Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acid esters
Reexamination Certificate
2002-10-17
2004-10-19
Desai, Rita (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acid esters
C514S539000, C514S522000, C562S455000, C560S043000
Reexamination Certificate
active
06806381
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to processes for the synthesis of organic molecules, specifically molecules that have activity as thyroid receptor ligands.
While the essential role of thyroid hormones in regulating metabolism in humans is well recognized, the discovery and development of new specific drugs for improving the treatment of hyperthyroidism and hypothyroidism has been slow. This has also limited the development of thyroid agonists and antagonists for treatment of other important clinical indications, such as hypercholesterolemia, obesity and cardiac arrhythmias.
Thyroid hormones affect the metabolism of virtually every cell of the body. At normal levels, these hormones maintain body weight, the metabolic rate, body temperature, and mood, and influence serum-low density lipoprotein (LDL) levels. Thus, in hypothyroidism there is weight gain, high levels of LDL cholesterol, and depression. In excess with hyperthyroidism, these hormones lead to weight loss, hypermetabolism, lowering of serum LDL levels, cardiac arrhythmias, heart failure, muscle weakness, bone loss in postmenopausal women, and anxiety.
Thyroid hormones are currently used primarily as replacement therapy for patients with hypothyroidism. Therapy with L-thyroxine returns metabolic functions to normal and can easily be monitored with routine serum measurements of levels of thyroid-stimulating hormone (TSH), thyroxine (3,5,3′,5′-tetraiodo-L-thyronine, or T
4
) and triiodothyronine (3,5,3′-triiodo-L-thyronine, or T
3
). However, replacement therapy, particularly in older individuals, is limited by certain of the deleterious effects of thyroid hormones.
In addition, some effects of thyroid hormones may be therapeutically useful in non-thyroid disorders if adverse effects can be minimized or eliminated. These potentially useful influences include weight reduction, lowering of serum LDL levels, amelioration of depression and stimulation of bone formation. Prior attempts to utilize thyroid hormones pharmacologically to treat these disorders have been limited by manifestations of hyperthyroidism, and in particular by cardiovascular toxicity.
Development of specific and selective thyroid hormone receptor agonists could lead to specific therapies for these common disorders while avoiding the cardiovascular and other toxicities of native thyroid hormones. Tissue-selective thyroid hormone agonists may be obtained by selective tissue uptake or extrusion, topical or local delivery, targeting to cells through other ligands attached to the agonist and targeting receptor subtypes. Thyroid hormone receptor agonists that interact selectively with the &bgr;-form of the thyroid hormone receptor offer an especially attractive method for avoiding cardio-toxicity.
Thyroid hormone receptors (TRs) are, like other nuclear receptors, single polypeptide chains. The various receptor forms appear to be products of two different genes &agr; and &bgr;. Further isoform differences are due to the fact that differential RNA processing results in at least two isoforms from each gene. The TR&agr;
1
, TR&bgr;
1
and TR&bgr;
2
isoforms bind thyroid hormone and act as ligand-regulated transcription factors. In adults, the TR&bgr;
1
isoform is the most prevalent form in most tissues, especially in the liver and muscle. The TR&agr;
1
isoform is prevalent in the pituitary and other parts of the central nervous system, does not bind thyroid hormones, and acts in many contexts as a transcriptional repressor. The TR&agr;
1
isoform is also widely distributed, although its levels are generally lower than those of the TR&bgr;
1
isoform. This isoform may be especially important for development. Whereas many mutations in the TR&bgr; gene have been found and lead to the syndrome of generalized resistance to thyroid hormone, mutations leading to impaired TR&agr; function have not been found.
A growing body of data suggest that many or most effects of thyroid hormones on the heart, and in particular on the heart rate and rhythm, are mediated through the &agr;-form of the TR&agr;
1
isoform, whereas most actions of the hormone such as on the liver, muscle and other tissues are mediated more through the &bgr;-forms of the receptor. Thus, a TR&bgr;-selective agonist might not elicit the cardiac rhythm and rate influences of the hormones but would elicit many other actions of the hormones. It is believed that the &agr;-form of the receptor is the major drive to heart rate for the following reasons:
1. tachycardia is very common in the syndrome of generalized resistance to thyroid hormone in which there are defective TR&bgr;-forms, and high circulating levels of T
4
and T
3
;
2. there was a tachycardia in the only described patient with a double deletion of the TR&bgr; gene (Takeda et al., J. Clin. Endrocrinol. & Metab. 1992, Vol. 74, p. 49);
3. a double knockout TR&agr; gene (but not &bgr;-gene) in the mouse has a slower pulse than control mice; and,
4. western blot analysis of human myocardial TRs show presence of the TR&agr;
1
, TR&agr;
2
and TR&bgr;
2
proteins, but not TR&bgr;
1
.
If these indications are correct, then a TR&bgr;-selective agonist could be used to mimic a number of thyroid hormone actions, while having a lesser effect on the heart. Such a compound may be used for: (1) replacement therapy in elderly subjects with hypothyroidism who are at risk for cardiovascular complications; (2) replacement therapy in elderly subjects with subclinical hypothyroidism who are at risk for cardiovascular complications; (3) obesity; (4) hypercholesterolemia due to elevations of plasma LDL levels; (5) depression; and, (6) osteoporosis in combination with a bone resorption inhibitor.
Thyroid receptor ligands of the formula I, below, have previously been synthesized by several methods including the method summarized in Scheme A (See U.S. patent application Ser. No. 09/761,050, filed Jan. 16, 2001.) The group G represents any group appropriate for protecting a hydroxyl moiety. The group Z represents a leaving group, such as a halogen. Examples of appropriate protecting groups G can be found, for example, in T. W. Greene & P. G. M. Wuts, “Protecting Groups in Organic Synthesis”, 3rd Edition, Wiley, 1999.
This route is not optimal, however, due to the exothermicity of the formation of the iodonium triflate salt which is an unisolated intermediate in the synthesis depicted in Scheme A. In addition, the isolated, bis-phenyl iodonium salt is an intractable gummy solid at room temperature, and the yield of the formation reaction is unpredictable. Further, the coupling reaction to form the mixed ether from the iodonium salt is not well adapted to commercial practice, because it takes place over an extended period of time, it requires unusual provisions to exclude light, and its yield is also unpredictable.
Accordingly, there is a need for improved processes for the preparation of thyroid receptor ligands, especially for processes that improve upon the safety and economic feasibility of the processes known in the art.
SUMMARY OF THE INVENTION
The present invention relates to the synthesis of compounds that have activity as thyroid receptor ligands, specifically compounds of formula I
wherein:
R
1
represents halogen, trifluoromethyl, an alkyl group of 1 to 6 carbons, or a cycloalkyl group of 3 to 7 carbons;
R
2
and R
3
are the same or different and represent hydrogen, halogen, an alkyl group of 1 to 4 carbons, or a cycloalkyl group of 3 to 6 carbons, at least one of R
2
and R
3
being other than hydrogen;
R
4
represents hydrogen or a lower alkyl group;
R
5
represents a carboxylic acid or an alkyl ester thereof; and
Y represents —(CH
2
)
n
— where n is an integer from 1 to 5, or a cis- or trans-ethylene group —CH—CH—;
and all stereoisomers thereof, prodrug esters thereof, and pharmaceutically acceptable salts thereof.
Compounds of formula I may be synthesized by reacting a compound of formula III with a phenol of formula A, wherein G is a protecting group, in the presence of a base to produce a compound of formula IV,
Chidambaram Ramakrishnan
Ghosh Arun
Kant Joydeep
Weaver Raymond E.
Yu Jurong
Baxam Deanna L.
Bristol--Myers Squibb Company
Desai Rita
Reyes Hector M.
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