JPH03232864A - Trisubstituted piperazine compound - Google Patents

Abstract

NEW MATERIAL:A compound shown by formula I [A is phenyl, condensed polycyclic hydrocarbon, heterocyclic, etc.; X is methylene, carbonyl or thiocarbonyl; G is (CH2)n-Z-R<6> (n) is 0-2; (z) is valence, O, S, SO, CO, etc.; R<6> is H, lower alkyl, etc.) ; R<1> to R<3> are lower alkyl] or a salt thereof. EXAMPLE:Methyl 1-(2,3-dimethoxy-6,7-dihydro-5H-benzocyclohepten-8- ylcarbonyl)-4-(3,4,5-trimethoxybenzoyl)piperazine-2-carboxylate. USE:An antagonist against blood platelet activating factor having excellent intestine absorption and being orally administrable besides injection administration. PREPARATION:A compound shown by the formula A-COOH and a compound shown by formula II are subjected to ordinary amide bond formation reaction in the presence of a base (e.g. triethylamine) in a solvent such as dioxane at -20 to 50 deg.C to give a compound shown by formula I.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of the Invention The present invention relates to trisubstituted piperazine compounds useful as pharmaceuticals. More specifically, the present invention provides platelet activating factor (P
AF) A formula useful as an antagonist [wherein A is an optionally substituted phenyl group, an optionally substituted fused polycyclic hydrocarbon group, an optionally substituted heterocyclic group, or a formula Ar- CR'=CR5- (in the formula, Ar represents an optionally substituted phenyl group, R4 and R5 each represent hydrogen or a lower alkyl group), and X represents a methylene group, a carbonyl group, group or thiocarbonyl group, G is the formula +CH2+nZ-R6(
In the formula, n represents an integer from O to 2, Z represents a bond, o, s,
so, so, co, coo.

OC○, 0CONR7, C0NR' or N R'(R
7 represents hydrogen, a lower alkyl group, a lower haloalkyl group, a lower alkenyl group or a lower alkoxycarbonyl group. ), and R6 is hydrogen or a lower alkyl group.

Represents a lower haloalkyl group, lower alkenyl group, lower alkynyl group or lower cycloalkyl group. However, n=
When it is an o, Z-bond, R6 is not hydrogen or a lower alkyl group. ), and R+, Rt and R3 each represent a lower alkyl group. ] or a salt thereof.

(Prior art and problems to be solved by the invention) PA
F has a phospholipid structure and is a chemical mediator that exists in living organisms. PAF has been shown to be closely involved in allergies, anaphylaxis-1 inflammation, and the like in vivo, and is also known to have strong blood pressure lowering effects and platelet aggregation effects. When PAF is administered to animals, the animals exhibit symptoms of shock and may even die. Shock symptoms caused by PAF are very similar to those caused by endotoxin, and it is thought that PAF is involved in endotoxin shock.

On the other hand, although various compounds having PAF antagonism are known, there are very few compounds that are satisfactory in terms of PAF antagonism in vivo.

Furthermore, even if the PAF antagonism in vivo is satisfactory,
Many compounds have restrictions on how they can be administered.

(Means for Solving the Problems) The present invention provides a compound represented by the above formula (1) and a salt thereof.

Regarding formula (I), the fused polycyclic hydrocarbon group represented by A includes bicyclic or tricyclic hydrocarbon groups that may be partially saturated, and specifically, pentalenyl,
Indenyl (IH-indenyl.

2H-indenyl), intanyl, naphthyl, dihydronaphthyl (1,2-dihydronaphthyl, 2,3-dihydronaphthyl), tetrahydronaphthyl (1,2°3.4
-tetrahydronaphthyl, etc.), hexahydronaphthyl (C2,3,4,5,6-hexahydronaphthyl, etc.)
, '/'dulenyl, heptarenyl, biphenylenylintercenyl (as-intercenyl, S-intercenyl),
Acenaphthylenyl, acenaphthynyl, phenalenyl, phenacytril, dihydrophenanthryl (1,2-dihydrophenanthryl), tetrahydrophenanthryl (
1,2,3,4-tetrahydrophenanthryl, etc.),
Hexahydrophenanthryl.

Anthryl Dihydro anthryl (9,10-dihydro anthryl), tetrahydro anthryl hexahydro anthryl, octahydro anthryl, fluorenyl (3H-fluorenyl, 9H-fluorenyl), dihydrofluorenyl, tetrahydrofur Olenylbenzocyclohebutenyl (5I4-benzocyclohebutenyl, etc.), dihydrobenzocyclohebutenyl (6,7-cyhydro5H-benzocyclohebutenyl, etc.), tetrahydrobenzocyclohebutenyl (6,7,8,9-tetrahydro 5■1-benzocyclohebutenyl, etc.), dibenzocyclohebutenyl (58-dibenzo[a, b]cyclohebutenyl, 5H-dibenzo[a, C]cyclohephthynyl), naphthocyclohebutenyl (6H-naphtho[ b] cyclohebutenyl), dihydronaphthocyclohebutenyl (7,8-dihydro-6H-naphtho[b]
cyclohebutenyl, etc.), benzocyclooctenyl, dihydrobenzocyclooctenyl (5,6-dihydrobenzocyclooctenyl, etc.), tetrahydrobenzocyclooctenyl (5,6,7,8-tetrahydrobenzocyclooctenyl, etc.) , hexahydrobenzocyclooctenyl, octahydrobenzocyclooctenyl, etc.
Examples include hydrocarbon groups formed by condensing two or three eight-membered rings.

Regarding formula (1), the heterocyclic group represented by A includes monocyclic, bicyclic, and tricyclic heterocyclic groups that may be partially saturated. Examples of the monocyclic heterocyclic group include pyridyl (2-pyridyl, 3-pyridyl, 4-pyridyl), thienyl (2-thienyl, 3-thienyl), furyl, thiazolyl (2-thiazolyl, 2-phenyl-4-
Thiazolyl.

2-(3-pyridyl)-4-thiazolyl, etc.),
1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur
Examples include 5- to 8-membered heterocyclic groups containing 5- to 8-membered heterocyclic groups.

As the optionally partially saturated bicyclic heterocyclic group,
Quinolyl (2-quinolyl, 3-quinolyl.

4-quinolyl, 5-quinolyl, 6-quinolyl, 7-quinolyl), isoquinolyl (3-isoquinolyl, etc.).

Indolyl (5-indolyl, etc.), benzothiazolyl (2-benzothiazolyl, etc.), 1,3-benzodioxolyl (1,3-benzodioxol-5yl, etc.),
Benzofuranyl (2-benzofuranyl etc.), 2.3-
Dihydrobenzofuranyl, benzopyranyl (2-henzopyranyl, 3-benzopyranyl, etc.), 3,4-dihydrobenzopyranyl, 1-benzoxepinyl (1-benzoxepin-4-yl, 1-benzoxepin-8-
yl, etc.), 2,3-dihydro-1-penzoxevinyl (2,3-dihydro-1-benzoxepin-4-yl).

2.3,4.5-Tetrahydro-1-penzoxevinyl, 1-benzothievinyl, 2,3-dihydro-1-benzothievinyl (2,3-dihydro-1-henzochepine-
4-yl, etc.), 2,3,4.5tetrahydro-1-benzothivinyl, 3.4-dihydro-2H-1,5-penzodioxevinyl, 2゜3-dihydro-1,4-benzo Dioxynyl [1°4-benzodioxanyl] (2,
3-dihydro-1゜4-benzodioxin-6-yl, etc.), chromenyl (2H-10men-3-yl, etc.),
chromanyl (such as 3-chromanil), imidazo[1,2-
a] Condensed bicyclic heterocyclic groups formed by condensing a benzene ring with a 5- to 8-membered heterocycle containing 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur, such as pyridyl, etc. It will be done.

Further, as the tricyclic heterocyclic group which may be partially saturated, dibenzofuranyl (2-dibenzofuranyl, etc.),
3.4-dihydrobenzopyranyl (such as 3,4-dihydrodibenzofuran-2-yl).

1.2,3.4-tetrahydrodibenzofuranyl, dibenzothiophenyl (2-dibenzothiophenyl, etc.),
3,4-dihydrodibenzothiophenyl (3゜4-
dihydrobenzothiophen-2-yl, etc.) 1.2,3
．． 4-tetrahydrodibenzothiophenyl (1,2,3
, 4-tetrahyF lopenzothiophen 2-yl),
naphtho[2,3-dl-R3-dioxolyl, 5,6-
cihydronaphtho[2,3-dl1,3-dioxolyl(
5,6-Sihydronaphtho [2°3-dl-1,3-dioxol-7-yl].

5.6,7.8-tetrahydronaphtho[2,3-dl1
．． 3-dioxoryl, naphtho[2,3-b]-1,4dioxanyl, 6,7-cyclohydronaphtho[2,3b]-1
,4-dioxanyl(6,7-cihydronaphtho[2,3
-b]-1,4-dioxan-8-yl, etc.), 5H-
cyclohebuta[f]-R3-benzodioxolyl, 6.
6 H-cyclohebuta [g] ■, 4-benzodioxanyl, 7,8-dihydro 6H-cyclohebuta [g
] -1,4-benzodioxanyl (7,8-dihydro-68-cyclohebuta[g]1,4-benzodioxan-9-yl), dibenzo-p-dioxinyl, xanthenyl, 1.2 dihydroxanthenyl, naphtho[2,
(i) such as (i)
1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur
(ii) a benzene ring and (iii) a Hensen ring or a 5- to 8-membered heterocycle containing 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur are fused together. Examples include a fused tricyclic heterocyclic group formed by forming.

Regarding formula (I), the formula Ar-CR'CR5- represented by A
Examples of the lower alkyl group represented by R4 or R5 in the styryl group include methylethylpropylisopropylbutylisobutyl, S+IC-butyl, Lc
Examples include alkyl groups having about 1 to 4 carbon atoms such as rt butyl.

A phenyl group represented by A above, a fused polycyclic hydrocarbon group,
The phenyl group moiety of a heterocyclic group or styryl group includes, for example, a lower alkyl group, a halo-lower alkyl group, a hydroquino-lower alkyl group, an acyloxy-lower alkyl group, a lower alkoxy/lower alkyl group, a lower alkoke group, a halo-lower alkoxy group. Alcoquine carbonyl lower alkoxy group, lower alkenyloxy group, aralkyloquine group,
Lower alkokine lower alkokene group, lower alkokene sulfonyl group, carboxyne group, carhamoyl group NN-lower alkylcarbamoyl group, N-lower alkylcarbamoyl group, halo group Noah7 group, 21-ro group hydroquine group, a/ Luoquine group, amine 7 group, lower alkylsulfonylamino group, anruamino M, lower alkoxy 7 carponylamino 7
The group may have one or more substituents (preferably 4 or less) such as a mercapto group, a lower alkylthio group, a lower alkylsulfinyl group, a lower alkylsulfonyl group, and an oxo group, The types of substituents when having two or more substituents L() may be the same or different.

Examples of lower alkyl groups as substituents include those having 1 to 4 carbon atoms such as methylethylpropylisopropylbutyl, isobutyl 5ec-butyl tert-butyl, etc.
Some alkyl groups can be mentioned.

For example, as a halo lower alkyl group! Examples include alkyl groups having about 1 to 4 carbon atoms and substituted with 1 to 3 groups such as lifluoromethyl, fluoromethyl, ritetramethylcycloethyl, and fluoroethyl. Examples of the hydroquine lower alkyl group include hydroquine alkyl groups having 1 to 4 carbon atoms such as hydroquinemethyl, hydroquinemethyl, hydroquinepropyl, and hydroquinemethyl. Examples of the acyloxy lower alkyl group include lower alkyl groups having 2 to 5 carbon atoms such as acetoquinethylhensoyloxyethyl, substituted with a 2-ruoquine group or a hensoyloxy group;
Examples include alkyl groups having about 1 to 4 carbon atoms. Examples of lower alkoxy lower alkyl groups include those substituted with an alkoxy group having about 1 to 4 carbon atoms, such as methoxyethyl, methoxy/ethyl, propoxyethylbutyneethylmethoxy/furopylmethoxybutylethoxy/propyl, and cyclophthyl. , an alkyl group having about 1 to 1 carbon number. An example of a lower alkokyne group is Metkine!・Alcoquine groups having about 1 to 4 carbon atoms such as quinine, propoxy, isopropoquine, butquine isobutoxy 5ec-phthoxy tert-butoxy. Examples of halo-lower alkoxy groups include chloroethquinefluoroe!・Xinfluoroethoxy, trifluoroethoxy)・
Kink 00 propoxy.

substituted with 1 to 3 halo groups such as chlorobutoxy,
Examples include alkoxy groups having about 1 to 4 carbon atoms. Lower alkoxycarbonyl A lower alkoxy group, where C is the number of carbon atoms in the alkoxy group, for example, methquinecarbonylmethoxye)-ki/carbonylmethoxye/f)-quinecarbonylmethoxycarbonylbropoxyethoxyethoxysulfonylethoxy. An example thereof is an alcogine group having about 1 to 4 carbon atoms and substituted with about 4 to about 4 alkoxy/hydroxysulfonyl groups. Examples of the lower alkenylokine group include alkenylokine groups having about 2 to 5 carbon atoms, such as vinyloxy and allyloxybutenylokyne. Examples of aralkyloxy groups include:
The lower alkyl moiety of hennluoquine, phenethyloxy, 3-phenylpropyluoquine, α-methylphenethyloxyα-methylhene/luoquine, α-ethylhenruoquine, β-ethylpheuntyluoquine, and β-methylphenyluoquine has 1 to 1 carbon atoms. Examples include tubonyl lower alkylthio groups of about 4. Examples of the lower alkokene group include those having 1 carbon atom, such as ethquin, methquin, methoxyethoxybutkin, ethquin, edkin, propoquin, etc.
- Substituted with about 71 alkoxy groups, having 1 to 4 carbon atoms
Alcoquine groups can be mentioned. Examples of the lower alkoxycarbonyl group include an alkoxy moiety such as metquinylsulfonyl, ethoxysulfonyl, propoxycarbonyl, and butoxycarbonyl, or an alkoxycarbonyl group having about 1 to 4 carbon atoms. Examples of the NN- lower alkylcarbamoyl group include 8. N, N-dimethylcarbamoyl, N, N-diethylcarbamoyl, N
Each alkyl moiety such as N-7propylcarhamoyl, N,N-7butylcarhamoylN-ethylN-methylcarbamoyl, or an N,N-dialkylcarbamoyl group and dialkyl moiety having about 1 to 4 carbon atoms. Examples include groups that form a 5- or 6-membered ring structure (eg, N-pyrrolidinylcarbonyl, piperidinocarbonyl). Examples of the N-lower alkylcarbamoyl group include N-methylcarbamoyl, N-ethylcarbamoyl, N-prohy;
Examples include an alkyl moiety or an N-alkylcarbamoyl group having about 1 to 4 carbon atoms, such as carbamoyl and N-phthylcarbamoyl. Examples of the halo group include halocare groups such as chloro, fluorobromo, and iodo.

Examples of acyloxy groups include acetoxy.

Examples include alkanoyloxy groups having about 2 to 5 carbon atoms, such as propanoyloxybutyryloxy pivaloyloxy, and hendiyloxy groups.

Examples of the lower alkylsulfonylamine group include alkylsulfonylamino groups having about 1 to 4 carbon atoms such as methanesulfonylamino and ethanesulfonylaminoto. Examples of the acylamide group include alkanoylamino groups having about 2 to 5 carbon atoms, such as acetamido, propanoylamino, butyrylamino, and pivaloylamino, and benzamide groups. Examples of the lower alkoxycarbonylamino group include alkoxycarbonylamino groups in which the alkoxy moiety has about 1 to 4 carbon atoms, such as methoxycarbonylamino, ethoxycarbonylamino, fluoroxysulfonylamino, butoxycarbonylamino. Examples of acyl groups include acetyl, propanoylbutyryl, pivaloyl, etc. having 2 carbon atoms.
Examples include about 5 to 5 alkanoyl groups and benzoyl groups. Examples of lower alkylthio groups include methylthio.

1 carbon number such as ethylthio, propylthio, butylthio
- About 4 alkylthio groups are mentioned. Examples of the lower alkylsulfinyl group include alkylsulfinyl groups having about 1 to 4 carbon atoms, such as methylsulfinyl, ethylsulfinyl, and propylsulfinyl butylsulfinyl. Examples of lower alkylsulfonyl groups include those having 1 to 4 carbon atoms, such as methylsulfonylethylsulfonylpropylsulfonyl and butylsulfonyl.
Examples include alkylsulfonyl groups.

Specific examples of the optionally substituted phenyl group shown in A above include 3,4-dimethoxyphenyl 3
4 5-trimethoxyphenyl, 3゜4,'5-triethoxyphenyl, 3-methoxy-5nitro-4-n-propoxyphenyl; 3.4dimethoxy-5-methylsulfonylphenyl 3chloro-4,5-dimethoxy Examples include phenyl.

” - Specific examples of the optionally substituted fused polycyclic hydrocarbon group represented by A include 1-naphthyl, 2-
Naphthyl, ■-methoxy-2-naphthyl, 3-methoxy-2-naphthyl, 6-methoxy-2-naphthyl, 6.7-
Diftquin-2-naphthyl, 5,6.7-drimethoxy-2-naphthyl, 6-butoxy-2-naphthyl, 6,7-
Diptoxy-2-naphthyl, 7-methoxy-1,2-dihydro-3-naphthyl, 6,7-simethoxyl, 2-dihydro-3-naphthyl, 7,8-dimethoxy-1,2-dihydro-4-naphthyl, 6,7. 8-trimethoxy-1,
2-dihydro-3-naphthyl, 6,7-jethoxy-1
, 2-dihydro-3-naphthyl, 6゜7-dipropoxy-12-dihydro-3-naphthyl, 6,7-diptoxy-1,2-dihydro-3-naphthyl, 7-benzyloxy-1,2-dihydro-3- Naphthyl, 7-hydroxyl+2-dihydro-3-naphthyl, 6,7-cybenzyloxy1,2-dihydro-3-naphthyl, 6,7-cyhydroxyl, 1,2-dihydro-3-naphthyl, 6-medoxyl .2,3.4-tetrahydro-2-naphthyl,
7-acetoxy-1,2-dihydro-3-naphthyl, 6
．． 7-diacedoxy1,2-dihydro-3-naphthyl,
7-penzoyloxy-L2dihydro-3-naphthyl,
6.7-dipenzoyloxy-1,2-dihydro-3-
naphthyl, 7-medoxy 8-nitro-1,2-dihydro-3-naphthyl 7-medoxy 6-nitro 1,2
-dihydro-3-naphthyl, 6,7-simethoxy8-
Nitro-1,2-dihydro-3-naphthyl, 7-nitoquinecarbonylmethoxy1,2-dihydro-3naphthyl 7-(2-methoxyethoxy)-1,2dihydro-3-
naphthyl, 6,8-dimethyl-12-/hydro-3-naphthyl, 6-hydroxymethyl-7-me]quin-1,
2-hydro-3-naphthyl 68-dimethyl-7-nitro-1,2-dihydro-3-naphthyl, 7-(2-hydroxyethoxy/)-1,2-hydro-3-naphthyl, 7
-(2,3-dimethoxypropoxy)-1,2-dihydro-3-naphthyl, 7-(3-methoxypropoxy)■,
2-dihydro-3-naphthyl 76.7-bis(2methoxyethoxy)-1,2-dihydro-3-naphthyl, 5,
6-Simethoxy-2-indanyl, 5゜6-Simethoxy-11(-2-indenyl, 3,4dimethoxy-6,7
-Sihydro 5H-8-benzocyclohebutenyl 23-
dimethoxy-6,7-dihydro 58-8-benzone clohebutenyl 2,3-jethoxy-6,7-dihydro-5
8-8henzocyclohebutenyl, 2,3-dipropoxy6,7-onehydro58-8-benzonechlorohebutenyl, 2,3-butoxy6,7-dihydro5H-8-
Benzone clohebutenyl, 2-benzyloxy-3-methoxy-6,7-dihydro5 H-8-benzocyclohebutenyl, 2-ethoxy-3-methoxy-6,7-dihydro-58-8henzocyclohebutenyl, 2- Propoquine-3methoxy-6,7-dihydro-58-8-benzocyclohebutenyl 2-butoxy-3-methoxy-6,7
-Sihydro5H-8-benzocyclohebutenyl, 3-
Methoxy-6,7-sihydro 5H-8-benzone clohebutenyl, 3-ethoxylo, 7-sihydro 58-8
-benzocyclohebutenyl, 3-propoxy-6,7-
Cyhydro 5H-8-hencyclohebutenyl, 3-butoxy6.7-benzocyclohebutenyl, 58-8-benzocyclohebutenyl, 2,3-dimethyl-6,7-dihydro 5H-8
-Hensin Chlohebutenyl, 3-hensyloxy-6,
7-cychtrow 5H-8-hensynchlohebutenyl, 6
．． 7-Sihydro 5H-8 Henson Chlohebutenyl, 1
,2.3-trimethoxy-6,7-sihydro5H-
8-hensynchlorohebutenyl, 7-nitoxy12-dihydro-3-naphthyl, 7-phropoquine-1,2-hydro-3-naphthyl, 7-putquine-1,2-dihydro-3-
naphthyl, 2,3-shiftquin-5,6,fu,8tetrahydro-9-benzone clooctenyl 5.6,7.8-
Tetrahydro-9-benzone clooctenyl, 2.3-
Dihydro-3-naphthyl, 1-intanyl, 2-intanyl, LH-2-indenyl 2,3-diphthoquine-6, 8,9-tetrahydro-51(-6-benzone clohebutenyl, 6-fudimethoxyl-hydroxy-2 -Naphthyl 6-mercabuto 2-naphthyl, 6-methylthi-2-naphthyl, 6-methanesulfonyl-2-naphthyl
1-oxo-1,2,3,4-tetrahydro-6-naphthyl, 1-oxo-1,2,3,4-tetrahydro-7-
naphthyl, 1-oxo-5-indanyl, 1-oxo-
6-intanyl, 1-hydroquine-1,2,3,4-tetrahydro-6-naphthyl, 1-hydroxy-1,2,
3,4-tetrahydro-7-naphthyl, ■-hydroxy-5-indanyl, 1-hydroxy-6-indanyl, 9
Examples include groups such as -oxo-2-fluorenyl, 9-hydroxy-2-fluorenyl, and 2-anthrachymer.

Examples of the optionally substituted monocyclic, bicyclic, or tricyclic heterocycle represented by A above include 3-coumarinyl, 6-medoxy-3-coumarinyl, 7-medoxy-3
-Coumarinyl, 6-methyl-3-coumarinyl, 7-n-butquin-3-coumarinyl, 6-medquin-2-pentufuranyl, 7-el-1-xy-2-benzofuranyl, l-hydroboxy1゜2.3.4- Tetrahydrodibenzothiophen-2yl, 3-oxospiro[benzofuran-2(
3H), 1'-cyclopropane]-5-yl, 3-human o-j-cisspiro[benciflaf-2 (3H), 1'-
cyclopropane]-5-yl, 7.8-dimethoxy2.
3-dihydro-1-benzoxepin-4yl, 7-medoxy2.3-dihydro-1-benzoxepin-4
-yl, 8-propocy 2,3 dihydro 1-benzoxepin~4-yl.

7-Medoxy8-methyl-2,3-dihydro1-benzoxepin-4-yl, 7,8-dimeth+cy2,3
, 4.5-tetrahydro-1-benzoxepine-4-
yl, 7-chloro-8-methoxy-2,3-dihydro-
1-benzoxepin-4-yl, 7,8-dimethyl-
23-dihydro l-benzoxepin-4-yl, 7,
8-dimethoxy-2,3-dihydro-1-benzothiepin-4-yl, 8-methoxy-2,3-dihydro-1benzothiepin-4-yl, 1-oxo-2,3 dihydro-
1-benzothiepin-4-yl, 1.1dioxo-2,
3-dihydro-1-benzothiepin-4-yl, 7,8
-dimethoxy-1-oxo2,3-dihydro-1-benzothiepin-4yl, 7,8-dimethoxy-1,1-dioxo-23-dihydro-1-benzothiepin-4-yl 2-(3-pyridyl)- Examples include 4-thiazolyl, 2-(3°4-dimethoxyphenyl)-4-thiazolyl, and the like.

The optionally substituted styryl group represented by A above (A
Specific examples of r -CR'-CR5- (in which each symbol has the same meaning as above) include p~methoxystyryl, p-methoxy-α-methylstyryl, 3,4-dimethoxy-α
-methylstyryl, p-methoxy-αethylstyryl,
314-dimethoxy-α-ethylstyryl, p-propoxy-α-methylstyryl.

Examples include 3,4-dimethoxy-β-methylstyryl.

The optionally substituted phenyl group represented by A or Ar is preferably a phenyl group substituted with 1 to 3 lower alkoxy groups (more preferably methoxy or ethoxy).

The optionally substituted heterocyclic group represented by A above includes optionally substituted oxygen-containing fused bicyclic or tricyclic heterocyclic groups (benzo-1,3 dioxolyl, coumarinyl, 2,3 -dihydro 1 penzoxevinyl, dibenzofuranyl, 5.6 dihydronaphtho[,2,3-d]
-1,3-dioxolyl, 6,7-cyhydrocyclohebuta[f]-1,3benzodioxolyl, etc.), and furthermore, compounds of the formula [wherein R'', R7', R8' and R
9' is a water lower alkyl group, a halo lower alkyl group, a hydroxy lower alkyl group, an acyloxy/lower alkyl group, a lower alkoxy lower alkyl group, a lower alkoxy group, a halo lower alkoxy group, a lower alkoxycarbonyl lower alkoxy group, a lower alkenyloxy group, respectively. group, aralkyloxy group, lower alkoxy lower alkoxy group, lower alkoxycarbonyl group, carboxy group, carbamoyl group, N,N-di-lower alkylcarbamoyl group, N-lower alkylcarbamoyl group.

Halo group, cyano group, nitro group, hydroxy group, acyloxy group, amine group, lower alkylsulfonylamino group,
Acylamino group, lower alkoxycarbonylamino group,
A heterocyclic group represented by an acyl group, a mercapto group, a lower alkylthio group, a lower alkylsulfinyl group, or a lower alkylsulfonyl group (more preferably hydrogen, a lower alkoxy group, or a lower alkyl group) is preferred, and among them, a heterocyclic group represented by the above formula , R8' and R9' represent hydrogen, and R? A heterocyclic group in which ' and R8' each represent a lower alkoxy group (more preferably methoxy or ethoxy) is preferred.

The optionally substituted fused polycyclic hydrocarbon group represented by A above is represented by the formula 1 (' In the formula 1, the broken line indicates the presence of a double bond (more preferably the presence of a double bond). ), n' represents an integer of 1 to 4 (more preferably 2 or 3), R2',
R"', R" and R5' are each hydrogen, lower alkyl group, halo lower alkyl group, hydroxy lower alkyl group, anluoquin lower alkyl group, lower alkoxy/lower alkyl group, lower alkoxy/ group, halo lower alkoxy/
group, lower alkoxycarbonyl lower alkoxy group, lower alkenyloxy group, aralkyloquine group, lower alkoxy lower alkoxy group lower alkoxy group, carboxy group, carbamoyl group, N,N--lower alkylcarbamoyl group, N-lower Alkylcarhamoyl group, halo group, anano group, 21, group H, loxy group, a/luoquine group, 7 groups, lower alkylsulfonylamino group, acylamino J: (, lower alkoxycarbonylamino group acyl group , mercapto group, lower alkylthio group, lower alkylsulfinyl group or lower alkylsulfonyl group (
More preferably hydrogen, lower alkyl group, aralkyl group, lower alkyl group, lower alkyl group, and hydrogen group.
A fused polycyclic hydrocarbon group represented by 1 is preferred, in which R2' and I5' in the above formula are hydrogen, and more preferably a fused polycyclic hydrocarbon group represented by In the formula, a broken line indicates that a double bond may be present (more preferably a double bond is present), Rbi indicates a lower alkokyne group (more preferably methquine or ethoxy), and n' is 1 to A fused polycyclic hydrocarbon group represented by the integer of 4 (more preferably 2 or 3) is preferred.

The lower alkyl group represented by R', R', or R3 has 1 carbon number, such as a methyl group, ethyl group, or propyl group.
~4 alkyl groups, RlR2 and R3 may be the same or different, or R'
It is preferred that both R' and R3 are methyl groups.

X is preferably a methylene group or a carbonyl group.

In the above formula (1), the substituent G is bonded to either the 2-position or the 3-position of the piperazine ring. In the group of the formula +CH7-)-nZ-R6 represented by G, R6
Examples of the lower alkyl group represented by
Examples include alkyl groups having about 1 to 4 carbon atoms such as -butyl and tert-butyl.

The lower haloalkyl group represented by Ro is, for example, an alkyl group having about 1 to 4 carbon atoms such as trifluoromethyl, 2.2.2-1-lifluoroethyl, and fluoromethyl, or a halocarbon group having about 1 to 3 carbon atoms. atoms (e.g., I-, Cρ,
Examples include haloalkyl groups substituted with T3 r.

Examples of the lower alkenyl group represented by <6 include alkenyl groups having about 2 to 4 carbon atoms such as 2-propenyl, 2-butenyl, and 2-methyl-2-propenyl.

Examples of the lower alkynyl group represented by R6 include alkynyl groups having about 2 to 4 carbon atoms, such as toehaethynyl, 2-propynyl, and 2-butynyl.

Examples of the lower cycloalkyl group represented by R6 include cyclopropyl, cyclobutyl, lyropentyl, and
3 or more carbon atoms such as chlorhexyl cyclofurobylmethyl
Examples include about 6 cycloalkyl groups.

In the above formula (I), in the group of the formula +CH2+nZR6 represented by G, when Z or CON R7 or NR', the lower alkyl group, lower haloalkyl group and lower alkenyl group represented by R7 are the groups represented by R6 above. Examples of the lower alkyl group, lower haloalkyl group, and lower alkenyl group represented by R7 include methoxysulfonyl, cyclocarbonyl, propoxycarbonyl,
Alkoxy moiety such as butoxycarbonyl or carbon number 1 to 4
Examples include alkoxycarbonyl groups.

R6 and R7 may be the same or different, and may form a 6-membered ring (eg, pyrrolidine, piperidine, etc.).

In the above formula (1), the formula represented by G +C1(, +nZR6
Among the groups, Z is o, coo or CON R7(R
7 represents hydrogen or lower alkyl (more preferably methyl or ethyl), and a group in which R6 represents hydrogen or lower alkyl (more preferably methyl or ethyl) is preferred.

Among the compounds represented by the above formula (1) [compound (I)], compounds represented by the formula [wherein X represents a methylene group or a carbonyl group, and A
is a phenyl group substituted with 2 to 3 lower alkoxy groups (more preferably methoxy or ethoxy) [wherein R10' represents a lower alkoxy group (more preferably methoxy or ethoxy)]. cyclic group or formula (wherein n' represents an integer of 2 or 3, Rbi is a lower alkoxy group (more preferably methoxy or ethoxy)
Ho G is a fused polycyclic hydrocarbon group represented by the formula +CH2+nZ-R6 (in the formula, n represents an integer of O to 2, and 2 is o, coo or CON R' (R7 is hydrogen or lower represents an alkyl group (more preferably methyl or ethyl), and R6 is hydrogen or lower alkyl (
(More preferably methyl or ethyl) or a pharmacologically acceptable acid addition salt thereof.

Compound (1) is an inorganic acid such as hydrogen chloride, hydrogen bromide, sulfuric acid, nitric acid, or phosphoric acid, such as acetic acid or tartaric acid.

Salts may be formed with organic acids such as citric acid, fumaric acid, maleic acid, toluenesulfonic acid, and methanesulfonic acid. A quaternary salt may also be formed with methyl iodide, ethyl iodide, propyl iodide, etc. The salt of compound (1) is preferably a pharmacologically acceptable salt, and more preferably a pharmacologically acceptable acid salt. Moreover, compound (I) may be a hydrate.

The compound (I) of the present invention has, for example, a compound represented by the formula: It can be produced by subjecting it to a dehydration condensation reaction.

The dehydration condensation reaction can be carried out, for example, by a conventional amide bond forming reaction. That is, by using an amide-forming reagent such as dicyclohexylcarbodiimide, N,N'carbonyldiimidazole, diphenylphosphate, and diethyl cyanophosphate alone, or by using compound (II), t=2,4.5-) Phenols such as cyclophenol, pentachlorophenol, pentafluorophenol, 2-nitrophenol or 4-nitrophenol or N-hydroxysuccinimide, 1-hydroxybenztriazole, N-hydroxypiperidine, N-hydroxy-5-norbornene-2, 3
N-) such as cyclohexylcarpoxiimide: l'roxy compound'i-condensation in the presence of a catalyst such as cyclohexylcarpoxiimide to convert it into an active ester, and then reacting with compound (III), or Alternatively, the reaction can be carried out by reacting the compound (n) with an acid chloride such as ethyl chlorocarbonate, isobutyl chlorocarbonate, or hennyl chlorocarbonate to convert it into a mixed acid anhydride, and then reacting it with the compound (ITJ). In the present amide bonding reaction, compound (IT) is reacted with compound (I) either as it is or after being converted into an active ester or mixed acid anhydride of compound (■). It can be accelerated by the addition of amines (eg triethylamine N-methylpiperidine). The reaction temperature is usually -200 to +50'C, preferably -10 to
The temperature is approximately +25°C, and commonly used solvents include oxanetetrahydrofuranacetonitrile, pyridineNN-7methylpormamide, N,N-7methylacetamide, dimethylforhoquine, N-methylpyrrolidone, chloroporm, and methylene chloride. It may be used alone or as a mixed solvent.

Further, the compound (T) of the present invention has the formula % () [wherein A has the same meaning as above and W represents a halogen atom]
It can also be produced by reacting the compound represented by with compound (III). This reaction is usually carried out in the presence of water or other organic solvents (e.g., acetonitrile, methylformamiton, methylacetamiton, methyl sulfoxide, tetrahydrofuranthene, toluene, ethyl acetate, chloroform, methylene chloride) alone or in combination. The process can be carried out by maintaining the temperature in the range of -20°C to +150°C in the absence of such a substance. At this time, for the purpose of accelerating the reaction rate, a base such as nonolium carbonate, sthorium hydroxide, sthorium hydrogen carbonate, pyrine, or triethylamine may be present in the reaction system.

The compound (1) of the present invention is, for example, a compound represented by the formula [wherein A and G have the same meanings as above] and a compound represented by the formula ([wherein R', R2, R3 and x have the same meanings as above, Y
is a halogen (X, a methylene group or a carbonyl group) or a formula RaS○2-O- (wherein R''i;i lower (C
.

4) alkyl, trifluoromethyl, phenyl or p
-) represents a methylene group). ] It can also be produced by reacting a compound represented by: The reaction is carried out using water or other organic solvents (
For example, the reaction can be carried out in a mixed solvent of acetonitrile lumamide, dimethylacetamide, tetrahydrofuran, acetone methyl, 7 ethyl ketone, and maintained at a temperature range of about -20° to +150'C.

At this time, a base such as potassium carbonate, sodium hydroxide, potassium hydroxide, pyridine triethylamine, etc. can be allowed to coexist in the reaction system.

In addition, in the formula (I), a compound of the present invention in which X is a carbonyl group is, for example, a compound (V) and a compound of the formula U, in which R', R
2 and R3 have the same meanings as above] and can also be produced by subjecting them to a dehydration condensation reaction. The dehydration condensation reaction can be carried out in the same manner as the dehydration condensation reaction between compound (II) and (1).

Further, in the compound of the present invention in which X in formula (1) is a methylene group, for example, compound (V) and a compound represented by the formula [wherein R', R' and R3 have the same meanings as above] are combined in a reducing manner. It can also be produced by condensation under certain conditions.

The reductive conditions include, for example, catalytic reduction using metals such as platinum, palladium, Raney nickel, and rhodium, or mixtures thereof with arbitrary carriers (e.g., carbon), such as lithium aluminum hydride, lithium borohydride,
Reduction with metal hydrogen compounds such as lithium cyanoborohydride, sodium cyanoborohydride, sodium cyanoborohydride, reduction with metal sodium, metal magnesium, etc. and alcohols, metals such as iron and zinc and hydrochloric acid,
Examples of reaction conditions include reduction with an acid such as acetic acid, electrolytic reduction, and reduction with a reductase. The above reaction is usually carried out in water or in an organic solvent (e.g. methanol).

Ethanol, ethyl ether, dioxane, methylene chloride, chloroform, benzene, toluene, acetic acid, N
, N-dimethylformamide, N,N-dimethylacetamide), and the reaction temperature varies depending on the reduction means, but is generally preferably about 120' to 1100'C. Although the purpose of this reaction can be sufficiently achieved at normal pressure, the reaction may be carried out under increased or reduced pressure if necessary.

Furthermore, in formula (I), G is -CH, ZR6 (Z=0°C0
0 or C0NH, and R8 represents a lower alkyl group, a lower haloalkyl group, or a lower alkenyl group), for example, a compound having the formula [wherein A, X, R', R2, R
3 has the same meaning as above] and a compound (IX) represented by the formula % formula % () 1 where Y' is a halogen atom or a formula Ra5O.

0-(In the formula, Ra is lower (C+-C4)7 Ru+/l
/, t+) fluoromethyl 1 phenyl or p-tolyl) 1 formula -COW (in the formula, W represents a halogen atom) 1 formula R11COOC〇- or 2N
It shows a group represented by C○, and R6 is a lower alkyl group.

It can also be produced by condensing a compound represented by a lower haloalkyl group or a lower alkenyl group.

The condensation reaction is produced by reacting compound (IX) with (X) in an aprotic solution (e.g. dimethylsulfoxide, tetrahydrofuran, toluene, acetonitrile, N,N-dimethylformamide, methylene chloride, etc.). I can do it.

Y' of compound (X) is a halogen atom or R''5O
3O (Ra has the same meaning as above), the compound (IX
) and (X) is an alkylation reaction, and the reaction can be accelerated by adding a base such as sodium hydride, sodium amide silver oxide, or n-butyllithium. The reaction temperature generally proceeds at about -20°C to +150°C.

Y' of compound (X) is -COW or R6C00CO-
, the reaction between compound (IX) and (X) is an acylation reaction, and the reaction can be accelerated by adding a base such as triethylamine, 4-dimethylaminopyridine, sodium hydrogen carbonate, potassium carbonate, etc. . The reaction temperature usually proceeds at about -20°C to +150°C.

When Y' in compound (X) represents NGO-, the reaction proceeds even without the addition of a catalyst, but the reaction can be further accelerated by adding a base such as triethylamine, pyridine or 4-dimethylamine/pyridine. . The reaction temperature is preferably about -20° to +150°C.

Further, in formula (I), G is -CH, ZR6(Z-0,S.

N R' (R7 has the same meaning as above), R8 is hydrogen,
For example, compounds of the formula [wherein A
, X, R', R2, R3 and Y have the same meanings as above], a compound (XT) represented by the formula
(XTI) [In the formula, Z is O, S, Ncho <"(R" has the same meaning as above)
and R'' has the same meaning as above].

The substitution reaction includes sodium hydride, sodium amide, silver oxide, sodium hydrogen carbonate, potassium carbonate, Inorganic bases such as thorium hydroxide and potassium hydroxide, or organic bases such as triethylamine pyrin, 4-N,N-methylaminopyrin, are allowed to coexist in the reaction system as a desalting agent for the purpose of promoting the reaction. It can be done by doing something. The reaction temperature is usually -2
It is carried out in a temperature range of about 0° to -150°C.

The target compound (+) of the present invention thus obtained is separated and purified from the reaction mixture by conventional separation and purification methods such as extraction concentration, neutralization,
It can be isolated by means such as filtration, recrystallization, color chromatography, and thin layer chromatography.

Compound (1) may exist in at least two stereoisomers. Both of these individual isomers and mixtures thereof are naturally included within the scope of the present invention, and these isomers can also be produced individually if desired. For example, starting compounds (ITI), () (IX) and (XT)
A single optical isomer of compound (1) can be obtained by carrying out the reaction described in "-" using a single isomer of each, or if the product is a mixture of two or more isomers. This can be accomplished using conventional separation methods, such as optically active acids (
(e.g., camphorsulfonic acid, tartaric acid, dibenzoyltartaric acid, etc.), chemically active bases (e.g., /nconine, nconnisin, quinine, quinine, α-methylhen/ruamine,
It is also possible to separate each isomer by a method of forming a salt with tehytroabethylamine (g), various chromatography, fractional recrystallization, and other separation methods.

Raw material compounds of the present invention (, n), (ffJ),
(V), (IX) and (X+) can be easily produced, for example, by the method shown in the following reaction formula.

For compound (II), a compound known in the literature may be used as it is, or a literature example, Jacques et al., Bull
．． SocChim. Fr. (Bretan Dou U・
Société Chiriki Tou France), 5 ] 2
(1950); Ilashem et al. Med. C
hem. (Nyanar of Métis/Nar Chemistry), Sat 9-, 2 2 9 (+976); Fubachi et al.

Chem. Pharm. Bull. (chemical·
and Firmantical Bulletin), Su6
, 504 (1978) Miyake et al., Chem. Ph
arm. Bull. , 3] , 2 3 2 9
(1983) Benbachi et al., Chem. Pharm. Bull
l. , 3 2, 1 3 0 (1984) Kyuzai et al.
J. Agr. Chem. SocJapan (Journal of the Japanese Society of Agricultural Chemistry), 27, 3] R8 (1953)
; Organic Syntheses, 2 6, 2 8 (194
6)] or a method analogous thereto. For example, the compound (rJ) has the formula [wherein E represents O, S or CH, R8, R9R
to, R II each represent a substituent defined in A above], the compound (n)
can be easily synthesized, for example, according to the following reaction formula.

Also, raw material compounds (I[I), (V), (IX)
and (XI) can be easily synthesized, for example, by the following reaction.

In addition, in the reaction formula shown below, ph represents a phenyl group,
Boc represents a tert-butyloxycarbonyl group,
A, G, X, Y, R', R'', R3, RG and Ra have the same meanings as above.

7 (Xlll) (X ■) (X I[I) (XV) (I'. Known (Xll) and (Xlll) (R”=C2Hs): E, Juc
ker and E, R15si, He1v, Chi
M, Acta, 45.2383 (1962) can be used as a starting material.

(X[II)-equivalent acid chloride or acid anhydride (
(XIV)
, (X■) and (XX) are obtained. The reaction solvent is methylene chloride, 1 acetonium!・Aprotic solvents such as lyl and tetrahydrofuran are used. The reaction temperature can be carried out at -20° to +100°C, but -20° to +100°C.
Approximately +306C is preferable.

The obtained (XTV) was obtained by protecting the amine 7 group with a tert-butyloxycarbonyl group or a pencil group to form (XV) by a conventional method, and then subjecting the ester group of (XV) to a substituent conversion reaction as necessary. attached to. This substituent conversion reaction includes (1) hydrolysis of the ester group, then amidation reaction of the obtained carboxyl group, and (2) NaB of the ester group.
Reduction reaction to alcohol with Ht, LiBH, LiAQH, 3) Alkylation reaction of the hydroxyl group of the obtained human loki 7 body (same modification as the alkylation reaction of (IX) with (X)), 4) Obtained After menlation or tosylation of the hydroxy-7-isomer, a substitution reaction with a nucleophile (eg, amines, mercaptans) (a reaction similar to the substitution reaction of (X I ) with (XII)) can be mentioned. Next, the protecting group tert-butyloxycarbonyl group (Boc
Deprotection of the group) can be carried out by reacting with hydrogen chloride in a solvent such as ethyl acetate, methanol, ethanol, or acetic acid, or by reacting with trifluoroacetic acid or trifluoromethanesulfonic acid in acetic acid. . Further, when the protecting group is a pencil group, it can be carried out by catalytic reduction reaction. Although the reaction temperature is 20' to +150°C, the desired product can usually be obtained at room temperature.

The reaction (XIV)→(X■) is a reduction reaction between an amide group and an ester group, and the reducing agent is LiApH4N a
A QH2(OC112C)-120CH3)2 is used. The reaction is carried out in a solvent such as oxano, tetrahydrofuran, toluene, and henzene ethyl ether, and the reaction proceeds in a temperature range of -200 to +100°C. After converting (XVI) to tert-butyloxysulfonylation (Boc conversion) L(X■), (X■) →
The conversion of (III ′) (X = CH,) is (XV) →
It can be carried out by the same reaction as (■') (X=CO). The reaction (X
+) → (XIV), (X■) and (XX) can be carried out under the same reaction conditions. The alkylation reaction is (X■
) and, for example, 3,4.5-)rimethoxybenzyl chloride, in an organic solvent such as methylene chloride, tetrahydrofuran, acetonitrile NN-dimethylformamide, toluene, etc., at a temperature of -20° to +1.50'C. I can do it. At this time, organic bases such as triethylamine pyridine, l-N, N-7 methylaminopyridine, or inorganic bases such as sodium carbonate, potassium carbonate, and thorium bicarbonate are allowed to coexist as a desalting agent.
It can accelerate the reaction. (XIX) → (III
″) reaction is (XV) → (III 'XX = G O
) can be carried out by a reaction similar to that of (XIIT
)→(XX) is a reaction similar to (XIIT)→(X[V), followed by tert-butyloxycarbonylation (
Boc conversion)L(X)N), and (XXr)→(I[”'
) can be produced by the same reaction as (XV) → (III') (X=CO).

(X■) → (XXII) → (III ”') is (XII
Acylation similar to I)→(XTV) followed by (XV)→(
It can be produced by the same reaction as III') (X=CO).

Compound (■') is a compound derived from an amino acid (
XXI[[) (e.g., Y, Ilamada, M,
5hibataT, Sugiura, S, Ka
to, and T, 5hioiri, J, OrgC
hem, 52.1252 (1987)) as a starting material. (XXIII) → (X
The reaction XIV) is a reductive amination reaction of a carbonyl group, in which (XXIII) and ethanolamine are mixed with methanol.

It can be produced by condensation reaction under reductive conditions in a single or mixed solvent such as ethanol, acetonitrile, and tetrahydrofuran.

The reductive conditions include, for example, catalytic reduction using a metal such as Raney nickel, palladium, rhodium, or a mixture thereof with an arbitrary carrier as a catalyst, such as lithium cyanoborohydride (LiBH3CN).

Reduction with metal hydride compounds such as sodium cyanoborohydride (NaBH3CN) and sodium borohydride (NaBH) can be used.

The reaction temperature varies depending on the reduction method, but it ranges from 20° to +]O
O'C level is preferable. (XXIV) → (XXV) is (
It can be carried out under the same acylation reaction or alkylation reaction conditions as in X■)→(XIX). (XXV) → (X
X W) is a ring-closing reaction after reacting (XXV) with methanesulfonyl chloride or p-toluenesulfonyl chloride in an aprotic solvent such as methylene chloride, tetrahydrofuran, or acetonitrile in the presence of a base such as triethylamine sodium bicarbonate. It can be manufactured by subjecting it to.

The ring-closing reaction can be carried out using sodium hydride, lithium hydride, or the like as a desalting agent.

The reaction solvent is preferably an aprotic polar solvent such as tetrahydrofuran acetonitrile or N,N-dimethylpolamide. The reaction temperature is -20° to +1
It can be carried out within a range of about 00°C. (XXVI)
can be subjected to a deprotection reaction to lead to ■').

(XIV) → (IX'), (XVI) → (IX'), (
XIK) → (■') (XXI) → (XX), (XXIV
)→(IX') acylation step is (XI[I)→(XI
Acylation can be carried out under the same reaction conditions as V).

(XIV) → (IX'), (XIX) → (IX'),
The reduction step in (X II ) → (XX) is a reduction reaction of an ester group to an alcohol, for example, by heating reduction in a mixed solvent of tetrahydrofuran and methanol using sodium borohydride (NaB H4) as a reducing agent, or by reducing hydrogen by heating in a mixed solvent of tetrahydrofuran and methanol. It can be produced by reacting lithium boronate in ethanol at room temperature using a reducing agent.

In the step (IX) → (XI), for example, when Y represents a norogen atom, (IX) is reacted at a temperature of -200 to +50 in a solvent such as methylene chloride, toluene, or ethyl acetate.
This can be carried out by reacting thionyl chloride in the presence of a base such as triethylamine at °C. Further, when Y represents Ra5o, -0-, the reaction can be carried out by, for example, reacting methanesulfonyl chloride instead of thionyl chloride under the same conditions.

(Action) Compound (I) and its salts exhibit excellent PAF antagonism and are effective against circulatory disorders caused by PAF, such as thrombosis,
Stroke (eg, cerebral hemorrhage, cerebral thrombosis), myocardial infarction, angina, thrombophlebitis, nephritis (eg, glomerulonephritis).

Diabetic nephropathy, shock (e.g., endotoxin shock seen in severe infections or after surgery, intravascular blood coagulation syndrome caused by endotoxin, anaphylactic shock, hemorrhagic shock); gastrointestinal disorders caused by PAF (e.g., gastric ulcer): diseases related to allergies and inflammation (e.g., bronchial asthma, xerosis), pneumonia; PA during organ transplantation
Rejection due to increased F production, organ (e.g. heart, liver,
It is useful as a preventive/therapeutic agent for organ failure during kidney) surgery.

Compound (1) and its salts also contain endothelin, which has a strong vascular smooth muscle and tracheal constriction effect.
thelin) [M, Yanagisawa et a
l,, Nature, 332, 4. ++(t9gg
)] diseases induced by excessive secretion (hyperendothelinism), such as hypertension and airway narrowing caused by endothelin [Y, Uchida et al., E.
ur, J. Pharmacol, 154.227
(1988)], as well as ischemic brain and heart diseases (e.g., stroke, angina pectoris, myocardial infarction, heart failure, arrhythmia) caused by endothelin at even higher concentrations (about 0.1 to 5 nmol IJj per 100 blood cycles). , renal impairment (e.g., nephritis),
It is useful for preventing and treating diseases such as poor circulation in various organs (eg, liver, lungs, and intestines) and asthma.

Compound (1) and its salts have low toxicity, so they can be administered to mammals (e.g., humans, rabbits, dogs, cats, rats,
It can be administered orally or parenterally to mice. Dosage is subject to administration.

Although it varies depending on the target disease, symptoms, and route of administration,
For example, when used for the prevention or treatment of shock in adults, compound (I) or a salt thereof is usually administered at a dose of about 0.01 to 20 mg/kg body weight, preferably 0.1 to 20 mg/kg body weight, preferably
~10 mg/kg body weight, more preferably 01~
It is convenient to administer about 2 mg/kg body weight by intravenous injection about 1 to 5 times a day, preferably about 1 to 3 times a day. In addition, compound (1) or a salt thereof may be administered at a dose of 0.01 to 1 Omg/kg body weight/min for about 1 hour, about 1 to 5 times a day, preferably once a day.
It can also be administered by drip injection up to three times. Similar amounts can be administered for other parenteral administrations and oral administrations. If symptoms of shock are particularly severe, the dose may be increased depending on the symptoms.

Furthermore, when administered orally for the prevention and treatment of diseases such as thrombosis, asthma, and nephritis in adults, the dose of compound (1) or its salt is usually 0.05 to 20 mg/dose.
It is convenient to administer about 1 to 5 mg/kg body weight, preferably about 0.2 to 5 mg/kg body weight, about 1 to 5 times a day, preferably about 1 to 3 times a day. Similar amounts can be administered for other parenteral administrations as well.

The pharmaceutical composition used for administration comprises an effective amount of compound (I)
or a salt thereof and a pharmacologically acceptable carrier or excipient, and the composition is provided in a dosage form suitable for oral or parenteral administration.

Compositions for oral administration include, for example, solid or liquid dosage forms, specifically tablets (including sugar-coated tablets and film-coated tablets), gunpowder, granules, and powders.

Capsules (including soft capsules), syrups,
Examples include emulsions and suspensions. Such compositions are produced by methods known per se and contain carriers or excipients commonly used in the pharmaceutical field. For example, carriers and excipients for tablets include lactose, starch, sucrose, and magnesium stearate.

Compositions for parenteral administration include, for example, injections,
Examples include small portions, ointments, poultices, and liniments, and examples of injections include intravenous injections, subcutaneous injections, membrane injections, intramuscular injections, and drip injections.

Such an injection can be prepared by a method known per se, for example, compound (I).
It is prepared by dissolving, suspending, or emulsifying the compound or a salt thereof in a sterile aqueous or oily liquid commonly used for injections.

Aqueous solutions for injection include physiological saline, isotonic solutions containing dextrose and other adjuvants, and suitable solubilizing agents, such as alcohol (e.g., ethanol), polyalcohols (e.g., propylene glycol, polyethylene glycol). ), nonionic surfactants [e.g. polysorbate 80. HCO'-50 (polyoxyethylene
e (50mol) adduct ofhydroge
It may be used in combination with other substances such as castor oil). Examples of oily liquids include sesame oil and Inuduura, and benzyl benzoate and Hensyl alcohol may be used in combination as solubilizing agents. The prepared injection solution is usually filled into a suitable ampoule and provided as an injection. Small portions for rectal administration are prepared by a method known per se, for example, by mixing compound (1) or a salt thereof with a common herbal drug base and molding the mixture.

In addition, each of the above compositions may contain other active ingredients as long as they do not cause unfavorable interactions when mixed with compound (I) or a salt thereof. For example, to a mammal suffering from an infectious disease, compound (1) or a salt thereof can be administered together with an antibiotic to prevent endotoxin infection.

(Example) The present invention will be explained in more detail with reference to Reference Examples and Examples below, but the present invention should not be limited to these.

Reference Example 1 Ethyl piperazine-2-carboxylate dihydrochloric acid 2.
0 g, triethylamine 12- and dichloromethane 4
Add 3,4.51 to the 0d mixture while stirring under water cooling.
- A solution of 1.85 g of rimethoxybenzoyl chloride dissolved in 25 d of dichloromethane is added dropwise. After stirring for 1 hour, the reaction solution was poured into ice water and extracted with methylene chloride. The organic layer is washed with water, dried, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:
Purification with ethyl acetate-acetone-hexane (2°1:2) gives 2.5 g of ethyl 4-(3,4',5-trimethoxybenzoyl)piperazine-2-carboxylate.
is obtained. This product becomes colorless crystals when recrystallized from ethyl acetate-hexane.

Melting point 114-115°C Elemental analysis value: Calculated value as C, 7H2, N, 00:
C, 57,94; H6,86/N795 actual value: C, 57,83; H, 6,9]; N, 7.
79 Reference Example 2 3.4.5- Trimethoxybenzoyl chloride 10.
A solution of 9 g dissolved in 100 turns of dichloromethane was added to 10.9 g of methyl piperazine-2-carboxylate dihydrochloride.
24 g of triethylamine, 18.7 g of triethylamine, and 200 g of dichloromethane over 1 hour while stirring under water cooling. The reaction solution was poured into ice water and extracted with dichloromethane. The organic layer was washed with water, dried, and then evaporated under reduced pressure. The crystals obtained from the residue are recrystallized from ethyl acetate and hexane to obtain 9.6 g of colorless needles of methyl 4-(3,4,5-)rimethoxybenzoyl)piperazine-2-carboxylate.

Melting point 113-114°C Elemental analysis value: Calculated value as C, 6H2, N206:
C, 56,80; H, 6,55; N, 8.2
8 actual measurement value C, 56, 72; H, 6, 68; N
, 8.43 Reference Example 3 A solution of 46 g of di-tert-butyl 2-carbonate dissolved in 15% dichloromethane was added to methyl 4-(3,4,5-)rimethoxyhenzoyl)piperazine obtained in Reference Example 1. It is added dropwise to a mixed solution of 5.0 g of -2-carboxylate, 2.2 g of triethylamine, and 507 dichloromethane over 15 minutes while stirring at room temperature. After stirring the reaction solution at room temperature for 2 hours, it was concentrated under reduced pressure. The residue is extracted with ethyl acetate. The organic layer was washed with water, dried, and then evaporated under reduced pressure. When the crystals obtained from the residue were recrystallized from ethyl acetate, methyl 1-tert-butquine carbonyl-4 (
3,4,5-)rimethoxypenzoyl)piperazine-2
6.3 g of colorless needles of carboxylate are obtained.

Melting point 161164°C Elemental analysis value: Calculated value as C7, H,, N, O,
C, 58,05; H, 6,90; N, 6.3
9 Actual measurement value: C, 57.9g, H, 6,82; N
, 6.48 Reference Example 4 Methanol 6-methyl 1-tert-butoxycarbonyl-4-(3,4,5-)rimethoxybenzoyl)
Piperazine-2-carboxylate 6.3 g, sodium borohydride 1.64 g and tetrahydrofuran 8
01n1. into the mixed solution while stirring under heating and reflux.
Drop in 30 minutes. Pour the reaction solution into ice water and extract with ethyl acetate. The organic layer was washed with water, dried, and then evaporated under reduced pressure. The crystals obtained from the residue were recrystallized from ethyl acetate-ether to give 1-tert-butoxycarbonyl-
4.15 g of colorless crystals of t-(3,4,5 trimethoxybenzoyl)piperazine-2-methanol are obtained.

Melting point 119-120'c Elemental analysis: Calculated as CzoH3ON 207: C, 58,52; H, 7,37; N, 6.
82 actual measurement value C, 58, 46, H, 7, 48; N,
6.70 Reference Example 5 1 tert-butoxycarbonyl-1-(3,45
-trimethoxybenzoyl)piperazine-2 Into a mixture of 12.0 g of methanol, 21.3 g of methyl iodide, and 50 g of dimethylformamide, 60 g of dimethylformamide was added while stirring under water cooling.
% sodium hydride is added little by little. After stirring for an additional 30 minutes, the reaction solution was poured into ice water and extracted with ethyl acetate. Dry the organic layer and concentrate. The residue was purified by silica gel column chromatography (eluent dichloromethane ethyl acetate-1:l) to give l ter
t-butoxycarbonyl-2-methoxymethyl-4(,
3,4,5-=)rimethoxybenzoyl)piperazine 1
2.5 g are obtained as colorless crystals.

Melting point 127°C Elemental analysis value: Calculated value as C3lH32NtO7:
C, 59,42; H, 7,60; N, 6.6
0 actual measurement value: C, 59,29; H, 7,61;
N, 6.52 Reference Example 6 12.0 g of 1-tert-butoxoxydicarbonyl-2-methoxybenzoyl-4-(3,4,5-trimethoxybenzoyl)piperazine was added to 50% of a 3N hydrochloric acid-ethyl acetate solution. Stir at room temperature for an hour. Filter the resulting precipitate,
Washing with ether gave 2-methoxymethyl-4-(3,
10.5 g of 4,5-)rimethoxybenzoyl)piperazine hydrochloride are obtained as colorless crystals. Melting point 210-
215°C elemental analysis value: C,, H,, N, 05・H
Calculated value as Ce: C, 53,26; H, 6,9
8; N, 7.76 actual measurement value, C, 53, 36, H, 6
,89: N, 7.53 Reference Example 7 Methyl 1-tert-butoxycarbonyl-4(3,
4,5-trimethoxybenzoyl)piperazine 2-carboxylate 500 mg, methanol 3d and water 3d
Add 100 mg of sodium hydroxide to the mixture and stir at room temperature for 30 minutes. The reaction solution was poured into 5% citric acid,
Extract with dichloromethane. The organic layer is dried and concentrated.

Recrystallization of the crude product from ethyl acetate yields I-tert
-butoxycarbonyl-4-(3,4,5-trimethoxybenzoyl)piperazine-2-carboxylic acid 400mg
is obtained as colorless crystals. Melting point 188-190°C
Elemental analysis value: C2oHtBN 208 (!- Calculated value: C, 56,60; H, 6,65; N,
6.60 actual measurement value C, 56, 26, H, 6, 63, N,
6.47 Reference Example 8 1-tert-butoxycarbonyl-4-(3,4゜5
2.6 g of dicyclohexylcarbodiimide is added to a mixture of 3.0 g of -1 helimethoxyhenzoyl)piperazine-2 carboxylic acid, 1.2 g of N-hydroquine succinimide, and 30 g of dioxane at room temperature and stirred for 5 hours. Dimethylamine hydrochloride 80g, triethylamine 10.
The active ester solution prepared in step 1 was added dropwise to a mixture of 0 g and 30 g of dioxane at O'C. The residue obtained by concentrating the reaction solution was dissolved in dichloromethane and added with 5% citric acid water.

After washing with saturated sodium bicarbonate solution, dry and concentrate. The crude product was subjected to silica gel column chromatography (ethyl acetate-methanol-9,1), and N,N dimethyl 1-te
rL-butoxycarbonyl-4(3,4,5-trimethoxybenzoyl)piperazine 2-carboxamide 2.1
g as colorless crystals. Melting point 146-147°C Elemental analysis value: Calculated value as C32H33N307:
C, 58,52; H, 7,37; N, 9.3
1 Actual measurement value: C, 58,40; H, 7,45;
N, 9.20 Reference Example 9 N,N-dimethyl 1 tert-butoxycarbonyl-4-(3,4,5-trimethoxybenzoyl)piperazine-2-carboxamide 2.0 g and 3N hydrochloric acid-
Stir the 20% ethyl acetate mixture at room temperature for 30 minutes. The residue obtained by concentrating the reaction solution is poured into saturated potassium carbonate water and extracted with dichloromethane. After drying the organic layer, it was concentrated to give N,N dimethyl 4-(3,4,5-1-
1.5 g of rimethoxybenzoyl)piperazine-2-carboxamide are obtained as colorless crystals. Melting point 167-16
8°C elemental analysis value: C17HtsN Calculated value as 30 s: C, 5111, 11, H, 7, 17, N,
11.96 Actual value: C, 58, 22, H, 7, 17;
N, 12.03 Reference Example 10 Ethyl 4-(3,4,5 trimethoxybenzoyl)piperazine-2-carboxylate 1 obtained in Reference Example 1
．． Og, benzyl chloride 0.54g.

A mixed solution of 0.8 g of potassium carbonate and 12 d of acetonitrile is heated under reflux for 5 hours while stirring. The reaction solution was poured into ice water and extracted with ethyl acetate.

The organic layer was washed with water, dried, and then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate:
Purification with acetone (2:l:1) yields 1.2 g of ethyl 1-hensyl-4-(3,4,5-trimethoxybenzoyl)piperazine-2-carboxylate as a colorless oil.
is obtained. When Honjima is converted to hydrochloride and recrystallized from ethanol, it becomes colorless crystals. Melting point: 162-165°C Elemental analysis value: Calculated value as C2-HsoN 208' HCQ: C, 60, +8. 8,6.52. N
, 5.85 Actual value: C, 60,09; H, 6,4
4: N, 5.80 Reference Example 11 Ethyl 1-benzyl 4-(3,
To a solution of 0.4 g of 4,5-)rimethoxybenzoyl)piperazine-2-carboxylate dissolved in 15-tetrahydrofuran was added sodium borohydride O, Ig, and while stirring, 2 d of methanol was heated under reflux for 30 min.
Drip in minutes. The reaction solution was concentrated under reduced pressure, poured into water, and extracted with ethyl acetate. The organic layer was washed with water, dried, and then evaporated under reduced pressure.

The residue was purified by silica gel column chromatography (acetone: ethyl acetate: hexane = 2:2:1), and the resulting crystals were recrystallized from ethyl acetate and hexane.
Colorless needles of 1-benzyl-4-(3,4,5-trimethoxybenzoyl)piperazine-2-methanol 0.2
4g is obtained.

Melting point 84-85°C Elemental analysis: Calculated as CttH28N to s: C, 65,98; H, 7,05; N, 7
．． 00 actual measurement value: C, 65,73; H, 6,96;
N, 6.99 Reference Example 12 1-Benzyl-4-(3,4,5-trimethoxybenzoyl)piperazine-2-methanol 1. Og to N, N-
A solution dissolved in 2 dimethylformamide was added with 0.15 g of sodium hydride and 4 mL of N,N-dimethylformamide.
Add dropwise to the mixed liquid at 0°C for 5 minutes while stirring. Then, 0.5 g of ethyl iodide was added at O'C, and the mixture was stirred at room temperature for 30 minutes. The reaction solution was poured into ice water and extracted with ethyl acetate. The organic layer was washed with water, dried, and then distilled off under reduced pressure to give 1-benzyl-2-ethoxymethyl-4 (3
, 1.0 g of a colorless oil of ,4,5-)rimethoxybenzoyl)piperazine are obtained. Honjima is converted into hydrochloride and recrystallized from acetone to obtain colorless needle crystals.

Melting point +30-132°C Elemental analysis value: C24H3,N 205・HCρ・1
Calculated value as /2H20: C, 60, 81; H, 7, 23; N
, 5.91 actual value C, 60, 68, H, 7, 45;
N, 5.72 Reference Example 13 In a solution of 10 g of 1-benzyl-2-ethoxymethyl-4-(3,4,5-trimethoxybenzoyl)piperazine hydrochloride obtained in Reference Example 12 dissolved in 15 parts of methanol. , 0.3 g of 10% palladium on carbon was added, and the mixture was stirred for 3 hours in a hydrogen stream.

The reaction solution was filtered, and the filtrate was distilled off under reduced pressure. When the obtained crystals are recrystallized from ethanol-ether, 3-ethoxymethyl-1-(3,4,5-)rimethoxybenzoyl)
0.8 g of colorless crystals of piperazine hydrochloride are obtained. Melting point: 203-204°C Elemental analysis: C, 7H,, N
,05・HCQ,・1/2H,O Calculated value: C, 53,19; H, 7,35; N
, 7.30 actual value: C, 53,42, H, 7,25;
N, 7.31 Reference Example 14 3-methoxymethyl l(3,4
A solution of 2.1 g of ,5-trimethoxybenzoyl)piperazine in tetrahydrofuran 10a is added dropwise to a suspension of 0.3 g of lithium aluminum hydride in 12 ml of ether at room temperature while stirring for 15 minutes. After stirring the reaction solution at 40°C for 1 hour, it was cooled to 0°C and added with 0.0% water. :M2,
0.3 parts of a 15% aqueous sodium hydroxide solution and 1 part of water are added in this order to decompose, and insoluble matter is filtered. The filtrate is concentrated under reduced pressure, the residue is dissolved in dilute hydrochloric acid, and then extracted with ethyl acetate. The aqueous layer is neutralized with sodium bicarbonate and extracted with dichloromethane. The organic layer was washed with water, dried, and then evaporated under reduced pressure to obtain 3-
1.4 g of methoxymethyl-1-(3',4.5-)rimethoxybenzyl)piperazine are obtained as a colorless oil.

Main island is converted to hydrochloride, and recrystallized from ethanol and ether to give colorless needle crystals.

Melting point: 162-165°C Elemental analysis: C1oH2[IN 20 a' 2
¥ (Calculated value as Cρ・1/2H20: C, 48,98; H, 7,45・N7
．． ]4 Actual measurement value: C, 49, 27, H, 7, 36; '
N, 6.97 Reference Example 15 2 Reference-15 Toxy-6,7-dihydro-5H A solution of 2.14 g of benzocyclohebutene-8-carbonyl chloride dissolved in 20% dichloromethane was dissolved in methyl piperazine-2-carboxylene 1.hydrochloric acid. The mixture was added dropwise over 40 minutes to a mixture of 1.75 g of salt, 32 g of triethylamine, and 40 g of dichloromethane while stirring with O'C. Pour the reaction solution into ice water and shake to mix. Separate the organic layer and evaporate under reduced pressure.

The residue is dissolved in 20 ml of IN=hydrochloric acid and extracted with ethyl acetate. After separating the aqueous layer, it is neutralized with sodium bicarbonate and extracted with dichloromethane. After drying the organic layer, evaporate under reduced pressure,
When the crystals obtained from the residue were recrystallized from ethyl acetate-hexane, methyl 4-(2,3-dimethoxy-6,7
245 g of colorless needles of 4-benzocyclohebuten-8-ylcarbonyl)piperazine-2-carboxylate are obtained.

Melting point 103-104°C Elemental analysis value, calculated value as C3°H26N 205:
C, 64,15; H, 7,00; N, 7.4
8 actual measurement value C, 6LO3; H, 7,02; N,
7.34 Reference Example 16 50 g of di-tert-butyl dicarbonate was added to 3 parts of dichloromethane.
The completely dissolved solution was added dropwise over 1 hour to a mixed solution of 5.0 g of methyl piperazine 2-carboxylate dihydrochloride, 7 g of triethylamine and 70 g of dichloromethane while stirring at O'C. The reaction solution was poured into ice water and extracted with dichloromethane. The organic layer was washed with water, dried, and then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent, dichloromethane:acetone:ethanol-5
- 5:1) gives 4.9 g of a colorless oil of methyl 4-tert-butoxycarbonylpiperazine-2-carboxylate.

Elemental analysis value・Calculated value as C,,H,oN204:
C, 54,08; H, 8,25; N, 11.4
7 Actual measurements: C, 54,46; H, 8,38;
N, 11.22 Reference Example 17 A solution obtained in Reference Example 16 was prepared by dissolving 1.6 g of 2.3-dimethox/-6.7-dihydro 5H-henzocyclohebutene-8-carbonyl chloride in 15% dichloromethane. methyl 4-tert-butoxycarbonylpiperazine-2-carboxylate], 8 g, triethylamine 1.3 g and dichloromethane 20
Add dropwise over 3 minutes at °C.

The reaction solution was poured into ice water and extracted with dichloromethane.

The organic layer was washed with water, dried, and then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate:
When purified with acetone-5:4:1), methyl 1-(
2.8 g of a colorless oil of 4-tert-butoxycarbonylpiperazine-2-carboxylate are obtained.

Elemental analysis value: C2,H3,N, Calculated value as 07: C,63,27; H,7,22; N,5.
90 actual measured value: C, 83,56; H, 7,36;
N, 5.71 Reference Example 18 Methyl obtained in Reference Example 17 1-(2,3-dimethoxy-6,7-sihydro 5H-benzocyclohebutene-
8-ylcarbonyl) -4-tertbutoxysulfonylpiperazine-2-carboxyleneh 1.7g to 4
．． Add to 10 g of a solution of 5N hydrochloric acid in ethyl acetate, and leave the reaction solution at room temperature for 5 hours.

The reaction solution was distilled off under reduced pressure, ether was added to the residue, the resulting precipitate was dried, and methyl 1-(2,3 dimethoxy-
6,7-dihythro5H-benzocyclohebutene-8
12 g of colorless powder of piperazine 2-carboxylate hydrochloride (-ylcarbonyl) are obtained.

Elemental analysis value C20H28N205'HC(!'1
Calculated value as /2H20 C,57,2], H,6,72・N66
7 Actual measurement value C, 57, 17; H, 6, 93; N
6.42 Reference Example 19 Methyl 4-(tertbutquine carbonyl)piperazine-2-carboxylate 3 obtained in Reference Example 16
．． 5g, 3,4.5-trimethoxybenzyl chloride 4
6g, potassium carbonate 60g and acetonitrile 8C7
The mixture was heated under reflux for 10 hours while stirring. After the reaction solution was concentrated under reduced pressure, it was added to water and extracted with ethyl acetate. Wash the organic layer with water.

After drying, evaporate under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate-32) to obtain methyl 4-tert-butoxycarbonyl-
]-(3,45-)IJ methoxyhensyl)piperazine-2-carboxylate 5.2 g of a colorless oil are obtained.

Elemental analysis value: C2IH32N 20? Calculated values as: C, 59, 4]; H, 7, 60; N, 6
．． 60 actual value C, 59,18; H, 7,83;
N, 6.34 Reference Example 20 4.5 Og of methyl 4-tert-butoxycarbonyl-1-(3,4,5-)rimethoxypencyl)piperazine-2-carboxylate obtained in Reference Example 19
Dissolved in 207% of N-hydrochloric acid (ethyl acetate solution) and dissolved at room temperature for 5%
Leave it for a while. When the reaction solution is concentrated under reduced pressure, methyl 1-
(3,4,5-trimethoxyhensyl)piperazine-2
-4.3 g of crystals of carboxylate hydrochloride are obtained.

When Honjima is recrystallized from ethanol, it becomes colorless needle crystals.

Melting point] 7701175° C elementary analysis value: C, 6H24N to s・2HCQ
・Calculated value as 1/2H20: C, 47, 30; H6, 70・N 6
．． 89 actual measurement value: C, 47, 16, H, 6, 89, N,
6.83 Reference Example 21 A solution of 1.44 g of N-benzyloxycarbonyloxy-5-norbornene-2,3-dicarboximide in 10 d of dichloromethane was mixed with 10 g of methyl piperazine-2-carboxylate dihydrochloride.

1.4 g of triethylamine and 12 g of dichloromethane
Drop into the mixed solution over 20 minutes while stirring under water cooling. After stirring the reaction solution for 30 minutes, it was poured into water and extracted with dichloromethane. The organic layer was washed with water, dried, and then evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (acetone/dichloromethane:hegyusan-3/2.1)
1.2 g of a colorless oil of methyl 4-benzyloxycarbonylpiperazine 2-carboxylate is obtained.

Elemental analysis value: C, 8, 8N20. Calculated value as
C, 60, 42: H, 6, 52; N, 10.07 Actual value: c,, so, tg; H, 6, 79; N
, 10.46 Reference Example 22 1.2 g of methyl 4-benzyloxycarbonylpiperazine-2-carboxylate obtained in Reference Example 21,)
While stirring a mixture of 0.9 g of ethylamine and 15 ml of dichloromethane at 0°C, a solution of 108 g of 3.4.5-trimethoxybenzoyl chloride in 10 d of dichloromethane was added dropwise over 5 minutes. After stirring the reaction solution at room temperature for 10 minutes, it was poured into water and extracted with dichloromethane. The organic layer was washed with water, dried, and then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate:acetone-2:2:1) to yield methyl 4-benzyloxycarbonyl-1(3,45-trimethoxybenzoyl)piperazine-2carboxylate as a colorless oil. 2.1 g of product is obtained.

Elemental analysis value: Calculated value as C2-H2eN20e: C, 61,01; H, 5,97; N, 5
．． 93 actual value: C, 61,39; H, 6,28;
N, 5.73 Reference Example 23 2.0 g of methyl 4-benzyloxycarbonyl-1-(34,5-trimethoxybenzoyl)piperazine-2-carboxylate obtained in Reference Example 22, 30% methanol and 10% palladium A mixture of 0.5 g of carbon is stirred for 1 hour at room temperature in a stream of hydrogen. The reaction solution was filtered and the filtrate was distilled off under reduced pressure to obtain 1.05 g of colorless crystals of methyl 1-(3,4,51-limethoxyhenzoyl)piperazine-2-carboxylate. When Honjima is recrystallized from ethyl acetate and hexane, it becomes colorless needle-shaped crystals.

Melting point: 134-135°C Elemental analysis: C, 8H22N20. Calculated value as:
C, 56,80; H, 6,55; N, 8.2
8 Actual measurements: C, 56,58; H, 6,63;
N, 8.06 Reference Example 24 A 15-rotational solution of 3.79 g of di-Lert-butyl dicarbonate in dichloromethane was mixed with the methyl 4-dicarbonate obtained in Reference Example 21.
It is added dropwise to a mixed solution of 4.4 g of (benzyloxycarbonyl)piperazine 2-carboxylate, 4 g of triethylamine and 40 d of dichloromethane over 5 minutes while stirring at 0°C. After stirring the reaction solution at room temperature for 2 hours, it was added to water and extracted with dichloromethane. The organic layer was washed with water, dried, and then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate-2:1) to produce methyl 4-benzyloxycarbonyl 1
55 g of a colorless oil of (tert-butoxycarbonyl)piperazine-2 carboxylate are obtained.

Elemental analysis value: C. Calculated value as 828N, 08:
C, 60,30; H, 6,93; N, 7.4
0 actual measurement value: C, 60, 12; H, 7, 18;
N, 7.15 Reference Example 25 A mixture of 5.4 g of methyl 4-benzyloxycarbonyl-1(tert-butoxycarbonyl)piperazine-2-carboxylate obtained in Reference Example 24 and 1.2 g of 10% palladium on carbon and 60 d of methanol. Stir for 4 hours at room temperature in a hydrogen stream. The reaction solution was filtered and the filtrate was distilled off under reduced pressure to obtain 3.3 g of a pale yellow oil of methyl 1-(tert-butoxycarbonyl)piperazine-2-carboxylate.

Elemental analysis values: C,,H,. Calculated value as N2O4:
C, 54,09; H, 8,25: N, 11.
47 actual measurements: C, 53,86; H, 8,49:
N, 11.18 Reference Example 26 Methyl 1 (tertbutoxycarbonyl)piperazine-2-carboxylate 3 obtained in Reference Example 25
．． 2g, 3,4.5-)rimethoxybenzyl chloride 3
．． 5g, potassium carbonate 4.0g and acetonitrile 8
The 0d mixture was heated under reflux for 6 hours while stirring. After concentrating the reaction solution under reduced pressure, it was extracted with ethyl acetate, and the organic layer was washed with water.
Dry and evaporate under reduced pressure.

The residue was purified by silica gel column chromatography (hexane:ethyl acetate-3:2), and the resulting crystals were recrystallized from ethyl acetate and hexane to give methyl 1-t.
3.0 g of colorless needles of ert-butoxycarbonyl-4-(3,4,5-1 rimethoxyhenzyl)piperazine 2-carboxylate are obtained. Melting point 113-114
°C Elemental analysis value: C2LH32N Calculated value as 207: C, 59,42; H, 7,60; N, 6.
60 actual value: C, 59,49; H, 7,67;
N, 6J9 Reference Example 27 3.0 g of methyl 1-tert-butoxycarbonyl-4-(3,4,5-trimethoxybenzyl)piperazine-2-carboxylate obtained in Reference Example 26 was added to 4.
Dissolve in 5N hydrochloric acid (ethyl acetate solution) and stir at room temperature for 3 hours. After concentrating the reaction solution under reduced pressure, the resulting crystals were recrystallized from ethanol to give methyl 4-(3,4
, 5-trimethoxybenzyl)piperazine-2-carboxylate, 2.5 g of colorless needles are obtained.

Melting point: 155-160°C Elemental analysis: C, llH,, N, 05.2HCρ.
Calculated value as H, 0: C, 4B, 27; H, 6, 80; N
, 6.75 Actual value: C, 4B, 49; H, 6, 6
4; N, 6.58 Reference Example 28 50.0 g of sodium dihydro-bis(2-methoxy)aluminate and 2507 nI of toluene.

to a mixture of ethyl 4-(3,4,5-tormethoxybenzoyl)piperazine-2-carboxyl-1I7.
A solution of 6 g dissolved in 10 CbJ of toluene is added dropwise over 1 hour while stirring at room temperature. After decomposing the excess reducing agent with 40% aqueous sodium hydroxide, the inorganic matter is filtered off, and the filtrate is concentrated under reduced pressure. The residue was recrystallized from methanol and
-(3,4,5trimethoxybenzyl)piperazine-2
- 10.5 g of methanol are obtained as colorless crystals.

Melting point: 93°C Elemental analysis: C, 5H2, N20. Calculated value as:
C, 60,79; H, 8,16; N, 9.45
Actual measurements: C, 60,77, H, 8,06, N, 9.1
8 Reference Example 29 A solution of 1.1 g of 2.3-dimethoxy-6,7-dihydro-5H benzocyclohebutene-8-carbonyl chloride dissolved in 127 nIl of dichloromethane was added to 1.0 g of ethyl piperazine-2-carboxylate hydrochloride, ) Add dropwise to a mixture of 0.5 g of ethylamine and 20 g of dichloromethane over 30 minutes while stirring under water cooling.

After stirring the reaction solution at 00C for 1 hour, it was poured into ice water and extracted with dichloromethane. After washing the organic layer with water and drying,
Distill under reduced pressure. The residue was subjected to silica gel column chromatography (hexane: ethyl acetate: acetone-11.1).
Purification with ethyl 4-(2,3-dimethoxy6.
1.2 g of crystals of 7-dihydro-511-benzocyclohepten-8-ylcarbonyl)piperazine-2-carboxylate are obtained. When this product is recrystallized from ethyl acetate and beef starch, it becomes colorless prismatic crystals. Melting point 105-1
06°0 Elemental analysis values: C2, N2. Calculated value as N, 05:
C, 64,93; H, 7,27; N, 7.2
1 Actual measurement value C, 64, 89: H, 7, 32; N
7.13 Reference Example 30 To a solution of 3.09 g of oxalyl chloride dissolved in 50 g of methylene chloride, dimethyl sulfoxide 2 was added at -78°C.
．． A solution of 86 g dissolved in 20% methylene chloride was added dropwise and stirred for 10 minutes. l -tert-butoxycarbonyl-4-( obtained in Reference Example 4) was added to the obtained reaction solution.
3,4,5-trimethoxybenzoyl)piperazine-2
- Add dropwise a solution of 5.0 g of methanol dissolved in 10% methylene chloride and stir for 20 minutes. Then, after adding 7.4 g of triethylamine, the reaction temperature was raised to room temperature.

The reaction solution was poured into ice water and extracted with methylene chloride.

The organic layer is washed with water, dried, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate to yield 4.1 g of colorless prismatic crystals of 1-tert-butoxycarbonyl-4-(3,4,5-trimethoxybenzoyl)piperazine-2-carbaldehyde.
is obtained.

Melting point 160-161℃ Elemental analysis value C20828N 20? Calculated value as:
C, 5g, 81; H6,91・N6.86 Actual value: C, 5g, 42; H, 7,01; N
, 6.75 Reference Example 31 1-tert-butoxycarbonyl-4-C3,4,,5-trimethoxybenzoyl obtained in Reference Example 30)
Piperazine-2-carbaldehyde 3.8 g.

Carbuethoxymethylenetriphenylphosphorane 39g
A mixture of 30- and toluene is stirred at 50°C for 3 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate) to yield ethyl 1tert-butoxycarbonyl-4-(3,4,5trimethoxybenzoyl)-2-
4.0 g of a colorless oil of piperazine acrylate are obtained. Dissolve this product in 4M ethanol, add 400 mg of 10% Pd-carbon, and stir at room temperature in a hydrogen stream for 8 hours. After removing the catalyst by filtration, the liquid was concentrated under reduced pressure, the resulting residue was dissolved in ethyl acetate IO-, 30 d of 4,5N hydrochloric acid-ethyl acetate was added, and the mixture was stirred at room temperature for 3 hours. When the precipitated crystals are collected by filtration and dried, ethyl 4-(3,4,5-)rimethoxybenzoyl)2-piperazinepropiocarbonate is obtained.
2.5 g of colorless crystals of the hydrochloride are obtained.

Melting point: 182-184°C Elemental analysis: C,, H, 8N20. - ) fc (Calculated value: C, 54,74H7,01N672 Actual value: C,54,53; H,7,04,N, 6.5
7 Reference Example 32 Ethyl 4-(3,4,5 trimethquinbenzoyl)-2-piperazine propionate obtained in Reference Example 31.
To a mixture of 1.3 g of hydrochloride, 315 mg of ) ethylamine, and 10 g of toluene, 9 g of a toluene solution of 3.4 M sodium bis(2-methynethoxy)aluminum hydride (Red-AC") was added dropwise at room temperature while stirring. After stirring for 3 hours, water was added to the reaction mixture and extracted with ethyl acetate.The organic layer was washed with water, dried, and concentrated under reduced pressure.

The resulting residue was made into a hydrochloride salt and recrystallized from ethanol to give 4-(3,4,5-trimethoxybenzyl)-2-
Colorless crystals of piperazinepropanol dihydrochloride 1.0g
or can be obtained.

Melting point 212-2]5°C Elemental analysis value C,7H2,N 204・2 Calculated value as HCρ・C,51,39; H,7,61;
N, 7.05 actual measurement value C, 51,29; H, 7,
78; N, 6.91 Example 1 370 mg of 2.3-dimethoxy-6,7-dihydro58benzcyclohebutene-8-carbonyl chloride was dissolved in 107 n1. of dichloromethane. 400 mg of methyl-4-(3,4,5-1-rimethquinhenzoyl)piperazine-2-carboxylate obtained in Reference Example 2,
The mixture was added dropwise to a mixture of 1 ml of triethylamine and 50 d of dichloromethane over 30 minutes while cooling with water. The reaction solution was washed with citric sprinkling and accumulated water, dried over magnesium sulfate, and then
Concentrated.

The residue was subjected to silica gel column chromatography (eluent: ethyl acetate-methanol-97:3), and methyl 1-(2,3-dimethoxy-6,7-dihydro 58
-benzcyclohepten-8-ylcarbonyl)-4-
450 mg of (3,4,,5-trimethoxybenzoyl)piperazine-2-carboxylate are obtained as colorless crystals. Melting point: 134°C Elemental analysis: C3oH=eN
20. Calculated value as -1/2H2o: C, 62, 38
: H, 6,46; N, 4.85 Actual value: C,
62,30; H, 6,31; N, 4.80 Example 2 2.3-dimethoxy-6,7-dihydro-5H benzcyclohebutene-8-carbonyl chloride 4,00 mg
500 mg of N,N-dimethyl 4-(34,5-trimethoxybenzoyl)piperazine-bivalent ruboxamide obtained in Reference Example 9 was dissolved in 10 volumes of dichloromethane.
, 1 part triethylamine, and 50 d dichloromethane over 30 minutes while cooling with water. Add the reaction solution to 5% citric acid water.

Wash with saturated aqueous NaHCO2, dry and concentrate under reduced pressure.

The residue was subjected to silica gel column chromatography (eluent: ethyl acetate) and N,N-dimethyl 1-(2,
3-Dimethoxy-6,7-cyhydro5H-benzcyclohebuten-8-ylcarbonyl)4-(3,4,5-
430 mg of 1-rimethoxybenzoyl)piperidine-2-carboxamide are obtained as colorless crystals. Melting point 190
-191℃ Elemental analysis value/Calculated value as C3lH38N308:
C, 64,01; H, 6,76; N, 7.22
Actual measurements: C, 63,83, H, 6,95, N, 7.0
1 Examples 3 to 6 N,N-dimethyl 4(3,4
, 5-1-rimethoxybenzoyl)piperazine-2-carboxamide and the corresponding acid chloride give the compounds of Examples 3-6.

(Left below) Example 7 A solution of 300 mg of 7.8-7methquine-2.3-dihydro-1-benzoxepine-4-carbonyl chloride dissolved in 10 d of dichloromethane was added to the 3-methoxymethyl-1 obtained in Reference Example 6. -(34,5-trimethoxybenzoyl)piperazine hydrochloride (400 mg), dichloromethane (30 mg) was added dropwise to a mixture of 30 d of dichloromethane under water cooling and stirring over 30 minutes. Add the reaction solution to citric acid water.

Wash with sodium bicarbonate solution, dry with magnesium sulfate, and concentrate. The residue was subjected to silica gel column chromatography (eluent: ethyl acetate-methanol-95=5), and 1
520 mg of -(7,8-dimethoxy-2,3 dihydro-1-benzoxepin-4-ylcarbonyl)-2-methoxymethyl-4-(3,4,5 trimethoxybenzoyl)piperazine are obtained as colorless crystals. Melting point 142°
C elemental analysis value: C211H36N 209・l/2
Calculated values as H, O: C, 61,58; H, 6,59; N
, 4.95 Actual value: C, 61,54; H, 6,4
9; N, 4.89 Example 8-18 3-methoxymethyl 1-(3
,4,5-)rimethoxybenzoyl)piperazine with the corresponding acid chloride to obtain the compounds of Examples 8-18.

(Left below) 9 100 Example 19 A solution of 0.36 g of 2.3-dimethoxy-6,7-dihydro-5H benzocyclohebutene-8-carboxylic acid chloride in dichloromethane (67 nf) obtained in Reference Example 14 was prepared. and 0.4 g of 3-methoxymethyl-1-(3°4.5-)rimethoxyhensyl)piperazine.

Add dropwise to a mixture of 0.3 g of triethylamine and 6 ml of dichlorotane at 0° C. while stirring.

After stirring the reaction solution at room temperature for 1 hour, it was added to water and extracted with dichloromethane. The organic layer was washed with water, dried, and then evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (
Hexane:ethyl acetate:acetone-2.2:1) yields 1-(2,3-dimethoxy-6,fusihydro-58-benzocyclohebuten-8-ylcarbonyl).
0.6 g of a colorless oil of -2-methoxymethyl-4-(3,4,5-1-rimethquinhenzyl)piperazine is obtained. When converted to the hydrochloride salt and treated with ether, it becomes a pale yellow powder.

Elemental analysis value: C3, H,, N207・HCff・4
15) Calculated value as 1.0: C, 60, 91; H, 7, 26; N
, 4.74 Actual value: C,60,92,H,6,! 18
; N, 4.75 Example 20 2.3-Dimethoxy-6,7-dihydro-5H benzone Clohepten-8-carbonyl chloride 0.3 g of dichloromethane 67 nIl was added to the 3-dihydro-5H obtained in Reference Example 13.
Ethoxymethyl-1-(3,4,5trimethoxybenzoyl)piperazine 0.41g, triethylamine 0.4
Add dropwise to a mixture of g and 8 volumes of dichloromethane over 3 minutes while stirring at 0°C. After stirring the reaction solution at room temperature for 1 hour, water was added and extracted with dichloromethane. Wash the organic layer with water.

After drying, evaporate under reduced pressure. The residue was purified by silica gel column chromatography (hexane, ethyl acetate, acetone-2).
21), ]-(2,3 dimethoxy-6,7
-Sihydro58-benzocyclohebuten-8-ylcarbonyl)-2-ethoxymethyl-4-(3,4,5-
) Rimethoxyhenzoyl) Piperazine colorless oil 0.
6g is obtained. When the main island is treated with ether, it becomes a colorless powder.

Elemental analysis values C3, H4, N20. Calculated value as:
C,65,48; H,7,09/H4,93 actual value C,65,18: H,7,25; N,4.
64 Example 21 A solution prepared by dissolving 0.38 of 2.3-7 methoxy-6.7-methyl 5H pentcyclohebutene-8-carbonyl chloride in dichloromethane was added to the methyl 1-(3, 4,5 trimethoxybenzoyl)
Piperazine-2-carboxylene 1.0°4g, triethylamine 0.3g and dichloromethane 8% '/T
Stir at 0°C and add dropwise over 3 minutes. After stirring the reaction solution at room temperature for 30 minutes, it was poured into water and extracted with dichloromethane. The organic layer was washed sequentially with dilute hydrochloric acid, aqueous sodium bicarbonate solution, and water, dried, and evaporated under reduced pressure to give methyl 4-(2,3-diftochyne-6, Fujihydro 5H-benzocyclohebuten-8-ylcarbonyl')-1. -(3,4,5-1-rimethoxyhenzoyl)piperazine-2-carboxylate crystals 0.63
g is obtained. Recrystallize Honjima from ethanol and ether to obtain colorless crystals.

Melting point 139-+40°C Elemental analysis value: Calculated value as C3oHseNwOe:
C, 63,37; H, 6,38; N, 4.9
3 actual measurements: C, 63, 24, H, 6, 22; N,
4.85 Example 22 A solution of 0.3 g of 4-methoxycinnamic acid chloride dissolved in dichloromethane was added to methyl 1-(3,4,5-)rimethquinbenzoyl)piperazine obtained in Reference Example 23. Oo in a mixture of 057 g of 2-carboxylate, 0.4 g of ethylamine and 12 g of dichloromethane.
Add dropwise over 3 minutes while stirring. After stirring the reaction solution at room temperature for 30 minutes, it was poured into water and extracted with dichloromethane. The organic layer was washed successively with dilute hydrochloric acid, aqueous sodium carbonate solution, and water, and then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate:acetone-2°2:1) to yield methyl 4-(4methoxycinnamoyl)-1-(3,4,5-trimethoxybenzoyl)piperazine. 0.6 g of a colorless oil of -2-carboxylate is obtained. When the main island is treated with ether, it becomes a colorless powder.

Calculated value as elemental analysis value “26H3oN208: C,
62,64; H, 6,07; N, 5.62 Actual value: C, 62J9. H, 6, 12; N, 5.
59 Example 23 Methyl 1-(2,3 dimethoxy-6,7-cyhydro 5H-benzocyclohebutene-
A mixture of 0.84 g of 3,4.5-)rimethoxyhendyl chloride, 0.8 g of FJ2 potassium, and 16 acetonitrile was heated under reflux for 7 hours while stirring. . Pour the reaction solution into water, extract with ethyl acetate, and wash the organic layer with water.

After drying, evaporate under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate:acetone-3:3:l') to obtain methyl 1(2,3-
1.6 g of a pale yellow oil of dimethoxy-6,7-hydro 5H/chlorohebuten-8-ylcarbonyl)4-(3,4,5-trimethoxybenzyl)piperazine-2-carboxylate is obtained. When the main island is converted into hydrochloride, it becomes a white powder.

Elemental analysis value: C3oH3sN2o e' HC
0, calculated value: C, 60,96; H, 6,6
5; N, 4.74 Actual value: C, 60, 82;
H, 6,92; N, 4.53 Example 24 Methyl I-(2,3-dimethoxy-6,7-cyhydro 5H-benzocyclohebutene-
8-ylcarbonyl)-4-(3,45-trimethoxybenzyl)piperazine-2-carboxylate 0.9 g
, 2.5 g of potassium carbonate, 10 ml of methanol and 8 ml of water
- Stir the mixture at 70°C for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was adjusted to pH 3-4 with 10% hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water, dried, and then evaporated under reduced pressure to give 1-(2,3-dimethoxy-6,7-dihydro 5
H-benzocyclohebuten-8-ylcarbonyl)4-
(3,4,5-)rimethoxybenzyl)piperazine-2
-0.45 g of carboxylic acid crystals are obtained.

When Honjima is recrystallized from ethyl acetate, it becomes colorless crystals.

Melting point 143-146°C Elemental analysis value. C2゜H38N208・3/2H
Calculated value as 20: C, 61,36; H, 6,93: N
, 4.94 Actual value: C, 61,33・86.72N
1-(2,3-dimethoxy-6 obtained for 4.98
fujihydro 58-benzocyclohebuten-8ylcarbonyl)-4-(3,4,5-trimethoxyhensyl)piperazine-2-carboxylic acid 0,4 g dimethylamine hydrochloride 0.3 g,) ethylamine 0585 g and N, While stirring under water cooling, 0.6 g of diethyl cyanophosphate was added dropwise to a mixture of 6% N-dimethylformamide. After stirring the reaction solution at room temperature for 40 minutes, it was poured into water and extracted with ethyl acetate.

The organic layer was washed with water, dried, and then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate)
When purified with acetone-1:l:1), NN-dimethyl-1-(2,3-dimethoxy-6,7-nitro5H-
benzocyclohebuten-8ylcarbonyl)-4-(3
,4,5-1-rimethoxy7benzyl)piperazine-2-
0.37 g of carboxamide crystals are obtained. When Honjima is recrystallized from ethyl acetate, it becomes colorless needle-shaped crystals.

Melting point 165-166°C Elemental analysis value: Calculated value as C3, H4, N307:
C, 65,59; H7, 28; N 7.40
Actual value C, 65,31・87.29N 7.23 Example 25 Methyl 4-(2,3 dimethoxy-6,7-cyhydro 5H-benzocyclohebutene- obtained in Reference Example 15)
A mixture of 2.0 g of 8-ylcarbonyl)piperazine 2-carboxylate, 1.5 g of 3,4.5-trimethoxybenzyl chloride, 1.5 g of potassium carbonate and 25 g of acetonitrile is heated under reflux for 15 hours while stirring. The reaction solution was concentrated under reduced pressure, and the residue was poured into water and extracted with ethyl acetate. The organic layer was washed with water, dried, and then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate-2; 2 l) to give methyl 1-(2,3-dimethoxy-6°7-sihydro-5H-benzocyclohebuten-8ylcarbonyl)- ]
-(3,4,5-)rimethoxybenzyl)piperazine-
2.6 g of a colorless oil of 2-carboxylate are obtained. When the main island is converted to hydrochloride and precipitated with ether, it becomes an off-white powder.

Elemental analysis value: Calculated value as C3oH38N208・HCσ: C, 60,96; H, 6,65; N,
4.74 actual measurement value C, 60,71; H, 6,85;
N, 4.48 Example 26 Methyl 1-(2,3dimethoxy-6,7-cyhydro5H-benzocyclohebuten-8-ylcarbonyl)-1-(3°4. 5-)rimethoxybenzyl)piperazine-2carboxylate 0.8
g, potassium carbonate 30g, methanol 10g and water 8g
Stir the dry mixture at 708C for 3 hours. The reaction solution was concentrated under reduced pressure, adjusted to pH 3-4 with 10% hydrochloric acid, and extracted with ethyl acetate. After washing the organic layer with water, drying, and distilling it off under reduced pressure,
4(2,3-dimethoxy-6,7-5H-pencisochlorohepten-8-ylcarbonyl)-1-(3°4.5-
0.7 g of crystals of 1-rimethoxypenzyl)piperazine-2 carboxylic acid are obtained. When Honjima is recrystallized from ethyl acetate, it becomes colorless crystals.

Melting point 142-144°C Elemental analysis value, C2°■-■3oN208・l/2H7
Calculated value as O: C, 63,37; H, 6,79; N
, 5.10 actual measurement C, 63, 34, H, 6, 72;
N, 5.05 then the obtained 4-(2,3-dimethoxy-6 fudihydro 5H-benzocyclohebutene-
0.6 g of 8ylcarbonyl l-]-(3,4,5-trimethoxybenzyl)piperazine-2-carboxylic acid.

Dimethylamine hydrochloride 0.3g, ) ethylamine 03g
0.5 g of diethyl cyanphosphate and 0.3 g of triethylamine are added dropwise to a mixture of 8% N,N-dimethylformamide and stirred under water cooling.

The reaction solution was stirred at room temperature for 2 hours, then added to ice water and extracted with ethyl acetate. The organic layer was washed with water, dried, and then evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (
When purified with hexane, ethyl acetate: acetone-1.1.1), N,N-dimethyl 4-(2,3-dimethoxy-
6,7-sihydro-5H-benzocyclohebutene-8-
Pale yellow M-like substance of 1-(34,5-)rimethoxyhenzyl)piperazine-2-carboxamito 0
．． 6g is obtained. When this product is converted to hydrochloride and recrystallized from ethanol, it becomes colorless crystals.

Melting point: 173-176°C Elemental analysis: C3, H,, N307/HCC-N2
Calculated value as 0: C, 59,85; H, 7,13; N
, 6.75 Actual value: C, 59,99; H, 6,8
7; N, 6.68 Example 27-1 Methyl 4-(2,3 dimethoxy-6,7-cyhydro-58-benzocyclohebutene-
8-ylcarbonyl)-1-(3゜4.5-trimethoxybenzyl)piperazine-2carboxylate 1,2
While heating and refluxing a mixture of 045 g of sodium borohydride and 20 g of tetrahydrofuran, 3 g of methanol was added dropwise over 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was added to water and extracted with ethyl acetate. The organic layer was washed with water, dried, and then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate: acetone-1:
1:1), 4-(2,3-7methoxy6
．． 1.1 g of colorless oil of 7-sihydro-58-benzocyclohebuten-8-ylcarbonyl)-1-(3,4,5 trimethoxybenzyl)piperazine-2-methanol
is obtained. When this product is converted to hydrochloride and treated with ether, it becomes a colorless powder.

Elemental analysis value, C2°H3,N 207・HCC・Calculated value as 1/2H20: C, 60,88; H, 7,05; N
, 4.90 actual value C, 60, 66; H, 7, 17
N, 4.69 Example 27-2 4-(2,3-methoxy6.7-7hydro-58-benzocyclohebuten-8-ylcarbonyl)-1-(3 , 4゜5-trimethoxybenzyl)piperazine-2-methanol 11g
A 3-dilute solution of N,N-dimethylformamide was added with 0.15 g of sodium hydride and N.

Add dropwise to a mixture of 4 ml of N-dimethylformamide over 3 minutes while stirring at 0°C. Then methyl iodide 0
．． After adding 5g, stir at room temperature for 1 hour. The reaction solution was added to ice water and extracted with ethyl acetate, and the organic layer was washed with water, dried, and then evaporated under reduced pressure. The residue was subjected to silica gel column chromatography.Bexane:ethylacetone acetate-221
), 1-(2,3-dimethoxy-6,7-
0.6 g of sihydro-5H-benzocyclohebuten-8-ylcarbonyl)-3-methoxymethyl-4-(3,4,5 trimethoxybenzyl)piperazine are obtained as a colorless oil. When this product is converted to hydrochloride and precipitated with ether, it becomes a colorless powder.

Elemental analysis value: C3, H,, N207-HCQ-41
Calculated value as 5H,O: C, 60,91; H, 7,26; N
, 4.74 actual value C, 61,06; H, 7,29
N, 4.70 Example 28 Ethyl 4-(2,3 dimethoxy-6,7-cyhydro-58-benzocyclohebutene- obtained in Reference Example 29)
3,4.
A solution of 0.65 g of 5-trimethoxybenzoyl chloride in dichloromethane 12d is added dropwise over 3 minutes. After stirring the reaction solution at room temperature for 1 hour, it was added to water and extracted with dichloromethane. The organic layer was washed successively with dilute hydrochloric acid, aqueous sodium bicarbonate solution, and water, dried, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate: acetone - 2:2:1) to obtain ethyl 4
-(2,3-dimethoxy-6,7-sihydro58-benzocyclohebuten-8ylcarbonyl)-1-(3,
4,5-1-rimethoxybenzoyl)piperazine-2-
1.4 g of a colorless oil of carboxylate are obtained. When this product is precipitated with ether and hexane, it becomes a colorless powder.

Elemental analysis value: C3, H38N Calculated value as 2011: C,,63,90; H,6,57; N,
4.81 Actual value C263°62; H, 6,59;
N, 4.67 Example 29 Ethyl 1-(2,3 dimethoxy-6,7-cyhydro-58-benzocyclohebutene- obtained in Example 28)
8-ylcarbonyl)-4-(3゜4.5-tritoxybenzoyl)piperazine-3carboxylate 0
, 5 g, potassium carbonate l, Og.

A mixture of 10 d of methanol and 10 d of water is stirred at 70° C. for 20 minutes. The reaction solution was concentrated under reduced pressure, the residue was added to water, acidified with dilute hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with water, dried, and evaporated under reduced pressure to give 1-(2,3-dimethoxy-6,7-sihydro-5H-benzocyclohebuten-8-ylcarbonyl)-4-(3,4,5-trimethoxybenzoyl). ) 0.38 g of crystals of piperazine-3-carboxylic acid are obtained. When this product is recrystallized from ethyl acetate, it becomes colorless crystals. Melting point 198-199°C Elemental analysis value: C2° Calculated value as H34N209: C,6
2,81; H, 6,18; N, 5.05 Actual value: C, 62,81; H, 6,25; N, 5.
045 g of 1-(2,3-dimethoxy-6 fudihydro 5H-benzocyclohebuten-8ylcarbonyl)-1-(3,4,5-trimethoxybenzoyl)piperazine-2-carboxylic acid, Add 0.6 g of diethyl cyanophosphate and 04 g of triethylamine while stirring a mixture of 0.37 g of dimethylamine hydrochloride, 0.7 g of triethylamine, and hexagonal N,N-dimethylformamide at O'C. After stirring for a minute, add to ice water and extract with ethyl acetate.

The organic layer was washed with water, dried once, and then evaporated under reduced pressure to give N,N-dimethyl 4-(2,3-dimethoxy-6,7-hydro 5
H-benzocyclohebuten-8-ylcarbonyl)1-
(3,4,5-)rimethquinbenzoyl)piperazine-
0.44 g of 2-carboxamide crystals are obtained. When this product is recrystallized from ethyl acetate, it becomes colorless needle crystals. Melting point: 177-178°C Elemental analysis: C3, H3°N
Calculated value as 308: C, 64,01; H, 6,7
6; N, 7.22 Actual value: C, 63,89;
H, 6,74: N, 7.04 Example 30-1 Ethyl 4-(2,3 dimethoxy-6,7-cyhydro 5H-benzocyclohebutene-
8-ylcarbonyl)-1-(3゜4.5-trimethoxybenzoyl)piperazine-2carboxylate 0.5
While heating and refluxing a mixture of 0.4 g of sodium borohydride and 151 nIl of tetrahydrofuran, 3 g of methanol was added dropwise over 40 minutes. The reaction solution was concentrated under reduced pressure, and the residue was extracted with ethyl acetate. The organic layer was washed with water, dried, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate/acetone-1:11).
) to give a colorless oil of 4-(2,3-dimethoxy-6 fudihydro-58-benzonechlorohepten-8ylcarbonyl)-1-(3,4,5-)rimethoxyhenzoyl)piperazine-2-methanol. 0.45 g of product is obtained. When this product is treated with ether, it becomes a colorless powder.

Elemental analysis value: Calculated value as C29H3eN20e: C, 64,43; H, 6,71; N, 5
．． 19 actual measurements: C, 64,18; H, 6,86;
N, 5.02 Example 30-2 4-(2,3-dimethoxy-6,7-cyhydro-5H-benzocyclohebutene-8 obtained in Example 30-1)
-ylcarbonyl)-1-(3,4,5trimethoxybenzoyl)piperazine-2-meth/-.l was added to a mixture of 0.07 g of sodium hydride and NN-dimethylformamide at 0°C. Add while stirring. Next, 0.2 g of methyl iodide was added and stirred at O'C for 30 minutes.

The reaction solution was added to ice water and extracted with ethyl acetate. The organic layer was sequentially washed with dilute hydrochloric acid, an aqueous solution of hydrogen carbonate, and ice water, dried, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate: acetone).
1:1:1), ■-(2,3-7methoxy6,7-sihydro5H-bendicyclohebutene-8
-ylcarbonyl)-3methoxymethyl-4-(3,4
,5-)rif-1-xybenzoyl)piperazine is obtained as a colorless oil. When the main island is treated with ether, it becomes a colorless powder.

Elemental analysis value: Calculated value as C30H38N 20 a: C, 64,97; H6,91N5.05 actual measurement C, 64,80; H, 7,13; N, 4.
79 Example 31 A solution of 0.53 g of 2.3-dimethoxy6.7-dihydro-5H benzocycloheptene 8-carbonyl chloride dissolved in 8% dichloromethane was dissolved in ethyl 4-(3
,4,5-trimethoxybenzoyl)piperazine-2-
The mixture was added dropwise over 3 minutes to a mixture of 7 g of Carpoki/Re 1), 05 g of triethylamine, and 15 g of dichloromethane while stirring at O'C. After stirring the reaction solution at room temperature for 2 hours, it was poured into ice water and extracted with dichloromethane. The organic layer was washed successively with dilute hydrochloric acid, an aqueous 17% sodium bicarbonate solution, and water, dried, and evaporated under reduced pressure. When the crystals obtained from the residue are recrystallized from ethyl acetate and hexane, ethyl 1
-(2,3-diftkin-6, hunhydro5I]-
benzocyclohebuten-8-ylcarbonyl)-4-(
3,4,5-1-rimethoxybenzoyl)piperazine-
0.9 g of colorless crystals of 2-carboxylate are obtained.

Melting point 108-110'C Elemental analysis value/CsIH38N Calculated value assuming 20°:
C, 63,90; H, 6,57; N, 4.8
1 Actual measurement: C, 63, 68, H, 6, 63; N, 4
．． 87 Example 32-1 Ethyl obtained in Example 31 1-(2,3-dimethoxy-6,7-dihydro-58-benzocyclohebutene-
8-ylcarbonyl)! -(3,4゜5-trimethoxybenzoyl)piperazine-2 carboxylate is reduced with sodium borohydride and methanol in tetrahydrofuran in the same manner as in Example 27-1 to produce 1-(2,3
-dimethoxy-6,7-sihydro-5H-benzonechlorohepten-8-ylcarbonyl)-4-(3,4,5-
Trimethoxybenzoyl)piperazine-2-methanol is obtained. When Honjima is recrystallized from ethyl acetate, colorless crystals (melting point 169°C) are obtained.

Elemental analysis value C2°H, 6N 20. Calculated value・
C, 64,43; H, 6,71; N, 5.18
Actual value C, 64, 18; H, 6, 66; N,
5.09 Example 32-2 l-(2,3-dimethoxy-67-dihydro5H-benzocyclohebuten-8-ylcarbonyl)-4-(3
,4,5-)rimethoxybenzoyl)piperazine-2-
30 mg of sodium hydride was added to a mixture of 290 mg of methanol and 50% of tetrahydrofuran at O'C, and the mixture was stirred for 2 hours. Next, 130 mg of methyl iodide was added and the mixture was further stirred at room temperature for 3 hours. Pour the reaction solution into ice water and extract with dichloromethane. Wash the extract with citric acid, dry and concentrate. The residue was subjected to silica gel column chromatography (eluent: ethyl acetate-hexane-4:1), and 1-(2,3-dimethoxy-6,7-dihydro 5H)
250 mg of -benzocyclohebuten-8-ylcarbonyl)2-methoxymethyl-4-(3,4,5-trimethoxybenzoyl)piperazine are obtained as colorless crystals. Melting point 137°C Elemental analysis value/Calculated value as C3oH38N208:
C, 64,97; H, 6,91; N, 5.05
Actual value: C, 63,58, H, 6,88; N, 4
．． 68 Example 33 A solution of 144 g of 2.3-dimethoxy-6,7-dihydro-5H benzocyclohebutene-8-carbonyl chloride dissolved in 18 d of dichloromethane was dissolved in methyl 1-(3,4゜5-trimethoxybenzyl)piperazine-2-carboxylate dihydrochloride 2.1
6 g,) was added dropwise to a mixture of 2.5 g of ethylamine and 251 nfl of dichloromethane over 5 minutes while stirring at 06C. After stirring the reaction solution at room temperature for 1 hour, it was poured into ice water and extracted with dichloromethane. Add 3/3 water to the organic layer.

After drying, evaporate under reduced pressure. The residue was purified by silica gel column chromatography (hexane, ethyl acetate-3:
3:l) to give methyl 4-(2,3-dimethoxy-6,7-cyhydro-5H-benzocyclohebuten-8-ylcarbonyl)-]-(3 , 4,5 trimethoxybenzyl)piperazine-2-carboxylate, 2.2 g of a colorless oil are obtained.

Example 34 A solution of 1.2 g of 2.3-dimethoxy-6,7-dihydro-5H benzocyclohebutene-8-carboxylic acid chloride dissolved in 15 g of dichloromethane was added to the methyl 4-<3. 4.5 trimethquin hensyl)
1.8 g of piperazine-2-carboxylate dihydrochloride,
Add dropwise to a mixture of 2.0 g of triethylamine and 20 g of dichloromethane over 5 minutes while stirring at 0°C. After stirring the reaction solution at room temperature for 2 hours, it was poured into ice water and extracted with dichloromethane. The organic layer was washed with water, dried, and then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate = 2 = 2.1) to give methyl 1-(2,3-dimethoxy-6,7), which is the same as the compound obtained in Example 23. -Shihidoro 5
8-benzocyclohebuten-8-ylcarbonyl)-4
-(3,4,5-trimethoxyhensyl)piperazine-
8 g of pale yellow oil of 2-carboxylate are obtained.

Example 35 1-(2,3-dimethoxy6.7 obtained in Example 27-1)
-Sihydro5H-benzocyclohebuten-8-ylcarbonyl)-4-(3,4,5-trimethoxyhensyl)piperazine-2-A mixture of 500 mg of methanol and 3 volumes of N,N-dimethylformamide was cooled to 0°C. 60%
Add 80 mg of oily hydrogenated sodium chloride little by little. 3
After stirring for 0 minutes, the reaction solution was cooled to -20°C, and a mixture of 200 mg of ethyl iodide and 1-N,N-dimethylformamide was added dropwise. After stirring at -20°C for 4 hours, the reaction solution was poured into ice water and extracted with methylene chloride. The organic layer was washed with water and dried with anhydrous magnesium sulfate.
Concentrate under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate-hexane-methanol 50:45:5).
420 mg of a colorless oil of 3-dimethoxy-6°7-cyhydro5H-benzocyclohebuten-8ylcarbonyl)-2-ethoxymethyl-4-(3,4,5-trimethoxybenzyl)piperazine are obtained. Dissolve Honjima in ethyl acetate, make the hydrochloride with 4N hydrochloric acid (ethyl acetate solution), add ethyl ether and leave to stand, colorless crystals of hydrochloride will form.

Melting point 169-171°C Elemental analysis value C3+ H-2N 20?・)(CQ
・Calculated value as l/2H20: C, 62,04; H, 7,39; N
, 4.67 actual value C, 62,45; H, 7,32
N, 4.75 Examples 36-39 By the same method as in Example 35, 1-(2,3 dimethoxy-6,7-cyhydro-5H-benzocyclohebuten-8-ylcarbonyl l-4-(3゜Reaction of 4.5-trimethoxybenzyl)piperazine-2methanol with an organic halide provides the compounds of Examples 36-39.

CH3CH2C1+2 H2C=CI(CI+2 HC:C-CL V:>cu2 C328-4N20?・HCl2・1/2H20 C32H4=N207・Cg C32H4ON20?' HC(I C+311+4N207・Cl2 62.58 7.55 4.56 (62 ,2987,7104,48) 63.72 7,19 4.64 (63,7087,3904,63) 63.94 6.87 4.66 (63,84) (6,87) (4,73)64 .22
7.35 4゜54 (64,10X7.60X4.58) 152-1.56 154-157 White powder White powder Example 40 1-(2,3 Dimethoxy6.7 Dihydro 5H-Hensin Chlohebutene-8- ylcarbonyl)−
4-(3,4,5-trimethoxybenzyl)piperazine-2-methanol 500 mg, acetic anhydride 153 mg
, 150 mg of triethylamine, 10 mg of 4-dimethylaminopyridine, and 5 rotations of methylene chloride are stirred at room temperature for 20 hours. Add methylene chloride to the reaction solution,
The organic layer is washed with aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate) to give 2-acetoxymethyl-1-(2,3
420 mg of -dimethoxy-6,7-sihydro-58-hencinchlohebuten-8-ylcarbonyl)-4-(3,4,5 trimethoxypencyl)piperazine are obtained. When this product is converted into a hydrochloride salt and recrystallized from ethanol, it becomes colorless prismatic crystals.

Melting point 135-139°C Elemental analysis value C3, H40N208・HC(・l/2H
Calculated value as 20: C, 60, 63; H, 6, 89; N
, 4.56 Actual value: C, 60,53; H, 7,0
3; N, 4.38 Example 41 1-(2,3-dimethoxy-6,7-dihydro 5H-benzocyclohebuten-8-ylcarbonyl)-4-(3
, 4,5-)rimethoxypencyl)piperazine-2-methanol 500 mg, methylisoanate], 00
A mixture of 200 mg of ethylamine and 5 volumes of methylene chloride is stirred at room temperature for 5 hours. Methylene chloride is added to the reaction solution, and the organic layer is washed with an aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (
Eluent, ethyl acetate-hexane-methanol-541)
When purified with
-2'-N-methylcarbamoyloxymethyl-4-(
3,4,5-trimethoxybenzyl)piperazine 440
mg is obtained.

When this product is converted into the hydrochloride salt and recrystallized from ethanol, it becomes colorless crystals. Melting point +61-163°C Elemental analysis value C3
,H4,N308・HCo,calculated value: C,60
,04; H, 6,83; N, 6.78 Actual value:
C, 60,01; H, 6,98; N, 6.4
9 Example 42 In a solution of 175 mg of oxalyl chloride dissolved in 1 dimethyl chloride, 2 dimethyl sulfoxide was added at -78°C.
A solution of 15 mg dissolved in 1 d of methylene chloride was added dropwise,
Stir for 10 minutes. To the obtained reaction solution, 1. −(2,
3-Dimethoxy-6,7-cyhydro-5H-benzocyclohebuten-8-ylcarbonyl)-4-(3,4,5
A solution of 500 mg of -trimethoxyhensyl)piperazine-2-methanol dissolved in dichloromethane chloride was added dropwise, and the mixture was stirred for 10 minutes. Then triethylamine 650
After adding mg, the reaction temperature is raised to room temperature. Then, water was added to the reaction solution, and the mixture was extracted with methylene chloride. The organic layer is washed with water, dried, and concentrated under reduced pressure. The residue was dissolved in 5 volumes of methanol, and 200ml of dimethylamine hydrochloride was added to the resulting solution.
g and 130 mg of sodium cyanoborohydride. The reaction solution was stirred at room temperature for 48 hours, then poured into an IN hydroxide solution and extracted with methylene chloride. The organic layer is washed with water, dried, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent methanol-ethyl acetate-15:85) to give 1-(2,
200 mg of 3dimethoxy-6,7-cyhydro-5H-benzocyclohebuten-8-ylcarbonyl)-2-dimethylaminomethyl-4-(3,4,5-)rimethoxyhenzyl)piperazine are obtained.

This product is converted into a hydrochloride salt, and when recrystallized from ethanol, it becomes colorless prismatic crystals.

Melting point 167-169°C Elemental analysis value C,, H,, N 308.2 Calculated value as HCC: C, 59,42; H, 7,24;
N, 6.71 Actual value: C, 59,18; H, 7J
3; N, 6.68 Example 43 To a solution of 360 mg of oxalyl chloride dissolved in 5 ml of methylene chloride was added 3 ml of dimethyl sulfoxide at -78°C.
A solution of 0 mg dissolved in 2 d of methylene chloride was added dropwise, and 1
Stir for 0 minutes. 1-(2,3-dimethoxy-67-dihydro-5H-benzocyclohebuten-8-ylcarbonyl)-4-(3,4,5-1-rimethoxypencyl)piperazine-2-methano was added to the resulting reaction solution. 750m
A solution of g dissolved in methylene chloride dichloromethane was added dropwise, and the mixture was stirred for 15 minutes. Next, 1 g of triethylamine was added to the reaction solution, and the reaction temperature was raised to room temperature. The reaction solution was poured into ice water and extracted with methylene chloride. The organic layer is washed with water, dried, and concentrated under reduced pressure. The resulting residue was dissolved in 10 ml of methanol, 1.4 g of diethylamine hydrochloride was added, and the mixture was stirred at 50° C. for 3 hours. After cooling, 90 mg of sodium cyanoborate was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour. The reaction solution was poured into ice water and extracted with methylene chloride.

The organic layer is washed with water, dried, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate-methanol-9,1) to yield 2-diethylaminomethyl-1-(2,3-dimethoxy-6,7-dihydro-58-benzocyclohebutene- 8-ylcarbonyl)! 230 mg of -(3,45-trimethoxypencyl)piperazine are obtained. When this product is converted into the hydrochloride salt and recrystallized from ethanol, it becomes colorless crystals.

Melting point 157-160°C Elemental analysis value C3sH-7N30e' Calculated value as 2HCQ: C, 60,54; H, 7,54; N
, 6.42 Actual value: C, 60,47; H, 7,6
0; N, 6.40 Example 44 1-(23-dimethoxy-6,7-dihydro5H-benzocyclohebuten-8-ylcarbonyl)-4-(3
, 4,5-trimethoxyhensyl)piperazine-2-methanol 500 mg, simethylsulfide 94
0mg,) so n-butylphosphine 2.0g and N
, N-dimethylformamide at room temperature for 20 min.
Stir for an hour. The reaction solution was poured into dilute hydrochloric acid and washed with ethyl ether. The aqueous layer is made alkaline with thorium bicarbonate and extracted with methylene chloride. The organic layer is washed with water, dried, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate) to yield 1
40 mg of -(2,3-dimethoxy-6,7-dihydro5H-benzocyclohebuten-8-ylcarbonyl)-2-methylthiomethyl-4-(3,4,5trimethoxybenzyl)piperazine are obtained. When this product is converted into hydrochloride, it becomes a colorless powder.

Elemental analysis value C3,H,oN206S -H(1!・2
Calculated value as H30・C, 57, 27; H,? , 21; N,
4.45 actual measurement value C, 57,50; H, 7,05,
N, 4.42 Example 45 To a mixture of 1.0 g of 4-(3,4,5-)rimethoxybenzyl)-2-piperazinepropanol obtained in Reference Example 32, 1.5 g of triethylamine, and 20 volumes of methylene chloride. , 23-dimethoxy-6,7 with stirring at 0°C.
A solution of 713 mg of -dihydro-5H-benzocyclohebutene-8-carbonyl chloride dissolved in methylene chloride is added dropwise. After stirring for 2 hours, add an aqueous sodium hydrogen carbonate solution to the reaction mixture and shake. The organic layer is separated, washed with water, dried, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: ethyl acetate-hexane-methanol-5:4:), and the resulting crude crystals were recrystallized from ethyl acetate to yield 1-(2,3-dimethyne-6). ,7-sihydro5H-benzocyclohebuten-8-ylcarbonyl)-4-(3,4,5-1-
1.05 g of colorless prismatic crystals of 2-piperazinepropanol (rimethoxybenzyl) are obtained.

Melting point 144-145°C Elemental analysis value Calculated value as C3, H4, N207: C
,67,13; H,7,63; N,5.05 actual value・C,66,76; H,7,74; N,4
．． 98 Example 46 1-(23-dimethoxy6.7-
Cyhydro 5H-benzocyclohebuten-8-ylcarbonyl) to 4-(3,4,5-tritoxybenzyl)
-2-piperazinepropanol 500mg to pyridine 2
Add 190 mg of p-toluenesulfonyl chloride to the slightly dissolved solution at 20°C and stir for 10 minutes. The reaction solution was poured into an aqueous sodium hydrogen carbonate solution and extracted with methylene chloride. The organic layer is washed with water, dried, and concentrated under reduced pressure. Add 340 mg of sodium borohydride to a solution of the residue dissolved in dimethyl sulfoxide, and heat at 80°C.
Stir for 1 hour. After cooling, the reaction mixture was poured into an aqueous solution of thorium hydrogen carbonate and extracted with ethyl acetate. The organic layer is washed with water, dried, and concentrated under reduced pressure.

The residue was purified by column chromatography on silica gel (eluent: ethyl acetate-hexane-methanol-54.1), and the resulting crude product was converted into a hydrochloride salt and recrystallized from ethanol to give 1-(2,3- Colorless prism crystals of dimethoxy-6,7-cyhydro5H-hendicyclohebuten-8-ylcarbonyl)-2-propyl-4-(3,4,5-trimethoxybenzyl)piperazine hydrochloride 22
You can get 0mg.

Melting point 172-176°C Elemental analysis value C3,i (calculated value as 42N 20 e・HCρ C,64,74,H,7,54,N,4.8
7 Actual measurement value C, 64, 50; H, 7, 44; N
, 4.80 Example 47 3-methoxymethyl-1 (3,4
,5-)rimethoxybenzyl)piperazine dihydrochloride 50
0mg, imidazo[1,2-a]pyridine-2-carboxylic acid 211mg,) ethylamine 657mg, N,N
- 277 mg of diethyl cyanophosphonate was added to a mixture of 3 dimethylformamides while stirring under water cooling with N,
Add the dissolved solution of N-dimethylformamide 1 dropwise and stir for 1 hour. The reaction solution was poured into ice water and extracted with ethyl acetate. The organic layer is washed with water, dried, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (
Eluent, ethyl acetate) and recrystallized from ethanol to give 2-[2-methoxymethyl-4-(3,4,5-
) colorless prismatic crystals of rimethoxybenzyl)piperazin-1ylcarbonyl]imidazo[L2-a]pyridine 35
4 mg is obtained.

Melting point 129-130'C Elemental analysis value CthH3ON Calculated value as 40 s:
C, 63,42, H, 6,65; N, 12.33
Actual value: C, 63,27; H, 6,65; N
, 1'2.43 Examples 48-51 3-methoxymethyl 1-(3
,4,5-)rimethoxybenzyl)piperazine dihydrochloride and carboxylic acids in the presence of triethylamine,
Condensation with diethyl cyanophosphonate in N-dimethylformamide (DMF) provides the compounds of Examples 48-51.

(Left below) Example 52 3g of 2methoxymethyl(3,4,5trimethoxyhendiyl)piperazine obtained in Reference Example 6, 0.52g of hydrochloride, 2-(3-pyridyl)thiazole-
4-carboxylic acid 0.3g, triethylamine 0.46g
In a mixture of 3 parts of N,N-dimethylformamide and 0.47 parts of diethyl cyanophosphate, stir under water cooling.
Drop g. After stirring the reaction solution at OoC for 1 hour,
Pour into ice water and extract with ethyl acetate. Wash the organic layer with water,
After drying, concentrate under reduced pressure. The residue was subjected to column chromatography on silica gel (eluent: AcOEt:C
Purification with H2C (!2:MeOH=10:9:1) yields 2-methquinmethyl-1-[2-(3-pyridyl)
thiazol4-ylcarbonyl]-4-(3,4,5-
)rimethoxybenzoyl)piperazine is obtained. Colorless needle crystals (recrystallized from ethanol), melting point 149-15
0°C elemental analysis (ic ff15HzsN40 as ・
Calculated value as I/3Hto: C, 57, 90; H
, 5,57; N, 10.80 Actual value: C, 58, 1
2; H5,52・N 10.86 Example 53 2-methoxymethyl-4 (3,4,
5-1-rimethoxybenzoyl)piperazine hydrochloride 0
．． Cyanoline was added to a mixture of 50 g, 2'-(3,4-dimethquinphenyl)thiazole-4-carboxylic acid, 0.37 g, I-liethylamine, 0.42 g, and N,N-dimethylformamide while stirring under water cooling. 0.46 g of diethyl acid is added dropwise. The reaction solution was stirred at OoC for 1 hour, then poured into ice water and extracted with ethyl acetate. The organic layer is washed with water, dried, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: Ac0Et
) to obtain 1-[2-(3,4-dimethoxyphenyl)thiazole-4-ylcarponi/l/]-2-methoxymethyl-4-(3,4,5-trimethoxybenzoyl)piperazine. . Colorless needle crystals (recrystallized from ethanol), melting point 149-151°C Elemental analysis value C
Calculated value C as 28H33N308S/1/2H20
, 57,92; H, 5,90; N, 7.24 Actual value: C, 5g, 22; H, 5,81; N,
7.36 Example 54 Ethyl 1-(2,3-dimethoxy-6, fushihitro 5H-benzocyclohebuten-8-ylcarbonyl)
-1.2 g of -4-(3,4,51-rimethoxyhenzoyl)piperazine-2-carboxylate in methanol 15
Add 3.0 g of potassium carbonate and 8 oz of water to the slightly dissolved solution, and stir at 70°C for 30 minutes. 50% water to reaction solution
Add chlorine and wash with ethyl acetate. The aqueous layer is acidified with dilute hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water, dried, and concentrated under reduced pressure to give 1-(2,3-shiftkin-6,fusihydro-58-benzocyclohebuten-8-ylcarbonyl)-4-(3,4,5-trimethoxybenzoyl)piperazine. 11 g of crude -2-carphonic acid are obtained as a colorless oil. 0.37 g of diphenylphosphoryl azide was added dropwise to a mixture of 0.75 g of main island, 014 g of ethylamine, and 4 ml of N,N-dimethylformamide while stirring under water cooling. Pour the reaction solution into ice water,
Extract with benzene. After washing the organic layer with water and drying, the total amount is about 20
The solvent is evaporated under reduced pressure until the mixture turns. After heating the resulting solution under reflux for 30 minutes, 5 turns of methanol was added and the mixture was further heated under reflux for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate-acetone-1:1:l), and the resulting crystals were recrystallized from ethyl acetate to give 1-(2, 0.6 g of colorless crystals of 3-diphthoquine-6fucyhydro-5H-benzocyclohebuten-8ylcarbonyl)-2-methoxycarbonylami/-4-(3,4,5-1somethoxyhenzoyl)piperazine are obtained. .

Melting point 143-145°C Elemental analysis value Calculated as C3oHsqN3oe:
C, 61,74; H, 6,39゛N, 7.20 Actual value C, 61,62; H, 6, +2; N, 7
．． 05 (Effect of the invention) Compound (I) of the present invention and its salt have excellent intestinal absorption,
It also shows excellent PAF antagonism when administered orally. Therefore, compound (1) and its salts can be administered orally as well as parenterally, such as by injection.

The effects of the present invention will be explained in more detail with reference to test examples below.

Test Example I Inhibitory effect on platelet aggregation by PAF Body weight 2-3k
g New Sealant White male rabbits were given citric acid as a blood clotting inhibitor (3.15% for 9 volumes of whole blood) under anesthesia.
(1 volume of citric acid) and blood was collected from the heart. This blood was centrifuged at 80 Orpm for 10 minutes, and platelet-rich plasma (
PRP) was obtained.

The remaining blood after PRP collection was centrifuged at 300 Orpm for 10 minutes to obtain platelet poor plasma (PPP). PRP to PP
The platelet count was adjusted to approximately 500,000/μρ by diluting with P. Platelet aggregation was measured using an 8-channel aggregometer (NBS H).
EMA TRACER6 Binary Bioscience, Ja
turbidimetry [Born, Nature,
194, 927-929 (1962)]. That is, after incubating PRP (250 μQ) in a siliconized cuvette for 3 minutes (37°C), the drug was dissolved in physiological saline (25 μC) or dissolved in 10 mM dimethyl sulfoxide, and then dissolved in physiological saline. Add the test substance (25 μC) prepared by diluting it with water,
After another 2 minutes, PAF (25 μg,
3 x 10-9 to I x 10-'M) to determine the maximum aggregation rate. Using the case of addition of physiological saline as a control, the inhibition rate was determined.

The results are shown in Table 1.

(Margin below) Platelet aggregation inhibitory effect (%) Drug concentration 3X10-6M 3X10-5M 61 100 9 6 100 100 75 100 100 100 100 1.00 00 60 100 84 100 43 100 80 100 100 100 88 100 1 00 100 100 +00 75 100 67 100 54 100 88 100 100 100 44 10046
47 10047
10048
10049 55
10050 100 100
51 63 10052
31 10053
100 100 Test Example 2 Suppressive effect on hypotension by PAF 5D (Jcff) male rats aged 6 to 8 weeks were subjected to cannulation of the femoral artery and vein under bendoparbital anesthesia, and were fasted overnight and used in the experiment.

Transducer (MUPo,
5-290-0- I[[, TOYOBALDWIN,
Japan) and polygraph (Sanei, J
Blood pressure was measured continuously using apan. PAF (0.5-1.0 μg/kg) dissolved in physiological saline so that blood pressure decreases by 30-45 maHg when blood pressure becomes constant.
, 250 μQ/kg) was injected through the venous cannula. PAF was injected again 30 minutes later, and the average of the two blood pressure reductions was used as a control. After blood pressure has recovered, reduce the drug by 5%
Oral administration of the test substance dissolved or suspended in physiological saline suspension of gum arabic (5 ml/kg) L, 1, 2.4
PAF was injected after hours. The inhibition rate of blood pressure reduction after administration was determined for the control versus the test subjects.

The results are shown in Table 2.

(Margin below) Example (mg/kg) Suppression rate (%) 00 2 00 9 8 1 7 4 00 00 00 00 00 00 00 00 00 00 00 5 8 1 4 4 00 00 00 00 00 00 0 00 00 00 00 9 8 6 00 0 00 00 9 00 7 4 6 1

Claims (1)

[Claims] Formula ▲ Numerical formula, chemical formula, table, etc. ▼ [In the formula, A is an optionally substituted phenyl group, an optionally substituted fused polycyclic hydrocarbon group, a substituted or a heterocyclic group with the formula Ar-CR^4=CR^5- (wherein, Ar represents an optionally substituted phenyl group, and R^4 and R^5 each represent hydrogen or a lower alkyl group); ), X represents a methylene group, carbonyl group, or thiocarbonyl group, and G represents a formula ▲ Numerical formula, chemical formula, table, etc. ▼ (where n represents an integer from 0 to 2) , Z is a bond, O, S, SO, SO_2, CO, C
OO, OCO, OCONR^7, CONR^7 or N
R^7 (R^7 represents hydrogen, lower alkyl group, lower haloalkyl group, lower alkenyl group or lower alkoxycarbonyl group), R^6 represents hydrogen, lower alkyl group, lower haloalkyl group, lower alkenyl group , represents a lower alkynyl group or a lower cycloalkyl group. however,
When n=0 and Z=bond, R^6 is neither hydrogen nor a lower alkyl group. ), R^1, R^
2 and R^3 each represent a lower alkyl group. ] or its salt.