U.S. patent application number 09/731729 was filed with the patent office on 2001-12-27 for benzamidine derivatives.
This patent application is currently assigned to AJINOMOTO CO., INC. Invention is credited to Fukuda, Yumiko, Kayahara, Takashi, Nakagawa, Tadakiyo, Sagi, Kazuyuki, Shoji, Masataka, Takahara, Akira, Takehana, Shunji, Yoshida, Kaoru.
Application Number | 20010056123 09/731729 |
Document ID | / |
Family ID | 26486362 |
Filed Date | 2001-12-27 |
United States Patent
Application |
20010056123 |
Kind Code |
A1 |
Nakagawa, Tadakiyo ; et
al. |
December 27, 2001 |
Benzamidine derivatives
Abstract
Benzamidine derivatives of the following formula, analogs
thereof and pharmaceutically acceptable salts thereof are provided.
These compounds have an effect of inhibiting activated
blood-coagulation factor X, and they are useful as agents for
preventing or treating various diseases caused by thrombi or
emboli. 1
Inventors: |
Nakagawa, Tadakiyo;
(Kawasaki-Shi, JP) ; Sagi, Kazuyuki;
(Kawasaki-Shi, JP) ; Yoshida, Kaoru;
(Kawasaki-Shi, JP) ; Fukuda, Yumiko;
(Kawasaki-Shi, JP) ; Shoji, Masataka;
(Kawasaki-Shi, JP) ; Takehana, Shunji;
(Kawasaki-Shi, JP) ; Kayahara, Takashi;
(Kawasaki-Shi, JP) ; Takahara, Akira;
(Kawasaki-Shi, JP) |
Correspondence
Address: |
OBLON, SPIVAK, McCLELLAND,
MAIER & NEUSTADT, P.C.
FOURTH FLOOR
1755 JEFFERSON DAVIS HIGHWAY
ARLINGTON
VA
22202
US
|
Assignee: |
AJINOMOTO CO., INC
Tokyo
JP
|
Family ID: |
26486362 |
Appl. No.: |
09/731729 |
Filed: |
December 8, 2000 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
09731729 |
Dec 8, 2000 |
|
|
|
PCT/JP99/03055 |
Jun 8, 1999 |
|
|
|
Current U.S.
Class: |
514/619 ;
514/631; 564/164; 564/228 |
Current CPC
Class: |
C07F 9/4015 20130101;
C07F 9/4056 20130101; C07D 233/26 20130101; C07C 257/18 20130101;
C07D 207/48 20130101; C07D 417/04 20130101; C07D 401/06 20130101;
C07F 9/65583 20130101; C07D 211/46 20130101; C07F 9/59 20130101;
C07D 401/04 20130101 |
Class at
Publication: |
514/619 ;
514/631; 564/164; 564/228 |
International
Class: |
C07C 233/00; C07C
235/00; C07C 237/00; C07C 239/00; C07C 281/00; A61K 031/165; A01N
037/18; A61K 031/155; A01N 037/52 |
Foreign Application Data
Date |
Code |
Application Number |
Jun 8, 1998 |
JP |
159627/1998 |
Jun 8, 1998 |
JP |
159628/1998 |
Claims
What is claimed is:
1. Benzamidine derivatives of the following general formula (1-1)
or pharmaceutically acceptable salts thereof: 16wherein L
represents an organic group of any of the following formulae (2) to
(5): 17wherein W in formulae (2), (3) and (5) represents a hydrogen
atom, an alkyl group having 1 to 6 carbon atoms, an aryl group
having 4 to 10 carbon atoms or an aralkyl group having 5 to 12
carbon atoms, one of D and D' in formula (3) represents a bond to Y
in general formula (1-1) and the other represents a hydrogen atom,
X in formula (2) represents a hydrogen atom, carboxyl group, an
alkoxycarbonyl group having 1 to 3 carbon atoms, an alkyl group
having 1 to 3 carbon atoms, which may have a substituent, or a
benzyl group which may have a substituent; the substituent being
selected from the group consisting of a carboxyl group,
alkoxycarbonyl groups having 2 to 8 carbon atoms, alkylsulfonyloxy
groups having 1 to 6 carbon atoms, piperidyloxy group,
iminoalkylpiperidyloxy groups having 6 to 10 carbon atoms,
alkoxycarbonylpiperidyloxy groups having 7 to 14 carbon atoms,
piperidylalkyl groups having 6 to 8 carbon atoms,
iminoalkylpiperidylalkyl groups having 7 to 11 carbon atoms,
alkoxycarbonylpiperidylalkyl groups having 8 to 15 carbon atoms,
pyrrolidinyloxy group, iminoalkylpyrrolidinyloxy groups having 5 to
9 carbon atoms, alkoxycarbonylpyrrolidinyloxy groups having 7 to 13
carbon atoms, amidino group, mono-or dialkylamidino groups having 2
to 7 carbon atoms, hydroxyl group, halogeno groups, indolyl group
and alkyl groups having 1 to 3 carbon atoms, X and W in formula (2)
may be bonded together to form a ring and, in this case, --W--X--
represents an ethylene group, trimethylene group or tetramethylene
group, when L is an organic group of any of formulae (2) to (4),
V.sub.1 represents a hydrogen atom, benzoyl, benzenesulfonyl,
2-naphthalenesulfonyl, piperazinecarbonyl, cinnamoyl,
piperidinecarbonyl, 4-methylthiazole-5-carbonyl, phenylacetyl,
phenylthiocarbonyl or benzimidoyl group, which may have a
substituent, or an alkanesulfonyl group having 1 to 6 carbon atoms,
which may have a substituent, and when L is an organic group of
formula (5), V.sub.1 represents an aryl group having 4 to 10 carbon
atoms, which may have a substituent, when L is an organic group of
any of formulae (2) to (5) and V.sub.1 has a substituent, the
substituent is selected from the group consisting of carboxyl
group, alkoxycarbonyl groups having 2 to 7 carbon atoms, carbamoyl
group, mono-or dialkylcarbamoyl groups having 2 to 7 carbon atoms,
amidino group, mono-or dialkylamidino groups having 2 to 7 carbon
atoms, acyl groups having 1 to 8 carbon atoms, halogeno groups,
amino group, mono-or dialkylamino groups having 1 to 6 carbon
atoms, arylamino groups having 4 to 6 carbon atoms,
alkoxycarbonylamino groups having 2 to 7 carbon atoms, aminoalkyl
groups having 1 to 3 carbon atoms, mono-or dialkylaminoalkyl groups
having 2 to 7 carbon atoms, N-alkyl-N-alkoxycarbonylaminoalkyl
groups having 4 to 10 carbon atoms, piperidyloxy group,
iminoalkylpiperidyloxy groups having 6 to 10 carbon atoms,
alkoxycarbonylpiperidyloxy groups having 8 to 14 carbon atoms,
pyrrolidinyloxy group, iminoalkylpyrrolidinyloxy groups having 5 to
9 carbon atoms, alkoxycarbonylpyrrolidinyloxy groups having 7 to 13
carbon atoms, hydroxycarbonylalkyl groups having 2 to 7 carbon
atoms, alkoxycarbonylalkyl groups having 3 to 8 carbon atoms,
hydroxycarbonylalkenyl groups having 3 to 7 carbon atoms,
alkoxycarbonylalkenyl groups having 4 to 8 carbon atoms, aryl
groups having 4 to 10 carbon atoms, arylalkenyl groups having 6 to
12 carbon atoms, alkoxyl groups having 1 to 10 carbon atoms, nitro
group, trifluoromethyl group, alkyl groups having 3 to 8 carbon
atoms, arylsulfonyl groups having 4 to 10 carbon atoms, arylalkyl
groups having 5 to 12 carbon atoms, piperazinecarbonyl group,
iminoalkylpiperazinecarbo- nyl groups having 7 to 10 carbon atoms,
piperazinesulfonyl group, iminoalkylpiperazinesulfonyl groups
having 6 to 9 carbon atoms, piperidylalkyl groups having 6 to 9
carbon atoms, iminoalkylpiperidylalky- l groups having 8 to 12
carbon atoms, piperidylidenealkyl groups having 6 to 9 carbon
atoms, iminoalkylpiperidylinealkyl groups having 8 to 12 carbon
atoms, guanidino group, dialkylguanidino groups having 3 to 5
carbon atoms, phosphono group, dialkoxyphosphoryl groups having 2
to 9 carbon atoms, monoalkoxyhydroxyphosphoryl groups having 1 to 4
carbon atoms, trialkylamidino groups having 4 to 7 carbon atoms,
dialkoxybenzoyl groups having 9 to 13 carbon atoms,
1-alkylpyridinio groups having 6 to 9 carbon atoms and groups of
the following formulae: 18wherein A in formulae (6) and (7)
represents a halogeno group, and B in formulae (8) and (9)
represents a hydrogen atom, an alkyl group having 1 to 6 carbon
atoms, a halogeno group or amino group, Y represents any of
following formulae (10) to (16): 19wherein n in formulae (10) and
(11) represents an integer of 0 to 2, R.sup.1 in formula (16)
represents a hydrogen atom, a hydroxycarbonylalkyl group having 2
to 7 carbon atoms, an alkoxycarbonylalkyl group having 3 to 8
carbon atoms or a hydroxycarbonylalkenyl group having 3 to 7 carbon
atoms, Z.sub.1 represents a group of any of following formulae (17)
to (24): 20wherein m in formulae (17), (19), (21) and (23)
represents an integer of 0 to 3, R.sup.2 in formulae (17), (18) and
(24) represents a hydroxyl group, an alkoxyl group having 1 to 5
carbon atoms, trifluoromethyl group, amino group or a mono-or
dialkylamino group having 1 to 6 carbon atoms, R.sup.3 in formula
(19) represents a hydrogen atom, an alkyl group having 1 to 6
carbon atoms or acetyl group, R.sup.4 in formulae (20) to (23)
represents hydrogen atom or an alkyl group having 1 to 6 carbon
atoms, R.sup.5 in formulae (22) and (23) represents a hydrogen atom
or an alkyl group having 1 to 6 carbon atoms, and R.sup.6 in
formula (24) represents a halogeno group.
2. The benzamidine derivatives or pharmaceutically acceptable salts
thereof according to claim 1, wherein, in general formula (1-1), L
represents an organic group of formula (2), W represents a hydrogen
atom and X represents a hydrogen atom, carboxymethyl group or
ethoxycarbonylmethyl group.
3. The benzamidine derivatives or pharmaceutically acceptable salts
thereof according to claim 1, wherein, in general formula (1-1), Y
represents an organic group of general formula (10) and n
represents an integer of 1 or 2.
4. The benzamidine derivatives or pharmaceutically acceptable salts
thereof according to claim 1 wherein V.sub.1 in general formula
(1-1) represents 1-acetimidoyl-4-piperidyloxybenzoyl group,
1-(4-pyridyl)-piperidine-4-carbonyl group,
1-(2,3,5,6-tetrafluoropyridine- -4-yl)-piperidine-4-carbonyl group,
1-(3,5-dichloropyridine-4-yl)-piperidi- ne-4-carbonyl group,
1-(6-chloropyridazine-3-yl)-piperidie-4-carbonyl group,
1-(pyridazine-3-yl)piperidine-4-carbonyl group,
1-(2-chloropyrimidine-4-yl)-piperidine-4-carbonyl group,
1-(pyrimidine-4-yl)-piperidine-4-carbonyl group,
1-(4-pyridine-4-ylmethyl- )-piperidine-4-carbonyl group,
1-(4-pyridine-4-carbonyl)-piperidine-4-carb- onyl group or
4-methyl-2-pyridyl-4-yl-thiazole-5-carbonyl group.
5. The benzamidine derivatives or pharmaceutically acceptable salts
thereof according to claim 1, wherein, Z.sub.1 in general formula
(1-1) represents a carboxyethyl group, ethoxycarbonylethyl group,
carboxyvinyl group, ethoxycarbonylvinyl group, carbamoylethyl
group, carbamoylvinyl group, carboxyl group, ethoxycarbonyl group,
methoxycarbonyl group, sulfoethyl group, sulfovinyl group,
phosphonovinyl group, diethoxyphosphorylvinyl group,
monoethoxyhydroxyphosphorylvinyl group, sulfonoethyl group,
diethoxyphosphorylethyl group, monoethoxyhydroxyphosphorylethyl
group, hydroxymethyl group, hydroxypropyl group or acetoxymethyl
group.
6. The benzamidine derivatives or pharmaceutically acceptable salts
thereof according to claim 1, wherein, in general formula (1-1), L
represents an organic group of formula (2), Y represents an organic
group of formula (10), V.sub.1 represents
1-acetimidoyl-4-piperidyloxybenzoyl group or
1-(4-pyridyl)-piperidine-4-carbonyl group, and Z.sub.1 represents a
carboxyethyl group, ethoxycarbonylethyl group, sulfoethyl group,
hydroxymethyl group or hydroxypropyl group.
7. The benzamidine derivatives or pharmaceutically acceptable salts
thereof according to claim 1, wherein, in general formula (1-1), L
represents an organic group of formulae (2) to (4), and Y
represents an organic group of formulae (10) to (13).
8. Benzamidine derivatives or pharmaceutically acceptable salts
thereof according to claim 1, wherein, in general formula (1-1),
when L represents an organic group of any of formulae (2) to (4),
V.sub.1 represents a hydrogen atom, benzoyl, benzenesulfonyl,
2-naphthalenesulfonyl, cinnamoyl, piperidinecarbonyl, phenylacetyl,
phenylthiocarbonyl or benzimidoyl group which may have a
substituent, or an alkanesulfonyl group, having 1 to 6 carbon
atoms, which may have a substituent; and when L is an organic group
of formula (5), V.sub.1 represents an aryl group, having 4 to 10
carbon atoms, which may have a substituent, when L represents an
organic group of any of formulae (2) to (5), the substituents of
V.sub.1 include a carboxyl group, alkoxycarbonyl groups having 2 to
7 carbon atoms, carbamoyl group, mono-or dialkylcarbamoyl groups
having 2 to 7 carbon atoms, trialkylamidino groups having 4 to 7
carbon atoms, amidino group, mono-or dialkylamidino groups having 2
to 7 carbon atoms, acyl groups having 1 to 8 carbon atoms, halogeno
groups, amino group, mono-or dialkylamino groups having 1 to 6
carbon atoms, arylamino groups having 4 to 6 carbon atoms,
alkoxycarbonylamino groups having 2 to 7 carbon atoms, aminoalkyl
groups having 1 to 3 carbon atoms, mono-or dialkylaminoalkyl groups
having 2 to 7 carbon atoms, N-alkyl-N-alkoxycarbonylaminoalkyl
groups having 4 to 10 carbon atoms, piperidyloxy group,
iminoalkylpiperidyloxy groups having 6 to 10 carbon atoms,
alkoxycarbonylpiperidyloxy groups having 8 to 14 carbon atoms,
pyrrolidinyloxy group, iminoalkylpyrrolidinyloxy groups having 5 to
9 carbon atoms, alkoxycarbonylpyrrolidinyloxy groups having 7 to 13
carbon atoms, hydroxycarbonylalkyl groups having 2 to 7 carbon
atoms, alkoxycarbonylalkyl groups having 3 to 8 carbon atoms,
hydroxycarbonylalkenyl groups having 3 to 7 carbon atoms,
alkoxycarbonylalkenyl groups having 4 to 8 carbon atoms, aryl
groups having 4 to 10 carbon atoms, arylalkenyl groups having 6 to
12 carbon atoms, alkoxyl groups having 1 to 10 carbon atoms, nitro
group, trifluoromethyl group, alkyl groups having 3 to 8 carbon
atoms, arylsulfonyl groups having 4 to 10 carbon atoms, arylalkyl
groups having 5 to 12 carbon atoms, piperazinecarbonyl group,
iminoalkylpiperazinecarbo- nyl groups having 7 to 10 carbon atoms,
piperazinesulfonyl group, iminoalkylpiperazinesulfonyl groups
having 6 to 9 carbon atoms, piperidylalkyl groups having 6 to 9
carbon atoms, iminoalkylpiperidylalky- l groups having 8 to 12
carbon atoms, piperidylidenealkyl groups having 6 to 9 carbon
atoms, iminoalkylpiperidylidenealkyl groups having 8 to 12 carbon
atoms, guanidino group, dialkylguanidino groups having 3 to 5
carbon atoms, phosphono group, dialkoxyphosphoryl groups having 2
to 9 carbon atoms or monoalkoxyhydroxyphosphoryl groups having 1 to
4 carbon atoms, Y represents any of formulae (10) to (16), n in
formulae (10) and (11) represents an integer of 1 or 2, and Z.sub.1
represents a group of formula (17) or (18) wherein m represents an
integer of 1 to 3, and R.sup.2 represents hydroxyl group, an
alkoxyl group having 1 to 5 carbon atoms, amino group or a mono-or
dialkylamino group having 1 to 6 carbon atoms.
9. The benzamidine derivatives or pharmaceutically acceptable salts
thereof according to claim 8, wherein, in general formula (1-1), L
represents an organic group of formula (2), W represents a hydrogen
atom and X represents a hydrogen atom, carboxymethyl group or
ethoxycarbonylmethyl group.
10. The benzamidine derivatives or pharmaceutically acceptable
salts thereof according to claim 8, wherein, in general formula
(1-1), Y represents an organic group of general formula (10) and n
represents an integer of 1.
11. The benzamidine derivatives or pharmaceutically acceptable
salts thereof according to claim 8, wherein, V.sub.1 in general
formula (1-1) represents 1-acetimidoyl-4-piperidyloxybenzoyl group
or 1-(4-pyridyl)-piperidine-4-carbonyl group.
12. The benzamidine derivatives or pharmaceutically acceptable
salts thereof according to claim 8, wherein, Z.sub.1 in general
formula (1-1) represents a carboxyethyl group, ethoxycarbonylethyl
group, carboxyvinyl group, ethoxycarbonylvinyl group,
carbamoylethyl group or carbamoylvinyl group.
13. The benzamidine derivatives or pharmaceutically acceptable
salts thereof according to claim 8, wherein, in general formula
(1-1), L represents an organic group of formula (2), Y represents
an organic group of formula (10), V.sub.1 represents
1-acetimidoyl-4-piperidyloxybenzoyl group or
1-(4-pyridyl)-piperidine-4-carbonyl group, and Z.sub.1 represents a
carboxyethyl group, ethoxycarbonylethyl group or carbamoylethyl
group.
14. Benzamidine derivatives of following general formula (1-2) or
pharmaceutically acceptable salts thereof, which have an effect of
inhibiting the activated blood coagulation factor X: 21wherein
Z.sub.11 represents carboxyethyl group, ethoxycarbonylethyl group,
hydroxymethyl group or hydroxypropyl group, and E represents an
oil-soluble organic group.
15. The benzamidine derivatives or pharmaceutically acceptable
salts thereof according to claim 14, wherein the oil-soluble
organic group E is the same as group -Y-L-V.sub.1 in general
formula (1-1), L represents an organic group of formula (2), Y
represents an organic group of formula (10), and V.sub.1 represents
1-acetimidoyl-4-piperidyloxybenzoyl group or
1-(4-pyridyl)-piperidine-4-carbonyl group.
16. Benzamidine derivatives of following general formula (1-3) or
pharmaceutically acceptable salts thereof: 22wherein L represents
an organic group of any of following formulae (2) to (5): 23wherein
W in formulae (2), (3) and (5) represents a hydrogen atom, an alkyl
group having 1 to 6 carbon atoms, an aryl group having 4 to 10
carbon atoms, an aralkyl group having 5 to 12 carbon atoms, one of
D and D' in formula (3) represents a bond to Y in general formula
(1) and the other represents a hydrogen atom, X in formula (2)
represents a hydrogen atom, a carboxyl group, an alkoxycarbonyl
group having 1 to 3 carbon atoms, an alkyl group having 1 to 3
carbon atoms, which may have a substituent, or a benzyl group,
which may have a substituent; the substituent being selected from
the group consisting of carboxyl group, alkoxycarbonyl groups
having 2 to 8 carbon atoms, alkylsulfonyloxy groups having 1 to 6
carbon atoms, piperidyloxy group, iminoalkylpiperidyloxy groups
having 6 to 10 carbon atoms, alkoxycarbonylpiperidyloxy groups
having 7 to 14 carbon atoms, piperidylalkyl groups having 6 to 8
carbon atoms, iminoalkylpiperidylalky- l groups having 7 to 11
carbon atoms, alkoxycarbonylpiperidylalkyl groups having 8 to 15
carbon atoms, pyrrolidinyloxy group, iminoalkylpyrrolidinyloxy
groups having 5 to 9 carbon atoms, alkoxycarbonylpyrrolidinyloxy
groups having 7 to 13 carbon atoms, amidino group, mono-or
dialkylamidino groups having 2 to 7 carbon atoms, hydroxyl group,
halogeno groups, indolyl group and alkyl groups having 1 to 3
carbon atoms, X and W in formula (2) may be bonded together to form
a ring and, in this case, --W--X-- represents ethylene group,
trimethylene group or tetramethylene group, when L is an organic
group of any of formulae (2) to (4), V.sub.2 represents benzoyl,
benzenesulfonyl, 2-naphthalenesulfonyl, cinnamoyl,
piperidinecarbonyl, phenylacetyl, phenylthiocarbonyl or benzimidoyl
group having a substituent, and when L is an organic group of
formula (5), V.sub.2 represents an aryl group having 4 to 10 carbon
atoms, which my have a substituent, when L is an organic group of
any of formulae (2) to (5), the substituents of V.sub.2 include
trialkylamidino groups having 4 to 7 carbon atoms, dialkoxybenzoyl
groups having 9 to 13 carbon atoms and 1-alkylpyridinio groups
having 6 to 9 carbon atoms, Y represents any of following formulae
(10) to (16): 24wherein n in formulae (10) and (11) represents an
integer of 1 or 2, R.sup.1 in formula (16) represents a hydrogen
atom, a hydroxycarbonylalkyl group having 2 to 7 carbon atoms, an
alkoxycarbonylalkyl group having 3 to 8 carbon atoms or a
hydroxycarbonylalkenyl group having 3 to 7 carbon atoms, Z.sub.2
represents a hydrogen atom, an alkyl group having 1 to 6 carbon
atoms, a halogeno group or a group of following formula (13-2):
25wherein R.sup.22 represents a carboxyl group or an alkoxycarbonyl
group having 2 to 5 carbon atoms.
17. The benzamidine derivatives or pharmaceutically acceptable
salts thereof according to claim 16, wherein, in general formula
(1-3), L represents an organic group of formula (2), W represents a
hydrogen atom, X represents a hydrogen atom, V.sub.2 represents
4-(3,4-dimethoxybenzoyl)- benzoyl group,
1-(1-methylpyridinium-4-yl)piperidine-4-carbonyl group or
4-(1-methyl-2-imidazoline-2-yl)benzoyl group, and Z.sub.2
represents a hydrogen atom or 2-carboxy-2-oxoethyl group.
18. The benzamidine derivatives or pharmaceutically acceptable
salts thereof according to claim 16, wherein, in general formula
(1-3), L represents an organic group of formula (2), W represents a
hydrogen atom, X represents a hydrogen atom, V.sub.2 represents
4-(1-methyl-2-imidazolin- e-2-yl)benzoyl group, and Z.sub.2
represents 2-carboxy-2-oxoethyl group.
19. Benzamidine derivatives of following general formula (1-4) or
pharmaceutically acceptable salts thereof: 26wherein L.sub.2
represents an organic group of following formulae (2) to (4):
27wherein W in formulae (2) and (3) represents a hydrogen atom, an
alkyl group having 1 to 6 carbon atoms, an aryl group having 4 to
10 carbon atoms or an aralkyl group having 5 to 12 carbon atoms,
one of D and D' in formula (3) represents a bond to Y.sub.2 in
general formula (1-4) and the other represents a hydrogen atom, X
in formula (2) represents a hydrogen atom, carboxyl group, an
alkoxycarbonyl group having 1 to 3 carbon atoms, an alkyl group
having 1 to 3 carbon atoms which may have a substituent or a benzyl
group which may have a substituent; the substituent being selected
from the group consisting of a carboxyl group, alkoxycarbonyl
groups having 2 to 8 carbon atoms, alkylsulfonyloxy groups having 1
to 6 carbon atoms, piperidyloxy group, iminoalkylpiperidyloxy
groups having 6 to 10 carbon atoms, alkoxycarbonylpiperidyloxy
groups having 7 to 14 carbon atoms, piperidylalkyl groups having 6
to 8 carbon atoms, iminoalkylpiperidylalkyl groups having 7 to 11
carbon atoms, alkoxycarbonylpiperidylalkyl groups having 8 to 15
carbon atoms, pyrrolidinyloxy group, iminoalkylpyrrolidinyloxy
groups having 5 to 9 carbon atoms, alkoxycarbonylpyrrolidinyloxy
groups having 7 to 13 carbon atoms, amidino group, mono-or
dialkylamidino groups having 2 to 7 carbon atoms, hydroxyl group,
halogeno groups, indolyl group and alkyl groups having 1 to 3
carbon atoms, X and W in formula (2) may be bonded together to form
a ring and, in this case, --W--X-- represents ethylene group,
trimethylene group or tetramethylene group, when L.sub.2 represents
an organic group of any of formulae (2) to (4), V.sub.1 represents
hydrogen atom, benzoyl, benzenesulfonyl, 2-naphthalenesulfonyl,
piperazinecarbonyl, cinnamoyl, piperidinecarbonyl,
4-methylthiazole-5-carbonyl, phenylacetyl, phenylthiocarbonyl or
benzimidoyl group, or an alkanesulfonyl group having 1 to 6 carbon
atoms, which may have a substituent, when L.sub.2 represents an
organic group of any of formulae (2) to (4) and V.sub.1 has a
substituent, the substituent is selected from the group consisting
of carboxyl group, alkoxycarbonyl groups having 2 to 7 carbon
atoms, carbamoyl group, mono-or dialkylcarbamoyl groups having 2 to
7 carbon atoms, amidino group, mono-or dialkylamidino groups having
2 to 7 carbon atoms, acyl groups having 1 to 8 carbon atoms,
halogeno groups, amino group, mono-or dialkylamino groups having 1
to 6 carbon atoms, arylamino groups having 4 to 6 carbon atoms,
alkoxycarbonylamino groups having 2 to 7 carbon atoms, aminoalkyl
groups having 1 to 3 carbon atoms, mono-or dialkylaminoalkyl groups
having 2 to 7 carbon atoms, N-alkyl-N-alkoxycarbonylaminoalkyl
groups having 4 to 10 carbon atoms, piperidyloxy group,
iminoalkylpiperidyloxy groups having 6 to 10 carbon atoms,
alkoxycarbonylpiperidyloxy groups having 8 to 14 carbon atoms,
pyrrolidinyloxy group, iminoalkylpyrrolidinyloxy groups having 5 to
9 carbon atoms, alkoxycarbonylpyrrolidinyloxy groups having 7 to 13
carbon atoms, hydroxycarbonylalkyl groups having 2 to 7 carbon
atoms, alkoxycarbonylalkyl groups having 3 to 8 carbon atoms,
hydroxycarbonylalkenyl groups having 3 to 7 carbon atoms,
alkoxycarbonylalkenyl groups having 4 to 8 carbon atoms, aryl
groups having 4 to 10 carbon atoms, arylalkenyl groups having 6 to
12 carbon atoms, alkoxyl groups having 1 to 10 carbon atoms, nitro
group, trifluoromethyl group, alkyl groups having 3 to 8 carbon
atoms, arylsulfonyl groups having 4 to 10 carbon atoms, arylalkyl
groups having 5 to 12 carbon atoms, piperazinecarbonyl group,
iminoalkylpiperazinecarbo- nyl groups having 7 to 10 carbon atoms,
piperazinesulfonyl group, iminoalkylpiperazinesulfonyl groups
having 6 to 9 carbon atoms, piperidylalkyl groups having 6 to 9
carbon atoms, iminoalkylpiperidylalky- l groups having 8 to 12
carbon atoms, piperidylidenealkyl groups having 6 to 9 carbon
atoms, iminoalkylpiperidylinealkyl groups having 8 to 12 carbon
atoms, guanidino group, dialkylguanidino groups having 3 to 5
carbon atoms, phosphono group, dialkoxyphosphoryl groups having 2
to 9 carbon atoms, monoalkoxyhydroxyphosphoryl groups having 1 to 4
carbon atoms, trialkylamidino groups having 4 to 7 carbon atoms,
dialkoxybenzoyl groups having 9 to 13 carbon atoms,
1-alkylpyridinio groups having 6 to 9 carbon atoms and groups of
the following formulae: 28wherein A in formulae (6) and (7)
represents a halogeno group, and B in formulae (8) and (9)
represents a hydrogen atom, an alkyl group having 1 to 6 carbon
atoms, a halogeno group or amino group, Y.sub.2 represents a group
of following formula (10) or (11): 29wherein n in formulae (10) and
(11) represents an integer of 0 to 2, and R.sup.3 represents a
hydrogen atom, an alkyl group having 1 to 6 carbon atoms or acetyl
group.
20. The benzamidine derivatives or pharmaceutically acceptable
salts thereof according to claim 19 wherein, in general formula
(1-4), L.sub.2 represents an organic group of formula (2), W
represents a hydrogen atom and X represents a hydrogen atom,
carboxymethyl group or ethoxycarbonylmethyl group.
21. The benzamidine derivatives or pharmaceutically acceptable
salts thereof according to claim 19 wherein, in general formula
(1-4), Y.sub.2 represents an organic group of formula (10) and n
represents an integer of 1 or 2.
22. The benzamidine derivatives or pharmaceutically acceptable
salts thereof according to claim 19, wherein V.sub.1 in general
formula (1-4) represents 1-acetimidoyl-4-piperidyloxybenzoyl group,
1-(4-pyridyl)-piperidine-4-carbonyl group,
1-(2,3,5,6-tetrafluoropyridine- -4-yl)-piperidine-4-carbonyl group,
1-(3,5-dichloropyridine-4-yl)-piperidi- ne-4-carbonyl group,
1-(6-chloropyridazine-3-yl)-piperidie-4-carbonyl group,
1-(pyridazine-3-yl)piperidine-4-carbonyl group,
1-(2-chloropyrimidine-4-yl)-piperidine-4-carbonyl group,
1-(pyridine-4-yl)-piperidine-4-carbonyl group,
1-(4-pyridine-4-ylmethyl)-- piperidine-4-carbonyl group,
1-(4-pyridine-4-carbonyl)-piperidine-4-carbon- yl group or
4-methyl-2-pyridyl-4-yl-thiazole-5-carbonyl group.
23. The benzamidine derivatives or pharmaceutically acceptable
salts thereof according to claim 19, wherein R.sup.3 in general
formula (1-4) represents a hydrogen atom.
24. The benzamidine derivatives or pharmaceutically acceptable
salts thereof according to claim 19 wherein, in general formula
(1-4), L.sub.2 represents an organic group of formula (2), Y
represents an organic group of formula (10), V.sub.1 represents
1-acetimidoyl-4-piperidyloxybenzoyl group or
1-(4-pyridyl)-piperidine-4-carbonyl group and R.sup.3 represents
hydrogen atom.
25. An anticoagulant or an agent for preventing or treating thrombi
or emboli, which contains any of the benzamidine derivatives and
salts thereof according to claims 1 to 7, 14 to 15 and 19 to 24 as
the active ingredient.
26. An anticoagulant or an agent for preventing or treating thrombi
or emboli, which contains any of the benzamidine derivatives and
salts thereof according to claims 8 to 13 as the active
ingredient.
27. An anticoagulant or an agent for preventing or treating thrombi
or emboli, which contains any of the benzamidine derivatives and
salts thereof according to claims 16 to 18 as the active
ingredient.
Description
BACKGROUND OF THE INVENTION
[0001] The present invention relates to new benzamidine derivatives
which can be orally administrated to exhibit a strong anticoagulant
effect by reversibly inhibiting activated blood-coagulation factor
X; anticoagulants containing them as active ingredients; and agents
for preventing or treating diseases caused by thrombi or emboli.
These diseases include, for example, cerebrovascular disorders such
as cerebral infarction, cerebral thrombosis, cerebral embolism,
transient ischemic attack (TIA) and subarachnoidal hemorrhage
(vasospasm); ischemic heart diseases such as acute and chronic
myocardial infarction, unstable angina and coronary thrombolysis;
pulmonary vascular disorders such as pulmonary infarction and
pulmonary embolism; peripheral obliteration; deep vein thrombosis;
disseminated intravascular coagulation syndrome; thrombus formation
after an artificial blood vessel-forming operation or artificial
valve substitution; re-occlusion and re-stenosis after a coronary
bypass-forming operation; re-occlusion and re-stenosis after
reconstructive operation for the blood circulation such as
percutaneous transluminal coronary angioplasty (PTCA) or
percutaneous transluminal coronary recanalization (PTCR); and
thrombus formation in the course of the extracorporeal
circulation.
[0002] As the habit of life is being westernized and people of
advanced ages are increasing in Japan, thrombotic and embolismic
patients such as those suffering from myocardial infarction,
cerebral thrombosis and peripheral thrombosis are increasing in
number year by year, and the treatment of patients with these
diseases is becoming more and more important in the society.
Anticoagulation treatment is included in the internal treatments
for the remedy and prevention of thrombosis, like radiotherapy and
antithrombocytic therapy.
[0003] Antithrombins were developed as thrombus-formation
inhibitors in the prior art. However, it has been known that since
thrombin not only controls the activation of fibrinogen to form
fibrin, which is the last step of the coagulation reaction, but
also deeply relates to the activation and coagulation of blood
platelets, the inhibition of the action of thrombin causes a danger
of causing hemorrhage. In addition, when antithrombins are orally
administered, the bioavailability thereof is low. At present, no
antithrombin which can be orally administered is available on the
market.
[0004] Since the activated blood coagulation factor X is positioned
at the juncture of an exogenous coagulation cascade reaction and an
endogenous coagulation cascade reaction and in the upstream of
thrombin, it is possible to inhibit the coagulation system more
efficiently and specifically, than the thrombin inhibition, by
inhibiting the factor X (THROMBOSIS RESEARCH, Vol. 19, pages 339 to
349; 1980).
DISCLOSURE OF THE INVENTION
[0005] The object of the present invention is to provide compounds
having an excellent effect of inhibiting the effect of activated
blood coagulation factor X.
[0006] Another object of the present invention is to provide
compounds having an effect of specifically inhibiting the effect of
activated blood coagulation factor X, which can be orally
administered.
[0007] Still another object of the present invention is to provide
a blood-coagulation inhibitor or an agent for preventing or
treating thrombosis of embolism, which contains one of the
above-described compounds.
[0008] After intensive investigations made under these
circumstances, the inventors have found that specified new
benzamidine derivatives have an excellent effect of inhibiting
activated blood coagulation factor X and are usable for preventing
and treating various diseases caused by thrombi and emboli. The
present invention has been completed on the basis of this
finding.
[0009] Namely, the present invention provides benzamidine
derivatives of following general formula (1-1), (1-2), (1-3) or
(1-4) or pharmaceutically acceptable salts thereof, and blood
coagulation inhibitors containing them as the active ingredients:
2
[0010] In general formula (1-1), L represents an organic group of
following formulae (2) to (5): 3
[0011] In formulae (2), (3) and (5), W represents hydrogen atom, an
alkyl group having 1 to 6 carbon atoms, an aryl group having 4 to
10 carbon atoms or an aralkyl group having 5 to 12 carbon atoms,
one of D and D' in formula (3) represents a bond to Y in general
formula (1-1) and the other represents hydrogen atom.
[0012] In formula (2), X represents hydrogen atom, carboxyl group,
an alkoxycarbonyl group having 1 to 3 carbon atoms, an alkyl group
having 1 to 3 carbon atoms which may have a substituent or benzyl
group which may have a substituent. The substituent is selected
from among carboxyl group, alkoxycarbonyl groups having 2 to 8
carbon atoms, alkylsulfonyloxy groups having 1 to 6 carbon atoms,
piperidyloxy group, iminoalkylpiperidyloxy groups having 6 to 10
carbon atoms, alkoxycarbonylpiperidyloxy groups having 7 to 14
carbon atoms, piperidylalkyl groups having 6 to 8 carbon atoms,
iminoalkylpiperidylalky- l groups having 7 to 11 carbon atoms,
alkoxycarbonylpiperidylalkyl groups having 8 to 15 carbon atoms,
pyrrolidinyloxy group, iminoalkylpyrrolidinyloxy groups having 5 to
9 carbon atoms, alkoxycarbonylpyrrolidinyloxy groups having 7 to 13
carbon atoms, amidino group, mono-or dialkylamidino groups having 2
to 7 carbon atoms, hydroxyl group, halogeno groups, indolyl group
and alkyl groups having 1 to 3 carbon atoms. In formula (2), X and
W may be bonded together to form a ring and, in this case, --W--X--
represents ethylene group, trimethylene group or tetramethylene
group.
[0013] When L is an organic group of any of formulae (2) to (4),
V.sub.1 represents hydrogen atom, benzoyl, benzenesulfonyl,
2-naphthalenesulfonyl, piperazinecarbonyl, cinnamoyl,
piperidinecarbonyl, 4-methylthiazole-5-carbonyl, phenylacetyl,
phenylthiocarbonyl or benzimidoyl group which may have a
substituent, or an alkanesulfonyl group having 1 to 6 carbon atoms,
which may have a substituent. When L is an organic group of formula
(5), V.sub.1 represents an aryl group having 4 to 10 carbon atoms,
which may have a substituent.
[0014] When L is an organic group of any of formulae (2) to (5) and
V.sub.1 has a substituent, the substituent is selected from among
carboxyl group, alkoxycarbonyl groups having 2 to 7 carbon atoms,
carbamoyl group, mono-or dialkylcarbamoyl groups having 2 to 7
carbon atoms, amidino group, mono-or dialkylamidino groups having 2
to 7 carbon atoms, acyl groups having 1 to 8 carbon atoms, halogeno
groups, amino group, mono- or dialkylamino groups having 1 to 6
carbon atoms, arylamino groups having 4 to 6 carbon atoms,
alkoxycarbonylamino groups having 2 to 7 carbon atoms, aminoalkyl
groups having 1 to 3 carbon atoms, mono- or dialkylaminoalkyl
groups having 2 to 7 carbon atoms,
N-alkyl-N-alkoxycarbonylaminoalkyl groups having 4 to 10 carbon
atoms, piperidyloxy group, iminoalkylpiperidyloxy groups having 6
to 10 carbon atoms, alkoxycarbonylpiperidyloxy groups having 8 to
14 carbon atoms, pyrrolidinyloxy group, iminoalkylpyrrolidinyloxy
groups having 5 to 9 carbon atoms, alkoxycarbonylpyrrolidinyloxy
groups having 7 to 13 carbon atoms, hydroxycarbonylalkyl groups
having 2 to 7 carbon atoms, alkoxycarbonylalkyl groups having 3 to
8 carbon atoms, hydroxycarbonylalkenyl groups having 3 to 7 carbon
atoms, alkoxycarbonylalkenyl groups having 4 to 8 carbon atoms,
aryl groups having 4 to 10 carbon atoms, arylalkenyl groups having
6 to 12 carbon atoms, alkoxyl groups having 1 to 10 carbon atoms,
nitro group, trifluoromethyl group, alkyl groups having 3 to 8
carbon atoms, arylsulfonyl groups having 4 to 10 carbon atoms,
arylalkyl groups having 5 to 12 carbon atoms, piperazinecarbonyl
group, iminoalkylpiperazinecarbo- nyl groups having 7 to 10 carbon
atoms, piperazinesulfonyl group, iminoalkylpiperazinesulfonyl
groups having 6 to 9 carbon atoms, piperidylalkyl groups having 6
to 9 carbon atoms, iminoalkylpiperidylalky- l groups having 8 to 12
carbon atoms, piperidylidenealkyl groups having 6 to 9 carbon
atoms, iminoalkylpiperidylinealkyl groups having 8 to 12 carbon
atoms, guanidino group, dialkylguanidino groups having 3 to 5
carbon atoms, phosphono group, dialkoxyphosphoryl groups having 2
to 9 carbon atoms, monoalkoxyhydroxyphosphoryl groups having 1 to 4
carbon atoms, trialkylamidino groups having 4 to 7 carbon atoms,
dialkoxybenzoyl groups having 9 to 13 carbon atoms,
1-alkylpyridinio groups having 6 to 9 carbon atoms and groups of
the following formulae: 4
[0015] In formulae (6) and (7), A represents a halogeno group, and
in formulae (8) and (9), B represents hydrogen atom, an alkyl group
having 1 to 6 carbon atoms, a halogeno group or amino group.
[0016] Y represents any of following formulae (10) to (16): 5
[0017] In formulae (10) and (11), n represents an integer of 0 to
2. In formula (16), R.sup.1 represents a hydrogen atom, a
hydroxycarbonylalkyl group having 2 to 7 carbon atoms, an
alkoxycarbonylalkyl group having 3 to 8 carbon atoms or a
hydroxycarbonylalkenyl group having 3 to 7 carbon atoms.
[0018] Z.sub.1 represents a group of any of following formulae (17)
to (24): 6
[0019] In formulae (17), (19), (21) and (23), m represents an
integer of 0 to 3. In formulae (17), (18) and (24), R.sup.2
represents hydroxyl group, an alkoxyl group having 1 to 5 carbon
atoms, trifluoromethyl group, amino group or a mono-or dialkylamino
group having 1 to 6 carbon atoms. In formula (19), R.sup.3
represents hydrogen atom, an alkyl group having 1 to 6 carbon atoms
or acetyl group. In formulae (20) to (230), R.sup.4 represents
hydrogen atom or an alkyl group having 1 to 6 carbon atoms. In
formulae (22) and (23), R.sup.5 represents hydrogen atom or an
alkyl group having 1 to 6 carbon atoms. In formula (24), R.sup.6
represents a halogeno group: 7
[0020] wherein Z.sub.11 represents carboxyethyl group,
ethoxycarbonylethyl group, hydroxymethyl group or hydroxypropyl
group, and E represents an oil-soluble organic group 8
[0021] In general formula (1-3), L represents an organic group of
any of formulae (2) to (5) in above general formula (1-1). In
formulae (2), (3) and (5), W is as defined in above general formula
(1-1). In general formula (2), X is as defined in above general
formula (1-1),
[0022] When L represents an organic group of formulae (2) to (4),
V.sub.2 represents benzoyl, benzenesulfonyl, 2-naphthalenesulfonyl,
cinnamoyl, piperidinecarbonyl, phenylacetyl, phenylthiocarbonyl or
benzimidoyl group having a substituent. When L is an organic group
of formula (5), V.sub.2 represents an aryl group having 4 to 10
carbon atoms, which may have a substituent.
[0023] When L represents an organic group of formulae (2) to (5),
the substituents of V.sub.2 include trialkylamidino groups having 4
to 7 carbon atoms, dialkoxybenzoyl groups having 9 to 13 carbon
atoms and 1-alkylpyridinio groups having 6 to 9 carbon atoms.
[0024] Y is represented by any of formulae (10) to (16) in above
general formula (1-1), wherein n represents an integer of 1 or 2,
and R.sup.1 is as defined above.
[0025] Z.sub.2 represents hydrogen atom, an alkyl group having 1 to
6 carbon atoms, a halogeno group or a group of following formula
(13-2): 9
[0026] In formula (13-2), R.sup.22 represents carboxyl group or an
alkoxycarbonyl group having 2 to 5 carbon atoms. 10
[0027] In general formula (1-4), L.sub.2 represents an organic
group represented by formulae (2) to (4) in general formula (1-1),
and W in formulae (2) and (3) and X in formula (2) are each as
defined in above general formula (1-1),
[0028] when L.sub.2 represents an organic group of formulae (2) to
(4), V.sub.1 is as defined in above general formula (1-1), and when
V.sub.1 has a substituent, the substituent is as defined in above
general formula (1-1), and
[0029] Y.sub.2 is any of formulae (10) and (11) in above general
formula (1-1), and R.sup.3 represents hydrogen atom, an alkyl group
having 1 to 6 carbon atoms or acetyl group.
BEST MODE FOR CARRYING OUT THE INVENTION
[0030] The alkyl groups in the present invention may be branched or
have a ring. For example, the alkyl groups include cyclohexylmethyl
group or the like. The term "aryl" herein involves not only
aromatic cyclic hydrocarbon groups but also aromatic heterocyclic
groups having 1 to 3 hetero-atoms selected from among O, N and S.
Examples of the aryl groups include phenyl, pyridyl, imidazolyl and
pyrrolyl groups. An example of the arylalkenyl groups is
2-(4-pyridyl)vinyl group. Dialkylamidino groups include
N,N-dialkylamidino groups and N,N'-dialkylamidino groups. The two
alkyl groups in the dialkylcarbamoyl groups, dialkylamidino groups,
dialkylamino groups, dialkylaminoalkyl groups, dialkylaminosulfonyl
groups and dialkylguanidino groups may be bonded together to form a
ring. In those groups, one of CH.sub.2's may be replaced with O, NH
or S. For example, dialkylcarbamoyl groups include, for example,
1-pyrrolidinecarbonyl group; dialkylamidino groups include, for
example, 2-imidazoline-2-yl group and
(pyrrolidine-1-yl)(imino)methyl group; and dialkylguanidino groups
include, for example, imidazoline-2-amino group. The acyl groups
include not only alkylcarbonyl groups but also arylcarbonyl groups.
For example, the acyl groups having 1 to 8 carbon atoms include
benzoyl group. The alkoxyl groups include, for example,
cyclohexyloxy group and phenoxyl group. The alkoxycarbonyl groups
include benzyloxycarbonyl group, etc. Preferred 1-alkylpyridinio
groups having 6 to 9 carbon atoms are all of those having 6 carbon
atoms or 7 to 9 carbon atoms.
[0031] The compounds of the present invention may have an
asymmetric carbon atom. These compounds include mixtures of various
stereoisomers such as geometrical isomers, tautomers and optical
isomers, and those isolated therefrom. The amidino group in the
compounds of the present invention may be replaced with a suitable
substituent which can be changed into the amidino group in vivo.
For example, hydrogen atom bonded to nitrogen atom having double
bond in amidino group bonded to the benzene ring in general
formulae (1-1) to (1-4) is replaced with hydroxyl group, an alkoxyl
group such as ethoxyl group, amino group, carboxyl group, an
alkoxycarbonyl group such as ethoxycarbonyl group, an alkylsulfonyl
group such as ethylsulfonyl group, carbamoyl group, carbamoyl group
in which one or two hydrogen atoms are replaced with an alkyl group
such as diethoxycarbamoyl group, formyl group, an acyl group such
as acetyl group or an alkylcarboxyl group such as acetoxyl
group.
[0032] L in general formula (1-1) is preferably that represented by
formulae (2) to (4), more preferably formulae (2) and (4), and
particularly formula (2).
[0033] W is preferably hydrogen atom or an alkyl group having 1 to
6 carbon atoms. W is particularly preferably hydrogen atom. X is
preferably hydrogen atom, a carboxyalkyl group having 2 or 3 carbon
atoms or an alkoxycarbonylalkyl group having 3 to 10 carbon atoms.
W is particularly preferably hydrogen atom, carboxymethyl group or
ethoxycarbonylmethyl group. X is preferably hydrogen atom, carboxyl
group, an alkyl group having 1 to 3 carbon atoms, which may have a
substituent, or benzyl group which may have a substituent. X is
particularly preferably hydrogen atom or an alkyl group having one
carbon atom and a substituent.
[0034] When X has a substituent, the substituent is, for example,
benzyloxycarbonyl group, carboxyl group, methoxycarbonyl group,
ethoxycarbonyl group, ethanesulfonyloxy group, butanesulfonyloxy
group, 4-piperidyloxy group, 1-acetimidoyl-4-piperidyloxy group,
(1-acetimidoyl-4-piperidyl)methyl group,
1-acetimidoyl-3-pyrrolidyloxy group, isopropyl group, 3-indolyl
group or iodine atom. In these substituents, carboxyl group is
particularly preferred.
[0035] V.sub.1 is preferably benzoyl group which may have a
substituent, piperidinecarbonyl group which may have a substituent
or pyridinecarbonyl group which may have a substituent. V.sub.1 is
more preferably benzoyl group having a substituent or
piperidinecarbonyl group having a substituent.
[0036] When V.sub.1 has a substituent, the substituent is
preferably 4-piperydyloxy group, 1-acetimidoyl-4-piperidyloxy
group, 4-pyridyl group, tetrafluoropyridyl group,
3,5-dichloropyridyl group, 6-chloropyridazyl group, pyridazyl
group, 2-chloropyrimidyl group, pyrimidyl group,
4-pyridine-4-ylmethyl group or 4-pyridylcarbonyl group. The
substituent is more preferably 1-acetimidoyl-4-piperidyloxy group
or 4-pyridyl group. V.sub.1 is particularly preferably either
1-acetimidoyl-4-piperidyloxybenzoyl group or
1-(4-pyridyl)-piperizine-4-c- arbonyl group.
[0037] It is more preferred that Y represents an organic group of
formula (10) wherein n is an integer of 1.
[0038] Z.sub.1 is preferably a group represented by formula (17),
(19), (21) or (23). Z.sub.1 is more preferably carboxyethyl group,
ethoxycarbonylethyl group, sulfoethyl group, phosphonoethyl group,
diethoxyphosphorylethyl group, monoethoxyhydroxyphosphorylethyl
group, hydroxymethyl group or hydroxypropyl group. Z.sub.1 is
particularly preferably carboxyethyl group, ethoxycarbonylethyl
group, hydroxymethyl group or hydroxypropyl group.
[0039] In the compounds of general formula (1-1), benzamidine
derivatives of general formula (1-1) wherein L represents an
organic group of formula (2), W represents hydrogen atom and X
represents any of hydrogen atom, carboxymethyl group and
ethoxycarbonylmethyl group, or pharmaceutically acceptable salts
thereof are preferred.
[0040] Benzamidine derivatives of general formula (1-1) wherein Y
represents an organic group of formula (10), and n represents an
integer of 1 or 2 or pharmaceutically acceptable salts thereof are
preferred.
[0041] Preferred compounds are benzamidine derivatives of general
formula (1-1) wherein V.sub.1 represents
1-acetimidoyl-4-piperidyloxybenzoyl group,
1-(4-pyridyl)-piperidine-4-carbonyl group, 1-(2,3,5,6-tetrafluorop-
yridine-4-yl)-piperidine-4-carbonyl group,
1-(3,5-dichloropyridine-4-yl)-p- iperidine-4-carbonyl group,
1-(6-chloropyridazine-3-yl)-piperidine-4-carbo- nyl group,
1-(pyridazine-3-yl)-piperidine-4-carbonyl group,
1-(2-chloropyrimidine-4-yl)-piperidine-4-carbonyl group,
1-(pyrimidine-4-yl)-piperidine-4-carbonyl group,
1-(4-pyridine-4-ylmethyl- )-piperidine-4-carbonyl group,
1-(4-pyridine-4-carbonyl)-piperidine-4-carb- onyl group or
4-methyl-2-pyridyl-4-ylthiazole-5-carbonyl group, or
pharmaceutically acceptable salts thereof.
[0042] Preferred compounds are benzamidine derivatives of general
formula (1-1) wherein Z.sub.1 represents carboxyethyl group,
ethoxycarbonylethyl group, carboxyvinyl group, ethoxycarbonylvinyl
group, carbamoylethyl group, carbamoylvinyl group, carboxyl group,
ethoxycarbonyl group, methoxycarbonyl group, sulfoethyl group,
sulfovinyl group, phosphonovinyl group, diethoxyphosphorylvinyl
group, monoethoxyhydroxyphosphorylvinyl group, phosphonoethyl
group, diethoxyphosphorylethyl group,
monoethoxyhydroxyphosphorylethyl group, hydroxymethyl group,
hydroxypropyl group or acetoxymethyl group, or pharmaceutically
acceptable salts thereof.
[0043] Preferred compounds are benzamidine derivatives of general
formula (1-1) wherein Y represents an organic group of formula
(10), V.sub.1 represents 1-acetimidoyl-4-piperidyloxybenzoyl group
or 1-(4-pyridyl)piperidine-4-carbonyl group and Z.sub.1 represents
carboxyethyl group, ethoxycarbonylethyl group, sulfoethyl group,
hydroxymethyl group or hydroxypropyl group, or pharmaceutically
acceptable salts thereof.
[0044] Preferred compounds are benzamidine derivatives of general
formula (1-1) wherein L represents an organic group of formulae (2)
to (4) and Y represents an organic group of formulae (10) to (13),
or pharmaceutically acceptable salts thereof.
[0045] Preferred benzamidine derivatives are those of general
formula (1-1) wherein, when L represents an organic group of
formulae (2) to (4), V.sub.1 represents hydrogen atom, benzoyl,
benzenesulfonyl, 2-naphthalenesulfonyl, cinnamoyl,
piperidinecarbonyl, phenylacetyl, phenylthiocarbonyl or benzimidoyl
group which may have a substituent or an alkanesulfonyl group
having 1 to 6 carbon group, which may have a substituent; when L
represents an organic group of formula (5), V.sub.1 represents an
aryl group having 4 to 10 carbon atoms, which may have a
substituent;
[0046] when L represents an organic group of formulae (2) to (5),
the substituents of V.sub.1 are carboxyl group, alkoxycarbonyl
groups having 2 to 7 carbon atoms, carbamoyl group, mono-or
dialkylcarbamoyl groups having 2 to 7 carbon atoms, trialkylamidino
groups having 4 to 7 carbon atoms, amidino group, mono-or
dialkylamidino groups having 2 to 7 carbon atoms, acyl groups
having 1 to 8 carbon atoms, halogeno groups, amino group, mono-or
dialkylamino groups having 1 to 6 carbon atoms, arylamino groups
having 4 to 6 carbon atoms, alkoxycarbonylamino groups having 2 to
7 carbon atoms, aminoalkyl groups having 1 to 3 carbon atoms,
mono-or dialkylaminoalkyl groups having 2 to 7 carbon atoms,
N-alkyl-N-alkoxycarbonylaminoalkyl groups having 4 to 10 carbon
atoms, piperidyloxy group, iminoalkylpiperidyloxy groups having 6
to 10 carbon atoms, alkoxycarbonylpiperidyloxy groups having 8 to
14 carbon atoms, pyrrolidinyloxy group, iminoalkylpyrrolidinyloxy
groups having 5 to 9 carbon atoms, alkoxycarbonylpyrrolidinyloxy
groups having 7 to 13 carbon atoms, hydroxycarbonylalkyl groups
having 2 to 7 carbon atoms, alkoxycarbonylalkyl groups having 3 to
8 carbon atoms, hydroxycarbonylalkenyl groups having 3 to 7 carbon
atoms, alkoxycarbonylalkenyl groups having 4 to 8 carbon atoms,
aryl groups having 4 to 10 carbon atoms, arylalkenyl groups having
6 to 12 carbon atoms, alkoxyl groups having 1 to 10 carbon atoms,
nitro group, trifluoromethyl group, alkyl groups having 3 to 8
carbon atoms, arylsulfonyl groups having 4 to 10 carbon atoms,
arylalkyl groups having 5 to 12 carbon atoms, piperazinecarbonyl
group, iminoalkylpiperazinecarbo- nyl groups having 7 to 10 carbon
atoms, piperazinesulfonyl group, iminoalkylpiperazinesulfonyl
groups having 6 to 9 carbon atoms, piperidylalkyl groups having 6
to 9 carbon atoms, iminoalkylpiperidylalky- l groups having 8 to 12
carbon atoms, piperidylidenealkyl groups having 6 to 9 carbon
atoms, iminoalkylpiperidylidenealkyl groups having 8 to 12 carbon
atoms, guanidino groups, dialkylguanidino groups having 3 to 5
carbon atoms, phosphono group, dialkoxyphosphoryl groups having 2
to 9 carbon atoms and monoalkoxyhydroxyphosphoryl groups having 1
to 4 carbon atoms,
[0047] Y represents a group of formulae (10) to (16), and n in
formulae (10) and (11) represents an integer of 1 or 2, Z.sub.1
represents a group of formulae (17) and (18) wherein m represents
an integer of 1 to 3, and R.sup.2 represents hydroxyl group, an
alkoxyl group having 1 to 5 carbon atoms, amino group or a mono-or
dialkylamino group having 1 to 6 carbon atoms, and pharmaceutically
acceptable salts thereof.
[0048] Preferably, L represents an organic group of formula (2), W
represents hydrogen atom and X represents hydrogen atom,
carboxymethyl group or ethoxycarbonylmethyl group.
[0049] Preferably, Y represents an organic group of formula (10)
and n represents an integer of 1.
[0050] Preferably, V.sub.1 represents
1-acetimidoyl-4-piperidyloxybenzoyl group or
1-(4-pyridyl)-piperizine-4-carbonyl group.
[0051] Preferably, Z.sub.1 represents carboxyethyl group,
ethoxycarbonylethyl group, carboxyvinyl group, ethoxycarbonylvinyl
group, carbamoylethyl group or carbamoylvinyl group.
[0052] Preferably, L represents an organic group of formula (2), Y
represents an organic group of formula (10), V.sub.1 represents
1-acetimidoyl-4-piperidyloxybenzoyl group or
1-(4-pyridyl)-piperizine-4-c- arbonyl group, and Z.sub.1 represents
carboxyethyl group, ethoxycarbonylethyl group or carbamoylethyl
group.
[0053] Benzamidine derivatives of general formula (1-2) and
pharmaceutically acceptable salts thereof have an effect of
inhibiting the activated blood coagulation factor X. In general
formula (1-2), Z.sub.11 is as defined above, and E represents an
oil-soluble organic group which, together with other groups in
general formula (1-2), imparts an effect of inhibiting the
activated blood coagulation factor X to the compounds of general
formula (1-2). The effect on the activated blood coagulation factor
X can be determined by a method described in Examples in this
specification. Groups E are those having a bonding group capable of
bonding to the benzene ring, a terminal aromatic group and/or a
heterocyclic group. They are organic groups which are, as a whole,
soluble in an oil. The bonding groups herein include aliphatic
organic groups, which may contain an oxygen atom or nitrogen atom,
such as alkylene groups and hydroxyalkylene groups. The terminal
aromatic groups and/or heterocyclic groups include phenyl group,
naphthyl group, piperidine group, pyridine group, etc. The
oil-soluble organic groups are preferably the same as
--Y--L--V.sub.1 in above formula (1-1) wherein L represents an
organic group of formula (2), Y represents an organic group of
formula (10) and V.sub.1 represents
1-acetimidoyl-4-piperidyloxybenzoy- l group or
1-(4-pyridyl)-piperidine-4-carbonyl group.
[0054] Preferred groups L and more preferred groups L in general
formula (1-3) are the same as those described above with reference
to general formula (1-1). When L is an organic group of above
formulae (2) to (5), V.sub.2 and substituents thereof are as
described above. Particularly preferred V.sub.2 is benzoyl group
having a substituent which is selected from among trialkylamidino
groups having 4 to 7 carbon atoms, dialkoxybenzoyl groups having 9
to 13 carbon atoms and 1-alkylpyridinio groups having 6 to 9 carbon
atoms.
[0055] V.sub.2 is preferably 4-(3,4-dimethoxybenzoyl)benzoyl group,
1-(1-methylpyridinium-4-yl)piperizine-4-carbonyl group or
4-(1-methyl-2-imidazoline-2-yl)benzoyl group.
[0056] Y is any of above formulae (10) to (16) in general formula
(1-1), and Z.sub.2 is hydrogen atom, an alkyl group having 1 to 6
carbon atoms, a halogeno group or a group of formula (13-2).
Preferred groups Y are the same as those in general formula (1-1).
A preferred group Z.sub.2 is that of formula (13-2) wherein
R.sub.22 is carboxyl group.
[0057] Preferably L in general formula (1-3) represents an organic
group of formula (2), W represents hydrogen atom, X represents
hydrogen atom, V.sub.2 represents 4-(3,4-dimethoxybenzoyl)benzoyl
group, 1-(1-methylpyridinium-4-yl)piperidine-4-carbonyl group or
4-(1-methyl-2-imidazoline-2-yl)benzoyl group and Z.sub.2 represents
hydrogen atom or 2-carboxy-2-oxoethyl group.
[0058] Preferably L in general formula (1-3) represents an organic
group of formula (2), W represents hydrogen atom, X represents
hydrogen atom, V.sub.2 represents
4-(1-methyl-2-imidazoline-2-yl)benzoyl group and Z.sub.2 represents
2-carboxy-2-oxoethyl group.
[0059] Preferred groups W, X and V.sub.1 and more preferred groups
W, X and V.sub.1 in general formula (1-4) are the same as those
described above with reference to general formula (1-1). L.sub.2 is
preferably that represented by formula (2) or (4). More preferably,
L.sub.2 is that represented by formula (2).
[0060] Y.sub.2 is preferably that represented by formula (10), and
R.sup.3 is preferably hydrogen atom, an alkyl group having 1 to 3
carbon atoms or acetyl group. R.sup.3 is more preferably hydrogen
atom.
[0061] In general formula (1-4), preferably, L.sub.2 represents an
organic group of formula (2), W represents hydrogen atom and X
represents any of hydrogen atom, carboxymethyl group and
ethoxycarbonylmethyl group.
[0062] In general formula (1-4), preferably Y.sub.2 represents an
organic group of formula (10), and n represents an integer of 1 or
2. Particularly preferably, n represents an integer of 1.
[0063] In general formula (1-4), V.sub.1 is preferably
1-acetimidoyl-4-piperidyloxybenzoyl group,
1-(4-pyridyl)-piperidine-4-car- bonyl group,
1-(2,3,5,6-tetrafluoropyridine-4-yl)-piperidine-4-carbonyl group,
1-(3,5-dichloropyridine-4-yl)-piperidine-4-carbonyl group,
1-(6-chloropyridazine-3-yl)-piperidine-4-carbonyl group,
1-(pyridazine-3-yl)-piperidine-4-carbonyl group,
1-(2-chloropyrimidine-4-- yl)-piperidine-4-carbonyl group,
1-(pyrimidine-4-yl)-piperizine-4-carbonyl group,
1-(4-pyridine-4-ylmethyl)-piperidine-4-carbonyl group,
1-(4-pyridine-4-carbonyl)-piperidine-4-carbonyl group or
4-methyl-2-pyridyl-4-ylthiazole-5-carbonyl group.
[0064] In general formula (1-4), preferably L.sub.2 represents an
organic group, Y represents an organic group of formula (10),
V.sub.1 represents 1-acetimidoyl-4-piperidyloxybenzoyl group or
1-(4-pyridyl)piperizine-4-ca- rbonyl group and R.sup.3 represents
hydrogen atom.
[0065] Typical processes for producing compounds of the present
invention are as follows:
[0066] A compound (27) can be obtained by reacting an aminoalkyl
halide (25), in which nitrogen is protected with benzyloxycarbonyl
group, t-butoxycarbonyl group base, with
3-hydroxy-4-iodobenzonitrile (26) in the presence of a base such as
potassium carbonate in a solvent such as dimethylformamide. An
acrylic acid derivative (28) can be derived from the obtained
compound (27) by, for example, condensing it with ethyl acrylate or
the like by, for example, Heck reaction in dimethylformamide or the
like as the solvent. The protecting group on the nitrogen of the
obtained compound (28) can be removed in, for example, an acidic
solution such as 4 N solution of hydrogen chloride in dioxane to
obtain a corresponding amine (29). 11
[0067] Prot in the above formulae represents a protecting group
such as Boc group or Z group, and Hal represents a halogen
atom.
[0068] Then, the amine (29) is reacted with a condensing agent in
the presence of a base such as triethylamine in a solvent such as
dimethylformamide. The amine is thus condensed with a carboxylic
acid to obtain an amide (30). 12
[0069] Cyano group in the amide (30) obtained as described above
can be converted into amidino group by reacting amide (30) with an
alcohol such as ethanol containing a hydrogen halide such as
hydrogen chloride and then reacting the reaction product with an
ammonium salt such as ammonium carbonate. By these reaction steps,
benzamidine derivative (31) of general formula (1-1) wherein L is
represented by formula (2), Y is represented by formula (10) and Z
is represented by formula (18) can be produced. 13
[0070] Benzamidine derivative (32) of general formula (1-1) wherein
L is represented by formula (2), Y is represented by formula (10)
and Z is represented by formula (17) can be produced by reacting
benzamidine derivative (31) in the presence of a catalyst such as
palladium/carbon in an alcohol such as methanol as the solvent in
hydrogen atmosphere and then hydrolyzing the reaction product in an
acidic aqueous solution such as concentrated hydrochloric acid.
14
[0071] The compounds produced as described above and salts thereof
can be isolated by the purification by a well-known method such as
extraction, concentration, concentration under reduced pressure,
extraction with a solvent, crystallization, recrystallization,
redissolution or various chromatographic techniques.
[0072] The salts of the benzamidine derivatives of the present
invention are pharmaceutically acceptable ones such as salts of
them with mineral acids, e.g. hydrochloric acid, hydrobromic acid,
sulfuric acid, nitric acid and phosphoric acid; and organic acids,
e.g. formic acid, acetic acid, trifluoroacetic aid, lactic acid,
salicylic acid, mandelic acid, citric acid, oxalic acid, maleic
acid, fumaric acid, tartaric acid, tannic acid, malic acid,
toluenesulfonic acid, methanesulfonic acid and benzenesulfonic
acid.
[0073] The compounds and salts thereof of the present invention are
administered as they are or in the form of various medicinal
compositions to patients. The dosage forms of the medicinal
compositions are, for example, tablets, powders, pills, granules,
capsules, suppositories, solutions, sugar-coated tablets and
depots. They can be prepared with ordinary preparation assistants
by an ordinary method. For example, the tablets are prepared by
mixing the benzamidine derivative, the active ingredient of the
present invention, with any of known adjuvants such as inert
diluents, e.g. lactose, calcium carbonate and calcium phosphate,
binders, e.g. acacia, corn starch and gelatin, extending agents,
e.g. alginic acid, corn starch and pre-gelatinized starch,
sweetening agents, e. g. sucrose, lactose and saccharin,
corrigents, e.g. peppermint and cherry, and lubricants, e.g.
magnesium stearate, talc and carboxymethyl cellulose.
[0074] When the benzamidine derivatives and salts thereof of the
present invention are used as the anticoagulants, they can be
administered either orally or parenterally. The dose which varies
depending on the age, body weight and conditions of the patient and
the administration method is usually 0.01 to 1,000 mg, preferably
0.1 to 50 mg, a day for adults in the oral administration, and 1
.mu.g to 100 mg, preferably 0.01 to 10 mg, in the parenteral
administration.
[0075] The following Examples will further illustrate the present
invention, which are only preferred embodiments of the invention
and which by no means limit the invention.
EXAMPLE 1
Synthesis of Ethyl
3-[4-amidino-2-(2-(4-(1-(1-acetimidoyl)-4-piperidyloxy)-
benzoylamino)ethoxy)phenyl]acrylate Bistrifluoroacetate
[0076] Step 1: Synthesis of ethyl
4-(1-t-butoxycarbonyl-4-piperidyloxy)ben- zoate:
[0077] 1.7 g (10.2 mmol) of ethyl 4-hydroxybenzoate, 1.76 g (9.3
mmol) of 1-t-butoxycarbonyl-4-hydroxypiperidine, obtained by
t-butoxycarbonylating 4-hydroxypiperidine with di-t-butyl
dicarbonate in an ordinary manner, and 2.44 g (9.3 mmol) of
triphenylphosphine were dissolved in 40 ml of tetrahydrofuran. 1.62
g (9.3 mmol) of diethyl azodicarboxylate was added to the obtained
solution at room temperature, and they were stirred overnight.
After the treatment with ethyl acetate as the extraction solvent in
an ordinary manner, the crude product was obtained. It was purified
by the silica gel column chromatography to obtain the title
compound.
[0078] Yield: 1.57 g (4.5 mmol) (44%)
[0079] H-NMR (CDCl3) d .delta. 1.38 (3H, t), 1.50 (9H, s)1.70-1.80
(2H, m), 1.90-2.00 (2H, m), 3.30-3.41 (2H, m), 3.63-3.75 (2H, m),
4.35 (2H, q), 4.55 (1H, m), 6.90 (2H, d), 8.00 (2H, d)
[0080] Step 2: Synthesis of
4-(1-t-butoxycarbonyl-4-piperidyloxy)benzoic acid:
[0081] 847 mg (2.43 mmol) of ethyl
4-(1-t-butoxycarbonyl-4-piperidyloxy)be- nzoate was dissolved in 50
ml of ethanol. 5 ml of 1 N sodium hydroxide solution was added to
the obtained solution, and they were stirred at room temperature
for 3 days. The reaction solution was concentrated and then treated
with ethyl acetate as the extraction solvent in an ordinary manner
to obtain the title compound.
[0082] Yield: 697 mg (2.2 mmol) (92%)
[0083] H-NMR (CDCl3) d .delta. 1.50 (9H, s), 1.70-2.00 (4H, m),
3.30-3.40 (2H, m), 3.65-3.75 (2H, m), 4.60 (1H, s), 6.95 (2H, d),
8.05 (2H, d)
[0084] Step 3: Synthesis of 3-hydroxy-4-iodobenzoic acid:
[0085] 30.0 g (217 mmol) of 3-hydroxybenzoic acid was dissolved in
200 ml of acetic acid. 53.0 g (326 mmol) of iodine monochloride was
added to the obtained solution at room temperature. After stirring
at 45.degree. C. for 15 hours, the solvent was evaporated under
reduced pressure. The residue thus obtained was washed with 500 ml
of 1% aqueous sodium thiosulfate solution twice and with 500 ml of
water twice and then dried to solid at 80.degree. C. under reduced
pressure to obtain the title compound.
[0086] Yield: 17.2 g (65.2 mmol) (30%)
[0087] MS (FAB, m/z) 265 (MH+)
[0088] H-NMR (DMSO-d6) .delta. 7.13 (1H, dd), 7.43 (1H, d), 7.80
(1H, d)
[0089] Step 4: Synthesis of 3-hydroxy-4-iodobenzonitrile:
[0090] 22.3 g (89.7 mmol) of 3-hydroxy-4-iodobenzoic acid was
dissolved in 300 ml of tetrahydrofuran. 19.7 ml (206 mmol) of ethyl
chloroformate and 28.7 ml (206 mmol) of triethylamine were added to
the obtained solution at 0.degree. C. After stirring for 15
minutes, triethylamine hydrochloride thus formed was separated by
the filtration. The filtrate was added to 300 ml of tetrahydrofuran
solution, obtained by bubbling ammonia, at 0.degree. C. After
stirring at room temperature for 10 hours, the solvent was
evaporated under reduced pressure. The obtained residue was
dissolved in 450 ml of dioxane. 17.4 ml (117 mmol) of anhydrous
trifluoroacetic anhydride and 21.8 ml (269 mmol) of pyridine were
added to the obtained solution at 0.degree. C. After stirring at
room temperature for 18 hours, the solvent was evaporated under
reduced pressure, and the residue was treated with chloroform as
the extraction solvent in an ordinary manner to obtain an oily
residue. The residue was dissolved in 180 ml of
tetrahydrofuran/methanol (1:1). 90 ml (90.0 mmol) of 1 N aqueous
sodium hydroxide solution was added to the obtained solution at
room temperature. After stirring them for 4 hours, the solvent was
evaporated under reduced pressure. The obtained residue was washed
with dichloromethane. After acidifying with 1 N hydrogen chloride,
the product was treated with ethyl acetate as the extraction
solvent in an ordinary manner to obtain the crude product, which
was then purified by the silica gel column chromatography to obtain
the title compound.
[0091] Yield: 9.29 g (37.9 mmol) (42%)
[0092] MS (FAB, m/z) 246 (MH+)
[0093] H-NMR (CDCl3) .delta. 5.63 (1H, br), 6.96 (1H, dd), 7.23
(1H, d), 7.79 (1H, d)
[0094] Step 5: Synthesis of t-butyl (2-bromoethyl)carbamate:
[0095] 9.22 g (45 mmol) of 2-bromoethylamine hydrobromide was
dissolved in 100 ml of dichloromethane. 7.64 ml (35 mmol) of
di-t-butyl dicarbonate, 10.0 g (99 mmol) of triethylamine and 100
mg (0.82 mmol) of 4-(dimethylamino)pyridine were added to the
obtained solution, and they were stirred overnight. The obtained
mixture was treated with dichloromethane as the extraction solvent
in an ordinary manner to obtain the title compound.
[0096] Yield: 5.99 g (26.7 mmol) (76%)
[0097] H-NMR (CDCl3) .delta. 1.45 (9H, s), 3.46 (2H, dt), 3.51 (2H,
t), 4.95 (1H, br)
[0098] Step 6: Synthesis of
3-[2-(t-butoxycarbonylamino)ethoxy]-4-iodobenz- onitrile:
[0099] 18.5 g (82.6 mmol) of t-butyl (2-bromoethyl)carbamate was
dissolved in 200 ml of DMF. 10.1 g (41.3 mmol) of
3-hydroxy-4-iodobenzonitrile and 5.7 g (41.3 mmol) of potassium
carbonate were added to the obtained solution, and they were
stirred at 75.degree. C. for 3 hours. After the treatment with
ethyl acetate as the extraction solvent in an ordinary manner, the
title compound was obtained.
[0100] Yield: 11.0 g (28.4 mmol) (69%).
[0101] H-NMR (CDCl3) .delta. 1.46 (9H, s), 3.62 (2H, dt), 4.12 (2H,
t), 7.02 (2H, d), 7.88 (2H, d).
[0102] Step 7: Synthesis of ethyl
3-[2-(2-(t-butoxycarbonylamino)ethoxy)-4-
-cyanophenyl]acrylate:
[0103] 11.0 g (28.4 mmol) of
3-[2-(t-butoxycarbonylamino)ethoxy]-4-iodoben- zonitrile was
dissolved in 200 ml of DMF. 15.4 ml (142 mmol) of ethyl acrylate,
20 ml (142 mmol) of triethylamine and 127 mg (0.567 mmol) of
palladium acetate were added to the obtained solution. They were
stirred at 100.degree. C. overnight and then treated with ethyl
acetate as the extraction solvent in an ordinary manner to obtain
the crude product. After the purification by the silica gel column
chromatography, the title compound was obtained.
[0104] Yield: 9.6 g (26.7 mmol) (94%)
[0105] H-NMR (CDCl3) .delta. 1.38 (3H, t), 1.46 (9H, s), 3.62 (2H,
dt), 4.16 (2H, t),4.28 (2H, q), 6.56 (1H, d), 7.16 (1H, d), 7.27
(1H, d), 7.60 (1H, d), 7.96 (1H, d)
[0106] Step 8: Synthesis of ethyl
3-[4-cyano-2-(2-(4-(1-t-butoxycarbonyl-4-
-piperidyloxy)benzoylamino)ethoxy)phenyl]acrylate:
[0107] 2.72 g (7.56 mmol) of ethyl
3-[2-(2-(t-butoxycarbonylamino)ethoxy)-- 4-cyanophenyl]acrylate was
dissolved in a mixture of 10 ml of dioxane and 20 ml of 4 N
solution of hydrogen chloride in dioxane, and the obtained solution
was stirred at room temperature for 4 hours.
[0108] The solvent was evaporated under reduced pressure, and the
obtained crude product was dissolved in 50 ml of dichloromethane.
2.67 g (8.32 mmol) of 4-(1-t-butoxycarbonyl-4-piperidyloxy)benzoic
acid, 1.59 g (8.32 mmol) of
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 1.12 g
(8.32 mmol) of 1-hydroxybenzotriazole and 3.16 ml (22.7 mmol) of
triethylamine were added to the obtained solution, and they were
stirred at room temperature overnight. After the treatment with
dichloromethane as the extraction solvent in an ordinary manner,
the obtained crude product was purified by the silica gel column
chromatography to obtain the title compound.
[0109] Yield: 3.0 g (5.33 mmol) (71%)
[0110] H-NMR (CDCl3) .delta. 1.33 (3H, t), 1.47 (9H, s), 1.64-1.79
(2H, m), 1.86-1.98 (2H, m), 3.24-3.42 (2H, m), 3.60-3.73 (2H, m),
3.92 (2H, dt), 4.24 (2H, q), 4.28 (2H, t), 4.45-4.53 (1H, m), 6.57
(1H, d), 6.77 (1H, t), 6.88 (2H, d), 7.18 (1H, d), 7.23 (1H, d),
7.58 (1H, d), 7.77 (2H, d), 7.97 (1H, d)
[0111] Step 9: Synthesis of ethyl
3-[4-amidino-2-(2-(4-(1-(1-acetimidoyl)--
4-piperidyloxy)benzoylamino)ethoxy)phenyl]acrylate
Bistrifluoroacetate:
[0112] 3.0 g (5.33 mmol) of ethyl
3-[4-cyano-2-(2-(4-(1-t-butoxycarbonyl-4-
-piperidyloxy)benzoylamino)ethoxy)phenyl]acrylate was dissolved in
a mixture of 4 ml of ethanol and 20 ml of 4 N solution of hydrogen
chloride in dioxane, and the obtained solution was stirred at room
temperature for 3 days. The solvent was evaporated, and the
obtained residue was dissolved in 20 ml of ethanol. 906 mg of
ammonium carbonate was added to the obtained solution, and they
were stirred at room temperature overnight. The solvent was
evaporated, and the obtained residue was dissolved in 20 ml of
ethanol. 3.28 g (26.7 mmol) of ethyl acetimidate and 7.42 ml (53.3
mmol) of triethylamine were added to the solution, and they were
stirred at room temperature overnight. The solvent was evaporated,
and the obtained crude product was subjected to reversed phase
high-performance liquid chromatography with silica gel chemically
bonded with octadodecyl group as the filler. After the elution with
a mixed solution of water and acetonitrile containing 0.1% (v/v) of
trifluoroacetic acid, the intended fraction was freeze-dried to
obtain the title compound.
[0113] Yield: 2.3 g (3.07 mmol) (37%)
[0114] MS (ESI, m/z) 522 (MH+)
[0115] H-NMR (DMSO-d6) .delta. 1.23 (3H, t), 1.67-1.87 (2H, m),
2.00-2.25 (2H, m), 2.29 (3H, s), 3.45-3.60 (2H, m), 3.66-3.77 (4H,
m), 4.17 (2H, q), 4.34 (2H,t), 4.73-4.76 (1H, m), 6.79 (1H, d),
7.05 (2H, t), 7.43 (1H, d), 7.56 (1H, d), 7.84 (2H, d), 7.92 (1H,
br), 7.97 (1H, d), 8.64 (2H, br), 9.19 (1H, br), 9.37 (4H, br)
EXAMPLE 2
Synthesis of
3-[4-amidino-2-(2-(4-(1-(1-acetimidoyl)-4-piperidyloxy)benzoy-
lamino)ethoxy)phenyl]acrylic Acid Bistrifluoroacetate
[0116] 550 mg (0.734 mmol) of ethyl
3-[4-amidino-2-(2-(4-(1-(1-acetimidoyl-
)-4-piperidyloxy)benzoylamino)ethoxy)phenyl]acrylate
bistrifluoroacetate was dissolved in 10 ml of concentrated
hydrochloric acid, and the obtained solution was stirred at
50.degree. C. for 6 hours. The solvent was evaporated and the
obtained crude product was treated in the same manner as that in
step 9 in Example 1 to obtain the title compound.
[0117] Yield: 440 mg (0.610 mol) (83%)
[0118] MS (ESI, m/z) 494 (MH+)
[0119] H-NMR (DMSO-d6) .delta. 1.67-1.87 (2H, m), 2.00-2.17 (2H,
m), 2.29 (3H, s), 3.45-3.59 (2H, m), 3.64-3.76 (4H, m), 4.33 (2H,
t), 4.73-4.87 (1H, m), 6.70 (1H, d), 7.06 (2H, d), 7.43 (1H, d),
7.54 (1H, br), 7.85 (2H, d), 7.90 (1H, br), 7.95 (1H, d), 8.62 (1H,
br), 8.70 (1H, t), 9.17 (1H, br), 9.28 (2H, br), 9.36 (2H, br).
EXAMPLE 3
Synthesis of ethyl
3-[4-amidino-2-(2-(4-(1-(1-acetimidoyl)-4-piperidyloxy)-
benzoylamino)ethoxy)phenyl]propionate Bistrifluoroacetate
[0120] 1.2 g (1.60 mmol) of ethyl
3-[4-amidino-2-(2-(4-(1-(1-acetimidoyl)--
4-piperidyloxy)benzoylamino)ethoxy)phenyl]acrylate
bistrifluoroacetate was dissolved in 50 ml of methanol. 100 mg of
palladium/carbon was added to the obtained solution, and they were
stirred in the presence of hydrogen overnight. The solvent was
evaporated and the obtained crude product was treated in the same
manner as that in step 9 in Example 1 to obtain the title
compound.
[0121] Yield: 1.1 g (1.46 mmol) (91%)
[0122] MS (ESI, m/z) 524 (MH+)
[0123] H-NMR (DMSO-d6) .delta. 1.16 (3H, t), 1.67-1.76 (2H, m),
2.00-2.25 (2H, m), 2.29 (3H, s), 2.58 (2H, t), 2.90 (2H, t),
3.46-3.58 (2H, m), 3.63-3.84 (4H, m), 3.98 (2H, q), 4.23 (2H, t),
4.74-4.87 (1H, m), 7.08 (1H, d), 7.36 (1H, br), 7.38 (2H, d), 7.84
(2H, d), 8.61 (2H, br), 9.11 (2H, br), 9.16 (1H, br), 9.24 (2H,
br)
EXAMPLE 4
Synthesis of
3-[4-amidino-2-(2-(4-(1-(1-acetimidoyl)-4-piperidyloxy)benzoy-
lamino)ethoxy)phenyl]propionic Acid Bistrifluoroacetate
[0124] 600 mg (0.799 mmol) of ethyl
3-[4-amidino-2-(2-(4-(1-(1-acetimidoyl-
)-4-piperidyloxy)benzoylamino)ethoxy)phenyl]propionate
bistrifluoroacetate was dissolved in 10 ml of concentrated
hydrochloric acid, and the obtained solution was stirred at
50.degree. C. for 4 hours. The solvent was evaporated and the
obtained crude product was treated in the same manner as that in
step 9 in Example 1 to obtain the title compound.
[0125] Yield: 480 mg (0.663 mol) (77%)
[0126] MS (ESI, m/z) 496 (MH+)
[0127] H-NMR (DMSO-d6) .delta. 1.66-1.87 (2H, m), 2.02-2.17 (2H,
m), 2.29 (3H, s), 2.52 (2H, t), 2.78 (2H, t), 3.44-3.62 (2H, m),
3.64-3.75 (4H, m), 4.42 (2H, t), 4.74-4.86 (1H, m), 7.06 (2H, d),
7.37 (1H, br), 7.39 (2H, d), 7.85 (2H, d), 8.64 (2H, br), 9.19 (1H,
d), 9.23 (2H, br), 9.25 (2H, br)
EXAMPLE 5
Synthesis of ethyl
3-[4-amidino-2-(2-((1-(pyridine-4-yl)piperidine-4-carbo-
nyl)amino)ethoxy)phenyl]propionate bistrifluoroacetate
[0128] Step 1 Synthesis of ethyl
1-(4-pyridyl)-4-piperidinecarboxylate:
[0129] 4.0 g (26.6 mmol) of 4-chloropyridine hydrochloride, 4.2 g
(26.6 mmol) of ethyl piperidine-4-carboxylate and 7.4 ml (53.2
mmol) of triethylamine were stirred in 100 ml of xylene at
130.degree. C. for 24 hours. After the treatment with
dichloromethane as the extraction solvent in an ordinary manner,
the obtained crude product was purified by the silica gel column
chromatography to obtain the title compound.
[0130] Yield: 2.95 g (12.6 mmol) (47%)
[0131] H-NMR (CDCl3) .delta. 1.25 (3H, t), 1.71-1.85 (2H, m), 2.00
(2H, d), 2.50-2.60 (1H, m), 2.90 (2H, t), 3.81 (2H, d), 4.20 (2H,
q), 6.66 (2H, d), 8.26 (2H, d)
[0132] Step 2: Synthesis of 1-(4-pyridyl)-4-piperidinecarboxylic
acid hydrochloride:
[0133] 2.95 g (12.6 mmol) of ethyl
1-(4-pyridyl)-4-piperidinecarboxylate was stirred in 100 ml of
dioxane. 50 ml of 1 N hydrochloric acid was added to the obtained
mixture, and they were stirred at 95.degree. C. for 20 hours. The
solvent was evaporated to obtain the crude title compound.
[0134] Yield: 3.21 g (11.5 mmol) (91%)
[0135] H-NMR (DMSO-d6) .delta. 1.54 (2H, t), 1.90 (2H, t),
2.60-2.70 (1H, m), 3.30 (2H, t), 4.10 (2H, d), 7.19 (2H, d), 8.20
(2H, d)
[0136] Step 3: Synthesis of ethyl
3-[4-cyano-2-(2-((1-(pyridine-4-yl)piper-
idine-4-carbonyl)amino)ethoxy)phenyl]acrylate:
[0137] 3.0 g (8.33 mmol) of ethyl
3-[2-(2-(t-butoxycarbonylamino)ethoxy)-4- -cyanophenyl]acrylate was
dissolved in a mixture of 20 ml of 4 N solution of hydrogen
chloride in dioxane and 10 ml of dioxane. The obtained solution was
stirred at room temperature for 4 hours. The solvent was evaporated
and the residue was dissolved in 50 ml of DMF. 2.22 g (9.17 mmol)
of 1-(4-pyridyl)-4-piperidinecarboxyic acid hydrochloride, 4.27 g
(9.17 mmol) of bromotripyrrolidinophosphonium hexafluorophosphate
and 3.48 ml (25.0 mmol) of triethylamine were added to the obtained
solution, and they were stirred at room temperature for 3 days. The
solvent was evaporated, and the obtained crude product was purified
by the silica gel column chromatography to obtain the title
compound.
[0138] Yield: 2.3 g (5.13 mmol) (62%)
[0139] H-NMR (DMSO-d6) .delta. 1.26 (3H, t), 1.50-1.68 (2H, m),
1.68-1.73 (2H, m), 2.62-2.68 (1H, m), 2.94-3.06 (2H, m), 3.40-3.53
(2H, m), 3.95-4.25 (6H, m),6.76 (1H, dd), 6.94 (2H, d), 7.44 (1H,
dd), 7.62 (1H, br), 7.83 (1H, dd), 7.90 (1H, d), 9.01 (1H, t), 8.15
(2H, d)
[0140] Step 4: Synthesis of ethyl
3-[4-amidino-2-(2-((1-(pyridine-4-yl)pip-
eridine-4-carbonyl)amino)ethoxy)phenyl]propionate
bistrifluoroacetate:
[0141] 2.3 g (5.13 mmol) of ethyl
3-[4-cyano-2-(2-((1-(pyridine-4-yl)piper-
idine-4-carbonyl)amino)ethoxy)phenyl]acrylate was dissolved in a
mixture of 20 ml of 4 N solution of hydrogen chloride in dioxane
and 4 ml of ethanol. The obtained solution was stirred at room
temperature for 4 days. The solvent was evaporated and the residue
was dissolved in 30 ml of ethanol. 872 mg of ammonium carbonate was
added to the obtained solution, and they were stirred at room
temperature overnight. The solvent was evaporated, and the residue
was dissolved in 30 ml of methanol. 200 mg of palladium/carbon was
added to the resultant solution, and they were stirred in the
presence of hydrogen overnight. The solvent was evaporated, and the
obtained crude product was treated in the same manner as that in
step 9 in Example 1 to obtain the title compound.
[0142] Yield: 1.5 g (2.16 mmol) (42%)
[0143] MS (ESI, m/z) 468 (MH+)
[0144] H-NMR (DMSO-d6) .delta. 1.15 (3H, t), 1.50-1.67 (2H, m),
1.76-1.81 (2H, m), 2.52-2.60 (1H, m), 2.62 (2H, dd), 2.89 (2H, dd),
3.15-3.28 (2H, m), 3.49 (2H, dt), 4.03 (2H, q), 4.12 (2H, t), 4.20
(2H, d), 7.19 (2H, d), 7.37 (3H, br), 8.18 (1H, d), 8.21 (2H, d),
9.23 (2H, br), 9.25 (2H, br)
EXAMPLE 6
Synthesis of
3-[4-amidino-2-(2-((1-pyridine-4-yl)piperidine-4-carbonyl)ami-
no)ethoxy)phenyl]propionic Acid Bistrifluoroacetate
[0145] 250 mg (0.359 mmol) of ethyl
3-[4-amidino-2-(2-((1-pyridine-4-yl)pi-
peridine-4-carbonyl)amino)ethoxy]phenyl]propionate
bistrifluoroacetate was dissolved in 10 ml of concentrated
hydrochloric acid, and the obtained solution was stirred at
50.degree. C. for 4 hours. The solvent was evaporated and the
obtained crude product was treated in the same manner as that in
step 9 in Example 1 to obtain the title compound.
[0146] Yield: 480 mg (0.330 mol) (92%)
[0147] MS (ESI, m/z) 440 (MH+)
[0148] H-NMR (DMSO-d6) .delta. 1.50-1.67 (2H, m), 1.76-1.92 (2H,
m), 2.54 (2H, dd), 2.55-2.67 (1H, m), 2.88 (2H, dd), 3.12-3.29 (2H,
m), 3.49 (2H, dt), 4.12 (2H, t), 4.20 (2H, d), 7.18 (2H, d), 7.36
(2H, br), 7.37 (1H, d), 8.18 (1H, d), 8.20 (2H, d), 9.14 (2H, br),
9.24 (2H, br)
EXAMPLE 7
Synthesis of Ethyl
(3R)-3-[4-amidino-2-(3-ethoxycarbonyl-2-(4-(1-(1-acetim-
idoyl)-4-piperidyloxy)benzoylamino)propoxy]phenyl]acrylate
Bistrifluoroacetate
[0149] Step 1: Synthesis of benzyl
(3R)-3-t-butoxycarbonylamino-4-hydroxyb- utanoate:
[0150] 15.0 g (46.4 mmol) of .beta.-benzyl
N-t-butoxycarbonyl-D-aspartate and 6.47 ml (46.4 mmol) of
triethylamine were dissolved in 230 ml of tetrahydrofuran. 4.4 ml
(46.4 mmol) of ethyl chloroformate was added to the obtained
solution under cooling with ice, and they were stirred for 15
minutes. Precipitates thus formed were removed by the filtration
under suction. 5 g of ice and 1.8 g (46.6 mmol) of sodium
borohydride were added to the filtrate under cooling with ice, and
they were stirred for 1.5 hours. Then 200 ml of 1 N aqueous
hydrogen chloride solution was added to the reaction mixture, and
they were further stirred at room temperature for one hour. After
the treatment with ethyl acetate as the extraction solvent in an
ordinary manner, the obtained crude product was purified by the
silica gel column chromatography to obtain the title compound.
[0151] Yield: 10.2 g (32.8 mmol) (71%)
[0152] H-NMR (CDCl3) d 1.42 (9H, s), 2.66 (2H, d), 3.65 (2H, dd),
4.00 (1H, ddt), 5.14 (2H, s), 7.35-7.40 (5H, m) Step 2: Synthesis
of benzyl
(3R)-3-t-butoxycarbonylamino-4-(5-cyano-2-iodophenoxy)butanoate:
[0153] 10.16 g (32.8 mmol) of benzyl
(3R)-3-t-butoxycarbonylamino-4-hydrox- ybutanoate was dissolved in
100 ml of toluene. 10.5 g (42.7 mmol) of
3-hydroxy-4-iodobenzonitrile, 11.2 g (42.7 mmol) of
triphenylphosphine and 7.4 g (42.7 mmol) of
N,N,N',N'-tetramethylazodicarboxamide were added to the obtained
solution under cooling with ice, and they were stirred at room
temperature overnight.
[0154] The solvent was evaporated, and the residue was purified by
the silica gel column chromatography to obtain the title
compound.
[0155] Yield: 11.9 g (22.1 mmol) (67%)
[0156] H-NMR (CDCl3) d 1.47 (9H, s), 2.90 (2H, t), 4.03 (1H, dd),
4.15 (1H, dd),4.40-4.50 (1H, m), 5.19 (2H, s), 7.01 (1H, d), 7.30
(1H, s), 7.35-7.40 (5H, m), 7.92 (1H, d)
[0157] Step 3: Synthesis of ethyl
(3R)-3-[2-(3-benzyloxycarbonyl-2-t-butox-
ycarbonylamino-propoxy)-4-cyanophenyl]acrylate:
[0158] 20.0 g (37.3 mmol) of benzyl
(3R)-3-t-butoxycarbonylamino-4-(5-cyan- o-2-iodophenoxy)butanoate
was dissolved in 150 ml of DMF. 10.1 ml (93.3 mmol) of ethyl
acrylate, 13 ml (93.3 mmol) of triethylamine and 167 mg (0.567
mmol) of palladium acetate were added to the obtained solution, and
they were stirred at 100.degree. C. overnight. After the treatment
with ethyl acetate as the extraction solvent in an ordinary manner,
the obtained crude product was purified by the silica gel column
chromatography to obtain the title compound.
[0159] Yield: 13 g (25.6 mmol) (69%)
[0160] H-NMR (CDCl3) .delta. 1.36 (3H, t), 1.44 (9H, s), 2.77-2.84
(2H, m), 4.03-4.22(2H, m), 4.24 (2H, q), 4.37-4.50 (1H, m), 5.16
(2H, s), 6.50 (1H, d), 7.19 (1H, d), 7.23-7.36 (6H, m), 7.61 (1H,
d), 7.93 (1H, d)
[0161] Step 4: Synthesis of ethyl
(3R)-3-[2-(2-amino-3-benzyloxycarbonyl-p-
ropoxy)-4-cyanophenyl]acrylate monohydrochloride:
[0162] 13 g (25.6 mmol) of ethyl
(3R)-3-[2-(3-benzyloxycarbonyl-2-t-butoxy-
carbonylamino-propoxy)-4-cyanophenyl]acrylate was dissolved in a
mixture of 20 ml of dioxane and 20 ml of 4 N solution of hydrogen
chloride in dioxane, and the obtained solution was stirred at room
temperature overnight. The solvent was evaporated under reduced
pressure to obtain the crude product.
[0163] Yield: 7.8 g (17.6 mmol) (69%)
[0164] Step 5: Synthesis of ethyl
(3R)-3-[2-(3-benzyloxycarbonyl-2-(4-(1-t-
-butoxycarbonyl-4-piperidyloxy)benzoylamino)propoxy)-4-cyanophenyl]acrylat-
e:
[0165] 3.5 g (7.87 mmol) of ethyl
(3R)-3-[2-(2-amino-3-benzyloxycarbonyl-p-
ropoxy)-4-cyanophenyl]acrylate monohydrochloride was dissolved in
50 ml of DMF. 2.8 g (8.65 mmol) of
4-(1-t-butoxycarbonyl-4-piperidyloxy)benzoic acid, 1.65 g (8.65
mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide
hydrochloride, 1.17 g (8.65 mmol) of 1-hydroxybenzotriazole and
3.28 ml (23.6 mmol) of triethylamine were added to the obtained
solution, and they were stirred at room temperature overnight.
After the treatment with ethyl acetate as the extraction solvent in
an ordinary manner, the obtained crude product was purified by the
silica gel column chromatography to obtain the title compound.
[0166] Yield: 3.2 g (4.50 mmol) (57%)
[0167] H-NMR (CDCl3) .delta. 1.32 (3H, t), 1.47 (9H, s), 1.66-1.83
(3H, m), 1.88-2.02 (2H, m), 2.83-3.07 (2H, m), 3.30-3.42 (2H, m),
3.63-3.78 (2H, m), 4.04-4.25 (2H, m), 4.27 (2H, q), 4.50-4.60 (2H,
m), 4.84-4.97 (1H, m), 5.30 (2H, s), 6.52 (1H, d), 6.91 (1H, d),
7.11 (1H, br), 7.29 (7H, br), 7.57 (1H, d), 7.73 (2H, d), 7.92 (1H,
d)
[0168] Step 6: Synthesis of ethyl
(3R)-3-[4-amidino-2-(3-ethoxycarbonyl-2--
(4-(1-(1-acetimidoyl)-4-piperidyloxy)benzoylamino)propoxy)phenyl]acrylate
bistrifluoroacetate:
[0169] 3.2 g (4.50 mmol) of ethyl
(3R)-3-[2-(3-benzyloxycarbonyl-2-(4-(1-t-
-butoxycarbonyl-4-piperidyloxy)benzoylamino)propoxy)-4-cyanophenyl]acrylat-
e was dissolved in a mixture of 25 ml of 4 N solution of hydrogen
chloride in dioxane and 5 ml of ethanol. The obtained solution was
stirred at room temperature for 4 days. The solvent was evaporated,
and the residue was dissolved in 20 ml of ethanol. 760 mg of
ammonium carbonate was added to the obtained solution, and they
were stirred at room temperature overnight. The solvent was
evaporated, and the obtained residue was dissolved in 50 ml of
ethanol. 3.0 g (26.7 mmol) of ethyl acetimidate and 5 ml (35.6
mmol) of triethylamine were added to the obtained solution, and
they were stirred at room temperature overnight. The solvent was
evaporated, and the obtained crude product was treated in the same
manner as that in step 9 in Example 1 to obtain the title
compound.
[0170] Yield: 550 mg (0.659 mmol) (17%)
[0171] MS (ESI, m/z) 608 (MH+)
[0172] H-NMR (DMSO-d6) .delta. 1.14 (3H, t), 1.22 (3H, t),
1.68-1.76 (2H, m), 2.00-2.16 (2H, m), 2.29 (3H, s), 2.80 (2H, d),
3.47-3.60 (2H, m), 3.70-3.85 (2H, m), 4.05 (2H, q), 4.14 (2H,
q),4.23-4.35 (2H, m), 4.70-4.88 (2H, m), 6.77 (1H, d), 7.06 (2H,
d), 7.43 (1H, d), 7.56 (1H, br), 7.82 (2H, d), 7.87 (1H, d), 7.97
(1H, d), 8.50 (1H, d), 8.60 (1H, br), 9.15 (1H, br), 9.23 (2H, br),
9.35 (2H, br)
EXAMPLE 8
Synthesis of
(3R)-3-[4-amidino-2-(3-ethoxycarbonyl-2-(4-(1-(1-acetimidoyl)-
-4-piperidyloxy)benzoylamino)propoxy)phenyl]acrylic Acid
Bistrifluoroacetate
[0173] 200 mg (0.240 mmol) of ethyl
(3R)-3-[4-amidino-2-(3-ethoxycarbonyl--
2-(4-(1-(1-acetimidoyl)-4-piperidyloxy)benzoylamino)propoxy)phenyl]acrylat-
e bistrifluoroacetate was dissolved in 5 ml of concentrated
hydrochloric acid, and the obtained solution was stirred at
50.degree. C. for 2 hours. The solvent was evaporated, and the
obtained crude product was treated in the same manner as that in
step 9 in Example 1 to obtain the title compound.
[0174] Yield: 120 mg (0.154 mmol) (64%)
[0175] MS (ESI, m/z) 552 (MH+)
[0176] H-NMR (DMSO-d6) .delta. 1.70-1.85 (2H, m), 2.00-2.14 (2H,
m), 2.29 (3H, s), 2.78 (2H, d), 3.71-3.84 (2H, m), 4.22-4.34 (2H,
m), 4.29 (2H, d), 4.62-4.73 (1H, m), 4.77-4.86 (1H, m), 6.68 (1H,
d), 7.06 (2H, d), 7.43 (1H, d), 7.56 (1H, br), 7.82 (2H, d), 7.86
(1H, d), 7.94 (1H, d), 8.50 (1H, d), 8.62 (1H, br), 9.17 (1H, br),
9.31 (2H, br), 9.32 (2H, br)
EXAMPLE 9
Synthesis of Ethyl
(3R)-4-[5-amidino-2-(2-ethoxycarbonylethyl)phenoxy]-3-[-
4-(1-(1-acetimidoyl)-4-piperidyloxy)benzoylamino]butanoate
Bistrifluoroacetate
[0177] 3.2 g (4.50 mmol) of ethyl
(3R)-3-[2-(3-benzyloxycarbonyl-2-(4-(1-t-
-butoxycarbonyl-4-piperidyloxy)benzoylamino)propoxy)-4-cyanophenyl]acrylat-
e was dissolved in a mixture of 25 ml of 4 N solution of hydrogen
chloride in dioxane and 5 ml of ethanol. The obtained solution was
stirred at room temperature for 4 days. The solvent was evaporated,
and the residue was dissolved in 20 ml of ethanol. 765 mg of
ammonium carbonate was added to the obtained solution, and they
were stirred at room temperature overnight. The solvent was
evaporated, and the obtained residue was dissolved in 50 ml of
ethanol. 2.77 g (26.7 mmol) of ethyl acetimidate and 5 ml (35.6
mmol) of triethylamine were added to the obtained solution, and
they were stirred at room temperature overnight. The solvent was
evaporated, and the obtained crude product was dissolved in 50 ml
of water containing 0.1% (v/v) of trifluoroacetic acid and then
purified by the reversed phase medium-pressure preparative
chromatography with silica gel packing material (LiChroprep RP-18
37.times.440 mm) chemically bonded to octadodecyl group, followed
by the elution with a mixed solvent of water and acetonitrile
containing 0.1% (v/v) of trifluoroacetic acid. The obtained
purified product was dissolved in 50 ml of methanol. 600 mg of
palladium/carbon was added to the obtained solution, and they were
stirred in the presence of hydrogen overnight. The solvent was
evaporated and the obtained crude product was treated in the same
manner as that in step 9 in Example 1 to obtain the title
compound.
[0178] Yield: 920 mg (1.10 mmol) (24%)
[0179] MS (ESI, m/z) 608 (MH+)
[0180] H-NMR (DMSO-d6) .delta. 1.13 (3H, t), 1.15 (3H, t),
1.67-1.86 (2H, m), 2.00-2.16 (2H, m), 2.29 (3H, s), 2.56 (2H, dd),
2.82 (2H, dd), 2.83-2.98 (2H, m), 3.47-3.62 (2H, m), 3.64-3.92 (2H,
m), 3.98 (2H, q), 4.06 (2H, q), 4.18 (2H, d), 4.67-4.88 (2H, m),
7.06 (2H, d), 7.37 (1H, br), 7.38 (2H, d), 7.82 (2H, d), 8.45 (1H,
d), 8.62 (1H, br), 9.11 (2H, br), 9.16 (1H, br), 9.23 (2H, br)
EXAMPLE 10
Synthesis of
(3R)-4-[5-amidino-2-(2-carboxyethyl)phenoxy]-3-[4-(1-(1-aceti-
midoyl)-4-piperidyloxy)benzoylamino]butanoic Acid
Bistrifluoroacetate
[0181] 500 mg (0.600 mmol) of ethyl
(3R)-4-[5-amidino-2-(2-ethoxycarbonyle-
thyl)phenoxy]-3-[4-(1-(1-acetimidoyl)-4-piperidyloxy)benzoylamino]butanoat-
e bistrifluoroacetate was dissolved in 5 ml of concentrated
hydrochloric acid, and the obtained solution was stirred at
50.degree. C. for 2 hours. The solvent was evaporated, and the
obtained crude product was treated in the same manner as that in
step 9 in Example 1 to obtain the title compound.
[0182] Yield: 340 mg (0.435 mmol) (73%)
[0183] MS (ESI, m/z) 554 (MH+)
[0184] H-NMR (DMSO-d6) .delta. 1.68-1.86 (2H, m), 2.00-2.17 (2H,
m), 2.29 (3H, s), 2.52 (2H, d), 2.76 (2H, dd), 2.83-2.96 (2H, m),
3.48-3.52 (2H, m), 3.69-3.76 (2H, m), 4.12-4.24 (2H, m), 4.63-4.73
(1H, m), 4.75-4.86 (1H, m), 7.06 (2H, d), 7.37 (1H, br), 7.39 (2H,
d), 7.83 (2H, d), 8.44 (1H, d), 8.61 (1H, br), 9.09 (2H, br), 9.15
(1H, br), 9.22 (2H, br)
EXAMPLE 11
Synthesis of
3-[4-amidino-2-(2-(4-(1-acetimidoyl-4-piperidyloxy)benzoylami-
no)ethoxy)phenyl]acrylamide Bistrifluoroacetate
[0185] Step 1: Synthesis of
3-[4-cyano-2-(2-(4-(1-t-butoxycarbonyl-4-piper-
idyloxy)benzoylamino)ethoxy)phenyl]acrylamide:
[0186] 3.0 g (5.33 mmol) of ethyl
3-[4-cyano-2-(2-(4-(1-t-butoxycarbonyl-4-
-piperidyloxy)benzoylamino)ethoxy)phenyl]acrylate was dissolved in
100 ml of ethanol. 15 ml of 1 N aqueous sodium hydroxide solution
was added to the obtained solution, and they were stirred at room
temperature overnight. The solvent was evaporated under reduced
pressure. 1 N aqueous hydrochloric acid/ice solution was added to
the obtained crude product, and they were treated with ethyl
acetate as the extraction solvent in an ordinary manner to obtain
the crude product. 30 ml of N,N-dimethylformamide, 0.75 g (5.55
mmol) of 1-hydroxybenzotriazole (hydrous), 1.40 g (25.2 mmol) of
ammonium carbamate, 2 ml (0.015 mmol) of triethylamine and 2.12 g
(11.09 mmol) of 1-(3-dimethylaminopropyl)-3-ethy- lcarbodiimide
hydrochloride were added to the crude product, and they were
stirred overnight. After the evaporation of the solvent followed by
the treatment with ethyl acetate as the extraction solvent in an
ordinary manner, the solvent was evaporated, and the obtained crude
product was purified by the silica gel column chromatography to
obtain the title compound.
[0187] Yield: 1.89 g (3.54 mmol) (66%)
[0188] H-NMR (CDCl3) .delta. 1.45 (9H, s), 1.60-2.00 (4H, m),
3.28-3.73 (4H, m), 4.02-4.23 (4H, m), 4.51 (1H, br), 5.60 (1H, br),
6.89 (2H, d), 7.00-7.68 (5H, m), 7.75 (2H, d)
[0189] Step 2: Synthesis of
3-[4-amidino-2-(2-(4-(1-acetamidoyl-benzoylami-
no)-4-piperidyloxy)ethoxy)phenyl]acrylamide
bistrifluoroacetate:
[0190] 1.89 g (3.54 mmol) of
3-[4-cyano-2-(2-(4-(1-t-butoxycarbonyl-4-pipe-
ridyloxy)benzoylamino)ethoxy)phenyl]acrylamide was dissolved in a
mixture of 40 ml of 4 N solution of hydrogen chloride in dioxane
and 4 ml of ethanol, and they were stirred at room temperature
overnight. The solvent was evaporated under reduced pressure, and
the residue was dissolved in 60 ml of ethanol. 0.97 g (17.15 mmol)
of ammonium carbamate was added to the obtained solution, and they
were stirred at room temperature overnight. The solvent was
evaporated, and the obtained crude product was treated in the same
manner as that in step 9 in Example 1 to obtain the purified
product. 1.86 g (3.37 mmol) of the purified product was dissolved
in 30 ml of ethanol. 1.27 g (10.29 mmol) of ethyl acetimide
hydrochloride and 2.4 ml (17.15 mmol) of triethylamine were added
to the obtained solution, and they were stirred overnight. The
solvent was evaporated, and the obtained crude product was treated
in the same manner as that in step 9 in Example 1 to obtain the
title compound.
[0191] Yield: 1.10 g (1.53 mmol) (43%)
[0192] MS (ESI, m/z) 493 (MH+)
[0193] H-NMR (DMSO) .delta. 1.68-2.18 (4H, m), 2.29 (3H, s),
3.45-3.90 (6H, m), 4.30 (2H, t), 4.80 (1H, br), 6.92 (1H, d), 7.10
(2H, d), 7.23 (1H, br), 7.45 (1H, d), 7.52 (1H, s), 7.62 (1H, d),
7.64 (1H, br), 7.74 (1H, d), 7.85 (2H, d), 8.62 (1H, br), 8.74 (1H,
t), 9.16 (1H, br), 9.22-9.42 (4H, m)
EXAMPLE 12
Synthesis of
3-[4-amidino-2-(2-(4-(1-acetamidoyl)-4-piperidyloxy)benzoylam-
ino)ethoxy)phenyl]propion Amide Bistrifluoroacetate
[0194] 1.10 g (1.53 mmol) of
3-[4-amidino-2-(2-(4-(1-acetimidoyl)benzoylam- ino)ethoxy)phenyl]
acrylamide bistrifluoroacetate was dissolved in 100 ml of ethanol.
220 mg of 10% palladium/carbon (50% hydrous) was added to the
obtained solution, and they were stirred in the presence of
hydrogen overnight. The reaction solution was filtered through
Celite. The solvent was evaporated, and the obtained crude product
was treated in the same manner as that in step 9 in Example 1 to
obtain the title compound.
[0195] Yield: 0.82 g (1.13 mmol) (74%)
[0196] MS (ESI, m/z) 495 (MH+)
[0197] H-NMR (DMSO) .delta. 1.68-2.17 (4H, m), 2.28 (3H, s), 2.35
(2H, t), 2.85 (2H, t), 3.47-3.85 (6H, m), 4.20 (2H, t), 4.80 (1H,
br), 6.80 (1H, br), 7.06 (2H, d), 7.30 (1H, br), 7.33-7.42 (3H, m),
7.85 (2H, d), 8.56-8.70 (2H, m), 9.07-9.28 (5H, m)
EXAMPLE 13
Synthesis of
(3R)-4-[5-amidino-2-(2-carboxyethyl)phenoxy]-3-[(1-(pyridine--
4-yl)piperidine-4-carbonyl)amino]butanoic Acid
Bistrifluoroacetate
[0198] Step 1: Synthesis of ethyl
(3R)-3-[2-(3-benzyloxycarbonyl-2-((1-(py-
ridine-4-yl)piperidine-4-carbonyl)amino)propoxy)-4-cyanophenyl]acrylate:
[0199] 7.50 g (14.7 mmol) of ethyl
(3R)-3-[2-(t-butoxycarbonylamino)-3-ben-
zyloxycarbonyl-propoxy]-4-cyanophenyl]acrylate was dissolved in a
mixture of 14.7 ml of dioxane and 22.1 ml of 4 N solution of
hydrogen chloride in dioxane, and the obtained solution was stirred
at room temperature for 4 hours. The solvent was evaporated. 6.73 g
(of 7.08 g in total) of the crude product obtained by evaporating
the solvent was dissolved in 70 ml of DMF. 3.74 g (15.4 mmol) of
1-(4-pyridyl)-4-piperidinecarboxylic acid hydrochloride, 3.08 g
(18.2 mmol) of 2-chloro-1,3-dimethylimidazonium chloride and 8.6 ml
(61.6 mmol) of triethylamine were added to the obtained solution at
10.degree. C., and they were stirred for 16 hours.
[0200] After the treatment with ethyl acetate as the extraction
solvent in an ordinary manner, the obtained crude product was
purified by the silica gel column chromatography to obtain the
title compound.
[0201] MS (HRFABH+) 597.27 (MH+)
[0202] Yield: 7.83 g (13.1 mmol) (94%)
[0203] H-NMR (DMSO) .delta. 1.23 (3H, t), 1.50-1.64 (2H, m),
1.69-1.83 (2H, m), 2.42-2.51 (1H, m), 2.62-2.77 (2H, m), 3.03-3.41
(2H, m), 4.06-4.38 (6H, m), 4.49-4.61(1H, m). 5.10 (2H, s), 6.74
(1H, d), 7.08 (2H, d), 7.36 (5H, br), 7.45 (1H, d), 7.62 (1H, br),
7.83 (1H, d), 7.92 (1H, d), 8.18 (3H,brd),
[0204] Step 2: Synthesis of
(3R)-4-[5-amidino-2-(2-carboxyethyl)phenoxy]-3-
-[(1-(pyridine-4-yl)piperidine-4-carbonyl)amino]butanoic acid
bistrifluoroacetate:
[0205] 5.37 g (9.0 mmol) of ethyl
(3R)-3-[2-(3-benzyloxycarbonyl-2-((1-pyr-
idine-4-yl)piperidine-4-carbonyl)amino)propoxy]-4-cyanophenyl]acrylate
was dissolved in a mixture of 45 ml of 4 N solution of hydrogen
chloride in dioxane and 9 ml of ethanol, and the obtained solution
was stirred at room temperature overnight. The solvent was
evaporated under reduced pressure, and the residue was dissolved in
36 ml of ethanol. 1.56 g (16.2 mmol) of ammonium carbonate was
added to the obtained solution, and they were stirred at room
temperature overnight. The solvent was evaporated. 5.48 g (of 6.09
g in total) of the crude product obtained by the evaporation of the
solvent was dissolved in 54 ml of methanol. 548 mg of 10%
palladium/carbon was added to the obtained solution, and they were
stirred in the presence of hydrogen overnight. The reaction
solution was filtered through Celite. The solvent was evaporated,
and 3.11 g (of 4.44 g in total) of the crude product obtained by
the evaporation of the solvent was dissolved in 28 ml of 6 N
aqueous hydrochloric acid solution. After stirring the obtained
solution at 60.degree. C. for 2 hours, the solvent was evaporated.
60% of the crude product obtained by the evaporation of the solvent
was treated in the same manner as that in step 9 in Example 1 to
obtain the title compound.
[0206] MS (ESI, m/z) 498 (MH+)
[0207] MS (HRFABH+) 498.24(MH+)
[0208] Yield: 1.34 g (1.85 mmol) (33%)
[0209] H-NMR (DMSO) .delta. 1.52-1.64 (2H, m), 1.78-1.88 (2H, m),
2.50-2.639 (5H, m), 2.81-2.96 (2H, m), 3.17-3.24 (2H, m), 4.07-4.23
(4H, m), 4.40-4.51 (1H, m). 7.19 (2H, d), 7.38 (3H, br), 8.17 (1H,
d), 8.23 (2H, d), 9.26 (2H, br), 9.43 (2H, br)
EXAMPLE 14
Synthesis of
N-[2-(5-amidino-2-hydroxyphenoxy)ethyl]-4-(1-acetimidoyl-4-pi-
peridyloxy)benzamide Bistrifluoroacetate
[0210] Step 1: Synthesis of 4-benzyloxy-3-hydroxybenzonitrile:
[0211] 1.0 g (7.41 mmol) of 3,4-dihydroxybenzonitrile was dissolved
in 10 ml of N,N-dimethylformamide. 1.12 g (8.15 mmol) of potassium
carbonate and 0.88 ml (7.41 mmol) of benzyl bromide were added to
the obtained solution, and they were stirred at 50.degree. C. for 2
hours. After the treatment with ethyl acetate as the extraction
solvent in an ordinary manner, the solvent was evaporated, and the
obtained residue was purified by the silica gel column
chromatography to obtain the title compound.
[0212] Yield: 1.06 g (4.71 mmol) (64%)
[0213] H-NMR (CDCl3) .delta. 5.17 (2H, s), 6.95 (1H, d), 7.18 (1H,
d), 7.20 (1H, d), 7.41 (5H, br)
[0214] Step 2: Synthesis of
4-benzyloxy-3-[2-(t-butoxycarbonylamino)ethoxy- ]benzonitrile:
[0215] 8.0 g (35.7 mmol) of t-butyl (2-bromoethyl)carbamate was
dissolved in 20 ml of DMF. 4.0 g (17.7 mmol) of
4-benzyloxy-3-hydroxybenzonitrile and 7.4 g (41.3 mmol) of
potassium carbonate were added to the obtained solution, and they
were stirred at 100.degree. C. for 3 hours. After the treatment
with ethyl acetate as the extraction solvent in an ordinary manner,
the solvent was evaporated, and the obtained residue was purified
by the silica gel column chromatography to obtain the title
compound.
[0216] Yield: 3.4 g (9.2 mmol) (52%)
[0217] H-NMR (CDCl3) .delta. 1.46 (9H, s), 3.74 (2H, dt), 4.11 (2H,
t), 5.15 (2H, d), 7.18 (1H, d), 7.20 (1H, d), 7.41 (5H, br)
[0218] Step 3: Synthesis of
3-(2-aminoethoxy)-4-benzyloxybenzonitrile:
[0219] 3.4 g (9.2 mmol) of
4-benzyloxy-3-[2-(t-butoxycarbonylamino)ethoxy]- benzonitrile was
dissolved in 40 ml of 4 N solution of hydrogen chloride in dioxane,
and the obtained solution was stirred overnight. The solvent was
evaporated to obtain hydrochloride of the crude title compound.
[0220] Yield: 3.0 g
[0221] Step 4: Synthesis of
N-[2-(5-cyano-2-benzyloxyphenoxy)ethyl]-4-(1-t-
-butoxycarbonyl-4-piperidyloxy)benzamide:
[0222] 1.06 g (3.50 mmol) of
3-(2-aminoethoxy)-4-benzyloxybenzonitrile hydrochloride was
dissolved in 15 ml of DMF. 1.23 g (3.84 mmol) of
4-(1-t-butoxycarbonyl-4-piperidyloxy)benzoic acid, 710 mg (4.2
mmol)) of 2-chloro-1,3-dimethylimidazonium chloride and 1.45 ml
(5.19 mmol) of triethylamine were added to the obtained solution,
and they were stirred overnight. After the treatment with
dichloromethane as the extraction solvent in an ordinary manner,
the solvent was evaporated, and the obtained residue was purified
by the silica gel column chromatography to obtain the title
compound.
[0223] Yield: 510 mg (0.89 mmol) (26%)
[0224] H-NMR (CDCl3) .delta. 1.47 (9H, s), 1.66-1.80 (2H, m),
1.83-1.97 (2H, m), 3.25-3.41 (2H, m), 3.61-3.73 (2H, m), 3.84 (2H,
dt), 4.20 (2H, t), 4.44-4.53 (1H, m), 5.16 (2H, d), 6.62 (1H, t),
6.84 (2H, d), 6.95 (1H, d), 7.15 (1H, d), 7.24 (1H, d), 7.28-7.42
(5H, m), 7.65 (2H, d)
[0225] Step 5: Synthesis of
N-[2-(5-amidino-2-hydroxyphenoxy)ethyl]-4-(4-p-
iperidyloxy)benzamide bistrifluoroacetate:
[0226] 510 mg (0.89 mmol) of
N-[2-(5-cyano-2-benzyloxyphenoxy)ethyl]-4-(1--
t-butoxycarbonyl-4-piperidyloxy)benzamide was dissolved in a
mixture of 5 ml of 4 N solution of hydrogen chloride in dioxane and
1 ml of ethanol, and the obtained solution was stirred for 3 days.
The solvent was evaporated, and the obtained crude product was
dissolved in 10 ml of ethanol. 500 mg of ammonium carbonate was
added to the obtained solution, and they were stirred overnight.
The solvent was evaporated, and the obtained crude product was
dissolved in 10 ml of ethanol. 50 mg of 10% palladium/carbon was
added to the obtained solution, and they were stirred in the
presence of hydrogen overnight. The reaction solution was filtered
through Celite. The solvent was evaporated, and the obtained crude
product was treated in the same manner as that in step 9 in Example
1 to obtain the title compound.
[0227] Yield: 300 mg (0.479 mmol) (54%)
[0228] MS (ESI, m/z) 399 (MH+)
[0229] H-NMR (DMSO) .delta. 1.68-1.87 (2H, m), 2.03-2.17 (2H, m),
3.02-3.16 (2H, m), 3.19-3.30 (2H, m), 3.65 (2H, dt), 4.14 (2H, t),
4.46-4.78 (1H, m), 6.95 (1H, d), 7.05 (2H, d), 7.36 (1H, d), 7.42
(1H, br), 7.82 (2H, d), 8.57 (1H, br), 8.84 (2H, br), 9.02 (2H,
br)
[0230] Step 6: Synthesis of
N-[2-(5-amidino-2-hydroxyphenoxy)ethyl]-4-(1-a-
cetimidoyl-4-piperidyloxy)benzamide Bistrifluoroacetate:
[0231] 300 mg (0.479 mmol) of
N-[2-(5-amidino-2-hydroxyphenoxy)ethyl]-4-(4-
-piperidyloxy)benzamide bistrifluoroacetate was dissolved in 10 ml
of ethanol. 500 mg (5.3 mmol) of ethyl acetimidate and 0.5 ml (3.5
mmol) of triethylamine were added to the obtained solution, and
they were stirred at room temperature overnight. The solvent was
evaporated, and the obtained crude product was treated in the same
manner as that in step 9 in Example 1 to obtain the title
compound.
[0232] Yield: 220 mg (0.33 mmol) (69%)
[0233] MS (ESI, m/z) 440 (MH+)
[0234] H-NMR (DMSO) .delta. 1.63-1.84 (2H, m), 1.99-2.10 (2H, m),
2.27 (1H, s), 3.40-3.56 (4H, m), 3.65 (2H, dt), 3.66-3.81 (2H, m),
4.14 (2H, t), 4.66-4.87 (1H, m), 6.96 (1H, d), 7.06 (2H, d), 7.37
(1H, d), 7.42 (1H, br), 7.82 (2H, d), 8.58 (1H, t), 8.62 (1H, br),
8.94 (2H, br), 9.03 (2H, br), 9.16 (1H, br)
EXAMPLE 15
Synthesis of
N-[2-(5-amidino-2-hydroxyphenoxy)ethyl]-1-(4-pyridyl)-4-piper-
idine-4-carboxamide Bistrifluoroacetate
[0235] 1.00 g (3.30 mmol) of
3-(2-aminoethoxy)-4-benzyloxybenzonitrile hydrochloride was
dissolved in 15 ml of DMF. 876 mg (3.62 mmol) of
1-(4-pyridyl)-4-piperidinecarboxylic acid hydrochloride, 837 mg
(4.95 mmol) of 2-chloro-1,3-dimethylimidazonium chloride and 1.4 ml
(9.9 mmol) of triethylamine were added to the obtained solution,
and they were stirred overnight. After the treatment with
dichloromethane as the extraction solvent in an ordinary manner,
the solvent was evaporated, and the obtained residue was dissolved
in a mixture of 10 ml of 4 N solution of hydrogen chloride in
dioxane and 2 ml of ethanol. The obtained solution was stirred for
3 days. The solvent was evaporated, and the obtained crude product
was dissolved in 10 ml of ethanol. 500 mg of ammonium carbonate was
added to the solution, and they were stirred overnight. The solvent
was evaporated, and the obtained crude product was dissolved in 10
ml of ethanol. 50 mg of 10% palladium/carbon was added to the
obtained solution, and they were stirred in the presence of
hydrogen overnight. The reaction solution was filtered through
Celite. The solvent was evaporated and the residue was treated in
the same manner as that in step 9 in Example 1 to obtain the title
compound.
[0236] Yield: 50 mg (0.082 mmol) (3%)
[0237] MS (ESI, m/z) 383 (MH+)
[0238] H-NMR (DMSO) .delta. 1.46-1.64 (2H, m), 1.75-1.91 (2H, m),
2.48-2.55 (2H, m), 3.04-3.26 (2H, m), 3.46 (2H, dt), 4.04 (2H, t),
4.17-4.29 (1H, m), 6.96 (1H, d), 7.12 (1H, d), 7.18 (2H, d), 7.27
(1H, br), 8.19 (1H, t), 8.20 (2H, d), 8.95 (1H, br), 8.98 (1H, br),
9.03 (1H, br), 9.05 (1H, br)
EXAMPLE 16
Synthesis of
3-[4-amidino-2-(3-((1-(pyridine-4-yl)piperidine-4-carbonyl)am-
ino)prop oxy)phenyl]propionic Acid Bistrifluoroacetate
[0239] Step 1: Synthesis of t-butyl (3-bromopropyl)carbamate:
[0240] The title compound was obtained from 18.4 g (84.2 mmol) of
3-bromopropylamine hydrobromide and 13.1 g (60 mmol) of di-t-butyl
dicarbonate in the same manner as that in step 5 in Example 1 to
obtain the title compound.
[0241] Yield: 11.8 g (50.0 mmol) (83%)
[0242] H-NMR (CDCl3) .delta. 1.42 (9H, s), 2.05 (2H, tt), 3.25 (2H,
dt), 3.45 (2H, t), 4.70 (1H, br)
[0243] Step 2: Synthesis of
3-[3-(t-butoxycarbonylamino)propoxy]-4-iodoben- zonitrile:
[0244] 10.0 g (42 mmol) of t-butyl (3-bromopropyl))carbamate was
dissolved in 100 ml of DMF. 5.1 g (21 mmol) of
3-hydroxy-4-iodobenzonitrile and 8.7 g (41.3 mmol) of potassium
carbonate were added to the obtained solution, and they were
stirred at 100.degree. C. for 2 hours. After the treatment with
ethyl acetate as the extraction solvent in an ordinary manner, the
obtained crude product was purified by the silica gel column
chromatography to obtain the title compound.
[0245] Yield: 8.2 g (20.4 mmol) (98%)
[0246] H-NMR (CDCl3) .delta. 1.46 (9H, s), 2.04 (2H, tt), 3.39 (2H,
t), 4.12 (2H, t), 6.98 (2H, br), 7.88 (1H, d).
[0247] Step 3: Synthesis of ethyl
3-[2-(3-(t-butoxycarbonylamino)propoxy)--
4-cyanophenyl]acrylate:
[0248] 4.5 g (11.2 mmol) of
3-[3-(t-butoxycarbonylamino)propoxy]-4-iodoben- zonitrile was
dissolved in 20 ml of DMF. 6.0 ml (56 mmol) of ethyl acrylate, 6.2
ml (56 mmol) of triethylamine and 56 mg (0.22 mmol) of palladium
acetate were added to the obtained solution, and they were stirred
at 100.degree. C. overnight. After the treatment with ethyl acetate
as the extraction solvent in an ordinary manner, the obtained crude
product was purified by the silica gel column chromatography to
obtain the title compound.
[0249] Yield: 3.8 g (10.2 mmol) (91%)
[0250] H-NMR (CDCl3) .delta. 1.33 (3H, t), 1.43 (9H, s), 2.08 (2H,
tt), 3.37 (2H, dt), 4.11 (2H, t), 4.26 (2H, q), 6.54 (1H, d), 7.14
(1H, br), 7.24 (1H, d), 7.56 (1H, d), 7.91 (1H, d)
[0251] Step 4: Synthesis of ethyl
3-[2-(3-aminopropoxy)-4-cyanophenyl]prop- ionate:
[0252] 3.8 g (10.2 mmol) of ethyl
3-[2-(3-(t-butoxycarbonylamino)propoxy)-- 4-cyanophenyl]acrylate
was dissolved in 100 ml of ethyl acetate. 700 mg of 10%
palladium/carbon (50% hydrous) was added to the obtained solution,
and they were stirred in the presence of hydrogen for 3 hours. The
reaction solution was filtered through Celite. The solvent was
evaporated, and the obtained crude product was dissolved in 50 ml
of 4 N solution of hydrogen chloride in dioxane. The obtained
solution was stirred overnight. The solvent was evaporated to
obtain hydrochloride of the crude title compound.
[0253] Yield: 2.4 g (7.5 mmol) (74%)
[0254] Step 5: Synthesis of
3-[4-cyano-2-(3-((1-(pyridine-4-yl)piperidine--
4-carbonyl)amino)propoxy)phenyl]propionic acid
bistrifluoroacetate:
[0255] 1.06 g (3.33 mmol) of ethyl
3-[2-(3-aminopropoxy)-4cyanophenyl]prop- ionate hydrochloride was
dissolved in 10 ml of DMF. 887 mg (3.6 mmol) of
1-(4-pyridyl)-4-piperidinecarboxylic acid hydrochloride, 844 mg
(5.0 mmol) of 2-chloro-1,3-dimethylimidazonium chloride and 1.4 ml
(9.9 mmol) of triethylamine were added to the obtained solution,
and they were stirred overnight. The solvent was evaporated, and
the obtained crude product was dissolved in a mixture of 20 ml of 4
N solution of hydrogen chloride in dioxane and 4 ml of ethanol, and
they were stirred for 3 days. The solvent was distilled off, and
the obtained crude product was dissolved in 20 ml of ethanol. 1000
mg of ammonium carbonate was added to the obtained solution, and
they were stirred overnight. The solvent was evaporated, and the
obtained crude product was dissolved in 10 ml of 6 N aqueous
hydrochloric acid solution, and the obtained solution was stirred
at 50.degree. C. for 2 hours. The solvent was evaporated, and the
obtained crude product was treated in the same manner as that in
step 9 in Example 1 to obtain the title compound.
[0256] Yield: 660 mg (0.97 mmol) (29%)
[0257] MS (ESI, m/z) 454 (MH+)
[0258] H-NMR (DMSO-d6) .delta. 1.46-1.66 (2H, m), 1.46-1.98 (4H,
m), 2.48 (2H, br), 2.52 (2H, t), 2.85 (2H, t), 3.18-3.27 (4H, m),
4.08 (2H, t), 4.20 (1H, br), 7.17 (1H, d), 7.32 (2H, d), 7.36 (1H,
d), 8.00 (1H, t), 8.19 (2H, d), 9.20 (2H, br), 9.24 (2H, br)
EXAMPLE 17
Synthesis of
3-[4-amidino-2-(2-((1-(2,3,5,6-tetrafluoropyridine-4-yl)piper-
idine-4-carbonyl)amino)ethoxy)phenyl]propionic Acid
Bistrifluoroacetate
[0259] Step 1: Synthesis of ethyl
1-(2,3,5,6-tetrafluoropyridyl-4-yl)-4-pi- peridinecarboxylate:
[0260] 1.1 g (6.5 mmol) of pentafluoropyridine, 1.1 g (6.5 mmol) of
ethyl piperidine-4-carboxylate and 2.27 ml (13.7 mmol) of
diisopropylethylamine were stirred in 5 ml of ethanol at room
temperature for 24 hours. After the treatment with ethyl acetate as
the extraction solvent in an ordinary manner, the obtained crude
product was purified by the silica gel column chromatography to
obtain the title compound.
[0261] Yield: 2.0 g (6.5 mmol) (100%)
[0262] H-NMR (CDCl3) .delta. 1.25 (3H, t), 1.78-1.93 (2H, m),
1.98-2.09 (2H, m), 2.46-2.60 (1H, m) 3.25 (2H, t), 3.69 (2H, d),
4.17 (2H, q)
[0263] Step 2: Synthesis of
1-(2,3,5,6-tetrafluoropyridyl-4-yl)-4-piperidi- necarboxylic acid
hydrochloride:
[0264] 2.0 g (6.5 mmol) of ethyl
1-(2,3,5,6-tetrafluoropyridyl-4-yl)-4-pip- eridinecarboxylate was
stirred in 5 ml of dioxane. 5 ml of 2 N hydrochloric acid was added
to the obtained mixture, and they were stirred at 95.degree. C. for
2 hours. The solvent was evaporated to obtain the crude title
compound.
[0265] Yield: 1.5 g (4.7 mmol) (73%)
[0266] Step 3: Synthesis of
3-[4-amidino-2-(2-((1-(2,3,5,6-tetrafluoropyri-
dine-4-yl)piperidine-4-carbonyl)amino)ethoxy)phenyl]propionic acid
bistrifluoroacetate:
[0267] 600 mg (2.15 mmol) of ethyl
3-[2-(2-aminoethoxy)-4-cyanophenyl]prop- ionate hydrochloride was
dissolved in 10 ml of DMF. 812 mg (2.6 mmol) of
1-(2,3,5,6-tetrafluoropyridyl-4-yl)-4-piperidinecarboxylic acid
hydrochloride, 560 mg (3.3 mmol) of
2-chloro-1,3-dimethylimidazonium chloride and 0.9 ml (6.5 mmol) of
triethylamine were added to the obtained solution, and they were
stirred overnight. The solvent was evaporated, and the obtained
crude product was dissolved in a mixture of 5 ml of 4 N solution of
hydrogen chloride in dioxane and 1 ml of ethanol, and they were
stirred for 3 days. The solvent was distilled off, and the obtained
crude product was dissolved in 20 ml of ethanol. 500 mg of ammonium
carbonate was added to the obtained solution, and they were stirred
overnight. The solvent was evaporated, and the obtained crude
product was dissolved in 10 ml of 6 N aqueous hydrochloric acid
solution, and the obtained solution was stirred at 50.degree. C.
for 2 hours. The solvent was evaporated, and the obtained crude
product was treated in the same manner as that in step 9 in Example
1 to obtain the title compound.
[0268] Yield: 100 mg (0.14 mmol) (5%)
[0269] MS (ESI, m/z) 512 (MH+)
[0270] H-NMR (DMSO-d6) .delta. 1.58-1.81 (4H, m), 2.33-2.41 (1H,
m), 2.54 (2H, t), 2.86 (2H, t), 3.12-3.23 (2H, m), 3.47 (2H, t),
3.66 (2H, d), 4.11 (2H, t), 7.31-7.38 (3H, d), 8.13 (1H, t), 9.00
(2H, br), 9.22 (2H, br)
EXAMPLE 18
Synthesis of
3-[4-amidino-2-(2-((1-(pyridine-4-ylmethyl)piperidine-4-carbo-
nyl)amino)ethoxy)phenyl]propionic Acid Bistrifluoroacetate
[0271] Step 1: Synthesis of ethyl
1-(pyridyl-4-ylmethyl)-4-piperidinecarbo- xylate:
[0272] 1.15 g (7.0 mmol) of picolyl chloride hydrochloride, 1.0 g
(6.4 mmol) of ethyl piperidine-4-carboxylate and 1.3 ml (9.6 mmol)
of triethylamine were stirred in 10 ml of DMF at room temperature
for 4 hours. After the treatment with ethyl acetate as the
extraction solvent in an ordinary manner, the obtained crude
product was purified by the silica gel column chromatography to
obtain the title compound.
[0273] Yield: 1.0 g (3.51 mmol) (55%)
[0274] H-NMR (CDCl3) .delta. 1.25 (3H, t), 1.64-1.96 (4H, m),
2.02-2.17 (2H, m), 2.22-2.40 (1H, m) 2.80 (2H, d), 3.49 (2H, s),
4.13 (2H, q)
[0275] Step 2: Synthesis of
3-[4-amidino-2-(2-((1-(pyridine-4-ylmethyl)pip-
eridine-4-carbonyl)amino)ethoxy)phenyl]propionic acid
bistrifluoroacetate:
[0276] 1.0 g (3.51 mmol) of ethyl
1-(pyridyl-4-ylmethyl)-4-piperidinecarbo- xylate was stirred in 10
ml of dioxane. 10 ml of 2 N hydrochloric acid was added to the
obtained mixture, and they were stirred at 95.degree. C. for 4
hours. The solvent was evaporated, and the obtained crude product
was dissolved in 10 ml of DMF. 812 mg (2.9 mmol) of ethyl
3-[2-(2-aminoethoxy)-4-cyanophenyl]propionate hydrochloride, 735 mg
(4.35 mmol) of 2-chloro-1,3-dimethylimidazonium chloride and 1.2 ml
(8.7 mmol) of triethylamine were added to the obtained solution,
and they were stirred overnight. The solvent was evaporated, and
the obtained crude product was dissolved in a mixture of 5 ml of 4
N solution of hydrogen chloride in dioxane and 1 ml of ethanol, and
the obtained solution was stirred for 3 days. The solvent was
evaporated, and the obtained crude product was dissolved in 20 ml
of ethanol. 500 mg of ammonium carbonate was added to the obtained
solution, and they were stirred overnight. The solvent was
evaporated, then the obtained crude product was dissolved in 10 ml
of 6 N aqueous hydrochloric acid solution, and the obtained
solution was stirred at 50.degree. C. for 2 hours. The solvent was
evaporated, and the obtained crude product was treated in the same
manner as that in step 9 in Example 1 to obtain the title
compound.
[0277] Yield: 70 mg (0.10 mmol) (3%)
[0278] MS (ESI, m/z) 454(MH+)
[0279] H-NMR (DMSO-d6) .delta. 1.65-1.96 (4H, m), 2.27-2.58 (3H,
m), 2.73-3.10 (4H, m), 3.29-3.56 (4H, m), 4.09 (2H, t), 4.35 (2H,
br), 7.35 (3H, br), 7.56 (2H, d), 8.25 (1H, t), 8.70 (2H, d), 9.16
(2H, br), 9.22 (2H, br)
EXAMPLE 19
Synthesis of
3-[4-amidino-2-(2-((1-(pyridine-4-carbonyl)piperidine-4-carbo-
nyl)amino)ethoxy)phenyl]propionic Acid Bistrifluoroacetate
[0280] Step 1: Synthesis of ethyl
1-(pyridyl-4-carbonyl)-4-piperidinecarbo- xylate:
[0281] 1.25 g (7.0 mmol) of isonicotinoyl chloride hydrochloride,
1.0 g (6.4 mmol) of ethyl piperidine-4-carboxylate and 1.3 ml (9.6
mmol) of triethylamine were stirred in 10 ml of DMF at room
temperature for 4 hours. After the treatment with ethyl acetate as
the extraction solvent in an ordinary manner, the obtained crude
product was purified by the silica gel column chromatography to
obtain the title compound.
[0282] Yield: 850 mg (2.84 mmol) (44%)
[0283] H-NMR (CDCl3) .delta. 1.27 (3H, t), 1.60-2.09 (4H, m),
2.02-2.17 (2H, m), 2.50-2.68 (1H, m) 3.06 (2H, d), 3.60 (1H, d),
4.18 (2H, q), 4.50 (2H, d),
[0284] Step 2: Synthesis of
3-[4-amidino-2-(2-((1-(pyridine-4-carbonyl)pip-
eridine-4-carbonyl)amino)ethoxy)phenyl]propionic acid
bistrifluoroacetate:
[0285] 850 mg (2.84 mmol) of ethyl
1-(pyridyl-4-carbonyl)-4-piperidinecarb- oxylate was stirred in 10
ml of dioxane. 10 ml of 2 N hydrochloric acid was added to the
obtained mixture, and they were stirred at 95.degree. C. for 4
hours. The solvent was evaporated, and the obtained crude product
was dissolved in 10 ml of DMF. 700 mg (2.5 mmol) of ethyl
3-[2-(2-aminoethoxy)-4-cyanophenyl]propionate hydrochloride, 634 mg
(3.75 mmol) of 2-chloro-1,3-dimethylimidazonium chloride and 1.74
ml (7.5 mmol) of triethylamine were added to the obtained solution,
and they were stirred overnight. The solvent was evaporated, and
the obtained crude product was dissolved in a mixture of 5 ml of 4
N solution of hydrogen chloride in dioxane and 1 ml of ethanol, and
they were stirred for 3 days. The solvent was evaporated, and the
obtained crude product was dissolved in 20 ml of ethanol. 500 mg of
ammonium carbonate was added to the obtained solution, and they
were stirred overnight. The solvent was evaporated, and the
obtained crude product was dissolved in 10 ml of 6 N aqueous
hydrochloric acid solution, and the obtained solution was stirred
at 50.degree. C. for 2 hours. The solvent was evaporated, and the
obtained crude product was treated in the same manner as that in
step 9 in Example 1 to obtain the title compound.
[0286] Yield: 100 mg (0.15 mmol) (5%)
[0287] MS (ESI, m/z) 454(MH+)
[0288] H-NMR (DMSO-d6) .delta. 1.37-1.84 (4H, m), 2.27-2.56 (3H,
m), 2.73-3.13 (4H, m), 3.29-3.56 (3H, m), 4.09 (2H, t), 4.42 (1H,
d), 7.21-7.33 (5H, m), 8.10 (1H, t), 8.67 (2H, d), 8.94 (2H, br),
9.21 (2H, br)
EXAMPLE 20
Synthesis of
3-[4-amidino-2-(2-((1-(3,5-dichloropyridine-4-yl)piperidine-4-
-carbonyl)amino)ethoxy)phenyl]propionic Acid
Bistrifluoroacetate
[0289] Step 1: Synthesis of ethyl
1-(3,5-dichloropyridine-4-yl)-4-piperidi- necarboxylate:
[0290] 2.0 g (11 mmol) of 3,4,5-trichloropyridine, 1.7 g (11 mmol)
of ethyl piperidine-4-carboxylate and 4.6 ml (33 mmol) of
triethylamine were stirred in 20 ml of xylene under heating under
reflux for 10 hours. After the treatment with ethyl acetate as the
extraction solvent in an ordinary manner, the obtained crude
product was purified by the silica gel column chromatography to
obtain the title compound.
[0291] Yield: 800 mg (2.6 mmol) (24%)
[0292] H-NMR (CDCl3) .delta. 1.28 (3H, t), 1.80-2.03 (4H, m),
2.44-2.58 (1H, m), 3.23-3.44 (4H, m), 4.17 (2H, q), 8.32 (2H,
s)
[0293] Step 2: Synthesis of ethyl
3-[4-cyano-2-(2-((1-(3,5-dichloropyridin-
e-4-yl)piperidine-4-carbonyl)amino)ethoxy)phenyl]propionate:
[0294] 2.0 g (6.5 mmol) of ethyl
1-(3,5-dichloropyridine-4-yl)-4-piperidin- ecarboxylate was stirred
in 5 ml of dioxane. 5 ml of 2 N hydrochloric acid was added to the
obtained mixture, and they were stirred at 95.degree. C. for 4
hours. The solvent was evaporated, and the obtained crude product
was dissolved in 10 ml of DMF. 612 mg (2.27 mmol) of ethyl
3-[2-(2-aminoethoxy)-4-cyanophenyl]propionate hydrochloride, 575 mg
(3.40 mmol) of 2-chloro-1,3-dimethylimidazonium chloride and 0.9 ml
(6.8 mmol) of triethylamine were added to the obtained solution,
and they were stirred overnight. After the treatment with ethyl
acetate as the extraction solvent in an ordinary manner, the
obtained crude product was purified by the silica gel column
chromatography to obtain the title compound.
[0295] Yield: 1.0 g (1.9 mmol) (73%)
[0296] H-NMR (CDCl3) .delta. 1.21 (3H, t), 1.83-2.06 (4H, m),
2.31-2.43 (2H, m), 2.46-2.60 (1H, m), 2.62 (2H, t), 3.00 (2H, t),
3.22-3.41 (4H, m), 3.73 (2H, dt), 4.03-4.11 (4H, m), 7.04 (1H, br),
7.22 (2H, d), 8.32 (2H, s)
[0297] Step 3: Synthesis of
3-[4-amidino-2-(2-((1-(3,5-dichloropyridine-4--
yl)piperidine-4-carbonyl)amino)ethoxy)phenyl]propionic acid
bistrifluoroacetate:
[0298] 1.0 g (1.9 mmol) of ethyl
3-[4-cyano-2-(2-((1-(3,5-dichloropyridine-
-4-yl)piperidine-4-carbonyl)amino)ethoxy)phenyl]propionate was
dissolved in a mixture of 10 ml of 4 N solution of hydrogen
chloride in dioxane and 2 ml of ethanol, and they were stirred for
3 days. The solvent was evaporated, and the obtained crude product
was dissolved in 20 ml of ethanol. 500 mg of ammonium carbonate was
added to the obtained solution, and they were stirred overnight.
The solvent was evaporated, and the obtained crude product was
dissolved in 10 ml of 6 N aqueous hydrochloric acid solution, and
the obtained solution was stirred at 50.degree. C. for 2 hours. The
solvent was evaporated, and the obtained crude product was treated
in the same manner as that in step 9 in Example 1 to obtain the
title compound.
[0299] Yield: 280 mg (0.38 mmol) (20%)
[0300] MS (ESI, m/z) 508 (MH+)
[0301] H-NMR (DMSO-d6) .delta. 1.62-1.78 (4H, m), 2.16-2.22 (1H,
m), 2.52 (2H, t), 2.87 (2H, t), 3.18-3.27 (4H, m), 3.46 (2H, t),
4.12 (2H, t), 7.30-7.41 (3H, m), 8.12 (1H, t), 8.41 (2H, s), 8.98
(2H, br), 9.22 (2H, br)
EXAMPLE 21
Synthesis of
3-[4-amidino-2-(2-((4-methyl-2-pyridyl-4-ylthiazole-5-carbony-
l)amino)ethoxy)phenyl]propionic Acid Bistrifluoroacetate
[0302] Step 1: Synthesis of ethyl
4-methyl-2-(4-pyridyl)thiazole-5-carboxy- late:
[0303] 2.76 g (20 mmol) of thioisonicotinamide and 3.6 g (22 mmol)
of ethyl 2-chloroacetacetate were heated under reflux in 30 ml of
ethanol for 20 hours. After the treatment with ethyl acetate as the
extraction solvent in an ordinary manner, the obtained crude
product was purified by the silica gel column chromatography to
obtain the title compound.
[0304] Yield: 2.0 g (8.1 mmol) (40%)
[0305] H-NMR (CDCl3) .delta. 1.40 (3H, t), 2.81 (3H, s), 4.38 (2H,
q), 7.81 (2H, d), 8.73 (2H, d)
[0306] Step 2: Synthesis of Ethyl
3-[4-cyano-2-(2-((4-methyl-2-pyridyl-4-y-
l-thiazole-5-carbonyl)amino)ethoxy)phenyl]propionate:
[0307] 1.58 g (6.37 mmol) of ethyl
4-methyl-2-(4-pyridyl)thiazole-5-carbox- ylate was stirred in 5 ml
of ethanol. 5 ml of 1 N sodium hydroxide was added to the obtained
mixture, and they were stirred at room temperature for 4 hours. 5
ml of 1 N hydrochloric acid was added to the reaction mixture. A
portion (700 mg) of the obtained crystals was dissolved in 10 ml of
DMF. 590 mg (2.12 mmol) of ethyl
3-[2-(2-aminoethoxy)-4-cyanophenyl- ]propionate hydrochloride, 539
mg (3.19 mmol) of 2-chloro-1,3-dimethylimid- azonium chloride and
1.3 ml (9.57 mmol) of triethylamine were added to the obtained
solution, and they were stirred overnight. After the treatment with
ethyl acetate as the extraction solvent in an ordinary manner, the
obtained crude product was purified by the silica gel column
chromatography to obtain the title compound.
[0308] Yield: 600 mg (1.29 mmol)
[0309] H-NMR (CDCl3) .delta. 1.15 (3H, t), 2.61 (2H, t), 3.01 (2H,
t), 3.92 (2H, dt), 4.03 (2H, q), 4.20 (2H, t), 7.07 (1H, br), 7.25
(2H, d), 7.80 (2H, d), 8.73 (2H, d)
[0310] Step 3: Synthesis of
3-[4-amidino-2-(2-((4-methyl-2-pyridyl-4-ylthi-
azole-5-carbonyl)amino)ethoxy)phenyl]propionic acid
bistrifluoroacetate:
[0311] 600 mg (1.29 mmol) of ethyl
3-[4-cyano-2-(2-((4-methyl-2-pyridyl-4--
yl-thiazole-5-carbonyl)amino)ethoxy)phenyl]propionate was dissolved
in a mixture of 10 ml of 4 N hydrogen chloride in dioxane and 2 ml
of ethanol, and they were stirred for 3 days. The solvent was
evaporated, and the obtained crude product was dissolved in 20 ml
of ethanol. 500 mg of ammonium carbonate was added to the obtained
solution, and they were stirred overnight. The solvent was
evaporated, and the obtained crude product was dissolved in 10 ml
of 6 N aqueous hydrochloric acid solution, and the obtained
solution was stirred at 50.degree. C. for 2 hours. The solvent was
evaporated, and the obtained crude product was treated in the same
manner as that in step 9 in Example 1 to obtain the title
compound.
[0312] Yield: 300 mg (0.44 mmol) (34%)
[0313] MS (ESI, m/z) 454(MH+)
[0314] H-NMR (DMSO-d6) .delta. 2.53 (2H, t), 2.63 (3H, s), 2.88
(2H, t), 3.68 (2H, dt), 4.23 (2H, t), 7.32-7.41 (3H, m), 7.88 (2H,
d), 8.66 (1H, t), 8.73 (2H, d), 9.05 (2H, br), 9.23 (2H, br)
EXAMPLE 22
Synthesis of
3-[4-amidino-2-(2-((1-(6-chloropyridazine-3-yl)piperidine-4-c-
arbonyl)amino)ethoxy)phenyl]propionic Acid Bistrifluoroacetate
[0315] Step 1: Synthesis of ethyl
1-(6-chloropyridazine-3-yl)-4-piperidine- carboxylate:
[0316] 2.0 g (13.4 mmol) of 3,6-dichloropyridazine, 2.3 g (14.8
mmol) of ethyl piperidine-4-carboxylate and 4.6 ml (33 mmol) of
triethylamine were stirred in 20 ml of DMF at 50.degree. C. for 4
hours. After the treatment with ethyl acetate as the extraction
solvent in an ordinary manner, the obtained crude product was
purified by the silica gel column chromatography to obtain the
title compound.
[0317] Yield: 1.58 g (5.86 mmol) (44%)
[0318] H-NMR (CDCl3) .delta. 1.26 (3H, t), 1.71-1.88 (2H, m),
1.97-2.06 (2H, m), 2.50-2.64 (1H, m), 3.03-3.17 (2H, m), 4.16 (2H,
q), 4.23 (2H, dt), 6.91 (1H, d), 7.18 (1H, d)
[0319] Step 2: Synthesis of
3-[4-amidino-2-(2-((1-(6-chloropyridazine-3-yl-
)piperidine-4-carbonyl)amino)ethoxy)phenyl]propionic acid
bistrifluoroacetate:
[0320] 600 mg (2.22 mmol) of ethyl
1-(6-chloropyridazine-3-yl)-4-piperidin- ecarboxylate was stirred
in 5 ml of dioxane. 5 ml of 2 N hydrochloric acid was added to the
obtained mixture, and they were stirred at 95.degree. C. for 4
hours. The solvent was evaporated, and the obtained crude product
was dissolved in 10 ml of DMF. 514 mg (1.85 mmol) of ethyl
3-[2-(2-aminoethoxy)-4-cyanophenyl]propionate hydrochloride, 470 mg
(2.78 mmol) of 2-chloro-1,3-dimethylimidazonium chloride and 0.77
ml (5.58 mmol) of triethylamine were added to the obtained
solution, and they were stirred overnight. After the treatment with
ethyl acetate as the extraction solvent in an ordinary manner, the
obtained crude product was dissolved in a mixture of 10 ml of 4 N
solution of hydrogen chloride in dioxane and 2 ml of ethanol, and
they were stirred for 3 days. The solvent was evaporated, and the
obtained crude product was dissolved in 20 ml of ethanol. 500 mg of
ammonium carbonate was added to the obtained solution, and they
were stirred overnight. The solvent was evaporated, then the
obtained crude product was dissolved in 10 ml of 6 N aqueous
hydrochloric acid solution, and the obtained solution was stirred
at 50.degree. C. for 2 hours. The solvent was evaporated, and the
obtained crude product was treated in the same manner as that in
step 9 in Example 1 to obtain the title compound.
[0321] Yield: 280 mg (0.40 mmol) (18%)
[0322] MS (ESI, m/z) 475 (MH+)
[0323] H-NMR (DMSO-d6) .delta. 1.43-1.62 (2H, m), 1.70-1.82 (2H,
m), 2.37-2.60 (3H, m), 2.77-3.01 (4H, m), 3.47 (2H, dt), 4.27 (2H,
t), 4.32 (2H, d), 7.23-7.42 (4H, m), 7.49 (1H, d), 8.14 (1H, t),
8.99 (2H, br), 9.24 (2H, br)
EXAMPLE 23
Synthesis of
3-[4-amidino-2-(2-((1-pyridazine-3-yl)piperidine-4-carboxyl)a-
mino)ethoxy)phenyl]propionamide Bistrifluoroacetate
[0324] 150 mg (0.21 mmol) of
3-[4-amidino-2-(2-((1-(6-chloropyridazine-3-y-
l)piperizine-4-carbonyl)amino)ethoxy)phenyl]propionic acid
bistrifluoroacetate was dissolved in 10 ml of ethanol. 10 mg of
Pd-C was added to the obtained solution, and they were stirred in
the presence of hydrogen at room temperature for 4 hours. The
reaction solution was filtered through Celite, and the obtained
crude product was treated in the same manner as that in step 9 in
Example 1 to obtain the title compound.
[0325] Yield: 50 mg (0.075 mmol) (36%)
[0326] MS (ESI, m/z) 441 (MH+)
[0327] H-NMR (DMSO-d6) .delta. 1.50-1.63 (2H, m), 1.77-1.91 (2H,
m), 2.51 (2H, t), 2.84 (2H, t), 3.00-3.19 (2H, m), 3.39-3.58 (1H,
m), 3.46 (2H, dt), 4.08 (2H, t), 4.27 (2H, d), 7.32 (1H, d), 7.34
(1H, d), 7.75 (1H, br), 8.15 (1H, t), 8.61 (1H, d), 9.05 (2H, br),
9.22 (2H, br)
EXAMPLE 24
Synthesis of
3-[4-amidino-2-(2-((1-(2-chloropyrimidine-4-yl)piperidine-4-c-
arbonyl)amino)ethoxy)phenyl]propionic Acid Bistrifluoroacetate
[0328] Step 1: Synthesis of ethyl
1-(2-chloropyrimidine-4-yl)-4-piperidine- carboxylate:
[0329] 2.0 g (13.4 mmol) of 2,4-dichloropyrimidine, 2.32 g (14.7
mmol) of ethyl piperidine-4-carboxylate and 4.6 ml (33 mmol) of
triethylamine were stirred in 20 ml of DMF at 50.degree. C. for 4
hours. After the treatment with ethyl acetate as the extraction
solvent in an ordinary manner, the obtained crude product was
purified by the silica gel column chromatography to obtain the
title compound.
[0330] Yield: 700 mg (2.60 mmol) (19%)
[0331] H-NMR (CDCl3) .delta. 1.26 (3H, t), 1.63-1.80 (2H, m),
1.92-2.09 (2H, m), 2.52-2.66 (1H, m), 3.03-3.19 (2H, m), 4.11-4.37
(4H, m), 6.39 (1H, d), 8.02 (1H, d)
[0332] Step 2: Synthesis of ethyl
3-[4-cyano-2-(2-((1-(2-chloropyrimidine--
4-yl)piperidine-4-carbonyl)amino)ethoxy)phenyl]propionate:
[0333] 700 mg (2.60 mmol) of ethyl
1-(2-chloropyridine-4-yl)-4-piperidinec- arboxylate was stirred in
5 ml of dioxane. 5 ml of 2 N hydrochloric acid was added to the
obtained mixture, and they were stirred at 95.degree. C. for 4
hours. The solvent was evaporated, and the obtained crude product
was dissolved in 10 ml of DMF. 600 mg (2.16 mmol) of ethyl
3-[2-(2-aminoethoxy)-4-cyanophenyl]propionate hydrochloride, 548 mg
(3.24 mmol) of 2-chloro-1,3-dimethylimidazonium chloride and 0.9 ml
(6.48 mmol) of triethylamine were added to the obtained solution,
and they were stirred overnight. After the treatment with ethyl
acetate as the extraction solvent in an ordinary manner, the
obtained crude product was purified by the silica gel column
chromatography to obtain the title compound.
[0334] Yield: 320 mg (0.66 mmol) (31%)
[0335] H-NMR (CDCl3) .delta. 1.25 (3H, t), 1.63-2.05 (4H, m), 2.60
(2H, t), 2.99 (2H, t), 3.00-3.21 (3H, m), 3.68 (2H, dt), 4.07 (2H,
t), 4.15 (2H, q), 4.18-4.41 (2H, m), 6.38 (1H, d), 7.02 (1H, bs),
7.23 (1H, bs), 8.00 (2H, br)
[0336] Step 3: Synthesis of
3-[4-amidino-2-(2-((1-(2-chloropyrimidine-4-yl-
)piperidine-4-carbonyl)amino)ethoxy]phenyl]propionic acid
bistrifluoroacetate:
[0337] 320 mg (0.66 mmol) of ethyl
3-[4-cyano-2-(2-((1-(2-chloropyrimidine-
-4-yl)piperidine-4-carbonyl)amino)ethoxy)phenyl]propionate was
dissolved in a mixture of 10 ml of 4 N solution of hydrogen
chloride in dioxane and 2 ml of ethanol, and they were stirred for
3 days. The solvent was evaporated, and the obtained crude product
was dissolved in 20 ml of ethanol. 500 mg of ammonium carbonate was
added to the obtained solution, and they were stirred overnight.
The solvent was evaporated, and the obtained crude product was
dissolved in 10 ml of 6 N aqueous hydrochloric acid solution, and
the obtained solution was stirred at 50.degree. C. for 2 hours. The
solvent was evaporated, and the obtained crude product was treated
in the same manner as that in step 9 in Example 1 to obtain the
title compound.
[0338] Yield: 50 mg (0.071 mmol) (11%)
[0339] MS (ESI, m/z) 475 (MH+)
[0340] H-NMR (DMSO-d6) .delta. 1.37-1.58 (2H, m), 1.63-2.01 (2H,
m), 2.54 (2H, t), 2.86 (2H, t), 2.94-3.24 (3H, m), 3.46 (2H, dt),
4.08 (2H, t), 4.20 (2H, br), 6.81 (1H, d), 7.32 (1H, d), 7.34 (2H,
d), 8.03 (1H, d), 8.13 (1H, t), 8.98 (2H, br), 9.21 (2H, br)
EXAMPLE 25
Synthesis of
3-[4-amidino-2-(2-((1-(pyrimidine-4-yl)piperidine-4-carbonyl)-
amino)ethoxy)phenyl]propionic Acid Bistrifluoroacetate
[0341] 50 mg (0.071 mmol) of
3-[4-amidino-2-(2-((1-(2-chloropyrimidine-4yl-
)piperizine-4-carbonyl)amino)ethoxy)phenyl]propionic acid
bistrifluoroacetate was dissolved in 5 ml of ethanol. 10 mg of
palladium/carbon was added to the obtained solution, and they were
stirred in the presence of hydrogen at room temperature for 4
hours. The reaction solution was filtered through Celite, the
solvent was evaporated and the obtained crude product was treated
in the same manner as that in step 9 in Example 1 to obtain the
title compound.
[0342] Yield: 18 mg (0.027 mmol) (38%)
[0343] MS (ESI, m/z) 441 (MH+)
[0344] H-NMR (DMSO-d6) .delta. 1.42-1.61 (2H, m), 1.70-1.91 (2H,
m), 2.54 (2H, t), 2.85 (2H, t), 3.03-3.24 (3H, m), 3.46 (2H, dt),
4.08 (2H, t), 4.46 (2H, br), 7.17 (1H, dd), 7.34 (2H, d), 7.38 (1H,
dd), 8.18 (3H, br), 9.18 (2H, br), 9.22 (2H, br)
EXAMPLE 26
Synthesis of
3-[4-amidino-(2R)-2-((1-(pyridine-4-yl)piperidine-4-carbonyl)-
pyrrolidine-2-ylmethoxy)phenyl]propionic Acid
Bistrifluoroacetate
[0345] Step 1: Synthesis of
1-t-butoxycarbonyl-(2R)-2-(p-tolylmethanesulfo-
nyloxymethyl)pyrrolidine:
[0346] 1 g of D-prolinol was dissolved in 24 ml of dioxane. 2.4 g
(10.5 mmol) of di-t-butyl carbanate and 5.3 ml of 2 M aqueous
sodium hydroxide solution were added to the obtained solution under
cooling with ice. They were stirred for 15 minutes and then at room
temperature for additional 2 hours. The solvent was evaporated, and
the residue was treated with ethyl acetate as the extraction
solvent in an ordinary manner to obtain the crude product. The
crude product was dissolved in 15 ml of dichloromethane. 2.23 g
(10.8 mmol) of tosyl chloride and 1.5 ml (10.5 mmol) of
triethylamine were added to the obtained solution, and they were
stirred at room temperature overnight. After the treatment in an
ordinary manner, the obtained crude product was purified by the
silica gel column chromatography to obtain the title compound.
[0347] Yield: 2.55 g (7.17 mmol) (72%)
[0348] H-NMR (CDCl3) .delta. 1.38 (9H,br), 1.70-2.00 (4H,m), 2.45
(3H,s), 3.30 (2H,br), 3.90 (1H, by), 4.10 (2H,br), 7.32 (2H,d),
7.78(2H,d).
[0349] Step 2: Synthesis of
4-iodo-3-[(2R)-(1-t-butoxycarbonyl-pyrrolidine-
-2-ylmethoxy)]benzonitrile:
[0350] 2.0 g (8.16 mmol) of 3-hydroxy-4-iodobenzonitrile was
dissolved in 20 ml of DMF. 5.8 g (16.3 mmol) of
1-t-butoxycarbonyl-(2R)-2-(p-tolylmeth-
anesulfonyloxymethyl)pyrrolidine and 3.37 g (24.4 mmol) of
potassium carbonate were added to the obtained solution, and they
were stirred at 50.degree. C. for 16 hours. 1.5 g (4.2 mmol) of
1-t-butoxycarbonyl-(2R)-2-
-(p-tolylmethanesulfonyloxymethyl)pyrrolidine was added to the
obtained mixture, and they were stirred at 50.degree. C. for 4
hours. After the treatment with ethyl acetate as the extraction
solvent in an ordinary manner, the obtained crude product was
purified by the silica gel column chromatography to obtain the
title compound.
[0351] Yield: 3.7 g (8.6 mmol)
[0352] H-NMR (CDCl3) .delta. 1.47 (9H, s), 1.78-2.19 (4H, m),
3.22-3.34 (2H, m), 3.83-4.04 (1H, m), 4.06-4.23 (2H, m), 3.03-3.41
(2H, m), 6.96 (1H, br), 7.08 (1H, br), 7.88 (1H, br)
[0353] Step 3: Synthesis of ethyl
3-[4-cyano-(2R)-2-(1-t-butoxycarbonylpyr-
rolidine-2-ylmethoxy)phenyl]acrylate:
[0354] 3.7 g (8.6 mmol) of
4-iodo-3-[(2R)-(1-t-butoxycarbonyl-pyrrolidine--
2-ylmethoxy)]benzonitrile was dissolved in 40 ml of DMF. 4.68 ml
(43 mmol) of ethyl acrylate, 6.1 ml (43 mmol) of triethylamine and
194 mg (0.85 mmol) of palladium acetate were added to the obtained
solution, and they were stirred at 100.degree. C. overnight. After
the treatment with ethyl acetate as the extraction solvent in an
ordinary manner, the obtained crude product was treated with ethyl
acetate as the extraction solvent in an ordinary manner to obtain
the crude product, which was purified by the silica gel column
chromatography to obtain the title compound.
[0355] Yield: 3.0 g (7.5 mmol) (87%)
[0356] H-NMR (CDCl3) .delta. 1.34 (3H, t), 1.46 (9H, s), 1.90-2.17
(4H, m), 3.31-3.55 (2H, m), 4.02-4.39 (3H, m), 4.27 (2H, q), 6.53
(1H, d), 7.13-7.28 (2H, m), 7.46-7.62 (1H, m), 7.93 (1H, d)
[0357] Step 4: Synthesis of ethyl
3-[4-cyano-(2R)-2-(pyrrolidine-2-ylmetho- xy)phenyl]propionate:
[0358] 3.0 g (7.5 mmol) of ethyl
3-[4-cyano-(2R)-2-(1-t-butoxycarbonyl-pyr-
rolidine-2-ylmethoxy)phenyl]acrylate was dissolved in 20 ml of
ethanol. 600 mg of 10% palladium/carbon (50% aqueous) was added to
the obtained solution, and they were stirred in the presence of
hydrogen overnight. The reaction solution was filtered through
Celite, and the solvent was evaporated. The obtained crude product
was dissolved in 10 ml of 4 N solution of hydrogen chloride in
dioxane, and the obtained solution was stirred at room temperature
for 3 hours. The solvent was evaporated to obtain hydrochloride of
the title compound.
[0359] Yield: 1.8 g (6.0 mmol) (79%)
[0360] Step 5: Synthesis of Ethyl
3-[4-cyano-(2R)-2-((1-(pyridine-4-yl)pip-
eridine-4-carbonyl)pyrrolidine-2-ylmethoxy)phenyl]propionate:
[0361] 570 mg (1.89 mmol) of ethyl
3-[4-cyano-(2R)-2-(pyrrolidine-2-ylmeth- oxy)phenyl]propionate was
dissolved in 10 ml of DMF. 504 mg (2.1 mmol) of
1-(4-pyridyl)-4-piperidinecarboxylic acid hydrochloride, 479 mg
(2.8 mmol) of 2-chloro-1,3-dimethylimidazonium chloride and 0.78 ml
(5.7 mmol) of triethylamine were added to the obtained solution,
and they were stirred overnight.
[0362] Yield: 600 mg (1.22 mmol) (65%)
[0363] H-NMR (DMSO-d6) .delta. 1.24 (3H, t), 1.48-1.75 (2H, m),
1.78-1.94 (2H, m), 1.95-2.20 (4H, m), 2.52-2.64 (3H, m), 2.80-3.03
(3H, m), 3.50-3.66 (2H, m), 3.82-4.00 (2H, m), 4.03-4.22 (4H, m),
4.40-4.52 (2H, m), 6.66 (2H, d), 7.11 (1H, br), 7.18-7.25 (2H, m),
8.24 (2H, d)
[0364] Step 6: Synthesis of
3-[4-amidino-(2R)-2-((1-(pyridine-4-yl)piperid-
ine-4-carbonyl)pyrrolidine-2-ylmethoxy)phenyl]propionic acid
bistrifluoroacetate:
[0365] 600 g (1.22 mmol) of ethyl
3-[4-cyano-(2R)-2-((1-(pyridine-4-yl)pip-
eridine-4-carbonyl)pyrrolidine-2-ylmethoxy)phenyl]propionate was
dissolved in a mixture of 5 ml of 4 N solution of hydrogen chloride
in dioxane and 1 ml of ethanol, and they were stirred for 3 days.
The solvent was evaporated, and the obtained crude product was
dissolved in 20 ml of ethanol. 500 mg of ammonium carbonate was
added to the obtained solution, and they were stirred overnight.
The solvent was evaporated, and the obtained crude product was
dissolved in 10 ml of 6 N aqueous hydrochloric acid solution. The
obtained solution was stirred at 50.degree. C. for 2 hours. The
solvent was evaporated, and the obtained crude product was treated
in the same manner as that in step 9 in Example 1 to obtain the
title compound.
[0366] Yield: 190 mg (0.27 mmol) (22%)
[0367] MS (ESI, m/z) 480 (MH+)
[0368] H-NMR (DMSO-d6) .delta. 1.28-1.60 (2H, m), 1.77-2.16 (6H,
m), 2.50 (2H, t), 2.77-3.00 (3H, m), 3.16-3.30 (2H, m), 3.52-3.78
(2H, m), 4.06-4.29 (5H, m), 7.17 (2H, d), 7.34 (2H, d), 7.36 (1H,
d), 8.19 (2H, t), 9.18 (2H, br), 9.21 (2H, br)
EXAMPLE 27
Synthesis of
3-[4-amidino-(2R)-2-((1-(2-naphthalenesulfonyl)pyrrolidine-2--
ylmethoxy)phenyl]propionic Acid Mono-trifluoroacetate:
[0369] 240 mg (0.79 mmol) of ethyl
3-[4-cyano-(2R)-2-(pyrrolidine-2-ylmeth- oxy)phenyl]propionate
hydrochloride was dissolved in 10 ml of DMF. 271 mg (1.2 mmol) of
2-naphthalenesulfonyl chloride and 0.22 ml (1.58 mmol) of
triethylamine were added to the obtained solution, and they were
stirred overnight. The solvent was evaporated, and the obtained
crude product was dissolved in a mixture of 5 ml of 4 N solution of
hydrogen chloride in dioxane and 1 ml of ethanol, and the obtained
solution was stirred for 3 days. the solvent was evaporated, and
the obtained crude product was dissolved in 20 ml of ethanol. 200
mg of ammonium carbonate was added to the obtained solution, and
they were stirred overnight. The solvent was evaporated, and the
obtained crude product was dissolved in 10 ml of 6 N aqueous
hydrochloric acid solution. The obtained solution was stirred at
50.degree. C. for 2 hours. The solvent was evaporated, and the
obtained crude product was treated in the same manner as that in
step 9 in Example 1 to obtain the title compound.
[0370] Yield: 8 mg (0.013 mmol) (2%)
[0371] MS (ESI, m/z) 482 (MH+)
[0372] H-NMR (DMSO-d6) .delta. 1.41-1.77 (2H, m), 1.81-1.94 (2H,
m), 2.50 (2H, t), 2.80 (2H, t), 3.17-3.44 (3H, m), 4.03-4.36 (2H,
m), 7.34 (1H, s), 7.36 (2H, d), 7.69 (2H, dd), 7.88 (1H, d), 8.12
(2H, dd), 8.52 (1H, s), 8.96 (2H, br), 9.26 (2H, br)
EXAMPLE 28 Synthesis of
(3R)-4-(5-amidino-2-hydroxyphenoxy)-3-[4-(1-acetim-
idoyl-4-piperidyloxy)benzoylamino]butanoic Acid
Bistrifluoroacetate
[0373] Step 1: Synthesis of benzyl
(3R)-3-t-butoxycarbonylamino-4-(5-cyano-
-2-benzyloxyphenoxy)butanoate:
[0374] 4.8 g (15.5 mmol) of benzyl
(3R)-3-t-butoxycarbonylamino-4-hydroxyb- utanoate was dissolved in
100 ml of tetrahydrofuran. 2.9 g (12.9 mmol) of
4-benzyloxy-3-hydroxybenzonitrile, 4.1 g (15.5 mmol) of
triphenylphosphine and 6.7 g (15.5 mmol) of diethyl
azodicarboxylate were added to the obtained solution under cooling
with ice, and they were stirred at room temperature overnight.
After the treatment with ethyl acetate as the extraction solvent in
an ordinary manner, the obtained crude product was purified by the
silica gel column chromatography to obtain the title compound.
[0375] Yield: 3.7 g (7.2 mmol) (56%)
[0376] H-NMR (CDCl3) .delta. 1.43 (9H, s), 2.64-2.83 (2H, m),
3.98-4.42 (3H, m), 5.12 (2H, d), 5.14 (2H, s), 6.97 (1H, d), 7.18
(1H, s), 7.28-7.40 (6H, m) Step 2: Synthesis of
(3R)-4-(5-amidino-2-hydroxyphenoxy-
)-3-[4-(1-acetimidoyl-4-piperidyloxy)benzoylamino]butanoic acid
bistrifluoroacetate:
[0377] 2.0 g (3.88 mmol) of benzyl
(3R)-3-t-butoxycarbonylamino-4-(5-cyano-
-2-benzyloxyphenoxy)butanoate was dissolved in 20 ml of 4 N
solution of hydrogen chloride in dioxane, and the obtained solution
was stirred at room temperature for 4 hours. The solvent was
evaporated and the obtained crude product was dissolved in 20 ml of
DMF. 1.36 g (4.26 mmol) of
4-(1-t-butoxycarbonyl-4-piperidyloxy)benzoic acid, 980 mg (5.82
mmol) of 2-chloro-1,3-dimethylimidazonium chloride and 1.6 ml (11.6
mmol) of triethylamine were added to the obtained solution, and
they were stirred for 16 hours. After the treatment with ethyl
acetate as the extraction solvent in an ordinary manner, the
obtained crude product was dissolved in a mixture of 20 ml of 4 N
solution of hydrogen chloride in dioxane and 5 ml of ethanol, and
they were stirred for 3 days. The solvent was evaporated, and the
obtained crude product was dissolved in 10 ml of ethanol. 500 mg of
ammonium carbonate was added to the obtained solution, and they
were stirred overnight. The solvent was evaporated, and the residue
was dissolved in 20 ml of ethanol. 2.0 g of ethyl acetimidate and 2
ml of triethylamine were added to the obtained solution, and they
were stirred at room temperature overnight. The solvent was
evaporated, and the obtained crude product was dissolved in 10 ml
of ethanol. 50 mg of 10% palladium/carbon was added to the obtained
solution, and they were stirred in the presence of hydrogen
overnight. The reaction liquid was filtered through Celite, and the
solvent was evaporated. The obtained crude product was dissolved in
10 ml of 6 N aqueous hydrogen chloride solution, and the obtained
solution was stirred at 60.degree. C. for 2 hours. The solvent was
evaporated, and the obtained crude product was treated in the same
manner as that in step 9 in Example 1 to obtain the title
compound.
[0378] Yield: 7.6 g (0.01 mmol) (0.3%)
[0379] MS (ESI, m/z) 498 (MH+)
[0380] H-NMR (DMSO) .delta. 1.62-1.85 (2H, m), 1.99-2.16 (2H, m),
2.27 (3H, s), 2.62-2.88 (2H, m), 3.40-3.58 (2H, m), 3.63-3.81 (2H,
m), 3.94-4.05 (1H, m), 4.60-4.82 (2H, m), 6.96 (1H, d), 7.06 (2H,
d), 7.17-7.24 (1H, m), 7.28-7.42 (1H, m), 7.79 (2H, d), 8.33 (1H,
d), 8.60 (1H, br), 8.86 (2H, br), 9.01 (2H, br), 9.14 (1H, br)
EXAMPLE 29
Synthesis of
(3R)-4-(5-amidino-2-hydroxyphenoxy)-3-[(1-(pyridine-4-yl)pipe-
ridine-4-carbonyl)amino]butanoic Acid Bistrifluoroacetate
[0381] Step 1: Synthesis of benzyl
(3R)-4-(5-cyano-2-benzyloxyphenoxy)-3-[-
(1-(pyridine-4-yl)piperidine-4-carbonyl)amino]butanoate:
[0382] 2.1 g (4.07 mmol) of benzyl
(3R)-3-t-butoxycarbonylamino-4-(5-cyano-
-2-benzyloxyphenoxy)butanoate was dissolved in 20 ml of 4 N
solution of hydrogen chloride in dioxane, and they were stirred at
room temperature for 4 hours. The solvent was evaporated and the
obtained crude product was dissolved in 20 ml of DMF. 1.08 g (1.03
mmol) of 1-(4-pyridyl)-4-piperidinecarboxylate hydrochloride, 1.03
g (6.11 mmol) of 2-chloro-1,3-dimethylimidazonium chloride and 1.7
ml (61.6 mmol) of triethylamine were added to the obtained
solution, and they were stirred for 16 hours. After the treatment
with ethyl acetate as the extraction solvent in an ordinary manner,
the obtained crude product was purified by the silica gel column
chromatography. 1.0 g (1.66 mmol) (of 2.0 g in total) of the
obtained product was dissolved in a mixture of 20 ml of 4 N
solution of hydrogen chloride in dioxane and 4 ml of ethanol, and
the obtained solution was stirred at room temperature for 3 days.
The solvent was evaporated under reduced pressure, and the obtained
crude product was dissolved in 20 ml of ethanol. 1.0 g of ammonium
carbonate was added to the obtained solution, and they were stirred
at room temperature overnight. The solvent was evaporated, and the
obtained crude product was dissolved in 10 ml of ethanol. 100 mg of
10% palladium/carbon was added to the obtained solution, and they
were stirred in the presence of hydrogen overnight. The reaction
liquid was filtered through Celite, and the solvent was evaporated.
The obtained crude product was dissolved in 28 ml of 6 N aqueous
hydrogen chloride solution, and the obtained solution was stirred
at 60.degree. C. for 2 hours. The solvent was evaporated, and the
obtained crude product was treated in the same manner as that in
step 9 in Example 1 to obtain the title compound.
[0383] Yield: 350 mg (0.52 mmol) (26%)
[0384] MS (ESI, m/z) 442 (MH+)
[0385] H-NMR (DMSO) .delta. 1.42-1.64 (2H, m), 1.76-1.84 (2H, m),
2.44-2.81 (3H, m), 3.17-3.28 (2H, m), 3.82-3.98 (1H, m), 4.02-4.22
(3H, m), 4.37-4.59 (1H, m), 6.98 (1H, d), 7.19 (2H, d), 7.38 (2H,
d), 8.07 (1H, d), 8.22 (2H, d), 8.87 (2H, br), 9.03 (2H, br)
EXAMPLE 30
Synthesis of Ethyl
3-[4-N-hydroxyamidino-2-(2-((1-(pyridine-4-yl)piperidin-
e-4-carbonyl)amino)ethoxy)phenyl]propionate Bistrifluoroacetate
[0386] 225 mg (0.50 mmol) of ethyl
3-[4-cyano-2-(2-((1-(pyridine-4-yl)pipe-
ridine-4-carbonyl)amino)ethoxy)phenyl]propionate was dissolved in
2.5 ml of ethanol. 0.10 ml (0.75 mmol) of triethylamine and 52 mg
(0.52 mmol) of hydroxylamine hydrochloride were added to the
obtained solution, and they were stirred at 80.degree. C. for 5
hours and then at room temperature for 16 hours. The solvent was
evaporated, and the obtained crude product was treated in the same
manner as that in step 9 in Example 1 to obtain the title
compound.
[0387] Yield: 170 mg (0.24 mmol) (50%)
[0388] MS (ESI, m/z) 484(MH+)
[0389] H-NMR (DMSO) .delta. 1.13 (2H, m), 1.44-1.66 (2H, m),
1.72-1.91 (2H, m), 2.48-2.56 (1H, m), 2.57 (2H, t), 2.85 (2H, t),
3.06-3.30 (2H, m), 3.45 (2H, dt), 4.01 (2H, q), 4.05 (2H, t),
4.11-4.25 (2H, m), 7.16 (2H, d), 7.18 (2H, br), 7.32 (1H, d), 8.18
(1H, d), 8.19 (2H, d)
EXAMPLE 31
Synthesis of Ethyl
(2S)-3-[4-amidino-2-[4-ethoxycarbonyl-2-[(1-(1-pyridine-
-4-yl)piperidine-4-carbonyl)amino]butoxy]phenyl]acrylate
Bistrifluoroacetate
[0390] Step 1: Synthesis of benzyl
(4S)-4-t-butoxycarbonylamino-5-hydroxyp- entanoate:
[0391] 15 g (44.5 mmol) of .gamma.-benzyl
N-t-butoxycarbonyl-D-glutamate and 6.2 ml (44.5 mmol) of
triethylamine were dissolved in 200 ml of tetrahydrofuran. 4.26 ml
(44.5 mmol) of ethyl chloroformate was added to the obtained
solution under cooling with ice, and they were stirred for 20
minutes. The precipitates thus formed were removed by the suction
filtration. 5 g of ice and 1.69 g (44.5 mmol) of sodium borohydride
were added to the filtrate under cooling with ice, and they were
stirred for 2 hours. 100 ml of 1 N aqueous hydrochloric acid
solution was added to the reaction mixture, and they were stirred
at room temperature for one hour. After the treatment with ethyl
acetate as the extraction solvent in an ordinary manner, the
obtained crude product was purified by the silica gel column
chromatography to obtain the title compound.
[0392] Yield: 9.2 g (28.5 mmol) (64%)
[0393] H-NMR (CDCl3) .delta. 1.44 (9H,s), 1.70-2.00 (2H,m),
2.28-2.58 (2H,m), 3.50-3.72 (2H,m), 4.80 (1H, br), 5.13 (2H,s),
7.35 (5H,s).
[0394] Step 2: Synthesis of benzyl
(4S)-4-t-butoxycarbonylamino-5-(5-cyano-
-2-iodophenoxy)pentanoate:
[0395] 7.5 g (23.2 mmol) of benzyl
(4S)-4-t-butoxycarbonylamino-5-hydroxyp- entanoate, 8.53 g (34.8
mmol) of iodocyanophenol and 9.13 g (34.8 mmol) of
triphenylphosphine were dissolved in 120 ml of toluene. 5.99 g
(34.8 mmol)) of diamide diazene dicarboxylic acid
bis(N,N-dimethylamide) was added to the obtained solution under
cooling with ice, and they were stirred at room temperature. The
solvent was evaporated. After the treatment with ethyl acetate as
the extraction solvent in an ordinary manner, the obtained crude
product was purified by the silica gel column chromatography to
obtain the title compound.
[0396] Yield: 3.44 g (6.25 mmol) (27%)
[0397] H-NMR (CDCl3) .delta. 1.44 (9H,s), 2.00-2.20 (2H,m), 2.58
(2H,t), 4.05 (2H,br), 4.85 (1H, br), 5.13 (2H,s), 6.90-7.10 (2H,m),
7.36 (5H,s), 7.87 (1H,d).
[0398] Step 3: Synthesis of ethyl
3-[(2S)-2-(2-t-butoxycarbonylamino-4-ben-
zoxycarbonyl-butoxy)-4-cyanophenyl]acrylate:
[0399] 1.64 g (2.98 mmol) of benzyl
(4S)-4-t-butoxycarbonylamino-5-(5-cyan- o-2-iodophenoxy)pentanoate
was dissolved in 30 ml of N,N-dimethylformamide (dehydrated). 0.65
ml (5.96 mmol) of ethyl acrylate, 2.1 ml (14.9 mmol) of
triethylamine and 14 mg (0.06 mmol) of palladium acetate were added
to the obtained solution, and they were stirred at 100.degree. C.
overnight. After the treatment with ethyl acetate as the extraction
solvent in an ordinary manner, the obtained crude product was
purified by the silica gel column chromatography to obtain the
title compound.
[0400] Yield: 1.42 g (2.71 mmol) (91%)
[0401] H-NMR (CDCl3) .delta. 1.31(3H,t), 1.43 (9H,s), 2.04 (2H,br),
2.54 (2H,t), 4.07 (2H, br), 4.26 (2H,q), 5.13 (2H,s), 6.50 (1H,d),
7.18 (1H,s), 7.27(1H,br), 7.35(5H,s), 7.57(1H,d), 7.97(1H,d).
[0402] Step 4: Synthesis of ethyl
(2S)-3-[4-amidino-2-[4-ethoxycarbonyl-2--
[(1-(1-pyridine-4-yl)piperidine-4-carbonyl)amino]butoxy]phenyl]acrylate
bistrifluoroacetate:
[0403] 1.42 g (2.71 mmol) of ethyl
3-[(2S)-2-(2-t-butoxycarbonylamino-4-be-
nzoxycarbonyl-butoxy)-4-cyanophenyl]acrylate was dissolved in a
mixture of 15 ml of dioxane and 15 ml of 4 N solution of hydrogen
chloride in dioxane, and the obtained solution was stirred at room
temperature for 3 hours. The solvent was evaporated under reduced
pressure, and the obtained crude product was dissolved in 10 ml of
N,N-dimethylformamide. 0.72 g (2.98 mmol) of
1-(4-pyridyl)piperidine-4-carboxylic acid hydrochloride and 0.55 g
(3.25 mmol) of 2-chloro-1,3-dimethylimidazoliniu- m chloride were
added to the obtained solution and then 2.3 ml (16.3 mmol) of
triethylamine was added to the obtained mixture under cooling with
ice, and they were stirred at room temperature overnight. The
solvent was evaporated, and the residue was dissolved in a mixture
of 35 ml of 4 N solution of hydrogen chloride in dioxane and 3.5 ml
of ethanol, and they were stirred at room temperature for 3 days.
The solvent was evaporated, and the residue was dissolved in 50 ml
of ethanol. 1.6 g (28.7 mmol) of ammonium carbonate was added to
the obtained solution, and they were stirred at room temperature
overnight. The solvent was evaporated, and the obtained crude
product was treated in the same manner as that in step 9 in Example
1 to obtain the title compound.
[0404] Yield: 387.6 mg (0.488 mmol) (36%)
[0405] MS (ESI, m/z) 566 (MH+)
[0406] H-NMR (DMSO-d6) .delta. 1.17 (3H,t), 1.23 (3H,t), 1.50-2.00
(4H,m), 2.30-2.65 (4H,m), 3.22 (2H,br), 4.00-4.30 (8H, m), 6.78
(1H,d), 7.18 (2H,d), 7.44 (1H, d), 7,52 (1H, s), 7.86 (1H, d), 7.98
(1H, d), 8.22 (2H, d), 9.13 (1H,br), 9.32 (1H,br), 9.35(1H,br).
EXAMPLE 32
Synthesis of
(2S)-3-[4-amidino-2-[4-carbonyl-2-[(1-(1-pyridine-4-yl)piperi-
dine-4-carbonyl) amino]butoxy]phenyl]acrylic Acid
Bistrifluoroacetate
[0407] 2.5 g of crude ethyl
(2S)-3-[4-amidino-2-[4-ethoxycarbonyl-2-[(1-(1-
-pyridine-4-yl)piperidine-4-carbonyl)amino]butoxy]phenyl]acrylate
bistrifluoroacetate was dissolved in 25 ml of 6 N aqueous
hydrochloric acid solution, and the obtained solution was stirred
at 80.degree. C. for 3 hours. The solvent was evaporated, and the
obtained crude product was treated in the same manner as that in
step 9 in Example 1 to obtain the title compound.
[0408] Yield: 131.54 mg (0.18 mmol) (14%)
[0409] MS (ESI, m/z) 510(MH+)
[0410] H-NMR (DMSO-d6) .delta. 1.52-1.96 (4H,m), 2.30 (2H,br),
2.60(2H,br), 3.22(2H,br), 4.00-4.28(4H,m), 6.68(1H,d), 7.18(2H,d),
7.44(1H,d), 7.52(1H,s), 7.81(1H,d), 7.94(1 H,d), 8.02(1H,d),
8.22(2H,d), 9.22(1H,br), 9.28(1H,br), 9.34(1H,br).
EXAMPLE 33
Synthesis of
(4S)-5-[5-amidino-2-[4-carboxy-ethyl]phenoxy]-4-[(1-(1-pyridi-
ne-4-yl)piperidine-4-carbonyl)amino]pentanoic Acid
Bistrifluoroacetate
[0411] 365 mg (0.46 mmol) of
(2S)-3-[4-amidino-2-[4-carbonyl-2-[(1-(1-pyri-
dine-4-yl)piperidine-4-carbonyl) amino]butoxy]phenyl]acrylate
bistrifluoroacetate was dissolved in a mixture of 10 ml of ethanol
and 0.1 ml of N,N-dimethylformamide. 15 mg of 10% palladium/carbon
(50% hydrous) was added to the obtained solution, and they were
stirred in the presence of hydrogen overnight. The solvent was
evaporated, and the obtained product was filtered through Celite
and then treated in the same manner as that in step 9 in Example 1
to obtain the title compound.
[0412] Yield: 34.2 mg (0.046 mmol) (10%)
[0413] MS (ESI, m/z) 512 (MH+)
[0414] H-NMR (DMSO-d6) .delta. 1.50-2.00(4H,m), 2.30(2H,br),
2.50-2.70(2H,m), 2.85(2H,br), 3.20(2H,br), 3.95-4.30(6H, m),
7.20(2H,d), 7.38(3H,m), 8.00(1H,d), 8.30(2H,d), 9.14(2H,m),
9.23(1H,br).
EXAMPLE 34
Synthesis of Methyl
4-amidino-2-[2-[(1-(1-pyridine-4-yl)piperidie-4-carbon-
yl)amino]ethoxy]benzoate Bistrifluoroacetate
[0415] Step 1: Synthesis of methyl
2-(2-(t-butoxycarbonylamino)ethoxy)-4-c- yanobenzoate:
[0416] 5 g (12.88 mmol) of
3-(2-(t-butoxycarbonylamino)ethoxy)-4-iodobenzo- nitrile was
dissolved in 60 ml of N,N-dimethylformamide (dehydrated). 3.6 ml
(25.8 mmol) of triethylamine, 10 ml (25.8 mmol) of methanol and 145
mg (0.644 mmol) of palladium acetate were added to the obtained
solution, and they were stirred in the presence of carbon monoxide
at 90.degree. C. for 6 hours. The solvent was evaporated. After the
treatment with ethyl acetate as the extraction solvent in an
ordinary manner, the obtained crude product was purified by the
silica gel column chromatography to obtain the title compound.
[0417] Yield: 4.11 g (12.82 mmol) (99.5%)
[0418] H-NMR (CDCl3) .delta. 1.44(9H,s), 3.61(2H,q), 3.94(3H,s),
4.12(2H,m), 5.38(1H,br), 7.21(1H, s), 7.38(1H,m), 7.87(1H,d).
[0419] Step 2: Synthesis of methyl
4-amidino-2-[2-[(1-(1-pyridine-4-yl)pip- eridine-4-carbonyl) amino]
ethoxy]benzoate bistrifluoroacetate:
[0420] 1.5 g (4.68 mmol) of methyl
2-(2-(t-butoxycarbonylamino)ethoxy-4-cy- anobenzoate was dissolved
in a mixture of 15 ml of dioxane and 15 ml of 4 N solution of
hydrogen chloride in dioxane, and the obtained solution was stirred
at room temperature for 3 hours. The obtained crude product was
dissolved in 6 ml of N,N-dimethylformamide (dehydrated). 0.32 g
(1.29 mmol) of 1-(4-pyridyl)piperidine-4-carboxylic acid
hydrochloride and 0.24 g (1.40 mmol) of
2-chloro-1,3-dimethylimidazolinium chloride were added to the
obtained solution and then 1 ml (7.02 mmol) of triethylamine was
added to the obtained mixture under cooling with ice, and they were
stirred at room temperature overnight. After the treatment with
chloroform as the extraction solvent in an ordinary manner, the
obtained crude product was dissolved in a mixture of 2 ml of 4 N
solution of hydrogen chloride in dioxane and 0.2 ml of ethanol, and
they were stirred at room temperature for 3 days. The solvent was
evaporated, and the residue was dissolved in 50 ml of ethanol. 0.14
g (2.45 mmol) of ammonium carbonate was added to the obtained
solution, and they were stirred at room temperature overnight. The
solvent was evaporated, and the obtained crude product was treated
in the same manner as that in step 9 in Example 1 to obtain the
title compound.
[0421] Yield: 92 mg (0.14 mmol) (12%)
[0422] MS (ESI, m/z) 426(MH+)
[0423] H-NMR (DMSO-d6) .delta. 1.50-1.90(4H,m), 2.60(2H,m),
3.23(2H,m), 3.45(2H,q), 3.85(3H,s), 4.18(3H,m), 7.20(2H,d),
7.44(1H,d), 7.53(1H,s), 7.80(1H,d), 8.09(1H,t), 8.22(2H,d),
9.40(2H,m), 9.43(1H,br).
EXAMPLE 35
Synthesis of Ethyl
4-amidino-2-[2-[(1-(1-pyridine-4-yl)piperidine-4-carbon-
yl)amino]ethoxy]benzoate Bistrifluoroacetate
[0424] The title compound was obtained as a by-product in step 2 in
Example 34.
[0425] Yield: 26 mg (0.039 mmol) (3%)
[0426] MS (ESI, m/z) 440(MH+)
[0427] H-NMR (DMSO-d6) .delta. 1.30(3H,t), 1.50-1.90(4H,m),
2.53-2.65(2H,m), 3.23(2H,t), 3.48(2H,q), 4.10-4.35(4H,m),
7.20(2H,d), 7.45(1H,d), 7.53(1H,s), 7.79(1H,d), 8.10(1H,t),
8.23(2H,d), 9.40(2H,br), 9.43(1H,br).
EXAMPLE 36
Synthesis of
4-amidino-2-[2-[(1-(1-pyridine-4-yl)piperidine-4-carbonyl)
amino]ethoxy]benzoic Acid Bistrifluoroacetate
[0428] 50 mg (0.077 mmol) of methyl
4-amidino-2-[2-[(1-(1-pyridine-4-yl)pi- peridine-4-carbonyl) amino]
ethoxy]benzoate bistrifluoroacetate obtained in Step 2 in Example
34 was dissolved in 1 ml of 6 N aqueous hydrochloric acid solution,
and the obtained solution was stirred at 90.degree. C. for 3 hours.
The solvent was evaporated, and the obtained crude product was
treated in the same manner as that in step 9 in Example 1 to obtain
the title compound.
[0429] Yield: 45.3 mg (0.071 mmol) (92%)
[0430] MS (ESI, m/z) 4 1 2 (MH+)
[0431] H-NMR (DMSO-d6) .delta. 1.50-1.67 (2H,m), 1.79-2.02 (2H,m),
2.53-2.74 (2H,m), 3.16-3.37 (2H,m), 3.47 (2H,q), 4.06-4,26 (3H,m),
7.20 (2H,d), 7.44 (1H,d), 7.53 (1H,br), 7.77 (1H,d), 8.09 (1H,t),
8.22 (2H,d), 9.42 (1H,br), 9.53 (2H,br).
EXAMPLE 37
Synthesis of
N-[2-(5-amidino-2-hydroxymethylphenoxy)ethyl]-1-(1-(1-pyridin-
e-4-yl)piperidine)carboxamide Bistrifluoroacetate
[0432] Step 1: Synthesis of
3-(2-(t-butoxycarbonylamino)ethoxy)-4-hydroxym-
ethylbenzonitrile:
[0433] 4.15 g (12.95 mmol) of methyl
2-(2-(t-butoxycarbonylamino)ethoxy)-4- -cyanobenzoate obtained in
the same manner as that in step 1 in Example 34 was dissolved in 60
ml of tetrahydrofuran (dehydrated). 3.2 ml (129.5 mmol) of 2 M
Lithium borohydride was added to the obtained solution under
cooling with ice, and they were stirred at room temperature
overnight.
[0434] The solvent was evaporated. After the treatment with ethyl
acetate as the extraction solvent in an ordinary manner, the
obtained crude product was purified by the silica gel column
chromatography to obtain the title compound.
[0435] Yield: 2.38 g (8.12 mmol) (63%)
[0436] H-NMR (CDCl3) .delta. 1.41 (9H,s), 3.00 (1H,br), 3.60
(2H,br), 4.10 (2H,t), 4.70 (2H,d), 4.95 (1H,br), 7.07 (1H,s), 7.30
(1H,d), 7.41 (1H,d).
[0437] Step 2: Synthesis of
N-[2-(5-amidino-2-hydroxymethylphenoxy)ethyl]--
1-(1-(1-pyridine-4-yl)piperidine)carboxamide
bistrifluoroacetate:
[0438] 2.38 g (8.12 mmol) of
3-(2-(t-butoxycarbonylamino)ethoxy)-4-hydroxy- methylbenzonitrile
was dissolved in a mixture of 20 ml of dioxane and 20 ml of 4 N
solution of hydrogen chloride in dioxane, and the obtained solution
was stirred at room temperature for 3 hours. The obtained crude
product was dissolved in 10 ml of N,N-dimethylformamide
(dehydrated). 1.25 g (5.1 mmol) of
1-(4-pyridyl)piperidine-4-carboxylic acid hydrochloride, 0.95 g
(5.6 mmol) of 2-chloro-1,3-dimethylimidazolinium chloride and 4 ml
(27.8 mmol) of triethylamine were added to the obtained solution,
and then and they were stirred at room temperature overnight. After
the treatment with dichloromethane as the extraction solvent in an
ordinary manner, the obtained crude product was dissolved in a
mixture of 20 ml of 4 N solution of hydrogen chloride in dioxane
and 2 ml of ethanol, and they were stirred at room temperature for
3 days. The solvent was evaporated, and the residue was dissolved
in 50 ml of ethanol. 1.3 g (23.15 mmol) of ammonium carbonate was
added to the obtained solution, and they were stirred at room
temperature overnight. The solvent was evaporated, and the obtained
crude product was treated in the same manner as that in step 9 in
Example 1 to obtain the title compound.
[0439] Yield: 275 mg (0.44 mmol) (11%)
[0440] MS (ESI, m/z) 398(MH+)
[0441] H-NMR (DMSO-d6) .delta. 1.50 (2H,br), 1.80 (2H,br), 2.60
(2H,br), 3.20 (2H,br), 3.47 (2H,m), 4.18-4.24 (3H,m), 4.58 (2H,s),
7.19 (2H,d), 7.35 (1H,s), 7.45(1H,d), 7.60(1H,d), 8.21(2H,d),
9.25(3H,m).
EXAMPLE 38
Synthesis of Methyl
4-amidino-2-[2-(4-[1-(1-acetimidoyl)-4-piperidyloxy]be-
nzoylamino)ethoxy]benzoate Bistrifluoroacetate
[0442] Step 1: Synthesis of Methyl
4-amidino-2-[2-(4-[1-(1-acetimidoyl)-4--
piperidyloxy]benzoylamino)ethoxy]benzoate Bistrifluoroacetate:
[0443] 0.586 g (2.35 mmol) of methyl
3-(2-aminoethoxy)-4-cyanobenzoate hydrochloride was dissolved in 10
ml of N,N-dimethylformamide (dehydrated). 0.82 g (2.56 mmol) of
4-(1-t-butoxycarbonyl-4-piperidyloxy)- benzoic acid and 0.48 g
(2.82 mmol) of 2-chloro-1,3-dimethylimidazolinium chloride were
added to the obtained solution, and then 2 ml (14.1 mmol) of
triethylamine was added to the obtained mixture under cooling with
ice. They were stirred at room temperature overnight. The solvent
was evaporated, and the obtained crude product was dissolved in a
mixture of 10 ml of dioxane and 10 ml of 4 N solution of hydrogen
chloride in dioxane, and the obtained solution was stirred at room
temperature for 4 hours. The solvent was evaporated, and the
residue was dissolved in 12 ml of ethanol. 0.87 g (7.05 mmol) of
ethyl acetimidate hydrochloride and 1.64 ml (11.75 mmol) of
triethylamine were added to the obtained solution, and they were
stirred at room temperature overnight. The solvent was evaporated,
and the residue was dissolved in a mixture of 20 ml of 4 N solution
of hydrogen chloride in dioxane and 3 ml of ethanol, and the
obtained solution was stirred at room temperature for 3 days. The
solvent was evaporated, and the obtained crude product was
dissolved in 10 ml of ethanol. 0.67 g (11.75 mmol) of ammonium
carbonate was added to the obtained solution, and they were stirred
at room temperature overnight. The solvent was evaporated, and the
obtained crude product was treated in the same manner as that in
step 9 in Example 1 to obtain the title compound.
[0444] Yield: 484.5 mg (0.68 mmol) (29%)
[0445] MS (ESI, m/z) 480(MH-)
[0446] H-NMR (DMSO-d6) .delta. 1.77(2H,br), 2.08(2H,br),
2.50(3H,s), 3.48-3.70(6H,m), 3.79(3H,s), 4.28(2H,br), 4.80(1H,br),
7.07(2H,d), 7.44(1H,d), 7.58(1H,s), 7.75-7.89(3H,m), 8.52(1H,br),
8.62(1H,br), 9.17(1H,br), 9.37 (1H,br), 9.42 (1H,br).
EXAMPLE 39
Synthesis of Ethyl
4-amidino-2-[2-(4-[1-(1-acetimidoyl)-4-piperidyloxy]ben-
zoylamino)ethoxy]benzoate Bistrifluoroacetate
[0447] The title compound was obtained as a by-product in step 2 in
Example 38.
[0448] Yield: 165.6 mg (0.23 mmol) (10%)
[0449] MS (ESI, m/z) 494(MH-)
[0450] H-NMR (DMSO-d6) .delta. 1.25 (3H,t), 1.77(2H,br),
2.08(2H,br), 2.29(3H,s), 3.48-3.85(6H,m), 4.20-4.35 (4H,m), 4.80
(1H,br), 7.07(2H,d), 7.44(1H,d), 7.58(1H,br), 7.77(1H,br), 7.84
(2H,d), 8.52(1H,br), 8.63(1H,br), 9.17(1H,br), 9.37 (1H,br), 9.42
(1H,br).
EXAMPLE 40
Synthesis of
4-amidino-2-[2-(4-[1-(1-acetimidoyl)-4-=piperidyloxy]benzoyla-
mino)ethoxy]benzoic Acid Bistrifluoroacetate
[0451] 0.3 g (0.423 mmol) of ethyl
4-amidino-2-[2-(4-[1-(1-acetimidoyl)-4--
piperidyloxy]benzoylamino)ethoxy]benzoate bistrifluoroacetate
obtained in Example 39 was dissolved in 10 ml of concentrated
hydrochloric acid solution, and the obtained solution was stirred
at 80.degree. C. for 3 hours. The solvent was evaporated, and the
obtained crude product was treated in the same manner as that in
step 9 in Example 1 to obtain the title compound.
[0452] Yield: 231.6 mg (0.333 mmol) (79%)
[0453] MS (ESI, m/z) 468 (MH+)
[0454] H-NMR (DMSO-d6) .delta. 1.77(2H,br), 2.08(2H,br),
2.29(3H,s), 3.48-3.85(6H,m), 4.28(2H,t), 4.80(1H,br), 7.07(2H,d),
7.42(1H,d), 7.58(1H,br), 7.78(1H,d), 7.84(2H,d), 8.50(1H,t),
8.63(1H,br), 9.17 (1H,br), 9.38(2H,br).
EXAMPLE 41
Synthesis of
2-[4-amidino-2-[2-[(1-(1-pyridine-4-yl)piperidine-4-carbonyl)-
amino]ethoxy]phenyl]vinylsulfonic Acid Bistrifluoroacetate
[0455] Step 1: Synthesis of
3-(2-(t-butoxycarbonylamino)ethoxy)-4-formylbe- nzonitrile:
[0456] 0.3 g (1.03 mmol) of
3-(2-(t-butoxycarbonylamino)ethoxy)-4-hydroxym- ethylbenzonitrile
obtained in the same manner as that in step 1 in Example 37 was
dissolved in 3 ml of dichloromethane (dehydrated). 0.36 g (4.1
mmol) of activated manganese dioxide was added to the obtained
solution in the presence of argon at room temperature, and they
were stirred overnight. The reaction liquid was filtered through
Celite to obtain the title compound.
[0457] Yield: 279 mg (0.962 mmol) (93%)
[0458] MS (ESI, m/z) 291 (MH-)
[0459] H-NMR (CDCl3) .delta. 1.53 (9H,s), 3.62 (2H,q), 4.20 (2H,t),
4.95 (1H, br), 7.35(2H,m), 7.93 (1H,d), 10.50 (1H,s).
[0460] Step 2: Synthesis of ethyl
3-[2-(2-(t-butoxycarbonylamino)ethoxy)-4-
-cyanophenyl]ethylenesulfonate:
[0461] 280 mg (1.15 mmol) of diethylphosphorylmethane sulfonate was
dissolved in 5 ml of triethylamine (dehydrated). 0.75 ml (1.15
mmol) of 1.54 M solution of n-butyllithium in hexane was added to
the obtained solution in the presence of argon at -78.degree. C.,
and they were stirred for 20 minutes. 279 mg (0.962 mmol) of
3-(2-(t-butoxycarbonylamin- o)ethoxy)-4-formylbenzonitrile was
added to the obtained mixture, and they were stirred at -78.degree.
C. for 45 minutes and then at room temperature for 3 hours. The
solvent was evaporated. After the treatment with dichloromethane as
the extraction solvent in an ordinary manner, the obtained crude
product was purified by the silica gel column chromatography to
obtain the title compound.
[0462] Yield: 197 mg (0.498 mmol) (52%)
[0463] MS (ESI, m/z) 367 (MH-)
[0464] H-NMR (CDCl3) .delta. 1.35-1.50 (12H,m), 3.58 (2H,br),
4.10-4.30 (4H,m), 5.00 (1H,br), 7.00 (1H,d), 7.20 (1H,s), 7.28
(1H,d), 7.63 (1H,d), 7.63 (1H,d), 7.78(1H,d).
[0465] Step 3: Synthesis of
2-[4-amidino-2-[2-[(1-(1-pyridine-4-yl)piperid-
ine-4-carbonyl)amino]ethoxy]phenyl]vinylsulfonic acid
bistrifluoroacetate:
[0466] 197 mg (0.498 mmol) of ethyl
3-[2-(2-(t-butoxycarbonylamino)ethoxy)-
-4-cyanophenyl)ethylenesulfonate was dissolved in a mixture of 2 ml
of dioxane and 2 ml of 4 N solution of hydrogen chloride in
dioxane, and the obtained solution was stirred at room temperature
for 3 hours. The solvent was evaporated, and the obtained crude
product was dissolved in 3 ml of N,N-dimethylformamide
(dehydrated). 134 mg (0.548 mmol) of
1-(4-pyridyl)-piperidine-4-carboxylic acid hydrochloride, 101 mg
(0.598 mmol) of 2-chloro-1,3-dimethylimidazolium chloride and 0.4
ml (3 mmol) of triethylamine were added to the obtained solution,
and they were stirred at room temperature for 3 hours. The solvent
was evaporated, and the residue was dissolved in a mixture of 2 ml
of ethanol and 20 ml of 4 N solution of hydrogen chloride in
dioxane, and the obtained solution was stirred at room temperature
for 3 days. The solvent was evaporated, and the residue was
dissolved in 20 ml of ethanol. 0.41 g (2.5 mmol) of ammonium
carbonate was added to the obtained solution, and they were stirred
at room temperature overnight. The solvent was evaporated, and the
obtained crude product was treated in the same manner as that in
step 9 in Example 1 to obtain the title compound.
[0467] Yield: 120.8 mg (0.172 mmol) (35%)
[0468] MS (ESI, m/z) 476(MH+)
[0469] H-NMR (DMSO-d6) .delta. 1.48-1.70 (2H,m), 1.80-2.00 (2H,m),
2.55-3.05 (3H,m), 3.22 (2H,t), 3.50 (2H,br), 4.22 (2H,br),
7.03-7.08 (1H,d), 7.18-7.50 (5H,m), 7.80 (1H,d), 8.19 (2H,d),9.05
(2H,s), 9.30 (2H,s).
EXAMPLE 42
Synthesis of
2-[4-amidino-2-[2-[(1-(1-pyridine-4-yl)piperidine-4-carbonyl)-
amino]ethoxy]phenyl]ethanesulfonic Acid Bistrifluoroacetate
[0470] 72.2 mg (0.103 mmol) of
2-(4-amidino-2-[2-[(1-(1-pyridine-4-yl)pipe- ridine-4-carbonyl)
amino] ethoxy]phenyl)vinylsulfonic acid bistrifluoroacetate
obtained in step 3 in Example 41 was dissolved in 20 ml of ethanol.
30 mg of 10% palladium/carbon (50% hydrous) was added to the
obtained solution in the presence of argon, and they were stirred
at room temperature in the presence of hydrogen overnight. After
the filtration through Celite, the obtained crude product was
treated in the same manner as that in step 9 in Example 1 to obtain
the title compound.
[0471] Yield: 10.5 mg (0.015 mmol) (15%)
[0472] MS (ESI, m/z) 474 (MH+)
[0473] H-NMR (DMSO-d6) .delta. 1.48-1.65(2H,m), 1.80-1.95 (2H,m),
2.60-3.05(5H,m), 3.20 (2H,br), 3.53 (2H,br), 4.08 (2H,br), 4.20
(2H,d), 7.14-7.25 (3H,m), 7.34 (1H,s), 7.41 (1H,d), 8.20 (2H,d),
8.48 (1H,br), 8.98 (2H,br), 9.22 (2H,br).
EXAMPLE 43
Synthesis of
N-[2-(5-amidino-2-hydroxypropylphenoxy)ethyl]-1-(1-(1-pyridin-
e-4-yl)piperidine)carboxamide Bistrifluoroacetate
[0474] Step 1: Synthesis of
3-(2-(t-butoxycarbonylamino)ethoxy)-4-(3-hydro-
xypropyl)benzonitrile:
[0475] 1.1 g (3.04 mmol) of ethyl
3-[2-(2-(t-butoxycarbonylamino)ethoxy)-4- -cyanophenyl]propionate
was dissolved in 15 ml of tetrahydrofuran (dehydrated). 1.5 ml (2.3
mmol) of 2 M Lithium borohydride was added to the obtained solution
under cooling with ice, and they were stirred at room temperature
overnight. The solvent was evaporated. After the treatment with
ethyl acetate as the extraction solvent in an ordinary manner, the
obtained crude product was purified by the silica gel column
chromatography to obtain the title compound.
[0476] Yield: 524 mg (1.64 mmol) (54%)
[0477] H-NMR (CDCl3) .delta. 1.45 (9H,s), 1.80 (2H,br), 2.80
(2H,t), 3.54-3.69 (4H,m), 4.02 (2H,t), 5.30 (1H,br), 7.03 (1H,s),
7.23-7.26 (2H,m).
[0478] Step 2: Synthesis of
N-[2-(5-amidino-2-hydroxypropylphenoxy)ethyl]--
1-(1-(1-pyridine-4-yl)piperidine)carboxamide
bistrifluoroacetate:
[0479] 524 mg (1.64 mmol) of
3-(2-(t-butoxycarbonylamino)ethoxy)-4-(3-hydr-
oxypropyl)benzonitrile was dissolved in a mixture of 4 ml of
dioxane and 4 ml of 4 N solution of hydrogen chloride in dioxane,
and the obtained solution was stirred at room temperature for 2
hours. The solvent was evaporated and the obtained crude product
was dissolved in 5 ml of N,N-dimethylformamide (dehydrated). 440 mg
(1.80 mmol) of 1-(4-pyridyl)piperidine-4-carboxylic acid
hydrochloride, 330 mg (1.97 mmol) of
2-chloro-1,3-dimethylimidazolinium chloride and 1.4 ml (9.84 mmol)
of triethylamine were added to the obtained solution, and they were
stirred at room temperature overnight. The solvent was evaporated,
and the obtained crude product was treated with dichloromethane as
the extraction solvent in an ordinary manner, and the obtained
crude product was dissolved in a mixture of 10 ml of 4 N solution
of hydrogen chloride in dioxane and 1 ml of ethanol, and they were
stirred at room temperature for 3 days. The solvent was evaporated,
and the residue was dissolved in 10 ml of ethanol. 0.46 g (8.2
mmol) of ammonium carbonate was added to the obtained solution, and
they were stirred at room temperature overnight. The solvent was
evaporated, and the obtained crude product was treated in the same
manner as that in step 9 in Example 1 to obtain the title
compound.
[0480] Yield: 178.5 mg (0.273 mmol) (17%)
[0481] MS (ESI, m/z) 426 (MH+)
[0482] H-NMR (DMSO-d6) .delta. 1.49-1.95 (6H,m), 2.55-2.75 (4H,m),
3.25 (2H,t), 3.50 (4H,br), 4.09 (2H,t), 4.20 (1H,br), 7.18 (1H,s),
7.35 (1H,d), 8.22(1H,d),9.19 (2H,br), 9.23 (2H,br).
EXAMPLE 44
Synthesis of Diethyl
2-(4-amidino-2-[2-[(1-(1-pyridine-4-yl)piperidine-4-c-
arbonyl)amino]ethoxy]phenyl)vinylphosphate Bistrifluoroacetate
[0483] Step 1: Synthesis of diethyl
2-[(2-(2-t-butoxycarbonylamino)ethoxy)-
-4-cyanophenyl]vinylphosphate:
[0484] 0.54 ml (2.18 mmol) of tetraethylmethylene diphosphonate was
dissolved in 10 ml of tetrahydrofuran (dehydrated). 1.5 ml (2.31
mmol) of 1.54 M solution of n-butyllithium in hexane was added to
the obtained solution in the presence of argon at -78.degree. C.,
and they were stirred for 20 minutes. 527 mg (1.82 mmol) of
3-(2-(t-butoxycarbonylamino- )ethoxy)-4-formylbenzonitrile obtained
in the same manner as that in step 1 in Example 41 was added to the
obtained mixture, and they were stirred at -78.degree. C. for 45
minutes and then at room temperature for 3 hours. The solvent was
evaporated. After the treatment with dichloromethane as the
extraction solvent in an ordinary manner, the obtained crude
product was purified by the silica gel column chromatography to
obtain the title compound.
[0485] Yield: 0.45 g (1.06 mmol) (58%)
[0486] H-NMR (CDCl3) .delta. 1.17-1.42 (6H,m), 1.47 (9H,s), 3.60
(2H,br), 3.96-4.23 (6H,m), 5.00 (1H,br), 6.40 (2H,m), 7.15 (1H,s),
7.27 (1H,d), 7.58 (1H,d).
[0487] Step 2: Synthesis of diethyl
[2-(4-amidino-2-[2-[(1-(1-pyridine-4-y-
l)piperidine-4-carbonyl)amino]ethoxy]phenyl)vinylphosphate
bistrifluoroacetate
[0488] 0.45 g (1.06 mmol) of diethyl
[2-[(2-(2-t-butoxycarbonylamino)ethox-
y)-4-cyanophenyljvinyl]phosphate was dissolved in a mixture of 5 ml
of dioxane and 5 ml of 4 N solution of hydrogen chloride in
dioxane, and the obtained solution was stirred at room temperature
for 3 hours. The solvent was evaporated, and the obtained crude
product was dissolved in 10 ml of N,N-dimethylformamide
(dehydrated). 0.29 g (1.2 mmol) of
1-(4-pyridyl)-4-piperidinecarboxylic acid hydrochloride, 0.5 g (2.8
mmol) of 2-chloro-1,3-dimethylimidazonium chloride and 1.8 ml (12.8
mmol) of triethylamine were added to the obtained solution, and
they were stirred overnight. After the treatment with
dichloromethane as the extraction solvent in an ordinary manner,
the obtained crude product was dissolved in a mixture of 5 ml of 4
N hydrogen chloride in dioxane and 0.5 ml of ethanol, and the
obtained solution was stirred at room temperature for 3 days. The
solvent was evaporated, and the residue was dissolved in 5 ml of
ethanol. 0.19 g (3.35 mmol) of ammonium carbonate was added to the
obtained solution, and they were stirred at room temperature
overnight. The solvent was evaporated, and the obtained crude
product was treated in the same manner as that in step 9 in Example
1 to obtain the title compound.
[0489] Yield: 155 mg (0.204 mmol) (31%)
[0490] MS (ESI, m/z) 530 (MH+)
[0491] H-NMR (DMSO-d6) .delta. 1.26 (6H,t), 1.50-1.92 (4H,m), 2.58
(2H,br), 3.22 (2H,t), 3.50 (2H,br), 4.03 (4H,m), 4.20 (3H,br), 6.77
(2H,m), 7.19 (2H,d), 7.40-7.74 (3H,m),7.96 (1H,d), 8.21
(2H,d),9.33(2H,br), 9.36(2H,br).
EXAMPLE 45
Synthesis of Monoethyl
[2-(4-amidino-2-[2-[(1-(1-pyridine-4-yl)piperidine--
4-carbonyl)amino]ethoxy]phenyl)vinyl]phosphate
Bistrifluoroacetate
[0492] This compound was a by-product obtained in step 2 in Example
44.
[0493] Yield: 63.4 mg (0.087 mmol) (13%)
[0494] MS (ESI, m/z) 502 (MH+)
[0495] H-NMR (DMSO-d6) .delta. 1.23 (3H,t), 1.50-1.95 (4H,m), 2.58
(2H,br), 3.22 (2H,t), 3.50 (2H,br), 3.95 (2H,m), 4.22 (3H,br), 6.71
(2H,m), 7.18 (2H,d), 7.38-7.66 (3H,m),7.92 (1H,d), 8.20
(2H,d),9.21(2H,br), 9.34(2H,br).
EXAMPLE 46
Synthesis of Monoethyl
[2-(4-amidino-2-[2-[(1-(1-pyridine-4-yl)piperidine--
4-carbonyl)amino]ethoxy]phenyl)ethyl]phosphate
Bistrifluoroacetate
[0496] 63.4 mg (0.087 mmol) of monoethyl
[2-(4-amidino-2-[2-[(1-(1-pyridin-
e-4-yl)piperidine-4-carbonyl)amino]ethoxy]phenyl)vinyl]phosphate
bistrifluoroacetate was dissolved in 2 ml of ethanol. 10 mg of 10%
palladium/carbon (50% hydrous) was added to the obtained solution
in the presence of argon, and they were stirred in the presence of
hydrogen at room temperature overnight. 2 ml of water was added to
the reaction mixture. The solvent was evaporated, and the obtained
crude product was treated in the same manner as that in step 9 in
Example 1 to obtain the title compound.
[0497] Yield: 43.1 mg (0.059 mmol) (68%)
[0498] MS (ESI, m/z) 504 (MH+)
[0499] H-NMR (DMSO-d6) .delta. 1.20 (3H,t), 1.58 (2H,br), 1.80-1.96
(4H,m), 2.62 (2H,br), 2.80 (2H,br), 3.21 (2H,t), 3.49 (2H,q),
3.88-3.98 (2H,m), 4.12 (2H,t), 4.20 (1H,br), 7.18 (2H,d), 7.37-7.42
(3H,m), 8.21 (2H,d), 8.28 (1H,br),9.18(2H,br), 9.25(2H,br).
EXAMPLE 47
Synthesis of Diethyl
[2-(4-amidino-2-[2-[(1-(1-pyridine-4-yl)piperidine-4--
carbonyl)amino] ethoxy]phenyl)ethyl]phosphate
Bistrifluoroacetate
[0500] 155 mg (0.204 mmol) of diethyl
[2-(4-amidino-2-[2-[(1-(1-pyridine-4-
-yl)piperidine-4-carbonyl)amino]ethoxy]phenyl)vinyl]phosphate
bistrifluoroacetate was dissolved in 2 ml of ethanol. 20 mg of 10%
palladium/carbon (50% hydrous) was added to the obtained solution
in the presence of argon, and they were stirred in the presence of
hydrogen at room temperature overnight. 2 ml of water was added to
the reaction mixture. The solvent was evaporated, and the obtained
crude product was treated in the same manner as that in step 9 in
Example 1 to obtain the title compound.
[0501] Yield: 26.75 mg (0.0352 mmol) (17%)
[0502] MS (ESI, m/z) 532 (MH+)
[0503] H-NMR (DMSO-d6) d 1.19 (6H,t), 1.59 (2H,br), 1.80(2H,br),
2.01 (2H,br), 2.58 (2H,br), 2.82 (2H,br), 3.19 (2H,t), 3.47
(2H,br), 3.91-4.00 (4H,m), 4.09-4.21(3H,m), 7.17 (2H,d), 7.36-7.41
(3H,m),8.19 (3H,br), 9.25(2H,br), 9.27(2H,br).
EXAMPLE 48
Synthesis of
3-[4-N-ethoxycarbonylamidino-2-(2-((1-(pyridine-4-yl)piperidi-
ne-4-carbonyl)amino)ethoxy)phenyl]propionic Acid
Bistrifluoroacetate
[0504] 200 mg (0.299 mmol) of
3-[4-amidino-2-(2-((1-(pyridine-4-yl)piperid-
ine-4-carbonyl)amino)ethoxy)phenyl]propionic acid
bistrifluoroacetate was dissolved in 5 ml of DMF. 0.124 ml (0.897
mmol) of triethylamine and 0.028 ml (0.299 mmol) of ethyl
chloroformate were added to the obtained solution, and they were
stirred at room temperature overnight. The solvent was evaporated,
and the obtained crude product was treated in the same manner as
that in step 9 in Example 1 to obtain the title compound.
[0505] Yield: 36 mg (0.049 mmol) (16%)
[0506] MS (ESI, m/z) 512 (MH+)
[0507] H-NMR (DMSO) .delta. 1.24 (3H, t), 1.44-1.62 (2H, m),
1.76-1.91 (2H, m), 2.32 (2H, t), 2.48-2.53 (1H, m), 2.81 (2H, t),
3.10-3.23 (2H, m), 3.46 (2H, dt), 4.08 (2H, t), 4.18 (2H, q),
4.19-4.23 (2H, m), 6.77 (1H, br), 7.17 (2H, d), 7.25 (1H, br), 7.42
(2H, d ), 8.15 (1H, d), 8.20 (2H, d)
EXAMPLE 49
Synthesis of
3-[4-N-hydroxyamidino-2-(2-((1-(pyridine-4-yl)piperidine-4-ca-
rbonyl)amino)ethoxy)phenyl]propionic Acid Bistrifluoroacetate
[0508] 50 mg (0.070 mmol) of ethyl
3-[4-N-hydroxyamidino-2-(2-((1-(pyridin-
e-4-yl)piperidine-4-carbonyl)amino)ethoxy)phenyl]propionate
bistrifluoroacetate was dissolved in 10 ml of 6 N aqueous
hydrochloric acid solution, and the obtained solution was stirred
at 60.degree. C. for 2 hours. The solvent was evaporated, and the
obtained crude product was treated in the same manner as that in
step 9 in Example 1 to obtain the title compound.
[0509] Yield: 24 mg (0.035 mmol) (50%)
[0510] MS (ESI, m/z) 455 (MH+)
[0511] H-NMR (DMSO) .delta. 1.44-1.65 (2H, m), 1.74-1.88 (2H, m),
2.48-2.56 (1H, m), 2.53 (2H, t), 2.84 (2H, t), 3.11-3.24 (2H, m),
3.45 (2H, dt), 4.08 (2H, t), 4.11-4.23 (2H, m), 7.16 (2H, d), 7.24
(2H, br), 7.34 (1H, d), 8.17 (1H, d ), 8.18 (2H, d), 8.92 (2H,
br)
EXAMPLE 50
Synthesis of
3-[4-N-acetoxyamidino-2-(2-((1-(pyridine-4-yl)piperidine-4-ca-
rbonyl)amino)ethoxy)phenyl]propionic Acid Bistrifluoroacetate
[0512] 24 mg (0.035 mmol) of
3-[4-N-hydroxyamidino-2-(2-((1-(pyridine-4-yl-
)piperidine-4-carbonyl)amino) ethoxy)phenyl]propionic acid
bistrifluoroacetate was dissolved in a mixture of 5 ml of acetic
acid and 0.08 ml of acetic anhydride, and the obtained solution was
stirred at room temperature for 3 hours. The solvent was
evaporated, and the obtained crude product was treated in the same
manner as that in step 9 in Example 1 to obtain the title
compound.
[0513] Yield: 2.6 mg (0.0035 mmol) (10%)
[0514] MS (ESI, m/z) 498 (MH+)
[0515] H-NMR (DMSO) .delta. 1.44-1.63 (2H, m), 1.78-1.90 (2H, m),
2.11 (3H, s), 2.48-2.56 (1H, m), 2.53 (2H, t), 2.80 (2H, t),
3.08-3.23 (2H, m), 3.45 (2H, dt), 4.04 (2H, t), 4.13-4.25 (2H, m),
6.74 (2H, br), 7.16-7.23 (5H, m), 8.11 (1H, t), 8.18 (2H, d)
EXAMPLE 51
Synthesis of
3-[4-amidino-2-]2-(4-(1-methyl-2-imidazoline-2-yl)benzoylamin-
o)ethoxy)phenyl]-2-oxopropionic Acid Bistrifluoroacetate
[0516] Step 1: Synthesis of 4-(1-methyl-2-imidazoline-2-yl)benzoic
acid monohydrochloride:
[0517] 1.8 g (10.3 mmol) of ethyl 4-cyanobenzoate was dissolved in
a mixture of 20 ml of 4 N solution of hydrogen chloride in dioxane
and 5 ml of ethanol, and the obtained solution was stirred at room
temperature for 3 days. The solvent was evaporated, and the residue
was washed with ethyl acetate. The obtained crude product was
dissolved in 20 ml of ethanol. 1.52 g (20.6 mmol) of
N-methylethylenediamine was added to the obtained solution, and
they were heated under reflux for 6 hours. The solvent was
evaporated, and the obtained crude product was treated with
dichloromethane as the extraction solvent in an ordinary manner.
The obtained crude product was dissolved in 10 ml of concentrated
hydrochloric acid, and the obtained solution was stirred at
50.degree. C. overnight. The solvent was evaporated to obtain the
crude title compound.
[0518] Yield: 1.37 g (5.71 mmol) (55%)
[0519] Step 2: Synthesis of 3-hydroxy-4-iodobenzoic acid:
[0520] 30.0 g (217 mmol) of 3-hydroxybenzoic acid was dissolved in
200 ml of acetic acid. 53.0 g (326 mmol) of iodine monochloride was
added to the obtained solution at room temperature. After stirring
at 45.degree. C. for 15 hours, the solvent was evaporated under
reduced pressure, and the obtained residue was washed with 500 ml
of 1% aqueous sodium thiosulfate solution twice and then with 500
ml of water twice, and dried to solid at 80.degree. C. under
reduced pressure to obtain the title compound.
[0521] Yield: 17.2 g (65.2 mmol) (30%)
[0522] MS (FAB, m/z) 265 (MH+)
[0523] H-NMR (DMSO-d6) .delta.: 7.13 (1H, dd), 7.43 (1H, d), 7.80
(1H, d)
[0524] Step 3 Synthesis of 3-hydroxy-4-iodobenzonitrile:
[0525] 22.3 g (89.7 mmol) of 3-hydroxy-4-iodobenzoic acid was
dissolved in 300 ml of tetrahydrofuran. 19.7 ml (206 mmol) of ethyl
chloroformate and 28.7 ml (206 mmol) of triethylamine were added to
the obtained solution at 0.degree. C. After stirring for 15
minutes, triethylamine hydrochloride thus formed was filtered out.
The filtrate was added to 300 ml of a tetrahydrofuran solution,
obtained by bubbling with ammonia, at 0.degree. C. After stirring
at room temperature for 10 hours, the solvent was evaporated under
reduced pressure, and the residue was dissolved in 450 ml of
dioxane. 17.4 ml (117 mmol) of anhydrous trifluoroacetic acid and
21.8 ml (269 mmol) of pyridine were added to the obtained solution
at 0.degree. C. After stirring at room temperature for 18 hours,
the solvent was evaporated under reduced pressure, and the residue
was treated with chloroform as the extraction solvent in an
ordinary manner to obtain an oily residue. The residue was
dissolved in 180 ml of tetrahydrofuran/methanol (1:1). 90 ml (90.0
mmol) of 1 N aqueous sodium hydroxide solution was added to the
obtained solution at room temperature. After stirring them for 4
hours, the solvent was evaporated under reduced pressure, and the
obtained residue was washed with dichloromethane. The reaction
mixture was acidified with 1 N hydrogen chloride and then treated
with ethyl acetate as the extraction solvent in an ordinary manner
to obtain the crude product, which was purified by the silica gel
column chromatography to obtain the title compound.
[0526] Yield: 9.29 g (37.9 mmol) (42%)
[0527] MS (FAB, m/z) 246 (MH+)
[0528] H-NMR (CDCl3) .delta.:5.63 (1H, br), 6.96 (1H, dd), 7.23
(1H, d), 7.79 (1H, d)
[0529] Step 4: Synthesis of t-butyl (2-bromoethyl)carbamate:
[0530] 9.22 g (45 mmol) of 2-bromoethylamine hydrobromide was
dissolved in 100 ml of dichloromethane. 7.64 g (35 mmol) of
di-t-butyl dicarbonate, 10.0 g (99 mmol) of triethylamine and 100
mg (0.82 mmol) of 4-(dimethylamino)pyridine were added to the
obtained solution, and they were stirred overnight. After the
treatment with dichloromethane as the extraction solvent in an
ordinary manner, the title compound was obtained.
[0531] Yield: 5.99 g (26.7 mmol) (76%)
[0532] H-NMR (CDCl3) .delta.:1.45 (9H, s), 3.46 (2H, dt), 3.51 (2H,
t), 4.95 (1H, br)
[0533] Step 5: Synthesis of
3-[2-(t-butoxycarbonylamino)ethoxy]-4-iodobenz- onitrile:
[0534] 18.5 g (82.6 mmol) of t-butyl (2-bromoethyl)carbamate was
dissolved in 200 ml of DMF. 10.1 g (41.3 mmol) of
3-hydroxy-4-iodobenzonitrile and 5.7 g (41.3 mmol) of potassium
carbonate were added to the obtained solution, and they were
stirred at 75.degree. C. for 3 hours. After the treatment with
ethyl acetate as the extraction solvent in an ordinary manner, the
title compound was obtained.
[0535] Yield: 11.0 g (28.4 mmol) (69%)
[0536] H-NMR (CDCl3) .delta.:1.46 (9H, s), 3.62 (2H, dt), 4.12 (2H,
t), 7.02 (2H, d),7.88 (2H, d).
[0537] Step 6: Synthesis of methyl
2-acetylamino-3-[2-(2-(t-butoxycarbonyl-
amino)ethoxy)-4-cyanophenyl]acrylate:
[0538] 18.0 g (46.4 mmol) of
3-[2-(t-butoxycarbonylamino)ethoxy]-4-iodoben- zonitrile was
dissolved in 200 ml of DMF. 13.3 g (92.8 mmol) of methyl
2-acetamidoacrylate, 2.82 g (9.28 mmol) of
tris(2-methylphenyl)phosphine, 1.04 g (4.64 mmol) of palladium
acetate and 12.9 ml (92.8 mmol) of triethylamine were added to the
obtained solution, and they were stirred at 115.degree. C. for 4
hours. The solvent was evaporated, and the obtained crude product
was purified by the silica gel column chromatography to obtain the
title compound.
[0539] Yield: 12.2 g (30.3 mmol) (65%)
[0540] H-NMR (CDCl3) .delta.:1.45 (9H, s), 2.03 (3H, s), 3.58 (2H,
dt), 3.89 (3H, s), 4.18 (2H, t), 7.17 (1H, br), 7.23 (1H, d),
7.35-7.42 (2H, m)
[0541] Step 7: Synthesis of methyl
2-acetylamino-3-[4-cyano-2-(2-(4-(1-met-
hyl-2-imidazoline-2-yl)benzoylamino)ethoxy)phenyl]acrylate
mono-trifluoroacetate:
[0542] 2.09 g (5.19 mmol) of methyl
2-acetylamino-3-[2-(2-(t-butoxycarbony-
lamino)ethoxy)-4-cyanophenyl]acrylate was dissolved in 10 ml of 4 N
solution of hydrogen chloride in dioxane and 10 ml of dioxane, and
the obtained solution was stirred at room temperature for 4 hours.
The solvent was evaporated, and the residue was dissolved in 10 ml
of DMF. 1.37 g (5.71 mmol) of
4-(1-methyl-2-imidazoline-2-yl)benzoic acid monohydrochloride, 1.10
g (5.71 mmol) of 1-(3-dimethylaminopropyl)-3-ethy- lcarbodiimide
hydrochloride, 777 mg (5.71 mmol) of 1-hydroxybenzotriazole and
2.17 ml (15.6 mmol) of triethylamine were added to the obtained
solution, and they were stirred at room temperature overnight. The
solvent was evaporated, and the obtained crude product was
subjected to the reversed phase high-performance liquid
chromatography with silica gel chemically bonded with octadodecyl
group. After the elution with a mixed solution of water and
acetonitrile containing 0.1% (v/v) of trifluoroacetic acid, the
intended fraction was freeze-dried to obtain the title
compound.
[0543] Yield: 2.0 g (3.32 mmol) (64%)
[0544] H-NMR (DMSO-d6) .delta.:1.95 (3H, s), 3.06 (3H, s), 3.65
(3H, s), 3.70 (2H, dt), 3.76-4.13 (4H, m), 4.29 (2H, t), 7.20 (1H,
s), 7.44 (1H, d), 7.63 (1H, d), 7.69 (1H, d), 7.79 (2H, d), 8.06
(2H, d), 8.94 (1H, t), 9.69 (1H, br)
[0545] Step 8: Synthesis of
3-[4-amidino-2-(2-(4-(1-methyl-2-imidazoline-2-
-yl)benzoylamino)ethoxy)phenyl]-2-oxopropionic acid
bistrifluoroacetate:
[0546] 2.0 g (3.32 mmol) of methyl
2-acetylamino-3-[4-cyano-2-(2-(4-(1-met- hyl-2-imidazoline
-2-yl)benzoylamino)ethoxy)phenyl]acrylate mono-trifluoroacetate was
dissolved in a mixture of 25 ml of 4 N solution of hydrogen
chloride in dioxane and 5 ml of ethanol, and the obtained solution
was stirred at room temperature for 4 days. The solvent was
evaporated, and the residue was dissolved in 20 ml of ethanol. 564
mg of ammonium carbonate was added to the obtained solution, and
they were stirred at room temperature overnight. The solvent was
evaporated, and the residue was dissolved in 10 ml of 6 N
hydrochloric acid, and the obtained solution was stirred at
80.degree. C. for 4 hours. The solvent was evaporated, and the
obtained crude product was treated in the same manner as that in
step 7 in Example 51 to obtain the title compound.
[0547] Yield: 430 mg (0.633 mmol) (19%)
[0548] MS (ESI, m/z) 452 (MH+)
[0549] H-NMR (DMSO-d6) .delta.: 3.05 (3H, s), 3.60-3.80 (2H, m),
3.78-4.40 (6H, m), 4.31 (2H, t), 6.81 (1H, s), 7.37-7.49 (3H, m),
7.73-7.85 (3H, m), 8.03-8.12 (3H, m), 9.05 (1H, t), 9.19-9.37 (5H,
m)
EXAMPLE 52
Synthesis of
3-[4-amidino-2-(2-((1-(1-methylpyridinium-4-yl)piperidine-4-c-
arbonyl)amino)ethoxy)phenyl]-2-oxopropionic acid
bistrifluoroacetate
[0550] Step 1: Synthesis of
1-(1-methylpyridinium-4-yl)piperidinecarboxyli- c acid:
[0551] 2.0 g (8.51 mmol) of ethyl
1-(4-pyridyl)-4-piperidinecarboxylate was dissolved in 10 ml of
methyl iodide, and the obtained solution was stirred at 40.degree.
C. for 4 hours. The solvent was evaporated, and the obtained crude
product was dissolved in 10 ml of concentrated hydrochloric acid,
and the obtained solution was stirred at 70.degree. C. overnight.
The solvent was evaporated to obtain the title compound.
[0552] Yield: 1.2 g (5.48 mmol)
[0553] Step 2: Synthesis of methyl
2-acetylamino-3-[4-cyano-2-(2-((1-(1-me-
thylpyridinium-4-yl)piperidine-4-carbonyl)amino)ethoxy)phenyl]acrylate:
[0554] 1.16 g (2.88 mmol) of methyl
2-acetylamino-3-[2-(2-(t-butoxycarbony-
lamino)ethoxy)-4-cyanophenyl]acrylate was dissolved in a mixture of
5 ml of 4 N solution of hydrogen chloride in dioxane and 5 ml of
dioxane, and the obtained solution was stirred at room temperature
for 4 hours. The solvent was evaporated, and the residue was
dissolved in 10 ml of DMF. 700 mg (3.17 mmol) of
1-(1-methylpyridinium-4-yl)piperidinecarboxylic acid, 1.47 g (3.17
mmol) of bromotripyrrolidinophosphonium hexafluorophosphate and
1.20 ml (8.64 mmol) of triethylamine were added to the obtained
solution, and they were stirred at room temperature overnight. The
solvent was evaporated, and the obtained crude product was treated
in the same manner as that in step 7 in Example 51 to obtain the
title compound.
[0555] Yield: 710 mg (1.41 mmol) (49%)
[0556] H-NMR (DMSO-d6) .delta.:1.47-1.68 (2H, m), 1.76-1.89 (2H,
m), 1.96 (3H, s), 2.53-2.64 (1H, m), 3.13-3.30 (2H, m), 3.44 (2H,
dt), 3.70 (3H, s), 3.88 (3H, s), 4.09-4.24 (4H, m), 7.18 (1H, br),
7.22 (2H, d), 7.43 (1H, d), 7.58 (1H, br), 7.69 (1H, d), 8.10 (1H,
t), 8.21 (2H, d), 9.69 (1H, br)
[0557] Step 3: Synthesis of
3-[4-amidino-2-(2-((1-(1-methylpyridinium-4-yl-
)piperidine-4-carbonyl)amino)ethoxy)phenyl]-2-oxopropionic acid
bistrifluoroacetate:
[0558] 710 mg (1.41 mmol) of methyl
2-acetylamino-3-[4-cyano-2-(2-((1-(1-m-
ethylpyridinium-4-yl)piperidine-4-carbonyl)amino)ethoxy)phenyl]acrylate
was dissolved in a mixture of 10 ml of 4 N solution of hydrogen
chloride in dioxane and 2 ml of ethanol, and the obtained solution
was stirred at room temperature for 4 dys. The solvent was
evaporated, and the obtained residue was dissolved in 10 ml of
ethanol. 239 mg of ammonium carbonate was added to the obtained
solution, and they were stirred at room temperature overnight. The
solvent was evaporated, and the residue was dissolved in 10 ml of 6
N hydrochloric acid, and the obtained solution was stirred at
80.degree. C. for 4 hours. The solvent was evaporated, and the
obtained crude product was treated in the same manner as that in
step 7 in Example 51 to obtain the title compound.
[0559] Yield: 30 mg (0.043 mmol) (3%)
[0560] H-NMR (DMSO-d6) .delta.:1.48-1.65 (2H, m), 1.76-1.88 (2H,
m), 2.54-2.65 (1H, m), 3.13-3.28 (2H, m), 3.33-3.52 (3H, m), 3.89
(3H, s), 3.97-4.27 (3H, m), 6.78 (1H, s), 7.20 (2H, d), 7.34-7.48
(2H, m), 8.13-8.26 (3H, m), 8.32 (1H, d), 9.15 (2H, br), 9.27 (2H,
br)
EXAMPLE 53
Synthesis of
N-[2-(3-amidinophenoxy)-ethyl]-4-(3,4-dimethoxybenzoyl)benzam-
ide:
[0561] Step 1: Synthesis of methyl
4-(3,4-dimethoxybenzoyl)benzoate:
[0562] 2.1 g (15.72 mmol) of aluminum chloride, a solution of 2.39
g (12.02 mmol) of monomethyl terephthalate chloride dissolved in 2
ml of dichloromethane and 1.2 ml (9.25 mmol) of
1,2-dimethoxybenzene dissolved in 2 ml of dichloromethane were
added to 10 ml of dichloromethane, and they were stirred overnight.
The reaction solution was poured into 5 g of 1 N hydrochloric
acid/ice. After the treatment with chloromethane as the extraction
solvent in an ordinary manner, the solvent was evaporated, and the
obtained residue was washed with ethyl acetate and dichloromethane
to obtain the title compound.
[0563] Yield: 1.3 g (4.33 mmol) (47%)
[0564] H-NMR (DMSO) .delta.: 3.82 (3H, s), 3.87 (3H, s), 3.92 (3H,
s), 7.08-7.14 (1H,d), 7.28-7.34 (1H, d), 7.38-7.42 (1H, d),
7.78-7.84 (2H, d), 8.08-8.14 (2H, d).
[0565] Step 2 Synthesis of 4-(3,4-dimethoxybenzoyl)benzoic
acid:
[0566] 1.3 g (4.33 mmol) of methyl 4-(3,4-dimethoxybenzoyl)benzoate
was dissolved in 50 ml of ethanol. 7 ml of 1 N sodium hydroxide
solution was added to the obtained solution, and they were stirred
overnight. The solvent was evaporated, and the residue was washed
with ethyl acetate and then filtered to obtain the title
compound.
[0567] Yield: 0.9 g (3.14 mmol) (73%)
[0568] H-NMR (DMSO) .delta.:3.82 (3H, s), 3.87 (3H, s), 7.08-7.14
(1H, d), 7.30-7.34(1H, d), 7.39-7.41 (1H, d), 7.76-7.82 (2H,
d).8.06-8.12 (2H, d).
[0569] Step 3: Synthesis of
3-[2-(t-butoxycarbonylamino)ethoxy]benzonitril- e:
[0570] 5.85 g (29 mmol) of t-butyl (2-bromoethyl)carbamate was
dissolved in 100 ml of dimethylformamide. 2.38 g (26.4 mmol) of
3-hydroxybenzonitrile, 3.04 g (53 mmol) of potassium carbonate and
4.31 g (53 mmol) of sodium iodide were added to the obtained
solution, and they were stirred at 50.degree. C. for 6 hours. After
the treatment with ethyl acetate as the extraction solvent in an
ordinary manner, the obtained crude product was purified by the
silica gel column chromatography to obtain the title compound.
[0571] Yield: 3.3 g (13.3 mmol) (51%)
[0572] H-NMR (CDCl3) .delta.:1.44 (1H, s), 3.55 (2H, dt), 4.05 (2H,
t), 4.95 (1H, brs), 7.12 (1H, d), 7.14 (1H, s), 7.26 (1H, d), 7.38
(1H, t)
[0573] Step 4: Synthesis of 3-(2-aminoethoxy)benzonitrile
monohydrochloride:
[0574] 1.41 g of 3-[2-(t-butoxycarbonylamino)ethoxy]benzonitrile
was dissolved in 20 ml of 4 N solution of hydrogen chloride in
dioxane, and the obtained solution was stirred at room temperature
for 2 hours. The solvent was evaporated, and the residue was
suspended in dichloromethane. The obtained suspension was filtered
to obtain hydrochloride of the title compound.
[0575] Yield: 0.89 g (4.48 mmol) (83%)
[0576] Step 5: Synthesis of
N-[2-(3-cyanophenoxy)ethyl]-4-(3,4-dimethoxybe-
nzoyl)benzamide:
[0577] 0.68 g (3.45 mmol) of 3-(2-aminoethoxy)benzonitrile
monohydrochloride was dissolved in 20 ml of N,N-dimethylformamide
(dehydrated). 0.9 g (3.14 mmol) of 4-(3,4-dimethoxybenzoyl)benzoic
acid, 0.47 g (3.45 mmol) of 1-hydroxybenzotriazole, 0.48 ml (3.45
mmol) of triethylamine and 0.66 g (3.45 mmol) of
1-(3-dimethylaminopropyl)-3-ethyl- carbodiimide hydrochloride were
added to the obtained solution, and they were stirred overnight.
The solvent was evaporated, and the residue was treated with ethyl
acetate as the extraction solvent in an ordinary manner to obtain
the title compound.
[0578] Yield: 1.4 g (3.25 mmol) (94%)
[0579] H-NMR (CDCl3) .delta.: 3.89-3.94 (2H, m), 3.94 (3H, s), 3.97
(3H, s), 4.18-4.24 (2H, t), 6.67 (1H, br), 6.87-6.92 (1H,
d).7.14-7.19 (2H, m), 7.20-7.44 (3H, m), 7.48-7.50 (1H, d),
7.79-7.83 (2H, d), 7.86-7.92 (2H, d).
[0580] Step 6: Synthesis of
N-[2-(3-amidinophenoxy)ethyl]-4-(3,4-dimethoxy-
benzoyl)benzamide:
[0581] 0.5 g (1.16 mmol) of
N-[2-(3-cyanophenoxy)ethyl]-4-(3,4-dimethoxybe- nzoyl)benzamide was
dissolved in 10 ml of N,N-dimethylformamide (dehydrated). 0.21 g
(2.32 mmol) of sodium hydrogensulfide dihydrate and 0.24 g (1.16
mmol) of magnesium chloride hexahydrate were added to the obtained
solution under cooling with ice, and they were stirred at room
temperature for 2.5 hours. After the treatment with ethyl acetate
as the extraction solvent in an ordinary manner, the solvent was
evaporated, and the obtained crude product was dissolved in 20 ml
of acetone. 0.56 ml (9.0 mmol) of methyl iodide was added to the
solution, and they were refluxed for 3 hours. The solvent was
evaporated, and the obtained crude product was washed with ethyl
acetate. After the filtration, the obtained crystals were dissolved
in 10 ml of methanol. 155 mg (2.0 mmol) of ammonium acetate was
added to the obtained solution, and they were stirred for 3 hours.
The solvent was evaporated, and the residue was treated in the same
manner as that in step 7 in Example 51 to obtain the title
compound.
[0582] Yield: 160 mg (0.285 mmol) (25%)
[0583] MS (ESI, m/z) 448 (MH+)
[0584] H-NMR (DMSO) .delta.: 3.68-3.75 (2H,q), 3.82 (3H, s), 3.87
(3H, s), 4.21-4.29 (2H, t), 7.09-7.13 (1H, d), 7.29-7.43 (5H, m),
7.50-7.58 (1H, t), 7.75-7.80 (2H, d), 7.98-8.04 (2H, d), 8.95-9.00
(1H, t), 9.10 (2H, s), 9.30 (2H, s).
EXAMPLE 54
Determination of Activity of Inhibiting the Activated
Blood-coagulation Factor X:
[0585] 130 .mu.l of 100 mM tris hydrochloride buffer adjusted to pH
8.4 was added to 10 .mu.l of an aqueous solution of a compound to
be tested. Then 10 .mu.l of a 0.5 unit/ml solution of activated
human blood coagulation factor X (a product of Enzyme Research Co.)
in tris hydrochloride of pH 8.4 was added to the resultant mixture.
After the incubation at room temperature for 10 minutes, 50 .mu.l
of a solution of
N-benzoyl-L-isoleucyl-L-glutamyl-glycyl-L-arginyl-P-nitroanilide
hydrochloride (a product of Peptide Institute, Inc.) adjusted to
0.8 mM with tris hydrochloride (pH 8.4) was added thereto. The
absorbance was determined and then the initial reaction rate was
determined. A control was prepared in the same manner as that
described above except that the solution of the compound to be
tested was replaced with 10 .mu.l of tris hydrochloride buffer
adjusted to pH 8.4. The absorbance was determined with MICROPLATE
READER Model 3550-UV (a product of BIO RAD) at a wave length of 405
nm at intervals of 15 seconds for 16 minutes. The negative
logarithm (pIC.sub.50) of a concentration of the test compound
which inhibits 50% of the activity (initial rate) of the activated
blood coagulation factor X in the absence of the test compound was
determined, and employed as the index of the activity of inhibiting
activated blood coagulation factor X.
[0586] The activities, of inhibiting activated blood coagulation
factor X, of representative compounds are shown in Table 1 given
below.
EXAMPLE 55
Determination of Thrombin-inhibiting Activity
[0587] 130 .mu.l of 100 mM tris hydrochloride buffer adjusted to pH
8.4 was added to 10 .mu.l of an aqueous solution of a test
compound. Then 10 .mu.l of a solution of human thrombin (a product
of SIGMA Co.) adjusted to 2 units/ml with tris hydrochloride buffer
of pH 8.4 was added to the resultant mixture. After the incubation
at room temperature for 10 minutes, 50 .mu.l of a solution of
D-phenylalanyl-L-pipecolyl-L-arginyl-P- -nitroanilide
dihydrochloride (S-2238; a product of Daiichi Kagaku Yakuhin Co.)
adjusted to 0.4 mM with tris hydrochloride buffer of pH 8.4 was
added thereto. The absorbance was determined and then the initial
reaction rate was determined. A control was prepared in the same
manner as that described above except that the solution of the
compound to be tested was replaced with 10 .mu.l of tris
hydrochloride buffer adjusted to pH 8.4. The absorbance was
determined with MICROPLATE READER Model 3550-UV (a product of MIO
RAD) at a wave length of 405 nm at intervals of 15 seconds for 16
minutes. The negative logarithm (pIC.sub.50) of a concentration of
the test compound which inhibits 50% of the activity (initial rate)
of the thrombin in the absence of the test compound was determined,
and employed as the index of the activity of inhibiting
thrombin.
[0588] The activities, of inhibiting thrombin, of representative
compounds are shown in Table 1 given below.
EXAMPLE 56
Determination of Blood Anticoagulating Activity
[0589] The blood anticoagulating activity was determined by a
prothrombin time (PT) determination method. The PT was determined
as follows: The blood was taken from healthy people. 3.8% aqueous
trisodium citrate solution was added to the blood in a volume ratio
of 1: 10. The blood plasma was separated by the centrifugation. 5
.mu.l of DMSO solution containing a test compound was added to 45
.mu.l of the blood plasma. After the incubation at room temperature
for 2 minutes, a test tube containing the blood plasma solution was
placed in Sysmex CA-3000 fully automatic blood coagulation
determination device (a product of Toa Medical Electronics Co.,
Ltd.), and incubated at 37.degree. C. for 3 minutes. 100 .mu.l of
Sysmex PT II (rabbit brain tissue thromboplastin, 13.2 mM calcium
chloride; a product of Toa Medical Electronics Co., Ltd.) was fed
into the test tube. PT was automatically determined with the
device. A sample containing 5 .mu.l of DMSO in place of the
solution of the test compound was used as the control. The negative
logarithm (PT2) of the concentration of the test compound which
elongated PT of the control to the twice as long was determined,
and employed as the index of the blood anticoagulating
activity.
1 TABLE 1 Activity of inhibiting Thrombin- activated blood
coagulation inhibiting activity factor X (pIC.sub.50) (pIC.sub.50)
Compd. of Ex. 2 7 <3.0 Compd. of Ex. 4 7.5 <3.0 Compd. of Ex.
5 7.2 5.2 Compd. of Ex. 6 7.4 <3.0 Compd. of Ex. 8 7 <3.0
Compd. of Ex. 9 7 5.5 Compd. of Ex. 10 7.4 <3.0 Compd. of Ex. 13
7.6 <3.1 Compd. of Ex. 14 7.8 <4.0 Compd. of Ex. 15 8 <4.0
Compd. of Ex. 26 7.8 <4.0 Compd. of Ex. 28 7.8 <4.0 Compd. of
Ex. 29 7.9 <4.0 Compd. of Ex. 37 7.3 <4.0 Compd. of Ex. 38 7
3.3 Compd. of Ex. 42 7.2 <3.3 Compd. of Ex. 43 7.8 <4.0
Compd. of Ex. 51 8.1 4.3 Compd. of Ex. 52 7.1 4.2
[0590] It is apparent from the results that the benzamidine
derivatives of the present invention have a specifically high
activity of inhibiting the activated blood coagulation factor X,
and they exhibit a high anticoagulating activity based on this
inhibiting activity.
[0591] The structural formulae of the compounds of the present
invention described in the Examples are given below. 15
[0592] Effect of the Invention:
[0593] The anticoagulant containing a compound of the present
invention or a salt thereof as the active ingredient has a
blood-coagulation inhibiting effect based on the excellent effect
of inhibiting activated blood-coagulation factor X. Therefore, the
compounds of the present invention are usable as agents for
preventing or treating diseases such as cerebrovascular disorders
such as cerebral infarction, cerebral thrombosis, cerebral
embolism, transient ischemic attack (TIA) and subarachnoidal
hemorrhage (vasospasm); ischemic heart diseases such as acute and
chronic myocardial infarction, unstable angina and coronary
thrombolysis; pulmonary vascular disorders such as pulmonary
infarction and pulmonary embolism; peripheral obliteration; deep
vein thrombosis; disseminated intravascular coagulation syndrome;
thrombus formation after an artificial blood vessel-forming
operation or artificial valve substitution; re-occlusion and
re-stenosis after a coronary bypass-forming operation; re-occlusion
and re-stenosis after reconstructive operation for the blood
circulation such as percutaneous transluminal coronary angioplasty
(PTCA) or percutaneous transluminal coronary recanalization (PTCR);
and thrombus formation in the course of the extracorporeal
circulation.
* * * * *