Amino acid-derived phosponamidic anhydrides and methods of...

Details Amino acid-derived phosponamidic anhydrides and methods of... Amino acid-derived phosponamidic anhydrides and methods of...

2000-08-15

2002-07-16

Higel, Floyd D. (Department: 1626)

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

Organic compounds

Carboxylic acid esters

C560S169000, C560S174000, C562S878000

Reexamination Certificate

active

06420592

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention is directed towards new phosphonamidic anhydrides and methods of forming those compounds. The compounds have a number of uses including as inhibitors of enzymes and regulators of plant growth.
2. Description of the Prior Art
Small peptides are excellent starting points for drug design because they have the potential to overcome the pharmacokinetic shortcomings of larger peptides, yet retain the desirable quality of molecular recognition. A number of dipeptides are currently being developed as novel pharmaceutical agents (see e.g., Blackburn et al.,
Bioorg. Med. Chem. Lett.,
7:823-26 (1997); Schullek et al.,
Anal. Biochem.,
246:20-29 (1997), each incorporated by reference herein). Unfortunately, even small peptides suffer from proteolytic instability which limits their use as drug candidates.
Anhydrides and their derivatives have a rich history both in terms of their synthetic utility as well as their biological relevance (see e.g., Tarbell,
Accounts Chem. Res.,
2:296-300 (1969); Martin et al.,
Chem.,
27:90-95 (1987), each incorporated by reference herein). Anhydrides are widely known to serve as potent inhibitors of a variety of enzymes (see e.g., Karibian et al.,
Biochemistry,
13:2891 (1974), incorporated by reference herein), with a number of anhydrides recently being reported as effective inactivators of various serine proteases (see e.g., Iijima et al.,
Biorg. Med. Chem. Lett.,
9:413 (1999), incorporated by reference herein).
Pyrophosphate and related analogs are a class of phosphorus-based anhydrides that have gained attention for their ability to inhibit osteoclastic bone resorption, and therefore are useful therapeutic agents to treat and prevent osteoporosis (see e.g., Sato et al.,
J. Med. Chem.,
42:1 (1999), incorporated by reference herein). Biphosphonates, synthetic nonhydrolyzable P—C—P analogs ofpyrophosphates, are highly effective agents for inhibiting osteoclastic bone resorption (see e.g., Russell et al.,
Bone,
25:97 (1999); Teronen et al.,
Ann. N.Y. Acad. Sci.,
878:453-65 (1999), each incorporated by reference herein). Biphosphonic acids have also proven to be effective inhibitors of squalene synthase, a crucial enzyme in the role of cholesterol biosynthesis. Thus, there is a need to develop new pyrophosphate analogs which improve the therapeutic properties of biphosphonates.
SUMMARY OF THE INVENTION
The present invention is broadly concerned with new phosphonamide compounds and methods of forming such compounds.
In more detail, the compounds are phosphonamidic anhydrides, and more particularly chiral phosphonamidic anhydrides. The preferred compounds are represented by a formula selected from the group consisting of
wherein:
each X is individually selected from the group consisting of oxygen, —NH, and —NOR
1
;
each R
1
is individually selected from the group consisting of hydrogen, substituted and unsubstituted amino acid side chains, and 2-15 mer peptides; and
each R
2
is individually selected from the group consisting of hydrogen, branched and unbranched alkyl groups (preferably C
1
-C
18
, more preferably C
1
-C
8
), branched and unbranched alkenyl groups (preferably C
2
-C
18
, more preferably C
2
-C
8
), branched and unbranched alkynyl groups (preferably C
2
-C
18
, more preferably C
2
-C
8
), allyl groups, acyl groups (preferably C
2
-C
18
, more preferably C
2
-C
8
) aryl groups (preferably C
6
-C
12
), 2-15 mer peptides, and benzyl groups.
Preferably at least one R
1
group comprises an amino acid side chain selected from the group consisting of
wherein each R
3
is individually selected from the group consisting of hydrogen, branched and unbranched alkyl groups (preferably C
1
-C
18
, more preferably C
1
-C
8
), branched and unbranched alkenyl groups (preferably C
2
-C
18
, more preferably C
2
-C
8
), branched and unbranched alkynyl groups (preferably C
2
-C
18
, more preferably C
2
-C
8
), allyl groups, aryl groups (preferably C
6
-C
12
), acyl groups (preferably C
2
-C
18
, more preferably C
2
-C
8
), and benzyl groups.
In a preferred embodiment, each R
1
is individually selected from the group consisting of —CH
3
, —CH
2
CH(R
4
)
2
, —CH
2
R
4
, and —CH(R
4
)
2
, with each R
4
being individually selected from the group consisting of alkyl groups (preferably methyl), aryl groups (preferably phenyl), and benzyl groups, and each R
2
is individually selected from the group consisting of —CH
3
and —CHCH
2
. Two particularly preferred compounds according to the invention comprise a formula selected from the group consisting of
The inventive compounds are formed by reacting an allylated compound with a phosphonic compound to form an intermediate compound which is the dimerized. Preferred allylated compounds comprise the formula
wherein:
R
1
is selected from the group consisting of hydrogen, substituted and unsubstituted amino acid side chains, and 2-15 mer peptides; and
R
2
is selected from the group consisting of hydrogen, branched and unbranched alkyl groups (preferably C
1
-C
18
, more preferably C
1
-C
8
), branched and unbranched alkenyl groups (preferably C
2
-C
18
, more preferably C
2
-C
8
), branched and unbranched alkynyl groups (preferably C
2
-C
18
, more preferably C
2
-C
8
), allyl groups, aryl groups (preferably C
6
-C
12
), acyl groups (preferably C
2
-C
18
, more preferably C
2
-C
8
), 2-15 mer peptides, and benzyl groups.
Preferred phosphonic compounds comprise the formula R
4
POY
2
,
wherein:
R
4
is selected from the group consisting of hydrogen, branched and unbranched alkyl groups (preferably C
1
-C
18
, more preferably C
1
-C
8
), branched and unbranched alkenyl groups (preferably C
2
-C
18
, more preferably C
2
-C
8
), branched and unbranched alkynyl groups (preferably C
2
-C
18
, more preferably C
2
-C
8
), allyl groups, aryl groups (preferably C
6
-C
12
), acyl groups (preferably C
2
-C
18
, more preferably C
2
-C
8
), 2-15 mer peptides, and benzyl groups; and
each Y is individually selected from the group consisting of the halogens.
The intermediate compound comprises a formula selected from the group consisting of
wherein:
R
1
is selected from the group consisting of hydrogen, substituted and unsubstituted amino acid side chains, and 2-15 mer peptides;
R
2
is selected from the group consisting of hydrogen, branched and unbranched alkyl groups (preferably C
1
-C
18
, more preferably C
1
-C
8
), branched and unbranched alkenyl groups (preferably C
2
-C
18
, more preferably C
2
-C
8
), branched and unbranched alkynyl groups (preferably C
2
-C
18
, more preferably C
2
-C
8
), allyl groups, aryl groups (preferably C
6
-C
12
), acyl groups (preferably C
2
-C
18
, more preferably C
2
-C
8
), 2-15 mer peptides, and benzyl groups; and
each Y is individually selected from the group consisting of the halogens.
Preparing the phosphonamide compounds according to the inventive methods results in a yield of those compounds of at least about 70%, and preferably at least about 95%, wherein the theoretical yield is taken as 100%.
Optionally, the phosphonamide compound can be subjected to a ring-closing metathesis reaction in the presence of a ring-closing catalyst to yield a bicyclic phosphonamide. Preferred ring-closing catalysts are olefin metathesis catalysts such as Grubbs catalysts (see e.g., U.S. Pat. Nos. 6,048,993, 5,917,071, 5,750,815, 5,710,298, 5,342,909, and 5,312,940, each incorporated by reference herein) as well as those disclosed by the following references, each also incorporated by reference herein: Matthias,
Org. Ltrs.,
1(6):953-56 (1999); Schrock,
Macromolecules,
29(19):6114-25 (1996); Zhu et al.,
J. Amer. Chem. Soc.,
121(36):8251-59 (1999); Alexander et al.,
J. Amer. Chem. Soc.,
120(16):4041-42 (1998); and Kingsbury et al.,
J. Amer. Chem. Soc.,
121(4):791-99 (1999).
Particularly preferred Grubbs catalysts are those selected from the group consisting of
Preferably the reacting step is carried out at a temperature of from about 15-80° C., and more preferably from about 30-55° C. Furthermore, the reacting st

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