AU7675098A - Aroyl-piperazine derivatives, their preparation and their use as tachykinin antagonists - Google Patents

Description

WO 98/57954 PCT/JP98/02613 1 DESCRIPTION AROYL-PIPERAZINE DERIVATIVES, THEIR PREPARATION AND THEIR USE AS TACHYKININ ANTAGONISTS 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 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. Accordingly, one object of the present invention is to provide new and useful 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. Another object of the present invention is to provide a process for the preparation of said piperazine derivatives and a salt thereof. A further object of the present invention is to provide a pharmaceutical composition comprising, as an active ingredient, said piperazine derivatives and a pharmaceutically acceptable salt thereof. Still further object of the present invention is to provide a use of said piperazine derivatives or a pharmaceutically acceptable salt thereof as Tachvkinin antagonist, especially Substance P antagonist, Neurokinin A antagonist or Neurokinin B antagonist, useful for treating or preventing Tachykinin-mediated diseases, for example, respiratory diseases such as asthma, bronchitis, rhinitis, cough, expectoration, and the like; ophthalmic diseases such WO 98/57954 PCT/JP98/02613 2 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 (e.g., migraine, headache, toothache, cancerous pain, back pain, etc.); and the like in human being or animals. Some piperazine derivatives having pharmaceutical activities such as Tachvkinin antagonism have been known as described in EP 0655442 Al and WO 97/22597 Al. DISCLOSURE OF INVENTION The object compound of the present invention can be represented by the following general formula (I) :

Y-R

2 0 w e e wherein Y is bond or lower alkylene,

R

1 is aryl which may have substituent(s), R is aryl or indolyl, each of which may have substituent(s),

R

3 is hydrogen or lower alkyl,

R

4 is pyridyl(lower)alkylamino(lower)alkynyl; D N-(lower alkyl)-N-[pyridyil(lower)alkyl]amino(lower) alkyl; hydroxy(lower)alkoxy(lower)alkyl; lower alkanoyl(lower)alkoxy(lower)alkyl; phenyl(lower)alkyl which has hydroxy(iower)alkyl or morpholinyl(lower) alkyvl; WO 98/57954 PCT/JP98/02613 3 ar(lower)alkoxycarbonyl: (2-pyridyl)(lower)alkyl which may have 1 to 3 substituent(s) selected from the group consisting of lower alkyl, lower alkoxy, lower alkoxycarbonyl, mono(or 5 di or tri)halo(lower)alkyl and halogen; (3-pyridyl)propyl which may have lower alkoxy or amino; (3-pyridyl)butyl which may have lower alkoxy or amino; pyridyl(lower)alkenyl which may have lower alkoxy or amino; 0 (2-pyridyl)(lower)alkynyl 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; (3-pyridyl)(lower)alkynyl which may have lower alkoxy or 5 amino; pyridyl, thiazolyl, imidazolyl or pyrazolyl, each of which may have substituent(s); imidazolyl(lower)alkyl which may have 1 or 2 substituent(s) selected from the group consisting of 0 lower alkyl, lower alkynyl, ar(lower)alkyl, pyridyl(lower)alkyl, mono(or di or tri)halo(lower)alkyl and halogen; pyrazolyl(lower)alkyl which may have hydroxy(lower)alkyl, carboxy(lower)alkyl, lower 5 alkoxycarbonyl(lower)alkyl, morpholinyl(lower)alkyl or morpholinylcarbonyl(lower)alkyl; thiazolyl(lower)alkyl which may have lower alkyl; piperidyl(lower)alkyl which may have hydroxy(lower)alkyl or lower alkoxy; 3 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 D alkoxy(lower)alkyl; WO 98/57954 PCT/JP98/02613 4 (3,5-dimethylmorpholino)(lower)alkyl; morpholino(lower)alkenyl which may have lower alkyl or lower alkoxy(lower)alkyl; (2- or 3-morpholinyl)(lower)alkenyl which may have lower 5 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 L0 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 .5 alkoxy; (dimethylmorpholino)(lower)alkynyl; homomorpholinyl(lower)alkynyl which have halogen; (morpholinylamino)propyl which may have lower alkanoyl; thiomorpholinyl(lower)alkynyl which may have 0 substituent(s); homomorpholinylamino(lower)alkyl; thiomorpholinylamino(lower)alkyl; or saturated heterocyclicimino(lower)alkyl, saturated heterocyclicaminocarbonyl(lower)alkyl or 5 saturated heterocyclic(lower)alkoxy(lower)alkyl, each of which may have substituent(s), provided that when

R

4 is 2-[N-methyl-N-(3-pyridylmethyl)amino]ethyl, 3-(3-pyridyl)propyl, 0 3-(3-pyridyl)-2-propynyl, 4-[(2-methoxymethyl)pyrrolidino]-2-butynyl, 4 -thiomorpholino-2-butynyl, 3-(morphlinoamino)propyl, 4-morpholino-2-butenyl, 4-morpholino-2-butynyl, or 5 4-(3,3-dimethylmorpholino)-2-butynyl, then WO 98/57954 PCT/JP98/02613 5

R

1 is not 3,5-bis(trifluoromethyl)phenyl. It is to be noted that the object compound (I) may include one or more stereoisomers due to asymmetric carbon atom(s) and 5 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 object compound (I) may occur due to the effect of the light, acid, base or the like, and the compound 0 obtained as the result of said isomerization or rearrangement is also included within the scope of the present invention. It is also to be noted that the solvating form of the compound (I) (e.g. hydrate, etc.) and any form of the crystal of the compound (I) are included within the scope of the 5 present invention. According to the present invention, the object compound (I) or a salt thereof can be prepared by processes which are illustrated in the following schemes. 0 Process 1

Y-R

2

Y-R

2 5 0 WI-R 4 0 R1 - - -H 1-R R1-- -R 4 (IV) 3 or a salt thereof 3 0 (II) (I) or its reactive derivative or a salt thereof at the imino group or a salt thereof 5 WO 98/57954 PCT/JP98/02613 6 Process 2

Y-R

2

Y-R

2 / _ reduction N -XR 5 Rl- -N N- Zi-R5 > 1 N NX-5 (ia) (Ib) or a salt thereof or a salt thereof Process 3

Y-R

2

Y-R

2 o 0 0 1 _ H 2

N-R

6 O

R-

- N

N-X

2 -C-OH > R--N N-X 2

-C-N-R

6 (V H 3 or a salt thereof 3 (III) (Ic) or its reactive derivative or a salt thereof at the carboxy group or a salt thereof Process 4 y-R 2 yR 2 0

H-R

7 0 RI--N N-X 3

-W

2

R

1 -C-N 'N-X-R 7 (VII) 3 or a salt 3 thereof (VI) (Id) or a salt thereof or a salt thereof WO 98/57954 PCT/JP98/02613 7 Process 5

Y-R

2

Y-R

2 OH-R8

O

I 0 0 5 R'-N N-Z 2

-W

3

H-R

8 Rl--N -Z2-R8 (IX) 3 or a salt 3 thereof (VIII) (le) or a salt thereof or a salt thereof 10 Process 6

Y-R

2

Y-R

2 1_ - H-R90 15 R1 -N N-Z 3

-W

4 H R1

-

C-N -Z 3

-R

9 (XI) \e 3 or a salt 3 thereof (X) (If) or a salt thereof or a salt thereof 20 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, 25 Z 2 is lower alkenylene,

R

5 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 30 3-pyridyl which may have lower alkoxy or amino,

R

6 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) 35 selected from the group consisting of lower alkyl, lower WO 98/57954 PCT/JP98/02613 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, 5 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 10 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; 3,5-dimethylmorpholino; 15 morpholinylamino which may have lower alkanoyl; homomorpholinylamino; or thiomorpholinylamino,

R

8 is morpholino which may have lower alkyl or lower alkoxy(lower)alkyl, 20 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, 25 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, 30 W 1 , W 2 , W 3 and W 4 are each a leaving group. As to the starting compounds (II), (III), (IV), (V), (VI), (VII), (VIII), (IX) and (X), some of them are novel and can be prepared by the procedures described in the 35 Preparations and Examples mentioned later or similar manners WO98/57954 PCT/JP98/02613 9 thereto. Suitable salts of the starting and object compounds are conventional non-toxic and pharmaceutically acceptable salt 5 and include an acid addition salt such as an organic acid salt (e.g. acetate, trifluoroacetate, fumarate, maleate, tartrate, methanesulfonate, benzenesulfonate, formate, toluenesulfonate, etc.), an inorganic acid salt (e.g. hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, 0 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 (e.g. sodium salt, potassium salt, etc.) and an alkaline earth metal salt (e.g. calcium salt, magnesium salt, etc.), an ammonium salt, an 5 organic base salt (e.g. trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt, N,N'-dibenzylethvlenediamine salt, etc.), or the like. In the above and subsequent descriptions of the present D 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 5 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 3 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, 5 l-(or 2- or 3-)hexenylene, methylvinylene, ethylvinylene, WO 98/57954 PCT/JP98/02613 10 1-(or 2- or 3-)methylpropenylene, 1-(or 2- or 3-) ethylpropenylene, 1-(or 2- or 3- or 4-)methyl-1-(or 2-) butenylene, and the like. Suitable "lower alkynylene" may include one having 2 to 5 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 L0 tri)halo(C 1 -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", .5 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 0 "3-pyridyl (lower)alkenyl", "saturated heterocyclic(lower)alkenyl", etc. may include vinyl, 1-(or 2-)propenyl, 1-(or 2- or 3-)butenyl, 1-(or 2- or 3- or 4-)pentenyl, 1-(or 2- or 3- or 4- or 5-)hexenyl, methylvinyl, ethylvinyl, 1-(or 2- or 3-)methyl-!-(or 2-)propenyl, 1-(or 2 5 or 3-)ethyl-1- (or 2-)propenyl, l-(or 2- or 3- or 4-)methyl-1 (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) 0 (lower)alkynyl", etc. may include ethynyl, 1-propynyl, propargyl, 1-methylpropargyl, !-(or 2- or 3-)butynyl, 1-(or 3-)methyl-2-butynyl, 1-(or 3-)ethyl-2-butynyl, 1-(or 3-)propyl-2-butynyl, l-(or 3-)isopropyl-2-butynyl, 1-(or 2- or 3- or 4-)pentynyl, 1-(or 2- or 3- or 4- or 5-) 5 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

-C

10 aryl and the most 5 preferred one is phenyl or naphthyl. Suitable "lower alkanoyl" and "lower alkanoyl" moiety in the term "lower alkanoyli(lower)alkoxy(lower)alkyl" may include formyl, acetyl, propanoyl, butanoyl, 2-methylpropanoyl, pentanoyl, 2,2-dimethylpropanoyl, hexanoyl D 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, 5 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 Dreferably 5 to 7 membered) 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 6 membered) heteromonocyclic group containing 1 or 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), for example, morpholinyl, homomorpholinyl, sydnnyl, etc.; saturated 3 to 8-memibered (more preferably 5 or 6 membered) 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 : WO98/57954 PCT/JP98/02613 12

(CH

2 )u (wherein u, m and n are each CH2)m integer of 1 to 6); 5 CH2)n saturated heterobicyclic group of the formula : L0 ,(CH2 )q -N (C2) (CH 2 )t (wherein q, r, s and t are each S\ / integer of 1 to 6); and the like.

CH

2 )r .5 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, 0 saturated heterocyclicaminocarbonyl(lower)alkyl or saturated heterocyclic(lower)alkoxy(lower)alkyl, each of which may have substituent(s)" may include lower alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, neopentyl, tert-pentyl, hexyl, etc.), 5 cyclo(lower)alkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.), lower alkylenedioxy (e.g., methylenedioxy, ethylenedioxy, propylenedioxy, etc.), lower alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, isobutoxy, tert-butoxy, pentyloxy, neopentyloxy, tert 0 pentyloxy, hexyloxy, etc.), lower alkoxy(lower)alkyl (e.g., methoxymethyl, ethoxymethyl, l-methoxyethyl, 2-methoxyethyl, l-ethoxyethyl, 2-ethoxyethyl, etc.), lower alkanoyl (e.g., formyl, acetyl, propionyl, butyryl, isobutyryl, etc.), lower alkoxycarbonyl (e.g., 5 methoxycarbonyl, ethoxycarbonyl, propylcarbonyl, WO 98/57954 PCT/JP98/02613 13 isopropylcarbonyl, etc.), lower alkenyl (e.g., 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 alkynyl (e.g., ethynyl, 1-propynyl, propargyl, 5 1-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)halo(lower)alkyl (e.g., fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, bromomethyl, dibromomethyl, tribromomethyl, 0 1 or 2-fluoroethyl, 1 or 2-bromoethyl, 1 or 2-chloroethyl, 1,1-difluoroethyl, 2,2-difluoroethyl, etc.), halogen (e.g., chlorine, bromine, fluorine and iodine), carboxy, protected carboxy, hydroxy, protected hydroxy, aryl (e.g., phenyl, naphthyl, etc.), ar(lower)alkyl such as phenyl(lower)alkyl 5 (e.g., benzyl, phenethyl, phenylpropyl, etc.), carboxy(lower)alkyl wherein lower alkyl moiety can be referred to the ones as exemplified above, protected carboxy(lower)alkyl wherein lower alkyl moiety can be referred to the ones as exemplified above, nitro, amino, 0 protected amino, lower alkylamino (e.g. methvlamino, ethylamino, isopropylamino, etc.), di(lower)alkylamino (e.g., dimethylamino, diethylamino, diisopropylamino, ethylmethylamino, isopropylmethylamino, ethylisopropylamino, etc.), hydroxy, hydroxy(lower)alkyl (e.g. hydroxymethyl, 5 hydroxyethyl, etc.), protected hydroxy(lower)alkyl, acyl, cyano, oxo, mercapto, lower alkylthio (e.g., methylthio, ethylthio, propylthio, isopropylthio, butylthio, etc.), lower alkylsulfinyl (e.g., methylsulfinyl, ethylsulfinyl, propylsulfinyl, isopropylsulfinyl, butylsulfinyl, etc.), 3 imino, morpholinyl (e.g., 2-morpholinyl, 3-morpholinyl, morpholino), bivalent group of the formula 5I WO98/57954 PCT/JP98/02613 14 carboxy(lower)alkyl (e.g., carboxymethyl, carboxyethyl, carboxypropyl, etc.), lower alkoxycarbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl, 5 pentyloxycarbonyl, neopentyloxycarbonyl, tert-pentyloxycarbonyl, hexyloxycarbonyl, etc.), spirocyclo(lower)alkyl (e.g., spirocyclopropyl, spirocyclobutyl, spirocyclopentyl, etc.), ar(lower)alkoxycarbonyli(lower)alkyl (e.g., 3 benzyloxycarbonylmethyl, benzyloxycarbonylethyl, benzyloxycarbonylpropyl, etc.), pyridyl(lower)alkyl (e.g., pyridylmethyl, pyridylethyl, etc.), carbamoyl, lower alkyvlcarbamoyl (e.g. methylcarbamoyl, ethylcarbamoyl, etc.), di(lower alkyl)carbamoyl (e.g. dimethylcarbamoyl, 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 (e.g. phenoxy, naphthoxy, ) etc.), an acid residue or the like. Suitable "acid residue" may be halogen (e.g. chl-orine, bromine, iodine, etc.), sulfonyloxy (e.g. methanesulfonyloxy, phenylsulfonyloxy, mesitylenesulfonyloxy, toluenesulfonyloxy, etc.) or the like. Preferred embodiments of the object compound (I) are as follows : Y is lower alkylene (more preferably C!-Cq alkylene, most preferably methylene);

R

1 is aryl (more preferably C 6

-C

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 PCT/JP98/02613 15 trihalo(lower)alkyl, most preferably trifluoromethyl), halogen (more preferably chlorine), lower alkylamino (more preferably C 1

-C

4 alkylamino, most preferably methylamino), di(lower)alkylamino (more preferably 5 di(C 1

-C

4 )alkylamino, most preferably dimethylamino) and nitro];

R

2 is aryl (more preferably C6-C 10 aryl, most preferably phenyl or naphthyl) or indolyl, each of which may have 1 to 3 (more preferably 1 or 2) substituent(s) [more 0 preferably substituent selected from the group consisting of lower alkyl (more preferably Cl-C 4 alkyl, most preferably methyl), mono(or di or tri)halo(lower)alkyl (more preferably mono(or di or tri)halo(C!-C4)alkyl, most preferably trifluoromethyl), 5 lower alkylenedioxy (more preferably C!-C 4 alkylenedioxy, most preferably methylenedioxy or ethylenedioxy), hydroxy, hydroxy(lower)alkyl (more preferably hydroxy(C 1

-C

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

-C

4 0 alkoxy, most preferably methoxy), lower alkylamino (more preferably C!-C4 alkylamino, -most preferably methylamino) and di(lower)alkylamino (more preferably di(C 1

-C

4 )alkylamino, most preferably dimethylamino)];

R

3 is hydrogen; and 5 R 4 is pyridyl(lower)alkylamino(lower)alkynyl (more preferably pyridyl(C!-C 4 )alkylamino(C 2

-C

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

-C

4 alkyl)-N-[pyridyl(C!-C4) 0 alkyl]amino(C 1

-C

4 )alkyl, most preferably 2-[N-methyl-N (3-pyridylmethyl)amino] ethyl]; hydroxy(lower)alkoxy(lower)alkyl (more preferably hydroxy(C -C 4) alkoxy(C

!

-C

4) alkyl, most preferably (hydroxyethoxy)ethyl); 5 lower alkanoyl(lower)alkoxy(lower)alkyl (more preferably WO98/57954 PCT/JP98/02613 16 Cl-C4 alkanoyl(C1-C4)alkoxy(C1-C4)alkyl, most preferably formylmethoxyethyl); phenyl(lower)alkyl (more preferably phenyl(Cl 1

-C

4 )alkyl, most preferably benzyl) which has hydroxy(lower)alkyl 5 (more preferably hydorxy(Cl-C 4 )alkyl, most preferably hydroxymethyl) or morpholinyl(lower)alkyl (more preferably morpholinyl(C1-C4)alkyl, most preferably morpholinomethyl) [more preferably a-(hydroxymethyl) benzyl or a-(morpholinomethyl)benzyl]; .0 ar(lower)alkoxycarbonyl (more preferably (C6-C10 aryl)(Cl-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 5 (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 Cl-C4 alkyl, most preferably methyl), lower alkoxy (more preferably Cl-C4 alkoxy, most preferably methoxy), lower 0 alkoxycarbonyl (more preferably Cl-C4 alkoxycarbonyl, most preferably methoxycarbonyl), mono(or di or tri)halo(lower)alkyl (more preferably trihalo(Cl-C 4

)

alkyl, most preferably trifluoromethyl) and halogen (more preferably fluorine)); 5 ( 3 -pyridyl)propyl (more preferably 3-(3-pyridyl)propyl) which may have lower alkoxy (more preferably Cl-C4 alkoxy, most preferably methoxy); (3-pyridyl)butyl (more preferably 4-(3-pyridyl)butyl); pyridyl(lower)alkenyl (more preferably pyridyl(C2-C4) 0 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 5 group consisting of lower alkyl (more preferably WO98/57954 PCT/JP98/02613 17 C1-C4 alkyl, most preferably methyl), lower alkoxy (more preferably C1-C4 alkoxy, most preferably methoxy), lower alkoxycarbonyl (more preferably Cl-C4 alkoxycarbonyl, most preferably methoxycarbonyl), mono (or di or tri) 5 halo(lower)alkyl (more preferably trihalo(Cl-C 4 )alkyl, most preferably trifluoromethyl) and halogen (more preferably fluorine); (3-pyridyl)(lower)alkynyl (more preferably (3-pyridyl) (C2-C4)alkynyl, most preferably 3-(3-pyridyl)-2-propynyl 0LO or 4 -(3-pyridyl)-3-butynyl) which may have lower alkoxy (more preferably C1-C4 alkoxy, most preferably methoxy) or amino; pyridyl, thiazolyl, imidazolyl or pyrazolyl, each of which may have 1 to 3 (more preferably 1 or 2) L5 substituent(s) [more preferably substituent selected from the group consisting of lower alkyl (more preferably C1-C4 alkyl, most preferably methyl or isopropyl), ar(lower)alkyl (more preferably phenyl

(C

1

-C

4 )alkyl, most preferably benzyl) and pyridyl ?0 (lower)alkyl (more preferably pyridyl(Cl-C 4 )alkyl, most preferably pyridylmethyl)]; imidazolyl(lower)alkyl (more preferably imidazolyl (Cl 1

-C

4 )alkyl, most preferably 3-(1H-imidazol-4-yl) propyl) which may have 1 or 2 substituent(s) selected .5 from the group consisting of lower alkyl (more preferably Cl-C4 alkyl, most preferably methyl or isopropyl), lower alkynyl (more preferably C2-C 5 alkynyl, most preferably propargyl), ar(lower)alkyl (more preferably phenyl(C 1

-C

4 )alkyl, most preferably 0 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(C1-C4)alkyl, most preferably trifluoromethyl) and halogen (more preferably fluorine); 5 pyrazolyl(lower)alkyl (more preferably pyrazolyl(C1-C4)- WO98/57954 PCT/JP98/02613 18 alkyl, most preferably (1H-pyrazol-4-yl)methyl or 3-(1H pyrazol-1-yl)propyl) which may have hydroxy(lower)alkyl (more preferably hydroxy(Cl-C 4 )alkyl, most preferably 2-hydroxyethyl), carboxy(lower)alkyl (more preferably 5 carboxy(Cl-C 4 )alkyl, most preferably carboxymethyl), lower alkoxycarbonyl(lower)alkyl (more preferably Cl-C4 alkoxycarbonyl(Cl-C 4 )alkyl, most preferably tert butoxycarbonylmethyl), morpholinyl(lower)alkyl (more preferably morpholinyl(Cl 1

-C

4 )alkyl, most preferably 10 2-morpholinoethyl) or morpholinylcarbonyl(lower)alkyl (more preferably morpholinylcarbonyl(Cl-C4)alkyl, most preferably morpholinocarbonylmethyl); thiazolyl(lower)alkyl (more preferably thiazoly(C 1

-C

4

)

alkyl, most preferably 4-thiazolymethyl) which may have 15 lower alkyl (more preferably Cl-C4 alkyl, most preferably methyl); piperidyl(lower)alkyl (more preferably piperidyl(C1-C4) alkyl, most preferably piperidylethyl) which may have hydroxy(lower)alkyl (more preferably hydroxy(C 1

-C

4

)

20 alkyl, most preferably hydroxymethyl) or lower alkoxy (more preferably Cl-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) 25 selected from the group consisting of ethyl, hydroxy (lower)alkyl (more preferably hydroxy(Cl-C 4 )alkyl, most preferably hydroxymethyl), halo(lower)alkyl (more preferably halo(Cl-C 4 )alkyl, most preferably fluoromethyl) and lower alkoxy(lower)alkyl (more 30 preferably Cl-C4 alkoxy(Cl-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 35 Cl-C4 alkyl, most preferably methyl) and lower WO98/57954 PCT/JP98/02613 19 alkoxy(lower)alkyl (more preferably Cl-C4 alkoxy (Cl 1

-C

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

(

3

,

5 -dimethylmorpholino)(C 1

-C

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

(C

2

-C

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 LO (more preferably Cl-C4 alkoxy(Cl-C 4 )alkyl, most preferably methoxymethyl); (2- or 3-morpholinyl)(lower)alkenyl (more preferably (2 or 3-morpholinyl)(C 2

-C

4 )alkenyl, most preferably 3-(2 or 3 -morpholinyl)-2-propenyl) which may have lower L5 alkoxycarbonyl (more preferably Cl-C4 alkoxycarbonyl, most preferably tert-butoxycarbonyl); pyrrolidinyl(lower)alkynyl (more preferably pyrrolidinyl

(C

2

-C

4 )alkynyl, most preferably 4-pyrrolidino-2-butynyl) which may have lower alkoxy(lower)alkyl (more preferably 20 Cl-C4 alkoxy(Cl-C 4 )alkyl, most preferably methoxymethyl); morpholinyl(lower).alkynyl (more preferably morpholinyl (C2-C4)alkynyl, most preferably 4-morpholino-2-butynyl or 3

-(

3 -morpholinyl)-2-propynyl) which may have 1 or 2 .5 substituent(s) selected from the group consisting of ethyl, propyl, isopropyl, isobutyl, spirocyclo(lower)alkyl (more preferably spirocyclo

(C

3

-C

6 )alkyl, most preferably, spirocyclopropyl), lower alkoxy(lower)alkyl (more preferably Cl-C4 alkoxy(Cl-C 4

)

0 alkyl, most preferably methoxymethyl or ethoxymethyl), hydroxy(lower)alkyl (more preferably hydroxy(Cl-C 4

)

alkyl, most preferably hydroxymethyl), carboxy(lower) alkyl (more preferably carboxy(Cl-C 4 )alkyl, most preferably carboxymethyl), di(lower)alkylcarbamoyl (more 5 preferably di(Cl-C 4 )alkylcarbamoyl, most preferably WO98/57954 PCT/JP98/02613 20 dimethylcarbamoyl), lower alkoxycarbonyl (more preferably Cl-C4 alkoxycarbonyl, most preferably ethoxycarbonyl) and halo(lower)alkyl (more preferably halo(Cl-C 4 )alkyl, most preferably fluoromethyl); 5 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-C4 alkoxy(C 1

-C

4 )alkyl, most preferably methoxymethyl); 10 (dimethylmorpholino)(lower)alkynyl (more preferably (dimethylmorpholino)(C 2

-C

4 )alkynyl, most preferably 4-(3,3-dimethylmorpholino)-2-butynyl, 4-(2,6-dimethylmorpholino)-2-butynyl or 4-(3,5-dimethylmorpholino)-2-butynyl); 15 homomorpholinyl(lower)alkynyl (more preferably homomorpholinyl(C2-C4)alkynyl, most preferably 4 -homomorpholino-2-butynyl) which may have halogen (more preferably fluorine); morpholinylaminopropyl (more preferably 3-(morpholino 20 amino)propyl) which may have lower alkanoyl (more preferably Cl-C4 alkanoyl, most preferably formyl); thiomorpholinyl(lower)alkynyl (more preferably thiomorpholinyl(C2-C4)alkynyl, most preferably 4 -thiomorpholino-2-butynyl); ?5 homomorpholinylamino(lower)alkyl (more preferably homomorpholinylamino(C1-C4)alkyl, more preferably homomorpholinoaminopropyl); thiomorpholinylamino(lower)al.kyl (more preferably thiomorpholinylamino(C1-C4)alkyl, more preferably 30 thiomorpholinoaminopropyl); or saturated heterocyclicimino(lower)alkyl (more preferably saturated heterocyclicimino(Cl-C4)alkyl, most preferably saturated heterocycliciminoethyl), saturated heterocyclicaminocarbonyl(lower)alkyl (more 5 preferably saturated heterocyclicaminocarbonyl(C1-C4)- WO98/57954 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(Cl-C 4 )alkyl, most 5 preferably saturated heterocyclicethoxyethyl) [wherein "saturated heterocyclic" moiety is saturated 3 to 8 membered (more preferably 5 to 7-membered) heteromonocyclic group containing 1 to 4 (more preferably 1 or 2) nitrogen atom(s) (more preferably .0 pyrrolidinyl, piperidyl or piperazinyl); saturated 3 to 8-membered (more preferably 5 to 7 membered) 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 5 homomorpholinyl); saturated 3 to 8-membered (more preferably 5 or 6 membered) 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); 0 or saturated heterocyclic group of the formula : ,(CH2)q -N (CH 2

)

s (C H 2 )t (wherein q, r, s and t are each S r Las defined above) 5 (CH2)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 0 from the group consisting of cyclo(lower)alkyl (more preferably cyclohexyl), lower alkanoyl (more preferably Cl-C4 alkanoyl, most preferably formyl), lower alkyl (more preferably Cl-C4 alkyl, most preferably methyl, ethyl, isopropyl or isobutyl), mono(or di or 5 tri)halo(lower)alkyl (more preferably monohalo(Cl-C 4

)-

WO98/57954 PCT/JP98/02613 22 alkyl or trihalo(C 1

-C

4 )alkyl, most preferably fluoromethyl or trifluoromethyl), lower alkoxy (more preferably Cl-C4 alkoxy, most preferably methoxy), lower alkoxy(lower)alkyl (more preferably Cl-C4 alkoxy(C 1

-C

4

)

5 alkyl, most preferably methoxymethyl), halogen (more preferably chlorine or fluorine), aryl (more preferably phenyl), cyano, oxo, bivalent group of the formula : 10 <J carboxy(lower)alkyl '(more preferably carboxy(Cl-C 4

)

alkyl, most preferably carboxypropyl), lower alkoxycarbonyl (more preferably Cl-C4 alkoxycarbonyl, most preferably tert-butoxycarbonyl), 15 spirocyclo(lower)alkyl (more preferably spirocyclo

(.C

1

-C

4 )alkyl, most preferably spirocyclopropyl), ar(lower)alkoxycarbonyl(lower)alkyl (more preferably benzyloxycarbonyl(C1-C4)alkyl, most preferably benzyloxycarbonylpropyl), hydroxy(lower)alkyl (more 20 preferably hydroxy(C 1

-C

4 )alkyl, most preferably hydroxymethyl), carbamoyl, lower alkylcarbamoyl (more preferably C1-C4 alkylcarbamoyl, most preferably methylcarbamoyl) and di(lower alkyl)carbamoyl (more preferably di(Cl-C 4 alkyl)carbamoyl, most preferably 25 dimethylcarbamoyl)]. More preferred embodiments of the object compound (I) are as follows : Y is lower alkylene (more preferably Cl-C4 alkylene, most 30 preferably methylene);

R

1 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 35 preferably bis(trihalo(lower)alkyl)phenyl or WO98/57954 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 5 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], 10 naphthyl or indolyl;

R

3 is hydrogen; and

R

4 is pyridyl(lower)alkylamino(lower)alkynyl (more preferably pyridyl(Cl 1

-C

4 )alkylamino(C 2

-C

4 )alkynyl, most preferably 4-[(3-pyridylmethyl)amino]-2-butynyl) or 15 (2-pyridyl)(lower)alkyl (more preferably (2-pyridyl) (C1-C4)alkyl, more preferably (2-pyridyl)propyl or (2-pyridyl)butyl, most preferably 3-(2-pyridyl)propyl. Another more preferred embodiments of the object 20 compound (I) are as follows : Y is lower alkylene,

R

1 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 25 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, 30 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 35 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; 5 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 .0 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 .5 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 0 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; 5 morpholinyl(lower)alkyl which has lower alkyl and lower alkoxy(lower)alkyl; (3,5-dimethylmorpholino)(lower)alkyl; morpholino(lower)alkenyl which may have lower alkyl or lower alkoxy(lower)alkyl; 0 (2- 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 5 substituent(s) selected from the group consisting of WO98/57954 PCT/JP98/02613 25 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; 5 morpholinyl(lower)alkynyl which has methyl and lower alkoxy(lower)alkyl; (dimethylmorpholino)(lower)alkynyl; or homomorpholinyl(lower)alkynyl which may have halogen. 10 The Processes 1 to 6 for preparing the object compound (I) of the present invention are explained in detail in the following. Process 1 L5 The object compound (I) 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 ?0 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 .5 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 0 solvent such as water, alcohol [e.g. 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 5 conventional solvents may also be used in a mixture with WO98/57954 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, 5 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. 10 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 15 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 20 derivative at the carboxy group or a salt thereof with the compound (V) 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, .5 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 [e.g. dialkylphosphoric acid, phenylphosphoric acid, diphenylphosphoric acid, 30 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 [e.g. acetic acid, propionic acid, butyric acid, .5 isobutyric acid, pivalic acid, valeric acid, isovaleric acid, WO98/57954 PCT/JP98/02613 27 2-ethylbutyric acid, trichloroacetic acid, etc.] or aromaticcarboxylic acid [e.g. benzoic acid, etc.]; a symmetrical and anhydride; an activated amide with imidazole, 4-substituted imidazole, dimethylpyrazole, 5 triazole or tetrazole; or an activated ester [e.g. cyanomethyl ester, methoxymethyl ester, dimethyliminomethyl

[(CH

3

)

2 N+=CH-] ester, vinyl ester, propargyl ester, p-nitrophenyl ester, 2,4-dinitrophenyl ester, trichlorophenyl ester, pentachlorophenyl ester, mesylphenyl ester, 10 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, 1-hydroxy-2-(lH)-pyridone, L5 N-hydroxysuccinimide, N-hydroxyphthalimide, l-hydroxy-lH benzotriazole, 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 20 solvent such as water, alcohol [e.g. 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 .5 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 0 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; 5 pentamethyleneketene-N-cyclohexylimine; WO98/57954 PCT/JP98/02613 28 diphenylketene-N-cyclohexylimine; ethoxyacetylene; 1-alkoxy-l-chloroethylene; trialkyl phosphite; ethyl polyphosphate; isopropyl polyphosphate; phosphorus oxychloride (phosphoryl chloride); phosphorus trichloride; 5 diphenyl phosphorylazide; thienyl chloride; oxalyl chloride; lower alkyl haloformate [e.g. ethyl chloroformate, isopropyl chloroformate, etc.]; triphenylphosphine; 2-ethyl-7 hydroxybenzisoxazolium salt; 2-ethyl-5-(m-sulfophenyl) isoxazolium hydroxide intramolecular salt; 10 1-(p-chlorobenzenesulfonyloxy)-6-chloro-lH-benzotriazole; 2-chloro-l-methylpyridinium iodide; 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride; so-called vilsmeier reagent prepared by the reaction of N,N dimethylformamide with thionyl chloride, phosgene, 15 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, 20 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. 25 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 30 in Example 30 mentioned later or similar manners thereto. Process 5 The object compound (le) or a salt thereof can be prepared by reacting the compound (VIII) or a salt thereof 35 with the compound (IX) or a salt thereof.

WO98/57954 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 5 The object compound (If) or a salt thereof can be prepared by reacting the compound (X) 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. 10 The object compound (I) 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 15 therefore are useful for treating or preventing Tachykinin mediated diseases, particularly Substance P-mediated diseases, for example, respiratory diseases such as asthma, bronchitis (e.g. chronic bronchitis, acute bronchitis and diffuse panbronchiolitis, etc.), rhinitis, couph, 20 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 25 the like; inflammatory diseases such as rheumatoid arthritis, osteoarthritis, and the like; pains or aches (e.g. migraine, headache, cluster headache, toothache, cancerous pain, back pain, neuralgia, etc.); and the like. 30 Further, it is expected that the object compound (I) 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, 35 irritable bowel syndrome, food allergy, and the like; WO98/57954 PCT/JP98/02613 30 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 5 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 10 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 15 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, 20 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 25 fibrosis; emesis (e.g. 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, 30 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 35 such as poison ivy; fibrosing and collagen diseases such as WO98/57954 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. 5 Furthermore, the object compound (I) and a pharmaceutically acceptable salt thereof of the present invention are Central Nervous System (CNS) penetrant. For therapeutic purpose, the compound (I) and a 10 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 15 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, 20 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, 25 wetting or emulsifying agents, buffers and other commonly used additives. While the dosage of the compound (I) 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 30 mg and 1000 mg of the compound (I) 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. 35 In order to show the utility of the object compound (I) WO98/57954 PCT/JP98/02613 32 and a pharmaceutically acceptable salt thereof, the pharmacological test data of some representative compounds of the present invention is shown in the following. 5 A. Evaluation of NK 1 antagonist transport efficiency to the cental nervous system using a h-NK 1 receptor binding assay [I] Test Method 10 (1) 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 15 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 ~i of the homogenate, 100 [l of 20 methanol, 500 pl 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. 25 (2) h-NK 1 receptor binding assay (a) Crude CHO cell membrane preparation CHO cells permanently expressing h-NK 1 receptors were 30 harvested and homogenized with a Dounce homogenizer at 40C in a buffer (0.25 M sucrose, 25 mM Tris-HCl (pH 7.4), 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 35 supernatants were combined and centrifuged (100,000 x g, 1 WO98/57954 PCT/JP98/02613 33 hour). The crude cell membranes thus isolated were resuspended in a buffer (25 mM Tris-HCl (pH 7.4), 10 mM MgCl 2 , 1 mM EDTA, 5 pg/ml p-APMSF) and stored at -80°C until use. 5 (b) 1 25 I-BH-Substance P binding to the prepared membrane Cell membranes (6 pg/ml) were incubated with 125I-BH Substance P (0.1 nM) with or without the extracted compounds 10 in 0.25 ml of a medium (50 mM Tris-HCl (pH 7.4), 5 mM MnC1 2 , 20 pg/ml chymostatin,. 40 pg/ml bacitracin, 4 pg/ml leupeptin, 5 pg/ml p-APMSF, 200pg/ml BSA) at 220C for 90 min. At the end of the incubation period, the contents were quickly filtered through a Blue Mat 11740 filter (pretreated with 15 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 7.4), 5 mM MnCl 2 ). The radioactivity was counted by using an auto gamma counter (Packard RIASTAR 5420A). All data presented are specific 20 binding defined as that displaceable by 3 RM unlabeled Substance P. [II] Test Result 25 All of the following Test Compounds showed more than 80% inhibition rate of 12 5I-BH-Substance P binding to h-NK 1 receptors at the dose of 1 mg/kg. Test Compounds : The object compounds of the Examples 30 1-(l), 5-(2), 6-(1), 15, 16-(2), 17, 18, 22, 29, 30, 38, 40, 45, 56-(2), 68, 70-(1), 70-(2), 71-(1), 71-(3), 71-(5), 71-(6), 73-(2), 73-(3), 76-(1), 76-(3), 77, 78-(3), 78-(4), 79-(1), 35 79-(2), 80-(1), 80-(2), 80-(3), 80-(4), WO98/57954 PCT/JP98/02613 34 80-(6), 80-(7), 81-(1), 81-(2), 81-(3), 81-(4), 81-(5), 81-(7), 81-(10), 82, 83-(2), 84, 85-(3), 89-(1), 89-(2), 90-(2), 90-(3), 90-(4), 90-(5) and 5 90-(6) B. Emesis in the ferret [I] Test Method 10 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 15 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. 20 [II] Test Result All of the following Test Compounds showed 100% inhibition rate of emesis in the ferret at the dose of 1.0 25 mg/kg. Test compounds : The object compounds of the Examples 4-(2), 26, 29, 40 and 41 30 (to be continued on the next page) WO 98/57954 PCT/JP98/02613 35 The following Preparations and Examples are given for the purpose of illustrating this invention. Preparation 1 5 A mixture of 3-bromopyridine (6.25 ml), propargyl alcohol (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 10 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 15 as eluent. The fractions containing the objective compound were collected and evaporated under reduced pressure to give 3-(3-pyridyl)-2-propyn-1-ol (7.9 g) as brownish crystals. IR (Nujol) 3160, 1480, 1460, 1400 cm -1 NMR (CDC1 3 , 5) : 3.87 (1H, t, J=5.9Hz), 4.51 (2H, d, 20 J=5.9Hz), 7.24-7.30 (1H, m), 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 (M+H) + 25 Preparation 2 The following compounds were obtained according to a similar manner to that of Preparation 1. (1) 4-(3-Pyridyl)-3-butyn-1-ol 30 NMR (CDC1 3 , 5) : 2.61 (IH, s), 2.71 (2H, t, J=6.3Hz), 3.85 (2H, t, J=6.3Hz), 7.19-7.25 (1H, m), 7.70 (1H, dd, J=2.0, 8.0Hz), 8.48 (1H, dd, J=1.4, 5.0Hz), 8.63 (1H, d, J=1.4Hz) MASS : 279, 148 (M+H) 35 WO 98/57954 PCT/JP98/02613 36 (2) 3-(6-Methoxypyridin-3-yl)-2-propyn-i-ol IR (Nujol) : 3300, 1610, 1560, 1490, 1460, 1370, 1350, 1310, 1300 cm

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1 NMR (CDCl 3 , 6) : 3.94 (3H, s), 4.52 (2H, s), 6.70 (IH, 5 dd, J=0.7, 8.6Hz), 7.60 (1H, dd, J=2.2, 8.6Hz), 8.30 (1H, d, J=2.2Hz) MASS : 164 (M+H) , 134 (3) 3-(4-Methoxypyridin-3-yl)-2-propyn-1-ol -*1 L0 IR (KBr) : 3172, 2854, 1585, 1498 cm NMR (CDCl3-, 5) : 3.90 (3H, s), 4.33 (2H, d, J=4.0Hz), 5.38 (1H, t, J=4.0Hz), 7.12 (1H, d, J=5.8Hz), 8.24 (2H, br s) MASS : 164 (M+H) , 134 5 (4) 3-[6-(tert-Butoxycarbonylamino)pyridin-3-yl]- 2 propyn-1-ol IR (Nujol) : 3500, 3210, 1725, 1625, 1600, 1580, 1430, 1380 cm -I 0 NMR (CDCl 3 , 6) : 1.54 (9H, s), 4.99 (2H, s), 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 (M+H)+, 175 5 Preparation 3 Thionyl chloride (11.9 g) was added dropwise to a solution of 3-(3-pyridyl)-2-propyn-1-ol (13.3 g) in dichloromethane (266 ml) at room temperature. After completion of the addition, the mixture was stirred for 2 0 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. 5 Preparation 4 WO98/57954 PCT/JP98/02613 37 The following compounds were obtained according to a similar manner to that of Preparation 3. (1) l-Chloro-3-(6-methoxypyridin-3-yl)-2-propyne 5 hydrochloride (2) 1-Chloro-3-(4-methoxypyridin-3-yl)-2-propyne hydrochloride 0 Precaration 5 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 0 C. After being stirred at the same temperature for 5 0.5 hour, a solution of sodium borohydride (1.86 g) in water (10 ml) 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. O 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-1-ol (1.0 g) as an oil. 5 NMR (CDC1 3 , 5) : 4.40 (2H, d, J=4.0Hz), 6.52 (1H, dt, J=4.0, 16.1Hz, trans), 6.65 (1H, d, J=16.1Hz, trans), 7.45 (1H, dd, J=5.6, 8.0Hz), 7.89 (1H, d, J=8.0Hz), 8.44 (1H, d, Je5.6Hz), 8.58 (1H, s) MASS 136 (M+H) 0 Preparation 6 Methane sulfonyl chloride (0.22 ml) was added to a mixture of (E)-3-(3-pyridyl)-2-propen-1-ol (0.36 g) and triethylamine (0.74 ml) in dichloromethane (5 ml) under 5 -10 0 C. After being stirred at the same temperature for 0.5 WO98/57954 PCT/JP98/02613 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-l yl methanesulfonate. 5 The crude mesylate was used at next step without further purification. Preparation 7 4-(3-Pyridyl)-3-butyn-1-yl methanesulfonate was obtained 0 according to a similar manner to that of Preparation 6. Preparation 8 The solution of 3-(3-pyridyl)-2-propyl-1-ol (300 mg) in methanol was hydrogenated using Lindlar catalyst for 4 hours 5 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 0 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 , 6) : 4.42 (2H, dd, J=1.6, 6.4Hz), 6.04 (1H, dd, J=6.4, 12.0Hz, cis), 6.52 (1H, d, 5 J=12.0Hz, cis), 7.25-7.31 (1H, m), 7.55 (1H, d, J=8.0Hz), 8.30-8.70 (2H, br s) MASS : 136 (M+H) + Preparation 9 0 A mixture of 4-formyl-l-methylimidazole (3.0 g) and triethylphosphonoacetate (6.3 g) in N,N-dimethylformamide (30 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 5 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-(1-methyl-1H 5 imidazol-4-yl)acrylate (4.63 g). IR (Nujol) : 2900, 1700, 1625 cm -1 NMR (CDC1 3 , 5) : 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, s), 7.45 (1H, s), 7.54 (1H, d, J=15.6Hz) 0 MASS : 181 (M+H) + Preparation 10 A solution of ethyl (E)-3-(l-methyl-1H-imidazol- 4 yl)acrylate (2.5 g) in tetrahydrofuran (100 ml) was 5 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-(l methyl-1H-imidazol-4-yl)propionate (2.63 g). 0 IR (Neat) : 2900, 1720 cm-1 NMR (CDCl 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, s), 4.16 (2H, q, J=7.1Hz), 6.64 (1H, s), 7.33 (1KH, s) MASS 183 (M+H)+ 5 Preparation 11 To an ice-cooled solution of ethyl 3-(1-methyl-lH imidazol-4-yl)propionate (2.63 g) in tetrahydrofuran (26 ml) was added lithium aluminum hydride (0.55 g) by small portions 0 under nitrogen atmosphere. After the mixture was stirred for 0.5 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 5 was washed with water and brine successively, dried over WO98/57954 PCT/JP98/02613 40 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 5 mg). IR (Neat) : 3250, 2900 cm-1 NMR (CDC1 3 , 5) : 1.86 (2H, m), 2.69 (2H, t, J=6.7Hz), 3.63 (3H, s), 3.73 (2H, t, J=6.0Hz), 6.62 (1H, s), 7.34 (1, s) 0 MASS : 141 (M+H) + Preparation 12 To a solution of oxaly! chloride (0.361 ml) in dichloromethane (10 ml) cooled below -650C with a dry ice 5 acetone bath, a solution of dimethyl sulfoxide (0.381 ml) in dichloromethane (1 ml) was added with efficient stirring over 10 minutes. After 20 minutes below -650C, a solution of 3-(1-methyl-1H-imidazol-4-yl)-1-propanol in dichloromethane (2 ml) was added to the mixture over 10 minutes below -65oC 0 and the mixture was stirred at the same temperature for 20 minutes and then at -450C ~ -400C for 30 minutes. After addition of triethylamine (1.0 mi) dropwise to the mixture over 1 minute followed by stirring for 30 minutes, the reaction mixture was concentrated in vacuo. The resulting 5 residue was purified by column chromatography on silica gel using dichloromethane-methanol (20:1) as eluent to give 3-(1 methyl-1H-imidazol-4-yl)propanol (103 mg). IR (Neat) : 1715 cm NMR (CDC1 3 , 5) : 2.85 (4H, m), 3.63 (3H, s), 6.63 (1H, 0 s), 7.34 (1H, s), 9.83 (1H, s) MASS : 139 (M+H)_ Preparation 13 The following compound was obtained according to a 5 similar manner to that of Preparation 12.

WO98/57954 PCT/JP98/02613 41 4-Formyl--l(triphenylmethyl)pyrazole NMR (DMSO-d 6 , 6) : 7.05-7.10 (6H, m), 7.36-7.41 (9H, im), 8.15 (2H, s), 9.81 (1H, s) 5 Preparation 14 To a solution of (3R)-4-benzvl-3-(hydroxymethyl) morpholine (13.67 g) in methanol (140 ml) and water (10 ml) was added amLmonium formate (10.4 g) and palladium on activated carbon (50%, 1.4 g). The resulting mixture was 0 stirred at 60C for 3 hours. After removal of insoluble material by filtration, the filtrate was concentrated under reduced pressure to give crude amine (16.43 g). To a solution of the obtained amine in tetrahydrofuran (160 ml) were added triethylamine (32.2 ml) and di-tert-butyl 5 dicarbonate (50.4 g) at 0oC. 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 0 was purified by column chromatography on a silica gel using a mixture of ethyl acetate and hexane (6:4) as eluent to give (3R)-4-(tert-butoxycarbonyl)-3-(hydroxymethvl)morpholine (8.64 g) as a colorless solid. NTR (CDC1 3 , 5) : 1.47 (9H, s), 3.16-3.24 (1H, m), 5 3.40-3.61 (2H, m), 3.71-4.00 (6H, m) Preparation 15 The following compound was obtained according to a similar manner to that of Preparation 14. 0 (2R,2S)-4-(tert-Butoxycarbonyl)-2-(hydroxymethyvl) morpholine IR (Neat) : 1695 cm-1 NMR (CDCl 3 , 5) : 1.47 (9H, m), 2.03 (1H, t, J=6.7Hz), 5 2.70-3.00 (2H, m), 3.45-3.74 (4H, m), 3.84-3.95 WO 98/57954 PCT/JP98/02613 42 (3H, m) Preparation 16 The following compounds were obtained according to a 5 similar manner to that of Preparation 12. (1) (3S)-4-(tert-Butoxycarbonyl)-3-formylmorpholine IR (KBr) : 1734, 1695 cm-1 NMR (CDC1 3 , 5) : 1.47 (9H, s), 3.00-3.30 (1H, m), 3.48 0 (1H, dt, J=2.8, 11.7Hz), 3.67 (1H, dt, J=4.2, 12.1Hz), 3.60-3.90 (2H, m), 4.25-4.50 (2H, m), 9.66 (1H, s) (2) (2R,2S)-4- (tert-Butoxycarbonyl)-2-formylmorpholine 5 IR (Neat) : 1737, 1681 cm - 1 NMR (CDCl 3 , 5) : 1.47 (9H, m), 2.80-5.00 (7H, m), 9.65 (1H, m) Preparation 17 0 The following compounds were obtained according to a similar manner to that of Preparation 9. (1) Ethyl (2E)-3-[(3R)-4-(tert-butoxycarbonyl)morpholin-3 yl]acrylate 5 IR (Neat) : 2978, 1716, 1697 cm -i NMR (CDCl 3 , 5) : 1.26 (3H, t, J=7.4Hz), 1.46 (9H, s), 3.16 (1H, dt, J=3.7, 13.2Hz), 3.49 (1H, dt, J=2.9, 11.9Hz), 3.69 (1H, dd, J-3.6, 11.7Hz), 3.80-3.99 (3H, m), 4.21 (2H, q, J=7.!Hz), 4.50-4.60 (1H, m), 0 5.93 (1H, dd, J=1.8, 15.9Hz), 6.99 (1H, dd, J=5.3, 15.9Hz) (2) Ethyl (2E)-3-[(2R,2S)-(4-tert-butoxycarbonyl)morpholin 2-yl] acrylate '5 IR (Neat) : 1737, 1681 cm- WO 98/57954 PCT/JP98/02613 43 NMR (CDC1 3 , 6) : 1.27 (3H, t, J=3.3Hz), 1.47 (9H, s), 2.30-3.10 (3H, m), 3.57 (1H, dt, J=2.7, 11.3Hz), 3.80-4.20 (3H, m), 4.21 (2H, q, J=7.!Hz), 6.12 (1H, dd, J=1.7, 15.8Hz), 6.83 (IH, dd, J=4.2, 15.8Hz) 5 Preparation 18 To a solution of ethyl (2E)-3-[(3R)-4-(tert butoxycarbonyl)morpholin-3-yllacrylate (1.0 g) in toluene (10 ml) was added diisobutylaluminum hydride (1.02 M in toluene, 0 7.6 ml) at -780C ~ -40 0 C. After stirring for 2 hours at 0°C, 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 5 mixture of ethyl acetate and hexane (3:7 ~ 4:6) as eluent to give (3R)-4-(tert-butoxycarbonyl)-3-[(E)-3-hydroxy-l propenyl]morpholine (0.71 g) as a colorless oil. IR (Neat) : 1691 cm NMR (CDCl 3 , 6) : 1.47 (9H, s), 3.17 (1H, dt, J=3.7, 0 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, m), 4.17-4.19 (2H, m), 4.40-4.50 (1H, m), 5.82-5.93 (2H, m) Preparation 19 .5 The following compound was obtained according to a similar manner to that of Preparation 18. (2R,2S)-4-(tert-Butoxycarbonyl)-2-[(E)-3-hydroxy-1 propenyl] morpholine 30 NMR (CDC1 3 , 5) : 1.47 (9H, s), 2.62-3.00 (2H, m), 3.56 (IH, dt, J=2.7, 11.4Hz), 3.81-3.94 (4H, m), 4.18 (2H, d, J=5.0Hz), 5.64-6.04 (2H, m) Preparation 20 35 The following compounds were obtained according to a WO 98/57954 PCT/JP98/02613 44 similar manner to that of Preparation 6. (1) (3R)-4-(tert-Butoxycarbonyl)-3-[(E)-3-methanesulfonyl oxy-l-propenyl ] morpholine 5 NMR (CDC1 3 , 5) 1.47 (9H, s), 3.02 (3H, s), 3.10-3.25 (1H, m), 3.48 (1H, dt, J=2.8, 11.5Hz), 3.63-3.93 (4H, m), 4.45-4.55 (IH, m), 4.74 (2H, d, J=6.2Hz), 5.75-5.86 (1H, m), 6.05 (1H, dd, J=5.5, 15.6Hz) 0 (2) (2R,2S)-4-(tert-Butoxycarbonyl)- 2 -[(E)-3-methane sulfonyloxy-1-propenyl ] morpholine N-MR (CDC! 3 , 5) : 1.47 (9H, m), 2.60-2.72 (1H, m), 2.89-3.02 (1H, m), 3.02 (3H, s), 3.55 (1H, dt, j=2.7, 11.4Hz), 3.82-4.00 (4H, m), 4.73 (2H, d, 5 J=5.1Hz), 5.79-6.01 (2H, m) Preparation 21 To a mixture of 1-amino-1-cyclopropanemethanol hydrochloride (1.1 g), benzaldehyde (945 mg) and 0 triethylamine (1.24 ml) in 1,2-dichloroethane (10 ml), sodium triacetoxyborohydride (5.66 g) was added with ice-cooling over 5 minutes. After being stirred at room temperature for 13 hours, the mixture was poured into aqueous sodium bicarbonate solution and stirred for several hours. The 5 organic layer was separated, dried over magnesium sulfate and evaporated under reduced pressure to give 1-(N-benzylamino) 1-cyclopropanemethanol (641 mg). IR (Nujol) : 3300-2700 cmin. MR (CDC1 3 , 5) : 0.50-0.77 (4H, m), 3.51 (2H, s), 0 3.84 (2H, s), 7.19-7.36 (5H, s) MASS : 178 (M+H) Preparation 22 The following compound was obtained according to a 5 similar manner to that of Preparation 19.

WO98/57954 PCT/JP98/02613 45 (2S)-2-(N-Benzylamino)-4-methyl-1-pentanol NMR (CDC1 3 , 5) : 0.84-0.94 (6H, m), 1.17-1.70 (3H, m), 2.72-2.81 (1H, m), 3.28 (1H, dd, J=6.0, 10.6Hz), 3.66 (1H, dd, J=3.9, 10.6Hz), 3.78 (2H, s), 7.20 5 7.38 (5H, m) MASS : 208 (M+H) + Preparation 23 Chloroacetyl chloride (421 mg) was added dropwise to a 10 mixture of 1-(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, 15 and concentrated under reduced pressure. A mixture of the oil obtained by the above procedure and potassium tert butoxide (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 20 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 25 under reduced pressure to give a solid of 4-benzyl-5-oxo-7 oxa-4-azaspiro[2.5]octane (695.3 mg). IR (KBr) : 3100-2800, 1643 cm

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1 NMR (DMSO-d 6 , 5) : 0.64-1.02 (4H, m), 3.69 (2H, s), 4.43 (2H, s), 4.45 (2H, s), 7.17-7.37 (2H, m) 30 MASS : 218 (M+H) + Preparation 24 The following compound was obtained according to a similar manner to that of Preparation 21. 35 WO 98/57954 PCT/JP98/02613 46 (5S)-4-Benzyl-5-(2-methylpropyl)-3-morpholinone IR (Neat) : 1655 cm-1 NMR (CDCl 3 , 6) : 0.83 (3H, d, J=6.3Hz), 0.95 (3H, d, J=6.4Hz), 1.33-1.60 (2H, m), 1.79-1.92 (1H, m), 5 3.08-3.17 (1H, m), 3.56-3.79 (1H, m), 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) + LO Preparation 25 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 L5 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 .0 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 25 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 30 hydrochloride (81 mg). IR (KBr) : 3350, 3000-2400 cm-1 NMR (CDC1 3 , 6) : 0.84-1.10 (4H, m), 3.75 (2H, s), 3.90-4.10 (4H, m), 10.11 (1H, br s) MASS : 114 (M+H)+ (free) 35 WO 98/57954 PCT/JP98/02613 47 Preparation 26 The following compound was obtained according to a similar manner to that of Preparation 23. 5 (3S)-4-Benzyl-3-(2-methylpropyl)morpholine NMR (CDCl 3 , 6) : 0.89 (3H, d, J=6.2Hz), 0.93 (3H, d, J=6.3Hz), 1.20-1.40 (1H, m), 1.46-1.61 (2H, m), 2.17-2.27 (1H, m), 2.40-2.50 (1iH, m), 2.59-2.68 (1H, m), 3.16 (1H, d, J=13.3Hz), 3.40 (1H, dd, 10 J=11.2, 7.8Hz), 3.59-3.83 (3H, m), 4.04 (1H, d, J=13.3Hz), 7.21-7.36 (5H, m) MASS : 234 (M+H) + Preparation 27 15 The following compound was obtained according to a similar manner to that of Preparation 23. (3S)-3-(2-Methylpropyl)morpholine hydrochloride NMR (DMSO-d 6 , 6) : 0.87 (3H, s), 0.90 (3H, s), 20 1.26-1.52 (2H, m), 1.65-1.78 (1H, m), 3.12-3.48 (4H, m), 3.69 (1H, dt, J=3.4, 12.3Hz), 3.87-3.95 (2H, m) MASS : 144 (M+H) + (free) 25 Preparation 28 A solution of 2-amino-5-bromopyridine (5.0 g) and di tert-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 30 residue was chromatographed on a silica gel using dichloromethane eluent. The fractions containing the objective compound were collected and concentrated under reduced pressure to give 2-(tert-butoxycarbonylamino)-5 bromopyridine (3.25 g). 35 IR (Nujol) : 3210, 1720, 1580, 1525, 1460, 1370 cm-1 WO 98/57954 PCT/JP98/02613 48 NMR (CDC1 3 , 5) : 1.56 (9H, s), 7.76 (1H, dd, J=2.5, 8.9Hz), 7.95 (1H, d, j=8.9Hz), 8.38 (1H, d, J=2.5Hz), 8.93 (1H, br s) 5 Preparation 29 To a solution of (2R)-4-benzyl-1-(3,5-dichlorobenzoyl) 2-(3,4-dimethylbenzyl)piperazine (5.03 g) in dichloromethane (50 ml) was added 1-chloroethyl chloroformate (1.51 ml) slowly at 0OC, and then the mixture was heated at reflux 0 under stirring. After 5.5 hours, the solvent was removed in vacuo and then the resulting residue was dissolved in methanol (20 ml) and refluxed for 0.5 hour. After removal of the solvent, the resulting residue was triturated with isopropyl ether to afford (2R)-1-(3,5-dichlorobenzoyl)-2 5 (3,4-dimethylbenzyl)piperazine hydrochloride (4.84 g). IR (Nujol) : 3350, 1625 cm NMR (DMSO-d 6 , 5) : 2.10-4.60 (15H, m), 6.50-9.70 (6H, m) MASS : 377 (M+H) (free) 0 Precaration 30 The following compounds were obtained according to a similar manner to that of Preparation 29. (1) (2R)-1-(3,5-Dichlorobenzoyv)-2-[(!H-indol-3-yl)methyl] 5 piperazine hydrochloride IR (KBr) 1637 cm NTM4R (DMSO-d 6 , 6) : 2.80-4.80 (9H, m), 6.80-10.20 (8H, m) MASS : 388 (M+H) + (free) 0 (2) (2R)-1-(3,5-Dichlorobenzovl)-2-(2-naphthylmethyl) piperazine hydrochloride NMR (DMSO-d 6 , 5) : 2.80-4.70 (9H, m), 6.50-8.00 (10H, m) MASS : 399 (M+H) + (free) 5 (3) (2R)-!-(3,5-Dichlorobenzoyl)-2-[4-(trifluoromethyl)- WO 98/57954 PCT/JP98/02613 49 benzyl]piperazine dihydrochloride -! IR (KBr) : 3430, 2930, 2790, 1648, 1164 cm NMR (DMSO-d 6 , 5) : 2.70-5.30 (9H, m), 6.50-7.90 (7H, m), 9.62 (1H, br s) 5 MASS 417 (M+H)'(free) (4) (2R)-!-[3,5-Bis(trifluoromethyl)benzoyll-2-(2-naphthyl methyl)piperazine hydrochloride IR (KEr) : 3700-3200, 1639, 1281, 1136 cm 0 NMR (DMSO-d 6 , 5) : 2.90-3.80 (7H, m), 4.40-5.30 (2H, m), 6.90-8.30 (10H, m) MASS 317 (M+H) + (free) Preparation 31 5 (2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(2 naphthylmethyl)piperazine fumarate (2 g) was treated with 10% aqueous sodium hydroxide solution (14 ml) and dichloromethane (14 mi). The organic layer was separated, washed with brine, dried over magnesium sulfate and evaporated under reduced 0 pressure. A mixture of free piperazine derivative obtained by the above procedure, potassium carbonate (0.76 g) and 1,4-dichloro-2-butyne (0.43 ml) in N,N-dimethylformamide (15 ml) was stirred for 4.5 hours at room temperature. The reaction mixture was poured into water (75 mi) and extracted 5 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 toluene and ethyl acetate (10:1) as eluent to give (2R)-1-[3,5-bis(trifluoromethyl)benzoyl] 0 4-(4-chloro-2-butynyl)-2-(2-naphthylmethyl)piperazine (1.18 g). IR (Neat) : 3600-3100, 1638, 1275, 1127, 900 cm 1 NMR (CDC1 3 , 5) : 2.31-5.30 (13H, m), 6.90-7.95 (10H, m) MASS 553 (M+H) + 5 WO 98/57954 PCT/JP98/02613 50 Example 1 (1) A mixture of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2 [(1H-indol-3-yl)methyl]piperazine (0.67 g), 1-chloro-3-(3 pyridyl)-2-propyne hydrochloride (0.3 g) and potassium 5 carbonate (0.52 g) in N,N-dimethylformamide (5 ml) was stirred for 5 hours at 50°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 purified 0 by column chromatography on silica gel using ethyl acetate as eluent to give (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2 [(lH-indol-3-yl)methyl]-4-[3-(3-pyridyl)-2-propynyl] piperazine (0.25 g) as a syrup. 5 (2) The following compound was prepared by treatment of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-[ (1H-indol-3-yl) methyl]-4-[3-(3-pyridyl)-2-propynyl]piperazine with 4N hydrochloric acid in ethyl acetate. 0 (2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-[ (1H-indol-3 yl)methyl]-4-[3- (3-pyridyl)-2-propynyl]piperazine dihydrochloride mp : 180-190 0 C 24.6. [aj] 4 6 : -10.50o (C=0.1, MeOH) 5 IR (Nujol) : 3600-3200, 2700-2500, 1643, 1530, 1428, 1361, 1280 cm NMR (DMSO-d 6 , 5) : 3.20-5.20 (11H, m), 6.40-8.30 (10H, nm), 8.74-8.80 (1H, m), 8,85-8.90 (2H, m), 10.90 11.10 (1H, m) 0 MLASS 571 (M+H)+ (free) Elemental Analysis Calcd. for C 30

H

2 4

F

6 N40-2HC1-1.8H 2 O : C 53.31, H 4.41, N 8.29 Found C 53.28, H 4.53, N 7.87 5 Examole 2 WO 98/57954 PCT/JP98/02613 The following compounds were obtained according to a similar manner to that of Example 1. (1) (2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4 5 dimethylbenzyl) -4-[3-(6-methoxypyridin-3-yl)-2 propynyl]piperazine dihydrochloride mi : 160-170 0 C ]42 . -14.720 (C=0.55, MeOH) IR (KBr) : 3600-3300, 2700-2500, 1648, 1617, 1494, L0 1430, 1280 cm NMR (DMSO-d 6 , 5) 2.05-2.20 (6H, m), 2.80-5.20 (11H, m), 3.90 (3H-, s), 6.50-8.40 (9H, m) MASS : 590 (M+H) + (free) Elemental Analysis Calcd. for C3 1

H

2 9

F

6

N

3 02-2HC1-0.5H 2 0 : L5 C 55.45, H 4.80, N 6.26 Found : C 55.28, H 4.86, N 6.12 (2) (2R)-l-[3,5-Bis(trifluoromethyl)benzoyl]-2-[ (1H-indol-3 yl)methyl]-4-[3-(6-methoxypyridin-3-yl)-2-propynyl] ?0 piperazine dihydrochloride mI : 183-189OC ['] 23.9 : -21.0' (C=0.55, MeOH) IR (KBr) 3600-3300, 2700-2500, 1644, 1602, 1494, 1428, 1280 cm 25 NMR (DMSO-d 6 , 5) : 3.20-5.20 (11H, m), 3.90 (3H, s), 6.60-8.40 (11H, m), 10.95 (1H, br s), 12.00-12.40 (2H, m) MASS : 600 (M+H) + (free) Elemental Analysis Calcd. for C 3 1

H

2 6

F

6

N

4 0 2 *2HC1H 2 0 : 10 C 53.85, H 4.37, N 8.10 Found C 53.90, H 4.36, N 8.02 (3) (2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-[ (1H-indol-3 yl)methyl] -4-[3-(2-pyridvl) -2-propynyl]piperazine 35 WO 98/57954 PCT/JP98/02613 52 Example 3 (2R) -1- [3, 5-Bis(trifiuoromethyl)benzoyl] -2-(3,4 dimethylbenzyl)-4-[3-(2-pyridyl)-2-propynyl]piperazine dihydrochioride (0.2 g) was made free with saturated aqueous 5 sodium bicarbonate solution and extracted with ethyl acetate. The extract was dried over magnesium sulfate and evaporated under reduced pressure. The resulting residue dissolved in methanol (10 ml) and the solution was hydrogenated over 10% palladium on activated carbon (50 mg) at room temperature 0 under 2-3 atoms. After removal of catalyst by filtration, the filtrate was concentrated under reduced pressure. The residue was treated with 4N hydrogen chloride in ethyl acetate solution to give (2R)-!-[3,5-bis(trifluoromethyl) benzoyl] -2-(3,4-dimethylbenzyl)-4-[3-(2-pyridyl)propyl] 5 piperazine dihydrochloride. mp 120-130'C [a] 4 .5 : -12.81' (C=0.32, MeOH) IR (Nujol) : 3600-3300, 2700-2500, 1635, 1450, 1380, -I 1280 cm 0 NMR (DMSO-d 6 , 5) : 2.00-5.20 (21H, m), 6.60-7.80 (5H, m), 7.80 (1H, d, J=8.0Hz), 7.88 (1H, t, J=7.0Hz), 8.18 (1H, s), 8.49 (1H, t, J=7.1Hz), 8.81 (iH, d, J=5.2Hz), 11.20-12.20 (211, m) MASS : 564 (M+H) + (free) 5 Elemental Analysis Calcd. for C 3 0

H

31

F

6

N

3 0-2HC ! ' 2.7H 2 0 : C 52.59, H 5.65, N 6.13 Found : C 52.66, H 5.78, N 5.77 Example 4 0 (1) (2R)-l-[3,5-Bis(trifluoromethyl)benzoyl]-2-[ (lH-indol-3 yl)methyl]l-4-[3-(3-pyridyl)propyl]piperazine dihydrochloride mp : 150-160 0 C [a] 2.9 : -2.86' (C=0.42, MeOH) 5 IR (KBr) : 3600-3000, 2700-2010, 1641, 1554, 1461, WO 98/57954 PCT/JP98/02613 53 1428, 1280 cm - ± NMR (DMSO-d 6 , 5) : 2.10-5.20 (S15H, m), 6.60-8.30 (9H, m), 8.45-8.55 (1H, m), 8.80-9.00 (2H, m), 10.95 11.05 (1H, m), 11.90-12.00 (2H, br s) 5 MASS : 575 (M+H) (free) Elemental Analysis Calcd. for C30H 2 8

F

6

N

4 0-2HC1-1.2H 2 0 : C 50.71, H 5.25, N 7.89 Found : C 50.65, H 5.35, N 7.20 0 (2) (2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-[ (1H-indol-3 yl)methyl]-4-[3-(2-pyridyl)propyl]piperazine dihydrochloride me : 80-100oC [a] 23.1 : -5.29' (C=0.86, MeOH) 5 IR (KBr) 3600-3300, 2700-2500, 1637, 1617, 1460, 1282 cm 1 NMR (DMSO-d 6 , 5) : 2.20-2.40 (2H, m), 3.10-5.20 (13H, m), 6.60-8.30 (10H, m), 8.49 (1H, d, J=7.8Hz), 8.80 (1H, d, J=5.0Hz), 10.90-11.05 (1H, br s) 0 MASS : 575 (M+H) + (free) Elemental Analysis Calcd. for C 30 H2 8

F

6 N40-2HC1-1.2H 2 O : C 53.85, H 4.88, N 8.37 Found : C 53.92, H 5.30, N 7.66 5 (3) (2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-[ (1H-indol-3 yl)methyl]-4-[4-(3-pyridyl)butyl]piperazine dihydrochloride mo : 140-145 0 C []2D2.3 : -8.33 (C=0.30, MeOH) [ID 0 IR (Nujol) : 3600-3000, 2700-2300, 1641, 1465, 1430, 1280 cm NMR (DMSO-d 6 , 6) : 1.60-5.20 (17H, m), 6.60-9.00 (12H, m), 11.00 (1H, br s), 11.59 (2H, br s) MASS : 589 (M+H) + (free) 5 Elemental Analysis Calcd. for C 3 1

H

3 0

F

6 N40O2HC1-2H 2 0

:

WO98/57954 PCT/JP98/02613 54 C 53.38, H 5.20, N 8.03 Found : C 53.47, H 5.28, N 7.51 Example 5 5 (1) Methanesulfonyl chloride (0.094 ml) was added to a mixture of (Z)-3-(3-pyvridyl)-2-propen-1-ol (0.15 g) and triethylamine (0.2 ml) in dichloromethane (2 ml) under -10°C. After being stirred at the same temperature for 0.5 hour, the reaction mixture was washed with saturated sodium 0 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-[(1H indol-3-y!)methyl]piperazine (0.5 g), powdered potassium carbonate (0.61 g) and catalytic amount of potassium iodide 5 in a mixed solvent of acetonitrile (10 ml) and N,N dimethyvlformamide (2 ml). The resulting mixture was stirred at 50OC 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 0 mixed solvent of dichloromethane and methanol as eluent. The fractions containing the objective compound were collected and evaporated under reduced pressure to give (2R)-1-[3,5 bis(trifluoromethyl)benzoyvl]-2-[(1H-indol-3-yl)methyl]-4 [(Z)-3-(3-pyridyl)-2-propenyl]piperazine (0.49 g) as a syrup. 5 NMR (CDC1-, 5) : 1.80-5.20 (11H, m), 5.97 (1H, dt, J=6.6, 11.7Hz, cis), 6.60 (1H, d, J=11.7Hz, cis), 6.80-8.00 (10H, m), 8.23 (1H, s), 8.45-8.60 (2H, m) MASS : 562 (M+H) + 0 (2) The following compound was prepared by treatment of (2R) -1-[3,5-bis(trifluoromethyl)benzoyl]-2-[(lH-indol-3-yl) methyl]-4-[(Z)-3-(3-pyridyl)-3-propenyl]piperazine with 4N hydrogen chloride in ethyl acetate. 5 (2R)- 1 -[3,5-Bis(trifluoromethyl)benzoyl]-2-[(1H-indol-3- WO 98/57954 PCT/JP98/02613 yl)methyl]-4-[(Z)-3-(3-pyridyl)-2-propenyl]piperazine dihydrochloride me : 165-177 0 C 2]2.9 +14.90 (C=0.50, MeOH) 5 IR (KBr) 3600-3300, 2700-2500, 1641, 1457, 1427, 1359, 1280, 1184 cm - 1 NMR (DMSO-d 6 , 6) : 3.00-5.20 (11H, m), 6.40-8.40 (12H, m), 8.70-8.85 (2H, m), 11.05 (IH, br s), 12.00 (2H, m) L0 MASS: 573 (M+H)+ (free) Elemental Analysis Calcd. for C 3 0

H

26

F

6

N

4 O02HCl-2.5H 2 O : C 52.18, H 4.82, N 8.11 Found C 52.34, H 4.73, N 8.01 L5 Example 6 The following compounds were obtained according to a similar manner to that of Example 5. (1) (2R)-1-[3,5-Bis(trifluoromethyvl)benzoyl]-2-(3,4 ?0 dimethylbenzyl)-4-[(E)-3-(3-pyridyl)-2-propenyl] piperazine dihydrochloride mI : 170-174 0 C 2]4.1 : -8.50' (C=0.20, MeOH) IR (KBr) 3600-3300, 2700-2500, 1643, 1554, 1432, 25 1367, 1280 cm NMR (DMSO-d 6 , 6) : 2.00-2.30 (6H, m), 2.80-5.20 (6H, m), 6.60-9.05 (12H, m) MASS : 562 (M+H) + (free) Elemental Analysis Calcd. for C 3 0

H

29

F

6

N

3 02HC12.0H 2 0 : 30 C 53.74, H 5.26, N 6.27 Found : C 53.71, H 5.33, N 5.83 (2) (2R)-1-[3,5-Bis(trifluoromethvl)benzoyl]-2-[ (lH-indol-3 yl)methyl] -4- [4-(3-pyridyl) -3-butynyl]piperazine 35 NMR (CDC! 3 , 6) : 2.20-5.20 (13H, m), 6.80-8.00 (10H, WO 98/57954 PCT/JP98/02613 56 m), 8.15 (1H, s), 8.49 (1H, d, J=3.8Hz), 8.64 (1H, br s) MASS : 585 (M+H)+ 5 (3) (2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4 dimethylbenzyl)-4-[3- (1H-pyrazol-1-yl)propyl]piperazine hydrochloride mp: 73-75'C []4.7 : -17.300 (C=0.50, MeOH) 0 IR (KBr) 1640 cm 1 NMR (DMSO-d 6 , 5) : 1.85-5.20 (21H, m), 6.20-8.30 (9H, m) MASS : 553 (M+H)+ (free) Elemental Analysis Calcd. for C2 8 H3 1 ClF 6

N

4 0-2H 2 0 : C 53.80, H 5.64, N 8.96 5 Found : C 53.67, H 5.56, N 7.83 Example 7 The following compounds were obtained according to a similar manner to that of Example 5-(2). 0 (1) (2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-[ (1H-indol-3 yl)methyl] -4-{3-(2-pyridyl)-2-propynyl]piperazine dihydrochloride mp : 160-166°C [a]4.7 : -16.800 (C=0.50, MeOH) 5 IR (KBr) : 3600-3200, 2700-2500, 1643, 1540, 1380, -I 1280 cm NMR (DMSO-d 6 , 5) : 3.20-5.20 (11H, m), 6.60-8.30 (11H, m), 8.65 (1H, d, J=2.7Hzj, 10.90-11.05 (1H, m) MASS : 571 (M+H) + (free), 607 0 Elemental Analysis Calcd. for C 3 0

H

24

F

6

N

4 0

-

2HCl-1.

SH 20 : C 53.74, H 4.36, N 8.36 Found : C 53.73, H 4.66, N 7.71 (2) (2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-[ (1H-indol-3 5 yl)methyl]l-4-[4-(3-pyridyl)-3-butynyl]piperazine WO 98/57954 PCT/JP98/02613 dihydrochloride mp : 175-185 0 C 21.7 []D1.7 : -10.30' (C=0.50, MeOH) IR (KBr) 3600-3300, 2700-2500, 1641, 1459, 1428, 5 1368, 1282 cm-I NMR (DMSO-d 6 , 5) : 3.20-5.20 (13H, m), 6.60-8.30 (9H, im), 8.65-8.85 (2H, m), 10.99 (1H, s), 11.90-12.10 (,2H, m) MASS : 585 (M+H) + (free) 0 Elemental Anavlysis Calcd. for C 31

H

26

F

6

N

4 0*2HCI11.2H20 : C 54.83, H 4.51, N 8.25 Found : C 54.79, H 4.87, N 7.67 Example 8 5 A mixture of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2 [(1H-indol-3-yl)methyl]-4--(4-chloro-2-butynyl)piperazine (0.25 g), (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 0 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 5 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-(methoxvmethyl) pyrrolidino]-2-butynyl]piperazine gihydrochloride (0.19 g). m :. 190-195 0 C 24.8 .3, 0 [X] 4 8 : +9.3 (C=0.50, MeOH) IR (Nujol) : 3600-3300, 2700-2500, 1641, 1552, 1428, 1280 cm -1 NMR (DMSO-d 6 , 5) : 1.6-2.40 (4H, m), 3.10-5.20 (18H, m), 6.60-8.30 (8H, m), 11.50-11.70 (3H, m) 5 MASS : 621 (M+H)

+

(free) WO98/57954 PCT/JP98/02613 58 Elemental Analysis Calcd. for C 32

H

3 4

F

6 N402-2HCl-1.5H 2 0 C 53.34, H 5.46, N 7.78 Found : C 53.35, H 5.54, N 7.60 5 Examnle 9 To a mixture of 3,5-dichlorobenzoic acid (2.6 g), (3R) 1-benzyl-3-(3,4-dimethylbenzyl)piperazine dihydrochloride (5.0 g) and triethvlamine (8.54 ml) in dichloromethane (80 ml) was added 2-chloro-1-methylpyridinium iodide (3.83 g) LO under ice-cooling, and then the mixture was stirred at room temperature 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 evaporated under reduced pressure. The resulting residue L5 was purified by column chromatography on silica gel using hexane-ethyl acetate (10:1) as eluent to give (2R)-4-benzyl 1-(3,5-dichlorobenzoyl)-2-(3,4-dimethylbenzyl)piperazine (5.58 g). IR (Nujol) : 2500, 1635 cm

-

1 !0 NMR (DMSO-d 6 , 6) : 1.90-2.30 (8H, m), 2.55-4.80 (9H, m), 6.50-7.15 (5H, m), 7.20-7.40 (SH, m), 7.59 (1H, br) MASS : 467 (M+H) + .5 Example 10 The following compound was obtained according to a similar manner to that of Example 9. (2R)-4-Benzyl-1-(3,5-dichlorobenzoyl)-2-[4 30 (trifluoromethyl)benzyl]piperazine IR (Neat) : 2942, 2809, 1641, 1070 cm NrR (DMSO-d 6 , 6) : 2.00-4.90 (11H, m), 6.59 (1H, s), 7.10-7.70 (11IH, m) MASS : 507 (M+H) WO98/57954 PCT/JP98/02613 Example 11 To a solution of (3R)-l-benzyl-3-(2 naphthylmethyl)piperazine (3.23 g) and triethylamine (4.3 ml) in dichloromethane (60 ml) was added a solution of 3,5 5 dichlorobenzoyvl chloride (6.0 g) in dichloromethane (10 ml) at 00C. 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 evaporated under reduced pressure. 10 The obtained residue was triturated with a mixture of dichloromethane and hexane to give (2R)-4-benzyl-!-(3,5-dichlorobenzoyl)-2-(2-naphthylmethyl) piperazine. NMR (DMSO-d 6 , 5) : 3.00-4.70 (9H, m), 6.66-7.86 (17H, m) 5 MASS : 689 (M+H) + (free) Example 12 The following compound was obtained according to a similar manner to that of Example 11. 20 (2R)-4-Benzyl-1-(3,5-dichlorobenzoyl)-2-[(1H-indol-3 yl)methyl]piperazine NMR (DMSO-d 6 , 6) : 2.10-4.60 (9H, m), 5.76 (2H, s), 6.70-7.68 (13H, m) 25 MASS : 388 (M+H) + (free) Example 13 The following compound was obtained according to a similar manner to that of Example 1-(1) 30 (2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(2 naphthylmethyl)-4-[3-(3-pyridyl)-2-propynyl]piperazine dihydrochloride me : 140-1500C 5 []5.

9 : -9.2 (C=0.50, MeOH) WO 98/57954 PCT/JP98/02613 60 IR (KBr) : 3700-3200, 3000-2300, 1644, 1550, 1428, 1367, 1280 cm NMR (DMSO-d 6 , 5): 2.20-5.20 (11H, m), 7.00-8.65 (14H, m) MASS : 582 (M+H) + (free) 5 Elemental Analysis Calcd. for C 31 H25F 6

N

4 O*2HC1-2.57H 20 : C 54.85, H 4.62, N 6.00 Found : C 54.85, H 4.56, N 5.86 Example 14 10 (1) Lindlar catalyst (Pd-CaCO3-PbO) (86 mg) was added to a solution of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]- 2

-(

2 naphthylmethyl)-4-[3-(3-pyridyl)-2-propynyl]piperazine in methanol (20 ml). The mixture was stirred for 2 hours under hydrogen at 25 0 C and filtered. The filtrate was concentrated 15 under reduced pressure and the resulting residue was chromatographed on silica gel using a mixed eluent of hexane and ethyl acetate. The faster eluting fractions were collected, concentrated under reduced pressure and treated with 4N hydrogen chloride in ethyl acetate to give (2R)-1 20 [3,5-bis(trifluoromethyl)benzoyl]-2-(2-naphthylmethyl)-4 [(2Z)-3-(3-pyridyl)-2-propenyl]piperazine dihydrochloride. mC : 130-150 0 C 2 .5 aD. : -25.200 (C=0.25, MeOH) IR (KBr) : 3700-2200, 1646, 1280 cm 25 NMR (DMSO-d 6 , 5): 2.00-5.20 (I1H, m), 6.30-8.90 (16H, m) MASS : 584 (M+H) + (free) Elemental Analysis Calcd. for C 32

H

27

F

6

N

3 02HCl-3.7H20 : C 53.19, H 5.07, N 5.82 Found : C 53.19, H 5.21, N 5.61 30 (2) The slower eluting fractions were collected, concentrated under reduced pressure and treated with 4N hydrogen chloride in ethyl acetate to give (2R)-l-[3,5 bis (trifluoromethyl)benzoyl]-2- (2-naphthylmethyl)-4-[3 35 (3-pyridyl)propyl ] piperazine dihydrochloride.

WO 98/57954 PCT/JP98/02613 61 m 1 : 38-148oC [ 6.4 : -28.60' (C=0.25, MeOH) [aD IR (KBr) : 3700-2200, 1646, 1280, 1135 cm - I NMR (DMSO-d 6 , 5): 2.00-5.20 (15H, m), 6.30-8.90 (14H, m) 5 MASS : 586 (M+H) + (free) Elemental Analysis Calcd. for C 32

H

29

F

6

N

3 0*2HC1*2.9H 2 0 : C 54.10, H 5.22, N 5.92 Found : C 54.11, H 5.37, N 5.70 10 Example 15 A mixture of (2R)-1-(3,5-dichlorobenzoyl)-2-(3,4 dimethylbenzyl)piperazine hydrochloride (400 mg) and 4-(4 chloro-2-butynyl)morpholine hydrochloride (223 mg) in dried acetonitrile (4.0 ml) was stirred at 50'C in the presence of 15 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 combined and then concentrated in vacuo. The resulting residue was 20 purified by column chromatography on silica gel using a mixture of ethyl acetate and methanol (10:1-) as eluent. The product obtained was dissolved in ethyl acetate and treated with 4N hydrogen chloride in ethyl acetate to give (2R)-1 (3,5-dichlorobenzoyl)-2-(3,4-dimethylbenzyl)-4-(4-morpholino 25 2-butynyl)piperazine dihydrochloride (221 mg). mp : 175oC (dec.) 2]7.9 : +6.800 (C=0.50, MeOH) LaID IR (Nujol) : 2400, 1640, 1120 cm -i NMR (DMSO-d 6 , 5) : 2.10-4.40 (21H, m), 6.69 (3H, br), 30 7.06 (2H, br), 7.61 (1iH, br) MASS : 514 (M+H) + (free) Elemental Analysis Calcd. for C 28

H

3 3 Cl 2

N

3 02-2HC12H20 : C 53.94, H 6.30, N 6.74 Found : C 53.86, H 6.15, N 6.41 35 WO 98/57954 PCT/JP98/02613 62 Example 16 The following compounds were obtained according to a similar manner to that of Example 15. 5 (1) (2R)-1-(3,5-Dichlorobenzoyl)-2-(3,4-dimethylbenzyl)-4 (4-thiomorpholino-2-butynyl)piperazine dihydrochloride mD : 128 0 C (dec.) 2]8.0 +: 6.400 (C=0.50, MeOH) IR (Nujol) 2400, 1635 cm 10 INMR (DMSO-d 6 , 5) : 2.05-4.70 (21H, m), 6.71 (3H, br), 7.04 (2H, br), 7.61 (1H, br) MASS 530 (M+H)+ (free) Elemental Analysis Calcd. for C 28

H

33 Cl 2

N

3 OS-2HCI-2H 2 0 : C 52.59, H 6.15, N 6.57 i5 Found : C 52.72, H 6.19, N 6.35 (2) (2R)-1-(3,5-Dichlorobenzoyl)-2-(3,4-dimethylbenzyl)-4 [(E)-4-morpholino-2-butenyl]piperazine dihydrochloride mp : >230 0 C 20 [c] 2 5.3 : +5.800 (C=0.50, MeOH) IR (KBr) 3426, 2927, 1120, 970 cm -1 NIMR (DMSO-d 6 , 5) 9 10-4.70 (23H, m), 6.17 (2H, br), 6.69 (3H, br), 7.07 (2H, br), 7.63 (1H, br) MASS : 516 (M+H) + (free) 25 Elemental Analysis Calcd. for C 2 8

H

37 Cl 4

N

3 02-0.5H20 : C 56.20, H 6.40, N 7.02 Found : C 56.20, H 6.29, N 6.89 (3) (2R)-1-(3,5-Dichlorobenzoyl)-2-[ (1H-indol-3-yl)methyl] 30 4-(4-thiomorpholino-2-butynyl)piperazine dihydrochloride me : 175 0 C (dec.) []D6.0 +26.0' (C=0.50, MeOH) (]D IR (KBr) 3407, 2543, 1639 cm NMR (DMSO-d 6 , 6) : 2.60-5.10 (21H, m), 6.70-7.80 (8H, 35 m), 11.02 (1H, br s) WO 98/57954 PCT/JP98/02613 63 IMASS 541 (M+H)' (free) Elemental Analysis Calcd. for C 28

H

32 Cl 4

N

4 OS-.5H 2 0 : C 52.43, H 5.50, N 8.73 Found : C 52.34, H 5.60, N 8.42 5 (4) (2R)-l-(3,5-Dichlorobenzoyl)-2-[ (lH-indol-3-yl)methyl] 4-(4-morpholino-2-butynyl)piperazine dihydrochloride me : 1650C (dec.) [ ]

D

6.0 : +27.500 (C=0.50, MeOH) 10 IR (KBr) : 3407, 1639, 1126 cm NMR (DMSO-d 6 , 5) : 2.80-5.20 (21H, m), 6.70-7.85 (8H, m), 11.00 (1H, br s) MASS : 525 (M+H) + (free) Elemental Analysis Calcd. for C28 32 C1 4

N

4 0 2 3H 2 0 : L5 C 51.55., H 5.87, N 8.59 Found : C 51.59, H 5.52, N 8.33 (5) (2R)-1-(3,5-Dichlorobenzoyl)-2-(2-naphthylmethyl)-4-(4 thiomorpholino-2-butynyl)piperazine dihydrochloride 0 mp : 1540C (dec.) 23.8 C [t 3 : -14.10 0 (C=0.50, MeOH) IR (KBr) : 3417, 2933, 2537, 1641 cm-1 NMR (DMSO-d 6 , .5) : 2.70-5.20 (21H, m), 6.56 (1H, br), 7.08 (1H, br), 7.53 (4H, br), 7.89 (4H, br) .5 MASS : 552 (M+H) + (free) Elemental Analysis Calcd. for C 3 0

H

33 C1 4

N

3 0S-1.5H20 : C 55.22, H 5.56, N 6.44 Found : C 55.09, H 5.64, N 6.31 30 (6) (2R)-1-(3,5-Dichlorobenzoyl)-2-(2-naphthylmethyl)-4-(4 morpholino-2-butynyl)piperazine dihydrochloride mI : 1710C (dec.) rj23.3 : -15.100 (C=0.50, MeOH) IR (KBr) : 3407, 2931, 2561, 1641, 971 cm 5 NMR (DMSO-d 6 , 5) : 3.00-5.20 (21H, m), 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 (M+H) + (free) Elemental Analysis Calcd. for C30H 33 C14N 3 02-H 2 0 C 57.43, H 5.62, N 6.70 5 Found : C 57.67, H 5.68, N 6.31 (7) (2R)-1-(3,5-Dichlorobenzoyl)-2-[4-(trifluoromethyl) benzyl]-4-(4-thiomorpholino-2-butynyl)piperazine dihydrochloride 0 mi : 172 0 C (dec.) 25.4 [a(]D : +15.800 (C=0.50, MeOH) IR (KBr) : 3430, 2917, 2524, 1641, 1068 cm-1 NMR (DMSO-d 6 , 5) : 2.70-5.20 (21H, m), 6.69 (1H, s), 7.10-7.30 (2H, m), 7.63 (4H, br) 5 MASS : 570 (M+H) + (free) Elemental Analysis Calcd. for C 2 7

H

30 C1 4

F

3

N

3 0S-0.5H 2 0 : C 49.71, H 4.79, N 6.44 Found : C 49.37, H 5.09, N 6.30 0 (8) (2R)-l-(3,5-Dichlorobenzovl)-2-[4-(trifluoromethyl) benzyl] -4-(4-morpholino-2-butynyl)piperazine dihydrochloride mp : 186'C (dec.) [a] 5.4 : +17.500 (C=0.50, MeOH) 5 IR (KBr) : 3421, 2935, 2553, 1644, 1068 cm - 1 NMR (DMSO-d 6 , 6) : 2.80-5.20 (21H, m), 6.72/ (1H, s), 7.10-7.40 (2H, m), 7.64 (4H, br) MASS : 554 (M+H) + (free) Elemental Analysis Calcd. for C 2 7

H

30 C1 4

F

3

N

3 0 2 *0.5H 2 0 : 0 C 50.96, H 4.91, N 6.60 Found : C 50.57, H 5.05, N 6.52 Example 17 A mixture of (2R)-1-(3,5-dichlorobenzoyl)-2-(3,4 5 dimethylbenzyl)piperazine hydrochloride (300 mg), 3-bromo-1- WO98/57954 PCT/JP98/02613 65 propanol (121 mg), potassium carbonate (251 mg) and potassium iodide (24 mg) in dried acetonitrile (3 ml) was stirred at 50 0 C for 10 hours. After being cooled to room temperature, the reaction mixture was filtered and the filtrate was 5 concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using ethyl acetate as eluent to give (2R)-l-(3,5-dichlorobenzoyl)-2-(3, 4-dimethylbenzyl)-4-(3-hydroxypropyl)piperazine as a syrup. Methanesulfonyl chloride (58 mg) was added to an ice-cooled 0 solution of the alcohol obtained at above procedure (210 mg) and triethylamine (97.6 mg) in dichloromethane (4 ml) over 1.5 hours. After being stirred for 1 hour, the reaction mixture was washed with saturated sodium bicarbonate solution, dried over magnesium sulfate and evaporated under 5 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 0 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. 5 me : 710C (dec.) [Ea]22.S : 1.000 (C=0.50, MeOH) IR (Nujol) : 3400, 2950, 1640, 1100 cm NMR (DMSO-d 6 , 5) 2.10-4.70. (23H, m), 6.68 (3H, br), 7.06 (25, br), 7.63 (1H, br) 0 MASS : 519 (M+H) + (free) Elemental Analysis Calcd. for C 2 7

H

3 8 Cl4N 4 02"2.5H20 : C 50.87, H 6.80, N 8.79 Found : C 51.03, H 7.15, N 8.84 5 Example 18 WO 98/57954 PCT/JP98/02613 66 Under nitrogen atmosphere, to a mixture of (2R)-1-[3,5 bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)piperazine (315 mg) and 3-(l-methyl-1H-imidazol-4-vl)propanal (98 mg) in dichloromethane (6 ml) was added sodium triacetoxyborohydride 5 (225 mg) and stirred at room temperature. After 4 hours, aqueous sodium bicarbonate solution was added to the mixture and the mixture was stirred for several minutes. The organic layer was separated, dried over sodium sulfate and evaporated under reduced pressure. The resulting residue was purified 10 by column chromatography on silica gel using dichloromethane methanol (10:1) as eluent and treated with 4N hydrogen chloride in ethyl acetate solution to give (2R)-!-[3,5 bis(trifluoromethyl)benzoyl] -2- (3,4-dimethylbenzyl)-4 [3- (l-methyl-1H-imidazol-4-yl)propyl]piperazine L5 dihydrochloride (187.1 mg). mp : 91'C (dec.) 24.2 [N]D : -11.20' (C=0.50, MeOH) IR (Nujol) : 1640 cm-1 NMR (DMSO-d 6 , 6) : 2.00-5.20 (21H, m), 6.67 (1H, br s), 20 6.90-7.20 (2H, m), 7.44 (1H, br s), 7.56 (1H, br s), 7.67 (IH, br s), 8.18 (1H, br s), 9.03 (1H, br s) MASS : 567 (M+H) (free) Elemental Analysis Calcd. for C 2 9

H

3 4Cl 2

F

6

N

4 0-3.SH 2 0 : 5 C 49.58, H 5.88, N 7.97 Found : C 49.71, H 5.90, N 7.79 Example 19 A mixture of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2 0 (3,4-dimethylbenzyl)piperazine (500 mg), 2-(2-chloroethoxy) ethanol (168 mg), potassium carbonate (233 mg) and potassium iodide (56 mg) in N,N-dimethylformamide (2 ml) was heated with stirring at 500C for 17 hours, 600C for 13 hours and 70'C for 1 hour. The reaction mixture was partitioned 5 between ethyl acetate and water. The organic layer was WO 98/57954 PCT/JP98/02613 67 washed with brine and dried over magnesium sulfate. After evancration of the solvent, the resulting residue was purified by column chromatography on silica gel using dichloromethane-methanol (10:1) as eluent to give (2R)-l 5 [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 NIMR (DMSO-d 6 , 5) : 2.03-4.93 (23H, m), 6.60-8.20 (6H, im) MIASS : 533 (M+H) + L0 Example 20 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 L5 -78oC under nitrogen atmosphere. After 15 minutes, (2R)-I [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 0 mg) was added at -45 0 C, and the whole was stirred at 0 0 C for 20 minutes and then treated with aqueous solution of ammonium chloride (2 ml). The organic layer was separated and dried over maanesium sulfate. After evaporation of the solvent, the resulting residue was purified by column chromatography 5 on silica gel using ethyl acetate as eluent to afford (2R)-l [3, 5-bis (trifluoromethyl)benzoyl] -2-(3,4-dimethylbenzyl)-4 [2-(formylmethoxy)ethyl]piperazine (171 mg). IR (Neat) : 3450, 174-0, 1640, 1440, 1280, 1130 cm 1 NMR (DMSO-d 6 , 5) : 1.91-4.91 (22H, m), 6.53-8.20 (6H, m) 0 YMASS : 351 (M+H) Example 21 To a stirred mixture of 3,3-dimethylmorpholine hydrochloride (63 mg) and triethylamine (42 mg) in 5 dichloromethane (5 ml) were added (2R)-1-[3,5- WO 98/57954 PCT/JP98/02613 68 bis(trifluoromethyl)benzoyl ]-2-(3,4-dimethylbenzyl)-4-[2 (formylmethoxy)ethyl]piperazine (200 mg) and sodium triacetoxyborohydride (120 mg) at room temperature. The resulting mixture was stirred for 1 hour and then treated 5 with aqueous 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 dichloromethane methanol (10:1) as eluent and treated with 4N hydrogen 0LO chloride in ethyl acetate to give (2R)-1-[3,5 bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4 [2-[2-(3,3-dimethylmorpholino)ethoxy]ethyl]piperazine dihydrochloride (193 mg) as a powder. 23 2]3 : -18.200 (C=0.50, MeOH) L5 IR (Neat) : 3450, 2600, 1640, 1430, 1280, 1140 cm

-

1 NMR (DMSO-d 6 , ) : 1.33 (6H, s), 2.04-5.23 (29H, m), 6.60-8.26 (6H, m) MASS : 630 (M+H) + (free) Elemental Analysis Calcd. for C 32

H

4 1

F

6

N

3 03-2HCl-3.32H 2 0 .0 C 50.41, H 6.56, N 5.51 Found C 50.41, H 6.29, N 5.31 Example 22 The following compound was obtained according to a similar manner to that of Example 21. .5 (2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4 dimethylbenzyl)-4-[2-(2-morpholinoethoxy)ethyl]piperazine dihydrochloride [] : -21.40 (C=0.50, MeOH) 0 IR (Neat): 3450, 2600, 1640, 1430, 1280, 1180, 1135 cm NMR (DMSO-d 6 , 5) : 2.08-5.20 (31H, m), 6.60-8.24 (6H, m) MASS : 602 (M+H)+ (free) Elemental Analysis Calcd. for C 30

H

37

F

6

N

3 03"2HCl-2.66H 2 0 : C 49.87, H 6.18, N 5.82 15 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 [(!H-indol-3-yl)methyl]-4-(3-methylsulfonyloxypropyl) piperazine (250 mg), 4-aminothiomorpholine (90 mg) and sodium 5 carbonate (180 mg) in methanol (5 ml) was stirred at reflux temperature for 3 hours. The reaction mixture was filtered and the filtrate was evapoorated under reduced pressure. The residue was purified by column chromatography on silica gel using ethyl acetate-methanol (10:1) as eluent and treated 0 with 4N hydrogen chloride in ethyl acetate (3 ml) to give (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-[ (1H-indol-3-yl) methyl]-4-[3-(thiomorpholinoamino)propyl]piperazine dihydrochloride (62 mg) as a powder. 27] -5.800 (C=0.50, MeOH) IND-I 5 IR (Neat) : 3300, 2500, 1630, 1420, 1275, 1130 cm 1 MR (DMSO-d 6 , 5) : 2.03-5.20 (23H, m), 6.60-8.24 (8H, m), 10.95 (1H, s) MASS : 614 (M+H) + (free) Elemental Analysis Calcd. for C 2 9

H

35 C1 2

F

6

N

5 0S-3H 2 0 : 0 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 5 (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 partitioned between 0 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 dichloromethane methanol (10:1) as eluent and treated with 4N hydrogen 5 chloride in ethyl acetate (0.2 ml) to give (2R)-1-[3,5-bis- WO 98/57954 PCT/JP98/02613 70 (trifiuoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-[2-(3 hydroxymethylpoiperidino)ethyl]piperazine dihydrochloride (85 mg). 25 [ 2]D : -5.300 (C=0.50, MeOH) 5 IR (Neat) : 3350, 2500, 1640, 1420, 1280, 1180, 1130 cm-1 NMR (DMSO-d 6 , 5) : 1.0-5.20 (30H, m), 6.66-8.31 (6H, m) TMASS : 586 (M+H)+ (free) Elemental Analysis Calcd. for C 30

H

39 C1 2

F

6

N

3 0 2 *3H20 .0 C 50.58, H 6.36, N 5.90 Found : C 50.58, H 6.24, N 5.87 Example 25 A mixture of (2R)-1-[3,5-bis(trifluoromethyi)benzoyl]-4 5 (4-chloro-2-butynyl)-2-(2-naphthylmethyl)piperazine (600 mg), 3,3-dimethylmorpholine hydrochloride (197 mg) and potassium carbonate (420 mg) in N,N-dimethylformamide (10 ml) was stirred at room temperature in the presence of potassium iodide (10 mg) for 2 days. The reaction mixture was 0 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). 5 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-(3,3 dimethylmorpholino)-2-butynyll]-2- (-naphthylmethyl)piperazine dihydrochloride (360 mg). 0 IR (KBr) : 3401, 2929, 2578, 2512, 1644, 1284, 1135 cm 1 NTMR (DMSO-d 6 , 5) 1.32 (3H, s), 1.39 (3H, s), 3.0-5.4 (19H, m), 7.0-8.2 (10H, m) MASS : 632 (M+H) + (free) Elemental Analysis Calcd. for C 34

H

3 7 C1 2

F

6

N

3 0 2 -2.5H 2 0 : 5 C 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 Examnie 26 Acetic anhydride (209 mg) was added to formic acid (94 5 mg). The resulting mixture was allowed to warm at 500C for 30 minutes and then added to (2R)-1-[3,5-bis(trifluoro methyl)benzoyl] -2-(3,4-dimethylbenzyl)-4-[3-(morpholino amino)propyl]piperazine (200 mg) at room temperature. The whole was stirred overnight and then evaporated under reduced L0 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-[(3-(N-formyl morpholinoamino)propyl]piperazine hydrochloride (112 mg). L5 []3 : -16.3' (C=0.50, MeOH) IR (Neat) : 3450, 2800, 2620, 1660, 1430, 1280, 1185, 1140 cm NMR (DMSO-d 6 , 5) : 1.94-5.16 (29H, m), 6.62-8.35 (7H, m) MASS : 615 (M+H) (free) .0 Elemental Analysis Calcd. for C 3 0

H

37 ClF 6

N

4 03-1.36H 2 0 : C 53.34, H 5.93, N 8.29 Found C 53.33, H 5.79, N 8.06 Example 27 .5 To a mixture of (2R)-1-[3,5-bis(trifluoromethyl) benzoyl]-2-(3,4-dimethylbenzyl)piperazine (3.71 g) and 4-formyl-1-(triphenylmethyl)pyrazole (3.66 g) in 1,2 dichloroethane (80 ml) was added sodium triacetoxyborohydride (2.86 g). After stirring at room temperature for 3 hours, 30 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 I5 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 quenched with 10% sodium hydroxide (150 ml) and aqueous sodium bicarbonate and extracted with dichioromethane. The extract was washed with aquecus sodium bicarbonate solution 5 and brine successively, 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 hexane (3:7) to give (2R)-1-[3,5 bis (trifluoromethyl)benzoyl] -2-(3,4-dimethylbenzyl)-4-(4 10 pyrazolylmethyl)piperazine (2.84 g). NTMR (DMSO-d 6 , 5) : 2.04-2.14 (6H, mn), 2.60-4.76 (11H, m), 6.49-6.54 (1H, m), 6.86-6.96 (2H, m), 7.45 (2H, br s), 7.64-7.68 (2H, m), 8.14 (1H, m) MASS : 525 (M+H) + 15 Example 28 Potassium carbonate (158 mg) and 2-bromoethanol (0.045 ml) were added to a solution of (2R)-1-[3,5 bis (trifluoromethyl)benzoyl ]-2-(3,4-dimethylbenzyl)-4-(4 20 pyrazolylmethyl)piperazine (300 mrg) in N,N-dimethylformamide (3 ml) at room temperature with stirring. 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 25 evaporated under reduced pressure. The obtained residue was Durified by column chromatography (30 ml) on silica gel using a mixture of ethyV acetate and hexane (3:7) to give (2R)-1 [3, 5-bis(trifluoromethyl)benzoyl]- -(3,4-dimethylbenzyl)-4 [[1-(2-hydroxyethyl)-lH-pyrazol-4-yl]methyl]piperazine (255.2 30 mg). IR (KBr) : 1640 cm-1 NMR (DMSO-d 6 , 5) : 2.04-2.15 (6H, m), 2.60-4.80 (11H, m), 3.67-3.75 (2H, m), 4.10 (2H, t, J=5.7Hz), 4.86 (1H, t, J=5.3Hz), 6.50-6.56 (1H, m), 6.90-6.98 (2H, 35 im), 7.36 (1H, br s), 7.43 (1H, br s), 7.61 ( 1 H, br WO 98/57954 PCT/JP98/02613 73 s), 7.67 (1H, br s), 8.13 (1H, br s) MASS : 569 (M+H)+ Example 29 5 To a solution of (2R)-1-[3,5-bis(trifluoromethyl) benzoyl]-2-(3,4-dimethylbenzyl)-4-[[l- (2-hydroxyethyl) -H pyrazol-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 LO 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 L5 morpholine (0.028 ml), potassium carbonate (74 mg) and potassium iodide (13 mg). After stirring at 70 0 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 .0 evaporated 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)-l-[3,5-bis(trifluoromethyl) .5 benzoyl]-2-(3,4-dimethylbenzyl)-4-[[1- (2-morpholinoethyl) -1H pyrazol-4-yl]methyl]piperazine dihydrochloride (188.7 mg) as a solid. m: 115-116'C 25 _ []5 : -9.70' (C=0.50, MeOH) 30 IR (KBr) : 1640 cmr NMR (DMSO-d 6 , 5) : 2.06-2.16 (6H, m), 2.85-5.00 (23H, m), 6.60-6.64 (1H, m), 6.91-7.08 (2H, m), 7.57 (1H, s), 7.74 (1H, br s), 7.78 (1H, br s), 8.10 (1H, br s), 8.18 (1H, br s) 5 MASS : 638 (M+H)

+

(free) WO 98/57954 PCT/JP98/02613 74 Example 30 A solution of (2R)-l-[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 5 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 (10 ml) using dichloromethane-methanol (30:1) as eluent. The obtained oil was dissolved in ethyl acetate and treated with L0 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-pyridyl methylamino)-2-butynyl]-2-(2-naphthylmethyl)piperazine trihydrochloride (60 mg) as a powder. L5 []2]9 : -20.80' (C=0.25, MeOH) IR (Neat) : 3650-3100, 2750-1950, 1630, 1273, 1122 cm-1 NRMR (DMSO-d 6 , 5): 2.60-5.30 (16H, m), 7.00-9.10 (14H, m) MASS : 625 (M+H) (free) Elemental Analysis Calcd. for C 34

H

33 Cl 3

F

6

N

4 0-3.3H 2 0 : ?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)-l-[3,5-bis(trifluoromethyl)benzoyl]-4 (4-chloro-2-butynyl)-2-(2-naphthylmethyl)piperazine (300 mg), 25 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 30 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 35 acetate to give (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-4- WO 98/57954 PCT/JP98/02613 75 [4-(cis-2,6-dimethylmorpholino)-2-butynyl] -2-(2 naphthylmethyl)piperazine dihydrochloride (170 mg). IR (KBr) : 3428, 2931, 2559, 1644, 1432, 1282, 1184 cm-1 NTMR (DMSO-d 6 , 5) : 1.13 (3H, s), 1.16 (3H, s), 5 2.60-5.40 (21H, m), 7.00-8.15 (10H, m) MASS : 632 (M+H) (free) Elemental Analysis Calcd. for C 3 4H 37 Cl2F 6

N

3 02-2H20 : C 55.14, H 5.58, N 5.67 Found : C 54.89, H 5.59, N 5.31 0 Example 32 The following compound was obtained according to a similar manner to that of Example 31. 5 1,3-[Bis(trifluoromethyl)benzoyl]-4-[4-(2-methylthiazol 4-yl)methyl]-2-[ (1H-indol-3-yl)methyl]piperazine hydrochloride NMR (DMSO-d 6 , ) : 2.65 (3H, s), 3.00-5.20 (11H, m), 6.80-8.24 (9H, m), 10.93 (1H, br d) 0 MASS 567 (M+H) + (free) Example 33 To a stirred mixture of (2R)-[3,5-bis(trifluoromethyl) benzoyl]-2-(3,4-dimethylbenzyl)piperazine (943 mg) and 5 potassium carbonate (880 mg) in dimethylformamide (10 ml) was added propargy! bromide (0.2 ml) at room temperature. After 1 hour, the reaction mixture was poured into water (100 ml) and extracted with ethyl acetate. The extract was washed with brine and concentrated under reduced pressure. The 0 obtained residue was purified by column chromatography on silica gel using a mixture of hexane and ethyl acetate (5:1) as eluent to give (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2 (3,4-dimethylbenzyl)-4-propargylpiperazine (1.09 g) as an oil. 5 NMR (DMSO-d 6 , 5) : 2.00-2.20 (6H, m), 2.20-5.00 (12H, WO 98/57954 PCT/JP98/02613 76 m), 6.60-8.20 (6H, m) MASS : 483 (M+H) + Examle 34 5 A mixture of (2R)-[3,5-bis(trifiuoromethyl)benzoyl]-2 (3,4-dimethylbenzyl)-4-propargylpiperazine (286 mg), (3S)-3 isopropylmorpholine hydrochloride (118 mg) and N,N diisopropylamine (92 mg) in dioxane (3 ml) was stirred at room temperature. Paraformaldehyde (22 mg) and copper(I) [0 chloride (10 mg) were added and the whole was stirred for 30 minutes and then heated at 800C for 4 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 hexane 15 and ethyl acetate (1:1) 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(trifluoro methyl)benzoyl]-4-[4-((3S)-3-isopropylmorpholino)-2-butynyl] 2-(3,4-dimethylbenzyl)piperazine dihydrochloride (190 mg). .0 IR (KBr) 3438, 2971, 2551, 1644, 1438, 1282, 1216, -!I 1135 cm NMR (DMSO-d 6 , 5) : 1.01 (6H, d, J=6.8Hz), 2.09-2.17 (6H, m), 2.36 (1i , m), 2.60-5.30 (22H, m), 6.60 8.30 (6H, m) .5 MASS : 624 (M+H)+ (free) Example 35 A mixture of (2R)-!-[3,5-bis(trifluoromethyl)benzoyl]-4 (4-chloro-2-butenyl)-2-(3,4-dimethylbenzyl)piperazine (150 0 mg), (3S)-3-isopropylmorpholine hydrochloride (47 mg) and powdered potassium carbonate (117 mg) in dry N,N dimethylformamide (1 ml) was stirred at 500C for 1.5 hours. The reaction mixture was poured into water (10 ml) and extracted with ethyl acetate. The extract was washed with 5 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 ethyl acetate as eluent. The obtained product was dissolved in ethyl acetate and treated with 4N hydrogen chloride in ethyl acetate to give 5 (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-4-[4-((3S)-3 isopropylmorpholino)-2-butenyl] -2- (3,4-dimethylbenzyl) piperazine dihydrochloride (110 mg). IR (KBr) : 3430, 2971, 2661, 1644, 1434, 1280, 1135, 985, 680 cm L0 NMR (DMSO-d 6 , 5) : 1.01 (6H, m), 2.00-2.20 (6H, m), 2.40 (1H, m), 2.60-5.20 (24H, m), 6.60-8.20 (6H, m) MLASS : 626 (M+H) + (free) Elemental Analysis Calcd. for C 3 3

H

43 C1 2

F

6 N302-3H20 : C 52.66, H 6.56, N 5.58 .5 Found : C 52.45, H 6.55, N 5.49 Example 36 To a stirred solution of (2R)-[3,5-bis(trifluoromethyl) benzoyl]-2-(3,4-dimethylbenzyl)-4-[2-((3R,3S)-3-hydroxy 0 methylpiperidino)ethyl]piperazine (133 mg) in N,N-dimethyl formamide (1 ml) was added 60% sodium hydride (109 mg) at ice-salt bath temperature. A solution of ethyl iodide (53 mg) in N,N-dimethylformamide (0.5 ml) was added and the whole was stirred for 15 minutes and then at room temperature for 1 5 hour. The reaction mixture was toured 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 0 eluent. The obtained product was dissolved in ethyl acetate and treated with 4N hydrogen chloride in ethyl acetate to give (2R)-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4 dimethylbenzyl)-4-[2- ( (3R,3S)-3-ethoxymethylpiperidino) ethyl]piperazine dihydrochoride (101 mg). 5 [~] 3 : -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, m), 1.12 (3H, t), 6.62-8.26 (6H, m) 5 MASS : 614 (M+H) (free) Example 37 The requisite mesviate was orecared by the treatment of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethyl 0 benzyl)-4-(2-hydroxyethyl)piperazine with methanesulfonyl chloride. A mixture of the mesylate (200 irg) and 4-hydroxv methylpiperidine 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 5 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 (5:1) as eluent. The obtained product was dissolved in ethyl acetate and treated with 4N hydrogen chloride in ethyl 0 acetate to give (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-4 [2- (4-hydroxymethylpiperidino) ethyl] -2- (3, 4-dimethylbenzyl) piperazine dihydrochloride (32 mg). [2]6 : -5.8' (C=0.50, MeOH) IR (KBr) : 3370, 2600, 1645, 1430, 1280, 1180, 1140 cm 5 NMR (DMSO-d 6 , 5) : 1.40-5.24 (30H, m), 6.60-8.24 (6H, m), 8.45 (1H, s) MASS : 586 (M+H) + (free) Elemental Analysis Calcd. forC 30

H

37

F

6

N

3 02-2HC1*4.85H20 : C 48.36, H 6.57, N 5.64 0 Found : C 48.31, H 5.95, N 4.96 ExamD!le 38 A mixture of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-4 (4-chloro-2-butynyl)-2-(3,4-dimethylbenzyl)piperazine (150 5 mg), (3S)-3-ethylmorpholine hydrochloride (47 mg) and WO98/57954 PCT/JP98/02613 79 powdered potassium carbonate (117 mg) in dry N,N dimethylformamide (1 ml) was stirred at 50oC for 1.5 hours. The reaction mixture was poured into water (10 ml) and extracted with ethyl acetate. The extract was washed with 5 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 hydrogen chloride in ethyl acetate to give LO (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-4-[4-((3S)-3 ethylmorpholino)-2-butynyl]-2-(3,4-dimethylbenzyl)piperazine dihydrochloride (177 mg). 26 []6 : 4.80 (C=0.50, MeOH) IR (KBr) : 3430, 2580, 1645, 1435, 1280, 1180, 1135 cm L5 ,NMR (DMSO-d 6 , 5) : 1.27 (3H, t), 1.45-5.20 (28H, m), 6.64-8.28 (6H, m) MASS 610 (M+H) (free) Elemental Analysis Calcd. for C 3 2

H

37

F

6

N

3 0 2 *2HCl*3.5H 2 0 : C 51.55, H 6.22, N 5.64 .0 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(trifluoromethyl)benzoyl]-2-(3,4-dimethyl 5 benzyl)-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,N dimethyvlformamide (1 ml) was heated at 50 0 C in the presence of potassium carbonate (85 mg). After 2 hours, the reaction 0 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 5 product was dissolved in ethyl acetate and treated with 4N WO 98/57954 PCT/JP98/02613 80 hydrogen chloride in ethyl acetate to give (2R)-1-[3,5-bis(tr ifluoromethyl)benzoyl]l-4-[2-((3S)-3-ethylmorpholino)ethyl]-2 (3,4-dimethylbenzyl)piperazine dihydrochloride (45 mg). 2/1 [f]D4 : 1.600 (C=0.50, MeOH) 5 IR (KBr) : 3430, 2610, 1645, 1435, 1280, 1180, 1135. cm NMR (DMSO-d 6 , 5) 0.95 (3H, s), 1.16-5.20 (28H, m), 6.64-8.24 (6H, m) MASS : 586 (M+H) + (free) 0 Elemental Analysis Calcd. for C 30

H

37

F

6

N

3 0 2 *2HCl1.8H 2 0 : C 52.15, H 6.21, N 6.08 Found : C 52.15, H 6.42, N 6.00 Example 40 5 A mixture of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-4 (2-methylsulfonyloxyethyl)-2-(2-naphthylmethyl)piperazine (200 mg), 3-(N-methylaminomethyl)pyridine dihydrochloride (73 mg) and triethylamine (120 mg) in dry methanol (5 ml) was refluxed for 4 hours. The reaction mixture was concentrated D under reduced pressure and the resulting residue was partitioned between ethyl acetate and aaueous sodium bicarbonate solution. The organic layer was washed with brine and dried over magnesium sulfate. After evaporation of the solvent, the residue was purified by column 5 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 hydrogen chloride in ethyl acetate (0.5 ml) to give (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-4 [2- [(N-methyl-N-(3-pyridylmethyl)amino]ethyl]-2-(2 ) naphthylmethyl)piperazine dihydrochloride (78 mg). []D5 : -12.90 (C=0.50, MeOH) IR (KBr) : 3410, 2600, 1640, 1430, 1280, 1180, 1135 cm NMR (DMSO-d 6 , 8) : 2.40-5.28 (15H, m), 2.74 (3H, s), 7.00-9.10 (14H, m) MASS : 615 (M+H)

+

(free) WO 98/57954 PCT/JP98/02613 81 Elemental Analysis Calcd. for C 33

H

32

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 5 Examole 41 The following compound was obtained according to a similar manner to that of Example 40. (2R)-l-[3,5-Bis(trifluoromethyl)benzoyl]-2-[ (IH-indol-3 0 yl)methyl]l-4-[2-[N-methyl-N-(3-pyridylmethyl)amino]ethyl] piverazine dihydrochloride 24 -0.80 (C= 0 .50, MeOH) IR (KBr) : 3400, 2600, 1640, 1280, 1180, 1135 cm NMR (DMSO-d 6 , 5) 1 12-5.20 (15H, m), 2.84 (3H, s), 5 6.63-9.00 (12H, m), 10,95 (1H, s) MASS : 604 (M+H) + Elemental Analysis Calcd. for C 31

H

3 1

F

6 N50*2HC1-4.5H 2 0 : C 49.15, H 5.59, N 9.24 Found : C 49.19, H 5.41, N 9.08 0 Example 42 To a stirred mixture of (2R)-1-[3,5-[bis(trifluoro methyl)benzoyl]-2-[ (H-indol-3-yl)methyll-4-[N-(1 piperazinyl)carbamoylmethyl]piperazine dihydrochloride (500 5 mg) and triethylamine (302 mg) in tetrahydrofuran (10 ml) was added a solution of benzy!vl 4-bromobutanoate (192 mg) in tetrahydrofuran (2 ml) at room temperature for 24 hours. As a part of starting material remained, the reaction mixture. was filtered and the filtrate was concentrated under reduced 0 pressure. To the resulting residue were added benzyl 4-bromobutanoate (192 mg), potassium carbonate (310 mg) and N,N-dimethylformamide (2 ml). The whole was stirred at room temperature for 7 hours and then diluted with ethyl acetate and filtered. The filtrate was washed with brine and dried 5 over magnesium sulfate. After evaporation 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 (5:1) as eluent to afford (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-4-[N-[4 (3-benzyloxycarbonylpropyl)piperazin-1-yl]carbamoylmethyl]-2 5 [(1H-indol-3-yl)methyl]piperazine (296 mg). IR (Neat) : 3250, 1720, 1670, 1630, 1430, 1350, 1270, 1120 cm NTMR (CDC! 3 , 6) : 1.60-3.66 (25H, m), 5.10 (2H, s), 6.80-7.86 (8H, m), 7.32 (SH, s), 8.21 (iH, s) 0 MASS : 773 (M+H) + Example 43 A mixture of (2R)-i-[3,5-bis(trifluoromethyl)benzoyl] 4- [N-[4-(3-benzyloxycarbonylpropyl)piperazin-1-yl] 5 carbamoylmethyl]-2-[ (1H-indol-3-yl)methyl]piperazine (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 0 C with stirring under a nitrogen atmosphere. After 1 hour, the reaction mixture was filtered and the 0 filtrate was concentrated under reduced pressure. The product was triturated with ethyl ether to give (2R)-1-[3,5 bis (trifluoromethyl)benzoyl] -4-[N- [4- (3-carboxypropyl) piperazin-1-yl]carbamoylmethyl] -2- [ (1H-indol-3-yl)methyl] piperazine (1.19 g) as a powder. 5 []D : -18.600 (C=0.50, MeOH) IR (Neat) : 3200, 1680, 1620, 1425, 1275, 1120 cm-1 NMR (CDC1 3 , 5) : 1.72-4.60 (25H, m), 6.71-7.93 (8H, m) MASS : 683 (MN+) + D Examnle 44 The following compounds were obtained according to a similar manner to that of Example 5-(1). (1) (2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-4-[(2E)-3 S[(3R)-4- (tert-butoxycarbonyl)morpholin-3-yll]-2- WO 98/57954 PCT/JP98/02613 83 propenyl] -2-(3,4-dimethylbenzyl)piperazine IR (Neat) : 2973, 1697, 1645 cm NMR (CDCI 3 , 5) 1.39 (9H, s), 2.00-2.16 (6H, m), 2.48-5.00 (18H, m), 5.40-5.80 (2H, m), 6.60-6.80 S (1H, m), 6.90-7.20 (2H, m), 7.30-7.70 (3H, m), 8.13 (1H, br s) MASS 670 (M+H) + (2) (2R)-1-[3,5-Bis(trifluoromethyvl)benzoyl]-4-[(2E)-3 0 [(2R,2S)-4-(tert-butoxycarbonyl)morpholin-2-yl]-2 propenyl]-2-(3,4-dimethylbenzyl)piperazine NMR (DMSO-d 6 , 5) : 1.41 (9H, s), 2.08-2.16 (6H, m), 2.50-4.80 (18H, m), 5.55-5.85 (2H, m), 6.60-6.80 (1H, m), 6.90-7.20 (2H, m), 7.30-7.70 (2H, m), 8.13 5 (1H, br s) MASS : 670 (M+H) + Example 45 A solution of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl] 0 4-[(2E)-3-[(3R)-4-(tert-butoxycarbonyl)morpholin-3-yl]-2 propenyl]-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 5 and stirred for 1 hour. The resulting precipitate was collected by filtration and dried under reduced pressure to give (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4 dimethylbenzyl)-4-[(2E)-3-[(3R)-3-morpholinyl]-2-propenyl] piperazine dihydrochloride (1.11 g) as a white powder. 3 m : 225-232 0 C 25

[C]

5 : -12.00' (C=0.50, MeOH) IR (KBr) : 1645 cm NMR (DMSO-d 6 , 5) : 2.10-2.18 (6H, m), 2.70-5.10 (18H, m), 5.80-6.25 (2H, m), 6.60-6.70 (1H, m), 6.90-7.20 5 (2H, m), 7.39-7.69 (2H, m), 8.15-8.20 (1H, m), WO 98/57954 PCT/JP98/02613 84 9.60-10.0 (2H, m) IMASS : 570 (M+H) + (free) Elemental Analysis Calcd. for C 2 9

H

33

F

6

N

3 0 2 *2HC1-1.0H 2 0 C 52.73, H 5.65, N 6.36 5 Found C 52.65, H 5.76, N 6.26 Example 46 To a solution of (2R)--[3,5-bis(trifluoromethyl) benzoyl] -2-(3,4-dimethylbenzyl)-4- (4-pyrazolylmethyl) LO piperazine (500 mg) and tert-butvl bromoacetate (225 mg) in N,N-dimethylformamide (7.5 ml) was added potassium carbonate (390 mg), and the mixture was stirred at 60'C for 7 hours. Water was added to the mixture and the resulting mixture was extracted with ethyl acetate. The organic layer was washed L5 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)-1-[3,5-bis(trifluoromethyl)benzoyl]-4 [[1-(tert-butoxycarbonylmethyl) -1H-pyrazol-4-yl]methyl]-2 0 (3,4-dimethylbenzyl)piperazine as an oil. N-NIR (DMSO-d 6 , 5) : 1.01 (9H, s), 2.05-2.15 (6H, s), 2.52-4.90 (11H, im), 4.90 (2H, s), 6.53-6.58 (1K, m), 6.90-7.00 (2H, m), 7.41 (2H, s), 7.65 (2H, s), 8.13 (IH, br s) 5 MASS : 639 (M+H) Example 47 A solution of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl] 4- [[1- (tert-butoxycarbonylmethyl)-iH-pyrazol-4-yi]imethyl]-2 0 (3,4-dimethylbenzyl)piperazine (425 mg) in dichloromethane (2.5 ml) was treated with trifluoroacetic acid (2.5 ml) at room temperature for 1 hour. The mixture was adjusted to pH 7.4 with aqueous sodium bicarbonate solution and evaporated under reduced pressure. The residue was washed with a '5 mixture of dichloromethane and methanol (9:1), and the WO98/57954 PCT/JP98/02613 85 solution was evaporated under reduced pressure and purified by column chromatography on a silica gel using a mixture of methanol and chloroform (1:9) as eluent and subseauent crystallization from ethyl acetate, isopropyl ether, and 5 hexane to give (2R)-1-[3,5-bis(trifluoromethyl)benzoyl] 4-[[1-(carboxymethyl)-1H-pyrazol-4-yl]methyl]-2-(3,4-dimethyl benzyl)piperazine (395 mg) as a white powder. mI : 223-230°C []2 5 : -15.10 ° (C=0.50, MeOH) 0 IR (KBr) : 1683, 1604 cm NMR (DMSO-d6, 6) : 2.06-2.15 (6H, mn), 2.52-4.90 (11H, m), 4.54 (2H, s), 6.50-6.60 (1H, m), 6.90-7.00 (2H, m), 7.31 (1H, s), 7.40 (1H, s), 7.57-7.64 (2H, m), 8.14 (1H, s) 5 Example 48 To a solution of (2R)-1-[3,5-bis(trifluoromethyl) benzoyl]-4-[[l1-(carboxymethyl)-1H-pyrazol-4-yl]methyl]-2 (3,4-dimethylbenzyl)piperazine (120 mg) in tetrahydrofuran (1 0 ml) were added 1-hydroxybenzotriazole hydrate (176 mg), 1 ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (240 mg) and morpholine (0.11 m!) at room temperature, and the mixture was stirred at room temperature overnight. The mixture was quenched with water, and extracted with ethyl 5 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 (1:9) as eluent to give a crude oil (76.7 mg). The oil was dissolved 0 in ethyl acetate (0.7 ml) and added 4N hydrogen chloride in ethyl acetate (0.15 ml) at room temperature. After the addition of isopropyl 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 5 [[1-(morpholinocarboxymethyl)-!H-pyrazol-4- WO 98/57954 PCT/JP98/02613 86 yl]methyl]piperazine hydrochloride (40 mg) as a powder. mp : 120-130 C 25 [a]5 : -19.400 (C=0.25, MeOH) IR (KBr) : 1649 cm 5 N-R (DMSO-d 6 , 5) 2.06-2.16 (6H, s), 2.52-5.00 (19H, m), 5.19 (2H, s), 6.55-6.62 (1H, m), 6.92-7.03 (2H, m), 7.44 (1H, s), 7.66-7.68 (2H, m), 7.92 (1H, br s), 8.19 (1H, br s) kMASS : 652 (M-+H)+ (free) 0 Elemental Analysis Calcd. for C 2 2

H

35

F

6

N

5 0 3 HC12.6H 2 0 : C 52.30, H 5.65, N 9.53 Found : C 52.58, H 5.63, N 9.22 Example 49 5 The following compound was obtained according to a similar manner to that of Example 34. (2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4 dimethylbenzyl)-4- [4- [(3S)-3-(2-methylpropyl)imorpholino]-2 0 butynyl ] piperazine dihydrochloride mI : 125-1380 C [a]D 5 : +13.900 (C=0.50, MeOH) D -i IR (KBr) : 1645 cm-1 NMR (DMSO-d 6 , 5) : 0.80-1.80 (9H, m), 2.09-2.18 (6H, 5 m), 2.83-5.13 (20H, m), 6.60-6.70 (1K, m), 6.96 7.14 (2 , m), 7.46 (1lH, br s), 7.67 (1H, br s), 8.16 (1H, br s) MASS : 638 (M+H) (free) Elemental Analysis Calcd. for C 34

H

4 3 Cl 2

F

6

N

3 02-1.1H20 : 0 C 55.91, H 6.24, N 5.75 Found : C 56.24, H 6.75, N 5.74 Example 50 The following compound was obtained according to a 5 similar manner to that of Example 31.

WO 98/57954 PCT/JP98/02613 87 (2R)-1-[3,5-Bis(trifluoromethyl)benzoyl] -2-(3,4 dimethylbenzyl)-4-[4-(7-oxa-4-azaspiro[2.5] octan-4-yl] -2 butynyl]piperazine dihydrochloride 27.9 [ D79 : -9.70' (C=0.50, MeOH) 5 IR (KBr) : 3700-3000, 2700-2200, 1645, 1534, 1463, 1280, 1184 cm-1 NMR (DMSO-d 6 , 6) : 0.90-1.00 (4H, m), 3.00-4.70 (19H, m), 6.60-8.20 (6H, m) MASS : 608 (M+H)+ (free) 10 Elemental Analysis Calcd. for C 32

H

35

F

6

N

3 0 2 -2HCl-2H 2 0 : C 53.64, H 5.77, N 5.86 Found : C 53.92, H 6.05, N 5.61 Example 51 15 The following compounds were obtained according to a similar manner to that of Example 1-(1). (1) (2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-[ (1H-indol-3 yl)methyl] -4-[3-(4-methoxypyridin-3-yl)-2-propynyl] 20 piperazine NMR (CDCl 3 , 6) : 2.00-5.20 (11H, m), 3.92 (3H, s), 6.80-8.00 (11H, m), 8.30 (1H, br s) MASS : 601 (M+H)+ (free) 25 (2) (2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4 dimethylbenzyl)-4-[3-(4-methoxypyridin-3-yl)-2 propynyl ] piperazine NMR (CDC1 3 , 5) : 2.00-5.20 (17H, m), 3.93 (3H, s), 6.60-8.80 (9H, m), 8.02 (1H, s), 8.30-8.50 (1H, m) 30 MASS : 590 (M+H) + Example 52 The following compounds were obtained according to a similar manner to that of Example 5-(2). 35 WO 98/57954 PCT/JP98/02613 83 (1) (2R)-l-[3,5-Bis(trifluoromethyl)benzoyl]-2-[ (1H-indol-3 yi) methyl -4- f 3- (4-methoxypyridin-3-yl) -2-propynyl] piperazine dihydrochloride mp : 162-167°C 5 []D6.6 : +4.900 (C=0.50, MeOH) IR (KBr) 3700-3300, 2700-2300, 1641, 1502, 1430, 1363, 1280 cm NMR (DMSO-d 6 , 5) : 3.00-5.20 (14H, m), 6.60-8.30 (9H, m), 8.80-9.90 (2H, m), 10.96 (iH, br s) 0 MASS : 601 (M+H) (free) Elemental Analysis Calcd. for C 3 1

H

26 F6N 4 02-2HCi-2.2H 2 0 : C 52.16, H 4.91, N 8.32 Found : C 52.21, H 4.58, N 7.86 5 (2) (2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4 dimethylbenzyl)-4-[3-(4-methoxypyridin-3-yl) -2 propynyl]piperazine dihydrochloride mp : 150-153°C [] 4.9 •: -7.450 (C=0.55, MeOH) 0 IR (KBr) 3600-3300, 2700-2200, 1639, 1500, 1430, 1317, 1280 cm NMR (DMSO-d 6 , 5) : 2.00-2.20 (6H, m), 2.80-5.20 (11H, m), 6.60-7.80 (6H, m), 8.20 (1K, br s), 8.81-8.97 (2H, m) 5 MASS : 590 (M+H) + (free) Elemental Analysis Calcd. for C 3 1

H

2 9

F

6

N

3 0 2 -2HC1-2.2H 2 0 : C 52.97, H 5.27, N 5.93 Found : .C 53.03, H 5.08, N 5.98 0 Example 53 The following compounds were obtained according to a similar manner to that of Example 3. (1) (2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-[ (1H-indol-3 5 yl)methyl] -4-[3-(4-methoxypyridin-3-yl)propyl] piperazine WO 98/57954 PCT/JP98/02613 89 dihydrochloride me : 165-170°C 24.9 . [a] D -1.91 (C=0.55, MeOH) IR (KBr) 3700-2300, 1643, 1502, 1432, 1363, 1280, 5 1222 cm NAR (DMSO-d6, 5) : 2.00-2.30 (2H, m), 2.60-5.20 (16H, m), 6.60-8.30 (9H, m), 8.70-8.90 (2H, m), 10.95 (1H, br s), 11.60-11.80 (2H, m) MLASS : 605 (M+H) + (free) 0 Elemental Analysis Calcd. for C 31

H

3 0

F

6 N40 2 -2HCl-2.8H20 : C 51.15, H 5.21, N 7.70 Found : C 51.11, H 5.40, N 7.61 (2) (2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4 5 dimethylbenzyl)-4-[3-(4-methoxypyridin-3-yl)propyl] piperazine dihydrochloride mn : 159-168 0 C 969 []2 6.9 -10.910 (C=0.55, MeOH) IR (KBr) : 3600-3300, 2700-2300, 1643, 1502, 1430, D 1361, 1280 cm-I NMR (DMSO-d 6 , 5) : 2.00-5.20 (21H, m), 4.13 (3H, s), 6.60-7.80 (6H, m), 8.20-8.30 (1H, m), 8.70-8.90 (2H, m), 11.60-11.90 (2H, m) MASS : 594 (M+H) + (free) 5 Elemental Analysis Calcd. for C 3 1

H

33

F

6

N

3 0 2 -2HC1-2.4H 2 0 : C 52.50, H 5.97, N 5.60 Found : C 52.46, H 5.65, N 5.92 Example 54 D A solution of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl] 2-[ (1H-indol-3-yi)methyl]-4-[3-[6-(tert-butoxycarbonylamino) pyridin-3-yl]-2-propynyi]piperazine (127 mg) prepared by a similar manner to that of Example 5-(1) and trifluoroacetic acid (5 ml) in dichloromethane (5 ml) was stirred at room 5 temperature for 2 hours. The reaction mixture was WO 98/57954 PCT/JP98/02613 90 concentrated under reduced pressure and the residue was partitioned between saturated aaueous sodium bicarbonate solution. The organic layer was separated, dried over magnesium sulfate and concentrated under reduced pressure. 5 The syrup obtained was dissolved into ethyl acetate and treated with 4N hydrogen chloride in ethyl acetate to give (2R) -- [3,5-bis (trifluoromethyl)benzoyli]-2-[ (1H-indol-3-yl) methyl] -4- [3-(6-anminopy-ovridin-3-yl)-2-propynyl]piperazine dihydrochloride (80 mg) 0 mO 190-195°C

P]

4 .0 : -13.47' (C=0.23, MeOH) IR (KBr) : 3600-3000, 2700-2500, 1668, 1619, 1428, 1359, 1280 cm - i NMR (DMSO-d 6 , 5) : 3.00-5.20 (11H, m), 6.60-7.50 (6H, 5 im), 7.70-8.30 (5H, m), 8.20-8.50 (2H, m), 11.95 11.10 (1H, br s) MASS : 586 (M+H) (free) Elemental Analysis Calcd. for C 30

H

2 5

F

6 N50-2HC1-2.5H20 : C 51.22, H 4.58, N 9.95 0 Found C 51.17, H 4.40, N 9.27 Example 55 The following compound was obtained according to a similar manner to that of Examule 54. 5 (2R)-1-[3,5-Bis(trifluoromethvl)benzoyl]-2-(3,4 dimethylbenzyl)-4- [3-(6-aminopyridin-3-yl) -2-propynyl] piperazine dihydrochloride mO : 183-189 0 C 3 IR (KBr) : 3600-2500, 1644, 1596, 1525, 1375, 1280 cm

-

1 NMR (DMSO-d 6 , 6) : 2.00-2.25 (6H, m), 2.80-5.25 (13H, m), 6.60-8.40 (9H, m), 8.00-8.80 (2H, m) MASS : 575 (M+H) + (free) Elemental Analysis Calcd. for C 3 0

H

2 8

F

6

N

4 0-2HCl-1.5H 2 0 : 5 C 53.42, H 4.93, N 8.31 WO 98/57954 PCT/JP98/02613 91 Found : C 53.08, H 5.01, N 8.12 Example 56 The following compounds were obtained according to a 5 similar manner to that of Example 5. (1) (2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(2 naphthylmethyl) -4- [3- (2-pyridvl) -2-propynyl]ipiperazine IR (KBr) 3700-3200, 1641, 1278, 1136 cm 0 NMR (DMSO-d6, 5) : 2.20-4.00 (9H, m), 4.30-5.20 (2H, im), 7.00-8.65 (14H, m) MASS : 582 (M+H) , 467 (2) ( 2 R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-[ (1H-indol-3 5 yl)methyl]-4-[ ( 2

E)-

3 -(3-pyridyl)-2-propenyl]piperazine dihydrochloride mC : 195-203 0 C 24.9 . [] . : -11.200 (C=0.50, MeOH) IR (KBr) 3600-3300, 2700-2500, 1644, 1430, 1363, 3 1280, 1184 cm NMR (DMSO-d 6 , 5) : 3.00-5.20 (11H, m), 6.60-7.60 (6H, m), 7.70-9.00 (8H, m), 11.00 (1H, br s), 12.00 12.40 (2H, m) MASS 573 (M+H) + (free) 5 Elemental Analysis Calcd. for C- 3 0

H

2 6 6

N

4 - 2 H C 12.5H20 : C 52.18, H 4.82, N 8.11 Found : C 51.94, H 4.77, N 7.77 (3) (2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4 ) dimethylbenzyl) -4- [ (2Z)-3- (3-pyridyl)-2-propenyl] oinerazine dihydrochloride mO 170-174oC [(a]23.0 : -7.30' (C=0.50, MeOH) IR (KBr) : 3600-3300, 2700-2500, 1644, 1550, 1430, 1363, 1280 cm

-

'

WO 98/57954 PCT/JP98/02613 92 NMR (DMSO-d 6 , 5) : 2.00-2.30 (6H, m), 2.80-5.20 (11H, m), 6.40-8.40 (10H, m), 8.70-8.85 (2H, m), 12.00 12.20 (2H, m) MLASS : 562 (M+H) + (free) 5 Elemental Analysis Calcd. for C 30

H

2 9

F

6 N30-2HCl-2.5H 2 0 : C 53.03, H 5.34, N 6.18 Found : C 52.99, H 5.41, N 5.91 (4) (2R)-l-[3,5-Bis(trifluoromethyl)benzoyl]-2-[(1H-indol-3 0 yl)imethyl]-4-[4-(2-pyridyl)-3-butynyl]piperazine NMR (CDCl 3 , 5) : 1.80-5.20 (13H, m), 6.80-8.00 (12H, m), 8.19 (iH, s), 8.55 (1H, d, J=4.0Hz) MASS : 585 (M+H) + 5 Example 57 The following compounds were obtained according to a similar manner to that of Example 5. (1) (2R)-1-[3,5-Bis(trifluoromethyvl)benzoyl]-2-(3,4 0 dimethylbenzyl)-4-[3-(6-methoxypyridin-3-yl)propyl] piperazine dihydrochloride mp : 127-137oC 22.5 .3 []2.5 : -15.93o (C=0.16, MeOH) IR (KBr) : 3600-3300, 2700-2500, 1646, 1556, 1434, 5 1280, 1184 cm-i NMR (DMSO-d 6 , 6) : 1.90-5.20 (21H, m), 3.84 (3H, s), 6.60-7.30 (4H, m), 7.40-7.80 (3H, m), 8.00-8.30 (2H, m) MASS : 594 (M+H) + (free) 0 Elemental Analysis Calcd. for C 3 1

H

33

F

6

N

3 02-2HC1-1.2H 2 0 C 54.11, H 5.48, N 6.11 Found C 54.09, H 5.75, N 5.83 (2) (2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-[ (1H-indol-3 5 yl)methyl]-4- [3-(6-methoxypyridin-3-yl)propyl] piperazine WO 98/57954 PCT/JP98/02613 93 dihydrochloride mO : 195-2000C [ 2]D2.6 : -2.030 (C=0.32, MeOH) IR (KBr) : 3600-3300, 2700-2300, 1644, 1556, 1494, 5 1432, 1363, 1280, 1180 cm - 1 NMR (DMSO-d 6 , 6) : 2.20-5.20 (15H, m), 3.79 (3H, s), 6.60-8.30 (11H, m), 10.95 (1iH, br s), 11.60-11.80 (2H, m) MASS : 605 (M+H) + (free) 0 Elemental Analysis Calcd. for C 31

H

30

F

6

N

4 02-2HCl1.5H20 : C 52.58, H 5.01, N 7.95 Found C 52.89, H 5.40, N 7.63 (3) (2R)-1-[3,5-Bis(trifluoromethyvl)benzoyl]-2-(2 5 naphthylmethyl)-4-[3- (2-pyridyl)propylj]piperazine dihydrochloride 26.8 -27.60' (C=0.50, MeOH) [ ] D IR (KBr) 3700-3000, 2700-2200, 1647, 1279, 1136 cm

-

1 NMR (DMSO-d 6 , 6) : 2.20-4.30 (13H, m), 4.40-5.40 (2H, 0 m), 7.00-8.90 (14H, m) MASS : 586 (M+H ) + (free) Elemental Analysis Calcd. for C 3 2

H

2 9

F

6

N

3 O*2HC*2.5H 2 0 : C 54.63, H 5.16, N 5.97 Found C 54.55, H 5.37, N 5.56 5 (4) (2R)-1-[3,5-Bis(trifluoromethvl)benzoyvl]-2-[ (lH-indol-3 yl)methyl] -4-[4-(2-pyridyl)butyl] piperazine dihydrochloride mi : 155-160 0 C 27.0 0 [a] D : +9.500 (C=0.10, MeOH) IR (KBr) 3700-3000, 2700-2200, 1641, 1459, 1428, 1280, 1137 cm -1 NMR (DMSO-d 6 , 6) 1.70-2.20 (4H, m), 2.60-5.20 (13H, m), 6.60-8.80 (12H, m), 11.00 (1H, br s), 11.40 5 11.80 (2H, m) WO98/57954 PCT/JP98/02613 94 MASS : 589 (M+H) + (free) Elemental Analysis Calcd. for C 31

H

3 0

F

6

N

4 0*2HCl-2.0H 2 0 : C 53.38, H 5.20, N 8.03 Found : C 53.34, H 5.38, N 7.78 5 Example 58 A mixture of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2 [(!H-indol-3-yl)methyl]piperazine (0.83 g), methyl a-bromophenylacetate (0.42 g), potassium carbonate (1.0 g) 0 in N,N-dimethylformamide (5 ml) was stirred at 50C 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 5 eluent to give a mixture of diastereoisomers, methyl (2R,2S) 2-[(2R)-!-[3,5-bis(trifluoromethyl)benzoyl]-2-[(1H-indol-3 yl)methyl]piperazin-4-yl]-2-phenylacetate (1.00 g). NMR (CDCl 3 , 5) : 2.00-5.20 (4H, m), 3.69 (3H, s), 6.70-8.20 (14H, m) 0 MASS 604 (M+H) + (free) Example 59 A solution of the mixture of diastereoisomers, methyl (2R,2S)-2-[(2R)-!-[3,5-bis(trifluoromethyl)benzoyl]-2-[(lH 5 indol-3-yl)methyl]piperazin-4-yl]-2-phenylacetate (360 mg) and 1N sodium hydroxide (1.5 m!) in methanol (5 ml) was stirred at 500C 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 D (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, (2R,2S)-2-[(2R)-1-[3,5 bis(trifluoromethyl)benzoyl]-2-[(!H-indol-3-yl)methyl] 5 piperazin-4-yl]-2-phenylacetic acid (0.33 g).

WO98/57954 PCT/JP98/02613 95 NMR (CDCl 3 , 6) : 2.20-5.80 (10H, m), 6.60-8.20 (14H, m) MASS 590 (M+H) + (free) Example 60 5 Isobutyl chloroformate (0.116 ml) was added dropwise to a suspension of the mixture of diastereoisomers, (2R,2S)-2 [(2R)-!-[3,5-bis(trifluoromethyl)benzoyll]-2-[ (IH-indol-3-yl) methyli]piperazin-4-yl]-2-phenylacetic acid (0.5 g) and N-methylmorpholine (0.103 ml) in 1,2-dimethoxyethane (3 ml) 0 under -18 0 C. After being stirred at the same temperature for 30 minutes, a solution of sodium borohydride (32 mg) in water (0.5 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 5 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 0 mixed eluent of dichloromethane and methanol. The fractions containing the objective compound were collected and evaporated under reduced pressure to give a mixture of diastereoisomers, (2R)-l-[3,5-bis(trifluoromethyl)benzoyl]-2 [(1H-indol-3-yl)methyl]-4-[(iR, 1S) -i-phenyl-2-hydroxyethyl] 5 piperazine (0.42 g). NMR (CDCl 3 , 5) : 1.90-5.20 (13H, m), 6.60-8.20 (14H, m) MASS : 576 (M+H) + ExamDle 61 0 Methanesulfonyl chloride (0.058 mi) was added to a solution of the mixture of diastereoisomers, (2R)-1-[3,5 bis(trifluoromethyl)benzoyl]-2-[(1H-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 5 -18oC. After being stirred at the same temperature for 30 WO98/57954 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 5 magnesium sulfate and evaporated under reduced pressure to give the corresponding mesylate. A mixture of the mesylate 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 0 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 5 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-[(1H-indol-3 yl)methyl1-4-[(1R or 1S)-1-phenyl-2-morpholinoethyl] 0 piperazine dihydrochloride. me : 203-207oC [ 1]D : 6.0 (C=0.25, MeOH) IR (KBr) : 3700-3300, 3100-2200, 1641, 1450, 1432, 1363, 1280 cm -1 5 NMR (DMSO-d 6 , 5) 2.40-5.20 (20H, m), 6.60-8.30 (8H, m), 10.95 (1H, s) MASS : 644 (M+H) (free) Elemental Analysis Calcd. for C34H 34

F

6

N

4 02 -2HC l2/3HO C 55.97, H 5.16, N 7.68 0 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 (2R)-1-[3,5 5 bis(trifluoromethyl)benzoyl]-2-[(1H-indol-3-vl)methyl]-4-[(1S WO 98/57954 PCT/JP98/02613 97 or iR)-1-phenyl-2-morpholinoethyl]piperazine dihydrochloride. mpn : 207-212 0 C [

D

21. : -3.330 (C=0.24, MeOH) IR (KBr) : 3700-3200, 3000-2300, 1643, 1450, 1432, 5 1280, 1182 cm NMR (DMSO-d 6 , 5) 2.40-5.20 (20H, m), 6.55-8.35 (8H, m), 10.95 (1H, s), 11.00-12.10 (2H, m) MASS : 644 (M+H) + (free) Elemental Analysis Calcd. for C 34

H

34

F

6

N

4 02.2HCl0.5H20 : 0 C 56.20, H 5.13, N 7.71 Found : C 56.15, H 5.52, N 7.32 Example 62 The following compound was obtained according to a 5 similar manner to that of Example 45. (2R)-1-[3,5-Bis(trifluoromethyvl)benzoyl]-2-(3,4 dimethylbenzyvl)-4-[3- [ (2R,2S)-2-morpholinyl] -2-propenyl] piperazine dihydrochloride 0 me : 160-163oC 5]D : -12.500 (C=0.50, MeOH) IR (KBr) 1645 cm NMR (DMSO-d 6 , 5) : 2.08-2.18 (6H, m), 2.55-5.10 (S18H, m), 5.80-6.20 (2H, m), 6.60-6.70 (1H, m), 6.90-7.20 5 (2H, m), 7.47-7.70 (2H, m), 8.15-8.20 (1H, m) MASS : 570 (M+H) (free) Elemental Analysis Calcd. for C 29 H35F 6 N302-2HCL-iL.0H 9 20 : C 52.59, H 5.65, N 6.34 Found C 52.85, H 5.97, N 6.16 0 Example 63 A mixture of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2 (3,4-dimethylbenzvl)piperazine (500 ng) and 1,8 diazabicyclo[5.4.0]undec-7-ene (1.5 ul) in tetrahydrofuran 5 (2.5 ml) was cooled to -30 0 C with stirring under nitrogen WO98/57954 PCT/JP98/02613 98 atmosphere. Acrolein (90%, 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 0 C. After 6 hours, the reaction mixture was 5 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 0 eluent to give (2R)-!-[3,5-bis(trifluoromethyl)benzoyl]-2 (3,4-dimethylbenzyl)-4-(2-formylethyl)piperazine (332 mg) as an oil. NMR (DMSO-d 6 , 6) : 1.60-4.90 (19H, m), 6.55-6.75 (1H, m), 6.90-7.15 (2H, m), 7.30-7.75 (2H, m), 8.13 (1H, 5 br s), 9.70 (1H, s) MASS : 501 (M+H)+ Example 64 To a stirred mixture of 4-amino-3,3-dimethylmorpholine 0 dihydrochloride (122 mg) in dichloromethane (5 ml) was added triethylamine (61 mg) at ice bath temperature. A solution of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethyl benzyl)-4-(2-formylethyl)piperazine (150 mg) in dichloromethane (2 ml) was added and the resulting mixture 5 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 0 ethyl acetate to give (2R)-1-[3,5-bis(trifluoromethyl) benzoyl]-2-(3,4-dimethylbenzyl)-4-[3-(3,3-dimethylmorpholino imino)propyllpiperazine dihydrochloride (122 mg). IR (KBr) : 3425, 2700, 2625, 1645, 1430, 1280, 1180, 1135 cm 5 NMR (DMSO-d 6 , 5) : 1.06-1.40 (6H, m), 2.00-2.40 (6H, WO98/57954 PCT/JP98/02613 99 nm), 2.60-5.80 (19H, m), 6.64-8.30 (6H, m), 10.00 12.18 (2H, m) MASS : 613 (M+H)'(free) Elemental Analysis Calcd. for C 31

H

3 8

F

6

N

4 02*2HCl-2H 2 0 : 5 C 51.60, H 6.15, N 7.76 Found C 51.82, H 6.49, N 7.29 Example 65 To a stirred mixture of 4-aminohomomorpholine 0 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-(3,4 dimethylbenzyl)-4-(2-formylethyl)piperazine (200 mg) in dichloromethane (2 ml) was added and the resulting mixture 5 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-(3,4 0 dimethylbenzyl)-4-[3-(homomorpholinoimino)propyl]piperazine (110 mg) and an intermediate. This compound was dissolved in methanol (5 ml) and sodium borohydride (17 mig) was added at ice bath temoerature. After 2 hours, additional sodium borohydride (40 mg) was added and the reaction mixture was 5 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 0 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 5 (homomorpholinoamino)propyl]piperazine dihydrochloride (66 WO98/57954 PCT/JP98/02613 100 mg). E] 27 : -13.70 (C=0.50, MeOH) IR (KBr) 3450, 2700, 2620, 1645, 1430, 1280, 1185, 1135 cm-1 S MASS : 601 (M+H) (free) Elemental Analysis Calcd. for C 3 0

H

38

F

6

N

4 02.2HCl-0.7H20 : C 52.51, H 6.08, N 8.17 Found : C 52.51, H 6.05, N 7.86 0LO 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 5 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 0 pressure to give a crude oil of (2R)-4-benzvl-1-tert butoxycarbonyl-l-(3,4-dimethylbenzyl)piperazine (49.6 g). NMR (CDC! 3 , 5) : 1.40 (9H, s), 1.90-2.06 (2H, m), 2.15-2.17 (6H, m), 2.60-4.4 (9H, m), 6.86-7.05 (3H, m), 7.20-7.39 (5H, m) 5 MASS (APCI) : 395 (M+H)

+

, 339, 295 Preparation 33 A solution of (2R)-4-benzyl-1-tert-butoxycarbonyl-2 (3,4-dimethylbenzyl)piperazine (48.5 g) in methanol (730 ml) 0 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 5 dichloromethane and methanol (10:1). The fractions WO98/57954 PCT/JP98/02613 101 containing the objective compound was collected and evaporated under reduced pressure to give an oil of (2R)-1 tert-butoxycarbonyl-2-(3, 4 -dimethylbenzyl)piperazine (33.7 g). 5 NMR (DMSO-d 6 , ) : 1.26 (9H, s), 2.15-2.17 (6H, m), 2.30-4.05 (10H, m), 6.86-7.05 (3H, m) MASS (APCI) : 305 (M+H)

+

, 249, 205 Preparation 34 0 A mixture of ( 2 R)-1-tert-butoxycarbohyl-2-(3,4 dimethylbenzyl)piperazine (29.0 g), 3,3-dimethyl-4-(4-chloro 2-butynyl)morpholinine hydrochloride (22.7 g), potassium carbonate (39.5 g) and potassium iodide (1.58 g) in N,N dimethylformamide (145 ml) was stirred at room temperature 5 for 2 hours, followed by 53 0 C for 3 hours. After being cooled to room temperature, the mixture was poured into ice water (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 0 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-(3,4 5 dimethylbenzyl)-4-[4-(3, 3 -dimethylmorpholino)-2-butynyl] piperazine (43.1 g). NMR (DMSO-d 6 , 6) : 0.95 (6H, s), 1.26 (9H, s), 2.03-4.20 (25H, m), 6.80-7.05 (3H, m) MASS (APCI) : 470 (M+H) PreDaration 35 A solution of 4N hydrogen chloride in ethyl acetate was added to a solution of ( 2 R)-1-tert-butoxycarbonyl-2-(3,4 dimethylbenzyl)-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 5 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 (3:1). The fractions containing 10 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)-l-[4-(3,3 dimethylmorpholino)-2-butynyl]piperazine trihydrochloride (37.7 g). L5 m : 264-272 0 C 27 -23.60 (C=0.5, MeOH) IR (KBr) : 3500-3400, 2900, 2570, 2480, 1637, 1626, 1508, 1455, 1180 cm NMR (DMSO-d 6 , 5) : 1.33 (3H, s), 1.39 (3H, s), 2.21 0 (6H, s), 2.80-4.60 (20H, m), 6.90-7.20 (3H, m), 9.90-10.40 (3H, m) MASS (APCI) : 370 (M+H) (free) Preparation 36 5 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide (0.22 ml) was added over 5 minutes to a mixture of (3R)-3-(3,4 dimethylbenzyl)-1-[4-(3,3-dimethylmorpholino)-2-butynyll] piperazine trihydrochloride (0.48 g) and 3,5-bis(trifluoromethyl)benzoic acid (0.27 g), 0 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 (40:1). The fractions 5 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 (2R)-l-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4 5 dimethylbenzyl)-4-[4-(3,3-dimethylmorpholino)-2-butynyl] piperazine dihydrochloride (525 g). mp : 180-190 0 C 28.3 ]D83 : -7.24- (C=1.05, MeOH) IR (Nujol) : 3300, 2700-2400, 1635 cm

-

1 L0 NMR (DMSO-d 6 , 5) : 1.30-1.40 (6H, m), 2.00-5.22 (25H, m), 6.60-8.20 (6H, m), 12.05-12.20 (2H, m) MASS (APCI) : 610 (M+1H) (free) Elemental Analysis Calcd. for C 32

H

37

F

6 N302*2HCl*2.5H 2 0 : C 52.82, H 6.09, N 5.68 5 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-2 0 butyne (6.9 ml) and potassium carbonate (9.8 g) in N,N dimethylformamide (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 5 evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using a mixed solvent of n-hexane and ethyl acetate (4:1). The fractions containing the objective compound was collected and evaporated under reduced pressure, and treated with 4N 0 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 , 5) : 1.35-1.39 (6H, m), 3.20-4.40 (8H, m), 4.56 (2H, s), 11.50-11.90 (1H, m) 5 MASS (APCI) : 202 (M+H) (free) , 204 WO 98/57954 PCT/JP98/02613 104 Preparation 38 A mixture of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2 (3,4-dimethylbenzyl)piperazine (3.0 g), propargyl bromide (0.84 g) and potassium carbonate (1.17 g) in N,N 5 dimethylformamide (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 pressure to give a syrup of (2R)-1-[3,5-bis 10 (trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-(2 propynyl)piperazine (3.80 g). NMR (DMSO-d 6 , 5) : 2.00-5.00 (18H, m), 6.66-8.20 (6H, m) MASS (APCI) : 483 (M+H) + 5 Preparation 39 A mixture of (2R)-1-[3, 5-bis(trifluoromethyl)benzoyl]-2

(

3

,

4 -dimethylbenzyl)-4-(2-propynyl)piperazine (0.49 g), 3,3 dimethylmorpholine hydrochloride (0.185 g), paraformaldehyde (62 mg), diisopropylethylamine (0.21 ml), and copper (1) 0 iodide (20 mg) in 1,4-dioxane (5 ml) was stirred at 70 0 C for 1.5 hours. After removal of the solvent by evaporation, the residue was purified by column chromatography on silica gel using a mixed solvent of dichloromethane and methanol (40:1). The fractions containing the objective compound was collected 5 and evaporated under reduced pressure to give a syrup of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4 dimethylbenzyl)-4-[4-(3,3-dimethylmorpholino)-2-butynyl] piperazine (0.45 g). NMR (CDCI 3 -, ) 0.97 (6H, s), 2.03-5.00 (25H, m), 0 6.66-8.23 (6H, m) MASS (APCI) : 610 (M+H) , 513 its hydrochloride mD : 185-188 0 C 28 6 ( [I]D -8.6 (C=0.18, MeOH) WO 98/57954 PCT/JP98/02613 105 IR (KBr) : 2928, 2585, 2515, 1633, 1433, 1279, 1180, 1132 cm-1 MMR (DMSO-d 6 , 6) : 1.33-1.40 (6H, m), 2.09-2.18 (6H, m), 2.50-5.20 (19H, m), 6.66-8.15 (6H, m) 5 MASS (APCI) : 610 (M+H) + (free) Preparation 40 A mixture of 37% aqueous formaldehyde (0.21 g), (2R)-1 [3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl) 0 piperazine (0.75 g), propargy! 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 5 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 0 (4:1). 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, m), 5.15 (1H, t, 5 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 0 similar manner to that of Example 39. (2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4 dimethylbenzyl)-4-[4-(3,3-dimethylmorpholino)-2-butynyl] piperazine 5 NMR (CDC 3 , 5) : 0.97 (6H, s), 2.03-5.00 (25H, m), WO98/57954 PCT/JP98/02613 106 6.66-8.23 (6H, m) MASS (APCI) : 610 (M+H) , 513 Preparation 42 5 A mixture of 3,3-dimethylmorpholine hydrochloride (30.0 g), propargyl bromide (16.4 ml) and potassium carbonate (63 g) in N,N-dimethylformamide (300 ml) was stirred at 45 - 48 0 C for 1.5 hours. After being cooled to room temperature, the mixture was poured into ice-water (800 ml) and extracted with 0 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, 5 which was collected by filtration and washed with isopropyl ether to give brownish crystals of 3,3-dimethyl-4-(2 propynyl)morpholine hydrochloride (35 g). IR (KBr) : 3500-3400, 2900, 2570, 2480, 1637, 1626, 1508, 1455, 1180 cm

-

1 0 NMR (DMSO-d 6 , 6) : 1.20-1.50 (6H, m), 3.20-4.20 (9H, m), 11.91 (1H, s) MASS (APCI) : 154 (M+H) (free) Preparation 43 5A mixture of 3,3-dimethyvl-4-(2-propynyl)morpholine hydrochloride (0.24 g), 37% aqueous formaldehyde (0.16 ml), (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4 dimethylbenzyl)piperazine (0.57 g), copper(II) sulfate pentahydrate (5 mg) and potassium iodide (20 mg) in D 1,4-dioxane (0.7 ml) was stirred at 90 0 C 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 107 and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using a mixed solvent of dichloromethane and methanol (40:1). The fractions containing the objective compound was collected and 5 evaporated 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)-l-[3,5-bis(trifluoromethyl) 10 benzoyl]-2-(3,4-dimethylbenzyi)-4-[4-(3,3-dimethyl morpholino)-2-butynyl]piperazine dihydrochloride (0.64 g). mn : 180-190 0 C 28.3 . -7 .24 (C=1.05 MeOH) IR (Nujol) : 3300, 2700-2400, 1635 cm L5 NMR (DMSO-d 6 , 5) : 1.30-1.40 (6H, m), 2.00-5.22 (25H, m), 6.60-8.20 (6H, m), 12.05-12.20 (2H, m) MASS (APCI) : 610 (M+lH) (free) Elemental Analysis Calcd. for C 32

H

37

F

6

N

3 0 2 -2HCl2.5H 2 0 : C 52.82, H 6.09, N 5.68 ?0 Found : C 52.84, H 5.89, N 5.78 Preparation 44 The following compounds were obtained according to a similar manner to that of Preparation 1. 5 (1) 3-[2-(4-Methoxy)pyridyl]-2-propyn-1-ol IR (KBr) : 3130, 1598, 1562, 1471, 1425 cmi NMR (DMSO-dy, 5) : 3.84 (3H, s), 4.31 (2-1, d, J=6.OHz), 5.41 (IH, t, J=6.0Hz), 6.97 (11, dd, J=2.6, 5.8Hz), 0 7.06 (1H, d, J=2.6Hz), 8.35 (1H, d, J=5.8Hz) MASS (APCI) : 164 (M+H) 134 (2) 3-[2-(4-Methoxycarbonyl)pyridyl]-2-propyn-1-ol IR (KBr) : 3133, 1598, 1568, 1430 cm

-

1 5 NMR (DMSO-d 6 , 5) : 3.91 (3H, s), 4.35 (2H, d, J=6.0Hz), WO98/57954 PCT/JP98/02613 108 5.75 (1H, d, J=6.0Hz), 7.70-7.80 (1H, m), 8.68 (1lH, d, J=5.0Hz), 8.78 (1H, d, J=5.0Hz) MASS (APCI) : 192 (M+H) + 5 Preparation 45 (1) 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 0 tetrahydrofuran, 29 ml) at 5oC under nitrogen atmosphere over 15 minutes. After 1 hour of stirring at 500, 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 5 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-(3,4 methylenedioxybenzyl)pyrazine (454 mg) as a colorless oil. 0 NMR (CDC! 3 , 5) 4.59 (2H, s), 5.93 (2H, s), 6.75-6.88 (3H, m), 8.44-8.56 (3H, m) MASS (APCI) 915 (M+H) (2) To a stirred solution of 2-(3,4-methylenedioxybenzyl) 5 pyrazine (317 mg) in dry tetrahydrofuran (12 mi) was added a solution of diisobutylaluminum hydride (0.95 M in n-hexane, 15.6 ml) at 5oC under nitrogen atmosphere. After 1 hour of stirring at 50C, the mixture was added saturated sodium sulfate solution until gas evolution ceased. The insoluble 0 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-methylenedioxy 5 benzyl)piperazine dihydrochloride (125 mg) as a powder.

WO98/57954 PCT/JP98/02613 109 NMR (DMSO-d 6 , 5) : 2.79-3.66 (9H, m), 6.02 (2H, s), 6.74-6.94 (3H, m), 9.79 (4H, br s) MASS (APCI) : 221 (M+H) (free) 5 Preparation 46 (1) To a stirred solution of 4-bromo-2-methylbenzoic acid (10.75 g) in tetrahydrofuran (50 ml) was added borane tetrahydrofuran complex (1 M in tetrahydrofuran, 150 ml) by syringe under nitrogen atmosphere at 50 and the mixture was i0 heated under reflux for 18 hours. After cooling, water (50 ml) and potassium carbonate (20 g) were added to the solution at 5 0 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 L5 concentrated under reduced pressure to give 4-bromo-2 methylbenzyl alcohol (9.55 g). This compound was used to the next reaction without further purification. (2) Tert-butylchlorodiphenylsilane (13.06 g) and imidazole 0 (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 5 magnesium sulfate, and concentrated under reduced pressure to give 1-bromo-4-(tert-butyldiphenylsilyloxym.ethyl)-3 methvlbenzene (20.5 a) as a colorless oil. NMR (DMSO-d 6 , 5) : 1.03 (9H, s), 2.14 (3H, s), 4.70 (2H, s), 7.34-7.71 (13H, m) 0 (3) To a stirred solution of 1-bromo-4-(tert butyldiphenylsilyloxymethyl)-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 5 -78 0 C. After 30 minutes of stirring at -78 0 C, N,N- WO 98/57954 PCT/JP98/02613 110 dimethylformamide (1.16 ml) was added to the solution at -780C and then the mixture was allowed to warm to 5oC over 1.5 hours. Saturated ammonium chloride solution (10 ml) was added to the mixture and the organic layer was separated, and 5 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-butyldiphenylsily v!oxymethyl)-3-methylbenzaldehyde (1.90 g) as a colorless oil .0 NMR (DMSO-d 6 , 5) : 1.06 9H, s), 2.20 (3H, s), 4.38 (2H, s), 7.37-7.83 (13H, m), 9.97 (1H, s) MASS (APCI) : 389 (M+H)+

(

4 ) To a stirred mixture of 4-(tert 5 butyldiphenylsilyloxyimethyl)-3-methyvlbenzaldehyde (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 mig) at 50C. The mixture was stirred for 1 hour at room temperature and then poured 0 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 i-acetvl-3 (4-tert-butyldiphenylsilyloxymethyl-3-methylphenyl)methylene 5 2,5-piperazinedione (1.88 g) as a powder. NTMR (DMSO-d 6 , 5) : 1.05 (9H, s), 1.99 (3H, s), 2.19 (3H, s)., 4.37 (2H, s), 4.77 (2H, s), 6.93 (1H, s), 7.40-7.69 (13H, m), 10.37 (1H, s) MASS (APCI) : 527 (M+H) + (5) A solution of l-acetyl-3-(4-tert butyldiphenylsilyloxymethyl-3-methylphenyl)methylene-2,5 piperazinedione (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 WO98/57954 PCT/JP98/02613 ili 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 5 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 L0 give 3 -(4-tert-butyldiphenylsilyloxymethyl-3-methylbenzyl) 2,5-piperazinedione (4.67 g) as a powder. NMR (DMSO-d 6 , 5) : 1.02 (9H, s), 2.12 (3H, s), 2.77-3.18 (3H, m), 3.37 (1H, m), 4.04 (1H, m), 4.72 (2H, s), 6.97-7.04 (2H, m), 7.29-7.66 (11H, m), .5 7.94 (1H, m), 8.14 (1H, m) MASS (APCI) : 487 (M+H) + (6) To a stirred solution of 3-(4-tert butyldiphenylsilyloxymethyl-3-methylbenzyl)-2,5 0 piperazinedione (1.46 g) in a mixture of tetrahydrofuran (40 ml) and 1,2-dimethoxyethane (40 ml) was added lithium aluminum hydride (683 mg) under nitrogen atmosphere at 5 0 C and the mixture was heated under reflux for 6 hours. After cooling, the reaction mixture was quenched by sequential 5 addition of water (1.5 ml), 150 sodium hydroxide solution (1.5 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 0 chromatographv on silica gel using a mixture of dichloromethane and methanol (50:1 - 20:1) to give 1,4 bis(benzyloxycarbonyl)-2-(4-hydroxymethyl-3 methylbenzyl)piperazine (242 mg) as a powder. NMR (DMSO-d 6 , 5) : 2.09 (3H, m), 2.58-3.22 (5H, m), 5 3.64-4.50 (6H, m), 4.82-5.21 (5H, m), 6.86-7.72 WO 98/57954 PCT/JP98/02613 112 (13H, m) (7) A solution of 1,4-bis(benzyloxycarbonyl)-2-(4 hydroxymethyl-3-methylbenzyl)piperazine (6.3 g) in methanol 5 (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-3 10 methylbenzyl)piperazine dihydrochloride (96 mg) as a powder. MASS (APCI) : 221 (M+H)+ (free) Preparation 47 (1) The following compound was obtained according to a 15 similar manner to that of Preparation 46-(4). 1-Acetyl-3-[1,4-benzodioxan-6-yl)methylene] -2,5 piperazinedione NMR (DMSO-d 6 , 6) : 2.48 (3H, s), 4.28 (4H, s), 4.35 20 (2H, s), 6.86-7.16 (4H, m), 10.30 (1H, s) MASS (APCI) : 303 (M+H) + (2) The following compound was obtained according to a similar manner to that of Preparation 46-(5). 25 3-[(1, 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, m), 3.00 (1H, m), 3.43 (1H, dd, J=17.4, 2.7Hz), 3.97 (1H, m), 4.20 (4H, s), 6.57-6.77 (3H, 30 m), 7.93 (1H, s), 8.10 (1H, m) MASS (APCI) : 263 (M+H) + (3) To a stirred suspension of 3-[(1,4-benzodioxan-6 yl)methyl]-2,5-piperazinedione (564 mg) in tetrahydrofuran 35 (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 5 bromide in acetic acid (10 ml). To the mixture was added n-hexane (100 ml) and the whole was stirred for 1 hour at 5°C. 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. LO NMR (DMSO-d 6 , 6) : 2.62-3.80 (9H, m), 4.23 (4H, s), 6.71-6.88 (3H, m) MASS (APCI) : 235 (M+H) + (free) Preparation 48 L5 (1) The following compound was obtained according to a similar manner to that of Preparation 46-(4). 1-Acetyl-3- [ (4-methoxy-3-methylphenyl)methylene]-2,5 piperazinedione ?0 NMR (DMSO-d 6 , 6) : 2.17 (3H, s), 2.49 (3H, s), 3.83 (3H, s), 4.35 (2H, s), 6.90 (1H, s), 6.94 (1H, d, J=15.7Hz), 7.32 (2H, m), 10.28 (1H, s) MASS (APCI) : 289 (M+H) + ?5 (2) 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 , 5) : 2.09 (3H, s), 2.73-3.04 (3H, m), 30 3.34 (1H, m), 3.75 (3H, s), 3.99 (1H, m), 6.81-6.97 (3H, m), 7.89 (1H, s), 8.11 (1H, m) MASS (APCI) : 249 (M+H) + (3) The following compound was obtained according to a 35 similar manner to that of Preparation 47-(3).

WO 98/57954 PCT/JP98/02613 114 2-(4-Methoxy-3-methylbenzyl)piperazine dihydrobromide MR (DMSO-d 6 , 6) : 2.09 (3H, s), 2.60-3.72 (9H, m), 3.78 (3H, s), 6.55 (2H, m), 6.87-7.14 (3H, m), 9.09 (2H, m) 5 MASS (APCI) : 221 (M+H) (free) Preparation 49 (1) The following compound was obtained according to a similar manner to that of Preparation 46-(4). L0 1-Acetyl-3-[(2,3-dimethoxyphenyl)methylene]-2,5 piperazinedione IR (KBr) : 1712, 1697, 1685, 1647, 1624, 1373, 1271, 1225 cm-i .5 NMR (DMSO-d 6 , 6) : 2.51 (3H, s), 3.74 (3H, s), 3.83 (3H, s), 4.35 (2H, s), 7.03-7.16 (4H, m), 10.07 (1H, s) MASS (APCI) : 305 (M+H) + 0 (2) A solution of 1-acetyl-3-[(2,3-dimethoxyphenyl) methylene]-2,5-piperazinedione (2.40 g) in a mixed solvent of tetrahydrofuran (120 ml) and methanol (80 ml) was hydrogenated using 10% palladium-carbon (50% wet, 0.55 g) at atmospheric pressure for 3 hours. The catalyst was removed 5 by filtration and the filtrate was concentrated under reduced pressure. The resulting precipitates were collected by filtration to give gray solid of 1-acetyl-3-(2,3 dimethoxybenzyl)-2,5-piperazinedioge (2.55 g). IR (KBr) : 3265, 1726, 1711, 1689, 1487, 1460, 1358, 0 1275, 1257 cm-i NMR (DMSO-d 6 , 5) : 2.42 (3H, s), 2.90-3.20 (2H, m), 3.57-3.83 (1H, m), 3.72 (3H, s), 3.79 (3H, s), 4.14-4.23 (2H, m), 6.74-7.04 (3H, m), 8.34 (1H, s) MASS (APCI) : 307 (M+H) 5 WO 98/57954 PCT/JP98/02613 115 (3) To a suspension of 1-acetyvl-3-(2,3-dimethoxybenzyl)-2,5 piperazinedione (2.49 g) in tetrahydrofuran (38 ml) was added hydrazine monohvdrate (0.43 ml) at room temperature and the mixture was stirred at the same temperature for 30 minutes. 5 The resulting precipitates were collected by filtration and washed with tetrahydrofuran to give powders of 3-(2,3 dimethoxybenzyl)-2,5-piperazinedione (1.40 g). IR (KBr) : 3195, 3053, 1682, 1658, 1460, 1271, 1078 cm NMR (DMSO-d 6 , 5) : 2.87-3.09 (2H, m), 3.42-3.54 (2H, LO m), 3.73 (3H, s), 3.79 (3H, s), 3.88-3.96 (1H, m), 6.73-7.02 (3H, m), 7.94-8.00 (2H, m) MASS (APCI) : 265 (M+H) + (4) A suspension of 3- (2, 3-dimethoxybenzyl)-2, 5 5 piperazinedione (1.26 g) in a mixed solvent of tetrahydrofuran (50 ml) and 1,2-dimethoxyethane (50 ml) was heated at 60 0 C with stirring and lithium aluminum hydride (0.905 g) was added thereto portionwise carefully. After the reaction mixture was heated at 700C with stirring for 3 0 hours, lithium aluminum hydride (0.20 g) and tetrahydrofuran (30 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 5 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 (0.97 g). IR (KBr) 2941, 1481, 1475, 1275, 1080 cm

-

1 NMIR (DMSO-d 6 , 6) 2.07-3.60 (9H, m), 3.69 (3H, s), 3.78 (3H, s), 6.71-7.00 (3H, m) MASS (APCI) : 237 (M+H) + 5 WO 98/57954 PCT/JP98/02613 116 (5) A solution of benzyloxycarbonyl chloride (0.59 g) in dichloromethane (3.0 ml) was added dronwise to a solution of 2-(2,3-dimethoxybenzyl)piperazine (0.91 g) and triethylamine (0.64 ml) in dichloromethane (18 ml) below 5 0 C over 5 minutes 5 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 0 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 (40:1). The 5 fractions containing the objective compound were collected and evaporated under reduced pressure to give colorless oil of !- (benzyloxycarbonyl)-3-(2,3-dimethoxybenzyl)piperazine (0.68 g). IR (KBr) : 1714, 1699, 1685, 1273, 1244, 1225 cm-1 0 NMR (CDC1 3 , 5) : 1.71 (1H, s), 2.23-3.00 (9H, m), 3.82 (3H, s), 3.86 (3H, s), 5.13 (2H, s), 6.74-7.03 (3H, m), 7.34 (5H, s) MASS (APCI) : 371 (M+H)V 5 Preparation 50 A solution of 1-[3,5-bis(trifluoromethyl)benzoyl]-4 (benzyloxycarbonyl)-2-(2,3-dimethoxybenzyl)piperazine (0.81 g) in methanol (20 mi) was hydrogenated over 10% palladium carbon (50% wet, 0.30 g) at room temperature under 0 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-[3,5 bis(trifluoromethyl)benzoyl]-2-(2,3-dimethoxybenzyl) piperazine (0.64 g). 5 IR (KBr) : 1645, 1635, 1281, 1184, 1134 cm- 1 WO 98/57954 PCT/JP98/02613 NMR (CDCl 3 , 5) : 2.60-5.30 (10H, m), 3.81 (3H, s), 3.82 (3H, s), 6.40-7.10 (3H, m), 7.20-8.49 (3H, m) MASS (APCI) : 477 (M+H)+ 5 Prenaration 51 (1) The following compound was obtained according to a similar manner to that of Preparation 46-(4). 1-Acetyl-3- [ (1H-indol-2-yl)methylene]-2,5 0 piperazinedione IR (KBr) : 3332, 1714, 1685, 1668, 1419, 1221 cm-1 NMR (DMSO-d 6 , 6) : 2.50 (3H, s), 4.38 (2H, s), 6.52-8.21 (6H, m), 9.84-12.00 (2H, br) MASS (APCI) : 284 (M+H) + 5 (2) The following compound was obtained according to a similar manner to that of Preparation 49-(2). 1-Acetyl-3- [ (1H-indol-2-yl)methyl]i-2,5-piperazinedione 0 IR (KBr) : 3325, 1730, 1697, 1682, 1653, 1456, 1205 cm NMR (DMSO-d 6 , 5) : 2.43 (3H, s), 2.80-5.25 (5H, m), 6.18-8.73 (6H, m), 10.96 (1H, s) MASS (APCI) : 286 (M+H) 5 (3) The following compound was obtained according to a similar manner to that of Preparation 49-(3). 3-[ (!H-Indol-2-yl)methyl] -2,57piperazinedione IR (KBr) : 3363, 3317, 1682, 1645, 1456, 1323 cm

-

1 0 NMR (DMSO-d 6 , 5) : 3.03-3.61 (4H, m), 4.09-4.15 (1H, m), 6.18 (1H, s), 6.89-7.05 (2H, m), 7.31 (1H, d, J=7.9Hz), 7.43 (1H, d, J=7.2Hz), 7.99 (1H, s), 8.11 (1H, s), 10.85 (IH, s) MASS (APCI) : 244 (M+H) + 5 WO 98/57954 PCT/JP98/02613 118 (4) The following compound was obtained according to a similar manner to that of Preparation 49-(4). 2-L (lH-Indol-2-yl)methyl]piperazine 5 IR (KBr) : 3305, 2941, 1653, 1456 cm NMR (DMSO-d 6 , 5) 1.80-3.70 (ilH, L), 6.12 (1H, s), 6.87-7.02 (2H, m), 7.27 (1H, d, J=7.9Hz), 7.40 (1H, d, J=6.9Hz), 10.89 (1H, s) MASS (APCI) : 216 (M+H) + 0 (5) The following compound was obtained according to a similar manner to that of Preparation 49-(5). I- (Benzyloxycarbonyl)-3- [ (!H-indol-2-yl)methyl] 5 Dicerazine IR (KBr) : 3303, 2908, 1697, 1684, 1456, 1433, 1248 cm-1 NMR (DMSO-d 6 , 6) : 2.34-2.90 (SH, m), 3.78-3.89 (2H, m), 5.03 (2H, s), 6.17 (1H, s), 6.90-7.04 (2H, m), 7.26-7.43 (7H, m), 10.93 (1H, s) 0 MASS (APCI) 350 (M+H) Preparation 52 The following compound was obtained according to a similar manner to that of Preparation 50. 5 1-[3,5-Bis (trifluoromethyl)benzoyl]-2-[ (1H-indol-2-yl) methyl] piperazine IR (KBr) : 1653, 1647, 1635, 1281, 1184, 1136 cm NMR (DMSO-d 6 , 5) : 2.50-4.90 (10H, m), 5.98-6.28 (1H, D m),6.90-7.42 (5H, m), 7.76-8.48 (2H, m), 10.59 11.03 (1H, m) MASS (APCI) : 456 (M+H)+ Preparation 53 5 (1) The following compound was obtained according to a WO 98/57954 PCT/JP98/02613 119 similar manner to that of Preparation 46-(4). 1-Acetyl-3-(3-methoxyphenyl)methylene-2,5 piperazinedione 5 NMR (DMSO-d 6 , 6) : 2.50 (3H, s), 3.79 (3H, s), 4.36 (2H, s), 6.9-7.0 (2H, m), 7.1-7.2 (2H, m), 7.3-7.4 (1H, m), 10.4 (1H, br s) MASS (APCI) : 275 (M+H) + 0 (2) The following compound was obtained according to a similar manner to that of Preparation 49-(2). 1-Acetyl-3-(3-methoxybenzyl)-2,5-piperazinedione N M4R (DMSO-d 6 , 6) : 2.42 (3H, s), 2.9-3.1 (2H, m), 3.33 5 (1H, d, J=17Hz), 3.71 (3H, s), 4.02 (1H, d, J=17Hz), 4.3-4.4 (1H, m), 6.7-6.9 (3H, m), 7.1-7.3 (1H, m), 8.43 (1iH, br s) MASS (APCI) : 277 (M+H) 0 (3) The following compound was obtained according to a similar manner to that of Preparation 49-(3). 3-(3-Methoxybenzyl)-2,5-piperazinedione NMR (DMSO-d 6 , 5) : 2.8-3.5 (4H, m), 3.71 (3H, s), 4.0 5 4.1 (1H, m), 6.7-6.9 (3H, m), 7.1-7.3 (1H, m), 7.91 (1H, br s), 8.13 (1H, br s) MASS (APCI) 235 (M+H) (4) The following compound was obtained according to a 0 similar manner to that of Preparation 49-(4). 2-(3-Methoxybenzyl)piperazine NMR (DMSO-d 6 , 5) : 2.2-2.9 (9H, m), 3.5-3.8 (2H, m), 3.73 (3H, s), 6.7-6.8 (3H, m), 7.1-7.3 (1H, m) 5 MASS (APCI) : 207 (M+H)

+

WO 98/57954 PCT/JP98/02613 120 (5) A solution of di-tert-butyvl dicarbonate (1.99 g) in tetrahydrofuran (20 ml) was added dropwise to a mixture of 2 (3-methoxybenzyl)piperazine (1.88 g) and triethylamine (1.90 ml) in tetrahydrofuran (19mi) with ice-water cooling. After 5 1 hour of stirring, ethyl acetate (100 ml) and water (50 ml) were added to the mixture. 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 using a mixture of dichloromethane and methanol 0 (40:1) to give 2-(3-methoxybenzyl)-4-(tert-butoxycarbonyl) piperazine (1.18 g) as an oil. NMR (DMSO-d 6 , 5) 1.34 (9H, s), 2.1-2.9 (8H, m), 3.6-3.8 (2H, m), 3.73 (3H, s), 6.7-6.8 (3H, m), 7.1-7.3 (1 , m) 5 MASS (APCI) : 307 (M+H) + (6) The following compound was obtained according to a similar manner to that of Example 86. 0 1-[3,5-Bis(trifluoromethyl)benzoyl]-4-tert butoxycarbonyl-2-(3-methoxybenzyl) piperazine NYMR (DMSO-d 6 , 5) : 1.44 (9H, s), 2.5-5.0 (12H, m), 6.5-8.3 (7H, m) MASS (APCI) : 447 (M+H) + 5 (7) The following compound was obtained according to a similar manner to that of Preparation 35. 1-[3,5-Bis(trifluoromethyvl) benzoyl]-3-(3-methoxybenzyl) 3 piperazine hydrochloride NIMR (DMSO-d 6 , 6) : 2.7-5.2 (12H, m), 6.4-8.3 (7H, m), 9.4-10.2 (2H, m) MASS (APCI) : 447 (M+H) + (free) Preparation 54 WO 98/57954 PCT/JP98/02613 121 (1) 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 5 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 diethyl 2-acetyvlamino-2-(3,4-dimethylbenzyl)malonate (11.8 g) 0 m : 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, m), 2.02-2.20 (6H, m), 3.30-3.50 (3H, m), 4.14 5 (2H, q, J=7.2Hz), 6.60-7.05 (3H, m), 7.97, 8.07 (1H, 2s) MASS (EI) : 335 (M)+, 276, 119 (2) Diethyl 2-acetylamino-2-(3,4-dimethylbenzyl)malonate 0 (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 5 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 D give crystals of N-acetyl-3,4-dimethyl-DL-phenylalanine (5.42 g) mp : 136-139 0 C IR (Nujol) : 3337, 2700-2400, 1710, 1610, 1540, 1450, 1380, 1355 cm MI\R (DMSO-d 6 , 6) : 1.67 (3H, s), 2.17-2.21 (6H, m), WO 98/57954 PCT/JP98/02613 122 2.60-3.15 (2H, m), 4.25-4.40 (1H, m), 6.90-7.05 (3H, m), 8.10-8.25 (1H, m) MASS (EI) : 235 (M)

+

, 176, 119 5 (3) 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 L). 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 0 C for 20 hours 0 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 g). The pH of the filtrate was adjusted to 1 with aqueous diluted 5 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 : 156-1590C 0 IR (Nujol) : 3400, 3350, 2500-2400, 1710, 1620, 1560, 1450 cm-1 NMR (DMSO-d 6 , 5) : 1.78 (3H, s), 2.16 (6H, s), 2.68 3.20 (2H, m), 4.28-4.40 (1H, m), 6.90-7.05 (3H, m), 8.18 (1H, d, J=8.0Hz), 12.61 (1H, s) 5 MASS (EI) : 235 (M)

+

, 176, 119 (4) A solution of N-acetyl-3,4-dimethylphenyl-D-alanine (5.0 g) in a mixture of concentrated hydrochloric acid (50 ml) and acetic acid (50 ml) was stirred under reflux for 20 hours. 0 After being cooled to room temperature, the resulting precipitates were collected by filtration and washed with ethyl acetate to give colorless crystals of 3,4 dimethylphenyl-D-alanine hydrochloride (3.75 g). mp : >2500C 5 [a]26 : -3.30 (C=1.0, MeOH) WO 98/57954 PCT/JP98/02613 123 IR (Nujol) : 2800-2400, 1730, 1600, 1500, 1480 cm-1 NMR (DMSO-d 6 , 5) : 2.19 (6H, s), 3.07 (2H, d, J=6.2Hz), 4.07 (1H, t, J=6.2Hz), 6.90-7.10 (3H, m), 8.30-8.60 (3H, m) 5 MASS (APCI) 194 (M+H) + (free) (5) Thionyl chloride (5.4 ml) was added dropwise to methanol (60 ml) below 5°C with ice-salt bath cooling and stirring was continued for 10 minutes at the same temperature. 3,4 0 Dimethylphenyl-D-alanine hydrochloride (5.0 g) was added to the mixture by small portions over 20 minutes at -15 0 C and the whole was stirred at room temperature for 6 hours, and evaporated under reduced pressure. The resulting solid was triturated with isopropyl ether to give colorless crystals of 5 3,4-dimethylphenyl-D-alanine methyl ester hydrochloride (5.10 g). mp : 190.0-190.5 0 C []0 : -10.36' (C=0.55, MeOH) IR (Nujol) : 3400, 1735 cm-2 0 NMR (DMSO-d 6 , 5) 2.19 (6H, s), 3.03 (1H, dd, J=7.3, 14.0Hz), 3.15 (1H, dd, J=5.7, 14.0Hz), 3.66 (3H, s), 4.16 (1H, dd, J=7.3, 5.7Hz), 6.93 (1H, d, J=7.6Hz), 6.99 (1H, s), 7.08 (1H, d, J=7.6Hz), 8.78 (3H, s) 5 MASS (APCI) : 208 (M+H) + (free) (6) Potassium carbonate (5.45 g) was added by small portions with ice-cooling to a mixture of 3,4-dimethylphenyl-D-alanine methyl ester hydrochloride (4.81 g) in a mixed solvent of 0 dichloromethane and water. Chloroacetyvl chloride (2.20 ml) was added to the mixture below 50C over 10 minutes and the whole was stirred for 30 minutes. The organic layer was separated, washed with brine, dried over magnesium sulfate, and evaporated under reduced pressure to give an oil of 5 methyl (2R)-2-(2-chloroacetylamino)-3-(3,4-dimethylphenyl)- WO 98/57954 PCT/JP98/02613 124 propionate (6.01 g). IR (Neat) : 3400, 1735, 1650, 1460 cm-1 NMR (CDCl 3 , 6) : 2.22 (6H, s), 3.08 (1H, d, J=5.7Hz), 3.74 (3H, s), 4.02 (2H, s), 4.77-4.87 (1H, m), 5 6.80-7.10 (4H, m) MASS (APCI) : 283 (M+H) , 441 (7) Benzylamine (5.4 ml) and potassium carbonate (4.08 g) were added successively to a solution of methyl (2R)-2-(2 .0 chloroacetylamino)-3-(3,4-dimethylphenyl)propionate (5.33 g) in N,N-dimethylformamide (25 ml) at 20 0 C. After 3 hours of stirring at 35°C, the mixture was poured into a mixture of ice-water (40 ml) and dichloromethane (40 ml). After the mixture was adjusted to pH 6 with concentrated hydrochloric 5 acid (ca. 1.4 ml), the organic layer 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-benzyl-3-(3,4-dimethylbenzyl)-2,5 0 piperazinedione (1.51 g). The filtrate was evaporated under reduced pressure to give an oil of methyl (2R)-2-[(2 benzylaminoacetyl)amino]-3-(3,4-dimethylphenyl)propionate (5.67 g). IR (Neat) : 3400, 1735, 1650, 1460 cm-1 5 NMR (CDCl 3 , 6) : 2.12-2.21 (6H, m), 3.04-3.10 (2H, m), 3.29 (2H, d, J=2.0Hz), 3.66 (2H, s), 3.74 (3H, s), 4.80-4.90 (1H, m), 6.80-7.40 (9H, m), 7.90-8.05 (1H, m) MASS (APCI) 355 (M+H) + 0 (8) A mixture of methyl (2R)-2-[(2-benzylaminoacetyl)amino] 3

-(

3

,

4 -dimethylphenyl)propionate (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, 5 isopropyl ether was added to the mixture. The resulting WO 98/57954 PCT/JP98/02613 125 precipitates were collected by filtration and washed with isopropyl ether to give colorless crystals of (3R)-l-benzyl 3

-(

3

,

4 -dimethylbenzyl)-2,5-piperazinedione (1.26 g). mp : 191-192°C 5 [ 5 : 23.30 (C=1, DMF) IR (Nujol) : 3180, 1640, 1500, 1340 cm -1 NMR (DMSO-d 6 , 5) : 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.!Hz), 3.46 (1H, d, J=17.1Hz), 0 4.22 (1KH, d, J=14.5Hz), 4.55 (1H, d, J=14.5Hz), 4.2-4.3 (1H, m), 6.7-6.9 (3H, m), 7.0-7.1 (2H, m), 7.2-7.3 (3H, m), 8.31 (1H, s) MASS : 323 (M+i) 5 (9) The following compound was obtained according to a similar manner to that of Preparation 49-(4) (3R)-1-Benzyl-3-(3,4-dimethylbenzyl)piperazine IR (Neat) : 3000-2750, 1670, 1500, 1450, 1360, 1320 cm-1 ) NMR (CDCl 3 , 5) : 2.26 (6H, m), 1.8-3.0 (9H, m), 3.4-3.6 (2H, m), 6.9-7.1 (3H, m), 7.2-7.5 (5H, m) MASS : 295 (M+1) its hydrochloride Smp 186-1880C [ 9.2 : +12.720 (C=0.55, MeOH) INDI IR (Nujol) : 3500, 2350 cm NMR (DMSO-d 6 , 5) 2.20 (6H, s), 2.73-3.90 (9H, m), 4.34 (1H, d, J=13.1Hz), 4.42 (1H, d, J=13.1Hz), 6.97 (1H, d, J=7.6Hz), 7.02 (1iH, s), 7.11 (1H, d, J=7.6Hz), 7.36-7.65 (5H, m) MASS (APCI) : 295 (M+H) + (free) (10) The following compound was obtained according to a similar manner to that of Example 86.

WO 98/57954 PCT/JP98/02613 126 (2R)--1[3, 5-Bis(trifluoromethyl)benzoyl]-2-(3,4 dimethylbenzyvl)-4-benzylpiperazine IR (Neat) : 3000-2700, 1640, 1500, 1430, 1350 cm

-

1 NMR (CDCi3, 6) : 2.1-2.3 (6H, m), 2.1-2.2 (2H, m), 2.6 5 3.7 (8H, m), 4.5-5.1 (1lH, m), 6.5-6.7 (2H, m), 6.9 7.6 (7H, m), 7.8-7.9 (2H, m) MASS : 535 (M+1) (11) A mixture of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2 0 (3,4-dimethyvibenzyl)-4-benzylpiperazine (2.94 g), 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 50 0 C under nitrogen atmosphere. The reaction mixture was cooled L5 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 0 dissolved in methanol and treated with fumaric acid (468 mg) to give colorless powder of fumaric acid salt (1:1) of (2R) 1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl) piperazine (0.24 g). mp : 186-188 0 C 5 [0] 3 -23.990 (C=0.55, MeOH) IR (Nujol) : 2320, 1720, 1705, 1630, 1270 cm NMR (DMSO-d 6 , 6) : 1.57-2.34 (6H, m), 2.56-5.08 (9H, m), 6.10-8.52 (11H, m) MASS (APCI) : 445 (M+H) + (free) 0 Preparation 55 (1) 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 0oC and the whole was stirred at room temperature for 5 2 hours. Sodium borohydride (11.5 g) was added thereto in WO 98/57954 PCT/JP98/02613 127 portions at 0 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-2 5 methyl-1,3-propanediol (28.54 g). NMR (CDCl 3 , 6) : 1.08 (3H, s), 3.54 (4H, s), 3.73 (2H, s), 7.20-7.45 (5H, m) MASS (APCI) 196 (M+H) + 10 (2) Chloroacetyl chloride (14.0 ml) was added dropwise to a mixture of 2 -benzvlamino-2-methyl-1,3-propanediol (28.5 g), potassium carbonate (30.3 g) in dichloromethane (150 ml) and water (150 ml) at 0 0 C, and the whole was stirred at room temperature for 2 hours. The mixture was extracted with L5 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 .0 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 5 mixture of ethyl acetate and n-hexane (1:1) as an eluent to give 4 -benzyl-5-hydroxymethyl-5-methyl-3-morpholinone (10.89 g). NMR (CDCl3, 5) : 1.12 (3H, sj, 2.50 (1H, br s), 3.44 (1H, d, J=11.7Hz), 3.56 (1H, d, J=11.9Hz), 3.67 0 (1H, d, J=11.7Hz), 3.98 (1H, d, J=11.9Hz), 4.29 (2H, s), 4.67 (2H, s), 7.10-7.40 (5H, m) MASS (APCI) 236 (M+H)+ (3) Sodium bis(2-methoxyethoxy)aluminum hydride (3.46 M 5 solution in toluene; 42 ml) was added to a solution of 4- WO98/57954 PCT/JP98/02613 128 benzyl-5-hydroxymethyl-5-methyl-3-morpholinone (10.77 g) in toluene (100 ml) at 0 0 C under nitrogen atmosphere and the whole was stirred at room temperature for 1 hour. Ethanol (20 ml) was added to the mixture at 0 0 C and the pH of the 5 mixture was adjusted to 12 by IN 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 10 extracted with ethyl acetate, dried over magnesium sulfate and evaporated in vacuo to give 4-benzyl-3-hydroxymethyl-3 methylmorpholine (9.35 g) as an oil. NMR (CDCl 3 , 6) : 1.12 (3H, s), 2.50-2.64 (2H, m), 3.10 4.05 (8H, m), 7.20-7.50 (5H, m) 15 MASS (APCI) : 222 (M+H) + (4) A solution of 4-benzyl-3-hydroxymethyl-3 methylmorpholine (1 g) in tetrahydrofuran (10 ml) was added dropwise to a suspension of sodium hydride (60% oil 20 .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 0 C for 1 hour. After cooling, ethyl acetate and water 25 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-3 30 methylmorpholine (0.77 g) as an oil. NMR (CDCl 3 , 5) : 1.15 (3H, s), 2.30-2.64 (2H, m), 3.20-3.70 (8H, m), 3.36 (3H, s), 7.14-7.40 (5H, m) MASS (APCI) : 236 (M+H) + 35 (5) 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 5 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. 0 mp : 80-90 0 C IR (KBr) : 3240-3270, 2976, 1090, 1049 cm -1 NMR (DMSO-d 6 , 5) : 1.29 (3H, s), 3.00-3.92 (8H, m), 3.36 (3H, s) MASS (APCI) : 146 (M+H)+ (free) 5 Preparation 56 (1) A solution of (3R)-4-benzvl-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 0 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 (0.31 ml) was added thereto and the mixture was stirred at 40 0 C for 1 hour. After cooling, the mixture was poured into ice water, and extracted with 5 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 (3:7) as an eluent togive (3R)-4-benzyl-3 methoxymethylmorpholine (0.88 g) as an oil. 0 NMR (CDCl 3 , 5) : 2.20-2.40 (1H, m), 2.56-2.86 (2H, m), 3.26-4.26 (8H, m), 3.34 (3H, s), 7.20-7.48 (5H, m) MASS (APCI) : 222 (M+H) + (2) The following compound was obtained according to a 5 similar manner to that of Preparation 55-(5).

WO 98/57954 PCT/JP98/02613 130 (3R) -3-Methoxymethylmorpholine hydrochloride mp : 150-152oC 2-1 []D' : +16.31 (C=0.42, MeOH) IR (KBr) : 2964, 2947, 2929, 2897, 2887, 2835, 2810, 5 2789, 2765, 2727, 2698, 2490, 1450, 1311, 1194, 1136, 1111, 1095 cm' INMR (DMSO-d 6 , 6) : 2.94-3.24 (2H, m), 3.31 (3H, s), 3.36-3.78 (5H, m), 3.80-3.98 (2H, m), 9.52 (2H, br s) 0 MASS (APCI) : 132 (M+H) + (free) Preparation 57 (1) The following compound was obtained according to a similar manner to that of Preparation 56-(1). 5 (3S) - 4 -Benzyl-3-methoxvymethylmorpholine NMR (CDCl 3 , 5) : 2.15-2.34 (1H, m), 2.54-2.72 (2H, m), 3.33 (3H, s), 3.33 (1H, d, J=13.5Hz), 3.40-3.90 (6H, m), 4.07 (1H, d, J=13.5Hz), 7.18-7.40 (5H, m) 0 MASS (APCI) : 222 (M+H) (2) The following compound was obtained according to a similar manner to that of Preparation 55-(5). 5 (3S)- 3 -Methoxymethylmorpholine hydrochloride mp : 150-1520C []D7 : -14.700 (C=0.50, MeOH) IR (KBr) : 2964, 2947, 2929, ,2887, 2833, 2810, 2789, 2765, 2727, 2698, 2490, 1450, 1311, 1194, 1136, 0 1111, 1095, 1041 cm NMR (DMSO-d 6 , 5) : 2.94-3.24 (2H, m), 3.31 (3H, s), 3.38-3.75 (5H, m), 3.84-3.96 (2H, m), 9.45 (2H, br s) MASS (APCI) : 132 (M+H) + (free) WO 98/57954 PCT/JP98/02613 131 Preparation 58 (1) The following compound was obtained according to a similar manner to that of Preparation 56-(1). 5 (3S)-4-Benzyl-3-ethoxymethylmorpholine NMR (CDCl 3 , 6) : 1.20 (3H, t, J=7.0Hz), 2.15-2.40 (1H, m), 2.54-2.84 (2H, m), 3.24-4.20 (10H, m), 7.20 7.45 (5H, m) MASS (APCI) : 236 (M+H) + 0 (2) The following compound was obtained according to a similar manner to that of Preparation 55-(5). (3S)-3-Ethoxymethylmorpholine hydrochloride 5 mp: 100-115 0 C [a]D7 : -13.070 (C=0.505, MeOH) IR (KBr) 2976, 2922, 2900, 2866, 2790, 2767, 2746, 2721, 2468, 1458, 1450, 1435, 1309, 1176, 1147, 1126, 1101, 1043, 1030 cm 0 MN4R (DMSO-d 6 , 6) 1.15 (3H, t, J=7.0Hz), 2.94-3.28 (2H, m), 3.28-3.80 (7H, m), 3.80-4.00 (2H, m), 9.47 (2H, br s) MASS (APCI) : 146 (M+H) + (free) 5 Preparation 59 The following compound was obtained according to a similar manner to that of Preparation 55-(5). (3S)-3-Hydroxvmethylmorpholine hydrochloride 0 mp : 123-126 0 C [ ]7 : -15.800 (C=0.44, MeOH) IR (KBr) : 3290-3480, 2945, 1105, 1047 cm-1 NMR (DMSO-d 6 , 5) : 2.86-4.00 (9H, m), 5.41 (1H, br s), 9.25 (1WH. br s), 9.56 (1H, br s) 5 MASS (APCI) : 118 (M+H) (free) WO98/57954 PCT/JP98/02613 132 Preparation 60 (1) Hexafluoropropene diethylamine complex (1.58 ml) was added dropwise to a solution of (3R)-4-benzyl-3 hydroxymethylmorpholine (1.5 g) in dichloromethane (100 ml) 5 at -30'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 10 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, 15 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-1,4-oxazepine. The obtained mixture was used to the next reaction without further 20 purification. (2) The crude mixture (2.2 g) obtained by the previous procedure, which contained mainly (3R)-4-benzyl-3-fluoro methylmorpholine and 4-benzyl-6-fluoroperhydro-l,4-oxazepine, 25 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, palladium carbon was removed by filtration and the filtrate was evaporated under reduced pressure. The two isomers were 30 separated by column chromatography using 2% of methanol in dichloromethane as an eluent to give (3R)-3 fluoromethylmorpholine and 6-fluoroperhydro-l,4-oxazepine (the former was less polar). The products were converted to their hydrochloride as a conventional manner using 4N 35 hydrogen chloride in ethyl acetate, respectively.

WO98/57954 PCT/JP98/02613 133 (3R)-3-Fluoromethylmorpholine hydrochloride (0.21 g) NMR (DMSO-d 6 , 6) : 3.02-3.34 (2H, m), 3.48-3.82 (3H, m), 3.82-4.10 (2H, m), 4.57 (1H, d, J=4.0Hz), 4.80 (1H, d, J=4.0Hz), 9.84 (2H, br s) 5 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, m), 3.40-3.60 (2H, m), 3.68-4.16 (4H, m), 4.94-5.30 (1H, m) 10 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 15 0OC and the mixture was stirred at 0 0 C for 15 minutes. A solution of (3S)-4-tert-butoxycarbonyl-3-formylmorpholine (1.5 g) in dichloromethane (15 ml) was added dropwise to the solution over 10 minutes at 0 0 C and stirred for 3 hours, and the mixture was added saturated sodium hydrogen carbonate 20 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 25 gel using a mixture of ethyl acetate and n-hexane (4:6) 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 30 solution at -78 0 C. After 30 minutes of stirring at -78 0 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 35 chromatography on silica gel using a mixture of ethyl acetate WO 98/57954 PCT/JP98/02613 134 and hexane (2:8) to give (3R)-4-tert-butoxycarbonyl-3 ethynylmorpholine (1.385 g) as a pale yellow oil. NMR (CDCl 3 , 6) : 1.48 (9H, s), 2.31 (1H, d, J=2.3Hz), 3.19-3.96 (6H, m), 4.74 (1H, br s) 5 MASS (APCI) : 112 (M-Boc) + Preparation 62 (1) The following compound was obtained according to a similar manner to that of Preparation 55-(5). LO (3S) -3-Ethoxycarbonylmorpholine hydrochloride NMR (CDCl 3 , 5) : 1.33 (3H, t, J=7.1Hz), 3.20-3.75 (2H, m), 3.90-4.30 (5H, m), 4.32 (2H, q, J=7.1Hz), 10.04 (1H, br s), 10.74 (1H, br s) .5 MASS (APCI) : 160 (M+H) + (free) (2) A mixture of (3S)-3-ethoxycarbonylmorpholine hydrochloride (0.3 g), propargyl bromide (0.34 ml) and potassium carbonate (0.91 g) in N,N-dimethylformamide (10 ml) 0 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 5 purified by column chromatography on silica gel with a mixture of ethyl acetate and n-hexane (3:7) 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, z, J=7.lHz), 2.28 (1H, t, 0 J=2.5Hz), 2.70-2.95 (2H, m), 3.40-4.05 (7H, m), 4.21 (2H, q, J=7.1Hz) MASS (APCI) : 198 (M+H) + Preparation 63 5 (1) Sodium triacetoxyborohydride (4.63 g) was added WO 98/57954 PCT/JP98/02613 135 portionwisely to a mixture of (R)-(-)-2-amino-1-butanol (1.5 g) and benzaldehyde (1.79 g) in dichloromethane (50 ml) at 0OC and the whole was stirred at room temperature overnight. The mixture was washed with sodium carbonate solution and 5 brine, dried over sodium sulfate, and evaporated in vacuo to give (R)-2-benzylamino-1-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 LO (4.6 g) in a mixture of acetone (20 ml) and water (20 ml) at 0OC. 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 L5 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 (M+H)

+

, 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) .0 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-5 .5 ethyl-3-morpholinone (2.33 g) as an oil. IR (Neat) : 1655, 1640, 1450, 1430, 1360, 1340, 1260, 1155, 1128 cm

-

1 NMR (CDCl 3 , 6) : 0.91 (3H, t, J=7.5Hz), 1.60-1.96 (2H, m), 2.94-3.14 (1H, m), 3.55-3.94 (2H, m), 3.92 (1H, 30 d, J=15.0Hz), 4.21 (1H, d, J=16.7Hz), 4.31 (1H, d, J=16.7Hz), 5.43 (1H, d, J=15.0Hz), 7.20-7.44 (5H, m) MASS (APCI) : 220 (M+H) + .5 WO 98/57954 PCT/JP98/02613 136 (2) A solution of ( 5 R)-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 5 hours. After cooling, 50% aqueous tetrahydrofuran solution (4 ml) was added thereto and stirring was continued for 15 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 10 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 (CDCl 3 , 5) : 0.93 (3H, t, J=7.5Hz), 1.44-1.94 (2H, m), 2.08-2.45 (2H, m), 2.54-2.70 (1H, m), 3.15 (1H, 15 d, J=13.3Hz), 3.55-3.86 (4H, m), 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 (15 20 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 25 triturated with ethyl acetate and the resulting precipitates were collected by filtration and dried to give (3R)-3-ethyl morpholine hydrochloride (1.0 g). mp : 223-225°C 28 5 [a]D : +9.5 (C=0.5, MeOH) 30 IR (KBr) : 2729, 2696, 2472, 1458, 1427, 1360, 1313, 1109, 1061 cm-1 NMR (DMSO-d 6 , 6) : 0.93 (3H, t, J=7.5Hz), 1.40-1.78 (2H, m), 2.88-3.55 (4H, m), 3.60-4.04 (3H, m), 9.60 '5 WO 98/57954 PCT/JP98/02613 (2H, br s) MASS (APCI) : 116 (M+H) + (free) Preparation 64 5 (1) The following compound was obtained according to a similar manner to that of Preparation 63-(1). (3S) -4-Benzvy -5-ethyl-3-mor-holinone IR (Neat) : 1653, 1462, 1348, 1263, 1155, 1122 cm-' 10 NMR (CDCl 3 , 5) : 0.91 (3H, t, J=7.5Hz), 1.60-1.96 (2H, m), 2.95-3.14 (1H, m), 3.58-3.94 (2H, m), 3.92 (1H, d, J=15.0Hz), 4.21 (1H, d, J=16.7Hz), 4.30 (1H, d, J=16.7Hz), 5.43 (1H, d, J=15.0Hz), 7.15-7.44 (SH, m) .5 MASS (APCI) : 220 (M+H) + (2) The following compound was obtained according to a similar manner to that of Preparation 63-(2). O0 (3S)-3-Ethylmorpholine hydrochloride me : 221-224oC [ D]26 -11.2o (C=0.5, MeOH) IR (KBE) 2729, 2625, 2472, 1454, 1356, 1313, 1109, 1061 cm 5 NMR (DMSO-d 6 , 5) : 0.93 (3H, t, J=7.5Hz), 1.40-1.78 (2H, m), 2.90-3.54 (4H, m), 3.60-4.04 (3H, m), 9.57 (2H, br s) MASS (APCI) : 116 (M+H)K (free) 0 Preparation 65 A mixture of 7 -oxa-4-azaspiro[2.5]octane hydrochloride (200 mg), 2-bromoethanol (0.28 ml) and potassium carbonate (550 mg) in N,N-dimethylformamide (2 ml) was stirred at 900C for 48 hours and cooled. The mixture was poured into brine 5 and extracted with dichloromethane. The extract was dried WO 98/57954 PCT/JP98/02613 138 over magnesium sulfate and evaporated under reduced pressure, and purified by column chromatography on silica gel using a mixture of methanol and chloroform (2:98) to give 4-(2 hydroxyethyl)- 7 -oxa-4-azaspiro[2.5]octane as an oil. This 5 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 on silica gei using a 0 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. MMR (CDCl 3 , 5) : 0.61-0.67 (2H, m), 0.95-1.05 (2H, m), 3.10-3.15 (2H, m), 3.22 (2H, t, J=6.9Hz), 3.50 (2H, 5 br s), 3.54-3.64 (2H, m), 3.80 (2H, t, J=4.7Hz) MASS (APCI) 176 (M+H)+ Preparation 66 A mixture of ( 3 R)-3-ethyimorpholine hydrochloride (0.2 0 g), 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 aqueous 5 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 (1:1) as an eluent to give (3R)-4-(4-chloro-2-butynyl)-3 D ethylmorpholine (0.2 g) as an oil. NPMIR (CDC1 3 , 5) : 0.89 (3H, t, J=7.5Hz), 1.20-1.74 (2H, m), 2.42-2.84 (3H, m), 3.20-3.90 (6H, m), 4.18 (2H, t, J=2.0Hz) MASS (APCI) : 202 (M+H) WO98/57954 PCT/JP98/02613 139 Preparation 67 (1) A mixture of (3S)-3,5-dimethylmorpholine hydrochloride (8.3 g), di-tert-butyl dicarbonate (14.34 g) and sodium hydroxide (5.48 g) in water (30 ml) were stirred at room 5 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) 10 as an eluent to give (3S,5S)-4-tert-butoxycarbonyl-3,5 dimethylmorpholine (3.55 g) and meso-4-tert-butoxycarbonyl 3,5-dimethylmorpholine (2.84 g) (the former was less polar). (3S,5S)-4-tert-Butoxycarbonyl-3,5-dimethylmorpholine (3.55 g) was dissolved in a mixture of dichloromethane (20 ml) and 15 trifluoroacetic acid (20 ml) and the mixture was stirred at room temperature for 2 hours. After removal of the solvent under reduced pressure, iN sodium hydroxide solution (20 ml) and dichoromethane were added thereto. The organic phase was separated, dried over magnesium sulfate, and was added 4N ?0 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

(

3 S,5S)-3,5-dimethylmorpholine hydrochloride (1.56 g) as a white solid. 25 mp : 172-173 0 C 26 []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 30 NMR (CDCl 3 , 5) : 1.50 (6H, d, J=6.5Hz), 3.44-4.08 (6H, m), 9.97 (2H, br s) MASS (APCI) : 116 (M+H) + (free) meso-3,5-Dimethylmorpholine hydrochloride (2.84 g) was 5 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 0 C IR (KBr) : 2981, 2945, 2929, 2873, 2860, 2808, 2802, 5 2773, 2748, 2735, 2727, 1672, 1624, 1205, 1182, 1138, 1117, 1057 cm-1 NMR (CDCl 3 , 6) : 1.35 (6H, d, J=6.6Hz), 3.22-4.00 (6H, m), 9.44 (1H, br s), 10.22 (1H, br s) MASS (APCI) 116 (M+H)+ (free) L0 (2) The following compound was obtained according to a similar manner to that of Preparation 66. (3S,5S)-4-,(4-Chloro-2-butynyl)-3,5-dimethylmorpholine L5 NMR (CDCl 3 , 6) : 1.06 (6H, d, J=6.5Hz), 2.95-3.14 (2H, m), 3.34-3.54 (4H, m), 3.72 (2H, dd, J=11.0, 3.1Hz), 4.16 (2H, t, J=2.1Hz) MASS (APCI) : 202 (M+H) + 0 Preparation 68 (1) The following compound was obtained according to a similar manner to that of Preparation 65. 2-(3,3-Dimethylmorpholin-4-yl)ethanol 5 NMR (DMSO-d 6 , 6) : 0.91 (6H, s), 2.3 (2H, t, J=6.7Hz), 2.4-2.5 (2H, m), 3.19 (2H, s), 3.3-3.4 (2H, m), 3.5-3.6 (2H, m), 4.27 (1H, t, J=5.4Hz) MASS (APCI) : 160 (M+H) + 0 (2) The following compound was obtained according to a similar manner to that of Preparation 65. 2-(3,3-Dimethylmorpholin-4-yl)ethyl methanesulfonate 5 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 5 similar manner to that of Preparation 62-(2) 4-(3-Chloropropyl)-3,3-dimethylmorpholine NMR (DMSO-d 6 , 5) : 0.92 (6H, s), 1.77 (2H, qui, J=6.4Hz), 2.3-2.5 (4H, m), 3.19 (2H, s), 3.55-3.60 10 (2H, m), 3.67 (2H, t, J=6.4Hz) MASS (APCI) 192 (M+H) + Preparation 70 (1) The following compound was obtained according to a 15 similar manner to that of Preparation 53-(5) starting from (3R)-1-benzyl-3-[ (lH-indol-3-yl)methyl]piperazine. (2R)-4-Benzyl-l-tert-butoxycarbonyl-2-[ (1H-indol-3-yl) methyl] piperazine 20 mp : 143-145 0 C IR (KBr) : 3305, 2976, 2922, 2810, 1664, 1454, 1425, 1367, 1336, 1299, 1261, 1223 cm-1 NMR (DMSO-d 6 , 5) : 1.00-1.50 (9H, m), 1.80-2.10 (2H, m), 2.60-4.30 (9H, m), 6.80-7.70 (10H, m), 10.72 25 (1H, br s) MASS (APCI) : 406 (M+H) + (2) The following compound was obtained according to a similar manner to that of Preparation 33. 30

(

2 R)-1-tert-Butoxycarbonyl-2-[ (lH-indol-3-yl)methyl] piperazine IR (KBr) : 3410, 3311, 2976, 2924, 1672, 1454, 1417, 1365, 1259 cm-1 35 NMR (DMSO-d 6 , 5) : 1.22 (9H, br s), 2.25-4.20 (10H, m), WO 98/57954 PCT/JP98/02613 142 6.88-7.70 (5H, m) 10.78 (1H, br s) MASS (APCI) : 316 (M+H) + (3) The following compound was obtained according to a 5 similar manner to that of Preparation 34. (2R)-l-tert-Butoxycarbonyl-4-[4-(3,3-dimethyl morpholino)-2-butynyl]-2- [ (1H-indol-3-yl)methyl] piperazine .0 IR (KBr) : 3500-3300, 2972, 2935, 1687, 1456, 1417, 1365, 1333, 1227 cm NMR (DMSO-d 6 , 6) : 0.94 (6H, s), 1.21 (9H, s), 1.82 2.20 (2H, m), 2.50-4.30 (17H, min), 6.85-7.66 (5H, m), 10.81 (1H, br s) 5 MASS (APCI) : 481 (M+H) + (4) The following compound was obtained according to a similar manner to that of Preparation 35. 0 ( 3

R)-!-[

4 -(3,3-Dimethylmorpholino)-2-butynyl]-3-[ (1H indol-3-yl)methyl]piperazine trihydrochrolide me : 209-230 0 C 26 9. []D6 : -10.9' (C=0.5, MeOH) IR (KBr) 3600-3300, 2900, 2700-2400, 1645, 1628, 5 1539, 1516, 1454, 1429, 1344 cm NMR (DMSO-d 6 , 5) : 1.20-1.50 (6H, m), 3.10-4.42 (20H, m), 6.95-7.80 (SH, m), 9.90-10.25 (2H, m), 11.15 (!H, br s), 11.90 (1H, br s) MASS (APCI) : 381 (M+H) (free) PreDaration 71 (1) Acetic acid (5.4 ml) was added to a solution of 2-amino 2 -methyl-1-propanol (8.4 g) and benzaldehyde (10 g) in 1,2 dichioroethane (140 ml) under ice-cooling. After 30 minutes of stirring at the same temperature, sodium WO98/57954 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 5 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-2 10 methyl-l-propanol (13.2 g). mp : 46.0-47.0OC IR (Nujol) : 3330, 3100, 2900, 1450, 1380, 1355 cm-1 NMR (DMSO-d6, 5) : 0.99 (6H, s), 3.23 (2H, d, J=3.9Hz), 3.62 (2H, s), 4.50-4.60 (1H, m), 7.16-7.36 (5H, m) 5 MASS (APCI) 180 (M+H) (2) 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. 0 Chloroacetyl chloride (2.95 ml) was added to the mixture over 25 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 5 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 0 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 (1:1) and the resulting crystals were 5 collected by filtration and washed with a mixed solvent of WO98/57954 PCT/JP98/02613 144 hexane and diisopropyl ether (1:1) to give colorless crystals of 4 -benzylamino-5,5-dimethyl-3-morpholinone (4.53 g) mI : 76-77oC IR (Nujol) : 1635, 1600, 1490, 1460, 1380, 1355 cm-1 5 NMR (CDC1 3 , 5) : 1.20 (6H, s), 3.61 (2H, s), 4.32 (2H, s), 4.64 (2H, s), 7.18-7.36 (5H, m) MASS (APCI) : 220 (M+H) + (3) 4-Benzyl-5,5-dimethyl-3-morpholinone (4.45 g) was added 10 to an ice-cooled suspension of lithium aluminum hydride (0.77 g) in dried tetrahydrofuran (20 ml) under nitrogen atmosphere. After 5 hours of stirring at 50°C, the reaction mixture was cooled below 5 0 C, and water (0.36 ml), 12% sodium hydroxide aqueous solution (0.36 ml) and water (1 ml) were 15 added thereto successively. After 30 minutes of stirring, the mixture was filtrated through Celite pad, and the pad 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 20 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 25 dissolved into a mixed solvent of ethanol (35 ml) and water (5 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 0 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 (1:1). The resulting crystals were collected by filtration and washed with a mixed solvent of ethanol and 5 n-hexane (1:1) to give colorless crystals of 3,3- WO 98/57954 PCT/JP98/02613 145 dimethylmorpholine hydrochloride (1.56 g). mp : 196-197oC IR (Nujol) : 3300, 2750, 2650, 2500, 1590, 1460 cm-1 NMR (DMSO-d 6 , 6) : 1.21 (6H, s), 3.05-3.11 (2H, m), 5 3.51 (2H, s), 3.76-3.81 (2H, m), 9.66 (2H, br s) Example 66 Paraformaldehyde (30 mg) and copper(I) iodide (9 mg) were added to a mixture of (2R)-1-[3,5-bis(trifluoromethyl) L0 benzoyl]- 2 -(3,4-dimethylbenzyl)piperazine (0.16 g), (3S)-3 ethoxycarbonyl-4-(2-propynyl)morpholine (0.08 g) and N,N diisopropylethylamine (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 5 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 (1:1) as an eluent to 0 give ( 2 R)-l-[3,5-bis(trifluoromethyl)benzoly]-2-(3,4 dimethylbenzyl)-4-[4-((3S)-3-ethoxycarbonylmorpholino)-2 butynyl]piperazine (0.21 g). NMR (CDCl 3 , 6) : 1.20-5.30 (31H, m), 6.55-7.90 (6H, m) MASS (APCI) : 654 (M+H) + 5 Example 67 The following compound was obtained according to a similar manner to that of Example 66. 0 ( 2 R)-l-[ 3 ,5-Bis(trifluoromethyl)benzoyl]-2-(3,4 dimethylbenzyl)-4-[3- [(3R) - (4-tert-butoxycarbonyl)morpholin 3-yl] - 2 -propynyl]piperazine NMR (DMSO-d 6 , 6) : 1.39 (9H, s), 2.09-2.17 (6H, m), 2.30-5.00 (18H, m), 6.60-8.15 (6H, m) 5 MASS (APCI) : 668 (M+H)+ (free) WO98/57954 PCT/JP98/02613 146 Example 68 To a solution of (2R)-1-[3,5-bis(trifluoromethyl) benzoyl]-2-(3,4-dimethylbenzyl)-4-[3-[(3R)-(4-tert butoxycarbonyl)morpholin-3-yl]-2-propynyl]piperazine (1.607 5 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] 10 piperazine dihydrochloride (1.43 g) as a solid. mp : 190-1910C 27 0 o [] : -14.00 (C=0.5, MeOH) IR (KBr) : 2927, 1643 cm-1 NMR (DMSO-d 6 , 6) : 2.10-2.18 (6H, m), 2.80-5.25 (18H, 15 m), 6.65-8.25 (6H, m) MASS (APCI) : 568 (M+H)+ (free) Example 69 Paraformaldehyde (0.034 g) and copper(I) iodide (12 mg) 20 were added to a mixture of (2R)-l-[3,5-bis(trifluoromethyl) benzoyl]-2-(3,4-dimethylbenzyl)-4-(2-propynyl)piperazine (0.21 g), (3S)-3-methoxymethylmorpholine (0.09 g) and N,N diisopropylethylamine (0.1 ml) in 1,4-dioxane (5 ml) and the whole was stirred at room temperature for 30 minutes and then 25 heated at 70 0 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 30 methanol in chloroform as an eluent to give (2R)-l-[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 35 evaporated in vacuo and the residue was triturated with a WO 98/57954 PCT/JP98/02613 147 mixture of ethyl acetate and isopropyl ether to give (2R)-1 [3,5-bis (trifluoromethyl)benzoyl] -2-(3, 4-dimethylbenzyl)-4 [4-((3S)-3-methoxvymiethyvlmorpholino)-2-butynyvi] piperazine dihydrochloride (0.16 g) 5 mn : 60-70 0 C U12D : -1.8 (C=0.

2 5, MeOH) IR (KBr) : 1684, 1645, 1512, 1460, 1448, 1431, 1371, 1365, 1325, 1281, 1184, 1136, 1072 cm

-

1 NMR (DMSO-d 6 , 6) : 2.00-2.28 (6H, m), 2.60-5.30 (25H, 0 m), 6.60-8.30 (6H, m) 4MASS (APCI) : 626 (M+H) + (free) Example 70 The following compounds were obtained according to a 5 similar manner to that of Example 69. (1) (2R)-1-[3,5-Bis(trifluoromethyvl)benzoyl]-2-(3,4 dimethylbenzyl)-4-[4-((3R)-3-fluoromethyvlmorpholino)-2 butynyl]piperazine dihydrochloride 0 m: 11 8-128

O

C 28 . [a] : -6.8' (C=0.25, MeOH) IR (KBr) : 1645, 1502, 1435, 1365, 1321, 1282, 1182, 1136, 1049 cm - ± NMR (DMSO-d 6 , 5) 2.00-2.30 (6H, m), 2.60-5.30 (22H, 5 m), 6.60-8.30 (6H, m) -MASS (APCI) : 614 (M+H)+ (free) (2) (2R)-1-[3,5-Bis(trifluoromethvl)benzoyl]-2-(3,4 dimethylbenzyl) -4-- [4- (tetrahydro-6-fluoro-l, 4-oxazeoin 3 4 (5H)-yl)-2-butynyl]piperazine dihydrochloride m : 90-1000C [L] 8 : +1.6 ° (C=0.25, MeOH) IR (KBr) : 1645, 1504, 1433, 1373, 1365, 1323, 1282, 1219 1182, 1136 cm NMR (DMSO-d 6 , 5) : 2.00-2.30 (6H, m), 2.60-5.30 (22H, WO 98/57954 PCT/JP98/02613 148 m), 6.60-8.28 (6H, nm) MASS (APCI) : 614 (M+H) (free) Example 71 5 The following compounds were obtained according to a similar manner to that of Example 31. (1) ( 2

R)-!-[

3 ,5-Bis(trifluoromethyl)benzoyl]-2-(3,4 dimethylbenzyl)-4- [4- (3-methoxymethyl-3 0 minethylmorpholino)-2-butynvl]piperazine dihydrochloride mP : 155-160 0 C [] 25 : -11.60 (C=0.25, MeOH) IR (KBr) 1645, 1437, 1362, 1323, 1281, 1219, 1182, 1138, 1055 cm 1 5 N~MR (DMSO-d 6 , 5) 1.20-1.50 (.3H, m), 2.05-2.26 (6H, m), 2.60-5.20 (24H, m), 6.60-8.30 (6H, m) LMASS (APCI) : 640 (M+H) (free) (2) ( 2 R)-l-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4 0 dimethylbenzyvl)-4-[4-((3S)-3-ethoxymethylmorpholino)-2 butynyl]piperazine dihydrochloride mID : 155-160 0 C 25 P ]D : +0.60 (C=0.25, MeOH) IR (KBr) : 1645, 1439, 1371, 1281, 1217, 1182, 1136, 5 1072, 1032 cm-i NMR (DMSO-d 6 , 5) 1.13 (3H, t, J=7.0Hz), 2.02-5.24 (30H, , 6.60-8.28 (6H, m) MASS (APCI) : 640 (M+H) + (free) 0 (3) ( 2 R)-1-[3,5-Bis(trifluoromethyvl)benzoyl]-2-(3,4 dimethylbenzyl)-4-[4-((3S, 5S)-3, 5-dimethylmorpholino)-2 butynyl]piperazine dihydrochloride m: 160-165 0 C 216 : +14.20 (C=0.25, MeOH) D IR (KBr) : 1657, 1649, 1643, 1433, 1356, 1281, 1186, WO 98/57954 PCT/JP98/02613 149 1136, 1109 cm

-

1 NMR (DMSO-d 6 , 6) : 1.10-1.45 (6H, m), 2.00-2.28 (6H, m), 2.60-5.20 (19H, m), 6.60-8.28 (6H, m) MASS (APCI) 610 (M+H) (free) 5 (4) ( 2 R)-i-[3,5-Bis(trifiuoromethyl)benzoyl]-2-(3,4 dimethylbenzyl)-4- [4-((3S)-3-hydroxymethylmorpholino)-2 butynyl]piperazine dihydrochloride mp : 130-150 0 C 28 .6 ° .2, 0 5c] 8 : -2.6' (C=0.25, MeOH) IR (KBr) : 1691, 1645, 1512, 1458, 1442, 1433, 1371, 1365, 1325, 1281, 1217, 1182, 1136, 1059 cm - ! NMR (DMSO-d6, 6) 2.00-2.30 (6H, m), 2.60-5.30 (22H, m), 6.60-8.28 (6H, m) 5 MASS (APCI) : 612 (M+H) + (free) (5) ( 2 R)-l-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4 dimethylbenzyl)-4- [4-((2S)-2-methoxymethylmorphoiino)-2 butynyl]piperazine dihydrochloride 3 mC : 85-950C [cz] : -4.71' (C=0.255, MeOH) IR (KBr) : 1641, 1631, 1442, 1281, 1134 cm - 1 NMR (DMSO-d 6 , 5) : 2.00-2.30 (6H, m), 2.60-5.28 (25H, m), 6.60-8.30 (6H, m) 5 LMASS (APCI) : 626 (M+H) + (free) (6) (2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4 dimethvibenzyl) -4- [4-((2R)-2-methoxymethylmorpholino)-2 butyvnyl]piperazine dihydrochloride ) m : 80-90°C 25 []21D : -15.00' (C=0.24, MeOH) IR (KBr) : 1657, 1649, 1641, 1631, 1441, 1431, 1281, 1186, 1176, 1136, 1109 cm - 1 INMR (DMSO-d 6 , 5) : 2.00-2.30 (6H, mn), 2.60-5.20 (25H, m), 6.60-8.30 (6H, m) WO 98/57954 PCT/JP98/02613 150 MASS (APCI) : 626 (M+H)+ (free) (7) (2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4 dimethylbenzyl)-4- [ (E)-4-((3R)-3-methoxymethyl 5 morpholino)-2-butenyl]piperazine dihydrochloride mp: 240-250 0 C 28 []D8 : -19.470 (C=0.19, MeOH) IR (KBr) : 1647, 1635, 1618, 1456, 1435, 1379, 1281, 1186, 1132, 1108 cm

-

1 10 NMR (DMSO-d 6 , 6) : 2.00-2.28 (6H, m), 2.60-5.20 (25H, m), 5.80-8.30 (8H, m) MASS (APCI) : 628 (M+H)+ (free) Example 72 15 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 550C for 12 20 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 25 ethyl acetate and n-hexane (2:3) as an eluent to give (2R)-1 [3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4 [4-((3S)-3-ethoxycarbonylmorpholino)-2-butynyl]piperazine (0.29 g) as an oil. NMR (CDC 3 , 6) : 1.20-5.30 (31H, m), 6.55-7.90 (6H, m) 30 MASS (APCI) : 654 (M+H) + Example 73 The following compounds were obtained according to a similar manner to that of Example 72. 35 WO 98/57954 PCT/JP98/02613 151 (1) ( 2 R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4 dimethylbenzyl)-4-[4-((3R)-3-ethylmorpholino)-2 butynyl]piperazine dihydrochloride []D7 : -22.70 (C=0.5, MeOH) 5 IR (KBr) : 3600, 1645, 1460, 1280, 1180, 1135 cm -1 NMR (DMSO-d 6 , 6) : 0.83-5.17 (31H, m), 6.62-8.24 (6H, m) MASS (APCI) : 610 (M+H) + (free) 10 (2) (2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-4-[4-((3S)-3 ethylmorpholino)-2-butynyl]-2-[ (1H-indol-3-yl)methyll piperazine dihydrochloride 28 []D : +11.20 (C=0.5, MeOH) IR (KBr) : 3365, 2600, 1645, 1430, 1280, 1180, 1135 cm -1 15 NMR (DMSO-d 6 , 6) : 0.67-5.20 (25H, m), 6.60-8.28 (8H, m), 10.96 (1H, s) MASS (APCI) : 621 (M+H)+ (free) (3.) ( 2 R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4 20 dimethylbenzyl)-4-[(E)-4-((3S)-3-methoxymethyl morpholino)-2-butenyl]piperazine dihydrochloride mp : 130-140oC 27 []D7 : +2.0 ° (C=0.25, MeOH) IR (KBr) : 1653, 1647, 1637, 1282, 1188, 1134 cm -1 25 NMR (DMSO-d 6 , 6) : 2.00-2.28 (6H, m), 2.70-5.28 (25H, m), 6.00-8.32 (8H, m) MASS (APCI) : 628 (M+H)+ (free) Example 74 30 A solution of ( 2 R)-1-[3,5-bis(trifluoromethyl)benzoyl] 2-(3,4-dimethylbenzyl)-4-[4-((3S)-3-ethoxycarbonyl morpholino)-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 35 removed under reduced pressure and the residual aqueous WO 98/57954 PCT/JP98/02613 152 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 (2R) -!-[3,5-bis (trifluoromethyl)benzoyl]-2-(3,4-dimethyl 5 benzyl)-4-[4-((3S)-3-carboxymorpholino)-2-butynyl]piperazine (0.26 g) as an oil. NMR (CDC 6 , 5) : 2.00-5.28 (26H, m), 6.50-7.90 (6H, m) MASS (APCI) : 626 (M+H) 0 ExamDle 75 A tetrahydrofuran solution of dimethylamine (2 M, 0.32 ml) was added to a mixture of (2R)-l-[3,5-bis(trifluoro methyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-[4-((3S)-3 carboxymorpholino)-2-butynyl]piperazine (0.13 g), 1 5 hydroxybenzotriazole (85 mg) and 1-(3-dimethylaminopropyvl)-3 ethylcarbodiimide hydrochloride (0.12 g) in N,N dimethvlformamide (5 ml), and the whole was stirred at room temperature for 5 hours. After the solvent was removed by evaporation, dichloromethane and sodium hydrogen carbonate 0 solution were added to the residue. 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 dichloromethane as an eluent to give (2R)-1-[3,5-bis(trifluoromethvl)benzoyl]-2 5 (3,4-dimethylbenzyl)-4-[4-((3S)-3-dimethylcarbamoyvl morpholino)-2-butynyl]piperazine. It was dissolved in ethyl acetate (10 ml) and the solution was added 4N hydrogen chloride in ethyl acetate (0.26 mi). The mixture was evaporated in vacuo and the residue was triturated with a ) mixture of ethyl acetate and isopropyl ether to give (2R)-1 [3,5-bis(trifluuoromethyl)benzoyvi-2- (3, 4-dimethvlbenzyl)-4 [4-((3S)-3-dimethylcarbamoylmorpholino)-2-butynyl]piperazine dihydrochloride (0.12 g) as a solid. me : 150-1600C 27 [27m -33.20 (C=0.25, MeOH) WO 98/57954 PCT/JP98/02613 153 IR (KBr) : 1653, 1506, 1433, 1371, 1325, 1281, 1182, 1136, 1063, 1026 cm NMR (DMSO-d 6 , 5) : 2.00-2.30 (6H, m), 2.60--5.20 (26H, m), 6.60-8.30 (6H, nm) 5 MASS (APCI) : 653 (M+H) + (free) Example 76 The following compounds were obtained according to a similar manner to that of ExamiDle 5. 0 (1) (2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-[ (1H-indol-3 yl)methyl]-4- {3-[2-(4-methoxy)pyridyl] -2-propynyl } piperazine dihydrochloride mD : 130-135 0 C 5 [a] : +2.80 (C=0.5, MeOH) IR (KBr) : 3600, 3314, 1640, 1625, 1430, 1280, 1180, 1135 cm NMR (DMSO-d 6 , 5) : 3.95 (3H, s), 2.74-5.24 (11H, m), 6.60-8.60 (11H, m), 10.92 (1H, s) 0 MASS (APCI) : 601 (M+H) + (free) (2) (2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4 dimethylbenzyl)-4-{3-[2-(4-methoxy)pyridyl]-2-propynyl} piperazine dihydrochloride 5 m3 : 95-1000C [c D : -6.20 (C=0.5, MeOH) IR (KBr) 3405, 2930, 2590, 1625, 1430, 1280, 1180, 1135 cm NMR (DMSO-d 6 , 5) : 2.51 (3H, s), 2.03-5.20 (17H, m), 6.66-8.66 (9H, m) MASS (APCI) : 590 (M+H) (free) (3) ( 2 R)-1---[3,5-Bis(trifluoromethyl)benzoyl]-2-[(!H-indol-3 yl) methyl] -4- {3-[2-(4-methyl)pyridyl] -2-propynyl } >piperazine dihydrochloride WO 98/57954 PCT/JP98/02613 154 mp : 150-1550C [ 27 3 o . D : -3.30 (C=0.5, MeOH) IR (KBr) : 3335, 1645, 1498, 1430, 1280, 1185 cm -1 NMR (DMSO-d 6 , 5) : 2.37 (3H, s), 2.10-5.24 (11H, m), 5 6.60-8.67 (11H, m), 10.93 (1H, s) MASS (APCI) : 585 (M+H) + (free) (4) ( 2 R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4 dimethylbenzyl)-4- { 3-[2-(4-methoxycarbonyl)pyridyl]-2 10 propynyl}piperazine dihydrochloride mp : 125-130'C 28 []D : -30.30 (C=0.5, MeOH) IR (KBr) : 2600, 1740, 1645, 1430, 1280, 1180 cm-1 NMR (DMSO-d 6 , 5) : 3.93 (3H, s), 2.00-5.20 (17H, m), 15 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 20 [(lH-indol-3-yl)methyl]piperazine (0.20 g), (3S,5S)-3,5 dimethyl-4-(4-chloro-2-butynyl)morpholine (0.11 g) and potassium carbonate (0.31 g) in N,N-dimethylformamide (4 ml) was stirred at 60'C for 3 hours. After cooling, the solvent was removed under reduced pressure and the residue was 25 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)-l 30 [ 3 ,5-bis(trifluoromethyl)benzoyl]-4-[4-((3S,5S)-3,5 dimethylmorpholino)-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 35 triturated with isopropyl ether to give (2R)-1-[3,5-bis- WO 98/57954 PCT/JP98/02613 155 (trifluoromethyl)benzoyl]-4-[4-((3S, 5S)-3.5-dimethyl morpholino)-2-butynyll-2-[ (1H-indol-3-yl)methyl] piperazine dihydrochioride (0.11 g). mC : 170-180 0 C 27 5 [] 7 : +21.570 (C=0.255, MeOH) IR (KBr) : 1645, 1637, 1458, 1431, 1360, 1281, 1184, 1136, 1111 cm-1 N1MR (DMSO-d 6 , 5) : 1.10-1.45 (6H, m), 2.70-5.30 (19H, m), 6.60-8.28 (8H, m) 0 MASS (APCI) : 621 (M+H)+ (free) Example 78 The following compounds were obtained according to a similar manner to that of Examele 77. 5 (1) (2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-4-[4-((3R)-3 ethylmorpholino)-2-butynyl]-2- [ (1H-indol-3-yl)methyl] piperazine dihydrochloride mP : 176-180oC 0 [a] 2 6 -12.20 (C=0.25, MeOH) IR (KBr) : 1635, 1454, 1437, 1358, 1333, 1281, 1223, 1182, 1138, 1068 cm NMR (DMSO-d 6 , 5) : 0.68-5.30 (25H, m), 6.55-8.30 (8H, m) , 10.95 (1H, s) 5 MASS (APCI) : 621 (M+H) + (free) (2) ( 2 R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-4-[3-(3,3 dimaethymorpholino)propyl]-2- [ (1H-indol-3-yl)methyl] piperazine dihydrochloride 0 m : 1 07-oC 27 [a2]7 : -7.00 (C=0.5, MeOH) IR (KBr) : 3500-3400, 2933, 2599, 1645, 1637, 1458, 1435, 1362, 1280 cm-1 NMR (DMSO-d 6 , 6) : 1.2-1.4 (6H, m), 2.1-1.6 (2H, m), D 2.7-5.2 (19H, m), 6.6-8.3 (8H, m), 10.9-11.8 (3H, WO 98/57954 PCT/JP98/02613 156 m) MASS (APCI) : 611 (M+H) + (free) (3) (2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4 5 dimethylbenzyl)-4-{2-[7-oxa-4-azaspiro[2.5]octan-4-yl] ethyl}}piperazine dihydrochloride mp : 110-1130C 28 . [c] D -13.80 (C=0.5, MeOH) IR (KBr) : 3435, 1645 cm-1 10 NMR (DMSO-d 6 , 5) : 0.80-0.95 (2H, m), 1.20-1.50 (2H, m), 2.11-2.19 (6H, m), 3.00-5.15 (19H, m), 6.65 8.17 (6H, m) MASS (APCI) : 584 (M+H)+ (free) 15 (4) (2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4 dimethylbenzyl)-4-[3-(3,3-dimethylmorpholino)propyl] piperazine dihydrochloride mp : 1970C [a]D : -17.80 (C=0.5, MeOH) 20 IR (KBr) : 3500-3400, 2933, 2692, 1645, 1637, 1456, 1430, 1435, 1280 cm-1 NMR (DMSO-d 6 , 5) : 1.33 (6H, s), 1.92-5.2 (27H, m), 6.6-8.3 (6H, m), 11.0-11.5 (2H, m) MASS (APCI) : 600 (M+H)+ (free) 25 Example 79 The following compounds were obtained according to a similar manner to that of Example 5. 30 (1) ( 2 R)-l-[3,5-Bis(trifluoromethyl)benzoyl]-4-[2-(3,3 dimethylmorpholino)ethyl]-2-[ (1H-indol-3-yl)methyl] piperazine dihydrochloride mp : 247-258*C 2]7 : -4.5 (C=0.5, MeOH) D35 IR (KBr) : 3500-3400, 1645, 1637, 1280 cm 35 IR (KBr) 3500-3400, 1645, 1637, 1280 cin 1 WO 98/57954 PCT/JP98/02613 157 NMR (DMSO-d 6 , 5) : 1.2-1.5 (6H, m), 2.8-5.3 (19H, m), 6.6-8.3 (8H, m), 11.0 (1H, br s), 11.5-12.1 (2H, m) MASS (APCI) 597 (M+H)+ (free) 5 (2) (2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4 dimethylbenzyl)-4-[2-(3,3-dimethylmorpholino)ethyl] piperazine dihydrochloride mp : 190-210 0 C 27 9 ° ]D : -13.90 (C=0.5, MeOH) 10 IR (KBr) : 3500-3400, 1643, 1450, 1430, 1384, 1363, 1280, 1185 cm-1 NMR (DMSO-d 6 , 6) : 1.40 (6H, s), 2.10-2.2 (6H, m), 2.7 5.2 (19H, m), 6.6-8.2 (6H, m), 11.6-12.2 (2H, m) MASS (APCI) : 586 (M+H)+ (free) 15 Example 80 The following compounds were obtained according to a similar manner to that of Example 39. 20 (1) (2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4 dimethylbenzyl)-4-[2-((3R)-3-ethylmorpholino)ethyl] piperazine dihydrochloride 28 o [(]D : -23.60 (C=0.5, MeOH) IR (KBr) : 3425, 2600, 1645, 1640, 1280, 1185, 1135 cm-1 25 MR (DMSO-d 6 , 5) : 0.95 (3H, t, J=7.2Hz), 1.57-5.20 (28H, m), 6.66-8.28 (6H, m) MASS (APCI) : 586 (M+H)+ (free) (2) (2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4 30 dimethylbenzyl)-4-[2-((3S)-3-hydroxymethylmorpholino) ethyl]piperazine dihydrochloride mp : 150-1600C [ 2D6 : -8.4' (C=0.25, MeOH) IR (KBr) : 1643, 1437, 1375, 1323, 1282, 1221, 1184, 35 1138, 1047 cm - 1 WO 98/57954 PCT/JP98/02613 158 NMNR (DMSO-d 6 , '5) : 2.00-2.28 (6H, m), 2.60-5.20 (23H, m), 6.58-8.28 (6H, m) MASS (APCI) : 588 (M+H) + (free) 5 (3) (2R)-1-[3,5-Bis(trifluoromethyl)benzoyl ]-2-(3,4 dimethylbenzyl)-4-[2-((2S)-2-methoxymethylmorpholino) ethyl]piperazine dihvdrochloride mo : 180-190 0 C 26 36 []6 : -12.360 (C=0.275, MeOH) 0 IR (KBr) : 1653, 1647, 1635, 1282, 1182, 1136 cm

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1 NMR (DMSO-d 6 , 5) : 2.00-5.20 (31H, mn), 6.60-8.30 (6H, m) MASS (APCI) : 602 (M+H)+ (free) (4) (2R)-1--[3,5-Bis(trifluoromethyl)benzoyvl]-2-(3,4 5 dimethylbenzyl) -4-[2-((3S)-3-methoxymethylmorpholino) ethyl]piperazine dihydrochloride m : 90-100oC []7 : -9.8' (C=0.25, MeOH) IR (KBr) : 1645, 1512, 1506, 1460, 1433, 1371, 1325, 0 1282, 1223, 1184, 1136, 1053 cm-1 NMR (DMSO-d 6 , 5) : 2.00-2.30 (6H, mi), 2.60-5.20 (25H, m), 6.60-8.40 (6H, nm) MASS (APCI) 602 (M+H) + (free) 5 (5) (2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4 dimiethylbenzyl)-4-[2-(2-methoxvymethylmorpholino)ethyl] piperazine dihvdrochloride me 150-154 0 C [ 28 -5.8' (C=0.5, MeOH) D IR (KBr) : 3463-3406, 1647 cm- 1 NMR (DMSO-d 6 , 5) 2.10-2.18 (6H, m), 2.40-5.10 (25H, m), 6.55-8.16 (6H, m) MASS (APCI) : 602 (M+H) + (free) 5 (6) (2R)-1-[3,5-Bis(trifluoromethyl)benzoyvl]-2-(3,4- WO 98/57954 PCT/JP98/02613 159 dimethylbenzyl)-4- [3-((3S)-3-methoxymethylmorpholino) propyl]piperazine dihydrochloride mp: 55-60'C [a]D 7 -1.4 ° (C=0.25, MeOH) 5 IR (KBr) : 1653, 1647, 1635, 1282, 1182, 1134, 1109 cm-1 NMR (DMSO-d6, 5) : 1.80-5.22 (33H, m), 6.60-8.30 (6H, m) MASS (APCI) : 616 (M+H)+ (free) (7) (2R)-l-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4 10 dimethylbenzyl)-4-[3-(2-methoxymethylmorpholino)propyl] piperazine hydrochloride mp: 145-155 0 C 28 9 o 8]D -11.9 (C=0.5, MeOH) IR (KBr) : 3455-3407, 1645 cm- 1 15 NMR (DMSO-d 6 , 5) : 2.10-2.19 (6H, m), 2.10-5.10 (27H, m), 6.68-8.17 (6H, m) MASS (APCI) : 616 (M+H)+ (free) (8) (2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-[ (1H-indol-3 20 yl)methyl]-4-[2-((3S)-3-methoxymethylmorpholino)ethyll piperazine dihydrochloride mp : 175-1850C 27 []D7 : -0.6' (C=0.25, MeOH) IR (KBr) : 1645, 1637, 1458, 1431, 1383, 1362, 1281, 25 1184, 1138, 1111 cm- 1 NMR (DMSO-d 6 , 5) : 2.80-5.28 (25H, m), 6.60-8.30 (8H, m) MASS (APCI) : 613 (M+H)+ (free) (9) (2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-[ (1H-indol-3 30 yl)methyl]-4-[2-((3R)-3-methoxymethylmorpholino)ethyl] piperazine dihydrochloride mp : 130-150 0 C 26 8 ° [a]D : -15.80 (C=0.25, MeOH) IR (KBr) : 1653, 1645, 1635, 1281 cm- 1 35 NMR (DMSO-d 6 , 5) : 2.60-5.25 (25H, m), 6.60-8.32 (8H, WO 98/57954 PCT/JP98/02613 160 m), 10.96 (iH, s) MASS (APCI) : 613 (M+H) + (free) (10) (2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4 5 dimethylbenzyl)-4-[3-((3R)-3-methoxymnethylmorpholino) propyl]piperazine dihydrochloride mI : 80-1000C .]U28 . -21.59' (C=0.22, MeOH) IR (KBr) : 1653, 1647, 1637, 1618, 1508, 1473, 1464, 0 1456, 14.48, 1435, 1431, 1385, 1373, 1363, 1281, 1215, 1184, 1136, 1109 cm-1 NMR (DMSO-d 6 , 5) : 2.00-5.40 (33H, m), 6.55-8.30 (6H, m) MASS (APCI) : 616 (M+H)+ (free) 5 Examiple 81 The following compounds were obtained according to a similar manner to that of Example 37. (1) (2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4 0 dimethylbenzyl)-4- [.2-((3R)-3-fluoromethylmorpholino) ethyl]piperazine dihydrochloride mp : 145-155 0 C 26 [c] 6 -19.2' (C=0.25, MeOH) IR (KBr) 1643, 1437, 1367, 1321, 1281, 1221, 1184, 5 1138, 1034 cm- 1 NMR (DMSO-d 6 , 5) : 2.00-2.28 (6H, m), 2.60-5.20 (22H, m), 6.60-8.32 (6H, m) MASS (APCI) : 590 (M+H) + (free) 3 (2) (2R)-1-[3,5 -Bis(trifluoromethvl)benzovl] -2- (3,4 dimethyibenzvl) -4-[2- (3-methoxymethyl-3 methylmorpholino)ethyl]piperazine dihydrochloride mp : 60-700C [ 2]7 -15.5 (C=0.3, MeOH) IR (KBr) : 1643, 1469, 1439, 1375, 1369, 1360, 1323, WO 98/57954 PCT/JP98/02613 161 1282, 1225, 1184, 1138 cm-! NMR (DMSO-d 6 , 6) : 1.10-1.50 (3H, s), 2.00-5.22 (30H, m), 6.60-8.30 (6H, m) MASS (APCI) : 616 (M+H) + (free) 5 (3) (2R)-1-[3,5-Bis(trifluoromethyl)benzovl]-2-(3,4 dimiethylbenzvl) -4- [2-((3S)-3-ethoxymethylmorpholino) ethyl]piperazine dihydrochloride mp : 60-65 C 0 [-] 8.2o (C=0.25, MeOH) IR (KBr) 1643, 1437, 1369, 1321, 1281, 1221, 1182, 1138, 1072, 1051 cmI NMR (DMSO-d6, 5) : 1.10-1.30 (3H, m), 2.00-5.25 (30H, min), 6.60-8.40 (6H, m) 5 MASS (APCI) : 616 (M+H) (free) (4) (2R)-1-[3,5-Bis(trifiuoromethyl)benzoyl]-2-(3,4 dimethvlbenzyi) -4-[2-((3R)-3-methoxymethylmorpholino) ethyllpiperazine dihydrochloride 0 mp : 90-100 0 C [a] : -26.48' (C=0.287, MeOH) IR (KBr) : 1635, 1469, 1454, 1437, 1375, 1369, 1360, 1321, 1282, 1221, 1184, 1136, 1074 cm

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1 NMR (DMSO-d 6 , 6) : 2.00-5.22 (31H, m), 6.60-8.28 (6H, m) 5 MASS (APCI) : 602 (M+H) + (free) (5) (2R)-1-[3,5-Bis(trifiuoromethyl)benzoyl]-2-(3,4 dimethvibenzyl) -4- [2-((2R)-2-methoxymrethylmorpholino) ethyl]piperazine dihydrochloride 0 mp : 160-1700C [a ]D7 : -17.400 (C=0.27, MeOH) IR (KBr) : 1645, 1454, 1431, 1383, 1363, 1321, 1281, 1215, 1184, 1138, 1109 cm N-MR (DMSO-d 6 , 5) : 2.00-2.28 (6H, m), 2.60-5.22 (25H, 5 m), 6.60-8.28 (6:, m) WO 98/57954 PCT/JP98/02613 162 MASS (APCI) : 602 (M+H) + (free) (6) (2R)-1-[3,5-Bis(trifiuoromethyl)benzoyl]-2-(2 naphthylmethyl)-4-[2-((3S) -3-ethylmorpholino)ethyl] 5 piperazine dihydrochioride 28 [2]D : -16.2o (C=0.5, MeOH) IR (KBr) : 3400, 2610, 1430, 1280, 1185, 1135 cm-i NMR (DMSO-d 6 , 5): 0.86-5.31 (25H, m), 7.00-8.20 (10H, m) MASS (APCI) : 608 (M+H) (free) 0 (7) (2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-[ (1H-indol-3 yl)methyl]-4-[2-((2S)-2-methoxymethylmorpholino)ethyl] piperazine dihydrochloride mP : 160-170 0 C 5 [ 7 : -3.0 (C=0.25, MeOH) IR (KEr) : 1645, 1637, 1618, 1458, 1429, 1362, 1281, 1184, 1138, 1109, 1099 cm- 1 N1R (DMSO-d , 6) : 2.60-5.30 (25H, m), 6.60-8.30 (8H, m) MASS (APCI) 613 (M+H) + (free) 0 (8) (2R)-1-[3,5-Bis(trifiuoromethyl)benzoyl]-2-[ (1H-indol-3 yl)methyvl]-4-[2-((2R)-2-methoxvymethylmorpholino)ethyl] piperazine dihydrochloride me 190-200'C 27 5 [u-D : -15.0' (C 0.24, MeOH) IR (KBr) : 1641, 1458, 1421, 1362, 1282, 1176, 1130, 1113, 1099, 1074 cmi NMR (DMSO-d 6 , 6) : 2.60-5.28 (25H, min), 6.60-8.28 (8H, m), 10.94 (1H, s) 0 MASS (APCI) : 613 (M+H) + (free) (9) (2R)-1-[3,5-Bis(trifiuoromethyvl)benzoyl]-2-[ (1H-indol-3 yl)rmethyl]-4-[2-((3S,5S)-3,5-dimethylmorpholino)ethyl] oinerazine dihvdrochloride 5 mD : 170-180 0

C

WO 98/57954 PCT/JP98/02613 163 []7 : +13.490 (C=0.315, MeOH) IR (KBr) 1645, 1637, 1458, 1448, 1429, 1362, 1281, 1184, 1136, 1111 cm NMR (DMSO-d 6 , 6) : 1.08-1.50 (6H, m), 2.60-5.20 (19H, 5 m), 6.55-8.30 (8H, im) MASS (APCI) : 597 (M+H) (free) (10) (2P)-!-[3,5-Bis(trifluoromethyl)benzoyl]-4-[2-((3R)-3 ethylmnorpholino)ethvyl]-2-[ (1H-indol-3-yl)methyll 0 nioerazine dihydrochloride 28 .9 = [] : -14.90 (C=0.5, MeOH) IR (KBr) 3365, 2590, 2470, 1645, 1430, 1280, 1185, 1140 cm NMR (DMSO-d 6 , 6) : 1.53-5.20 (25H, m), 6.60-8.28 (SH, 5 m), 10.95 (1H, s) MASS (APCI) 597 (M+H) + (free) (11) (2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]i-4-[L2-((3S)-3 ethylmorpholino)ethyl]-2-[ (1H-indol-3-yl)methyl] 0 cioerazine dihydrochloride []D8 : +6.00 (C=0.5, MeOH) IR (KBr) 3300, 2670, 2610, 1645, 1430, 1280, 1180, 1140 cm NMR (DMSO-d6, 6) : 0.84-5.20 (25H, m), 6.64-8.28 (8H, 5 m), 10.94 (IH, s) MASS (APCI) 597 (M+H) (free) Example 82 A solution of (2R)-1-[3,5-bis(trifluoromethyv)benzoyl] D 2-(3,4-dimethylbenzyl)-4- [4-((3S)-3-methoxymethylmnorpholino) 2-butynyl]piperazine (0.09 g) in methanol (10 ml) was hydrogenated in the presence of 10% palladium-carbon (40 mg) at room temperature. After 1 hour, Dalladium-carbon was removed by filtration and the filtrate was evaporated under D reduced pressure. The residue was purified by column WO 98/57954 PCT/JP98/02613 164 chromatography on silica gel with a mixture of methanol and ethyl acetate as an eluent to give (2R)-l-[3,5-bis (trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)- 4

-[

4 -((3S) 3-methoxymethylmorpholino)butyl]piperazi-ne. It was dissolved 5 in ethyl 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 triturated with a mixture of ethyl acetate and isopropyl ether to give (2R)-1 [3,5-bis (trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4 L0 [4-((3S)-3-methoxymethylmorpholino)butyl]piperazine dihydrochloride (0.03 g) as a solid. NMR (DMSO-d 6 , 5) : 1.60-2.00 (4H, m), 2.00-2.30 (6H, m), 2.60-5.20 (25H, m), 6.60-8.30 (6H, m), 10.40 1 .60 (2H, im) L5 MASS (APCIT) : 630 (M+H) + (free) Example 83 The following compounds were obtained according to a similar manner to that of Example 82. .0 (1) (2R)-l-[3,5-Bis(trifluoromethyl)benzoyl]-2-( 3 ,4 dimethylbenzyl)-4-{3-[2-(4-methoxy)pyridyl]lpropyl} piperazine dihydrochloride mO : 130-140'C 25 [ 8] : -10.4' (C=0.5, MeOH) IR (KBr) : 3425, 2400, 1640, 1500, 1430, 1280, 1180, 1135 cm

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1 NMR (DMSO-d 6 , 5) : 4.08 (3H, s), 2.05-5.14 (21H, m), 6.60-8.72 (9H, m) 30 LMASS (APCI) : 594 (M+H) + (free) (2) (2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-[ (1H-indol-3 yl)methyl]-4-{3-[2-(4-methyl)pyridyl]lpropyl}piperazine dihydrochloride 5 mD : 120-130 0

C

WO 98/57954 PCT/JP98/02613 165 [2]7 : -5.00 (C=0.5, MeOH) IR (KBr) 3420, 1645, 1498, 1430, 1280, 1135 cm

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1 NMR (DMSO-d 6 , 5) : 2.55 (3H, s), 2.14-5.20 (15H, m), 6.64-8.74 (11H, m), 10.95 (1H, s) 5 MASS (APCI) 589 (M+H) T+ (free) (3) (2R)-1-[3,5-Bis(trifluoromethyvl)benzoyl]-2-(3,4 dimethylbenzyl)-4-{3-[2-(4-methoxycarbonyl)pyridyl] propyi}piperazine dihydrochloride 0 m : 115-125OC 28 ]28D : -11.70 (C=0.5, MeOH) IR (KBr) 2650, 2625, 1740, 1645, 1460, 1280, 1135 cm NMR (DMSO-d 6 , 5) : 3.92 (3H, s), 2.07-5.14 (21H, m), 6.60-8.78 (9H, m) 5 MASS (APCI) : 622 (M+H) (free) Example 84 To a stirred suspension of 2-(3,4-methylenedioxybenzyl) piperazine dihydrochloride (104 mg) and potassium carbonate 0 (196 mg) in N,N-dimethylformamide (4 ml) was added 4-(4 chloro-2-butynyl)-3,3-dimethylmorpholine hydrochloride (84.5 mg) at 5°C under nitrogen atmosphere and the mixture was gradually warmed to room temperature over night. To the above stirred suspension was added 3,5-bis(trifluoromethyl) 5 benzoyl chloride (98.2 mg) at 5 0 C and the mixture was stirred for 1 hour at this temperature. The mixture was extracted with ethvyl 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 0 dichloromethane and methanol (50:1) gave 1-[3,5-bis (trifluoromethyl)benzoyl]-4-[4-(3,3-dimethylmorpholino)-2 butynyl]-2-(3,4-methylenedioxybenzyl)piperazine, which was dissolved in ethyl acetate and treated with 4N hydrogen chloride in ethyl acetate to give 1-[3,5-bis 5 (trifluoromethyl)benzoyll]-4-[4- (3,3-dimethylmorpholino)-2- WO 98/57954 PCT/JP98/02613 166 butynyl] -2-(3,4-methylenedioxybenzyl)piperazine dihydrochloride (107 mg) as a powder. NMR (DMSO-d 6 , 5) : 1.32 (6H, mi), 2.20-5.00 (19H, m), 5.96 (2H, s), 6.43-8.17 (6H, m) 5 MASS (APCI) : 626 (M+H) (free) Example 85 The following compounds were obtained according to a similar manner to that of ExamDle 84. 0 (1) 1-[3,5-Bis(trifluoromethyvl)benzoyl]l-4-[4-(3,3 dimethylmorpholino)-2-butynyll]-2-(4-hydroxymethyl-3 methylbenzyl)piperazine dihydrochloride RMR (DMSO-d 6 , 5) : 1.32-1.38 (6H, m), 2.00-5.22 (25H, 5 m), 6 .55-8.17 (6H, m) MASS (APCI) : 626 (M+H) (free) (2) 2-[(1,4-Benzodioxan-6-vl)methyl]-1-[3,5-bis (trifluoromethyl)benzoyl]-4-[4-(3, 3-dimethylmorpholino) 0 2-butynyl]piperazine dihydrochloride NMR (DMSO-d 6 , 5) : 1.21-1.23 (6H, m), 2.62-5.00 (23H, m), 6.37-8.48 (6H, m) LMASS (APCI) : 640 (M+H) (free) 5 (3) 1-[3,5-Bis(trifluoromethyl)benzoyl]-4-[4-( 3

,

3 dimethylmorpholino)-2-butynyl] -2-(4-methoxy-3 methylbenzyl)piperazine dihydrochloride MR (DMSO-d 6 , 5) : 1.33-1.40 (6H, m), 2.00-5.22 (25H, m), 6.64-8.15 (6H, m) 0 MASS (APCI) : 626 (M+H) + (free) Example 86 To a mixed solution of 1-(benzyloxycarbonyl)-3-(2,3 dimethoxybenzyl)piperazine (0.65 g) and triethylamine (0.293 5 ml) in dichloromethane (17 ml) was added dropwise 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 5 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) 10 using a mixed solvent of n-hexane and ethyl acetate (2:1). 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). 15 IR (KBr) : 1732, 1714, 1705, 1647, 1431, 1281, 1134 cm

-

1 NMR (CDC1 3 , 6) : 2.60-4.70 (9H, m), 3.79 (6H, s), 5.20 (2H, s), 6.40-8.60 (11H, m) MASS (APCI) : 611 (M+H) + 20 Example 87 A mixture of 1-[3,5-bis(trifluoromethyl)benzoyl]-2-(2,3 dimethoxybenzyl)piperazine (0.192 g), 3,3-dimethyl-4-(4 chloro-2-butynyl)morpholinine hydrochloride (0.106 g), 25 potassium carbonate (0.167 g) and potassium iodide (67 mg) in N,N-dimethylformamide (1.3 ml) was stirred at 65 0 C for 90 minutes and cooled. The mixture was poured into ice-water (30 ml) and the whole was adjusted to pH 9 with sodium bicarbonate, and extracted with ethyl acetate (30 ml). The 30 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 35 collected and evaporated under reduced pressure to give a WO 98/57954 PCT/JP98/02613 168 colorless oil of 1-[3,5-bis(trifluoromethyl)benzoyl]-2-(2,3 dimethoxybenzyl)-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 5 ethyl acetate solution (0.30 ml) under ice-cooling, and evaporated under reduced pressure to give colorless powder of --[3, 5-bis(trifluoromethyl)benzoyl]-2- (2,3-dimethoxybenzyl) 4-[4- (3,3-dimethylmorpholino)-2-butynyl]piperazine dihydrochloride (0.18 g). 0 me : 1700C IR (KBr) : 2933, 2575, 1647, 1637, 1433, 1281, 1186, 1136 cm -1 NMIR (DMSO-d 6 , 5) : 1.33 (3H, s), 1.41 (3H, s), 2.60 5.20 (19H, m), 3.75 (6H, s), 6.50-7.00 (3H, m), 5 7.50-8.20 (3H, m) MASS (APCI) : 642 (M+H) + (free) Example 88 The following compound was obtained according to a 0 similar manner to that of Example 86. - [3, 5-Bis(trifluoromethyl)benzoyl] -4-(benzyloxy carbonyl)-2-[ (H-indol-2-yl)methyl]piperazine IR (KBr) : 1714, 1699, 1684, 1647, 1635, 1458, 1281 cm-1 5 TNMR (DMSO-d 6 , 5) : 2.60-5.10 (9H, m), 5.15 (2H, s), 5.98-8.48 (13H, m), 10.58-11.04 (1H, m) MASS (APCI) 590 (M+H) + Example 89 0 The following compounds were obtained according to a similar manner to that of Example 87. (1) !-[3,5-Bis(trifluoromethyl)benzoyl]-2-[ (1H-indol-2-yl) methyl]-4-[4- (3,3-dimethylmorpholino)-2-butynyl] 5 piperazine dihydrochioride WO 98/57954 PCT/JP98/02613 169 m : 185°C IR (KBr) : 1651, 1647, 1637, 1281, 1188, 1136 cm-1 NMR (DMSO-d 6 , 5) : 1.31 (3H, s), 1.40 (3H, s), 3.00 5.22 (19H, m), 6.02-6.40 (1H, m), 6.90-8.20 (7H, 5 m), 11.70-11.17 (1H, im) MASS (APCI) 621 (M+H) (free) (2) 1- [3,5-Bis (trifluoromethvl)benzoyl]-2-(3-methoxybenzyl) 4- [4-(3, 3-dimethyl)morphoiino-2-butynyl]piperazine 0 dihydrochloride m : 223-225 0 C IR (KBr) : 3600-3300, 2900, 2600-2300, 1647, 1635, 1458, 1435, 1280 cm NMR (DMSO-d 6 , 5) : 1.32 (3H, s), 1.40 (3H, s), 2.8-5.2 5 (22H, m), 6.5-8.20 (7H, m), 12.1-12.6 (2H, m) MASS (APCI) : 612 (M+H)~ (free) Example 90 The following compounds were obtained according to a 0 similar manner to that of Example 9. (1) (2R)-4-[4-(3,3-Dimethylmorpholino)-2-butynyl]-2-[ (1H indol-3-yl)methyl] -1-[3-(methylamino)-5 (trifluoromethyl)benzoyl]piperazine dihydrochloride 5 mp : 215-230 0 C [00D7 : +41.80 (C=0.5, MeOH) IR (KBr) : 3600-3300, 2900, 2600-2300, 1645, 1624, 1614, 1458, 1419 Cm

-

1 NMR (DMSO-d 6 , 5) : 1.20-1.50 (6H, m), 2.69 (3H, s), 0 2.90-5.30 (19H, m), 6.55-7.90 (9H, m), 10.98 (1H, br s), 11.90-12.60 (2H, m) MASS (APCI) : 582 (M+H) (free) (2) (2R) -1- [3-(Dimethylamino)-5-(trifluoromethyl)benzoyl]-4 5 [4-(3,3-dimethylmorpholino)-2-butynyl]-2-[ (1H-indol-3- WO 98/57954 PCT/JP98/02613 170 yl)methyl]piperazine dihydrochloride mp : 210-225oC 27 [c]D +31.80 (C=0.5, MeOH) IR (KBr) 3600-3300, 2900, 2600-2300, 1653, 1647, 5 1635, 1558, 1541, 1508, 1473, 1458, 1419 cm-1 NMR (DMSO-d 6 , 5) : 1.20-1.50 (6H, m), 2.70-5.28 (19H, m), 2.94 (6H, s), 6.48-7.90 (8H, m), 10.99 (1H, br s), 12.00-12.50 (2H, m) MASS (APCI) 596 (M+H) (free) 0 (3) (2R)-4-[4-(3,3-Dimethylmorpholino)-2-butynyl]-2-[ (1H indol-3-yl)methyl]-1-[3-nitro-5-(trifluoromethyl) benzoyl]piperazine dihydrochloride me : 198-220 0 C 5 IR (KBr) : 3600-3300, 2900, 2600-2300, 1645, 1635, 1543, 1471, 1458, 1421, 1358, 1331 cm - 1 NMR (DMSO-d 6 , 5) : 1.33 (3H, s), 1.41 (3H, s), 2.80 5.22 (19H, m), 6.50-8.62 (8H, m), 10.99 (1H, s), 11.80-12.60 (2H, m) 0 MASS (APCI) : 598 (M+H) (free) (4) (2R)-2-(3,4-Dimethylbenzyl)-4-[4-(3,3-dimethyl morpholino)-2-butynyl]-1- [3-(methylamino)-5 (trifluoromethyl)benzoyl]piperazine dihydrochloride 5 me 195-2050C []D7 : +10.80 (C=0.5, MeOH) IR (KBr) 3600-3300, 2900, 2600-2300, 1647, 1635, 1616, 1456, 1419 cm

-

1 MR (DMSO-d 6 , 5) : 1.32 (3H, s), 1.40 (3H, s), 2.00 0 2.30 (6H, m), 2.70 (3H, s), 2.90-5.20 (19H, m), 6.20-7.20 (7H, m), 12.22 (2H, br s) MASS (APCI) : 571 (M+H) + (free) (5) (2R)-1-F[3-(Dimethylamino)-5-(trifluoromethyl)benzoyl]-2 5 (3,4-dimethylbenzyl)-4-[4- (3,3-dimethylmorpholino)-2- WO 98/57954 PCT/JP98/02613 171 butynyl]piperazine dihydrochloride mp : 108-1850C 27 [a]D : +8.80' (C=0.5, MeOH) IR (KBr) : 3600-3300, 2900, 2600-2300, 1647, 1635, 5 1616, 1608, 1506, 1456, 1425 cm-1 NMR (DMSO-d 6 , 5) : 1.32 (3H, s), 1.40 (3H, s), 2.02 2.30 (6H, m), 2.95 (6H, s.), 3.00-5.25 (19H, m), 6.20-7.20 (6H, m), 12.28 (2H, br s) MASS (APCI) : 585 (M+H)+ (free) 10 (6) ( 2 R)-2-(3,4-Dimethylbenzyl)-4-[4-(3,3-dimethyl morpholino)-2-butynyl] -1- [3-nitro-5-(trifluoromethyl) benzoyl]piperazine dihydrochloride mp : 157-200oC 15 [a]26 : +19.50 (C=0.5, MeOH) IR (KBr) : 3600-3300, 2900, 2600-2300, 1647, 1637, 1543, 1456, 1423, 1356, 1330, 1319 cm-1 NMR (DMSO-d6, 5) : 1.33 (3H, s), 1.41 (3H, s), 1.95 2.34 (6H, , 2.62-5.20 (19H, m), 6.60-8.60 (6H, 20 m), 12.10-12.50 (2H, m) MASS (APCI) : 587 (M+H)+ (free) Preparation 72 The following compounds were obtained by a similar 25 manner to that of Preparation 38. (1) ( 2 R)-l-[3,5-Bis(trifluoromethyl)benzoyl]-2-[ (1H-indol-3 yl)methyl]-4-( 2 -hydroxyethyl)piperazine IR (Neat) : 3300, 2930, 2800, 1623 cm-1 30 NMR (DMSO-d 6 , ) : 2.00-5.00 (14H, m), 6.60-8.28 (8H, m), 10.86 (1H, s) MASS (APCI) : 500 (M+H) + (2) ( 2 R)-l-[3,5-Bis(trifluoromethyl)benzoyll]-2-(3,4 35 dimethylbenzyl)-4-( 2 -hydroxyethyl)piperazine WO 98/57954 PCT/JP98/02613 172 IR (Neat) : 3400, 1640, 1430, 1280, 1170 cm-1 NMR (DMSO-d 6 , 5) : 2.00-5.00 (20H, m), 6.60-8.20 (6H, m) Preparation 73 5 The following compounds were obtained by a similar manner to that of Example 39. (1) (2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-[ (1H-indol-3 yl)methyl]-4-(2-methanesulfonyloxyethyl)piperazine 10 IR (Neat) : 3340, 3300, 3000, 2930, 2800, 1624 cm - 1 NMR (DMSO-d 6 , ) : 2.10-4.70 (13H, m), 3.24 (3H, s), 6.26-8.28 (SH, m), 10.90 (1H, s) MASS (APCI) : 578 (M+H) + 15 (2) (2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4 dimethylbenzyl)-4-(2-methanesulfonyloxyethyl)piperazine IR (Neat) : 1640, 1430, 1280, 1150 cm-1 NMR (DMSO-d 6 , 5) : 2.00-5.00 (23H, m), 6.60-8.20 (6H, m) MASS (APCI) 567, 489 20 Preparation 74 The following compound was obtained by a similar manner to that of Preparation 37. 25 ( 2 R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-[ (1H-indol-3 yl)methyl]-4-(4-chloro-2-butynyl)piperazine IR (Neat) : 3300, 3050, 2800, 2600, 1630, 1430 cm - 1 NMR (CDC 3 , 6) : 2.20-5.30 (1,3H, m), 6.75-8.20 (8H, m) MASS (APCI) 542 (M+H) + 30 Preparation 75 (1) The following compound was obtained by a similar manner to that of Preparation 46-(4). 35 1-Acetyl-3-(3-methoxy-4-methylphenyl)methylene-2,5- WO 98/57954 PCT/JP98/02613 173 piperazinedione NMR (DMSO-d 6 , 6). : 2.17 (3H, s), 2.50 (3H, s), 3.83 (3H, s), 4.37 (2H, s), 6.95 (1H, s), 7.08-7.22 (3H, m), 10.33 (1H, s) 5 MASS (APCI) : 289 (M+H) + (2) The following compound was obtained by a similar manner to that of Preparation 46-(5). 10 3-(3-Methoxy-4-methylbenzyl)-2,5-piperazinedione NMR (DMSO-d 6 , 5) : 2.11 (3H, s), 2.75 (1H, d, J=17.4Hz), 2.84 (1H, m), 3.05 (1H, dd, J=13.4, 4.5Hz), 3.35 (1H, m), 3.73 (3H, s), 4.04 (1H, m), 6.63 (1H, d, J=7.4Hz), 6.73 (1H, s), 7.03 (1H, d, 15 J=7.4Hz), 7.88 (1H, m), 8.13 (1H, m) MASS (APCI) : 249 (M+H) + (3) The following compound was obtained by a similar manner to that of Preparation 47-(3). 20 2-(3-Methoxy-4-methylbenzyl)piperazine dihydrobromide NMR (DMSO-d 6 , ) : 2.13 (3H, s), 2.78-3.78 (9H, m), 3.81 (3H, s), 6.73-7.15 (3H, m), 9.11 (4H, m) MASS (APCI) : 221 (M+H)+ (free) 25 (4) A stirred solution of 2-(3-methoxy-4-methylbenzyl) piperazine dihydrobromide (240 mg) in 48% hydrobromic acid (8 ml) was heated under reflux for 48,hours. After cooling, the mixture was concentrated under reduced pressure. The residue 30 was triturated with ethyl acetate and the resulting precipitates were collected by filtration, and washed with ethyl acetate to give 2

-(

3 -hydroxy-4-methylbenzyl)piperazine dihydrobromide (175 mg) as a powder. NMR (DMSO-d 6 , 6) : 2.11 (3H, s), 2.67-3.78 (9H, m), 35 "6.70-6.95 (3H, m), 9.09 (4H, m) WO 98/57954 PCT/JP98/02613 174 MASS (APCI) 207 (M+H)+ (free) Example 91 The following compounds were obtained by a similar 5 manner to that of Example 84. (1) 1-[3,5-Bis(trifluoromethyl)benzoyl]-4-[4-(3,3 dimethylmorpholino)-2-butynyl] -2-(3-hydroxy-4-methylbenzyl) piperazine dihydrochloride 0 NMR (DMSO-d 6 , 5) : 1.32-1.38 (6H, m), 2.08 (3H, s), 2.68-5.03 (20H, m), 6.18-8.20 (6H, m) MASS (APCI) : 612 (M+H) + (free) (2) 1-[3,5-Bis(trifluoromethyl)benzoyl]l-4-[4-(3,3 .5 dimethylmorpholino)-2-butynyl] -2-(3-methoxy-4 methylbenzyl)piperazine dihydrochloride NMR (DMSO-d 6 , 5) : 1.33-1.38 (6H, m), 2.10 (3H, s), 2.73-5.10 (22H, m), 6.40-8.18 (6H, m) MASS (APCI) : 626 (M+H) + (free) .0 (3) 1-[3,5-Bis(trifluoromethyl)benzoyl]-4-[4-(3,3 dimethylmorpholino)-2-butynyl] -2-(4-hydroxy-3 methylbenzyl)piperazine dihydrochloride NMR (DMSO-d 6 , 5) : 1.32-1.38 (6H, m), 2.09 (3H, s), .5 2.73-4.98 (20H, m), 6.55-8.20 (6H, m) MASS (APCI) 612 (M+H)+ (free) Preparation 76 The following compound was obtained according to a 30 similar manner to that of Preparation 75-(4). 2-(4-Hydroxy-3-methylbenzyl)piperazine dihydrobromide NMR (DMSO-d 6 , 5) : 2.10 (3H, s), 2.67-3.57 (9H, m), 6.57-7.11 (3H, m), 9.12-9.39 (5H, m) 35 MASS (APCI) : 207 (M+H)+ (free) WO98/57954 PCT/JP98/02613 175 Preparation 77 (1) The following compound was obtained according to a similar manner to that of Preparation 46-(4). 5 1-Acetyl-3-(3-nitrophenyl)methylene-2,5-piperazinedione mp : 190-200°C NMR (DMSO-d 6 , 5) : 2.51 (3H, s), 4.32 (2H, s), 7.03 (1H, s), 7.65 (1H, m), 7.94 (1H, d, J=7.8Hz), 8.16 (1H, dd, J=1.6, 7.8Hz), 8.37 (1H, d, J=1.6Hz), 0 10.80 (1H, br s) MASS (APCI) : 290 (M+H) + 79 (2) A mixture of 1-acetyl-3-(3-nitrophenyl)methylene-2,5 piperazinedione (10.2 g), triethylamine (6.43 ml) and di 5 tert-butyl dicarbonate (23.5 g) in N,N-dimethylformamide (50 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 0 acetate and water. The 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 dichloromethane and methanol (20:1). The fractions containing the objective compound were 5 collected and evaporated under reduced pressure. The resulting precipitates were collected by filtration and washed with methanol to give 1-acetyl-3-[3-(tert butoxycarbonylamino)benzyl]-2,5-piperazinedione (1.3 g) as colorless powders. 0 mp : 189-190 0 C IR (KBr) : 3334, 1727, 1704, 1681, 1602, 1590, 1540 cm-1 NMR (DMSO-d 6 , 5) : 1.46 (9H, s), 2.43 (3H, s), 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, 5 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, m), 7.23 (1H, d, J=7.Hz), 7.43 (1H, s), 7.42 (1H, d, J=2.8Hz), 9.32 (1H, s) MASS (APCI) 306 (M-(CH 3

)

3 ) + 5 (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 : 230-233oC 0 IR (KBr) : 3301, 3212, 3083, 2981, 1716, 1675, 1608 cm-1 NMR (DMSO-d 6 , 5) : 1.47 (9H, s), 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, m), 6.78 (1H, d, J=7.8Hz), 7.14 (1H, m), 5 7.30-7.35 (2H, m), 7.91 (1H, br s), 8.13 (1H, br s), 9.30 (1H, s) MASS (APCI) : 320 (M+H)

+

, 264 (4) A solution of 3-[3-(tert-butoxycarbonylamino)benzyl]-2 ,5 0 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 5 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 (25:1). The fractions 0 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 : 160-161oC 5 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, J=3.0Hz), 4.21 (2H, d, J=6.0Hz), 6.16 (1H, m), 6.33 5 (1H, d, J=7.4Hz), 6.41-6.45 (2H, m), 6.92 (1H, m), 7.18-7.33 (5H, m), 7.78 (1H, br s), 8.04 (1H, d, J=2.2Hz) MASS (APCI) : 310 (M+H) + 10 (5) A suspension of 2-[3-(benzylamino)benzyl]-3,6 piperazinedione (0.45 g), 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,N dimethylformamide (5 ml) was stirred for 5 hours at room 15 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 20 chromatography on silica gel using a mixture of dichloromethane and methanol (10:1). The fractions containing the objective compound were collected and evaporated under reduced pressure. The resulting precipitates were collected by filtration and washed with 25 isopropyl alcohol to give 2-[3-(N-benzyl-N methylamino)benzyl]-3,6-piperazinedione (0.46 g) as colorless crystals. NMR (DMSO-d 6 , 6) : 2.71-3.03 (3H, m), 2.94 (3H, s), 3.27-3.37 (1H, m), 4.00-4.05 (1H, m), 4.53 (2H, s), 6.42 (1H, 30 d, J=7.5Hz), 6.57-6.61 (2H, m), 6.98-7.06 (1H, m), 7.16-7.34 (5H, m), 7.85 (1H, s), 8.09 (1H, d, J=2.2Hz) MASS (APCI) : 324 (M+H) + (6) The following compound was obtained according to a 35 similar manner to that of Preparation 49-(4).

WO 98/57954 PCT/JP98/02613 178 2-[3-(N-Benzyl-N-methylamino)benzyl]piperazine The compound was used to the next step without further purification. 5 Preparation 78 The following compound was obtained according to a similar manner to that of Preparation 50. 10 1-[3,5-Bis(trifluoromethyl)benzoyl]-2-[3-(N-methylamino) benzyl] piperazine NMR (CDCl 3 , ) : 2.20-5.20 (10H, m), 2.99 (3H, s), 6.00-7.40 (7H, m), 8.16 (1H, s) MASS (APCI) : 446 (M+H) + 15 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. 20 1-[3,5-Bis(trifluoromethyl)benzoyl]-2-[3-N-benzyl-N methylamino)benzyl] -4-(benzyloxycarbonyl)piperazine IR (Neat) : 1705, 1645, 1605, 1505 cm

-

1 NMR (CDC1 3 , 5) : 2.60-4.80 (14H, m), 5.18 (2H, s), 6.10 25 7.40 (16H, m), 7.84 (1H, s) MASS (APCI) : 670 (M+H) + Example 93 The following compound was obtained according to a 30 similar manner to that of Example 87. 1-[3,5-Bis(trifluoromethyl)benzoyl]-4-[4-(3,3-dimethyl morpholino)-2-butynyl]-2-[3-(N-methylamino)benzyl]piperazine IR (Neat) : 3400, 1680, 1640, 1610 cm- 1 35 NMR (CDCl 3 , 5) : 1.06 (6H, br s), 2.10-5.20 (20H, m), WO 98/57954 PCT/JP98/02613 179 3.34 (3H, s), 5.95-7.80 (7H, m) MASS (APCI) : 611 (M+H) + 5 its trihydrochloride mp : 192-195 0 C IR (KBr) : 3500-3300, 3000-2800, 2700-2300, 1644 cm-1 NMR (CDCl 3 , 6) : 1.36 (6H, s), 2.71-2.81 (3H, m), 3.20 5.20 (20H, m), 6.60-8.21 (7H, m) 0 MASS (APCI) : 611 (M+H)+ (free) Example 94 A suspension of 1-[3,5-bis(trifluoromethyl)benzoyl]-4 [4-(3, 3-dimethylmorpholino)-2-butynyl]-2-[3-(N-methylamino) 5 benzyl]piperazine (0.19 g), 37% aqueous formaldehyde (50 ipl), sodium triacetoxyborohydride (79 mg) and acetic acid (22 li) in dichloromethane (5 ml) was stirred for 2 hours at room temperature. Then additional 37% aqueous formaldehyde (25 Yl), acetic acid (10 yi) and sodium triacetoxyborohydride (40 0 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 5 residue was purified by column chromatography on silica gel using a mixture of dichloromethane and methanol (40:1). 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-[3,5 0 bis(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 5 NMR (DMSO-d 6 , 6) : 1.32 (3H, s), 1.41 (3H, s), 2.91 WO 98/57954 PCT/JP98/02613 180 (3H, s), 3.03 (3H, s), 3.20-5.20 (19H, m), 6.40 8.25 (7H, m) MASS (APCI) : 625 (M+H)+ (free) 5

Claims (10)

1. A compound of the formula : Y-R

2 R -C-N N-R R 3 0 wherein Y is bond or lower alkylene, R 1 is aryl which may have substituent(s), R 2 is aryl or indolyl, each of which may have 5 substituent(s), R 3 is hydrogen or lower alkyl, R 4 is pyridyl(lower)alkylamino(lower)alkynyl; N-(lower alkyl)-N-[pyridyl(lower)alkyl]amino (lower)alkyl; 20 hydroxy(lower)alkoxy(lower)alkyl; lower alkanoyl(lower)alkoxy(lower)alkyl; phenyl(lower)alkyl which has hydroxy(lower)alkyl or morpholinyl(lower)alkyl; ar(lower)alkoxycarbonyl; 25 (2-pyridyl)(lower)alkyl 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; (3-pyridyl)propyl which may have lower alkoxy or 30 amino; (3-pyridyl)butyl which may have lower alkoxy or amino; pyridyl(lower)alkenyl which may have lower alkoxy or amino; 35 (2-pyridyl)(lower)alkynyl which may have 1 to 3 WO 98/57954 PCT/JP98/02613 182 substituent(s) selected from the group consisting of lower alkyl, lower alkoxy, lower alkoxycarbonyl, mono(or di or tri)halo(lower)alkyl and halogen; (3-pyridyl)(lower)alkynyl which may have lower 5 alkoxy or amino; pyridyl, thiazolyl, imidazolyl or pyrazolyl, each of which may have substituent(s); imidazolyl(lower)alkyl which may have 1 or 2 substituent(s) selected from the group consisting 0LO of lower alkyl, lower alkynyl, ar(lower)alkyl, pyridyl(lower)alkyl, mono(or di or tri)halo(lower)alkyl and halogen; pyrazolyl(lower)alkyl which may have hydroxy(lower)alkyl, carboxy(lower)alkyl, lower L5 alkoxycarbonyl(lower)alkyl, morpholinyl(lower)alkyl or morpholinylcarbonyl(lower)alkyl; thiazolyl(lower)alkyl which may have lower alkyl; piperidyl(lower)alkyl which may have hydroxy(lower)alkyl or lower alkoxy; .0 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 .5 lower alkoxy(lower)alkyl; (3,5-dimethylmorpholino)(lower)alkyl; morpholino(lower)alkenyl which may have lower alkyl or lower alkoxy(lower)alkyl; (2- or 3-morpholinyl)(lower)alkenyl which may have 0 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 .5 of ethyl, propyl, isopropyl, isobutyl, WO98/57954 PCT/JP98/02613 183 spirocyclo(lower)alkyl, lower alkoxy(lower)alkyl, hydroxy(lower)alkyl, carboxy(lower)alkyl, di(lower alkyl)carbamoyl, lower alkoxycarbonyl and halo(lower)alkyl; 5 morpholinyl(lower)alkynyl which has methyl and lower alkoxy; (dimethylmorpholino)(lower)alkynyl; homomorpholinyl(lower)alkynyl which have halogen; (morpholinylamino)propyl which may have lower 0 alkanoyl; thiomorpholinyl(lower)alkynyl which may have substituent(s); homomorpholinylamino(lower)alkyl; thiomorpholinylamino(lower)alkyl; or 5 saturated heterocyclicimino(lower)alkyl, saturated heterocyclicaminocarbonyl(lower)alkyl or saturated heterocyclic(lower)alkoxy(lower)alkyl, each of which may have substituent(s), provided that when 0 R 4 is 2-[N-methyl-N-(3-pyridylmethyl)amino]ethyl,

3-(3-pyridyl)propyl, 3-(3-pyridyl)-2-propynyl,

4-[(2-methoxymethyl)pyrrolidino]-2-butynyl, 4-thiomorpholino-2-butynyl, 5 3-(morphlinoamino)propyl, 4 -morpholino-2-butenyl, 4 -morpholino-2-butynyl, or 4-(3,3-dimethylmorpholino)-2-butynyl, then R 1 is not 3,5-bis(trifluoromethyl)phenyl, 0 and a salt thereof. 2. The compound of claim 1, in which Y is lower alkylene, R 1 is C6-C 10 aryl which may have 1 or 2 substituent(s) 5 selected from the group consisting of mono(or di WO 98/57954 PCT/JP98/02613 184 or tri)halo(lower)alkyl, halogen, lower alkylamino, di(lower)alkylamino and nitro, R 2 is C 6 -C 10 aryl or indolyl, each of which may have 1 to 3 substituent(s) selected from the group 5 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 L0 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, lower alkoxycarbonyl, mono(or di or tri)halo(lower)alkyl and halogen; L5 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 0 substituent(s) selected from the group consisting of lower alkyl, 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 5 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-lIH-imidazol-4-yl)(lower)alkyl which has 1 0 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 5 hydroxy(lower)alkyl or lowe.r alkoxy; WO 98/57954 PCT/JP98/02613 185 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; 5 morpholinyl(lower)alkyl which has lower alkyl and lower alkoxy(lower)alkyl; (3,5-dimethylmorpholino)(lower)alkyl; morpholino(lower)alkenyl which may have lower alkyl or lower alkoxy(lower)alkyl; 0 (2- 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 5 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 0 halo(lower)alkyl; morpholinyl(lower)alkynyl which has methyl and lower alkoxy(lower)alkyl; (dimethylmorpholino)(lower)alkynyl; or homomorpholinyl(lower)alkynyl which may have 5 halogen. 3. The compound of claim 2, in which Y is lower alkylene, R 1 is phenyl which has 1 or 2 substituent(s) selected 0 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 have 1 or 2 substituent(s) selected from the group consisting 5 of lower alkyl, trihalo(lower)alkyl, lower WO 98/57954 PCT/JP98/02613 186 alkylenedioxy, hydroxy, hydroxy(lower)alkyl, lower alkoxy, lower alkylamino and di(lower)alkylamino, R 3 is hydrogen, and R 4 is (2-pyridyl)propyl which may have 1 to 3 5 substituent(s) selected from the group consisting of lower alkyl, lower alkoxy, mono(or di or tri)halo(lower)alkyl and halogen; morpholinyl(lower)alkyl which has 1 or 2 substituent(s) selected from the group consisting L0 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, L5 spirocyclo(lower)alkyl, lower alkoxy(lower)alkyl, hydroxy(lower)alkyl, carboxy(lower)alkyl, di(lower alkyl)carbamoyl, lower alkoxycarbonyl and halo(lower)alkyl. .0 4. A compound of claim 3, which is selected from the group consisting of (1) (2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-4-[4 ((3S)-3-ethylmorpholino)-2-butynyll]-2- [ (1H-indol-3 yl)methyl] piperazine, ?5 (2) ( 2 R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4 dimethylbenzyl)-4-[2-((2S)-2-methoxymethyl morpholino)ethyl]piperazine, (3) (2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4 dimethylbenzyl)-4-[2-((3R)-3-methoxymethyl 30 morpholino)ethyl] piperazine, (4) ( 2 R)-1-[3,5-Bis(trifluoromethyl)benzoyl[-2-(3,4 dimethylbenzyl)-4-[2-((2R)-2-methoxymethyl morpholino)ethyl] piperazine, (5) ( 2 R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-[(lH 15 indol-3-yl)methyl]-4-[2-((2S)-2-methoxymethyl- WO 98/57954 PCT/JP98/02613 187 morpholino)ethyl]piperazine, and (6) ( 2 R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-4-[2 ((3R)-3-ethylmorpholino)ethyl]-2- [ (lH-indol-3-yl) methyl] piperazine 5 or a pharmaceutically acceptable salt thereof.

5. A process for the preparation of the compound of claim 1 or a salt thereof, which comprises, 10 (1) reacting a compound of the formula (II) : Y-R 2 0 R--N -H (II) 15 \ / wherein R 1 , R 2 , R 3 and Y are each as defined in claim 1, or a salt thereof, with a compound of the formula 20 (III) : W1-R4 (IV) wherein R 4 is as defined in claim 1 and 25 W 1 is a leaving group, or a salt thereof to give a compound of the formula (I) : Y-R 2 30 0 RI-NN -R 4 (I) 35 wherein R3 , R 2, R 3, R 4 and Y are each as defined in 35 wherein R , R , R , R 4 and Y are each as defined in WO98/57954 PCT/JP98/02613 188 claim 1, or a salt thereof, (2) subjecting a compound of the formula (Ia) : y-R 2 0 Ri- -N N-Z 1 -R 5 (Ia) 10 wherein R 1 , R 2 , R 3 and Y are each as defined above, R 5 is 2-pyridyl which may have 1 to 3 substituent(s) selected from the group consisting of lower alkyl, lower alkoxy, 15 lower alkoxycarbonyl, mono(or di or tri)halo(lower)alkyl and halogen; or 3-pyridyl which may have lower alkoxy or amino, and Z 1 is lower alkynylene, 20 or a salt thereof to a reduction reaction to give a compound of the formula (Ib) : Y-R 2 0 25 RI- -N -X-R 5 (Ib) wherein R1, R 2 , R 3 , Y and R 5 are each as defined above, 30 and X 1 is lower alkylene, or a salt thereof, (3) reacting a compound of the formula (III) : 35 WO98/57954 PCT/JP98/02613 189 Y-R 2 Ri- -N-X2-_-OH (III) o 0 5 "13 wherein R 1 , R 2 , R 3 and Y are each as defined above, and 0 X 2 is lower alkylene, or its reactive derivative at the carboxy group or a salt thereof with a compound of the formula (V) : H 2 N-R 6 (V) 5 wherein R 6 is saturated heterocyclic which may have substituent(s), or a salt thereof to give a compound (Ic) : 0 0 Y-R 2 o 0 R1l- -N -X 2 - -N-R6 (Ic) 3/ H \3 5 wherein R 1 , R 2 , R 3 , R 6 , X 2 and Y are each as defined above, (4) reacting a compound of the formula (VI) : 0 Y-R 2 1- 0- -- (VI) R5 N -X3-W2 5 WO 98/57954 PCT/JP98/02613 190 wherein R1, R 2 , R 3 and Y are each as defined above, X 3 is lower alkylene and W2 is a leaving group, or a salt thereof with a compound of the formula 5 (VII) : H-R 7 (VII) wherein R 7 is pyridyl(lower)alkylamino; N-(lower alkyl)-N-[pyridyl(lower)alkyl] amino; L0 1-imidazolyl which may have 1 or 2 substituent(s) selected from the group consisting of lower alkyl, lower alkynyl, ar(lower)alkyl, pyridyl(lower)alkyl, mono(or di or tri)halo(lower)alkyl and 5 halogen; 1-pyrazolyl which may have hydroxy(lower)alkyl, carboxy(lower)alkyl, lower alkoxycarbonyl(lower)alkyl, morpholinyl(lower)alkyl or 0 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 5 consisting of ethyl, hydroxy(lower)alkyl, halo(lower)alkyl and lower alkoxy (lower)alkyl; morpholino which has lower alkyl and lower alkoxy(lower)alkyl; 0 3, 5-dimethylmorpholino; morpholinylamino which may have lower alkanoyl; homomorpholinylamino; or thiomorpholinylamino, 5 or a salt thereof to give a compound of the formula WO 98/57954 PCT/JP98/02613 191 (Id) Y-R 2 0 R1- -N N-X3-R 7 (Id) 5 '3 wherein R 1 , R 2 , R 3 , R 7 , X 3 and Y are each as defined above, 10 or a salt thereof, (5) reacting a compound of the formula (VIII) : Y-R 2 15 0 Rl- -N -Z2W3 (VIII) 20 wherein R1, R 2 , R 3 and Y are each as defined above, Z 2 is lower alkenylene, and W 3 is a leaving group, or a salt thereof with a compound of the formula (IX) 25 H-R 8 (IX) wherein R 8 is morpholino which may have lower alkyl or lower alkoxy(lower)alkyl, or a salt thereof to give a compound of the formula 30 (le) : Y-R 2 0 R1- -N N%-Z2-R8 (le) 353 WO98/57954 PCT/JP98/02613 192 wherein R1, R 2 , R 3 , R 8 , Y and Z2 are as defined as above, or a salt thereof, 5 (6) reacting compound of the formula (X) : y-R 2 0 LO RI- -N '--Z3-W4 (X) wherein R 1, R 2 , R 3 and Y are each as defined above, L.5 Z 3 is a lower alkynylene and W 4 is a leaving group, or a salt thereof with a compound of the formula (XI) H-R 9 (XI) ?0 wherein R 9 is pyrrolidino which may have lower alkoxy(lower)alkyl; morpholino which may have 1 or 2 substituent(s) selected from the group ?5 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 30 halo(lower)alkyl; morpholino which has methyl and lower alkoxy; dimethylmorpholino; or homomorpholino which has halogen, 5 or a salt thereof to give a compound of the formula WO 98/57954 PCT/JP98/02613 193 (If) Y-R 2 0 5 R- -N -Z 3 -R 9 (If) wherein R1, R 2 , R 3 , R 9 , Y and Z 3 are each as defined 10 above, or a salt thereof.

6. A pharmaceutical composition which comprises, as an active ingredient, a compound of claim 1 or a 15 pharmaceutically acceptable salt thereof in admixture with pharmaceutically acceptable carriers.

7. A compound of claim 1 for use as a medicament. 20

8. A method for treating or preventing Tachykinin-mediated diseases which comprises administering an effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof to human being or animals. 25

9. A compound of claim 1 for use as Tachykinin antagonist.

10 . Use of a compound of claim 1 for manufacture of a medicament for treating or preventing Tachykinin mediated diseases. 30 35