Organic compounds -- part of the class 532-570 series – Organic compounds – Sulfur containing
Reexamination Certificate
2000-11-17
2002-04-09
Rotman, Alan L. (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Sulfur containing
C570S235000, C570S182000
Reexamination Certificate
active
06369275
ABSTRACT:
BACKGROUND OF THE INVENTION
This invention concerns a process for making certain anti-inflammatory compounds. In particular, the application concerns a process for making compounds of formula I as disclosed hereinunder, which compounds are potent cyclooxygenase-2 inhibitors.
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. Up until recently, only one form of cyclooxygenase had been characterized, this corresponding to cyclooxygenase-1 or the constitutive enzyme, as originally identified in bovine seminal vesicles. Recently the gene for a second inducible form of cyclooxygenase (cyclooxygenase-2) has been cloned, sequenced and characterized from chicken, murine and human sources. This enzyme is distinct from the cyclooxygenase-1 which has now also been cloned, sequenced and characterized from sheep, murine and human sources. The second form of cyclooxygenase, cyclooxygenase-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, cyclooxygenase-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, cyclooxygenase-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 cyclooxygenase-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.
WO 96/24585 published Aug. 15, 1996 and WO 96/10012, published Apr. 4, 1996 disclose methods of making 2-aryl-3-aryl-pyridines. In the invention as disclosed hereinunder, 2-aryl-3-aryl-pyridines are prepared in a simple to conduct, 2 step conversion of a Weinreb amide to the penultimate ketosulfone from readily available starting materials. It is, therefore, surprisingly convenient and more efficient than the previously described procedure, in which the 2-aryl-3-aryl pyridine was constructed by serial stepwise addition of the aryl groups to the central pyridine ring. Moreover, the process of the instant invention is also surprisingly superior in that expensive palladium reagents are not required nor is the cumbersome protection/deprotection sequense of the prior art process.
SUMMARY OF THE INVENTION
The invention encompasses a process for making cyclooxygenase-2 intermediates such as the compound of structural formula 5.
Compound 5 is useful in making potent cyclooxygenase-2 inhibitors of structural formula I, which are useful in the treatment of inflammation and other cyclooxygenase-2 mediated diseases
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
1-4
alkoxy,
(d) C
1-4
alkylthio,
(e) CN,
(f) C
1-4
alkyl,
(g) C
1-4
fluoroalkyl, and
R
2
is chosen from the group consisting of
(a) F, Cl, Br, I
(b) CN,
(c) azide.
DETAILED DESCRIPTION OF THE INVENTION
In a first aspect, the invention encompasses a process for making a compound of Formula 5, which is a COX-2 intermediate,
the process comprising:
reacting a compound of formula 13
wherein X is a halogen belonging to the group consisting of chlorine, bromine and fluorine,
with a compound of formula 9
wherein 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
1-4
alkoxy,
(d) C
1-4
alkylthio,
(e) CN,
(f) C
1-4
alkyl,
(g) C
1-4
fluoroalkyl,
to yield a compound of formula 15
wherein Ar is described above,
and oxidizing the compound of formula 15 using an oxidizing agent, and optionally a catalyst and an acid to yield a compound of formula 5.
In a second aspect, the invention encompasses a process for making a compound of formula 13
wherein X is a halogen belonging to the group consisting of chlorine, bromine and fluorine,
comprising reacting a compound of formula 12
with magnesium in the presence of a solvent/co-solvent mixture to yield a compound of formula 13.
In a third aspect, the invention encompasses a process for making 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
1-4
alkoxy,
(d) C
1-4
alkylthio,
(e) CN,
(f) C
1-4
alkyl,
(g) C
1-4
fluoroalkyl, and
R
2
is chosen from the group consisting of
(a) F, Cl, Br, I
(b) CN,
(c) azide;
comprising reacting a compound of formula 12
wherein X is a halogen belonging to the group consisting of iodine, chlorine, bromine and fluorine,
with magnesium in the presence of a solvent/co-solvent mixture to yield a compound of formula 13
reacting the compound of formula 13 with a compound of formula 9
wherein Ar is described above,
to yield a compound of formula 15
wherein Ar is described above,
and oxidizing the compound of formula 15 using an oxidizing agent and optionally a catalyst under acid conditions to yield a compound of formula
wherein R1 is described above, condensing a compound of formula A1 or A2
under acidic conditions, optionally in the presence of a non-reactive solvent and in the presence of an ammonium reagent, with compound 5 to yield a compound of Formula I.
In a fourth aspect of the invention, the process encompasses a method for making a compound of formula II:
comprising reacting a compound of formula 12
wherein X is a halogen belonging to the group consisting of iodide, chloride, bromide and fluoride;
with magnesium in the presence of a solvent/co-solvent mixture to yield a compound of formula 13
reacting the compound of formula 13 with a compound of formula 9a
to yield a compound of formula 15a
and oxidizing the compound of formula 15a using an oxidizing agent and optionally a catalyst under acid conditions to yield a compound of formula
condensing a compound of formula A1 or A2
wherein R
2
is F, Cl, Br, I, CN, or azide;
under acidic conditions, and optionally in the presence of a non-reactive solvent and in the presence of an ammonium reagent, with compound 5a
to yield a compound of Formula II.
A further aspect of this invention is realized when A1 is employed wherein the acidic condition consists of the addition of acetic or propionic acid, the non-reactive solvent is tetrahydrofuran, dioxane, C
1-6
alkanol, chlorobenzene, dichlorobenze, xylene or toluene and the ammonium reagent is ammonia, ammonium acetate or ammonium propionate.
A further aspect of this invention is realized when A2 is employed wherein the acidic condition consists of the addition of acetic acid, methanesulfonic acid or propionic acid or a mixture thereof, preferably a mixture of propionic acid and methanesulfonic acid, the non-reactive solvent
Davies Ian W.
Gerena Linda
Journet Michel
Larsen Robert D.
Pye Philip J.
Billups Richard C.
Desai Rita
Merck & Co. , Inc.
Rose David L.
Rotman Alan L.
LandOfFree
Process for making diaryl pyridines useful as cox-2 inhibitors does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Process for making diaryl pyridines useful as cox-2 inhibitors, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Process for making diaryl pyridines useful as cox-2 inhibitors will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2924079