Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2003-03-27
2004-08-17
Davis, Zinna Northington (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S015000, C546S144000, C546S146000, C514S307000
Reexamination Certificate
active
06777422
ABSTRACT:
FIELD OF THE INVENTION
This invention relates generally to substituted tetrahydroisoquinolines that act as modulators of mammalian complement C5a receptors, and to the use of such compounds for treating a variety of inflammatory and immune system disorders. The invention further relates to the use of such compounds as probes for the localization of C5a receptors.
BACKGROUND OF THE INVENTION
C5a, a 74 amino acid peptide, is generated in the complement cascade by the cleavage of the complement protein C5 by the complement C5 convertase enzyme. C5a has both anaphylatoxic (e.g., bronchoconstricting and vascular spasmogenic) and chemotactic effects. Therefore, it is active in engendering both the vascular and cellular phases of inflammatory responses. Because it is a plasma protein and, therefore, generally almost instantly available at a site of an inciting stimulus, it is a key mediator in terms of initiating the complex series of events that results in augmentation and amplification of an initial inflammatory stimulus. The anaphylatoxic and chemotactic effects of the C5a peptide are believed to be mediated through its interaction with the C5a receptor (CD88 antigen), a 52 kD membrane bound G-protein coupled receptor (GPCR). C5a is a potent chemoattractant for polymorphonuclear leukocytes, bringing neutrophils, basophils, eosinophils and monocytes to sites of inflammation and/or cellular injury. C5a is one of the most potent chemotactic agents known for a wide variety of inflammatory cell types. C5a also “primes” or prepares neutrophils for various antibacterial functions (e.g., phagocytosis). Additionally, C5a stimulates the release of inflammatory mediators (e.g., histamines, TNF-&agr;, IL-1, IL-6, IL-8, prostaglandins, and leukotrienes) and the release of lysosomal enzymes and other cytotoxic components from granulocytes. Among its other actions, C5a also promotes the production of activated oxygen radicals and the contraction of smooth muscle.
Considerable experimental evidence implicates increased levels of C5a in a number of autoimmune diseases and inflammatory and related disorders.
Agents that block the binding of C5a to its receptor other agents, including inverse agonists, which modulate signal transduction associated with C5a-receptor interactions, can inhibit the pathogenic events, including chemotaxis, associated with anaphylatoxin activity contributing to such inflammatory and autoimmune conditions.
SUMMARY OF THE INVENTION
The present invention provides substituted tetrahydroisoquinolines and related compounds that are modulators of C5a receptor. Such modulators preferably inhibit C5a receptor activation and/or C5a receptor-mediated signal transduction. Within certain aspects, compounds provided herein and the pharmaceutically acceptable salts thereof are characterized by Formula I:
wherein: x is 1, 2 or 3.
R, in Formula I, represents from 0 to 4 substituents independently chosen from halogen, hydroxy, optionally substituted alkoxy, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, cyano, amino, nitro, —COOH, carboxamide, optionally substituted mono- and di-alkyl amino, optionally substituted haloalkyl, and optionally substituted haloalkoxy.
R
1
is selected from alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, aryl, heteroaryl, (aryl)alkyl, (heteroaryl)alkyl, and indanyl, each of which is optionally substituted.
R
2
, R
3
and each occurrence of R
4
are independently selected from hydrogen, halogen, optionally substituted alkyl, and optionally substituted alkoxy.
R
5
and R
6
are independently selected from (i) hydrogen, halogen, hydroxy, amino, and cyano; and (ii) alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, and mono- and di-(alkyl)amino, each of which is optionally substituted.
R
7
is (a) (i) hydrogen; or (ii) alkyl, alkenyl, alkynyl, alkoxy or arylalkyl, each of which is optionally substituted; and Ar
1
is: (i) phenyl, naphthyl, biphenyl, or heterocycle, each of which is optionally substituted; or (ii) optionally substituted phenyl fused to a 5- to 7-membered saturated or partially unsaturated ring having from 5 to 7 ring atoms, with 0, 1, or 2 ring atoms independently chosen from N, O and S, and with remaining ring atoms being carbon,
or
R
7
is (b) taken together with Ar
1
and the carbon atom to which R
7
and Ar
1
are attached to form an optionally substituted group of the formula:
wherein p is an integer from 1 to about 3.
Ar
2
is (i) optionally substituted aryl or (ii) optionally substituted heteroaryl having 5 to 7 ring atoms and from 1 to 3 ring heteroatoms independently selected from N, O and S.
Within certain aspects, compounds as described above exhibit an IC
50
value no greater than 1 &mgr;M, 500 nM, 200 nM, 100 nM, 50 nM, 25 nM, 10 nM or 5 nM in a standard C5a receptor-mediated chemotaxis assay, radioligand binding assay, or calcium mobilization assay. Preferred C5a receptors are mammalian receptors that and may either be cloned, recombinantly expressed receptors or naturally expressed receptors. In certain embodiments the C5a receptors are primate C5a receptors, including human C5a receptors. In certain embodiments, C5a receptor modulators described herein exhibit an affinity for human C5a receptors that is higher than for non-primate C5a receptors; for example in certain embodiments compounds of Formula I exhibit 5-fold or 10-fold greater affinity for human C5a receptors that for most or all non-primate C5a receptors.
Certain aspects of the invention are directed to compounds of Formula I, above, that bind specifically to C5a receptors, and preferably also exhibit an IC
50
value no greater than 1 &mgr;M, 500 nM, 200 nM, 100 nM, 50 nM, 25 nM, 10 nM or 5 nM in a standard C5a receptor-mediated chemotaxis assay, radioligand binding assay, calcium mobilization assay.
The invention further provides, within certain embodiments, compounds of Formula I, that exhibit less than 5% agonist activity in a GTP binding assay.
The present invention further provides, within other aspects, pharmaceutical compositions comprising at least one compound or salt as described above (or a prodrug or hydrate thereof) in combination with a physiologically acceptable carrier or excipient.
The present invention provides, within further aspects, methods for treating a patient suffering from a condition responsive to C5a receptor modulation (e.g., a human or non-human animal, such as a domesticated companion animal or livestock animal). Such methods generally comprise administering to the patient a C5a receptor modulatory amount of at least one compound or salt as described above. For example, the invention comprises methods for treating a patient in need of anti-inflammatory treatment or immune treatment with an effective amount of a compound of the invention, e.g. an amount of a compound of the invention sufficient to yield a plasma concentration of the compound (or its active metabolite, if a pro-drug) or high enough to inhibit white blood cell (e.g., neutrophil) chemotaxis in vitro. Treatment of humans, domesticated companion animals (pets) or livestock animals suffering such conditions with an effective amount of a compound of the invention is contemplated by the invention. For treating non-human animals of any particular species, a compound exhibiting high affinity for the C5a receptor of that particular species is preferred.
Within further aspects, methods are provided for inhibiting signal transduction activity of a cellular C5a receptor, comprising contacting a cell expressing a C5a receptor with an effective amount of at least one compound or salt as described above. Such contact may occur in vivo or in vitro. In certain embodiments, the signal transduction activity inhibited is calcium conductance. In other embodiments, the signal transduction activity inhibited is C5a receptor-mediated cellular chemotaxis, and the method comprises contacting mammalian white blood cells with a C5a receptor modulatory amount of a compound or salt as described above.
Methods are further provided, within other aspe
Currie Kevin
Lee Kyungae
Mitchell Scott
Ohliger Robert
Zhang Lu Yan
Davis Zinna Northington
Fidel Seth A.
Kaklecek Ann T.
Neurogen Corp.
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