Cyclic amine compounds as CCR5 antagonists

Details Cyclic amine compounds as CCR5 antagonists Cyclic amine compounds as CCR5 antagonists

2002-03-29

2003-05-13

Coleman, Brenda (Department: 1624)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

Reexamination Certificate

active

06562978

ABSTRACT:

This application is a 371 of PCT/JP00/06755 filed Sep. 29, 2000.
TECHNICAL FIELD
The present invention relates to cyclic amine compounds, which are useful for the treatment of acquired immunodeficiency syndrome (AIDS), their production and use and pharmaceutical compositions containing them.
BACKGROUND ART
HIV,(human immunodeficiency virus) protease inhibitors have been developed for the treatment of AIDS and use of the protease inhibitors in combination with two conventional HIV reverse transcriptase inhibitors has provided further progress in the treatment of AIDS. However, these drugs and their combination use are not sufficient to eradicate AIDS, and new anti-AIDS drugs having different activities and mechanisms are therefore required.
CD4 is a known receptor from which HIV invades a target cell. Recently, CCR5 has been discovered as a second receptor of macrophage-tropic HIV. CCR5 is a G protein-coupled chemokine receptor having seven transmembrane domains. This chemokine receptor is thought to play an essential role in establishment and spread of HIV infection. In fact, it is reported that a person who is resistant to HIV infection in spite of several exposures retains mutation of homo deletion of CCR5 gene. Therefore, a CCR5 antagonist is expected to be a new anti-HIV drug.
As chemokine receptor antagonists, there are known aromatic urea derivatives (J. Biol. Chem., 1998, 273, 10095-10098.), benzodiazepine derivatives (Japanese unexamined patent publication No.9-249570), cyclam derivatives (Nat. Med., 1998, 4, 72-77.), spiro piperidine derivatives (WO98/25604,25605,), acridine derivatives (WO98/30218), xanthene derivatives (WO98/04554), haloperidol derivatives (J. Biol. Chem., 1998, 273, 15687-15692., WO98/24325, 02151.), benzazocine-type compound (Japanese unexamined patent publication No.9-25572), benzimidazole derivatives (WO98/06703), piperazine and diazepine derivatives (WO97/44329), 3-di-substituted piperidine derivatives (Japanese unexamined patent publication No.9-249566), 4-substituted piperidine derivatives (WO99/04794), substituted pyrrolidine derivatives (WO99/09984, WO99/38514), etc. However, so far, there has been no report that a CCR5 antagonist is developed as a therapeutic agent of AIDS.
DISCLOSURE OF INVENTION
In order to investigate an anti-AIDS drug having CCR5 antagonistic activity, it is necessary to clone CCR5 gene from human tissue derived cDNA library, to ligate said gene with a vector for expression in animal cells, to introduce said gene into animal cells and to obtain cells expressing CCR5. In addition, with using this transformant, it is necessary to screen a compound which strongly inhibits binding of CC chemokine RANTES, natural ligand, to CCR5 (which strongly antagonizes CCR5). However, so far there has been no report on a low molecule compound having CCR5 antagonistic activity.
The present inventors diligently made extensive studies on compounds having CCR5 antagonistic activity and, as a result, they found that a compound shown be the formula (I) or a salt thereof unexpectedly possesses potent CCR5 antagonistic activity and inhibition of HIV infection to human peripheral mononuclear cells (especially AIDS), and also that the compound has superior absorbability when orally administered. Based on the finding, the present invention was accomplished.
More specifically, the present invention relates to:
(1) A compound of the formula:
(wherein R
1
is a hydrogen atom, a hydrocarbon group which may be substituted, a non-aromatic heterocyclic group which may be substituted, R
2
is a hydrocarbon group which may be substituted, a non-aromatic heterocyclic group which may be substituted, or R
1
and R
2
may combine to each other together with A to form a heterocyclic group which may be substituted; A is N or N
+
—R
5
. Y
−
(R
5
is a hydrocarbon group; Y
−
is a counter anion); R
3
is a cyclic hydrocarbon group which may be substituted or a heterocyclic group which may be substituted; n is 0 or 1; R
4
is a hydrogen atom, a hydrocarbon group which may be substituted, a heterocyclic group which may be substituted, an alkoxy group which may be substituted, an aryloxy group which may be substituted, or an amino group which may be substituted, E is a divalent aliphatic hydrocarbon group which may be substituted by a group other than an oxo group; G
1
is a bond, CO or SO
2
; G
2
is CO, SO
2
, NHCO, CONH or OCO; J is methine or a nitrogen atom; and each of Q and R is a bond or a divalent C
1-3
aliphatic hydrocarbon which may be substituted; provided that J is methine when G
2
is OCO, that one of Q and R is not a bond when the other is a bond and that each of Q and R is not substituted by an oxo group when G
1
is a bond) or a salt thereof.
(2) A compound as shown in the above (1), wherein R
1
is a hydrogen atom, a hydrocarbon group selected from Group 2 which may be substituted by member(s) selected from Group 1, a 3- to 8-membered saturated or unsaturated non-aromatic heterocyclic group which may be substituted by member(s) selected from Group 1; R
2
is a hydrocarbon group selected from Group 2 which may be substituted by member(s) selected from Group 1 or a 3- to 8-membered saturated or unsaturated non-aromatic heterocyclic group which may be substituted by member(s) selected from Group 1, or R
1
and R
2
may combine each other together with A to form a heterocyclic group selected from Group 4 which may be substituted by member(s) selected from Group 3; A is N or N
+
—R
5
. Y
−
(Y
−
is Cl
−
, Br
−
, I
−
, NO
3
−
, SO
4
2−
, PO
4
3−
or CH
3
SO
3
−
; R
5
is a hydrocarbon group selected from Group 2); R
3
is a cyclic hydrocarbon group selected from Group 5 which may be substituted by member(s) selected from Group 1 or a heterocyclic group selected from Group 6 which may be substituted by member(s) selected from Group 1; R
4
is a hydrogen atom, a hydrocarbon group selected from Group 2 which may be substituted by member(s) selected from Group 1, a heterocyclic group, selected from Group 6 which may be substituted by member(s) selected from Group 1, a C
1-6
alkoxy group which may be substituted by member(s) selected from Group 7, a C
6-14
aryloxy group which may be substituted by member(s) selected from Group 8, an amino group which may be substituted by member(s) selected from Group 9 or a cyclic-amino group selected from Group 10; E is a divalent aliphatic hydrocarbon group selected from Group 12 which may be substituted by member(s) other than oxo group(s) and selected from Group 11; each of Q and R is a bond or a divalent C
1-3
aliphatic hydrocarbon group selected from Group 13 which may be substituted by member(s) selected from Group 11.
Group 1
(1) a C
1-6
alkyl group which may be substituted by member(s) selected from Group 14, (2) a C
2-6
alkenyl group which may be substituted by member(s) selected from Group 14, (3) a C
2-6
alkynyl group which may be substituted by member(s) selected from Group 14, (4) a C
6-14
aryl group which may be substituted by member(s) selected from Group 14, (5) a C
3-7
cycloalkyl group which may be substituted by member(s) selected from Group 14, (6) a C
3-6
cycloalkenyl group which may be substituted by member(s) selected from Group 14, (7) a heterocyclic group selected from Group 16 which may be substituted by member(s) selected from Group 15, (8) an amino group which may be substituted by a C
1-6
alkyl-imidoyl(s), formyl-imidoyl(s), amidino(s) or member(s) selected from Group 17, (9) a cyclic-amino group which may be substituted by member(s) selected from Group 10, (10) an imidoyl group which may be substituted by member(s) selected from Group 17, (11) an amidino group which may be substituted by member(s) selected from Group 17, (12) a hydroxyl group which may be substituted by a member selected from Group 17, (13) a thiol group which may be substituted by a member selected from Group 17, (14) a carboxyl group, (15) a C
1-6
alkoxy-carbonyl group which may be substituted by member(s) selected from Group 18, (16) a C
7-

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