U.S. patent application number 11/832895 was filed with the patent office on 2010-04-29 for novel benzamidine compound.
This patent application is currently assigned to Ajinomoto Co., Inc.. Invention is credited to Kayo OTANI, Yuki SAITOU, Masaru TAKAYANAGI, Shunji TAKEHANA.
Application Number | 20100105731 11/832895 |
Document ID | / |
Family ID | 36777370 |
Filed Date | 2010-04-29 |
United States Patent
Application |
20100105731 |
Kind Code |
A2 |
TAKAYANAGI; Masaru ; et
al. |
April 29, 2010 |
NOVEL BENZAMIDINE COMPOUND
Abstract
Compounds represented by formula (1) and pharmaceutically
acceptable salt thereofs: ##STR1## wherein each symbol is as
defined in the specification, are useful as inhibitors of an
activated blood coagulation factor X. Compositions which contain,
as an active ingredient, an FXa selective low-molecular weight FXa
inhibitor having a short serum half-life are particularly useful as
anticoagulants for an extracorporeal blood circuit.
Inventors: |
TAKAYANAGI; Masaru;
(Kawasaki-shi, Kanagawa, JP) ; TAKEHANA; Shunji;
(Kawasaki-shi, Kanagawa, JP) ; OTANI; Kayo;
(Kawasaki-shi, Kanagawa, JP) ; SAITOU; Yuki;
(Kawasaki-shi, Kanagawa, JP) |
Correspondence
Address: |
OBLON, SPIVAK, MCCLELLAND MAIER & NEUSTADT, L.L.P.
1940 DUKE STREET
ALEXANDRIA
VA
22314
UNITED STATES
703-413-3000
703-413-2220
patentdocket@oblon.com
|
Assignee: |
Ajinomoto Co., Inc.
15-1, Kyobashi 1-chome, Chuo-ku
Tokyo
JP
104-8315
|
Prior
Publication: |
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Document Identifier |
Publication Date |
|
US 20080021065 A1 |
January 24, 2008 |
|
|
Family ID: |
36777370 |
Appl. No.: |
11/832895 |
Filed: |
August 2, 2007 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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PCT/JP06/302202 |
Feb 2, 2006 |
|
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11832895 |
Aug 2, 2007 |
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Current U.S.
Class: |
514/318 ;
514/428; 546/194; 548/569 |
Current CPC
Class: |
C07D 211/46 20130101;
A61M 1/3672 20130101; C07D 295/13 20130101; C07D 233/26 20130101;
C07D 211/62 20130101; C07C 257/18 20130101; C07D 401/04 20130101;
C07D 207/22 20130101 |
Class at
Publication: |
514/318 ;
514/428; 546/194; 548/569 |
International
Class: |
A61K 31/454 20060101
A61K031/454; A61K 31/40 20060101 A61K031/40; A61P 7/02 20060101
A61P007/02; C07D 207/06 20060101 C07D207/06; C07D 211/08 20060101
C07D211/08 |
Foreign Application Data
Date |
Code |
Application Number |
Feb 2, 2005 |
JP |
2005-026949 |
Claims
1. A compound represented by formula (1): ##STR51## wherein, in the
formula (1), ring A and ring B are the same or different and each
is a C.sub.6-10 aryl group, a C.sub.1-10 heteroaryl group, a
C.sub.2-8 nitrogen-containing non-aromatic heterocyclic group, or a
C.sub.3-10 cycloalkyl group; T is a hydrogen atom, a hydroxyl
group, a C.sub.1-10 alkoxy group optionally having substituent(s),
a C.sub.1-10 acyloxy group optionally having substituent(s), a
carbamoyloxy group optionally having substituent(s), a
thiocarbamoyloxy group optionally having substituent(s), an amino
group, a halogeno substituent, a cyano group, a nitro group, a
C.sub.1-10 alkyl group optionally having substituent(s), a
C.sub.1-10 alkylamino group optionally having substituent(s), a
C.sub.1-10 alkylthio group optionally having substituent(s), a
C.sub.1-10 acylamino group optionally having substituent(s), a
carboxyl group, a C.sub.2-10 alkoxycarbonyl group optionally having
substituent(s), a carbamoyl group optionally having substituent(s),
or a thiocarbamoyl group optionally having substituent(s); U is a
hydrogen atom, a C.sub.1-10 alkyl group optionally having
substituent(s), a carboxyl group, a C.sub.2-10 alkoxycarbonyl group
optionally having substituent(s), or a carbamoyl group optionally
having substituent(s), V is a hydrogen atom, a halogeno
substituent, a hydroxyl group, a C.sub.1-10 alkyl group optionally
having substituent(s), a C.sub.1-10 alkoxy group optionally having
substituent(s), a C.sub.1-10 alkylamino group optionally having
substituent(s), a C.sub.1-10 alkylthio group optionally having
substituent(s), a cyano group, a nitro group, a carboxyl group, or
a carbamoyl group optionally having substituent(s); W is a
C.sub.1-10 heteroaryl group, or a group represented by formula
(2-1), (2-2), or (2-3), ##STR52## wherein: in the formula (2-1), Q
is a C.sub.1-6 alkyl group, an amino group optionally substituted
by C.sub.1-10 alkyl group(s), or a C.sub.2-8 nitrogen-containing
heterocyclic group having a bond at the nitrogen atom; in the
formula (2-2), R is a C.sub.1-6 alkyl group; and m is an integer of
1-3; and in the formula (2-3), ring C is a C.sub.2-8
nitrogen-containing heterocyclic group, Y is a nitrogen atom
optionally substituted by a C.sub.1-6 alkyl group, an oxygen atom,
a sulfur atom, or a methylene group; and Z is a hydrogen atom, an
amidino group optionally substituted by C.sub.1-6 alkyl group(s),
or a C.sub.1-6 alkyl group optionally having an imino group at the
1-position; X is a nitrogen atom optionally substituted by a
C.sub.1-6 alkyl group, an oxygen atom, a sulfur atom, or a
methylene group; and n is an integer of 1-3, or a pharmaceutically
acceptable salt thereof.
2. A compound according to claim 1, which is represented by formula
(1-2): ##STR53## wherein T is bonded to the 3-position or the
4-position of the benzamidine ring, or a pharmaceutically
acceptable salt thereof.
3. A compound according to claim 2, wherein, in the formula (1-2),
X is an oxygen atom or a sulfur atom; U is a hydrogen atom or a
C.sub.1-6 alkyl group; T is a hydrogen atom, a hydroxyl group, a
C.sub.1-10 alkoxy group optionally having substituent(s), a
C.sub.2-10 acyloxy group optionally having substituent(s), a
carbamoyloxy group optionally having substituent(s), or a
thiocarbamoyloxy group optionally having substituent(s); and n is
an integer of 1-2, or a pharmaceutically acceptable salt
thereof.
4. A, compound according to claim 3, wherein, in the formula (1-2),
ring A is a phenyl group, a pyridyl group, a thiophenyl group, a
piperidinyl group, or a piperazinyl group; and V is a hydrogen
atom, a halogeno substituent, or a C.sub.1-6 alkyl group, or a
pharmaceutically acceptable salt thereof.
5. A compound according to claim 4, wherein, in the formula (1-2),
W is a pyridyl group, or a group represented by formula (2-1),
(2-2), or (2-3), wherein: when W is a group of formula (2-1), Q is
an amino group, a C.sub.1-10 alkylamino group, or a C.sub.2-8
nitrogen-containing heterocyclic group having a bond at the
nitrogen atom, When W is a group of formula (2-3), ring C is a
C.sub.2-8 nitrogen-containing heterocyclic group; Y is an oxygen
atom, a sulfur atom or a methylene group; and Z is a hydrogen atom,
an amidino group, or a C.sub.1-6 alkyl group optionally having an
imino group at the 1-position, or a pharmaceutically acceptable
salt thereof.
6. A pharmaceutical composition, comprising a compound according to
claim 1 or a pharmaceutically acceptable salt thereof and a
pharmaceutically acceptable carrier.
7. A pharmaceutical composition, comprising a compound according to
claim 2 or a pharmaceutically acceptable salt thereof and a
pharmaceutically acceptable carrier.
8. A pharmaceutical composition, comprising a compound according to
claim 3 or a pharmaceutically acceptable salt thereof and a
pharmaceutically acceptable carrier.
9. A pharmaceutical composition, comprising a compound according to
claim 4 or a pharmaceutically acceptable salt thereof and a
pharmaceutically acceptable carrier.
10. A pharmaceutical composition, comprising a compound according
to claim 5 or a pharmaceutically acceptable salt thereof and a
pharmaceutically acceptable carrier
11. A method of inhibiting an activated blood coagulation factor X,
which comprises applying an effective amount of a compound
according to claim 1 or a pharmaceutically acceptable salt
thereof.
12. The method of claim 11, which comprises administering an
effective amount of said compound or a pharmaceutically acceptable
salt thereof to a subject in need thereof.
13. The method of claim 11, which comprises applying an effective
amount of said compound or a pharmaceutically acceptable salt
thereof to an extracorporeal blood circuit.
14. A method for reducing coagulation, which comprises applying an
effective amount of a compound according to claim 1 or a
pharmaceutically acceptable salt thereof.
15. The method of claim 14, which comprises administering an
effective amount of said compound or a pharmaceutically acceptable
salt thereof to a subject in need thereof.
16. The method of claim 14, which comprises applying an effective
amount of said compound or a pharmaceutically acceptable salt
thereof to an extracorporeal blood circuit
17. A dialysate or a dialysate concentrate comprising a compound
according to claim 1 or a pharmaceutically acceptable salt
thereof.
18. An anticoagulant for an extracorporeal blood circuit comprising
a low-molecular weight FXa inhibitor as an active ingredient.
19. The anticoagulant for an extracorporeal blood circuit of claim
18, wherein said low-molecular weight FXa inhibitor is rapidly
cleared from the blood.
20. The anticoagulant for an extracorporeal blood circuit of claim
19, wherein said low-molecular weight FXa inhibitor is FXa
selective.
21. A method for reducing coagulation, which encompasses applying
an effective amount of a low-molecular weight FXa inhibitor.
22. The method of claim 21, which comprises applying an effective
amount of said low-molecular weight FXa inhibitor to an
extracorporeal blood circuit.
23. The method of claim 21, which comprises administering an
effective amount of said low-molecular weight FXa inhibitor to a
subject in need thereof.
24. A package, comprising a low-molecular weight FXa inhibitor, and
a written instruction, which indicates that said low-molecular
weight FXa inhibitor can be used or should be used as an
anticoagulant.
Description
CROSS REFERENCES TO RELATED APPLICATIONS
[0001] This application is a continuation of International Patent
Application No. PCT/JP2006/2302202, filed on Feb. 2, 2006, and
claims priority to Japanese Patent Application No. 2005-026949
filed on Feb. 2, 2005, both of which are incorporated herein by
reference in their entireties.
BACKGROUND OF THE INVENTION
[0002] 1. Field of the Invention
[0003] The present invention relates to novel benzamidine compounds
which exhibit an activated blood coagulation factor X (hereinafter
sometimes to be abbreviated as FXa) inhibitory activity. The
present invention also related to a method of producing such
compounds, intermediates useful for producing such compounds, and
uses of such a benzamidine compound. The present invention also
relates to a low-molecular weight FXa inhibitor, particularly the
use of a low-molecular weight FXa inhibitor having a short
half-life in blood, for an extracorporeal blood circuit and the
like.
[0004] 2. Discussion of the Background
[0005] Extracorporeal blood circulation is an artificial blood
circulation through a blood circuit constructed outside the body.
Generally, by the extracorporeal blood circulation, the blood is
circulated in a circuit from a body via an extracorporeal
artificial blood flow tube to an apparatus for a given treatment,
for example, an artificial heart lung apparatus, blood purifying
device and the like, and then into the body. An extracorporeal
blood circulation treatment is sometimes required during a blood
purification therapy such as hemodialysis, blood filtration,
hemodialysis filtration, plasma exchange, and the like, a
heart-lung bypass during open-heart operation and the like. As the
blood purification device, a dialyzer and the like are typically
mentioned.
[0006] When the blood is in contact with a foreign substance, the
intrinsic blood coagulation cascade is generally activated, and the
blood is finally coagulated and loses flowability. An
extracorporeal blood circuit consisting of artificial blood flow
tubes and various apparatuses, which is used for extracorporeal
blood circulation is a foreign substance, and the blood coagulates
upon contact therewith. Therefore, a treatment to prevent blood
coagulation in the extracorporeal blood circuit by some means is
needed.
[0007] Conventionally, anticoagulants such as unfractionated
heparin, low-molecular-weight heparin and the like are used for the
prevention of thrombus in the extracorporeal blood circuit.
[0008] However, unfractionated heparin cannot be used for patients
with a high risk of bleeding since, it has a risk of creating a
propensity toward hemorrhage due to its thrombin inhibitory
activity in addition to the FXa inhibitory activity.
Low-molecular-weight heparin is a pharmaceutical agent that
inhibits FXa more selectively as compared to thrombin by a chemical
treatment of heparin, and is free of a thrombin inhibitory
activity. Thus, low-molecular-weight heparin shows a low tendency
of causing bleeding, and has been used for patients having a
tendency of bleeding. On the other hand, however, since
low-molecular-weight heparin has a long disappearance half-life,
hemostasis is difficult when the bleeding symptom is observed.
[0009] Furthermore, some serine protease inhibitors also have an
anticoagulant action. For example, nafamostat mesilate is used for
some extracorporeal blood circulations such as hemodialysis and the
like. Since nafamostat mesilate has a short disappearance half-life
in the body, it is also used for patients with a bleeding lesion.
However, nafamostat mesilate does not have a strong inhibitory
activity against FXa and thrombin, and shows a weak anticoagulant
effect.
[0010] As mentioned above, all the pharmaceutical agents have
problems yet to be solved, and there is a demand for a more
effective and safe pharmaceutical agent.
[0011] Patients with an extracorporeal circuit face the problem of
blood coagulation only when the circuit is used. Thus, the
situation often varies from that of patients requiring continuous
prevention of blood coagulation. It has not been assumed heretofore
that a selective low-molecular weight FXa inhibitor with a short
half-life in blood can be used safely and conveniently as an
anticoagulant for the prevention of blood coagulation in an
extracorporeal blood circuit, and that the treatment of and
attention to hemostasis necessary after the completion of the
extracorporeal blood circulation can be clearly reduced.
[0012] As a benzamidine compound that exhibits an anticoagulation
activity based on a selective FXa inhibitory action, the compounds
described in WO98/31661 and WO99/64392 are known. However, these
compounds are clearly structurally different from the compound of
the present invention which contain an ester structure in the
molecular main chain.
SUMMARY OF THE INVENTION
[0013] Accordingly, it is one object of the present invention to
provide novel benzamidine compounds and pharmaceutically acceptable
salts thereof.
[0014] It is another object of the present invention to provide
novel benzamidine compounds and pharmaceutically acceptable salts
thereof which inhibit activated blood coagulation factor X.
[0015] It is another object of the present invention to provide
novel methods of producing such a benzamidine compound or
pharmaceutically acceptable salt thereof.
[0016] It is another object of the present invention to provide
novel intermediates which are useful for preparing such a
benzamidine compound or pharmaceutically acceptable salt
thereof.
[0017] It is another object of the present invention to provide
novel activated blood coagulation factor X inhibitors, which
comprise such a benzamidine compound or pharmaceutically acceptable
salt thereof.
[0018] It is another object of the present invention to provide
novel anticoagulants, which comprise such a benzamidine compound or
pharmaceutically acceptable salt thereof.
[0019] It is another object of the present invention to provide
novel pharmaceutical compositions which contain such a benzamidine
compound or pharmaceutically acceptable salt thereof.
[0020] It is another object of the present invention to provide
novel anticoagulants and pharmaceutical compositions for an
extracorporeal blood circuit.
[0021] It is another object of the present invention to provide
novel methods of preventing thrombus formation in an extracorporeal
blood circuit.
[0022] These and other objects, which will become apparent during
the following detailed description, have been achieved by the
inventors' discovery that particular novel benzamidine derivatives
having an ester bond in the molecule, which is represented by
A'-COO--B' wherein A' and B' are organic groups, and at least one
of them containing an amidino group or guanidino group structure,
have a superior activated blood coagulation factor X inhibitory
activity and a short half-life in blood, and are useful as blood
anticoagulants for the extracorporeal blood circuit.
[0023] Accordingly, the present invention provides the
following:
[0024] (1) A compound represented by the formula (1): ##STR2##
wherein, in formula (1),
[0025] ring A and ring B are the same or different and each is a
C.sub.6-10 aryl group, a C.sub.1-10 heteroaryl group, a C.sub.2-8
nitrogen-containing non-aromatic heterocyclic group or a C.sub.3-10
cycloalkyl group;
[0026] T is a hydrogen atom, a hydroxyl group, a C.sub.1-10 alkoxy
group optionally having substituent(s), a C.sub.1-10 acyloxy group
optionally having substituent(s), a carbamoyloxy group optionally
having substituent(s), a thiocarbamoyloxy group optionally having
substituent(s), an amino group, a halogen atom, a cyano group, a
nitro group, a C.sub.1-10 alkyl group optionally having
substituent(s), a C.sub.1-10 alkylamino group optionally having
substituent(s), a C.sub.1-10 alkylthio group optionally having
substituent(s), a C.sub.1-10 acylamino group optionally having
substituent(s), a carboxyl group, a C.sub.2-10 alkoxycarbonyl group
optionally having substituent(s), a carbamoyl group optionally
having substituent(s), or a thiocarbamoyl group optionally having
substituent(s);
[0027] U is a hydrogen atom, a C.sub.1-10 alkyl group optionally
having substituent(s), a carboxyl group, a C.sub.2-10
alkoxycarbonyl group optionally having substituent(s), or a
carbamoyl group optionally having substituent(s);
[0028] V is a hydrogen atom, a halogen atom, a hydroxyl group, a
C.sub.1-10 alkyl group optionally having substituent(s), a
C.sub.1-10 alkoxy group optionally having substituent(s), a
C.sub.1-10 alkylamino group optionally having substituent(s), a
C.sub.1-10 allylthio group optionally having substituent(s), a
cyano group, a nitro group, a carboxyl group, or a carbamoyl group
optionally having substituent(s);
[0029] W is a C.sub.1-10 heteroaryl group, or a group represented
by the following formula (2-1), (2-2) or (2-3), ##STR3##
[0030] wherein in the formula (2-1),
[0031] Q is a C.sub.1-6 alkyl group, an amino group optionally
substituted by C.sub.1-10 alkyl group(s), or a C.sub.2-8
nitrogen-containing heterocyclic group having a bond at the
nitrogen atom;
[0032] in the formula (2-2),
[0033] R is a C.sub.1-6 alkyl group, and
[0034] m is an integer of 1-3; and
[0035] in the formula (2-3),
[0036] ring C is a C.sub.2-8 nitrogen-containing heterocyclic
group,
[0037] Y is a nitrogen atom optionally substituted by a C.sub.1-6
alkyl group, an oxygen atom, a sulfur atom, or a methylene group;
and
[0038] Z is a hydrogen atom, an amidino group optionally
substituted by C.sub.1-6 alkyl group(s), or a C.sub.1-6 alkyl group
optionally having an imino group at the 1-position;
[0039] X is a nitrogen atom optionally substituted by a C.sub.1-6
alkyl group, an oxygen atom, a sulfur atom, or a methylene group;
and
[0040] n is an integer of 1-3,
or a pharmaceutically acceptable salt thereof.
[0041] (2) The compound of the above-mentioned (1), which is
represented by the following formula (1-2): ##STR4##
[0042] wherein ring A, T, U, V, W, X, and n are defined as the
above-mentioned (1); and
[0043] T substitutes the benzamidine at the 3-position or the
4-position,
or a pharmaceutically acceptable salt thereof.
[0044] (3) The compound of the above-mentioned (2), wherein, in the
formula (1-2),
[0045] X is an oxygen atom or a sulfur atom;
[0046] U is a hydrogen atom or a C.sub.1-6 alkyl group;
[0047] T is a hydrogen atom, a hydroxyl group, a C.sub.1-10 alkoxy
group optionally having substituent(s), a C.sub.2-10 acyloxy group
optionally having substituent(s), a carbamoyloxy group optionally
having substituent(s), or a thiocarbamoyloxy group optionally
having substituent(s); and
[0048] n is arm integer of 1-2,
or a pharmaceutically acceptable salt thereof.
[0049] (4) The compound of the above-mentioned (3), wherein, in the
formula (1-2),
[0050] ring A is a phenyl group, a pyridyl group, a thiophenyl
group, a piperidinyl group, or a piperazinyl group; and
[0051] V is a hydrogen atom, a halogen atom, or a C.sub.1-6 alkyl
group,
or a pharmaceutically acceptable salt thereof.
[0052] (5) The compound of the above-mentioned (4), wherein, in the
formula (1-2),
[0053] W is a pyridyl group, or a group represented by the formula
(2-1), (2-2) or (2-3), in the formula (2-1);
[0054] Q is an amino group, a C.sub.1-10 alkylamino group, or a
C.sub.2-8 nitrogen-containing heterocyclic group having a bond at
the nitrogen atom;
[0055] in the formula (2-3),
[0056] ring C is a C.sub.2-8 nitrogen-containing heterocyclic
group;
[0057] Y is an oxygen atom, a sulfur atom, or a methylene group;
and
[0058] Z is a hydrogen atom, an amidino group, or a C.sub.1-6 alkyl
group optionally having an imino group at the 1-position,
or a pharmaceutically acceptable salt thereof.
[0059] (6) A pharmaceutical composition comprising a compound of
any of the above-mentioned (1) to (5) or a pharmaceutically
acceptable salt thereof.
[0060] (7) The pharmaceutical composition of the above-mentioned
(6), which is an activated blood coagulation factor X
inhibitor.
[0061] (8) The pharmaceutical composition of the above-mentioned
(6), which is an anticoagulant.
[0062] (9) Tire pharmaceutical composition of the above-mentioned
(8), which is an anticoagulant for an extracorporeal blood circuit
in use.
[0063] (10) The pharmaceutical composition of the above-mentioned
(9), wherein the extracorporeal blood circuit is used for
hemodialysis.
[0064] (11) A method of inhibiting an activated blood coagulation
factor X, which comprises administering an effective amount of a
compound of any of the above-mentioned (1) to (5) or a
pharmaceutically acceptable salt thereof to a subject in need
thereof.
[0065] (12) Use of the compound of any of the above-mentioned (1)
to (5) or a pharmaceutically acceptable salt thereof for the
production of an activated blood coagulation factor X
inhibitor.
[0066] (13) A method for anticoagulation, which comprises applying
the compound of any of the above-mentioned (1) to (5) or a
pharmaceutically acceptable salt thereof.
[0067] (14) Use of the compound of any of the above-mentioned (1)
to (5) or a pharmaceutically acceptable salt thereof for the
production of an anticoagulant.
[0068] (15) A dialysate or a dialysate concentrate comprising the
compound of any of the above-mentioned (1) to (5) or a
pharmaceutically acceptable salt thereof.
[0069] (16) in anticoagulant for an extracorporeal blood circuit
comprising low-molecular weight FXa inhibitor as an active
ingredient.
[0070] (17) The anticoagulant for an extracorporeal blood circuit
of the above-mentioned (16), wherein the low-molecular weight FXa
inhibitor is rapidly cleared from the blood.
[0071] (18) The anticoagulant for an extracorporeal blood circuit
of the above-mentioned (17), wherein the low-molecular weight FXa
inhibitor is FXa selective.
[0072] (19) The method for anticoagulation, which encompasses
application of a low-molecular weight FXa inhibitor.
[0073] (20) The method for anticoagulation of the above-mentioned
(19), which is used for an extracorporeal blood circuit.
[0074] (21) Use of a low-molecular weight FXa inhibitor for the
production of an anticoagulant.
[0075] (22) Use of the above-mentioned (21) for the production of
an anticoagulant to be applied to an extracorporeal blood
circuit.
[0076] (23) A commercial package comprising a low-molecular weight
FXa inhibitor, and a written instruction regarding the
low-molecular weight FXa inhibitor, which indicates that the
low-molecular weight FXa inhibitor can be used or should be used as
an anticoagulant.
BRIEF DESCRIPTION OF THE DRAWINGS
[0077] A more complete appreciation of the invention and many of
the attendant advantages thereof will be readily obtained as the
same become better understood by reference to the following
detailed description when considered in connection with the
accompanying drawings, wherein:
[0078] FIG. 1 shows the time course changes of the arterial circuit
pressure in dog dialysis models (FIG. 1A, saline administration
group; FIG. 1B, Example 20 administration group (5 mg/hour); and
FIG. 1C, Example 20 administration group (15 mg/hour), N=5).
[0079] FIG. 2 shows the bleeding time in the dog dialysis
models.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0080] The terms to be used in the present specification are
defined as follows.
[0081] The term aryl group refers to an optionally substituted
monocyclic-bicyclic aromatic hydrocarbon ring group, or phenyl
group to which a 5- to 8-membered cycloalkyl ring (e.g.,
cyclopentane ring, cyclohexane ring, cycloheptane ring, cyclooctane
ring, etc.) has been condensed. For example, phenyl group, naphthyl
group, indanyl group, and tetrahydronaphthalenyl group can be
mentioned. Generally, the aryl group has 6-14 carbon atoms, and
C.sub.6-10 aryl groups are preferable. Phenyl group and naphthyl
group are more preferable, and a phenyl group is particularly
preferable.
[0082] The term heteroaryl group refers to a 5- to 10-membered
monocyclic-bicyclic aromatic hetero ring group containing, as ring
atom, 1 to 6 hetero atoms selected from oxygen atom, sulfur atom,
and nitrogen atom, which optionally has substituent(s). As examples
of the aromatic hetero rings encompassed in the heteroaryl group,
for example, pyridine ring, pyridazine ring, pyrimidine ring,
pyrazine ring, furan ring, thiophene ring, pyrrole ring, isoxazole
ring, oxazole ring, isothiazole ring, thiazole ring, pyrazole ring,
imidazole ring, oxadiazole ring, thiadiazole ring, triazole ring,
tetrazole ring, benzofuran ring, benzothiophene ring, indole ring,
isoindole ring, benzoxazole ring, benzothiazole ring, benzimidazole
ring (=benzoimidazole ring), indazole ring, benzisoxazole ring,
benzisothiazole ring, benzofurazan ring, benzothiadiazol ring,
purine ring, quinoline ring, isoquinoline ring, cinnoline ring,
phthalazine ring, quinazoline ring, quinoxaline ring, pteridine
ring, imidazooxazole ring, imidazothiazole ring, imidazoimidazole
ring, and the like can be mentioned. Generally, a heteroaryl group
having 1-10 carbon atoms is preferable, a C.sub.1-9 heteroaryl
group is more preferable. Pyridine ring, pyridazine ring,
pyrimidine ring, pyrazine ring, furan ring, thiophene ring, pyrrole
ring, isoxazole ring, oxazole ring, isothiazole ring, thiazole
ring, pyrazole ring, imidazole ring, oxadiazol ring, thiadiazol
ring, triazole ring and tetrazole ring are further preferable, and
pyridine ring and thiophene ring are particularly preferable.
[0083] The term non-aromatic heterocyclic group (i.e., aliphatic
heterocyclic group) refers to a 4- to 12-membered
monocyclic-bicyclic non-aromatic heterocyclic group containing, as
ring atom, 1 to 4 hetero atoms selected from oxygen atom, sulfur
atom and nitrogen atom. Preferably, the group has 1 to 9 carbon
atoms. Furthermore, any of the carbon atoms as ring atoms may be
substituted by oxo group(s), and the ring may include double
bond(s) or triple bond(s). Moreover, the ring may be condensed with
benzene ring optionally having substituent(s). As the non-aromatic
heterocycle, for example, pyrrolidine ring, pyrazolidine ring,
imidazolidine ring, pyrroline ring, pyrazoline ring, imidazoline
ring, tetrahydrofuran ring, tetrahydrothiophene ring,
tetrahydroquinoline ring, tetrahydroisoquinoline ring, thiazolidine
ring, piperidine ring, piperazine ring, quinuclidine ring,
tetrahydropyran ring, morpholine ring, thiomorpholine ring,
dioxolane ring, homopiperidine ring, homopiperazine ring, indoline
ring, isoindoline ring, chroman ring, isochroman ring and the like
can be mentioned. Preferably C.sub.2-8 non-aromatic heterocycle,
more preferably pyrrolidine ring, pyrroline ring, tetrahydrofuran
ring, tetrahydrothiophene ring, piperidine ring, piperazine ring,
morpholine ring, thiomorpholine ring, homopiperidine ring and
homopiperazine ring, particularly preferably pyrrolidine ring,
piperidine ring, and homopiperidine ring can be mentioned.
[0084] The term nitrogen-containing non-aromatic heterocyclic group
(i.e., nitrogen-containing aliphatic heterocyclic group) refers to
the above-mentioned non-aromatic heterocyclic group containing
nitrogen atom(s) in the ring. As the nitrogen-containing
non-aromatic heterocycle, pyrrolidine ring, piperidine ring,
homopiperidine ring, piperazine ring, tetrahydroquinoline ring,
tetrahydroisoquinoline ring, and pyrroline ring are preferable.
Generally those having 1-9 carbon atoms, preferably those having
2-9 carbon atoms can be mentioned, a nitrogen-containing
non-aromatic heterocyclic group having 2 to 8 (carbon atoms is more
preferable, and pyrrolidine ring, piperidine ring, and piperazine
are particularly preferable.
[0085] The term cycloalkyl group refers to an aliphatic hydrocarbon
ring group, and the group may contain double bond(s) in its ring.
As the aliphatic hydrocarbon ring, for example, cycl)propane ring,
cyclobutane ring, cyclopentane ring, cyclohexane ring, cycloheptane
ring, cyclooctane ring, cyclohexene ring, cyclopentene ring, and
the like can be mentioned. Preferably, a C.sub.3-10 cycloalkyl
group can be mentioned, and more preferably cyclohexane ring can be
mentioned.
[0086] The alkyl group moiety for alkyl group, or alkylthio group,
alkylamino group, alkoxy group, alkoxycarbonyl group, and the like,
is a straight chain, branched chain, cyclic or partially cyclic
alkyl group. For example, methyl group, ethyl group, propyl group,
isopropyl group, butyl group, isobutyl group, sec-butyl group,
tert-butyl group, cyclopropylmethyl group, pentyl group, isopentyl
group, neopentyl group, hexyl group, heptyl group, octyl group,
nonyl group, decyl group, 1,1-dimethyl-propyl group, cyclopropyl
group, cyclobutyl group, cyclopentyl group, cyclohexyl group,
cycloheptyl group, cyclooctyl group, and the like can be mentioned.
A C.sub.1-10 alkyl group is preferable, a C.sub.1-6 alkyl group is
more preferable, methyl group, ethyl group, isopropyl group,
isobutyl group and cyclopropyl group are more preferable, and a
C.sub.1-3 alkyl group is particularly preferable. Methyl group,
ethyl group, isopropyl group, and cyclopropyl group are still more
preferable.
[0087] Examples of the C.sub.1-10 alkylthio group include
methylthio group, ethylthio group, propylthio group, isopropylthio
group, butylthio group, isobutylthio group, sec-butylthio group,
tert-butylthio group, cyclopropylmethylthio group, pentylthio
group, isopentylthio group, neopentylthio group, hexylthio group,
heptylthio group, octylthio group, nonylthio group, decylthio
group, 1,1-dimethyl-propylthio group, cyclopropylthio group,
cyclobutylthio group, cyclopentylthio group, cyclohexylthio group,
cycloheptylthio group, cyclooctylthio group, and the like.
[0088] Examples of the C.sub.1-10 alkylamino group include
methylamino group, ethylamino group, propylamino group,
isopropylamino group, butylamino group, isobutylamino group,
sec-butylamino group, tert-butylamino group, cyclopropylmethylamino
group, pentylamino group, isopentylamino group, neopentylamino
group, hexylamino group, heptylamino group, octylamino group,
nonylamino group, decylamino group, 1,1-dimethyl-propylamino group,
cyclopropylamino group, cyclobutylamino group, cyclopentylamino
group, cyclohexylamino group, cycloheptylamino group,
cyclooctylamino group; dimethylamino group, diethylamino group,
dipropylamino group, diisopropylamino group, dibutylamino group,
diisobutylamino group, di-sec-butylamino group, di-tert-butylamino
group, di(cyclopropylmethyl)amino group, dipentylamino group,
diisopentylamino group, dineopentylamino group, dihexylamino group;
N-methyl-N-ethylamino group, N-methyl-N-propylamino group,
N-methyl-N-isopropylamino group, N-methyl-N-butylamino group,
N-methyl-N-isobutylamino group, N-methyl-N-sec-butylamino group,
N-methyl-N-tert-butylamino group, N-ethyl-N-propylamino group,
N-ethyl-N-isopropylamino group, N-ethyl-N-butylamino group,
N-ethyl-N-isobutylamino group, N-ethyl-N-sec-butylamino group,
N-ethyl-N-tert-butylamino group, and the like.
[0089] Examples of the C.sub.1-10 alkoxy group include methoxy
group, ethoxy group, propoxy group, isopropoxy group, butoxy group,
isobutoxy group, sec-butoxy group, tert-butoxy group,
cyclopropylmethoxy group, pentyloxy group, isopentyloxy group,
neopentyloxy group, hexyloxy group, heptyloxy group, octyloxy
group, nonyloxy group, decyloxy group, 1,1-dimethyl-propoxy group,
cyclopropoxy group, cyclobutoxy group, cyclopentyloxy group,
cyclohexyloxy group, cycloheptyloxy group, cyclooctyloxy group, and
the like.
[0090] Examples of the C.sub.2-10 alkoxycarbonyl group include
methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group,
isopropoxycarbonyl group, butoxycarbonyl group, isobutoxycarbonyl
group, sec-butoxycarbonyl group, tert-butoxycarbonyl group,
cyclopropylmethoxycarbonyl group, pentyloxycarbonyl group,
isopentyloxycarbonyl group, neopentyloxycarbonyl group,
hexyloxycarbonyl group, heptyloxycarbonyl group, octyloxycarbonyl
group, nonyloxycarbonyl group, 1,1-dimethyl-propoxycarbonyl group,
cyclopropoxycarbonyl group, cyclobutoxycarbonyl group,
cyclopentyloxycarbonyl group, cyclohexyloxycarbonyl group,
cycloheptyloxycarbonyl group, cyclooctyloxycarbonyl group, and the
like.
[0091] As the acyl group as the component of acyl group, or acyloxy
group, acylamino group, and the like, a C.sub.1-11 acyl group such
as formyl group, a C.sub.2-10 alkylcarbonyl group (e.g., acetyl
group, ethylcarbonyl group, propylcarbonyl group, isopropylcarbonyl
group, butylcarbonyl group, isobutylcarbonyl group,
sec-butylcarbonyl group, tert-butylcarbonyl group,
cyclopropylmethylcarbonyl group, pentylcarbonyl group,
isopentylcarbonyl group, neopentylcarbonyl group, hexylcarbonyl
group, heptylcarbonyl group, octylcarbonyl group, nonylcarbonyl
group, 1,1-dimethyl-propylcarbonyl group, cyclopropylcarbonyl
group, cyclobutylcarbonyl group, cyclopentylcarbonyl group,
cyclohexylcarbonyl group, cycloheptylcarbonyl group,
cyclooctylcarbonyl group, etc.), a C.sub.2-11 arylcarbonyl group
(e.g., benzoyl group, 1-naphthylcarbonyl group, 2-naphthylcarbonyl
group, etc.), and the like can be mentioned. Of these, a C.sub.1-10
acyl group is preferable, and a C.sub.1-7 acyl group is more
preferable. Particularly, a C.sub.1-6 acyl group is preferable.
[0092] Examples of the C.sub.1-11 acyloxy group include formyloxy
group, C.sub.2-10 alkylcarbonyloxy group (e.g., acetyloxy group,
ethylcarbonyloxy group, propylcarbonyloxy group,
isopropylcarbonyloxy group, butylcarbonyloxy group,
isobutylcarbonyloxy group, sec-butylcarbonyloxy group,
tert-butylcarbonyloxy group, cyclopropylmethylcarbonyloxy group,
pentylcarbonyloxy group, isopentylcarbonyloxy group,
neopentylcarbonyloxy group, hexylcarbonyloxy group,
heptylcarbonyloxy group, octylcarbonyloxy group, nonylcarbonyloxy
group, 1,1-dimethyl-propylcarbonyloxy group, cyclopropylcarbonyloxy
group, cyclobutylcarbonyloxy group, cyclopentylcarbonyloxy group,
cyclohexylcarbonyloxy group, cycloheptylcarbonyloxy group,
cyclooctylcarbonyloxy group, etc.), a C.sub.2-11 arylcarbonyloxy
group (e.g., benzoyloxy group, etc.), and the like. A C.sub.1-10
acyloxy group is preferable, and a C.sub.1-7 acyloxy group is more
preferable.
[0093] Examples of the C.sub.1-11 acylamino group include
formylamino group, a C.sub.2-10 alkylcarbonylamino group (e.g.,
acetylamino group, ethylcarbonylamino group, propylcarbonylamino
group, isopropylcarbonylamino group, butylcarbonylamino group,
isobutylcarbonylamino group, sec-butylcarbonylamino group,
tert-butylcarbonylamino group, cyclopropylmethylcarbonylamino
group, pentylcarbonylamino group, isopentylcarbonylamino group,
neopentylcarbonylamino group, hexylcarbonylamino group,
heptylcarbonylamino group, octylcarbonylamino group,
nonylcarbonylamino group, 1,1-dimethyl-propylcarbonylamino group,
cyclopropylcarbonylamino group, cyclobutylcarbonylamino group,
cyclopentylcarbonylamino group, cyclohexylcarbonylamino group,
cycloheptylcarbonylamino group, cyclooctylcarbonylamino group,
etc.), a C.sub.2-11 arylcarbonylamino group (e.g., benzoylamino
group, etc.) and the like. A C.sub.1-10 acylamino group is
preferable, and a C.sub.1-7 acylamino group is more preferable.
[0094] The term nitrogen-containing heterocyclic group refers to
the above-mentioned nitrogen-containing non-aromatic heterocyclic
group, and the above-mentioned heteroaryl group containing nitrogen
atom(s) in the ring, and a C.sub.2-8 nitrogen-containing
heterocyclic group is preferable; pyrrolidinyl group, piperidinyl
group, homopiperidinyl group, morpholinyl group, thiomorpholinyl
group, piperazinyl group, pyrrolinyl group, imidazolyl group,
pyridyl group, and pyrrolyl group are more preferable; and
pyrrolidinyl group, piperidinyl group, morpholinyl group,
thiomorpholinyl group, and piperazinyl group are more
preferable.
[0095] The term halogen atom refers to fluoro atom, chloro atom,
bromo atom, and iodo atom. Preferably, fluoro atom and chloro atom
can be mentioned.
[0096] The alkylamino group, or the alkylamino moiety as a
component for the carbamoyl or thiocarbamoyl substituted by alkyl
group(s) (cases where the substituent is alkyl group(s) in
carbamoyl group, thiocarbamoyl group, carbamoyloxy group,
thiocarbamoyloxy group, and the like, each of which optionally
having substituent(s)), and the like, encompasses both
monoalkylamino groups and dialkylamino groups. In the dialkylamino
groups, the alkyl group may bond to form a ring (e.g.,
nitrogen-containing heterocycle in the above-mentioned
nitrogen-containing heterocyclic group, etc.).
[0097] In the present specification, examples of the substituent
for "optionally having substituent(s)" include, for example,
(1) halogen atom,
(2) hydroxyl group,
(3) amino group,
(4) C.sub.1-10 alkyl group, preferably C.sub.1-6 alkyl group,
(5) C.sub.2-10 alkenyl group, preferably C.sub.2-6 alkenyl group
(e.g., vinyl group, allyl group, isopropenyl group, 1-butenyl
group, 2-butenyl group, 3-butenyl group, butadienyl group,
2-methylallyl group, hexatrienyl group, 3-octenyl group, etc.),
(6) C.sub.2-10 alkynyl group, preferably C.sub.2-6 alkynyl group
(e.g., ethynyl group, 2-propynyl group, isopropynyl group, butynyl
group, tert-butynyl group, 3-hexynyl group, etc.),
(7) C.sub.1-10 alkoxy group, preferably C.sub.1-6 alkoxy group,
(8) C.sub.1-10 alkylamino group, preferably C.sub.1-6 alkylamino
group,
(9) cyano group,
(10) guanidino group,
(11) carboxyl group,
(12) carbamoyl group,
(13) C.sub.6-14 aryl group, preferably C.sub.6-10 aryl group,
(14) C.sub.1-10 heteroaryl group, preferably C.sub.1-9 heteroaryl
group,
(15) C.sub.3-10 cycloalkyl group, preferably C.sub.3-8 cycloalkyl
group,
(16) nitrogen-containing non-aromatic heterocyclic group having 1-9
carbon atoms, preferably C.sub.2-8 nitrogen-containing non-aromatic
heterocyclic group,
(17) C.sub.1-10 alkylthio group, preferably C.sub.1-6 alkylthio
group,
(18) C.sub.1-10 acyloxy group, preferably C.sub.1-6 acyloxy
group,
(19) C.sub.1-10 acylamino group, preferably C.sub.1-6 acylamino
group,
[0098] (20) C.sub.1-10 alkylsulfonamide group, preferably C.sub.1-6
alkylsulfonamide group (e.g., methylsulfonamide group,
ethylsulfonamide group, propylsulfonamide group,
isopropylsulfonamide group, butylsulfonamide group,
isobutylsulfonamide group, sec-butylsulfonamide group,
tert-butylsulfonamide group, cyclopropylmethylsulfonamide group,
pentylsulfonamide group, isopentylsulfonamide group,
neopentylsulfonamide group, hexylsulfonamide group,
heptylsulfonamide group, octylsulfonamide group, nonylsulfonamide
group, decylsulfonamide group, 1,1-dimethyl-propylsulfonamide
group, cyclopropylsulfonamide group, cyclobutylsulfonamide group,
cyclopentylsulfonamide group, cyclohaxylsulfonamide group,
cycloheptylsulfonamide group, cyclooctylsulfonamide group,
etc.),
(21) C.sub.2-10 alkoxycarbonyl group, preferably C.sub.2-7
alkoxycarbonyl group, and the like can be mentioned.
[0099] As the substituent, preferably,
(1) halogen atom,
(2) hydroxyl group,
(3) amino group,
(4) C.sub.1-6 alkyl group,
(5) C.sub.2-6 alkenyl group,
(6) C.sub.2-6 alkynyl group,
(7) C.sub.1-6 alkoxy group,
(8) C.sub.1-6 alkylamino group,
(9) cyano group,
(10) guanidin) group,
(11) carboxyl group,
(12) carbamoyl group,
(13) C.sub.1-6 acylamino group,
(14) C.sub.3-8 cycloalkyl group,
(15) C.sub.1-6 alkylthio group,
(16) C.sub.1-10 acyloxy group, more preferably C.sub.1-6 acyloxy
group,
(17) C.sub.1-6 alkylsulfonamide group and
(18) C.sub.2-10 alkoxycarbonyl group,
can be mentioned.
[0100] The number and position of the substituent are not
particularly limited.
[0101] The compound represented by the formula (1) of the present
invention (hereinafter sometimes to be abbreviated to compound (1))
also encompasses various steric isomers such as geometric isomers,
tautomers, optical isomers, and the like, and mixtures and isolated
forms thereof.
[0102] In the above-mentioned formula (1),
[0103] as a group represented by ring A, phenyl group, naphthyl
group, thienyl group, pyridyl group, piperidinyl group, and
tetrahydroisoquinolyl group are preferable. Of these, phenyl group
is particularly preferable.
[0104] The positions of the substituents V and W and the carbonyl
group on ring A are not specifically limited so long they are
substitutable positions on ring A.
[0105] As V, hydrogen atom is preferable.
[0106] As W, imino(pyrrolidin-1-yl)methyl group,
(1-(1-iminoethyl)piperidin-4-yl)oxy group, and
{1-aminopiperidin-4-yl}oxy group are preferable.
[0107] As the group represented by ring B, phenyl group, thienyl
group, pyridyl group, pyrimidyl group, pyridazinyl group, pyrazyl
group, and piperidinyl group are preferable. Of these, phenyl group
and piperidinyl group are particularly preferable.
[0108] The positions of the substituents T and X and the amidino
group on ring B are not specifically limited so long they are
substitutable positions on ring B.
[0109] As T, hydrogen atom, hydroxyl group, methoxy group, ethoxy
group, propoxy group, isobutoxy group, 2-hydroxyethoxy group,
cyanomethoxy group, carboxymethoxy group, 2-cyanoethyl group,
2-carboxyethyl group, dimethylthiocarbamoyl group,
cyclopropylmethoxy group, 1-pyrrolidinylethoxy group, aminoethyl
group, acetylaminoethyl group, acyloxy group, dimethylcarbamoyl
group, and 1-pyrrolidinylcarbonyl group are preferable. Hydrogen
atom, hydroxyl group, methoxy group, ethoxy group, propoxy group,
isobutoxy group, 2-hydroxyethoxy group, cyanomethoxy group,
carboxymethoxy group, 2-cyanoethyl group, and 2-carboxyethyl group
are more preferable. Of these, hydroxyl group, 2-hydroxyethoxy
group and cyanomethoxy group are particularly preferable. Although
the substitutable position of T on ring B is not particularly
limited, where ring, B is 6-membered ring group, the substitutable
position of T is the 3- or 4-position, preferably the 4-position,
when substitutable position of the amidino group in the formula (1)
is the 1-position.
[0110] As U, hydrogen atom and methyl group are preferable.
[0111] As V, hydrogen atom, fluoro atom, chloro atom, methoxy
group, benzyloxy group and hydroxyl group are preferable, and
hydrogen atom is particularly preferable.
[0112] W is C.sub.1-10 heteroaryl group, or a group represented by
the following formula (2-1), (2-2) or (2-3). ##STR5## wherein each
symbol is as defined in the present specification.
[0113] As W, 4-pyridyl group, amidino group, 1-iminoethyl group,
imino(pyrrolidin-1-yl)methyl group, and imino(pyrroline-1-yl)methyl
group can be preferably mentioned, and particularly preferably,
imino(pyrrolidin-1-yl)methyl group can be mentioned.
[0114] In the formula (2-1),
[0115] Q is C.sub.1-6 alkyl group, amino group optionally
substituted by C.sub.1-10 alkyl group (which may be either mono- or
di-substituted (see the above-mentioned "C.sub.1-10 alkylamino
group")), or C.sub.2-8 nitrogen-containing heterocyclic group
having a bond at the nitrogen atom.
[0116] Examples of the C.sub.1-6 alkyl group include methyl group,
ethyl group, propyl group, isopropyl group, butyl group, isobutyl
group, sec-butyl group, tert-butyl group, cyclopropylmethyl group,
pentyl group, isopentyl group, neopentyl group, hexyl group,
1,1-dimethyl-propyl group, cyclopropyl group, cyclobutyl group,
cyclopentyl group, and cyclohexyl group. Furthermore, examples of
the C.sub.2-8 nitrogen-containing heterocyclic group include
pyrrolidinyl group, piperidinyl group, homopiperidinyl group,
morpholinyl group, thiomorpholinyl group, piperazinyl group,
imidazolinyl group, pyrrolinyl group, pyridyl group, and pyrrolyl
group. As Q, 1-pyrrolidinyl group and 1-pyrrolinyl group are
preferable. As the group represented by the formula (2-1),
imino(pyrrolidin-1-yl)methyl group is preferable.
[0117] In the formula (2-2), R is C.sub.1-6 alkyl group, and m is
an integer of 1-3.
[0118] Examples of the C.sub.1-6 alkyl group include methyl group,
ethyl group, propyl group, isopropyl group, butyl group, isobutyl
group, sec-butyl group, tert-butyl group, cyclopropylmethyl group,
pentyl group, isopentyl group, neopentyl group, hexyl group,
1,1-dimethyl-propyl group, cyclopropyl group, cyclobutyl group,
cyclopentyl group, and cyclohexyl group.
[0119] In the formula (2-2), R is preferably methyl group, and m is
preferably 1. As the group represented by the formula (2-2),
1-methyl-4,5-dihydro-1H-imidazol-2-yl group is preferable.
[0120] In the formula (2-3),
[0121] ring C is C.sub.2-8 nitrogen-containing heterocyclic group,
and examples of the nitrogen-containing heterocyclic group include
pyrrolidinyl group, piperidinyl group, homopiperidinyl group,
morpholinyl group, thiomorpholinyl group, piperazinyl group,
imidazolinyl group, pyrrolinyl group, pyridyl group, and pyrrolyl
group, and preferable examples include pyrrolidinyl group,
piperidyl group, and homopiperidyl group. Of these, piperidyl group
is particularly preferable.
[0122] Y is any of nitrogen atom optionally substituted by
C.sub.1-6 alkyl group (i.e., nitrogen atom substituted by C.sub.1-6
alkyl group or --NH--), oxygen atom (--O--), sulfur atom (--S--),
and methylene group (--CH.sub.2--). As the C.sub.1-6 alkyl group as
the substituent, methyl group, ethyl group, propyl group, isopropyl
group, butyl group, isobutyl group, sec-butyl group, tert-butyl
group, cyclopropylmethyl group, pentyl group, isopentyl group,
neopentyl group, hexyl group, 1,1-dimethyl-propyl group,
cyclopropyl group, cyclobutyl group, cyclopentyl group, and
cyclohexyl group can be mentioned. As Y, oxygen atom is
preferable.
[0123] Z is hydrogen atom, amidino group optionally substituted by
C.sub.1-6 alkyl group, or C.sub.1-6 alkyl group optionally having
imino group at the 1-position. For Z, as the C.sub.1-6 alkyl group,
methyl group, ethyl group, propyl group, isopropyl group, butyl
group, isobutyl group, sec-butyl group, tert-butyl group,
cyclopropylmethyl group, pentyl group, isopentyl group, neopentyl
group, hexyl group, 1,1-dimethyl-propyl group, cyclopropyl group,
cyclobutyl group, cyclopentyl group, and cyclohexyl group can be
mentioned. As Z, amidino group and 1-iminoethyl group are
preferable.
[0124] As the group represented by the formula (2-3),
1-(1-iminoethyl)-4-piperidinyloxy group or
1-amidino-4-piperidinyloxy group is preferable.
[0125] The positions of the substituents Z and Y on ring C are not
particularly limited so long as they are substitutable positions on
ring C.
[0126] In the formula (1),
[0127] X is any of nitrogen atom optionally substituted by
C.sub.1-6 alkyl group (i.e., nitrogen atom substituted by C.sub.1-6
alkyl group and --NH--), oxygen atom (--O--), sulfur atom (--S--)
or methylene group (--CH.sub.2--). As X, nitrogen atom (--NH--),
oxygen atom (--O--) and sulfur atom (--S--) are preferable, oxygen
atom and sulfur atom are more preferable, and oxygen atom is
particularly preferable.
[0128] n is an integer of 1-3, preferably 1 or 2, and more
preferably 1.
[0129] In the present invention, compounds having combinations of
the preferable groups represented by the above-mentioned symbols
are preferable.
[0130] More specifically, a compound represented by the following
formula (1-2) is preferable. ##STR6## wherein ring A, T, U, V, W, X
and n are as defined in the above-mentioned formula (1), and the 3-
or 4-position on the benzamidine is substituted by T.
[0131] In the formula (1-2), as W-A(V)--,
4-[imino(pyrrolidin-1-yl)methyl]-phenyl group,
4-(1-(1-iminoethyl)-4-piperidinyloxy)phenyl group, and
4-(1-amidino-4-piperidinyloxy)phenyl group are preferable.
[0132] T is preferably hydrogen atom, 2-hydroxyethoxy group,
methoxy group, cyanomethoxy group, hydroxyl group, 2-methylpropoxy
group (isobutoxy group), or acetyloxy group, and as the
substitutable position, the 4-position is preferable.
[0133] As X, oxygen atom and sulfur atom are preferable, and oxygen
atom is more preferable,
[0134] n is preferably 1, and
[0135] U is preferably hydrogen atom or C.sub.1-6 alkyl group, and
more preferably hydrogen atom, methyl group, or ethyl group.
[0136] Furthermore, a compound of the formula (1-2), wherein
[0137] X is oxygen atom or sulfur atom,
[0138] U is hydrogen atom or C.sub.1-6 alkyl group,
[0139] T is hydrogen atom, hydroxyl group, C.sub.1-10 alkoxy group
optionally having substituent(s), C.sub.2-10 acyloxy group
optionally having substituent(s), carbamoyloxy group optionally
having substituent(s), or thiocarbamoyloxy group optionally having
substituent(s), and
[0140] n is an integer of 1-2
is more preferable.
[0141] In this case, a compound wherein ring A is phenyl group,
pyridyl group, thiophenyl group, piperidinyl group, or piperazinyl
group, and V is hydrogen atom, halogen atom, or C.sub.1-6 alkyl
group is more preferable.
[0142] Moreover, a compound wherein
[0143] W is any of pyridyl group, or a group represented by the
formula (2-1), (2-2), or (2-3), wherein
[0144] in the formula (2-1), Q is amino group, C.sub.1-10
alkylamino group, or C.sub.2-8 nitrogen-containing heterocyclic
group having a bond at the nitrogen atom, and in the formula (2-3),
ring C is any of C.sub.2-8 nitrogen-containing heterocyclic group,
and Y is oxygen atom, sulfur atom and methylene group, and
[0145] Z is hydrogen atom, amidino group, or C.sub.1-6 alkyl group
optionally having imino group at the 1-position, is more
preferable.
[0146] More specifically, the compounds described in Examples, but
are not limited thereto, are preferable.
[0147] The present invention also relates to an anticoagulant for
use in an extracorporeal blood circuit containing a low-molecular
weight FXa inhibitor as an active ingredient and a method for
preventing formation of thrombus in an extracorporeal blood
circuit, which method comprises incorporating a low-molecular
weight FXa inhibitor as a component of the circuit. In the present
specification, the "low-molecular weight FXa inhibitor" refers to
the above-mentioned compound represented by the formula (1) and a
pharmaceutically acceptable salt thereof, or a compound having a
molecular weight of not more than 1000, which has FXa inhibitory
activity, preferably the compound represented by the formula (1).
More specifically, as the compound having a molecular weight of not
more than 1000, which has FXa inhibitory activity, for example, the
compounds disclosed in WO99/52895, WO99/10316, WO2000/59876,
WO2002/28827, WO01/74791, WO96/16940, and WO2002/42270, all of
which are incorporated herein by reference, can be mentioned.
[0148] Furthermore, as the above-mentioned low-molecular weight FXa
inhibitor, one that disappears quickly in the blood is preferable.
In the present specification, the phrase "disappears quickly in the
blood" means that the disappearance half-life in vivo or the
half-life measured in the stability test in the plasma shown in the
below-mentioned Experimental Example 4 is from 0.5 minutes to 10
minutes, preferably from 0.5 minutes to 5 minutes. Moreover, as the
above-mentioned low-molecular weight FXa inhibitor, those which are
FXa selective are preferable, more specifically those having a
difference between pIC.sub.50(FXa) and pIC.sub.50(IIa), i.e.,
pIC.sub.50(FXa)-pIC.sub.50(IIa), of not less than 2.5 in the system
for evaluating inhibitory activity shown in the below-mentioned
Experimental Examples 1 and 2.
[0149] The term extracorporeal blood circulation refers to
artificial blood circulation via a blood circuit constituted
outside of a living organism, and the extracorporeal blood circuit
refers to a blood circuit used for the extracorporeal blood
circulation. Examples include a blood circuit made by connecting a
living organism and an artificial organ when utilizing an
artificial organ, and more specifically, for example, those used
during use of an artificial heart-lung machine and during
hemodialysis can be mentioned. In the present invention, an
extracorporeal blood circuit used during hemodialysis is
particularly preferable.
[0150] The representative production methods of the compounds
represented by the formula (1) of the present invention
(hereinafter sometimes to be abbreviated as compound (1)) are
explained below. However, those of ordinary skill in the art will
understand that the present invention is not limited by the
following production methods.
[0151] In the formula (1), when ring A is an aryl group or
heteroaryl group and W is a group represented by the formula (2-1)
or (2-2), the intermediate (4) and intermediate (5) can be obtained
in the method shown below. Specifically, for example, a
cyanoarylcarboxylic acid such as 4-cyanobenzoic acid and the like
or a cyanoheteroaiylcarboxylic acid is dissolved in a solvent, for
example, an alcohol: R.sup.1OH (wherein R.sup.1 is an alkyl group)
such as methanol, ethanol and the like, and an acid, for example,
hydrogen chloride gas, is blown into the mixture, whereby imidate
(3) can be obtained. The obtained imidate (3) is reacted with, for
example, an ammonium salt or a primary or secondary amine:
R.sup.2R.sup.3NH (wherein R.sup.2 and R.sup.3 are each the same or
different and each is hydrogen atom or alkyl group, or R.sup.2 and
R.sup.3 may form, together with the nitrogen atom to which they are
bonded, to form C.sub.2-8 nitrogen-containing heterocyclic group),
such as ammonia, ammonium carbonate or the like, in a solvent, for
example, an alcohol such as methanol, ethanol and the like, whereby
amidine derivative (4) wherein W is represented by the formula
(2-1) in the formula (1) can be obtained. Alternatively, using a
similar manner, cyclic amidine derivative (5) wherein W is
represented by the formula (2-2) in the formula (1) can be obtained
by reacting imidate (3) with, for example, a diaminoalkane:
R.sup.4--NH--CH.sub.2--(CH.sub.2).sub.m--NH.sub.2 (wherein R.sup.4
is alkyl group, and m is an integer of 1-3) such as
N-methylethylenediamine and the like. ##STR7## wherein each symbol
is as defined above.
[0152] In the Formula (1), when ring A is nitrogen-containing
non-aromatic heterocyclic group and W is amidino group optionally
having substituent(s) (e.g., C.sub.1-10 alkyl group, etc.) or
1-imino-alkyl group (e.g., 1-iminoethyl group), intermediate (6)
can be obtained by the following method. That is, for example, a
nitrogen-containing non-aromatic heterocycle carboxylic acid ester
such as ethyl isonipecotate and the like can be dissolved in a
solvent, for example, an alcohol such as methanol, ethanol, and the
like in the presence of a base, for example, an organic base such
as diisopropylethylamine, reacted with, for example, ethyl
acetimidate or 1H-pyrazole-1-carboxamidine, whereby intermediate
(6) can be obtained. ##STR8## wherein each symbol is as defined
above, and R.sup.5 is alkyl group.
[0153] The thus-obtained intermediates (4), (5), and (6) can be
each converted to intermediate (7) in the following methods.
Specifically, intermediate (4), (5), or (6), is mixed, without any
solvent, for example, with a halogeno alcohol:
HO--CH(U)--(CH.sub.2).sub.n--X' (wherein U and n are as defined
above, X' is a leaving group such as halogen atom (e.g., fluorine
atom, chlorine atom, bromine atom, iodine atom, etc.) and the like)
such as 2-bromoethanol, 3-bromopropanol, and the like, a catalytic
amount of organic acid, for example, an inorganic acid such as
hydrochloric acid, sulfuric acid, and the like, or an organic acid
such as p-toluenesulfonic acid, methanesulfonic acid, and the like
is added to the mixture, and the mixture is heated, whereby
intermediate (7) can be obtained. ##STR9## wherein each symbol is
as defined above.
[0154] When ring A is aryl group or heteroaryl group, W is the
group represented by the formula (2-3), and X is oxygen atom in the
formula (1), intermediate (7) can be obtained by the method shown
below. Specifically, for example, a nitrogen-containing heterocycle
having a hydroxyl group and its nitrogen atom is protected by a
suitable protecting group (Prot) that can be removed under acidic
condition (e.g., tert-butoxycarbonyl group, etc.), such as
N-tert-butoxycarbonyl-4-hydroxypiperidine and the like, and for
example, an arylcarboxylate or heteroarylcarboxylate having
hydroxyl group such as ethyl 4-hydroxybenzoate and the like are
dissolved in a solvent such as THF and the like, and reacted with
diethylazodicarboxylic acid (DEAD) and triphenylphosphine, whereby
ether (8) (wherein R.sup.6 is alkyl group) can be obtained. The
thus-obtained ether (8), is mixed, without solvent, with, for
example, a halogeno alcohol: HO--CH(U)--(CH.sub.2).sub.n--X'
(wherein U and n are as defined above and X' is a leaving group
such as halogen atom (e.g., fluorine atom, chlorine atom, bromine
atom, and iodine atom, etc.) such as 2-bromoethanol,
3-bromopropanol, and the like. A catalytic amount of acid, for
example, an inorganic acid such as hydrochloric acid, sulfuric
acid, and the like, or an organic acid such as p-toluenesulfonic
acid, methanesulfonic acid, and the like is added to the mixture,
and the mixture is heated to remove the protecting group (Prot) on
the nitrogen atom, whereby halogenoalkyl ester (9) can be obtained.
The thus-obtained halogenoalkyl ester (9) is dissolved in a
solvent, for example, an alcohol such as methanol, ethanol, and the
like, and in the presence of a base, for example, an organic base
such as diisopropylethylamine, reacted with, for example, ethyl
acetimidate or 1H-pyrazole-1-carboxamidine, whereby intermediate
(7) can be obtained. ##STR10## wherein each symbol is as defined
above.
[0155] When T is hydrogen atom or halogen atom in the formula (1),
intermediate compound (12) can be in synthesized in the following
method. Specifically, for example, a cyanohydroxyaryl such as
3-cyanophenol and the like or cyanohydroxyheteroaryl is dissolved
in a solvent, for example, an alcohol: R.sup.7OH (wherein R.sup.7
is alkyl group) such as methanol, ethanol, and the like, and an
acid, for example, hydrogen chloride gas is blown into the mixture,
whereby imidate (10) can be obtained. The thus-obtained imidate
(10) is reacted with all ammonium salt, for example, ammonia or
ammonium carbonate, and the like, using a solvent, for example,
methanol, ethanol, and the like, whereby amidine (11) can be
obtained. The thus-obtained amidine (11) and the above-mentioned
intermediate (7) are dissolved in a solvent, for example,
dimethylformamide, and a base, for example, an inorganic base such
as potassium carbonate, cesium carbonate, and the like is added to
the mixture and the mixture is heated, whereby compound (12)
wherein T is hydrogen atom or halogen atom can be obtained.
##STR11## wherein each symbol is as defined above.
[0156] When T is attached to ring B via an oxygen atom such as
hydroxyl group, alkoxy group optionally having substituent(s),
acyloxy group optionally having substituent(s), carbamoyloxy group
optionally having substituent(s) and the like in the formula (1),
compound (17) can be synthesized by the following method.
[0157] Specifically, for example, a cyanodihydroxyaryl such as
3,4-dihydroxybenzonitrile and the like or a
cyanodihydroxyheteroaryl is dissolved in a solvent such as
dimethylformamide and reacted with benzyl halide: Bn-X.sup.a
(wherein Bn is benzyl group and X.sup.a is halogen atom) and the
like in the presence of a base, for example, an inorganic base such
as potassium carbonate and heated, whereby nitrile (13) in which
benzyl group is selectively attached to one hydroxyl group can be
obtained. The thus-obtained nitrile (13) is dissolved in a solvent,
for example, an alcohol: R.sup.8OH (wherein R.sup.8 is alkyl group)
such as methanol, ethanol, and the like, and an acid, for example,
hydrogen chloride gas is blown into the mixture, whereby imidate
(14) can be obtained. The thus-obtained imidate (14) is reacted
with an ammonium salt such as ammonia or ammonium carbonate, and
the like in a solvent, for example, an alcohol such as methanol,
ethanol, and the like, whereby amidine (15) can be obtained. The
thus-obtained amidine (15) and the above-mentioned intermediate (7)
were dissolved in a solvent, for example, dimethylformamide, a
base, for example, an inorganic base such as potassium carbonate,
cesium carbonate, and the like is added to the mixture, and the
mixture is heated, whereby intermediate (16) can be obtained. The
thus-obtained intermediate (16) is dissolved in a solvent, for
example, an alcohol such as methanol, ethanol, and the like or
acetic acid, and subjected to catalytic reduction in the presence
of a catalytic amount of palladium carbon, whereby compound (17)
wherein T is hydroxyl, group can be obtained. ##STR12## wherein
each symbol is as defined above.
[0158] Furthermore, compound (17) wherein T is hydroxyl group is
dissolved in a solvent, for example, dimethylformamide, and reacted
with an alkyl halide: X.sup.b--R.sup.9 (wherein X.sup.b is a
halogen atom, R.sup.9 is an alkyl group optionally having
substituent(s)), an acyl halide: X.sup.c--CO--R.sup.10 (wherein
X.sup.c is a halogen atom, R.sup.10 is alkyl group optionally
having substituent(s) or aryl group optionally having
substituent(s)), or a carbamoyl halide:
X.sup.d--CO--NR.sup.11R.sup.12 (wherein X.sup.d is a halogen atom,
R.sup.11 and R.sup.12 are the same or different and each is
hydrogen atom, or the "substituent" as defined above) in the
presence of a base, for example, a inorganic base such as sodium
hydrogencarbonate, potassium carbonate, cesium carbonate, and the
like, whereby compound (18) wherein T is alkoxy group optionally
having substituent(s), compound (19) wherein T is acyloxy group
optionally having substituent(s), and compound (20) wherein T is
carbamoyloxy group optionally having substituent(s) can be
obtained, respectively. ##STR13## wherein each symbol is as defined
above.
[0159] When the compound represented by the formula (1) of the
present invention may form a salt, the salt may be a
pharmaceutically acceptable salt, and examples in the case when an
acidic group such as a carboxyl group and the like exists in the
formula include an ammonium salt; a salt with an alkali metal such
as sodium, potassium, and the like; a salt with an alkaline earth
metal such as calcium, magnesium, and the like; an aluminum salt; a
zinc salt; a salt with an organic amine such as triethylamine,
ethanolamine, morpholine, piperidine, dicyclohexylamine, and the
like; and a salt with a basic amino acid such as arginine, lysine
and the like.
[0160] Examples of the salt in the case where a basic group exists
in the formula include a salt with an inorganic acid such as
hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid,
hydrogen bromide acid, and the like; a salt with an organic
carboxylic acid such as acetic acid, trifluoroacetic acid (TFA),
citric acid, benzoic acid, maleic acid, fumaric acid, tartaric
acid, succinic acid, tannic acid, butyric acid, hibenzoic acid,
pamoic acid, enanthic acid, decane acid, teoclic acid, salicylic
acid, lactic acid, oxalic acid, mandelic acid, malic acid, and the
like; and a salt with an organic sulfonic acid such as
methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid,
and the like. As the method of forming salts, mixing the compound
of the formula (1) and a necessary acid or base in a suitable
amount ratio in a solvent or a dispersing agent, or subjecting
another salt form to cation exchange or anion exchange can be
mentioned.
[0161] The compound of the present invention also encompasses
solvates, for example, hydrates, alcoholates, and the like, of the
compound represented by the formula (1).
[0162] The compound of the present invention can be prepared in the
form of a prodrug. The prodrug in the present invention refers to a
compound that is converted to the compound of the present invention
in vivo. For example, when an active parent form comprises a
carboxyl group or phosphoric acid group, examples of the prodrug
include esters thereof, amides thereof, and the like. When an
active parent form comprises an amino group, examples of the
prodrug include amides thereof, carbamates thereof, and the like.
When an active parent form comprises a hydroxyl group, examples of
the prodrug include esters thereof, carbonates thereof, carbamates
thereof, and the like. When the compound of the present invention
is prepared in the form of a prodrug, the prodrug may be bonded to
an amino acid or a saccharide.
[0163] The compound (1) of the present invention or a
pharmaceutically acceptable salt thereof can be directly
administered to a target or after formulation into a pharmaceutical
composition by a conventional method using a conventional
formulation aid. Examples of the dosage form for the pharmaceutical
composition include tablets, powders, injections, freeze-dry
injections, or, pills, granules, capsules, suppositories, liquids,
sugar-coated agents, depots, syrups, suspensions, emulsions,
troches, hypoglottis, patches, intraoral disintegrants (tablet),
inhalants, enteroclysis, ointments, cloth adhesive agents, tapes,
eye drops, and the like.
[0164] The compound or pharmaceutical composition of the present
invention is administrated into a circuit for extracorporeal blood
circulation or to a patient. Examples of preferable methods for the
administration include direct administration into an extracorporeal
blood circuit for circulation, intravenous administration,
intramuscular administrations and subcutaneous administration. In
some cases, oral administration, rectal administration, intranasal
administrations or sublingual administration can be used. For
direct administration into a circuit for extracorporeal blood
circulation, the compound or pharmaceutical composition is
preferably administered from a site of a circulation circuit
drawing the blood from the body, which site is located as close as
possible to the body. In the case of hemodialysis and the like, a
generally installed injecting port can be utilized.
[0165] The administration subject is not particularly limited, and
examples thereof include mammals (e.g., mouse, rat, hamster,
rabbit, cat, dog, swine, bovine, sheep, horse, monkey, human, etc.)
and the like.
[0166] In addition, as a manner of providing the compound of the
present invention or a pharmaceutically acceptable salt thereof or
a pharmaceutical composition comprising the compound or the salt as
an anticoagulant for hemodialysis, for example, a manner wherein a
FXa inhibitor composition is directly used in a dialyzer by
dissolving or dispersing the composition in a dialysate prior to
use, as well as a manner wherein the composition is provided in the
form of a dialysate or a dialysate concentrate comprising a FXa
inhibitor, may be mentioned. Examples of the dialysate concentrate
include a powder preparation for an artificial kidney, which can be
prepared, for example, by concentrating, a dialysate comprising a
FXa inhibitor by freeze-drying and the like. The dialysate
concentrate can be diluted prior to use, for example, with purified
water by an appropriate method to afford a dialysate.
[0167] The compound or pharmaceutical composition of the present
invention may be administered at once or continuously, in one
portion or several portions as necessary, in one operation of
extracorporeal blood circulation. The dose of the compound of the
present invention or pharmaceutical composition may be from 0.01 mg
to 10 g, preferably from 1 mg to 1,000 mg, as an active ingredient
compound per one operation of extracorporeal blood circulation or
per one day, which can be appropriately increased or decreased
according to the age, body weight, symptom, and the like of the
patient/target. While the appropriate concentration of the active
ingredient compound in the dialysate depends on the compound to be
used, severity of the disease to be treated and characteristic of
the patient to be treated, the average concentration of the usable
compound in the plasma at appropriate equilibrium generally
includes a concentration within the range of from 0.0001 to
1000mol/L, preferably from 0.005 to 20mol/L.
[0168] The compound represented by the formula (1) and the
pharmaceutically acceptable salt thereof can be utilized as a
therapeutic or prophylactic drug for various diseases in which a
FXa-dependent coagulation process is involved in the pathology.
Examples of the disease include, besides the above-mentioned
thrombus formation during extracorporeal blood circulation,
cerebral infarction, cerebral thrombus, cerebral embolism,
transient cerebral ischemic attack (TIA), acute and chronic
myocardial infarction, unstable angina pectoris, pulmonary
embolism, peripheral arterial occlusive disease, deep vein
thrombosis, disseminated intravascular coagulation syndrome,
thrombus formation after artificial vascular prosthesis or
replacement of artificial valve, reocclusion and restenosis after
coronary-artery bypass surgery, reocclusion and restenosis after
reconstruction of blood vessel such as percutaneous transluminal
coronary angioplasty (PTCA), percutaneous transluminal coronary
recanaryzation (PTCR) and the like, and the like.
[0169] Other features of the invention will become apparent in the
course of the following descriptions of exemplary embodiments which
are given for illustration of the invention and are not intended to
be limiting thereof.
EXAMPLES
Example 1
2-{3-amidinophenoxy}ethyl 1-pyridin-4-ylpiperidine-4-carboxylate
ditrifluoroacetate
Step 1. Synthesis of 2-(3-cyanophenoxy)ethyl acetate
[0170] 3-Cyanophenol (10.1 g, 84.8 mmol) and potassium carbonate
(19.5 g, 141 mmol) were suspended in acetone (280 ml), 2-bromoethyl
acetate (7.8 ml, 70.7 mmol) was added, and the mixture was stirred
at 50.degree. C. for 8 hours. Sodium iodide (1.06 g, 7.07 mmol) was
added to the reaction mixture, and the mixture was heated under
reflux for two nights and concentrated under reduced pressure. The
residue was diluted with ethyl acetate, and the mixture was washed
with 1N sodium hydroxide, 1N hydrochloric acid, and saturated
brine, and dried over anhydrous sodium sulfate. The solvent was
evaporated under reduced pressure to give the title compound
without purification.
[0171] yield 8.94 g (43.6 mmol, 51%)
[0172] .sup.1H-NMR (CDCl.sub.3) .delta. 2.11 (3H, s), 4.20 (2H,
br), 4.44 (2H, br), 7.14-7.16 (1H, m), 7.26-7.28 (1H, m), 7.36-7.41
(1H, m).
Step 2. Synthesis of 3-(2-hydroxyethoxy)benzonitrile
[0173] 2-(3-Cyanophenoxy)ethyl acetate (3.01 g, 14.7 mmol) obtained
in Step 1 was dissolved in a mixed solvent of methanol and
tetrahydrofuran (1:1), and 2N lithium hydroxide solution (14.7 ml)
was added under ice-cooling. The mixture was stirred at room
temperature for 45 min, 3N hydrochloric acid (10 ml) was added
under ice-cooling, and the mixture was concentrated under reduced
pressure. The residue was diluted with ethyl acetate, and the
mixture was washed with 1N hydrochloric acid, saturated aqueous
sodium hydrogencarbonate solution, and saturated brine, and dried
over anhydrous sodium sulfate. The solvent was evaporated under
reduced pressure. The obtained residue was purified by silica gel
chromatography (hexane:ethyl acetate 85:15-55:45) to give the title
compound.
[0174] yield 1.75 g (10.7 mmol, 73%)
[0175] .sup.1H-NMR (CDCl.sub.3) .delta. 3.98-4.01 (2H, m),
4.09-4.12 (2H, m), 7.15-7.18 (2H, m), 7.25-7.28 (1H, m), 7.36-7.42
(1H, m).
Step 3. Synthesis of
tert-butyl[3-(2-hydroxyethoxy)phenyl](imino)methylcarbamate
[0176] 3-(2-Hydroxyethoxy)benzonitrile (1.60 g, 9.81 mmol) obtained
in Step 2 was dissolved in anhydrous ethanol (570 .mu.l) and 4N
hydrochloric acid/1,4-dioxane solution (5.1 ml), and the mixture
was stirred in a closed system at room temperature for two nights.
The solvent was evaporated under reduced pressure, anhydrous
ethanol (30 ml) and ammonium carbonate (4.7 g, 49 mmol) were added
to the obtained residue, and the mixture was stirred at room
temperature for 6 hours. The solvent was evaporated under reduced
pressure, and the obtained residue was suspended in
dimethylformamide (20 ml). Triethylamine (4.1 ml, 29.4 mmol) and a
solution (10 ml) of di-tert-butyldicarbonate (4.28 g, 19.6 mmol) in
dimethylformamide were added dropwise under ice-cooling, and the
mixture was stirred at room temperature overnight.
N,N-Dimethylethylenediamine (2.2 ml, 19.6 mmol) was added under
ice-cooling, and the mixture was stirred at room temperature for 30
minutes and concentrated under reduced pressure. The residue was
diluted with ethyl acetate, and the mixture was Cashed with
saturated aqueous ammonium chloride solution, saturated aqueous
sodium hydrogencarbonate solution, and saturated brine, and dried
over anhydrous sodium sulfate. The organic layer was filtered
through silica gel, and the solvent was evaporated under reduced
pressure to give the title compound.
[0177] yield 64.5 mg (0.127 mmol, 37%)
[0178] MS (ESI, m/z) 281 (MH+)
[0179] .sup.1H-NMR (CDCl.sub.3) .delta. 1.55 (9H, s), 3.95 (2H, t),
4.13 (2H, t), 7.04-7.08 (1H, m), 7.30-7.36 (2H, m), 7.44-7.45 (1H,
m).
Step 4. Synthesis of
2-{3-[[(tert-butoxycarbonyl)amino](imino)methyl]phenoxy}ethyl
1-pyridin-4-ylpiperidine-4-carboxylate
[0180] 1-Pyridin-4-ylpiperidine-4-carboxylic acid hydrochloride
(573 mg, 2.36 mmol) was suspended in dichloromethane (15 ml), and
oxalyl chloride (403 .mu.l, 4.72 mmol) and a catalytic amount of
DMF were added. The mixture was stirred at room temperature for 15
minutes and concentrated under reduced pressure, tetrahydrofuran
(15 ml) and triethylamine (658 .mu.l) were added to the residue,
and tert-butyl[3-(2-hydroxyethoxy)phenyl](imino)methylcarbamate
(440 mg, 1.57 mmol) obtained in Step 3 was added under ice-cooling.
The mixture was stirred at room temperature for 30 minutes, and the
solvent was evaporated under reduced pressure. The obtained residue
was subjected to reversed-phase HPLC using, as a filler, silica gel
to which octadodecyl group was chemically bonded, and eluted with a
mixed solution of water and acetonitrile, which contains 0.1%
trifluoroacetic acid (v/v), and the objective fraction was
lyophilized to give the title compound.
[0181] yield 85.4 mg (0.147 mmol, 9.3%)
[0182] MS (ESI, m/z) 469 (MH+)
Step 5. Synthesis of 2-{3-amidinophenoxy}ethyl
1-pyridin-4-ylpiperidine-4-carboxylate ditrifluoroacetate
[0183]
2-{3-[[(tert-Butoxycarbonyl)amino](imino)methyl]phenoxy}ethyl
1-pyridin-4-ylpiperidine-4-carboxylate (85 mg, 0.147 mmol) obtained
in Step 4 was dissolved in glacial acetic acid (2 ml), and
trifluoroacetic acid (3 ml) was added thereto. The mixture was
stirred at room temperature for 1.5 hours, and concentrated under
reduced pressure, and the obtained residue was purified by
reversed-phase HPLC in the same manner as in Step 4 to give the
title compound.
[0184] yield 57.0 mg (0.0955 mmol, 65%)
[0185] MS (ESI, m/z) 369 (MH+)
[0186] .sup.1H-NMR (DMSO-d.sub.6) .delta. 1.56-1.70 (2H, m),
1.9.5-2.01 (2H, m), 2.85 (1H, sept), 3.28-3.37 (2H, m), 4.11-4.16
(2H, m), 4.31-4.32 (2H, m), 4.42-4.43 (2H, m), 7.19-7.22 (2H, m),
7.30-7.34 (1H, m), 7.42-7.44 (2H, m), 7.54 (1H, t), 8.24 (2H, d),
9.34 (2H, s), 9.57 (2H, s).
Example 2
2-{3-amidinophenoxy}ethyl 4-[imino(pyrrolidin-1-yl)methyl]benzoate
ditrifluoroacetate
Step 1. Synthesis of 3-hydroxybenzamidine trifluoroacetate
[0187] To 3-cyanophenol (5.00 g, 42.0 mmol) were added anhydrous
ethanol (6.1 ml, 210 mmol) and 4N hydrochloric acid/1,4-dioxane
solution (55 ml), and the mixture was stirred in a closed system at
room temperature for three nights. The solvent was evaporated under
reduced pressure, and the obtained residue was added slowly at
-78.degree. C. to ethanol (210 ml) into which ammonia gas had been
blown at the same temperature for 30 minutes. The temperature was
gradually raised to room temperature, and the mixture was stirred
overnight. The solvent was evaporated under reduced pressure,
diethyl ether and ethanol were added to the residue, and the
precipitated crystals (5.89 g) were collected by filtration. 2 g
thereof was purified by reversed-phase HPLC in the same manner as
in Step 4 of Example 1 to give the title compound.
[0188] yield 964 mg (3.85 mmol, 27%)
[0189] MS (ESI, m/z) 137 (MH+)
[0190] .sup.1H-NMR (DMSO-d.sub.6) .delta. 7.11-7.22 (3H, m), 7.41
(1H, t), 9.24 (4H, s).
Step 2. Synthesis of 4-[imino(pyrrolidin-1-yl)methyl]benzoic acid
hydrochloride
[0191] 4-Cyanobenzoic acid (10.0 g, 68.0 mmol) was dissolved in
anhydrous ethanol (10 ml) and 4N hydrochloric acid/1,4-dioxane 90
ml, and the mixture was stirred in a closed system at room
temperature for two nights, and further stirred in an open system
for at 35.degree. C. 3 hours. The solvent was evaporated under
reduced pressure, and the obtained residue was suspended in
anhydrous ethanol (100 ml), and pyrrolidine (11.4 ml, 136 mmol) was
added thereto, and the mixture was stirred at room temperature
overnight. The precipitated crystals were collected by filtration,
and washed with diethyl ether containing a small amount of 4N
hydrochloric acid/1,4-dioxane, and the crystals were collected by
filtration to give the title compound.
[0192] yield 5.56 g (25.5 mmol, 37%)
[0193] MS (ESI, m/z) 219 (MH+)
[0194] .sup.1H-NMR (CD.sub.3OD) .delta. 1.94-2.02 (2H, m),
2.14-2.23 (2H, m), 3.49 (2H, t), 3.63 (2H, t), 7.58 (2H, d), 8.08
(2H, d).
Step 3. Synthesis of 2-bromoethyl
4-[imino(pyrrolidin-1-yl)methyl]benzoate trifluoroacetate
[0195] 4-[Imino(pyrrolin-1-yl)methyl]benzoic acid hydrochloride
(2.17 g, 8.52 mmol) obtained in Step 2 was dissolved in
2-bromoethanol (20 ml), p-toluenesulfonic acid monohydrate (162 mg,
0.852 mmol) was added thereto, and the mixture was stirred at
85.degree. C. overnight. The solvent was evaporated under reduced
pressure, and the obtained residue was purified by reversed-phase
HPLC in the same manner as in Step 4 of Example 1 to give the title
compound.
[0196] yield 3.39 g (7.72 mmol, 91%)
[0197] MS (ESI, m/z) 325 (MH+)
[0198] .sup.1H-NMR (DMSO-d.sub.6) .delta. 1.85 (2H, quint), 2.04
(21H, quint), 3.34 (2H, t), 3.54 (2H, t), 3.83 (2H, t), 4.63 (2H,
t), 7.80 (2H, d), 8.15 (2H, d), 8.91 (1H, s), 9.37 (1H, d).
Step 4. Synthesis of 2-{3-amidinophenoxy}ethyl
4-[imino(pyrrolidin-1-yl)methyl]benzoate ditrifluoroacetate
[0199] 3-Hydroxybenzamidine trifluoroacetate (1.19 g, 6.92 mmol)
obtained in Step 1, 2-bromoethyl
4-[imino(pyrrolidin-1-yl)methyl]benzoate trifluoroacetate (1.52 g,
3.46 mmol) obtained in Step 3, and cesium carbonate (4.51 g, 13.8
mmol) were stirred at 50.degree. C. overnight in anhydrous
N,N-dimethylformamide (35 ml). 3N hydrochloric acid (9 ml) was
added under ice-cooling, the solvent was evaporated under reduced
pressure, and the obtained residue was purified by reversed-phase
HPLC in the same manner as in Step 4 of Example 1 to give the title
compound.
[0200] yield 404 mg (0.664 mmol, 19%)
[0201] MS (ESI, m/z) 381 (MH+)
[0202] .sup.1H-NMR (DMSO-d.sub.6) .delta. 1.86 (2H, quint), 2.06
(2H, quint), 3.34 (2H, t), 3.56 (2H, t), 4.47 (2H, m), 4.71 (2H,
m), 7.35-7.44 (3H, m), 7.79 (2H, d), 8.14 (2H, d), 8.94 (1H, s),
9.32 (4H, d), 9.39 (1H, s).
Example 3
2-{3-amidinophenoxy}ethyl
4-({N-methyl-N-[2-methylaminoethyl]-amino}carbonyl)benzoate
ditrifluoroacetate
Step 1. Synthesis of
2-{4-[(2-bromoethoxy)carbonyl]phenyl}-1,3-dimethyl-4,5-dihydro-1H-imidazo-
-3-lium trifluoroacetate
[0203] 4-Cyanobenzoic acid (10.1 g, 68.9 mmol) was dissolved in
anhydrous ethanol (10 ml) and 4N hydrochloric acid/1,4-dioxane (100
ml), and the mixture was stirred in a closed system at room
temperature for two nights. The solvent was evaporated under
reduced pressure, and the obtained residue was suspended in
anhydrous ethanol (50 ml). N,N'-Dimethylethylenediamine (7.4 ml,
68.9 mmol) was added, and the mixture was stirred at room
temperature overnight. The solvent was evaporated under reduced
pressure, and the obtained residue (500 mg, 1.77 mmol) was
dissolved in 2-bromoethanol (3 ml). p-Toluenesulfonic acid
monohydrate (5 mg) was added, and the mixture was stirred at
50.degree. C. for 2 days. The temperature was raised to 70.degree.
C., and the mixture was further stirred overnight. The solvent was
evaporated under reduced pressure, and the obtained residue was
purified by reversed-phase HPLC in the same manner as in Step 4 of
Example 1 to give the title compound.
[0204] yield 310 mg (0.706 mmol, 40%)
[0205] MS (ESI, m/z) 325 (MH+)
Step 2. Synthesis of 2-{3-amidinophenoxy}ethyl
4-({N-methyl-N-[2-methylaminoethyl]-amino}carbonyl)benzoate
ditrifluoroacetate
[0206]
2-{4-[(2-Bromoethoxy)carbonyl]phenyl}-1,3-dimethyl-4,5-dihydro-1H--
imidazo-3-lium trifluoroacetate (136 mg, 0.310 mmol) obtained in
Step 1,3-hydroxybenzamidine trifluoroacetate (93 mg, 0.372 mmol)
obtained in Step 1 of Example 2, and potassium carbonate (129 mg,
0.930 mmol) were suspended in N,N-dimethylformamide (3.5 ml), and
the mixture was stirred at 50.degree. C. for 2 hours. The solvent
was evaporated under reduced pressure, and the obtained residue was
purified by reversed-phase HPLC in the same manner as in Step 4 of
Example 1 to give the title compound.
[0207] yield 40.4 mg (0.0644 mmol, 21%)
[0208] MS (ESI, m/z) 399 (MH+)
[0209] .sup.1H-NMR (DMSO-d.sub.6) .delta. 2.65 (3H, s), 2.89 (3H,
s), 3.22 (2H, br), 3.76 (2H, br), 4.47 (2H, br), 4.68 (2H, br),
7.36-7.42 (1H, m), 7.45-7.46 (2H, m), 7.52-7.58 (1H, m), 7.63-7.66
(2H, m), 8.03 (2H, dd), 8.75 (2H, br), 9.33 (2H, s), 9.50 (2H,
s).
Example 4
2-{3-amidinophenoxy}ethyl
4-methyl-1-pyridin-4-ylpiperidine-4-carboxylate
ditrifluoroacetate
Step 1. Synthesis of 1-tert-butyl 4-ethyl
4-methylpiperidine-1,4-dicarboxylate
[0210] Ethyl N-tert-butoxycarbonyl isonipecotate (2.0 g, 7.8 mmol)
was dissolved in THF (40 ml), and 2.0 M-THF solution (7.8 ml, 15.5
mmol) of lithium diisopropylamide was added dropwise at -78.degree.
C. After stirring for 10 minutes, iodomethane (1.21 ml, 19.4 mmol)
was added, and the temperature was raised to 0.degree. C. over 3
hours. The reaction was quenched with saturated aqueous ammonium
chloride solution (10 ml), and the solvent was evaporated under
reduced pressure. The residue was diluted with ethyl acetate, and
the mixture was washed with 1N hydrochloric acid, 1N aqueous sodium
hydroxide solution and saturated brine, the organic layer was dried
over anhydrous magnesium sulfate, and concentrated under reduced
pressure. The obtained residue was purified by the silica gel
chromatography (hexane:ethyl acetate 100:0-1:4) to give the title
compound.
[0211] yield 1.92 g (7.08 mmol, 91%)
[0212] .sup.1H-NMR (CDCl.sub.3) .delta. 1.13 (3H, s), 1.20 (3H, t),
1.40 (9H, s), 1.30 (2H, br t), 2.00 (2H, br d), 2.93 (2H, hr t),
3.71 (2H, br d), 4.11 (2H, q).
Step 2. Synthesis of ethyl
4-methyl-1-pyridin-4-ylpiperidine-4-carboxylate
[0213] 1-tert-Butyl 4-ethyl 4-methylpiperidine-1,4-dicarboxylate
(500 mg, 1.84 mmol) obtained in Step 1 was dissolved in 4N
hydrochloric acid/1,4-dioxane (4 ml), and the mixture was stirred
at room temperature for 30 minutes. The solvent was evaporated
under reduced pressure, and the obtained residue was dissolved in
ethanol (18.4 ml). 4-Chloropyridine hydrochloride (276 mg, 1.84
mmol) and triethylamine (2.57 ml, 18.4 mmol) were added thereto,
and the reaction mixture was stirred at 170.degree. C. overnight in
a sealed tube. The mixture was concentrated under reduced pressure,
and the obtained residue was purified by silica gel chromatography
(hexane:ethyl acetate 95:5-10:90) to give the title compound.
[0214] yield 198 mg (0.78 mmol, 43%)
[0215] MS (ESI, m/z) 249 (MH+)
[0216] .sup.1H-NMR (CDCl.sub.3) .delta. 1.24 (3H, s), 1.27 (3H, t),
1.51 (2H, ddd), 2.20 (2H, br d), 3.04 (2H, ddd), 3.61 (2H, ddd),
4.18 (2H, q), 6.64 (2H, d), 8.24 (2H, d).
Step 3. Synthesis of 4-methyl-1-pyridin-4-ylpiperidine-4-carboxylic
acid trifluoroacetate
[0217] Ethyl 4-methyl-1-pyridin-4-ylpiperidine-4-carboxylate (100
mg, 0.40 mmol) obtained in Step 2 was dissolved in methanol (1 ml),
1N lithium hydroxide aqueous solution (2.0 ml, 2.0 mmol) was added,
and the mixture was stirred at room temperature for 2 hours. The
reaction was quenched with 1N hydrochloric acid (4 ml), the solvent
was evaporated under reduced pressure, and the obtained residue was
purified by reversed-phase HPLC in the same manner as in Step 4 of
Example 1 to give the title compound.
[0218] yield 115 mg (0.34 mmol, 86%)
[0219] MS (ESI, m/2) 221 (MH+)
[0220] .sup.1H-NMR (DMSO-d.sub.6) .delta. 1.20 (3H, s), 1.51 (2H,
ddd), 2.20 (2H, br d), 3.04 (2H, ddd), 3.61 (2H, ddd), 7.20 (2H,
d), 8.22 (2H, d).
Step 4. Synthesis of 2-{3-amidinophenoxy}ethyl
4-methyl-1-pyridin-4-ylpiperidine-4-carboxylate
ditrifluoroacetate
[0221] 4-Methyl-1-pyridin-4-ylpiperidine-4-carboxylic acid
trifluoroacetate (58 mg, 0.17 mmol) obtained in Step 3 was
suspended in dichloromethane (1.5 ml), DMF (5 .mu.L) and oxalyl
chloride (148 .mu.L, 0.86 mmol) were added, and the mixture was
stirred for 15 minutes. The solvent was evaporated under reduced
pressure, and the obtained residue was dissolved in dichloromethane
(0.5 ml). A catalytic amount of DMAP and
tert-butyl[3-(2-hydroxyethoxy)phenyl](imino)methylcarbamate (96 mg,
0.34 mmol) obtained in Step 3 of Example 1 were added thereto, and
the mixture was stirred at room temperature for 10 minutes.
Pyridine (20 .mu.L) was added, and the mixture was stirred for 1
hour. Acetic acid (1 ml) and trifluoroacetic acid (2 ml) were added
to the reaction mixture, and the mixture was stirred at room
temperature for 1 hour. The solvent was evaporated under reduced
pressure, and the obtained residue was purified by reversed-phase
HPLC in the same manner as in Step 4 of Example 1 to give the title
compound.
[0222] yield 4.1 mg (0.007 mmol, 4%)
[0223] MS (ESI, m/z) 383 (MH+)
[0224] .sup.1H-NMR (DMSO-d.sub.6) .delta. 1.21 (3H, s), 1.51 (2H,
ddd), 2.10 (2H, br d), 3.34 (2H, ddd), 3.96 (2H, ddd), 4.49 (2H,
br), 4.60 (2H, br), 7.20 (2H, d), 7.22-7.60 (4H, m), 8.22 (2H, d),
9.32 (4H, s).
Example 5
2-{3-amidinophenoxy}ethyl
4-(1-methyl-4,5-dihydro-1H-imidazol-2-yl)benzoate
ditrifluoroacetate
Step 1. Synthesis of 2-bromoethyl
4-(1-methyl-4,5-dihydro-1H-imidazol-2-yl)benzoate
trifluoroacetate
[0225] 4-Cyanobenzoic acid (5.00 g, 34.0 mmol) was dissolved in
anhydrous ethanol (3.9 ml) and 4N hydrochloric acid/1,4-dioxane (36
ml), and the mixture was stirred in a closed system at room
temperature for three nights. The solvent was evaporated under
reduced pressure, and the obtained residue (1.53 g) was suspended
in anhydrous ethanol 25 ml. N-Methylethylenediamine (700 .mu.l, 7.9
mmol) was added thereto, and the mixture was stirred at room
temperature overnight. The reaction mixture was concentrated under
reduced pressure, and the obtained residue was dissolved in
2-bromoethanol (7 ml). p-Toluenesulfonic acid monohydrate (about 10
mg) was added thereto, and the mixture was stirred at 70.degree. C.
overnight. p-Toluenesulfonic acid (10 mg) was added again, and the
mixture was stirred at 70.degree. C. overnight. The solvent was
evaporated under reduced pressure, and the residue was purified by
reversed-phase HPLC in the same manner as in Step 4 of Example 1 to
give the title compound.
[0226] yield 360 mg (0.847 mmol, about 21%)
[0227] MS (ESI, m/z) 311 (MH+)
Step 2. Synthesis of 2-{3-amidinophenoxy}ethyl
4-(1-methyl-4,5-dihydro-1H-imidazol-2-yl)benzoate
ditrifluoroacetate
[0228] 3-Hydroxybenzamidine trifluoroacetate (42 mg, 0.168 mmol)
obtained in Step 1 of Example 2,2-bromoethyl
4-(1-methyl-4,5-dihydro-1H-imidazol-2-yl)benzoate trifluoroacetate
(59.5 mg, 0.140 mmol) obtained in Step 1, and potassium carbonate
(58.0 mg, 0.42 mmol) were suspended in N,N-dimethylformamide (1
ml), and the mixture was stirred at 50.degree. C. for 6.5 hours.
The reaction mixture was ice-cooled, 1N hydrochloric acid (840
.mu.l) was added, and the mixture was sufficiently stirred, and
concentrated under reduced pressure. The obtained residue was
purified by reversed-phase HPLC in the same manner as in Step 4 of
Example 1 to give the title compound.
[0229] yield 25.4 mg (0.0427 mmol, 31%)
[0230] MS (ESI, m/z) 367 (MH+)
[0231] .sup.1H-NMR (DMSO-d.sub.6) .delta. 3.04 (3H, s), 3.92-4.13
(4H, m), 4.48 (2H, br), 4.71 (2H, br), 7.30-7.58 (4H, m), 7.85 (2H,
d), 8.18 (2H, d), 9.33 (2H, s), 9.43 (2H, s), 10.59 (1H, s).
Example 6
2-{5-amidino-2-hydroxyphenoxy}ethyl
4-[imino(pyrrolidin-1-yl)methyl]benzoate ditrifluoroacetate
Step 1. Synthesis of 4-(benzyloxy)-3-hydroxybenzonitrile
[0232] 3,4-Dihydroxybenzonitrile (5.20 g, 38.5 mmol) and potassium
carbonate (5.85 g, 42.4 mmol) were suspended in
N,N-dimethylformamide (120 ml), benzyl bromide (4.58 ml) was added,
and the mixture was stirred at 50.degree. C. for 3 hours. The
solvent was evaporated under reduced pressure, and the residue was
diluted with ethyl acetate. The mixture was washed with 1N
hydrochloric acid and saturated brine, dried over anhydrous
magnesium sulfate, and concentrated under reduced pressure. The
obtained residue was purified by silica gel chromatography
(hexane:ethyl acetate 8:1-4:1) to give the title compound.
[0233] yield 6.02 g (26.8 mmol, 70%)
[0234] .sup.1H-NMR (CDCl.sub.3) .delta. 5.17 (2H, s), 5.91 (1H, s),
6.97 (1H, s), 7.16 (1H, d), 7.18 (1H, d), 7.41 (5H, s).
Step 2. Synthesis of 4-(benzyloxy)-3-hydroxybenzamidine
trifluoroacetate
[0235] 4-(1-Benzyloxy)-3-hydroxybenzonitrile (4.35 g, 19.3 mmol)
obtained in Step 1 was dissolved in anhydrous ethanol (3 ml) and 4N
hydrochloric acid/1,4-dioxane solution (27 ml), and the mixture was
stirred in a closed system at room temperature for two nights. The
solvent was evaporated under reduced pressure, anhydrous ethanol
(60 ml) and ammonium carbonate (9.27 g, 96.5 mmol) were added to
the obtained residue, and the mixture was stirred at room
temperature for 4 hours. The solvent was evaporated under reduced
pressure, and the obtained residue was purified by reversed-phase
HPLC in the same manner as in Step 4 of Example 1 to give the title
compound.
[0236] yield 1.56 mg (6.42 mmol, 33%)
[0237] MS (ESI, m/z) 243 (MH+)
[0238] .sup.1H-NMR (DMSO-d.sub.6) .delta. 5.26 (2H, s), 7.18-7.26
(3H, m), 7.30-7.42 (3H, m), 7.48-7.50 (2H, m), 8.98 (2H, s), 9.05
(2H, s), 9.73 (1H, s).
Step 3. Synthesis of 2-{5-amidino-2-hydroxyphenoxy}ethyl
4-[imino(pyrrolidin-1-yl)methyl]benzoate ditrifluoroacetate
[0239] 4-(Benzyloxy)-3-hydroxybenzamidine trifluoroacetate (101 mg,
0.284 mmol) obtained in Step 2,2-bromoethyl
4-[imino(pyrrolidin-1-yl)methyl]benzoate trifluoroacetate (125 mg,
0.284 mmol) obtained in Step 3 of Example 2, and cesium carbonate
(277 mg, 0.852 mmol) were suspended in anhydrous
N,N-dimethylformamide, and the mixture was stirred at 50.degree. C.
for 5 hours. The reaction mixture was ice-cooled, 1N hydrochloric
acid (2 ml) was added, and the mixture was sufficiently stirred at
room temperature, and concentrated under reduced pressure. The
obtained residue was dissolved in 0.1N hydrochloric acid, the
mixture was washed twice with ethyl acetate, and the aqueous layer
was freeze-dried. Ethanol (10 ml) and 10% palladium-carbon (45 mg)
were added to the residue, and the mixture was stirred for 5 hours
under hydrogen atmosphere. After filtration through celite, the
solvent was evaporated under reduced pressure, and the obtained
residue was purified by reversed-phase HPLC in the same manner as
in Step 4 of Example 1 to give the title compound.
[0240] yield 46.6 mg (0.0746 mmol, 26%)
[0241] MS (ESI, m/z) 397 (MH+)
[0242] .sup.1H-NMR (DMSO-d.sub.6) .delta. 1.86 (2H, quint), 2.06
(2H, quint), 3.34 (2H, t), 3.56 (2H, t), 4.45 (2H, br), 4.69 (2H,
br), 6.99 (1H, d), 7.41 (1H, dd), 7.52 (1H, d), 7.79 (2H, d), 8.13
(2H, d), 8.95 (1H, s), 9.02 (2H, s), 9.06 (2H, s), 9.39 (1H,
s).
Example 7
2-{5-amidino-2-hydroxyphenoxy}ethyl
4-[(1-(1-iminoethyl)piperidin-4-yl)oxy]benzoate
ditrifluoroacetate
Step 1. Synthesis of 3-bromoethyl 4-(piperidin-4-yloxy)benzoate
[0243] Using 4-{[1-(tert-butoxycarbonyl)piperidin-4-yloxybenzoate
(5.00 g, 15.5 mmol) as a starting material and in the same manner
as; in Step 2 of Example 2, the title compound was obtained. This
compound in a crude state was used for the next reaction.
[0244] MS (ESI, m/z) 328 (MH+)
Step 2. Synthesis of 2-bromoethyl
4-[(1-(1-iminoethyl)piperidin-4-yl)oxy]benzoate
trifluoroacetate
[0245] 3-Bromoethyl 4-(piperidin-4-yloxy)benzoate (about 14.8 mmol)
obtained in Step 1 was dissolved in anhydrous ethanol (70 ml), and
ethyl acetimidate hydrochloride (3.66 g, 29.6 mmol) and
diisopropylethylamine (10.3 ml, 59.2 mmol) were added. The mixture
was stirred at room temperature overnight, and concentrated under
reduced pressure, and the residue was purified by reversed-phase
HPLC in the same manner as in Step 4 of Example 1 to give the title
compound.
[0246] yield 4.87 g (10.1 mmol, 65%)
[0247] MS (ESI, m/12) 369 (MH+)
Step 3. Synthesis of 2-[5-amidino-2-(benzyloxy)phenoxy]ethyl
4-[(1-(1-iminoethyl)piperidin-4-yl)oxy]benzoate
ditrifluoroacetate
[0248] To 2-bromoethyl
4-[(1-(1-iminoethyl)piperidin-4-yl)oxy]benzoate trifluoroacetate
(254 mg, 0.526 mmol) obtained in Step
2,4-(benzyloxy)-3-hydroxybenzamidine trifluoroacetate (187 mg,
0.526 mmol) obtained in Step 2 of Example 6, and cesium carbonate
(51.5 mg, 1.58 mmol) was added anhydrous N,N-dimethylformamide (5
ml), and the mixture was stirred at 50.degree. C. overnight. 1N
Hydrochloric acid (3.2 ml) was added under ice-cooling, the mixture
was concentrated under reduced pressure, and the obtained residue
was purified by reversed-phase HPLC in the same manner as in Step 4
of Example 1 to give the title compound.
[0249] yield 71.0 mg (0.0936 mmol, 18%)
[0250] MS (ESI, m/z) 531 (MH+)
Step 4. Synthesis of 2-{5-amidino-2-hydroxyphenoxy}ethyl
4-[(1-(1-iminoethyl)piperidin-4-yl)oxy]benzoate
ditrifluoroacetate
[0251] 2-[5-Amidino-2-(benzyloxy)phenoxy]ethyl
4-[(1-(1-iminoethyl)piperidin-4-yl)oxy]benzoate ditrifluoroacetate
(71 mg, 0.0936 mmol) obtained in Step 3 was dissolved in ethanol (2
ml), 10% palladium-carbon (7 mg) was added thereto, and the mixture
was stirred for 2 hours under hydrogen atmosphere. After filtration
through celite, the solvent was evaporated under reduced pressure,
and the obtained residue was purified by reversed-phase HPLC in the
same manner as in Step 4 of Example 1 to give the title
compound.
[0252] yield 56.7 mg (0.0847 mmol, 91%)
[0253] MS (ESI, m/2) 440 (MH+)
[0254] .sup.1H-NMR (DMSO-d.sub.6) .delta. 1.79 (2H, br), 2.08 (2H,
br), 2.30 (3H, s), 3.52-3.58 (2H, m), 3.72-3.73 (2H, m), 4.42 (2H,
br), 4.61 (2H, br), 4.85 (1H, br), 7.00 (1H, dd), 7.12 (2H, d),
7.40-7.44 (1H, m), 7.53-7.54 (1H, m), 7.91 (2H, dd), 8.70 (1H, s),
9.09 (2H, s), 9.16 (2H, s), 9.25 (1H, s).
Example 8
2-{5-amidino-2-hydroxyphenoxy}ethyl
4-({1-amidinopiperidin-4-yl}oxy)benzoate ditrifluoroacetate
Step 1. Synthesis of 2-bromoethyl
4-({1-amidinopiperidin-4-yl}oxy)benzoate trifluoroacetate
[0255] 3-Bromoethyl 4-(piperidin-4-yloxy)benzoate trifluoroacetate
(540 mg, 1.22 mmol) and 1H-pyrazole-1-carboxamidine hydrochloride
(215 mg) were dissolved in anhydrous acetonitrile (12 ml),
diisopropylethylamine (425 .mu.l) was added thereto, and the
mixture was stirred for 3.5 hours. The reaction mixture was
concentrated under reduced pressure, and the residue was purified
by reversed-phase HPLC in the same manner as in Step 4 of Example 1
to give the title compound.
[0256] yield 224 mg (0.463 mmol, 38%)
[0257] MS (ESI, m/2) 370 (MH+)
Step 2. Synthesis of 2-[5-amidino-2-(benzyloxy)phenoxy]ethyl
4-({1-amidinopiperidin-4-yl}oxy)benzoate ditrifluoroacetate
[0258] Using 2-bromoethyl 4-({1-amidinopiperidin-4-yl}oxy)benzoate
trifluoroacetate (224 mg, 0.463 mmol) obtained in Step
1,4-(benzyloxy)-3-hydroxybenzamidine trifluoroacetate (165 mg,
0.463 mmol) obtained in Step 2 of Example 6, and cesium carbonate
45.3 mg (1.39 mmol) and in the same manner as in Step 3 of Example
7, the title compound was obtained.
[0259] yield 137 mg (0.181 mmol, 39%)
[0260] MS (ESI, m/z) 531 (MH+)
Step 3. Synthesis of 2-{5-amidino-2-hydroxyphenoxy}ethyl
4-({1-amidinopiperidin-4-yl}oxy)benzoate ditrifluoroacetate
[0261] Using 2-[5-amidino-2-(benzyloxy)phenoxy]ethyl
4-({1-amidinopiperidin-4-yl}oxy)benzoate ditrifluoroacetate (137
mg, 0.181 mmol) obtained in Step 2 and 10% palladium-carbon (14 mg)
and in the same manner as in Step 4 of Example 7, the title
compound was obtained.
[0262] MS (ESI, m/z) 441 (MH+)
[0263] .sup.1H-NMR (DMSO-d.sub.6) .delta. 1.63-1.71 (2H, m),
2.00-2.08 (2H, m), 3.34-3.41 (2H, m), 3.64-3.70 (2H, m), 4.41 (2H,
br), 4.60 (2H, br), 4.75-4.80 (1H, m), 6.98 (1H, d), 7.11 (2H, d),
7.40 (1H, dd), 7.47 (4H, s), 7.50 (1H, d), 7.90 (22H, d), 8.94 (1H,
s), 9.05 (1H, s).
Example 9
2-(5-amidino-2-hydroxyphenoxy)ethyl
1-(1-iminoethyl)-4-methylpiperidine-4-carboxylate
ditrifluoroacetate
Step 1. Synthesis of 2-bromoethyl
1-(1-iminoethyl)-4-methylpiperidine-4-carboxylate
[0264] 1-tert-Butyl 4-ethyl 4-methylpiperidine-1,4-dicarboxylate
(250 mg, 0.92 mmol) obtained in Step 1 of Example 4 was dissolved
in 4N hydrochloric acid/1,4-dioxane (8 ml), and the mixture was
stirred at room temperature for 2 hours. The solvent was evaporated
under reduced pressure, and the obtained residue was dissolved in
ethanol (9 ml). Ethyl acetimidate hydrochloride (228 mg, 1.84 mmol)
and diisopropylethylamine (642 ml, 3.69, mmol) were added thereto,
and the mixture was stirred at room temperature for 2 days. The
solvent was evaporated under reduced pressure, and the obtained
residue was dissolved in 2-bromoethanol (2.5 ml). p-Toluenesulfonic
acid monohydrate (5 mg) was added, and the mixture was stirred at
90.degree. C. for two nights. The solvent was evaporated under
reduced pressure, and the obtained residue was purified by
reversed-phase HPLC in the same manner as in Step 4 of Example 1 to
give the title compound.
[0265] yield 298 mg (0.735 mmol, 80%)
[0266] MS (ESI, m/z) 292 (MH+)
Step 2. Synthesis of 2-(5-amidino-2-hydroxyphenoxy)ethyl
1-(1-iminoethyl)-4-methylpiperidine-4-carboxylate
ditrifluoroacetate
[0267] Using 2-bromoethyl
1-(1-iminoethyl)-4-methylpiperidine-4-carboxylate (96 mg, 0.24
mmol) obtained in Step 1 and in the same manner as in Step 3 of
Example 6, the title compound was obtained.
[0268] yield 24.8 mg (0.042 mmol, 18%)
[0269] MS (ESI, m/z) 363 (MH+)
[0270] .sup.1H-NMR (DMSO-d.sub.6) .delta. 1.19 (3H, s), 1.56 (2H,
ddd), 2.05 (2H, ddd), 2.24 (3H, s), 3.26 (2H, ddd), 3.77 (2H, ddd),
4.31 (2H, br), 4.48 (2H, br), 6.99 (1H, d), 7.40 (1H, d), 7.47 (1H,
s), 8.58 (1H, s), 9.07 (4H, s), 9.18 (1H, s).
Example 10
2-(5-amidino-2-hydroxyphenoxy)ethyl
1-amidino-4-methylpiperidine-4-carboxylate ditrifluoroacetate
[0271] Using 1H-pyrazole-1-carboxamidine hydrochloride instead of
ethyl acetimidate hydrochloride and in the same manner as in Step 1
and 2 of Example 9, the title compound was obtained.
[0272] MS (ESI, m/z) 364 (MH+)
[0273] .sup.1H-NMR (DMSO-d.sub.6) .delta. 1.18 (3H, s), 1.45 (2H,
ddd), 2.00 (2H, ddd), 3.14 (2H, ddd), 3.62 (2H, ddd), 4.30 (2H,
br), 4.47 (2H, br), 6.98 (1H, d), 7.40 (1H, dd), 7.46 (1H, d), 7.50
(4H, s), 9.07 (2H, s), 9.13 (2H, s).
Example 11
(2R)-3-{5-amidino-2-hydroxyphenoxy}-2-propyl
4-[imino(pyrrolidin-1-yl)methyl]benzoate ditrifluoroacetate
Step 1. Synthesis of
(2R)-3-{[(4-methylphenyl)sulfonyl]oxy}-2-propyl
4-[imino(pyrrolidin-1-yl)methyl]benzoate trifluoroacetate
[0274] 4-[Imino(pyrrolidin-1-yl)methyl]benzoic acid hydrochloride
(100 mg, 0.39 mmol) obtained in Step 2 of Example 2,
(2R)-1,2-propanediol-1-tosylate (1 g) and p-toluenesulfonic acid
monohydrate (10 mg) were heated at 90.degree. C. for 3 days. The
residue was purified by reversed-phase HPLC in the same manner as
in Step 4 of Example 1 to give the title compound.
[0275] yield 45.1 mg (0.083 mmol, 21%)
[0276] MS (ESI, m/z) 431 (MH+)
Step 2. Synthesis of (2R)-3-bromo-2-propyl
4-[imino(pyrrolidin-1-yl)methyl]benzoate trifluoroacetate
[0277] (2R)-3-{[(4-methylphenyl)sulfonyl]oxy}-2-propyl
4-[imino(pyrrolidin-1-yl)methyl]benzoate trifluoroacetate (45.1 mg,
0.083 mmol) obtained in Step 1 was dissolved in DMF (2 ml), lithium
bromide (72 mg, 0.83 mmol) was added thereto, and the mixture was
stirred at 50.degree. C. for 2 days. The solvent was evaporated
under reduced pressure, and the obtained residue was purified by
reversed-phase HPLC in the same manner as in Step 4 of Example 1 to
give the title compound.
[0278] yield 29.1 mg (0.064 mmol, 77%)
[0279] MS (ESI, m/z) 340 (MH+)
[0280] .sup.1H-NMR (DMSO-d.sub.6) .delta. 1.41 (3H, d), 1.86 (2H,
quint), 2.06 (2H, quint), 3.36 (2H, t), 3.56 (2H, t), 3.77 (1H,
dd), 3.85 (1H, dd), 5.29 (1H, ddd), 7.81 (2H, d), 8.15 (2H, d),
8.96 (1H, s), 9.38 (1H, s).
Step 3. Synthesis of (2R)-3-{5-amidino-2-hydroxyphenoxy}-2-propyl
4-[imino(pyrrolidin-1-yl)methyl]benzoate ditrifluoroacetate
[0281] Using (1R)-2-bromo-1-methylethyl
4-[imino(pyrrolidin-1-yl)methyl]benzoate trifluoroacetate (29.1 mg,
0.064 mmol) obtained in Step 2 and in the same manner as in Step 3
of Example 6, the title compound was obtained.
[0282] yield 2.4 mg (0.004 mmol, 6%)
[0283] MS (ESI, m/z) 411 (MH+)
Example 12
{4-amidino-2-[2-({4-[imino(pyrrolidin-1-yl)methyl]benzoyl}oxy)ethoxy]pheno-
xy}acetic acid ditrifluoroacetate
Step 1. Synthesis of
2-{5-amidino-2-[benzyloxycarbonylmethoxy]phenoxy}ethyl
4-[imino(pyrrolidin-1-yl)methyl]benzoate ditrifluoroacetate
[0284] The compound of Example 6 (50 mg, 0.08 mmol) was dissolved
in DMF (0.8 ml), benzyl bromoacetate (12.7 .mu.L, 0.08 mmol) and
potassium carbonate (33 mg, 0.24 mmol) were added thereto, and the
mixture was stirred at 40.degree. C. overnight. The reaction was
quenched with 1N hydrochloric acid (1 ml), the solvent was
evaporated under reduced pressure, and the obtained residue was
purified by reversed-phase HPLC in the same manner as in Step 4 of
Example 1 to give the title compound.
[0285] yield 12.8 mg (0.017 mmol, 21%)
[0286] MS (ESI, m/z) 545 (MH+)
Step 2. Synthesis of
{4-amidino-2-[2-({4-[imino(pyrrolidin-1-yl)methyl]benzoyl}oxy)ethoxy]phen-
oxy}acetic acid ditrifluoroacetate
[0287] 2-{5-Amidino-2-[benzyloxycarbonylmethoxy]phenoxy}ethyl
4-[imino(pyrrolidin-1-yl)methyl]benzoate ditrifluoroacetate (12.8
mg, 0.017 mmol) obtained in Step 1 was dissolved in ethanol (1 ml),
10% palladium-carbon (5 mg) was added thereto, and the mixture was
stirred for 3 hours under hydrogen atmosphere. After filtration
through celite, the solvent was evaporated under reduced pressure,
and the obtained residue was purified by reversed-phase HPLC in the
same manner as in Step 4 of Example 1 to give the title
compound.
[0288] yield 10.1 mg (0.015 mmol, 87%)
[0289] MS (ESI, m/z) 455 (MH+)
[0290] .sup.1H-NMR (DMSO-d.sub.6) .delta. 1.84 (2H, quint), 2.04
(2H, quint), 3.34 (2H, t), 3.56 (2H, t), 4.48 (2H, br), 4.69 (2H,
br), 4.84 (2H, s), 7.11 (1H, d), 7.47 (1H, dd), 7.55 (1H, d), 7.79
(2H, d), 8.13 (2H, d), 8.94 (1H, s), 9.14 (2H, s), 9.17 (2H, s),
9.39 (1H, s).
Example 13
2-[5-amidino-2-(2-hydroxyethoxy)phenoxy]ethyl
4-[imino(pyrrolidin-1-yl)methyl]benzoate ditrifluoroacetate
Step 1. Synthesis of
2-{5-amidino-2-[2-(benzyloxy)ethoxy]phenoxy}ethyl
4-[imino(pyrrolidin-1-yl)methyl]benzoate ditrifluoroacetate
[0291] An operation in the same manner as in Step 1 of Example 12
was performed using benzyl 2-bromoethyl ether (12.5 .mu.L, 0.08
mmol) instead of benzyl bromoacetate, and potassium carbonate (33
mg, 0.24 mmol), and the mixture was stirred at 40.degree. C.
overnight. The reaction was quenched with 1N hydrochloric acid (1
ml), the solvent was evaporated under reduced pressure, and the
obtained residue was purified by reversed-phase HPLC in the same
manner as in Step 4 of Example 1 to give the title compound.
[0292] yield 22.3 mg (0.029 mmol, 37%)
[0293] MS (ESI, m/z) 531 (MH+)
Step 2. Synthesis of 2-[5-amidino-2-(2-hydroxyethoxy)phenoxy]ethyl
4-[imino(pyrrolidin-1-yl)methyl]benzoate ditrifluoroacetate
[0294] 2-{5-Amidino-2-[2-(benzyloxy)ethoxy]phenoxy}ethyl
4-[imino(pyrrolidin-1-yl)methyl]benzoate ditrifluoroacetate (22.3
mg, 0.029 mmol) obtained in Step 1 was dissolved in acetic acid (1
ml), 10% palladium-carbon (5 mg) was added thereto, and the mixture
was stirred for 3 hours under hydrogen atmosphere. After filtration
through celite, the solvent was evaporated under reduced pressure,
and the obtained residue was purified by reversed-phase HPLC in the
same manner as in Step 4 of Example 1 to give the title
compound.
[0295] yield 14.0 mg (0.021 mmol, 72%)
[0296] MS (ESI, m/z) 441 (MH+)
[0297] .sup.1H-NMR (DMSO-d.sub.6) .delta. 1.87 (2H, quint), 2.06
(2H, quint), 3.34 (2H, t), 3.56 (2H, t), 3.70 (2H, t), 4.11 (2H,
t), 4.47 (2H, br), 4.70 (2H, br), 7.23 (1H, d), 7.53 (1H, dd), 7.56
(1H, d), 7.79 (2H, d), 8.12 (2H, d), 8.98 (1H, s), 9.17 (2H, s),
9.24 (2H, s), 9.41 (1H, s).
Example 14
[4-amidino-2-(2-{[4-({1-(1-iminoethyl)piperidin-4-yl}oxy)benzoyl]oxy}ethox-
y)phenoxy]acetic acid ditrifluoroacetate
[0298] The compound of Example 7 (200 mg, 0.299 mmol) and potassium
carbonate (124 mg, 0.897 mmol) were suspended in acetonitrile (3
ml), benzyl bromoacetate (56.9 .mu.l, 0.359 mmol) was added
thereto, and the mixture was stirred at 40.degree. C. overnight. 1N
Hydrochloric acid (1.8 ml) was added under ice-cooling, and the
mixture was concentrated under reduced pressure. The obtained
residue was dissolved in ethanol (3 ml), 10% palladium-carbon (45
mg) was added thereto, and the mixture was stirred overnight under
hydrogen atmosphere. After filtration through celite, the solvent
was evaporated under reduced pressure, and the obtained residue was
purified by reversed-phase HPLC in the same manner as in Step 4 of
Example 1 to give the title compound.
[0299] yield 53.8 mg (0.074 mmol, 25%)
[0300] MS (ESI, m/z) 498 (MH+)
[0301] .sup.1H-NMR (DMSO-d.sub.6) .delta. 1.75-1.83 (2H, m),
2.00-2.06 (2H, m), 2.29 (3H, s), 3.40-3.56 (4H, m), 4.46 (2H, br),
4.61 (2H, br), 4.80 (1H, br), 4.85 (2H, s), 7.10 (2H, d), 7.11 (1H,
d), 7.47 (1H, d), 7.52 (1H, dd), 7.92 (2H, d), 8.59 (1H, s), 8.87
(1H, s), 9.14 (4H, s).
Example 15
[4-amidino-2-(2-{[4-({1-amidinopiperidin-4-yl}oxy)benzoyl]oxy}ethoxy)pheno-
xy]acetic acid ditrifluoroacetate
Step 1. Synthesis of 2-{5-amidino-2-[benzyloxycarbonylmethoxy}ethyl
4-({1-amidinopiperidin-4-yl}oxy)benzoate ditrifluoroacetate
[0302] The compound of Example 8 (740 mg, 1.11 mmol) and potassium
carbonate (459 mg, 3.31 mmol) were suspended in dehydrated DMF,
benzyl bromoacetate (211 .mu.l, 1.33 mmol) was added thereto, and
the mixture was stirred at 40.degree. C. for 3 hours. 1N
Hydrochloric acid (7 ml) was added under ice-cooling, the mixture
was concentrated under reduced pressure, and the obtained residue
was purified by reversed-phase HPLC in the same manner as in Step 4
of Example 1 to give the title compound.
[0303] yield 445 mg (0.544 mmol, 49%)
[0304] MS (ESI, m/z) 589 (MH+)
Step 2. Synthesis of
[4-amidino-2-(2-{[4-({1-amidinopiperidin-4-yl}oxy)benzoyl]oxy}ethoxy)phen-
oxy]acetic acid ditrifluoroacetate
[0305] 2-{5-Amidino-2-[benzyloxycarbonylmethoxy}ethyl
4-({1-amidinopiperidin-4-yl}oxy)benzoate ditrifluoroacetate (445
mg, 0.544 mmol) obtained in Step 1 and 10% palladium-carbon (70 mg)
were suspended in a mixed solvent of ethanol (15 ml), 1,4-dioxane
(2 ml) and water (4 ml), and the mixture was stirred for 2 hours
under hydrogen atmosphere. After filtration through celite, the
solvent was evaporated under reduced pressure, and the obtained
residue was purified by reversed-phase HPLC in the same manner as
in Step 4 of Example 1 to give the title compound.
[0306] yield 375 mg (0.515 mmol, 95%)
[0307] MS (ESI, m/z) 499 (MH+)
[0308] .sup.1H-NMR (DMSO-d.sub.6) .delta. 1.63-1.70 (2H, m),
2.00-2.06 (2H, m), 3.35-3.41 (2H, m), 3.65-3.69 (2H, m), 4.44 (2H,
br), 4.61 (2H, br), 4.76-4.80 (1H, m), 4.85 (2H, s), 7.09-7.12 (3H,
m), 7.45 (1H, d), 7.50 (4H, s), 7.54 (1H, d), 7.91 (2H, d), 9.14
(4H, d).
Example 16
2-{3-amidinophenoxy}ethyl
4-[(1-(1-iminoethyl)piperidin-4-yl)oxy]benzoate
ditrifluoroacetate
Step 1. Synthesis of benzyl
4-{4-[(2-bromoethoxy)carbonyl]phenoxy}piperidine-1-carboxylate
[0309] 3-Bromoethyl 4-(piperidin-4-yloxy)benzoate trifluoroacetate
(11.0 g, 24.9 mmol) was dissolved in dichloromethane (150 ml), and
triethylamine (5.20 ml, 37.3 mmol) and benzyloxycarbonyl chloride
(5.27 ml, 37.3 mmol) were added thereto under ice-cooling. The
mixture was stirred at room temperature for 4 hours, and
ice-cooled. N,N-Dimethylethylenediamine (4.1 ml, 37.3 mmol) was
added thereto, the mixture was stirred at room temperature for 30
minutes. Saturated aqueous sodium hydrogencarbonate solution (100
ml) was added thereto, and the mixture was concentrated under
reduced pressure. The obtained residue was diluted with ethyl
acetate, and the organic layer was washed with 1N hydrochloric acid
and saturated brine, and dried over anhydrous sodium sulfate. The
solvent was evaporated under reduced pressure, and the residue was
purified by silica gel chromatography (hexane:ethyl acetate
9:1-4:1) to give the title compound.
[0310] yield 4.99 g (10.8 mmol, 43%)
[0311] MS (ESI, m/z) 462 (MH+)
Step 2. Synthesis of 2-{3-amidinophenoxy}ethyl
4-(piperidin-4-yloxy)benzoate
[0312] 3-Hydroxybenzamidine trifluoroacetate (298 mg, 1.19 mmol)
obtained in Step 1 of Example 2, benzyl
4-{4-[(2-bromoethoxy)carbonyl]phenoxy}piperidine-1-carboxylate (500
mg, 1.08 mmol), and cesium carbonate (717 mg, 2.20 mmol) were
suspended in dehydrated DMF, and the mixture was stirred at
50.degree. C. for 6 hours. The reaction mixture was ice-cooled, and
1N hydrochloric acid (4.5 ml) was added to the mixture and the
mixture was concentrated under reduced pressure. The obtained
residue was diluted with ethyl acetate, and the mixture was washed
with 0.1N hydrochloric acid and saturated brine, and dried over
anhydrous sodium sulfate. The solvent was evaporated, and the
obtained crude product (about 700 mg) was dissolved in ethanol (15
ml). 10% Palladium-carbon (105 mg) was added thereto, and the
mixture was stirred for 5.5 hours under hydrogen atmosphere. After
filtration through celite, the solvent was evaporated to give the
title compound as a crude product. This compound in a crude state
was used for the next reaction.
[0313] yield 538 mg (1.4 mmol, quantitative)
Step 3. Synthesis of 2-{3-amidinophenoxy}ethyl
4-[(1-(1-iminoethyl)piperidin-4-yl)oxy]benzoate
ditrifluoroacetate
[0314] Using 2-{3-amidinophenoxy}ethyl
4-(piperidin-4-yloxy)benzoate 179 mg (0.467 mmol) obtained in Step
2 as a starting material and according to the synthetic method of
Step 2 of Example 7, the title compound was obtained.
[0315] yield 70.4 mg (0.108 mmol, 23%)
[0316] MS (ESI, m/z) 424 (MH+)
[0317] .sup.1H-NMR (DMSO-d.sub.6) .delta. 1.78 (2H, br), 2.08 (2H,
br), 2.31 (3H, s), 3.52-3.59 (2H, m), 3.73-3.83 (2H, m), 4.45 (2H,
br), 4.62 (2H, br), 4.82-4.88 (1H, m), 7.13 (2H, d), 7.35-7.38 (1H,
m), 7.42-7.47 (2H, m), 7.55 (1H, t), 7.92 (2H, d), 8.72 (1H, s),
9.27 (1H, s), 9.34 (2H, s), 9.56 (2H, s).
Example 17
2-{3-amidinophenoxy}ethyl 4-({1-amidinopiperidin-4-yl}oxy)benzoate
ditrifluoroacetate
[0318] Using 2-{3-amidinophenoxy}ethyl
4-(piperidin-4-yloxy)benzoate (179 mg, 0.467 mmol) as a starting
material and according to the synthetic method of Step 1 of Example
8, the title compound was obtained.
[0319] yield 66.2 mg (0.101 mmol, 22%)
[0320] MS (ESI, m/z) 425 (MH+)
[0321] .sup.1H-NMR (DMSO-d.sub.6) .delta. 1.64-1.72 (2H, m),
2.00-2.08 (2H, m), 3.37-3.43 (2H, m), 3.65-3.71 (2H, m), 4.44 (2H,
br), 4.62 (2H, br), 4.78-4.93 (1H, m), 7.12 (2H, d), 7.35-7.38 (1H,
m), 7.42-7.47 (2H, m), 7.55 (1H, t), 7.62 (4H, s), 7.92 (2H, d),
9.34 (2H, s), 9.57 (2H, s).
Example 18
2-{5-amidino-2-methoxyphenoxy}ethyl
4-[imino(pyrrolidin-1-yl)methyl]benzoate ditrifluoroacetate
[0322] Using iodomethane instead of benzyl bromoacetate and in the
same manner as in Step 1 of Example 12, the title compound was
obtained.
[0323] yield 6.8 mg (0.011 mmol, 27%)
[0324] MS (ESI, m/z) 411 (MH+)
[0325] .sup.1H-NMR (DMSO-d.sub.6) .delta. 1.86 (2H, quint), 2.06
(2H, quint), 3.34 (2H, t), 3.56 (2H, t), 3.84 (3H, s), 4.46 (2H,
br), 4.70 (2H, br), 7.20 (1H, d), 7.53 (1H, dd), 7.54 (1H, d), 7.80
(2H, d), 8.13 (2H, d), 8.96 (1H, s), 9.13 (2H, s), 9.17.degree.
(2H, s), 9.40 (1H, s).
Example 19
2-{5-amidino-2-ethoxyphenoxy}ethyl
4-[imino(pyrrolidin-1-yl)methyl]benzoate ditrifluoroacetate
[0326] Using iodoethane instead of benzyl bromoacetate and in the
same manner as in Step 1 of Example 12, the title compound was
obtained.
[0327] yield 10 mg (0.016 mmol, 38%)
[0328] MS (ESI, m/z) 425 (MH+)
[0329] .sup.1H-NMR (DMSO-d.sub.6) .delta. 1.29 (3H, t), 1.87 (2H,
quint), 2.06 (2H, quint), 3.34 (2H, t), 3.56 (2H, t), 4.12 (2H, q),
4.46 (2H, br), 4.70 (2H, br), 7.18 (1H, d), 7.53 (1H, dd), 7.57
(1H, d), 7.80 (2H, d), 8.12 (2H, d), 8.98 (1H, s), 9.17 (4H, s),
9.42 (1H, s).
Example 20
2-[5-amidino-2-(cyanomethoxy)phenoxy]ethyl
4-[imino(pyrrolidin-1-yl)methyl]benzoate ditrifluoroacetate
[0330] Using iodoacetonitrile instead of benzyl bromoacetate and in
the same manner as in Step 1 of Example 12, the title compound was
obtained.
[0331] yield 277 mg (0.417 mmol, 52%)
[0332] MS (ESI, m/z) 435 (MH+)
[0333] .sup.1H-NMR (DMSO-d.sub.6) .delta. 1.84 (2H, quint), 2.04
(2H, quint), 3.32 (2H, t), 3.54 (2H, t), 4.48 (2H, br), 4.70 (2H,
br), 5.27 (2H, s), 7.34 (1H, d), 7.53 (1H, dd), 7.59 (1H, d), 7.77
(2H, d), 8.13 (2H, d), 8.93 (1H, s), 9.23 (4H, s), 9.38 (1H,
s).
Example 21
2-(5-amidino-2-{[(dimethylamino)thiocarbonyl]oxy}phenoxy)ethyl
4-{imino(pyrrolidin-1-yl)methyl}benzoate ditrifluoroacetate
[0334] Using N,N-dimethylthiocarbamoyl chloride instead of benzyl
bromoacetate and in the same manner as in Step 1 of Example 12, the
title compound was obtained.
[0335] yield 4 mg (0.006 mmol, 14%)
[0336] MS (ESI, m/z) 484 (MH+)
[0337] .sup.1H-NMR (DMSO-d.sub.6) .delta. 1.90 (2H, quint), 2.01
(2H, quint), 3.16 (3H, s), 3.24 (3H, s), 3.35 (2H, t), 3.86 (2H,
t), 4.46 (2H, br), 4.69 (2H, br), 7.00 (1H, d), 7.41 (1H, dd), 7.52
(1H, d), 7.63 (2H, d), 8.13 (2H, d), 8.97 (2H, s), 9.07 (2H, s),
9.28 (1H, s), 9.34 (1H, s).
Example 22
2-[5-amidino-2-(cyclopropylmethoxy)phenoxy]ethyl
4-[imino(pyrrolidin-1-yl)methyl]benzoate ditrifluoroacetate
[0338] Using (bromomethyl)cyclopropane instead of benzyl
bromoacetate and in the same manner as in Step 1 of Example 12, the
title compound was obtained.
[0339] yield 5.35 mg (0.00788 mmol, 16%)
[0340] MS (ESI, m/z) 450 (MH+)
[0341] .sup.1H-NMR (DMSO-d.sub.6) .delta. 0.26-0.28 (2H, m),
0.47-0.52 (2H, m), 1.17 (1H, br), 1.81-1.87 (2H, m), 2.01-2.06 (2H,
m), 3.31 (2H, br), 3.54 (2H, br), 3.91 (2H, d), 4.45 (2H, br), 4.69
(2H, br), 7.16 (1H, d), 7.47-7.53 (2H, m), 7.78 (2H, d), 8.11 (2H,
d), 8.93 (1H, s), 9.05 (2H, s), 9.13 (2H, s), 9.38 (1H, s).
Example 23
2-{5-amidino-2-propoxyphenoxy}ethyl
4-[imino(pyrrolidin-1-yl)methyl]benzoate ditrifluoroacetate
[0342] Using n-propyl bromide instead of benzyl bromoacetate and in
the same manner as in Step 1 of Example 12, the title compound was
obtained.
[0343] yield 4.94 mg (0.00741 mmol, 15%)
[0344] MS (ESI, m/z) 438 (MH+)
[0345] .sup.1H-NMR (DMSO-d.sub.6) .delta. 0.89 (3H, t), 1.66 (2H,
sext), 1.83-1.89 (2H, m), 2.00-2.07 (2H, m), 3.31 (2H, t), 3.54
(2H, t), 4.00 (2H, t), 4.43 (2H, br), 4.68 (2H, br), 7.18 (1H, d),
7.49-7.52 (2H, m), 7.77 (2H, d), 8.10 (2H, d), 8.92 (1H, s), 9.05
(2H, s), 9.13 (2H, s), 9.38 (1H, s).
Example 24
2-{5-amidino-2-isobutoxyphenoxy}ethyl
4-[imino(pyrrolidin-1-yl)methyl]benzoate ditrifluoroacetate
[0346] Using isobutyl bromide instead of benzyl bromoacetate and in
the same manner as in Step 1 of Example 12, the title compound was
obtained.
[0347] yield 6.94 mg (0.0102 mmol, 21%)
[0348] MS (ESI, m/z) 452 (MH+)
[0349] .sup.1H-NMR (DMSO-d.sub.6) .delta. 0.89 (6H, d), 1.82-2.06
(5H, m), 3.30 (2H, t), 3.54 (2H, t), 3.80 (2H, d), 4.42 (2H, br),
4.68 (2H, br), 7.17 (1H, d), 7.48-7.52 (2H, m), 7.76 (2H, d), 8.09
(2H, d), 8.94 (1H, s), 9.13 (4H, d), 9.38 (1H, s).
Example 25
2-{5-amidino-2-(2-pyrrolidin-1-ylethoxy)phenoxy}ethyl
4-[imino(pyrrolidin-1-yl)methyl]benzoate tritrifluoroacetate
[0350] Using 1-(2-chloroethyl)pyrrolidine hydrochloride instead of
benzyl bromoacetate, sodium iodide and in the same manner as in
Step 1 of Example 12, the title compound was obtained.
[0351] yield 10.3 mg (0.0123 mmol, 26%)
[0352] MS (ESI, m/z) 493 (MH+)
[0353] .sup.1H-NMR (DMSO-d.sub.6) .delta. 1.72-1.87 (4H, m), 2.03
(2H, q), 3.10 (2H, br), 3.31 (2H, t), 3.52-3.60 (6H, m), 4.38-4.46
(4H, m), 4.68 (2H, br), 7.26 (1H, d), 7.49-7.57 (2H, m), 7.78 (2H,
d), 8.11 (2H, d), 8.96 (1H, s), 9.21-9.23 (4H, m), 9.41 (1H,
s).
Example 26
2-{2-(2-aminoethoxy)-5-amidinophenoxy}ethyl
4-[imino(pyrrolidin-1-yl)methyl]benzoate tritrifluoroacetate
Step 1. Synthesis of
2-(5-amidino-2-{2-[(tert-butoxycarbonyl)amino]ethoxy}phenoxy)ethyl
4-[imino(pyrrolidin-1-yl)methyl]benzoate ditrifluoroacetate
[0354] Using 2-(tert-butoxycarbonyl)aminoethyl bromide instead of
benzyl bromoacetate and in the same manner as in Step 1 of Example
12, the title compound was obtained.
[0355] yield 30.7 mg (0.0400 mmol, 28%)
[0356] MS (ESI, m/z) 539 (MH+)
Step 2. Synthesis of 2-{2-(2-aminoethoxy)-5-amidinophenoxy}ethyl
4-[imino(pyrrolidin-1-yl)methyl]benzoate tritrifluoroacetate
[0357] To
2-(5-amidino-2-{2-[(tert-butoxycarbonyl)amino]ethoxy}phenoxy)et-
hyl 4-[imino(pyrrolidin-1-yl)methyl]benzoate ditrifluoroacetate
(30.7 mg, 0.0400 mmol) obtained in Step 1 were added anhydrous
1,4-dioxane (0.5 ml), dehydrated DMF (1 ml) and 4N hydrochloric
acid/1,4-dioxane (2 ml), and the mixture was stirred at room
temperature for 50 minutes. The solvent was evaporated under
reduced pressure, and the obtained residue was purified by
reversed-phase HPLC in the same manner as in Step 4 of Example 1 to
give the title compound.
[0358] yield 32.0 mg (0.0409 mmol, 100%)
[0359] MS (ESI, m/z) 439 (MH+)
[0360] .sup.1H-NMR (DMSO-d.sub.6) .delta. 1.80-1.89 (2H, m),
2.00-2.06 (2H, m), 3.18-3.34 (4H, m), 3.55 (2H, t), 4.28 (2H, t),
4.48 (2H, br), 4.69 (2H, br), 7.26 (1H, d), 7.53 (1H, dd), 7.60
(1H, d), 7.77 (2H, d), 8.10 (2H, d), 8.18 (3H, br), 8.99 (1H, s),
9.23 (2H, s), 9.36 (2H, s), 9.42 (1H, s).
Example 27
2-{2-[2-(acetamido)ethoxy]-5-amidinophenoxy}ethyl
4-[imino(pyrrolidin-1-yl)methyl]benzoate ditrifluoroacetate
[0361] The compound of Example 26 (30.2 mg, 0.0386 mmol) was
dissolved in pyridine (390 .mu.l), acetic anhydride (3.65 .mu.l,
0.0386 mmol) was added thereto, and the mixture was stirred at room
temperature for 1 hour. The solvent was evaporated under reduced
pressure, and the obtained residue was purified by reversed-phase
HPLC in the same manner as in Step 4 of Example 1 to give the title
compound.
[0362] yield 30.0 mg (0.0422 mmol, 109%)
[0363] MS (ESI, m/z) 481 (MH+)
[0364] .sup.1H-NMR (DMSO-d.sub.6) .delta. 1.73-1.89 (5H, m),
2.02-2.08 (2H, m), 3.32-3.37 (4H, m), 3.56 (2H, t), 4.07 (2H, t),
4.47 (2H, br), 4.68 (2H, br), 7.24 (1H, d), 7.51-7.57 (2H, m), 7.79
(2H, d), 8.11-8.13 (3H, m), 8.97 (1H, s), 9.18 (2H, s), 9.23 (2H,
s), 9.41 (1H, s).
Example 28
2-{2-(acetoxy)-5-amidinophenoxy}ethyl
4-[imino(pyrrolidin-1-yl)methyl]benzoate ditrifluoroacetate
[0365] Using acetyl chloride instead of benzyl bromoacetate and in
the same manner as in Step 1 of Example 12, the title compound was
obtained.
[0366] yield 7.52 mg (0.0113 mmol, 24%)
[0367] MS (ESI, m/z) 438 (MH+)
[0368] .sup.1H-NMR (DMSO-d.sub.6) .delta. 1.83-1.91 (2H, m),
2.02-2.11 (2H, m), 2.18-2.20 (3H, m), 3.35 (2H, t), 3.57 (2H, t),
4.47 (2H, br), 4.71 (2H, br), 7.36 (1H, d), 7.43-7.49 (1H, m), 7.64
(1H, d), 7.79-7.82 (2H, m), 8.13-8.16 (2H, m), 8.95 (1H, s),
9.34-9.41 (5H, m).
Example 29
2-(5-amidino-2-{[(dimethylamino)carbonyl]oxy}phenoxy)ethyl
4-[imino(pyrrolidin-1-yl)methyl]benzoate ditrifluoroacetate
[0369] Using N,N-dimethylcarbamoyl chloride instead of benzyl
bromoacetate and in the same manner as in Step 1 of Example 12, the
title compound was obtained.
[0370] yield 4.31 mg (0.00605 mmol, 13%)
[0371] MS (ESI, m/z) 467 (MH+)
[0372] .sup.1H-NMR (DMSO-d.sub.6) .delta. 1.86 (2H, quint), 2.06
(12H, quint), 2.75 (3H, s), 2.92-3.01 (5H, m), 3.32 (2H, t), 3.55
(2H, t), 4.48 (2H, br), 4.68 (2H, br), 7.37 (1H, d), 7.45 (1H, dd),
7.61 (1H, d), 7.79 (12H, d), 8.14 (2H, d), 8.93 (1H, s), 9.23 (2H,
s), 9.32 (2H, s), 9.39 (1H, s).
Example 30
4-amidino-2-[2-({4-[imino(pyrrolidin-1-yl)methyl]benzoyl}oxy)ethoxy]phenyl
pyrrolidine-1-carboxylate ditrifluoroacetate
[0373] Using 1-pyrrolidinecarbonyl chloride instead of benzyl
bromoacetate, potassium hydrogencarbonate instead of potassium
carbonate, and in the same manner as in Step 1 of Example 12, the
title compound was obtained.
[0374] yield 9.43 mg (0.0131 mmol, 27%)
[0375] MS (ESI, m/z) 493 (MH+)
[0376] .sup.1H-NMR (DMSO-d.sub.6) .delta. 1.70-1.78 (4H, m), 1.85
(2H, quint), 2.04 (2H, quint), 3.14 (2H, t), 3.30 (2H, t), 3.38
(2H, t), 3.54 (2H, t), 4.46 (2H, br), 4.66 (2H, br), 7.34 (1H, d),
7.44 (1H, dd), 7.59 (1H, d), 7.78 (2H, d), 8.11 (2H, d), 8.93 (1H,
s), 9.31 (4H, s), 9.39 (1H, s).
Example 31
3-{5-amidino-2-hydroxyphenoxy}propyl
4-[imino(pyrrolidin-1-yl)methyl]benzoate ditrifluoroacetate
Step 1. Synthesis of 3-bromopropyl
4-[imino(pyrrolidin-1-yl)methyl]benzoate trifluoroacetate
[0377] Ethyl 4-imino(pyrrolidin-1-yl)methyl]benzoate
trifluoroacetate (706 mg, 1.96 mmol) and p-toluenesulfonic acid
monohydrate (186 mg, 0.98 mmol) were dissolved in
3-bromo-1-propanol (5 ml), and the mixture was stirred at
90.degree. C. overnight. The solvent was evaporated under reduced
pressure, and the obtained residue was purified by reversed-phase
HPLC in the same manner as in Step 4 of Example 1 to give the title
compound.
[0378] yield 537 mg (1.19 mmol, 61%)
[0379] MS (ESI, m/z) 339 (MH+)
Step 2. Synthesis of 3-{5-amidino-2-hydroxyphenoxy}propyl
4-[imino(pyrrolidin-1-yl)methyl]benzoate ditrifluoroacetate
[0380] Using 3-bromopropyl 4-[imino(pyrrolidin-1-yl)methyl]benzoate
trifluoroacetate instead of 2-bromoethyl
4-[imino(pyrrolidin-1-yl)methyl]benzoate trifluoroacetate and in
the same manner as in Step 3 of Example 6, the title compound was
obtained.
[0381] yield 25.9 mg (0.0405 mmol, 26%)
[0382] MS (ESI, m/z) 410 (MH+)
[0383] .sup.1H-NMR (DMSO-d.sub.6) .delta. 1.84-1.91 (2H, m),
2.02-2.11 (2H, m), 2.23-2.29 (2H, m), 3.34 (2H, t), 3.56 (2H, t),
4.23 (2H, t), 4.53 (2H, t), 6.98 (1H, d), 7.38 (1H, dd), 7.45 (1H,
d), 7.78 (2H, d), 8.17 (2H, d), 8.91-8.92 (3H, m), 9.05 (2H, s),
9.38 (1H, s).
Example 32
{4-amidino-2-[3-({4-[imino(pyrrolidin-1-yl)methyl]benzoyl}oxy)propoxy]phen-
oxy}acetic acid ditrifluoroacetate
Step 1. Synthesis of
3-{5-amidino-2-[benzyloxycarbonylmethoxy]phenoxy}propyl
4-[imino(pyrrolidin-1-yl)methyl]benzoate trifluoroacetate
[0384] Using the compound of Example 31 instead of the compound of
Example 8 and in the same manner as in Step 1 of Example 15, the
title compound was obtained.
[0385] yield 18.0 mg (0.0229 mmol, 46%)
[0386] MS (ESI, m/z) 558 (MH+)
Step 2. Synthesis of
{4-amidino-2-[3-({4-[imino(pyrrolidin-1-yl)methyl]benzoyl}oxy)propoxy]phe-
noxy}acetic acid ditrifluoroacetate
[0387] Using
3-{5-amidino-2-[benzyloxycarbonylmethoxy]phenoxy}propyl
4-[imino(pyrrolidin-1-yl)methyl]benzoate trifluoroacetate instead
of 2-{5-amidino-2-[2-(benzyloxy)]-2-oxoethoxy}ethyl
4-({1-amidinopiperidin-4-yl)oxy}benzoate ditrifluoroacetate and in
the same manner as in Step 2 of Example 15, the title compound was
obtained.
[0388] yield 12.8 mg (0.0184 mmol, 80%)
[0389] MS (ESI, m/z) 468 (MH+)
[0390] .sup.1H-NMR (DMSO-d.sub.6) .delta. 1.84 (2H, quint), 2.04
(2H, quint), 2.24 (2H, quint), 3.32 (2H, t), 3.54 (2H, t), 4.25
(2H, t), 4.48 (2H, t), 4.81 (2H, s), 7.07 (1H, d), 7.43 (1H, dd),
7.47 (1H, d), 7.76 (2H, d), 8.15 (2H, d), 8.92 (1H, s), 9.13 (4H,
d), 9.37 (1H, s).
Example 33
2-[5-amidino-2-(cyanomethoxy)phenoxy]ethyl
4-[(1-(1-iminoethyl)piperidin-4-yl)oxy]benzoate
ditrifluoroacetate
[0391] The compound of Example 7 (22 mg, 0.033 mmol) and potassium
carbonate (14 mg, 0.101 mmol) were suspended in dehydrated DMF (2
ml), and iodoacetonitrile (6 .mu.l, 0.036 mmol) was added thereto.
The mixture was stirred at room temperature for 4 hours, and
ice-cooled, and 1N hydrochloric acid 0.5 ml was added thereto. The
mixture was concentrated under reduced pressure, and the obtained
residue was purified by reversed-phase HPLC in the same manner as
in Step 4 of Example 1 to give the title compound.
[0392] yield 15.3 mg (0.022 mmol, 66%)
[0393] MS (ESI, m/z) 480 (MH+)
[0394] .sup.1H-NMR (DMSO-d.sub.6) .delta. 1.75-1.83 (2H, m),
2.05-2.18 (2H, m), 2.30 (3H, s), 3.48-3.60 (2H, m), 3.70-3.8.5 (2H,
m), 4.47 (2H, br), 4.64 (2H, br), 4.84 (1H, br), 5.30 (2H, s), 7.12
(2H, d), 7.36 (1H, d), 7.54 (1H, dd), 7.61 (1H, d), 7.912 (2H, d),
8.66 (1H, s), 9.21 (1H, s), 9.25 (2H, s), 9.29 (4H, s).
Example 34
2-[5-amidino-2-(cyanomethoxy)phenoxy]ethyl
4-({1-amidinopiperidin-4-yl}oxy)benzoate ditrifluoroacetate
[0395] The compound of Example 8 (25 mg, 0.037 mmol) and potassium
carbonate (16 mg, 0.116 mmol) were suspended in dehydrated DMF (2
ml) and iodoacetonitrile (7 .mu.l, 0.041 mmol) was added. The
mixture was stirred at room temperature for 4 hours, and
ice-cooled, and 1N hydrochloric acid 0.5 ml was added thereto. The
mixture was concentrated under reduced pressure, and the obtained
residue was purified by reversed-phase HPLC in the same manner as
in Step 4 of Example 1 to give the title compound.
[0396] yield 9.8 mg (0.014 mmol, 37%)
[0397] MS (ESI, m/z) 481 (MH+)
[0398] .sup.1H-NMR (DMSO-d.sub.6) .delta. 1.60-1.72 (2H, m),
1.98-2.08 (2H, m), 3.32-3.43 (2H, m), 3.62-3.72 (2H, br), 4.46 (2H,
br), 4.63 (2H, br), 4.79 (1H, br), 5.30 (2H, s), 7.11 (2H, d), 7.36
(1H, d), 7.48 (4H, s), 7.54 (1H, dd), 7.60 (1H, d), 7.91 (2H, d),
9.16 (1H, s), 9.21 (2H, s), 9.22 (4H, s).
Example 35
2-{3-amidino-5-hydroxyphenoxy}ethyl
4-[imino(pyrrolidin-1-yl)methyl]benzoate ditrifluoroacetate
Step 1. Synthesis of 3-(benzyloxy)-5-hydroxybenzonitrile
[0399] Using 3,5-dihydroxybenzonitrile instead of
3,4-dihydroxybenzonitrile and in the same manner as in Step 1 of
Example 6, the title compound was obtained.
[0400] yield 756 mg (3.36 mmol, 23%)
[0401] MS (ESI, m/z) 225 (MH+)
Step 2. Synthesis of 3-(benzyloxy)-5-hydroxybenzamidine
trifluoroacetate
[0402] Using 3-(benzyloxy)-5-hydroxybenzonitrile instead of
4-(benzyloxy)-3-hydroxybenzonitrile and in the same manner as in
Step 2 of Example 6, the title compound was obtained.
[0403] yield 506 mg (1.42 mmol, 43%)
[0404] MS (ESI, m/z) 242 (MH+)
[0405] .sup.1H-NMR (DMSO-d.sub.6) .delta. 5.13 (2H, s), 6.75-6.77
(2H, m), 6.89 (1H, s), 7.31-7.46 (5H, m), 9.10 (2H, s). 9.22 (2H,
s).
Step 3. Synthesis of 2-{3-amidino-5-hydroxyphenoxy}ethyl
4-[imino(pyrrolidin-1-yl)methyl]benzoate ditrifluoroacetate
[0406] Using 3-(benzyloxy)-5-hydroxybenzamidine trifluoroacetate
instead of 4-(benzyloxy)-3-hydroxybenzamidine trifluoroacetate and
in the same manner as in Step 3 of Example 6, the title compound
was obtained.
[0407] yield 60.0 mg (0.0961 mmol, 17%)
[0408] MS (ESI, m/z) 396 (MH+)
[0409] .sup.1H-NMR (DMSO-d.sub.6) .delta. 1.84 (2H, quint), 2.03
(2H, quint), 3.31 (2H, t), 3.53 (2H, t), 4.37 (2H, br), 4.65 (2H,
br), 6.69-6.70 (1H, m), 6.77 (1H, s), 6.84 (1H, s), 7.77 (2H, d),
8.12 (2H, d), 8.91 (1H, s), 9.13 (2H, s), 9.19 (2H, s), 9.36 (2H,
s).
Example 36
{3-amidino-5-[2-({4-[imino(pyrrolidin
1-yl)methyl]benzoyl}oxy)ethoxy]phenoxy}acetic acid
ditrifluoroacetate
Step 1. Synthesis of
2-{3-amidino-5-[benzyloxycarbonylmethoxy]phenoxy}ethyl
4-[iminopyrrolidin-1-yl)methyl]benzoate trifluoroacetate
[0410] Using the compound of Example 35 instead of the compound of
Example 8 and in the same manner as in Step 1 of Example 15, the
title compound was obtained.
[0411] yield 2.3 mg; (0.00298 mmol) yield 7.5%
[0412] MS (ESI, m/z) 544 (MH+)
Step 2. Synthesis of
{3-amidino-5-[2-({4-[iminopyrrolidin-1-yl)methyl]benzoyl}oxy)ethoxy]pheno-
xy}acetic acid ditrifluoroacetate
[0413] Using 2-{3-amidino-5-[benzyloxycarbonylmethoxy]phenoxy}ethyl
4-[imino(pyrrolidin-1-yl)methyl]benzoate trifluoroacetate instead
of 2-{5-amidino-2-benzyloxycarbonylmethoxy}ethyl
4-({1-amidinopiperidin-4-yl}oxy)benzoate ditrifluoroacetate and in
the same manner as in Step 2 of Example 15, the title compound was
obtained.
[0414] yield 3.76 mg (0.00551 mmol) yield quantitative
[0415] MS (ESI, m/z) 454 (MH+)
[0416] .sup.1H-NMR (DMSO-d.sub.6) .delta. 1.84 (2H, quint), 2.03
(0.2H, quint), 3.31 (2H, t), 3.53 (2H, t), 4.43 (2H, br), 4.66 (2H,
br), 4.77 (2H, s), 6.90 (1H, m), 7.01 (1H, s), 7.06 (1H, s), 7.77
(2H, d), 8.12 (2H, d), 8.92 (1H, s), 9.23 (2H, s), 9.28 (2H, s),
9.38 (1H, s).
Example 37
2-(3-amidinophenoxy)ethyl
6-[imino(pyrrolidin-1-yl)methyl]nicotinate tritrifluoroacetate
Step 1. Synthesis of 6-[imino(pyrrolidin-1-yl)methyl]nicotinic acid
dihydrochloride
[0417] 6-Cyanonicotinic acid (4.15 g, 28.0 mmol) was dissolved in
anhydrous ethanol (3.2 ml) and 4N hydrochloric acid/1,4-dioxane (30
ml), and the mixture was stirred in a closed system at room
temperature for two nights. The solvent was evaporated under
reduced pressure, and the obtained residue was suspended in
anhydrous ethanol (90 ml). Pyrrolidine (2.34 ml, 28.0 mmol) was
added thereto, and the mixture was stirred at room temperature for
3 days. Pyrrolidine (3.51 ml, 42.0 mmol) was added again, and the
mixture was stirred for 2.5 hours. The solvent was evaporated under
reduced pressure, and water aid ethanol were added to the obtained
residue. The precipitate was removed by filtration, ethanol was
evaporated under reduced pressure, and the obtained aqueous
solution was lyophilized to give the title compound without
purification operation.
[0418] yield 10.0 g (34.5 mmol) yield quantitative
[0419] MS (ESI, m/z) 220 (MH+)
Step 2. Synthesis of 2-bromoethyl
6-[imino(pyrrolidin-1-yl)methyl]nicotinate ditrifluoroacetate
[0420] 6-[Imino(pyrrolidin-1-yl)methyl]nicotinic acid
dihydrochloride (10.0 g, 34.5 mmol) obtained in Step 1 was
dissolved in 2-bromoethanol (50 ml), p-toluenesulfonic acid
monohydrate (856 mg, 4.5 mmol) was added thereto, and the mixture
was stirred at 85.degree. C. for two nights. The solvent was
evaporated under reduced pressure, and the obtained residue was
purified by reversed-phase HPLC in the same manner as in Step 4 of
Example 1 to give the title compound.
[0421] yield 1.27 g (2.29 mmol, 7%)
[0422] MS (ESI, m/z) 326 (MH+)
[0423] .sup.1H-NMR (DMSO-d.sub.6) .delta. 1.89 (2H, quint), 2.06
(2H, quint), 3.47 (2H, t), 3.61 (2H, t), 3.87 (2H, t), 4.70 (2H,
t), 8.01 (1H, d), 8.60 (1H, dd), 9.13 (1H, s), 9.25 (1H, m), 9.57
(1H, s).
Step 3. Synthesis of 2-(3-amidinophenoxy)ethyl
6-[imino(pyrrolidin-1-yl)methyl]nicotinate tritrifluoroacetate
[0424] 3-Hydroxybenzamidine trifluoroacetate (152 mg, 0.606 mmol)
obtained in Step 1 of Example 2,2-bromoethyl
6-[imino(pyrrolidin-1-yl)methyl]nicotinate ditrifluoroacetate (345
mg, 0.606 mmol) obtained in Step 2, and cesium carbonate (790 mg,
2.42 mmol) were stirred at 50.degree. C. overnight in anhydrous
N,N-dimethylformamide (6 ml). 1N Hydrochloric acid (4.5 ml) was
added to the mixture under ice-cooling, the solvent was evaporated
under reduced pressure, and the obtained residue was purified by
reversed-phase HPLC in the same manner as in Step 4 of Example 1 to
give the title compound.
[0425] yield 24.1 mg, (0.0356 mmol, 6%)
[0426] MS (ESI, m/z) 382 (MH+)
[0427] .sup.1H-NMR (DMSO-d.sub.6) .delta. 1.88 (2H, quint), 2.06
(2H, quint), 3.45 (2K t), 3.61 (2.times.t), 4.49 (2H, m), 4.74 (2H,
m), 7.33-7.58 (4H, m), 7.99 (1H, d), 8.58 (1H, dd), 9.17 (1H, s),
9.22 (1H, m), 9.32 (4H, s), 9.60 (1H, s).
[0428] The structural formulas of the compounds described in the
Examples are shown in Table 1. In the formulas, TFA means
trifluoroacetic acid. TABLE-US-00001 TABLE 1 compound of Ex. 1
##STR14## compound of Ex. 2 ##STR15## compound of Ex. 3 ##STR16##
compound of Ex. 4 ##STR17## compound of Ex. 5 ##STR18## compound of
Ex. 6 ##STR19## compound of Ex. 7 ##STR20## compound of Ex. 8
##STR21## compound of Ex. 9 ##STR22## compound of Ex. 10 ##STR23##
compound of Ex. 11 ##STR24## compound of Ex. 12 ##STR25## compound
of Ex. 13 ##STR26## compound of Ex. 14 ##STR27## compound of Ex. 15
##STR28## compound of Ex. 16 ##STR29## compound of Ex. 17 ##STR30##
compound of Ex. 18 ##STR31## compound of Ex. 19 ##STR32## compound
of Ex. 20 ##STR33## compound of Ex. 21 ##STR34## compound of Ex. 22
##STR35## compound of Ex. 23 ##STR36## compound of Ex. 24 ##STR37##
compound of Ex. 25 ##STR38## compound of Ex. 26 ##STR39## compound
of Ex. 27 ##STR40## compound of Ex. 28 ##STR41## compound of Ex. 29
##STR42## compound of Ex. 30 ##STR43## compound of Ex. 31 ##STR44##
compound of Ex. 32 ##STR45## compound of Ex. 33 ##STR46## compound
of Ex. 34 ##STR47## compound of Ex. 35 ##STR48## compound of Ex. 36
##STR49## compound of Ex. 37 ##STR50##
Experimental Example 1
Determination of Activated Factor X Activity-Inhibitory
Activity
[0429] Using a 96 well plate (#3396, Costar), 0.015 U/ml FXa (10
.mu.L) and a test compound (10 .mu.L) were blended with 100 mM
Tris-HCl buffer (130 .mu.L) containing 0.02% Tween 20, 0.1% PEG6000
and 0.2 M NaCl for 10 minutes, and a substrate for color
development (0.2 mM S-2222 50 .mu.L) was added thereto. Using a
Microplate reader Benchmark Plus (BIO-RAD), the reaction rate was
measured from the time course changes at absorbance 405 nm. The
reaction rate of the control was taken as 100% and the negative
logarithm of the concentration capable of suppressing 50% of the
reaction rate of the control was taken as the pIC.sub.50 value. The
results are shown in Table 2.
Experiment Example 2
Determination of Activated Factor II (FIIa, Thrombin)-Inhibitory
Activity
[0430] Using a 96 well plate (#3396, Costar), 0.125 U/ml activated
factor IIa (thrombin) (10 .mu.L) and a test compound (10 .mu.L)
were blended with 100 mM Tris-HCl buffer (130 .mu.L) containing
0.02% Tween 20, 0.1% PEG6000 and 0.2 M NaCl for 10 minutes, and a
substrate for color development (0.1 mM S-2238 50 .mu.L) was added
thereto. Using a Microplate reader Benchmark Plus (BIO-RAD), the
reaction rate was measured from the time course changes at
absorbance 405 nm. The reaction rate of the control was taken as
100% and the negative logarithm of the concentration capable of
suppressing 50% of the reaction rate of the control was taken as
the pIC.sub.50 value. The results are shown in Table 2.
Experimental Example 3
Determination of Anticoagulant Activity
[0431] The aPTT measurement method using an automatic blood
coagulation time measuring device, Sysmex CA-3000 (TOA Medical
Electronics Co., Ltd.) was performed. A solution (5 .mu.l) of the
test compound was placed in a sample tube (SU-40, TOA Medical
Electronics Co., Ltd.), human plasma (hemolyance coagulation
control I, iatron Laboratory, 45 .mu.l) was added and the mixture
was incubated at 37.degree. C. for 3 minutes. To the plasma
solution were added dataphay.cndot.APTT (rabbit brain-derived
cephalin, DADE Behring Co., Ltd., 50 .mu.l) and 0.02 M calcium
chloride (50 .mu.l), and the time up to the coagulation of plasma
was automatically measured. The anticoagulation activity is shown
as the negative logarithm of the concentration prolonging the aPTT
of the control to two-fold (paPTT2). The results are shown in Table
2.
Experimental Example 4
Evaluation of Stability in Plasma
[0432] A 100 .mu.M solution (5 .mu.l) of the test compound was
added to human plasma (495 .mu.l) (final drug concentration, 10
.mu.M), and the mixture was incubated at 37.degree. C. Samples
(each 50 .mu.l) were taken at 0 minutes, 3 minutes, 10 minutes, and
20 minutes after addition of the drug solution, diluted with
distilled water (50 .mu.l), and the reaction was quenched by adding
100% acetonitrile (300 .mu.l) and blending them. After
deproteinization by centrifugation at 15000 rpm for 5 minutes, the
mixture was concentrated to dryness by a centrifugal evaporator.
The sample was dissolved in 120 .mu.l of 0.1% aqueous TFA, the peak
area or height of the test compound was calculated by HPLC, and the
disappearance half-life was determined. The results are shown in
Table 2 (T.sub.1/2). TABLE-US-00002 TABLE 2 pIC.sub.50 (FXa)
pIC.sub.50 (IIa) paPTT2 T.sub.1/2 (minutes) compound of 8.5 4.1 6
1.6 Ex. 6 compound of 7.8 4.2 6.4 2.7 Ex. 13 compound of 7.2
<4.0 5.4 1.7 Ex. 16 compound of 7.2 <4.0 5.1 5.6 Ex. 17
compound of 6.6 <4.0 5.2 1.1 Ex. 18 compound of 7.9 5.2 6.1 2.1
Ex. 20 compound of 7.4 4.9 5.8 0.7 Ex. 24 compound of 8.4 5.8 6.4
3.5 Ex. 28 compound of 6.7 <4.0 5.2 N.T. Ex. 37
Experimental Example 5
Evaluation of Dog Dialysis Model
1. Surgical Operation.
[0433] Beagles ( , 11 kg-15 kg, Nosan Corp., Japan) were
anesthetized with pentobarbital (30 mg/kg, Tokyo Chemical Industry
Co., Ltd.) by intravenous administration from the cephalic vein of
the forefoot. A tracheostomy tube was inserted and artificial
breathing was started. Placing needles [14G (serflow placing
needle, Termo Corp.), 16G (happycath, Medikit Co., Led), 18G
(serflow placing needle, Termo Corp.)] were punctured into the left
femoral vein, right femoral artery, and right cephalic vein of the
forefoot, respectively, and an outer shunt (Senko Medical
Instrument Mfg. CO., Ltd.) filled with saline was set to the
femoral vein and artery. For hemodialysis, a hemodialysis device
for one person (DBG-01, Nikkiso Co., Ltd.), a hollow fiber dialyzer
(FB-50, triacetate (CTA) film, Nipro Corp.) and sodium bicarbonate
dialysate (AK-sorita.cndot.DL, Shimizu Corp.) were used.
2. Experiment Procedure.
[0434] The experiment was performed under the conditions of blood
flow 80 ml/minute, dialysate flow 300 ml/minute, water removal
amount 0 ml/minute. During dialysis, pentobarbital (12 mg/kg/hour)
was continuously administered from the cephalic vein of the
forefoot to maintain anesthesia. The control and test compounds
were continuously administered into the arterial blood circuit (B)
at 5 ml/hour.
[0435] For the antithrombus action, suppression of an increase in
the arterial circuit pressure was used as an index, and the
dialysis time was up to the time point when the arterial circuit
pressure reached 300 mmHg or 4 hours after the start of the
dialysis. In addition, the bleeding time at 2 hour after the start
of the administration (15 minutes later for the control since it
does not reach 2 hours) was measured by the Template method.
[0436] As shown in FIG. 1, the compound of Example 20 suppressed an
increase in the arterial circuit pressure, and the dialysis was
possible for 4 hours. In addition, the bleeding time of the
compound of Example 20, was of the same level as the control (FIG.
2).
[0437] From the foregoing results, the compound of the present
invention is considered to be usable for the prevention of blood
circuit coagulation during extracorporeal blood circulation, and
become a safe therapeutic drug free of a blood bleeding
prolongation action.
INDUSTRIAL APPLICABILITY
[0438] A compound represented by the formula (1) and a
pharmaceutically acceptable salt thereof have a high FXa inhibitory
activity and anticoagulant action, as shown in the aforementioned
Experimental Examples, and can be used as activated blood
coagulation factor X inhibitors/anticoagulants for various diseases
in which an FXa-dependent coagulation process is involved in the
pathology. For example, they can be used as therapeutic or
prophylactic drugs for any of thrombus formation during
extracorporeal blood circulation, cerebral infarction, cerebral
thrombus, cerebral embolism, transient cerebral ischemic attack
(TIA), acute and chronic myocardial infarction, unstable angina
pectoris, pulmonary obliteration, peripheral arterial obstruction,
deep vein thrombosis, disseminated intravascular coagulation
syndrome, thrombus formation after artificial vascular prosthesis
or replacement of artificial valve, reocclusion and restenosis
after coronary-artery bypass surgery, reocclusion and restenosis
after reconstruction of blood vessel such as percutaneous
transluminal coronary angioplasty (PTCA), percutaneous transluminal
coronary recanaryzation (PTCR), and the like.
[0439] Particularly, a compound represented by the formula (1) and
a pharmaceutically acceptable salt thereof are useful as
anticoagulants for an extracorporeal blood circuit (e.g.,
hemodialyzer, artificial heart lung apparatus, etc.).
[0440] In addition, a compound represented by the formula (1) and a
pharmaceutically acceptable salt thereof are rapidly cleared from
the blood. That is, since the serum half-life is short, hemostasis
is easy when the bleeding symptom is observed during
administration. Thus, they are useful as anticoagulants that can be
used safely.
[0441] Moreover, a compound represented by the formula (1) shows
low thrombin inhibitory activity and is an FXa selective inhibitor
and anticoagulant that can be used safely from the aspect of
bleeding risk.
[0442] Furthermore, a low-molecular weight FXa inhibitor, for
example, a compound represented by the formula (1), is useful as an
anticoagulant to be used for an extracorporeal blood
circulation/extracorporeal blood circuit.
[0443] Particularly, an FXa selective low-molecular weight FXa
inhibitor, for example, a compound represented by the formula (1),
whose clearance from the blood is rapid, i.e., serum half-life is
short, can be used safely and conveniently as an anticoagulant for
an extracorporeal blood circuit that prevents blood coagulation,
and is useful because a treatment of and attention to hemostasis
necessary after the completion of the extracorporeal blood
circulation can be clearly reduced.
[0444] The present invention can also provide a method for
preventing formation of thrombus in an extracorporeal blood
circuit, which method comprises incorporating a low-molecular
weight FXa inhibitor as a component of the circuit.
[0445] Where a numerical limit or range is stated herein, the
endpoints are included. Also, all values and subranges within a
numerical limit or range are specifically included as if explicitly
written out.
[0446] Obviously, numerous modifications and variations of the
present invention are possible in light of the above teachings. It
is therefore to be understood that, within the scope of the
appended claims, the invention may be practiced otherwise than as
specifically described herein.
[0447] All patents and other references mentioned above are
incorporated in full herein by this reference, the same as if set
forth at length.
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