Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-11-02
2003-01-14
Berch, Mark L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C546S175000, C546S187000, C546S194000, C546S209000, C544S133000, C548S182000, C548S183000, C548S186000, C548S187000, C514S314000, C514S316000, C514S326000, C514S369000
Reexamination Certificate
active
06506751
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to certain thiazolidinone derivatives useful as modulators of the chemokine receptors, including CCR-1, CCR-2, CCR-2A, CCR-2B, CCR-3, CCR-4, CCR-5, CXCR-1, CXCR-2, CXCR-3, and/or CXCR-4 and to pharmaceutical compositions that include these compounds and a pharmaceutically acceptable carrier. In addition, the present invention is directed to methods for inhibiting HIV infectivity.
2. Summary of the Related Art
Chemokines mediate a range of proinflammatory effects on leukocytes, such as chemotaxis, degranulation, and intigran activation (Baggiolini et al.,
Adv. Immunol.,
1994;55:97-179; Oppenheim et al.,
Annu. Rev. Immunol.,
1991; 9:617-648; Miller et al.,
Crit. Rev. Immunol.,
1992;12:17-46). These effects are mediated by binding to the seven-transmembrane-spanning G-protein coupled receptors (Baggiolini et al.,
Adv. Immunol.,
1994;55:97-179; Murphy,
Annu. Rev. Immunol.,
1994;12:593-633; Schall et al.,
Curr. Opin. Immunol.,
1994;6:865-873; Gerard et al.,
Curr. Opin. Immunol.,
1994;6;140-145; Mackay,
Curr. Bio.,
In press). Chemokine receptors also serve as co-receptors for HIV-1 entry into cells. This came from observations that RANTES, MIP-1&agr;, and MIP-1&bgr; suppressed infection of susceptible cells in vitro by macrophage-tropic primary HIV-1 isolates (Cocchi et al.,
Science
(Wash. D.C.), 1995;270:1811-1815). The chemokine receptor CXCR-4 is found to support infection and cell fusion of CD4
+
cells by laboratory-adapted, T-tropic HIV-1 strains (Feng et al.,
Science
(Wash. D.C.), 1996;272:872-877). CCR-5, a RANTES, MIP-1&agr;, and MIP-1&bgr; receptor, is subsequently identified as the principle co-receptor for primary macrophage-tropic strains (Choe et al.,
Cell,
1996;85:1135-1148; Alkhatib et al.,
Science
(Wash. D.C.), 1996;272:1955-1958; Doranz et al.,
Cell,
1996;85:1149-1158; Deng et al.,
Nature
(Lond.) 1996;381:661-666; Dragic et al.,
Nature
(Lond.), 1996;381:667-3). The importance of CCR-5 for HIV-1 transmission is underscored by the observation that certain individuals who had been repeatedly exposed to HIV-1 but remained uninfected had a defect in CCR-5 expression (Liu et al.,
Cell,
1996; 86:367-377; Samson et al.,
Nature
(Lond.), 1996;382:722-725; Dean et al.,
Science
(Wash. D.C.), 1996;273:1856-1862; Huang et al.,
Nature Med.,
1996;2:1240-1243). These noninfectable individuals are found to be homozygous for a defective CCR-5 allele that contains an internal 32-base pair deletion (CCR-5 &Dgr;32). The truncated protein encoded by this gene is apparently not expressed at the cell surface. CCR-5 &Dgr;32 homozygous individuals comprise ~1% of the Caucasian population and heterozygous individuals comprise ~20%. In studies of about 2700 HIV-1 infected individuals, no &Dgr;32 homozygotes are found. Individuals who are heterozygous for &Dgr;32 CCR-5 allele have been shown to progress more slowly to AIDS than wild-type homozygous individuals (Samson et al.,
Nature
(Lond.), 1996;382:722-725; Dean et al.,
Science
(Wash. D.C.), 1996;273:1856-1862; Huang et al.,
Nature Med.,
1996;2:1240-1243). Thus, the identity of CCR-5 as the principle co-receptor for primary HIV isolates provides an opportunity to understand disease pathogenesis, and more importantly to identify a new avenue for the treatment of HIV-1 infection.
The instant invention is a series of finctionalized heterocycles that block the CD-4/GP-120 interaction with CCR-5 receptor, and thus can be useful in the treatment of HIV infection manifested in AIDS.
SUMMARY OF THE INVENTION
The compounds of the invention are useful in a method of modulating chemokine receptor activity in a patient in need of such modulation, the method comprising the administration of an effective amount of the compound to a subject, preferably mammalian, in need thereof.
The present invention is directed to the use of thiazolidinone derivatives as modulators of chemokine receptor activity. In particular, these compounds are useful as modulators of chemokine receptors, including CCR-1, CCR-2, CCR-2A, CCR-2B, CCR-3, CCR-4, CCR-5, CXCR-3, CXCR1, CXCR2, and/or CXCR-4. In particular, the compounds of the present invention are preferred as modulators of the chemokine receptor CCR-5.
The compounds of the invention are those having the structure of Formula 1:
R
1
and R
2
are independently hydrogen, lower alkyl, halogen, hydroxy, or lower alkoxy; or
aryl, arylalkyl, heteroaryl, or heteroarylalkyl where each ring is optionally substituted independently with up to three groups selected from halogen, lower alkyl, lower alkoxy, hydroxy, carboxy, alkoxycarbonyl, cyano, nitro, trifluoromethyl, amino, mono- or dialkylamino, carbamoyl, carboxyalkyl, alkoxycarbonylalkyl, sulfamoyl, or carbonylamino, provided R
1
and R
2
are not both hydroxy or lower alkoxy;
R
3
and R
4
independently represent hydrogen, lower alkyl, cycloalkyl, aminoalkyl, or mono- or dialkylaminoalkyl; or
aryl or heteroaryl optionally substituted with up to three groups selected from halogen, lower alkyl, lower alkoxy, hydroxy, carboxy, alkoxycarbonyl, cyano, nitro, trifluoromethyl, amino, mono- or dialkylamino, carbamoyl, carboxyalkyl, alkoxycarbonylalkyl, sulfamoyl, or carbonylamino;
R
5
represents a carbocyclic group containing from 3-7 members, up to two of which members are optionally heteroatoms selected from oxygen and nitrogen, where the carbocyclic group is optionally substituted with one or two groups selected from halogen, lower alkyl, lower alkoxy, mono- or dialkylamino, aryl, arylalkyl, or a heterocyclic group; or
R
5
is (CR
6
R
7
)—(CH
2
)
n
—XR
8
R
9
;
X is S or N;
R
6
and R
7
independently represent hydrogen, lower alkyl, hydroxy, amino, or mono- or dialkylamino;
n is 0, 1, 2, 3, or 4; and
R
8
and R
9
independently represent hydrogen, lower alkyl, lower alkenyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, or cycloalkyl; or
R
8
and R
9
together with the nitrogen to which they are attached form a heterocyclic ring containing from 5-7 members, up to two of which members are optionally heteroatoms selected from oxygen, sulfur, and nitrogen, where the heterocyclic group is optionally substituted with one or two groups selected from halogen, lower alkyl, lower alkoxy, mono- or dialkylamino, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkyl, or heterocyclic group.
Preferred compounds have Formula Ia
wherein R
22
and R
33
independently are hydrogen, halo, alkyl, and trihaloalkyl, and R
5
is as defined above. Especially preferred are such compounds wherein R
5
is alkyl such as propyl, substituted with a heterocyclic group such as piperidyl, piperazinyl, or morpholinyl, and where such heterocyclic group is unsubstituted or substituted with a cyclic or heterocyclic group such as cyclohexyl, pyridinyl, morpholino, piperidinyl, or pyrinidyl.
Another preferred set of compounds have Formula Ib
wherein R
3
and R
4
together form a heteroaryl ring such as pyridyl, pyrrolyl, and thienyl, R
22
is hydrogen, halo, alkyl, and haloalkyl, and R
5
is as defined above, and especially substituted alkyl.
The instant invention includes pharmaceutical compositions of compounds of Formula I and methods of using the compounds for modulating chemokine receptor activity, preventing or treating infection by HIV, delaying the onset of AIDS, treating AIDS, and treating inflammatory disease.
DETAILED DESCRIPTION OF THE INVENTION
The novel compounds encompassed by the instant invention are those described by the general Formula I set forth above, and the pharmaceutically acceptable salts, esters, amides, and prodrugs thereof.
Preferred compounds of Formula I are those in which R
4
is hydrogen; R
3
is dialkylaminoalkyl or aryl, heteroaryl, or cycloalkyl optionally substituted with halogen, lower alkyl, lower alkoxy, amino, or mono- or dialkylamino; A is S; and R
1
is hydrogen; R
2
is aryl or heteroaryl optionally substituted with halogen, lower alkyl, lower alkoxy, amino, or mono- or dialkylamino.
In addition to the compounds of Formula I, the invention
Justus Stephanie Elizabeth Ault
Lee Helen Tsenwhei
Pontrello Jason Keith
Roth Bruce David
Sexton Karen Elaine
Berch Mark L.
DeConti, Jr. Giulio A.
Hanley Elizabeth A.
Lahive & Cockfield LLP
Millennium Pharmaceuticals Inc.
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