Substituted pyridines as selective cyclooxygenase-2 inhibitors

Details Substituted pyridines as selective cyclooxygenase-2 inhibitors Substituted pyridines as selective cyclooxygenase-2 inhibitors

2001-10-30

2003-07-22

Seaman, D. Margaret (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C546S257000, C546S258000

Reexamination Certificate

active

06596736

ABSTRACT:

BACKGROUND OF THE INVENTION
This invention relates to methods of treating cyclooxygenase mediated diseases and certain pharmaceutical compositions therefor.
Non-steroidal, antiinflammatory drugs exert most of their antiinflammatory, analgesic and antipyretic activity and inhibit hormone-induced uterine contractions and certain types of cancer growth through inhibition of prostaglandin G/H synthase, also known as cyclooxygenase. Initially, only one form of cyclooxygenase was known, this corresponding to cyclooxygenase-1 (COX-1) or the constitutive enzyme, as originally identified in bovine seminal vesicles. More recently the gene for a second inducible form of cyclooxygenase, cyclooxygenase-2 (COX-2) has been cloned, sequenced and characterized initially from chicken, murine and human sources. This enzyme is distinct from the COX-1 which has been cloned, sequenced and characterized from various sources including the sheep, the mouse and man. The second form of cyclooxygenase, COX-2, is rapidly and readily inducible by a number of agents including mitogens, endotoxin, hormones, cytokines and growth factors. As prostaglandins have both physiological and pathological roles, we have concluded that the constitutive enzyme, COX-1, is responsible, in large part, for endogenous basal release of prostaglandins and hence is important in their physiological functions such as the maintenance of gastrointestinal integrity and renal blood flow. In contrast, we have concluded that the inducible form, COX-2, is mainly responsible for the pathological effects of prostaglandins where rapid induction of the enzyme would occur in response to such agents as inflammatory agents, hormones, growth factors, and cytokines. Thus, a selective inhibitor of COX-2 will have similar antiinflammatory, antipyretic and analgesic properties to a conventional non-steroidal antiinflammatory drug, and in addition would inhibit hormone-induced uterine contractions and have potential anti-cancer effects, but will have a diminished ability to induce some of the mechanism-based side effects. In particular, such a compound should have a reduced potential for gastrointestinal toxicity, a reduced potential for renal side effects, a reduced effect on bleeding times and possibly a lessened ability to induce asthma attacks in aspirin-sensitive asthmatic subjects.
Furthermore, such a compound will also inhibit prostanoid-induced smooth muscle contraction by preventing the synthesis of contractile prostanoids and hence may be of use in the treatment of dysmenorrhea, premature labour, asthma and eosinophil related disorders. It will also be of use in the treatment of Alzheimer's disease, for decreasing bone loss particularly in postmenopausal women (i.e. treatment of osteoporosis) and for the treatment of glaucoma.
The potential utilities of selective cyclooxygenase-2 inhibitors are discussed in the following articles:
1. John Vane, “Towards a better aspirin” in
Nature
, Vol. 367, pp. 215-216, 1994.
2. Bruno Battistini, Regina Botting and Y. S. Bakhle, “COX-1 and COX-2: Toward the Development of More Selective NSAIDs” in
Drug News and Perspectives
, Vol. 7, pp. 501-512, 1994.
3. David B. Reitz and Karen Seibert, “Selective Cyclooxygenase Inhibitors” in
Annual Reports in Medicinal Chemistry
, James A. Bristol, Editor, Vol. 30, pp. 179-188, 1995.
4. Don E. Griswold and Jerry L. Adams, “Constituative Cyclooxygenase (COX-1) and Inducible Cyclooxygenase (COX-2): Rationale for Selective Inhibition and Progress to Date” in
Medicinal Research Reviews
, Vol. 16, pp. 181-206, 1996.
WO 96/10012 (DuPont Merck, Apr. 4, 1996) discloses compounds represented by Formula A as being useful in the treatment of COX-2 mediated diseases, by virtue of their selective inhibition of COX-2 rather than COX-1. We have now discovered that a subset of the compounds represented by A, in which -J-K-L- is —NCHCH—, X is a bond, R
1
is aromatic and R
3
and R
4
are not both hydrogen show unexpectedly superior selectivity for the inhibition of COX-2 over COX-1 and/or superior potency as compared to the closest species disclosed in 96/10012. This subset of compounds is the subject of the present invention and is represented by Formula I.
Of the over 175 specific compounds disclosed in WO 96/10012, only 4 of them are pyridines, and none of these latter contain a substituent (R
3
or R
4
in A) on the pyridine ring.
WO 96/16934 (Searle, Jun. 6, 1996) discloses compounds represented by structure B as being useful for the treatment of inflammation and related disorders. Chemically, these compounds differ from those of the present invention in that the central of the three aromatic rings is benzene rather than pyridine.
SUMMARY OF THE INVENTION
The invention encompasses the novel compound of Formula I as well as a method of treating COX-2 mediated diseases comprising administration to a patient in need of such treatment of a non-toxic therapeutically effective amount of a compound of Formula I.
The invention also encompasses certain pharmaceutical compositions for treatment of COX-2 mediated diseases comprising compounds of Formula I.
DETAILED DESCRIPTION OF THE INVENTION
The invention encompasses the novel compound of Formula I as well as a method of treating COX-2 mediated diseases comprising administration to a patient in need of such treatment of a non-toxic therapeutically effective amount of a compound of Formula I
wherein:
R
1
is selected from the group consisting of
(a) CH
3
,
(b) NH
2
,
(c) NHC(O)CF
3
,
(d) NHCH
3
;
Ar is a mono-, di-, or trisubstituted phenyl or pyridinyl (or the N-oxide thereof), wherein the substituents are chosen from the group consisting of
(a) hydrogen,
(b) halo,
(c) C
1-6
alkoxy,
(d) C
1-6
alkylthio,
(e) CN,
(f) C
1-6
alkyl,
(g) C
1-6
fluoroalkyl,
(h) N
3
,
(i) —CO
2
R
3
,
(j) hydroxy,
(k) —C(R
4
)(R
5
)—OH,
(l) —C
1-6
alkyl—CO
2
—R
6
,
(m) C
1-6
fluoroalkoxy;
R
2
is chosen from the group consisting of
(a) halo,
(b) C
1-6
alkoxy,
(c) C
1-6
alkylthio,
(d) CN,
(e) C
1-6
alkyl,
(f) C
1-6
fluoroalkyl,
(g) N
3
,
(h) —CO
2
R
7
,
(i) hydroxy,
(j) —C(R
8
)(R
9
)—OH,
(k) —C
1-6
alkyl—CO
2
—R
10
,
(l) C
1-6
fluoroalkoxy,
(m) NO
2
,
(n) NR
11
R
12
, and
(o) NHCOR
13
,
R
3
, R
4
, R
5
, R
6
, R
7
, R
8
, R
9
, R
10
, R
11
, R
12
, R
13
, are each independantly chosen from the group consisting of
(a) hydrogen, and
(b) C
1-6
alkyl,
or R
4
and R
5
, R
8
and R
9
or R
11
and R
12
together with the atom to which they are attached form a saturated monocyclic ring of 3, 4, 5, 6 or 7 atoms.
Apt alkyl groups include methyl, ethyl, n-propyl, iso-propyl and butyl, pentyl and hexyl groups. A favoured alkyl group is the methyl group. In general R
4
and R
5
, R
8
and R
9
and R
11
and R
12
are not residues of the above-mentioned monocyclic rings. When ‘alkyl’ is part of a composite term such as alkoxy, alkylthio, fluoroalkyl, fluoroalkoxy then the above meaning of alkyl refers also to the composite term.
A preferred sub-genus of formula I is that wherein Ar is a mono-, or disubstituted pyridinyl. Within this sub-genus, the 3-pyridinyl isomers, such as those of formula Ic, are particularly preferred.
When Ar is di-substituted phenyl is particularly apt that one or both of the substituents are hydrogen.
Another preferred sub-genus of formula I is that wherein Ar is a mono- or disubstituted phenyl.
When Ar is di-substituted phenyl it is particularly apt that one of the substituents is hydrogen or fluorine and the second is hydrogen, fluorine, chlorine, methyl, methoxyl or trifluoromethyl.
Another preferred sub-genus of formula I is that wherein R
1
is CH
3
or NH
2
. Generally, CH
3
is preferred for COX-2 specificity and NH
2
is preferred for potency.
Another preferred sub-genus of formula I is that wherein R
2
is halo, CH
3
or CF
3
.
Another preferred sub-genus of formula I is that wherein the substituents on Ar are chosen from the group consisting of
(a) hydrogen,
(b) halo,
(c) C
1-4
alkoxy,
(d) C
1-4
alkylthio,
(e) C
1-4
alkyl,
(f) CF
3
, and
(g) CN.
In one aspect the invention is directed to compounds of formula I
wherein:
R
1
is

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