Thyromimetic organic compounds

Details Thyromimetic organic compounds Thyromimetic organic compounds

2001-09-28

2004-09-14

Raymond, Richard L. (Department: 1624)

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

Organic compounds

Carboxylic acid esters

C560S143000, C562S433000, C564S155000, C540S544000, C540S553000, C540S607000, C544S170000, C544S386000, C548S185000, C548S215000, C548S253000

Reexamination Certificate

active

06790978

ABSTRACT:

SUMMARY OF THE INVENTION
The present invention relates to novel compounds of the formula
in which
W is O, S, S(O) or S(O)
2
;
X is —SR4, —S(O)R4, —S(O)
2
R4, or —S(O)
2
NR5R6; or X is —C(O)NR5R6 provided that —C(O)NR5R6 is located at the 3′-, 4′- or 5′-position;
Y is O or H
2
;
Z is hydrogen, halogen, hydroxy, optionally substituted alkoxy, aralkoxy, acyloxy or alkoxycarbonyloxy;
R is hydrogen, halogen, trifluoromethyl, lower alkyl or cycloalkyl;
Q is 5-tetrazolyl; or Q is —C(O)R1 wherein R1 is hydroxy, optionally substituted alkoxy, aryloxy, heteroaryloxy, aralkoxy, cycloalkoxy, heteroaralkoxy or —NR5R6;
R2 is hydrogen, halogen or alkyl;
R3 is halogen or alkyl;
R4 is optionally substituted alkyl, aryl, aralkyl, heteroaralkyl or heteroaryl;
R5, R6 and R7 are independently hydrogen, optionally substituted alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl; or R5 and R6 combined are alkylene optionally interrupted by O, S, S(O), S(O)
2
or NR7 which together with the nitrogen atom to which they are attached form a 5- to 7- membered ring;
n represents zero or an integer from 1 to 4; and pharmaceutically acceptable salts thereof.
The compounds of the invention are thyromimetic agents which can be used to prevent and/or treat diseases associated with an imbalance of thyroid hormones, such as hypo- and hyper-thyroidism, obesity, osteoporosis and depression. The compounds of the invention are, in particular, hypolipedemic agents which enhance the clearance of cholesterol from circulation, particularly the clearance of cholesterol in the form of low density lipoproteins (LDL). They, inter alia, upregulate hepatic LDL receptor function in mammals. Thus, they are useful for reducing total cholesterol plasma levels in mammals, in particular for reducing levels of LDL-cholesterol. Furthermore, such compounds also lower elevated lipoprotein (a) [Lp(a)] levels, an independent cardiovascular risk factor, in mammals. The compounds of the invention can therefore be used for the prevention and/or treatment of occlusive cardiovascular conditions in which hyperlipidemia and hyperlipoproteinemia are implicated, such as atherosclerosis and coronary heart disease in mammals.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides for compounds of formula I, pharmaceutical compositions comprising such compounds and for methods of using such compounds.
Listed below are definitions of various terms used to describe the compounds of the instant invention. These definitions apply to the terms as they are used throughout the specification (unless they are otherwise limited in specific instances either individually or as part of a larger group).
The term “optionally substituted alkyl” refers to unsubstituted or substituted straight or branched chain hydrocarbon groups having 1 to 20 carbon atoms, preferably 1 to 7 carbon atoms. Exemplary unsubstituted alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpenthyl, octyl and the like. Substituted alkyl groups include, but are not limited to, alkyl groups substituted by one or more (e.g. two or three) of the following groups: halo, lower alkenyl, hydroxy, cycloalkyl, alkanoyl, alkoxy, alkyloxyalkoxy, alkanoyloxy, amino, alkylamino, dialkylamino, dialkylaminocarbonyl, alkanoylamino, thiol, alkylthio, alkylthiono, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, sulfonamido, nitro, cyano, carboxy, alkoxycarbonyl, aryl, aralkyl, aralkoxy, guanidino, heterocyclyl including indolyl, imidazolyl, furyl, thienyl, thiazolyl, pyrrolidyl, pyridyl, pyrimidyl, piperidyl, morpholinyl and the like. Preferred substituents of substituted alkyl, especially of substituted alkyl of variable R1 being substituted alkoxy, are lower alkyl, cycloalkyl, lower alkenyl, benzyl, mono or disubstituted lower alkyl, e.g. &ohgr;-(amino, mono- or di-lower alkylamino, carboxy, lower alkoxycarbonyl)-lower alkyl, &agr;-(lower alkanoyloxy, lower alkoxycarbonyl or di-lower alkylaminocarbonyl)-lower alkyl, such as pivaloyloxy-methyl.
The term “lower alkyl” refers to those alkyl groups as described above having 1 to 7, preferably 1 to 4 carbon atoms.
The term “halogen” or “halo” refers to fluorine, chlorine, bromine and iodine.
The term “alkenyl” refers to any of the above alkyl groups having at least 2 carbon atoms and further containing at least one carbon to carbon double bond. Groups having two to four carbon atoms are preferred.
The term “alkylene” refers to a straight chain bridge of 1 to 6 carbon atoms connected by single bonds (e.g., —(CH
2
)
X
— wherein x is 1 to 6), which may be substituted with 1 to 3 lower alkyl groups.
The term “cycloalkyl” refers to cyclic hydrocarbon groups of 3 to 8 carbon atoms.
The term “alkoxy” refers to alkyl-O—.
The term “acyl” refers to alkanoyl, aroyl, heteroaroyl, arylalkanoyl or heteroarylalkanoyl.
The term “alkanoyl” refers to alkyl-C(O)—.
The term “alkanoyloxy” refers to alkyl-C(O)—O—.
The terms “alkylamino” and “dialkylamino” refer to (alkyl)NH—and (alkyl)
2
N—, respectively.
The term “alkanoylamino” refers to alkyl-C(O)—NH—.
The term “alkylthio” refers to alkyl-S—.
The term “alkylthiono” refers to alkyl-S(O)—.
The term “alkylsulfonyl” refers to alkyl-S(O)
2
—.
The term “alkoxycarbonyl” refers to alkyl-O—C(O)—.
The term “alkoxycarbonyloxy” refers to alkyl-O—C(O)O—.
The term “alkyl” as referred to in the above definitions relates to optionally substituted alkyl as defined above.
The term “aryl” refers to monocyclic or bicyclic aromatic hydrocarbon groups having 6 to 12 carbon atoms in the ring portion, such as phenyl, naphthyl, tetrahydronaphthyl, and biphenyl groups, each of which may optionally be substituted by one to four substituents such as alkyl, halo, hydroxy, alkoxy, alkanoyl, alkanoyloxy, amino, alkylamino, dialkylamino, alkanoyl-amino, thiol, alkylthio, nitro, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, alkyl-thiono, alkyl-sulfonyl, sulfonamido, heterocyclyl and the like.
The term “monocyclic aryl” refers to optionally substituted phenyl as described under aryl.
The term “aralkyl” refers to an aryl group bonded directly through an alkyl group, such as benzyl.
The term “aralkoxy” refers to an aryl group bonded through an alkoxy group.
The term “arylsulfonyl” refers to aryl-S(O)
2
—.
The term “aroyl” refers to aryl-C(O)—.
The term “heterocyclyl” refers to an optionally substituted, fully saturated or unsaturated, aromatic or nonaromatic cyclic group, for example, which is a 4 to 7 membered monocyclic, 7 to 11 membered bicyclic, or 10 to 15 membered tricyclic ring system, which has at least one heteroatom in at least one carbon atom-containing ring. Each ring of the heterocyclic group containing a heteroatom may have 1, 2, 3 or 4 heteroatoms selected from nitrogen atoms, oxygen atoms and sulfur atoms, where the nitrogen and sulfur heteroatoms may also optionally be oxidized. The heterocyclic group may be attached at a heteroatom or carbon atom.
Exemplary monocyclic heterocyclic groups include pyrrolidinyl, pyrrolyl, pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl, tetrazolyl, imidazolinyl, imidazolidinyl, oxazolyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolyl, thiadiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, furyl, tetrahydrofuryl, thienyl, oxadiazolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, 4-piperidonyl, pyridyl, 2-pyridone, N-lower alkyl-pyridone, e.g. N-lower alkyl-2-pyridone, pyrazinyl, pyrimidinyl, pyridazinyl, tetrahydropyranyl, morpholinyl, thiamorpholinyl, S-oxo-thiamorpholinyl S,S-dioxo-thiamorpholinyl, 1,3-dioxolane and tetrahydro-1,1-dioxothienyl, and the like.
Exemplary bicyclic heterocyclic groups include indolyl, benzothiazolyl, benzoxazolyl, benzothienyl, quinuclidinyl, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuryl, chromonyl, coumarinyl, benzopyranyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl, furopyridinyl (such as furo[2,3-c]pyridinyl, furo&ls

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