Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-04-16
2001-10-23
Ramsuer, Robert W. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C544S159000, C562S431000
Reexamination Certificate
active
06306854
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to certain novel PPAR alpha activating compounds, processes for their preparation, pharmaceutical compositions containing the compounds, and uses of the compounds as therapeutic agents.
Obesity can be described as a state of excessive accumulation of body fat, and is widely considered to be a major public health problem. Treatment of obesity remains a problem.
Certain fibrate compounds are described in WO92/10468. Such compounds are said to be useful in the prophylaxis and treatment of atherosclerosis.
PCT publication WO95/18533 describes methods of identifying activators and antagonists of peroxisome proliferator activated receptor (“PPAR”) and activators of retinoic acid receptor gamma. The disclosure discusses treating obesity.
BRIEF DESCRIPTION OF THE INVENTION
Briefly, in one aspect, the present invention provides compounds of Formula (1) and esters, salts, and physiologically functional derivatives thereof
wherein m is from 0 to 20, R
6
is selected from the group consisting of hydrogen and
and R
8
is selected from the group consisting of
where y is 0, 1, or 2, each alk is independently hydrogen or alkyl group containing 1 to 6 carbon atoms, each R group is independently hydrogen, halogen, cyano, —NO
2
, phenyl, straight or branched alkyl or fluoroalkyl containing 1 to 6 carbon atoms and which can contain hetero atoms such as nitrogen, oxygen, or sulfur and which can contain functional groups such as ketone or ester, cycloalkyl containing 3 to 7 carbon atoms, or two R groups bonded to adjacent carbon atoms can, together with the carbon atoms to which they are bonded, form an aliphatic or aromatic ring or multi ring system, and where each depicted ring has no more than 3 alk groups or R groups that are not hydrogen. Preferably, the compounds of Formula (1) are PPAR alpha activating compounds.
The compounds of Formula (1) are generally PPAR alpha activating compounds, and therefore are useful in the treatment of a PPAR alpha mediated disease, risk factor, or condition, in particular, obesity and dyslipidemia. Therefore, in another aspect of the invention there is provided a method of treating a PPAR alpha mediated disease, risk factor, or condition, in particular obesity and dyslipidemia, comprising administering to an individual in need thereof a therapeutically effective amount of a PPAR alpha activating compound of Formula (1). The invention further provides the use of a PPAR alpha activating compound of Formula (1) for the manufacture of a medicament for the treatment of a PPAR alpha mediated disease, risk factor, or condition, in particular obesity and dyslipidemia.
The invention further provides compounds of Formula (1) for use in therapy, and pharmaceutical compositions comprising a compound of Formula (1).
The invention also provides methods for preparing the compounds and pharmaceutical compositions of the invention.
As used herein, unless otherwise indicated, the term alkyl or words containing the terms such as fluoroalkyl, can be either straight chain or branched chain. For example, a 3-carbon alkyl group can be either n-propyl or i-propyl.
DETAILED DESCRIPTION OF THE INVENTION
Preferably, the compounds of Formula (1) are PPAR alpha activating compounds. More preferable compounds are those that, in addition to being PPAR alpha activating compounds, are selective activators of PPAR alpha. By “PPAR activating compound”, or “PPAR activator”, or the like, is meant those compounds which achieve 50% activation of human PPAR (“hPPAR”) alpha (in the Transfection assay described below) at concentrations of 10
−5
M or less, as exemplified in the working examples. By selective, is meant those compounds which selectively activate PPAR alpha over PPAR gamma such that the ratio
EC
50
PPAR
Gamma
EC
50
PPAR
Alpha
is at least 10, as exemplified in the working examples. Most preferred are those compounds such that this ratio is at least 100.
Preferably, each R
6
and R
8
has no more than 2 R groups and no more than 2 alk groups that are other than hydrogen. Most preferably, all R groups and all alk groups are hydrogen.
Particularly preferred compounds are those where y is 0, m is from 0 to 6, and each alk and each R group is hydrogen.
Examples of suitable compounds of Formula (1) are
2-(4-(2-(1-(4-Biphenylethyl)-3-cyclohexylureido)ethyl)phenylthio)-2-methylpropionic acid
2-(4-(2-(1-(2-(4-Morpholinophenyl)ethyl)-3-cyclohexylureido)ethyl)phenylthio)-2-methylpropionic acid
2-(4-(2-(1-(Cyclohexanebutyl)-3-cyclohexylureido)ethyl)phenylthio)-2-methylpropionic acid
2-(4-(2-(1-Heptyl-3-(2,4-difluorophenyl)ureido)ethyl)phenylthio)-2-methylpropionic acid
2-(4-(2-(1-(2-Chloro4-(2-trifluoromethylphenyl)phenylmethyl)-3-(cyclohexyl)ureido)ethyl)phenylthio)-2-methylpropionic acid
and esters, salts, and physiologically functional derivatives thereof.
Particularly preferred compounds of Formula (1) are
2-(4-(2-(1-(4-Biphenylethyl)-3-cyclohexylureido)ethyl)phenylthio)-2-methylpropionic acid
2-(4-(2-(1-(2-(4-Morpholinophenyl)ethyl)-3-cyclohexylureido)ethyl)phenylthio)-2-methylpropionic acid
2-(4-(2-(1-(Cyclohexanebutyl)-3-cyclohexylureido)ethyl)phenylthio)-2-methylpropionic acid
and esters, salts, and physiologically functional derivatives thereof.
The compounds of this invention can be prepared in a variety of ways. For example, the compounds of Formula (1) can be prepared by reacting the compounds of Formulas (2), (3), and (4),
to give compounds of the invention of Formula (1) wherein R
6
, R
8
, and m are as defined above. Synthetic routes will also be illustrated in the working examples below.
The compounds of the present invention may be utilized in the form of a pharmaceutically acceptable salt or solvate thereof. Preferred salts of compounds of Formula (1) are those that are physiologically acceptable. However, non-physiologically acceptable salts are within the scope of the present invention for use as intermediates in the preparation of the compounds of the invention and their physiologically acceptable salts and physiologically functional derivatives.
The “physiologically functional derivatives” referred to herein are compounds which are converted in vivo to a compound of Formula (1) or one of its physiologically acceptable salts.
Many of the compounds of this invention will contain one or more stereocenters. The present invention includes all possible stereoisomers, tautomers, and geometric isomers of the compounds, including optically enriched compositions as well as the racemic mixtures. When an enantiomerically enriched composition is desired, it may be obtained either by resolution of the final product or by stereospecific synthesis from either isomerically pure starting material or any convenient intermediate. Resolution of the final product, an intermediate, or a starting material may be effected by any suitable method. See, for example, Stereochemistry of Carbon Compounds, by E. L. Eliel (Mcgraw Hill, 1962) and Tables of Resolving Agents, by S. H. Wilen.
Reference to “treatment” includes prophylaxis as well as the treatment of established of established diseases or symptoms. Moreover, it will be appreciated that the amount of a compound of the invention required for use in treatment will vary with the nature of the condition being treated and the age and the condition of the patient and will be ultimately at the discretion of that attendant physician or veterinarian.
PPAR alpha, gamma, and delta are recognized subtypes of PPARs. The PPARs are known to bind to their target genes as heterodimers with RXR. The present invention provides PPAR alpha activating compounds for use in the treatment of obesity, dyslipidemia, and other PPAR alpha mediated diseases, conditions, or risk factors. More particularly, the present invention provides PPAR alpha activators useful in the treatment of Alzheimer's disease, atherosclerosis, obesity, inflammation, cancer, psoriasis, pancreatitis, and various disease risk factors. Most preferably the PPAR alpha activa
Brown Peter Jonathan
Chapman, Jr. James Mood
Oplinger Jeffrey Alan
Stuart Ludwig William
Willson Timothy Mark
Brink Robert H.
GlaxoSmithKline
Ramsuer Robert W.
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