Alpha-ketoamide derivatives

Details Alpha-ketoamide derivatives Alpha-ketoamide derivatives

1999-05-04

2001-02-13

Low, Christopher S. F. (Department: 1654)

Chemistry: natural resins or derivatives; peptides or proteins;

Peptides of 3 to 100 amino acid residues

6 to 7 amino acid residues in defined sequence

C514S017400

Reexamination Certificate

active

06187905

ABSTRACT:

BACKGROUND OF THE INVENTION
The present invention is concerned with &agr;-ketoamide derivatives and a process for their manufacture. The invention is also concerned with pharmaceutical preparations containing these derivatives and with the use of these derivatives as medicaments, especially antiviral medicaments.
SUMMARY OF THE INVENTION
The &agr;-ketoamide derivatives provided by the present invention are compounds of the general formula
wherein
R
1
represents lower alkyl, halo-lower alkyl, cyano-lower alkyl, lower alkylthio-lower alkyl, aryl-lower alkylthio-lower alkyl, aryl-lower alkyl, heteroaryl-lower alkyl, lower alkenyl, or lower alkynyl;
R
2
represents lower alkyl, hydroxy-lower alkyl, carboxy-lower alkyl, aryl-lower alkyl, aminocarbonyl-lower alkyl, lower cycloalkyl-lower alkyl, aryl-lower alkoxy-aryl-lower alkyl, heteroaryl-lower alkyl, or dihalo aryl lower alkoxy aryl-lower alkyl;
R
3
represents hydrogen or lower alkyl;
R
2
and R
3
together form a cyclic bridge selected from the group consisting of —CH
2
—CH
2
—, —CH
2
—CH
2
—CH
2
—, —CHOH—CH
2
—, —CH
2
—CHOH—, —CH
2
—CH
2
—CHOH—, —CH
2
—CHOH—CH
2
—, and —CHOH—CH
2
—CH
2
—;
R
4
represents lower alkyl, hydroxy-lower alkyl, lower cycloalkyl-lower alkyl, carboxy-lower alkyl, aryl-lower alkyl, aryl-lower alkoxy-aryl-lower alkyl, aryl-lower alkoxy-lower alkyl, aryl-lower alkoxycarbonyl-lower alkyl, lower alkylthio-lower alkyl, cyano-lower alkylthio-lower alkyl, aryl-lower alkylthio-lower alkyl, lower alkenyl, aryl, heteroaryl-lower alkyl, arylsulphonyl-guanidino-lower alkyl, acetamidothio-lower alkyl, lower alkylcarbonylamino-lower alkyl, formamido-lower alkyl, or lower cycloalkyl;
R
5
represents lower alkyl, hydroxy-lower alkyl, lower alkylthio-lower alkyl, aryl-lower alkyl, aryl-lower alkylthio-lower alkyl, cyano-lower alkylthio-lower alkyl, lower cycloalkyl, lower cycloalkyl-lower alkyl, aryl-lower alkoxycarbonyl-lower alkyl, aryl-lower alkoxy-aryl-lower alkyl, aryl, arylsulphonyl-guanidino-lower alkyl, aryl-lower alkoxy-lower alkyl, heteroaryl-lower alkyl, or formamido-lower alkyl;
R
6
represents hydrogen or lower alkyl;
R
7
represents hydrogen, lower alkyl, carboxy-lower alkyl, hydroxy-lower alkyl, aryl-lower alkyl, lower cycloalkyl-lower alkyl, lower cycloalkyl, aryl, heteroaryl-lower alkyl, nitroguanidino-lower alkyl, aryl-lower alkoxy-lower alkyl, aryl-lower alkylthio-lower alkyl, aryl-lower alkoxycarbonyl-lower alkyl, arylsulphonylguanidino-lower alkyl, acetamidothio-lower alkyl, lower alkylsulphonyl-lower alkyl, heteroaryl-lower alkyl, aryl-lower alkoxy-aryl-lower alkyl, aryl-lower alkoxy-heteroaryl-lower alkyl, lower alkylcarbonyloxy-lower alkyl, lower alkylcarbonylamino-lower alkyl, aryl-lower alkyl-heteroaryl-lower alkyl, lower alkenyloxycarbonyl-lower alkyl, lower alkylthio-lower alkyl, formamido-lower alkyl, or nitro substituted aryl-lower alkyl;
R
8
represents lower alkyl, lower cycloalkyl, lower cycloalkyl-lower alkyl, carboxy-lower alkyl, hydroxy-lower alkyl, hydroxy substituted aryl-lower alkyl, aryl-lower alkyl, mercapto-lower alkyl, lower alkylsulphonyl-lower alkyl, aryl-lower alkoxy-lower alkyl, aryl-heteroaryl-lower alkyl, aryl-lower alkoxy-aryl-lower alkyl, nitroguanidino-lower alkyl, aryl, acetamidothio-lower alkyl, aryl-sulphonylguanidino-lower alkyl, aminocarbonyl-lower alkyl, aryl-lower alkoxy-lower alkyl-heteroaryl-lower alkyl, lower alkylsulphinyl-lower alkyl, lower alkylamino-carbonyl-lower alkyl, heteroaryl-lower alkyl, lower alkylthio-lower alkyl or formamido-lower alkyl; and
R
9
represents hydrogen or lower alkyl; or
R
8
and R
9
together form a cyclic bridge selected from the group consisting of —CH
2
—CH
2
—, CH
2
—, —CH
2
—S—CH
2
—, —CH
2
—CH
2
—S—, and —S—CH
2
—CH
2
—;
R
10
represents lower alkylcarbonyl, carboxy-lower alkylcarbonyl, arylcarbonyl, lower alkoxycarbonyl, aryl-lower alkoxycarbonyl, aryl-lower alkylcarbonyl, heteroaryl-lower alkylcarbonyl, arylamino-carbonyl-lower alkylcarbonyl, heteroarylthio-lower alkylcarbonyl, heteroarylcarbonyl, hydroxyfluorenylcarbonyl, heteroarylcarbonyl-lower alkylcarbonyl, lower alkoxy-lower alkylcarbonyl, aryl-carbonyl-lower alkylcarbonyl, lower alkoxy-lower alkoxy-lower-alkoxy-lower alkylcarbonyl, aryl-carbonyl-amino-lower alkylcarbonyl, heterocyclylcarbonyl, lower alkyl-carbonyloxy-lower alkylcarbonyl, aryloxy-lower alkylcarbonyl, lower alkynylcarbonyl, lower cyclo alkylcarbonyl, di(lower alkyl)amino-lower alkylcarbonyl, aryl-lower alkoxycarbonylamino-lower alkylcarbonyl, lower alkoxy-lower alkylcarbonyl, lower alkylcarbonylamino-lower alkenylcarbonyl, heterocyclyl-lower alkylcarbonyl, lower alkylthio-lower alkylcarbonyl, lower alkoxycarbonyl-lower alkylcarbonyl, aryl-lower alkenylcarbonyl, lower cycloalkenylcarbonyl, di(lower alkyl)aminocarbonyl-lower alkylcarbonyl, halo-lower alkylcarbonyl, lower alkenylcarbonyl, lower alkylcarbonylamino-lower alkylcarbonyl, lower cycloalkyl-lower alkylcarbonyl, lower alkylsulphonyl, arylsulphonyl arylaminocarbonyloxy-lower alkylcarbonyl, lower alkylsulphonyl-lower alkylcarbonyl, lower alkylcarbonyl-lower alkylcarbonyl, hydroxy-halo-lower alkylcarbonyl, di(lower alkoxy)phosphinyl-lower alkylcarbonyl, mono or di (lower alkylamino) lower alkyl carbonyl, mono or di (lower alkyl) amino substituted arylcarbonyl, lower alkoxy lower cycloalkylcarbonyl, lower alkyl substituted arylcarbonyl lower alkylcarbonyl, cyclo lower alkylcarbonyl, aryl substituted cyclo lower alkyl carbonyl, or nitro substituted aryl-lower alkylcarbonyl; and
R
11
and R
12
each individually represent hydrogen, lower alkyl, aryl, heteroaryl, aryl-lower alkyl, diaryl-lower alkyl, lower cycloalkyl-lower alkyl, lower alkylaminocarbonyl-lower alkyl, lower alkylthio-lower alkyl, lower alkoxy, hydroxy, lower alkoxy substituted aryl-lower alkyl, nitro substituted aryl lower alkyl, hydroxy substituted aryl lower alkyl or hydroxylower alkyl substituted aryl lower alkyl and heteroaryl-lower alkyl;
and salts thereof.
The &agr;-ketoamide derivatives provided by the present invention inhibit proteinases of viral origin, such as HCV protease, and can be used in the treatment of viral infections, especially viral infections caused by hepatitis C, hepatitis G and human GB viruses.
DETAILED DESCRIPTION OF THE INVENTION
As used herein, the term “lower alkyl” denotes a straight-chain or branched-chain alkyl group containing 1-7, preferably 1-4, carbon atoms, e.g. methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec.butyl, tert.butyl, n-pentyl, neopentyl and the like. The term “lower alkenyl” denotes a straight-chain or branched-chain alkenyl group containing 2-7 carbon atoms, e.g. vinyl, allyl, n-propenyl, n-butenyl and the like, and the term “lower alkynyl” denotes a straight-chain or branched-chain alkynyl group containing 2-7 carbon atoms, e.g. propargyl, 5-hexynyl, 6-heptynyl and the like. The term “lower cycloalkyl” denotes a cycloalkyl group which contains 3-7 carbon atoms, i.e. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, and which can be unsubstituted or substituted, e.g. by halo, lower alkyl, lower alkoxy or lower alkyl-carbonyl. The term “lower cycloalkenyl” denotes a cycloalkenyl group containing 3-7 carbon atoms, i.e. cyclopropenyl, cyclobutenyl, cyclopenteny, cyclohexenyl and cycloheptenyl. The term “lower alkoxy” denotes a lower alkyl group as defined hereinbefore, which is bonded via an oxygen atom, e.g. methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert.butoxy and the like. The term “aryl” denotes a monocyclic or polycyclic aromatic group, e.g. phenyl, naphthyl or the like, which is unsubstituted or substituted by one or more substituents selected from e.g. lower alkyl, nitro, lower alkoxy, halo, hydroxy, hydroxy-lower alkyl, e.g. hydroxymethyl, halo-lower alkyl, e.g. trifluoromethyl or other groups such as lower alkyl amino (such as dimethyl amino) and sulphamoyl and acetamido groups. The term “heteroaryl” denotes a 5- or 6-membered aromatic heterocyclic ring, heterocyclic rings contain one or two heteroatoms, which may be the same or different that contain N, O and S as the heteroatom(s) a

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