Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-01-31
2001-07-24
Dentz, Bernard (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S302000, C514S303000, C514S300000, C546S113000, C546S114000, C546S115000, C546S082000, C546S084000
Reexamination Certificate
active
06265418
ABSTRACT:
This application is the national phase under 35 U.S.C. § 371 of PCT International Application No. PCT/JP98/03422 which has an International filing date of Jul. 31, 1998, which designated the United States of America.
1. Technical Field
The present invention relates to a novel N-acylamino acid amide compound having an excellent platelet aggregation inhibiting action, etc., and useful as a prophylactic agent or treating agent of diseases to which a fibrinogen receptor pertains, embolism and thrombosis, or a pharmaceutically acceptable salt thereof and a preparation intermediate of said compound.
2. Background Art
Recently, it has been attracted attention that a medicine (fibrinogen receptor antagonist) which directly inhibits the bonding between a platelet membrane glycoprotein GPIIb/IIIa complex (fibrinogen receptor) and fibrinogen is an anti-platelet medicine which inhibits aggregation of platelets due to stimulation by all the intrinsic platelet aggregation causing substances.
Until now, it has been reported that a peptide derivative such as Arg-Gly-Asp-Ser (hereinafter abbreviated to as RGDS.), etc. (see Thrombosys, Res., 56, 6, 687 (1989)) or a compound having a piperidino group or an amidino group (see EP 478 363 A2 publication, EP 529 858 A1 publication, WO 93 07867 publication, J. Med. Chem., 35, 4383 (1992), J. Med. Chem., 39, 3139 (1996)), etc. have an antagonistic action against a fibrinogen receptor and have a platelet aggregation inhibiting action, and suggested that they are hopeful as a treating or prophylactic medicine of various diseases to which formation of thrombus pertains.
However, the above-mentioned compounds are still not sufficient in their effects as a medical product in respect of oral absorptive property or stability in vivo, etc.
An object of the present invention is to provide a compound having excellent fibrinogen receptor antagonistic action and having excellent oral absorptive property and durability.
The present inventors have earnestly studied and as a result, they have found a novel N-acylamino acid amide compound and its preparation intermediate to accomplish the present invention.
DISCLOSURE OF THE INVENTION
That is, the present invention relates to an N-acylamino acid amide compound represented by the following formula (I):
wherein R
1
represents a hydrogen atom or a C
1
to C
4
alkyl group;
R
2
represents a hydrogen atom, a C
1
to C
4
alkyl group, a benzyl group which may be substituted or a pyridylmethyl group which may be substituted (said substituent is a hydroxyl group, a nitro group, a cyano group, a trifluoromethyl group, a carboxyl group, an amino group, a benzoylamino group, a halogen atom, a C
1
to C
4
alkyl group, a C
1
to C
4
alkoxy group, a C
7
to C
10
aralkyloxy group, a (C
1
to C
4
alkoxy)carbonyl group, a C
1
to C
6
alkanoylamino group, a C
1
to C
4
alkylsulfonylamino group, a phenylsulfonylamino group which may be substituted (said substituent is a halogen atom, a methyl group or a methoxy group) or a C
7
to C
10
aralkylsulfonylamino group);
A represents the formula (a-1):
wherein R
3
, R
4
and R
5
each independently represents a hydrogen atom, a hydroxyl group, a C
1
to C
4
alkyl group, a C
7
to C
10
aralkyl group, a C
1
to C
6
alkanoyl group, a (C
2
to C
6
alkanoyl)oxymethyl group, a (C
1
to C
10
alkoxy)carbonyl group, a (C
3
to C
7
cycloalkoxy)carbonyl group, a (C
2
to C
6
alkenyl)oxycarbonyl group, a (C
7
to C
10
aralkyl)oxycarbonyl group, a phenoxycarbonyl group which may be substituted (said substituent is a C
1
to C
10
alkyl group or a C
1
to C
10
alkoxy group), a (C
1
to C
2
alkoxy)carbonyl group substituted by a C
1
to C
4
alkoxy group, a (C
2
to C
6
alkanoyl)oxymethoxycarbonyl group, an aromatic acyloxymethoxycarbonyl group (the aromatic ring portion is a phenyl group or a pyridyl group) or an alkylene group formed by R
4
and R
5
in combination and may contain therein one hetero atom selected from the group consisting of O, N and S,
Y
1
represents a phenylene group which may be substituted (said substituent is a halogen atom, a C
1
to C
4
alkyl group or a C
1
to C
4
alkoxy group) or a 5- or 6-membered divalent heteroaromatic ring group containing 1 or 2 hetero atoms selected from the group consisting of O, N and S, or represents the formula (a-2):
wherein R
6
represents a hydrogen atom, a C
1
to C
4
alkyl group, a C
7
to C
10
aralkyl group, a C
1
to C
6
alkanoyl group, a (C
2
to C
6
alkanoyl)oxymethyl group or a (C
1
to C
4
alkoxy)carbonyl group; X represents a nitrogen atom or >CH— group; Y
2
represents a —(CH
2
)
m
— group (where m=1, 2 or 3), a —CH═CH— group (cis or trans), a —C≡C— group, a —CH
2
—CH═CH— group (cis or trans), a —CH═CH—CH
2
— group (cis or trans), a —CH
2
—C≡C— group, a —C≡C—CH
2
— group, a —OCH
2
— group, a —SCH
2
— group, a —OCH
2
CH
2
— group, a —CH
2
OCH
2
— group, a —SCH
2
CH
2
— group or a —CH
2
SCH
2
— group; and n is 1, 2 or 3;
B represents the formula (b):
wherein A
1
, A
2
, A
3
, A
4
and A
5
represent atoms selected from the group consisting of C, N, O and S, and the 5-membered ring formed by A
1
to A
5
represents a heteroaromatic ring containing 1 or 2 hetero atoms selected from the group consisting of N, O and S, said heteroaromatic ring has, as an essential component, a —CH
2
Z group, and as a desired component, it may be substituted by R
9
(R
9
represents a hydroxyl group, a trifluoromethyl group, a C
1
to C
4
alkyl group, a C
1
to C
4
alkoxy group or a (C
7
to C
10
aralkyl)oxycarbonyl group),
R
7
and R
8
each represents a hydrogen atom, or a C
2
to C
3
alkylene group formed by R
7
and R
8
in combination thereof,
Z represents a carboxyl group which may be protected, and o and p each represents 0 or 1,
or a pharmaceutically acceptable salt thereof.
Moreover, the present invention relates to a compound represented by the general formula (II):
wherein A
1
, A
2
, A
3
, A
4
, A
5
, R
7
, R
8
, R
9
, Z, o and p have the same meanings as defined above, and Q represents a hydrogen atom, a (C
1
-C
4
alkoxy)carbonyl group, a benzyloxycarbonyl group or a trityl group,
which is useful as a preparation intermediate of the compound having the formula (I), or a salt thereof.
BEST MODE FOR CARRYING OUT THE INVENTION
As the C
1
to C
4
alkyl group shown by R
1
in the compound represented by the formula (I) (hereinafter also referred to as Compound (I)) of the present invention, there may be mentioned, for example, a straight or branched C
1
to C
4
alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, etc.
R
1
is preferably a hydrogen atom, methyl, ethyl and propyl groups, more preferably a hydrogen atom or a methyl group, particularly preferably a hydrogen atom.
As the C
1
to C
4
alkyl group shown by R
2
, the group having the same meaning as those defined in the above mentioned R
1
, preferably a methyl, isopropyl, isobutyl and s-butyl groups, more preferably a methyl group.
As the pyridylmethyl group shown by R
2
, there may be mentioned, for example, a 2-pyridylmethyl, 3-pyridylmethyl and 4-pyridylmethyl groups. It is preferably a 3-pyridylmethyl and 4-pyridylmethyl groups, more preferably a 4-pyridylmethyl group.
The benzyl group or the pyridylmethyl group shown by R
2
may have a substituent on the aromatic ring, and as the substituent, there may be mentioned, for example, a hydroxyl group; a nitro group; a cyano group; a trifluoromethyl group; a carboxyl group; a benzoylamino group; an amino group; a halogen atom such as a fluorine, chlorine, bromine and iodine atoms; the C
1
to C
4
alkyl group having the same meanings as defined in R
1
; a C
1
to C
4
alkoxy group such as a methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, s-butoxy and t-butoxy groups; a C
7
to C
10
aralkyloxy group such as a benzyloxy, phenethyloxy, phenylpropoxy and phenylbutoxy groups; a (C
1
to C
4
alkoxy)carbonyl group the alkoxy portion of which has the same meaning as defined above such as a methoxycarbonyl, ethoxycarbonyl, prop
Baba Kousuke
Kuroki Yoshiaki
Motoyama Takahiro
Takata Katsunori
Tanaka Masayuki
Birch, Stewart, Kolasch and Birch LLP
Dentz Bernard
Ube Industries Ltd.
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