Organic compounds -- part of the class 532-570 series – Organic compounds – Oxygen containing
Reexamination Certificate
2002-10-15
2004-04-27
Davis, Zinna Northington (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Oxygen containing
C568S808000
Reexamination Certificate
active
06727392
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to a process for the preparation of non-steroidal glucocorticoid receptor modulators.
Nuclear receptors are classically defined as a family of ligand dependent transcription factors, that are activated in response to ligand binding (R. M. Evans, 240 Science, 889 (1988)). Members of this family include the following receptors: glucocorticoid, mineralocorticoid, androgen, progesterone and estrogen. Naturally occurring ligands to these receptors are low molecular weight molecules that play an important role in health and in many diseases. Excesses or deficiencies of these ligands can have profound physiological consequences. As an example, glucocorticoid excess results in Cushing's Syndrome, while glucocorticoid insufficiency results in Addison's Disease.
The glucocorticoid receptor (GR) is present in glucocorticoid responsive cells where it resides in the cytosol in an inactive state until it is stimulated by an agonist. Upon stimulation the glucocorticoid receptor translocates to the cell nucleus where it specifically interacts with DNA and/or protein(s) and regulates transcription in a glucocorticoid responsive manner. Two examples of proteins that interact with the glucocorticoid receptor are the transcription factors, API and NF&kgr;-B. Such interactions result in inhibition of API- and NF&kgr;-B-mediated transcription and are believed to be responsible for some of the anti-inflammatory activity of endogenously administered glucocorticoids. In addition, glucocorticoids may also exert physiologic effects independent of nuclear transcription. Biologically relevant glucocorticoid receptor agonists include cortisol and corticosterone. Many synthetic glucocorticoid receptor agonists exist including dexamethasone, prednisone and prednisilone. By definition, glucocorticoid receptor antagonists bind to the receptor and prevent glucocorticoid receptor agonists from binding and eliciting GR mediated events, including transcription. RU486 is an example of a non-selective glucocorticoid receptor antagonist.
SUMMARY OF THE INVENTION
The present invention relates to a process for preparing a compound of the formula
comprising reacting a compound of the formula
with an amide of the formula
in the presence of 1,1′-carbonyldiimazole.
The present invention further relates to a process for preparing a compound of the formula
comprising reacting a compound of the formula
with aqueous sodium hydroxide in a polar protic solvent.
The present invention further relates to a process for preparing a compound of the formula
comprising reducing a compound of the formula
with hydrogen in the presence of a catalyst.
The present invention further relates to a process for preparing a compound of the formula
comprising reacting the compound of the formula
with trifluoromethylpropyne.
The present invention further relates to a process for preparing a compound of the formula
comprising reducing a compound of the formula
with hydrogen in the presence of a catalyst and potassium carbonate.
The present invention further relates to a process for preparing a compound of the formula
comprising reacting a compound of the formula
with a cyanide source in the presence of a catalyst.
The present invention further relates to a process for preparing a compound of the formula
comprising reacting a compound of the formula
with sodium methoxy.
The present invention further relates to a process for preparing a compound of the formula
comprising reacting a compound of the formula
with methyl vinyl ketone.
The present invention further relates to a process for preparing a compound of the formula
comprising reacting a compound of the formula
with pyrrolidine followed by reacting the resultant pyrrolidine enamine intermediate with a benzyl halide.
The present invention relates to a process for preparing a compound of the formula
comprising (a) reacting a compound of the formula
with pyrrolidine followed by reacting the resultant pyrrolidine enamine intermediate with a benzyl halide to form the compound of formula IX
(b) reacting the compound of formula IX so formed with methyl vinyl ketone to form the compound of formula VIII
(c) reacting the compound of formula VIII so formed with sodium methoxy to form the compound of formula VII
(d) reacting the compound of formula VII so formed with a cyanide source in the presence of a catalyst to form the compound of formula VI
(e) reducing the compound of formula VI so formed with hydrogen in the presence of a catalyst and potassium carbonate to form the compound of formula V
(f) reacting the compound of formula V so formed with trifluoromethylpropyne to form the compound of formula IV
(g) reducing the compound of formula IV so formed with hydrogen in the presence of a catalyst to form the compound of formula III
(h) reacting the compound of formula III so formed with aqueous sodium hydroxide in a polar protic solvent to form the compound of formula II
(i) reacting the compound of formula II so formed with an amide of the formula
in the presence of 1,1′-carbonyldiimazole.
The present invention relates to a process for prepairing a compound of the formula
comprising reacting the compound of the formula
with methyl vinyl ketone.
The present invention further relates to a process for preparing a compound of the formula
comprising reacting a compound of the formula
with a benzyl halide.
The present invention further relates to a process for preparing a compound of the formula
comprising reacting the compound of the formula
with an amine of the formula
The present invention relates to a process for preparing a compound of the formula
comprising reacting the compound of the formula
with a borane or a borate.
The present invention relates to a process for preparing a compound of the formula
comprising reacting a compound of the formula
with a compound of the formula
The present invention further relates to a process for preparing a compound of the formula
comprising reacting the compound of the formula
with trimethylsilyl trifluoromethane.
The present invention relates to a process for preparing a compound of the formula
comprising reacting a compound of the formula
with an amine of the formula
in the presence of 1,1′carbonydiimidazole.
The present invention relates to a process for preparing a compound of the formula
comprising reacting the compound of the formula
with aqueous sodium hydroxide in a polar protic solvent.
The present invention relates to a process for preparing a compound of then formula
comprising reducing the compound of formula XIII
with hydrogen in the presence of a catalyst.
The present invention further relates to a process for preparing a compound of the formula
is formed comprising reacting the compound of the formula
with trifluoromethylpropyne.
The present invention further relates to a process for preparing a compound of the formula
is formed comprising reducing the compound of formula XV
with hydrogen in the presence of a catalyst.
The present invention further relates to a process for preparing a compound of the formula
comprising reacting the compound of the formula
with a cyanide source.
The present invention relates to a compound of the formula
The present invention relates to a compound of the formula
The present invention relates to a compound of the formula
The present invention relates to a compound of the formula
The present invention relates to a compound of the formula
The present invention relates to a compound of the formula
DETAILED DESCRIPTION OF THE INVENTION
In reaction 1 of Preparation A, the compound of formula X is converted to the corresponding compound of formula XXIII, by reacting X with an amine compound of the formula
in the presence of a polar aprotic solvent, such as toluene. The reaction is stirred at a temperature between about 90° C. to about 150° C., preferably about 115° C., for a time period between about 0.5 hours to about 12 hours, preferably about 2 hours.
In reaction 2 of Preparation
Murry Jerry A.
White Timothy D.
Davis Zinna Northington
Grolz Edward W.
Pfizer Inc.
Scully Scott Murphy & Presser
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