Organic compounds -- part of the class 532-570 series – Organic compounds – Four or more ring nitrogens in the bicyclo ring system
Reexamination Certificate
2000-09-27
2004-09-07
Kifle, Bruck (Department: 1624)
Organic compounds -- part of the class 532-570 series
Organic compounds
Four or more ring nitrogens in the bicyclo ring system
C514S242000
Reexamination Certificate
active
06787652
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to novel thyroid receptor ligands and, more particularly, relates to novel 6-azauracils, and derivatives thereof, which are useful in the treatment of obesity, overweight condition, hyperlipidemia, thyroid disease, hypothyroidism, thyroid cancer and related disorders and diseases such as diabetes mellitus, atherosclerosis, hypertension, coronary heart disease, hypercholesteremia, depression, osteoporosis, cardiac arrhythmias, glaucoma and congestive heart failure. Also provided are methods, pharmaceutical compositions and kits for treating such diseases and disorders.
BACKGROUND OF THE INVENTION
It is generally accepted that thyroid hormones, specifically, biologically active iodothyronines, are critical to normal development and to maintaining metabolic homeostasis. Thyroid hormones stimulate the metabolism of cholesterol to bile acids and enhance the lipolytic responses of fat cells to other hormones.
Thyroid hormones also affect cardiac function both directly and indirectly, e.g., by increasing the metabolic rate. For example, tachycardia, increased stroke volume, increased cardiac index, cardiac hypertrophy, decreased peripheral vascular resistance and increased pulse pressure are observed in patients with hyperthyroidism.
Disorders of the thyroid are generally treated with hormone replacement by administering either naturally occurring thyroid hormones or thyromimetic analogues which mimic the effects of thyroid hormones.
Two naturally occurring thyroid hormones, namely, thyroxine or 3,5,3′,5′-tetraiodo-L-thyronine (commonly referred to as “T
4
”) and 3,5,3′-triiodo-L-thyronine (commonly referred to as “T
3
”), are shown below:
T
3
is the more biologically active of the two and, as will be appreciated from the structural formulae provided above, differs from T
4
by the absence of the 5′ iodine. T
3
may be produced directly from the thyroid gland, or, in peripheral tissues, by the removal of the 5′ iodine by deiodinase enzymes. Thyromimetic analogs are often designed to be structurally similar to T
3
. In addition, naturally occurring metabolites of T
3
are known.
As discussed above, thyroid hormones affect cardiac functioning, for example, by causing an increase in the heart rate and, accordingly, an increase in oxygen consumption. While the increase in oxygen consumption may result in certain desired metabolic effects, nonetheless, it does place an extra burden on the heart, which in some situations, may give rise to damaging side effects. Therefore, as is known in the art, such as described by A. H. Underwood et al. in an article published in
Nature
, Vol. 324: pp. 425-429 (1986), efforts have been made to synthesize thyroid hormone analogs which function to lower lipids and serum cholesterol without generating the adverse cardiac effects referred to above.
Certain 6-azauracils and derivatives thereof are known in the art. U.S. Pat. Nos. 3,905,971 and 3,912,723 disclose certain 2-phenyl-as-triazine-3,5(2H,4H)diones and certain 2-substituted-phenyl-as-triazine-3,5(2H,4H)diones and their use as agents for the control of coccidiosis.
U.S. Pat. Nos. 3,883,527 and 3,883,528 disclose processes for producing certain 2-aryl-as-triazine-3,5(2H,4H)-diones, which are useful as coccidiostats.
Canadian Patent Nos. 979457 and 992538 disclose certain 2-phenyl-as-triazine-3,5(2H, 4H)diones, derivatives thereof, compositions containing said compounds and process for preparing said compounds, which compounds are useful in controlling coccidiosis.
U.S. Pat. Nos. 3,896,172 and 3,852,289 disclose processes for preparing certain 1,2,4-triazine-3,5(2H,4H)diones having a p-chlorophenylthio-substituted 2-aryl moiety, which compounds are useful as coccidiostats.
U.S. Pat. Nos. 3,882,115 and 3,883,525 disclose processes for preparing certain 1,2,4-triazine-3,5(2H,4H)diones having a 2-aryl moiety which is substituted with, for example, 2-chlorophenoxy and 2-chloro-4-(N-methyl-N-ethylsulfamoyl)phenoxy.
U.S. Pat. No. 5,256,631 and South African Patent No. 91/7390 disclose certain substituted 1,2,4-triazinediones, processes for preparing them and their use as antiprotozoal agents. German Patent No. 25 32 363 discloses certain 1,2,4-triazin-3,5(2H,4H)-dione compounds having a 4-amino-phenoxy-substituted 2-phenyl group. South African Patent No. 73/9126 discloses a process for preparing certain 2-aryl-6-carboxy-1,2,4-triazine-3,5(2H,4H)-diones.
U.S. Pat. No. 4,640,917 discloses substituted 2-phenyl-hexahydro-1,2,4-triazine-3,5-diones which are useful for controlling protozoal diseases. U.S. Pat. No. 4,198,407 discloses certain substituted 2-phenyl-1,2,4-triazine-3,5(2H,4H)-diones and coccidiostatic agents containing them.
Published European Patent Application 0 737 672 discloses a method of producing 1,2,4-triazin-3-one derivatives having a substituent at the 2-position.
U.S. Pat. No. 4,239,888 discloses certain 1-phenyluracils and their utility as coccidiostats.
B. L. Mylari et al., J.Med.Chem. 1977, 20, 475-483; M. W. Miller et al., J.Med.Chem. 1979, 22, 1483-1487; and M. W. Miller et al., J.Med.Chem. 1980, 23, 1083-1087; discloses certain anticoccidial derivatives of 6-azauracil.
M. W. Miller et al., J.Med.Chem. 1981, 24,1337-1342, discloses certain anticoccidial derivatives of 6-azauracil having phenyl sulfide and phenyl sulfone side chains.
R. D. Carroll et al., J.Med.Chem. 1983, 26, 96-100, discloses certain anticoccidial derivatives of 6-azauracil having a p-benzophenone side chain.
K.-B. Rhyu et al., J. Chem. Inf. Comput. Sci. (1996), 36(3), 620; K.-B. Rhyu et al., J. Chem. Inf. Comput. Sci. (1995), 35(4), 771-8; A. C. Good et al., J. Med. Chem. (1993). 36(20), 2929-37; J. W. McFarland, J. Med. Chem. (1992), 35 (14), 2543-50; and J. W. McFarland et al., J. Med. Chem. (1991). 34 (6), 1908-11; disclose various techniques for studying the quantitative structure-activity relationships among certain anticoccidial 2-(substituted phenyl)-1,2,4-triazine-3,5 (2H,4H)-diones.
A. N. Chekhlov et al., Dokl. Akad. Nauk (1993), 329 (5), 603-7, discloses the molecular and crystal structure of 2-[3,5-dichloro-4-(m-trifluoromethylphenylthio)phenyl]-1,2,4-triazine-3,5(2H,4H)-dione.
N. S. Zefirov et al., Dokl. Akad. Nauk (1992), 327 (4-6), 504-8, discloses the quantitative relationship between the structure of 2-substituted 1,2,4-triazine-3,5(2H,4H)-diones and their anticoccidial activity.
A. P. Ricketts et al., Antimicrob. Agents Chemother. (1992), 36 (10), 2338-41, discloses the study of the relationship between the in vitro anticoccidial activity and the in vivo efficacy of compounds such as the aryl triazine compound, 3-chloro-4-[2-chloro-4-(4,5-dihydro-3,5-dioxo-1,2,4-triazin-2(3H)-yl)-6-methylphenoxy]-N-ethyl-N-methyl-benzenesulfonamide.
M. J. Lynch and S. K. Figdor, J. Agric. Food Chem. (1977), 25 (6),1344-53, disclose tissue residue and comparative metabolism studies on tiazuril, 2-[3,5-dimethyl-4-(4-chlorophenylthio)phenyl-as-triazine-3,5 (2H, 4H)dione, in the chicken, rat, dog and monkey.
J. F. Ryley et al., Parasitology (1974), 68 (Pt. 1), 69-79, discloses the anticoccidial activity of an azauracil derivative, 2-[3,5-dichloro-4-(4-chlorophenylthio)phenyl-as-triazine-3,5 (2H, 4H)dione.
All of the documents cited herein, including the foregoing, are incorporated by reference herein in their entireties.
SUMMARY OF THE INVENTION
isomers thereof, prodrugs of said compounds or isomers, or pharmaceutically acceptable salts of said compounds, isomers or prodrugs; wherein W is (a) —O—, (b) —S(O)
m
—, (c) —NR
30
—, (d) —C(O)—, (e) —HC═CH—, (f) —CH
2
—, (g)- CHF—, (h) —CF
2
— or (i) —CH(OH)—;
R
1
and R
2
are independently (a) hydrogen, (b) halogen, (c) —(C
1
-C
6
)alkyl, (d) —CN, (e) —OR
12
or (f) -trifluoromethyl;
R
3
is (a) hydrogen, (b) halogen, (c) —(C
1
-C
6
)alkyl optionally substituted with one to three substituents independently selected from the group consisting of halogen, —OCF
3
and —CF
3
, (d) —CN, (e) —OR
12
, (f) -trifluoromethyl, (g) —NO
2
, (h) —SO
2
—R
13
, (i) —C(O)
2
R
Chiang Yuan-Ching P.
Dow Robert L.
Estep Kimberly G.
Dixon J. Michael
Kifle Bruck
Pfizer Inc.
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