Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2003-02-20
2004-02-10
Aulakh, C. S. (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C546S271400, C546S275400, C546S271100, C546S272100
Reexamination Certificate
active
06689888
ABSTRACT:
FIELD OF THE INVENTION
The present invention provides processes and intermediates useful in the preparation of certain &bgr;
3
-adrenergic receptor agonists, which agonists are useful in treating, inter alia, hypoglycemia, and obesity, and for increasing the content of lean meat in edible animals.
BACKGROUND OF THE INVENTION
Diabetes mellitus is characterized by metabolic defects in the production and utilization of carbohydrates which result in the failure to maintain appropriate blood sugar levels. The results of these defects include, inter alia, elevated blood glucose or hyperglycemia. Research in the treatment of diabetes has centered on attempts to normalize fasting and postprandial blood glucose levels. Current treatments include administration of exogenous insulin, oral administration of drugs, and dietary therapies.
Two major forms of diabetes mellitus are recognized. Type 1 diabetes, or insulin-dependent diabetes mellitus (IDDM), is the result of an absolute deficiency of insulin, the hormone that regulates carbohydrate utilization. Type 2 diabetes, or non-insulin-dependent diabetes mellitus (NIDDM), often occurs with normal, or even elevated, levels of insulin and appears to be the result of the inability of tissues to respond appropriately to insulin. Most Type 2 diabetic patients are also obese.
Obesity constitutes a major health risk that leads to mortality and incidence of Type 2 diabetes mellitus, hypertension, and dyslipidemia. In the United States, more than 50% of the adult population is overweight, and almost 25% of the population is considered to be obese. The incidence of obesity is increasing in the United States at a three-percent cumulative annual growth rate. While the vast majority of obesity occurs in the United States and Europe, the prevalence of obesity is also increasing in Japan. Furthermore, obesity is a devastating disease which can also wreak havoc on an individual's mental health and self-esteem, which can ultimately affect a person's ability to interact socially with others. Unfortunately, the precise etiology of obesity is complex and poorly understood, and societal stereotypes and presumptions regarding obesity only tend to exacerbate the psychological effects of the disease. Because of the impact of obesity on society in general, much effort has been expended in efforts to treat obesity, however, success in the long-term treatment and/or prevention thereof remains elusive.
In response thereto, a diversity of therapeutic agents have been developed including, for example, &bgr;
3
-adrenergic receptor activators/agonists. Activation of &bgr;
3
-adrenergic receptors is known to stimulate lipolysis (e.g., the breakdown of adipose tissue triglycerides into glycerol and fatty acids) and metabolic rate (energy expenditure), thereby promoting the loss of fat mass. Accordingly, compounds that stimulate &bgr;
3
-adrenergic receptors are useful as anti-obesity agents. In addition, compounds that are &bgr;
3
-adrenergic receptor agonists have hypoglycemic activity, however, the precise mechanism of this effect is presently unknown.
Commonly assigned U.S. Provisional Application No. 60/242,274, filed Oct. 20, 2000, and incorporated herein by reference, discloses certain &bgr;
3
-adrenergic receptor agonists of the general structural Formula (I),
the stereoisomers and prodrugs thereof, and the pharmaceutically acceptable salts of the compounds, stereoisomers, and prodrugs.
The instant invention provides processes useful in the preparation of certain &bgr;
3
-adrenergic receptor agonists of structural Formula (I), which agonists are disclosed in detail hereinbelow. The invention further provides intermediates useful in the preparation of such agonists, and processes useful in the production of such intermediates.
SUMMARY OF THE INVENTION
The present invention provides processes useful in the preparation of certain &bgr;
3
-adrenergic receptor agonists of the structural formula
the pharmaceutically acceptable salts thereof, and the hydrates of said pharmaceutically acceptable salts, wherein HET is as defined hereinbelow. The invention further provides intermediates useful in the preparation of such agonists, and processes useful in the production of such intermediates.
DETAILED DESCRIPTION
The present invention provides processes useful in the preparation of certain &bgr;
3
-adrenergic receptor agonists of the structural formula
the pharmaceutically acceptable salts thereof, and the hydrates of said pharmaceutically acceptable salts, wherein HET is a heterocyclic moiety selected from the group consisting of oxazolyl, pyrazolyl, and thiazolyl.
The invention further provides intermediates useful in the preparation of such agonists, and processes useful in the production of such intermediates. These enantioselective processes, to be described in greater detail hereinbelow, proceed in a convergent manner, utilize a minimum number of starting materials, and furnish products retaining an overall high degree of enantiospecificity.
In one aspect of the present invention, there is provided a process for preparing a compound of the structural formula
a pharmaceutically acceptable salt thereof, or a hydrate of said pharmaceutically acceptable salt, which process comprises the steps of:
(a) reducing an &agr;-bromoketone derivative of the structural formula
or an acid addition salt thereof, to form an (R)-bromoalcohol derivative of the structural formula
(b) protecting the (R)-bromoalcohol derivative of Step (a) to form an O-protected derivative of the structural formula
(c) condensing the O-protected derivative of Step (b) with an amine of the structural formula
to produce an O-protected derivative of the structural formula
(d) deprotecting the O-protected derivative of Step (c) to form the compound of the structural formula
wherein:
HET is a heterocyclic moiety selected from the group consisting of oxazolyl, pyrazolyl, and thiazolyl; and
P is an O-protecting moiety selected from the group consisting of —SiR
1
R
2
R
3
, —CH
2
Ph, —CH
2
(p-CH
3
OPh), —CH(OCH
2
CH
3
)CH
3
, and
wherein R
1
, R
2
, and R
3
are, independently, (C
1
-C
6
)alkyl, or phenyl.
Preferably, P is —SiR
1
R
2
R
3
, and HET is a heterocyclic moiety selected from the group consisting of 2-oxazolyl, 4-oxazolyl, 3-pyrazolyl, 4-pyrazolyl, 2-thiazolyl, and 4-thiazolyl. The process wherein P represents —SiR
1
R
2
R
3
, wherein R
1
and R
2
are both —CH
3
, and R
3
is —C(CH
3
)
3
is especially preferred.
The stereospecific reduction step, denoted hereinabove as Step (a), preferably employs a fungal reducing agent. Generally, the use of fungal and/or microbial reducing agents in the stereospecific biotransformation of pharmaceutical intermediates is known. See, for example, R. N. Patel, Advances in Applied Microbiology, 43, 91-140 (1997). Specifically, the stereospecific reduction of &agr;-haloketones with various microorganisms is also generally known. See, for example, R. N. Patel, et al., JAOCS, 75 (11), 1473-1482 (1998), which discloses the use of
Agrobacterium tumefaciens
ATCC 15955
, Alcaligenes eutrophus
ATCC 17697
, Arthrobacter petroleophagus
ATCC 21494
, Debaryomyces hansenil
ATCC 66354, Mycobacterium sp. ATCC 29676
, Rhodococcus rhodochorous
ATCC 14347
, Hansenula anomala
SC 13833
, H. anomala
ATCC 16142
, H. saturnus
SC 13829, and
Spingomonas paucimobilis
SC 16113 in the stereospecific reduction of &agr;-bromoketones. The fungal reducing agent utilized in reduction Step (a) of the instant invention preferably comprises
Absidia cylindrospora
ATCC 22751 (American Type Culture Collection, Rockville, Md.). The aforementioned reduction step affords the corresponding (R)-bromoalcohol in a highly enantioselective yield, i.e. >90% enantiomeric excess. Preferably, the (R)-bromoalcohol so formed in the stereospecific reduction Step (a) is then isolated, either as a free base, or an acid addition salt thereof.
The (R)-bromoalcohol product formed in the stereospecific reduction Step (a) is then O-protected. Synthetic methods of protecting alcohol functional group
Chambers Robert J.
Dugger Robert W.
Kang Ming
Tao Yong
Wong John W.
Aulakh C. S.
Benson Gregg C.
Musser Arlene K.
Pfizer Inc.
Richardson Peter C.
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