Carboxyl substituted chroman derivatives useful as beta 3...

Details Carboxyl substituted chroman derivatives useful as beta 3... Carboxyl substituted chroman derivatives useful as beta 3...

2002-08-21

2004-09-28

Robinson, Binta M. (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S272000, C514S274000, C514S275000, C544S297000, C544S322000, C544S326000, C544S329000

Reexamination Certificate

active

06797714

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to novel chroman compounds, intermediates useful for their preparation, pharmaceutical compositions containing such compounds, and methods of selectively 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 alpha-adrenergic and 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 subclassified as beta-1, beta-2 and beta-3 adrenoreceptors. 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 selective for 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 hyper-triglyceridaemia, hypercholesterolaemia and in lowering high density lipoprotein levels as well as in the treatment of atherosclerotic and cardiovascular diseases and related conditions.
Treatment of such chronic diseases with agonists that are selective for beta-3 adrenoreceptors decreases the potential for undesirable side effects caused by beta-1 or beta-2 receptor stimulation such as increased heart rate (beta-1) and muscle tremor (beta-2). It has now been found that certain novel chroman derivatives are effective as selective beta-3 agonists and are useful in the treatment of beta-3 mediated conditions.
DESCRIPTION OF THE INVENTION
This invention specifically relates to chroman compounds of formula I:
wherein:
R is hydrogen, hydroxy, oxo, halogen, C
1
-C
10
haloalkyl, C
1
-C
10
alkyl, cyano, nitro, 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
, NR
1
CO
2
R
1
, C
1
-C
10
alkyl, phenyl, pyrrole or a 5- or 6-membered heterocyclic ring with from 1 to 4 heteroatoms selected from O, S, and N, each moiety being optionally substituted with hydroxy, halogen, cyano, NR
1
R
1
, SR
1
, trifluoromethyl, OR
1
, C
3
-C
8
cycloaklyl, phenyl, NR
1
COR
2
, COR
2
, SO
2
R
2
, OCOR
2
, NR
1
SO
2
R
2
, NR
1
CO
2
R
1
, C
1
-C
10
alkyl, C
1
-C
10
alkoxy, and OR, and each ring moiety being optionally fused to a 5-membered heterocyclic ring containing from 1 to 4 hetero atoms selected from O, S, and N, the fused heterocyclic ring being optionally fused to a phenyl ring or optionally substituted with oxo;
R
1
is hydrogen, C
1
-C
10
alkyl optionally substituted with 1 to 4 substituents selected from hydroxy, halogen, CO
2
H, CO
2
C
1
-C
10
alkyl, SO
2
C
1
-C
10
alkyl, C
1
-C
10
alkoxy; or C
3
-C
8
cycloalkyl, phenyl or naphthyl each optionally substituted with 1 to 4 substituents selected from halogen, nitro, oxo, C
1
-C
10
alkyl, C
1
-C
10
alkoxy, C
1
-C
10
alkylthio;
R
2
is R
1
or NR
1
R
1
;
Ar
1
is phenyl, or a 5- or 6-membered heterocyclic ring with from 1 to 4 heteroatoms selected from O, S, and N, each moiety being optionally fused to a 5-membered heterocyclic ring containing from 1 to 4 heteroatoms selected from O, S, and N, the fused heterocyclic ring being optionally fused to a phenyl ring or substituted with oxo;
m is 1, 2, or 3;
n is independently in each instance 0, 1, or 2;
X is C
1
-C
4
alkyl optionally substituted with halogen;
R
4
is hydroxy, C
1
-C
10
alkoxy, O—R
1
or NR
1
R
1
, and pharmaceutically acceptable salts and esters thereof.
The terms identified above have the following meaning throughout:
C
1
-C
4
alkyl and C
1
-C
10
alkyl each means straight or branched chain alkyl groups having from one to about four or from one to about ten carbon atoms respectively, 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, propyenyl, ethynyl, and the like.
C
1
-C
10
haloalkyl means straight or branched chain alkyl groups having from about one to about ten carbon atoms, the alkyl groups being substituted 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 and at least one oxygen atom 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.
C
3
-C
8
cycloalkyl means saturated monocyclic alkyl groups of from 3 to about 8 carbon atoms, and includes such groups as cyclopropyl, cyclopentyl, cyclohexyl, and the like.
C
1
-C
10
alklthio means straight or branched chain thioalkyl groups having from one to about ten atoms selected from C and S and containing at least one or more S atoms, and includes such groups as thiomethyl, thioethyl, 2-thiopropyl, 2,4-dithiohexyl, 8-methyl-2,4-dithiaethane, and the like.
Halogen includes fluorine, chlorine, bromine and iodine.
Ar
1
includes phenyl and such heterocyclic groups as pyridyl, quinolinyl, pyrimidinyl, pyrrolyl, thienyl, furanyl, imidazolyl, thiazolyl, benzimidazolyl, thiadiazolyl, benzothiadiazolyl, indolyl, indolinyl, benzodioxolyl, benzodioxanyl, benzothiophenyl, benzoxazinyl, benzisoxazolyl, benzothiazolyl, tetrahydronaphthyl, dihydrobenzofurnayl, tetrahydroquinolinly, fluropyridine, thienopyridine, 2-tetrazolo-[1,5a]pyridin-6-yl, benzofuranyl, carbazolyl, dibenzothiofuranyl, 2-tetrazolo-[1,5a]pyridin-6-yl, and the like.
C
1
-C
10
heteroalkyl means straight or branched chain saturated or unsaturated heteroalkyl groups having from one to about ten atoms selected from C, N, O, and S and containing at least one hetero atom, and includes such groups as ethers, amines, sulfides and the like.
When any moiety is described as being substituted, it can have one or more of the indicated substituents that can be located at any available position on the moiety. When there are two or more substituents on any moiety, each term shall be defined independently of any other in each occurrence. For example, NR
1
R
1
may represent NH
2
, NHCH
3
, N(CH
3
)CH
2
CH
2
CH
3
, and the like.
The —(X)
n
—(CO)
n
R
4
side chain may be attached to the chroman moiety at any available position on the phenyl portion of the chroman moiety.
Illustrative examples of the compounds of this invention include the following compounds of Formula I:
2-{[2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-methyl}-chroman-6-carboxylic acid ethyl ester,
{2-[(2-Hydroxy-2-pyridin-3-yl-ethylamino)-methyl]-chroman-6-yl}-acetic acid,
3-{2-[(2-Hydroxy-2-pyridin-3-yl-ethylamino)-methyl]-chroman-6-yl}-propionic acid ethyl ester,
3-{2-[(2-Hydroxy-2-pyridin-3-yl-ethylamino)-methyl]-chroman-6-yl}-propionic acid,
2-{[2-(6-Amino-pyridin-3-yl)-2-hydroxy-ethylamino]-methyl}-chroman-6-carboxylic acid ethyl ester,
2-{[2-(6-Amino-pyridin-3-yl)-2-hydroxy-ethylamino]-methyl}-chroman-6-carboxylic acid,
(2-{[2-(6-Amino-pyridin-3-yl)-2-hydroxy-ethylamino]-methyl}-chroman-6-yl)-acetic acid ethyl ester,
(2-{[2-(6-Amino-pyridin-3-yl)-2-hydroxy-ethylamino]-methyl}-chroman-6-yl)-acetic acid,
3-(2

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