Antiviral medicaments

Details Antiviral medicaments Antiviral medicaments

1999-03-10

2002-04-16

Celsa, Bennett (Department: 1627)

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

C530S330000, C514S002600, C514S017400, C514S018700, C424S189100

Reexamination Certificate

active

06372883

ABSTRACT:

BACKGROUND OF THE INVENTION
The present invention is concerned with amino acid 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 antiviral medicaments provided in accordance with the present invention are amino acid derivatives represented by the general formula
wherein
E represents —CHO or —B(OH)
2
;
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 R
2a
or R
2b
;
R
2a
represents lower alkyl, hydroxy-lower alkyl, carboxy-lower alkyl, aryl-lower alkyl, aminocarbonyl-lower alkyl or lower cycloalkyl-lower alkyl;
R
2b
represents aryl-lower alkoxy-aryl-lower alkyl or heteroaryl-lower alkyl;
R
3
represents hydrogen or lower alkyl; or
R
2
and R
3
together represent di- or trimethylene optionally substituted by hydroxy;
R
4
represents lower alkyl, hydroxy-lower alkyl, lower cycloalkyl-lower alkyl, carboxy-lower alkyl, aryl-lower alkyl, lower alkylthio-lower alkyl, cyano-lower alkylthio-lower alkyl, aryl-lower alkylthio-lower alkyl, lower alkenyl, aryl or lower cycloalkyl;
R
5
represents R
5a
or R
5b
;
R
5a
represents lower alkyl, hydroxy-lower alkyl, lower alkylthio-lower alkyl, aryl-lower alkyl, aryl-lower alkylthio-lower alkyl, cyano-lower alkylthio-lower alkyl or lower cycloalkyl;
R
5b
represents lower cycloalkyl-lower alkyl;
R
6
represents hydrogen or lower alkyl;
R
7
represents R
7a
or R
7b
;
R
7a
represents lower alkyl, hydroxy-lower alkyl, carboxy-lower alkyl, aryl-lower alkyl, lower cycloalkyl-lower alkyl or lower cycloalkyl;
R
7b
represents aryl-lower alkylthio-lower alkyl, aryl-lower alkoxy-aryl-lower alkyl, aryl-lower alkoxycarbonyl-lower alkyl, aryl-lower alkylcarbonyl-lower alkyl, nitroguanidino-lower alkyl, arylsulfonyl-guanidino-lower alkyl, lower alkylsulfonyl-lower alkyl, acetamidomethylthio-lower alkyl, aryl or heteroaryl-lower alkyl;
R
8
represents R
8a
or R
8b
;
R
8a
represents lower alkyl, hydroxy-lower alkyl, carboxy-lower alkyl or aryl-lower alkyl;
R
8b
represents mercapto-lower alkyl, lower alkylsulfonyl-lower alkyl, aryl-lower alkoxy-lower alkyl or aryl-heteroaryl-lower alkyl;
R
9
represents R
9a
or R
9b
;
R
9a
represents lower alkylcarbonyl, carboxy-lower alkylcarbonyl, arylcarbonyl, lower alkylsulfonyl, arylsulfonyl, lower alkoxycarbonyl or aryl-lower alkoxycarbonyl; and
R
9b
represents aryl-lower alkylcarbonyl, heteroaryl-lower alkylcarbonyl, arylaminocarbonyl-lower alkylcarbonyl, heteroarylthio-lower alkylcarbonyl, heteroarylcarbonyl, hydroxyfluorenylcarbonyl, heteroarylcarbonyl-lower alkylcarbonyl, lower alkoxy-lower alkylcarbonyl, arylcarbonyl-lower alkylcarbonyl, lower alkoxy-lower alkoxy-lower alkoxy-lower alkylcarbonyl, arylcarbonylamino-lower alkylcarbonyl, lower cycloalkyl-lower alkylcarbonyl, lower alkylcarbonyl-lower cycloalkyl-lower alkylcarbonyl, lower alkylcarbonylamino-lower alkylcarbonyl, heterocyclylcarbonyl, lower alkylcarbonyloxy-lower alkylcarbonyl, lower alkoxycarbonyl-lower alkylcarbonyl, aryloxy-lower alkylcarbonyl, lower alkynylcarbonyl or lower cycloalkylcarbonyl;
provided that R
2
, R
5
, R
7
, R
8
and R
9
do not simultaneously represent R
2a
, R
5a
, R
7a
, R
8a
and R
9a
, respectively;
and salts of acidic compounds of formula I with bases. The compounds of formula I inhibit proteinases of viral origin 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
The antiviral medicaments provided in accordance with the present invention are amino acid derivatives represented by the general formula
wherein
E represents —CHO or —B(OH)
2
;
R
1
is selected from the group consisting of 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 and lower alkynyl;
R
2
represents R
2a
or R
2b
;
R
2a
is selected from the group consisting of lower alkyl, hydroxy-lower alkyl, carboxy-lower alkyl, aryl-lower alkyl, aminocarbonyl-lower alkyl and lower cycloalkyl-lower alkyl;
R
2b
represents aryl-lower alkoxy-aryl-lower alkyl or heteroaryl-lower alkyl;
R
3
represents hydrogen or lower alkyl; or
R
2
and R
3
together represent di-or trimethylene optionally substituted by hydroxy;
R
4
is selected from the group consisting of lower alkyl, hydroxy-lower alkyl, lower cyclo-alkyl-lower alkyl, carboxy-lower alkyl, aryl-lower alkyl, lower alkylthio-lower alkyl, cyano-lower alkylthio-lower alkyl, aryl-lower alkylthio-lower alkyl, lower alkenyl, aryl and lower cycloalkyl;
R
5
represents R
5a
or R
5b
;
R
5a
is selected from the group consisting of lower alkyl, hydroxy-lower alkyl, lower alkylthio-lower alkyl, aryl-lower alkyl, aryl-lower alkylthio-lower alkyl, cyano-lower alkylthio-lower alkyl and lower cycloalkyl;
R
5b
represents lower cycloalkyl-lower alkyl;
R
6
represents hydrogen or lower alkyl;
R
7
represents R
7a
or R
7b
;
R
7a
is selected from the group consisting of lower alkyl, hydroxy-lower alkyl, carboxy-lower alkyl, aryl-lower alkyl, lower cycloalkyl-lower alkyl and lower cycloalkyl;
R
7b
is selected from the group consisting of aryl-lower alkylthio-lower alkyl, aryl-lower alkoxy-aryl-lower alkyl, aryl-lower alkoxycarbonyl-lower alkyl, aryl-lower alkylcarbonyl-lower alkyl, nitroguanidino-lower alkyl, arylsulfonyl-guanidino-lower alkyl, lower alkylsulfonyl-lower alkyl, acetamidomethylthio-lower alkyl, aryl and heteroaryl-lower alkyl;
R
8
represents R
8a
or R
8b
;
R
8a
is selected from the group consisting of lower alkyl, hydroxy-lower alkyl, carboxy-lower alkyl and aryl-lower alkyl;
R
8b
is selected from the group consisting of mercapto-lower alkyl, lower alkylsulfonyl-lower alkyl, aryl-lower alkoxy-lower alkyl and aryl-heteroaryl-lower alkyl;
R
9
represents R
9a
or R
9b
;
R
9a
is selected from the group consisting of lower alkylcarbonyl, carboxy-lower alkyl-carbonyl, arylcarbonyl, lower alkylsulfonyl, arylsulfonyl, lower alkoxycarbonyl and aryl-lower alkoxycarbonyl; and
R
9b
is selected from the group consisting of aryl-lower alkylcarbonyl, heteroaryl-lower alkylcarbonyl, arylaminocarbonyl-lower alkylcarbonyl, heteroarylthio-lower alkylcarbonyl, heteroaryl-carbonyl, hydroxyfluorenylcarbonyl, heteroarylcarbonyl-lower alkylcarbonyl, lower alkoxy-lower alkylcarbonyl, arylcarbonyl-lower alkylcarbonyl, lower alkoxy-lower alkoxy-lower alkoxy-lower alkylcarbonyl, arylcarbonylamino-lower alkylcarbonyl, lower cycloalkyl-lower alkylcarbonyl, lower alkylcarbonyl-lower cycloalkyl-lower alkylcarbonyl, lower alkylcarbonylamino-lower alkylcarbonyl, heterocyclylcarbonyl, lower alkylcarbonyloxy-lower alkylcarbonyl, lower alkoxycarbonyl-lower alkylcarbonyl, aryloxy-lower alkyl-carbonyl, lower alkynylcarbonyl and lower cycloalkylcarbonyl;
with the proviso that R
2
, R
5
, R
7
, R
8
and R
9
do not simultaneously represent R
2a
, R
5a
, R
7a
, R
8a
and R
9a
, respectively;
and salts of acidic compounds of formula I with bases.
As used herein, the term “lower alkyl” denotes a straight-chain or branched-chain alkyl group containing 1-7, e.g. methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec.butyl, tert.butyl, n-pentyl, neopentyl, preferably 1-4, carbon atoms, 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 “cycloalkyl” denotes a cycloalkyl group containing 3-7 carbon atoms, i.e. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. The term “lower alkoxy” denotes a lower alkyl group as defined he

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