JP2951875B2 - Bicyclic compound and platelet aggregation inhibitor containing the same - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

[0001] The present invention relates to a platelet aggregation inhibitor containing a novel bicyclic compound and a derivative thereof.

[0002]

BACKGROUND OF THE INVENTION Since the discovery that platelets play an important role in the development of thrombosis, various drugs that inhibit platelet aggregation have been used for the treatment of thrombosis. Platelet aggregation is triggered by various stimuli such as ADP, collagen, epinephrine, thrombin, thromboxane A ₂ , and platelet activating factor, so antiplatelet drugs only inhibit platelet aggregation by limited types of stimuli It was effective and its effectiveness was limited. On the other hand, the final process of platelet aggregation is the binding of platelets to each other via fibrinogen, and this process is common regardless of the type of stimulus that causes aggregation. Thus, recently, drugs that directly inhibit the binding of platelets to fibrinogen have attracted attention as antiplatelet drugs having an inhibitory effect on all aggregation-inducing stimuli. The binding site of fibrinogen to platelets is the glycoprotein GPIIb / IIIa present in the platelet membrane, and the -Arg-Gly-Asp- structure in the fibrinogen molecule is the minimum amino acid sequence required for binding to GPIIb / IIIa Is revealed, -Arg-Gly-
Drugs of the Future, 19 (2), 1 have reported many linear or cyclic peptides containing the amino acid sequence of Asp- or non-peptide compounds mimicking the structure thereof.
35 (1994), 19 (5), 461 (1994). Common structures of non-peptide compounds known so far include an acidic group such as a carboxyl group corresponding to the carboxyl group of aspartic acid, an amidino group corresponding to the guanidino group of arginine, a guanidino group, a piperazinyl group or an aminomethyl group. Basic groups were present at a certain distance, and diversity was found in the skeleton structure connecting the acidic groups and the basic groups. A compound having a bicyclic compound in which two 6-membered rings are fused to this skeleton structure is disclosed in PCT International Application No. WO 94/29273. However, the compounds specifically disclosed in WO 94/29273 are only three compounds having a tetrahydroisoquinoline structure,
Inhibitory effect their human platelet aggregation 1~13μ an IC ₅₀
M, and its activity is still insufficient as an antiplatelet drug.

[0003]

An object of the present invention is to provide a novel compound having a very strong platelet aggregation inhibitory action based on a fibrinogen antagonistic action. In addition, thrombosis such as ischemic heart disease, ischemic brain disease, peripheral circulation disorder, arterial thrombosis, arteriosclerosis, pulmonary vascular disorder, or after percutaneous transluminal coronary angioplasty or after percutaneous transluminal coronary artery reopening An object of the present invention is to provide a preventive or therapeutic agent for restenosis and reocclusion of stenosis.

[0004]

The present inventors have conducted intensive studies on non-peptide compounds having a fibrinogen antagonistic effect, and as a result, have found a novel bicyclic compound having a very strong platelet aggregation inhibitory effect. Completed.
That is, the present invention relates to a compound represented by the general formula (1):

[0005]

Embedded image Wherein, A represents an amidino group, guanidino group or aminomethyl group, B is _{-CH 2 O -, - OCH 2} -, - CH
^{_{2 N (R 1) -,}} - N (R 1) CH 2 -, - CON (R 1)
— Or —N (R ¹ ) CO— (R ¹ represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms), and W—X represents —C
H ₂ —CH ＝, —CH ₂ —N ＝ or —CH ＝ C ＝, Y represents —CH ₂ — or —O—, and Z represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms. Or a salt thereof.

Further, the present invention is a platelet aggregation inhibitor comprising a compound represented by the general formula (1) as an active ingredient. The present invention also provides thrombosis, comprising a compound represented by the general formula (1) as an active ingredient, or after percutaneous transluminal coronary angioplasty or after percutaneous transluminal coronary artery reopening. It is a prophylactic or therapeutic agent for restenosis and restenosis. Further, the present invention provides a compound represented by the general formula (2):

[0007]

Embedded image [Wherein G is a cyano group or HN = C (OR ² )-(R ²
Represents shown) an alkyl group having 1 to 4 hydrogen atoms or carbon atoms, B is _{-CH 2 O -, - OCH 2} -, - CH 2 N
(R ¹ ) —, —N (R ¹ ) CH ₂ —, —CON (R ¹ ) — or —N (R ¹ ) CO— (R ¹ is a hydrogen atom or a carbon atom
WX represents —CH _2.
-CH =, - CH ₂ -N = or -CH = C = represents,
Y is -CH ₂ - or -O- and represents, Z is comprises a compound or a salt thereof represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms]. The compound represented by the general formula (2) is very useful as a synthetic intermediate of the compound in which A is an amidino group in the general formula (1).

[0008]

DESCRIPTION OF THE PREFERRED EMBODIMENTS The present invention will be described below in detail.
In the present invention, the alkyl group having 1 to 4 carbon atoms means a methyl group, an ethyl group, a n-propyl group, an isopropyl group, an isobutyl group, a sec-butyl group, a tert-butyl group,
-Refers to a butyl group. _{-CH 2 -CH =, - CH 2} -N =,
“=” In —CH ＝ C ＝ or HN ＝ C (OR ² ) — (R ² represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms)
Indicates two connecting hands. The representative compounds represented by the general formula (1) of the present invention are specifically exemplified below as Compound Nos. 1-132, but are not limited thereto. This compound number is referred to in the following Examples, Pharmacological Test Examples and Formulation Examples.

(1) 7-[(4-amidinobenzoyl)
Amino] -1,2,3,4-tetrahydronaphthalene-
2-acetic acid, (2) 7-[(4-amidinobenzoyl) amino] -1,2,3,4-tetrahydronaphthalene-2
-Methyl acetate, (3) 7-[(4-amidinobenzoyl) amino] -1,2,3,4-tetrahydronaphthalene-2-ethyl acetate, (4) 7-[(4-amidinobenzoyl) amino]- N-propyl 1,2,3,4-tetrahydronaphthalene-2-acetate, (5) 7-[(4
-Amidinobenzoyl) amino] -1,2,3,4-tetrahydronaphthalene-2-acetic acid isopropyl,
(6) 7-[(4-amidinobenzoyl) amino]-
1,2,3,4-tetrahydronaphthalene-2-acetic acid
n-butyl, (7) 7-[(4-amidinobenzoyl)
Amino] -1,2,3,4-tetrahydronaphthalene-
Sec-butyl 2-acetate, (8) 7-[(4-amidinobenzoyl) amino] -1,2,3,4-tetrahydronaphthalene-2-tert-butyl acetate, (9) 7
-[N- (4-amidinophenyl) carbamoyl]-
1,2,3,4-tetrahydronaphthalene-2-acetic acid,
(10) 7- [N- (4-amidinophenyl) carbamoyl] -1,2,3,4-tetrahydronaphthalene-2
-Methyl acetate,

(11) ethyl 7- [N- (4-amidinophenyl) carbamoyl] -1,2,3,4-tetrahydronaphthalene-2-acetate; (12) 7- [N- (4
-Amidinophenyl) carbamoyl] -1,2,3,4
-Tetrahydronaphthalene-2-n-propyl acetate,
(13) 7- [N- (4-amidinophenyl) carbamoyl] -1,2,3,4-tetrahydronaphthalene-2
-Isopropyl acetate, (14) 7- [N- (4-amidinophenyl) carbamoyl] -1,2,3,4-tetrahydronaphthalene-2-n-butyl acetate, (15)
7- [N- (4-amidinophenyl) carbamoyl]-
1,2,3,4-tetrahydronaphthalene-2-acetic acid
sec-butyl, (16) tert-butyl 7- [N- (4-amidinophenyl) carbamoyl] -1,2,3,4-tetrahydronaphthalene-2-acetate, (17)
6-[(4-amidinobenzoyl) amino] chroman-
3-acetic acid, (18) 6-[(4-amidinobenzoyl)
Amino] chroman-3-methyl acetate, (19) 6-
[(4-amidinobenzoyl) amino] chroman-3-
Ethyl acetate, (20) 6-[(4-amidinobenzoyl) amino] chroman-3-n-propyl acetate,

(21) n-butyl 6-[(4-amidinobenzoyl) amino] chroman-3-acetate, (2
2) sec-butyl 6-[(4-amidinobenzoyl) amino] chroman-3-acetate, (23) 6-[(4-
Amidinobenzoyl) amino] chroman-3-acetic acid t
tert-butyl, (24) 6- [N- (4-amidinophenyl) carbamoyl] chroman-3-acetic acid, (25)
Methyl 6- [N- (4-amidinophenyl) carbamoyl] chroman-3-acetate, (26) 6- [N- (4-
(Amidinophenyl) carbamoyl] chroman-3-ethyl acetate, (27) 6- [N- (4-amidinophenyl) carbamoyl] chroman-3-acetic acid tert-butyl, (28) 7-[(4-amidinobenzoyl) amino ] -1,2,3,4-tetrahydroisoquinoline-2
-Acetic acid, (29) 7-[(4-amidinobenzoyl) amino] -1,2,3,4-tetrahydroisoquinoline-
Methyl 2-acetate, (30) 7-[(4-amidinobenzoyl) amino] -1,2,3,4-tetrahydroisoquinoline-2-ethyl acetate,

(31) n-propyl 7-[(4-amidinobenzoyl) amino] -1,2,3,4-tetrahydroisoquinoline-2-acetate, (32) 7-[(4-
Amidinobenzoyl) amino] -1,2,3,4-tetrahydroisoquinoline-2-acetic acid isopropyl, (3
3) 7-[(4-amidinobenzoyl) amino] -1,
2,3,4-tetrahydroisoquinoline-2-acetic acid n
-Butyl, (34) 7-[(4-amidinobenzoyl)
Amino] -1,2,3,4-tetrahydroisoquinoline-2-acetic acid sec-butyl, (35) 7-[(4-amidinobenzoyl) amino] -1,2,3,4-tetrahydroisoquinoline-2-acetic acid tert-butyl,
(36) 7- [N- (4-amidinophenyl) carbamoyl] -1,2,3,4-tetrahydroisoquinoline-
2-acetic acid, (37) 7- [N- (4-amidinophenyl) carbamoyl] -1,2,3,4-tetrahydroisoquinoline-2-ethyl acetate, (38) 7- [N-
(4-amidinophenyl) carbamoyl] -1,2,2
N-propyl 3,4-tetrahydroisoquinoline-2-acetate, (39) 7- [N- (4-amidinophenyl)
Carbamoyl] -1,2,3,4-tetrahydroisoquinoline-2-acetic acid n-butyl, (40) 7- [N-
(4-amidinophenyl) carbamoyl] -1,2,2
3,4-tetrahydroisoquinoline-2-acetic acid ter
t-butyl,

(41) 7-[(4-amidinobenzoyl) amino] -3,4-dihydronaphthalene-2-acetic acid, (42) 7-[(4-amidinobenzoyl) amino] -3,4-dihydronaphthalene -Methyl acetate, (43) 7-[(4-amidinobenzoyl) amino] -3,4-dihydronaphthalene-2-ethyl acetate, (44) 7- [N- (4-amidinophenyl) carbamoyl]- 3,4-dihydronaphthalene-2-acetic acid,
(45) 7- [N- (4-amidinophenyl) carbamoyl] -3,4-dihydronaphthalene-2-acetate, (46) 7- [N- (4-amidinophenyl) carbamoyl] -3,4- Dihydronaphthalene-2-acetic acid
Ethyl, (47) 7- [N- (4-amidinobenzoyl) -N-methylamino] -1,2,3,4-tetrahydronaphthalene-2-acetic acid, (48) 7- [N- (4-
Amidinobenzoyl) -N-methylamino] -1,2,2.
Ethyl 3,4-tetrahydronaphthalene-2-acetate,
(49) 7- [N- (4-amidinobenzoyl) -N-
Methylamino] -1,2,3,4-tetrahydronaphthalene-2-n-butyl acetate, (50) 7- [N- (4
-Amidinobenzoyl) -N-ethylamino] -1,
2,3,4-tetrahydronaphthalene-2-acetic acid,

(51) 7- [N- (4-amidinobenzoyl) -Nn-propylamino] -1,2,3,4-
Tetrahydronaphthalene-2-acetic acid, (52) 7- [N
-(4-Amidinobenzoyl) -N-isopropylamino] -1,2,3,4-tetrahydronaphthalene-2-
Acetic acid, (53) 7- [N- (4-amidinobenzoyl)
-Nn-butylamino] -1,2,3,4-tetrahydronaphthalene-2-acetic acid, (54) 7- [N- (4-
Amidinobenzoyl) -N-sec-butylamino]-
1,2,3,4-tetrahydronaphthalene-2-acetic acid,
(55) 7- [N- (4-amidinobenzoyl) -N-
Isobutylamino] -1,2,3,4-tetrahydronaphthalene-2-acetic acid, (56) 7- [N- (4-amidinophenyl) -N-methylcarbamoyl] -1,2,2
3,4-tetrahydronaphthalene-2-acetic acid, (57)
7- [N- (4-amidinophenyl) -N-methylcarbamoyl] -1,2,3,4-tetrahydronaphthalene-2-ethyl acetate, (58) 7- [N- (4-amidinophenyl) -N -Methylcarbamoyl] -1,2,2
N-propyl 3,4-tetrahydronaphthalene-2-acetate, (59) 7- [N- (4-amidinophenyl)-
N-methylcarbamoyl] -1,2,3,4-tetrahydronaphthalene-2-tert-butyl acetate, (6
0) 7- [N- (4-amidinophenyl) -N-ethylcarbamoyl] -1,2,3,4-tetrahydronaphthalene-2-acetic acid,

(61) 7- [N- (4-amidinophenyl) -Nn-propylcarbamoyl] -1,2,3,
4-tetrahydronaphthalene-2-acetic acid, (62) 7-
[N- (4-amidinophenyl) -N-isopropylcarbamoyl] -1,2,3,4-tetrahydronaphthalene-2-acetic acid, (63) 7- [N- (4-amidinophenyl) -Nn- Butylcarbamoyl] -1,2,3,
4-tetrahydronaphthalene-2-acetic acid, (64) 7-
[N- (4-amidinophenyl) -N-sec-butylcarbamoyl] -1,2,3,4-tetrahydronaphthalene-2-acetic acid, (65) 7- [N- (4-amidinophenyl) -N- Isobutylcarbamoyl] -1,2,2
3,4-tetrahydronaphthalene-2-acetic acid, (66)
6- [N- (4-amidinobenzoyl) -N-methylamino] chroman-3-acetic acid, (67) 6- [N- (4-
Amidinobenzoyl) -N-methylamino] chroman-
3-ethyl acetate, (68) 6- [N- (4-amidinobenzoyl) -N-methylamino] chroman-3-acetic acid n-propyl, (69) 6- [N- (4-amidinobenzoyl) -N -Methylamino] chroman-3-acetic acid
tert-butyl, (70) 6- [N- (4-amidinobenzoyl) -Nn-propylamino] chroman-3
-Acetic acid,

(71) 6- [N- (4-amidinobenzoyl) -Nn-butylamino] chroman-3-acetic acid,
(72) 6- [N- (4-amidinophenyl) -N-methylcarbamoyl] chroman-3-acetic acid, (73) 6-
[N- (4-amidinophenyl) -N-methylcarbamoyl] chroman-3-acetate, (74) 6- [N
-(4-amidinophenyl) -N-methylcarbamoyl] chroman-3-n-butyl acetate, (75) 6-
[N- (4-amidinophenyl) -N-ethylcarbamoyl] chroman-3-acetic acid, (76) 6- [N- (4-
Amidinophenyl) -Nn-propylcarbamoyl]
Chroman-3-acetic acid, (77) 6- [N- (4-amidinophenyl) -NN-butylcarbamoyl] chroman-3-acetic acid, (78) 7- [N- (4-amidinobenzoyl) -N -Methylamino] -1,2,3,4-tetrahydroisoquinoline-2-acetic acid, (79) 7- [N-
(4-amidinophenyl) -N-methylcarbamoyl]
-1,2,3,4-tetrahydroisoquinoline-2-acetic acid, (80) 7-[(4-amidinobenzyl) oxy]
-1,2,3,4-tetrahydronaphthalene-2-acetic acid,

(81) 7-[(4-amidinobenzyl)
Oxy] -1,2,3,4-tetrahydronaphthalene-
Methyl 2-acetate, (82) 7-[(4-Amidinophenoxy) methyl] -1,2,3,4-tetrahydronaphthalene-2-acetic acid, (83) 7-[(4-Amidinophenoxy) methyl]- Ethyl 1,2,3,4-tetrahydronaphthalene-2-acetate, (84) 7-[(4-amidinobenzyl) amino] -1,2,3,4-tetrahydronaphthalene-2-acetic acid, (85) 7 -[(4-amidinobenzyl) amino] -1,2,3,4-tetrahydronaphthalene-2-ethyl acetate, (86) 7- [N-
(4-amidinobenzyl) -N-methylamino] -1,
2,3,4-tetrahydronaphthalene-2-acetic acid, (8
7) 7- [N- (4-amidinobenzyl) -N-methylamino] -1,2,3,4-tetrahydronaphthalene-
2-ethyl acetate, (88) 7- [N- (4-amidinobenzyl) -Nn-butylamino] -1,2,3,4
-Tetrahydronaphthalene-2-acetic acid, (89) 6-
[(4-Amidinobenzyl) oxy] chroman-3-acetic acid, (90) 6-[(4-amidinobenzyl) oxy]
Chroman-3-ethyl acetate,

(91) 7-[(4-amidinobenzyl)
Oxy] -3,4-dihydronaphthalene-2-acetic acid,
(92) 7-[(4-amidinobenzyl) oxy]-
Methyl 3,4-dihydronaphthalene-2-acetate, (9
3) 7-[(4-guanidinobenzoyl) amino]-
1,2,3,4-tetrahydronaphthalene-2-acetic acid,
(94) 7-[(4-guanidinobenzoyl) amino]
Methyl-1,2,3,4-tetrahydronaphthalene-2-acetate, (95) 7-[(4-guanidinobenzoyl) amino] -1,2,3,4-tetrahydronaphthalene-2-acetate, (96) ) 7-[(4-Guanidinobenzoyl) amino] -1,2,3,4-tetrahydronaphthalene-2-n-propyl acetate, (97) 7-
[(4-guanidinobenzoyl) amino] -1,2,2
3,4-tetrahydronaphthalene-2-acetic acid tert
-Butyl, (98) 7- [N- (4-guanidinophenyl) carbamoyl] -1,2,3,4-tetrahydronaphthalene-2-acetic acid, (99) 7- [N- (4-guanidinophenyl) carbamoyl ] -1,2,3,4-tetrahydronaphthalene-2-ethyl acetate, (100) 7
-[N- (4-guanidinophenyl) carbamoyl]-
1,2,3,4-tetrahydronaphthalene-2-acetic acid
n-propyl,

(101) tert-butyl 7- [N- (4-guanidinophenyl) carbamoyl] -1,2,3,4-tetrahydronaphthalene-2-acetate;
2) 6-[(4-Guanidinobenzoyl) amino] chroman-3-acetic acid, (103) 6-[(4-guanidinobenzoyl) amino] chroman-3-acetate, (10
4) n-propyl 6-[(4-guanidinobenzoyl) amino] chroman-3-acetate, (105) 6-[(4-
Guanidinobenzoyl) amino] chroman-3-acetic acid t
tert-butyl, (106) 6- [N- (4-guanidinophenyl) carbamoyl] chroman-3-acetic acid, (1
07) 6- [N- (4-guanidinophenyl) carbamoyl] chroman-3-ethyl acetate, (108) 6-
[N- (4-guanidinophenyl) carbamoyl] chroman-3-tert-butyl acetate, (109) 7-
[(4-guanidinobenzoyl) amino] -1,2,2
3,4-tetrahydroisoquinoline-2-acetic acid, (11
0) 7-[(4-guanidinobenzoyl) amino]-
1,2,3,4-tetrahydroisoquinoline-2-ethyl acetate,

(111) 7- [N- (4-guanidinophenyl) carbamoyl] -1,2,3,4-tetrahydroisoquinoline-2-acetic acid, (112) 7- [N- (4
-Guanidinophenyl) carbamoyl] -1,2,3,
Ethyl 4-tetrahydroisoquinoline-2-acetate,
(113) 7-[(4-guanidinobenzoyl) amino] -3,4-dihydronaphthalene-2-acetic acid, (11
4) 7-[(4-guanidinobenzyl) oxy] -1,
2,3,4-tetrahydronaphthalene-2-acetic acid, (1
15) 7-[(4-guanidinobenzyl) amino]-
1,2,3,4-tetrahydronaphthalene-2-acetic acid,
(116) 7-[(4-guanidinophenoxy) methyl] -1,2,3,4-tetrahydronaphthalene-2-
Acetic acid, (117) 7- [N- (4-guanidinobenzyl) -N-methylamino] -1,2,3,4-tetrahydronaphthalene-2-acetic acid, (118) 7- [N- (4
-Guanidinobenzoyl) -N-methylamino] -1,
2,3,4-tetrahydronaphthalene-2-acetic acid, (1
19) 7- [N- (4-guanidinophenyl) -N-methylcarbamoyl] -1,2,3,4-tetrahydronaphthalene-2-acetic acid, (120) 7- [N- (4-guanidinophenyl)- N-ethylcarbamoyl] -1,
2,3,4-tetrahydronaphthalene-2-acetic acid,

(121) 7- [N- (4-guanidinophenyl) -Nn-butylcarbamoyl] -1,2,2
3,4-tetrahydronaphthalene-2-acetic acid, (12
2) 6-[(4-guanidinobenzyl) oxy] chroman-3-acetic acid, (123) 7-[(4-aminomethylbenzoyl) amino] -1,2,3,4-tetrahydronaphthalene-2-acetic acid, (124) 7-[(4-Aminomethylbenzoyl) amino] -1,2,3,4-tetrahydronaphthalene-2-ethyl acetate, (125) 7-
[N- (4-aminomethylphenyl) carbamoyl]-
1,2,3,4-tetrahydronaphthalene-2-acetic acid,
(126) 6-[(4-aminomethylbenzoyl) amino] chroman-3-acetic acid, (127) 7-[(4-aminomethylbenzoyl) amino] -3,4-dihydronaphthalene-2-acetic acid, (128 ) 7-[(4-Aminomethylbenzoyl) amino] -1,2,3,4-tetrahydroisoquinoline-2-acetic acid, (129) 7-[(4-aminomethylbenzyl) oxy] -1,2,3 , 4-Tetrahydronaphthalene-2-acetic acid, (130) 7-[(4
-Aminomethylbenzyl) amino] -1,2,3,4-
Tetrahydronaphthalene-2-acetic acid, (131) 7-
[(4-Aminomethylphenoxy) methyl] -1,2,2
3,4-tetrahydronaphthalene-2-acetic acid, (13
2) 6-[(4-aminomethylbenzyl) oxy] chroman-3-acetic acid

The compound of the present invention represented by the general formula (1)
In a preferred compound, A is an amidino group and B is
-CH_TwoO-, -OCH_Two-, -CH_TwoN (R¹)-, -N
(R ¹) CH_Two-, -CON (R¹)-Or -N (R¹)
CO- (R¹Is the same as defined above), and W
-X is -CH_Two-CH =, -CH_Two-N = or -CH
= C =, and Y is -CH_Two-Or -O-,
Z represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms
Compound.

In the compound of the present invention represented by the general formula (1), more preferably, A is an amidino group;
B represents —CON (R ¹ ) — or —N (R ¹ ) CO— (R
¹ is the same as defined above), and WX represents-
CH ₂ —CH ＝ or —CH ₂ —N =, and Y is —C
H ₂ — or —O—, wherein Z is a hydrogen atom or an alkyl group having 1 to 4 carbon atoms.

In the compound represented by the general formula (1) of the present invention, more preferably, A is an amidino group, and B is -CON (R ¹ )-or -N (R ¹ ) CO
— (R ¹ represents a hydrogen atom or a methyl group),
W—X is —CH ₂ —CH ＝ or —CH ₂ —N =, Y is —CH ₂ — or —O—, and Z is a hydrogen atom or an alkyl group having 1 to 4 carbon atoms. It is a compound represented.

The most preferred compound represented by the general formula (1) of the present invention is 7-[(4-amidinobenzoyl) amino] -1,2,3,4-tetrahydronaphthalene-2-acetic acid, -[N- (4-amidinophenyl) carbamoyl] -1,2,3,4-tetrahydronaphthalene-2-acetic acid, 6-[(4-amidinobenzoyl) amino] chroman-3-acetic acid or 7-[(4 -Amidinobenzoyl) amino] -1,2,3,4-tetrahydroisoquinoline-2-acetic acid, and 7-[(4-amidinobenzoyl) amino] -1,2,3,4-tetrahydronaphthalene-2-acetic acid Acetic acid, 7- [N- (4-amidinophenyl) carbamoyl] -1,2,3,4-tetrahydronaphthalene-2-acetic acid or 6-[(4-amidinobenzoyl) amino Chroman-3-acetic acid, and most preferred.

When the compound represented by the general formula (1) of the present invention has an asymmetric carbon atom in the molecule, any of the optical isomers having the R configuration or the S configuration with respect to the asymmetric carbon atom may be used. Included in the present invention. Further, salts of the compound represented by the general formula (1) of the present invention can also be exemplified as specific compounds of the present invention. Examples of the salt of the compound represented by the general formula (1) of the present invention include inorganic acid salts such as hydrochloride, hydrobromide, sulfate, nitrate and phosphate, and acetates.
Tartrate, citrate, fumarate, maleate,
Organic acid salts such as toluenesulfonic acid salt and methanesulfonic acid salt, and further, when Z is a hydrogen atom, metal salts such as sodium salt, potassium salt, calcium salt and aluminum salt, or primary amines such as ammonia And pharmacologically acceptable salts such as salts with organic bases such as secondary amines such as dimethylamine and tertiary amines such as triethylamine.

When the compound represented by the general formula (1) of the present invention is a compound wherein A is an amidino group, the compound represented by the general formula (2) of the present invention is particularly effective as a synthetic intermediate. Used for A specific example is Compound No. 1.
Specific examples are shown below as 33 to 164, but are not limited thereto. In addition, this compound number is
Reference is made in the following examples.

(133) ethyl 7-[(4-cyanobenzoyl) amino] -1,2,3,4-tetrahydronaphthalene-2-acetate, (134) 7-[[4- (ethoxyiminomethyl) benzoyl] Amino] -1,2,2
Ethyl 3,4-tetrahydronaphthalene-2-acetate,
(135) n-propyl 7-[[4- (n-propoxyiminomethyl) benzoyl] amino] -1,2,3,4-tetrahydronaphthalene-2-acetate, (136)
7-[[4- (n-Butoxyiminomethyl) benzoyl] amino] -1,2,3,4-tetrahydronaphthalene-2-n-butyl acetate, (137) 7- [N- (4
-Cyanophenyl) carbamoyl] -1,2,3,4-
Ethyl tetrahydronaphthalene-2-acetate, (13
8) 7- [N- (4-cyanophenyl) carbamoyl]
Tert-butyl-1,2,3,4-tetrahydronaphthalene-2-acetate, (139) 7- [N- [4- (ethoxyiminomethyl) phenyl] carbamoyl] -1,
Ethyl 2,3,4-tetrahydronaphthalene-2-acetate, (140) 7- [N- [4- (n-butoxyiminomethyl) phenyl] carbamoyl] -1,2,3,4-
N-butyl tetrahydronaphthalene-2-acetate, (1
41) Ethyl 6-[(4-cyanobenzoyl) amino] chroman-3-acetate, (142) 6-[[4- (ethoxyiminomethyl) benzoyl] amino] chroman-3.
-Ethyl acetate,

(143) Ethyl 6- [N- (4-cyanophenyl) carbamoyl] chroman-3-acetate, (1
44) Ethyl 6- [N- [4- (ethoxyiminomethyl) phenyl] carbamoyl] chroman-3-acetate;
(145) 7-[(4-cyanobenzoyl) amino]-
Ethyl 1,2,3,4-tetrahydroisoquinoline-2-acetate, (146) 7-[[4- (ethoxyiminomethyl) benzoyl] amino] -1,2,3,4-tetrahydroisoquinoline-2-acetate , (147) 7
-[[4- (n-butoxyiminomethyl) benzoyl]
Amino] -1,2,3,4-tetrahydroisoquinoline-2-n-butyl acetate, (148) 7- [N- (4-
Cyanophenyl) carbamoyl] -1,2,3,4-tetrahydroisoquinoline-2-tert-butyl acetate, (149) 7- [N- [4- (ethoxyiminomethyl) phenyl] carbamoyl] -1,2,3 , 4-Tetrahydroisoquinoline-2-ethyl acetate, (150)
7- [N- (4-cyanobenzoyl) -N-methylamino] -1,2,3,4-tetrahydronaphthalene-2-
Ethyl acetate, (151) 7- [N- [4- (ethoxyiminomethyl) benzoyl] -N-methylamino]-
1,2,3,4-tetrahydronaphthalene-2-acetic acid
Ethyl, (152) 7- [N- (4-cyanophenyl)
-N-methylcarbamoyl] -1,2,3,4-tetrahydronaphthalene-2-tert-butyl acetate,

(153) 7- [N- [4- (ethoxyiminomethyl) phenyl] -N-methylcarbamoyl]-
1,2,3,4-tetrahydronaphthalene-2-acetic acid
Ethyl, (154) 7- [N- (4-cyanophenyl)
-Nn-butylcarbamoyl] -1,2,3,4-tetrahydronaphthalene-2-ethyl acetate, (155)
7- [N- [4- (ethoxyiminomethyl) phenyl]
-Nn-butylcarbamoyl] -1,2,3,4-tetrahydronaphthalene-2-ethyl acetate, (156)
7-[(4-cyanobenzyl) oxy] -1,2,3
Methyl 4-tetrahydronaphthalene-2-acetate, (1
57) Methyl 7-[[4- (methoxyiminomethyl) benzyl] oxy] -1,2,3,4-tetrahydronaphthalene-2-acetate, (158) 7-[[4- (ethoxyiminomethyl) benzyl] Oxy] -1,2,3,
Ethyl 4-tetrahydronaphthalene-2-acetate, (1
59) 7-[(4-cyanophenoxy) methyl] -1,
Ethyl 2,3,4-tetrahydronaphthalene-2-acetate, (160) 7-[[4- (ethoxyiminomethyl)
Phenoxy] methyl] -1,2,3,4-tetrahydronaphthalene-2-ethyl acetate, (161) 6-[(4
-Cyanobenzyl) oxy] chroman-3-ethyl acetate, (162) 6-[[4- (ethoxyiminomethyl)
[Benzyl] oxy] chroman-3-ethyl acetate, (1
63) 7-[(4-Cyanobenzyl) oxy] -3,4
-Methyl dihydronaphthalene-2-acetate, (164)
7-[[4- (methoxyiminomethyl) benzyl] oxy] -3,4-dihydronaphthalene-2-acetate methyl,

In the case where the intermediate compound represented by the general formula (2) of the present invention has an asymmetric carbon atom in the molecule, any of the R configuration and the S configuration can be used for the asymmetric carbon atom. Are included in the present invention. Further, these salts can also be exemplified as specific compounds of the present invention. For example, inorganic acid salts such as hydrochloride, hydrobromide, sulfate, nitrate and phosphate, or acetate, tartrate, citrate, fumarate, maleate, toluene sulfonate, methanesulfonic acid Pharmaceutically acceptable salts such as organic acids such as salts.

The compound represented by the general formula (1) of the present invention can be produced, for example, by the following method. (A) Method General formula (3)

[0033]

Embedded image (Where A is as defined above) and a compound represented by the general formula (4)

[0034]

Embedded image Wherein WX, Y, Z and R ¹ have the same meanings as defined above, or a condensation reaction of the compound represented by the general formula (5):

[0035]

Embedded image (Wherein A and R ¹ have the same meanings as defined above) and a compound represented by the general formula (6)

[0036]

Embedded image (Wherein WX, Y and Z have the same meanings as defined above). (B) Method General formula (7)

[0037]

Embedded image Wherein A is as defined above, and a compound represented by the general formula (8):

[0038]

Embedded image [Wherein, W—X, Y, and Z have the same meanings as described above, and D represents —OH or —N (R ¹ ) H (R ¹ has the same meaning as the above definition)]. Or a condensation reaction of the general formula (9)

[0039]

Embedded image (Wherein A and D have the same meanings as defined above) and a compound represented by the general formula (10)

[0040]

Embedded image (Wherein WX, Y and Z have the same meanings as defined above). (C) Method Formula (11)

[0041]

Embedded image Or a compound represented by the general formula (4) is subjected to a condensation reaction or a compound represented by the general formula (12)

[0042]

Embedded image (Wherein R ¹ has the same meaning as defined above) and the compound represented by the general formula (6) are subjected to a condensation reaction or the compound represented by the formula (13)

[0043]

Embedded image Or a compound represented by the general formula (8) is subjected to a condensation reaction, or a compound represented by the general formula (14)

[0044]

Embedded image (Wherein D is as defined above) and a compound represented by the general formula (10) obtained by a condensation reaction with a compound represented by the general formula (10).

[0045]

Embedded image (Wherein, B, WX, Y and Z are as defined above)
A method of converting a cyano group of a compound represented by the formula into an amidino group by a known method. (D) Method General formula (16)

[0046]

Embedded image (Wherein E represents an amino group protected with a tert-butoxycarbonyl group or a benzyloxycarbonyl group) and a compound represented by the general formula (4), 17) [Formula 19]

[0047]

Embedded image (Wherein E and R ¹ are as defined above) and the compound represented by the general formula (6) are subjected to a condensation reaction or the compound represented by the general formula (18)

[0048]

Embedded image (Wherein E is as defined above) and the compound represented by the general formula (8) are subjected to a condensation reaction, or the compound represented by the general formula (19)

[0049]

Embedded image (Wherein E and D have the same meanings as defined above) and a compound represented by the general formula (10), which is obtained by a condensation reaction.

[0050]

Embedded image (Wherein, E, B, W—X, Y and Z have the same meanings as defined above), by treating the compound with an acid such as trifluoroacetic acid or hydrogen chloride;
General formula (21) obtained by performing a catalytic hydrogenation reaction in the presence of a catalyst such as Pt.

[0051]

Embedded image (Wherein, B, WX, Y and Z are as defined above)
A method of converting an amino group of a compound represented by the formula into a guanidino group by a known method. The compound represented by the general formula (2) can be produced by the above-mentioned method (c) or the following method. (E) Method Formula (22)

[0052]

Embedded image Or a compound represented by the general formula (4) is subjected to a condensation reaction or a compound represented by the general formula (23)

[0053]

Embedded image (Wherein R ¹ is as defined above) and the compound represented by the general formula (6) are subjected to a condensation reaction or the compound represented by the formula (24)

[0054]

Embedded image Or a compound represented by the general formula (8) is subjected to a condensation reaction, or a compound represented by the general formula (25)

[0055]

Embedded image (Where D is as defined above) and a compound represented by the general formula (10) obtained by a condensation reaction with the compound represented by the general formula (10).

[0056]

Embedded image (Wherein, B, WX, Y and Z are as defined above)
A method of converting a bromo group of a compound represented by the formula into a cyano group by a known method.

(F) Method The cyano group of the compound represented by the general formula (15) is converted to HN = C (O
R ² ) — (R ² is as defined above). As the condensation reaction in the method (a), an amide bond forming reaction in a normal peptide can be used. For example, using an amide bond forming reagent such as dicyclohexylcarbodiimide, N, N'-carbonyldiimidazole, diphenylphosphoric azide, ethyl cyanophosphate, or deriving a carboxyl group into an active ester, mixed acid anhydride or acid chloride It can be carried out by a method of reacting with an amino group. In the condensation reaction, the amidino group, guanidino group or amino group present is present as a salt of an inorganic acid, for example, hydrogen chloride, sulfuric acid, hydrogen bromide, or protected by a tert-butoxycarbonyl group or a benzyloxycarbonyl group. Is preferred. In any case of the above condensation reaction,
The reaction can be promoted by the addition of a base, preferably an organic base, such as triethylamine, N-methylpiperidine, 4-dimethylaminopyridine and the like. The reaction temperature is usually −20 to 50 ° C., and preferably 0 ° C. to around room temperature. As a commonly used solvent, for example, dioxane,
Examples include tetrahydrofuran, acetonitrile, N, N-dimethylformamide, chloroform, methylene chloride and the like, and they may be used alone or as a mixed solvent.

As the condensation reaction in the method (b), the reaction can be carried out by a method known per se, for example, in the presence of a base such as sodium carbonate, sodium alkoxide and sodium hydride. As the solvent, methanol, ethanol, 2-butanone, N, N-dimethylformamide or the like is used alone or in combination. The reaction temperature is usually from room temperature to 100 ° C., preferably 5
It can be performed at 0 to 70 ° C. (A) method and (b)
In the method, Z is preferably an alkyl group having 1 to 4 carbon atoms.

The condensation reaction in the method (c) can be carried out by a method according to the method (a) or the method (b). The conversion of the cyano group to the amidino group can be carried out by a method known per se, for example, by passing hydrogen chloride gas in a solvent such as ethanol to thereby convert the cyano group to HN = C (OR ² )-(R ² Can be carried out by converting it into an imidate represented by the same definition) and reacting it with ammonium acetate or ammonium chloride in ethanol. The reaction temperature is usually −20 to 50 ° C., preferably 0 to 50 ° C.
20 ° C.

The condensation reaction in the method (d) can be carried out by a method according to the method (a) or the method (b). The conversion of the amino group to the guanidino group is carried out by a method known per se.
For example, it can be carried out by reacting an amino compound of the general formula (21) with S-methylisothiourea sulfate in the presence of a base such as sodium carbonate and sodium hydroxide. As the solvent, methanol, ethanol, dioxane, N, N-dimethylformamide or the like is used alone or in combination. The reaction temperature is usually from room temperature to 100 ° C, preferably from 40 to 70 ° C.

The condensation reaction in the method (e) can be carried out by a method according to the method (a) or the method (b). The conversion of the bromo group to the cyano group can be carried out by a method known per se, for example, in a solvent such as pyridine, quinoline, N, N-dimethylformamide or N-methylpyrrolidone, or a mixed solvent thereof. It can be carried out by reacting cuprous copper. The reaction temperature is usually 100 to 250 ° C, preferably 150 to 200 ° C.
° C.

In the method (f), the cyano group HN = C (O
Conversion to an imidate represented by the formula: R ² )-(R ² is as defined above) can be performed by a method known per se, for example,
The reaction can be performed by reacting a hydrogen chloride gas with a cyano group in a solvent such as methanol or ethanol.
The reaction temperature is generally −20 to 50 ° C., preferably 0 ° C. to room temperature. Alternatively, the reaction can be carried out by reacting sodium alkoxide in a solvent such as methanol or ethanol. The reaction temperature is usually -50 to 100C, preferably room temperature to 50C.

When Z in the compound of the present invention represented by the general formula (1) is an alkyl group having 1 to 4 carbon atoms, it can be removed by a method known per se. For example, a compound having a methyl ester group or an ethyl ester group may be treated with a base such as aqueous or alcoholic sodium hydroxide to hydrolyze the ester group, or with an acid such as hydrochloric acid or acetic acid. To obtain a free carboxylic acid derivative. The salt of the compound represented by the general formula (1) of the present invention can be obtained by the reaction itself for producing the compound represented by the general formula (1) of the present invention. , A base can be added to produce a salt of the compound represented by the general formula (1) of the present invention.
The thus-obtained compound represented by the general formula (1) of the present invention can be obtained by a conventional separation and purification means such as extraction, concentration, neutralization,
It can be isolated from the reaction mixture by using means such as filtration, recrystallization, and column chromatography.

The compounds of the present invention represented by the general formula (1) and salts thereof are platelet aggregation inhibitors having GPIIb / IIIa antagonism and inhibit platelet thrombus formation. Peripheral circulatory disorders such as vascular thromboangitis (Berger's disease), Raynaud's disease, diabetic complications (eg, diabetic retinopathy, diabetic nephropathy, etc.), venous thrombosis (eg, deep vein thrombosis, etc.), angina pectoris (Eg, stable angina, unstable angina including urgency infarction, etc.), myocardial infarction (eg, acute myocardial infarction, etc.), ischemic heart disease such as coronary artery thrombosis, cerebral infarction (eg, cerebral thrombosis, cerebral embolism) Ischemic brain diseases such as transient cerebral ischemia (TIA), cerebral vasospasm after hemorrhage (eg, cerebral vasospasm after subarachnoid hemorrhage, etc.), pulmonary vascular disorders (eg, pulmonary thrombosis) , Pulmonary embolism, etc.), arterial thrombosis, arteriosclerosis It is useful as agents and therapeutic agents. Furthermore, prevention of restenosis and reocclusion after percutaneous transluminal coronary angioplasty (PTCA) or percutaneous transluminal coronary artery revascularization (PTCR), tissue plasminogen activator (tP
A) It is useful for prevention of reocclusion after administration, prevention of thrombocytopenia by dialysis, prevention of thrombosis by artificial blood vessels and organs, disseminated intravascular coagulation (DIC), inflammation (for example,
It is useful as a prophylactic and therapeutic agent such as nephritis, etc., an inhibitor of cancer metastasis, and a prophylactic and therapeutic agent for immune diseases. Further, the compound represented by the general formula (1) of the present invention can be used in combination with an antiplatelet drug or an anticoagulant drug such as heparin, aspirin or warfarin.

The compound of the present invention represented by the general formula (1) or a salt thereof did not cause any death even when a dose exceeding the effective dose was administered to mice. When a composition containing the compound represented by the general formula (1) of the present invention or a salt thereof as an active ingredient is used as a platelet aggregation inhibitor, the dose and dosage form are the physical properties of the compound, the symptoms to be administered, and the like. However, when administered orally, 1 adult per day
１，1,000 mg can be used as dosage forms such as tablets, granules, powders, suspensions, capsules and the like. In the case of parenteral administration, 1 to 500 mg per day for an adult can be administered in the form of injections, suppositories, isotonic solutions for infusions and the like.

Formulation can be carried out according to a known method. For example, in the case of tablets, excipients include corn starch, lactose, crystalline cellulose, etc., binders include hydroxypropylcellulose, carboxymethylcellulose, gum arabic, etc., and disintegrants include starch, agar, calcium carbonate, etc. As a lubricant, magnesium stearate, talc or the like is used. These tablets may be coated with sugar coating, gelatin coating and the like. In the case of injection, a non-aqueous solution using cottonseed oil, corn oil, peanut oil, olive oil, or a suspension or emulsion in the presence of a suitable surfactant by adding water to the compound of the present invention. It can be a liquid or a formulation such as an aqueous solution dissolved in physiological saline. The content of the active ingredient in the preparation is not particularly limited, but is usually 1 to 90 together with the solid preparation and the liquid preparation.
%.

[0067]

The present invention will be described below in detail with reference to examples.
The present invention is not limited to these. The number in parentheses after the compound name is the number of the compound exemplified in the detailed description. Example 1 7-[(4-cyanobenzoyl) amino] -1,2,2
Synthesis of Ethyl 3,4-tetrahydronaphthalene-2-acetate (Compound No. 133) (1-1) 7-Nitro-3,4-dihydro- (1H) -2-naphthalenone, which is a starting material, was prepared according to J. Med. Chem.,
32 , 2128-2134 (1989). Ethyl diethyl phosphonoacetate (13.4 g) was dissolved in ethylene glycol dimethyl ether (100 ml), 60% sodium hydride (2.4 g) was added little by little under cooling, and the mixture was stirred at room temperature for 1 hour. In the solution, 7-nitro-3,4-dihydro- (1H)
-2-Naphthalenone (9.5 g) was added, and the mixture was stirred at room temperature for 3 hours. The reaction solution was poured into ice water and extracted with ethyl acetate, and the extract was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the concentrated residue was purified by silica gel column chromatography (developing agent; ethyl acetate: n-hexane = 1: 5) to give 7-nitro-3,4-dihydro- (1H).
Ethyl-2-naphthylidene acetate (5.8 g) was obtained.

(1-2) 7-amino-1,2,3,4- obtained by subjecting the compound obtained in the step (1-1) to a catalytic hydrogenation reaction with a Pd catalyst in the presence of an aqueous hydrochloric acid solution.
Ethyl tetrahydronaphthalene-2-acetate hydrochloride (1.5 g) and 4-cyanobenzoyl chloride (1.1 g) were suspended in chloroform (30 ml), and triethylamine (1.8 ml) was added under cooling. After stirring at room temperature for 1 hour, the chloroform layer was washed successively with a 1N aqueous hydrochloric acid solution, water, a saturated aqueous sodium hydrogen carbonate solution and a saturated saline solution, and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the concentrated residue was purified by silica gel column chromatography (eluent; ethanol: chloroform = 1: 50) to obtain the title compound (0.89 g). mp: 122-124 ° C. ¹ H NMR (270 MHz, CDCl ₃ ) δ ppm: 7.96 (d, 2H, J = 8.8 Hz), 7.79
(d, 2H, J = 8.8Hz), 7.36-7.29 (m, 2H), 7.09 (d, 1H, J = 8.8H
z), 4.17 (q, 2H, J = 7.3Hz), 2.95-2.80 (m, 3H), 2.57-2.36
(m, 3H), 2.27 (br, 1H), 2.04-1.93 (m, 1H), 1.57-1.36 (m,
1H), 1.28 (t, 3H, J = 7.3Hz)

Example 2 7-[[4- (ethoxyiminomethyl) benzoyl] amino] -1,2,3,4-tetrahydronaphthalene-2
-Synthesis of hydrochloride of ethyl acetate (Compound No. 134) The compound (0.85 g) obtained in Step (1-2) of Example 1 was suspended in ethanol (20 mL), and cooled to 0 ° C or lower. Hydrochloric acid gas was passed through the solution for 1 hour so that the temperature did not exceed 10 ° C. The mixture was stirred overnight at room temperature, and after confirming disappearance of the starting materials, the solvent was distilled off under reduced pressure and dried to give the title compound (0.83
g) was obtained. mp: 216-218 ° C ¹ H NMR (270 MHz, DMSO-d ₆ ) δ ppm: 10.46 (s, 1 H), 8.25 (d, 2 H,
J = 8.1Hz), 8.17 (d, 2H, J = 8.1Hz), 7.52 (m, 2H), 7.06 (d, 1
H, J = 8.8Hz), 4.66 (q, 2H, J = 7.3Hz), 4.10 (q, 2H, J = 7.3H
z), 2.88-2.68 (m, 3H), 2.50-2.33 (m, 3H), 2.12 (br, 1
H), 1.88 (br, 1H), 1.51 (t, 3H, J = 7.3 Hz), 1.51-1.32 (m, 1
H), 1.23 (t, 3H, J = 7.3Hz)

Example 3 7-[(4-Amidinobenzoyl) amino] -1,2,2
Synthesis of hydrochloride of ethyl 3,4-tetrahydronaphthalene-2-acetate (Compound No. 3) The compound (0.83 g) obtained in Example 2 was ethanol (20 mL).
And ammonium acetate (1.96 g) was added thereto, followed by stirring at room temperature overnight. The reaction solution was distilled off under reduced pressure, and the concentrated residue was recrystallized from ethanol to obtain the title compound (0.7 g). mp: 207-210 ° C ¹ H NMR (270 MHz, DMSO-d ₆ ) δ ppm: 8.30 (s, 4H), 8.08 (d, 2H, J
= 8.8Hz), 7.92 (d, 2H, J = 8.8Hz), 7.50-7.48 (m, 2H), 7.05
(d, 1H, J = 8.8Hz), 4.10 (q, 2H, J = 7.3Hz), 2.85-2.74 (m, 3
H), 2.47-2.35 (m, 3H), 2.14 (br, 1H), 1.91-1.87 (m, 1
H), 1.49-1.34 (m, 1H), 1.21 (t, 3H, J = 7.3Hz)

Example 4 7-[(4-Amidinobenzoyl) amino] -1,2,2
Synthesis of hydrochloride salt of 3,4-tetrahydronaphthalene-2-acetic acid (compound No. 1) The compound (0.1 g) obtained in Example 3 was suspended in ethanol (10 ml), and a 2N aqueous sodium hydroxide solution (1.2 ml) was added. In addition,
Stirred overnight at room temperature. Most of the solvent is distilled off under reduced pressure,
The concentrated residue was acidified with a 3N aqueous hydrochloric acid solution, and the resulting precipitate was collected by filtration and washed well with water to give the title compound (0.07 g). mp: 236-238 ° C ¹ H NMR (270 MHz, TFA-d) δ ppm: 8.20 (d, 2H, J = 8.8 Hz), 8.03
(d, 2H, J = 8.8Hz), 7.68-7.65 (m, 2H), 7.34 (d, 1H, J = 8.8H
z), 3.07-2.96 (m, 3H), 2.69-2.59 (m, 3H), 2.41 (br, 1
H), 2.15-2.11 (m, 1H), 1.71-1.56 (m, 1H) APCI-MS: m / e = 352 (M ⁺ +1)

Example 5 7- [N- (4-cyanophenyl) carbamoyl]-
1,2,3,4-tetrahydronaphthalene-2-acetic acid
Synthesis of tert-butyl (Compound No. 138) (5-1) Starting material 7-methoxycarbonyl-3,
4-dihydro- (2H) -1-naphthalenone is Tetrah
It was synthesized according to edron Lett., 33 (38), 5492-5502 (1992).
7-methoxycarbonyl-3,4-dihydro- (2H)
-1-naphthalenone (24.1 g) in methanol (150 ml),
It was dissolved in a mixed solution of tetrahydrofuran (50 ml), and sodium borohydride (5 g) was added little by little under ice cooling. Five
After stirring at ℃ for 1 hour, the reaction solution was distilled off under reduced pressure. The concentrated residue was adjusted to pH 2 by adding a 2N aqueous hydrochloric acid solution, and extracted with chloroform. After the extract was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to give 7-methoxycarbonyl-
A crude product of 1,2,3,4-tetrahydro-1-naphthol was obtained. Dissolve this compound in benzene (150ml)
Amberlyst 15 (5 g) was added, a Dean-Stark apparatus was attached, and the mixture was heated under reflux for 2 hours. After cooling, the reaction solution was filtered and the solvent was distilled off under reduced pressure. The concentrated residue is subjected to silica gel column chromatography (developing agent; ethyl acetate: n-hexane =
1:10) to give 7-methoxycarbonyl-3,4
-Dihydronaphthalene (19.2 g) was obtained.

(5-2) Compound (18.5 g) obtained in step (5-1), m-chloroperbenzoic acid (9.4 g) having a content of 80%
Was stirred at room temperature for 3 hours. An aqueous sodium hydrogen carbonate solution and an aqueous sodium sulfite solution were added to the reaction solution to stop the reaction, and the organic layer was extracted with chloroform. The extract was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel column chromatography (developing agent; n-hexane: chloroform = 3: 1) to give 1,2-epoxy-7.
-Methoxycarbonyl-1,2,3,4-tetrahydronaphthalene (8.42 g) was obtained.

(5-3) The compound (1.3 g) obtained in the step (5-2) was dissolved in benzene (20 ml), and zinc iodide (2.
5 g) was added and the mixture was stirred at room temperature for 6 hours under light shielding. The reaction mixture was filtered and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (developing agent; chloroform: ethyl acetate = 20: 1) to give 7-methoxycarbonyl-3,4-dihydro-. (1H) -2-Naphthalenone (1.1 g) was obtained.

(5-4) The compound (1.1 g) obtained in the step (5-3) and tert-butoxycarbonylmethylenetriphenylphosphorane (3.8 g) were dissolved in toluene (30 ml), and the mixture was dissolved at 100 ° C. for 5 hours. Heated to reflux. The solvent was distilled off under reduced pressure, and the concentrated residue was purified by silica gel column chromatography (developing agent; ethyl acetate: n-hexane = 1: 5) to give 7-methoxycarbonyl-1,2,3,4-tetrahydro- Tert-Butyl 2-naphthylideneacetate (0.85 g) was obtained.

(5-5) The compound (0.8 g) obtained in the step (5-4) was subjected to catalytic hydrogenation reaction using a Pd catalyst to give a compound (7-5).
There was obtained tert-butyl-methoxycarbonyl-1,2,3,4-tetrahydronaphthalene-2-acetate (0.8 g). (5-6) The compound (0.8 g) obtained in the step (5-5) was subjected to the same reaction as in Example 4 to give 7-carboxy-1,2,3,4-tetrahydronaphthalene-2-acetic acid. Tert-butyl (0.71 g) was obtained.

(5-7) The compound (0.7 g) obtained in the step (5-6) and oxalyl chloride (1.5 ml) were mixed with toluene (5 ml).
And 1 drop of N, N-dimethylformamide was added thereto, followed by stirring at room temperature for 1 hour. The solvent was distilled off under reduced pressure to obtain the corresponding acid chloride. The obtained acid chloride was dissolved in tetrahydrofuran (5 ml), and 4-aminobenzonitrile (0.35 g), pyridine (1 ml) and 4-dimethylaminopyridine (50 mg) were added, and the mixture was stirred at room temperature for 4 hours. An aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with chloroform. The extract was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain a crude product. Purification by silica gel column chromatography (chloroform: ethyl acetate = 5: 1) gave the title compound (0.47 g). mp: 152-154 ° C ¹ H NMR (270 MHz, CDCl ₃ ) δ ppm: 7.96 (brs, 1H), 7.79 (d, 2H, J
= 8.8Hz), 7.65 (d, 2H, J = 8.8Hz), 7.55-7.54 (m, 2H), 7.20
(d, 1H, J = 8.1Hz), 3.01-2.85 (m, 3H), 2.60-2.49 (m, 1H),
2.33-2.21 (m, 3H), 2.04-1.95 (m, 1H), 1.48 (s, 9H), 1.51
-1.48 (m, 1H)

Example 6 7- [N- (4-amidinophenyl) carbamoyl]-
1,2,3,4-tetrahydronaphthalene-2-acetic acid
Synthesis of Hydrochloride of Ethyl (Compound No. 11) To the compound (0.45 g) obtained in Step (5-7) of Example 5,
The title compound (0.38 g) was obtained by carrying out the same reaction as in Example 2 and Example 3. mp: 216-217 ° C ¹ H NMR (270 MHz, DMSO-d ₆ ) δ ppm: 7.97 (d, 2H, J = 8.8 Hz), 7.8
1 (d, 2H, J = 8.8Hz), 7.72-7.70 (m, 2H), 7.20 (d, 1H, J = 8.1H
z), 4.13 (q, 2H, J = 6.6Hz), 2.98-2.74 (m, 3H), 2.60-2.50
(m, 1H), 2.45 (d, 2H, J = 7.3Hz), 2.26-2.08 (m, 1H), 1.96
1.87 (m, 1H), 1.53-1.38 (m, 1H), 1.21 (t, 3H, J = 6.6Hz)

Example 7 7- [N- (4-amidinophenyl) carbamoyl]-
Synthesis of hydrochloride salt of 1,2,3,4-tetrahydronaphthalene-2-acetic acid (Compound No. 9) Compound (0.1 g) was obtained. mp: 230 ° C or higher ¹ H NMR (270 MHz, TFA-d) δ ppm: 8.00 (d, 2H, J = 8.8 Hz), 7.93
(d, 2H, J = 8.8Hz), 7.68-7.65 (m, 2H), 7.34 (d, 1H, J = 8.8H
z), 3.14-3.00 (m, 3H), 2.74-2.65 (m, 3H), 2.53-2.13 (m,
1H), 1.75-1.60 (m, 1H)

Example 8 6-[(4-cyanobenzoyl) amino] chroman-3
-Synthesis of ethyl acetate (Compound No. 141) (8-1) Fuming nitric acid (40 ml) was cooled to -30 to -35 ° C,
With stirring, 4-chromanone (5.8 g) was added over about 30 minutes. After further stirring at the same temperature for 30 minutes, the reaction solution was poured into ice water. The mixture was extracted with ethyl acetate (500 ml), the extract was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The crude product was washed with a mixed solution of n-hexane: ethyl acetate (1: 1) to obtain 6-nitro-4-chromanone (5.4 g).

(8-2) The compound (5.4 g) obtained in step (8-1) was subjected to the same reaction as in step (5-1) of Example 5 to give 6-nitro- (2H)- Chromen (4.9
g) was obtained. (8-3) Compound (4.9 g) obtained in step (8-2) was subjected to the same reaction as in step (5-2) of Example 5 to give 3,4-epoxy-6-nitro-chroman. (4.0g)
I got (8-4) Compound (3.9 g) obtained in step (8-3) was subjected to the same reaction as in step (5-3) of Example 5 to give 6-nitro-3-chromanone (3.5 g). I got (8-5) The compound (3.5 g) obtained in step (8-4) was subjected to the same reaction as in step (1-1) of Example 1 to give ethyl 6-nitro-3-chromanylideneacetate (2 .
5g) was obtained.

(8-6) Ethyl 6-aminochroman-3-acetate (1.3 g) obtained by subjecting the compound obtained in step (8-5) to catalytic hydrogenation reaction with a Pd catalyst and
-Cyanobenzoyl chloride (1.1 g) was subjected to the same reaction as in step (1-2) of Example 1 to give the title compound (0.89 g). mp: 165-166 ° C ¹ H NMR (270 MHz, CDCl ₃ ) δ ppm: 7.95 (d, 2H, J = 8.1 Hz), 7.78
(d, 2H, J = 8.8Hz), 7.72 (d, 1H, J = 2.2Hz), 7.20 (dd, 1H, J =
(8.8, 2.2Hz), 6.81 (d, 1H, J = 8.8Hz), 4.25-4.20 (m, 1H),
4.15 (q, 2H, J = 7.3Hz), 3.94-3.86 (m, 1H), 3.03-2.92 (m, 1
H), 2.62-2.52 (m, 2H), 2.47-2.30 (m, 2H), 1.28 (t, 3H, J =
(7.3Hz)

Example 9 Ethyl 6-[[4- (ethoxyiminomethyl) benzoyl] amino] chroman-3-acetate (Compound No. 14)
Synthesis of hydrochloride salt of 2) Compound (1.0 g) obtained in step (8-6) of Example 8 was subjected to the same reaction as in Example 2 to give the title compound (0.
9g). mp: 239-240 ° C. ¹ H NMR (270 MHz, DMSO-d ₆ ) δ ppm: 10.41 (s, 1 H), 8.24 (d, 2
H, J = 8.8Hz), 8.17 (d, 2H, J = 8.8Hz), 7.48 (m, 2H), 6.77
(d, 1H, J = 8.8Hz), 4.66 (q, 2H, J = 7.3Hz), 4.20-4.10 (m, 1
H), 4.11 (q, 2H, J = 7.3 Hz), 3.82 (m, 1H), 2.90 (m, 1H), 2.
60-2.32 (m, 4H), 1.51 (t, 3H, J = 7.3Hz), 1.21 (t, 3H, J = 7.3
Hz)

Example 10 6-[(4-amidinobenzoyl) amino] chroman-
3-Synthesis of Ethyl Acetate (Compound No. 19) Hydrochloride The title compound (0.34 g, amorphous) was obtained by subjecting the compound (0.5 g) obtained in Example 9 to the same reaction as in Example 3. . ¹ H NMR (270 MHz, DMSO-d ₆ ) δ ppm: 10.26 (s, 1 H), 8.29 (s, 4
H), 8.10 (d, 2H, J = 8.8Hz), 7.92 (d, 2H, J = 8.8Hz), 7.50
(s, 1H), 7.45 (dd, 1H, J = 8.8,2.2Hz), 6.74 (d, 1H, J = 8.
8), 4.20-4.07 (m, 3H), 3.85-3.82 (m, 1H), 2.92-2.86 (m, 3H)
1H), 2.55-2.33 (m, 4H), 1.21 (t, 3H, J = 7.3Hz)

Example 11 6-[(4-amidinobenzoyl) amino] chroman-
Synthesis of hydrochloride salt of 3-acetic acid (Compound No. 17) The compound (0.34 g) obtained in Example 10 was subjected to the same reaction as in Example 4 to obtain the title compound (0.22 g, amorphous). ¹ H NMR (270 MHz, DMSO-d ₆ ) δ ppm: 10.31 (s, 1 H), 9.50 (brs,
2H), 9.22 (brs, 2H), 8.14 (d, 2H, J = 8.8 Hz), 7.94 (d, 2H, J
= 8.8Hz), 7.50 (s, 1H), 7.45 (dd, 1H, J = 8.8, 2.2Hz), 6.7
5 (d, 1H, J = 8.8), 4.20-4.16 (m, 1H), 3.85-3.78 (m, 1H),
2.91-2.85 (m, 1H) 、 2.57-2.51 (m, 4H)

Example 12 7-[(4-Cyanobenzoyl) amino] -1,2,2
Synthesis of hydrochloride of ethyl 3,4-tetrahydroisoquinoline-2-acetate (Compound No. 145) (12-1) 7-nitro-1,2,3,4 as a starting material
-Tetrahydroisoquinoline is a Heterocyclic Chemist
Synthesized according to ry, 22 , 329 (1985). 7-nitro-1,
2,3,4-tetrahydroisoquinoline (2.89 g) was dissolved in ethanol (20 ml), and triethylamine (3.9 m
l) and ethyl bromoacetate (2.25 g) were added and the mixture was heated under reflux.
After 1 hour, most of the solvent was distilled off under reduced pressure, the concentrated residue was extracted with ethyl acetate, and the extract was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the crude product was subjected to silica gel column chromatography (developing agent; ethyl acetate: n-
Hexane = 1: 3) and treated with hydrochloric acid / dioxane solution to give 7-nitro-1,2,3,4-
Ethyl tetrahydroisoquinoline-2-acetic acid hydrochloride (2.14 g) was obtained.

(12-2) The compound (2.14 g) obtained in the step (12-1) was suspended in ethanol (30 ml), and a catalytic hydrogenation reaction was carried out using a Pd catalyst. 7-Amino-1,2,3,4-tetrahydroisoquinoline-2- obtained
Ethyl acetate was converted to the dihydrochloride (2.18 g) with a hydrochloric acid / dioxane solution. The dihydrochloride (2.18 g) was mixed with 4-cyanobenzoyl chloride (1.41 g) and chloroform (3
0 ml), triethylamine (3.2 ml) was added thereto under cooling, and the mixture was stirred at room temperature for 1 hour. The chloroform layer was washed successively with water, saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the crude product was subjected to silica gel column chromatography (developing agent; ethanol:
Purification with chloroform = 1: 50) and treatment with a hydrochloric acid / dioxane solution gave the title compound (2.24 g, amorphous). ¹ H NMR (270 MHz, DMSO-d ₆ ) δ ppm: 10.62 (s, 1 H), 8.14 (d, 2
H, J = 8.8Hz), 8.01 (d, 2H, J = 8.8Hz), 7.75-7.63 (m, 2H),
7.25 (d, 1H, J = 8.8Hz), 4.50 (brs, 2H), 4.35 (s, 2H), 4.27
(q, 2H, J = 7.3Hz), 3.50 (brs, 2H), 3.10 (br, 2H)

Example 13 7-[(4-Amidinobenzoyl) amino] -1,2,2
Synthesis of dihydrochloride of ethyl 3,4-tetrahydroisoquinoline-2-acetate (Compound No. 30) Compound (1.0 g) obtained in step (12-2) of Example 12
Then, the same reaction as in Example 2 and Example 3 was performed to obtain the title compound (0.7 g). mp: 172-173 ° C. ¹ H NMR (270 MHz, DMSO-d ₆ ) δ ppm: 10.38 (s, 1 H), 8.30 (s, 4
H), 8.14 (d, 2H, J = 8.8Hz), 7.94 (d, 2H, J = 8.8Hz), 7.54
(s, 1H), 7.50 (dd, 1H, J = 8.8,2.2Hz), 7.10 (d, 1H, J = 8.8H
z), 4.13 (q, 2H, J = 7.3 Hz), 3.70 (s, 2H), 3.42 (s, 2H), 2.
80 (s, 4H), 1.22 (t, 3H, J = 7.3Hz)

Example 14 7-[(4-Amidinobenzoyl) amino] -1,2,2
Synthesis of dihydrochloride of 3,4-tetrahydroisoquinoline-2-acetic acid (Compound No. 28) The title compound (0.03 g) was obtained. mp: 238-240 ° C (decomposition) ¹ H NMR (270 MHz, DMSO-d ₆ ) δ ppm: 10.43 (s, 1 H), 9.49 (brs,
2H), 9.36 (brs, 2H), 8.16 (d, 2H, J = 8.8 Hz), 7.96 (d, 2H, J
= 8.8Hz), 7.61 (s, 1H), 7.55 (dd, 1H, J = 8.8, 2.2Hz), 7.1
2 (d, 2H, J = 8.8Hz), 3.82 (s, 2H), 3.37 (s, 2H), 2.93-2.75
(m, 4H)

Example 15 7- [N- (4-cyanophenyl) carbamoyl]-
Synthesis of tert-butyl 1,2,3,4-tetrahydroisoquinoline-2-acetate (Compound No. 148) (15
-1) 7-Methoxyisoquinoline as a starting compound was obtained from J. Org.
m., 38 (21), 3701 (1973). A mixture of 7-methoxyisoquinoline (7.4 g) and pyridine hydrochloride (30 g) was heated and stirred at 180 ° C. for 6 hours. After cooling, the mixture was dissolved in ethyl acetate and washed with saturated saline. The ethyl acetate layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 7-hydroxyisoquinoline (4.43 g). This compound was dissolved in methylene chloride (100 ml), pyridine (5.5 ml) was added, and methanesulfonic anhydride (6.6 ml) was added dropwise. After stirring for 1 hour under ice cooling, a saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with chloroform. After the extract was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (developing agent; ethyl acetate: n-hexane = 1: 3) to obtain 7-Isoquinolinyl lomethanesulfonic acid (9.18 g) was obtained.

(15-2) In a 500 ml autoclave, the compound (8.6 g) obtained in the step (15-1), triethylamine (9.0 ml), tetrakis (triphenylphosphine) palladium (1.07 g), 1,3-bis (diphenylphosphino) propane (0.38 g) was added to methanol (30 m
l) and dissolved in N, N-dimethylformamide (60 ml). After filling with carbon monoxide (15 kg / cm ² ), the mixture was stirred at 70 ° C. for 3 hours. After cooling, the reaction solution was concentrated under reduced pressure, and purified by silica gel column chromatography (developing agent; chloroform: ethyl acetate = 10: 1) to obtain 7-methoxycarbonylisoquinoline (5.39 g).

(15-3) The compound (5.39 g) obtained in the step (15-2), tert-butyl bromoacetate (6.7 g)
g) was dissolved in acetonitrile (50 ml) and heated under reflux for 6 hours. After cooling, the deposited precipitate was collected by filtration and washed with isopropyl ether. The obtained solid was dried under reduced pressure to obtain 7-methoxycarbonyl-2-tert-butoxycarbonylmethylisoquinolinium bromide (8.75 g).

(15-4) The compound (7.3 g) obtained in the step (15-3) was suspended in methanol (60 ml) and cooled with ice. To this was added sodium borohydride (1.45 g) little by little. After stirring for 30 minutes under ice cooling, water (1 ml) was added, and the solvent was distilled off under reduced pressure. The mixture was extracted with a saturated saline-chloroform system, and the organic layer was dried over anhydrous magnesium sulfate. The crude product obtained by evaporating the solvent under reduced pressure was subjected to silica gel column chromatography (developing agent; chloroform:
Purification by ethyl acetate = 20: 1) gave tert-butyl 7-methoxycarbonyl-1,2,3,4-tetrahydroisoquinoline-2-acetate (3.4 g).

(15-5) The compound (2.4 g) obtained in the step (15-4) was dissolved in methanol (30 ml), and an aqueous solution of barium hydroxide octahydrate (1.1 g) was added under ice-cooling. (20m
l) was added. After stirring at room temperature for 7 hours, methanol was distilled off under reduced pressure, and the pH was adjusted to 4.5 with a 1N aqueous hydrochloric acid solution. It was concentrated under reduced pressure, and the obtained crude product was purified by ODS column chromatography (developing agent; methanol: water = 1: 2) to give 7-carboxy-1,2,3,4-tetrahydroisoquinoline-2. -Tert-butyl acetate (0.9 g) was obtained.

(15-6) The compound (0.84 g) obtained in the step (15-5), 4-aminobenzonitrile (0.35 g)
g), 1-hydroxybenzotriazole monohydrate (0.4
1 g) in methylene chloride (20 ml) and tetrahydrofuran (10
ml), and the mixture was ice-cooled. Dicyclohexylcarbodiimide (0.61 g) was added to this solution, and the mixture was stirred under ice cooling for 1 hour and at room temperature overnight. The resulting dicyclohexylurea was removed by filtration, the reaction solution was concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (eluent; chloroform: methanol = 30: 1) to give the title compound (0.54 g). I got mp: 180 ° C. (decomposition) ¹ H NMR (270 MHz, CDCl ₃ ) δ ppm: 7.85 to 7.70 (m, 2H), 7.65 (d, 2
H, J = 8.8Hz), 7.33 (d, 2H, J = 8.8Hz), 7.15 (d, 1H, J = 2.2H
z), 3.83 (s, 2H), 3.33 (s, 2H), 2.99-2.86 (m, 4H), 1.50
(s, 9H)

Example 16 7- [N- (4-amidinophenyl) carbamoyl]-
Synthesis of dihydrochloride of 1,2,3,4-tetrahydroisoquinoline-2-acetic acid (Compound No. 36) Compound (0.5-6) obtained in step (15-6) of Example 15
g) was subjected to the same reaction as in Examples 2 and 3 to give 7- [N- (4-amidinophenyl) carbamoyl] -1,2,3,4-tetrahydroisoquinoline-2-ethyl acetate 2 The hydrochloride was obtained. This compound was dissolved in ethanol (20 ml) without purification, reacted in the same manner as in Example 4, and purified by ODS column chromatography (developing agent; water: methanol = 2: 1) to give the title compound ( 0.12 g). mp: 230 ° C. or higher ¹ H NMR (270 MHz, DMSO-d ₆ ) δ ppm: 10.45 (s, 1 H), 9.46 (brs, 2
H), 9.35 (brs, 2H), 7.64 (d, 2H, J = 8.8 Hz), 7.32 (d, 2H, J =
(8.8Hz), 7.20-7.18 (m, 2H), 7.15 (d, 1H, J = 2.2Hz), 3.83
(s, 2H), 3.33 (s, 2H), 2.99-2.86 (m, 4H)

Example 17 7- [N- (4-cyanobenzoyl) -N-methylamino] -1,2,3,4-tetrahydronaphthalene-2-
Synthesis of ethyl acetate (Compound No. 150) (17-1)
7- [N- (t-butoxycarbonyl) amino]-
1,2,3,4-tetrahydronaphthalene-2-acetic acid
Ethyl (0.67 g) was added to N, N-dimethylformamide (10 m
l), 60% sodium hydride (0.096 g) was added under cooling, and the mixture was stirred at room temperature for 5 minutes. Methyl iodide (0.57 g) was added dropwise and left overnight at room temperature. After evaporating the reaction solution under reduced pressure, the concentrated residue was extracted with ethyl acetate, and the extract was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (developing agent; ethyl acetate: n-hexane = 1: 10) to give 7- [N
-(T-butoxycarbonyl) -N-methylamino]-
1,2,3,4-tetrahydronaphthalene-2-acetic acid
Ethyl (0.67 g) was obtained. (17-2) Step (17-
Hydrochloride (0.56 g) obtained by treating the compound obtained in 1) with a hydrochloric acid / dioxane solution was subjected to the same reaction as in step (1-2) of Example 1 to give the title compound (0.5 g). , An oil). ¹ H NMR (270 MHz, CDCl ₃ ) δ ppm: 7.62 (d, 2 H, J = 8.8 Hz), 7.40
(d, 2H, J = 8.8Hz), 6.95-6.83 (m, 3H), 4.07 (q, 2H, J = 7.3H
z), 3.33 (s, 3H), 2.74-2.65 (m, 3H), 2.45-2.22 (m, 3H),
2.08-2.04 (m, 1H), 1.84-1.80 (m, 1H), 1.41-1.37 (m, 1
H), 1.19 (t, 3H, J = 7.3Hz)

Example 18 7- [N- (4-Amidinobenzoyl) -N-methylamino] -1,2,3,4-tetrahydronaphthalene-2
-Synthesis of hydrochloride of ethyl acetate (Compound No. 48) Compound (0.5) obtained in Step (17-2) of Example 17
g) was subjected to the same reaction as in Example 2 and Example 3 to give the title compound (0.37 g). mp: 188-189 ° C ¹ H NMR (270 MHz, DMSO-d ₆ ) δ ppm: 8.29 (s, 4 H), 7.63 (d, 2 H, J
= 8.8Hz), 7.41 (d, 2H, J = 8.8Hz), 6.95-6.83 (m, 3H), 4.07
(q, 2H, J = 7.3Hz), 3.33 (s, 3H), 2.74-2.68 (m, 3H), 2.45-
2.27 (m, 3H), 2.08-2.04 (m, 1H), 1.84-1.80 (m, 1H), 1.41
-1.37 (m, 1H), 1.19 (t, 3H, J = 7.3Hz)

Example 19 7- [N- (4-amidinobenzoyl) -N-methylamino] -1,2,3,4-tetrahydronaphthalene-2
-Synthesis of hydrochloride of acetic acid (Compound No. 47) The title compound (0.07 g) was obtained by subjecting the compound (0.1 g) obtained in Example 18 to the same reaction as in Example 4. mp: 250 ° C. or higher ¹ H NMR (270 MHz, DMSO-d ₆ ) δ ppm: 9.30 (brs, 2H), 9.07 (brs,
2H), 7.66 (d, 2H, J = 8.8Hz), 7.42 (d, 2H, J = 8.8Hz), 6.90-
6.83 (m, 3H), 3.33 (s, 3H), 2.75-2.60 (m, 3H), 2.45-2.25
(m, 3H), 2.09-2.04 (m, 1H), 1.88-1.80 (m, 1H), 1.42-1.3
7 (m, 1H)

Example 20 7- [N- (4-cyanophenyl) -N-methylcarbamoyl] -1,2,3,4-tetrahydronaphthalene-
Synthesis of tert-butyl 2-acetate (Compound No. 152) (20-1) A solution of 4-aminobenzonitrile (2.0 g) and pyridine (2.7 ml) in methylene chloride (20 ml) was cooled with ice, and trifluoroacetic anhydride ( 2.8 ml) was added dropwise over 2 minutes. After stirring for 1 hour, a saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give N- (4-cyanophenyl).
-Α, α, α-Trifluoroacetamide (3.85 g) was obtained. This compound was dissolved in 2-butanone (40 ml), and powdered potassium hydroxide (3.3 g) and methyl iodide (3.7 ml)
Was added and heated under reflux for 1 hour. After cooling, the solvent was distilled off under reduced pressure to obtain an oil. This is suspended in water (40 ml) and
Stirred at C for 1 hour. After cooling, the reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure. The obtained crude product is subjected to silica gel column chromatography (developing agent; ethyl acetate:
Purification by n-hexane = 1: 3) gave 4-methylaminobenzonitrile (1.82 g).

(20-2) Step (5-6) of Example 5
The compound (1.0 g) obtained in the above was suspended in toluene (5 ml),
Oxalyl chloride (0.6 ml) and one drop of N, N-dimethylformamide were added, and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, the mixture was concentrated under reduced pressure to obtain a corresponding acid chloride. This acid chloride was dissolved in chloroform (5 ml), and the solution was treated in step (20-
To a chloroform solution (10 ml) of the compound (0.68 g) obtained in 1) and 4-dimethylaminopyridine (0.63 g) was added dropwise under ice-cooling, and the mixture was stirred at room temperature overnight. Saturated aqueous sodium hydrogen carbonate was added to the reaction solution, extracted with chloroform, and the extract was dried over anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (eluent; ethyl acetate: n-hexane = 1: 2) to give the title compound (0.96 g, oil). ¹ H NMR (270 MHz, CDCl ₃ ) δ ppm: 7.53 (dt, 2H, J = 8.8, 2.2H
z), 7.14 (dt, 2H, J = 8.8, 2.2Hz), 7.11 (s, 1H), 6.90 (d, 1
H, J = 8.8Hz), 6.86 (d, 1H, J = 8.8Hz), 3.50 (s, 3H), 2.80-
2.73 (m, 3H), 2.43-1.90 (m, 5H), 1.46 (s, 9H), 1.45-1.36
(m, 1H)

Example 21 Synthesis of hydrochloride of ethyl 7- [N- (4-amidinophenyl) -N-methylcarbamoyl] -1,2,3,4-tetrahydronaphthalene-2-acetate (Compound No. 57) Compound (0.96) obtained in Step (20-2) of Example 20
g) was subjected to the same reaction as in Example 2 and Example 3 to give the title compound (1.03 g). mp: 178-180 ° C (decomposition) ¹ H NMR (270 MHz, DMSO-d ₆ ) δ ppm: 7.72 (d, 2H, J = 8.1 Hz), 7.3
7 (d, 2H, J = 8.1Hz), 7.08 (s, 1H), 6.96 (d, 1H, J = 8.1Hz),
6.91 (d, 1H, J = 8.1Hz), 4.07 (q, 2H, J = 7.3Hz), 3.38 (s, 3
H), 2.75-1.26 (m, 9H), 1.18 (t, 3H, J = 7.3Hz)

Example 22 Synthesis Example of Hydrochloride of 7- [N- (4-Amidinophenyl) -N-methylcarbamoyl] -1,2,3,4-tetrahydronaphthalene-2-acetic acid (Compound No. 56) 2
The same reaction as in Example 4 was performed on the compound (0.3 g) obtained in 1 to give the title compound (0.17 g). mp: 200 ° C (decomposition) ¹ H NMR (270 MHz, DMSO-d ₆ ) δ ppm: 7.69 (d, 2 H, J = 8.1 Hz), 7.3
3 (d, 2H, J = 8.1Hz), 7.08 (s, 1H), 6.96 (d, 1H, J = 8.1Hz),
6.91 (d, 1H, J = 8.8Hz), 3.35 (s, 3H), 2.82-1.21 (m, 9H)

Example 23 7-[(4-Cyanobenzyl) oxy] -1,2,3
Synthesis of methyl 4-tetrahydronaphthalene-2-acetate (Compound No. 156) The starting material, methyl 7-hydroxy-1,2,3,4-tetrahydronaphthalene-2-acetate, was obtained from HELVETICA CHIM.
Synthesized according to ICA ACTA, 71 , 1156 (1988). Methyl 7-hydroxy-1,2,3,4-tetrahydronaphthalene-2-acetate (1.2 g) and 4-cyanobenzyl bromide (1.60 g) were dissolved in 2-butanone (50 ml), and potassium carbonate (1.51 g) was added. In addition, the mixture was heated under reflux for 12 hours. Most of the reaction solution was distilled off under reduced pressure, water was added to the concentrated residue, and the mixture was extracted with ethyl acetate. After the extract was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the concentrated residue was purified by silica gel column chromatography (developing agent; ethyl acetate: n-hexane = 1: 3) to give the title compound (1.7).
g) was obtained. mp: 120-122 ° C ¹ H NMR (270 MHz, CDCl ₃ ) δ ppm: 7.65 (d, 2H, J = 8.8 Hz), 7.44
(d, 2H, J = 8.8Hz), 6.75 (dd, 1H, J = 8.8,2.2Hz), 6.70 (s, 1
H), 5.18 (s, 2H), 3.60 (s, 3H), 2.75-2.60 (m, 3H), 2.45
2.25 (m, 3H), 2.09-2.04 (m, 1H), 1.88-1.80 (m, 1H), 1.42
-1.30 (m, 1H)

Example 24 7-[(4-Amidinobenzyl) oxy] -1,2,2
Synthesis of Hydrochloride of Methyl 3,4-tetrahydronaphthalene-2-acetate (Compound No. 81) The compound (1.7 g) obtained in Example 23 was converted into methanol (30 mL).
And cooled to 0 ° C. or lower. The reaction temperature is 1
Hydrochloric acid gas was passed for 1 hour so as not to exceed 0 ° C. After stirring at room temperature to confirm the disappearance of the raw materials, methanol was distilled off under reduced pressure. The concentrated residue was dissolved in methanol (30 ml), ammonium acetate (1.96 g) was added, and the mixture was stirred at room temperature overnight. The solvent is distilled off under reduced pressure, and the concentrated residue is subjected to a silica gel column chromatography (developing agent; methanol: chloroform: acetic acid =
1: 10: 0.5) to give the title compound (1.3 g)
I got mp: 177-179 ° C ¹ H NMR (270 MHz, DMSO-d ₆ ) δ ppm: 9.34 (brs, 2H), 9.02 (brs,
2H), 7.82 (d, 2H, J = 8.8Hz), 7.65 (d, 2H, J = 8.8Hz), 6.97
(d, 1H, J = 8.1Hz), 6.75 (dd, 1H, J = 8.1,2.2Hz), 6.70 (s, 1
H), 5.18 (s, 2H), 3.61 (s, 3H), 2.81-2.69 (m, 3H), 2.44-
2.35 (m, 3H), 2.07-2.00 (m, 1H), 1.87-1.83 (m, 1H), 1.45
-1.30 (m, 1H)

Example 25 7-[(4-Amidinobenzyl) oxy] -1,2,2
Synthesis of hydrochloride of 3,4-tetrahydronaphthalene-2-acetic acid (Compound No. 80) The compound (0.95 g) obtained in Example 24 was treated with methanol (10 m
l) and performing the same reaction as in Example 4 to obtain the title compound (0.9 g). mp: 251-253 ° C. ¹ H NMR (270 MHz, DMSO-d ₆ ) δ ppm: 9.32 (brs, 2H), 8.97 (brs,
2H), 7.82 (d, 2H, J = 8.8Hz), 7.65 (d, 2H, J = 8.8Hz), 6.97
(d, 1H, J = 8.8Hz), 6.75 (dd, 1H, J = 8.8,2.2Hz), 6.70 (s, 1
H), 5.22 (s, 2H), 2.90-2.60 (m, 3H), 2.40-2.22 (m, 3H),
2.07-2.00 (m, 1H), 1.87-1.83 (m, 1H), 1.45-1.30 (m, 1H)

Example 26 7-[(4-cyanophenoxy) methyl] -1,2,2
Synthesis of ethyl 3,4-tetrahydronaphthalene-2-acetate (Compound No. 159) (26-1) The starting compound, 7-methoxycarbonyl-3,4-dihydronaphthalene, was prepared in Step (5-1) of Example 5. Synthesized according to the following procedure. A solution of sodium bis (2-methoxyethoxy) aluminum hydride (20 g) (70% toluene solution) in tetrahydrofuran (80 ml) was ice-cooled, and a solution of 7-methoxycarbonyl-3,4-dihydronaphthalene (10 g) in tetrahydrofuran (20 ml). Was added dropwise. After stirring at room temperature for 1 hour, 3N hydrochloric acid aqueous solution (1
00ml) was carefully added, the solution was acidified and the organic layer was extracted with ether. After the extract was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the concentrated residue was mixed with n-hexane. The generated crystals were collected by filtration to obtain 7-hydroxymethyl-3,4-dihydronaphthalene (7.56 g).

(26-2) The compound (7.38 g) obtained in the step (26-1), 4-cyanophenol (6.04 g) and diethyl azodicarboxylate (12.0 g) were dissolved in tetrahydrofuran (150 ml), and the solution was cooled on ice. Lower triphenylphosphine (1
3.3g) was added little by little. After stirring for 1 hour under ice cooling, a 1N sodium hydroxide solution (100 ml) was added to the reaction solution, and the mixture was further stirred for 30 minutes. The reaction mixture was extracted with ether, and the extract was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained concentrated residue was subjected to silica gel column chromatography (developing agent; ethyl acetate: n-hexane =
1: 3) and purified by 7-[(4-cyanophenoxy) methyl] -3,4-dihydronaphthalene (8.63 g).
I got

(26-3) The compound (8.2 g) obtained in the step (26-2) was subjected to the same reaction as in the step (5-2) of Example 5 to give 7-[(4-cyano Phenoxy)
Methyl] -1,2-epoxy-1,2,3,4-tetrahydronaphthalene (7.3 g) was obtained. (26-4) Compound (7.3 g) obtained in step (26-3)
Then, by performing the same reaction as in step (5-3) of Example 5, 7-[(4-cyanophenoxy) methyl]-
3,4-dihydro- (1H) -2-naphthalenone (4.8
g) was obtained. (26-5) Compound (4.74) obtained in step (26-4)
g) was subjected to the same reaction as in step (1-1) of Example 1 to give 7-[(4-cyanophenoxy) methyl].
Ethyl -3,4-dihydro- (1H) -2-naphthylidenecarboxylate (4.1 g) was obtained.

(26-6) The compound (4.0 g) obtained in the step (26-5) was mixed with chloroform (50 ml) and ethanol (50 ml).
ml) and subjected to a catalytic hydrogenation reaction using a Pd catalyst. The reaction solution was filtered through celite, and the solvent was distilled off under reduced pressure.
The title compound (3.92 g) was obtained. mp: 51-52 ° C ¹ H NMR (270 MHz, CDCl ₃ ) δ ppm: 7.58 (d, 2H, J = 8.8 Hz), 7.15
7.08 (m, 3H), 7.01 (d, 2H, J = 8.8Hz), 5.03 (s, 2H), 4.17
(q, 2H, J = 7.3Hz), 2.96-2.81 (m, 3H), 2.51 (dd, 1H, J = 16.
1,9.5Hz), 2.38 (d, 1H, J = 8.1Hz), 2.37 (d, 1H, J = 5.9Hz),
2.39-2.20 (m, 1H), 1.56-1.40 (m, 1H), 1.28 (t, 1H, J = 7.3H
z)

Example 27 7-[(4-Amidinophenoxy) methyl] -1,2,2
Synthesis of hydrochloride of ethyl 3,4-tetrahydronaphthalene-2-acetate (Compound No. 83) Compound (3.5 g) obtained in step (26-6) of Example 26
Then, the same reaction as in Example 2 and Example 3 was performed to obtain the title compound (2.15 g). mp: 210-212 ° C. ¹ H NMR (270 MHz, DMSO-d ₆ ) δ ppm: 7.59 (d, 2 H, J = 8.8 Hz), 7.3
4-7.22 (m, 3H), 7.03 (d, 2H, J = 8.8Hz), 5.08 (s, 2H), 4.13
(q, 2H, J = 7.3Hz), 2.92-2.77 (m, 3H), 2.58-2.48 (m, 1H),
2.43-2.20 (m, 3H), 1.54-1.40 (m, 1H), 1.21 (t, 3H, J = 7.3H
z)

Example 28 7-[(4-Amidinophenoxy) methyl] -1,2,2
Synthesis of hydrochloride salt of 3,4-tetrahydronaphthalene-2-acetic acid (compound No. 82) The compound (1.0 g) obtained in Example 27 was dissolved in acetic acid (20 ml), and the mixture was heated under reflux for 2 hours. The solvent was distilled off under reduced pressure, and the obtained crude product was re-suspended in ethanol, 1M hydrochloric acid-ethanol solution (10 ml) was added, and the mixture was further stirred for 1 hour. The solution was concentrated under reduced pressure and washed sequentially with water, ethanol and chloroform to obtain the title compound (0.22 g). mp: 230 ° C or higher ¹ H NMR (270 MHz, TFA-d) δ ppm: 7.63 (d, 2H, J = 8.8 Hz), 7.39-
7.27 (m, 3H), 7.07 (d, 2H, J = 8.8 Hz), 5.11 (s, 2H), 3.16
3.02 (m, 3H), 2.72-2.62 (m, 1H), 2.55-2.35 (m, 3H), 1.69
-1.55 (m, 1H)

Example 29 7-[(4-Amidinobenzyl) amino] -1,2,2
Ethyl 3,4-tetrahydronaphthalene-2-acetate
Synthesis of dihydrochloride of (Compound No. 85) 7-amino-1,2,3,3 obtained by subjecting the compound obtained in step (1-1) of Example 1 to a catalytic hydrogenation reaction using a Pd catalyst. The title compound (0.54 g) was obtained by carrying out the same reaction as in Example 23 using ethyl 4-tetrahydronaphthalene-2-acetate hydrochloride (1.5 g) and 4-amidinobenzylbromide hydrochloride (1.39 g). mp: 175-177 ° C ¹ H NMR (270 MHz, DMSO-d ₆ ) δ ppm: 9.30 (brs, 2H), 8.96 (br
s, 2H), 7.78 (d, 2H, J = 8.8Hz), 7.62 (d, 2H, J = 8.8Hz), 6.8
5 (d, 1H, J = 8.8Hz), 6.57 (dd, 1H, J = 8.8,2.2Hz), 6.53 (s, 1
H), 4.43 (s, 2H), 4.08 (q, 2H, J = 7.34 Hz), 2.76-2.64 (m, 3
H), 2.38-2.27 (m, 3H), 2.08-1.80 (m, 2H), 1.41-1.29 (m,
1H), 1.15 (t, 3H, J = 7.3Hz)

Example 30 7-[(4-Amidinobenzyl) amino] -1,2,2
Synthesis of dihydrochloride of 3,4-tetrahydronaphthalene-2-acetic acid (compound No. 84) The compound (0.1 g) obtained in Example 29 was dissolved in 20% acetic acid (10 ml), and 5 drops of concentrated hydrochloric acid was added. Heated to reflux for an hour. After evaporating the solvent under reduced pressure, the residue was dissolved in a small amount of ethanol, and the precipitate formed by adding ether was collected by filtration and dried to obtain the title compound (0.5 g, amorphous). ¹ H NMR (270 MHz, DMSO-d ₆ ) δ ppm: 9.22 (brs, 2H), 8.85 (brs,
2H), 7.73 (d, 2H, J = 8.8 Hz), 7.56 (d, 2H, J = 8.8 Hz), 6.73
(d, 1H, J = 8.8Hz), 6.38 (dd, 1H, J = 8.8,2.2Hz), 6.25 (s, 1
H), 4.35 (s, 2H), 2.76-2.64 (m, 3H), 2.38-2.27 (m, 3H),
2.08-1.80 (m, 2H), 1.41-1.29 (m, 1H)

Example 31 6-[(4-cyanobenzyl) oxy] chroman-3-
Synthesis of ethyl acetate (Compound No. 161) (31-1) 6-methoxy-3-chromanone as a starting material was synthesized according to J. Med. Chem., 31 , 688-691 (1988).
6-methoxy-3-chromanone (2.66 g) was subjected to the same reaction as in step (1-1) of Example 1 to give 6-methoxy-3-chromanone.
-Ethyl chromanylidene acetate (2.7 g) was obtained. (31-2) Compound (2.7 g) obtained in step (31-1)
Then, the same reaction as in step (5-5) of Example 5 was carried out to give ethyl 6-methoxychroman-3-acetate (2.
66g).

(31-3) The compound (2.6 g) obtained in the step (31-2) was dissolved in acetonitrile (20 ml), and sodium iodide (2.4 g) and trimethylsilane chloride (2.0 m
l) was added and heated to reflux. After 1 hour, open in ice water and extract with ethyl acetate, extract 10% sodium thiosulfate,
The extract was washed successively with saturated saline and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the concentrated residue was purified by silica gel column chromatography (developing agent; ethyl acetate: n-hexane = 1: 3) to obtain ethyl 6-hydroxychroman-3-acetate (2.4 g). Was.

(31-4) The compound (2.4 g) obtained in step (31-3) was subjected to the same reaction as in Example 23 to give the title compound (3.5 g, oil). ¹ H NMR (270 MHz, CDCl ₃ ) δ ppm: 7.67 (d, 2H, J = 8.1 Hz), 7.52
(d, 2H, J = 8.8Hz), 6.76-6.72 (m, 2H), 6.65 (d, 1H, J = 8.8H
z), 5.04 (s, 2H), 4.20-4.12 (m, 3H), 3.88-3.80 (m, 1H),
2.95-2.88 (m, 1H), 2.57-2.34 (m, 4H), 1.27 (t, 3H, J = 7.3H
z)

Example 32 6-[(4-Amidinobenzyl) oxy] chroman-3
-Synthesis of hydrochloride of ethyl acetate (Compound No. 90) Compound (1.0 g) obtained in Step (31-4) of Example 31
Then, the same reaction as in Example 2 and Example 3 was performed to obtain the title compound (0.81 g). mp: 157-160 ° C ¹ H NMR (270 MHz, DMSO-d ₆ ) δ ppm: 8.31 (s, 4H), 7.82 (d, 2H, J
= 8.8Hz), 7.62 (d, 2H, J = 8.8Hz), 6.75-6.65 (m, 4H), 5.12
(s, 2H), 4.13-4.05 (m, 3H), 3.77-3.70 (m, 1H), 2.88-2.8
2 (m, 1H), 2.56-2.29 (m, 4H), 1.20 (t, 3H, J = 7.3Hz)

Example 33 6-[(4-Amidinobenzyl) oxy] chroman-3
-Synthesis of hydrochloride of acetic acid (Compound No. 89) The compound (0.29 g) obtained in Example 32 was subjected to the same reaction as in Example 4 to give the title compound (0.2 g). mp: 222-224 ° C ¹ H NMR (270 MHz, DMSO-d ₆ ) δ ppm: 9.32 (brs, 2H), 8.97 (brs,
2H), 7.82 (d, 2H, J = 8.8 Hz), 7.65 (d, 2H, J = 8.8 Hz), 6.74
6.65 (m, 4H), 5.14 (s, 2H), 4.13-4.09 (m, 1H), 3.76-3.70
(m, 1H), 2.86-2.81 (m, 1H), 2.35-2.22 (m, 4H)

Example 34 Methyl 7-[(4-cyanobenzyl) oxy] -3,4-dihydronaphthalene-2-acetate (Compound No. 16)
Synthesis of 3) (34-1) 7-methoxy-1-oxo-1,2,3,4-tetrahydronaphthalene-2- as a raw material compound
Acetic acid was synthesized according to J. Med. Chem., 32 , 2277-2282 (1989). Under cooling, thionyl chloride (1.8m) was added to methanol (20ml).
l) was added dropwise little by little. After 10 minutes, 7-methoxy-1-
Oxo-1,2,3,4-tetrahydronaphthalene-2
-Acetic acid (1.5 g) was added and the mixture was stirred at room temperature overnight. The solvent was distilled off under reduced pressure to obtain methyl 7-methoxy-1,2,3,4-tetrahydronaphthalene-2-acetate (1.6 g).

(34-2) The compound (1.6 g) obtained in the step (34-1) was subjected to the same reaction as in the step (5-1) of Example 5 to give 7-methoxy-3,4. -Methyl dihydronaphthalene-2-acetate (0.73 g) was obtained. (34-3) Compound (0.71) obtained in step (34-2)
In g), the same reaction as in step (31-3) of Example 31 was performed to obtain methyl 7-hydroxy-3,4-dihydronaphthalene-2-acetate (0.36 g). (34-4) Compound (0.36) obtained in step (34-3)
The same reaction as in Example 23 was performed on g) to give the title compound (0.5 g). mp: 140-142 ° C. ¹ H NMR (270 MHz, DMSO-d ₆ ) δ ppm: 7.75 (d, 2 H, J = 8.8 Hz), 7.5
0 (d, 2H, J = 8.8Hz), 7.02 (d, 1H, J = 8.8Hz), 6.76-6.72 (m, 2
H), 6.29 (s, 2H), 5.18 (s, 2H), 3.62 (s, 3H), 3.14 (s, 2
H), 2.70-2.65 (m, 2H), 2.34-2.22 (m, 2H)

Example 35 Methyl 7-[(4-amidinobenzyl) oxy] -3,4-dihydronaphthalene-2-acetate (Compound No. 9)
Synthesis of hydrochloride salt of 2) Compound (0.4 g) obtained in step (34-4) of Example 34
Then, the same reaction as in Example 2 and Example 3 was performed to obtain the title compound (0.22 g). mp: 192-194 ° C ¹ H NMR (270 MHz, DMSO-d ₆ ) δ ppm: 8.32 (s, 4H), 7.78 (d, 2H, J
= 8.8Hz), 7.59 (d, 2H, J = 8.8Hz), 7.02 (d, 1H, J = 8.8Hz),
6.76-6.72 (m, 2H), 6.29 (s, 2H), 5.18 (s, 2H), 3.62 (s, 3
H), 3.14 (s, 2H), 2.70-2.65 (m, 2H), 2.34-2.22 (m, 2H)

Example 36 Synthesis of hydrochloride of 7-[(4-amidinobenzyl) oxy] -3,4-dihydronaphthalene-2-acetic acid (Compound No. 91) To the compound (0.20 g) obtained in Example 35 By performing the same reaction as in Example 4, the title compound (0.1 g) was obtained. mp: 218 to 220 ° C ¹ H NMR (270 MHz, DMSO-d ₆ ) δ ppm: 9.30 (brs, 2H), 9.07 (brs,
2H), 7.84 (d, 2H, J = 8.8Hz), 7.65 (d, 2H, J = 8.8Hz), 7.02
(d, 1H, J = 8.8Hz), 6.75-6.71 (m, 2H), 6.27 (s, 1H), 5.21
(s, 2H), 3.14 (s, 2H), 2.70-2.64 (m, 2H), 2.26-2.20 (m, 2
H)

Example 37 7-[(4-Guanidinobenzoyl) amino] -1,
Synthesis of hydrochloride of ethyl 2,3,4-tetrahydronaphthalene-2-acetate (Compound No. 95) 4-guanidinobenzoic acid hydrochloride (0.63 g) and 7-amino-1,2,3,4-tetrahydronaphthalene- Ethyl 2-acetate hydrochloride (0.79 g) was dissolved in N, N-dimethylformamide (20 ml). Under cooling, 4-dimethylaminopyridine (0.036 g), triethylamine (0.41 ml) and dicyclohexylcarbodiimide (0.64 g) were added. Stirred overnight at room temperature. The precipitate was filtered and the filtrate was evaporated under reduced pressure. A saturated aqueous sodium hydrogen carbonate solution was added to the concentrated residue, and the precipitate was filtered. The precipitate is treated with a hydrochloric acid / dioxane solution to give a hydrochloride, whereby the title compound (0.5%) is obtained.
g) was obtained. mp: 100 ° C (decomposition) ¹ H NMR (270 MHz, DMSO-d ₆ ) δ ppm: 10.15-10.04 (m, 2H), 8.05
-8.02 (m, 2H), 7.68-7.34 (m, 7H), 7.05-7.02 (m, 1H), 4.1
1 (q, 2H, J = 7.3Hz), 2.85-2.74 (m, 3H), 2.49-2.35 (m, 3
H), 2.28-2.13 (m, 1H), 1.91-1.78 (m, 1H), 1.49-1.38 (m,
1H), 1.21 (t, 3H, J = 7.3Hz)

Example 38 7-[(4-Guanidinobenzoyl) amino] -1,
Synthesis of hydrochloride salt of 2,3,4-tetrahydronaphthalene-2-acetic acid (Compound No. 93) The compound (0.1 g) obtained in Example 37 was subjected to the same reaction as in Example 30 to give the title compound ( 0.07 g). mp: 140 ° C (decomposition) ¹ H NMR (270 MHz, DMSO-d ₆ ) δ ppm: 10.09-10.00 (m, 2H), 8.05
-8.02 (m, 2H), 7.63-7.34 (m, 7H), 2.86-2.74 (m, 3H), 2.3
9-2.24 (m, 3H), 2.10-2.08 (m, 1H), 1.90-1.87 (m, 1H), 1.
45-1.33 (m, 1H)

Example 39 7-[(4-Aminomethylbenzoyl) amino] -1,
Synthesis of hydrochloride of ethyl 2,3,4-tetrahydronaphthalene-2-acetate (Compound No. 124) (39-1) 4- (t-butoxycarbonylaminomethyl) benzoic acid (0.49 g), 7-amino-1 , 2,3
A mixed solution of ethyl 4-tetrahydronaphthalene-2-acetic acid hydrochloride (1.06 g) was subjected to the same reaction as in Example 37 to give 7-[[(4-t-butoxycarbonylaminomethyl) benzoyl] amino]-. 1,2,3,4-
Ethyl tetrahydronaphthalene-2-acetate (0.74 g)
I got (39-2) The compound (0.74 g) obtained in the step (39-1) was dissolved in a hydrochloric acid / dioxane solution and stirred at room temperature for 1 hour. After evaporating the reaction solution under reduced pressure, ether was added to the concentrated residue, and the resulting precipitate was collected by filtration and dried to give the title compound (0.51 g). mp: 199-201 ° C ¹ H NMR (270 MHz, DMSO-d ₆ ) δ ppm: 10.12 (s, 1 H), 8.39 (brs, 3
H), 8.00 (d, 2H, J = 8.8Hz), 7.60 (d, 2H, J = 8.8Hz), 7.50-
7.47 (m, 2H), 7.03 (d, 1H, J = 8.8Hz), 4.14-4.06 (m, 4H),
2.86-2.75 (m, 3H), 2.49-2.25 (m, 3H), 2.13-2.09 (m, 1
H), 1.91-1.87 (m, 1H), 1.49-1.34 (m, 1H), 1.21 (t, 3H)

Example 40 7-[(4-Aminomethylbenzoyl) amino] -1,
Synthesis of hydrochloride salt of 2,3,4-tetrahydronaphthalene-2-acetic acid (Compound No. 123) (40-1) To the compound (0.74 g) obtained in step (39-1) of Example 39, Example 4 By performing the same reaction as above, 7-[[4- (t-butoxycarbonylaminomethyl) benzoyl] amino] -1,2,3,4-tetrahydronaphthalene-2-acetic acid (0.69 g) was obtained. (40-2) Compound (0.69) obtained in step (40-1)
The same reaction as in step (39-2) of Example 39 was performed on g) to give the title compound (0.51 g, amorphous). ¹ H NMR (270 MHz, DMSO-d ₆ ) δ ppm: 10.10 (s, 1 H), 8.33 (brs, 3
H), 8.00 (d, 2H, J = 8.8Hz), 7.60 (d, 2H, J = 8.8Hz), 7.49-
7.47 (m, 2H), 7.03 (d, 1H, J = 8.8Hz), 4.12 (d, 2H, J = 5.8H
z), 2.86-2.75 (m, 3H), 2.49-2.25 (m, 3H), 2.15-2.09 (m, 3H)
1H) 、 1.92-1.87 (m, 1H) 、 1.49-1.34 (m, 1H)

Production Example Synthesis of 7-[(4-amidinobenzoyl) amino] -1-oxo-3,4-dihydro-isoquinolone-2-acetic acid hydrochloride (Preparation-1) Starting material 7-nitro-1- Oxo
3,4-Dihydroisoquinolone is available from J. Chem. Soc. Perkin.
I, 180, (1977) and J. Org. Chem., 48 , 3220, (1983). . 7-Nitro-1-oxo-3,4-dihydroisoquinolone (2.0 g) was suspended in xylene (100 ml), and 60% sodium hydride (0.5 g) was added at room temperature. 1
After heating under reflux for an hour, ethyl bromoacetate (2.3 ml) was added, and the mixture was further heated under reflux for 1 hour. After cooling to room temperature, the reaction mixture was poured into water and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Oxo-3,4-dihydroisoquinolone-2-ethyl acetate (0.67 g) was obtained.

(Production-2) The compound (0.67 g) obtained in the step (Production-1) was dissolved in ethanol (10 ml), and 1N hydrochloric acid /
An ethanol solution (0.5 ml) was added. This was subjected to a catalytic hydrogenation reaction using a Pd catalyst, and the obtained compound was washed with ether to give 7-amino-1-oxo-3,4.
-Dihydroisoquinolone-2-ethyl acetate hydrochloride (0.65 g) was obtained. (Production-3) The compound (0.62 g) obtained in the step (Production-2) was combined with 4-cyanobenzoyl chloride (0.49 g) in Example 1.
By performing the same reaction as in step (1-2) of the above, 7-
[(4-cyanobenzoyl) amino] -1-oxo-
Ethyl 3,4-dihydroisoquinolone-2-acetate (0.
85 g).

(Production-4) The compound (0.55 g) obtained in step (Production-3) was subjected to the same reaction as in Examples 2 and 3 to give 7-[(4-amidinobenzoyl) amino. ] -1-oxo-3,4-dihydroisoquinolone-
Ethyl 2-acetate hydrochloride (0.56 g) was obtained. (Product-5) Compound (0.52 g) obtained in step (Product-4)
Then, the same reaction as in Example 4 was carried out to obtain the title compound (0.28 g). mp: 295-297 ° C (decomposition) ¹ H NMR (270 MHz, TFA-d) δ ppm: 8.25 (m, 3H), 8.03 (m, 3H),
7.49 (d, 1H, J = 8.8Hz), 4.68 (s, 2H), 3.94 (t, 2H, J = 7.3H
z), 3.27 (t, 2H, J = 7.3Hz)

Pharmacological Test Examples Guinea Pig Platelet Aggregation Inhibitory Effect Test Method Blood was collected from male guinea pigs using a syringe containing 3.8% sodium citrate (1 to 9 blood) as an anticoagulant. Then, platelet rich plasma (platelet rich plasma,
The following PRP) was obtained. The remaining blood from which the PRP was separated
Centrifuge at 200xg for 15 minutes and platelet poor plasma (platelet po
or plasma (hereinafter PPP). The platelet count was measured using an automatic platelet counter (SysmexPL-100 manufactured by Toa Medical Electronics).
PRP was diluted with PPP to 300,000 cells / μl. Platelet aggregation is measured by a 6-channel aggregometer (HEMA TRACER
1NKK) was measured as follows. PRP (240μl)
After heating at 37 ° C for 2 minutes, the solvent of the test drug (control)
Alternatively, various concentrations of a test drug (30 μl) were added, and 2 minutes later, 30 μl of adenosine diphosphate (final concentration: 5 μM) was added to induce platelet aggregation. The inhibition rate was determined by comparing the maximum aggregation rate between the control and the test drug group. The test drug concentration (IC ₅₀ ) at the time of 50% inhibition was determined from the inhibition rate and the test drug concentration, and used as an index of the platelet aggregation inhibitory action. The results are shown in Table 1 [Table 1].

[0132]

[Table 1]

2. Human Platelet Aggregation Inhibition Effect Test Method Blood was collected from a healthy person using a syringe, and 3.8% sodium citrate (1 ratio to 9 blood) was added as an anticoagulant. Then, platelet-rich plasma (platelet rich plasma, hereinafter
PRP). 1,200 xg of remaining blood separated from PRP
Centrifuge for 20 minutes in platelet poor
asma, hereinafter PPP). The platelet count was measured with an automatic platelet counting device (SysmexPL-100, manufactured by Toa Medical Electronics Co., Ltd.), and PRP was diluted with PPP to about 250,000 / μl. Platelet aggregation is measured by a 6-channel aggregometer (HEMA TRACER 1 NK
K) was measured as follows. 37 PRP (240 μl)
After heating at 2 ° C for 2 minutes, add the test drug solvent (control) or various concentrations of the test drug (30 μl), and after 2 minutes,
30 μl of adenosine diphosphate (final concentration: 5 μM) was added to induce platelet aggregation. The inhibition rate was determined by comparing the maximum aggregation rate between the control and the test drug group. The test drug concentration (I
_C50 ) was determined and used as an index of the platelet aggregation inhibitory action. The results are shown in Table 2 [Table 2].

[0134]

[Table 2] From the above test results, in the compound represented by the general formula (1) of the present invention, B is -CON (R ¹ )-or -N
(R ¹ ) CO- (R ¹ is as defined above), and W-
X is -CH ₂ -CH =, Y is -CH ₂ -, - compound O-, which showed particularly good platelet aggregation inhibitory activity. Further, the compounds of Production Examples are compounds disclosed in WO94 / 29273, and the compounds represented by the general formula (1) of the present invention were superior to the compounds disclosed in WO94 / 29273 in inhibiting platelet aggregation.

Formulation Examples When the compound of the present invention represented by the general formula (1) is used as a therapeutic agent for thrombosis, it can be used, for example, by the following formulation. Formulation Example 1 (Tablet) 7-[(4-amidinobenzoyl) amino] -1,2,2
3,4-tetrahydronaphthalene-2-acetic acid (Compound No. 1) (50 g), lactose (38 g), corn starch (35
g) and crystalline cellulose (20 g) were mixed well, kneaded and granulated with a solution of hydroxypropiocellulose (5 g) in water, and dried at 50 ° C. for 4 hours. Magnesium stearate (2 g) was added to the mixture, mixed well, and made into tablets at a weight of 150 mg per tablet using a tableting machine to obtain tablets.

Formulation Example 2 (Capsule) 7- [N- (4-amidinophenyl) carbamoyl]-
1,2,3,4-tetrahydronaphthalene-2-acetic acid (Compound No. 9) (100 g), lactose (70 g), corn starch (70 g), crystalline cellulose (40 g), and magnesium stearate (6 g) were mixed well. . This was filled into hard capsules in an amount of 300 mg by a capsule filling machine to obtain capsules.

Formulation Example 3 (Granules) 6-[(4-amidinobenzoyl) amino] chroman-
3-acetic acid (Compound No. 17) (100 g), lactose (150 g),
Corn starch (140 g) and crystalline cellulose (80
g) was mixed well, and this was kneaded and granulated with a solution of hydroxylpropylcellulose (20 g) dissolved in water (400 ml), and dried at 50 ° C. for 4 hours. This was sized with a 12-mesh screen, and magnesium stearate (8 g) was added and mixed well to obtain granules.

Formulation Example 4 (Injection) 7- [N- (4-amidinophenyl) carbamoyl]-
1,2,3,4-Tetrahydronaphthalene-2-acetic acid (Compound No. 9) (0.5 g) was sealed in an ampoule together with 5.0 ml of cottonseed oil to give a non-aqueous injection. In the case of an injection for infusion, HCO-60 (1.
The solution was prepared as a solution to which 0 g) was added, and was suspended in 0.9% physiological saline (200 ml) before use.

[0139]

As described above, the compound of the present invention has an excellent platelet aggregation inhibitory action based on fibrinogen antagonism, and ischemic heart disease, ischemic brain disease, peripheral circulation disorder, arterial thrombus, It is useful for prevention or treatment of thrombosis such as arteriosclerosis and pulmonary vascular disorder, or restenosis and reocclusion after percutaneous transluminal coronary angioplasty or percutaneous transluminal coronary artery reopening.

──────────────────────────────────────────────────の Continued on the front page (51) Int.Cl. ⁶ Identification code FI A61K 31/47 606 A61K 31/47 606 C07C 251/48 C07C 251/48 255/57 255/57 255/60 255/60 279 / 18 279/18 C07D 217/16 C07D 217/16 311/58 31/58 1900-1 Togo, Mobara-shi, Mitsui-Higashi Pressure Chemical Co., Ltd. (72) Inventor Kohei Yazawa 1900-1, Togo, Mobara-shi, Chiba Pref. −511538 (JP, A) (58) Fields investigated (Int. Cl. ⁶ , DB name) CA (STN) CAOLD (STN) REGISTRY (STN)

Claims (9)

(57) [Claims] 1. A compound of the general formula (1) Wherein, A represents an amidino group, guanidino group or aminomethyl group, B is _{-CH 2 O -, - OCH 2} -, - CH
^{_{2 N (R 1) -,}} - N (R 1) CH 2 -, - CON (R 1)
— Or —N (R ¹ ) CO— (R ¹ represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms), and W—X represents —C
H ₂ —CH ＝, —CH ₂ —N ＝ or —CH ＝ C ＝, Y represents —CH ₂ — or —O—, and Z represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms. Or a salt thereof. 2. The compound according to claim 1, wherein A is an amidino group, or a salt thereof. 3. B is -CON (R ¹ )-or -N
(R ¹⁾ a CO-, W-X is a compound or its salt according to claim 2, wherein a -CH ₂ -CH = or -CH ₂ -N =. 4. The compound according to claim 3, wherein R ¹ is a hydrogen atom, or a salt thereof. 5. 7-[(4-Amidinobenzoyl) amino] -1,2,3,4-tetrahydronaphthalene-2-
Acetic acid or 7- [N- (4-amidinophenyl) carbamoyl] -1,2,3,4-tetrahydronaphthalene-2-acetic acid or 6-[(4-amidinobenzoyl)
Amino] chroman-3-acetic acid or 7-[(4-amidinobenzoyl) amino] -1,2,3,4-tetrahydroisoquinoline-2-acetic acid. 6. A platelet aggregation inhibitor comprising the compound according to any one of claims 1 to 5 as an active ingredient. 7. A thrombosis or a post-percutaneous transluminal coronary angioplasty or reperfusion through a percutaneous transluminal coronary artery, which comprises the compound according to any one of claims 1 to 5 as an active ingredient. Prevention or treatment of post-operative restenosis and restenosis. 8. A compound of the general formula (2) [Wherein G is a cyano group or HN = C (OR ² )-(R ²
Represents shown) an alkyl group having 1 to 4 hydrogen atoms or carbon atoms, B is _{-CH 2 O -, - OCH 2} -, - CH 2 N
(R ¹ ) —, —N (R ¹ ) CH ₂ —, —CON (R ¹ ) — or —N (R ¹ ) CO— (R ¹ is a hydrogen atom or a carbon atom
WX represents —CH _2.
-CH =, - CH ₂ -N = or -CH = C = represents,
Y is -CH ₂ - represents or -O-, Z is or a salt thereof represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms]. 9. B is -CONH- or -NHCO-, W-X is -CH ₂ -CH = or -CH ₂ -N =, Y is -CH ₂ - is or -O- wherein Item 10. The compound according to item 8, or a salt thereof.