Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acid esters
Reexamination Certificate
2003-02-04
2004-07-06
Killos, Paul J. (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acid esters
C514S532000
Reexamination Certificate
active
06759546
ABSTRACT:
BACKGROUND OF THE INVENTION
FIELD OF INVENTION
The present invention relates to compounds that have the property of reducing serum glucose and serum triglyceride levels in diabetic mammals without the undesirable property of reducing serum thyroxine levels. More particularly, the present invention relates to 3,5-di-iso-propyl-heptatrienoic acid derivatives having the above-noted biological property.
Compounds that have retinoid-like activity are well known in the art, and are described in numerous United States and other patents and in scientific publications. It is generally known and accepted in the art that retinoid-like activity is useful for treating animals of the mammalian species, including humans, for curing or alleviating the symptoms and conditions of numerous diseases and conditions. It is now general knowledge in the art that two main types of retinoid receptors exist in mammals (and other organisms). The two main types or families of receptors are respectively designated the RARs and RXRs. Within each type there are subtypes; in the RAR family the subtypes are designated RAR
&agr;
, RAR
&bgr;
and RAR
&ggr;
, in RXR the subtypes are: RXR
&agr;
, RXR
&bgr;
and RXR
&ggr;
. It has also been established in the art that the distribution of the two main retinoid receptor types, and of the several sub-types is not uniform in the various tissues and organs of mammalian organisms. Moreover, it is generally accepted in the art that many unwanted side effects of retinoids are mediated by one or more of the RAR receptor subtypes. Accordingly, among compounds having agonist-like activity at retinoid receptors, specificity or selectivity for one of the main types or families, and even specificity or selectivity for one or more subtypes within a family of receptors, is considered a desirable pharmacological property.
For a general overview of the retinoid receptors see Mangelsdorf et al. (1994) The Retinoid Receptors In: The Retinoids, edited by Sporn et al. p 319-349. Raven Press, Ltd., New York. For another general overview see Dawson and William H. Okamura, Chemistry and Biology of Synthetic Retinoids, published by CRC Press Inc., 1990, pages 324-356. The following further patents are of interest as background to the present invention: U.S. Pat. Nos. 5,721,103; 5,801,253; 6,326,397; PCT Publications WO 97/12853 and WO 01/19770.
Relatively recently it has become known that certain retinoid compounds are capable of reducing serum glucose levels in diabetic mammals. Mukheijee, R.; Davies, P. J.; Crombie, D. L. Bishoff, E. D.; Cesario, R. M.; Jow Hamann, L. G.; Boehm, M. F.; Mondon, C. E.; Nadzan, A. M.; Paterniti, J. R. Jr.; Heyman, R. A. Sensitization of Diabetic and Obese Mice to Insulin by Retinoid X Receptor Agonists.
Nature
1997, 386 (6623), 407-410. The compound (2E, 4E, 1′S, 2′S)-3-methyl-5-[2′-methyl-2′-(5, 5,8,8-tetramethyl-5,6, 7,8-tetrahydro-naphthalen-2-yl)-cyclopropyl]-penta-2,4-dienoic acid, described in U.S. Pat. No. 6,114,533 has this property. A disadvantage of the prior art retinoid compounds that reduce serum glucose levels is that their administration usually also results in the pharmacologically undesirable reduction of seruim thyroxine levels and in a transient increase in serum triglyceride levels. The present invention is directed to novel compounds that do not have these undesirable side effects.
SUMMARY OF THE INVENTION
The present invention relates to compounds of Formula 1
where R
1
is alkyl of 1 to 3 carbons;
R
2
is independently H or F;
R
3
is propyl or iso-propyl, and
R
4
is is H, alkyl of 1 to 6 carbons, CH
2
OR
5
or CH
2
OCOR
5
where R
5
is alkyl of 1 to 3 carbons, or a pharmaceutically acceptable salt of said compound.
The present invention also relates to pharmaceutical compositions incorporating the compounds of Formula 1 and to methods of treatment of diabetic mammals with pharmaceutical compositions containing one or more compounds of Formula 1 to reduce serum glucose levels in said mammals. The present invention also relates to the methods of using the compounds of the invention to treat diseases and conditions that are responsive to treatment by retinoids.
DETAILED DESCRIPTION OF THE INVENTION
GENERAL EMBODIMENTS AND SYNTHETIC METHODOLOGY
Definitions
The term alkyl refers to and covers any and all groups which are known as normal alkyl and branched-chain alkyl.
A pharmaceutically acceptable salt may be prepared for any compound in this invention having a functionality capable of forming a salt, for example an acid functionality. A pharmaceutically acceptable salt is any salt which retains the activity of the parent compound and does not impart any deleterious or untoward effect on the subject to which it is administered and in the context in which it is administered.
Pharmaceutically acceptable salts may be derived from organic or inorganic bases. The salt may be a mono or polyvalent ion. Of particular interest are the inorganic ions, sodium, potassium, calcium, and magnesium. Organic salts may be made with amines, particularly ammonium salts such as mono-, di- and trialkyl amines or ethanol amines. Salts may also be formed with caffeine, tromethamine and similar molecules.
The compounds of the present invention include olephinic double bonds about which trans and cis (E and Z) stereoisomerism can exist. The compounds of the present invention have the specific orientations of substituents relative to the double bonds as is indicated in the name of the respective compound, and/or by specific showing in the structural formula of the orientation of the substituents relative to the respective double bonds.
Some of the compounds of the present invention may contain one or more chiral centers and therefore may exist in enantiomeric and diastereomeric forms. The scope of the present invention is intended to cover the trans and cis (E and Z) isomers as specifically shown and/or named, as well as pure enantiomers (optical isomers), diastereomers, mixtures of diastereomers and racemic mixtures of enantiomers.
Reaction Scheme 1 discloses a presently preferred synthetic route to compounds of the invention. Although this synthetic route is general, the cis and/or trans isomerism of the compounds of the invention is indicated properly in the formulas.
Referring now to Reaction Scheme 1, the starting material is 2,4-diisopropyl-phenol (Intermediate 1 that can be obtained from 3,5-diisopropylsalicylic acid, as is shown in Reaction Scheme 3 below) is brominated in acetic acid as a solvent to yield 2-bromo4,6-diisopropyl-phenol (Intermediate 2).
Bromo-4,6-diisopropyl-phenol is then reacted with a reagent of the formula R
3
X
1
in the presence of base, to give 1-bromo-3,5-diisopropyl-2-alkyloxy-benzene (Formula 2). The variable R
3
is defined as in connection with Formula 1 and X
1
is a leaving group. In the synthesis of the presently preferred compounds of the invention R
3
X
1
is propyl iodide. The compound of Formula 2 is then reacted with tri-iso-propylborate in the presence of strong base, such as butyl lithium, at cold temperature to provide 2-alkoxy-3,5-diisopropyl-phenylboronic acid (Formula 3). The boronic acid derivative (Formula 3) is reacted with a 3-iodo-pent-en-1-ol derivative (Reagent 4) in the presence tetrakis(triphenylphosphine)palladium (0) catalyst and base (such as sodium carbonate) to provide a 3-(3,5-diisopropyl-2-alkoxy-phenyl)-pent-2-en-1-ol derivative (Formula 5). The variables R
1
and R
2
of Reagent 4 are defined as in connection with Formula 1. 3-Iodo-pent-2-en-1-ol (available from
Synthesis
, 1995, 47-55.) serves as an example and is utilized in the synthesis of a preferred compound of the invention. Other reagents within the scope of the formula of Reagent 4 are either available commercially, or from the chemical literature, or can be synthesized by one of ordinary skill in the art by apparent modifications of known literature procedures.
The 3-(3,5-diisopropyl-2-alkoxy-phenyl)-pent-2-en-1-ol derivative (Formula 5) is subjected to oxidation with N-methylmorpholine-N-oxide (N
Beard Richard L.
Chandratratna Roshantha A.
Vasudevan Jayasree
Yuan Haiqing
Allergan Inc.
Baran Robert J.
Killos Paul J.
Szekeres Gabor L.
Voet Martin A.
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