Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Phosphorus containing other than solely as part of an...
Reexamination Certificate
2000-09-13
2001-07-31
Powers, Fiona T. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Phosphorus containing other than solely as part of an...
C514S119000, C514S254080, C514S331000, C514S354000, C514S357000, C514S400000, C514S336000, C514S617000
Reexamination Certificate
active
06268354
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a pharmaceutical composition for antagonizing CCR5 comprising an anilide derivative.
BACKGROUND ART
Recently, HIV (human immunodeficiency virus) protease inhibitors are developed for method of the treatment of AIDS (acquired immunological deficient syndrome) and use of the protease inhibitors in combination with conventional two HIV reverse transcriptase inhibitors provides with a further progress of the treatment of AIDS. However, these drugs and their combination use are not sufficient for the eradication of AIDS, and development of new anti-AIDS drugs having different activity and mechanism are sought for.
As a receptor from which HIV invades to a target cell, CD4 is so far known, and recently CCR5 as a second receptor of macrophage-tropic HIV and CXCR4 as a second receptor of T cell-tropic HIV, each of which is G protein-coupled chemokine receptor having seven transmembrane domains, are respectively found out. These chemokine receptors are 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. However, so far, there has been no report that a CCR5 antagonist is developed as a therapeutic agent of AIDS.
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 invention is to provide a pharmaceutical composition which is useful for the treatment or prophylaxis of infectious disease of HIV and, in particular, AIDS and which comprises an anilide derivative having CCR5 antagonistic activity.
DISCLOSURE OF INVENTION
The present inventors diligently made extensive studies on compounds having CCR5 antagonistic activity and, as a result, they found that an anilide derivative of the following formula (I′) or a salt thereof [hereinafter, referred to as Compound (I′)] unexpectedly possesses potent CCR5 antagonistic activity and clinically desirable pharmaceutical effect (e.g. remarkable inhibition of HIV infection to human peripheral mononuclear cells, etc.). Based on the finding, the present invention was accomplished.
More specifically, the present invention relates to
(1) a pharmaceutical composition for antagonizing CCR5 (or a pharmaceutical composition for inhibiting binding of a ligand to CCR5 or a pharmaceutical composition for antagonizing binding of a ligand of CCR5 to CCR5) which comprises a compound of the formula (I′):
wherein
R
1
is an optionally substituted 5- to 6-membered ring,
W is a divalent group of the formula:
wherein the ring A is an optionally substituted 5- to 6-membered aromatic ring, X is an optionally substituted carbon atom, an optionally substituted nitrogen atom, sulfur atom or oxygen atom, the ring B is an optionally substituted 5- to 7-membered ring, Z is a chemical bond or a divalent group, R
2
is (1) an optionally substituted amino group in which a nitrogen atom may form a quaternary ammonium, (2) an optionally substituted nitrogen-containing heterocyclic ring group which may contain a sulfur atom or an oxygen atom as ring constituting atoms and wherein a nitrogen atom may form a quaternary ammonium, (3) a group binding through a sulfur atom or (4) a group of the formula:
wherein k is 0 or 1, and when k is 0, a phosphorus atom may form a phosphonium; and R
5
′ and R
6
′ are independently an optionally substituted hydrocarbon group, an optionally substituted hydroxy group or an optionally substituted amino group, and R
5
′ and R
6
′ may bind to each other to form a cyclic group together with the adjacent phosphorus atom, or a salt thereof;
(2) a composition of the above (1), wherein R
1
is benzene, furan, thiophene, pyridine, cyclopentane, cyclohexane, pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine or tetrahydropyran, each of which may be substituted;
(3) a composition of the above (1), wherein R
1
is an optionally substituted benzene;
(4) a composition of the above (1), wherein the ring A is furan, thiophene, pyrrole, pyridine or benzene, each of which may be substituted;
(5) a composition of the above (1), wherein the ring A is an optionally substituted benzene;
(6) a composition of the above (1), wherein W is a group of the formula:
wherein each symbol is as defined in the above (1);
(7) a composition of the above (1), wherein W is a group of the formula:
wherein each symbol is as defined in the above (1);
(8) a composition of the above (7), wherein the ring B is a 5- to 7-membered ring group of the formula:
wherein Y is —Y′—(CH
2
)
m
— (Y′ is —S—, —O—, —NH— or —CH
2
—, and m is an integer of 0-2), —CH═CH— or —N═CH—), which may have a substituent at any possible position;
(9) a composition of the above (8), wherein Y is —Y′—(CH
2
)
2
— (Y′ is —S—, —O—, —NH— or —CH
2
—);
(10) a composition of the above (8), wherein Y is —(CH
2
)
2
—, —(CH
2
)
3
— or —O—(CH
2
)
2
—;
(11) a composition of the above (10), wherein the ring A is an optionally substituted benzene;
(12) a composition of the above (1), wherein Z is an optionally substituted C
1-3
alkylene;
(13) a composition of the above (1), wherein Z is a divalent group of the formula: —Z′—(CH
2
)
n
— (Z′ is —CH(OH)—, —C(O)— or —CH
2
—, and n is an integer of 0-2) in which an optional methylene group may be substituted;
(14) a composition of the above (1), wherein Z is methylene;
(15) a composition of the above (1), wherein Z is substituted at para position of the benzene ring;
(16) a composition of the above (1), wherein R
2
is (1) an optionally substituted amino group in which a nitrogen atom may form a quaternary ammonium, (2) an optionally substituted nitrogen-containing heterocyclic ring group which may contain a sulfur atom or an oxygen atom as ring constituting atoms and wherein a nitrogen atom may form a quaternary ammonium, (3) a group binding through a sulfur atom or (4) a group of the formula:
wherein k is 0 or 1, and when k is 0, a phosphorus atom may form a phosphonium; and R
5
and R
6
are independently an optionally substituted hydrocarbon group or an optionally substituted amino group, and R
5
and R
6
may bind to each other to form a cyclic group together with the adjacent phosphorus atom;
(17) a composition of the above (1), wherein R
2
is (1) an optionally substituted amino group in which a nitrogen atom may form a quaternary ammonium, (2) an optionally substituted nitrogen-containing heterocyclic ring group which may contain a sulfur atom or an oxygen atom as ring constituting atoms and wherein a nitrogen atom may form a quaternary ammonium or (3) a group of the formula:
wherein R
5
and R
6
are independently an optionally substituted hydrocarbon group, and R
5
and R
6
may bind to each other to form a cyclic group together with the adjacent phosphorus atom;
(18) a composition of the above (1), wherein R
2
is an optionally substituted amino group wherein a nitrogen atom may form a quaternary ammonium;
(19) a composition of the above (1), wherein R
2
is a group of the formula: —N
+
RR′R″ wherein R, R′ and R″ are independently an optionally substituted aliphatic hydrocarbon group or an optionally substituted alicyclic heterocyclic ring group;
(20) a pharmaceutical composition for antagonizing CCR5 which comprises a compound of the formula:
wherein R
1
i
Aramaki Yoshio
Baba Masanori
Kanzaki Naoyuki
Kuroshima Ken-ichi
Nishimura Osamu
Powers Fiona T.
Takeda Chemical Industries Ltd.
Wenderoth , Lind & Ponack, L.L.P.
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