Acetamide derivatives and protease inhibitors

Details Acetamide derivatives and protease inhibitors Acetamide derivatives and protease inhibitors

1999-03-01

2001-08-07

Raymond, Richard L. (Department: 1611)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C544S319000

Reexamination Certificate

active

06271238

ABSTRACT:

TECHNICAL FIELD
The present invention relates to novel acetamide derivatives having a substituted heterocyclic group and consecutive dicarbonyl structures, for example 1-pyrimidinylacetamide compounds, 4-pyrazinylacetamide compounds, 4-triazinylacetamide compounds etc., and relates to inhibitors for chymotrypsin type proteases, particularly chymase inhibitors. The present compounds are useful as a preventive or therapeutic agent for diseases in which chymotrypsin type proteases are considered to, generally 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 accompanied by angiogenesis and atheroma, nephritis and renal insufficiency etc. The present invention encompasses intermediates useful for synthesis of heterocyclic amide compounds having consecutive dicarbonyl structures, a process, for producing the heterocyclic amide compounds, and a pharmaceutical composition containing such heterocyclic amide compounds as the active ingredient, and a method of using the same.
BACKGROUND OF THE INVENTION
It is known that chymase belongs to chymotrypsin type proteases in 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 (30):
(1) Novel acetamide derivatives represented by the following chemical formula (I) or pharmacologically acceptable salts thereof.
wherein R
0
is a phenyl group whose ring may have one or more substituent groups selected from group A defined below (group A; group A represents halogen, nitro, a hydroxyl group, a lower alkoxy group, a lower alkyl group, or a halogen-substituted lower alkyl group);
R
1
is (i) aryl, (ii) heteroaryl or (iii) C
1-6
, straight-chain, branched or cyclic alkyl group, which may independently have one or more substituent groups defined with respect to group A; or R
1
may independently have one or more substituent groups selected from group B 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
on the above groups (i) to (iii) (among which R
a
to R
c
are independently hydrogen, lower alkyl or substituted lower alkyl; or R
a
to R
c
are independently aryl (1-7C) alkyl, heteroaryl (1-7C) alkyl, aryl and heteroaryl, among which the aryl or heteroaryl ring may have one or more, usually 1 to 3, substituent groups selected from the above-defined group A. The substituted lower alkyl has 1 to 3 atoms or groups selected from halogen, nitro and hydroxyl group as substituent group); or R
1
may have the following defined one or more of cyclic group G as a substituent group on the above groups (i) to (iii) (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 a substituent group);
R
2
represents (1-8C) alkyl, aryl (1-7C) alkyl, heteroaryl (1-7C) alkyl, and aryl; or R
2
represents the above-defined group B or (1-8C) alkyl having group B as a substituent group; or (1-8C) alkyl having the above-defined cyclic group G as a substituent group;
R
3
is hydrogen; or R
3
is (i) D(CH
2
)
0-3
.CO, (ii) D.CO.E.CO or (iii) D.SO
2
.E.CO as an acyl group; or R
3
is D(CH
2
)
0-3
.SO
2
or D.COE.SO
2
as a sulfonyl group (wherein group D represents hydrogen, a 1-6C straight-chain, branched or cyclic alkyl group, aryl group, halogeno lower alkyl, halogeno lower alkoxy, amino, lower alkoxyamino, halogeno lower alkylamino, 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
b
S and the above-defined group G; and group E represents a divalent crosslinking group containing 1 to 6 carbon atoms); or R
3
is an urea group represented by group R
b
R
c
NCO; or R
3
is thiourea represented by R
b
R
c
N.CS; or R
3
is R
a
;
X and Y independently represent a nitrogen atom or a carbon atom and may be substituted by groups represented by R
a
to R
c
; and
Z represents a polymethylene group wherein hydrogen atoms on the polymethylene group may independently be replaced by R
a
and R
b
.
(2) Novel acetamide derivatives according to the above item (1) or pharmacologically acceptable salts thereof, wherein R
2
in formula (I) represents the followings:
R
2
is a (1-8C) alkyl, aryl (1-7C) alkyl, heteroaryl (1-7C) alkyl and aryl; or R
2
is the above-defined group B (provided that when Y is a nitrogen atom and X is a carbon atom in formula (I), R
2
represents groups other than OR
a
or NR
b
R
c
), or (1-8C) alkyl having the group B as a substituent group; or (1-8C) alkyl having the above-defined cyclic group G as a substituent group.
(3) Novel acetamide derivatives according to the above item (1) or (2) or pharmacologically acceptable salts thereof, wherein the cyclic group G represents a group selected from the group consisting of pyridyloxy, 2-oxo-1,2-dihydropyridine-1-yl, pyrimidyloxy, pyrazyloxy, pyridazyloxy, piperazine-1-yl optionally having a lower alkyl or aryl lower alkyl group at the 4-position, pyrrolidine-1-yl, piperidine-1-yl, 4-morpholine-4-yl, and pyrrole-1-yl.
(4) Novel acetamide derivatives according to the above item (1) or pharmacologically acceptable salts thereof, wherein the respective symbol in formula (I) represents the followings:
R
0
is a phenyl group whose ring may have 1 to 5 substituent groups selected from group A consisting of halogen, a hydroxyl group, a lower alkoxy group, a lower alkyl group, and a trifluoromethyl group;
R
1
is phenyl, thienyl, furyl, pyridyl, pyrrolyl or a C1-6 straight-chain, branched or cyclic alkyl group which may independently have one or more substituent groups defined above for group A; or R
1
may have one or more substituent groups selected from group B 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
on the above phenyl, thienyl, furyl, pyridyl, pyrrolyl or C1-6 straight-chain, branched or cyclic alkyl group (among which R
a
to R
c
are independently hydrogen and lower alkyl; or R
a
to R
c
are independently aryl (1-7C) alkyl, heteroaryl (1-7C) alkyl, aryl and heteroaryl, wherein the aryl or heteroaryl ring may have one or more substituent groups selected from group A); or R
1
may have one or more of cyclic group G selected from the group consisting of pyridyloxy, 2-oxo-1,2-dihydropyridine-1-yl, pyrimidyloxy, pyrazyloxy, pyridazyloxy, piperazine-1-y

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