, 1280, 1180, i135 cm -I NINR (DMSO-d 6 5) 3.95 (3H, 2.74-5.24 (11H, mn), 6.60-8.60 (1lH, mn), 10.92 (1H, s) MAkSS (APCI) 601 (free) 2 R)-l-[L3,5-Bis(trif"luoroinethvijbenzoy1]-2-1f3-,Adiineth ylbenzyl)-4-{3-[2- (4-iethoxv)pyridyl]--oropynyl}p'nerazine dihydrochioride MO 95-1000C [a' 2 8 -6.20 MeOH) IR 3405, 21930, 2590, 1625, 1430, 1280, 1180, 1135 cn- I\ThP. (DMSO-d 6 5 2.51 (3H, 2.03-5.20 (17H, mn), 6.66-8.66 (9H, m) KMkSS (APCI) 59-0 (M+HK- (f re e) r fLo o e h l b n o l l 3 v1)rnethvll-4-{3-[2- (4-methvl)pyridl]i-2-prorynyl}poiperazine dihydrochioride WO 98/57954 PCT/JP98/02613 154 mp 150-155°C [a]27 -3.3 MeOH) IR (KBr) 3335, 1645, 1498, 1430, 1280, 1185 cm-1 NMR (DMSO-d6, 2.37 (3H, 2.10-5.24 (11H, m), 6.60-8.67 (11H, 10.93 (1H, s) MASS (APCI) 585 (M+H) (free) 2 R)-1-[3,5-Bis(trifluoromethyl)benzoyl] dimethylbenzyl)-4-{3-[2-(4-methoxycarbonyl)pyridyl]-2propynyl}piperazine dihydrochloride mp 125-130°C 28 ]D -30.3* MeOH) IR (KBr) 2600, 1740, 1645, 1430, 1280, 1180 cm 1 NMR (DMSO-d6, 5) 3.93 (3H, 2.00-5.20 (17H, m), 6.60-8.90 (9H, m) MASS (APCI) :618 (M+H) (free) Example 77 A mixture of 2 R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2- (H-indol-3-yl)methyl]piperazine (0.20 (3S,5S)-3,5dimethyl-4-(4-chloro-2-butynyl)morpholine (0.11 g) and potassium carbonate (0.31 g) in N,N-dimethylformamide (4 ml) was stirred at 600C for 3 hours. After cooling, the solvent was removed under reduced pressure and the residue was partitioned between ethyl acetate and sodium hydrogen carbonate solution. The organic layer was separated, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by column chromatography on silica gel with 3% of methanol in ethyl acetate as an eluent to give (2R)-1- 3 ,5-bis(trifluoromethyl)benzoyl]-4-[4-((3S,5S)-3,5dimethylmorpholino)-2-butynyl]-2-[(1H-indol-3-yl)methyl piperazine. It was dissolved in ethyl acetate and the solution was added 4N hydrogen chloride in ethyl acetate.

The mixture was evaporated in vacuo and the residue was triturated with isopropyl ether to give (2R)-1-[3,5-bis- WO 98/57954 PCT/JP98/02613 1545 (trifluoronlethv-,l)benzoyli]-4-[4-( 3

S

9 morphoiino)-2-butynvli F (1Ht-incol-3-yl)methylipiperazine dihydrochioride (0.11 g).

nP170-18001,- S a27 +21.57' (C=0.255, MeOH) !R 1645, 1637, 1458, 1431, 1360, 1281, 1184, 1136, 11111 m1 NMR (JDMSO-d 6 5) 1.10-1.45 (6H, ni,2.70-5.30 (19H, mn), 6.60-8.28 in) MALSS (APCI) 621 (free) Examiole 78 The following compounds were obtained according to a similar manner to that of Examiple 77.

2 -R)--r3,5-Bis(tr -ifluoromethyl)benzovil4[4-((3R)-3et-hylmorholino)-2-butvjj' (lH-indol-3-yl)rnethyl]piperazine dihvdrochloride MO 176-180 0

C

Fcaj2 6 -12.20 (C=0.25, MeOH) 1635, 14514, 1437, 1358, 1333, 1281, 1223, 1182, 1138, 1068 c-1 NMR (DMSO-d,-, 5) 0.68-5.30 (25H, mn), 6.55-8.30 (8H, 1 0. 95 (1Hi, s) MASS (APCI) 621 1 (free) 2 )--[i5Bi(trifluoroietv)benzoyly43( dimnethvi-mor-oholinc)poropyi1 (1-indol-3-yl)inethyl] pipe razine dihvdrochloride :i 107- 0

C

11 5 -7.00 MeOH) IR 30-3400, 2933, 2599, 1645, 1637, 1458, 1435, 1362, 1280 cm NM-R (DMSO-d 6 6) :1.2-1.4 in), 2.1-1.6 (2H, mn), 2.7-5.2 (19H, in), 6.6-8.3 mn), 10.9-11.8 (3H, WO 98/57954 PCT/JP98/02613 156

M)

MASS (APCI) 611 (free) 2 R) 5-Bis (trifluoromethyl) ben zoyl 1 4dimethylbenzyl)-4-12-[7-oxa-4-azaspiro[25]octan-4-ylI ethyl} piperazine dihydrochioride mp 110-1130C [(X28 -13.80 MeOH) IR (KBr) 3435, 1645 cm- 1 NMR (DMSO-d 6 6) 0.80-0.95 (2H, 1.20-1.50 (2H, 2.11-2.19 (6H, 3.00-5.15 (19H, 6.65- 8.17 (6H, m) MASS (APCI) 584 (free) 2 R)-1-[3,5-Bis(trifluoromethyl)benzoyl-2.(3,4 dimethylbenzyl)-4-f3-(3,3-dimethylmorpholino)propyl]piperazine dihydrochioride mp 197 0

C

27 [aIcD 17.8* MeOH) IR (KBr) 3500-3400, 2933, 2692, 1645, 1637, 1456, 1430, 1435, 1280 cm 1 NMR (DMSO-d 6 6) 1.33 (6H, 1.92-5.2 (27H, m), 6.6-8.3 (6H, 11.0-11.5 (2H, m) MASS (APCI) 600 (free) Example 79 The following compounds were obtained according to a similar manner to that of Example 2 3 ,5-Bis(trifluoromethyl)benzoylp4.[2(3,3dimethylmIorpholino) ethyl] 2- (H-inclol-3-yl)methyl]piperazine dihydrochioride mp 247-258 0

C

27 [a]D -4.50 MeCH) IR (KBr) 3500-3400, 1645, 1637, 1280 cmf 1 WO 98/57954 PCT/JP98/02613 157 NNR (DMSO-d 6 5) 1.2-1.5 (6H, rn), 2.8-5.3 (19H, in), 6. 6-8. 3 (8H, mn), 11 .0 (1 H, br s) 11. 5- 12. 1 (2H, m) MASS (APCI) 597 (free) 1 3, 5-Bi s(tri fluorome th yl) ben zoyl-2 (3,4 dimethylbenzyl) 4 3 -dimnethylinorphol1ino) e thylpiperazine dihydrochioride mp :190-210 0

C

27 -1 .0 5 eH 13.90 MeH IR (KBr) 3500-3400, 1643, 1450, 1430, 1384, 1363, 1280, 1185 cin 1 NMR (DMSO-d 6 65) :1.40 (6H, 2.10-2.2 (6H, mn), 2.7- 5.2 (19H, in), 6.6-8.2 (6H, mn), 11.6-12.2 (2H, in) MASS (APCI) 586 (free) Example The following compounds were obtained according to a similar manner to that of Example 39.

(2R)-1-[3,5-Bis(trifluoroinethyl)benzoyl]-2-(3,4dimethylbenzyl) ((3K)-3-ethylinorpholino) ethyl] piperazine dihydrochioride 28 -23.6* MeOH) [a]ID IR (KBr) :3425, 2600, 1645, 1640, 1280, 1185, 1135 cm'1 NMR (DMSO-d 6 6) 0.95 (3H, t, J=7.2Hz), 1.57-5.20 (28H, in), 6.66-8.28 (6H, in) MASS (APCI) 586 (free) (2R)-1-[3,5-Bis(trifluorometh~yl)benzoyl]-2-(3,4dimethylbenzyl) (3S) -3-hydroxynethylinorpholino) ethyl] piperazine dihydrochioride mp 150-160 0

C

26I (C=0.25, MeOll) IR (KBr) 1643, 1437, 1375, 1323, 1282, 1221, 1184, 1138, 1047 cmrJ 1 WO 98/57954 PCT/JP98/02613 150 M-TvR (DIMSO-d6, 5) 2.00-2.28 (6H, inq), 2.60-5.20 (23H, mn), 6.5'8-8.28 (6H, i) MASS (APCI) 588 (free) 5-Bis(trifluoroinethyl) ben zoyli,-2-?(3, 4 aiinethylbenzyl)-- -2-rnethoxvrnethylinorpoholjno) e-thylljpirerazine dihvcrochloride mo 180-190 0

C

[cc] t 12.36' (C=0.275S, MeOH) !R :1653, 1647, 1635, 1282, 1182, 1136 cmi NNMR (D-MSO-d 6 5) :2.00-.5.20 (31H, mn), 6.60-8.30 (6H, mn) MASS (APCT) 602 (free) (2R)-1-[3.5-Bisltrifluoroinethyl)benzovil2-

A.-

diiethylber.zyl,) ((3S)-3-rnethoxvrnethyliorpholino)ethyllpiperazine dihydrochioride Y127 9.80 (C=0.25, MeOH) IR (KBr) 1645, 1512, 1506, 1460, 1433, 1371, 1325, 1282, 1223, 1184, 1136, '1053 c--n7' NMR (DMSO-d 6 5) 2.00-2.30 (6K, mn), 2.60-5.20 mn), 6.60-8.4-0 (6H, n) MASS (APCI) 602 (free) (2R)-1--[3,5-Bis(trifluoroinethyl)benzoyl]-2-(3,4diinethylbenzyl) (2-iethoxvnethylinorpholino) ethyl] Piperaziie dihvdrochloride MoD 150-154 0 1- 28 MeOK) T R 3463-3406, 1647 cmn 1 N\TMR (DMSO-d 6 6) 2.10-2.18 (6H, ra), 2.40-5.10 mn), 6.55-8.16 (6H, mn) MASS (APCI) 602 (free) (2R.-)-l-3,5-Bis(tri'fluoroiethyl)benzoyi]-2-(3,4- WO 98/57954 PCT/JP98/02613 159 dimethylbenzyl) (3S) -3-inethoxyiethylmorpholino) propyllpiperazine dihydrochioride mp :55-60*C [27] 1.40 (C=0.25, MeOi) IR (KBr) :1653, 1647, 1635, 1282, 1182, 1134, 1109 c- NMP. (DMSO-i 6 5) :1.80-5.22 (33H, mn), 6.60-8.30 (6H, mn) MASS (APCI) 616 (free) (2R) 5-Bis (trifluoroiethyl)benzoyl] (3,4dimethylbenzyl)-4-[3- (2-inethoxymethylmorpholino)propyl]piperazine hydrochloride mp :145-1550C I(X 28 -11.9* MeOH) IR (KBr) 3455-3407, 1645 crrG 1 NNR (DMSO-d 6 6) 2.10-2.19 mn), 2.10-5.10 (27H, mn), 6.68-8.17 m) MASS (APCI) 616 (free) (2R) 5-Bis (trifluoromethyl)benzoyl] (H-indol-3yl)methyl]-4-[2- (3S) -3-inethoxymethyliorpholino) ethyl]piperazine dihydrochioricle mp :175-1850C 27X D 0.6' (C=0.25, MeOH) IR (KBr) 1645, 1637, 1458, 1431, 1383, 1362, 1291, 1184, 1138, 1111 cm- 1 NMR (DMSO-6 5) :2.80-5.28 (25H, mn), 6.60-8.30 (8H, in) MASS (APCI) 613 (free) 2 R)-1-[3,5-Bis(trifluoroinethyl)benzoyl]-2-[ (1H-indol-3yl)methyl]-4- -3-methoxymethylmorpholino) ethyl]piperazine dihydrochioride inp 130-1500C [a]26 15-80 (C=0.25, MeOH) IR (KBr) :1653, 1645, 1635, 1281 cmf 1 NMR (DMSO-d 6 5) :2.60-5.25 (25H-, mn), 6.60-8.32 (8H, WO 98/57954 PCT/JP98/02613 160 mn), 10.96 (1K, s) MASS (APCI) 613 (free) (2R)-1-[3,5-Bis(trifluoromethy1)benzoylj-2-(3,4dimethylbernzvl) C1(3R) -3-rnethoxyrnethflmnor-pho-lino) propyl ]pi-cerazine dihydrochloride MD:80-100 0

C

28l -21 .59c (C=0.22, MeOHW IR (KBr) 1653, 1647, 1637, 1618, 1508, 1473, 1464, 1456, 1&48, 14-5, 1431, 1385, 1373, 1363, 1281, 1215, 1184, 1136, 1109 cm 1 i NMIR (DMSO-d 6 5) :2.00-5.40 (33H, mn), 6.55-8.30 (6H, m) MASS (APCI) 0'16 (free) Examnle 81 The following- compounds were obtained according to a similar manner to that of Example 37.

2 R)-1-[3,5-Bis(trifluoromethvl)benzoyl]-2-(3,4dimethylbenzyl)-4- -3-fluoromethylmorpholino) ethylipiperazine dihvdrochloride mp 145-155 0

C

2ai 6 -19.20 (C=0-25, MeOH) IR (KBr) 1643, 1437, 1367, 1321, 1281, 1221, 1184, 1138, 1034 crtCL NIMR (DMSO-d 6 5) 2. 00-2. 28 (6H, in), 2. 60- 5. 20 (22H, mn), 6. 60-8 .32 mn) MASS (APCI) 590 (free) (2-R)-iL-[3,5-Bis(trifiluorometLhv1,)benzoy1l1-2-(3,4dimnethylben zyl) (3-rethoxyrethyl-3met -hylmorpholino) ethy1]p-inerazine dihydrochloride r :60-70 0

C

[a1 27 _15.50 MeOH) IR 1643, 1469, 1439, 1375, 1369, 1360, 1323, WO 98/57954 WO 9857954PCT/JP98/02613 1282, 1225, 1184, 1138 c- NMR (DMSO-d 6 6 1.10-1.50 (3H, 2.00-5.22 mn), 6. 60- 8. 30 mn) MASS (APOT) 616 (free) (2.R)--[3,5-Bis(tLrifluoronethyl,)benzovli-2- (3,4dirnethvlbenzvl -3-ethoxymethymorpholino) erthvlijpiiDerazine dihvdrochloride mp :60-65* 0

C

7 -8.20 (C=0.25, MeOH) IR (KDr) 1643, 1437, 1369, 1321, 1281, 1221, 1182, 1138, 1072, 1051 rC NNR-; (DYISO-dF, 5) 1.10-1.30 (3H, mn), 2.00-5.25 mn), 6.60-31.40 (6H, m) MASS (APOTI) 616 CM+H' (free) (2--R)-1--[3,5-Bis(triLfluoromethvl)benzoyl]-2-(3,4diinethvlbenzyl)-4- -3-inethoxyrnethvmorpholino) ethvllpiperazine dihydrochioride MIDp 90-100 0

C

2" -26.480 (C=0.28'1, MeOH) IR kK~r) 1635, 1469, 14541, 1437, 13751, 1369, 1360, 1321, 1282, 1221, 1184, 1136, 1074 c NMR (DMSO-d 6 5) :2.00-5.22 (31H, mn),.6.60-8.28 (6H, mn) MASS (APCI) 602 (,free) (2R)-1-[3,5r--Bis(tLrif.Luoroinethyl)benzoyl]-2- (3,4dirnethvlbenzyl) (2R) -2-rnetho~xvrneLhyimoroholino) ethyl] Diperazine dihydrochloride nip :160-170 0

C

27 -17.40* (C=0.27, MeOH) TR (KBr, 1645, 1454, 1431, 13183, 136-3, 1321, 1281, 1215, 1184, 1138, 1109 cr. m NMR (DMSO-d 6 5) 2. 00-2.28 (6H, 2. 60-5. 22 in), 6.60-8.28 (6H, m) WO 98/57954 PCT/JP98/02613 162 MASS (APCI) 602 (free) (2R)--[3,5-B-*is(trif--luorornethyl)benzoyL'J--2-),2naphthvlmethyl) 2- (3S) -3--ethylmorpholino) ethyl]I S pinerazine CdihvdrcchlIoride 2~j 8 -16.20 MeCH) IR 3400, 2610, 1430, 1280, 1185, 1-135 crrJi NMR (DMSO-d 6 0. 86-5S. 31 (25K n, 7. 00- 8. 20 (1OH, rin) MKASS (APICI) :608 (M+HJ- (free) (2R) f3, 5-Bis_-(tri-FlIuoromethvl)benzovl']-2-f (1H-inclol--3yl) methyl]-4-[(2- -2-methoxvlethylmorpholino) ethyl] piperazine dihvdrochioride rr 160-170 0

C

3.00 (C=0.25, MeOH) I.R (KEr) 1645, 1637, 1618, 1458, 1429, 1362, 1281, 118 4, 113 8, 110U-9, 109 9 1 N.R 5) 2.60-5.30 (25H, mn), 6.60-8.30 (8H, in.) MASS (APCI) 613 (M+HK (free) (2-P)-1-[3,5-Bis(tri L1uoromethvl)benzoy1]-2-[ (1H-indol-3yl)inethvll-4- (2R)-2-iethoxvrethyimorpholino) ethyl]ploerazine diLhvdrochloride i 190-200'C f& 2 15.0' MeOH) IR (KBr) :16-41, 1458, 1421, 1362, 1262, 1176, 1130, 1113, 1099, 10-74 cmn INMR (DMSO-d 6 :2.60-5.28 (25H, mn), 6.60-8.28 (8H-, mn), 10.94 (1H, s) MASS (APCI) 613 (free) (2R-D)-1-[3,5-Bis(triffluorornethyl)benzoyl]1-2-[ (1H-indol-3yIL)inethyl]-4-[2-( (3S,5S)-3,5-diinethvlmroholi,:no)ethyllninerazine dihvdrochloride MD 17 0-1800oC WO 98/57954 PCT/JP98/02613 163 CO 27 +13.49' (C=0.313, MeOH) 1R \IKBr) 1645, 1637, 14580, 1448, 1429, 1362, 1281, 1 1 84, 1 13 6, 1111_ cmn NMIR (DMS-d 6 5)1.08-1.50 (6H, 2.60-5.20 (19H, mn), 6.55-8.30 (SH, mn) MASS (APCI) 597 (free) i-;luorornethv.-L)benzovi1-4-[2-((3R)-3ethylmorpholino)etLhv-l-j-2- 1,hT-irndol-3-yl)methy11rninerazine dihvdrochlor--ide [a3I D. 14.90 MeOK) IR (KBr) 3365, 2590, 2470, 1645, 1430, 1280, 1185, 1140 c NNR,1P (DMSO-d 6 5) 1.53-5-20 (25H, in), 6.60-8.28 (8H-, mn), 10.95 1, s) MASS (APCI) 597 +(fre (11) !'Th)P)-1-[3n),5-Bis.-(trifl,-=uoromethyl)benzoyji-4-[-((Ik3S)-3et'Lhylrnoroholino)ethyl-2-[ (1H-indol-3-yl)methyl]- TDi-oeraziLne di4hvdrochloride 28I (C0O.5, MeOH) IR 3300, 2670, 2610, 1645, 1430, 1280, 1180, 1140 cm- NMR (DMSO-d6, 5) 0.84-5.20 (25H, in), 6.64-8.28 (8H, MASS (APT) 59' (free) Exampvle 82 A solution of C2R) -1-[3,5-bis(tri-fluoromet-hvl,)benzovl]- 3, 4-dimethylbenzyl)-4- f4- -3--nethoxymethlinorpholino)- 2-butynvllpiperazine (0.09 g) in methanol (10 ml) was hydrogenated in the presence of 10%' Daliadium-carbon (40 mng) at room temperature. After 1 hour, naliadium-carbon was removed by filtration and the filltrate was evaporated under reduced poressure. The residue was puriffied by column WO 98/57954 PCT/JP98/02613 164 chromatography on sil 1 ica gel1 with a mixture of methanol and ethyl acetate as an eluent to give (2R)-1-[3,5-bis- (tri-fluoromethvl)benzoyl]-2- (3,4-dimethvlbenzvl)-4-[4-((3S)- 3-methoxvmethvlmorpholino)butyl~pipoerazi-ne. It was dissolved in e-thyl acetate (10 ml) and 4N hydrogen chloride in ethyl acetate (0.5 ml) was added thereto. The mixture was evaporated in vacuo and the residue was tritura-ted witLh a mixture of ethyl acetLate and iso-propyl ether to give (2R)-1- 3, S-bis (trif luoromethyl) benzoyl]1-2- 4 -din ethylbenzyl) -4- ((3S)-3-methoxymethylmorpholino)butyllpiperazine dihydrochloride (0.03 g) as a solid.

NN,_R (DMSO-d 6 1.60-2.00 (4H, in), 2.00-2.30 (6H', in2.60-5.20 (25H, 6.60-8.30 (6H, 10.40- 11 60 2 1 ,,in) 13 MASS (APOT) 630 (free) Examp~le 83 The following compounds were obtained according to a similar manner to that of Example 82.

(2R)-l-[3,5-Bis(trifl'uorornethyl)benzoyl7,-2-(3,4direthylbenzyl)-4-{3- (4-iethoxy)pyridyllpropoyl}piperazine dihydrochloride mp 130-140 0

C

2528 -10.4' MeOH) IR 3425, 2400, 1640, 1500, 1430, 1280, 1180, 1135 cirJ 1 NNR (DMSO-d 6 5) 4.08 2.05-5.14 (21H, mn), 6.60-3.729 (9K, mn) MAS(APCI) 594 1free) (2R)-1-[3,5-Bis(trifluoroinethyl)benzovl]-2-[(lH-indol-3yl)metLhyl]-4-{3- (4--ethvl)pyridyllpropyllpiperazine dihydrochioride M'O 120-130 0

C

WO 98/57954 PCT/JP98/02613 16S 2 7 5.0' MeQH) IR (KBr) 3420, 1645, 1498, 1430, 1280, 1135 cmJ 1 NM'R (DMSO-d 6 5 2.55 (3H, 2.14-5.20 (15H, in), 6.64-8-74 (11H, in), 10.95 (1H, s) TMASS (APOI) 589 (free) (21R) 5-Bis (trifluoromethvl)benzoyll-2- 4diinethylbenzyl)-4-{3- (4-rethoxycarbonyl)pyridyl]pro'oyllpiperazine dihydrochioride 1 M1 0 115- 125So 0 ft] 2 8 11. 7' IR (KBr) :2650, 2625, 1740, -1645, 1460, 1280, 1135 cmf 1 NTNR (DMSO-d 6 ,5 3.92 (3H, 2.07-5.1,1- (21H, mn), 6_60-8.78 (9H, mn) MAkSS (APCI) '622 (free) Example 84 To a stirred suspension of 2-(3,4-methylenedioxybenzyl)pi-perazine dihydrochioride (104 mng) and potassium carbonate (196 mg) in N,14-dimethylformamide (4 ml) was added 4-(4chloro-2-buatynvl) 3-dimethylmor-oholine hydrochloride (84.5 mng) at under nitrogen atmosphere and tLhe mixture was gradually warmed to room temperature over night. To the above stirred suspension was added benzoyl chloride (98.2 mng) at Soc and the mixture was stirred for 1 hour at this temperature. The mixture was extracted with e'Lhv- 1 acetate and the extract was washed with water, and dried over magnesium sulfate. The usual work up followed by flash chromatography on silica gel with a mixture of dichloromethane and methanol (50:1) gave (trifluoromethyl) benzoyl] 3-diinethylinorpholino) -2butynyl]J-2- (3,4-methvlenedioxybenzyl)poiperazi:-ne, which was dissolved in ethyl acetate and treated wi-th 4N hydrogen chloride in ethyl acetate to give 3 5 (-trifluoroin.ethyl)benzoyl]-4-[4d- 3-dimethylinorpholino) -2- WO 98/57954 PCT/JP98/02613 1.66 but-ynvl]-2- 4-rethvlenedioxvbenzvl) pipoerazi*ne dihydrochioride (107 mg) as a powder.

NNR (DMSO-d 6 5) 1.32 (6H, mn), 2.20-5.00 (19H, mn), 5.96 (2H, s) 6.43-8.17 1(6H, m) MASS (APCI) 626 (free) Exam~ole The following compounds were obtained according to a similar manner to that of Examnvle 84.

1-[3J,5-Bis(trifluoroinethvl)benzoyl)-4-[4-13-,3diinethvlinorpholino) -2-butyriyl]-2- (4-hydroxymetLhyiethvlbenzyl) pilperazine dihydrochioride NM-Y.R (DIMSO-da, 5) 1.32-1.38 (6H, mn), 2.00-3.22 mn), 6.-55S- 8.1I 7 (6 H, mn) MASS (A-PCI) 626 (free) (1,4-Benzodioxan-6-vl)iethyl]-i,-[3,5-bis- (trifluoroiethyl)benzoyl]-4-[4- (3,3 -diinethylinorpholino) 2-butynyllpiperazine dihydrochioride NMR(DMOc 6 5 1.21-1.23 (6H, rn), 2.62-5.00 (23H, mn), 6.37-8.48 (6H, mn) MAkSS (APCI) 640 (M+HKW: (free) 1-[3,5-Bis(tLrifluoroinethyl)benzoylii-4-{4-( 3 3 diinethylinorpholino) -2-butynyl] (4-methoxy-3iethvlbenzvl) pip'era zinc diLhvdrochioride NIMR (DMSO-d 6 5) 1.33-1.401(6-", 2.00-5.22 mn), 6'.64-8.15 (6H, mn) MASS (APCI) 626 (free) Examnole 86 To a mixed solution of 1-(benzyloxvcarbonyl)-3-( 2 3 dimethoxybenzyl)piperazine (0.65 g) and triethylamine (0.293 ml) in dichioromethane (17 ml!) was added dro-owise a solution WO 98/57954 PCT/JP98/02613 167 of 3,5-bis(trifluoromethyl)benzoyl chloride (0.534 g) in dichloromethane (2.5 ml) under ice-cooling. After being stirred at the same temperature for 2 hours, the reaction mixture was poured into a mixed solvent of water (40 ml) and dichloromethane (25 ml) and the whole was adjusted to pH 9 with aqueous sodium hydrogen carbonate solution. The organic layer was separated, washed with brine, dried over sodium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (10 g) using a mixed solvent of n-hexane and ethyl acetate The fractions containing the objective compound were collected and evaporated under reduced pressure to give 1-[3,5-bis(trifluoromethyl)benzoyl]-4- (benzyloxycarbonyl)-2- (2,3-dimethoxybenzyl)piperazine (0.84 g).

IR (KBr) 1732, 1714, 1705, 1647, 1431, 1281, 1134 cm-1 NMR (CDC1 3 6) 2.60-4.70 (9H, 3.79 (6H, 5.20 (2H, 6.40-8.60 (11H, m) MASS (APCI) 611 (M+H) Example 87 A mixture of 1-[3,5-bis(trifluoromethyl)benzoyl]-2-(2,3dimethoxybenzyl)piperazine (0.192 3,3-dimethyl-4-(4chloro-2-butynyl)morpholinine hydrochloride (0.106 g), potassium carbonate (0.167 g) and potassium iodide (67 mg) in N,N-dimethylformamide (1.3 ml) was stirred at 65 0 C for minutes and cooled. The mixture was poured into ice-water ml) and the whole was adjusted to pH 9 with sodium bicarbonate, and extracted with ethyl acetate (30 ml). The extract was washed with brine (30 ml), dried over sodium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (8 g) using a mixed solvent of dichloromethane and methanol (40:1).

The fractions containing the objective compound were collected and evaporated under reduced pressure to give a WO 98/57954 PCT/P98/02613 168 colorless oil of 1-(3,5-bis(tri4luoromethyl)benzoyl]-2-(2,3dimethoxybenzyl)-4-(4-(3,3-dimethylmorpholino)-2-butynyl]piperazine. The oil was dissolved in ethyl acetate (2 ml) and the solution was treated with 4N hydrogen chloride in ethyl acetate solution (0.30 ml) under ice-cooling, and evaporated under reduced pressure to give colorless powder of [3,5-bis(trifluoromethl)benzovl]-2-- (2,3-dimethoxybenzvl)- (3,3-dimethvlorholino)-2-butynyllpiperazine dihydrochloride (0.18 g).

mo 17000 TR (KBr) 2933, 2575, 1647, 1637, 1433, 1281, 1186, 1136 cirC 1 n (DMSO-d~ I) 1.33 (3H, 1.41 (3H, 2.60- 5.20 (19H, 3.75 6.50-7.00 (3K, m), 7.50-8.20 (3H, m) IMAS S (APOC) 642 (free) Examnle 88 The following compound was obtained according to a similar manner to that of Example 86.

-r3 ,5-Bis(trifluoromethyl)benzoyl]-4-(benzyloxycarbonyl) (H-indol-2-vl)iethyljpiperazine IR 1714, 1699, 1684, 1647, 1635, 1453, 1281 cm- 1 NNR (DMSO-d 6 6) 2.60-5.10 (9H, 5.15 (2H, s), 5.98-8.48 (13K, 10.58-11.04 (iH, m) MA S (APCI) 590 Exainole 89 The following compounds were obtained according to a similar manner to that of Example 87.

l-[3,5-Bis(trifluoromethyl)benzoyl]-2-'((H-indol-2-yl)methyl]-4-14- (3,3-dimethylmorpholino)-2-butynyl]piperazine dihydrochioride WO 98/57954 PCT/JP98/02613 169 mo 85C MOO -18 IR (KBr) 1651, 1647, 1637, 1281, 1188, 1136 cm' NMR (DMSO-d 6 5) 1.31 (3H, 1.40 (3H, 3.00- 5.22 (19H, 6.02-6.40 (1H, 6.90-8.20 (7H, m) i, 11 70 -11. 17 (1 H, m) MASS (APCI) 621 (free) 1 F 3 ,5-Bis (trifluoromethvl)benzoyl]-2- (3-methoxybenzvl)- (3,3-dimethyl)morpholino-2-buynyl]pperazife dihvdrochioride MoD 223-225 0

C

IR (KBr) 3600-3300, 2900, 2600-2300, 1647, 1635, 1458, 1435, 1280 cm- N-MR (DMSO-d 6 5) 1.32 (3H, 1.40 (3H, 2.8-5.2 (22H, 6.5-8.20 (7H, in), 12.1-12.6 (2H, m) MASS (APCI) 612 (kfree) Exainole The following compounds were obtained according to a similar manner to that of Example 9.

(2R) P'4- 3 -Dimethylinorpholino) -2-butyfyl2 (Hindol-3-yl)methvl]-l-[3-(methylamino) (trifluoromethyl)benzoyllpiperazine dihydrochioride mp 215-230*C 27 +41.8' MeOH) [aID IR (KBr) 3600-3300, 2900, 2600-2300, 1645, 1624, 1614, 1458, 1419 Cm 1 NMR (DMSO-d 6 ,5 1.20-1.50 (6H, in), 2.69 (3H, s), 2.90-5.30 (19H, -6.55-7.90 (9H, 10.98 (1H, br 11.90-12.60 (2H, i) MASS (APCI) 582 (free) (2R)-1-[3-(Dimethvlamino)--(tri luromethyl )benzoylV- 4 (4-(3,3-dimethyliorpholino)-2-butynyll-2-[(lN-indol-3- WO 98/57954 PCT/JP98/02613 170 yl)methyl] oiperazine dihydrochioride np 210-2250C fc]j +31.80 MeOH) IR (KBr) 3600-3300, 2900, 2600-2300, 1653, 1647, 1635, 1558, 1541, 1508, 1473, 1458, 1419 cm 1 i NMR (DMSO-d 6 1.20-1.50 (6H, 2.70-5.28 (19H, 2.94 (6H, 6.48-7.90 (8H, mn), 10.99 (1H, br 12.00-12.50 (2H, m) MATS kS (APC) 596 (free) (2R)-4-[4-(3,3-Diinethyliorholino)-2-butyfyl]-2-[(1Hindol-3-yl)methylj-1-[3-nitro-5-(trifluoromethyl)benzoyl]piperazine dihydrochioride MT 198-2200C IR (KEr) 3600-3300, 2900, 2600-2300, 1645, 1635, 1543, 1471, 1458, 1421, 1358, 1331 cm 1 NMR (DMSO-d 6 5) 1.33 (3H, 1.41 (3H, 2.80- 5.22 (19, 6.50-8.62 (8H, 10.99 (1H, s), 11.80-12.60 (2H, m) MASS (APCI) 598 (MH)V (free) (2R)-2-(3,4-Diethylbenzl)-4-[4-(3,3-dimethyliorpholino)-2-butynyl]-l-[3-(methylamino)-5- (trifluoromethyl)benlzoyl1piperazine dihydrochioride mD 195-2050C 27 +10.80 MeO) IR (KBr) 3600-3300, 2900, 2600-2300, 1647, 1635, 1616, 1456, 1419 NWMR (DMSO-d 6 5) 1.32 (3H, 1.40 (3H, 2.00- O 2.30 (6K, 2.70 (3K, 2.90-5.20 (19K, m), 6.20-7.20 (7H, 12.22 (2H, br s) MAS S (APCI) 571 (tree) (Dimethyl amino)- S- (trifluoromethyl) benzoyl]-2- (3,4-diiethylbenzyl)-4-[4- (3,3-dimethylmorpholino)-2- WO 98/57954 PCT/JP98/02613 171 butynyl.piperazine dihydrochioride mp 108-185 0

C

(a]27 +8.80' MeOH) IR (KBr) 3600-3300, 2900, 2600-2300, 1647, 1635, 1616, 1608, 1506, 1456, 1425 cm- 1 NMR (DMSO-d 6 6) 1.32 (3H, 1.40 (3H, 2.02- 2.30 (6H, 2.95 (6H, 3.00-5.25 (19H, i), 6.20-7.20 12.28 (2H, br s) MASS (APCI) 585 (free) 2

R)-

2 -(3,4-Dimethylbenzyl)-4-[4-(3,3-diethyliorpholino)-2-butynyl-l-[3-nitro-5-(trifluoromethyl)benzoyllpiperazine dihydrochioride mp 157-2000C [a]26 +19.50 MeOH) IR (KBr) 3600-3300, 2900, 2600-2300, 1647, 1637, 1543, 1456, 1423, 1356, 1330, 1319 cm 1 NMR (DMSO-d 6 5) 1.33 (3H, 1.41 (3H, 1.95- 2.34 2.62-5.20 (19H, 6.60-8.60 (6H, 12.10-12.50 (2H, m) MASS (APCI) 587 CM+H)+ (free) Preparation 72 The following compounds were obtained by a similar manner to that of Preparation 38.

2 R)-l-(3,5-Bis(trifluoromethyl)benzoyll-2q(1H-indol-3yl)methyl]-4-(2-hydroxyethylypiperazine IR (Neat) 3300, 2930, 2800, 1623 cm- 1 NMR (DMSO-d,6, 5) 2.00-5.00 (14H, 6.60-8.28 (8H, 10.86 (1H, s) MASS (APCI) 500 (M+H) 2 R)-l-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,.4dimethylbenzyl)-4-( 2 -hydroxyethyl)piperazine WO 98/57954 PCT/JP98/02613 172 IR (Neat) 3400, 1640, 1430, 1280, 1170 cmf 1 NMR (DMSO-d 6 5) :2.00-5.00 (20H, in), 6.60-8.20 (6H. mn) Preparation 73 The following compounds were obtained by a similar manner to that of Example 39.

2 R)-l-[3,5-Bis(trifluoromethyl)benzoyll2-[(1H-indol>3 yl)methyl]-4- C2-methanesulfonyloxyethyl~piperazine IR (Neat) :3340, 3300, 3000, 2930, 2800, 1624 crrJ 1 NMR '(DMSO-d 6 6) 2.10-4.70 (13H, mn), 3.24 (3H, s), 6.26-8.28 (8H, mn), 10.90 (1H, s) MASS (APCI) 578 2 R)-l-[3,5-Bis(trifluoromethyl)benzoyl..2C3,4diinethylbenzyl) 2 -methanesulfonyloxyethyl)piperazine IR (Neat) :1640, 1430, 1280, 1150 cmrJ 1 NMR (DMSO-d 6 5) :2.00-5.00 (23H, in), 6.60-8.20 (6H, m) MASS (AFCI) 567, 489 Preparation 74 The following compound was obtained by a similar manner to that of Preparation 37.

2 3 ,5-Bis(trifluoromethyl)benzoyl21H...indol.3yl)inethyl]-4- 4 -chloro-2-butynyl)piperazine IR (Neat) :3300, 3050, 2800, 2600, 1630, 1430 cm- 1 NMR (CDCl 3 6) 2.20-5.30 (1,3H, in), 6.75-8.20 (8H, m) MASS (APCI) 542 Preparation The following compound was obtained by a similar manner to that of Preparation 46-(4).

1-Acetyl-3- 3 -iethoxy-4-methylphenyl)methylene-2,5- WO 98/57954 PCT/JP98/02613 173 piperazinedione NMR (DMSO-d 6 2.17 (3H, 2.50 (3H, 3.83 (3H, 4.37 (2H, 6.95 (1H, 7.08-7.22 (3H/1 mn), 10.33 (1H, s) MASS (APCI) 289 The following compound was obtained by a similar manner to that of Preparation 46-(5).

3- 3 -Methoxy-4-methylbenzyl) 2 NMR (DMSO-d 6 5) :2.11 (3H, s) 2.75 (1H, d, J=17.4Hz), 2.84 (1H, in), 3.05 (1H, dd, J=13.4, 3.35 (1H, in), 3.73 (3H, 4.04 (1H, in), 6.63 (1H, d, J=7.4Hz), 6.73 (1H, 7.03 (1H, d, J=7.4Hz), 7.88 (1H, mn), 8.13 (1H, mn) MASS (APCI) :249 The following compound was obtained by a similar manner to that of Preparation 47-(3).

2- 3 -Methoxy-4-methylbenzyl) piperazine dihydrobronide NMR (DMSO-d 6 5) :2.13 (3H, 2.78-3.78 (9H, mn), 3.81 (3H, 6.73-7.15 (3H, in), 9.11 (4H, in) MASS (APOI) 221 (free) A stirred solution of 2 -(3-inethoxy-4-methylbenzyl)piperazine dihydrobroinide (240 ing) in 48% hydrobromic acid (8 ml) was heated under reflux for 48,hours. After cooling, the mixture was concentrated under reduced pressure. The residue was triturated with ethyl acetate and the resulting precipitates were collected by filtration, and washed with ethyl acetate to give 2 3 -hydroxy-4-inethylbenzyl)piperazine dihydrobroinide (175 mng) as a powder.

NMR (DMSO-d 6 a) 2.11 (3H, 2.67-3.78 in), '6.70-6.95 (3H, mn), 9.09 M4, m) WO 98/57954 PCT/JP98/02613 174 MASS (APOI) 207 (free) Example 91 The following compounds were obtained by a similar manner to that of Example 84.

1-[3,5-Bis(trifluoromethyl)benzoyl]-4-[4-(3,3dimethylmorpholino) -2-butynyl] (3-hycroxy-4-methylbenzyl) piperazine dihydrochloride NNR (DMSO-d 6 6) 1.32-1.38 (6H, in), 2.08 (3H, s), 2.68-5.03 (20H, in), 6.18-8.20 (6H, m) MASS (APCI) :612 (free) 1-[3,5-Bis(trifluorornethyl)benzoyl]-4-[4-(3,3dimethylmorpholino) -2--butynyl]-2- (3-methoxy-4methylbenzyl) piperazine dihydrochloride NMR (DMSO-d 6 6) 1.33-1.38 (6H, mn), 2.10 (3H, s), 2.73-5.10 (22H, in), 6.40-8.18 (6H, mn) MASS (APCI) 626 (free) 1-[3,5-Bis(trifluoromethyl)benzoyl]-4-[4-(3,3dimethylmorpholino) -2-butynyl--2-(4-hydroxy-3methylbenzyl) piperazine dihydrochloricle NNR (DMSO-d 6 6) :1.32-1.38 (6H, mn), 2.09 (3H, s), 2.73-4.98 (20H, in), 6.55-8.20 (6H, mn) MASS (APCI) 612 (free) Preparation 76 The following compound was obtained according-to a similar manner to that of Preparation 75-(4).

2- (4-Hydroxy-3-methylbenzyl) piperazine dihydrobromide NI4R (DMSO-d 6 6) 2.10 2.67-3.57 in), 6.57-7..11 (3H1, in), 9.12-9.39 (5H, in) MASS (APCI) :207 (free) WO 98/57954 PCT/JP98/02613 175 Preparation 77 The following compound was obtained according to a similar manner to that of Preparation 46-(4).

l-Acetyl-3- 3 -nitrophenyl)methylene-2, mp: 190-200°C NMR (DMSO-d 6 6) 2.51 (3H, 4.32 (2H, 7.03 (1H, 7.65 (1H, 7.94 (1H, d, J=7.8Hz), 8.16 (1H, dd, J=1.6, 7.8Hz), 8.37 (1H, d, J=1.6Hz), 10.80 (1H, br s) MASS (APCI) :290 79 A mixture of l-acetyl-3-(3-nitrophenyl)methylene-2, piperazinedione (10.2 triethylamine (6.43 ml) and ditert-butyl dicarbonate (23.5 g) in N,N-dimethylformamide ml) was hydrogenated over 10% palladium-carbon (50% wet, 1 g) at room temperature under 2-3 atmospheres. After removal of catalyst by filtration, the filtrate was concentrated by evaporation, the residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was pur-i-fied by column chromatography on silica gel using a mixture of dichloromethane and methanol The fractions containing the objective compound were collected and evaporated under reduced pressure. The resulting precipitates were collected by filtration and washed with methanol to give l-acetyl-3-[3-(tertbutoxycarbonylamino)benzyl]-2, 5-piperazinedione (1.3 g) as colorless powders.

mp 189-190°C IR (KBr) 3334, 1727, 1704, 1681, 1602, 1590, 1540 cm-1 NMR (DMSO-d 6 6) 1.46 (9H, 2.43 (3H, 2.94 (1H, dd, J=6.4, 14.2Hz), 3.10 (1H, dd, J=6.4, 14.2), 3.15 (1H, d, J=17.4Hz), 3.96 (1H, d, J=17.4Hz), 4.30-4.35 (1H, m) 6.58 (1H, d, WO 98/57954 PCT/JP98/02613 176 J=7.1Hz), 7.15 (1H, 7.23 (1H, d, J=7.Hz), 7.43 (1H, 7.42 (1H, d, J=2.8Hz), 9.32 (1H, s) MASS (APCI) 306 (M-(CH 3 3 The following compound was obtained according to a similar manner to that of Preparation 46-(5).

3-[3-(tert-Butoxycarbonylamino)benzyl]-2,5-piperazinedione mp 230-233°C IR (KBr) 3301, 3212, 3083, 2981, 1716, 1675, 1608 cm- 1 NMR (DMSO-d 6 5) 1.47 (9H, 2.89 (1H, dd, J=5.3, 9.1Hz), 2.95 (1H, d, J=17.0Hz), 2.96 (1H, dd, J=5.3, 9.1Hz), 3.36 (1H, dd, J=3.8, 17.0Hz), 3.95- 4.00 (1H, 6.78 (1H, d, J=7.8Hz), 7.14 (1H, m), 7.30-7.35 (2H, 7.91 (1H, br 8.13 (1H, br 9.30 (1H, s) MASS (APCI) 320 (M+H) 264 A solution of 3 3 piperazinedione (0.75 g) in trifluoroacetic acid (10 ml) was stirred for 4 hours at room temperature. After removal of the solvent by evaporation, the residue was dissolved in a mixture of dichloromethane (10 ml) and methanol (3 ml) and thereto benzaldehyde (0.742 g) and sodium triacetoxyborohydride (2.11 g) were added. The whole was stirred for 2 hours at room temperature and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using, a mixture of dichloromethane and methanol The fractions containing the objective compound were collected and triturated with isopropyl alcohol to give 2-[3- (benzylamino)benzyl]-3,6-piperazinedione (0.43 g) as colorless crystals.

mp 160-161 0

C

IR (KBr) 3168, 3056, 2975, 2867, 1677, 1606, 1550 cm-1 WO 98/57954 PCT/JP98/02613 177 NMR (DMSO-d 6 6) 2.86 (1H, d, J=17.2Hz), 2.82 (1H, dd, J=4.8, 13.3Hz), 2.92 (1H, dd, J=4.8, 13.3Hz), 3.33 (1H, dd, J=3.0, 17.2Hz), 3.96 (1H, d, 4.21 (2H, d, J=6.0Hz), 6.16 (1H, 6.33 (1H, d, J=7.4Hz), 6.41-6.45 (2H, 6.92 (1H, m), 7.18-7.33 (5H, 7.78 (1H, br 8.04 (1H, d, J=2.2Hz) MASS (APCI) 310 (M+H) A suspension of 2-[3-(benzylamino)benzyl]-3,6piperazinedione (0.45 37% aqueous formaldehyde (81 mg), sodium triacetoxyborohydride (0.62 g) and acetic acid (175 mg) in a mixture of 1,2-dichloroethane (15 ml) and N,Ndimethylformamide (5 ml) was stirred for 5 hours at room temperature. Then additional 37% aqueous formaldehyde (0.1 ml), acetic acid (0.2 ml) and sodium triacetoxyborohydride (0.60 g) were added to the reaction mixture and the whole was stirred for further 2 hours. The mixture was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel using a mixture of dichloromethane and methanol The fractions containing the objective compound were collected and evaporated under reduced pressure. The resulting precipitates were collected by filtration and washed with isopropyl alcohol to give 2-[3-(N-benzyl-Nmethylamino)benzyl]-3,6-piperazinedione (0.46 g) as colorless crystals.

NMR (DMSO-d 6 6) 2.71-3.03 (3H, 2,94 (3H, s), 3.27-3.37 (1H, 4.00-4.05 (1H, 4.53 (2H, 6.42 (1H, d, J=7.5Hz), 6.57-6.61 (2H, 6.98-7.06 (lH, 7.16-7.34 7.85 (1H, 8.09 (1H, d, J=2.2Hz) MASS (APCI) 324 (M+H) The following compound was obtained according to a similar manner to that of Preparation 49-(4).

WO 98/57954 PCT/JP98/02613 178 2- (N-Benzyl-N-methylamino)benzyl]piperazine The compound was used to the next step without further purification.

Preparation 78 The following compound was obtained according to a similar manner to that of Preparation 1-[3,5-Bis(trifluoromethyl)benzoyl]-2-[3-(N-methylamino)benzyl]piperazine NMR (CDC1 3 6) 2.20-5.20 (10H, 2.99 (3H, s), 6.00-7.40 (7H, 8.16 (1H, s) MASS (APCI) 446 (M+H) Example 92 The following compound was obtained according to a similar manner to that of Preparation 49-(5) through a similar manner to that of Example 86.

1-[3,5-Bis(trifluoromethyl)benzoyl]-2-[3-N-benzyl-Nmethylamino)benzyl]-4-(benzyloxycarbonyl)piperazine IR (Neat) 1705, 1645, 1605, 1505 cm 1 NMR (CDC1 3 6) 2.60-4.80 (14H, 5.18 (2H, 6.10- 7.40 (16H, 7.84 (1H, s) MASS (APCI) 670 (M+H) Example 93 The following compound was obtained according to a similar manner to that of Example 87.

1-[3,5-Bis(trifluoromethyl)benzoyl]-4-[4-(3,3-dimethylmorpholino)-2-butynyl]-2-[3-(N-methylamino)benzyl]piperazine IR (Neat) 3400, 1680, 1640, 1610 cm 1 NMR (CDC13, 6) 1.06 (6H, br 2.10-5.20 (20H, m), WO 98/57954 PCT/P98/02613 179 3.34 (3H, 5.95-7.80 (7H, m) MASS (APCI) 611 (M+H) its trihydrochloride mp 192-195°C IR (KBr) 3500-3300, 3000-2800, 2700-2300, 1644 cm 1 NMR (CDC1 3 1.36 (6H, 2.71-2.81 (3H, 3.20- 5.20 (20H, 6.60-8.21 (7H, m) MASS (APCI) 611 (free) Example 94 A suspension of 1-[3,5-bis(trifluoromethyl)benzoyl]-4- [4-(3,3-dimethylmorpholino)-2-butynyl]-2-[3-(N-methylamino) benzyl]piperazine (0.19 37% aqueous formaldehyde (50 pl), sodium triacetoxyborohydride (79 mg) and acetic acid (22 4l) in dichloromethane (5 ml) was stirred for 2 hours at room temperature. Then additional 37% aqueous formaldehyde pd), acetic acid (10 pl) and sodium triacetoxyborohydride mg) were added to the reaction mixture and the whole was stirred for further 1 hour. The mixture was poured into aqueous saturated sodium hydrogen carbonate solution and extracted with dichloromethane. The extract was dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using a mixture of dichloromethane and methanol The fractions containing the objective compound were collected and evaporated under reduced pressure and treated with 4N hydrogen chloride in ethyl acetate solution to give 1-[3,5bis (trifluoromethyl)benzoyl]-2-[3-(N,N-dimethylamino)benzyl]- 4-[4-(3,3-dimethylmorpholino)-2-butynyl]piperazine trihydrochloride (0.21 g).

mp 205-210°C IR (KBr) 3500-3300, 2900-2500, 1644 cm-1 NMR (DMSO-d 6 6) 1.32 (3H, 1.41 (3H, 2.91 P.\OPER\M KR\SPECI\76750-98-316 doc- 180- (3H, 3.03 (3H, s) 3.20-5.20 (19H, 6.40-8.25 (7H, m) MASS (APCI) 625 (M+H) (free) Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of 10 integers or steps.

The reference to any prior art in this specification is not, and should not be taken as, an acknowledgment or any form of suggestion that that prior art forms part of the common general knowledge in Australia.

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Claims (5)

1. A compound of the formula O Y-R 2 1II p R'-C-N N-R 4 R 3 wherein Y is lower alkylene, R 1 is phenyl which has 1 or 2 substituent(s) selected from 10 the group consisting of trihalo(lower)alkyl, halogen, lower alkylamino, di(lower)alkylamino and nitro, R 2 is phenyl or indolyl, each of which is substituted by hydroxy and a substituent selected from the group consisting of lower alkyl, trihalo(lower)alkyl, lower alkylenedioxy, hydroxy, hydroxy(lower)alkyl, lower alkoxy, lower alkylamino and di(lower)alkylamino, R 3 is hydrogen, and R 4 is morpholinyl(lower)alkyl which has 1 or 2 substituent(s) selected from the group consisting of ethyl, hydroxy(lower)alkyl, halo(lower)alkyl and lower alkoxy(lower)alkyl; morpholinyl(lower)alkynyl which may have 1 or 2 substituent(s) selected from the group consisting of ethyl, propyl, isopropyl, isobutyl, spirocyclo(lower)alkyl, lower alkoxy(lower)alkyl, hydroxy(lower)alkyl, carboxy(lower)alkyl, di(lower S. alkyl)carbamoyl, lower alkoxycarbonyl and halo(lower)alkyl, 4c- w~i o-o0 P.OPER\IMKR\SPECl\76750-98.316doe- 12111/01 -182- or a salt thereof.

2. A compound of claim 1, which is selected from the group consisting of 1-[3,5-Bis(trifluoromethyl)benzoyl]-4-[4-(3,3- dimethylmorpholino)-2-butynyl]-2-(3-hydroxy-4- methylbenzyl)piperazine, 1-[3,5-Bis(trifluoromethyl)benzoyl]-4-[4-(3,3- dimethylmorpholino)-2-butynyl]-2-(4-hydroxy-3- 10 methylbenzyl)piperazine or a pharmaceutically acceptable salt thereof.

3. A process for the preparation of the compound of claim 1 or a salt thereof, which comprises, reacting a compound of the formula (II): O Y-R 2 S:.R -C-N N-H (II) *3 R 3 wherein R 1 R R 3 and Y are each as defined in claim 1, or a salt thereof, with a compound of the formula (IV): W1-R 4 (IV) wherein R 4 is as defined in claim 1 and W 1 is a leaving group, or a salt thereof to give a compound of the A-4, formula "A J v~ P:IOPER\IKR\SPEC1\76750-98-316 doc-12/1 01

183- 0 Y-R 2 II 4 R -C-N N-R 4 R 3 wherein R R R 3 R 4 and Y are each as defined in claim 1, or a salt thereof, or reacting a compound of the formula (VI): *r 0 Y-R 2 R-C-N N-X 3 -W 2 R 3 (VI) wherein R R 2 R 3 and Y are each as defined above, X 3 is lower alkylene and W 2 is a leaving group, or a salt thereof with a compound of the formula (VII): H-R 7 (VII) /o? f wherein R 7 is morpholino which has 1 or 2 substituent(s) selected from the group consisting of ethyl, hydroxy(lower)alkyl, halo(lower)alkyl and lower alkoxy(lower)alkyl, or a salt thereof to give a compound of the formula (Id) P:\OPER\MKR\SPECI\76750-98-316 doc-12/1101 -184- 0 Y-R 2 1 11 R -C-N N-X 3 -R (Id) R 3 wherein R 1 R 2 R 3 R7, X 3 and Y are each as defined above, 5 or a salt thereof. 9O 4. A pharmaceutical composition which comprises, as an active ingredient, a compound of claim 1 or a pharmaceutically acceptable salt thereof in admixture with pharmaceutically acceptable carriers. A compound of claim 1 for use as a medicament. 6. A method for treating or preventing Tachykinin-mediated 15 diseases which comprises administering an effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof to human being or animals. 7. A compound of claim 1 for use as Tachykinin antagonist. 8. Use of a compound of claim 1 for manufacture of a medicament for treating or preventing Tachykinin-mediated diseases. P:\OPERMKR\SPECIh76750-98-3I6dom.12/ 1101

185- 9. A compound of claim 1, a process for its preparation, a composition comprising it or methods of treatment or use involving it, substantially as hereinbefore described with reference to the examples. DATED this 13th day of November, 2001 Fujisawa Pharmaceutical Co., Ltd. 0@ 0 0 00060 *0 By DAVIES COLLISON CAVE S. Patent Attorneys for the Applicant 0 we 0 0*S* @0 S :0w S 0500*0 a 000* 0 9 0*S0 *S6500 S 0 S. 05 S 0 S 0 ~e 4' LL 1 4 2