Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-08-08
2001-10-09
Rotman, Alan L. (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C544S300000, C546S268100, C514S274000
Reexamination Certificate
active
06300337
ABSTRACT:
DESCRIPTION
1. Technical Field
The present invention relates to a heterocyclic compound having substituents containing a consecutive dicarbonyl structure, particularly to a 1-pyrimidinylacetamide compound, an 1-pyrazinylacetamide compound, a 4-triazinylacetamide compound, and relates to an inhibitor for chymotrypsin type proteases. The present compound is useful as a preventive or therapeutic agent for diseases in which chymotrypsin type proteases are generally considered to participate. For example, chymotrypsin type proteases are considered to participate directly or indirectly in diseases such as asthma, allergy, inflammations, rheumatism, hypertension, heart failure, myocardial infarction, cardiac hypertrophy, vascular injuries complicated with angiogenesis and atheroma, nephritis and renal failure. The present invention encompasses an intermediate useful for synthesis of the heterocyclic amide compound having a consecutive dicarbonyl structure, a process for producing said heterocyclic amide compound, a pharmaceutical composition containing said heterocyclic amide compound as the active ingredient, and a pharmaceutical use of said heterocyclic amide compound for the treatment of humane diseases, particularly for the treatment of the above diseases.
2. Background Art
It is known that chymase belongs to chymotrypsin type proteases among serine proteases and is a cytotoxic protein accumulated in secretory granules in mast cells and released upon stimulation. Further, it is recently reported in Circ. Res., 66, 883 (1994) that chymase possesses the action of converting angiotensin I into angiotensin II involved in blood pressure regulation in vivo. Further, it is also known that a chymase inhibitor inhibits release of histamine from mast cells (J. Cell. Biochem., 38, 291 (1988)) and release of a cytotoxic protein from eosinophils (Arch. Biochem. Biophys., 312, 67, (1994)). That is, it is known generally at present that chymase is involved not only in cytotoxicity but also in release of various mediators in vivo.
Further, the action of chymase varies depending on the type of animal, and it is reported that there is a great difference in the action particularly between human or dog and rodent (Proc. Natl. Acad. Sci. USA, 84, 364 (1987)).
As a compound inhibiting chymase, only an inhibitor for chymotrypsin as a digestive enzyme is known at present and is not satisfactory in inhibitory activity, selectivity of inhibition toward other proteases, stability of the compound in vivo, toxicity etc. and it has not been developed as a pharmaceutical composition. Accordingly, there is demand for a highly safe chymase inhibitor which at low concentration, selectively inhibits chymase.
DISCLOSURE OF THE INVENTION
Under these circumstances, the present inventors made extensive studies to find chymase inhibitors in order to solve the above problems, and as a result, they arrived at the present invention.
That is, the present invention relates to the following items 1 to 13:
1. A novel acetamide derivative represented by the following Formula 1 or the pharmacologically acceptable salt thereof.
wherein R
0
is a phenyl group whose ring may have one or more substituent groups selected from the group consisting of a halogen, a hydroxyl group, a lower alkoxy group, a lower alkyl group, and a halogenomethyl group defined as group A;
R
1
is (1) an aryl group, (2) a heteroaryl group or (3) a 1-6C straight-chain, branched or cyclic alkyl group, which may independently have one or more substituent groups defined as group A; or R
1
may have one or more substituent groups selected from the group consisting of OR
a
, COOR
a
, CONR
b
R
c
, NR
b
R
c
, NR
b
CHO, NR
b
COR
a
, SO
2
OR
a
, SO
2
R
a
, CONR
b
SO
2
R
a
and P(O) (OR
a
)
2
as defined as group B on the above groups (1) to (3) (where each R
a
to R
c
is independently a hydrogen, a lower or a substituted lower alkyl; or each R
a
to R
c
is independently an aryl (1-7C) alkyl group, a heteroaryl (1-7C) alkyl, an aryl and a heteroaryl, among which the aryl or the heteroaryl may have one or more, usually 1 to 3, substituent groups selected from the group of above-defined group A on the ring; or R
1
may have one or more substituent groups defined below as cyclic group G on the above groups (1) to (3) (cyclic group G; cyclic group G represents a heterocyclic group consisting of a 5- or 6-membered ring containing 1 to 3 oxygen or nitrogen atoms and may have substituent groups);
R
2
represents a (1-8C)alkyl, an aryl (1-7C) alkyl group, a heteroaryl (1-7C)alkyl, and an aryl; or R
2
represents the above-defined group B or a (1-8C) alkyl having the group B as a substituent group; or a (1-8C) alkyl having the above-defined cyclic group G as a substituent group;
X and Y independently represents a nitrogen atom or a carbon atom and may be substituted by groups represented by above-mentioned R
a
to R
c
;
Z represents a methylene group or a polymethylene group, and may have substituents;
J represents a carbonyl group, or a methylene group whose two hydrogens may be independently substituted by above-mentioned R
a
or R
b
;
L represents an amino group as shown by R
3
R
a
N, or R
3
O where R
3
is a hydrogen; or R
3
is (1) D(CH
2
)
0-3
.CO, (2) D.CO.E.CO or (3) D.SO
2
.E.CO as an acyl group; or R
3
is D(CH
2
)
0-3
.SO
2
or D.CO.E. SO
2
as a sulfonyl group (wherein group D represents a hydrogen, a 1-6C straight-chain, branched or cyclic alkyl group, trifluoromethyl, 2,2,2-trifluoroethoxy, amino, methoxyamino, 2,2,2-trifluoroethylamino, R
b
R
c
N, R
b
R
c
N.O, R
a
O, R
a
, R
a
OCO, R
b
R
c
NCO, R
a
SO
2
NR
b
, R
a
S and the above-defined group G; and group E represents a divalent crosslinking group containing 1 to 6 carbon atoms, and may contain 1-3 hetero atoms selected from the group of oxygen, nitrogen and sulfur); or R
3
is a thiourea represented by R
b
R
c
N.CS; or R
3
is an urea represented by R
b
R
c
N. CO; or R
3
is R
a
. R
a
to R
c
show the same respective meanings as defined in R
1
.
2. A novel acetamide derivative or the pharmacologically acceptable salt thereof according to the above item 1, wherein said R
0
, R
1
, R
2
, X, Y, Z, J, and in Formula 1 are the respective followings:
R
0
is a phenyl group whose ring may have 1-3 substituent groups selected from the group consisting of a halogen, a hydroxyl group, a lower alkoxy group, a lower alkyl group, and a halogenomethyl group defined as group A;
R
1
is a phenyl group whose ring may have one substituent group above-defined as group A; or R
1
is a phenyl group whose ring may have one substituent group selected from the group consisting of OR
a
, COOR
a
, CONR
b
R
c
, NR
b
R
c
, NR
b
CHO, NR
b
COR
a
, SO
2
OR
a
, SO
2
R
a
, CONR
b
SO
2
R
a
and P(O) (OR
a
)
2
as defined as group B (where each R
a
to R
c
is independently a hydrogen, a lower or a substituted lower alkyl; or each R
a
to R
c
is independently an aryl (1-3C) alkyl, a heteroaryl (1-3C) alkyl, an alkyl, an aryl and a heteroaryl, among which the aryl or the heteroaryl may have one substituent group selected from the group of above-defined group A on the ring).
R
2
represents a (1-4C) alkyl, an aryl (1-3C) alkyl, a heteroaryl (1-3C) alkyl, and an aryl; or R represents the above-defined group B or a (1-3C) alkyl having group B as a substituent group; or a (1-3C) alkyl group having the above-defined cyclic group G as a substituent group, where the cyclic group G represents a cyclic group selected from the group consisting of piperazin-1-yl which may have a lower alkyl group or an arylmethyl group at the 4-position, pyrrolidin-1-yl, piperidin-1-yl, 4-morpholin-1-yl, 2-oxo-1,2-dihydropyridin-1-yl, pyridyloxy, pyrazyloxy, pyridazyloxy, and pyrrol-1-yl;
X and Y independently represents a nitrogen atom or an unsubstituted carbon atom;
Z represents a methylene group;
J represents a carbonyl group, or a methylene group;
L represents R
3
O or an amino group as shown by R
3
R
a
N where R
3
is a hydrogen; or R
3
is (1) D.(CH
2
)
0-3
.CO, (2) D.CO.E.CO or (3) D.SO
2
.E.CO as an acyl group; or R
3
is D.(CH
2
)
0-3
.SO
2
or D.
Ishida Koichi
Suzuki Yoshikazu
Desai Rita
Nields & Lemack
Nippon Kayaku Kabushiki Kaisha
Rotman Alan L.
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