Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-03-27
2001-05-22
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
06235771
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a novel anilide derivative, production and use thereof.
BACKGROUND ART
Recently, HIV (human immunodeficiency virus) protease inhibitors have been 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 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 a G protein-coupled chemokine receptor having seven transmembrane domains, are respectively known. 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 have been 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 a human tissue derived cDNA library, to ligate said gene with a vector for expression in animal cell , 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 novel anilide derivative which is useful for the treatment or prevention of infectious disease of HIV and, in particular, AIDS and also which is suitable for oral administration, production and use thereof
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.) and also that Compound (I) has superior absorb ability when orally administered. Based on the finding present invention was accomplished.
More specifically, the present invention relates to
(1) A compound of the formula (I):
wherein R
1
is an optionally substituted 5- to 6-membered ring; the ring A is an optionally substituted 6- to 7-membered ring; the ring B is an optionally substituted benzene ring; n is an integer of 1 or 2; 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; and a pro-drug of the compound or a salt thereof as described in the above (1);
(2) A compound as described in 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 compound as described in the above (1), wherein R
1
is an optionally substituted benzene;
(4) A compound as described in the above (1), wherein the ring A is a group of the formula:
wherein Y is —(CH
2
)
m
— (m is an integer of 1 or 2), —CH═CH— or —N═CH—, which may have a substituent at any possible position;
(5) A compound as described in the above (4), wherein Y is —(CH
2
)
m
— (m is an integer of 1 or 2);
(6) A compound as described in the above (4), wherein Y is —(CH
2
)
2
—;
(7) A compound as described in the above (1), wherein the ring B is a benzene which may be substituted with a substituent selected from the class consisting of a halogen atom, a C
1-4
alkyl group optionally substituted with a halogen atom and a C
1-4
alkoxy group optionally substituted with a halogen atom;
(8) A compound as described in the above (1), wherein n is 2;
(9) A compound as described in the above (1), wherein Z is an optionally substituted C
1-3
alkylene;
(10) A compound as described in 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;
(11) A compound as described in the above (1), wherein Z is methylene;
(12) A compound as described in the above (1), wherein R
2
is (1) an optionally substituted amino group, (2) an optionally substituted nitrogen-containing heterocyclic ring group which may contain a sulfur atom or an oxygen atom as ring constituting atoms, (3) a group binding through a sulfur atom or (4) a group of the formula:
wherein k is 0 or 1; 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;
(13) A compound as described in the above (1), wherein R
2
is (1) an optionally substituted amino group, (2) an optionally substituted nitrogen-containing heterocyclic ring group which may contain a sulfur atom or an oxygen atom as ring constituting atoms 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;
(14) A compound as described in the above (1), wherein R
2
is a group of the formula: —NRR′ wherein R and R′ are independently an optionally substituted aliphatic hydrocarbon group (aliphatic acyclic hydrocarbon group and aliphatic cyclic hydrocarbon group) or an optionally substituted non-aromatic heterocyclic ring group;
(15) A compound as described in the above (14), wherein R is an optionally substituted acyclic hydrocarbon group and R′ is an optionally substituted alicyclic hydrocarbon group (aliphatic cyclic hydrocarbon group) or an optionally substituted non-aromatic heterocyclic ring group;
(16) A compound as described in the above 14), wherein R is an optionally substituted C
1-6
alkyl group and R′ is an optionally substituted C
3-8
cycloalkyl group or an optionally substituted saturated heterocyclic ring group;
(17) A compound as described in the above (16), wherein R′ is an optionally substituted cyclohexyl, an optionally substituted tetrahydropyranyl, an optionally substituted tetrahydrothiopyranyl or an optionally substituted piperidyl;
(18) A compound selected from the class consisting of N-[4-[N-methyl-N-(tetrahydropyran-4-yl)aminomethyl]phenyl]-7-(4-propoxyphenyl-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide, 7-(4-butoxyphenyl)-N-[4-[N-methyl-N-(tetrahydropyran-4-yl)aminomethyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide, 7-[4
Baba Masanori
Kanzaki Naoyuki
Nishimura Osamu
Seto Masaki
Shiraishi Mitsuru
Chao Mark
Lambkin Deborah C.
Riesen Philippe Y.
Takeda Chemical Industries Ltd.
LandOfFree
Anilide derivative, production and use thereof does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Anilide derivative, production and use thereof, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Anilide derivative, production and use thereof will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2521794