US 6,271,238 B1Granted

Acetamide derivatives and protease inhibitors

AssigneeNippon Kayaku Kabushiki Kaisha

InventorsYoshikazu Suzuki, Koichi Ishida

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Abstract

The present invention relates to novel acetamide compounds having a substituted heterocyclic group and consecutive dicarbonyl structures, for example, 1-pyrimidinylacetamide compounds, and these compounds have inhibitory activity on chymotrypsin type proteases and are useful as inhibitors for said enzymes, particularly as chymase inhibitors. The novel acetamide compounds of the present invention are shown in formula (I) below: wherein R0 is substituted or unsubstituted phenyl; R1 is aryl or heteroaryl which may be substituted or unsubstituted; R2 is substituted or unsubstituted alkyl, arylalkyl, or heteroarylalkyl; R3 is hydrogen; acyl group; sulfonyl group; isocyanate group; thiourea; a lower alkyl or a substituted lower alkyl; aryl (1-7C) alkyl, heteroaryl (1-7C) alkyl, aryl and heteroaryl; X represents a carbon atom and Y represents a nitrogen atom; and Z is a polymethylene group wherein a hydrogen atom in the polymethylene may be replaced.

Claims21

Dependent claims

Novel acetamide compounds represented by the following chemical formula (I) or pharmacologically acceptable salts thereof:

wherein R0 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);
R1 is (i) aryl or (ii) heteroaryl which may independently have one or more substituent groups defined with respect to group A;
or R1 may independently have one or more substituent groups selected from OH, COOH, NH2, CONH2, NHCHO and group B consisting of ORa, COORa, CONRbRc, NRbRc, NRbCHO and NRbCORa on the above groups (i) or (ii) (among which Ra to Rc are independently lower alkyl or substituted lower alkyl;
or Ra to Rc 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 and nitro group as substituent group;
or R1 may have one or more of the following defined cyclic group G on the above groups (i) or (ii) (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);
R2 represents (1-8C) alkyl, aryl (1-7C) alkyl, heteroaryl (1-7C) alkyl, and aryl;
or R2 represents OH, NH2, NHCHO, 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;
R3 is hydrogen;
or R3 is (i) D(CH2)0-3CO, (ii) DCOECO or (iii) DSO2ECO as an acyl group;
or R3 is D(CH2)0-3SO2 or DCOESO2 as a sulfonyl group (wherein group D represents hydrogen, a C1-6 straight-chain, branched or cyclic alkyl group, aryl group, halogeno lower alkyl, halogeno lower alkoxy, lower alkoxyamino, halogeno lower alkylamino, RbRcN, RbRcNO, RaO, Ra, RaOCO, RbRcNCO, RaSO2NRb, RaS and the above-defined group G;
and group E represents a divalent crosslinking group containing 1 to 6 carbon atoms);
or R3 is thiourea represented by RbRcNCS;
or R3 is Ra ;
X represents a carbon atom, which may be substituted by groups represented by Ra to Rc, and Y represents a nitrogen atom;
and
Z represents a polymethylene group wherein hydrogen atoms on the polymethylene group may independently be replaced by Ra and Rb.

17 more elements

(A) 2-(5-Amino-6-oxo-2-phenyl-1,6-dihydropyrimidine-1-yl)-N-(2,3-dioxo-1-phenylmethyl)butyl-acetamide,

(B) 2-(5-amino-6-oxo-2-phenyl-1,6-dihydropyrimidine-1-yl)-N-(2,3-dioxo-6-phenyl-1-phenylmethyl)hexylacetamide,
(C) 2-(5-amino-6-oxo-2-phenyl-1,6-dihydropyrimidine-1-yl)-N-(2,3-dioxo-5-phenyl-1-phenylmethyl)pentylacetamide,
(D) 2-(5-amino-6-oxo-2-phenyl-1,6-dihydropyrimidine-1-yl)-N-(2,3-dioxo-1-phenylmethyl)heptylacetamide,
(E) 2-(5-amino-6-oxo-2-phenyl-1,6-dihydropyrimidine-1-yl)-N-(2,3-dioxo-3-phenyl-1-phenylmethyl)propylacetamide, (F) 2-(5-amino-6-oxo-2-phenyl-1,6-dihydropyrimidine-1-yl)-N-(6-carboxyl-2,3-dioxo-1-phenylmethyl)hexylacetamide,
(G) 2-(5-amino-6-oxo-2-phenyl-1,6-dihydropyrimidine-1-yl)-N-{2,3-dioxo-1-(3-fluoro-4-hydroxyphenyl)methyl)butylacetamide,
(H) 2-(5-amino-6-oxo-2-phenyl-1,6-dihydropyrimidine-1-yl)-N-{2,3-dioxo-1-(3-fluorophenyl)methyl}butylacetamide,
(I) 2-(5-amino-6-oxo-2-phenyl-1,6-dihydropyrimidine-1-yl)-N-{2,3-dioxo-1-(3-chlorophenyl)methyl}butylacetamide,
(J) 2-(5-amino-6-oxo-2-phenyl-1,6-dihydropyrimidine-1-yl)-N-{2,3-dioxo-1-(3-methylphenyl)methyl}butylacetamide,
(K) 2-(5-amino-6-oxo-2-phenyl-1,6-dihydropyrimidine-1-yl)-N-{2,3-dioxo-1-(4-fluorophenyl)methyl}butylacetamide,
(L) 2-(5-amino-6-oxo-2-phenyl-1,6-dihydropyrimidine-1-yl)-N-{2,3-dioxo-1-(4-chlorophenyl)methyl}butylacetamide,
(M) 2-(5-amino-6-oxo-2-phenyl-1,6-dihydropyrimidine-1-yl)-N-{2,3-dioxo-6-ethoxycarbonyl-1-(3-fluorophenyl)methyl}hexylacetamide,
(N) 2-(5-amino-6-oxo-2-phenyl-1,6-dihydro-pyrimidine-1-yl)-N-{1-(3-fluorophenyl)methyl-7-(4-methyl-piperazine-1-yl)-2,3,7-trioxo}heptylacetamide,
(O) 2-(5-amino-6-oxo-2-phenyl-1,6-dihydropyrimidine-1-yl)-N-{2,3-dioxo-6-(4-morpholine-4-yl)1-phenylmethyl}hexylacetamide,
(P) 2-(5-amino-6-oxo-2-phenyl-1,6-dihydropyrimidine-1-yl)-N-{2,3-dioxo-6-(2-oxo-1,2-dihydropyridine-1-yl)-1-phenyl-methyl}hexylacetamide,
(Q) 2-(5-amino-6-oxo-2-phenyl-1,6-dihydropyrimidine-1-yl)-N-{2,3-dioxo-1-phenylmethyl-6-(2-pyridyloxy)}hexylacetamide,
(T) 2-(5-t-butyloxycarbonylamino-6-oxo-2-phenyl-1,6-dihydropyrimidine-1-yl)-N-(2,3-dioxo-1-phenylmethyl)butylacetamide,
(U) 2-(5-t-butyloxycarbonyl-amino-6-oxo-2-phenyl-1,6-dihydropyrimidine-1-yl)-N-(2,3-dioxo-1-phenylmethyl)hexylacetamide,
(V) 2-(5-t-butyloxycarbonylamino-6-oxo-2-phenyl-1,6-dihydropyrimidine-1-yl)-N-(2,3-dioxo-1-phenylmethyl) heptylacetamide,
(W) 2-{5-(3-tetrahydrofuroylamino)-6-oxo-2-phenyl-1,6-dihydropyrimidine-1-yl}-N-(2,3-dioxo-6-phenyl-1-phenylmethyl) hexylacetamide,
(X) 2-(5-amino-6-oxo-2-phenyl-1,6-dihydro-pyrimidine-1-yl)-N-{2,3-dioxo-1-(2-fluorophenyl)methyl}butylacetamide, or pharmacologically acceptable salts thereof.

17 more elements

Dependencies are inferred from the claim text.