Process for preparing substituted pyridines

Details Process for preparing substituted pyridines Process for preparing substituted pyridines

2001-03-28

2003-02-11

Davis, Zinna Northington (Department: 1625)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C546S283100, C546S339000

Reexamination Certificate

active

06518431

ABSTRACT:

BACKGROUND OF THE INVENTION
The present invention relates to a process for preparing substituted pyridines which are intermediates in the synthesis of &bgr;-adrenergic receptor agonists useful as hypoglycemic and antiobesity agents, increasing lean meat deposition and/or improving the lean meat to fat ratio in edible animals. The &bgr;-adrenergic receptor agonists further possess utility in the treatment of intestinal motility disease disorders, depression, prostate disease, dyslipidemia and airway inflammatory disorders such as asthma and obstructive lung disease.
The disease diabetes mellitus is characterized by metabolic defects in production and/or utilization of carbohydrates which result in the failure to maintain appropriate blood sugar levels. The result of these defects is 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 I diabetes, or insulin-dependent diabetes, is the result of an absolute deficiency of insulin, the hormone which regulates carbohydrate utilization. Type II diabetes, or non-insulin dependent diabetes, 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 of the Type II diabetics are also obese.
The &bgr;-adrenergic receptor agonists effectively lower blood glucose levels when administered orally to mammals with hyperglycemia or diabetes.
The &bgr;-adrenergic receptor agonists also reduce body weight or decrease weight gain when administered to mammals. The ability of &bgr;-adrenergic receptor agonists to affect weight gain is due to activation of &bgr;-adrenergic receptors which stimulate the metabolism of adipose tissue.
&bgr;-Adrenergic receptors have been categorized into &bgr;
1
-, &bgr;
2
- and &bgr;
3
-subtypes. Agonists of &bgr;-receptors promote the activation of adenyl cyclase. Activation of &bgr;
1
-receptors invokes increases in heart rate while activation of &bgr;
2
-receptors induces relaxation of skeletal muscle tissue which produces a drop in blood pressure and the onset of smooth muscle tremors. Activation of &bgr;
3
-receptors is known to stimulate lipolysis (the breakdown of adipose tissue triglycerides to glycerol and free fatty acids) and metabolic rate (energy expenditure), and thereby promote the loss of fat mass. Compounds that stimulate &bgr;-receptors are, therefore, useful as anti-obesity agents, and can also be used to increase the content of lean meat in edible animals. In addition, compounds which are &bgr;
3
-receptor agonists have hypoglycemic and/or anti-diabetic activity, but the mechanism of this effect is unknown.
Until recently &bgr;
3
-adrenergic receptors were thought to be found predominantly in adipose tissue. &bgr;
3
-Receptors are now known to be located in such diverse tissues as the intestine (
J. Clin. Invest.,
91, 344 (1993)) and the brain (
Eur. J. Pharm.,
219,193 (1992)). Stimulation of &bgr;
3
-receptors have been demonstrated to cause relaxation of smooth muscle in colon, trachea and bronchi.
Life Sciences,
44(19), 1411 (1989);
Br. J. Pharm.,
112, 55 (1994);
Br. J. Pharmacol,
110, 1311 (1993). For example, stimulation of &bgr;
3
-receptors has been found to induce relaxation of histamine-contracted guinea pig ileum,
J. Pharm. Exp. Ther.,
260, 1, 192 (1992).
The &bgr;
3
-receptor is also expressed in human prostate. Because stimulation of &bgr;
3
-receptors cause relaxation of smooth muscles that have been shown to express the &bgr;
3
-receptor (e.g. intestine), one skilled in the art would predict relaxation of prostate smooth muscle. Therefore, &bgr;
3
-agonists will be useful for the treatment or prevention of prostate disease.
SUMMARY OF THE INVENTION
The present invention relates to a process for preparing a compound of the formula
wherein n is 0, 1, 2 or 3;
R
1
is hydrogen or halo;
each R
2
is independently hydrogen, halo, trifluoromethyl, cyano, SR
4
, OR
4
, SO
2
R
4
, OCOR
5
, or (C
1
-C
10
)alkyl wherein the alkyl group is optionally substituted by hydroxy, halo, cyano, N(R
4
)
2
, SR
4
, trifluoromethyl, OR
4
, (C
3
-C
8
)cycloalkyl, (C
6
-C
10
)aryl, NR
4
COR
5
, COR
5
, SO
2
R
5
, OCOR
5
, NR
4
SO
2
R
5
or NR
4
CO
2
R
4
;
R
3
is tetrahydrofuranyl, tetrahydropyranyl or a silyl protecting group;
X is halo, methanesulfonyloxy, benzenesulfonyloxy, p-toluenesulfonyloxy, m-nitrobenzenesulfonyloxy or p-nitrobenzenexulfonyloxy;
R
4
and R
5
, for each occurrence, are each independently selected from
hydrogen, (C
1
-C
10
)alkyl, (C
1
-C
10
)alkoxy, (C
3
-C
8
)cycloalkyl,(C
6
-C
10
)aryl, (C
2
-C
9
)heterocycloalkyl, (C
2
-C
9
)heteroaryl or (C
1
-C
6
)aryl wherein the alkyl group is optionally substituted by the group consisting of hydroxy, halo, carboxy, (C
1
-C
10
)alkyl-CO
2
, (C
1
-C
10
)alkylsulfonyl, (C
3
-C
8
)cycloalkyl, (C
1
-C
10
)alkoxy, or (C
1
-C
6
)alkyl; and wherein the aryl, heterocycloalkyl and heteroaryl groups are optionally substituted by one to four groups consisting of halo, nitro, oxo, ((C
1
-C
6
)alkyl)
2
amino, pyrrolidine, piperidine, (C
1
-C
10
)alkyl, (C
1
-C
10
)alkoxy, (C
1
-C
10
)alkylthio and (C
1
-C
10
)alkyl wherein the alkyl group is optionally substituted by one to four groups selected from hydroxy, halo, carboxy, (C
1
-C
6
)alkyl-CO
2
, (C
1
-C
6
)alkylsulfonyl, (C
3
-C
8
)cycloalkyl and (C
1
-C
6
)alkoxy;
or R
5
is N(R
4
)
2
wherein R
4
is as defined above;
comprising reacting a compound of the formula
wherein n, R
1
, R
2
and X are as defined above, with a silyating agent in the presence of a base.
The term “alkyl”, as used herein, as well as the alkyl moieties of other groups referred to herein (e.g., alkoxy), may be linear or branched, and they may also be cyclic (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl) or be linear or branched and contain cyclic moieties. Unless otherwise indicated, halogen includes fluorine, chlorine, bromine, and iodine.
The term “halo”, as used herein, unless otherwise indicated, includes fluoro, chloro, bromo or iodo.
(C
2
-C
9
)Heterocycloalkyl when used herein includes, but is not limited to, pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydropyranyl, pyranyl, thiopyranyl, aziridinyl, oxiranyl, methylenedioxyl, chromenyl, barbituryl, isoxazolidinyl, 1,3-oxazolidin-3-yl, isothiazolidinyl, 1,3-thiazolidin-3-yl, 1,2-pyrazolidin-2-yl, 1,3-pyrazolidin-1-yl, piperidinyl, thiomorpholinyl, 1,2-tetrahydrothiazin-2-yl, 1,3-tetrahydrothiazin-3-yl, tetrahydrothiadiazinyl, morpholinyl, 1,2-tetrahydrodiazin-2-yl, 1,3-tetrahydrodiazin-1-yl, tetrahydroazepinyl, piperazinyl, chromanyl, etc.
(C
2
-C
9
)Heteroaryl when used herein includes, but is not limited to, furyl, thienyl, thiazolyl, pyrazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrrolyl, triazolyl, tetrazolyl, imidazolyl, 1,3,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-oxadiazolyl, 1,3,5-thiadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, 1,2,4-triazinyl, 1,2,3-triazinyl, 1,3,5-triazinyl, pyrazolo[3,4-b]pyridinyl, cinnolinyl, pteridinyl, purinyl, 6,7-dihydro-5H-[1]pyrindinyl, benzo[b]thiophenyl, 5, 6, 7, 8-tetrahydro-quinolin-3-yl, benzoxazolyl, benzothiazolyl, benzisothiazolyl, benzisoxazolyl, benzimidazolyl, thianaphthenyl, isothianaphthenyl, benzofuranyl, isobenzofuranyl, isoindolyl, indolyl, indolizinyl, indazolyl, isoquinolyl, quinolyl, phthalazinyl, quinoxalinyl, quinazolinyl, benzoxazinyl, etc.
The term “silyl protecting group”, when used herein includes, but is not limited to, trimethylsilyl, triethylsilyl, triisopropylsilyl, dimethylisopropylsilyl, diethylisopropylsilyl, dimethylthexylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl, diphenylmethylsilyl, and t-butylmethoxyphenylsilyl.
The present invention further rela

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