Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-06-07
2002-05-28
Ponnaluri, Padmashri (Department: 1627)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C435S091500, C514S277000, C514S365000, C514S368000, C514S372000, C514S374000, C514S378000, C514S396000, C514S399000, C514S406000, C514S427000, C514S439000, C514S473000, C514S690000, C514S764000, C544S139000, C546S192000, C546S271400, C546S272100, C546S334000, C548S146000, C548S154000, C548S162000, C548S204000, C548S206000, C548S215000, C548S225000, C548S228000, C548S229000, C548S234000, C548S235000, C548S236000, C548S240000, C548S243000, C548S245000, C548S248000, C548S311100, C548S311400, C548S315400, C548S
Reexamination Certificate
active
06395724
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to novel multibinding compounds (agents) that inhibit the enzyme cyclooxygenase-2 (COX-2) and to pharmaceutical compositions comprising such compounds. Accordingly, the multibinding compounds and pharmaceutical compositions of this invention are useful in the treatment and prevention of various disorders mediated by COX-2, such as inflammation, pain, fever and the like.
2. References
The following publications are cited in this application as superscript numbers:
1 W. L. Smith et al.,
Adv. Immunol
. 1996, 62, 167-215.
2 D. Picot et al.,
Nature
1994, 367, 243-249.
3 C. Luong et al.,
Nat. Struct. Biol
. 1996, 3, 927-933.
4 R. G. Kurumbail et al.,
Nature
1996, 384, 644-688.
5 J. K. Gierse et al,
J. Biol. Chem
. 1996, 271, 15810-15814.
6 E. Wong et al.,
J. Biol. Chem
. 1997, 272, 9280-9286.
7 P. Prasit et al.,
Annual Reports in Medicinal Chemistry
1997, 32, 211-220.
8
J. Med. Chem
. 1997, 40, 1619-1633; 1634-1647.
All of the above publications are herein incorporated by reference in their entirety to the same extent as if each individual publication was specifically and individually indicated to be incorporated by reference in its entirety.
State of the Art
Cyclooxygenase (COX) catalyzes the conversion of arachidonic acid to prostaglandin H2, the first committed step in the biosynthesis of prostaglandins, such as prostacyclin and thromoxanes.
1
It has been known for some time that the enzyme COX is the target of certain non-steroidal anti-inflammatory drugs (NSAIDs), such as aspirin, ibuprofen, naproxen, indomethacin and the like. More recently, it has been discovered that there are two isoforms of COX, designated COX-1 and COX-2.
The COX-1 isozyme is constitutively expressed in many tissue types where it produces relatively small amounts of prostaglandins necessary for maintaining organ and tissue homeostasis. In constrast, COX-2 is transiently expressed in a limited number of cell types, including synovial cells, fibroblasts, macrophages and monocytes. In such cells, high level expression of COX-2 is rapidly induced in response to certain inflammatory agents, hormones, growth factors, cytokines and the like, resulting in various disorders such as inflammation, pain, fever and the like.
Unfortunately, most currently-marketed NSAIDs are typically equipotent inhibitors of both isozymes of COX. Since such drugs inhibit COX-1 as well as COX-2, they interfere with various prostaglandin-regulated processes not associated with the inflammation process and other related disorders. As a result, many NSAIDs cause severe side effects, such as stomach ulcers and renal damage, which limit their effectiveness as therapeutics. Accordingly, selective inhibitors of COX-2 would have significant advantages over currently-marketed NSAIDs.
It has now been discovered that selective COX-2 inhibitors having surprising and unexpected properties can be prepared by linking from 2 to 10 ligands to one or more linkers, wherein each ligand is a moiety capable of binding to COX-2. Such multibinding compounds provide improved biological and/or therapeutic effects compared to the aggregate of the unlinked ligands due to their multibinding properties.
SUMMARY OF THE INVENTION
This invention is directed to novel multibinding compounds (agents) that inhibit cyclooxygenase-2 (COX-2). The multibinding compounds of this invention are useful in the treatment and prevention of disorders mediated by COX-2, such as inflammation, pain, fever and the like.
Accordingly, in one of its composition aspects, this invention provides a multibinding compound comprising from 2 to 10 ligands covalently attached to one or more linkers wherein each of said ligands independently comprises a moiety capable of binding to cyclooxygenase-2; and pharmaceutically-acceptable salts thereof.
In another of its composition aspects, this invention provides a multibinding compound of formula I:
(
L
)
p
(
X
)
q
I
wherein each L is independently a ligand comprising a moiety capable of binding to cyclooxygenase-2; each X is independently a linker; p is an integer of from 2 to 10; and q is an integer of from 1 to 20; and pharmaceutically-acceptable salts thereof.
Preferably, q is less than p in the multibinding compounds of this invention.
Preferably, each ligand, L, in the multibinding compound of formula I is independently selected from a compound of formula IA, IB or IC:
wherein
ring A, together with the atoms to which it is attached, forms a 4, 5 or 6-membered carbocyclic or heterocyclic ring selected from the group consisting of aryl, cycloalkenyl, substituted cycloalkenyl, heteroaryl and heterocyclic;
ring B, together with the atoms to which it is attached, forms a 4, 5 or 6-membered heterocyclic ring selected from the group consisting of heteroaryl and heterocyclic;
ring C, together with the atoms to which it is attached, forms a 4, 5 or 6-membered heterocyclic ring selected from the group consisting of heteroaryl and heterocyclic;
R
1
is selected from the group consisting of —SO
2
CH
3
, —SO
2
NH
2
, —SO
2
NHC(O)CF
3
, —SO(NH)NH
2
and —SO(NH)NHC(O)CF
3
;
each R
2
is independently selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkoxycarbonyl, amino, substituted amino, azido, carboxyl, cyano, cycloalkyl, substituted cycloalkyl, halo, hydroxyl, nitro, thioalkoxy and substituted thioalkoxy;
R
3
is a covalent bond linking the ligand to a linker; and
&agr; is an integer from 0 to 3; and pharmaceutically-acceptable salts thereof.
Preferably, in the ligands of formula IA, ring A, together with the atoms to which it is attached, forms a cyclobut-2-en-1-one, thiazole, isothiazole, thiadiazole, oxazole, isoxazole, 5(H)-furanone, benzene, pyridine, imidazopyridine, imidazothiazole or thiazolotriazole ring.
In the ligands of formula IB, ring B, together with the atoms to which it is attached, preferably forms a pyrazole ring.
Preferably, in the ligands of formula IC, ring C, together with the atoms to which it is attached, forms an imidazole ring.
In still another of its composition aspects, this invention provides a multibinding compound of formula II:
L′—X′—L′
II
wherein each L′ is independently a ligand comprising a moiety capable of binding to cyclooxygenase-2 and X′ is a linker; and pharmaceutically-acceptable salts thereof.
Preferably, in the multibinding compound of formula II, each ligand, L′, is independently selected from the group consisting of:
(a) a compound of formula IIA:
wherein
R
4
is selected from the group consisting of —SO
2
CH
3
, —SO
2
NH
2
, —SO
2
NHC(O)CF
3
, —SO(NH)NH
2
and —SO(NH)NHC(O)CF
3
;
each R
5
is independently selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkoxycarbonyl, amino, substituted amino, azido, carboxyl, cyano, cycloalkyl, substituted cycloalkyl, halo, hydroxyl, nitro, thioalkoxy and substituted thioalkoxy;
R
6
is selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, cyano, fluoro and heteroaryl;
R
7
is a covalent bond linking the ligand to a linker; and
b is an integer from 0 to 3;
(b) a compound of formula IIB:
wherein
R
8
is selected from the group consisting of —SO
2
CH
3
, —SO
2
NH
2
, —SO
2
NHC(O)CF
3
, —SO(NH)NH
2
and —SO(NH)NHC(O)CF
3
;
each R
9
is independently selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkoxycarbonyl, amino, substituted amino, azido, carboxyl, cyano, cycloalkyl, substituted cycloalkyl, halo, hydroxyl, nitro, thioalkoxy and substituted thioalkoxy;
R
10
is a covalent bond linking the ligand to a linker;
R
11
is selected from the group consisting of hydrogen, alkyl, substituted alkyl and fluoro; and
c is an integer from 0 to 3; and
(c) a compound of formula IIC:
wherein
R
12
is selected from the group consisting of —SO
2
CH
3
, —SO
2
NH
2
, —SO
2
NHC(O)CF
3
, —SO(NH)NH
2
and —SO(NH)NHC(O)CF
3
;
each R
13
is independently selected from the group
Griffin John H.
Higgins Deborah L.
Judice J. Kevin
Advanced Medicine, Inc.
Boone David K.
Garcia Maurie E.
Hagenah Jeffrey A.
Ponnaluri Padmashri
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