Dipeptide compounds and their use as antiviral agents

Details Dipeptide compounds and their use as antiviral agents Dipeptide compounds and their use as antiviral agents

2001-08-27

2004-01-06

Low, Christopher S. F. (Department: 1653)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Peptide containing doai

C548S535000

Reexamination Certificate

active

06673772

ABSTRACT:

TECHNICAL FIELD
The present invention relates to a novel dipeptide compound which inhibits enzymatic activity of an HIV protease and to an anti-AIDS medicine which suppresses in vivo HIV growth utilizing the HIV protease inhibitory activity of the dipeptide compound.
DESCRIPTION OF BACKGROUND ART
Human immunodeficiency viruses (HIV) which induce AIDS produce a Gag protein, reverse transcriptase, or the like used for formation of the viruses as a precursor protein in host cells. The precursor proteins can function only when cut into a specific size using a protease (HIV protease) originating from viruses. An HIV protease inhibitor which inhibits the activity of the HIV protease and thereby blocks formation and maturation of infectious virus particles can be used as an anti-virus agent. Several such HIV protease inhibitors have already been reported.
One kind of such compounds is synthetic peptide-like compounds called a substrate transition state mimetic (T. Robins et al., J. Acquire. Immun. Defic. Syndr., 6, 162, 1993, etc.). The compounds which have been reported to be useful as an HIV protease inhibitor include a hydroxyethyl amine derivative such as Ro31-8959 which contains a phenylalanine &phgr; [CH(OH)CH
2
N] decahydroisoquinoline carboxylic acid skeleton similar to an amino acid sequence selectively cut by an HIV protease, -Tyr*Pro-, or -Phe*Pro-(N. A. Roberts, et al., Science, 248, 358-361, 1990), a hydroxymethylcarboxamide derivative such as a peptide containing a phenylalanine &phgr; [CH(OH)CON] proline-like skeleton (T. F. Tam, et al., J. Med. Chem., 35, 1318-1320, 1992), and the like.
The inventors of the present invention have previously found that a synthetic peptide compound containing a 3-amino-2-hydroxy-4-phenylbutanoic acid in the skeleton structure strongly inhibits HIV protease activity and is useful as an anti-AIDS medicine. The inventors have proposed such a peptide as an HIV protease inhibitor (Japanese Patent Application Laid-open No. 10-025242, etc.).
However, when administering such an HIV protease inhibitor orally or parenterally, it is difficult to maintain its concentration in blood sufficiently high to suppress duplication of viruses in infected cells in the body. Quite a few HIV protease inhibitors therefore remain still in the clinical test stage. One reason for this is incapability of the medical component to reach inside the cells due to interaction with proteins (particularly &agr;
1
-acidic glycoproteins) which are present in plasma (e.g. J. K. Lazdins, et al., The Journal of Infectious Diseases, 175, 1063-1070, 1997). In view of this situation, development of a compound exhibiting a strong anti-virus action which is less affected by plasma proteins has been desired.
DISCLOSURE OF THE INVENTION
The present invention has been achieved in view of the above situation and has an object of providing a novel dipeptide compound which can exhibit a strong action and can maintain a high concentration in cells in the presence of plasma proteins, as compared with conventional HIV protease inhibitors comprising a substrate transition state mimetic peptide compound heretofore proposed as an anti-AIDS medicine. Another object of the present invention is to provide an anti-AIDS medicine comprising the novel dipeptide compound as an effective component, which can achieve a curative effect at a small dose.
The present invention relates to novel dipeptide compounds represented by the following formula (I) or (II), or pharmaceutically acceptable salts thereof,
wherein R
1
, R
2
, and R
3
independently represent a linear or branched, saturated or unsaturated lower alkyl group, alkoxyl group, alkylamino group, or dialkylamino group having 1-4 carbon atoms (with a carbon atom being either replaced by an oxygen atom or not), a halogeno group, or a hydrogen atom, provided that all of the R
1
, R
2
, and R
3
are not a hydrogen atom at the same, R
2
and R
3
may form a ring together; R
4
represents a linear or branched lower alkyl group having 1-4 carbon atoms or a hydrogen atom; X is a methylene group or a sulfur atom; Y represents a five or six member monocyclic or polycyclic hydrocarbon group, a heterocyclic group having a structure in which one or more carbon atom in the monocyclic or polycyclic hydrocarbon group is replaced by a hetero atom, an aryloxyalkyl group having 12 or less carbon atoms, in which the aromatic ring may be substituted with an alkyl group, alkoxy group, halogeno group, amino group or hydroxyl group; and Z represents an aliphatic hydrocarbon group having 1-6 carbon atoms or an aromatic hydrocarbon group having 12 or less carbon atoms in which the aromatic ring may be substituted with an alkyl group, alkoxy group, or halogeno group, or one or more carbon atom in the aromatic hydrocarbon group may be replaced by a hetero atom.
The present invention preferably relates to a dipeptide compound of the above formula (I) or (II), in which Y is a group represented by the following formula (III) or (IV), and Z is a group represented by the following formula (V) or a linear or branched lower alkyl group having 6 or less carbon atoms, or a pharmaceutically acceptable salt thereof,
wherein R
5
represents a linear or branched lower alkyl group having 1-4 carbon atoms or a halogeno group, R
6
represents an amino group or hydroxyl group, R
7
, R
8
, and R
9
represent a hydrogen, a methyl group, or a fluoro group, R
10
-R
14
individually represent a linear or branched lower alkyl or alkoxy group having 1-4 carbon atoms, a halogeno group, or a hydroxyl group,
R
15
-R
19
individually represent a linear or branched lower alkyl or alkoxy group having 1-4 carbon atoms, a halogeno group, or a hydrogen atom, Q is an alkylene group, n is 0 or 1, and m is 0-6.
The present invention preferably relates to a novel dipeptide compound having a methyl group for R
4
and a sulfur atom for X in the above formula (I) or (II), and to a pharmaceutically acceptable salt thereof.
The other preferable compounds of the present invention is a novel dipeptide compound having the group of the formula (III) for Y and the group of the formula (V) for Z in the above formula (I) or (II), and a pharmaceutically acceptable salt thereof. In this instance, preferably R
5
is a methyl group or a chloro group, R
6
is a hydroxyl group or amino group, and R
7
-R
9
are a hydrogen, and more preferably R
15
is a methyl group, R
16
-R
18
is a hydrogen, and R
19
is a methyl group or a hydrogen.
Furthermore, among the dipeptide compounds or pharmaceutically acceptable salts thereof, having the group of the formula (III) for Y, the group of the formula (V) for Z, a methyl group or chloro group for R
5
, a hydroxyl group or amino group for R
6
, a hydrogen for R
7
-R
9
, a methyl group for R
15
, a hydrogen for R
16
-R
18
, and a methyl group or hydrogen for R
19
in the above formula (I) or (II), a compound having a hydrogen for R
1
, a linear or branched, saturated or unsaturated lower alkoxy group having 1-4 carbon atoms, in which the carbon atoms may be replaced by oxygen atoms, or a hydrogen for R
2
or R
3
(R
2
and R
3
must not be hydrogen at the same time), or having a ring formed by R
2
and R
3
in combination, is more preferable. A particularly preferable compound is that having a hydrogen for R
1
, a methoxy group, ethoxy group, or hydrogen for R
2
or R
3
(provided that R
2
and R
3
must not be hydrogen at the same time), or a methylenedioxy group as a ring formed by R
2
and R
3
in combination.
The present invention relates to an anti-AIDS medicine comprising one of these novel dipeptide compounds or a pharmaceutically acceptable salt thereof as an effective component.
The dipeptide compound of the present invention is a hydroxymethylcarboxamide derivative, which is an &agr;-aminocarboxamide containing a 3-amino-2-hydroxy-4-substituted-phenylbutanoyl skeleton and a five-membered ring connected via an amide bond, as a substrate transition state mimetic structure essential for HIV protease inhibition activity. In the dipeptide compound of the present in

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