JPH08231486A - Bicyclic compound and blood platelet coagulation inhibitor containing the same - Google Patents

Abstract

PURPOSE: To obtain a new bicyclic compound having excellent blood platelet coagulation inhibitory action, thus useful as a preventive for ischemic cardiopathy, etc. CONSTITUTION: This new compound is expressed by the formula (A is amidino, guanidido or aminomethyl; B is CH2 O, OCH2 , etc ; W-X is CH2 -CH=, CH2 -N=, etc.; Yis CH2 or O; Z is H or a 1-4C alkyl), e.g. 7-[(4-cyanobenzoyl)amino]-1,2,3,4- tetrahydronaphthalene-2-acetic ethyl ester. The illustrated compound is obtained by reaction of diethylphosphonoacetic ethyl ester with 7-hydro-3,4-dihydro(1H)-2-- naphthalenone in ethylene glycol dimethyl ether in the presence of NaH.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a platelet aggregation inhibitor containing a novel bicyclic compound and its derivative.

[0002]

2. Description of the Related Art Since it was revealed 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 that antiplatelet drugs inhibit only 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 mutual binding of platelets via fibrinogen, and this process is common regardless of the type of stimulus that causes aggregation. Therefore, recently, a drug that directly inhibits the binding between platelets and fibrinogen has been attracting attention as an antiplatelet drug having an inhibitory effect on all aggregation-stimulating 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-
A large number of linear peptides or cyclic peptides containing the Asp-amino acid sequence or non-peptide compounds simulating the structure have been reported Drug of the Future, 19 (2), 1
35 (1994), 19 (5), 461 (1994). So far, common structures of non-peptide compounds include acidic groups such as carboxyl group corresponding to the carboxyl group of aspartic acid, amidino group corresponding to guanidino group of arginine, guanidino group, piperazinyl group or aminomethyl group. The basic groups were present at a certain distance, and diversity was recognized in the skeleton structure connecting the acidic and basic groups. A compound having a bicyclic compound in which two 6-membered rings are fused to this skeletal structure is disclosed in PCT International Application WO94 / 29273. However, the compounds specifically disclosed in WO94 / 29273 are only three compounds having a tetrahydroisoquinoline structure,
Their inhibitory effect on human platelet aggregation is IC ₅₀ of 1 to 13 µ.
M, the activity is still insufficient as an antiplatelet drug.

[0003]

DISCLOSURE OF THE INVENTION The present invention is to provide a novel compound having a very strong platelet aggregation inhibitory action based on a fibrinogen antagonistic action. Thrombosis such as ischemic heart disease, ischemic brain disease, peripheral circulatory disorder, arterial thrombosis, arteriosclerosis, pulmonary vascular disorder, or after percutaneous transluminal coronary angioplasty or percutaneous transluminal coronary revascularization It is an object of the present invention to provide a preventive or therapeutic agent for restenosis and restenosis.

[0004]

Means for Solving the Problems As a result of extensive studies on non-peptide compounds having a fibrinogen antagonistic action, the present inventors have found a novel bicyclic compound having a very strong platelet aggregation inhibitory action, and Completed
That is, the present invention provides 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) represents, W-X may, -C
_{H 2 -CH =, - CH 2} -N = or represents -CH = C =, Y is -CH ₂ - represents or -O-, Z represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms] Is a novel compound represented by or a salt thereof.

Furthermore, the present invention is a platelet aggregation inhibitor characterized by containing a compound represented by the general formula (1) as an active ingredient. The present invention also includes a compound represented by the general formula (1) as an active ingredient, thrombosis, or after percutaneous transluminal coronary angioplasty or percutaneous transluminal coronary artery recanalization. It is a preventive or therapeutic agent for restenosis and reocclusion. The present invention also provides a compound represented by the general formula (2)

[0007]

[Chemical 4] [In the formula, 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 1 number hydrogen or C
Represents an alkyl group of 4 to 4), and W—X is —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 for a compound in which A is an amidino group in the general formula (1).

[0008]

BEST MODE FOR CARRYING OUT THE INVENTION The present invention will be described in detail below.
In the present invention, the alkyl group having 1 to 4 carbon atoms means a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, n.
-Refers to a butyl group. _{-CH 2 -CH =, - CH 2} -N =,
-CH = C = or ^{HN = C (OR 2) -} (R 2 represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms) of the "="
Indicates a hand of two bonds. Representative compounds represented by the general formula (1) of the present invention are specifically exemplified below as compound numbers 1-132, but the invention is not limited thereto. In addition, 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]- 1,2,3,4-tetrahydronaphthalene-2-n-propyl acetate, (5) 7-[(4
-Amidinobenzoyl) amino] -1,2,3,4-tetrahydronaphthalene-2-isopropyl acetate,
(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-
2-sec-butyl 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) 7- [N- (4-amidinophenyl) carbamoyl] -1,2,3,4-tetrahydronaphthalene-2-ethyl 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-acetic acid n-butyl, (15)
7- [N- (4-amidinophenyl) carbamoyl]-
1,2,3,4-tetrahydronaphthalene-2-acetic acid
sec-butyl, (16) 7- [N- (4-amidinophenyl) carbamoyl] -1,2,3,4-tetrahydronaphthalene-2-acetate tert-butyl, (17)
6-[(4-amidinobenzoyl) amino] chroman-
3-acetic acid, (18) 6-[(4-amidinobenzoyl)
Amino] chroman-3-acetic acid methyl, (19) 6-
[(4-Amidinobenzoyl) amino] chroman-3-
Ethyl acetate, (20) 6-[(4-amidinobenzoyl) amino] chroman-3-n-propyl acetate,

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

(31) 7-[(4-amidinobenzoyl) amino] -1,2,3,4-tetrahydroisoquinoline-2-acetic acid n-propyl, (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,
3,4-Tetrahydroisoquinoline-2-acetic acid n-propyl, (39) 7- [N- (4-amidinophenyl)
Carbamoyl] -1,2,3,4-tetrahydroisoquinoline-2-acetic acid n-butyl, (40) 7- [N-
(4-Amidinophenyl) carbamoyl] -1,2,
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 2-Methyl-2-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 methyl, (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,
3,4-tetrahydronaphthalene-2-ethyl acetate,
(49) 7- [N- (4-amidinobenzoyl) -N-
Methylamino] -1,2,3,4-tetrahydronaphthalene-2-acetic acid n-butyl, (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)
-N-n-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,
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,
3,4-Tetrahydronaphthalene-2-acetic acid n-propyl, (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] -1,2,3,3
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,
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-ethyl 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) -N-n-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-
2-Acetic acid methyl, (82) 7-[(4-amidinophenoxy) methyl] -1,2,3,4-tetrahydronaphthalene-2-acetic acid, (83) 7-[(4-amidinophenoxy) methyl]- 1,2,3,4-Tetrahydronaphthalene-2-acetic acid ethyl, (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-acetic acid n-propyl, (97) 7-
[(4-guanidinobenzoyl) amino] -1,2,
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) 7- [N- (4-guanidinophenyl) carbamoyl] -1,2,3,4-tetrahydronaphthalene-2-tert-butyl acetate, (10)
2) 6-[(4-guanidinobenzoyl) amino] chroman-3-acetic acid, (103) 6-[(4-guanidinobenzoyl) amino] chroman-3-ethyl acetate, (10)
4) 6-[(4-guanidinobenzoyl) amino] chroman-3-n-propyl acetate, (105) 6-[(4-
Guanidinobenzoyl) amino] chroman-3-acetic acid t
ert-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,
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,
4-tetrahydroisoquinoline-2-ethyl 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,
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,
3,4-tetrahydronaphthalene-2-acetic acid, (13
2) 6-[(4-aminomethylbenzyl) oxy] chroman-3-acetic acid

The compound represented by the general formula (1) of the present invention is
In the preferred compound, A is an amidino group and B is
-CH₂O-, -OCH₂-, -CH₂N (R¹)-, -N
(R ¹) CH₂-, -CON (R¹)-Or -N (R¹)
CO- (R¹Is as defined above) and W
-X is -CH₂-CH =, -CH₂-N = or -CH
= C = and Y is -CH₂-Or -O-,
Z is a hydrogen atom or an alkyl group having 1 to 4 carbon atoms.
Compound.

A more preferred compound of the compounds represented by the general formula (1) of the present invention is that A is an amidino group,
B is, -CON (R ¹⁾ - or -N (R ¹⁾ CO- (R
¹ has the same meaning as defined above, and W-X is-
CH ₂ -CH = or a -CH ₂ -N =, Y is, -C
H ₂ — or —O—, and Z is a compound represented by a hydrogen atom or an alkyl group having 1 to 4 carbon atoms.

Among the compounds represented by the general formula (1) of the present invention, an even more preferable compound is that 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 a -CH ₂ -CH = or -CH ₂ -N =, Y is -CH ₂ - or -O-, and the Z is a hydrogen atom or an alkyl group having 1 to 4 carbon atoms It is the 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, 7 -[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-tetrahydrisoquinoline-2-acetic acid, 7-[(4-amidinobenzoyl) amino] -1,2,3,4-tetrahydronaphthalene-2- 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 optical isomer of R configuration or S configuration with respect to these asymmetric carbon atoms can be used. Included in the present invention. Moreover, the salt of the compound represented by the general formula (1) of the present invention can be exemplified as a specific compound 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, or acetate,
Tartrate, citrate, fumarate, maleate,
Organic acid salts such as toluene sulfonate and methane sulfonate, and further metal salts such as sodium salt, potassium salt, calcium salt, aluminum salt when Z is a hydrogen atom, or primary amines such as ammonia. , A pharmaceutically acceptable salt such as a salt with an organic base such as a secondary amine such as dimethylamine and a tertiary amine such as triethylamine.

In the compound represented by the general formula (1) of the present invention, 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. Specific example is compound No. 1
33 to 164 are specifically exemplified below, but the present invention is not limited thereto. The compound number is
Reference is made to the examples below.

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

(143) Ethyl 6- [N- (4-cyanophenyl) carbamoyl] chroman-3-acetate, (1
44) 6- [N- [4- (Ethoxyiminomethyl) phenyl] carbamoyl] chroman-3-ethyl acetate,
(145) 7-[(4-cyanobenzoyl) amino]-
1,2,3,4-Tetrahydroisoquinoline-2-acetic acid ethyl, (146) 7-[[4- (ethoxyiminomethyl) benzoyl] amino] -1,2,3,4-tetrahydroisoquinoline-2-acetic acid ethyl , (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-acetate tert-butyl,

(153) 7- [N- [4- (ethoxyiminomethyl) phenyl] -N-methylcarbamoyl]-
1,2,3,4-tetrahydronaphthalene-2-acetic acid
Ethyl, (154) 7- [N- (4-cyanophenyl)
-N-n-butylcarbamoyl] -1,2,3,4-tetrahydronaphthalene-2-ethyl acetate, (155)
7- [N- [4- (ethoxyiminomethyl) phenyl]
-N-n-butylcarbamoyl] -1,2,3,4-tetrahydronaphthalene-2-ethyl acetate, (156)
7-[(4-cyanobenzyl) oxy] -1,2,3
Methyl 4-tetrahydronaphthalene-2-acetate, (1
57) 7-[[4- (Methoxyiminomethyl) benzyl] oxy] -1,2,3,4-tetrahydronaphthalene-2-acetic acid methyl, (158) 7-[[4- (ethoxyiminomethyl) benzyl] Oxy] -1,2,3
4-Tetrahydronaphthalene-2-ethyl 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-methyl acetate,

Also, in the intermediate compound represented by the general formula (2) of the present invention, when the compound has an asymmetric carbon atom in the molecule, the R configuration or the S configuration is selected for these asymmetric carbon atoms. The optical isomers of are also included in the present invention. Furthermore, these salts can also be exemplified as the specific compounds of the present invention. For example, inorganic acid salts such as hydrochloride, hydrobromide, sulfate, nitrate, phosphate, etc., or acetate, tartrate, citrate, fumarate, maleate, toluenesulfonate, methanesulfonate. Examples thereof include pharmacologically acceptable salts such as salts and organic acids.

The compound represented by the general formula (1) of the present invention can be produced, for example, by the following method. Method (a) General formula (3) [Chemical formula 5]

[0033]

Embedded image (Wherein A is as defined above) and a compound of the general formula (4)

[0034]

[Chemical 6] (Wherein W—X, Y, Z and R ¹ have the same meanings as defined above), or a method of subjecting the compound to a condensation reaction, or the general formula (5)

[0035]

[Chemical 7] (Wherein A and R ¹ have the same meanings as defined above) and a compound represented by the general formula (6)

[0036]

Embedded image (In the formula, W-X, Y and Z have the same meanings as defined above) A method of subjecting the compound to a condensation reaction. Method (b) General formula (7) [Chemical formula 9]

[0037]

[Chemical 9] (Wherein A is as defined above) and a compound of the general formula (8)

[0038]

[Chemical 10] [Wherein W-X, Y and Z have the same meanings as defined above, and D represents -OH or -N (R ¹ ) H (R ¹ has the same meanings as defined above)] Or a general formula (9) [Chemical formula 11]

[0039]

[Chemical 11] (Wherein A and D have the same meanings as defined above) and a compound represented by the general formula (10)

[0040]

[Chemical 12] (In the formula, W-X, Y and Z have the same meanings as defined above) A method of subjecting the compound to a condensation reaction. (C) Method (11) [Chemical Formula 13]

[0041]

[Chemical 13] Or a compound represented by the general formula (4) is subjected to a condensation reaction,

[0042]

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

[0043]

[Chemical 15] 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 the compound represented by the general formula (10) is subjected to a condensation reaction to obtain a compound represented by the general formula (15)

[0045]

[Chemical 17] (In the formula, B, W-X, Y and Z have the same meanings as defined above.)
A method of converting the cyano group of the compound represented by the above into an amidino group by a known method. (D) method General formula (16) [Chemical formula 18]

[0046]

Embedded image (In the formula, E represents an amino group protected by a tert-butoxycarbonyl group or a benzyloxycarbonyl group) and a compound represented by the general formula (4) are subjected to a condensation reaction or a general formula ( 17) [Chemical 19]

[0047]

[Chemical 19] (Wherein E and R ¹ have the same meanings as defined above) and the compound represented by the general formula (6) is 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) is subjected to a condensation reaction, or the compound represented by the general formula (19)

[0049]

[Chemical 21] (Wherein E and D have the same meanings as defined above) and the compound represented by the general formula (10) is subjected to a condensation reaction to obtain a compound represented by the general formula (20)

[0050]

[Chemical formula 22] (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, or Pd,
A general formula (21) [Chemical formula 23] obtained by carrying out a catalytic hydrogenation reaction in the presence of a catalyst such as Pt

[0051]

[Chemical formula 23] (In the formula, B, W-X, Y and Z have the same meanings as defined above.)
A method of converting the amino group of the compound represented by to 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 (22) [Chemical formula 24]

[0052]

[Chemical formula 24] The compound represented by the formula (4) and the compound represented by the general formula (4) are subjected to a condensation reaction, or the compound represented by the general formula (23)

[0053]

[Chemical 25] (Wherein R ¹ has the same meaning as defined above) and the compound represented by the general formula (6) is subjected to a condensation reaction, or a compound represented by the formula (24)

[0054]

[Chemical formula 26] 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]

[Chemical 27] (Wherein D has the same meaning as defined above) and the compound represented by the general formula (10) undergoes a condensation reaction to obtain a compound represented by the general formula (26)

[0056]

[Chemical 28] (In the formula, B, W-X, Y and Z have the same meanings as defined above.)
A method of converting the bromine group of the compound represented by the above into a cyano group by a known method.

Method (f) The cyano group of the compound represented by the general formula (15) is converted into HN═C (O
R ² )-(R ² is as defined above). As the condensation reaction of the method (a), an amide bond forming reaction in an ordinary peptide can be used. For example, an amide bond-forming reagent such as dicyclohexylcarbodiimide, N, N'-carbonyldiimidazole, diphenylphosphoric acid azide or ethyl cyanophosphate is used, or a carboxyl group is derivatized into an active ester, a mixed acid anhydride or an 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 such as hydrogen chloride, sulfuric acid or hydrogen bromide, or protected by a tert-butoxycarbonyl group or a benzyloxycarbonyl group. Is preferred. In any of the above cases, the condensation reaction
The reaction can be accelerated 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., preferably 0 ° C. to around room temperature, and a solvent usually used is, for example, dioxane,
Tetrahydrofuran, acetonitrile, N, N-dimethylformamide, chloroform, methylene chloride and the like can be mentioned, and they may be used alone or as a mixed solvent.

As the condensation reaction of the method (b), the reaction can be carried out by a method known per se in the presence of a base such as sodium carbonate, sodium alkoxide or sodium hydride. As the solvent, methanol, ethanol, 2-butanone, N, N-dimethylformamide or the like may be used alone or in combination. The reaction temperature is usually 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 a cyano group into an amidino group is carried out by a method known per se, for example, by passing hydrogen chloride gas in a solvent such as ethanol, to convert the cyano group to HN═C (OR ² ) — (R ² is as described above. It 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
It is 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). Conversion of an amino group to a guanidino group can be carried out by a method known per se.
For example, it can be carried out by reacting the amino compound of the general formula (21) with S-methylisothiourea sulfate in the presence of a base such as sodium carbonate or sodium hydroxide. As the solvent, methanol, ethanol, dioxane, N, N-dimethylformamide or the like may be used alone or in combination. The reaction temperature is usually room temperature to 100 ° C, preferably 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 a bromine group into a 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 cyanide thereof in a solvent. It can be carried out by reacting monocopper. The reaction temperature is generally 100 to 250 ° C., preferably 150 to 200.
° C.

HN = C (O of the cyano group in method (f)
The conversion to an imidate represented by R ² )-(R ² has the same meaning as defined above) can be carried out by a method known per se, for example,
It can be carried out by reacting 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, it can be carried out by reacting sodium alkoxide in a solvent such as methanol or ethanol. The reaction temperature is generally -50 to 100 ° C, preferably room temperature to 50 ° C.

In the compound represented by the general formula (1) of the present invention, when Z 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 is treated with a base such as aqueous or alcoholic sodium hydroxide to hydrolyze the ester group, or treated with an acid such as hydrochloric acid or acetic acid. Thus, a free carboxylic acid derivative can be obtained. 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. It is also possible to produce a salt of the compound represented by the general formula (1) of the present invention by adding a base.
The thus obtained compound represented by the general formula (1) of the present invention can be isolated or purified by conventional means such as extraction, concentration, neutralization,
It can be isolated from the reaction mixture by using means such as filtration, recrystallization, column chromatography and the like.

The compound represented by the general formula (1) and salts thereof of the present invention are platelet aggregation inhibitors having a GPIIb / IIIa antagonistic action and inhibit platelet thrombus formation. Peripheral circulatory disorders such as thromboangiitis (Buerger's disease), Raynaud's disease, diabetic complications (eg diabetic retinopathy, diabetic nephropathy, etc.), venous thrombosis (eg deep vein thrombosis, etc.), angina (For example, stable angina, unstable angina including urgent 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 bleeding (eg, cerebral vasospasm after subarachnoid hemorrhage, etc.), pulmonary vascular disorders (eg, pulmonary thrombosis) , Pulmonary embolism, etc., arterial thrombosis, prognosis of 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 revascularization (PTCR), tissue plasminogen activator (tP)
A) It is useful for prevention of re-occlusion 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 for nephritis, etc., a cancer metastasis inhibitor, an immune disease prophylactic and therapeutic agent, and the like. Furthermore, 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, and warfarin.

The compound represented by the general formula (1) of the present invention or a salt thereof did not die even when administered to a mouse at a dose exceeding the effective dose. 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, its dose and dosage form are the physical properties of the compound, symptoms to be administered, etc. It naturally varies depending on
Up to 1,000 mg can be used as dosage forms such as tablets, granules, powders, suspensions and capsules. When administered parenterally, 1 to 500 mg per day for an adult can be administered as a dosage form such as an injection, a suppository, an isotonic solution for infusion.

The formulation can be performed according to a known method. For example, in the case of tablets, as excipients, corn starch, lactose, crystalline cellulose, etc., as binders, hydroxypropyl cellulose, carboxymethyl cellulose, gum arabic, etc., and as disintegrants, starch, agar, calcium carbonate, etc. As the lubricant, magnesium stearate, talc, etc. are used. Further, these tablets may be coated with sugar coating, gelatin coating or the like. When used as an injection, a non-aqueous solution of 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 may be a liquid or a preparation such as an aqueous solution dissolved in physiological saline or the like. The content of the active ingredient in the preparation is not particularly limited, but is usually 1 to 90 with the solid preparation and the liquid preparation.
%.

[0067]

The present invention will be described in detail below with reference to examples.
The present invention is not limited to these. The numbers in parentheses after the compound name are the numbers of the compounds exemplified in the detailed description. Example 1 7-[(4-cyanobenzoyl) amino] -1,2,
Synthesis of 3,4-tetrahydronaphthalene-2-ethyl acetate (Compound No. 133) (1-1) The starting compound, 7-nitro-3,4-dihydro- (1H) -2-naphthalenone, is described in J. Med. Chem.,
32 , 2128-2134 (1989). Ethyl diethylphosphonoacetate (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 hr. 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), and 7-nitro-3,4-dihydro- (1H).
2-Ethyl naphthylidene acetate (5.8 g) was obtained.

(1-2) 7-Amino-1,2,3,4-obtained by subjecting the compound obtained in step (1-1) to catalytic hydrogenation reaction with a Pd catalyst in the presence of an aqueous hydrochloric acid solution.
Tetrahydronaphthalene-2-acetic acid ethyl 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 1N aqueous hydrochloric acid solution, water, saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the concentrated residue was purified by silica gel column chromatography (developing agent; ethanol: chloroform = 1: 50) to obtain the title compound (0.89 g). mp: 122-124 ° C ¹ H NMR (270 MHz, CDCl ₃ ) δppm: 7.96 (d, 2H, J = 8.8Hz), 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 the step (1-2) of Example 1 was suspended in ethanol (20 ml) and cooled to 0 ° C or lower. Hydrochloric acid gas was bubbled through the solution for 1 hour so that the temperature did not exceed 10 ° C. After stirring at room temperature overnight and confirming the disappearance of the starting materials, the solvent was distilled off under reduced pressure and the title compound (0.83
g) was obtained. mp: 216 to 218 ° C ¹ H NMR (270 MHz, DMSO-d ₆ ) δppm: 10.46 (s, 1H), 8.25 (d, 2H,
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 = 7.3Hz), 1.51-1.32 (m, 1
H), 1.23 (t, 3H, J = 7.3Hz)

Example 3 7-[(4-amidinobenzoyl) amino] -1,2,
Synthesis of Hydrochloride of 3,4-Tetrahydronaphthalene-2-ethyl acetate (Compound No. 3) The compound (0.83 g) obtained in Example 2 was converted into ethanol (20 ml).
, Ammonium acetate (1.96 g) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was evaporated under reduced pressure, and the concentrated residue was recrystallized from ethanol to give the title compound (0.7 g). mp: 207-210 ° C ¹ H NMR (270 MHz, DMSO-d ₆ ) δppm: 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,
Synthesis of Hydrochloride 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,
Stir overnight at room temperature. Most of the solvent was distilled off under reduced pressure,
The concentrated residue was acidified by adding a 3N aqueous hydrochloric acid solution, and the generated precipitate was collected by filtration and washed well with water to obtain the title compound (0.07 g). mp: 236-238 ° C ¹ H NMR (270MHz, TFA-d) δppm: 8.20 (d, 2H, J = 8.8Hz), 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 for 1 hour at ℃, the reaction solution was distilled off under reduced pressure. The concentrated residue was adjusted to pH 2 with 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 (150 ml),
Amberlyst 15 (5 g) was added, and 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 was subjected to silica gel column chromatography (developing agent; ethyl acetate: n-hexane =
1:10) and 7-methoxycarbonyl-3,4
-Dihydronaphthalene (19.2g) was obtained.

(5-2) Compound (18.5 g) obtained in step (5-1), m-chloroperbenzoic acid having a content of 80% (9.4 g)
The chloroform solution of was stirred at room temperature for 3 hours. The reaction was stopped by adding an aqueous sodium hydrogen carbonate solution and an aqueous sodium sulfite solution to the reaction solution, 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 in the dark. The crude product obtained by filtering the reaction solution and concentrating under reduced pressure was purified by silica gel column chromatography (developing agent: chloroform: ethyl acetate = 20: 1) to obtain 7-methoxycarbonyl-3,4-dihydro-. (1H) -2-naphthalenone (1.1 g) was obtained.

(5-4) The compound (1.1 g) obtained in step (5-3) and tert-butoxycarbonylmethylenetriphenylphosphorane (3.8 g) were dissolved in toluene (30 ml), and the mixture was heated 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), and 7-methoxycarbonyl-1,2,3,4-tetrahydro- Tert-Butyl 2-naphthylidene acetate (0.85 g) was obtained.

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

(5-7) The compound (0.7 g) obtained in step (5-6) and oxalyl chloride (1.5 ml) were added to toluene (5 ml).
The resulting solution was dissolved in, 1 drop of N, N-dimethylformamide was added, and the mixture was stirred 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), 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. 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 ) δppm: 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 performing the same reactions as in Example 2 and Example 3. mp: 216-217 ° C ¹ H NMR (270 MHz, DMSO-d ₆ ) δppm: 7.97 (d, 2H, J = 8.8Hz), 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 of 1,2,3,4-Tetrahydronaphthalene-2-acetic Acid (Compound No. 9) The compound (0.14 g) obtained in Example 6 was subjected to the same reaction as in Example 4 to give the title. A compound (0.1 g) was obtained. mp: 230 ° C or higher ¹ H NMR (270 MHz, TFA-d) δppm: 8.00 (d, 2H, J = 8.8Hz), 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) Cool fuming nitric acid (40 ml) to -30 to -35 ° C,
4-Chromanone (5.8 g) was added with stirring over about 30 minutes. After 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 evaporated 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 reacted in the same manner as in step (5-1) of Example 5 to give 6-nitro- (2H)-. Chromen (4.9
g) was obtained. (8-3) The compound (4.9 g) obtained in the step (8-2) was reacted in the same manner as in the step (5-2) of Example 5 to give 3,4-epoxy-6-nitro-chroman. (4.0g)
I got (8-4) 6-nitro-3-chromanone (3.5 g) was obtained by subjecting the compound (3.9 g) obtained in step (8-3) to the same reaction as in step (5-3) of Example 5. Got (8-5) By subjecting the compound (3.5 g) obtained in the step (8-4) to the same reaction as in the step (1-1) of Example 1, ethyl 6-nitro-3-chromanilideneacetate (2 .
5g) was obtained.

(8-6) The compound obtained in the step (8-5) was subjected to catalytic hydrogenation reaction using a Pd catalyst to obtain 6-aminochroman-3-ethyl acetate (1.3 g) and 4
-Cyanobenzoyl chloride (1.1 g) was reacted in the same manner as in Step (1-2) of Example 1 to obtain the title compound (0.89 g). mp: 165-166 ° C ¹ H NMR (270MHz, CDCl ₃ ) δppm: 7.95 (d, 2H, J = 8.1Hz), 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 of 2) The compound (1.0 g) obtained in the step (8-6) of Example 8 was reacted in the same manner as in Example 2 to give the title compound (0.
9g) was obtained. mp: 239-240 ° C ¹ H NMR (270MHz, DMSO-d ₆ ) δppm: 10.41 (s, 1H), 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 = 7.3Hz), 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-
Synthesis of Hydrochloride of 3-Ethyl Acetate (Compound No. 19) The compound (0.5 g) obtained in Example 9 was reacted in the same manner as in Example 3 to obtain the title compound (0.34 g, amorphous). . ¹ HNMR (270MHz, DMSO-d ₆ ) δppm: 10.26 (s, 1H), 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,
1H), 2.55-2.33 (m, 4H), 1.21 (t, 3H, J = 7.3Hz)

Example 11 6-[(4-amidinobenzoyl) amino] chroman-
Synthesis of Hydrochloride of 3-Acetic Acid (Compound No. 17) The compound (0.34 g) obtained in Example 10 was reacted in the same manner as in Example 4 to obtain the title compound (0.22 g, amorphous). ¹ HNMR (270MHz, DMSO-d ₆ ) δppm: 10.31 (s, 1H), 9.50 (brs,
2H), 9.22 (brs, 2H), 8.14 (d, 2H, J = 8.8Hz), 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,
Synthesis of Hydrochloride of 3,4-Tetrahydroisoquinoline-2-ethyl acetate (Compound No. 145) (12-1) 7-Nitro-1,2,3,4 as a starting material
-Tetrahydroisoquinoline is a Heterocyclic Chemist
ry, 22 , 329 (1985). 7-nitro-1,
Dissolve 2,3,4-tetrahydroisoquinoline (2.89g) in ethanol (20ml) and add triethylamine (3.9m).
l) and ethyl bromoacetate (2.25 g) were added and the mixture was heated to 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-).
7-nitro-1,2,3,4-by purification with hexane = 1: 3) and treatment with hydrochloric acid / dioxane solution
Tetrahydroisoquinoline-2-acetic acid ethyl 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 catalytic hydrogenation reaction was carried out using a Pd catalyst. Obtained 7-amino-1,2,3,4-tetrahydroisoquinoline-2-
Ethyl acetate was converted to the dihydrochloride salt (2.18g) with hydrochloric acid / dioxane solution. The dihydrochloride (2.18 g) was added to 4-cyanobenzoyl chloride (1.41 g) and chloroform (3
0 ml), triethylamine (3.2 ml) was added under cooling, and the mixture was stirred at room temperature for 1 hr. 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:
It was purified with chloroform = 1: 50) and treated with a hydrochloric acid / dioxane solution to obtain the title compound (2.24 g, amorphous). ¹ HNMR (270MHz, DMSO-d ₆ ) δppm: 10.62 (s, 1H), 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,
Synthesis of dihydrochloride of 3,4-tetrahydroisoquinoline-2-ethyl acetate (Compound No. 30) Compound obtained in step (12-2) of Example 12 (1.0 g)
The title compound (0.7 g) was obtained by carrying out the same reaction as in Example 2 and Example 3. mp: 172-173 ° C ¹ H NMR (270MHz, DMSO-d ₆ ) δppm: 10.38 (s, 1H), 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 = 7.3Hz), 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,
Synthesis of dihydrochloride of 3,4-tetrahydroisoquinoline-2-acetic acid (Compound No. 28) The compound (0.1 g) obtained in Example 13 was reacted in the same manner as in Example 4 to give the title compound (0.03 g) was obtained. mp: 238 to 240 ° C (decomposition) ¹ H NMR (270 MHz, DMSO-d ₆ ) δppm: 10.43 (s, 1H), 9.49 (brs,
2H), 9.36 (brs, 2H), 8.16 (d, 2H, J = 8.8Hz), 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) The starting compound, 7-methoxyisoquinoline, is J.Org.Che.
m., 38 (21), 3701 (1973). A mixture of 7-methoxyisoquinoline (7.4 g) and pyridine hydrochloride (30 g) was heated with stirring at 180 ° C. for 6 hours. After allowing to cool, the mixture was dissolved in ethyl acetate and washed with saturated brine. 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 anhydrous methanesulfonic acid (6.6 ml) was added dropwise. After stirring for 1 hour under ice cooling, saturated aqueous sodium hydrogen carbonate was added to the reaction solution, and the mixture was extracted with chloroform. The extract was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (developing agent; ethyl acetate: n-hexane = 1: 3) to obtain trifluoro. There was obtained 7-isoquinolinyl methanesulfonate (9.18 g).

(15-2) Compound (8.6 g) obtained in step (15-1), triethylamine (9.0 ml), tetrakis (triphenylphosphine) palladium (1.07 g) in 500 ml autoclave, 1,3-bis (diphenylphosphino) propane (0.38g) was added to methanol (30m
l), dissolved in N, N-dimethylformamide (60 ml). After charging with carbon monoxide (15 kg / cm ² ), the mixture was stirred at 70 ° C. for 3 hours. After allowing to cool, 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) Compound (5.39 g) obtained in step (15-2), tert-butyl bromoacetate (6.7
g) was dissolved in acetonitrile (50 ml) and heated under reflux for 6 hours. After allowing to cool, 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 ice-cooled. Sodium borohydride (1.45 g) was added little by little to this. After stirring for 30 minutes under ice cooling, water (1 ml) was added and the solvent was evaporated under reduced pressure. It was extracted with saturated saline-chloroform system, and the organic layer was dried over anhydrous magnesium sulfate. The crude product obtained by distilling off the solvent under reduced pressure was subjected to silica gel column chromatography (developing agent; chloroform:
Purification with ethyl acetate = 20: 1) gave 7-methoxycarbonyl-1,2,3,4-tetrahydroisoquinoline-2-tert-butyl 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. By concentrating under reduced pressure and purifying the obtained crude product by ODS column chromatography (developing agent; methanol: water = 1: 2), 7-carboxy-1,2,3,4-tetrahydroisoquinoline-2 was obtained. -Tert-butyl acetate (0.9 g) was obtained.

(15-6) Compound (0.84 g) obtained in step (15-5), 4-aminobenzonitrile (0.35 g)
g), 1-hydroxybenzotriazole monohydrate (0.4
1g) methylene chloride (20ml) and tetrahydrofuran (10g)
ml) mixed solvent and 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 produced dicyclohexylurea was filtered off, the reaction solution was concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (developing agent; chloroform: methanol = 30: 1) to give the title compound (0.54 g) Got mp: 180 ° C (decomposition) ¹ H NMR (270 MHz, CDCl ₃ ) δppm: 7.85-7.70 (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) The compound obtained in the step (15-6) of Example 15 (0.5
By performing the same reaction as in Example 2 and Example 3 on g), 7- [N- (4-amidinophenyl) carbamoyl] -1,2,3,4-tetrahydroisoquinoline-2-ethyl acetate 2 The hydrochloride salt was obtained. This compound was dissolved in ethanol (20 ml) without purification, the same reaction as in Example 4 was performed, and the product was purified by ODS column chromatography (developing agent; water: methanol = 2: 1) to give the title compound ( 0.12 g) was obtained. mp: 230 ° C or higher ¹ H NMR (270 MHz, DMSO-d ₆ ) δppm: 10.45 (s, 1H), 9.46 (brs, 2
H), 9.35 (brs, 2H), 7.64 (d, 2H, J = 8.8Hz), 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 (0.67g) was added to N, N-dimethylformamide (10m
It was dissolved in 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 the mixture was left at room temperature overnight. The reaction solution was evaporated 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 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
Obtained ethyl (0.67 g). (17-2) Step (17-
Hydrochloric acid (0.56 g) obtained by treating the compound obtained in 1) with a hydrochloric acid / dioxane solution is subjected to the same reaction as in Step (1-2) of Example 1 to give the title compound (0.5 g). , An oily substance) was obtained. ¹ H NMR (270 MHz, CDCl ₃ ) δppm: 7.62 (d, 2H, J = 8.8Hz), 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) The compound obtained in Step (17-2) of Example 17 (0.5
The title compound (0.37 g) was obtained by performing the same reaction as in Example 2 and Example 3 on g). mp: 188-189 ° C ¹ H NMR (270 MHz, DMSO-d ₆ ) δppm: 8.29 (s, 4H), 7.63 (d, 2H, 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 compound (0.1 g) obtained in Example 18 was reacted in the same manner as in Example 4 to obtain the title compound (0.07 g). mp: 250 ° C or higher ¹ H NMR (270 MHz, DMSO-d ₆ ) δppm: 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 ice-cooled and trifluoroacetic anhydride ( 2.8 ml) was added dropwise over 2 minutes. After stirring for 1 hour, saturated aqueous sodium hydrogen carbonate 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 the mixture was heated to reflux for 1 hour. After cooling, the solvent was distilled off under reduced pressure to obtain an oily substance. Suspend this in water (40 ml) and
The mixture was stirred at 0 ° C for 1 hour. After cooling, the reaction solution was filtered through Celite, and the filtrate was concentrated under reduced pressure. The resulting crude product was 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 1. was suspended in toluene (5 ml),
Oxalyl chloride (0.6 ml) and 1 drop of N, N-dimethylformamide were added, and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain the corresponding acid chloride. This acid chloride was dissolved in chloroform (5 ml) and the step (20-
The compound (0.68 g) obtained in 1) and 4-dimethylaminopyridine (0.63 g) were added dropwise to a chloroform solution (10 ml) under ice cooling, and the mixture was stirred overnight at room temperature. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, extraction was performed 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 (developing agent; ethyl acetate: n-hexane = 1: 2) to obtain the title compound (0.96 g, oily substance). ¹ H NMR (270 MHz, CDCl ₃ ) δppm: 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 7- [N- (4-amidinophenyl) -N-methylcarbamoyl] -1,2,3,4-tetrahydronaphthalene-2-acetate (compound No. 57) The compound obtained in the step (20-2) of Example 20 (0.96
The title compound (1.03 g) was obtained by performing the same reaction as in Example 2 and Example 3 on g). mp: 178-180 ° C (decomposition) ¹ H NMR (270 MHz, DMSO-d ₆ ) δppm: 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) Two
The compound (0.3 g) obtained in 1 was reacted in the same manner as in Example 4 to obtain the title compound (0.17 g). mp: 200 ° C. (decomposition) ¹ H NMR (270 MHz, DMSO-d ₆ ) δppm: 7.69 (d, 2H, 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) Methyl 7-hydroxy-1,2,3,4-tetrahydronaphthalene-2-acetate as a raw material is HELVETICA CHIM
It was 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. The extract was dried over anhydrous magnesium sulfate, the solvent was evaporated 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 (270MHz, CDCl ₃ ) δppm: 7.65 (d, 2H, J = 8.8Hz), 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,
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 was cooled to 0 ° C or lower. The solution has a reaction temperature of 1
Hydrochloric acid gas was bubbled through for 1 hour so as not to exceed 0 ° C. After stirring at room temperature and confirming 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 was distilled off under reduced pressure, and the concentrated residue was subjected to silica gel column chromatography (developing agent; methanol: chloroform: acetic acid =
1: 10: 0.5) and the title compound (1.3 g)
I got mp: 177-179 ° C ¹ H NMR (270 MHz, DMSO-d ₆ ) δppm: 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,
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
It was dissolved in l) and the same reaction as in Example 4 was carried out to obtain the title compound (0.9 g). mp: 251-253 ° C ¹ H NMR (270 MHz, DMSO-d ₆ ) δppm: 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,
Synthesis of ethyl 3,4-tetrahydronaphthalene-2-acetate (Compound No. 159) (26-1) The starting material compound, 7-methoxycarbonyl-3,4-dihydronaphthalene, is used in the step (5-1) of Example 5. Was synthesized according to. A solution of sodium bis (2-methoxyethoxy) aluminum hydride (20 g) (70% toluene solution) in tetrahydrofuran (80 ml) was ice-cooled, and 7-methoxycarbonyl-3,4-dihydronaphthalene (10 g) in tetrahydrofuran (20 ml). Was dripped. After stirring at room temperature for 1 hour, the mixture was cooled with ice to a 3N aqueous hydrochloric acid solution (1
00 ml) was added carefully to acidify the solution and the organic layer was extracted with ether. The extract was dried over anhydrous magnesium sulfate, the solvent was evaporated 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 cooled with ice. Lower triphenylphosphine (1
3.3 g) was added little by little. After stirring for 1 hour under ice cooling, 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) to give 7-[(4-cyanophenoxy) methyl] -3,4-dihydronaphthalene (8.63 g)
I got

(26-3) The compound (8.2 g) obtained in step (26-2) was subjected to the same reaction as in 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)
By performing the same reaction as in step (1-1) of Example 1 on g), 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 g).
ml) and subjected to catalytic hydrogenation reaction with a Pd catalyst. The reaction solution was filtered through Celite, 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 ) δppm: 7.58 (d, 2H, J = 8.8Hz), 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,
Synthesis of Hydrochloride of Ethyl 3,4-Tetrahydronaphthalene-2-acetate (Compound No. 83) Compound obtained in step (26-6) of Example 26 (3.5 g)
The same reaction as in Example 2 and Example 3 was performed to give the title compound (2.15 g). mp: 210-212 ° C ¹ H NMR (270 MHz, DMSO-d ₆ ) δppm: 7.59 (d, 2H, J = 8.8Hz), 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,
Synthesis of Hydrochloride 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 evaporated under reduced pressure, the obtained crude product was resuspended in ethanol, 1M hydrochloric acid-ethanol solution (10 ml) was added, and the mixture was further stirred for 1 hr. The solution was concentrated under reduced pressure and washed successively with water, ethanol and chloroform to give the title compound (0.22g). mp: 230 ° C or higher ¹ H NMR (270 MHz, TFA-d) δppm: 7.63 (d, 2H, J = 8.8Hz), 7.39-
7.27 (m, 3H), 7.07 (d, 2H, J = 8.8Hz), 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,
3,4-Tetrahydronaphthalene-2-acetic acid ethyl
Synthesis of dihydrochloride of (Compound No. 85) 7-Amino-1,2,3, obtained by subjecting the compound obtained in the step (1-1) of Example 1 to catalytic hydrogenation reaction using a Pd catalyst 4-Tetrahydronaphthalene-2-acetic acid ethyl hydrochloride (1.5 g) and 4-amidinobenzyl bromide hydrochloride (1.39 g) were reacted in the same manner as in Example 23 to obtain the title compound (0.54 g). mp: 175-177 ° C ¹ H NMR (270 MHz, DMSO-d ₆ ) δppm: 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 = 7.34Hz), 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,
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 to give 2 Heated to reflux for hours. The solvent was distilled off under reduced pressure, the residue was dissolved in a small amount of ethanol, ether was added, and the resulting precipitate was collected by filtration and dried to obtain the title compound (0.5 g, amorphous). ¹ H NMR (270 MHz, DMSO-d ₆ ) δppm: 9.22 (brs, 2H), 8.85 (brs,
2H), 7.73 (d, 2H, J = 8.8Hz), 7.56 (d, 2H, J = 8.8Hz), 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) The starting material 6-methoxy-3-chromanone was synthesized according to J. Med. Chem., 31 , 688-691 (1988).
6-Methoxy-3-chromanone (2.66 g) was reacted in the same manner as in step (1-1) of Example 1 to give 6-methoxy-3.
-Ethyl chromanilidene acetate (2.7 g) was obtained. (31-2) Compound (2.7 g) obtained in step (31-1)
Then, by performing the same reaction as in Step (5-5) of Example 5, ethyl 6-methoxychroman-3-ethyl acetate (2.
66 g) was obtained.

(31-3) The compound (2.6 g) obtained in the step (31-2) was dissolved in acetonitrile (20 ml), sodium iodide (2.4 g) and trimethylsilane chloride (2.0 m).
l) was added and the mixture was heated to reflux. After 1 hour, it was poured into ice water and extracted with ethyl acetate, and the extract was mixed with 10% sodium thiosulfate,
It 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 6-hydroxychroman-3-ethyl acetate (2.4 g). It was

(31-4) The compound (2.4 g) obtained in the step (31-3) was reacted in the same manner as in Example 23 to obtain the title compound (3.5 g, oily substance). ¹ H NMR (270 MHz, CDCl ₃ ) δppm: 7.67 (d, 2H, J = 8.1Hz), 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 obtained in Step (31-4) of Example 31 (1.0 g)
The title compound (0.81 g) was obtained by carrying out the same reaction as in Example 2 and Example 3 above. mp: 157-160 ° C ¹ H NMR (270 MHz, DMSO-d ₆ ) δppm: 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 Hydrochloric Acid Salt of Acetic Acid (Compound No. 89) The compound (0.29 g) obtained in Example 32 was reacted in the same manner as in Example 4 to obtain the title compound (0.2 g). mp: 222-224 ° C ¹ H NMR (270 MHz, DMSO-d ₆ ) δppm: 9.32 (brs, 2H), 8.97 (brs,
2H), 7.82 (d, 2H, J = 8.8Hz), 7.65 (d, 2H, J = 8.8Hz), 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- which is 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 dripped 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 overnight at room temperature. The solvent was distilled off under reduced pressure to obtain methyl 7-methoxy-1,2,3,4-tetrahydronaphthalene-2-acetic acid (1.6 g).

(34-2) The compound (1.6 g) obtained in the step (34-1) was reacted in the same manner 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 the step (34-2)
The same reaction as in step (31-3) of Example 31 was performed on g) to obtain methyl 7-hydroxy-3,4-dihydronaphthalene-2-acetate (0.36 g). (34-4) Compound (0.36 obtained in step (34-3)
By subjecting g) to the same reaction as in Example 23, the title compound (0.5 g) was obtained. mp: 140-142 ° C ¹ H NMR (270 MHz, DMSO-d ₆ ) δppm: 7.75 (d, 2H, 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 obtained in step (34-4) of Example 34 (0.4 g)
The title compound (0.22 g) was obtained by performing the same reaction as in Example 2 and Example 3 above. mp: 192-194 ° C ¹ H NMR (270 MHz, DMSO-d ₆ ) δppm: 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) Compound (0.20 g) obtained in Example 35 The title compound (0.1 g) was obtained by carrying out the same reaction as in Example 4. mp: 218-220 ° C ¹ H NMR (270 MHz, DMSO-d ₆ ) δppm: 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- 2-Acetic acid ethyl hydrochloride (0.79 g) was dissolved in N, N-dimethylformamide (20 ml), and 4-dimethylaminopyridine (0.036 g), triethylamine (0.41 ml) and dicyclohexylcarbodiimide (0.64 g) were added under cooling. Stir 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 was treated with a hydrochloric acid / dioxane solution to give the hydrochloride, which gave the title compound (0.5
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 of 2,3,4-Tetrahydronaphthalene-2-acetic Acid (Compound No. 93) The compound (0.1 g) obtained in Example 37 was reacted in the same manner as in Example 30 to give the title compound ( 0.07g) was obtained. mp: 140 ° C (decomposition) ¹ H NMR (270 MHz, DMSO-d ₆ ) δppm: 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 4-tetrahydronaphthalene-2-acetic acid ethyl hydrochloride (1.06 g) was treated in the same manner as in Example 37 to give 7-[[(4-t-butoxycarbonylaminomethyl) benzoyl] amino]-. 1,2,3,4-
Tetrahydronaphthalene-2-ethyl acetate (0.74g)
I got (39-2) The compound (0.74 g) obtained in step (39-1) was dissolved in a hydrochloric acid / dioxane solution, and the mixture was stirred at room temperature for 1 hour. The reaction solution was evaporated under reduced pressure, ether was added to the concentrated residue, and the formed precipitate was collected by filtration and dried to give the title compound (0.51 g). mp: 199-201 ° C ¹ H NMR (270MHz, DMSO-d ₆ ) δppm: 10.12 (s, 1H), 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 of 2,3,4-Tetrahydronaphthalene-2-acetic Acid (Compound No. 123) (40-1) The compound (0.74 g) obtained in the step (39-1) of Example 39 was added to the compound of Example 4 A similar reaction to that of 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 the step (40-1)
By subjecting g) to the same reaction as in Step (39-2) of Example 39, the title compound (0.51 g, amorphous) was obtained. ¹ H NMR (270 MHz, DMSO-d ₆ ) δppm: 10.10 (s, 1H), 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,
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 (Production-1) 7-nitro-1- of the starting compound Oxo-
3,4-Dihydroisoquinolone is available from J. Chem. Soc. Perkin
It was synthesized according to 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 heated under reflux for an additional 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, the solvent was evaporated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (developing agent; chloroform: methanol = 40: 1) to obtain 7-nitro-1- Ethyl oxo-3,4-dihydroisoquinolone-2-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 product was subjected to 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-acetic acid ethyl 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
[(4-Cyanobenzoyl) amino] -1-oxo-
Ethyl 3,4-dihydroisoquinolone-2-acetate (0.
85g) was obtained.

(Production-4) The compound (0.55 g) obtained in the step (Production-3) was subjected to the same reaction as in Example 2 and Example 3 to give 7-[(4-amidinobenzoyl) amino. ] -1-oxo-3,4-dihydroisoquinolone-
2-Ethyl acetate ethyl hydrochloride (0.56 g) was obtained. (Production-5) Compound (0.52 g) obtained in the step (Production-4)
Then, the same reaction as in Example 4 was carried out to obtain the title compound (0.28 g). mp: 295~297 ℃ ^{(decomposition) 1 HNMR (270MHz, TFA-} d) δppm: 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)

Example of Pharmacological Test 1. Test method for guinea pig platelet aggregation inhibition test method Blood was collected from male guinea pigs using a syringe containing 3.8% sodium citrate (a ratio of 1 to 9 blood) as an anticoagulant. Then, it is centrifuged at 120 xg for 15 minutes at room temperature to obtain platelet rich plasma,
The following PRP) was obtained. The remaining blood from which PRP was separated
Centrifuge at 200xg for 15 minutes to remove platelet poor plasma (platelet po
or plasma, hereinafter referred to as PPP). Platelet count is measured with an automatic platelet counter (Sysmex PL-100 manufactured by Toa Medical Electronics) and
PRP was diluted with PPP to give 300,000 cells / μl. Platelet aggregability is 6 channel aggregometer (HEMA TRACER
1NKK) was used to measure as follows. PRP (240 μl)
After heating at 37 ℃ for 2 minutes, the solvent for the test drug (control)
Alternatively, various concentrations of the 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 calculated by comparing the maximum aggregation rate of the control drug and the test drug group. The concentration of the test drug at 50% inhibition (IC ₅₀ ) was determined from the inhibition rate and the concentration of the test drug, 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 Inhibitory Action 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, at room temperature, it is centrifuged at 120 xg for 15 minutes to obtain platelet rich plasma (platelet rich plasma,
PRP). 1,200xg of remaining blood after PRP separation
Centrifuge at 20 ° C for 20 minutes to remove platelet poor plasma (platelet poor pl
asma, hereinafter PPP). The number of platelets was measured by an automatic platelet counter (Sysmex PL-100 manufactured by Toa Iyo Denshi), and PRP was diluted with PPP to be about 250,000 cells / μl. Platelet aggregability is 6 channel aggregometer (HEMA TRACER 1 NK
(Manufactured by K) was measured as follows. 37 PRP (240 μl)
After heating for 2 minutes at ℃, add the test drug solvent (control) or various concentrations of test drug (30 μl), and after 2 minutes,
Platelet aggregation was induced by adding 30 μl of adenosine diphosphate (final concentration: 5 μM). The inhibition rate was calculated by comparing the maximum aggregation rate of the control drug and the test drug group. Concentration of test drug at 50% inhibition (I
C ₅₀ ) 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, 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), W-
A compound in which X is —CH ₂ —CH═ and Y is —CH ₂ — or —O— exhibited a particularly excellent platelet aggregation inhibitory action. Further, the compound of Production Example is the compound disclosed in WO94 / 29273, and in comparison, the compound represented by the general formula (1) of the present invention was excellent in the platelet aggregation inhibitory action.

Formulation Example When the compound represented by the general formula (1) of the present invention 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,
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, and this was kneaded and granulated with a solution of hydroxypropiocellulose (5 g) dissolved in water, and dried at 50 ° C. for 4 hours. Magnesium stearate (2 g) was added thereto and mixed well, and tablets were obtained using a tableting machine at a weight of 150 mg per tablet.

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. . A hard capsule was filled with 300 mg of this using a capsule filling machine to obtain a capsule.

Formulation Example 3 (Granule) 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 hydroxylpropyl cellulose (20 g) dissolved in water (400 ml), and dried at 50 ° C. for 4 hours. After granulating this with a 12-mesh screen, magnesium stearate (8 g) was added and mixed well to give a granule.

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

[0139]

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

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical indication location A61K 31/535 ABR A61K 31/535 ABR C07C 233/80 9547-4H C07C 233/80 251/34 251 / 34 255/57 255/57 257/18 257/18 279/18 279/18 311/18 7419-4H 311/18 311/44 7419-4H 311/44 C07D 217/16 C07D 217/16 311/58 311 / 58 335/06 335/06 (72) Inventor Mitsuhiko Miyamoto 30 Asamu-cho, Omuta-shi, Fukuoka Mitsui Toatsu Chemical Co., Ltd. (72) Inventor Hiroyuki Yamashita 1144 Togo, Mobara-shi, Chiba Mitsui Toatsu Chemical Co., Ltd. In-company (72) Kenji Kibayashi 1 Mitsui Toatsu Chemical Co., Ltd., 1900 Togo, Mobara-shi, Chiba Prefecture (72) Inventor Takanori Toyon 1 1900 Togo, Mobara-shi, Chiba Prefecture, Mitsui Toatsu Chemical Co., Ltd. (72 ) Inventor Kohei Yazawa Shigeru Chiba City Togo 1900 address of 1 Mitsui Toatsu in the Chemical Co., Ltd.

Claims (9)

[Claims] 1. General formula (1) [Chemical 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) represents, W-X may, -C
_{H 2 -CH =, - CH 2} -N = or represents -CH = C =, Y is -CH ₂ - represents or -O-, Z represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms] Or a salt thereof. 2. The compound or salt thereof according to claim 1, wherein A is an amidino group. 3. B is --CON (R ¹ )-or --N
The compound or a salt thereof according to claim ₂ , which is (R ¹ ) CO— and W—X is —CH ₂ —CH═ or —CH ₂ —N═. 4. The compound or salt thereof according to claim 3, wherein R ¹ is a hydrogen atom. 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 claim 1 as an active ingredient. 7. Thrombosis or percutaneous transluminal coronary angioplasty or percutaneous transluminal coronary recanalization, which comprises the compound according to any one of claims 1 to 5 as an active ingredient. A preventive or therapeutic drug for post-operative restenosis and re-occlusion. 8. General formula (2) [Chemical formula 2] [In the formula, 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 1 number hydrogen or C
Represents an alkyl group of 4 to 4), and W—X is —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 9. A compound or a salt thereof according to item 8.