Cyclic compounds and uses thereof

Details Cyclic compounds and uses thereof Cyclic compounds and uses thereof

2001-11-02

2003-09-30

Lambkin, Deborah C. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C549S009000

Reexamination Certificate

active

06627651

ABSTRACT:

This application is 371 of PCT/JP00/02825 Apr. 28, 2000.
1. Technical Field
The present invention relates to novel cyclic ring compounds, which possess CCR antagonistic actions, particularly a CCR5 antagonistic action, and uses thereof.
2. Background Art
In recent years, inhibitors of HIV (human immunodeficiency virus) protease have been developed as therapeutic agents against AIDS (acquired immunodeficiency syndrome), and the use of these drugs in combination with the two HIV reverse transcriptase inhibitors, which have been heretofore employed, have brought a remarkable progress in the treatment of AIDS, whereas this progress is not yet sufficient for eradicating AIDS, whereby the development of new anti-AIDS drugs, which act by still another mechanism, has been desired.
CD4 has been known for some time as a receptor through which HIV enters the target cells, while G-protein-coupled, seven trans-membrane chemokine receptors called CCR5 and CXCR4 have recently been found out as the second group of receptors for macrophage-trophic HIV and T-cell-trophic HIV, respectively, and it is speculated that these chemokine receptors play essential roles in the establishment of infection and transmission of HIV. In fact, there is a report that people who remained resistant to HIV infection in spite of repeated exposures were found to have homozygous deletion in CCR5 gene. Therefore, CCR5 antagonists are expected to be new anti-HIV drugs, and examples of synthesizing new anilide derivatives possessing the CCR5-antagonistic activity are described in patent applications such as PCT/JP98/05708 (WO99/32100), Japanese Patent Application No. 1998-234388 (WO00/10965) and Japanese Patent Application No. 1998-363404 (PCT/JP99/07148), whereas there have so far been no report on commercialization of CCR5 antagonists as the therapeutic agents against AIDS.
DISCLOSURE OF THE INVENTION
The present invention is to provide novel bicyclic ring compounds, which are useful as the prophylactic and therapeutic agents against HIV infectious diseases, particularly AIDS, on the basis of CCR antagonistic actions, particularly a CCR5 antagonistic action.
As a result of intensive investigations on compounds possessing a CCR5 antagonistic action, the present inventors have found that compounds represented by the following formula (I) or salts thereof (hereinafter, may be designated as compounds (I)) possess clinically desirable, medicinal effects such as exhibition of CCR antagonistic actions, particularly an excellent CCR5 antagonistic action, and the like, completing the present invention on the basis of this finding.
In other words, the present invention relates to:
(1) A compound represented by formula (I)
R
1
—X
1
—W—X
2
—Z
1
—Z
2
—R
2
 [wherein R
1
indicates a 5- to 6-membered cyclic ring group that may be substituted, X
1
indicates a bond or a bivalent group, in which the number of atoms constituting the straight-chain portion is 1 to 4, W indicates a bivalent group that is represented by formula
 (wherein each of ring A and ring B indicates a 5- to 7-membered cyclic ring group that may be substituted, each of E
1
and E
4
indicates the carbon atom that may be substituted or the nitrogen atom that may be substituted, each of E
2
and E
3
indicates the carbon atom that may be substituted or the nitrogen atom that may be substituted, the sulfur atom that may be oxidized or the oxygen atom and each of a and b indicates to be a single bond or a double bond), X
2
indicates a bivalent group, in which the number of atoms constituting the straight-chain portion is 1 to 4, Z
1
indicates a bond or a bivalent cyclic ring group, Z
2
indicates a bond or a bivalent cyclic ring group, in which the number of atoms constituting the straight-chain portion is 1 to 4, and R
2
indicates (1) an amino group that may be substituted, where the nitrogen atom may be converted into a quaternary ammonium or the N-oxide, (2) a nitrogen-containing, heterocyclic ring group that may be substituted and may contain the sulfur atom or the oxygen atom as a ring-constituting atom, where the nitrogen atom may be converted into a quaternary ammonium or the N-oxide, (3) a group that is bonded via the sulfur atom, (4) a group represented by formula
 (wherein k indicates 0 or 1, the phosphorus atom may form a phosphonium salt when k is 0, and each of R
5′
and R
6′
indicates the hydrocarbon atom that may be substituted, the hydroxyl group that may be substituted or an amino group that may be substituted (preferably, the hydrocarbon atom that may be substituted or an amino group that may be substituted; more preferably the hydrocarbon atom that may be substituted) and R
5′
and R
6′
may bind each other to form a cyclic ring group together with the adjacent phosphorus atom), (5) an amidino group that may be substituted or (6) a guanidino group that may be substituted] [provided that, when a group represented by formula R
1
—X
1
—W—X
2
—Z
1
—Z
2
— indicates a group represented by formula
 (wherein R
1
indicates the same meaning as described above, W′ indicates a bivalent group represented by formula
 (wherein ring A′ indicates a 5- to 6-membered aromatic ring that may be substituted, X indicates the carbon atom that may be substituted, the nitrogen atom that may be substituted, the sulfur atom or the oxygen atom and ring B′ indicates a 5- to 7-membered ring that may be substituted) and Z indicates a bivalent group, in which the number of atoms constituting the straight-chain portion is 1 to 4, R
2
indicates an amidino group that may be substituted or a guanidino group that may be substituted; when a group represented by formula R
1
—X
1
—W—X
2
—Z
1
—Z
2
— indicates a group represented by formula
 (wherein R
1
and X
1
indicate the same meanings as described above, ring A″ indicates a benzene ring that may be substituted, Q
1
indicates a bivalent group, in which ring B″ forms a 5- to 7-membered ring, Q
2
indicates the hydrogen atom, a hydrocarbon group that may be substituted, a heterocyclic ring group that may be substituted and Q
3
indicates a bond or a bivalent group), R
2
does not indicate a group represented by formula
 (wherein each of R
5″
and R
6″
indicates the hydroxyl group that may be substituted and R
5″
and R
6″
may bind each other to form a cyclic ring group together with the adjacent phosphorus atom)], or salts thereof;
(2) A prodrug of the compound or the salt thereof as described in the above-mentioned item (1);
(3) The compound as described in the above-mentioned item (1), wherein R
1
is a group that is formed by removing one hydrogen atom from benzene, furan, thiophene, pyridine, cyclopentane, cyclohexane, pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine or tetrahydrofuran, each of which may be substituted;
(4) The compound as described in the above-mentioned item (1), wherein X
1
is a phenyl that may be substituted;
(5) The compound as described in the above-mentioned item (1), wherein R
1
is a bond, —(CH
2
)
a′
— [a′ indicates an integer of 1 to 4], —(CH
2
)
b′
—X
3
— [b′ indicates an integer of 0 to 3 and X
3
indicates an imino group that may be substituted, the carbonyl group, the oxygen atom or the sulfur atom that may be oxidized], —CH═CH—, —C≡C—, —CO—NH— or —SO
2
—NH—;
(6) The compound as described in the above-mentioned item (1), wherein X
1
is a bond;
(7) The compound as described in the above-mentioned item (1), wherein X
1
is —(CH
2
)
b′
—X
3
— [b′ indicates an integer of 0 to 3, and X
3
indicates an imino group that may be substituted, the carbonyl group, the oxygen atom or the sulfur atom that may be oxidized];
(8) The compound as described in the above-mentioned item (1), wherein ring A is furan, thiophene, pyrrole, pyridine, pyran or benzene, each of which may be substituted;
(9) The compound as described in the above-mentioned item (1), wherein ring A is a benzene t

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