Urea compounds, process for producing the same and use thereof

Details Urea compounds, process for producing the same and use thereof Urea compounds, process for producing the same and use thereof

2002-04-05

2004-09-07

Mekane, Joseph (Department: 1625)

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

Organic compounds

Chalcogen in the nitrogen containing substituent

C544S061000, C544S111000, C544S113000, C544S114000, C544S116000, C544S117000, C544S121000, C544S127000, C544S124000, C544S128000, C544S129000, C544S180000, C544S182000, C544S224000, C544S238000, C544S242000, C544S258000, C544S283000, C544S284000, C544S353000, C546S186000, C546S187000, C546S188000, C546S190000, C546S192000, C546S194000, C546S195000, C546S196000, C546S197000, C546S200000, C546S201000, C546S202000, C546S205000, C546S207000, C546S208000, C546S209000, C546S210000, C546S213000, C546S214000

Reexamination Certificate

active

06787650

ABSTRACT:

TECHNICAL FIELD
The present invention relates to urea compounds which are useful for the treatment of acquired immunodeficiency syndrome (AIDS), their production and use.
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 based on 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 THE 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, which is natural ligand, to 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 represented by the formula (I) or a salt thereof exhibits superior CCR5 antagonistic activity and is useful for inhibition of HIV infection to human peripheral blood mononuclear cells (especially medicament for treatment or prevention of 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 hydrocarbon group which may be substituted;
R
2
is a cyclic hydrocarbon group which may be substituted or a heterocyclic group which may be substituted;
R
3
is a halogen atom, a carbamoyl group which may be substituted, a sulfamoyl group which may be substituted, an acyl group derived from a sulfonic acid, a C
1-4
alkyl group which may be substituted, a C
1-4
alkoxy group which may be substituted, an amino group which may be substituted, a nitro group or a cyano group;
R
4
is a hydrogen atom or a hydroxy group;
n is an integer of 0 or 1;
p is an integer of 0 or 1 to 4];
or a salt thereof,
(2) the compound as shown in the above (1), wherein R
3
is a halogen atom, a C
1-4
alkyl group which may be substituted, a C
1-4
alkoxy group which may be substituted, an amino group which may be substituted, a nitro group or a cyano group,
(3) the compound as shown in the above (1), wherein R
1
is an alicyclic hydrocarbon group which may be substituted or an aryl group which may be substituted,
(4) the compound as shown in the above (1), wherein R
1
is a hydrocarbon group which may be substituted by 1 to 4 substituent(s) selected from 1) a hydrocarbon group which may be substituted, 2) an heterocyclic group which may be substituted, 3) a C
1-4
alkoxy group which may be substituted, 4) a C
1-4
alkylthio group which may be substituted, 5) a C
2-6
alkoxycarbonyl group which may be substituted, 6) a C
1-6
alkanoyl group which may be substituted, 7) an amino group which may be substituted, 8) a cyclic amino group, 9) a halogen atom, 10) a nitro group, 11) a cyano group, 12) a carbamoyl group which may be substituted, 13) a sulfamoyl group which may be substituted and 14) an acyl group derived from a sulfonic acid,
(5) the compound as shown in the above (1), wherein R
1
is a hydrocarbon group which may be substituted by 1 to 4 substituent(s) selected from 1) a hydrocarbon group which may be substituted, 2) a heterocyclic group which may be substituted, 3) a C
1-4
alkoxy group which may be substituted, 4) a C
1-4
alkylthio group which may be substituted, 5) a C
2-6
alkoxycarbonyl group which may be substituted, 6) an amino group which may be substituted, 7) a halogen atom, B) a nitro group and 9) a cyano group,
(6) the compound as shown in the above (1), wherein R
1
is a hydrocarbon group which may be substituted by 1 to 4 substituent(s) selected from 1) a hydrocarbon group which may be substituted, 2) a heterocyclic group which may be substituted, 3) a C
1-4
alkylthio group which may be substituted, 4) a C
2-6
alkoxycarbonyl group which may be substituted, 5) an amino group which may be substituted, 6) a halogen atom and 7) a nitro group,
(7) the compound as shown in the above (1), wherein R
2
is an cyclic hydrocarbon group which may be substituted,
(8) the compound as shown in the above (1), wherein R
3
is a halogen, a carbamoyl group which may be substituted, a sulfamoyl group which may be substituted or an acyl group derived from a sulfonic acid,
(9) the compound as shown in the above (1), wherein R
3
is a halogen,
(10) the compound as shown in the above (1), wherein R
4
is a hydrogen atom,
(11) the compound as shown in the above (1), wherein n is 0,
(12) the compound as shown in the above (1), wherein R
1
is a hydrocarbon group selected from Group 3 which may be substituted by member(s) selected from Group 1; R
2
is a cyclic hydrocarbon group selected from Group 10 which may be substituted by member(s) selected from Group 2, or a heterocyclic group selected from Group 4 which may be substituted by member(s) selected from Group 2; R
3
is a halogen atom, a carbamoyl group, a N-mono-substituted carbamoyl group which is substituted by a member selected from Group 11, a N,N-di-substituted carbamoyl group which is substituted by a member selected from Group 11 and a member selected from Group 14, a cyclic aminocarbonyl group selected from Group 17, a sulfamoyl group, N-mono-substituted sulfamoyl group which is substituted by a member selected from Group 11, a N,N-di-substituted sulfamoyl group which is substituted by a member selected from Group 11 and a member selected from Group 14, a cyclic aminosulfonyl group selected from Group 20, an acyl group derived from a sulfonic acid selected from Group 15, a C
1-4
alkyl group which may be substituted by member(s) selected from Group 2, a C
1-4
alkoxy group which may be substituted by member(s) selected from Group 2, an amino group which may be substituted by member(s) selected from Group 8, a cyclic amino group selected from Group 9, a nitro group or a cyano group.
[In the above,
Group I includes
1) a hydrocarbon group which selected from Group 3 which may be substituted by member(s) selected from Group 2,

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