Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Ester doai
Reexamination Certificate
2001-03-28
2003-12-16
Richter, Johann (Department: 1621)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Ester doai
C514S563000, C560S011000, C560S036000, C560S044000, C560S045000, C562S441000, C562S449000, C562S457000, C206S570000
Reexamination Certificate
active
06664291
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to novel thyroid receptor ligands and, more particularly, relates to malonamic acids, and derivatives thereof, which are useful in the treatment of obesity, overweight condition, hyperlipidemia, glaucoma, cardiac arrhythmias, skin disorders, thyroid disease, hypothyroidism, thyroid cancer and related disorders and diseases such as diabetes mellitus, atherosclerosis, hypertension, coronary heart disease, congestive heart failure, hypercholesteremia, depression, osteoporosis and hair loss. The present invention also provides methods, pharmaceutical compositions and kits for treating such diseases and disorders.
BACKGROUND OF THE INVENTION
Thyroid hormones are important in normal development and in maintaining metabolic homeostasis. For example, 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 gland are generally treated by administering either naturally occurring thyroid hormones or analogues that mimic the effects of thyroid hormones. Such analogues are called thyromimetics or thyroid receptor ligands.
Two naturally occurring thyroid hormones, 3,5,3′,5′-tetraiodo-L-thyronine (also referred to as “T
4
” or thyroxine) and 3,5,3′-triiodo-L-thyronine (also referred to as “T
3
”), are shown below:
T
3
is more biologically active than T
4
, and differs from T
4
by the absence of the 5′ iodine. T
3
may be produced directly in the thyroid gland, or in peripheral tissues, by the removal of the 5′ iodine of T
4
by deiodinase enzymes. Thyroid receptor ligands can be 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 heart rate, and accordingly, an increase in oxygen consumption. While the increase in oxygen consumption can 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 described in A. H. Underwood et al.,
Nature,
324: 425429 (1986), efforts have been made to synthesize thyroid hormone analogs that function to lower lipids and serum cholesterol, without generating the adverse cardiac effects referred to above.
U.S. Pat. Nos. 4,766,121; 4,826,876; 4,910,305; and 5,061,798 disclose thyroid hormone mimetics, namely, 3,5-dibromo-3′-[6-oxo-3(1H)-pyridazinylmethyl]-thyronines.
U.S. Pat. No. 5,284,971 discloses thyromimetic cholesterol lowering agents, namely, 4-(3-cyclohexyl-4-hydroxy or -methoxy phenylsulfonyl)-3,5 dibromo-phenylacetic acid compounds.
U.S. Pat. Nos. 5,401,772 (also published European Patent Application 0 580 550); 5,654,468 and 5,569,674 disclose certain lipid lowering agents, namely, heteroacetic acid derivatives, more specifically oxamic acid derivatives, which compete with radiolabeled T
3
in binding assays using rat liver nuclei and plasma membrane preparations.
Certain oxamic acids and derivatives thereof are known in the art, e.g., U.S. Pat. No. 4,069,343 describes the use of certain oxamic acids to prevent immediate type hypersensitivity reactions; U.S. Pat. No. 4,554,290 describes the use of certain oxamic acids to control pests on animals and plants; and U.S. Pat. No. 5,232,947 describes the use of certain oxamic acids to improve damaged cerebral functions of the brain.
In addition, certain oxamic acid derivatives of thyroid hormones are known in the art. For example, N. Yokoyama et al. in an article published in the
Journal of Medicinal Chemistry,
38 (4): 695-707 (1995) describe replacing a —CH
2
group in a naturally occurring metabolite of T
3
with an —NH group resulting in —HNCOCO
2
H. Likewise, R. E. Steele et al. in an article published in International Congressional Service (Atherosclerosis X) 106: 321-324 (1995) and Z. F. Stephan et al. in an article published in Atherosclerosis, 126: 53-63 (1996), describe a certain oxamic acid derivative useful as a lipid-lowering thyromimetic agent that has reduced adverse cardiac activities.
Commonly assigned International Patent Application Publication No. WO 00/51971, published Sep. 8, 2000, and commonly assigned published European Patent Application EP 1 033 364, published Sep. 6, 2000, disclose certain oxamic acids and derivatives thereof as thyroid receptor ligands. Commonly assigned U.S. nonprovisional patent application, Ser. No. 09/671668, filed Sep. 27, 1999, discloses certain 6-azauracil derivatives as thyroid receptor ligands. Commonly assigned U.S. provisional patent application, Ser. No. 60/177987, filed Jan. 25, 2000, discloses certain tetrazole compounds as thyroid receptor ligands.
D. M. T. Chan et al.,
Tetrahedron Letters,
39: 2933-2936 (1998) discloses new N- and O-arylations with phenylboronic acids and cupric acetate.
International Patent Application Publication No. WO 00/58279, published Oct. 5, 2000, discloses diaryl derivatives and their use as medicaments.
International Patent Application Publication No. WO 00/07972, published Feb. 17, 2000, discloses glucocorticoid and thyroid hormone receptor ligands for the treatment of metabolic disorders.
International Patent Application Publication No. WO 00/39077, published Jul. 6, 2000, discloses novel thyroid receptor ligands.
A. H. Taylor et al., “Beneficial Effects of a Novel Thyromimetic on Lipoprotein Metabolism,”
Molecular Pharmacology,
52:542-547 (1997), discloses beneficial effects of a novel thyromimetic on lipoprotein metabolism.
J. L. Stanton et al., “Synthesis and Biological Activity of Phenoxyphenyl Oxamic Acid Derivatives Related to L-Thyronine,”
Bioorganic & Medicinal Chemistry Letters,
10: 1661-1663 (2000), discloses the synthesis and biological activity of phenoxyphenyl oxamic acid derivatives related to L-thyronine.
International Patent Application Publication No. WO 00/72810, published Dec. 7, 2000, discloses a method of treating hair loss using certain sulfonyl thyromimetic compounds. International Patent Application Publication No. WO 00/72811, published Dec. 7, 2000, discloses methods of treating hair loss using certain compounds described therein. International Patent Application Publication No. WO 00/72812, published Dec. 7, 2000, discloses methods of treating hair loss using certain diphenylether derivatives. International Patent Application Publication No. WO 00/72813, published Dec. 7, 2000, discloses methods of treating hair loss using certain diphenylmethane derivatives. International Patent Application Publication No. WO 00/72920, published Dec. 7, 2000, discloses certain substituted biaryl ether compounds and compositions for treating hair loss. International Patent Application Publication No. WO 00/73292, published Dec. 7, 2000, discloses certain biaryl compounds and compositions for treating hair loss.
Obesity is a major health risk that leads to increased mortality and incidence of Type 2 diabetes mellitus, hypertension and dyslipidemia. In the U.S. more than 50% of the adult population is overweight, and almost ¼ of the population is considered to be obese (BMI greater than or equal to 30). The incidence of obesity is increasing in the U.S. at a 3% cumulative annual growth rate. While the vast majority of obesity occurs in the U.S. and Europe, the prevalence of obesity is also increasing in Japan. The prevalence of obesity in adults is 10%-25% in most countries of western Europe.
Obesity is a devastating disease. In addition to harming physical health, obesity can wreak havoc on mental health because obesity affects self-esteem, which ultimately can affect a person's abi
Aspnes Gary E.
Chiang Yuan-Ching P.
Estep Kimberly G.
Dixon J. Michael
Gammill Martha A.
Pfizer Inc.
Richter Johann
Zucker Paul A.
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