Organic compounds -- part of the class 532-570 series – Organic compounds – Four or more ring nitrogens in the bicyclo ring system
Reexamination Certificate
2001-01-05
2003-02-04
Shah, Mukund J. (Department: 1624)
Organic compounds -- part of the class 532-570 series
Organic compounds
Four or more ring nitrogens in the bicyclo ring system
C548S251000, C548S187000, C548S338100, C548S180000, C548S125000, C548S127000, C548S375100, C548S261000, C548S495000, C546S175000, C546S247000, C546S337000, C544S236000, C544S367000, C544S311000, C562S444000, C549S441000, C549S493000, C549S315000, C549S058000
Reexamination Certificate
active
06515124
ABSTRACT:
BACKGROUND OF THE INVENTION
Cell-mediated immune reactions are the basis of autoimmune diseases, and inflammation of tissue plays a part in such diseases. Activation of T cells is a causitive factor in numerous inflammatory diseases, particularly psoriasis (and including: graft rejection, dermatitis, asthma, and rheumatoid arthritis).
T cell activation is the central event in the inflammatory response, which is accompanied by a recruitment of peripheral blood leukocytes to the site of inflammation or injury, leukocyte adhesion to vascular endothelium, and migration from the circulation to sites of inflammation.
T-cell activation is mediated by the T cell receptor (TCR) (A. S. Shaw and M. L. Dustin,
Immunity
6: 361 (1997)), whose activation in turn requires engagement of at least two types of T cell surface receptors. A key T cell surface receptor in this process is a member of the CD-11 integrin family—lymphocyte function associated antigen-1 or LFA-1, (also known as CD11a/CD18), which mediates lymphocyte adhesion and activation leading to normal immune response, as well as to several pathological states (Dustin, M. L., Shaw, A. S.,
Science
283: 649-650 (1999), Springer, T. A.,
Nature
346:425-434 (1990)).
LFA-1 binds to certain specific intercellular adhesion molecules (ICAMs) found on endothelium, leukocytes and other cell types. These ICAMs, known as ICAM-1, -2, and -3 are members of the immunoglobulin superfamily. Blocking the binding of ICAM ligands to CD11integrin receptors has been found to inhibit various undesired T-cell dependent immune responses, such as skin graft and bone marrow rejection, and development of diabetes mellitus. For example, anti-CD11a Mabs inhibit T-cell activation (Kuypers et al.,
Res. Immunol
., 140: 461 (1989)), T-cell dependant B-cell proliferation and differentiation (Davignon et al.,
J. Immunol
., 127: 590 (1981)). Such blocking has up till now been performed by antibodies. Thus, antagonists of LFA-1, that is antibodies or other molecules which prevent ICAMs from binding to the LFA-1 receptor but do not themselves activate the receptor, are useful in preventing diseases related to unwanted T-cell activation, such as psoriasis, graft rejection, dermatitis, asthma, and rheumatoid arthritis.
Small molecules are preferable to antibodies for treatment purposes for numerous reasons including increased tissue penetration, reduced immunogenicity, and in general lower risk. This is especially important in treatment of psoriasis. Thus developing small molecule compounds which are LFA-1 antagonists is an important step in combatting psoriasis.
SUMMARY OF THE INVENTION
The compounds of this invention are active as LFA-1 antagonists. This activity enables these compounds to prevent the inflammation which is a consequence of T cell activation, and accordingly reduce or eliminate the inflammatory skin disease psoriasis.
This invention is directed to compounds of formulae 1, 1a-1g, 1-1, 1-1a-1-1c, and prodrugs of formulae 2 and 2-1, pharmaceutical compositions containing these compounds, and methods of treating psoriasis with these compounds.
DETAILED DESCRIPTION OF THE INVENTION
This invention is directed to compounds of formula 1 and formula
1-1
:
R
1
is hydrogen, hydroxy, amino or halogen, R
2
is hydrogen, hydroxy, or halogen and R
3
is hydrogen
where R
1
is hydrogen and R
2
and R
3
taken together with the ethenylene group connecting them form phenyl, pyrrole, pyrroline, oxopyrroline, pyrazole, triazole, or imidazole. In both formula 1 and formula
1-1
, A is one of the following groups,
R
4
and R
5
are hydrogen, methyl, ethyl or halogen (except that R
4
and R
5
cannot both be hydrogen), and B can be selected from any one of the following 7 groups, namely:
1) B is hydrogen, or lower alkyl; or
2) B is
Here, R
6
R
7
R
8
and R
9
are independently hydrogen, hydroxy, aminosulfonyl, halogen, lower alkoxy, cyano, amino, lower alkyl, lower alkyl amino, or nitro; or
3) B is
Here, R
10
is hydrogen, hydroxy, halogen, or lower alkyl and C is a five- or six-membered ring with 0 to 3 heteroatoms which are selected from nitrogen, oxygen, and sulfur. The ring may have no heteroatoms, or up to 3 heteroatoms which can be N, O, and S in any chemically appropriate combination. This ring may be unsubstituted or mono- or di- substituted with lower alkyl, cycloalkyl, amino, or substituted amino; or
4B is
where X and Y are independently methylene or nitrogen; or
5) B is
Here, at least one of T, U, V, or W is nitrogen, and any of T, U, V or W which is carbon may be substituted with lower alkyl, lower alkyl amino, lower alkoxy, hydroxy, aminosulfonyl, halogen, cyano, amino, or nitro, i.e. for any compound of this invention where B is (5), any position (from among T, U, V or W) which is carbon and not nitrogen, may have one of the substituents listed; or
wherein Y is carbon or nitrogen; or
7) B is a five-membered aromatic ring. The ring may have 1 to 3 heteroatoms which are selected from nitrogen, oxygen, and sulfur (in any chemically appropriate combination). The ring may be unsubstituted or mono- or di- substituted at any position with lower alkyl, cycloalkyl, trifluoroloweralkyl, amino, halogen, substituted amino. The ring may also be fused with a 5 or 6 membered aromatic ring. The fused ring may contain 0 to 3 heteroatoms which heteroatoms are selected from nitrogen, oxygen, and sulfur (i.e. the fused ring may have no heteroatoms, or up to 3 heteroatoms which can be N, O, and S in any chemically appropriate combination). The ring may in particular be fused with phenyl.
Hereinafter, the groups from which B may be selected will be referred to (for convenience) by number, e.g. (1), (2), (3), (4), (5), (6), and (7)
In any compound of this invention (such as compounds of formulae 1, 1a-1g, 1-1, 1-1a-1-1c, 2, 2-1, and particularly those in the paragraph below) where B is (5), it is preferred that V be nitrogen, i.e. B is
and T, U, or W are nitrogen or carbon. Any of T, U, or W which is carbon may be substituted with lower alkyl, lower alkyl amino, lower alkoxy, hydroxy, aminosulfonyl, halogen, cyano, amino, or nitro.
In any compound of this invention where B is the five-membered aromatic ring (7), it is preferred that one of the 1 to 3 heteroatoms of the ring be located at a position which is two positions from the attachment point (of the ring to the rest of the molecule depicted for example in formula 1 or 1-1). It is also preferred for any compound of this invention (such as compounds of formulae 1, 1a-1g, 1-1, 1-1a-1-1c, 2, 2-1, and particularly the compound described in this paragraph and those of the above paragraphs) where B is the five-membered aromatic ring (7) and is fused with a five or six membered aromatic ring with 0 to 3 heteroatoms, such as phenyl, that the positions of fusion are not adjacent to the attachment point.
Especially preferred compounds of this invention are compounds of formula 1 where R
1
is hydroxy or amino and R
2
and R
3
are hydrogen and compounds of formula 1-1 where R
2
and R
3
together with the ethenylene to which they are attached form phenyl, pyrazole or pyrrole. In these compounds, A is
R
4
and R
5
are lower alkyl or halogen;
and B is
where R
11
is hydrogen, lower alkyl, substituted amino, or amino and R
12
is hydrogen, trifluoroloweralkyl or lower alkyl. All variants of these compounds are specifically contemplated by this invention. For example, compounds of formula 1 where R
1
is hydroxy or amino or compounds of formula 1-1 where R
2
and R
3
together with the ethenylene to which they are attached form phenyl, pyrazole or pyrrole and A is
and B is the benzotriazole, or the same compounds where B is the thiazole, or the quinoline, or the aminosulfonylphenyl, are included.
Similarly compounds of formula 1 or formula 1-1 as above where A is
and B is the benzotriazole, or the same compound where B is the thiazole, or the quinoline, or the aminosulfonylphenyl, are included. Also part of this invention are such compounds where A is
It is preferred that R
4
and R
5
are methyl or ha
Fotouhi Nader
Gillespie Paul
Guthrie Robert William
Pietranico-Cole Sherrie Lynn
Yun Weiya
Hoffman-La Roche Inc.
Johnston George W.
Shah Mukund J.
Tramaloni Dennis P.
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