Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-09-10
2004-08-24
Solola, T. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S252130, C514S337000, C514S365000, C544S153000, C544S376000, C546S196000, C548S202000, C548S215000, C548S311400, C549S467000
Reexamination Certificate
active
06780859
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to novel benzofuran and dihydrobenzofuran compounds, pharmaceutical compositions containing such compounds, and methods of treating beta-3 adrenoreceptor-mediated conditions with such compositions.
BACKGROUND OF THE INVENTION
Adrenoreceptors, or adrenergic receptors, are sites on effector organs that are innervated by postganglionic adrenergic fibers of the sympathetic nervous system, and are classified as either alpha-adrenergic or beta-adrenergic receptors. Alpha-adrenergic receptors respond to norepinephrine and to such blocking agents as phenoxybenzamine and phentolamine, whereas beta-adrenergic receptors respond to epinephrine and to such blocking agents as propranolol.
Beta-adrenergic receptors are sub-classified as beta-1, beta-2, and beta-3 adrenoreceptors. Generally, beta-1 stimulation causes cardiostimulation, whereas beta-2 stimulation causes bronchodilation and vasodilation.
Beta-3 receptors are found on the cell surface of both white and brown adipocytes where their stimulation promotes both lipolysis and energy expenditure. Agonists of beta-3 adrenoreceptors are known to be useful in the treatment of hyperglycemia (diabetes) and obesity in mammals, as well as in the treatment of gastrointestinal disorders and neurogenetic inflammation (U.S. Pat. No. 5,561,142). Additionally, they are known to lower triglyceride and cholesterol levels and to raise high-density lipoprotein (HDL) levels in mammals (U.S. Pat. No. 5,451,677). Accordingly, they are useful in the treatment of conditions such as hypertriglyceridemia, hypercholesterolemia and low HDL levels as well as in the treatment of atherosclerotic and cardiovascular diseases and related conditions. Agonists of beta-3 adrenoreceptors are also useful in treating patients with Syndrome X, impaired fasting glucose, and/or impaired glucose tolerance.
Additionally, the compounds of this invention are effective in the treatment of ocular hypertension and glaucoma, and in the treatment of urinary disorders including pollakiuria and incontinence, as well as in the treatment of prostate disease and as topical anti-inflammatory agents.
It has now been found that certain novel benzofuran and dihydrobenzofuran derivatives are effective as beta-3 adrenoreceptor agonists and are useful in the treatment of beta-3 adrenoreceptor-mediated conditions.
DESCRIPTION OF THE INVENTION
The invention specifically relates to benzofuran compounds of Formula I:
wherein:
---
represents a single or double bond;
R is hydroxy, oxo, halo, cyano, nitro, C
1
-C
10
alkyl, C
1
-C
10
haloalkyl, CF
3
, NR
1
R
1
, SR
1
, OR
1
, SO
2
R
2
, OCOR
2
, NR
1
COR
2
, COR
2
, NR
1
SO
2
R
2
, phenyl, or a 5- or 6-membered heterocyclic ring with from 1 to 4 heteroatoms selected from O, S, and N,
each cyclic moiety being optionally substituted with one or more substituents independently selected from hydroxy, R
1
, halo, cyano, NR
1
R
1
, SR
1
, CF
3
, OR
1
, C
3
-C
8
cycloalkyl, NR
1
COR
2
, COR
2
, SO
2
R
2
, OCOR
2
, NR
1
SO
2
R
2
, C
1
-C
10
alkyl, and C
1
-C
10
alkoxy;
R
1
is hydrogen or C
1
-C
10
alkyl optionally substituted with 1 to 4 substituents each independently selected from hydroxy, halo, CO
2
H, CO
2
(C
1
-C
10
alkyl), C
1
-C
10
alkoxy, and phenyl optionally substituted with CO
2
H, CO
2
(C
1
-C
10
alkyl) or C
1
-C
10
alkyl; or
C
3
-C
8
cycloalkyl, phenyl or naphthyl, each optionally substituted with 1 to 4 substituents, and each independently selected from halo, nitro, oxo, C
1
-C
10
alkyl, C
1
-C
10
alkoxy, and C
1
-C
10
alkylthio;
R
2
is R
1
, OR
1
, NR
1
R
1
or a 5- or 6-membered heterocyclic ring with one or more heteroatoms selected from O, S, and N, said heterocyclic ring being optionally substituted with R
1
;
Ar is phenyl optionally fused to a 5- or 6-membered heterocyclic ring containing 1 to 4 heteroatoms each independently selected from O, S, and N, wherein the heterocyclic ring in turn is optionally fused to another phenyl ring; or a 5- or 6-membered heterocyclic ring containing 1 to 4 heteroatoms each independently selected from N, S, and O, optionally fused to a phenyl ring;
Y is C
1
-C
10
alkyl optionally substituted with 1 to 4 substituents each independently selected from hydroxy, halo, CO
2
H, CO
2
(C
1
-C
10
alkyl), C
1
-C
10
alkoxy, C
1
-C
10
alkylthio, and phenyl optionally substituted with CO
2
H, CO
2
(C
1
-C
10
alkyl), or C
1
-C
10
alkyl; or
phenyl optionally fused to another phenyl ring or to a 5- or 6-membered heterocyclic ring containing 1 to 4 heteroatoms selected from N, S, and O; or
a 5- or 6-membered heterocyclic ring containing one or more heteroatoms selected from N, S, and O, optionally fused to a phenyl ring;
each cyclic moiety being optionally substituted with one or more substituents independently selected from COR
2
, halo, NO
2
, OR
1
, R
1
, SR
1
, NR
1
R
1
, (C
1
-C
10
alkyl) OR
2
, phenyl or tetrazolo;
a is 0, 1, 2, 3, 4, or 5; and
d is 1 or 2;
and pharmaceutically acceptable salts and esters thereof.
The terms identified above have the following meaning throughout:
C
1
-C
10
alkyl means straight or branched chain alkyl groups having from one to about ten carbon atoms, which may be saturated, unsaturated, or partially saturated. Such groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, as well as vinyl, allyl, propynyl, butenyl, butadienyl, isopropenyl, methyleneyl, ethylenyl, propenyl, ethynyl, and the like.
C
1
-C
10
haloalkyl means straight or branched chain alkyl groups having from one to about ten carbon atoms where any C—C bond may be saturated or unsaturated, the alkyl groups being substituted at any available carbon atom with one or more halogen atoms. Such groups include trifluoromethyl, trichloromethyl, pentafluoroethyl, fluoromethyl, fluoroethylenyl, 6-chlorohexyl, and the like.
The term C
1
-C
10
alkoxy means C
1
-C
10
alkyl radicals as defined above bonded through an oxygen (—O—) linkage. Such groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, and the like.
The term C
1
-C
10
alkylthio means C
1
-C
10
alkyl radicals as defined above bonded through a sulfur (—S—) linkage. Such groups include methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, sec-butylthio, tert-butylthio, and the like.
C
3
-C
8
cycloalkyl means saturated mono cyclic alkyl groups of from 3 to about 8 carbon atoms. Such groups include cyclopropyl, cyclopentyl, cyclohexyl, and the like.
Halo includes fluoro, chloro, bromo, and iodo, unless specifically stated otherwise.
Each of R
2
, Ar, and Y includes any 5- or 6-membered saturated or unsaturated heterocyclic group having any combination of one or more N, S, or O atoms, with the point of attachment being at any available position on the heterocyclic ring. Where there is more than one heteroatom in a single cyclic group, each heteroatom may be chosen independently of any other heteroatom, in each occurrence. These moieties include, but are not limited to, such 5-membered heterocylic groups as furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, tetrahydrofuryl, dihydrofuryl, pyrrolidinyl, pyrrolinyl, dihydrothienyl, tetrahydrothienyl, dioxolyl, oxazolinyl, oxazolidinyl, isoxazolinyl, isoxazolidinyl, thiazolinyl, thiazolidinyl, isothiazolinyl, isothiazolidinyl, imidazolinyl, imidazolidinyl, pyrazolinyl, pyrazolidinyl, triazolyl, triazolinyl, triazolidinyl, oxadiazolyl, thiadiazolyl, furazanyl, tetrazolyl, and the like. Such moieties also include, but are not limited to, such 6-membered heterocyclic rings such as pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyranyl, dihydropyranyl, thiopyranyl, triazinyl, dioxanyl, piperidinyl, piperazinyl, pyrazinyl, morpholinyl, and the like.
Each of Ar and Y also includes phenyl fused to any 5- or 6-membered heterocyclic ring described above to form a bicyclic moiety, which may be saturated or unsaturated and may have any combination of one or more N, S, or O atoms, with the point of attachment being any at availa
Burke Michael J.
Ladouceur Gaetan H.
Schoen William R.
Bayer Pharmaceuticals Corporation
Pellegrino Susan M.
Solola T.
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