Indole derivatives having an antiviral activity

Details Indole derivatives having an antiviral activity Indole derivatives having an antiviral activity

2001-08-15

2003-01-14

Solola, T. A. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C548S493000

Reexamination Certificate

active

06506787

ABSTRACT:

TECHNICAL FIELD
This invention relates to novel compounds having an antiviral activity, in detail indole derivatives having an inhibitory activity against viral integrase, and pharmaceutical compositions containing them, especially anti-HIV drugs.
BACKGROUND ART
Among viruses, human immunodeficiency virus (HIV), a kind of retrovirus, is known to cause acquired immunodeficiency syndrome (AIDS). The drug for treatment of AIDS is mainly selected from the group of reverse transcriptase inhibitors (AZT, 3TC, and the like) and protcase inhibitors (Indinavir and the like), but they are proved to be accompanied by side effects such as nephropathy and the emergence of resistant virus. Thus, the development of anti-HIV drugs having the other mechanism of action has been desired.
In the above circumstance, integrase has recently been thought to be noteworthy, which is an enzyme relating to the site-specific insertion of viral DNA into chromosome in animal cells, and the research for anti-HIV drugs based on said enzyme inhibition activity is performed ((1) Proc. Natl. Acad. Sci. USA 61 (3), 1013-1020 (1968), KOURILSKY P et al.; (2) J. VIROL. METHODS (NETHERLANDS), 17/1-2(55-61) (1987), F Barin et al.; (3) Proc. Natl. Acad. Sci. USA 90: 2399 (1993), Fesen. MR (1993); (4) CDC AIDS Weekly Pagination:P2 (1990), DeNoon, DJ). Some integrase inhibitors has recently been reported, for example, peptide derivatives described in U.S. Pat. No. 5,578,573, tetrahydronaphthyl derivatives described in GB 2306476A, and acrydone derivatives described in WO 97/38999.
Additionally, in the literature, Khim. Geterotsikl. Soedin. 1973, (11), 1519, some kind of indole derivatives are described, but their therapeutic activity is not described. Moreover, in U.S. Pat. No. 5,475,109, non-condensed heterocyclic compounds substituted with dioxobutanoic acid are described to be useful as an anti influenza viral drug, whose mechanism of the action is the inhibition of cap-dependent endonuclease.
DISCLOSURE OF INVENTION
In the circumstance above, the development of a novel integrase inhibitor is desired. The present inventors have studied intensively to find out that novel indole derivatives have an inhibitory action on integrase, and are useful as antiviral drugs, especially anti-HIV drugs, to accomplish the present invention shown below.
(1) A compound of the formula:
wherein
R
1
is hydrogen, lower alkyl, cycloalkyl lower alkyl, lower alkylsulfonyl, lower alkylcarbonyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted arylsulfonyl, optionally substituted arylcarbonyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, optionally substituted heteroarylsulfonyl, lower alkoxycarbonyl, optionally substituted sulfamoyl, or optionally substituted carbamoyl;
R
2
is hydrogen, lower alkyl, lower alkylcarbonyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted arylcarbonyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, optionally substituted arylthio, optionally substituted arylsulfinyl, optionally substituted arylsulfonyl, optionally substituted heterocyclyl lower alkyl, or optionally substituted heterocyclyl sulfonyl;
R
3
, R
4
, R
5
, and R
6
each is independently hydrogen, halogen, trihalogenated lower alkyl, hydroxy, lower alkoxy, nitro, amino, optionally esterified carboxy, optionally substituted aralkyloxy, or optionally substituted arylsulfonyloxy;
X is hydroxy or optionally substituted amino;
Y is COOR (R is hydrogen or an ester residue), optionally substituted aryl, or optionally substituted heteroaryl,
provided that a compound wherein R
1
, R
2
, R
3
, R
5
, and R
6
each is hydrogen; R
4
is hydrogen, methoxy, or chloro; X is hydroxy; and Y is COOC
2
H
5
is excluded, (hereinafter referred to as a compound (I)), a tautomer, or a pharmaceutically acceptable salt, or a hydrate thereof.
(2) The compound according to above (1) wherein R
1
and R
2
are not hydrogens at the same time when Y is COOR (R is as defined above).
(3) The compound according to above (1) wherein R
1
and R
2
are not hydrogens at the same time when X is hydroxy and Y is COOR (R is as defined above).
(4) The compound according to any one of above (1)-(3) wherein R
1
is hydrogen or optionally substituted arylsulfonyl.
(5) The compound according to any one of above (1)-(3) wherein R
2
is hydrogen, optionally substituted aryl, or optionally substituted aralkyl.
(6) The compound according to any one of above (1)-(3) wherein R
3
, R
4
, R
5
, and R
6
each is independently hydrogen or halogen.
(7) The compound according to above (6) wherein R
3
, R
5
, and R
6
are all hydrogens.
(8) The compound according to any one of above (1)-(3) wherein X is hydroxy.
(9) The compound according to above (1) wherein Y is optionally substituted heteroaryl.
(10) The compound according to above (9) wherein said heteroaryl is a 5-or 6-membered ring containing at least one nitrogen atom.
(11) The compound according to above (10) wherein said heteroaryl is tetrazolyl, triazolyl, or imidazolyl.
(12) The compound according to any one of above (1)-(3) wherein R
1
is hydrogen or optionally substituted arylsulfonyl; R
2
is hydrogen, optionally substituted aryl, or optionally substituted aralkyl; R
3
, R
4
, R
5
, and R
6
each is independently hydrogen or halogen; X is hydroxy.
(13) The compound according to above (1) wherein R
1
is hydrogen or optionally substituted arylsulfonyl; R
2
is hydrogen, optionally substituted aryl, or optionally substituted aralkyl; R
3
, R
4
, R
5
, and R
6
each is independently hydrogen or halogen; X is hydroxy; Y is optionally substituted heteroaryl.
(14) The compound according to above (13) wherein R
1
is hydrogen or phenylsulfonyl optionally substituted with halogen; R
2
is hydrogen, phenyl optionally substituted with halogen, or phenylmethyl optionally substituted with halogen; R
4
is halogen; R
3
, R
5
, and R
6
are all hydrogens at the same time; X is hydroxy; Y is tetrazolyl.
(15) A pharmaceutical composition containing, as an active ingredient, an indole derivative having a group of the formula: —C(O)CH═C(X)Y (wherein X and Y are as defined above) at the 3-position.
(16) A pharmaceutical composition containing the compound according to any one of above (1)-(14) as an active ingredient.
(17) A composition for inhibiting integrase which contains the compound according to any one of above (1)-(14).
(18) An antiviral composition which contains the compound according to any one of above (1)-(14).
(19) An anti-HIV composition which contains the compound according to any one of above (1)-(14).
(20) An anti-HIV medical mixture comprising a reverse transcriptase inhibitor and/or a protease inhibitor in addition to the integrase inhibitor according to above (17).
The compound (I) of the present invention is characterized in that the indole ring has a group of the formula: —C(O)CH═C(X)Y at the 3-position.
The terms used in the specification are explained below. Each term by itself or as part of (an)other substituent(s) means the same unless particularly mentioned.
The term “lower alkyl” is, for example, a C1-C6 straight or branched chain alkyl group, which includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, n-hexyl, isohexyl, and the like. A preferable embodiment is C1-C4 alkyl, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and tert-butyl.
The term “lower alkoxy” is, for example, a C1-C6 straight or branched chain alkoxy group, which includes methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentyloxy, isopentyloxy, n-hexyloxy, isohexyloxy, and the like. A preferable embodiment is C1-C4 alkoxy, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, and the like.
The term “cycloalkyl lower alkyl” is, for example, the above-mentioned lower alkyl group substituted with C3-C6 cycloalkyl, which includes cyclopropyl methyl, 2-cyclopropyl ethyl, 4-

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