Organic compounds -- part of the class 532-570 series – Organic compounds – Four or more ring nitrogens in the bicyclo ring system
Reexamination Certificate
2002-05-03
2003-08-19
Raymond, Richard L. (Department: 1624)
Organic compounds -- part of the class 532-570 series
Organic compounds
Four or more ring nitrogens in the bicyclo ring system
C544S162000, C544S171000, C544S365000, C544S399000, C546S208000, C546S226000, C546S242000, C546S246000, C548S569000, C560S017000, C560S168000, C562S440000, C564S162000, C564S163000, C564S194000
Reexamination Certificate
active
06608196
ABSTRACT:
TECHNICAL FIELD
This invention primarily relates to a method for synthesis of structurally diverse pyruvate-derived compounds using a parallel approach on a solid phase support.
BACKGROUND ART
Pyruvate is a three-carbon (triose) ketoacid that is produced in biological systems in the end stages of glycolysis, a product of sugar metabolism. It is also a breakdown product of certain amino acids (alanine, glycine, cysteine, serine). Pyruvate can be reduced to lactate in the cytoplasm, a fermentative event in mammalian cells, or oxidatively decarboxylated to acetyl CoA in the mitochondrion.
Pyruvate itself, as well as certain pyruvate derivatives, have been promoted for use in treating disorders and promoting health. For example, pyruvate is sold as a dietary supplement for use in promoting weight loss and enhancing energy. It has also been suggested as a therapeutic intervention for clinical management of myocardial insufficiency (Mallet, R. T. (2000) “Pyruvate: metabolic protector of cardiac performance,”
Proc. Soc. Exp. Biol. Med
. 223(2):136-148) and the prevention of the adverse effects of myocardial ischemia. U.S. Pat. No. 5,294,641 discloses the use of pyruvate for treating a patient prior to or during heart trauma. U.S. Pat. No. 5,075,210 describes the use of pyruvate or pyruvate salts as a component in a cardioplegic solution and in preservation solutions for the heart before transplantation. U.S. Pat. No. 5,395,822 describes the use of certain pyruvate salts to protect against neuronal degeneration as a consequence of ischemia.
U.S. Pat. No. 6,086,789 describes certain pyruvate derivatives as useful for dermatologic indications as well as in treating diabetic ketosis, myocardial ischemia, injured organs and in lowering cholesterol and preventing acute hepatic effects of ethanol. Related U.S. Pat. No. 5,968,727 describes the use of pyruvate thiolesters, such as cysteine, methionine and homocysteine, and glycerol pyruvate esters and dihydroxyacetone-pyruvate esters, in organ preservation solutions and for ischemia.
Similarly, pyruvate and pyruvyl amino acid conjugates have been suggested for use in diabetes (e.g., U.S. Pat. Nos. 5,047,427 and 5,256,697).
Heretofore, pyruvate derivatives and analogs have been synthesized using standard solution chemical methods. While such methods may be effective for a specific compound, they can be cumbersome when it is desirable to produce a large number of structurally similar compounds. The present invention provides a solid phase synthetic method that facilitates rapid synthesis and purification of a wide variety of pyruvate analogues, modified pyruvate analogues, and pyruvate-derived compounds, as defined below. In addition, the invention provides the basis for combinatorial approaches to producing and selecting pyruvate-derived compounds for use in any of a number of medical and cosmetic indications, including, but not limited to those described above. Using the methods provided, libraries of compounds can be formed and active compositions selected, using specified criteria and standard selection methods. All references disclosed herein are hereby incorporated in their entirety.
DISCLOSURE OF THE INVENTION
Methods for the solid phase synthesis of structurally diverse pyruvate-derived compounds are provided. These methods also encompass a parallel approach in which, after a given step the intermediates, tethered to the solid support, may be easily split and parallel synthetic pathways pursued to yield a number of different products. The methods described herein may be used to synthesize a variety of pyruvate-derived compounds, including, for example, but not limited to oximes, pyruvate analogues, modified pyruvate analogues, esters of pyruvate, including, but not limited to, polyol-pyruvate esters, pyruvate amides, pyruvate thioesters, glycerol-pyruvate esters, and dihydroxyacetone-pyruvate esters. These methods may be used with diverse classes of starting materials subsequently yielding a wide variety of functional groups. Such compounds have a wide variety of uses, both medical and as health supplements.
Accordingly, in a particular embodiment a method including a process for the synthesis of pyruvate-derived compounds, wherein the process comprises the steps, preferably but not necessarily, in order of
a) forming an imine at the ketone position of an alpha-keto acid comprising &bgr;-leaving group with a solid-supported hydroxylamine to form a solid-supported intermediate;
b) esterifying the solid-supported intermediate formed in step a with a compound R
1
—OH to form an R
1
-substituted solid-supported intermediate;
c) performing a nucleophilic substitution of the R
1
-substituted solid-supported intermediate obtained in step b with a compound R
2
X(H) to form an R
2
-substituted solid-supported intermediate; and, optionally,
d) cleaving the R
2
-substituted solid-supported intermediate obtained in step c from the solid support to yield a pyruvate-derived compound.
Alpha-keto acids comprising a &bgr;-leaving group, preferably a pyruvic acid containing a &bgr;-leaving group such as a halogen, may be used to practice the present invention. Leaving groups are well known in the art. Examples of such compounds include 3-bromopyruvic acid, commonly known as bromopyruvic acid, and commercially available from Aldrich (Milwaukee, Wis.). Other examples of substituted pyruvic acids of use in the methods presented herein include chloropyruvic acid and iodopyruvic acid. Other examples of good leaving groups include, but are not limited to, mesylate and tosylate.
R-groups, including R
1
—OH, R
2
X— and R
3
— of use in the methods of the present invention are described herein, as are exemplary R
3
-containing acyl compounds. Additionally, examples of such are shown in Schemes A, B, C, D, E and F.
Further embodiments described herein may also include one or a combination of additional steps of, for example:
i) (a) reducing the R
2
-substituted solid-supported intermediate to an amine to form an amine-substituted solid supported intermediate; and,
(b) acylating the amine-substituted solid-supported intermediate with R
3
CO— to form an R
3
-substituted solid-supported intermediate;
wherein the above steps ia and ib are performed after step c and prior to step d described above; and,
optionally,
ii) splitting the solid support into multiple portions;
wherein the solid support comprises an intermediate formed in any one of the preceding steps, and wherein step ii) may be performed after any one or more of steps b, c, ia or ib; and,
optionally, iii) hydrolyzing a solid-supported intermediate formed in the preceding step from the solid support to yield a pyruvate analog,
wherein step iii is performed immediately after any one or more of steps b and c when performed prior to step d; and,
optionally
iv) purifying the pyruvate-derived compound,
wherein the pyruvate-derived compound is formed after cleavage or hydrolysis of the compound from the solid support.
In another embodiment is provided a process for the synthesis of a pyruvate-derived compound, wherein the process comprises the steps of:
forming an imine at the ketone position of a pyruvic acid substituted with a leaving group at carbon 3 with a solid-supported hydroxylamine to form a solid-supported intermediate;
performing a nucleophilic substitution of the solid-supported intermediate with a compound R
2
X(H), wherein R
2
and X are as defined herein;
esterifying the solid-supported intermediate with a compound R
1
OH or R
1
SH, or forming an amide with a compound HNR
1
R
1a
, wherein R
1
and R
1a
are as defined herein; and
cleaving the solid-supported intermediate from the solid support to yield a pyruvate-derived compound.
In particular examples, R
2
is an optionally substituted phenyl, heterocycle or heteroaryl, where the heterocycle or heteroaryl contain, independently, one or more nitrogen, and/or oxygen, and/or sulfur atoms, and/or selenium,
where the one or more substituent on the phenyl, heterocycle or heteroaryl is independently substituted with one or more of hydroxy, alkyl, alkeny
Callaway Wyeth B.
Janagani Satyanarayana
Sessler Jonathan L.
Wang Bing
Galileo Pharmaceuticals, Inc.
Morrison & Foerster / LLP
Raymond Richard L.
Tucker Zachary C.
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