Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-05-26
2002-04-23
Solola, T. A. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C549S424000
Reexamination Certificate
active
06376536
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a quaternary ammonium salt which has CCR5 antagonistic activity and which is used for the treatment or prevention of infectious disease of HIV, etc.
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.
DISCLOSURE OF INVENTION
The present invention is to provide a quaternary ammonium salt having CCR5 antagonistic activity and less toxicity; and a composition for antagonizing CCR5 (a drug for the treatment or prevention of infectious disease of HIV (in particular, AIDS), etc.) comprising said quaternary ammonium salt.
The present inventors diligently made extensive studies on compounds having CCR5 antagonistic activity and less toxicity, as a result, they found that a quaternary ammonium salt of the following formula (I) [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 solubility, physicochemical properties (stability, anti-coloring effect, etc.), etc. and is useful for applying as an injection. 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 an optionally substituted phenyl or an optionally substituted thienyl; Y is —CH
2
—, —S— or —O—; and R
2
, R
3
and R
4
are independently an optionally substituted aliphatic hydrocarbon group or an optionally substituted alicyclic heterocyclic ring group; or a pro-drug thereof;
(2) a compound of the above (1), wherein R
2
and R
3
are independently an optionally substituted acyclic hydrocarbon group;
(3) a compound of the above (1), wherein R
2
and R
3
are independently an optionally substituted alkyl group;
(4) a compound of the above (1), wherein R
4
is an optionally substituted alicyclic hydrocarbon group or an optionally substituted alicyclic heterocyclic ring group;
(5) a compound of the above (4), wherein the alicyclic hydrocarbon group is cycloalkyl;
(6) a compound of the above (4), wherein the alicyclic hydrocarbon group is cyclohexyl;
(7) a compound of the above (4), wherein the alicyclic heterocyclic ring group is a saturated alicyclic heterocyclic ring group;
(8) a compound of the above (4), wherein the alicyclic heterocyclic ring group is tetrahydropyranyl, tetrahydrothiopyranyl or piperidyl;
(9) N,N-Dimethyl-N-(4-(((2-(4-methylphenyl)-6,7-dihydro-5H-benzocyclohepten-8-yl)carbonyl)amino)benzyl)-N-(4-tetrahydropyranyl)ammonium chloride;
(10) N,N-Dimethyl-N-(((7-(4-methylphenyl)-2,3-dihydro-1-benzoxepin-4-yl)carbonyl)amino)benzyl)-N-(4-oxocyclohexyl)ammonium chloride;
(11) N-(4-(((7-(4-Ethoxyphenyl)-2,3-dihydro-1-benzoxepin-4-yl)carbonyl)amino)benzyl)-N,N-dimethyl-N-(4-tetrahydropyranyl)ammonium chloride;
(12) a pharmaceutical composition which comprises a compound of the above (1);
(13) a pharmaceutical composition for antagonizing CCR5 which comprises a compound of the above (9);
(14) a composition of the above (13), which is for the treatment or prevention of infectious disease of HIV;
(15) a composition of the above (13), which is for the treatment or prevention of AIDS;
(16) a composition of the above (13), which is for the prevention of the progression of AIDS;
(17) a composition of the above (13), which is used in combination with a protease inhibitor and/or a reverse transcriptases inhibitor;
(18) a composition of the above (17), wherein the reverse transcriptase inhibitor is zidovudine, didanosine, zalcitabine, lamivudine, stavudine, nevirapine, delavirdine, efavirenz 0r abacavir;
(19) a composition of the above (17), wherein the protease inhibitor is saquinavir, ritonavir, indinavir or nelfinavir;
(20) use of the compound of the above (9) in combination with a protease inhibitor and/or a reverse transcriptase inhibitor for the treatment or prevention of infectious disease of HIV; etc.
In the above formula (I), example of the “substituents” which the “phenyl group” and the “thienyl group” of the “optionally substituted phenyl group” and “optionally substituted thienyl group” represented by R
1
may have include halogen atom, nitro, cyano, an optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted hydroxy group, an optionally substituted thiol group, an optionally substituted amino group, an optionally substituted acyl, an optionally esterified carboxyl group, an optionally substituted aromatic group, etc.
Examples of the halogen as the substituents for R
1
include fluorine, chlorine, bromine, iodine, etc. Among others, fluorine and chlorine are preferable.
Examples of the alkyl in the optionally substituted alkyl as the substituents for R
1
include a straight or branched C
1-10
alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, etc., and preferably lower (C
1-6
) alkyl.
Examples of the substituents in the optionally substituted alkyl include halogen (e.g. fluorine, chlorine, bromine, iodine, etc.), nitro, cyano, hydroxy group, thiol group, amino group, carboxyl group, an optionally halogenated C
1-4
alkoxy (e.g. methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, etc.), C
2-4
alkanoyl (e.g. acetyl, propionyl, etc.), C
1-4
alkylsulfonyl (e.g. methanesulfonyl, ethanesulfonyl, etc.), etc., and the number of the substituents are preferably 1 to 3.
Examples of the cycloalkyl in the optionally substituted cycloalkyl as the substituents for R
1
include C
3-7
cycloalkyl, etc. such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc.
Examples of the substituents in the optionally substituted cycloalkyl include halogen (e.g. fluorine, chlorine, bromine, iodine, etc.), nitro, cyano, hydroxy group, thiol group, amino group, carboxyl group, an optionally halogenated C
1-4
alkyl (e.g. trifluoromethyl, methyl, ethyl, etc.), an optionally halogenated C
1-4
alkoxy (e.g. methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, etc.), C
2-4
alkanoyl (e.g. acetyl, propionyl, etc.), C
1-4
alkylsulfonyl (e.g. methanesulfonyl, ethanesulfonyl, etc.), etc., and the number of the substituents are preferably 1 to 3.
Examples of the substituents in the optionally substituted hydroxy group as the substituents for R
1
include
(1) an optionally substituted alkyl (e.g. C
1-10
alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl,.etc., preferably lower (C
1-6
) alkyl, etc.);
(2) an optionally substituted cycloalkyl (e.g. C
3-7
cycloalkyl, etc. such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc.);
(3) an optionally substituted alkenyl (e.g. C
2-10
alkenyl such as a
Aramaki Yoshio
Baba Masanori
Kanzaki Naoyuki
Nishimura Osamu
Shiraishi Mitsuru
Solola T. A.
Takeda Chemical Industries Ltd.
Wenderoth , Lind & Ponack, L.L.P.
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