Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-10-11
2004-10-26
McKane, Joseph K. (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
active
06809204
ABSTRACT:
The present invention relates to substituted isoxazoles and 2-isoxazolines, and processes for their preparation. In addition the invention relates to compounds that serve as useful intermediates in the preparation of these heterocycles. Substituted isoxazoles are useful in the treatment of inflammation and inflammation-related disorders, including arthritis.
Selective inhibitors of cyclooxygenase-2 (COX-2) have demonstrated effective anti-inflammatory activity. Other antiinflammatory agents, e.g., NSAIDs, inhibit both the constitutive form of cyclooxygenase (COX-1), and the inducible form of the enzyme, COX-2.
COX-1 is a constitutive cyclooxygenase isoform and is mainly responsible for the synthesis of cytoprotective prostaglandins in the GI tract and the synthesis of thromboxane which triggers platelet aggregation in blood platelets. COX-2 is inducible and short-lived except in the case of certain tumors where it is constitutively activated. COX-2 expression is stimulated in response to endotoxins, cytokines, hormones, growth factors and mitogens. These observations suggest that COX-1 and COX-2 serve different physiological and pathophysiological functions. It has been suggested that COX-2 activity is mainly responsible for the pathological effects of prostaglandins where induction of the enzyme occurs in response to inflammatory agents, hormones, growth factors and cytokines. U.S. Pat. No. 5,604,253, incorporated herein by reference, for a discusses the advantages of selective COX-2 inhibition. Principally, a selective COX-2 inhibitor is expected to possess similar antiinflammatory, antipyretic and analgesic properties to conventional NSAIDs but with reduced potential for gastrointestinal toxicity, and a reduced potential for renal side effects.
A particularly effective structural class of selective COX-2 inhibitors are the 3,4-diaryl-substituted isoxazoles. For example, the compound, 4 [5-methyl-3-phenyl-isoxazol-1-yl]benzenesulfonamide (also known as Valdecoxib®) is useful for the treatment of a number of inflammation disorders, including osteoarthritis and rheumatoid arthritis. In addition, the sodium salt of N-[[(5-methyl-3-phenylisoxazol-4-yl)-phenyl]sulfonyl]propanamide (also known as Parecoxib®), a prodrug of Valdecoxib®, is particularly effective in parenteral compositions for acute pain management.
Talley et al. (U.S. Pat. No. 5,932,598 and
J. Med. Chem
. 2000, 43, 775-777) disclose the preparation of Valdecoxib® and related derivatives from deoxybenzoin. In the preparation, deoxybenzoin is treated with hydroxylamine, and the resulting oxime is deprotonated and condensed with an ester, e.g., ethyl acetate, to form an isoxazoline intermediate. The isoxazoline intermediate is converted to Valdecoxib® by treatment with chlorosulphonic acid, followed by aqueous ammonia. Parecoxib sodium® can be prepared by acylation of Valdecoxib® with propionic anhydride (Talley et al.,
J. Med. Chem
. 2000, 43, 1661-1663).
Also of interest for their COX-2 inhibitory activity and antiinflammatory activity are closely related analogs of Vaidecoxib®, as well as processes for their preparation.
SUMMARY OF THE INVENTION
In one embodiment, the invention relates to a process for the preparation of a compound of the formula I
wherein R
1
is selected from the group consisting of hydrogen, trihalomethyl, preferably trifluoromethyl; C
1
-C
6
alkyl, preferably C
1
-C
3
alkyl, most preferably methyl; and a group of the formula II
wherein R
3
and R
4
are independently selected from the group consisting of hydrogen; amino; halogen; preferably chlorine, fluorine and bromine; hydroxyl; nitro; C
1
-C
6
alkyl, preferably C
1
-C
3
alkyl; C
1
-C
6
alkoxy, preferably C
1
-C
3
alkoxy; carboxy; C
1
-C
6
trihaloalkyl, preferably trihalomethyl, most preferably trifluoromethyl; cyano; alkylsulfonyl; sulfamyl; phosphonato; and hydroxyalkyl, preferably C
1
-C
6
hydroxyalkyl;
Y is a group of the formula
wherein
R
2
is selected from the group consisting of C
1
-C
6
alkyl, preferably C
1
-C
3
alkyl; C
1
-C
6
alkanoylamino; and amino; and
R
5
is selected from the group consisting of hydrogen; amino; halogen; preferably chlorine, fluorine and bromine; hydroxyl; nitro; C
1
-C
6
alkyl, particularly C
1
-C
3
alkyl; C
1
-C
6
alkoxy, particularly C
1
-C
3
alkoxy, preferably methoxy; carboxy; C
1
-C
6
trihaloalkyl, preferably trihalomethyl, most preferably trifluoromethyl; cyano, phosphonato, and hydroxyalkyl, preferably C
1
-C
6
hydroxyalkyl; and
Z is selected from the group consisting of substituted and unsubstituted aryl.
The process has the step of contacting an oxime of the formula III
with an oxidizing agent and reacting the resulting nitrile oxide with an alkyne of the formula IV
In another embodiment, the invention relates to a compound of the formula IX
and pharmaceutically acceptable salts thereof, wherein R
1
is selected from the group consisting of hydrogen; trihalomethyl, preferably trifluoromethyl; C
1
-C
6
alkyl, preferably C
1
-C
3
alkyl, most preferably methyl; and a group of the formula II
wherein R
3
and R
4
are independently selected from the group consisting of hydrogen; amino; halogen, preferably chlorine, fluorine and bromine; hydroxyl; nitro; C
1
-C
6
alkyl, preferably C
1
-C
3
alkyl; C
1
-C
6
alkoxy, preferably C
1
-C
3
alkoxy; carboxy; C
1
-C
6
trihaloalkyl, preferably trihalomethyl, most preferably trifluoromethyl; cyano; alkylsulfonyl; sulfamyl; phosphonato; and hydroxyalkyl;
Y is a group of the formula
wherein
R
2
is selected from the group consisting of C
1
-C
6
alkyl, preferably C
1
-C
3
alkyl; C
1
-C
5
alkanoylamino; and amino; and
R
5
is selected from the group consisting of hydrogen; amino; halogen; preferably chlorine, fluorine and bromine; hydroxyl; nitro; C
1
-C
6
alkyl, particularly C
1
-C
3
alkyl; C
1
-C
6
alkoxy, particularly C
1
-C
3
alkoxy, preferably methoxy; carboxy; C
1
-C
6
trihaloalkyl, preferably trihalomethyl, most preferably trifluoromethyl; cyano; phosphonato, and hydroxyalkyl, preferably C
1
-C
6
hydroxyalkyl; and
Z is selected from the group consisting of substituted and unsubstituted aryl.
In preferred embodiments of the compound of formula IX, R
2
is amino. In particularly preferred embodiments, R
2
is amino or propionylamino, R
1
is methyl, R
5
is hydrogen and Z is phenyl.
In other preferred embodiments of the compound of formula IX, R
2
is C
1
-C
6
alkanoylamino, preferably n-propionylamino. In particularly preferred embodiments, R
2
is propionylamino, R
1
is methyl, R
5
is hydrogen and Z is phenyl.
The invention is also directed to isolated optical isomers of compounds according to formulas IX. By “isolated” means a compound which has been substantially purified from the corresponding optical isomer(s) of the same formula. The isomers can be purified by techniques that are well known in the art. For example, optical isomers can be separated by formation of diastereomeric addition salts with homochiral amines or acids. Alternatively, optical isomers can be separated by chiral chromatography on columns packed with chiral packing materials. Preferably, the isolated isomer is at least about 80%, more preferably, at least 90% pure, even more preferably at least 98% pure, most preferably at least about 99% pure, by weight. Preferably, the stereoisomer isolated is the one possessing the more potent antiinflammatory activity.
The invention is also directed to a pharmaceutical composition of one or more compounds of formula IX in combination with a pharmaceutically acceptable carrier.
According to another embodiment of the invention, a method for treating a cyclooxygenase-mediated disease is provided, that includes the step of administering an effective amount of a compound of the formula IX to an animal in need of such treatment. The terms “animal”, “subject” and “patient” include human beings.
The compounds of the formula IX are prepared by a process that includes the step of contacting an oxime of the formula III
with an oxidizing agent and reacting the resulting nitrile oxide wit
Bell Stanley C.
Reddy M. V. Ramana
Dechert LLP
McKane Joseph K.
Onconova Therapeutics Inc.
Ryan John W.
Saeed Kamal
LandOfFree
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