Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-12-07
2004-03-02
Berch, Mark L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S309000, C514S337000, C514S395000, C514S456000, C514S411000, C514S414000, C514S443000, C514S365000, C514S374000, C514S320000, C514S382000, C514S406000, C546S141000, C546S282700, C546S283100, C546S196000, C548S305100, C548S427000, C548S454000, C548S201000, C548S236000, C548S252000, C548S364400, C544S151000, C549S405000, C549S407000, C549S051000, C549S055000
Reexamination Certificate
active
06699860
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to novel chroman 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 levels in mammals (U.S. Pat. No. 5,451,677). Accordingly, they are useful in the treatment of conditions such as hypertriglyceridaemia, hypercholesterolaemia and in lowering high-density lipoprotein levels as well as in the treatment of atherosclerotic and cardiovascular diseases and related conditions. In addition, beta-3 adrenoreceptor agonists may also be useful in treating patients with impaired fasting glucose, impaired glucose tolerance, and type 2 diabetes.
Additionally, it is also believed that the compounds of this invention are effective in the treatment of ocular hypertension and glaucoma, and in the treatment of urological disorders including benign prostatic hyperplasia 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 chroman derivatives are effective as beta-3 agonists and are useful in the treatment of beta-3 mediated conditions.
DESCRIPTION OF THE INVENTION
This invention relates to chroman compounds of Formula I wherein,
R is hydroxy, oxo, halo, cyano, nitro, C
1
-C
10
alkyl optionally substituted with phenyl, 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 heterocycle with 1 to 4 heteroatoms selected independently from O, S, and N, each cyclic moiety being optionally substituted with 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, or C
1
-C
10
alkoxy;
R
1
is hydrogen, (CH
2
)
d
—O—(CH
2
)
d
R
5
, where each d is selected independently, or C
1
-C
10
alkyl optionally substituted with 1 to 4 substituents each independently selected from hydroxy, halo, CO
2
C
1
-C
4
alkyl, CO
2
H, S(O)
b
C
1
-C
10
alkyl, C
1
-C
10
alkoxy, and phenyl optionally substituted with CO
2
C
1
-C
4
alkyl or CO
2
H, or C
3
-C
8
cycloalkyl, phenyl, or naphthyl, each optionally substituted with 1 to 4 substituents each independently selected from halo, nitro, oxo, C
1
-C
10
alkyl, C
1
-C
10
alkoxy, and C
1
-C
10
alkylthio; and
when two R
1
groups are attached to N as NR
1
R
1
, these R
1
groups may form together with the nitrogen to which they are attached, a heterocyclic ring containing 4 to 7 C atoms, 1 to 2 N atoms, and 0 to 1 O or S atoms;
R
2
is R
1
; OR
1
; NR
1
R
1
; NHS(O)
b
phenyl optionally substituted with C
1
-C
4
alkyl, C
1
-C
4
alkoxy, halo, or nitro; NHS(O)
b
naphthyl; NHS(O)
b
C
1
-C
10
alkyl; or a 5- or 6-membered heterocycle with one or more heteroatoms selected independently from O, S, and N, said heterocyclic moiety being optionally substituted with R
1
;
R
3
is hydrogen, C
1
-C
10
alkyl, benzyl, or COR
2
;
R
4
is hydrogen, C
1
-C
10
alkyl, C
1
-C
10
alkyl-phenyl, C
1
-C
10
alkyl-pyridine;
R
5
is hydrogen or COOH;
Ar is phenyl optionally fused to a cyclohexyl, phenyl, or a 5- or 6-membered heterocycle containing one or more heteroatoms each independently selected from O, S, and N, said bicyclic moiety being optionally fused to phenyl, or a 5- or 6-membered heterocycle containing one or more heteroatoms each independently selected from N, S, and O, optionally fused to phenyl;
X is O or S(O)
b
;
Y is halo, R
1
, OR
1
SR
1
, CO
2
R
1
, NR
1
R
1
, S(O)
b
-phenyl-CO
2
R
1
, or phenyl optionally fused to another phenyl ring or to a 5- or 6-membered heterocycle containing one or more heteroatoms each independently selected from N, S, and O, or a 5- or 6-membered heterocycle containing one or more heteroatoms each independently 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; OR
1
; NR
1
R
1
; R
1
; C
1
-C
10
COR
2
; phenyl optionally substituted with halo, C
1
-C
4
alkyl, or C
1
C
4
alkoxy; tetrazolo; or
where, when the two R
4
groups attached to the same C are both alkyl, they optionally may be joined so that, when taken together with the C to which they are attached, they form a spiro ring of 3, 5, or 6 C atoms, or where the R
4
attached to N and one R
4
attached to the adjacent C are both alkyl, they optionally may be joined so that, taken together with the atoms to which they are attached, they form a 5- or 6-membered heterocycle;
a is 0, 1, 2, 3, 4, or 5;
b is 0, 1, or 2;
d is 1, 2, or 3;
e 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, and includes such groups as trifluoromethyl, trichloromethyl, pentafluoroethyl, fluoromethyl, 6-chlorohexyl, and the like.
The term C
1
-C
10
alkoxy means straight or branched chain alkoxy groups having from one to about ten carbon atoms where any C—C bond may be saturated or unsaturated, and includes such groups as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, and the like.
The term C
1
-C
10
alkylthio means straight or branched chain alkylthio groups having from one to about ten carbon atoms where any C—C bond may be saturated or unsaturated, and includes such groups as 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, and includes such groups as cyclopropyl, cyclopentyl, cyclohexyl, and the like.
Halo includes fluoro, chloro, bromo, and iodo, unless specifically stated otherwise.
R
2
, Ar and Y each 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 shall be chosen independently of any other heteroatom, in each occurrence. These moieties include such 5-membered heterocylic groups as furyl, thienyl,
Bullock William H.
Campbell Ann-Marie
Ehrlich Paul P.
Ladouceur Gaetan H.
Liu Qingjie
Bayer Pharmaceuticals Corporation
Berch Mark L.
Habte Kahsay
Pellegrino Susan M.
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